WO2025119351A1 - Gpr139 agonist - Google Patents

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

The present application relates to the field of medicinal chemistry, and in particular to a compound as a GPR139 agonist, a composition containing the compound, and an application thereof in treating diseases associated with GPR139.

Background Art

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 between different species, such as the homology of the GPRL39 protein sequence in humans, mice and rats is over 94%. GPR139 mRNA is mainly expressed in the human central nervous system (CNS), especially in the basal ganglia and hypothalamus, and may be involved in motor control, regulating food intake and metabolism. The consistent expression of GPR139 mRNA in the central nervous system provides evidence for different species that it plays a specific role in regulation and GPRl39 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).

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 in the LHb (Wang et al, Science, 2019, 365: 1267-73). The habenula is also a brain area related to addiction. 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 the withdrawal hyperalgesia of alcohol-dependent rats (Kononoff et al, eNeuro, 2018, 5: ENEURO.0153-18.2018). In the morphine addiction experiment, 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 T R Soc B, 2007, 362: 1641-54).

Since GRP139 can be used as a potential target for neurological diseases, multiple research institutions and pharmaceutical companies have developed a series of GPR139 regulators, among which TAK041 is currently used to treat anhedonia symptoms after severe depression.

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

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.

Therefore, in the first aspect, the present application provides 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 R5 are ...6-10 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 R5 are independently selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, 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 R5 ₁ 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 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, 4-10 membered heterocycloalkenyl, or 5-10 membered heteroaryl 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, C2-10 alkenyl, C2-10 alkynyl, or -C(O)R ₉ , wherein R ₉ is selected from -OH, halogen, or C1-3 alkyl;

R ₂ 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;

R ₃ 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, -NH ₂ , or -NHCH ₂ COOH;

_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.

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

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 R5 are ... ₁ together with the atoms to which they are respectively attached form a C4-6 cycloalkenyl, a 4-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl; 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.

In some embodiments, R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

In some embodiments, R ₃ is selected from deuterium, C1-3 alkyl, which is optionally substituted with one or more groups selected from deuterium, -OH, halogen, oxo, or -NH ₂ .

In some embodiments, R ₄ is selected from H or deuterium.

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

In some embodiments, R ₁ and R ₅ 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 R 5 or R 5 and R 5 are each independently selected from H, deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl, -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 R ₅ or R ₅ and R 5 are each independently selected from H, deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl, ₁ together with their respective atoms to which they are attached form a C5-6 cycloalkenyl, a 5-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl which is optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl, C2-4 alkenyl, or -O-C1-3 alkyl.

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, optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl. Or two adjacent R ₅ or R ₅ and R ₁ 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 or -O-C1-3 alkyl.

In some embodiments, R ₃ is selected from methyl and R ₄ is selected from H.

In some embodiments, R ₁ and R ₅ are each independently selected from isopropyl, phenyl, cyclopropyl, or Or two adjacent R ₅ or R ₅ and R ₁ 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.

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):

wherein R ₁ , R ₂ , R ₅ , Q ₁ , Q ₂ and n are as defined above, Q ₄ 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)R ₉ , wherein R ₉ is selected from -OH, halogen or C1-3 alkyl, and q is an integer from 0 to 2, and when q is 2, R ₁₀ may be the same or different.

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

wherein R ₁ 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different;

Q ₃ is selected from O, S, -CH ₂ - or -N(R ₇ )- wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and

R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

In some embodiments, _R1 is selected from the group consisting of:

Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I.

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

wherein Q ₃ is selected from O, S, -CH ₂ - or -N(R ₇ )- and wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R ₈ is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

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

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

wherein R ₁ 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 the group consisting of 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different;

Q ₃ is selected from O, S, -CH ₂ - or -N(R ₇ )- wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and

R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

In some embodiments, _R1 is selected from the group consisting of:

Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I.

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

wherein Q ₃ is selected from O, S, -CH ₂ - or -N(R ₇ )- and wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R ₈ is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

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

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

wherein R ₁ 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different;

Q ₃ is selected from O, S, -CH ₂ - or -N(R ₇ )- wherein _R7 is selected from H or C1-3 alkyl, preferably H and methyl, and

R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

In some embodiments, _R1 is selected from the group consisting of:

Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I.

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

wherein R ₁₀ is independently selected from -H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-5 alkenyl, or -C(O)R ₉ , wherein R ₉ is selected from -OH, halogen or C1-3 alkyl, preferably R ₁₀ is independently selected from -H, C1-3 alkyl, C2-3 alkenyl.

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

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

wherein R ₁₀ is independently selected from -H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-5 alkenyl, or -C(O)R ₉ , wherein R ₉ is selected from -OH, halogen or C1-3 alkyl, preferably R ₁₀ is independently selected from -H, C1-3 alkyl, C2-3 alkenyl.

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

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

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

in represents a double bond, and

wherein Q ₁ and Q ₂ are each independently selected from N or CR ₅ , provided that Q ₁ and Q ₂ are not N at the same time,

wherein R ₁ and R ₅ 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 R _{5 on adjacent carbons or R 5} and R ₅ are independently selected from ₁ together with the carbon to which they are each attached form a C4-10 cycloalkenyl or a 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, 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)R ₉ , wherein R ₉ is selected from -OH, halogen or C1-3 alkyl;

R ₂ 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;

R ₃ 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, -NH ₂ , or -NHCH ₂ COOH;

_R4 is selected from H, deuterium, -OH or -O-glucuronide; and

wherein m is an integer selected from 0-2, and n is an integer selected from 0-5.

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

In some embodiments, R ₁ and R ₅ 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 R 5 on adjacent carbons or R ₅ and R ₅ are ... ₁ together with the carbon to which they are respectively attached form a C4-6 cycloalkenyl or a 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 with one or more groups selected from the following: deuterium, -F, -Cl, -Br, -OH, -O-C1-3 alkyl, or C1-3 alkyl.

In some embodiments, R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

In some embodiments, R ₃ is selected from deuterium, C1-3 alkyl, which is optionally substituted with one or more groups selected from deuterium, -OH, halogen, oxo, or -NH ₂ .

In some embodiments, R ₄ is selected from H or deuterium.

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

In some embodiments, R ₁ and R ₅ 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 R ₅ on adjacent carbons or R ₅ and R ₁ together with the carbon to which they are each attached together 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.

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, optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl. Or two R ₅ on adjacent carbons or R ₅ and R ₁ 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 group optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl.

In some embodiments, R ₃ is selected from methyl and R ₄ is selected from H.

In some embodiments, R ₁ and R ₅ are each independently selected from isopropyl, phenyl, cyclopropyl, or Or two R ₅ on adjacent carbons or R ₅ and R ₁ 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.

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):

wherein R ₁ , R ₂ , R ₅ , Q ₁ , Q ₂ and n are as defined above, and wherein in formula (I-1) Represents a double bond.

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

wherein R ₁ 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different;

Q ₃ is selected from O, S, -CH ₂ - or -N(R ₇ )- wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and

R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

In some embodiments, _R1 is selected from the group consisting of:

Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I.

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

wherein Q ₃ is selected from O, S, -CH ₂ - or -N(R ₇ )- and wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R ₈ is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

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

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

wherein R ₁ 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different;

Q ₃ is selected from O, S, -CH ₂ - or -N(R ₇ )- wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and

R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

In some embodiments, _R1 is selected from the group consisting of:

Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I.

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

wherein Q ₃ is selected from O, S, -CH ₂ - or -N(R ₇ )- and wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R ₈ is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

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

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

wherein R ₁ 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different;

Q ₃ is selected from O, S, -CH ₂ - or -N(R ₇ )- wherein _R7 is selected from H or C1-3 alkyl, preferably H and methyl, and

R ₂ 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, further preferably -CF ₃ or -OCF ₃ , preferably -OCF ₃ .

In some embodiments, _R1 is selected from the group consisting of:

Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I.

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.

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.

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.

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.

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.

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

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, fibromyalgia.

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

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.

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 following: antidepressants, antipsychotics, antianxiety drugs, sedatives, hypnotics, tranquilizers.

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

In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and technologies are also described in many publications.

definition

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.

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

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.

In the present 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.

In the present 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.

In the present 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, C1-10 alkyl 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), for example, a straight chain alkyl with 1 to 10 carbon atoms and a branched alkyl with 3 to 10 carbon atoms may be included. Preferably, the alkyl group generally contains 1 to 5 carbon atoms, i.e., C1-5 alkyl. Also preferably, the alkyl group may contain 1 to 3 carbon atoms, i.e., C1-3 alkyl. 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.

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.

In the present application, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same 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.

In the present application, the term "alkenyl" refers to a straight or branched, non-cyclic unsaturated hydrocarbon group having a specified carbon atom, 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 2-10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 2-5 carbon atoms. Examples of C2-5 alkenyl groups include, but are not limited to, vinyl, 1-propene-1-yl, 1-propene-2-yl, 2-propene-1-yl, 2-methyl-1-propene-1-yl, 2-methyl-2-propene-1-yl, 1-butene-1-yl, 1-butene-2-yl, 2-butene-1-yl, 2-butene-2-yl, 3-butene-1-yl, 3-butene-2-yl, 1,3-butadiene-1-yl, 1,3-butadiene-2-yl, 1-pentene-1-yl, 2-pentene-1-yl, 2-pentene-2-yl, 3-pentene-1-yl, 3-pentene-3-yl, 4-pentene-1-yl, 4-pentene-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-propene-1-yl is more preferred than 2-propene-1-yl. Without being limited by theory, in the present application, the term "alkenyl" also encompasses groups having both unsaturated double bonds and unsaturated triple bonds in a straight chain of carbon atoms and/or in a straight chain.

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 following: deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkynyl, halogenated C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

In the present application, the 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. Examples of C2-5 alkynyl groups include, but are not limited to, ethynyl, 1-propynyl-1-yl, 2-propynyl-1-yl, 1-butynyl-1-yl, 2-butynyl-1-yl, 3-butynyl-1-yl, 3-butynyl-2-yl, 1-pentynyl-1-yl, 2-pentynyl-1-yl, 3-pentynyl-1-yl, 4-pentynyl-1-yl, etc. The alkynyl group 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.

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 following: deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, halogenated C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

In the present application, "aryl" refers to any functional group or substituent derived from an aromatic carbocyclic ring. The aryl group can be a monocyclic aryl group (e.g., phenyl) or a polycyclic aryl group. In other words, the aryl group can be a monocyclic aryl group, a condensed ring aryl group, two or more monocyclic aryl groups connected by a carbon-carbon bond, a monocyclic aryl group and a condensed ring aryl group connected by a carbon-carbon bond, and two or more condensed ring aryl groups connected by a carbon-carbon bond. That is, unless otherwise specified, two or more aromatic groups connected by a carbon-carbon bond can also be regarded as the aryl group of the present application. Among them, the condensed ring aryl group can, for example, include a bicyclic condensed aryl group (e.g., naphthyl), a tricyclic condensed aryl group (e.g., phenanthrenyl, fluorenyl, anthracenyl), etc. The aryl group 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 groups. 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.

In the present application, the aryl 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 following: deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, halogenated C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

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 of structures such as spirocyclic, bridged, and cyclic. 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 (such as 1-methylcyclopropyl and 2-methylcyclopropyl), are 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.

In the present application, the cycloalkyl group may be optionally substituted by one or more substituents which are the same or different from each other, for example, by one or more groups selected from the following: deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, halogenated C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

In the present application, the term "cycloalkenyl" refers to a cyclic aliphatic ring structure having 1 or 2 unsaturated double bonds. C4-10 cycloalkenyl refers to a cycloalkenyl (i.e., excluding the number of carbon atoms in the substituent) including 4-10 (e.g., 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 bridge 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 to cyclobutene-3-yl.

In the present application, the cycloalkenyl group may be optionally substituted by one or more substituents which are the same or different from each other, for example, by one or more groups selected from the following: deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, halogenated C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

In the present application, the term "heterocycloalkenyl" refers to a cyclic unsaturated group in which one or two carbon atoms in the cycloalkenyl group are each independently replaced by a heteroatom selected from N, O and S. There are no adjacent oxygen and/or sulfur atoms 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 is present as a ring atom, respectively. Non-limiting examples of suitable monocyclic azacycloalkenyl 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, etc. Non-limiting examples of suitable oxacycloalkenyl groups include 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2,5-dihydrofuranyl, fluorodihydrofuranyl, and the like. Non-limiting examples of suitable polycyclic oxacycloalkenyl groups are 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitable monocyclic thiacycloalkenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.

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 following: deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, halogenated C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

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 may be one or more of B, O, N, P, Si, Se and S. The heteroaryl group may be a monocyclic heteroaryl group or a polycyclic (e.g., bicyclic) heteroaryl group, in other words, the heteroaryl group may be a single aromatic ring system or a plurality of aromatic ring systems conjugated by carbon-carbon bonds, and any aromatic ring system may be an aromatic monocyclic ring or an aromatic condensed ring. For example, heteroaryl groups may include, but are not limited to, thienyl, furanyl, 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.

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.

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 usually 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 include, but are not limited to, oxirane, thioethanethiol, 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, pyranonyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, azepanyl, oxepanyl, thiepanyl. The heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

In the present application, the heterocycloalkyl group may also be optionally substituted by one or more substituents which are the same or different from each other, for example, by one or more groups selected from the following: deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, halogenated C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

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

"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.

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

Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

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.

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

In the present 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. The _same also applies to the definitions of _R3 , _R4 , _R5 , _R6 , _R7 , _R8 , R9, _R10 , _Q1 , _Q2 , _Q3 and _Q4 in the present application.

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. For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts formed between amino groups and acids, such as 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 amino salts formed 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, glycerophosphate, gluconate, hemibisulfate, heptanoate, hexanoate, hydroiodide, 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 halogen anions, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates and arylsulfonates. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

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

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, local, in the form of ophthalmic preparations or by inhalation.

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

When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol 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, and the like. The composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer as needed. Oral formulations may contain standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (1990).

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.

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 in the present application include antidepressants, antianxiety drugs, antipsychotics, sedatives, hypnotics, or tranquilizers.

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.

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.

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

In the compound of formula I,

wherein each R ₁ 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 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, 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;

R ₂ 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;

R ₃ 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, -NH ₂ , or -NHCH ₂ COOH;

_R4 is selected from H, deuterium, -OH or -O-glucuronide;

_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 R5 are selected from ₁ together with the atoms to which they are respectively attached form a C4-10 cycloalkenyl, a 4-10 membered heterocycloalkenyl, or a 5-10 membered heteroaryl; 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, 4-10 membered heterocycloalkenyl, or 5-10 membered heteroaryl 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, C2-10 alkenyl, or -C(O)R ₆ , wherein R ₆ is selected from -OH, halogen, or C1-3 alkyl; and

wherein m is an integer selected from 0-2, and n is an integer selected from 0-5.

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):

The compound of formula I provided herein may exist as a salt, complex, solvate, hydrate and liquid crystal, or may exist in a solid state in an amorphous, crystalline or mixed form thereof. The compound of formula I may also be isotopically labeled, produced by the administration of a prodrug, or formed after administration to form a metabolite with the desired pharmacological activity. The compound of formula (I) may be a stereoisomer, a tautomer or a combination thereof.

The term "solvate" refers to a compound that exists in combination with a certain solvent molecule. 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" used in this article 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 in this article. The term "isotope-labeled" refers to a compound obtained by replacing any atom in the compound with its isotope atom. Examples of isotopes that can be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as ^2H , ^3H , ^13C , ^11C , ^{14C, 15N} , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F and ^36Cl , ^respectively . 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 under biological conditions to become active compounds, or they have no or only low activity in their unreactive form. "Metabolites" refer to compounds formed in vivo after administration of pharmacologically active compounds. "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 functional group isomers resulting from the rapid shift of an atom in two positions in a molecule, such as the very typical enol-keto tautomers.

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).

Some exemplary compounds of Formula I can be produced by one or more of the following synthetic schemes. The substituent identifiers R ₁ , R ₂ , R ₅ in the schemes have the meanings as defined above for the compounds of Formula I.

Synthesis Scheme A

Synthesis Scheme B

Synthesis Scheme C

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

Example

Examples are provided below to help understand the present invention. However, it should be understood that these examples are only used to illustrate the present invention, but do not constitute any limitation. The actual protection scope of the present invention is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of the present invention.

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

Table 1.

Table 2. List of preferred compounds

Example 1: Synthesis of Compound BR-028723

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/H ₂ O (15 mL, 7:1) was added Pd(dppf)Cl ₂ (414.4 mg, 1.79 mmol) and Na ₂ CO ₃ (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 Na ₂ SO ₄ , filtered and concentrated to give 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

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 K ₂ CO ₃ (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 Na ₂ SO ₄ , 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

Step 3: To a solution of methyl 2-(6-oxo-5-phenylpyrimidin-1(6H)-yl)acetate (800 mg, 3.28 mmol) in THF/H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated to give a gray solid 2-(6-oxo-5-phenylpyrimidin-1(6H)-yl)acetic acid (600 mg, 2.61 mmol, yield = 79.57%). LCMS (ESI) m/z: [m+H] ⁺ 231.0

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 and 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.

¹ H-NMR (400MHz, DMSO-d ₆ )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).

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

Example 2: Synthesis of Compound BR-028724

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 the 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

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 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 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 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

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, yield 92.25%). LCMS (ESI) m/z: [m+H] ⁺ 231.3

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 mL) and extracted with ethyl acetate (3x 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 2-(6-oxo-4-phenyl-pyrimidin-1-yl)-N-[(1S)-1-phenylethyl]acetamide (92 mg, 275.96 μmol, 31.77% yield).

¹ H-NMR (400MHz, DMSO-d ₆ )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).

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

Example 3: Synthesis of Compound BR-028725

The same method as Example 2: Synthesis of compound BR-028724 was used, except that the starting material 3-oxo-3-phenyl-propionic acid ethyl ester was changed to 3-oxohexanoic acid ethyl ester (2000 mg, 12.64 mmol).

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

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

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

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

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 4: Synthesis of Compound BR-028811

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 Na ₂ CO ₃ . The reaction mixture was stirred at 150° C. for 12 hours. Water (30 mL) was added, the combined aqueous layer was extracted with ethyl acetate (3×50 mL), the combined organic layer was 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.

LCMS (ESI) m/z: [m+H] ⁺ 137.0.

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, the combined aqueous layers were extracted with ethyl acetate (3×50 mL), and 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.

¹ H NMR (400MHz, DMSO-d ₆ )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),6.3 0-6.15(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).

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

Example 5: Synthesis of Compound BR-028812

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

LCMS (ESI) m/z: [m+H] ⁺ 139.0

Step 2: To a solution of 5-propyl-1H-pyrimidin-6-one (100 mg, 723.76 μmol) in DMF (9.96 mL), (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) were added. After the reaction was completed, water (30 mL) was added, the combined aqueous layer was extracted with ethyl acetate (3×50 mL), the combined organic layer was 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-propylpyrimidin-1-yl)-N-[(1S)-1-phenylethyl]acetamide (15.7 mg, 52.44 μmol, 7.25% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 6: Synthesis of Compound BR-029039

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), 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 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)

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 7: Synthesis of Compound BR-029131

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 min, then methyl 2-oxocyclopentane-1-carboxylate (3800 mg, 26.73 mmol) was added and stirred for 4 h. 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 sodium sulfate, filtered and concentrated to give a 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

Step 2: Under _N2 atmosphere, 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) were added to a solution of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopentane-1-carboxylate (6500 mg, 23.70 mmol) in DMF (50 mL) under N2 atmosphere. The mixture was heated to 60°C and stirred for 12 hours under N2 atmosphere. 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

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.H2O (6.61 g, 157.41 mmol). The mixture was heated to 60 °C and stirred under N2 atmosphere for 12 h. Lcms showed 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 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.

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), DIPEA (1.42 g, 11.02 mol, 1.92 mL). The mixture was stirred at room temperature for 4 h. Lcms showed the reaction was complete. The residue was diluted with water (50 ml), 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)

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

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 h. Lcms showed the reaction was complete. The solvent was removed under reduced pressure to give the crude product. The residue was diluted with water (50 ml), 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 100% ethyl acetate in PE) to give 2,5,6,7-tetrahydrocyclopenta[c]pyridin-1-one (100 mg, 739.85 μmol, 50.00% yield)

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

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 K2CO3 (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. 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 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)

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 8: Synthesis of Compound BR-029218

To a solution of 5,7-dihydro-3H-furano[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),

Drying over sodium sulfate, filtering and concentration afforded a crude product which was purified by preparative HPLC (TFA) to afford 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).

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 9: Synthesis of Compound BR-032121

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

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 for 12 hours under a nitrogen atmosphere. 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), 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

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.H ₂ O (648.30 mg, 15.45 mmol). The mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. LCMS showed the reaction was complete. The pH was adjusted to 7 with aqueous HCl and the solvent was removed under reduced pressure to give the 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 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 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.

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 K ₂ CO ₃ (545.01 mg, 3.94 mmol) at 0° C. The mixture was stirred at room temperature for 15 minutes, then 2-bromo-N-[(1S)-1-phenylethyl]acetamide (477.38 mg, 1.97% mmol) was added and stirred for 4 hours. LCMS showed completion. 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 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)

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 10: Synthesis of Compound BR-032122

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 showed that 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).

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 11 Synthesis of Compound BR-032146

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 N ₂ overnight. Concentrated and purified by column chromatography (DCM:MeOH=20:1) to give 5-phenyl-1H-pyrimidin-6-one (953 mg, 5.26 mmol, 20.45% yield, 95% purity) as a light grey solid.

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

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

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.

LCMS (ESI) m/z: [M+H] ⁺ 231.0

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 with 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 reactant was stirred at room temperature for 16 hours. The mixture was added with 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.

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 12 Synthesis of Compound BR-032148

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 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.

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 13 Synthesis of Compound BR-032183

To a mixture of (1S)-1-[4-(trifluoromethoxy)phenyl]ethylamine (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 completion of the reaction, 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.86 (d, J = 7.7 Hz, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.70–7.64 (m, 2H), 7.49–7.29 (m, 7H), 4.96 (p, J = 7.0 Hz, 1H), 4.69 (s, 2H), 1.39 (d, J = 7.0 Hz, 3H). LCMS (ESI) m/z: [M+H] ⁺ 418.2; purity = 98.45% (214 nm); retention time = 2.85 min.

Example 14 Synthesis of Compound BR-032184

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)ethane-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 give BR-032184 (6 mg, 14.95 μmol, 4.30% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 15 Synthesis of Compound BR-032185

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)ethylamine (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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (d, J = 7.8 Hz, 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 = 7.0 Hz, 3H). LCMS (ESI) m/z: [M+H] ⁺ 368.0; purity = 97.24% (254 nm);

Example 16 Synthesis of Compound BR-032186

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 reactant 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 BR-032186 (38.1 mg, 101.09 μmol, 29.09% yield, 98% purity) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 17 Synthesis of Compound BR-032280

To a solution of 2-(6-oxo-5-phenyl-pyrimidin-1-yl)acetic acid (80 mg, 347.50 μmol), (1S)-1-(4-fluorophenyl)ethylamine (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)

m/z:[M+H] ⁺ 352.38

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (d, J = 7.8 Hz, 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 = 7.0 Hz, 3H). LCMS (ESI) m/z: [M+H] ⁺ 352.38; purity = 100% (254 nm); retention time = 6.639 min.

Example 18 Synthesis of Compound BR-032281

2-Bromo-N-[(1S)-1-phenylethyl]acetamide (112.49 mg, 4646.62 μmol) and potassium carbonate (128.43 mg, 929.24 μmol) were added to a solution of 3-phenyl-1H-pyrazine-2-one (80 mg, 464.62 μmol) in DMF (3 mL). The mixture was stirred at 25 ° C for 12 hours. The mixture was purified by preparative HPLC to obtain 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).

¹ H NMR (400MHz, DMSO-d ₆ )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,3 H),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)

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

Example 19 Synthesis of Compound BR-032282

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 give BR-032282 (8.1 mg, 19.41 μmol, 4.18% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.82(d,J＝7.7Hz,1H),8.27–8.20(m,2H),7.65(d,J＝4.2Hz,1H),7.51–7.40(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)

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

Example 20 Synthesis of Compound BR-032338

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

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 completed, water (30 mL) was added to the mixture and extracted with EtOAc (30 mL×2). The combined organic layer was 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.

¹ H NMR (400MHz, DMSO-d ₆ )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).

LCMS(ESI)m/z:[M+H] ⁺ 384.30

Example 21 Synthesis of Compound BR-032370

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 h. After completion of the reaction, 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.

Step 2: To a solution of 2-chloro-5,7-dihydro-3H-furano[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 nitrogen atmosphere. The reaction mixture was stirred at 25 °C under _H2 for 1 h. The mixture was filtered to give 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (230 mg) as a yellow solid.

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

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 give BR-032370 (5 mg, 13.04 μmol, 5.32% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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)

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

Example 22 Synthesis of Compound BR-032414

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-benzyliodooxy-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 the crude product. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3x 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).

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 23 Synthesis of Compound BR-032415

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)ethylamine (97.62 mg, 621.15 μmol) was added and stirred for 4 h. 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).

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 24 Synthesis of Compound BR-032435

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 showed that the reaction was complete. The residue was diluted with water (50 mL), extracted with ethyl acetate (3x 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).

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 25 Synthesis of Compound BR-032436

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) was added Cs ₂ CO ₃ (6.93 g, 21.27 mmol) and Pd(dppf)Cl ₂ (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 (3×100 mL), and the combined organic layers were washed with water (3×100 mL), brine (2×100 mL), dried over sodium sulfate (150 g), and concentrated in vacuo. The crude product was purified by a chromatographic column 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

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 aqueous sodium chloride 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

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 K ₂ CO ₃ (53.94 mg, 390.28 μmol). The reaction mixture was stirred at 25 °C for 2 hours. LCMS analysis indicated total consumption of starting material. The mixture was filtered and water (50 mL) was added to the filtrate. The combined aqueous layers were extracted with ethyl acetate (3×100 mL), and the combined organic layers were washed with water (3×100 mL), brine (2×100 mL), dried over sodium sulfate (10 g), and concentrated in vacuo. The obtained 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.

¹ H NMR (400MHz, DMSO-d ₆ )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).

Example 26 Synthesis of Compound BR-032437

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 K ₂ CO ₃ (53.94 mg, 390.28 μmol). The reaction mixture was stirred at 25°C for 2 hours. LCMS analysis showed that the starting material disappeared. The reaction mixture was filtered and water (50 mL) was added to the filtrate. The combined aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic layer was washed with water (3×100 mL), 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.

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 27 Synthesis of Compound BR-032438

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 give BR-032438 (17.8 mg, 48.85 μmol, 11.80% yield).

¹ H NMR (400MHz, DMSO-d ₆ )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),6.23–6.15(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)

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

Example 28 Synthesis of Compound BR-032439

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)ethylamine (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), HOBT (95.12 mg, 704 μmol) at 0° C. After completion of the reaction, the mixture was purified by preparative HPLC to give BR-032439 (12.2 mg, 36.71 μmol, 8.87% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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,1 H),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)

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

Example 29 Synthesis of Compound BR-032479

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 Cs ₂ CO ₃ (445.88 mg, 1.37 mmol). The reaction was stirred at rt for 2 hours. The product was purified by gradient purification with PE/EA = 1:1 to 1:2 to obtain tert-butyl 2-(1-oxo-2,7-naphthyridin-2-yl)acetate (166 mg, yield 93%).

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). Then _N2 was replaced by _H2 and stirred at room temperature for 2 h. After the starting material was completely converted, the solution was filtered through a celite pad and washed with EA. The organic solvent was removed to obtain 40 mg of crude product tert-butyl 2-(1-oxo-5,6,7,8-tetrahydro-2,7-naphthyridin-2-yl)acetate.

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), then add 37% aqueous formaldehyde solution (4.54 mg, 151.33 μmol, 4.20 μL). Heat the reaction to 85 ° C and stir overnight under N ₂ atmosphere. After the reaction of the raw materials is complete, the reactants are filtered through a celite pad and concentrated under vacuum. 30 mg of crude product 2-(7-methyl-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-2-yl)acetic acid is obtained.

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]ethylamine (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 detected the total consumption of the starting material, extracted with EA, collected the organic layer and concentrated in vacuo, and the residue was purified by HPLC. The product BR-032479 (4.5 mg, yield 15.6%) was obtained.

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.

Example 30 Synthesis of Compound BR-032480

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 detected by LCMS and the mixture was purified by preparative HPLC to give BR-032480 (15.2 mg, 45.95 μmol, 11.10% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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)

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

Example 31 Synthesis of Compound BR-032481

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)ethylamine (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 by LCMS, the mixture was purified by preparative HPLC to give BR-032481 (18.5 mg, 58.85 μmol, 14.21% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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,1 H),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)

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

Example 32 Synthesis of Compound BR-032482

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) were added 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). 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.

LCMS showed 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 (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).

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 33 Synthesis of Compound BR-032483

Step ₁ : A mixture of 3-bromo-1H-pyridin-2-one (308.07 mg, 1.77 mmol), potassium trans-1-propenyl trifluoroborate (262.00 mg, 1.77 mmol) and Na ₂ CO ₃ (469.15 mg, 4.43 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Pd(dppf)Cl ₂ (129.55 mg, 177.06 μmol) under N 2. 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.

LCMS(ESI)m/z:[M+H] ⁺ 172.19

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 K ₂ CO ₃ (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 afford BR-032483 (30 mg, 78.87 μmol, 21.32% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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] ⁺ 397.37

Example 34 Synthesis of Compound BR-032484

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 K ₂ CO ₃ (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 give BR-032484 (52 mg, 175.46 μmol, 47.43% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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).

LCMS(ESI)m/z:[M+H] ⁺ 397.37

Example 35 Synthesis of Compound BR-032491

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)Cl ₂ (150 mg, 205.00 μmol) and Na ₂ CO ₃ (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 that 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

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 _K2CO3 (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.

¹ H NMR (400MHz, DMSO-d ₆ )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),7.34–7.27(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).LCMS(ESI)m/z:[M+H] ^+417.40

Example 36 Synthesis of Compound BR-032492

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 K ₂ CO ₃ (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 give BR-032492 (80 mg, 240.68 μmol, 82.41% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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

Example 37 Synthesis of Compound BR-032493

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. It was then heated to room temperature and stirred for 12 hours. The mixture was added with 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).

LCMS (ESI) m/z: [M+H] ⁺ 277.0

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.

LCMS(ESI)m/z:[M+H] ⁺ 225.00

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 a white solid 4 (336 mg, 2.43 mmol, yield 54.57%). LCMS (ESI) m/z: [M+H] ⁺ 139.0

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

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.

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

Step 6: To a solution of 2-bromo-N-[(1S)-1-phenylethyl]acetamide (20 mg, 82.61 μmol) and 3,5-dihydro-1H-furano[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 give BR-032493 (7.5 mg, 25.14 μmol, 30.43% yield) as a white solid.

LCMS (ESI) m/z: [M+H] ⁺ 299.0

¹ H NMR (400MHz, DMSO-d ₆ )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)

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

Example 38 Synthesis of Compound BR-032524

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 well for 16 hours. TLC analysis showed that the reaction was complete. Water (10 mL) was added, extracted with DCM (10 mL x 2), and then the combined organic layers were washed with water (10 mL x 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).

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 that the conversion of the starting material was complete. Water (30 mL) was added, and the combined aqueous layers were extracted with ethyl acetate (3×10 mL), and the combined organic layers were washed with brine (2×10 mL), dried over anhydrous sodium sulfate (1 g), and concentrated in vacuo. The crude material was purified by flash column chromatography (EA/PE of 3:97) to give the target compound 4-(2-trimethylsilylethynyl)-2,5-dihydrothiophene-3-carboxylic acid methyl ester (1.14 g, 4.74 mmol, 29.12% yield).

Step 3: A mixture of 4-(2-trimethylsilylethynyl)-2,5-dihydrothiophene-3-carboxylate (1.14 g, 4.74 mmol) and LiOH.H ₂ O (97.65 mg, 9.48 mmol) in MeOH (4 mL), THF (4 mL) and water (2 mL) was stirred at 60 °C for 3 h. Concentrate and adjust pH to 3 with HCl (1.0 M). Water (10 mL) was added, the combined aqueous layers were extracted with EA (3×10 mL), and the combined organic layers were dried with brine (2×10 mL), sodium sulfate (10 g), and concentrated in vacuo. 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

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), NH ₄ HCO ₃ (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). Concentrated and purified by flash column chromatography (eluent: 17% MeOH in DCM) to give 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

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 detected that the raw material was completely converted. Then the pH was adjusted to 5.0 with citric acid and the organic solvent was removed by vacuum concentration. Water (10 mL) was added, and the combined aqueous layer was extracted with DCM (3×10 mL), and the combined organic layer was 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 obtain 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

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 K ₂ CO ₃ (43.30 mg, 313.31 μmol) and the reaction mixture was stirred at room temperature for 16 hours. LCMS analysis indicated total consumption of 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-dihydrothiopheno[3,4-c]pyridin-5-yl)-N-[(1R)-1-phenylethyl]acetamide (2 mg, 6.36 μmol, 4.06% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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)

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

Example 39 Synthesis of Compound BR-032525

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)Cl ₂ (41.82 mg, 57.15 μmol) and Na ₂ CO ₃ (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 starting material. 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 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.

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 K ₂ CO ₃ (22.28 mg, 161.23 μmol). The reaction mixture was stirred at 25° C. for 2 hours. LCMS analysis indicated the completion of the reaction. 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 afford the target compound BR-032525 (6.3 mg, 15.54 μmol, 19.28% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (d, J = 7.6 Hz, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.77–7.66 (m, 3H), 7.57 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 2.2 Hz, 1H), 5.04–4.96 (m, 1H), 4.70 (d, J = 2.2 Hz, 2H), 3.88 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H). LCMS (ESI) m/z: [M+H] ⁺ 406.3; purity = 100% (254 nm); retention time = 1.79 min.

Example 40 Synthesis of Compound BR-032530

Step ₁ : 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 dioxaborane (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) under N2 atmosphere. 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, yield 32.20%). LCMS (ESI) m/z: [M+H] ⁺ 191.0

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 give BR-032530 (2.2 mg, 5.25 μmol, 6.51% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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)

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

Example 41 Synthesis of Compound BR-032531

Step ₁ : 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 Na ₂ CO ₃ (365.49 mg, 3.45 mmol, 144.35 μL) in dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl ₂ (67.28 mg, 91.96 μmol) under N 2 atmosphere. 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

Step 2: To a solution of 3-(1-methylpyrazol-3-yl)-1H-pyridin-2-one (20 mg, 114.16 μmol), 2-bromo-N-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]acetamide (35.40 mg, 114.16 μmol) in DMF (4 mL) was added _{K2CO3 (} 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 give BR-032531 (14 mg, 34.62 μmol, 30.33% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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＝2.2Hz,1H),6.2 9(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

Example 42 Synthesis of Compound BR-032532

Step ₁ : 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 Na ₂ CO ₃ (365.49 mg, 3.45 mmol, 144.35 μL) in dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl ₂ (67.28 mg, 91.96 μmol) under N 2 atmosphere. 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

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 K ₂ CO ₃ (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 give BR-032532 (11 mg, 27.20 μmol, 15.92% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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)..

LCMS (ESI) m/z: [M+H] ⁺ 405.6

Example 43 Synthesis of Compound BR-032533

Step ₁ : 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) under N2 atmosphere - 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, 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

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 K ₂ CO ₃ (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, 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.

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 44 Synthesis of Compound BR-032540

Step 1: At -78 °C, DIEA (3.87 g, 29.93 mmol, 5.21 mL) and Tf ₂ O (8.44 g, 29.93% mmol, 5.04 mL) were added to a DCM solution of 1 (7000 mg, 27.21 mmol), then slowly warmed to room temperature and further stirred for 15 hours. The mixture was diluted with DCM, washed with saturated NaHCO ₃ and brine, and the organic phases were combined, dried and concentrated to give a 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

Step 2: Under _N2 atmosphere, CuI (415.78 mg, 2.18 mmol, 73.98 μL), ethynyltrimethylsilane (2.36 g, 24.01 mmol), 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 for 12 hours under _N2 atmosphere. LCMS showed 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 anhydrous sodium sulfate, filtered and concentrated to give a 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

Step 3: To a solution of 3 (5800 mg, 17.93 mmol) in MeOH (5 mL) and water (1 mL) was added LiOH.H ₂ O (2.26 g, 53.79 mmol). The mixture was heated to 60 °C and stirred for 12 h under N ₂ atmosphere. LCMS showed 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 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 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.

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), NH ₄ HCO ₃ (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 the reaction was complete. The residue was diluted with water (50 mL), 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)

m/z:[M+H] ⁺ 237.3

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), 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 anhydrous sodium sulfate, filtered and concentrated to give a crude product, which 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

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 K ₂ CO ₃ (22.28 mg, 161.23 μmol). The reaction mixture was stirred at 25 °C for 2 hours. LCMS analysis indicated total consumption of starting materials. 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 target compound 7 (700 mg, 1.76 mmol, 59.44% yield) as a white solid. LCMS (ESI) m/z: [m+H] + 398.3

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 that the reaction was complete. The mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the target compound BR-032540 (11.1 mg, 37.33 μmol, 24.73% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 45 Synthesis of Compound BR-032541

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 NaBH ₃ CN (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), extracted with ethyl acetate (3×50 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 a crude product. The crude product was purified by preparative HPLC to give BR-032541 (18.9 mg, 60.70 μmol, 36.10% yield).

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Example 46 Synthesis of Compound BR-032542

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 was 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 give BR-032542 (24.8 mg, 73.07 μmol, yield 36.21%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (dd, J = 8.0, 2.0 Hz, 1H), 7.61 (d, J = 6.8 Hz, 1H), 7.44–7.13 (m, 5H), 6.30 (t, J = 6.9 Hz, 1H), 4.97–4.88 (m, 1H), 4.76 (s, 1H), 4.63 (d, J = 3.0 Hz, 2H), 4.58–4.50 (m, 2H), 4.33 (d, J = 3.0 Hz, 1H), 2.03 (d, J = 5.6 Hz, 3H), 1.38 (d, J = 7.0 Hz, 3H). LCMS (ESI) m/z: [M+H] ⁺ 340.2; purity = 100% (254 nm); retention time = 1.42 min

Example 47 Synthesis of Compound BR-032543

Step 1: 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) under N2 atmosphere. The mixture was then stirred at 98 °C for 16 h. 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 and concentrated. The residue was then purified by flash column chromatography (10 g, 3% in DCM) The crude product was purified by evaporation 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

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 K ₂ CO ₃ (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 give 5 (18 mg, 36.62 μmol, 37.86% yield). LCMS (ESI) m/z: [M+H] ⁺ 490.3

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

¹ H NMR (400MHz, DMSO-d ₆ )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).

LCMS (ESI) m/z: [M+H] ⁺ 392.2

Example 48 Synthesis of Compound BR-032580

Step 1: To a solution of ₂ (200 mg, 900.65 μmol), 5-bromo-1H-pyrimidin-6-one (173.36 mg, 990.71 μmol) and Na ₂ CO ₃ (286.37 mg, 2.70 mmol) in dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl ₂ (52.72 mg, 72.05 μmol) under N 2 atmosphere. The mixture was then stirred at 98 °C for 16 h. 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

Step 2: _{K2CO3 (} 38.76 mg, 280.45 μmol) was added to a solution of 4 (146.30 mg, 448.63 μmol) and 3 (32 mg, 168.27 μmol) in DMF (1.5 mL). The reaction mixture was stirred at 60 °C for 16 h. The crude product was purified by preparative HPLC to give BR-032580 (30.05 mg, 69.02 μmol, 49.22% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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).

LCMS (ESI) m/z: [M+H] ⁺ 436.2

Example 49 Synthesis of Compound BR-032582

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 Na ₂ CO ₃ (286.37 mg, 2.70 mmol) in dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl ₂ (52.72 mg, 72.05 μmol) under N 2 atmosphere. The mixture was then stirred at 120° C. for 12 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, 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

Step 2: To a solution of 4 (50.01 mg, 153.37 μmol) in DMF (2 mL) was added K ₂ CO ₃ (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 give BR-032582 (22.1 mg, 50.76 μmol, 33.10% yield).

¹ H NMR (400MHz, DMSO-d ₆ )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)

LCMS(ESI)m/z:[M+H] ⁺ 436.07

Example 50 Synthesis of Compound BR-032622

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).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.76 (d, J = 7.7 Hz, 1H), 7.64-7.24 (m, 5H), 6.29 (d, J = 6.8 Hz, 1H), 5.07-4.76 (m, 5H), 4.63 (s, 2H), 1.39 (d, J = 7.0 Hz, 3H).

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

Example 51 Synthesis of Compound BR-032708

Step 1: 5-bromopyrimidin-4-one (100 mg, 571.48 μmol), 3-fluorophenylboronic acid (119.94 mg, 857.22 μmol), Pd(dppf)Cl ₂ (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 H ₂ O (0.5 mL) were added, and then reacted at 100° C. overnight. After the reaction was completed, water was added to quench, 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).

Step 2: Take 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) and add them to a reaction bottle. React at room temperature for 2 h. After the reaction, add water, extract with DCM, concentrate under reduced pressure to remove the solvent, and separate by reverse phase chromatography to obtain BR-032708 (23 mg, yield 49%).

¹ H NMR (600MHz, DMSO-d ₆ )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

Example 52 Synthesis of Compound BR-032709

Same as Example 51: Synthesis of compound BR-032708, except that the starting material 3-fluoroboric acid was changed to 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (83.18 mg, 428.61 μmol).

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

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

¹ H NMR (600MHz, DMSO-d ₆ )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 .

Example 53 Synthesis of Compound BR-032832

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 bottle 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 (S)-2-(5-bromo-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (23 mg, yield 49%).

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.

Example 54 Synthesis of Compound BR-032710

(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), PdCl ₂ (dppf) (8.71 mg, 11.90 μmol), sodium carbonate (37.84 mg, 356.99 μmol) were added to a Schlenk reaction tube, replaced with nitrogen atmosphere, and Dioxane (1.5 mL) and H ₂ O (0.5 mL), and then react at 100 ° C overnight. After the reaction, water was added, extracted with DCM, and concentrated under reduced pressure to remove the solvent. Reverse phase chromatography was used to prepare (S)-2-(5-(2,5-dihydrofuran-3-yl)-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (28 mg, yield 52%).

¹ H NMR (600MHz, DMSO-d ₆ )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.

Example 55 Synthesis of Compound BR-032711

Same as Example 54: Synthesis of Compound BR-032710, except that the starting material 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane was replaced with (4-chloro-3-fluorophenyl)boric acid (18.67 mg, 107.10 μmol). (S)-2-(5-(4-chloro-3-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (18 mg, yield 51%) was obtained.

¹ H NMR (600MHz, Methanol-d ₄ )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.

Example 56 Synthesis of Compound BR-032712

Same as Example 54: Synthesis of Compound BR-032710, except that the starting material 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane was replaced with (3-chlorophenyl)boronic acid (16.75 mg, 107.10 μmol). (S)-2-(5-(3-chlorophenyl)-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (22 mg, yield 67%) was obtained.

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 .

Example 57 Synthesis of Compound BR-032713

Same as Example 54: Synthesis of Compound BR-032710, except that the starting material 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane was replaced with pyridin-4-ylboronic acid (13.16 mg, 107.10 μmol). (S)-2-(6-oxo-5-(pyridin-4-yl)pyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (23 mg, yield 74%) was obtained.

¹ H NMR (600MHz, Methanol-d ₄ )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 .

Example 58 Synthesis of Compound BR-032714

Same as Example 54: Synthesis of Compound BR-032710, except that the starting material 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane was replaced with pyridin-3-ylboronic acid (13.16 mg, 107.10 μmol). (S)-2-(6-oxo-5-(pyridin-3-yl)pyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (20 mg, yield 64%) was obtained.

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 .

Example 59 Synthesis of Compound BR-032758

Same as Example 54: Synthesis of Compound BR-032710, except that the starting material 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane was replaced with (3-chloro-4-methoxyphenyl)boric acid (19.96 mg, 107.10 μmol). (S)-2-(5-(3-chloro-4-methoxyphenyl)-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (11 mg, yield 31%) was obtained.

¹ H NMR (400MHz, Methanol-d ₄ )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 .

Example 60 Synthesis of Compound BR-032759

The same method as 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 changed to 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, yield 52%) was obtained.

¹ H NMR (400MHz, Methanol-d ₄ )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 .

Example 61 Synthesis of Compound BR-032833

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

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.

Example 62 Synthesis of Compound BR-032828

Synthesis of BR-032828: Same as Example 54, thick preparative plate purification gave 20 mg of product (yield 64%).

¹ H 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 .

Example 63 Synthesis of Compound BR-032847

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 bottle, connected to a hydrogen balloon, replaced with a hydrogen atmosphere, and reacted at room temperature for 1 h. After the reaction was completed, the solution was filtered and concentrated under reduced pressure to remove the solvent. Reverse phase chromatography was used to obtain 8 mg of the product BR-032847 (yield 52%).

¹ H NMR (600MHz, Methanol-d ₄ )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.

Example 64 Synthesis of Compound BR-032848

As in Example 1, 26 mg of product was obtained by thick preparative plate purification (yield 86%).

¹ H NMR (600MHz, Methanol-d ₄ )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.

Example 65 Synthesis of Compound BR-032849

As in Example 1, 24 mg of the product was obtained by thick preparative plate purification (yield 80%).

¹ H NMR (600MHz, Methanol-d ₄ )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＝2.7H z,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.

Example 66 Synthesis of Compound BR-032850

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, 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.

Step 1: As in Example 1, thick preparative plate purification gave 20 mg of product (yield 74%).

¹ H NMR (600MHz, Methanol-d ₄ )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 .

Example 67 Synthesis of Compound BR-032876

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 bottle, 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%).

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

¹ H NMR (600MHz, Methanol-d ₄ )δ7.52–7.40(m,3H),7.26–7.18(m,2H),6.13(d,J＝7.3Hz,1H),5.03(q,J＝7.0Hz,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 .

Example 68 Synthesis of Compound BR-032882

As in Example 1, 30 mg of the product was obtained by thick preparative plate purification (yield 81%).

¹ H NMR (600MHz, Methanol-d ₄ )δ7.59–7.50(m,2H),7.49–7.42(m,2H),7.22(d,J＝8.3Hz,2H),6.53(dd,J＝9.1,1.3Hz,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 .

Example 69 Synthesis of Compound BR-032921

As in Example 2, thick preparative plate purification gave 11 mg of product (yield 39%).

¹ H NMR (400MHz, Methanol-d ₄ )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 .

Example 70 Synthesis of Compound BR-033019

As in Example 1, the thick preparative plate was purified to obtain 13 mg of product BR-033019 (yield 51%).

¹ H NMR (400MHz, DMSO-d ₆ )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,2H),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.

Example 71 Synthesis of Compound BR-033084

BR-033019 (35 mg, 83.30 μmol), cyclopropylboronic acid (10.73 mg, 124.95 μmol), PdCl ₂ (dppf) (6.09 mg, 8.33 μmol), and sodium carbonate (26.49 mg, 249.89 μmol) were added to a Schlenk reaction tube, replaced with a nitrogen atmosphere, and dioxane (1.5 mL) and H ₂ O (0.5 mL) were added, and then reacted at 100° C. overnight. After the reaction was completed, water was added, extracted with DCM, concentrated under reduced pressure to remove the solvent, and purified by reverse phase chromatography to obtain 8 mg of BR-033084 product.

¹ H NMR (600MHz, Methanol-d ₄ )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),4.6 4(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 .

Example 72 Synthesis of Compound BR-033552

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.

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

Step 2: Bicyclo[1.1.1]pentane-1-carbonyl chloride (290.00 mg, 2.22 mmol) and ACN (8 mL) were added to a reaction flask, stirred at 0°C for 5 min, and then trimethylsilylated diazomethane (2M hexane solution, 1.01 g, 8.88 mmol) was added dropwise. The reaction was allowed to react at room temperature for 5.5 h. After the reaction was completed, 10% citric acid aqueous solution was added to quench the reaction. Most of the solvent was dried by spin drying, and ethyl acetate was added. The mixture was extracted with 10% citric acid aqueous solution, water, saturated NaHCO ₃ , and saturated brine, respectively. The solvent was removed by concentration under reduced pressure, and 200 mg of the product 1-(bicyclo[1.1.1]pentan-1-yl)-2-diazacycloethane-1-one was obtained by column separation. Gradient: PE:EA=100:0 to 94:6, TLC:PE:EA=10:1 Rf=0.5, LC-Ms m/z[M+H] ⁺ 137.2

Step 3: 1-(Bicyclo[1.1.1]pentan-1-yl)-2-diazoethane-1-one (200 mg, 1.47 mmol), THF (30 mL), H ₂ O (5.00 mL) were added to a reaction flask, silver benzoate (67.27 mg, 293.79 μmol), 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 reacted with ultrasonic waves at room temperature for 0.5 h. After the reaction, most of the solvent was dried by rotary evaporation, acidified with 1 M HCl, added with water, extracted with ethyl acetate, and concentrated under reduced pressure to remove the solvent. The product, bicyclo[1.1.1]pentane-1-acetic acid, was directly used in the next step. MS m/z [M+H] ⁺ 125.2

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

Step 5: Add bicyclo[1.1.1]pentane-1-acetic acid ethyl ester (180 mg, 1.17 mmol) into the reaction bottle, replace the atmosphere with nitrogen, add THF (2 mL), add 2M LDA (0.76 mL, 162.55 mg, 1.52 mmol) dropwise at -50°C, stir the reaction for 20 min, add ethyl formate (129.71 mg, 1.75 mmol, 140.83 μL), react at room temperature overnight, add water after the reaction is completed, extract with DCM, and concentrate under reduced pressure to remove the solvent to obtain the crude product 2-(bicyclo[1.1.1]pentan-1-yl)-3-oxopropanoic acid ethyl ester, which is directly processed into the next step without purification.

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 bottle 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=100:0to 96:4, TLC:DCM:MeOH=20:1Rf=0.5, MS m/z[M+H] ⁺ 195.2.

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 bottle, 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.

Step 8: As in Example 1, reverse phase chromatography was used for purification to obtain 14.6 mg of product (yield 28%).

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.

Example 73 Synthesis of Compound BR-033588

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%).

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 .

Example 74 Synthesis of Compound BR-033601

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

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 .

Example 75 Synthesis of Compound BR-033602

BR-033601 (8 mg, 20.98 μmol), Pd/C (10%, 2 mg), and MeOH (1 mL) were added to the reaction bottle, connected to a hydrogen balloon, replaced with a hydrogen atmosphere, and reacted 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.

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 .

Example 76 Synthesis of Compound BR-033680

Step 1: Same as step 5 in Example 72, ethyl cyclobutyl-1-acetate (180 mg, 1.17 mmol) was added to the reaction flask, replaced with nitrogen atmosphere, THF (2 mL) was added, and 2 M LDA (0.76 mL, 162.55 mg, 1.52 mmol) was added dropwise at -50 °C. After stirring the reaction for 20 min, ethyl formate (129.71 mg, 1.75 mmol, 140.83 μL) was added. 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 and concentrated under reduced pressure to give the crude product 2-cyclobutyl-3-oxo-propionic acid ethyl ester, which was directly carried out to the next step without purification.

Step 2: Same as Step 6 in Example 72, 2-cyclobutyl-3-oxo-propionic acid ethyl ester (220 mg, 1290 μmol), thiourea (110 mg, 1450 μmol, 78.29 μL), and MeOH (3.5 mL) were added to the reaction bottle and reacted at 70°C for 3 h. After the reaction was completed, 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.

Step 3: Same as Step 7 in 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 bottle, connected to a hydrogen balloon, replaced with a hydrogen atmosphere, and reacted at 70°C overnight. After the reaction was completed, the reaction was filtered, and the solvent was removed by concentration under reduced pressure, and used directly in the next step. MS: m/z [M+H] ⁺ 151.2.

Step 4: As in Example 1, the product BR-033680 was obtained by reverse phase chromatography purification.

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 .

Example 77 Synthesis of Compound BR-033831

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.

Step 2: Add 5-cyclopropyl-4,6-dimethoxypyrimidine (30 mg, 166.48 μmol) and DCM (0.5 mL) to a 10 mL reaction bottle, add boron tribromide (150 μL, 2 mol/L in DCM solution) at 0°C, stir at room temperature overnight, detect whether there is any residual raw material, add methanol at 0°C to quench, concentrate to remove the solvent, and proceed to the next step without purification.

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

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.

Example 78 Synthesis of Compound BR-033833

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

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 .

Example 79 Synthesis of Compound BR-033834

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

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 .

Example 80 Synthesis of Compound BR-033875

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

Example 81 Synthesis of Compound BR-033878

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%).

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 .

Example 82 Synthesis of Compound BR-009267

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 bottle 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%). ¹ H 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

Example 83 Synthesis of Compound BR-034294

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.

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 whether there is any residual raw material, add methanol at 0°C to quench, concentrate to remove the solvent, and proceed to the next step without purification.

Step 3: Same as Example 77, reverse phase chromatography purification gave 34 mg of product (yield 85%).

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 .

Example 84 Synthesis of Compound BR-034295

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.

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 whether there is any residual raw material, add methanol at 0°C to quench, concentrate to remove the solvent, and proceed to the next step without purification.

Step 3: Same as Example 77, reverse phase chromatography purification gave 19.5 mg of product (yield 76%).

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.

Example 85 Synthesis of Compound BR-034594

BR-034295 (5 mg, 12.03 μmol), Pd/C (10%, 0.5 mg), 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 the reaction, 2.7 mg of the product was obtained by filtration and separation using Agilent preparation method. (Yield 57%).

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 .

Example 86 Synthesis of Compound BR-034716

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

Step 2: Add 5-cyclopropyl-4-methoxypyrimidine (200 mg, 1.33 mmol) and DCM (3 mL) to a 10 mL reaction bottle, add boron tribromide (3.3 mL, 2 mol/L in DCM solution) at 0°C, stir at 50°C overnight, detect whether there is residual raw material, add methanol at 0°C to quench, concentrate to remove the solvent, and proceed to the next step without purification.

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), HATU (435.66 mg, 1.15 mmol) were dissolved in MeCN (3 mL), and then DBU (201.27 mg, 1.32 mmol, 197.71 μL) was added, and the mixture was reacted at 75°C for 24 h. After the reaction, saturated ammonium chloride solution was added, and the mixture was extracted with DCM, and the solvent was removed by concentration under reduced pressure. 20 mg of the product was obtained by large plate separation. LC-Ms m/z [M+H] ⁺ 265.2.

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). 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, the solvent was dried and used directly in the next step without purification.

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

(1S)-1-[4-(Trifluoromethoxy)phenyl]ethylamine (5.91 mg, 28.82 μmol), HATU (21.91 mg, 57.63 μmol), DIPEA (14.90 mg, 115.27 μmol, 20.08 μL), 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

Example 87 Synthesis of Compound BR-034717

Same as Example 54: Synthesis of Compound BR-032710, 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 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.

Example 88 Synthesis of Compound BR-034891

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

¹ H NMR: 400MHz, CDCl ₃ δ7.68(s,1H),7.63(s,1H),5.31(s,2H),3.86(s,3H).

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 showed that the raw material was completely reacted and the product was generated. The reaction solution was cooled to room temperature, filtered, and the filter cake was collected to obtain a crude product compound 4 (193 mg). The product was a yellow solid, which was directly used in the next step.

¹ H NMR: ENBJ240001-060-P1A1, 400MHz, DMSO-d ₆ δ8.44(d,J＝0.8Hz,1H),7.91(s,1H),7.75(d,J＝0.8Hz,1H),7.53–7.06(m,1H).

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), and the reaction solution was stirred at 20°C for 2 hours. LCMS and TLC (petroleum ether: ethyl acetate = 10: 1) showed that the raw materials were completely reacted. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (silica, ethyl acetate: petroleum ether = 0-50%) to obtain compound 6 (587 mg, 50% purity, 1.17 mmol, yield 82.7%). ¹ H NMR: DMSO-d ₆ δ8.54(s,1H),8.18(s,1H),7.87(s,1H),4.60(s,2H),1.43(s,9H).

Step 4: Trifluoroacetic acid (0.5 mL) was added to a solution of compound 6 (50.0 mg, 0.200 mmol) in dichloromethane (0.5 mL) at 0°C, and the reaction was stirred at 20°C for 12 hours. LCMS (ENBJ240001-068-P1M1) showed that the starting material was completely reacted and ~60% of the product was monitored. The reaction solution was concentrated under reduced pressure to give the crude product compound 7 (40.0 mg). The product was a yellow oil and was directly used in the next step.

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 thereto at 0°C, and the reactants were stirred at 20°C for 12 hours. LCMS showed that the raw materials were completely reacted and the product was monitored. The mixture was concentrated under reduced pressure and purified by prep-HPLC (column type: Gemini, mobile phase: acetonitrile/water (0.1% TFA), gradient: 30-70%) to obtain compound BR-034891 (33.6 mg, 99.9% purity, 0.0880 mmol, 42.7% yield).

¹ H NMR: ENBJ240001-069-P1A1, 400MHz, DMSO-d ₆ δ8.81(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] ⁺

Example 89 Synthesis of Compound BR-034892

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

¹ H NMR: DMSO-d ₆ δ8.79(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),4.9 6(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] ⁺

Example 90 Synthesis of Compound BR-034942

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.

¹ H NMR: DMSO-d ₆ δ8.80(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),4.9 6(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] ⁺

Example 91 Synthesis of Compound BR-040742

Step 1: At 0°C, a solution of NBS (390 mg, 0.0022 mmol) in DMF (0.5 mL) was added dropwise to a solution of compound 6 (1.09 g, 0.0044 mol) in DMF (9 mL) in Example 88, and the reaction solution was stirred at 50°C for 1 hour. A solution of NBS (390 mg, 0.0022 mmol) in DMF (0.5 mL) was added to the reaction solution at 0°C, and the reaction solution was stirred at 50°C for 1 hour. LCMS showed that the raw material was completely reacted and accompanied by the target product. The reaction solution was diluted with water (200 mL), extracted with ethyl acetate (100 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified by normal phase column chromatography (silica, ethyl acetate: petroleum ether = 0-30%) to obtain compound 1 (814 mg, 0.0025 mol, 83.3% yield).

¹ H NMR: 400MHz, DMSO-d ₆ δ8.55(s,1H),8.20(s,1H),4.57(s,2H),1.44(s,9H).MS(ESI)m/z＝329.0[M+H] ⁺

Step 2: Compound 1 (300 mg, 0.911 mmol), K ₃ PO ₄ (387 mg, 1.82 mmol) and compound 2 (146 mg, 1.09 mmol) were dissolved in dioxane: water = 5:1 (10 mL), Pd(dppf)Cl ₂ (66.7 mg, 0.0911 mmol) was added thereto, and the reaction solution was stirred for 12 hours at 100°C under a nitrogen atmosphere (15 Psi). LCMS and TLC (petroleum ether: ethyl acetate = 3:1, Rf(P1) = 0.30) showed that the raw materials reacted completely and the product was generated. The reaction solution was filtered through diatomaceous earth, the filtrate was collected and concentrated under reduced pressure, and the crude product was separated and purified by normal column chromatography (silica, ethyl acetate: petroleum ether = 0-25%) to obtain compound 3 (244 mg, 0.883 mmol, 96.8% yield).

¹ H NMR: 400MHz, DMSO-d ₆ δ8.47(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).

Step 3: Add trifluoroacetic acid (1 mL) to a solution of compound 3 (40.0 mg, 0.145 mmol) in dichloromethane (1 mL), and stir the reactants at 20°C for 3 hours. LCMS showed that the raw materials were completely reacted and the product was monitored. The reaction solution was concentrated under reduced pressure to obtain a crude product, compound 4 (31.0 mg, crude). The product was a yellow oil and was used directly in the next step.

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), T ₄ P (203 mg, 0.282 mmol) was added thereto at 0°C, and the reactants were stirred at 20°C for 12 hours. LCMS showed that the starting materials were completely reacted and the product was monitored. The mixture was concentrated under reduced pressure and subjected to prep-HPLC (column type: Gemini, mobile phase: acetonitrile/water (0.1% FA), gradient: 40-70%) to obtain compound BR-040742 (32.4 mg, 99.4% purity, 0.0791 mmol, 56.1% yield).

^1H NMR: 400MHz, DMSO-d ₆ δ8.80(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] ⁺

Example 92 Synthesis of Compound BR-040769

Step 1: Compound 3 (80.0 mg, 0.289 mmol) obtained in Example 91 was dissolved in methanol (6 mL), palladium carbon (30.8 mg, 0.289 mmol) was added thereto, and the reaction solution was stirred for 2 hours under a hydrogen atmosphere (15Ps i) at 20°C. LCMS showed that the raw material was completely reacted and the product was monitored. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to obtain compound 1 (79.0 mg, crude).

¹ H NMR: 400MHz, DMSO-d ₆ δ8.37(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).

Step 2: Add trifluoroacetic acid (2 mL) to a solution of compound 1 (79.0 mg, 0.284 mmol) in dichloromethane (2 mL) at 0°C, and stir the reactants at 20°C for 12 hours. LCMS showed that the raw materials were completely reacted and the product was detected. The reaction solution was concentrated under reduced pressure to obtain a crude product, compound 2 (60.0 mg, crude). The product was a yellow oil and was directly used in the next step.

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

(55.4 mg, 0.270 mmol) was dissolved in tetrahydrofuran (4 mL), T ₄ P (389 mg, 0.540 mmol, 50 wt.% in EtOAC) was added thereto at 0°C, and the reactants were stirred at 20°C for 12 hours. LCMS detection showed that the raw materials were completely reacted and the product was monitored. The mixture was concentrated under reduced pressure and subjected to prep-HPLC (column type: Gemini, mobile phase: acetonitrile/water (0.1% FA), gradient: 30-70%) to obtain compound BR-040769 (85.69 mg, 99.9% purity, 0.209 mmol, 77.4% yield).

^1H NMR: 400MHz, DMSO-d ₆ δ8.80(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,1 H),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] ⁺

Example 93 Synthesis of Compound BR-040820

Step 1: Compound 1 (200 mg, 0.607 mmol) of 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 thereto, and the reaction solution was stirred at 80° C. under nitrogen atmosphere for 4 hours. LCMS showed that the product was generated. The reaction solution was concentrated under reduced pressure, and the crude product was separated 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] ⁺

Step 2: Add trifluoroacetic acid (1.5 mL) to a solution of compound 2 (15.0 mg, 0.0517 mmol) in dichloromethane (1.5 mL), and stir the reactants at 20°C for 4 hours. LCMS showed that the raw materials were completely reacted and the product was monitored. The reaction solution was concentrated under reduced pressure to obtain a crude product, compound 3 (12.0 mg, crude). The product was a yellow oil and was directly used in the next step.

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), T ₄ P (73.8 mg, 0.102 mmol) was added thereto at 0°C, and the reactants were stirred at 20°C for 4 hours. LCMS detection showed that the raw materials were completely reacted and the products were generated. The mixture was concentrated under reduced pressure and subjected to prep-HPLC (column type: Gemini, mobile phase: acetonitrile/water (0.1% FA), gradient: 30-70%) to obtain compound BR-040820 (14.36 mg, 98.1% purity, 0.0334 mmol, 65.2% yield).

^1H NMR: 400MHz, DMSO-d ₆ δ8.79(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] ⁺

Example 94 Synthesis of Compound BR-040844

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

¹ H NMR: CDCl ₃ δ7.41(s,1H),4.48(s,2H),2.60(s,3H),1.50(s,9H).MS(ESI)m/z＝342.90[M+H] ⁺

Step 2: Pd(PPh ₃ ) ₄ (67.3 mg, 0.0582 mmol) was added to a mixed 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), and the mixture was stirred at 100° C. for 12 hours in a nitrogen atmosphere. LCMS detection results showed that the reaction raw materials were consumed and the target product was generated. The reaction solution was filtered and the filtrate 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 = 0-48%) to obtain compound 4 (51.0 mg, 0.183 mmol, 31.4% yield) as a yellow oil.

¹ H NMR: CDCl ₃ δ7.39(s,1H),4.48(s,2H),2.65(s,6H),1.50(s,9H).MS(ESI)m/z＝279.05[M+H] ⁺

Step 3: At 0°C, TFA (1 mL) was added to a solution of compound 4 (41.0 mg, 0.147 mmol) in DCM (2 mL), and the mixture was stirred at 20°C for 2 hours. LCMS results showed that the reaction raw materials were consumed and the target product was generated. 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 6 (32.6 mg, crude) was a yellow oil.

Step 4: At 0°C, T4P (211 mg, 50 wt.% in ethyl acetate) was added 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), and the mixture was stirred at 20°C for 12 hours. LCMS test results showed that the reaction raw materials were consumed and the target product was generated. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (mobile phase: methanol/dichloromethane = 0-3%) to obtain BR-040844 (58.3 mg, 0.142 mmol, 99.77% purity, 96.8% yield) as a white solid.

¹ H NMR: DMSO-d ₆ δ8.78(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] ⁺

Example 95 Synthesis of Compound BR-040845

Step 1: Compound 2 (470 mg, 2.41 mmol) was added to a DMF (10 mL) solution of compound 1 (300 mg, 2.01 mmol) and potassium carbonate (555 mg, 4.02 mmol) at 0°C, and the mixture was stirred at 20°C for 4 hours. LCMS detection results showed that the reaction raw materials were consumed and the target product was generated. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel 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] ⁺

Step 2: Add TFA (3 mL) to a solution of compound 3 (320 mg, 1.21 mmol) in DCM (10 mL), and stir the mixture at 200 °C for 3 hours. LCMS results showed that the reaction starting materials were consumed and the target product was generated. 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 a white solid. MS (ESI) m/z = 208.1 [M + 1] ⁺

Step 3: At 0°C, T ₄ P (695 mg, 50 wt.% in ethyl acetate) was added 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), and the mixture was stirred at 20°C for 12 hours. LCMS detection results showed that the reaction raw materials were consumed and about 80% of the target product was generated. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (mobile phase: ACN-H2O (0.1% FA), gradient: 45-90%) to obtain BR-040845 (96.15 mg, 0.243 mmol, 50.4% yield) as a white solid.

¹ H NMR: DMSO-d ₆ δ8.78(d,J＝7.6Hz,1H),7.87(s,1H),7.39(m,5H),6.37(d,J＝2.4Hz,1H),4.96(p,J＝6.8 Hz,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] ⁺

Test Example 1: Human GPR139 FLIPR Assay to determine compound activity

CHO K1 cells were seeded at a density of 100,000 cells in a 10 cm 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 read 10 readings (1 reading per second), initially as a baseline before adding 10 μl 3x JNJ-63533054 solution (prepared in HBSS buffer containing 0.1% BSA). Fluorescence intensity was recorded within 2 minutes after the addition of the drug for agonist activity detection. Using different concentrations of the test compound, JNJ-63533054 was used as the standard molecule, and its E _max value was defined as 100%. GraphPad Prism 8.0 was used to analyze the data by nonlinear regression, and the activity results (EC ₅₀ and Emax%) of some compounds measured using FLIPR Assay were shown in Tables 3A and 3B, respectively.


EC ₅₀ <50nM: +++++; 50nM≤EC ₅₀ <100nM: ++++; 100nM≤EC ₅₀ <300nM: +++; 300nM
≤EC ₅₀ <500 nM: ++; 500 nM ≤EC ₅₀ : +E _max (maximum effect) refers to the maximum biological effect or response intensity produced by the test compound under given experimental conditions.

Test Example 2: NFAT-Luc assay for compound activity

The 293T-GPR139-NFAT reporter gene stable cell line was inoculated in a 96-well white-walled transparent bottom cell culture plate with 40,000 cells per well using DMEM medium containing 10% FBS, and placed in a 37°C, 5% _CO2 incubator for overnight culture. The next day, the test compound was diluted in a 3-fold gradient with DMEM medium without FBS (30μM, 10μM, 3.3μM, 1.1μM, 0.37μM, 0.12μM, 0.04μM, 0.014μM). The cell plate cultured overnight was removed from the incubator, the original culture medium in the well plate was discarded, and the prepared DMEM culture medium containing different concentrations of the test compound was added. Continue to be placed in a 37°C, 5% _CO2 incubator and incubated for 6 hours. After the cell incubation is completed, the cell culture plate and luciferase detection reagent (purchased from Promega steady-glo luciferase assay system) are placed at room temperature and equilibrated for 30 minutes. 100 μL of the balanced detection reagent was added to the 96-well plate and incubated at room temperature for 10 minutes. Fluorescence was detected using a full-function microplate reader (BioTek synergyNeo2), where TAK-041 was used as a standard molecule and its Emax value was defined as 100%. Graphpad prim 8.0 nonlinear regression algorithm was used to analyze the data, and the EC ₅₀ and E _max results of some compounds determined using NFAT-Luc are shown in Tables 4A and 4B, respectively.



EC ₅₀ <1μM: +++++; 1μM≤EC ₅₀ <10μM: ++++; 10μM≤EC ₅₀ <20μM: +++; 20μM
≤EC ₅₀ <30 μM: ++; 30 μM ≤EC ₅₀ : +E _max (maximum effect) refers to the maximum biological effect or response intensity produced by the test compound under given experimental conditions.

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

Claims (39)

The compound shown in Formula I, or a pharmaceutically acceptable salt thereof
wherein Q ₁ is selected from N or CR ₅ and Q ₂ is selected from N, NR ₅ or CR ₅ , 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 R5 are ...6-10 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 R5 are independently selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, 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 R5 ₁ 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 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, 4-10 membered heterocycloalkenyl, or 5-10 membered heteroaryl 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, C2-10 alkenyl, C2-10 alkynyl, or -C(O)R ₉ , wherein R ₉ is selected from -OH, halogen, or C1-3 alkyl; R ₂ 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; R ₃ 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, -NH ₂ , or -NHCH ₂ COOH; _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. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein represents a double bond; and wherein Q ₁ and Q ₂ are each independently selected from N or CR ₅ , provided that Q ₁ and Q ₂ are not N at the same time, wherein R ₁ and R ₅ 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 R _{5 on adjacent carbons or R 5} and R ₅ are independently selected from ₁ together with the carbon to which they are each attached form a C4-10 cycloalkenyl or a 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, 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)R ₉ , wherein R ₉ is selected from -OH, halogen or C1-3 alkyl; R ₂ 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; R ₃ 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, -NH ₂ , or -NHCH ₂ COOH; _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. 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 ... ₁ 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 said -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; and/or wherein R ₂ 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 -CF ₃ or -OCF ₃ , more preferably -OCF ₃ ; and/or wherein R ₃ 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 -NH ₂ ; and/or wherein R ₄ is selected from H or deuterium; and/or wherein m is 0 or 1, and/or n is 0, 1 or 2. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₅ 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 R ₅ on adjacent carbons or R ₅ ... ₁ together with the carbon to which they are attached form a C4-6 cycloalkenyl or a 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 with one or more groups selected from the following: deuterium, -F, -Cl, -Br, -OH, -O-C1-3 alkyl, or C1-3 alkyl; and/or wherein R ₂ 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 -CF ₃ or -OCF ₃ , more preferably -OCF ₃ ; and/or wherein R ₃ 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 -NH ₂ ; and/or wherein R ₄ is selected from H or deuterium; and/or wherein m is 0 or 1, and/or n is 0, 1 or 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₅ 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 R 5 or R 5 and R 5 are each independently selected from H, 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 R ₅ or R ₅ and R ₁ together with their respective atoms to which they are attached form a C5-6 cycloalkenyl, a 5-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl which is optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl, C2-4 alkenyl, or -O-C1-3 alkyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₅ 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 R ₅ or R ₅ and R ₁ 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. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₅ 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 R _{5 on adjacent carbons or R 5 and} R ₁ together with the carbon to which they are each attached together 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. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₅ 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 R ₅ on adjacent carbons or R ₅ and R ₁ 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 group optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₃ is selected from methyl and R ₄ is selected from H. 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 optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl. Or two adjacent R ₅ or R ₅ and R ₁ 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. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₅ are each independently selected from isopropyl, phenyl, cyclopropyl, or Or two R ₅ on adjacent carbons or R ₅ and R ₁ 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. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as shown in any one of formula (I-1) to formula (I-5):
wherein R ₁ , R ₂ , R ₅ , Q ₁ , Q ₂ and n are as defined in claim 1 , Q ₄ 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)R ₉ , wherein R ₉ is selected from -OH, halogen or C1-3 alkyl, and q is an integer from 0 to 2, and when q is 2, R ₁₀ may be the same or different. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound has a structure as shown in any one of formula (I-1) to formula (I-4):
wherein R ₁ , R ₂ , R ₅ , Q ₁ , Q ₂ and n are as defined in claim 2, and wherein in formula (I-1) Represents a double bond. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as shown in formula (I-2i):
wherein R ₁ 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 the group consisting of 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different; Q ₃ is selected from O, S, -CH ₂ - or wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and R ₂ 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, further preferably -CF ₃ or -OCF ₃ , more preferably -OCF ₃ . The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from the group consisting of: Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound has a structure as shown in formula (I-2i):
wherein R ₁ 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different; Q3 is selected from O, S, _-CH2- or wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and R ₂ 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, further preferably -CF ₃ or -OCF ₃ , more preferably -OCF ₃ . The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from the group consisting of: Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound has a structure as shown in formula (I-2ii):
wherein Q ₃ is selected from O, S, -CH ₂ - or And wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R ₈ is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R ₂ 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 -CF ₃ or -OCF ₃ , more preferably -OCF ₃ . 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: 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 R ₁ 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 the group consisting of 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different; Q ₃ is selected from O, S, -CH ₂ - or wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and R ₂ 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, further preferably -CF ₃ or -OCF ₃ , more preferably -OCF ₃ . The compound according to claim 20 or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from the group consisting of: Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound has a structure as shown in formula (I-3i):
wherein R ₁ 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different; Q ₃ is selected from O, S, -CH ₂ - or wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and R ₂ 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, further preferably -CF ₃ or -OCF ₃ , more preferably -OCF ₃ . The compound according to claim 22 or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from the group consisting of: Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound has a structure as shown in formula (I-3ii):
wherein Q ₃ is selected from O, S, -CH ₂ - or And wherein R ₇ is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R ₈ is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R ₂ 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 -CF ₃ or -OCF ₃ , more preferably -OCF ₃ . 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:
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as shown in formula (I-4i):
wherein R ₁ 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 the group consisting of 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different; Q ₃ is selected from O, S, -CH ₂ - or wherein _R7 is selected from H or C1-3 alkyl, preferably H and methyl, and R ₂ 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, further preferably -CF ₃ or -OCF ₃ , more preferably -OCF ₃ . The compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from the group consisting of: Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound has a structure as shown in formula (I-4i):
wherein R ₁ 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, R ₁ 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 R ₆ 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, R ₆ may be the same or different; Q ₃ is selected from O, S, -CH ₂ - or wherein _R7 is selected from H or C1-3 alkyl, preferably H and methyl, and R ₂ 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, further preferably -CF ₃ or -OCF ₃ , more preferably -OCF ₃ . The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from the group consisting of: Br, methyl, ethyl, propyl, isopropyl, -O-CH ₃ , wherein each X is independently selected from F, Cl, Br or I. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as shown in formula (I-5i):
wherein R ₁₀ is independently selected from -H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-5 alkenyl, or -C(O)R ₉ , wherein R ₉ is selected from -OH, halogen or C1-3 alkyl, preferably R ₁₀ is independently selected from -H, C1-3 alkyl, C2-3 alkenyl. The 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:
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as shown in formula (I-5ii):
wherein R ₁₀ is independently selected from -H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-5 alkenyl, or -C(O)R ₉ , wherein R ₉ is selected from -OH, halogen or C1-3 alkyl, preferably R ₁₀ is independently selected from -H, C1-3 alkyl, C2-3 alkenyl. The 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:
The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof:




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. The pharmaceutical composition of claim 35, for use in treating a disease, disorder or condition associated with GPR139, wherein the disease, disorder or condition 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. The pharmaceutical composition of claim 35, further comprising one or more other active ingredients selected from the group consisting of antidepressants, antipsychotics, antianxiety drugs, sedatives, hypnotics, or tranquilizers. 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. 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.