Nicotinamide phosphoribosyltransferase agonist and use thereof

Abstract

Provided are a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer or isotope-labeled compound thereof, a pharmaceutical composition thereof, and a use thereof in preparation of a drug, a dietary supplement, a health care product, a pet food, a pet health care product, a cosmetic, a skin care product and medical aesthetics for preventing and treating NAD+ reduction-related diseases caused by aging or other reasons. Ring A, ring B, X1, Y1, Y2, Z, R, R0-R3, n, and m in formula (I) are as defined in the description.

Description

Nicotinamide phosphoribosyltransferase agonists and their uses

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit from PCT International Application No. PCT / CN2024 / 127307, filed with the China National Intellectual Property Administration on October 25, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This application pertains to the pharmaceutical field and relates to a class of compounds that activate nicotinamide phosphoribosyltransferase (NAMPT) and their uses. Background Technology

[0004] Nicotinamide adenine dinucleotide (NAD+) is an abundant metabolite that plays a crucial role in maintaining cellular homeostasis. NAD+ acts as a cofactor in various redox reactions involved in energy production, glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, fatty acid oxidation, and serine biosynthesis. Simultaneously, NAD+ serves as a substrate for various signaling enzymes, such as sirtuins, PARP, and cADPRS. In these reactions, NAD+ is degraded into ADP-ribose and nicotinamide (NAM), which can be recycled. Because NAD+'s multiple functions directly and indirectly affect many key cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cellular senescence, and immune cell function, these cellular processes and functions are essential for maintaining tissue and metabolic homeostasis and healthy aging.

[0005] It is worth noting that NAD+ levels gradually decline with age. This decline is associated with downregulation of mitochondrial energy production, mitochondrial decay, oxidative stress, DNA damage, cognitive impairment, and inflammatory conditions. Therefore, NAD+ deficiency is linked to many age-related diseases and aging, including neurodegenerative diseases, cancer, cardiovascular diseases, metabolic diseases, muscle loss, and the decline of various bodily functions. Numerous studies have shown that many age-related diseases can be slowed or even reversed by restoring NAD+ levels. Increasing NAD+ levels can improve insulin sensitivity, reverse mitochondrial dysfunction, and activate longevity genes, thereby achieving the goal of delaying aging and treating age-related diseases.

[0006] Therefore, targeting NAD+ metabolism has become a potential anti-aging therapy that can improve age-related diseases and extend healthy lifespan.

[0007] Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway. Functional NAMPT forms a homodimer, catalyzing the conversion of nicotinamide (NAM) and 5-phosphoribosyl-1-pyrophosphate (PRPP) into NMN. NAMPT is widely expressed in humans, especially in bone marrow, liver, muscle, and adipose tissue. Activation of NAMPT can effectively increase NAD+ levels in cells. NAMPT gene deletion in mice is embryonic lethal, indicating the necessity of this pathway for maintaining NAD+ levels. NAMPT treats diseases by regulating the body's inflammatory response, apoptosis, glucose metabolism, and oxidative stress through the regulation of NAD+ levels in tissues or cells. Evidence suggests that activation of NAMPT has significant therapeutic effects on neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), cardiovascular diseases such as diabetic cardiomyopathy, metabolic diseases, and age-related symptoms or diseases. Summary of the Invention

[0008] This application provides compounds that act as NAMPT agonists, which can regulate NAD+ levels in tissues and cells of the body. These compounds can be used to prepare drugs for the prevention and treatment of diseases related to aging or NAD+ reduction. The application also provides their uses in dietary supplements, health products, pet food supplements, cosmetics, and skin care products.

[0009] On the one hand, this application provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, tautomers, enantiomers, diastereomers, or isotopically labeled compounds thereof:

[0010] in:

[0011] Ring A is heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, and Y1 is selected from aryl, heteroaryl, halogen, alkyl, alkyl-substituted amino, alkoxy, heterocycloalkyl and cycloalkyl, and Y2 is absent; each R is independently selected from halogen, -CN, alkyl, alkoxy and cycloalkyl;

[0012] or

[0013] Y1 and Y2 together with X1 and carbon atoms attached thereto form ring C, and ring A and ring C together constitute a benzo[a]aromatic ring, a benzo[hetero]aromatic ring, a benzo[a]cycloalkyl ring, a benzo[a]cycloalkenyl ring, a benzo[a]heterocycloalkyl ring or a benzo[a]heterocycloalkenyl ring, and ring A and ring C are each independently and optionally substituted by one, two or three substituents independently selected from halogens, alkyl groups, alkoxy groups and haloalkyl groups;

[0014] Ring B is phenyl, heteroaryl, benzo[a]heteroaryl, or benzo[a]heterocyclic.

[0015] It can be a single bond or a double bond;

[0016] Z is selected from CR”R”, O, S, (CR”R”) p "and NR", where "R" is independently selected from H and alkyl; or Z is formed together with the adjacent CR1R2. Structural fragments or cycloalkyl groups; or Z is CR”R” and the two R” together with the carbon atoms attached to them form cycloalkyl groups;

[0017] Each R0 is independently selected from -OH, -NH2, NHR4, NHCOR4 and NHSO2R4, wherein R4 is independently selected from alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, aryl and heteroaryl;

[0018] X1 is selected from N, NH, NR', CH, CH2, CR' or CHR', wherein R' is selected from halogen, -CN, alkyl and alkoxy, and N is optionally oxidized;

[0019] R1, R2, and R3 are each independently selected from H and alkyl groups; or R1 and R2 together with the carbon atom attached to them form a cycloalkyl group;

[0020] n is 0, 1, 2, 3, 4 or 5;

[0021] m can be 0, 1, 2, 3, or 4;

[0022] p can be 0, 2, 3, 4 or 5.

[0023] The compound of formula (I) in this application does not include

[0024] In the above formula (I), the X1 atom connected to Y2 and the C atom connected to Y1 are adjacent, and the C atom connected to Y1 and the C atom connected to Z are adjacent.

[0025] In some embodiments, ring A is a heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, and Y1 is selected from halogens, alkyl, alkyl-substituted amino, alkoxy, heterocycloalkyl, and cycloalkyl, and Y2 is absent; each R is independently selected from halogens, -CN, alkyl, alkoxy, and cycloalkyl.

[0026] In some implementation schemes,

[0027] Ring A is a heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, and Y1 is selected from halogen, alkyl, alkoxy, and cycloalkyl, while Y2 is absent;

[0028] or

[0029] Y1 and Y2 together with X1 and carbon atoms attached thereto form ring C, and ring A and ring C together constitute a benzo[a]aromatic ring, a benzo[hetero]aromatic ring, a benzo[a]cycloalkyl ring, a benzo[a]cycloalkenyl ring, a benzo[a]heterocycloalkyl ring or a benzo[a]heterocycloalkenyl ring, and ring A and ring C are each independently and optionally substituted by one, two or three substituents independently selected from halogens, alkyl groups, alkoxy groups and haloalkyl groups;

[0030] Ring B is phenyl, heteroaryl, benzo[a]heteroaryl, or benzo[a]heterocyclic.

[0031] It can be a single bond or a double bond;

[0032] Z is selected from CR”R”, O, S and NR”, where R” is independently selected from H and alkyl groups;

[0033] Each R0 is independently selected from -OH, -NH2, NHCOR4 and NHSO2R4, wherein R4 is independently selected from alkyl, alkoxy, haloalkyl and haloalkoxy;

[0034] Each R is independently selected from halogen, -CN, alkyl, alkoxy, and cycloalkyl;

[0035] X1 is selected from N, NH, NR', CH, CH2, CR' or CHR', wherein R' is selected from halogen, -CN, alkyl and alkoxy, and N is optionally oxidized;

[0036] R1, R2, and R3 are each independently selected from H and alkyl groups;

[0037] n is 0, 1, 2, 3, 4 or 5;

[0038] m can be 0, 1, 2, 3, or 4.

[0039] In some embodiments, ring A is a 5-6 membered heteroaryl, a 5-7 membered cycloalkyl, a 5-7 membered cycloalkenyl, a 5-7 membered heterocycloalkyl, or a 5-7 membered heterocycloalkenyl.

[0040] In some embodiments, ring A is a 5-6-membered heteroaryl, a 5-7-membered cycloalkyl, a 5-7-membered cycloalkenyl, a 5-7-membered heterocycloalkyl, or a 5-7-membered heterocycloalkenyl, wherein each of the 5-6-membered heteroaryl, 5-7-membered heterocycloalkyl, or 5-7-membered heterocycloalkenyl independently contains one, two, or three heteroatoms independently selected from N, O, and S.

[0041] In some embodiments, ring A is a 5-6 membered heteroaryl, a 5-7 membered cycloalkyl, or a 5-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl and the 5-7 membered heterocycloalkyl each independently contain one, two, or three heteroatoms independently selected from N, O, and S.

[0042] In some embodiments, ring A is a 6-membered heteroaryl, cyclohexyl, or 6-membered heterocycloalkyl, wherein the 6-membered heteroaryl and 6-membered heterocycloalkyl each independently contain one, two, or three N atoms.

[0043] In some embodiments, ring A is pyridyl, pyrazinyl, pyrimidinyl, or cyclohexyl.

[0044] In some embodiments, ring A is a 5-6 membered heteroaryl or a 5-6 membered cycloalkyl, wherein the 5-6 membered heteroaryl contains one or two N atoms.

[0045] In some embodiments, ring A is a 6-membered heteroaryl or cyclohexyl group, wherein the 6-membered heteroaryl group contains one or two N atoms.

[0046] In some embodiments, ring A is a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains one or two N atoms.

[0047] In some embodiments, ring A is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, or cyclohexyl.

[0048] In some embodiments, ring A is pyridyl, pyrazinyl, or pyrimidinyl.

[0049] In some implementations, ring A is Where “*” represents the connection site with Y1 and “**” represents the connection site with Z.

[0050] In some implementations, ring A is

[0051] In some implementations, ring A is In some implementations, ring A is

[0052] In the above implementation scheme, m is 0 or 1.

[0053] In some implementations, Y1 is selected from halogens, C 1-6 Alkyl, C 1-6 Alkyl-substituted amino, C 1-6 Alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, and Y2 is not present.

[0054] In some implementations, Y1 is selected from halogens, C 1-4 Alkyl, C 1-4 Alkyl-substituted amino, C 1-4Alkoxy, 3-5 membered cycloalkyl and 4-5 membered heterocycloalkyl (e.g., 1-azacyclobutane or 1-pyrrolidinyl), and Y2 is absent.

[0055] In some implementations, Y1 is selected from C 1-6 Alkyl or C 1-6 An alkyl-substituted amino group, and Y2 is not present.

[0056] In some implementations, Y1 is C(CH3)3 or N(CH3)2, and Y2 is not present.

[0057] In some implementations, Y1 is C(CH3)3, and Y2 does not exist.

[0058] In some implementations, Y1 is selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy and 3-6 membered cycloalkyl groups, and Y2 is absent.

[0059] In some embodiments, Y1 is selected from 6-10 aryl groups; 5-6 heteroaryl groups; C(CH3)3; halogens; amino groups substituted with C1, C2, C3, C4, C5, or C6 alkyl groups; C 1、 C2, C3, C4, C5 or C6 alkoxy; 3, 4, 5 or 6-membered cycloalkyl and 3, 4, 5 or 6-membered heterocycloalkyl, and Y2 is absent.

[0060] In some embodiments, Y1 is selected from C(CH3)3; halogen; amino group substituted with C1, C2, C3, C4, C5 or C6 alkyl groups; C 1、 C2, C3, C4, C5 or C6 alkoxy; 3, 4, 5 or 6-membered cycloalkyl and 3, 4, 5 or 6-membered heterocycloalkyl, and Y2 is absent.

[0061] In some embodiments, Y1 is selected from C(CH3)3; an amino group substituted with a C1, C2, C3, C4, C5, or C6 alkyl group; a C2, C3, C4, C5, or C6 alkoxy group; a 3, 4, 5, or 6-membered cycloalkyl group and a 3, 4, 5, or 6-membered heterocycloalkyl group, and Y2 is absent. In some embodiments, Y1 is selected from an amino group substituted with a C1, C2, or C3 alkyl group; C2, C3, C4, C5, or C6 alkoxy group; a 3, 4, 5, or 6-membered cycloalkyl group; and a 3, 4, 5, or 6-membered heterocycloalkyl group. 1、 C2 or C3 alkoxy; 3, 4, 5 or 6-membered cycloalkyl and 3, 4, 5 or 6-membered heterocycloalkyl, and Y2 is absent, wherein the 3, 4, 5 or 6-membered heterocycloalkyl contains one or two heteroatoms independently selected from N and O and one N atom is attached to ring A; or the 3, 4, 5 or 6-membered heterocycloalkyl contains one N atom and the N atom is attached to ring A.

[0062] In some embodiments, Y1 is selected from 3, 4, 5, or 6-membered heterocyclic alkyl groups, and Y2 is absent, wherein the 3, 4, 5, or 6-membered heterocyclic alkyl group contains one or two heteroatoms independently selected from N, O, and S, and one N atom is attached to ring A; or the 3, 4, 5, or 6-membered heterocyclic alkyl group contains one N atom, and the N atom is attached to ring A.

[0063] In some embodiments, Y1 is selected from C(CH3)3, N(CH3)2, OCH(CH3)2, OC(CH3)3, Cl, 1-azacyclobutane, 1-pyrrolidinyl, Cyclopropyl, cyclobutyl, cyclopentyl, 1-piperazinyl, 4-methyl-1-piperazinyl, and morpholinyl, and Y2 is absent.

[0064] In some embodiments, Y1 is C(CH3)3, 1-pyrrolidinyl, 1-azacyclobutyl, cyclopentyl, cyclopropyl, N(CH3)2 or OCH(CH3)2, and Y2 is absent.

[0065] In some embodiments, Y1 is C(CH3)3, 1-pyrrolidinyl or 1-azacyclobutane, and Y2 is absent.

[0066] In some embodiments, Y1 is 1-pyrrolidinyl or 1-azacyclobutane, and Y2 is absent.

[0067] In some embodiments, ring A and ring C together constitute a benzo6-10 membered aromatic ring, a benzo5-6 membered heteroaromatic ring, a benzo5-7 membered alkyl ring, a benzo5-7 membered alkenyl ring, a benzo5-7 membered heteroalkyl ring, or a benzo5-7 membered heteroalkene ring, wherein each of the benzo5-6 membered heteroaromatic ring, the benzo5-7 membered heteroalkyl ring, and the benzo5-7 membered heteroalkene ring independently contains one, two, or three heteroatoms independently selected from N, O, and S.

[0068] In some embodiments, ring A and ring C together constitute a benzo6-10 membered aromatic ring, a benzo5-6 membered heteroaromatic ring, a benzo5-6 membered alkyl ring, or a benzo5-6 membered heteroalkyl ring, wherein the benzo5-6 membered heteroaromatic ring and the benzo5-6 membered heteroalkyl ring each independently contain one, two, or three N atoms.

[0069] In some embodiments, when ring A and ring C together constitute a benzo6-10 membered aromatic ring, a benzo5-6 membered heteroaromatic ring, a benzo5-6 membered cycloalkyl ring, or a benzo5-6 membered heteroalkyl ring, the ring connected to Z is a benzene ring (i.e., ring A is a benzene ring).

[0070] In some embodiments, when ring A and ring C together constitute a benzo5-6 membered heteroaromatic ring, a benzo5-6 membered cycloalkyl ring, or a benzo5-6 membered heteroalkyl ring, the ring connected to Z is a heteroaromatic ring, a cycloalkyl ring, or a heteroalkyl ring (i.e., ring C is a benzene ring).

[0071] In some embodiments, ring A and ring C together constitute a naphthyl, tetrahydronaphthyl, indoleyl, indolineyl, quinolinyl, isoquinolinyl, quinazolinyl, or indenyl. In some embodiments, ring A and ring C together constitute a quinazolinyl or isoquinolinyl.

[0072] In some embodiments, ring A and ring C together constitute naphthyl, tetrahydronaphthyl, indoleyl, indolineyl, quinolinyl, isoquinolinyl, or indanyl.

[0073] In the above embodiments, ring A and ring C can each be independently and optionally selected from one, two, or three halogens. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups.

[0074] In the above embodiments, the ring C is optionally selected independently by one, two, or three halogens, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups.

[0075] In the above embodiments, ring C is optionally substituted with one or two substituents independently selected from F, Cl, CH3, C2H5, OCH3, CF3, CH2F, and CHF2. In the above embodiments, ring C is optionally substituted with one CH3 group.

[0076] In the above implementation scheme, m is 0.

[0077] In some implementations, structural fragments for:

[0078] In some implementations, structural fragments for:

[0079] In some implementations, structural fragments for:

[0080] In some implementations, structural fragments for:

[0081] In some embodiments, ring B is a phenyl, a 5-6 heteroaryl, a benzo5-6 heteroaryl, or a benzo5-6 heterocyclic alkyl, wherein each of the 5-6 heteroaryl, benzo5-6 heteroaryl, and benzo5-6 heterocyclic alkyl groups independently contains one, two, or three heteroatoms independently selected from N, O, and S.

[0082] In some embodiments, ring B is a phenyl, a 6-membered heteroaryl, a benzo5-membered heteroaryl, or a benzo5-membered heterocycloalkyl, wherein the 6-membered heteroaryl, benzo5-membered heteroaryl, and benzo5-membered heterocycloalkyl each independently contains one or two heteroatoms independently selected from N and O.

[0083] In some embodiments, ring B is a phenyl group substituted with a hydroxyl or amino group, or a pyrimidinyl group substituted with a hydroxyl or amino group; or ring B is benzoxazol-2-one.

[0084] In some embodiments, ring B is phenyl, pyrimidinyl, or benzoxazol-2-one.

[0085] In some implementations, ring B is phenyl or benzoxazol-2-one.

[0086] In some embodiments, ring B is a phenyl group or a benzoxazol-2-one linked to NR3 at the 6-position.

[0087] In some implementations, Z is selected from CR”R”, O, S, (CR”R”) p "and NR", where "R" is independently selected from H and C. 1-6 Alkyl group; or Z together with the adjacent CR1R2 to form Structural fragments or 3-5 membered cycloalkyl groups; or Z is CR”R” and the two R” together with the carbon atoms attached to them form 3-5 membered cycloalkyl groups.

[0088] In some implementations, Z is selected from CR”R”, O, S and NR”, where R” is independently selected from H and C. 1-6 Alkyl group; or Z together with the adjacent CR1R2 to form Structural fragments.

[0089] In some implementations, Z is selected from CR”R”, O, S and NR”, where R” is independently selected from H and C. 1-3 Alkyl group; or Z together with the adjacent CR1R2 to form Structural fragment; or Z is CR”R” and the two R” together with the carbon atom attached to them form a 3-5 membered cycloalkyl group.

[0090] In some implementations, Z is selected from CR”R”, S and NR”, where R” is independently selected from H and C”. 1-3 Alkyl group; or Z together with the adjacent CR1R2 to form Structural fragment; or Z is CR”R” and the two R” together with the carbon atom attached to them form a 3-5 membered cycloalkyl group.

[0091] In some implementations, Z is CH2, O, S, or NH; or Z is formed together with the adjacent CR1R2. Structural fragments.

[0092] In some implementations, Z is selected from CR”R”, O, S and NR”, where R” is independently selected from H and C. 1-6 alkyl.

[0093] In some implementations, Z is selected from CR”R”, O, S and NR”, where R” is independently selected from H and C. 1-3 alkyl.

[0094] In some implementations, Z is CH2, O, S, or NH.

[0095] In some embodiments, Z is CH2, O, S, NH, C(CH3)2, NCH3, CHCH3, or cyclopropyl, or Z is formed together with the adjacent CR1R2. Structural fragments or Structural fragments.

[0096] In some embodiments, Z is CH2, S, NH, C(CH3)2, NCH3, CHCH3, or cyclopropyl, or Z is formed together with the adjacent CR1R2. Structural fragments or Structural fragments.

[0097] In some implementations, Z is CH2, O, S, NH, CHCH3, or Z is formed together with the adjacent CR1R2. Structural fragments or Structural fragments.

[0098] In some implementations, Z is CH2, S, NH, CHCH3, or Z is formed together with the adjacent CR1R2. Structural fragments or Structural fragments.

[0099] In some implementations, Z is CH2, O, or CHCH3.

[0100] In some implementations, Z is CH2 or CHCH3.

[0101] In some implementations, Z is CH2 or O.

[0102] In some implementations, Z is O.

[0103] In some implementations, structural fragments for

[0104] In some implementations, structural fragments for

[0105] In some implementations, structural fragments for

[0106] In some implementations, structural fragments for

[0107] In some implementations, structural fragments for

[0108] In some embodiments, each R0 is independently selected from -OH, -NH2, NHR4, NHCOR4, and NHSO2R4, wherein R4 is independently selected from C 1-6 Alkyl, 3-5 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 6-10 aryl, and 5-6 heteroaryl groups. In some embodiments, each R0 is independently selected from -OH, -NH2, NHCOR4, and NHSO2R4, wherein R4 is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups.

[0109] In some embodiments, each R0 is independently selected from -OH, -NH2, NHCOR4, or NHSO2R4, wherein R4 is independently selected from C 1-4 Alkyl, C 1-3 Alkoxy, C 1-4 Halogenated alkyl and C 1-3 Halogenated alkoxy groups.

[0110] In some implementations, n is 1, and R0 is selected from -OH, NHR4, NHCOR4, and NHSO2R4, wherein R4 is independently selected from C 1-6 Alkyl, 3-5 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and 6-10 aryl groups.

[0111] In some embodiments, ring B is phenyl, n is 1, and R0 is located at the para position of the phenyl C atom bonded to NR3.

[0112] In some embodiments, ring B is benzoxazole-2-one, and n is 0. In some embodiments, ring B is benzoxazole-2-one linked to NR3 at position 6, and n is 0.

[0113] In some embodiments, R0 is -OH, -NH2, -NHC(CH3)3, -NH-2-oxazolyl, -NH-cyclopropyl, -NHSO2CH3, -NHCOCF3, -NHCOCH3, -NHCOC(CH3)3, or -NHCO-cyclopropyl.

[0114] In some implementations, R0 is -OH, -NH2, or -NHCOCH3.

[0115] In some implementations, R0 is -OH or -NHCOCH3.

[0116] In some embodiments, ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is -OH, -NHC(CH3)3, -NH-2-oxazolyl, -NH-cyclopropyl, -NHSO2CH3, -NHCOCF3, -NHCOCH3, -NHCOC(CH3)3 or -NHCO-cyclopropyl.

[0117] In some embodiments, ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is -OH, -NHCOCH3, -NHCO-cyclopropyl, -NHSO2CH3 or -NH-cyclopropyl.

[0118] In some embodiments, ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is -OH, -NHCOCH3 or -NHCO-cyclopropyl.

[0119] In some embodiments, X1 is selected from N, NH, NR', CH, CH2, CR', or CHR', wherein R' is selected from halogens, -CN, C 1- 6-alkyl and C 1-6 The alkoxy group, N is optionally oxidized, wherein R' is not a halogen when X1 is NR'.

[0120] In some embodiments, X1 is selected from N, CH or CH2, wherein N is optionally oxidized.

[0121] In some implementations, X1 is selected from N, CH or CH2.

[0122] In some implementations, X1 is selected from N or CH.

[0123] In some implementations, X1 is selected from N, NH, or NR', where R' is selected from -CN, C 1-6 Alkyl and C 1-6 Alkyl group.

[0124] In some embodiments, X1 is selected from CH, CH2, CR', or CHR', where R' is selected from halogen, -CN, C 1-6 Alkyl and C 1-6 Alkyl group.

[0125] In some implementations, Y1 is selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy and 3-6 membered cycloalkyl groups, and Y2 is absent.

[0126] In some implementations, R1, R2, and R3 are each independently selected from H and C. 1-6 Alkyl groups. In some embodiments, R1, R2, and R3 are each independently selected from H and C. 1-3 Alkyl group. In some embodiments, R1, R2, and R3 are each independently selected from H and CH3. In some embodiments, R1 and R2 are each independently selected from H and CH3, and R3 is H.

[0127] In some implementations, R1, R2, and R3 are all H.

[0128] In some implementations, Z is O or CH2, and R1, R2 and R3 are all H.

[0129] In some implementations, each R is independently selected from halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group.

[0130] In some implementations, each R is independently selected from -F, -CN, and -OCH3.

[0131] In some implementations, each R is independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and 3-6 membered cycloalkyl.

[0132] In some implementations, R can be connected to X1 when Y2 is not present.

[0133] In some implementations, n is 0, 1, 2, or 3. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3.

[0134] In some implementations, m is 0, 1, 2, or 3. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2.

[0135] In some implementations, p is 0 or 2.

[0136] In some embodiments, ring B is phenyl, n is 1, and R0 is located at the para position (i.e., R0 is located at the para position of the phenyl C atom connected to NR3).

[0137] In some embodiments, ring B is phenyl, n is 1, R0 is located at the para position (i.e., R0 is located at the para position of the phenyl C atom connected to NR3) and is -OH or -NHCOCH3.

[0138] In some implementation schemes:

[0139] Ring A is a 6-membered heteroaryl, cyclohexyl, or 6-membered heterocycloalkyl group, wherein the 6-membered heteroaryl and 6-membered heterocycloalkyl groups each independently contain one or two nitrogen atoms, and Y1 is selected from halogens, C... 1-4 Alkyl, C 1-4 Alkoxy and 3-6 membered cycloalkyl groups, and Y2 is absent;

[0140] or

[0141] Y1 and Y2, together with X1 and the carbon atom attached to them, form ring C. Ring A and ring C together constitute a benzo6-10 membered aromatic ring, a benzo5-6 membered heteroaromatic ring, a benzo5-6 membered alkyl ring, or a benzo5-6 membered heteroalkyl ring. The benzo5-6 membered heteroaromatic ring and the benzo5-7 membered heteroalkyl ring each independently contain one, two, or three nitrogen atoms, and the ring C is optionally selected by one, two, or three atoms independently from halogens, carbon, and nitrogen. 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkyl groups;

[0142] Ring B is phenyl, 6-membered heteroaryl, benzo5-membered heteroaryl, or benzo5-membered heterocyclic alkyl, wherein the 6-membered heteroaryl, benzo5-membered heteroaryl, and benzo5-membered heterocyclic alkyl each independently contains one or two heteroatoms independently selected from N and O;

[0143] Z is O;

[0144] R0 is -OH, -NH2, or -NHCOCH3 (R0 is located at the para position), and n is 1;

[0145] R represents halogen, -CN, or C. 1-4 Alkyl and C 1-4 Alkoxy;

[0146] X1 is selected from N, CH or CH2, wherein N is optionally oxidized;

[0147] R1, R2, and R3 are each independently selected from H and C. 1-3 alkyl;

[0148] m can be 0, 1, 2, or 3.

[0149] In some implementation schemes:

[0150] Ring A is a 6-membered heteroaryl or cyclohexyl group, wherein the 6-membered heteroaryl group contains one or two nitrogen atoms, and Y1 is selected from C1. 1-4 Alkyl or C 1-4 Alkyl-substituted amino groups, and Y2 is absent;

[0151] or

[0152] Y1 and Y2, together with X1 and the carbon atom attached thereto, form ring C. Ring A and ring C together constitute a benzo6-10 membered aromatic ring, a benzo5-6 membered heteroaromatic ring, a benzo5-6 membered alkyl ring, or a benzo5-6 membered heteroalkyl ring. The benzo5-6 membered heteroaromatic ring and the benzo5-6 membered heteroalkyl ring each independently contain one, two, or three nitrogen atoms, and the ring C is optionally selected by one, two, or three atoms independently from halogens, carbon, and nitrogen. 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkyl groups;

[0153] Ring B is a phenyl or a benzo5-membered heterocyclic alkyl group, wherein the benzo5-membered heterocyclic alkyl group contains one or two heteroatoms independently selected from N and O;

[0154] Z is CH2, O, S, or NH; or Z is formed together with the adjacent CR1R2. Structural fragments;

[0155] R0 is -OH, -NHCOCF3, -NHSO2CH3 or -NHCOCH3 (R0 is located in the para position) and n is 1;

[0156] R represents halogen, -CN, or C. 1-4 Alkyl and C 1-4 Alkoxy;

[0157] X1 is selected from N, CH or CH2;

[0158] R1, R2, and R3 are each independently selected from H and C. 1-3 alkyl;

[0159] m is 0 or 1.

[0160] In some implementation schemes:

[0161] Ring A is a 6-membered heteroaryl or cyclohexyl group, wherein the 6-membered heteroaryl group contains one or two N atoms, and Y1 is C(CH3)3, and Y2 is absent; R is -F or -CN;

[0162] or

[0163] Y1 and Y2, together with X1 and the carbon atom attached thereto, form ring C. Ring A and ring C together constitute a naphthyl, a benzo6-membered heteroaromatic ring, or a benzo5-membered alkyl ring, wherein ring C is optionally selected by one or two independently from C. 1-4 Alkyl and C 1-4 Substituents of haloalkyl groups;

[0164] Ring B is phenyl or benzoxazol-2-one;

[0165] Z is O, S, or CH2; or Z is formed together with the adjacent CR1R2. Structural fragments;

[0166] R0 is -OH, -NHCOCH3, or -NHSO2CH3 (R0 is located in the para position), and n is 1;

[0167] X1 is selected from N, CH or CH2;

[0168] R1, R2 and R3 are all H;

[0169] m is 0 or 1.

[0170] In some implementation schemes:

[0171] Ring A is a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains one or two N atoms, and Y1 is C(CH3)3, and Y2 is absent; R is -F or -CN;

[0172] or

[0173] Y1 and Y2, together with X1 and the carbon atom attached thereto, form a ring C. Ring A and ring C together constitute a naphthyl group, wherein the ring C is optionally surrounded by one carbon atom. 1-4 Alkyl substitution;

[0174] Ring B is phenyl or benzoxazol-2-one;

[0175] Z is O or CH2; or Z forms together with the adjacent CR1R2. Structural fragments;

[0176] R0 is -OH or -NHCOCH3 (R0 is located at the para position), and n is 1;

[0177] X1 is selected from N or CH;

[0178] R1, R2 and R3 are all H;

[0179] m is 0 or 1.

[0180] In some implementation schemes:

[0181] Ring A is pyridyl, pyrazinyl, or pyrimidinyl, and Y1 is C(CH3)3, while Y2 is absent;

[0182] Ring B is phenyl or benzoxazol-2-one;

[0183] Z is either O or CH2;

[0184] R0 is -OH or -NHCOCH3 (R0 is located at the para position), and n is 1;

[0185] X1 is selected from N or CH;

[0186] R1, R2, and R3 are all H; and

[0187] m is 0.

[0188] In some implementation schemes,

[0189] Ring A is a 5-6 membered heteroaryl or a 5-6 membered cycloalkyl, wherein the 5-6 membered heteroaryl contains one or two N atoms; Y1 is selected from C(CH3)3; halogen; amino group substituted with C1, C2, C3, C4, C5 or C6 alkyl; C1, C2, C3, C4, C5 or C6 alkoxy group; 3, 4, 5 or 6 membered cycloalkyl and 3, 4, 5 or 6 membered heterocycloalkyl, and Y2 is absent, wherein the 3, 4, 5 or 6 membered heterocycloalkyl ring contains one or two heteroatoms independently selected from N, O and S and has one N atom attached to ring A;

[0190] Alternatively, ring A and ring C together form a benzo6-10 membered aromatic ring, a benzo5-6 membered heteroaromatic ring, a benzo5-6 membered alkyl ring, or a benzo5-6 membered heteroalkyl ring, wherein the benzo5-6 membered heteroaromatic ring and the benzo5-6 membered heteroalkyl ring each independently contain one or two nitrogen atoms; ring C is optionally selected by one, two, or three independently from halogens, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups;

[0191] Z can be CH2, O, S, NH, C(CH3)2, NCH3, CHCH3, or cyclopropyl, or Z can be formed together with the adjacent CR1R2. Structural fragments or Structural fragments;

[0192] Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom bonded to NR3, and R0 is selected from -OH, -NH2, NHR4, NHCOR4, and NHSO2R4, where R4 is independently selected from C. 1-6 Alkyl, 3-5 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 6-10 aryl and 5-6 heteroaryl; or ring B is benzoxazol-2-one and n is 0;

[0193] X1 is selected from N, CH or CH2;

[0194] R1, R2, and R3 are each independently selected from H and C. 1-6 alkyl;

[0195] m is 0 or 1, R is halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group.

[0196] In some implementation schemes,

[0197] Ring A is a 6-membered heteroaryl or cyclohexyl group, wherein the 6-membered heteroaryl group contains one or two nitrogen atoms; Y1 is selected from C(CH3)3; an amino group substituted with a C1, C2, C3, C4, C5 or C6 alkyl group; a C2, C3, C4, C5 or C6 alkoxy group; a 3, 4, 5 or 6-membered cycloalkyl group and a 3, 4, 5 or 6-membered heterocycloalkyl group, and Y2 is absent, wherein the 3, 4, 5 or 6-membered heterocycloalkyl ring contains one nitrogen atom, and the nitrogen atom is attached to ring A;

[0198] Alternatively, ring A and ring C together form naphthyl, tetrahydronaphthyl, indolyl, indololinyl, quinolinyl, isoquinolinyl, quinazolinyl, or indanyl; ring C is optionally substituted by one or two substituents independently selected from F, Cl, CH3, C2H5, OCH3, CF3, CH2F, and CHF2;

[0199] Z can be CH2, O, S, NH, CHCH3, or Z can be formed together with the adjacent CR1R2. Structural fragments or Structural fragments;

[0200] Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom attached to NR3, and R0 is -OH, -NHC(CH3)3, -NH-2-oxazolyl, -NH-cyclopropyl, -NHSO2CH3, -NHCOCF3, -NHCOCH3, -NHCOC(CH3)3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one, n is 0;

[0201] X1 is selected from N, CH or CH2;

[0202] R1, R2, and R3 are each independently selected from H and C. 1-3 alkyl;

[0203] m is 0 or 1, and R is -F, -CN, or -OCH3.

[0204] In some embodiments, ring A is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or cyclohexyl; Y1 is selected from C(CH3)3, N(CH3)2, OCH(CH3)2, OC(CH3)3, Cl, 1-azacyclobutane, 1-pyrrolidinyl, Cyclopropyl, cyclobutyl, cyclopentyl, 1-piperazinyl, 4-methyl-1-piperazinyl, and morpholinyl, and Y2 is absent; or ring A and ring C together form naphthyl, tetrahydronaphthyl, indolyl, indololinyl, quinolinyl, isoquinolinyl, quinazolinyl, or indanyl (or ring A and ring C together form isoquinolinyl or quinazolinyl); ring C is optionally substituted by one or two substituents independently selected from F, Cl, CH3, C2H5, OCH3, CF3, CH2F, and CHF2 (or ring C is optionally substituted by one CH3);

[0205] Z can be CH2, O, S, NH, CHCH3, or Z can be formed together with the adjacent CR1R2. Structural fragments or Structural fragments;

[0206] Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom bonded to NR3, and R0 is -OH, -NHC(CH3)3, -NH-2-oxazolyl, -NH-cyclopropyl, -NHSO2CH3, -NHCOCF3, -NHCOCH3, -NHCOC(CH3)3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one bonded to NR3 at position 6, n is 0;

[0207] X1 is selected from N, CH or CH2;

[0208] R1, R2, and R3 are each independently selected from H and CH3;

[0209] m is 0 or 1, and R is -F, -CN, or -OCH3.

[0210] In some embodiments, ring A is pyridinyl, pyrazinyl, or pyrimidinyl; Y1 is C(CH3)3, 1-pyrrolidinyl, or 1-azacyclobutane, and Y2 is absent; or ring A and ring C together form a quinazolinyl group, with Z attached at position 4 and a methyl group substituted at position 6.

[0211] Z represents CH2, O, or CHCH3;

[0212] Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom attached to NR3, and R0 is -OH, -NHCOCH3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one attached to NR3 at position 6, n is 0;

[0213] X1 is selected from N or CH;

[0214] R1, R2 and R3 are all H;

[0215] m is 0.

[0216] In some embodiments, ring A is pyridinyl, pyrazinyl, or pyrimidinyl; Y1 is C(CH3)3, 1-pyrrolidinyl, or 1-azacyclobutane, and Y2 is absent; or ring A and ring C together form a quinazolinyl group, with Z attached at position 4 and a methyl group substituted at position 6.

[0217] Z is CH2 or CHCH3;

[0218] Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom attached to NR3, and R0 is -OH, -NHCOCH3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one attached to NR3 at position 6, n is 0;

[0219] X1 is selected from N or CH;

[0220] R1, R2 and R3 are all H;

[0221] m is 0.

[0222] In some embodiments, ring A is pyridinyl, pyrazinyl, or pyrimidinyl; Y1 is 1-pyrrolidinyl or 1-azacyclobutane, and Y2 is absent; or ring A and ring C together form a quinazolinyl group, with Z attached at position 4 and a methyl group substituted at position 6.

[0223] Z represents CH2, O, or CHCH3;

[0224] Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom attached to NR3, and R0 is -OH, -NHCOCH3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one attached to NR3 at position 6, n is 0;

[0225] X1 is selected from N or CH;

[0226] R1, R2 and R3 are all H;

[0227] m is 0.

[0228] In some embodiments, when Z is O, ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom attached to NR3, and R0 is OH or NHC(O)CH3, Y1 is selected from halogens; amino groups substituted with C1, C2, C3, C4, C5, or C6 alkyl groups; C 1、 C2, C3, C4, C5 or C6 alkoxy; 3, 4, 5 or 6-membered cycloalkyl and 3, 4, 5 or 6-membered heterocycloalkyl, and Y2 is absent, wherein the 3, 4, 5 or 6-membered heterocycloalkyl contains at least one N atom and the N atom is attached to ring A.

[0229] In some embodiments, when Z is O, ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is OH or NHC(O)CH3, Y1 is a 3, 4, 5, or 6-membered heterocyclic alkyl group containing an N atom connected to ring A.

[0230] In some embodiments, when Z is O, ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is OH or NHC(O)CH3, Y1 is 1-azacyclobutane or 1-pyrrolidinyl.

[0231] In some embodiments, when Z is O, Y1 is tert-butyl, ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is NHC(O)CH3, ring A is not pyridyl.

[0232] In some embodiments, when Z is O, Y1 is tert-butyl, ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is NHC(O)CH3, ring A is pyrimidinyl or pyrazinyl.

[0233] In some embodiments, when Z is O, Y1 is tert-butyl, ring B is benzoxazol-2-one, ring A is not pyridyl and / or ring A and ring C do not co-form a naphthyl group.

[0234] In some embodiments, when Z is O, Y1 is tert-butyl, ring B is benzoxazol-2-one, and ring A is pyrimidinyl or pyrazinyl.

[0235] In some embodiments, when Z is O, ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is OH, Y1 is not tert-butyl.

[0236] In some embodiments, the compound of formula (I) is a compound of formula (II), formula (III), formula (IV), or formula (V):

[0237] Z, X1, Y1, Y2, and R1-R3 in equations (II) to (V) are as defined in any of the above embodiments;

[0238] X2 is selected from N, NH, NR, CH, CH2, CR or CHR, wherein R is selected from halogen, -CN, alkyl, alkoxy and 3-6 membered cycloalkyl, and N is optionally oxidized;

[0239] X3 is selected from N, NH, NR, CH, CH2, CR or CHR, wherein R is selected from halogen, -CN, alkyl, alkoxy and 3-6 membered cycloalkyl, and N is optionally oxidized;

[0240] X4 is selected from N, NH, NR, CH, CH2, CR or CHR, wherein R is selected from halogen, -CN, alkyl, alkoxy and 3-6 membered cycloalkyl, and N is optionally oxidized;

[0241] The condition is that ring A contains a maximum of 3 N atoms;

[0242] R5 to R8 are each independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy;

[0243] R9 is -OH, -NHCOR 10 or -NHSO2R 10 , where R 10 Selected independently from C 1-4 Alkyl, C 1-3 Alkoxy, C 1-4 Halogenated alkyl and C 1-3 Haloalkoxy group; or R9 is -OH, -NHSO2CH3, -NHCOCF3 or -NHCOCH3; or R9 is -OH or -NHCOCH3.

[0244] R9 in equations (III) and (IV) is defined as R0 in any of the above embodiments.

[0245] In some embodiments, R9 is -OH, -NHC(CH3)3, -NH-2-oxazolyl, -NH-cyclopropyl, -NHSO2CH3, -NHCOCF3, -NHCOCH3, -NHCOC(CH3)3, or -NHCO-cyclopropyl. In some embodiments, R9 is -OH, -NHCOCH3, -NHCO-cyclopropyl, -NHSO2CH3, or -NH-cyclopropyl. In some embodiments, R9 is -OH, -NHCOCH3, or -NHCO-cyclopropyl.

[0246] In some implementations, R5 to R8 in formulas (II) to (V) are all H.

[0247] In some implementations, Z in equations (II) to (V) is O.

[0248] In some implementations, Z in formulas (II) to (V) is CH2.

[0249] In some implementations, R1 to R3 in equations (II) to (V) are all H.

[0250] In some embodiments, the compound of formula (I) is a compound of formula (II) or a compound of formula (III):

[0251] Z, X1, Y1, Y2, and R1-R3 in equations (II) and (III) are as defined above;

[0252] X2 is selected from N, NH, NR, CH, CH2, CR or CHR, wherein R is selected from halogen, -CN, alkyl, alkoxy and 3-6 membered cycloalkyl, and N is optionally oxidized;

[0253] X3 is selected from N, NH, NR, CH, CH2, CR or CHR, wherein R is selected from halogen, -CN, alkyl, alkoxy and 3-6 membered cycloalkyl, and N is optionally oxidized;

[0254] X4 is selected from N, NH, NR, CH, CH2, CR or CHR, wherein R is selected from halogen, -CN, alkyl, alkoxy and 3-6 membered cycloalkyl, and N is optionally oxidized;

[0255] The condition is that ring A contains a maximum of 3 N atoms;

[0256] R5 to R8 are each independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkyl group.

[0257] When ring A is a 6-membered heteroaryl group, X2, X3, and X4 are each independently selected from N, CH, and CR, where each R is independently selected from halogen, -CN, and C. 1-6 Alkyl and C 1-6 The alkoxy group, N is optionally oxidized; or X2, X3 and X4 are each independently selected from N or CH;

[0258] When ring A is cyclohexyl, X2, X3, and X4 are each independently selected from CH2 and CHR, where each R is independently selected from C. 1-6 Alkyl and 3-6 membered cycloalkyl;

[0259] When ring A is a 6-membered heterocyclic alkyl group, X2, X3, and X4 are each independently selected from NH, NR, CH2, and CHR, where each R is independently selected from C. 1-6 Alkyl and 3-6 membered cycloalkyl;

[0260] The condition is that when ring A is a 6-membered heteroaryl or a 6-membered heterocyclic alkyl, ring A contains one or two N atoms.

[0261] In some embodiments, ring A is a 6-membered heteroaryl group, X1 is N, and X2-X4 are CH or CR; X2 is N, and X1, X3 and X4 are CH or CR; X4 is N, and X1-X3 are CH or CR; X1 and X3 are N, and X2 and X3 are CH or CR; or X1 and X4 are N, and X2 and X3 are CH or CR.

[0262] In some embodiments, in formula (II), formula (IV) or formula (V), ring A is pyridinyl, pyrazinyl, pyrazinyl, pyrimidinyl or cyclohexyl, Y1 is tert-butyl, Y2 is absent, and when A is pyridinyl, the N atom is optionally oxidized.

[0263] In some embodiments, in formula (II), ring A is pyridyl, pyrazinyl, pyrimidinyl, or cyclohexyl, Y1 is tert-butyl, Y2 is absent, and when A is pyridyl, the N atom is optionally oxidized.

[0264] In some implementations, the structural fragments in equation (I) In equation (II), (IV), or (V), ring A together with Y1 and Y2 forms one of the following structures:

[0265] In some implementations, the structural fragments in equation (I) In equation (II), (IV), or (V), ring A together with Y1 and Y2 forms one of the following structures:

[0266] In some implementations, the structural fragments in equation (I) In equation (II), (IV), or (V), ring A together with Y1 and Y2 forms one of the following structures:

[0267] In some implementations, in formula (II), formula (IV) or formula (V), ring A together with Y1 and Y2 forms one of the following structures:

[0268] In some implementations, in equations (II), (IV), and (V), ring A together with Y1 and Y2 forms one of the following structures:

[0269] In some implementations, in equation (II), ring A together with Y1 and Y2 forms one of the following structures:

[0270] In some embodiments, in formula (III), ring A is pyridyl, pyrazinyl, pyrimidinyl, or cyclohexyl, Y1 is tert-butyl, Y2 is absent, and when A is pyridyl, the N atom is optionally oxidized.

[0271] In some implementations, in equation (III), ring A together with Y1 and Y2 forms one of the following structures:

[0272] In some implementations, in equation (III), ring A together with Y1 and Y2 forms one of the following structures:

[0273] In some embodiments, in formulas (II), (III), (IV), or (V), Y1 and Y2 together with X1 and the carbon atom attached thereto form a ring C, and ring A and ring C together constitute a naphthyl, tetrahydronaphthyl, indoleyl, indolinyl, quinolinyl, isoquinolinyl, or indanyl, and the above groups are optionally selected by one or two of them from halogens, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups.

[0274] In some embodiments, in formula (II), (III), (IV), or (V), Y1 and Y2 together with X1 and the carbon atom attached thereto form a ring C, and the ring A and the ring C together form one of the following structures: Each of the structures (ring C) is independently and optionally selected from one or two halogens, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups.

[0275] In some embodiments, in formula (II), (III), (IV), or (V), Y1 and Y2 together with X1 and the carbon atom attached thereto form a ring C, and the ring A and the ring C together form one of the following structures: Each of the structures (ring C) is independently and optionally selected from one or two halogens, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups.

[0276] In some embodiments, the above structure (ring C) is independently substituted by one or two substituents selected from -F, -Cl, -CH3, -C2H5, -OCH3, -CH2F, -CHF2 and -CF3.

[0277] In some embodiments, in formula (II), (III), (IV), or (V), Y1 and Y2 together with X1 and the carbon atom attached thereto form a ring C, and the ring A and the ring C together form one of the following structures:

[0278] In some embodiments, in formula (II), (III), (IV), or (V), Y1 and Y2 together with X1 and the carbon atom attached thereto form a ring C, and the ring A and the ring C together form one of the following structures:

[0279] In some implementations, R1 to R3 are all H.

[0280] In some implementations, R5 through R8 are all H.

[0281] In some implementation schemes,

[0282] Structural fragments in equation (I) In equation (II), (IV), or (V), ring A together with Y1 and Y2 forms one of the following structures:

[0283] Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is -OH, -NHCOCH3, -NHCO-cyclopropyl, -NHSO2CH3 or -NH-cyclopropyl; or ring B is benzoxazol-2-one, n is 0;

[0284] Structural fragments for or structural fragments for

[0285] In some implementation schemes,

[0286] Structural fragments in equation (I) In equation (II), (IV), or (V), ring A together with Y1 and Y2 forms one of the following structures:

[0287] Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is -OH, -NHCOCH3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one, n is 0;

[0288] Structural fragments for or structural fragments for

[0289] In some implementations, when structural fragments for At that time, (1) structural fragment In equation (II), (IV), or (V), ring A together with Y1 and Y2 forms one of the following structures: Or (2) ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is -NHCOCH3 or -NHCO-cyclopropyl, and ring A is not pyridinyl; or (3) ring B is benzoxazol-2-one, n is 0, ring A is not pyridinyl, and ring A together with Y1 and Y2 does not form a naphthyl group.

[0290] In some implementations, the isotope-labeled compound is a deuterated compound.

[0291] In some implementations, this application includes the variables defined above and their implementations, as well as any combination thereof.

[0292] In the above embodiments, the heteroaryl, heterocyclic and heterocyclic groups may each independently contain one or two heteroatoms independently selected from N, O and S; or contain one or two heteroatoms independently selected from N and O; or contain one or two N atoms.

[0293] The compounds of formula (I) of this application, or their pharmaceutically acceptable salts, solvates, tautomers, enantiomers, diastereomers, or isotopically labeled compounds, are selected from the following compounds or their pharmaceutically acceptable salts, solvates, tautomers, enantiomers, diastereomers, or isotopically labeled compounds:

[0294] The compounds of formula (I) of this application, or their pharmaceutically acceptable salts, solvates, tautomers, enantiomers, diastereomers, or isotopically labeled compounds, are selected from the following compounds or their pharmaceutically acceptable salts, solvates, tautomers, enantiomers, diastereomers, or isotopically labeled compounds:

[0295] The compounds of formula (I) of this application, or their pharmaceutically acceptable salts, solvates, tautomers, enantiomers, diastereomers, or isotopically labeled compounds, are selected from the following compounds or their pharmaceutically acceptable salts, solvates, tautomers, enantiomers, diastereomers, or isotopically labeled compounds:

[0296] The compounds of formula (I) of this application, or their pharmaceutically acceptable salts, solvates, tautomers, enantiomers, diastereomers, or isotopically labeled compounds, are selected from the following compounds or their pharmaceutically acceptable salts, solvates, tautomers, enantiomers, diastereomers, or isotopically labeled compounds: NPL-46, NPL-47, NPL-51, NPL-52, NPL-54, NPL-57, NPL-61, NPL-63, NPL-66, NPL-67, NPL-70, NPL-71, NPL-72, NPL-73, NPL-74, NPL-75, NPL-76, NPL-79, NPL-80, NPL-81, NPL-82, and NPL-9. 4. NPL-96, NPL-97, NPL-99, NPL-100, NPL-106, NPL-107, NPL-111, NPL-115, NPL-116, NPL-121, NPL-124, NPL-125, NPL-126, NPL-129, NPL-132, NPL-133, NPL-134, NPL-137, NPL-139, NPL-140, NPL-144, NPL-149, NPL-151, NPL-152, NPL-153, NPL-154, NPL-158, NPL-159, NPL-160, NPL-161, NPL-162, or NPL-174.

[0297] The compounds of formula (I) of this application, or their pharmaceutically acceptable salts, solvates, tautomers, enantiomers, diastereomers, or isotopically labeled compounds, are selected from the following compounds or their pharmaceutically acceptable salts, solvates, tautomers, enantiomers, diastereomers, or isotopically labeled compounds: NPL-1, NPL-2, NPL-4, NPL-6, NPL-8, NPL-9, NPL-10, NPL-12, NPL-13, NPL-16, NPL-17, NPL-18, NPL-19, NPL-20, NPL-24, NPL-25, NPL-26, NPL-27, NPL-28, NPL-29, NPL-30, NPL-31, NPL-32, NPL-35, NPL-36, or NPL-37.

[0298] In some embodiments, the compounds in this application do not include the following compounds: NPL-1 to NPL-37.

[0299] In some implementations, when Z is 0, the structural fragment for At that time, structural fragments Not for

[0300] When Z is 0, structural fragment for At that time, structural fragments Not for as well as

[0301] When Z is 0, structural fragment for At that time, structural fragments Not for

[0302] On the other hand, this application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, and one or more pharmaceutically acceptable excipients.

[0303] In some embodiments, the excipients include one or more of diluents, fillers, binders, wetting agents, absorption promoters, surfactants, lubricants, and stabilizers.

[0304] In some embodiments, the pharmaceutical composition is a pharmaceutical preparation selected from tablets, capsules, pills, granules, drop pills, aerosols, sprays, nasal drops, inhalers, suppositories, enemas, intramuscular injection preparations, intravenous injection preparations, intra-articular injection preparations, ointments, or patches.

[0305] On the other hand, this application provides the use of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer or isotopically labeled compound thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for the prevention or treatment of diseases caused by aging or NAD+ reduction.

[0306] On the other hand, this application provides the use of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer or isotopically labeled compound thereof, or the pharmaceutical composition thereof, in the prevention or treatment of diseases caused by aging or NAD+ reduction.

[0307] On the other hand, this application provides a method for treating diseases caused by aging or NAD+ reduction, the method comprising administering to a mammal, preferably a human, a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, or the pharmaceutical composition thereof.

[0308] On the other hand, this application provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof for the prevention or treatment of diseases caused by aging or NAD+ reduction, or a pharmaceutical composition thereof.

[0309] In some implementations, the diseases caused by aging or decreased NAD+ are those caused by a decrease in NAD+ levels due to age or other conditions, including chronic demyelinating diseases of the nervous system, amyotrophic lateral sclerosis, Huntington's disease, chronic traumatic encephalopathy and frontotemporal dementia, AIDS-related neurodegeneration, Alzheimer's disease, neurodegenerative diseases including Parkinson's disease, mild to moderate cognitive impairment, obesity, diabetes, type 2 diabetes, diabetic nephropathy, premature ovarian failure, polycystic ovary syndrome, hypertension, COVID-19 coronavirus infection, mitochondrial myopathy, mitochondrial encephalomyopathy, and progressive neurodegeneration. Ophthalmoplegia, chronic obstructive pulmonary disease, heart failure, atherosclerosis, coronary artery disease, dyslipidemia, cardiometabolic disease, diabetic peripheral neuropathy, sarcopenia, Duchenne muscular dystrophy, chronic kidney disease, acute kidney injury, peripheral artery disease, chemotherapy-induced peripheral neuropathy, Friedrich's ataxia, multiple sclerosis, progressive multiple sclerosis, non-alcoholic fatty liver disease, alcoholic liver disease, cystic fibrosis, osteoarthritis, cerebral ischemia, cerebral hemorrhage, ischemic or hemorrhagic stroke, myocardial ischemia, cardiomyopathy, corneal injury, glaucoma, dry eye, macular degeneration, retinal degeneration and premature aging.

[0310] In some implementations, the diseases caused by aging or decreased NAD+ include chronic demyelinating diseases of the nervous system, amyotrophic lateral sclerosis, Huntington's disease, chronic traumatic encephalopathy and frontotemporal dementia, AIDS-related neurodegeneration, neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, mild to moderate cognitive impairment, obesity, diabetes, type 2 diabetes, diabetic nephropathy, hypertension, COVID-19 coronavirus infection, mitochondrial myopathy, mitochondrial encephalomyopathy, progressive ophthalmoplegia, chronic obstructive pulmonary disease, heart failure, atherosclerosis, coronary artery disease, and dyslipidemia. Common diseases include: cardiometabolic diseases, diabetic peripheral neuropathy, chronic kidney disease, acute kidney injury, peripheral artery disease, chemotherapy-induced peripheral neuropathy, Friedrich's ataxia, multiple sclerosis, progressive multiple sclerosis, non-alcoholic fatty liver disease, alcoholic liver disease, cystic fibrosis, osteoarthritis, cerebral ischemia, cerebral hemorrhage, ischemic or hemorrhagic stroke, myocardial ischemia, cardiomyopathy, corneal injury, glaucoma, dry eye syndrome, macular degeneration, retinal degeneration, skin-related diseases (such as psoriasis, scleroderma), progeria, reproductive aging-related diseases, and diseases related to muscle aging, injury, or developmental disorders.

[0311] In some implementations, the diseases caused by aging or decreased NAD+ include diseases related to reproductive aging, preferably diseases related to oocyte aging, such as premature ovarian failure, polycystic ovary syndrome, and recurrent miscarriage.

[0312] In some implementations, the diseases caused by aging or reduced NAD+ include diseases related to muscle aging, injury, or dysplasia, preferably sarcopenia, Duchenne muscular dystrophy (DMD), etc.

[0313] On the other hand, this application provides the use of the compound of formula (I) or its pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer or isotopically labeled compound, or the pharmaceutical composition thereof in the preparation of dietary supplements, health products or pet food health products, for improving skin symptoms, cosmetics or skin care products or medical aesthetics.

[0314] In some implementations, the dietary supplement or health product is used for anti-aging, anti-fatigue, and / or improving the mental state during menopause.

[0315] On the other hand, this application provides the use of the compound of formula (I) or its pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer or isotopically labeled compound, or the pharmaceutical composition thereof in improving skin symptoms, preparing cosmetics or skin care products or medical aesthetics.

[0316] In some implementations, the cosmetic or skin care product or medical aesthetic product is used as an anti-wrinkle agent, anti-aging agent, skin protectant, moisturizer and / or antioxidant.

[0317] In some implementations, the pet food additives or health products described in this application are used for anti-aging, brightening of pet fur, and prevention or treatment of pet obesity.

[0318] In some embodiments, the mammals include, but are not limited to, humans, mice, rats, cattle, sheep, horses, dogs, cats, pigs, or monkeys.

[0319] This application provides compounds that act as NAMPT agonists, which can regulate NAD+ levels in tissues and cells of the body. The compound of formula (I) of this application, or its pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound, or the pharmaceutical composition thereof, has one or more of the following beneficial effects: protective against cytotoxicity caused by FK866-induced NAD+ reduction; good NAMPT activation in vitro; significantly increasing NAD+ at the cellular level; effectively increasing the amount of NAD+ in the skin through topical application; promoting muscle regeneration by promoting cell differentiation (e.g., C2C12 cells); treating related diseases by promoting the regeneration and repair of myofibrils at sites of muscle injury; achieving anti-wrinkle effects by effectively increasing collagen expression in cells (e.g., HSF cells); achieving anti-aging effects by significantly reducing the expression of the aging gene p16; achieving antioxidant effects by significantly reducing ROS expression; achieving whitening effects by significantly inhibiting tyrosinase activity; enhancing mitochondrial function; repairing DNA damage; and / or, achieving anti-ovarian aging effects by promoting the maturation of aging oocytes.

[0320] Terminology Definitions and Explanations

[0321] Unless otherwise stated, the terms used in this disclosure have the following meanings: the definitions of groups and terms recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0322] In this article Indicates the connection site.

[0323] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds disclosed herein can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.

[0324] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0325] The compounds disclosed herein may have asymmetric atoms such as carbon, sulfur, nitrogen, and phosphorus atoms, or asymmetric double bonds, and therefore may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E- and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof or other mixtures, such as mixtures enriched with enantiomers or diastereomers. All such isomers and mixtures thereof are within the scope of the definition of the compounds disclosed herein. Alkyl groups or other substituents may contain additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms. All such isomers involved in all substituents, and mixtures thereof, are also included within the scope of the definition of the compounds disclosed herein. The compounds containing asymmetric atoms disclosed herein can be isolated in optically active pure form or in racemic form. The optically active pure form can be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0326] The term "substitution" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0327] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0328] When any variable (e.g., n, R) a R b When a group appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is surrounded by two R... b Replaced, then each Rb Each has its own independent options.

[0329] C in this article m -C n It refers to having an integer number of carbon atoms in the range mn. For example, "C1-C 10 "" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0330] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group can be straight-chain or branched. The term "C1-C6 alkyl" can be understood to refer to a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, i.e., C1, C2, C3, C4, C5, or C6 alkyl. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2 ... Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" can be understood as referring to alkyl groups having 1 to 6 carbon atoms, specific examples including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C4 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 4 carbon atoms.

[0331] The term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group that is substituted with one or more halogens such as F, Cl, Br or I, including monosubstituted, polysubstituted or fully substituted.

[0332] The term "alkoxy" refers to a group formed by the loss of a hydrogen atom from a hydroxyl group in a straight-chain or branched alcohol, and can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C6 alkoxy" may further include "C1-C4 alkoxy". The term "C1-C4 haloalkoxy" refers to C1-C4 haloalkyl-O-.

[0333] The term "cycloalkyl" refers to a saturated carbon ring existing in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "3- to 6-membered cycloalkyl" can be understood to mean a saturated monocyclic, fused, spirocyclic, or bridged ring having 3 to 6 (3, 4, 5, or 6) carbon atoms. The term "5- to 7-membered cycloalkyl" can be understood to mean a saturated monocyclic, fused, spirocyclic, or bridged ring having 5 to 7 (5, 6, or 7) carbon atoms. Specific examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "3- to 6-membered cycloalkyl" can be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 (3, 4, 5, or 6) carbon atoms, specific examples including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0334] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated) and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocyclic group is typically a 3- to 12-membered, 3- to 10-membered, 3- to 8-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 6- to 7-membered, 3- to 7-membered, 4- to 6-membered, or 5- to 8-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, or nitrogen (preferably 1 or 2 heteroatoms). In some embodiments, the heterocyclic group contains 1 or 2 heteroatoms independently selected from N and O. Non-limiting examples of heterocyclic groups include, but are not limited to, oxazol-2-one, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, azacyclic butyl, azacyclic heptyl, etc.

[0335] The term "heterocyclic alkyl" refers to a saturated cyclic group existing in the form of a monocyclic, fused, bridged, or spirocyclic ring, wherein the ring atoms contain one, two, or one to three heteroatoms or heteroatom groups (i.e., groups containing heteroatoms). These "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-. A "heterocyclic alkyl" may contain one to three heteroatoms independently selected from N, O, and S, or one or two heteroatoms independently selected from N and O; or one or two nitrogen atoms. The term "5-7 membered heterocyclic alkyl" refers to a heterocyclic alkyl group with 5, 6, or 7 ring atoms, and its ring atoms contain one, two, or one to three heteroatoms independently selected from the heteroatoms or heteroatom groups described above. Specific examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, or tetrahydropyrazolyl; specific examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothioranyl, morpholinyl, piperazine, 1,4-thiaoxalyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, or 1,4-dithiaalkyl; specific examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxaheptanyl, or thioheptanyl.

[0336] The term "heterocyclic alkenyl" refers to a cyclic group containing at least one double bond and existing in the form of a monocyclic, fused, bridged, or spirocyclic ring, wherein the ring atoms contain one, two, or one to three heteroatoms or heteroatom groups (i.e., atomic groups containing heteroatoms). These "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-. The term "5-7-membered heterocyclic alkenyl" refers to a heterocyclic alkenyl group with 5, 6, or 7 ring atoms, and its ring atoms contain one, two, or one to three heteroatoms or heteroatom groups independently selected from those described above. Examples of 5-7-membered heterocyclic alkenyl groups include, but are not limited to, 2,3-dihydropyrroleyl.

[0337] The term "aryl" refers to an aromatic ring group consisting of a single-carbon monocyclic or fused polycyclic aromatic ring with a conjugated π-electron system. Aryl groups can have 6-20, 6-14, 6-12, or 6-10 carbon atoms. Particularly noteworthy are rings with 6 carbon atoms ("6-membered aryl"), such as phenyl; or rings with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or rings with 10 carbon atoms ("C9 aryl"). 10Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl; or rings having 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups; or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. The term "C6-C" is used. 10 "Aryl" can be understood as an aryl group having 6 to 10 carbon atoms. Specifically, it refers to a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0338] The term "heteroaryl" or "heteroaromatic ring" refers to an aromatic monocyclic or fused polycyclic system containing at least one (1, 2, or 3) ring atoms selected from N, O, and S, with the remaining ring atoms being C aromatic cyclic groups. The term "5-7 membered heteroaryl" can be understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, or 7 ring atoms, and may contain 1-3 heteroatoms independently selected from N, O, and S, or 1 or 2 heteroatoms independently selected from N and O; or 1 or 2 nitrogen atoms. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl or isindolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl and their benzo[derivatives], such as quinolinyl, quinazolinyl or isoquinolinyl; or acrylinyl, inazinyl, purinyl and their benzo[derivatives]; or cyclolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acrylinyl, phenazinyl, phenothiazinyl or phenothiazinyl. The term "6-membered heteroaryl" refers to an aromatic ring system having 6 ring atoms, and containing 1 to 3, preferably 1 to 2, heteroatoms independently selected from N, O and S (e.g., containing 1 or 2 N atoms).

[0339] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0340] The term "cyano" refers to the -CN group.

[0341] The term "hydroxyl group" refers to the -OH group.

[0342] The term "benzoxazole-2-one" refers to

[0343] The term "heteroatom" includes atoms of any element other than carbon or hydrogen. In some embodiments, the heteroatom is selected from boron, nitrogen, oxygen, sulfur, silicon, and phosphorus. In some embodiments, the heteroatom is selected from N, O, and S. In some embodiments, the heteroatom is N.

[0344] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0345] (i) Suppress the disease or disease state, that is, curb its development;

[0346] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0347] The term “prevention” means administering the compound or formulation described in this application to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0348] The term "therapeutic effective amount" means: (i) the amount of the disclosed compound used to treat a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by someone skilled in the art based on their own knowledge and the content of this disclosure.

[0349] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0350] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of an acid or base, including salts formed by a compound with an inorganic or organic acid, and salts formed by a compound with an inorganic or organic base.

[0351] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism.

[0352] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0353] The word “comprise” or “include” and its English variants such as comprises or comprising can be understood as having an open, non-exclusive meaning, that is, “including but not limited to”.

[0354] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0355] Certain isotope-labeled compounds of this disclosure (e.g., using...) 3 H and 14 C-labeling can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0356] The pharmaceutical compositions disclosed herein can be prepared by combining the disclosed compounds with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, capsules, pills, granules, drop pills, aerosols, sprays, nasal drops, inhalers, suppositories, enemas, intramuscular injections, intravenous injections, intra-articular injections, ointments or patches, etc.

[0357] Typical routes of administration of the disclosed compounds or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0358] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, emulsification, freeze drying, etc.

[0359] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this disclosure to be formulated into tablets, capsules, pills, granules, drops, etc., for oral administration to patients.

[0360] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain a tablet or sugar-coated core. Suitable excipients include, but are not limited to, one or more of the following: diluents, fillers, binders, humectants, absorption enhancers, surfactants, lubricants, and stabilizers.

[0361] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0362] In all methods of administration of the compound of general formula (I) described herein, the daily dose is from 0.01 mg / kg to 200 mg / kg body weight, preferably from 0.05 mg / kg to 50 mg / kg body weight, in the form of single or separate doses. Attached Figure Description

[0363] Figure 1 (including Figures (A) to (J): Activation effect of the compounds of this application on NAMPT.

[0364] Figure 2: The effect of the compound of this application on increasing NAD+ levels in cells.

[0365] Figure 3: The effect of the compound of this application on increasing NAD+ levels in skin tissue.

[0366] Figure 4: The differentiation-promoting effect of the compound of this application on C2C12 cells.

[0367] Figure 5: Protective effect of the compound of this application on a mouse muscle injury model.

[0368] Figure 6: The promoting effect of the compound of this application on the expression of type I collagen in cells.

[0369] Figure 7: The protective effect of the compound of this application on cell senescence.

[0370] Figure 8: Antioxidant activity of the compounds in this application.

[0371] Figure 9: Whitening effect of the compound in this application.

[0372] Figure 10: The effect of the compound in this application on enhancing mitochondrial function.

[0373] Figure 11: The effect of the compound of this application on repairing DNA damage.

[0374] Figure 12: Effect of the compound of this application on the maturation rate of oocytes in aged mice. Detailed Implementation

[0375] The invention is described in detail below with reference to embodiments, but this does not imply any adverse limitation of the present disclosure. The present disclosure has been described in detail herein, including specific embodiments thereof, and various changes to the specific embodiments thereof will be apparent to those skilled in the art without departing from the spirit and scope of the present disclosure. All reagents used in this disclosure are commercially available and can be used without further purification.

[0376] Unless otherwise stated, the proportions expressed for mixed solvents are volume-based.

[0377] Unless otherwise stated, % refers to wt%.

[0378] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0379] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻¹⁰. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS).

[0380] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0381] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0382] Example 1: Synthesis of the compound

[0383] Synthesis of NPL-1

[0384] Step 1: Preparation of NPL-1-A1

[0385] NPL-1-A0 (0.20 g, 1.32 mmol) was dissolved in 5 mL of acetonitrile, and potassium carbonate (548 mg, 3.97 mmol) and ethyl bromoacetate (331 mg, 1.98 mmol) were added. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered and concentrated, and the residue was purified by column chromatography to give a yellow oily compound NPL-1-A1 (300 mg, yield 93.5%).

[0386] MS(ESI)m / z = 238.2[M+H] +

[0387] 1 HNMR(400MHz,CHLOROFORM-d)δ8.25-8.06(m,1H),7.14-7.07(m,1H),7.02-6.96( m,1H),4.68-4.61(m,2H),4.34-4.22(m,2H),1.48-1.43(m,9H),1.33-1.27(m,3H)

[0388] Step 2: Preparation of NPL-1-A2

[0389] NPL-1-A1 (300 mg, 1.24 mmol) was dissolved in 5 mL of methanol and 5 mL of water, and lithium hydroxide monohydrate (159 mg, 3.79 mmol) was added. The reaction mixture was stirred at 20 °C for 2 hours. The pH of the reaction mixture was adjusted to 1-2 with 1 N hydrochloric acid, and the solution was extracted twice with 20 mL of dichloromethane. The aqueous phase was lyophilized to give a yellow oily compound NPL-1-A2 (250 mg, crude product).

[0390] MS(ESI)m / z = 210.2[M+H] +

[0391] 1 HNMR(400MHz,DMSO-d6)δ8.34-8.28(m,1H),8.01-7.92(m,1H),7.78-7.66(m,1H),5.02-4.94(m,2H),1.53-1.44(m,9H)

[0392] Step 3: Preparation of NPL-1

[0393] NPL-1-A2 (250 mg, 1.19 mmol, 1.00 eq) and 4-aminophenol (156 mg, 1.43 mmol, 1.20 eq) were dissolved in 5 mL of dimethylformamide. N,N-diisopropylethylamine (463 mg, 3.58 mmol, 3.00 eq) was added, and the mixture was stirred for 5 minutes. Then, 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridinium cation 1-hexafluorophosphate oxide (681 mg, 1.79 mmol, 1.50 eq) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into 5 mL of water and extracted twice with 5 mL of ethyl acetate. The organic phase was washed with 5 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by liquid chromatography to give a white solid compound NPL-1 (165 mg, yield 45.0%).

[0394] MS(ESI)m / z = 301.0[M+H] +

[0395] 1 HNMR (400MHz, DMSO-d6) : δ10.06-9.81(m,1H),9.28-9.16(m,1H),8.23-8.01(m,1H),7.44-7.35(m,2H),7.33-7 .26(m,1H),7.23-7.17(m,1H),6.77-6.67(m,2H),4.80-4.65(m,2H),1.45-1.31(m,9H)

[0396] The compounds in Table 1 below were prepared using the same method as in the examples described above, either commercially available compounds or intermediate compounds prepared by the method shown.

[0397] Table 1

[0398] Synthesis of NPL-5

[0399] Step 1: Synthesis of NPL-5-A1

[0400] Ethyl 2-[(1-methyl-1H-indol-7-yl)oxo]acetate (NPL-5-A0) (1 g, 4.29 mmol) was dissolved in 10 mL of acetic acid, and sodium cyanoborohydride (538.81 mg, 8.57 mmol) was added. The mixture was stirred at 25 °C for 2 hours. The reaction solution was poured into 20 mL of water and extracted twice with 30 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give a yellow oily compound NPL-5-A1 (965 mg, yield 95.67%).

[0401] MS(ESI)m / z = 235.9[M+H] +

[0402] 1 HNMR (400MHz, CHLOROFORM-d): δ6.80 (d, J=6.9Hz, 1H), 6.70-6.54 (m, 2H), 4.59 (s, 2H), 4.28 (d, J= 7.1Hz,2H),3.30(t,J=8.5Hz,2H),3.07(d,J=1.3Hz,3H),3.00-2.83(m,2H),1.31(t,J=7.2Hz,3H)

[0403] Step 2: Synthesis of NPL-5-A2

[0404] NPL-5-A1 (865 mg, 3.68 mmol) was dissolved in 2.5 mL of methanol and 2.5 mL of water, and lithium hydroxide monohydrate (308.56 mg, 7.35 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS monitoring showed that the starting material was completely consumed. The pH of the reaction mixture was adjusted to 6-7 with 1 mol / L hydrochloric acid, and then directly lyophilized to obtain a yellow solid compound NPL-5-A2 (992 mg, crude product).

[0405] MS(ESI)m / z = 208.0[M+H] +

[0406] Step 3: Synthesis of NPL-5

[0407] NPL-5-A2 (500 mg, 2.41 mmol) was dissolved in 10 mL of dimethylformamide, and 4-aminophenol (394.95 mg, 3.62 mmol, 564.22 μL) and N,N-diisopropylethylamine (1.56 g, 12.06 mmol, 2.10 mL) were added in portions at 0–5 °C. The reaction mixture was then stirred at 25 °C for 16 hours. The reaction mixture was poured into 30 mL of water and extracted twice with 30 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give a light brown solid compound NPL-5 (149.06 mg, yield 20.26%).

[0408] MS(ESI)m / z=299.0[M+H]+

[0409] 1 HNMR(400MHz,DMSO-d6)δ9.80(s,1H),9.23(s,1H),7.49-7.31(m,2H),6.80-6.67(m,4H) ,6.64-6.52(m,1H),4.56(s,2H),3.26-3.16(m,2H),2.96(s,3H),2.86(t,J=8.4Hz,2H).

[0410] Synthesis of NPL-9

[0411] Step 1: Synthesis of NPL-9-A1

[0412] 2-Methoxy-3-pyridinecarboxylic acid methyl ester (NPL-9-A0) (8.00 g, 47.9 mmol) was dissolved in 80 mL of tetrahydrofuran, and methyl magnesium bromide (3 M, 31.9 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was quenched in 100 mL of saturated ammonium chloride, extracted twice with 100 mL of ethyl acetate, and the combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow solid compound NPL-9-A1 (5.05 g, yield 58.4%).

[0413] MS(ESI)m / z = 168.2[M+H] +

[0414] 1HNMR (400MHz, DMSO-d6): δ8.05-7.95(m,1H),7.86(dd,J=1.9,7.4Hz,1H),6.95(dd,J=4.9,7.4Hz,1H),3.88-3.84(m,3H),1.47-1.41(m,6H)

[0415] Step 2: Synthesis of NPL-9-A2

[0416] NPL-9-A1 (2.00 g, 12.0 mmol) was placed in a clean 100 mL flask under ice bath conditions and purged with nitrogen. Then, thionyl chloride (7.12 g, 59.8 mmol, 4.34 mL) was added, and the reaction mixture was stirred at 0 °C for 2 hours. 4 mL of dichloromethane was added to ensure homogeneity. The reaction solution was dried under reduced pressure, and the residue was dissolved in 30 mL of dichloroethane. The solution was cooled to -65 °C, and trimethylaluminum (2 M, 17.9 mL) was slowly added while stirring at -65 °C for 3 hours. The mixture was then heated to 85 °C and stirred for 24 hours. The reaction solution was slowly cooled to 0 °C, quenched by slowly adding 40 mL of 10% sodium bicarbonate solution, and extracted twice with 100 mL of dichloromethane. The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow solid compound NPL-9-A2 (650 mg, yield 14.4%).

[0417] MS(ESI)m / z = 168.2[M+H] +

[0418] 1 HNMR (400MHz, DMSO-d6): δ11.63-10.99(m,1H),7.38-7.05(m,2H),6.29-5.92(m,1H),1.37-1.14(m,9H)

[0419] Step 3: Synthesis of NPL-9-A3

[0420] NPL-9-A2 (350 mg, 2.31 mmol, 1.00 eq) was dissolved in 10 mL of acetonitrile, and silver carbonate (1.91 g, 6.94 mmol, 3.00 eq) and ethyl bromoacetate (464 mg, 2.78 mmol, 1.20 eq) were added. The reaction mixture was stirred at 80 °C for 3 hours under a nitrogen atmosphere. LC-MS analysis showed that 44.2% of the product was formed. The reaction mixture was poured into 10 mL of water, extracted twice with 10 mL of ethyl acetate, washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow oily compound NPL-9-A3 (135 mg, yield 22.1%).

[0421] MS(ESI)m / z = 238.2[M+H] +

[0422] 1 HNMR (400MHz, CHLOROFORM-d): δ7.98-7.86(m,1H),7.59-7.49(m,1H),6.91-6.79(m ,1H),5.01-4.91(m,2H),4.28-4.16(m,2H),1.43-1.40(m,9H),1.25(t,J=7.1Hz,3H)

[0423] Step 4: Synthesis of NPL-9-A4

[0424] NPL-9-A3 (130 mg, 548 μmol) was dissolved in 5 mL of tetrahydrofuran and 5 mL of water, and lithium hydroxide monohydrate (69.0 mg, 1.64 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was extracted twice with dichloromethane, and the aqueous phase was lyophilized to give a white solid compound NPL-9-A4 (200 mg, crude product).

[0425] MS(ESI)m / z = 210.2[M+H] +

[0426] 1 HNMR(400MHz,D2O): δ7.99-7.82(m,1H),7.81-7.67(m,1H),7.08-6.89(m,1H),4.73-4.70(m,2H),1.43-1.37(m,9H)

[0427] Step 5: Synthesis of NPL-9

[0428] NPL-9-A4 (180 mg, 860 μmol) and 4-aminophenol (93.9 mg, 860 μmol) were dissolved in 9 mL of N,N-dimethylformamide, followed by the addition of N,N-diisopropylethylamine (334 mg, 2.58 mmol) and 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridinium cation 1-hexafluorophosphate oxide (654 mg, 1.72 mmol). The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into 10 mL of water and extracted twice with 10 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give a yellow solid compound NPL-9 (11.2 mg, yield 4.19%).

[0429] MS(ESI)m / z = 300.9[M+H] +

[0430] 1 HNMR(400MHz,DMSO-d6)δ9.85(s,1H),9.19(s,1H),7.95(dd,J=4.9,1.8Hz,1H),7.60(dd,J=7.5,1.8 Hz,1H),7.43–7.25(m,2H),6.95(dd,J=7.4,4.9Hz,1H),6.75–6.60(m,2H),4.95(s,2H),1.38(s,9H).

[0431] The compounds in Table 2 below were prepared using the same method as in the examples described above, either commercially available compounds or intermediate compounds prepared by the method shown.

[0432] Table 2

[0433] Synthesis of NPL-10 / NPL-11

[0434] Step 1: Synthesis of NPL-10-A1

[0435] 2-tert-butylcyclohexane-1-ol (NPL-10-A0) (1 g, 6.40 mmol) was dissolved in 10 mL of dichloromethane, and rhodium acetate dimer (84.85 mg, 191.98 μmol) was added. This mixture was stirred for 5 minutes at 25 °C under a nitrogen atmosphere. Ethyl diazonium acetate (912.74 mg, 6.40 mmol, 841.23 μL) was dissolved in 4 mL of dichloromethane and slowly added dropwise to the above mixture. This reaction solution was stirred for 16 hours at 25 °C under a nitrogen atmosphere. The reaction was analyzed by TLC (petroleum ether:ethyl acetate = 20:1, SM:R). f =0.26,R f =0.32; Product: R f =0.43,R f =0.49) New spots were observed to form. The reaction solution was directly loaded onto the sample using a wet method and purified by column chromatography to obtain a yellow oily compound NPL-10-A1 (1.11 g, crude product).

[0436] Step 2: Synthesis of NPL-10-A2

[0437] NPL-10-A1 (1.4 g, 5.78 mmol, 1 eq) was dissolved in 6 mL of methanol and 6 mL of water, and lithium hydroxide monohydrate (727.23 mg, 17.33 mmol, 3 eq) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was analyzed by TLC (petroleum ether:ethyl acetate = 20:1, SM:R). f =0.43, Rf=0.49; Product: Rf =0.01,R f =0.08) The starting material was monitored to be almost completely reacted and new spots were formed. The reaction solution was poured into 20 mL of water, extracted with 30 mL of ethyl acetate, and then the aqueous phase was freeze-dried to give a white solid compound NPL-10-A2 (1.59 g, crude product).

[0438] Step 3: Synthesis of NPL-10 and NPL-11

[0439] NPL-10-A2 (1.59 g, 7.42 mmol) was dissolved in 10 mL of dimethylformamide. 4-Aminophenol (809.66 mg, 7.42 mmol, 1.16 mL) and N,N-diisopropylethylamine (1.56 g, 12.06 mmol, 2.10 mL) were added. Then, 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridinium cation 1-hexafluorophosphate (4.23 g, 11.13 mmol) was added in portions at 0–5 °C. The reaction mixture was stirred at 25 °C for 2 hours. Then, 3 drops of ammonia were added to the reaction mixture, and the mixture was stirred at 25 °C for 10 minutes. The reaction solution was poured into 20 mL of water and extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography and preparative liquid chromatography to give white solid compound NPL-10 (7.98 mg, yield 0.35%) and white solid compound NPL-11 (70.63 mg, yield 3.11%).

[0440] NPL-10:

[0441] MS(ESI)m / z = 306.3[M+H] +

[0442] 1 HNMR (400MHz, DMSO-d6): δ9.29-9.00(m,2H),7.46-7.24(m,2H),6.78-6.59(m,2H),4.13-4.01(m,1H),3.95-3.79(m,1H ),3.30-3.20(m,1H),2.12-2.03(m,1H),1.84-1.71(m,1H),1.70-1.57(m,2H),1.34-1.09(m,4H),0.96(s,9H),0.92(br d,J=3.5Hz,1H)

[0443] NPL-11:

[0444] MS(ESI)m / z = 306.2[M+H] +

[0445] 1 HNMR (400MHz, DMSO-d6): δ9.44-8.93(m,2H),7.43-7.12(m,2H),6.80-6.62( m,2H),4.04(d,J=14.0Hz,1H),3.88(d,J=14.1Hz,2H),2.08(s,1H),2.02(br d,J=14.0Hz,1H),1.75(br d,J=12.6Hz,1H),1.66-1.43(m,3H),1.42-1.32(m,1H),1.29-1.11(m,2H),1.10-1.03(m,1H),0.94(s,9H)

[0446] The compounds in Table 3 below were prepared using the same method as in the examples described above, either commercially available compounds or intermediate compounds prepared by the methods shown.

[0447] Table 3

[0448] Synthesis of NPL-12

[0449] Step 1: Preparation of NPL-12-A1

[0450] NPL-12-A0 (500 mg, 2.24 mmol) was dissolved in 5 mL of acetonitrile, and potassium carbonate (929.39 mg, 6.72 mmol) and ethyl bromoacetate (449.20 mg, 2.69 mmol) were added. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was poured into 20 mL of water and extracted twice with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give a yellow oily compound NPL-12-A1 (627 mg, yield 90.48%).

[0451] MS(ESI)m / z = 309.0 [M+H] +

[0452] 1 H NMR (400MHz, CHLOROFORM-d): δ = 8.53 (d, J = 1.8Hz, 1H), 7.71-7.64 (m, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7 .38(d,J=7.6Hz,1H),6.75(d,J=7.5Hz,1H),4.81(s,2H),4.31(d,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H)

[0453] Step 2: Preparation of NPL-12-A2

[0454] NPL-12-A1 (587 mg, 1.90 mmol) was dissolved in 5 mL of dimethylformamide, and trimethyl-1,3,5,2,4,6-trioxaprohexane (953.42 mg, 3.80 mmol), cesium carbonate (1.24 g, 3.80 mmol), and tetrakis(triphenylphosphine)palladium (109.70 mg, 94.94 μmol) were added. The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into 20 mL of water and extracted twice with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give a yellow oily compound NPL-12-A2 (388 mg, yield 83.65%).

[0455] MS(ESI)m / z = 244.9[M+H] +

[0456] 1 HNMR (400MHz, CHLOROFORM-d): δ8.11(s,1H),7.67(s,1H),7.40(s,1H),7.32(dd,J=1.5,8.4Hz,1H),7 .26-7.22(m,1H),6.68(s,1H),4.78(s,2H),4.28(q,J=7.1Hz,2H),2.51(s,3H),1.29(t,J=7.1Hz,3H)

[0457] Step 3: Preparation of NPL-12-A3

[0458] NPL-12-A2 (368 mg, 1.51 mmol) was dissolved in 2 mL of methanol and 2 mL of water, and lithium hydroxide monohydrate (126.43 mg, 3.01 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. The pH of the reaction mixture was adjusted to 2-3 with 1 N hydrochloric acid, then poured into 10 mL of water. The mixture was extracted twice with 10 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a yellow solid compound NPL-12-A3 (259 mg, yield 79.51%).

[0459] MS(ESI)m / z = 217.0[M+H] +

[0460] 1H NMR (400MHz, CHLOROFORM-d): δ = 8.10 (s, 1H), 7.73 (d, J = 8.3Hz, 1H), 7.46 (s, 1H), 7.3 6(dd,J=1.2,8.4Hz,1H),7.30(s,1H),6.74(d,J=7.5Hz,1H),4.89(s,2H),2.55(s,3H)

[0461] Step 4: Preparation of NPL-12

[0462] NPL-12-A3 (239 mg, 1.11 mmol) was dissolved in 5 mL of dimethylformamide, and 4-aminophenol (132.68 mg, 1.22 mmol) and N,N-diisopropylethylamine (428.55 mg, 3.32 mmol) were added. Then, 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridinium cation 1-hexafluorophosphate (630.40 mg, 1.66 mmol) was added in portions at 0-5 °C. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, 3 drops of ammonia water were added dropwise to the reaction mixture, and then the mixture was stirred for 15 minutes. The reaction solution was poured into 20 mL of water and extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by preparative liquid chromatography to give a white solid compound NPL-12 (180.57 mg, yield 52.88%).

[0463] MS(ESI)m / z = 308.2[M+H] +

[0464] 1 HNMR(400MHz,CHLOROFORM-d)δ8.24(br s,1H),8.03(s,1H),7.78(br d,J=8.3Hz,1H),7.51(br d,J=8.5Hz,1H),7.46-7.38(m,3H),7.34(br t,J=7.6Hz,1H),6.94-6.77(m,3H),4.99(br s,1H),4.82(s,2H),2.59(s,3H)

[0465] The compounds in Table 4 below were prepared using the same method as in the examples described above, either commercially available compounds or intermediate compounds prepared by the methods shown.

[0466] Table 4

[0467] Synthesis of NPL-20

[0468] Step 1: Synthesis of NPL-20-A1

[0469] NPL-20-A0 (200 mg, 1.32 mmol) was dissolved in 4 mL of tetrahydrofuran. Butyllithium (2.5 M, 1.06 mL) was added under a nitrogen atmosphere at -65 °C and the mixture was stirred for 1 hour. Iodine (403 mg, 1.59 mmol) was dissolved in 2 mL of tetrahydrofuran and slowly added to the reaction mixture. The mixture was stirred at -65 °C for 2 hours. The reaction mixture was slowly poured into 10 mL of ice water and extracted twice with 10 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow solid compound NPL-20-A1 (210 mg, yield 54.7%).

[0470] MS(ESI)m / z = 278.0[M+H] +

[0471] 1 HNMR(400MHz,CHLOROFORM-d): δ7.44-7.33(m,1H),6.75-6.64(m,1H),5.36-5.13(m,1H),1.46-1.36(m,9H)

[0472] Step 2: Synthesis of NPL-20-A2

[0473] NPL-20-A1 (190 mg, 686 μmol) was dissolved in 5 mL of N,N-dimethylformamide, and cuprous cyanide (307 mg, 3.43 mmol) was added. The reaction mixture was stirred at 140 °C for 2 hours. The reaction mixture was poured into 10 mL of water and extracted twice with 10 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow oily compound NPL-20-A2 (60.0 mg, yield 49.7%).

[0474] MS(ESI)m / z = 177.2[M+H] +

[0475] Step 3: Synthesis of NPL-20-A3

[0476] NPL-20-A2 (50.0 mg, 284 μmol) was dissolved in 2 mL of N,N-dimethylformamide, and cesium carbonate (277 mg, 851 μmol) and tert-butyl bromoacetate (66.4 mg, 340 μmol) were added. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into 5 mL of water and extracted twice with 5 mL of ethyl acetate. The organic phase was washed with 5 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give an orange solid compound NPL-20-A3 (55.0 mg, yield 40.5%).

[0477] MS(ESI)m / z = 291.2[M+H] +

[0478] 1 HNMR (400MHz, DMSO-d6): δ7.91-7.86(m,1H),7.48-7.40(m,1H),4.92-4.85(m,2H),1.45-1.42(m,9H),1.39-1.36(m,9H)

[0479] Step 4: Synthesis of NPL-20-A4

[0480] NPL-20-A3 was dissolved in 3 mL of dichloromethane, and trifluoroacetic acid (4.61 g, 40.4 mmol, 3 mL) was added. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to give a yellow solid compound NPL-20-A4 (42.0 mg, crude product).

[0481] MS(ESI)m / z = 235.2[M+H] +

[0482] 1 HNMR (400MHz, DMSO-d6): δ7.92-7.85(m,1H),7.51-7.43(m,1H),4.96-4.88(m,2H),1.40-1.34(m,9H)

[0483] Step 5: Synthesis of NPL-20

[0484] NPL-20-A4 (37.0 mg, 158 μmol) and 4-aminophenol (25.9 mg, 237 μmol) were dissolved in 2 mL of N,N-dimethylformamide, followed by the addition of N,N-diisopropylethylamine (61.2 mg, 474 μmol) and 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridinium cation 1-hexafluorophosphate oxide (90.1 mg, 237 μmol). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into 5 mL of water and extracted twice with 5 mL of ethyl acetate. The organic phase was washed with 5 mL of saturated brine, dried over anhydrous magnesium sulfate, and filtered. The concentrated residue was purified by preparative liquid chromatography to give an off-white solid (NPL-20, 30.0 mg, yield 57.2%).

[0485] MS(ESI)m / z = 325.7[M+H] +

[0486] 1 HNMR (400MHz, DMSO-d6): δ10.04-9.98(m,1H),9.26(s,1H),7.93-7.87(m,1H),7.47-7. 43(m,1H),7.40-7.33(m,2H),6.74-6.67(m,2H),4.96-4.87(m,2H),1.42-1.35(m,9H).

[0487] Synthesis of NPL-22

[0488] Step 1: Synthesis of NPL-22-A1

[0489] 4-Methoxypyridine-3-carboxylic acid methyl ester (NPL-22-A0, 5.00 g, 29.9 mmol) was dissolved in 80 mL of tetrahydrofuran, and methyl magnesium bromide (3 M, 19.9 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was quenched in 80 mL of saturated ammonium chloride, extracted twice with 80 mL of ethyl acetate, and the combined organic phases were washed with 80 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow solid compound NPL-22-A1 (4.33 g, yield 79.7%).

[0490] MS(ESI)m / z = 168.0 [M+H] +

[0491] 1HNMR (400MHz, CHLOROFORM-d): δ8.67-8.21(m,2H),6.95-6.68(m,1H),3.96-3.88(m,3H),3.82-3.20(m,1H),1.70-1.49(m,6H).

[0492] Step 2: Synthesis of NPL-22-A2

[0493] NPL-22-A1 (4.33 g, 23.9 mmol) was placed in a clean 250 mL flask under ice bath conditions and purged with nitrogen. Then, thionyl chloride (15.4 g, 129 mmol, 9.40 mL) was added, and the reaction mixture was stirred at 0 °C for 2 hours. 5 mL of dichloromethane was added to ensure homogeneity. The reaction solution was dried under reduced pressure, and the residue was dissolved in 80 mL of dichloroethane. The solution was cooled to -35 °C, and trimethylaluminum (2 M, 17.9 mL) was slowly added while stirring at -35 °C for 3 hours. The mixture was then heated to 85 °C and stirred for 16 hours. The reaction solution was slowly cooled to 0 °C, quenched by slowly adding 40 mL of 10% sodium bicarbonate solution, and extracted twice with 100 mL of dichloromethane. The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow liquid compound, NPL-22-A2 (650 mg, yield 14.4%).

[0494] MS(ESI)m / z = 166.2[M+H] +

[0495] 1 HNMR (400MHz, DMSO-d6): δ8.35-8.25(m,2H),7.04-6.94(m,1H),3.91-3.82(m,3H),1.38-1.30(m,9H)

[0496] Step 3: Synthesis of NPL-22-A3

[0497] 3-tert-butyl-4-methoxypyridine (NPL-22-A2) (0.48 g, 2.91 mmol, 1.00 eq) was dissolved in 10 mL of toluene, and then hydroiodic acid (3.40 g, 26.58 mmol, 2 mL, 9.15 eq) was added. The reaction mixture was stirred at 115 °C for 16 hours. The reaction mixture was poured into 10 mL of water and extracted twice with 10 mL of dichloromethane. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow solid compound NPL-22-A3 (240 mg, yield 47.8%).

[0498] MS(ESI)m / z=152.2[M+H]+

[0499] Step 4: Synthesis of NPL-22-A4

[0500] NPL-22-A3 (480 mg, 3.17 mmol) was dissolved in 10 mL of toluene, and then phosphorus oxychloride (2.43 g, 15.9 mmol, 1.48 mL) was added. The reaction mixture was stirred at 110 °C for 3 hours. The reaction mixture was poured into 10 mL of saturated sodium bicarbonate solution and extracted twice with 10 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow oily compound NPL-22-A4 (235 mg, yield 42.0%).

[0501] MS(ESI)m / z = 170.2[M+H] +

[0502] 1 HNMR (400MHz, CHLOROFORM-d): δ8.58-8.49(m,1H),8.27-8.19(m,1H),7.19-7.15(m,1H),1.43-1.37(m,9H).

[0503] Step 5: Synthesis of NPL-22-A5

[0504] NPL-22-A4 (235 mg, 1.39 mmol) was dissolved in 5 mL of acetic acid, and then hydrogen peroxide (1.56 g, 13.8 mmol, 1.32 mL, 30% purity) was added. The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was poured into 5 mL of saturated sodium bicarbonate solution and extracted twice with 5 mL of ethyl acetate. The organic phase was washed successively with 5 mL of sodium thiosulfate and 5 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow oily compound NPL-22-A5 (248 mg, yield 90.94%).

[0505] MS(ESI)m / z = 186.1 [M+H] +

[0506] 1 HNMR (400MHz, CHLOROFORM-d): δ8.30-8.21(m,1H),8.05-7.96(m,1H),7.22-7.16(m,1H),1.56-1.30(m,9H).

[0507] Step 6: Synthesis of NPL-22-A6 and NPL-22-A7

[0508] NPL-22-A5 (150 mg, 808 μmol) was dissolved in 3 mL of dioxane and 3 mL of water. Potassium hydroxide (136 mg, 2.42 mmol), 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl (34.3 mg, 80.8 μmol), and tris(dibenzylacetone)palladium (74.0 mg, 80.8 μmol) were added. The reaction mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. Then, the mixture was cooled to 25 °C, and ethyl bromoacetate (229 mg, 1.37 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was directly purified by liquid chromatography to give white solid compounds NPL-22-A6 (37.0 mg, 19.5% yield) and NPL-22-A7 (70.0 mg, 32.5% yield).

[0509] Step 6: Synthesis of NPL-22

[0510] NPL-22-A7 (30.0 mg, 133 μmol) and 4-aminophenol (21.8 mg, 200 μmol) were dissolved in 1 mL of N,N-dimethylformamide, followed by the addition of N,N-diisopropylethylamine (51.6 mg, 400 μmol) and 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridinium cation 1-hexafluorophosphate oxide (76.0 mg, 200 μmol). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was directly purified by liquid chromatography to obtain a brown solid (NPL-22, 22.0 mg, yield 50.9%).

[0511] MS(ESI)m / z = 317.2[M+H] +

[0512] 1 HNMR(400MHz,ACETONITRILE-d3)δ8.83-8.69(m,1H),8.62-8.53(m,2H),7.98-7.89 (m,1H),7.42-7.33(m,2H),6.84-6.75(m,2H),5.10-4.97(m,2H),1.46-1.36(m,9H)

[0513] Synthesis of NPL-24

[0514] Step 1: Synthesis of NPL-24-A1

[0515] 2-tert-butylpyridin-3-phenol (NPL-24-A0, 0.20 g, 1.32 mmol) was dissolved in 5 mL of acetonitrile, and potassium carbonate (548 mg, 3.97 mmol) and ethyl bromoacetate (331 mg, 1.98 mmol) were added. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered and concentrated, and the residue was purified by column chromatography to give a yellow oily substance, ethyl-2-((2-(tert-butyl)pyridin-3-yl)oxo)acetate (NPL-24-A1, 300 mg, yield 93.5%).

[0516] 1 H NMR(400MHz,CHLOROFORM-d)δ8.25-8.06(m,1H),7.14-7.07(m,1H),7.02-6.96(m ,1H),4.68-4.61(m,2H),4.34-4.22(m,2H),1.48-1.43(m,9H),1.33-1.27(m,3H)

[0517] Step 2: Synthesis of NPL-24-A2

[0518] NPL-24-A1 (100 mg, 421.42 μmol) was dissolved in 2 mL of tetrahydrofuran and 1 mL of water, and lithium hydroxide monohydrate (35.37 mg, 842.84 μmol) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was then evaporated to dryness under reduced pressure and used directly in the next step of the reaction. A white solid compound, NPL-24-A2 (88 mg, yield 99.80%), was obtained.

[0519] Step 3: Preparation of NPL-24

[0520] 6-Amino-2,3-dihydro-1,3-benzoxazol-2-one (69.46 mg, 462.62 μmol) was dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (108.71 mg, 841.13 μmol), NPL-24-A2 (88 mg, 420.57 μmol), and 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridinium cation 1-hexafluorophosphate oxide (239.87 mg, 630.85 μmol) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was poured into 50 mL of water and extracted twice with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by preparative liquid chromatography to obtain a white solid compound NPL-24 (27.64 mg, yield 19.25%).

[0521] MS(ESI)m / z = 342.2[M+H] +

[0522] 1 HNMR(400MHz,DMSO-d6)δ11.62(s,1H),10.59(s,1H),8.30-8.19(m,1H),7.88(br d,J=7.9Hz,1H),7.73-7.58(m,2H),7.29(dd,J=1.9,8.4Hz,1H),7.06(d,J=8.4Hz,1H),5.04(s,2H),1.50(s,9H).

[0523] The compounds in Table 5 below were prepared using the same methods as in the examples described above, either commercially available compounds or intermediate compounds prepared by reference.

[0524] Table 5

[0525] Synthesis of NPL-26

[0526] Step 1: Synthesis of NPL-26-A1

[0527] 4-Bromo-2-tert-butylpyridin-3-phenol (NPL-26-A0, 852 mg, 3.70 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and cesium carbonate (3.62 g, 11.1 mmol) and ethyl bromoacetate (742 mg, 4.44 mmol) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into 50 mL of water and extracted five times with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography to give colorless oily ethyl 2-[(4-bromo-2-tert-butylpyridin-3-yl)oxo]acetate (NPL-26-A1, 1.05 g, yield 89.7%).

[0528] 1 HNMR (400MHz, DMSO-d6) δ7.46-7.38(m,1H),7.36-7.28(m,1H),4.90(s,2H),4.23-4.19(m,2H),1.36(s,9H),1.20(s,3H).

[0529] Step 2: Synthesis of NPL-26-A2

[0530] Ethyl 2-[(4-bromo-2-tert-butylpyridin-3-yl)oxo]acetate ethyl (NPL-26-A1, 1.05 g, 3.32 mmol) was dissolved in 10 mL of dioxane. Tert-butyl carbamate (778 mg, 6.64 mmol), potassium carbonate (918 mg, 6.64 mmol), 4,5-bis(diphenylphosphine-99-dimethyloxaxanthracene) (384 mg, 664 μmol) and palladium acetate (149 mg, 664 μmol) were added under a nitrogen atmosphere. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The reaction solution was poured into 50 mL of water and extracted five times with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was used directly in the next step to obtain colorless oily ethyl 2-[(4-{[(tert-butoxy)carbonyl]amino}-2-tert-butylpyridin-3-yl)oxo]acetate (NPL-26-A2, 900 mg, yield 76.9%).

[0531] Step 3: Synthesis of NPL-26-A3

[0532] Ethyl 2-[(4-{[(tert-butoxy)carbonyl]amino}-2-tert-butylpyridin-3-yl)oxo]acetate (NPL-26-A2, 700 mg, 1.99 mmol) was dissolved in 20 mL of dichloromethane, and trifluoroacetic acid (2.26 g, 19.9 mmol, 10.0 eq) was added. The reaction mixture was stirred at 25 °C for 2 hours. After filtration and concentration, the reaction mixture was purified by preparative liquid chromatography to obtain a yellow oily compound, ethyl 2-[(4-amino-2-tert-butylpyridin-3-yl)oxo]acetate (NPL-26-A3, 100 mg, yield 20.0%).

[0533] 1 HNMR(400MHz,DMSO-d6)δ8.13-7.96(m,1H),7.88(br d,J=9.4Hz,1H),6.90(d,J=9.5Hz,1H),4.86(s,2H),4.21-4.14(m,2H),1.45(s,9H),1.22(t,J=7.1Hz,3H).

[0534] Step 4: Synthesis of NPL-26-A4

[0535] Ethyl 2-[(4-amino-2-tert-butylpyridin-3-yl)oxo]acetic acid (NPL-26-A3, 100 mg, 396 μmol) was dissolved in 1 mL of tetrahydrofuran and 1 mL of water, and lithium hydroxide monohydrate (49.9 mg, 1.19 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. The pH of the reaction mixture was adjusted to 2–3 with 1 mol / L hydrochloric acid, poured into 10 mL of water, and extracted twice with 10 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by preparative liquid chromatography to obtain a white solid 2-[(4-amino-2-tert-butylpyridin-3-yl)oxo]acetic acid (NPL-26-A4, 40.0 mg, yield 45.0%).

[0536] 1 HNMR: (400MHz, DMSO-d6) δ8.02-7.81(m,2H),6.95-6.80(m,1H),4.75(s,2H),1.44(s,9H).

[0537] Step 5: Synthesis of NPL-26-A5

[0538] Sodium nitrite (14.8 mg, 214 μmol) was dissolved in 2 mL of hydrofluoric acid and added to 2 mL of tetrahydrofuran containing 2-[(4-amino-2-tert-butylpyridin-3-yl)oxo]acetic acid (NPL-26-A4, 40.0 mg, 178 μmol). The reaction mixture was stirred at -60 to 40 °C for 2 hours. The reaction mixture was poured into 100 mL of ice water and extracted twice with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by preparative liquid chromatography to obtain a yellow solid 2-[(2-tert-butyl-4-fluoropyridin-3-yl)oxo]acetic acid (NPL-26-A5, 15.0 mg, yield 37.0%).

[0539] Step 6: Synthesis of NPL-26

[0540] 2-[(2-tert-butyl-4-fluoropyridin-3-yl)oxo]acetic acid (NPL-26-A 5, 15.0 mg, 66.0 μmol) and 4-aminophenol (14.4 mg, 132 μmol) were dissolved in 1 mL of N,N-dimethylformamide, followed by the addition of N,N-diisopropylethylamine (25.6 mg, 198 μmol, 3.00 eq) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylurea tetrafluoroborate (37.7 mg, 99.0 μmol, 1.50 eq). The reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was poured into 3 mL of water and extracted twice with 3 mL of ethyl acetate. The organic phase was washed with 3 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by preparative liquid chromatography to obtain a white solid 2-[(2-tert-butyl-4-fluoropyridin-3-yl)oxo]-N-(4-hydroxyphenyl)acetate (NPL-26, 6.00 mg, yield 27.4%).

[0541] MS(ESI)m / z = 319.1 [M+H] +

[0542] 1 HNMR(400MHz,ACETONITRILE-d3)δ8.37(br s,1H),7.48(dd,J=6.7,8.7Hz,1H),7.40(d,J=8.9Hz,2H),6.99(br s,1H),6.87-6.77(m,3H),4.64(s,2H),1.43(s,9H)

[0543] Synthesis of NPL-27

[0544] Step 1: Synthesis of NPL-27-A1

[0545] To 25 mL of toluene containing 3-tert-butyl-4-chloropyridine (NPL-22-A4, 891 mg, 5.25 mmol) and ethyl 2-hydroxy acetate (1.64 g, 15.76 mmol, 1.52 mL), palladium acetate (235.82 mg, 1.05 mmol), cesium carbonate (5.13 g, 15.76 mmol), and 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl (1.12 g, 2.63 mmol) were added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered and concentrated to give a brown solid ethyl 2-[(3-tert-butylpyridin-4-yl)oxo]acetate (NPL-27-A1, 2.42 g, crude product).

[0546] MS(ESI)m / z = 238.0(M+H)+

[0547] Step 2: Synthesis of NPL-27-A2

[0548] Ethyl 2-[(3-tert-butylpyridin-4-yl)oxo]acetic acid (NPL-27-A1, 2.02 g, 8.51 mmol) was dissolved in a mixture of 8 mL methanol, 8 mL tetrahydrofuran, and 8 mL water. Lithium hydroxide monohydrate (714.44 mg, 17.03 mmol) was added to the mixture, and the reaction solution was stirred at 25 °C for 2 hours. The pH of the reaction solution was adjusted to 7 with 1 N hydrochloric acid, and then extracted twice with 30 mL ethyl acetate. The aqueous phase was concentrated to give a yellow solid 2-[(3-tert-butylpyridin-4-yl)oxo]acetic acid (NPL-27-A2, 1.55 g, crude product).

[0549] MS(ESI)m / z = 210.1(M+H) +

[0550] 1 H NMR (400MHz, DMSO-d6) δ8.28-8.10 (m, 2H), 6.76 (d, J = 5.6Hz, 1H), 4.38 (s, 2H), 1.37 (s, 9H)

[0551] Step 3: Synthesis of NPL-27

[0552] 2-[(3-tert-butylpyridin-4-yl)oxo]acetic acid (NPL-27-A2, 700 mg, 3.35 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and 4-aminophenol (730.14 mg, 6.69 mmol) and N,N-diisopropylethylamine (1.30 g, 10.04 mmol) were added. Then, 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridinium cation 1-hexafluorophosphate (3.18 g, 8.36 mmol) was added in portions at 0–5 °C. The reaction solution was stirred at 35 °C for 2 hours. The reaction solution was filtered, and the filtrate was purified by preparative liquid chromatography to obtain a white solid 2-[(3-tert-butylpyridin-4-yl)oxo]-N-(4-hydroxyphenyl)acetate (NPL-27, 50.63 mg, yield 5.04%).

[0553] MS(ESI)m / z = 301.2(M+H) +

[0554] 1H NMR (400MHz, DMSO-d6) δ9.98 (s, 1H), 9.24 (br s, 1H), 8.40-8.13 (m, 2H), 7.38 (br d, J = 8.8Hz, 2H), 6.90 (d, J = 5.6Hz, 1H), 6.71 (br d,J=8.8Hz,2H),4.81(s,2H),1.39(s,9H).

[0555] Synthesis of NPL-33

[0556] Step 1: Synthesis of NPL-33-A1

[0557] 2-tert-butylpyridine-3-phenol (NPL-33-A0, 3.30 g, 21.88 mmol) was dissolved in 40 mL of acetonitrile, and then N-chlorosuccinimide (2.48 g, 18.6 mmol) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was quenched in 25 mL of water, extracted twice with 25 mL of ethyl acetate, washed with 25 mL of saturated brine, dried over anhydrous magnesium sulfate, and the concentrated crude product was purified by preparative liquid chromatography to obtain a white solid 2-tert-butyl-6-chloropyridine-3-phenol (NPL-33-A1, 110 mg, yield 2.50%).

[0558] 1 H NMR(400MHz,DMSO-d6)δ7.82(d,J=5.0Hz,1H),7.23(d,J=5.0Hz,1H),1.32(s,9H)

[0559] Step 2: Synthesis of NPL-33-A2

[0560] 2-tert-butyl-6-chloropyridin-3-phenol (NPL-33-A1, 110 mg, 593 μmol) and ethyl bromoacetate (198 mg, 1.19 mmol) were dissolved in 2 mL of N,N-dimethylformamide, and then cesium carbonate (579 mg, 1.78 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into 5 mL of water and extracted twice with 5 mL of ethyl acetate. The organic phase was washed with 5 mL of saturated brine, dried over anhydrous magnesium sulfate, and filtered. The concentrated crude product was purified by column chromatography to give a white solid ethyl-2-[(2-tert-butyl-6-chloropyridin-3-yl)oxo]acetate (NPL-33-A2, 114 mg, yield 62.7%).

[0561] 1H NMR (400MHz, DMSO-d6) δ8.22(d,J=5.0Hz,1H),7.45(d,J=5.1Hz,1H),4.75(s,2H),4.22(q,J=7.1Hz,2H),1.35(s,9H),1.24(t,J=7.1Hz,3H)

[0562] Step 3: Synthesis of NPL-33-A3

[0563] Ethyl-2-[(2-tert-butyl-6-chloropyridin-3-yl)oxo]acetate (NPL-33-A2, 100 mg, 368 μmol) and sodium ethoxide (663 mg, 3.68 mmol, 30% purity) were dissolved in 2 mL of methanol, and then cuprous iodide (210 mg, 1.10 mmol) was added. The reaction solution was stirred at 80 °C for 16 hours. After filtration, the filtrate was directly purified by preparative liquid chromatography to obtain a white solid 2-[(2-tert-butyl-6-methoxypyridin-3-yl)oxo]acetic acid (NPL-33-A2, 100 mg, 368 μmol) and sodium ethoxide (663 mg, 3.68 mmol, 30% purity) in 2 mL of methanol, and then cuprous iodide (210 mg, 1.10 mmol) was added.

[0564] NPL-33-A3, 45.0 mg, yield 47.6%.

[0565] Step 4: Synthesis of NPL-33

[0566] 2-[(2-tert-butyl-6-methoxypyridin-3-yl)oxo]acetic acid (NPL-33-A3, 40.0 mg, 167 μmol) and 4-aminophenol (36.5 mg, 334 μmol) were dissolved in 2 mL of N,N-dimethylformamide, followed by the addition of 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridinium cation-1-oxafluorophosphate (95.4 mg, 251 μmol, 1.50 eq) and N,N-diisopropylethylamine (64.8 mg, 502 μmol). The reaction mixture was stirred at 25 °C for 3 hours. The reaction solution was poured into 3 mL of water and extracted twice with 3 mL of ethyl acetate. The organic phase was washed with 3 mL of saturated brine, dried over anhydrous magnesium sulfate, and the concentrated crude product was purified by preparative liquid chromatography to obtain an off-white solid compound NPL-33 (25.0 mg, yield 45.3%).

[0567] MS(ESI)m / z = 331.2[M+H] +

[0568] 1H NMR (400MHz, DMSO-d6) δ9.62(s,1H),9.23(s,1H),8.13(d,J=5.4Hz,1H),7.42(br d,J=8.6Hz,2H),7.04(d,J=5.4Hz,1H),6.71(br d,J=8.8Hz,2H),4.51(s,2H),3.84(s,3H),1.36(s,9H).

[0569] Synthesis of NPL-34

[0570] Step 1: Synthesis of NPL-34-A1

[0571] N-Boc-L-tert-leucine (NPL-34-A0, 50.0 g, 216 mmol) was dissolved in 500 mL of tetrahydrofuran. Isobutyl chloroformate (38.4 g, 281 mmol) was added at 0 °C and stirred for 0.5 hours, followed by the addition of ammonia (50.5 g, 432 mmol, 30% purity). The reaction mixture was stirred at 25 °C for 1.5 hours. The residue obtained after concentration under reduced pressure was dissolved in 200 mL of ethyl acetate, washed twice with 100 mL of saturated citric acid, and then twice with 100 mL of saturated sodium bicarbonate. The solution was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain colorless oily tert-butyl N-[(1S)-1-aminocarbonyl-2,2-dimethylpropyl]aminomethyl ester (NPL-34-A1, 75.0 g, crude product).

[0572] Step 2: Synthesis of NPL-34-A2

[0573] Tert-butyl N-[(1S)-1-aminocarbonyl-2,2-dimethylpropyl]aminomethyl ester (NPL-34-A1, 70.0 g, 304 mmol) was dissolved in 120 mL of dioxane, and then 210 mL of dioxane hydrochloride (2 M) was added. The reaction solution was stirred at 25 °C for 16 hours. The reaction solution was filtered to obtain a white solid (2S)-2-amino-3,3-dimethylbutyramide (NPL-34-A2, 20 g, crude product).

[0574] Step 3: Synthesis of NPL-34-A3

[0575] (2S)-2-amino-3,3-dimethylbutyramide (NPL-34-A2, 17.0 g, 102 mmol hydrochloride) was dissolved in 100 mL of anhydrous methanol, followed by the addition of 51 mL of sodium hydroxide aqueous solution (10 M, 5.00 eq) and glyoxal (14.8 g, 102 mmol, 13.3 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was then poured into a mixture of 10 mL of acetic acid and 50 mL of water, and extracted twice with 200 mL of ethyl acetate. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, and filtered. The concentrated crude product was purified by silica gel column chromatography to obtain a yellow solid, 3-tert-butyl-1,2-dihydropyrazin-2-one (NPL-34-A3, 2.60 g, yield 16.1%).

[0576] 1 H NMR(400MHz,CHLOROFORM-d)δ7.40(d,J=4.0Hz,1H),7.14(d,J=4.0Hz,1H),1.42(s,9H)

[0577] Step 4: Synthesis of NPL-34-A4

[0578] 3-tert-butyl-1,2-dihydropyrazin-2-one (NPL-34-A3, 1.00 g, 6.57 mmol) was dissolved in phosphorus oxychloride (20.2 g, 131 mmol), followed by the addition of phosphorus pentachloride (4.10 g, 19.7 mmol, 3.00 eq). The reaction mixture was stirred at 105 °C for 16 hours. The residue obtained after filtration and concentration was dissolved in 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated sodium bicarbonate solution and saturated brine, respectively, dried over anhydrous magnesium sulfate, and purified by column chromatography to obtain a yellow oily 2-tert-butyl-3-chloropyrazine (NPL-34-A4, 673 mg, yield 47.8%).

[0579] 1 H NMR(400MHz,CHLOROFORM-d)δ8.43(d,J=2.4Hz,1H),8.21(d,J=2.4Hz,1H),1.52(s,9H)

[0580] Step 5: Synthesis of NPL-34-A5

[0581] 2-tert-butyl-3-chloropyrazine (NPL-34-A4, 330 mg, 1.93 mmol) and ethyl-2-hydroxyacetate (604 mg, 5.80 mmol) were dissolved in 10 mL of toluene, followed by the addition of cesium carbonate (1.89 g, 5.80 mmol), palladium acetate (86.8 mg, 387 μmol), and 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl (411 mg, 967 μmol). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction solution was quenched in 10 mL of water, extracted twice with 10 mL of ethyl acetate, washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, and filtered. The concentrated crude product was then subjected to preparative liquid chromatography to obtain yellow oily ethyl-2-[(3-tert-butylpyrazin-2-yl)oxo]acetic acid (NPL-34-A5, 90.0 mg, yield 18.8%).

[0582] 1 H NMR (400MHz, DMSO-d6) δ8.16-8.12(m,1H),8.01(d,J=2.8Hz,1H),5.03(s,2H),4.16-4.08(m,2H),1.39(s,9H),1.16(t,J=7.1Hz,3H)

[0583] Step 6: Synthesis of NPL-34

[0584] Ethyl-2-[(3-tert-butylpyrazin-2-yl)oxo]acetic acid (NPL-34-A5, 40.0 mg, 167.87 μmol) was dissolved in 2 mL of dimethyl sulfoxide, and sodium hydroxide aqueous solution (134 mg, 671 μmol, 20% purity) was added. The reaction solution was stirred at 25 °C for 0.5 hours. Then, triethylamine (84.9 mg, 839 μmol), 4-aminophenol (36.6 mg, 336 μmol), and 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridine cation 1-hexafluorophosphate oxide (191 mg, 504 μmol) were added. The reaction solution was stirred at 25 °C for 2.5 hours. The reaction solution was poured into 5 mL of water and extracted twice with 5 mL of ethyl acetate. The organic phase was washed with 5 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by preparative liquid chromatography to obtain a white solid 2-[(3-tert-butylpyrazine-2-yl)oxo]-N-(4-hydroxyphenyl)acetate (NPL-34, 14.2 mg, yield 28.0%).

[0585] MS(ESI)m / z = 302.2[M+H] +

[0586] 1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.12(d,J=2.8Hz,1H),8.00(d,J=2.8Hz ,1H),7.35(d,J=8.9Hz,2H),6.68(d,J=8.9Hz,2H),5.01(s,2H),1.40(s,9H).

[0587] Synthesis of NPL-44

[0588] Step 1: Synthesis of NPL-44-A1

[0589] Cyclohexene oxide (NPL-44-A0, 1.00 g, 10.2 mmol, 1.03 mL) was dissolved in 4 mL of ethanol, 8 mL of tetrahydrofuran, and 8 mL of water. Potassium carbonate (8.45 g, 61.1 mmol) and dimethylamine hydrochloride (4.15 g, 51.0 mmol, 4.67 mL) were then added. The reaction mixture was stirred at 90 °C for 16 hours, followed by stirring at 25 °C for 72 hours. The reaction mixture was poured into 10 mL of water and extracted twice with 10 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a yellow oily (1R,2R)-2-(dimethylamino)cyclohexane-1-ol (NPL-44-A1, 770 mg, crude product).

[0590] 1 H NMR(400MHz,CHLOROFORM-d)δ4.21-3.62(m,1H),3.33(dt,J=4.7,9.7Hz,1H),2.26(s,6H),2.22-2.05(m,2H),1.84-1.61(m,3H),1.36-1.02(m,4H)

[0591] Step 2: Synthesis of NPL-44-A2

[0592] (1R,2R)-2-(dimethylamino)cyclohexane-1-ol (NPL-44-A1, 570 mg, 3.98 mmol) was dissolved in 10 mL of dichloroethane, followed by the addition of rhodium dimer acetate (88.0 mg, 199 μmol) and ethyl diazonate (590 mg, 5.17 mmol). The reaction mixture was stirred at 80 °C for 3 hours under a nitrogen atmosphere. The crude product was used directly in the next step without monitoring. After filtration and evaporation, a black oily ethyl 2-{[(1R,2R)-2-(dimethylamino)cyclohexyl]oxo}acetate (NPL-44-A2, 912 mg, crude product) was obtained.

[0593] Step 3: Synthesis of NPL-44

[0594] Ethyl 2-{[(1R,2R)-2-(dimethylamino)cyclohexyl]oxo}acetate (NPL-44-A2, 912.00 mg, 3.98 mmol) was dissolved in 10 mL of dimethyl sulfoxide, followed by the addition of 20% sodium hydroxide aqueous solution (3.18 g, 15.9 mmol, 20% w / w). The reaction mixture was stirred at 25 °C for 0.5 h. Then, triethylamine (2.01 g, 19.9 mmol), 4-aminophenol (434 mg, 3.98 mmol, 620 μL), and 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridinium cation 1-hexafluorophosphate oxide (4.54 g, 11.9 mmol) were added. The reaction mixture was stirred at 25 °C for 2.5 h. The reaction solution was poured into 10 mL of water and extracted twice with 10 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was then prepared by preparative liquid chromatography to obtain a brown solid 2-{[(1R,2R)-2-(dimethylamino)cyclohexyl]oxo}-N-(4-hydroxyphenyl)acetamide (NPL-44, 9.70 mg, yield 0.84%).

[0595] MS(ESI)m / z = 293.0(M+H) +

[0596] 1 H NMR (400MHz, DMSO-d6) δ10.64(br s,1H),9.23(br s,1H),7.32(br d,J=8.5Hz,2H),6.72(br d,J=8.4Hz,2H),4.12-4.01(m,1H),3.99-3.89(m,1H),3.29-3.21(m,1H),2.41(br d,J=9.0Hz,1H),2.23(s,6H),2.08(br d,J=9.4Hz,1H),1.82(br s,1H),1.65(br d,J=14.9Hz,2H),1.11(br d,J=8.1Hz,4H)

[0597] Synthesis of NPL-50

[0598] Step 1: Synthesis of NPL-50-A1

[0599] Under nitrogen protection, 7-bromo-1-hydroxynaphthalene (NPL-50-A0, 1.8 g, 8.1 mmol) was dissolved in 1,4-dioxane (30 mL) and water (10 mL). Potassium carbonate (3.4 g, 24.2 mmol) and methylboric acid (2.4 g, 40.4 mmol) were then added sequentially. After three nitrogen purgings, 1,1-bis(diphenylphosphine)ferrocene palladium chloride (0.6 g, 0.8 mmol) was rapidly added. After three more nitrogen purgings, the reaction mixture was stirred at 90 °C for 24 hours. The reaction mixture was separated, and the aqueous phase was extracted with dichloromethane (40 mL × 3). The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 7-methylnaphthyl-1-phenol (NPL-50-A1, 750 mg, 58.8%), a white solid.

[0600] MS(ESI)m / z = 159.3 [M+H] +

[0601] 1 H NMR (400MHz, CDCl3) δ7.94(s,1H),7.72(d,J=8.4Hz,1H),7.40(d,J=8.2Hz,1H),7.33(d ,J=8.4Hz,1H),7.24(t,J=7.9Hz,1H),6.79(d,J=7.4Hz,1H),5.21(s,1H),2.54(s,3H).

[0602] Step 2: Synthesis of NPL-50-A2

[0603] 7-Methylnaphthyl-1-phenol (NPL-50-A1, 680 mg, 4.3 mmol) was dissolved in dichloromethane (40 mL), and N,N-diisopropylethylamine (2.3 mL, 12.9 mol) and trifluoromethanesulfonic anhydride (1.1 mL, 6.5 mmol) were added sequentially at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added to quench the reaction. The reaction mixture was separated, the aqueous phase was extracted with dichloromethane (40 mL × 3), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product 7-methylnaphthyl-1-yltrifluoromethanesulfonate (NPL-50-A2, 1.0 g, 80.2%), a yellow oily liquid.

[0604] 1 H NMR (400MHz, CDCl3) δ7.84-7.78(m,3H),7.47–7.37(m,3H),2.58(s,3H).

[0605] Step 3: Synthesis of NPL-50-A3

[0606] Under nitrogen protection, 7-methylnaphthyl-1-yltrifluoromethanesulfonate (NPL-50-A2, 1 g, 3.5 mmol) was dissolved in 1,4-dioxane (50 mL) and water (10 mL). Potassium carbonate (1.4 g, 10.3 mmol) and ethyl 3-(4,4,5,5-tetramethyl-[1,3,2]dioxoboron-2-yl)acrylate (1.6 g, 6.9 mmol) were then added sequentially. After three nitrogen purgings, 1,1-bis(diphenylphosphine)ferrocene palladium chloride (0.3 g, 0.4 mmol) was rapidly added, followed by three more nitrogen purgings. The reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain (E)-3-(7-methylnaphthyl-1-yl)ethyl acrylate (NPL-50-A3, 720 mg, 87.0%), a yellow oily liquid.

[0607] MS(ESI)m / z = 241.1[M+H] +

[0608] 1 H NMR (400MHz, CDCl3) δ8.53(d,J=15.7Hz,1H),7.96(s,1H),7.85(d,J=8.2Hz,1H),7.77(d,J=8.3Hz,1H),7.72(d,J=7.2Hz,1H),7.4 1(t,J=7.7Hz,1H),7.37(dd,J=8.4,1.2Hz,1H),6.52(d,J=15.7Hz,1H),4.33(q,J=7.1Hz,2H),2.57(s,3H),1.39(t,J=7.1Hz,3H).

[0609] Step 4: Synthesis of NPL-50-A4

[0610] Ethyl (E)-3-(7-methylnaphthyl-1-yl)acrylate (NPL-50-A3, 720 mg, 3.0 mmol) was dissolved in EtOH (15 mL), palladium on carbon (319 mg, 0.3 mmol) was added, and hydrogen was purged three times. The reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under vacuum to obtain ethyl 3-(7-methylnaphthyl-1-yl)propionate (NPL-50-A4, 720 mg, 99.2%), a yellow oily liquid.

[0611] MS(ESI)m / z = 243.1[M+H] +

[0612] 1 H NMR (400MHz, CDCl3) δ7.79 (s, 1H), 7.76 (d, J = 8.4Hz, 1H), 7.71–7.66 (m, 1H), 7.35–7.29 (m, 3H), 4.17(q,J=7.1Hz,2H),3.43–3.35(m,2H),2.78–2.73(m,2H),2.55(s,3H),1.25(t,J=7.1Hz,3H).

[0613] Step 5: Synthesis of NPL-50-A5

[0614] Ethyl 3-(7-methylnaphthyl-1-yl)propionate (NPL-50-A4, 720 mg, 3.0 mmol) was dissolved in tetrahydrofuran (8 mL) and water (8 mL), and lithium hydroxide (142 mg, 5.9 mmol) was added and the mixture was stirred for 4 hours. After the reaction was complete, 1 N hydrochloric acid (10 mL) was added to adjust the reaction solution to acidity, and a white solid precipitated. Filtering yielded 3-(7-methylnaphthyl-1-yl)propionic acid (NPL-50-A5, 500 mg, 78.5%), a white solid, which was used directly in the next step.

[0615] MS(ESI)m / z=213.2[MH] -

[0616] Step 6: Synthesis of NPL-50

[0617] 3-(7-methylnaphthyl-1-yl)propionic acid (NPL-50-A5, 100 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (213 mg, 0.6 mmol), N,N-diisopropylethylamine (0.2 mL, 1.4 mmol), and 4-aminophenol (61 mg, 0.6 mmol) and stirring overnight. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to give N-(4-hydroxyphenyl)-3-(7-methylnaphthyl-1-yl)propionamide (NPL-50, 38 mg, 26.7%), a white solid.

[0618] MS(ESI)m / z = 306.2[M+H] +

[0619] 1H NMR (400MHz, DMSO-d6) δ9.66(s,1H),9.14(s,1H),7.90(s,1H),7.82(d,J=8.3Hz,1H),7.72(dd,J=6.5,2.9Hz ,1H),7.36(ddd,J=6.6,4.5,2.4Hz,5H),6.70–6.66(m,2H),3.36(s,2H),2.68(t,J=7.7Hz,2H),2.52(s,3H).

[0620] The compounds in Table 6 below were prepared using the same methods as in the examples described above, either commercially available compounds or intermediate compounds prepared by reference.

[0621] Table 6

[0622] Synthesis of NPL-51

[0623] Step 1: Synthesis of NPL-51-A1

[0624] Ethyl (E)-3-(4-(tert-butyl)pyrimidin-5-yl)acrylate (NPL-58-A2, 1.3 g, 5.6 mmol) and palladium on carbon (0.6 g, 0.6 mmol) were dissolved in methanol (50 mL), and the mixture was stirred overnight at room temperature after purging with hydrogen. After the reaction was complete, the reaction solution was filtered, concentrated under vacuum to obtain a crude product, and then purified by silica gel column chromatography to obtain methyl 3-(4-(tert-butyl)pyrimidin-5-yl)propionate (NPL-51-A1, 1.0 g, 81.1%), a pale yellow solid.

[0625] MS(ESI)m / z = 223.1[M+H] +

[0626] 1 H NMR (400MHz, CDCl3) δ8.91(s,1H),8.37(s,1H),3.66(s,3H),3.12(dd,J=9.2,7.2Hz,2H),2.58(dd,J=9.2,7.2Hz,2H),1.38(s,9H).

[0627] Step 2: Synthesis of NPL-51-A2

[0628] Ethyl 3-(4-(tert-butyl)pyrimidin-5-yl)propionate (NPL-51-A1, 1.0 g, 4.5 mmol) was dissolved in methanol (20 mL) and water (10 mL). Lithium hydroxide (216 mg, 9.0 mmol) was added with stirring at room temperature, and the reaction was carried out at room temperature for 1.5 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 5 by adding 1 N hydrochloric acid solution. The reaction solution was then concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 3-(4-(tert-butyl)pyrimidin-5-yl)propionic acid (NPL-51-A2, 750 mg, yield 80.0%), a yellow solid.

[0629] MS(ESI)m / z = 209.1 [M+H] +

[0630] 1 H NMR (400MHz, DMSO-d6): δ8.92(s,1H),8.58(s,1H),3.14–3.01(m,2H),2.66–2.56(m,2H),1.38(s,9H).

[0631] Step 3: Synthesis of NPL-51

[0632] 3-(4-(tert-butyl)pyrimidin-5-yl)propionic acid (NPL-51-A2, 100 mg, 0.5 mmol), p-aminophenol (63 mg, 0.6 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (219 mg, 0.6 mmol) were dissolved in dichloromethane (12 mL). N,N-diisopropylethylamine (186 mg, 1.4 mmol) was added with stirring at room temperature, and the reaction was carried out for 3 hours at room temperature. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation to obtain the product 3-(4-(tert-butyl)pyrimidin-5-yl)-N-(4-hydroxyphenyl)propionamide (NPL-51, 40 mg, yield 27.8%), a brown solid.

[0633] MS(ESI)m / z = 300.1[M+H] +

[0634] 1 H NMR (400MHz, DMSO-d6): δ9.73(s,1H),9.17(brs,1H),8.92(s,1H),8.58(s,1H),7.35(d, J=8.8Hz,2H),6.68(d,J=8.8Hz,2H),3.17–3.10(m,2H),2.65–2.58(m,2H),1.41(s,9H).

[0635] The compounds in Table 7 below were prepared using the same methods as in the examples described above, either commercially available compounds or intermediate compounds prepared by reference.

[0636] Table 7

[0637] Synthesis of NPL-61

[0638] Step 1: Synthesis of NPL-61-A1

[0639] 2,3-Dibromopyridine (NPL-61-A0, 10 g, 42.2 mmol) and cuprous iodide (0.4 g, 2.1 mmol) were dissolved in anhydrous tetrahydrofuran (200 mL). After purging with nitrogen three times, tert-butylmagnesium chloride (37.2 mL, 1.7 M in THF, 63.3 mmol) was added dropwise at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated ammonium chloride, extracted with EA, and the organic phase was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography to give the product 3-bromo-2-tert-butylpyridine (NPL-61-A1, 600 mg, 6.6%), a yellow oily liquid.

[0640] MS(ESI)m / z = 214.0[M+H] +

[0641] 1 H NMR (400MHz, CDCl3) δ8.40(dd,J=4.5,1.6Hz,1H),7.77(dd,J=7.9,1.6Hz,1H),6.91(dd,J=7.9,4.5Hz,1H),1.47(s,9H).

[0642] Step 2: Synthesis of NPL-61-A2

[0643] Under nitrogen protection, 3-bromo-2-tert-butylpyridine (NPL-61-A1, 600 mg, 2.8 mmol) was dissolved in 1,4-dioxane (12 mL) and water (4 mL), followed by the sequential addition of potassium carbonate (1.1 g, 8.4 mmol), ethyl 3-(4,4,5,5-tetramethyl-[1,3,2]dioxborane-2-yl)acrylate (1.2 g, 5.6 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (0.2 g, 0.3 mmol). After three nitrogen purgings, the reaction mixture was stirred overnight at 80 °C. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain product (E)-3-(2-(tert-butyl)pyridine)acrylate (NPL-61-A2, 180 mg, 27.5%), a yellow oily liquid.

[0644] MS(ESI)m / z = 234.1[M+H] +

[0645] 1 H NMR (400MHz, CDCl3) δ8.51(dd,J=4.7,1.7Hz,1H),8.33(d,J=15.7Hz,1H),7.67(dd,J=7.7,1.7Hz,1H),7.1 4(dd,J=7.7,4.7Hz,1H),6.16(d,J=15.6Hz,1H),4.27(q,J=7.1Hz,2H),1.45(s,9H),1.34(t,J=7.1Hz,3H).

[0646] Step 3: Synthesis of NPL-61-A3

[0647] Ethyl (E)-3-(2-(tert-butyl)pyridine)acrylate (NPL-61-A2, 180 mg, 0.8 mmol) was dissolved in methanol (5 mL), and palladium on carbon catalyst (87.3 mg, 0.8 mmol) was added, followed by three purgings with hydrogen. The reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under vacuum to obtain ethyl 3-(2-(tert-butyl)pyridine)propionate (NPL-61-A3, 180 mg, 99.1%), a yellow oily liquid.

[0648] MS(ESI)m / z = 236.2[M+H] +

[0649] 1H NMR (400MHz, CDCl3) δ8.39 (dd, J=4.6, 1.7Hz, 1H), 7.44 (dd, J=7.7, 1.7Hz, 1H), 7.07 (dd, J=7.7, 4.6Hz, 1H) ,4.17(q,J=7.1Hz,2H),3.18(dd,J=9.3,7.2Hz,2H),2.63–2.58(m,2H),1.45(s,9H),1.28(d,J=7.1Hz,3H).

[0650] Step 4: Synthesis of NPL-61-A4

[0651] Ethyl 3-(2-(tert-butyl)pyridine)propionate (NPL-61-A3, 180 mg, 0.8 mmol) was dissolved in tetrahydrofuran (4 mL) and water (4 mL), and lithium hydroxide (39 mg, 1.6 mmol) was added and stirred for 4 hours. After the reaction was completed, 1 N hydrochloric acid (2 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product 3-(2-(tert-butyl)pyridine)propionic acid (NPL-61-A4, 160 mg, 94.9%), a yellow oily liquid.

[0652] MS(ESI)m / z = 208.2[M+H] +

[0653] Step 5: Synthesis of NPL-61

[0654] 3-(2-(tert-butyl)pyridine)propionic acid (NPL-61-A4, 160 mg, 0.7 mmol) was dissolved in dichloromethane (20 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (352 mg, 0.9 mmol), N,N-diisopropylethylamine (0.4 mL, 2.3 mmol), and 4-aminoacetanilide (139 mg, 0.9 mmol) and stirring at room temperature for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was separated by reverse phase to obtain product NPL-61 (52 mg, 22.6%), a white solid.

[0655] MS(ESI)m / z = 340.1[M+H] +

[0656] 1H NMR (400MHz, DMSO-d6) δ9.89(s,1H),9.85(s,1H),8.32(dd,J=4.6,1.8Hz,1H),7.61(dd,J=7.7,1.7Hz,1H),7.49(s, 4H), 7.18 (dd, J=7.7, 4.6Hz, 1H), 3.13 (dd, J=9.1, 6.9Hz, 2H), 2.61 (dd, J=9.2, 6.9Hz, 2H), 2.01 (s, 3H), 1.41 (s, 9H).

[0657] Synthesis of NPL-58

[0658] Step 1: Synthesis of NPL-58-A1

[0659] Cuprous iodide (1.7 g, 8.8 mmol) and 5-bromo-4-chloropyrimidine (NPL-58-A0, 17 g, 87.9 mmol) were dissolved in anhydrous tetrahydrofuran (500 mL) at room temperature. The mixture was purged with nitrogen, and tert-butylmagnesium chloride (103 mL, 1.7 M in THF, 175.8 mmol) was slowly added at 0 °C. After the addition was complete, the mixture was heated to room temperature and stirred overnight. Once the reaction was complete, a saturated ammonium chloride solution was added at 0 °C to quench the reaction. The mixture was separated, extracted twice with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. The crude product was then purified by silica gel column chromatography to obtain 5-bromo-4-tert-butylpyrimidine (NPL-58-A1, 2.4 g, yield 12.7%), a yellow oil.

[0660] MS(ESI)m / z = 215.0[M+H] +

[0661] 1 H NMR (400MHz, DMSO-d6) δ8.94(s,1H),8.66(s,1H),1.45(s,9H).

[0662] Step 2: Synthesis of NPL-58-A2

[0663] 5-Bromo-4-tert-butylpyrimidine (NPL-58-A1, 3.3 g, 15.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.1 g, 1.5 mmol), and potassium carbonate (6.4 g, 46.0 mmol) were dissolved in dioxane (80 mL) and water (16 mL). After purging with nitrogen three times, 2-(ethoxycarbonyl)vinylacetic acid dimethyl butylene glycol ester (3.5 g, 15.3 mmol) was rapidly added. The mixture was stirred at 80 °C for 3 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to a higher temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product (E)-3-(4-(tert-butyl)pyrimidin-5-yl)ethyl acrylate (NPL-58-A2, 2.3 g, yield 64.0%), a yellow oil.

[0664] MS(ESI)m / z = 235.1[M+H] +

[0665] 1 H NMR (400MHz, CDCl3): δ9.09 (s, 1H), 8.61 (s, 1H), 8.18 (d, J = 15.8Hz, 1H), 6.22 (d,J=15.8Hz,1H),4.30(q,J=7.1Hz,2H),1.44(s,9H),1.36(t,J=7.1Hz,3H).

[0666] Step 3: Synthesis of NPL-58-A3

[0667] Ethyl (E)-3-(4-(tert-butyl)pyrimidin-5-yl)acrylate (NPL-58-A2, 900 mg, 3.8 mmol) was dissolved in methanol (20 mL) and water (10 mL). Lithium hydroxide (184 mg, 7.7 mmol) was added with stirring at room temperature, and the reaction was carried out for 1.5 hours at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 5 by adding 1 N hydrochloric acid solution. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product (E)-3-(4-(tert-butyl)pyrimidin-5-yl)acrylate (NPL-58-A3, 0.7 g, yield 85.2%), a white solid.

[0668] MS(ESI)m / z = 207.1[M+H] +

[0669] 1 H NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 8.82 (s, 1H), 8.02 (d, J = 15.8Hz, 1H), 6.41 (d, J = 15.7Hz, 1H), 1.38 (s, 9H).

[0670] Step 4: Synthesis of NPL-58

[0671] (E)-3-(4-(tert-butyl)pyrimidin-5-yl)acrylic acid (NPL-58-A3, 170 mg, 0.8 mmol), 4-aminophenol (108 mg, 1.0 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (376 mg, 1.0 mmol) were dissolved in dichloromethane (12 mL). N,N-diisopropylethylamine (320 mg, 2.5 mmol) was added with stirring at room temperature, and the reaction was carried out for 3 hours at room temperature. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation to obtain the product 3-(4-(tert-butyl)pyrimidin-5-yl)-N-(4-hydroxyphenyl)acrylamide (NPL-58, 45 mg, yield 18.4%), a yellow solid.

[0672] MS(ESI)m / z = 298.1 [M+H] +

[0673] 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),9.27(s,1H),9.09(s,1H),8.73(s,1H),7.97(d,J= 15.4Hz,1H),7.52–7.47(m,2H),6.75–6.71(m,2H),6.58(d,J=15.4Hz,1H),1.40(s,9H).

[0674] The compounds in Table 8 below were prepared using the same methods as in the examples described above, either commercially available compounds or intermediate compounds prepared by reference.

[0675] Table 8

[0676] Synthesis of NPL-59

[0677] Step 1: Synthesis of NPL-59-A1

[0678] Under nitrogen protection, 1-bromo-2-(tert-butyl)benzene (NPL-59-A0, 2.0 g, 9.4 mmol) was dissolved in 1,4-dioxane (36 mL) and water (12 mL). Potassium carbonate (3.9 g, 28.1 mmol) and ethyl 3-(4,4,5,5-tetramethyl-[1,3,2]dioxoboron-2-yl)acrylate (4.2 g, 18.8 mmol) were then added sequentially. After three nitrogen purgings, 1,1-bis(diphenylphosphine)ferrocene palladium chloride (0.7 g, 0.9 mmol) was rapidly added. After three more nitrogen purgings, the reaction mixture was stirred overnight at 80 °C. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(2-(tert-butyl)phenyl)acrylate (NPL-59-A1, 1.3 g, yield 59.6%), a yellow oily liquid.

[0679] MS(ESI)m / z = 233.3[M+H] +

[0680] 1 H NMR(400MHz, CDCl3)δ8.45(d,J=15.6Hz,1H),7.47–7.39(m,2H),7.31(t,J=7.8,1H),7.21(t,J =7.4Hz, 1H), 6.16 (d, J = 15.6Hz, 1H), 4.27 (q, J = 7.1Hz, 2H), 1.44 (s, 9H), 1.35 (t, J = 7.1Hz, 3H).

[0681] Step 2: Synthesis of NPL-59-A2

[0682] Ethyl (E)-3-(2-(tert-butyl)phenyl)acrylate (NPL-59-A1, 600 mg, 2.58 mmol) was dissolved in isopropanol (50 mL), and palladium on carbon (275 mg, 0.3 mmol) and rhodium-diene dimer of norbornene (12 mg, 0.03 mmol) were added, followed by three purgings with hydrogen. The reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under vacuum to give ethyl 3-(2-(tert-butyl)cyclohexyl)propionate (NPL-59-A2, 610 mg, yield 98.3%), a yellow oily liquid.

[0683] Step 3: Synthesis of NPL-59-A3

[0684] Ethyl 3-(2-(tert-butyl)cyclohexyl)propionate (NPL-59-A2, 1.3 g, 5.5 mmol) was dissolved in tetrahydrofuran (15 mL) and water (15 mL), and lithium hydroxide (0.3 g, 10.9 mmol) was added and the mixture was stirred for 4 hours. After the reaction was completed, 1N hydrochloric acid (10 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain crude 3-(2-(tert-butyl)cyclohexyl)propionic acid (NPL-59-A3, 1.1 g, yield 94.3%), a yellow oily liquid, which was used directly in the next step.

[0685] MS(ESI)m / z=211.2[MH] -

[0686] Step 4: Synthesis of NPL-59

[0687] 3-(2-(tert-butyl)cyclohexyl)propionic acid (NPL-59-A3, 500 mg, 2.4 mmol) was dissolved in dichloromethane (20 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.1 g, 2.8 mmol), N,N-diisopropylethylamine (1.2 mL, 7.1 mmol), and 4-aminophenol (308 mg, 2.8 mmol) and stirring overnight. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was subjected to reverse phase separation to obtain product NPL-59 (253 mg, yield 35.4%), a white solid.

[0688] MS(ESI)m / z = 304.2[M+H] +

[0689] 1 H NMR(400MHz,DMSO-d6)δ9.60(s,1H),7.37–7.32(m,2H),6.69–6.64(m,2H),2.32–2.23(m,1H),2.17–2.08(m,1H) ),1.91–1.73(m,4H),1.68–1.58(m,1H),1.50–1.44(m,1H),1.41–1.30(m,2H),1.27–1.16(m,4H),0.89(s,9H).

[0690] Synthesis of NPL-60

[0691] Step 1: Synthesis of NPL-60-A1

[0692] 3-tert-butyl-1,2-dihydropyrazin-2-one (NPL-34-A3, 1.8 g, 11.8 mmol) was dissolved in dichloromethane (50 mL), and N,N-diisopropylethylamine (6.2 mL, 35.5 mmol) and trifluoromethanesulfonic anhydride (3.0 mL, 17.7 mmol) were added sequentially at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added to quench the reaction. The reaction mixture was separated, the aqueous phase was extracted with dichloromethane (40 mL × 3), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product 3-(tert-butyl)pyrazin-2-yltrifluoromethanesulfonate (NPL-60-A1, 2.1 g, yield 62.5%), a yellow oily liquid.

[0693] 1 H NMR (400MHz, CDCl3) δ8.54 (d, J = 2.4Hz, 1H), 8.16 (d, J = 2.4Hz, 1H), 1.45 (s, 9H).

[0694] Step 2: Synthesis of NPL-60-A2

[0695] Under nitrogen protection, 3-(tert-butyl)pyrazin-2-yltrifluoromethanesulfonate (NPL-60-A1, 2.1 g, 7.4 mmol) was dissolved in 1,4-dioxane (27 mL) and water (9 mL). Potassium carbonate (3.1 g, 22.2 mmol) and ethyl 3-(4,4,5,5-tetramethyl-[1,3,2]dioxoboron-2-yl)acrylate (3.3 g, 14.8 mmol) were added sequentially. After three nitrogen purgings, 1,1-bis(diphenylphosphine)ferrocene palladium chloride (0.5 g, 0.7 mmol) was rapidly added, followed by three more nitrogen purgings. The reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain (E)-3-(3-(tert-butyl)pyrazin-2-yl)ethyl acrylate (NPL-60-A2, 0.8 g, yield 46.2%), a yellow oily liquid.

[0696] MS(ESI)m / z = 235.2[M+H] +

[0697] 1H NMR (400MHz, CDCl3) δ8.44(d,J=2.2Hz,1H),8.41(d,J=2.2Hz,1H),8.24(d,J=15.1Hz, 1H), 6.97 (d, J = 15.1Hz, 1H), 4.29 (q, J = 7.1Hz, 2H), 1.49 (s, 9H), 1.35 (t, J = 5.9Hz, 3H).

[0698] Step 3: Synthesis of NPL-60-A3

[0699] Ethyl (E)-3-(3-(tert-butyl)pyrazin-2-yl)acrylate (NPL-60-A2, 0.8 g, 3.4 mmol) was dissolved in tetrahydrofuran (12 mL) and water (12 mL), and lithium hydroxide (163 mg, 6.8 mmol) was added and stirred for 4 hours. After the reaction was completed, 1 N hydrochloric acid (10 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(3-(tert-butyl)pyrazin-2-yl)acrylic acid (NPL-60-A3, 0.5 g, yield 78.5%), a white solid.

[0700] MS(ESI)m / z = 207.2[M+H] +

[0701] 1 H NMR (400MHz, CDCl3) δ8.47(d,J=2.3Hz,1H),8.45(d,J=2.3Hz,1H),8.34(d,J=15.1Hz,1H),7.00(d,J=15.1Hz,1H),1.50(s,9H).

[0702] Step 4: Synthesis of NPL-60

[0703] (E)-3-(3-(tert-butyl)pyrazin-2-yl)acrylic acid (NPL-60-A3, 120 mg, 0.6 mmol) was dissolved in dichloromethane (5 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (265 mg, 0.7 mmol), N,N-diisopropylethylamine (0.3 mL, 1.8 mmol), and 4-aminophenol (76 mg, 0.7 mmol) and stirring for 3 hours. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was subjected to reverse phase separation to obtain the product (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-hydroxyphenyl)acrylamide (NPL-60, 36 mg, yield 20.8%), a yellow solid.

[0704] MS(ESI)m / z = 298.1 [M+H] +

[0705] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.27(s,1H),8.55(q,J=2.3Hz,2H),8.06(d,J=1 4.7Hz,1H),7.57–7.44(m,2H),7.31(d,J=14.7Hz,1H),6.78–6.69(m,2H),1.46(s,9H).

[0706] The compounds in Table 9 below were prepared using the same methods as in the examples described above, either commercially available compounds or intermediate compounds prepared by reference.

[0707] Table 9

[0708] Synthesis of NPL-62

[0709] Step 1: Synthesis of NPL-62-A1

[0710] Cuprous iodide (0.3 g, 1.4 mmol) and 4-chloro-5-methoxypyrimidine (NPL-62-A0, 4 g, 27.7 mmol) were dissolved in anhydrous tetrahydrofuran (100 mL) at room temperature. The mixture was purged with nitrogen three times. Tert-butylmagnesium chloride (42 mL, 41.5 mmol, 1 M in THF) was slowly added at 0 °C. After the addition was complete, the mixture was heated to room temperature and stirred overnight. After the reaction was complete, a saturated ammonium chloride solution was added at 0 °C to quench the reaction. The mixture was separated, extracted twice with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography to obtain 5-methoxy-4-tert-butylpyrimidine (NPL-62-A1, 720 mg, yield 15.6%), a yellow oil.

[0711] MS(ESI)m / z = 167.1 [M+H] +

[0712] 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),8.30(s,1H),3.87(s,3H),1.32(s,9H).

[0713] Step 2: Synthesis of NPL-62-A2

[0714] 5-Methoxy-4-tert-butylpyrimidine (NPL-62-A1, 550 mg, 3.3 mmol) was dissolved in hydrobromic acid-acetic acid solution (8 mL), sealed in a tube, and stirred overnight at 100 °C. After the reaction was complete, the mixture was cooled to room temperature, and the pH of the reaction solution was adjusted to 5 by adding saturated sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the product 5-hydroxy-4-tert-butylpyrimidine (NPL-62-A2, 350 mg, yield 69.5%) was purified by silica gel column chromatography as a white solid.

[0715] MS(ESI)m / z = 153.1 [M+H] +

[0716] 1 H NMR (400MHz, DMSO-d6): δ8.64(s,1H),8.11(s,1H),1.39(s,9H).

[0717] Step 3: Synthesis of NPL-62-A3

[0718] 5-Hydroxy-4-tert-butylpyrimidine (NPL-62-A2, 350 mg, 2.30 mmol), potassium carbonate (953 mg, 6.9 mmol), and methyl bromoacetate (0.7 mL, 4.6 mmol) were dissolved in acetone (20 mL) and reacted at 50 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain methyl 2-((4-(tert-butyl)pyrimidin-5-yl)oxy)acetate (NPL-62-A3, 270 mg, yield 52.4%), a yellow oil.

[0719] MS(ESI)m / z = 225.0[M+H] +

[0720] 1 H NMR (400MHz, DMSO-d6): δ8.73(s,1H),8.05(s,1H),4.69(s,2H),3.77(s,3H),1.38(s,9H).

[0721] Step 4: Synthesis of NPL-62-A4

[0722] Methyl 2-((4-(tert-butyl)pyrimidin-5-yl)oxy)acetate (NPL-62-A3, 270 mg, 1.2 mmol) was dissolved in methanol (6 mL) and water (3 mL). Lithium hydroxide (58 mg, 2.4 mmol) was added with stirring at room temperature, and the reaction was carried out at room temperature for 1.5 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 5 by adding 1 N hydrochloric acid solution. After concentration under reduced pressure, the product 2-((4-(tert-butyl)pyrimidin-5-yl)oxy)acetic acid (NPL-62-A4, 240 mg, yield 94.8%) was purified by silica gel column chromatography to obtain the product 2-((4-(tert-butyl)pyrimidin-5-yl)oxy)acetic acid (NPL-62-A4, 240 mg, yield 94.8%), a yellow solid.

[0723] MS(ESI)m / z = 211.1[M+H] +

[0724] 1 H NMR (400MHz, DMSO-d6): δ8.68(s,1H),8.34(s,1H),4.84(s,2H),3.17(s,1H),1.38(s,9H).

[0725] Step 5: Synthesis of NPL-62

[0726] 2-((4-(tert-butyl)pyrimidin-5-yl)oxy)acetic acid (NPL-62-A4, 80 mg, 0.4 mmol), 4-methanesulfonamide aniline (85 mg, 0.5 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (174 mg, 0.5 mmol) were dissolved in DMF (5 mL). N,N-diisopropylethylamine (148 mg, 1.1 mmol) was added with stirring at room temperature, and the reaction was carried out for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation to obtain the product 2-((4-(tert-butyl)pyrimidin-5-yl)oxy)-N-(4-(methanesulfonamide)phenyl)acetamide (NPL-62, 55 mg, yield 38.2%), a pale yellow solid.

[0727] MS(ESI)m / z = 379.2 [M+H] +

[0728] 1 H NMR (400MHz, DMSO-d6): δ10.25(s,1H),9.58(s,1H),8.71(s,1H),8.39(s,1H),7 .56(d,J=8.9Hz,2H),7.20–7.15(m,2H),4.94(s,2H),2.93(s,3H),1.40(s,9H).

[0729] The compounds in Table 10 below were prepared using the same methods as in the examples described above, either commercially available compounds or intermediate compounds prepared by reference.

[0730] Table 10

[0731] Synthesis of NPL-67

[0732] Step 1: Synthesis of NPL-67

[0733] (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-(methylsulfonamido)phenyl)acrylamide (NPL-65, 30 mg, 0.1 mmol) was dissolved in methanol (3 mL), and palladium on carbon catalyst (10 mg, 0.01 mmol) was added, followed by three purgings with hydrogen. The reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse phase separation to obtain the product N-(4-acetamidophenyl)-3-(3-(tert-butyl)pyrazin-2-yl)propionamide (NPL-67, 28 mg, 92.8%), a white solid.

[0734] MS(ESI)m / z = 341.3[M+H] +

[0735] 1 H NMR (400MHz, DMSO-d6): δ9.93(s,1H),9.83(s,1H),8.38(dd,J=9.9,2.4Hz,2H),7.50 –7.44(m,4H),3.27(d,J=7.7Hz,2H),2.83(t,J=7.4Hz,2H),2.00(s,3H),1.44(s,9H).

[0736] Synthesis of NPL-69

[0737] Step 1: Synthesis of NPL-69-A1

[0738] 3-(tert-butyl)pyrazin-2(1H)-one (NPL-69-A0, 2.5 g, 16.4 mmol) was dissolved in N,N-dimethylformamide (60 mL), followed by the sequential addition of potassium carbonate (4.5 g, 32.9 mmol) and methyl bromoacetate (7.9 mL, 49.3 mmol). The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solution was diluted with water (30 mL) and ethyl acetate (40 mL). The mixture was separated, and the organic phase was washed with water (30 mL × 3) and saturated brine (50 mL × 3). After drying with anhydrous sodium sulfate, the solution was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product methyl 2-((3-(tert-butyl)pyrazin-2-yl)oxy)acetate (NPL-69-A1, 250 mg, yield 6.8%), a colorless oily liquid.

[0739] MS(ESI)m / z = 225.1[M+H] +

[0740] 1 H NMR (400MHz, CDCl3) δ8.08 (d, J = 2.7Hz, 1H), 7.87 (d, J = 2.7Hz, 1H), 4.97 (s, 2H), 3.76 (s, 3H), 1.44 (s, 9H).

[0741] Step 2: Synthesis of NPL-69-A2

[0742] Methyl 2-((3-(tert-butyl)pyrazin-2-yl)oxy)acetate (NPL-69-A1, 250 mg, 1.1 mmol) was dissolved in tetrahydrofuran (6 mL) and water (6 mL), and lithium hydroxide (53 mg, 2.2 mmol) was added and stirred for 4 hours. After the reaction was completed, 1 N hydrochloric acid (5 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to give the product 2-((3-(tert-butyl)pyrazin-2-yl)oxy)acetic acid (NPL-69-A2, 230 mg, yield 98.1%), a white solid, which was directly used in the next step.

[0743] MS(ESI)m / z = 211.2[M+H] +

[0744] Step 3: Synthesis of NPL-69

[0745] 2-((3-(tert-butyl)pyrazin-2-yl)oxy)acetic acid (NPL-69-A2, 50 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (109 mg, 0.3 mmol), N,N-diisopropylethylamine (92 mg, 0.7 mmol), and 4-methanesulfonamide aniline (61 mg, 0.6 mmol) and stirring overnight. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to reverse phase separation to obtain the product 2-((3-(tert-butyl)pyrazin-2-yl)oxy)-N-(4-(methanesulfonamide)phenyl)acetamide (NPL-69, 35 mg, yield 38.9%), a yellow solid.

[0746] MS(ESI)m / z = 379.2 [M+H] +

[0747] 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),9.54(s,1H),8.12(d,J=2.7Hz,1H),8.00(d,J=2.7 Hz,1H),7.53(d,J=8.9Hz,2H),7.17–7.13(m,2H),5.05(s,2H),2.92(s,3H),1.41(s,9H).

[0748] The compounds in Table 11 below were prepared using the same method as in the examples described above, either commercially available compounds or intermediate compounds prepared by the method shown.

[0749] Table 11

[0750] NPL-70 Synthesis

[0751] 2-((3-(tert-butyl)pyrazin-2-yl)oxy)acetic acid (NPL-69-A2, 50 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (109 mg, 0.3 mmol), N,N-diisopropylethylamine (92 mg, 0.7 mmol), and 4-acetamidoaniline (43 mg, 0.3 mmol) and stirring overnight. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to reverse-phase separation to obtain the product N-(4-acetamidophenyl)-2-((3-(tert-butyl)pyrazin-2-yl)oxy)acetamide (NPL-70, 23 mg, 28.2%), a white solid.

[0752] MS(ESI)m / z = 343.2[M+H] +

[0753] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),9.86(s,1H),8.12(d,J=2.7Hz,1H),8.01(d,J=2.7Hz,1H),7.49(s,4H),5.04(s,2H),2.01(s,3H),1.41(s,9H).

[0754] Synthesis of NPL-71

[0755] 2-((3-(tert-butyl)pyrazin-2-yl)oxy)acetic acid (NPL-69-A2, 120 mg, 0.6 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (260 mg, 0.7 mmol), N,N-diisopropylethylamine (221 mg, 1.7 mmol), and 6-aminobenzo[d]oxazol-2(3H)-one (103 mg, 0.7 mmol) and stirring overnight. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by reverse phase to obtain the product 2-((3-(tert-butyl)pyrazin-2-yl)oxy)-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetamide (NPL-71, 15 mg, 7.7%), a yellow solid.

[0756] MS(ESI)m / z = 343.2[M+H] +

[0757] 1H NMR (400MHz, DMSO-d6) δ11.54(s,1H),10.28(s,1H),8.13(d,J=2.5Hz,1H),8.01(d,J=2.5H z,1H),7.65(s,1H),7.23(d,J=8.6Hz,1H),7.03(d,J=8.4Hz,1H),5.06(s,2H),1.41(s,9H).

[0758] Synthesis of NPL-74

[0759] (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-hydroxyphenyl)acrylamide (NPL-60, 60 mg, 0.2 mmol) was dissolved in methanol (4 mL), and palladium on carbon catalyst (21 mg, 0.02 mmol) was added, followed by three purgings with hydrogen. The reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse phase separation to obtain the product 3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-hydroxyphenyl)propionamide (NPL-74, 13 mg, 21.5%), an orange solid.

[0760] MS(ESI)m / z = 300.3[M+H] +

[0761] 1 H NMR (400MHz, DMSO-d6) δ9.73(s,1H),9.10(s,1H),8.40(d,J=2.4Hz,1H),8.37(d,J=2.4Hz,1H),7 .37–7.33(m,2H),6.68–6.64(m,2H),3.30–3.25(m,2H),2.79(dd,J=8.2,6.7Hz,2H),1.43(s,9H).

[0762] Synthesis of NPL-76

[0763] (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acrylamide (NPL-68, 30 mg, 0.1 mmol) was dissolved in methanol (4 mL), and palladium on carbon catalyst (9 mg, 0.01 mmol) was added, followed by three purgings with hydrogen. The reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse phase separation to obtain 3-(3-(tert-butyl)pyrazin-2-yl)-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)propionamide (NPL-76, 14 mg, 46.4%), a white solid.

[0764] MS(ESI)m / z = 341.3[M+H] +

[0765] 1 H NMR (400MHz, DMSO-d6) δ11.49(s,1H),10.07(s,1H),8.38(dd,J=8.5,2.3Hz,2H),7.68(d,J=1.7Hz,1H),7. 22(dd,J=8.4,1.8Hz,1H),7.00(d,J=8.4Hz,1H),3.29(t,J=7.5Hz,2H),2.85(t,J=7.4Hz,2H),1.44(s,9H).

[0766] Synthesis of NPL-79

[0767] Step 1: Synthesis of NPL-79-A1

[0768] 5-Bromo-4-methoxypyrimidine (NPL-79-A0, 9.5 g, 50.3 mmol), nickel acetylacetonate (0.7 g, 2.5 mmol), lithium chloride (7.5 g, 175.9 mmol), magnesium chloride (4.8 g, 50.3 mmol), and zinc powder (6.5 g, 100.5 mmol) were dissolved in anhydrous N,N-dimethylacetamide (200 mL) at room temperature. After purging with nitrogen three times, 4-methoxypyridine (5.5 g, 50.3 mmol) and tert-butane bromide (10.3 g, 75.4 mmol) were added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was complete, water was added to quench the reaction, and the mixture was separated and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 5-tert-butyl-4-methoxypyrimidine (NPL-79-A1, 1.2 g, 7.2 mmol, 14.4%), a colorless oil.

[0769] MS(ESI)m / z = 167.1 [M+H]+

[0770] 1 H NMR (400MHz, CDCl3): δ8.62(s,1H),8.34(s,1H),4.01(s,3H),1.35(s,9H).

[0771] Step 2: Synthesis of NPL-79-A2

[0772] 5-tert-butyl-4-methoxypyrimidine (NPL-79-A1, 1.2 g, 7.2 mmol) was dissolved in a hydrobromic acid-acetic acid solution (20 mL), sealed in a tube, and stirred overnight at 100 °C. After the reaction was complete, the solution was cooled to room temperature and concentrated under reduced pressure to obtain 5-tert-butyl-4-hydroxypyrimidine (NPL-79-A2, 1.1 g, 97.8%), a yellow oil.

[0773] MS(ESI)m / z = 153.1 [M+H] +

[0774] 1 H NMR (400MHz, CDCl3): δ9.01(s,1H),7.81(s,1H),1.28(s,9H).

[0775] Step 3: Synthesis of NPL-79-A3

[0776] 5-tert-butyl-4-hydroxypyrimidine (NPL-79-A2, 1.1 g, 7.1 mmol) was dissolved in acetonitrile (25 mL), and phosphorus oxychloride (10 mL) was added at room temperature. The reaction mixture was stirred overnight in an oil bath at 80 °C. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain 5-tert-butyl-4-chloropyrimidine (NPL-79-A3, 1.2 g, 99.3%), a yellow oil.

[0777] MS(ESI)m / z = 171.0 [M+H] +

[0778] Step 4: Synthesis of NPL-79-A4

[0779] 5-tert-butyl-4-chloropyrimidine (NPL-79-A3, 1.0 g, 5.9 mmol) and methyl glycolate (0.8 g, 8.8 mmol) were dissolved in N,N-dimethylformamide (15 mL). After purging with nitrogen three times, sodium hydride (0.3 g, 7.0 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phase was washed with water. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2-((5-(tert-butyl)pyrimidin-4-yl)oxy)acetate (NPL-79-A4, 500 mg, 38.0%), a yellow oil.

[0780] Step 5: Synthesis of NPL-79-A5

[0781] Crude methyl 2-((5-(tert-butyl)pyrimidin-4-yl)oxy)acetic acid (NPL-79-A4, 500 mg, 2.2 mmol) was dissolved in methanol (8 mL) and water (4 mL). Lithium hydroxide (184 mg, 7.7 mmol) was added with stirring at room temperature, and the reaction was carried out for 1.5 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 5 by adding 1 N hydrochloric acid solution. After concentration under reduced pressure, the product 2-((5-(tert-butyl)pyrimidin-4-yl)oxy)acetic acid (NPL-79-A5, 150 mg, 32.00%) was purified by silica gel column chromatography to obtain the product 2-((5-(tert-butyl)pyrimidin-4-yl)oxy)acetic acid (NPL-79-A5, 150 mg, 32.00%), a yellow solid.

[0782] MS(ESI)m / z = 211.1[M+H] +

[0783] Step 6: Synthesis of NPL-79

[0784] 2-((5-(tert-butyl)pyrimidin-4-yl)oxy)acetic acid (NPL-79-A5, 50 mg, 0.2 mmol), 4-acetamidoaniline (60 mg, 0.4 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (108 mg, 0.3 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (61 mg, 0.5 mmol) was added with stirring at room temperature and the reaction was carried out for 3 hours. After the reaction was completed, the mixture was filtered, and the filtrate was purified by reverse phase separation (Triart C18, 250*20.0mm.D., S-5um, 12nm, eluent: 20%-95% acetonitrile / water (0.1% sodium bicarbonate)) to give the product 2-((5-(tert-butyl)pyrimidin-4-yl)oxy)-N-(4-(acetamido)phenyl)acetamide (NPL-79, 33mg, 40.5%), a white solid.

[0785] MS(ESI)m / z = 343.1 [M+H]+

[0786] 1 H NMR (400MHz, DMSO-d6): δ10.17(s,1H),9.86(s,1H),8.60(s,1H),8.43(s,1H),7.49(s,4H),5.09(s,2H),2.01(s,3H),1.39(s,9H).

[0787] NPL-80 Synthesis

[0788] Step 1: Synthesis of NPL-80-A1

[0789] 2-tert-butyl-3-hydroxypyridine (NPL-80-A0, 200 mg, 1.3 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (0.7 mL, 4.0 mmol) and trifluoromethanesulfonic anhydride (0.4 mL, 2.0 mmol) were added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, H2O was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography to give 2-tert-butylpyridine-3-yltrifluoromethanesulfonate (NPL-80-A1, 250 mg, yield 66.7%), a pale yellow oil.

[0790] MS(ESI)m / z = 284.0 [M+H] +

[0791] 1 H NMR (400MHz, DMSO-d6) δ8.62(dd,J=4.5,1.2Hz,1H),7.82(dd,J=8.4,1.2Hz,1H),7.52(dd,J=8.4,4.5Hz,1H),1.41(s,9H).

[0792] Step 2: Synthesis of NPL-80-A2

[0793] 2-tert-butylpyridin-3-yltrifluoromethanesulfonate (NPL-80-A1, 230 mg, 0.8 mmol) and methyl mercaptoacetate (129 mg, 1.2 mmol) were dissolved in 1,4-dioxane (2 mL), followed by the sequential addition of N,N-diisopropylethylamine (315 mg, 2.4 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (47 mg, 0.08 mmol), and tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol). The reaction mixture was purged with nitrogen three times, and then microwaved at 110 °C for 1 hour. After cooling to room temperature, the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: 0%-20% petroleum ether / ethyl acetate) to give methyl 2-((2-(tert-butyl)pyridin-3-yl)thio)acetate (NPL-80-A2, 130 mg, yield 67.0%), a yellow oil.

[0794] MS(ESI)m / z = 240.1[M+H] +

[0795] 1 H NMR (400MHz, CDCl3) δ8.32(dd,J=4.6,1.6Hz,1H),7.65(dd,J=7.9,1.6Hz,1H),7.03(dd,J=7.9,4.6Hz,1H),3.64(s,3H),3.59(s,2H),1.45(s,9H).

[0796] Step 3: Synthesis of NPL-80-A3

[0797] Methyl 2-((2-(tert-butyl)pyridin-3-yl)thio)acetate (NPL-80-A2, 124 mg, 0.5 mmol) was dissolved in methanol (3 mL) and water (1 mL), followed by the addition of LiOH (65 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with 1 N hydrochloric acid, and the reaction mixture was concentrated to dryness under reduced pressure to give 2-((2-(tert-butyl)pyridin-3-yl)thio)acetic acid (NPL-80-A3, 116 mg, 99% yield), a yellow oil.

[0798] MS(ESI)m / z = 225.9[M+H] +

[0799] Step 4: Synthesis of NPL-80

[0800] 2-((2-(tert-butyl)pyridin-3-yl)thio)acetic acid (NPL-80-A3, 116 mg, 0.5 mmol) and 4-aminophenol (84 mg, 0.8 mmol) were dissolved in dichloromethane (5.0 mL). N,N-diisopropylethylamine (250 mg, 1.9 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (367 mg, 1.0 mmol) were added sequentially at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent in the reaction system was removed by concentration under reduced pressure. The crude product was then purified by reverse-phase reaction to obtain 2-((2-(tert-butyl)pyridin-3-yl)mercapto)-N-(4-hydroxy)acetamide (NPL-80, 35 mg, yield 17.2%), a white powder.

[0801] MS(ESI)m / z = 316.9[M+H] +

[0802] 1 H NMR (400MHz, DMSO-d6) δ9.97(s,1H),9.22(s,1H),8.30(dd,J=4.6,1.6Hz,1H),7.89(dd,J=8.0,1.6H z,1H),7.33–7.27(m,2H),7.22(dd,J=7.9,4.6Hz,1H),6.73–6.63(m,2H),3.84(s,2H),1.46(s,9H).

[0803] Synthesis of NPL-81

[0804] Step 1: Synthesis of NPL-81-A1

[0805] Nickel acetylacetonate (0.4 g, 1.5 mmol), magnesium chloride (2.9 g, 30 mmol), zinc powder (3.9 g, 60 mmol), and lithium chloride (4.5 g, 105 mmol) were dissolved in anhydrous N,N-dimethylacetamide (120 mL). Then, 3-amino-4-bromopyridine (NPL-81-A0, 5.2 g, 30 mmol), 4-methoxypyridine (6.2 g, 30 mmol), and tert-butane bromide (4.9 mL, 45 mmol) were added sequentially, followed by nitrogen purging three times. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography to give 3-amino-4-tert-butylpyridine (NPL-81-A1, 2.5 g, 55.5%), a yellow oily liquid.

[0806] MS(ESI)m / z = 151.1[M+H] +

[0807] Step 2: Synthesis of NPL-81-A2

[0808] 3-Amino-4-tert-butylpyridine (NPL-81-A1, 1.0 g, 6.7 mmol) was dissolved in acetonitrile (30 mL), and sodium nitrite (2.3 g, 33.3 mmol) and concentrated hydrochloric acid (0.6 mL) were added sequentially at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Subsequently, copper bromide (7.4 g, 33.3 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography to obtain 3-bromo-4-tert-butylpyridine (NPL-81-A2, 420 mg, 29.5%), a yellow oily liquid.

[0809] MS(ESI)m / z = 214.0[M+H] +

[0810] Step 3: Synthesis of NPL-81-A3

[0811] Under nitrogen protection, 3-bromo-4-tert-butylpyridine (NPL-81-A2, 440 mg, 2.1 mmol) was dissolved in 1,4-dioxane (15 mL) and water (5 mL). Then, ethyl 3-(4,4,5,5-tetramethyl-[1,3,2]dioxoboron-2-yl)acrylate (0.9 mL, 4.1 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (150 mg, 0.2 mmol), and potassium carbonate (852 mg, 6.2 mmol) were added sequentially. After three nitrogen purgings, the reaction mixture was stirred overnight at 80 °C. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(4-tert-butylpyridine)acrylate (NPL-81-A3, 250 mg, 52.1%), a yellow oily liquid.

[0812] MS(ESI)m / z = 234.1[M+H] +

[0813] 1 H NMR (400MHz, CDCl3) δ8.54(s,1H),8.49(d,J=5.4Hz,1H),8.28(d,J=15.7Hz,1H),7.29(d,J=5.4 Hz,1H),6.21(d,J=15.7Hz,1H),4.29(dt,J=7.1,3.6Hz,2H),1.41(s,9H),1.35(t,J=7.1Hz,3H).

[0814] Step 4: Synthesis of NPL-81-A4

[0815] Ethyl (E)-3-(4-tert-butylpyridine)acrylate (NPL-81-A3, 250 mg, 1.1 mmol) was dissolved in methanol (5 mL), palladium on carbon (114 mg, 1.1 mmol) was added, and hydrogen was purged three times. The reaction mixture was stirred overnight under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under vacuum to obtain ethyl 3-(4-tert-butylpyridine)propionate (NPL-81-A4, 250 mg, 99.1%), a yellow oily liquid.

[0816] MS(ESI)m / z = 236.1[M+H] +

[0817] Step 5: Synthesis of NPL-81-A5

[0818] Ethyl 3-(4-tert-butylpyridine)propionate (NPL-81-A4, 250 mg, 1.1 mmol) was dissolved in tetrahydrofuran (8 mL) and water (2 mL), and lithium hydroxide (51 mg, 2.1 mmol) was added and stirred for 4 hours. After the reaction was completed, 1 N hydrochloric acid (4 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product 3-(4-tert-butylpyridine)propionic acid (NPL-81-A5, 130 mg, 59.0%), a yellow oil.

[0819] MS(ESI)m / z = 208.1[M+H] +

[0820] 1 H NMR (400MHz, CD3OD) δ8.38(s,1H),8.29(d,J=5.3Hz,1H),7.43(d,J=5.5Hz,1H),3.30–3.20(m,2H),2.68–2.62(m,2H),1.47(s,9H).

[0821] Step 6: Synthesis of NPL-81

[0822] 3-(4-tert-butyl-pyridine)propionic acid (NPL-81-A5, 50 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg, 0.3 mmol), N,N-diisopropylethylamine (0.1 mL, 0.7 mmol), and 4-aminophenol (32 mg, 0.3 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse-phase separation to obtain the product 3-(4-tert-butyl-pyridine-3-yl)-N-(4-phenol)propionamide (NPL-81, 25 mg, 34.7%), a yellow solid.

[0823] MS(ESI)m / z = 299.1 [M+H] +

[0824] 1 H NMR (400MHz, DMSO-d6) δ9.71(s,1H),9.15(s,1H),8.38(d,J=7.5Hz,1H),8.29(d,J=5.3Hz,1H),7.39–7.34(m,2H) ,7.26(d,J=5.4Hz,1H),6.70–6.66(m,2H),3.14(dd,J=9.3,6.9Hz,2H),2.59(dd,J=9.3,6.8Hz,2H),1.38(s,9H).

[0825] NPL-82 Synthesis

[0826] Step 1: Synthesis of NPL-82-A1

[0827] 2-Amino-3-bromopyridine (9 g, 52.0 mmol), 4-methoxypyridine (5.3 mL, 52.0 mmol), tert-butane bromide (8.4 mL, 78.0 mmol), nickel acetylacetonate (0.7 g, 2.6 mmol), magnesium chloride (4.9 g, 52.0 mmol), zinc powder (6.8 g, 104.0 mmol), and lithium chloride (7.7 g, 182.1 mmol) were dissolved in anhydrous N,N-dimethylacetamide (150 mL), and the mixture was purged with nitrogen three times. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the mixture was filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the product 2-amino-3-tert-butylpyridine (NPL-82-A1, 2.0 g, 25.6%), a yellow oily liquid.

[0828] MS(ESI)m / z = 151.1[M+H] +

[0829] Step 2: Synthesis of NPL-82-A2

[0830] 2-Amino-3-tert-butylpyridine (2.0 g, 13.3 mmol) was dissolved in acetonitrile (30 mL), and sodium nitrite (4.6 g, 66.6 mmol) and hydrochloric acid (1.1 mL, 13.3 mmol) were added sequentially at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Then, copper bromide (6.0 g, 26.6 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The mixture was filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give the product 2-bromo-3-tert-butylpyridine (NPL-82-A2, 290 mg, 10.2%), a yellow oily liquid.

[0831] MS(ESI)m / z = 214.0[M+H] +

[0832] Step 3: Synthesis of NPL-82-A3

[0833] Under nitrogen protection, 2-bromo-3-tert-butylpyridine (290 mg, 1.4 mmol) was dissolved in 1,4-dioxane (12 mL) and water (2 mL). Potassium carbonate (562 mg, 4.1 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxoboron-2-yl)ethyl acrylate (612 mg, 2.7 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (99 mg, 0.1 mmol) were added sequentially. After three nitrogen purgings, the reaction mixture was stirred overnight at 80 °C. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-2-(3-tert-butylpyridine)ethyl acrylate (NPL-82-A3, 180 mg, 57.0%), a yellow oily liquid.

[0834] MS(ESI)m / z = 234.2[M+H] +

[0835] 1 H NMR (400MHz, CDCl3) δ8.47(dd,J=4.5,1.4Hz,1H),8.34(d,J=15.1Hz,1H),7.73(dd,J=8.1,1.5H z,1H),7.21(dd,J=8.1,4.5Hz,1H),6.92(d,J=15.1Hz,1H),4.28(q,J=7.1Hz,2H),1.47(s,9H).

[0836] Step 4: Synthesis of NPL-82-A4

[0837] Ethyl (E)-2-(3-tert-butylpyridine)acrylate (180 mg, 0.8 mmol) was dissolved in methanol (4 mL) and water (2 mL), and lithium hydroxide (37 mg, 1.6 mmol) was added and stirred for 2 hours. After the reaction was completed, 1 N hydrochloric acid (4 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-2-(3-tert-butylpyridine)acrylate (NPL-82-A4, 120 mg, 75.8%), a yellow solid.

[0838] MS(ESI)m / z = 206.1[M+H] +

[0839] Step 5: Synthesis of NPL-82-A5

[0840] (E)-2-(3-tert-butylpyridine)acrylic acid (110 mg, 0.5 mmol) was dissolved in dichloromethane (3 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (306 mg, 0.8 mmol), N,N-diisopropylethylamine (0.3 mL, 1.6 mmol), and 4-aminophenol (70 mg, 0.6 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(3-tert-butylpyridine-2-yl)-N-(4-phenol)acrylamide (NPL-82-A5, 100 mg, 63.0%), a yellow oily liquid.

[0841] MS(ESI)m / z = 297.1 [M+H] +

[0842] Step 6: Synthesis of NPL-82

[0843] (E)-3-(3-tert-butyl-pyridin-2-yl)-N-(4-phenol)acrylamide (100 mg, 0.3 mmol) was dissolved in methanol (3 mL), and palladium on carbon catalyst (36 mg, 0.1 mmol) was added, followed by three purgings with hydrogen. The reaction mixture was stirred overnight under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse phase separation to obtain the product 3-(3-tert-butyl-pyridin-2-yl)-N-(4-phenol)propionamide (NPL-82, 11.0 mg, 10.6%), a white solid.

[0844] MS(ESI)m / z = 299.1 [M+H] +

[0845] 1H NMR (400MHz, DMSO-d6) δ9.74(s,1H),9.12(s,1H),8.38(s,1H),7.74(s,1H),7.37(d,J=8.8Hz, 2H),7.20(s,1H),6.67(d,J=8.8Hz,2H),3.24(d,J=7.6Hz,2H),2.79–2.74(m,2H),1.41(s,9H).

[0846] Synthesis of NPL-96

[0847] Step 1: Synthesis of NPL-96-A1

[0848] Crude 5-tert-butyl-4-chloropyrimidine (2.0 g, 11.7 mmol) and dimethyl butylene glycol 2-(ethoxycarbonyl)vinylacetate (3.7 g, 17.6 mmol) were dissolved in dioxane (30 mL) and water (10 mL). After purging with nitrogen three times, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.9 g, 1.2 mmol) and potassium carbonate (4.9 g, 35.2 mmol) were added. The mixture was stirred at 80 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product (E)-3-(5-(tert-butyl)pyrimidin-4-yl)ethyl acrylate (NPL-96-A1, 290 mg, 10.6%), a yellow oil.

[0849] MS(ESI)m / z = 235.1

[0850] 1 H NMR (400MHz, CDCl3) δ9.05 (s, 1H), 8.80 (s, 1H), 8.18 (d, J = 15.1Hz, 1H), 7.13 (d,J=15.1Hz,1H),4.30(q,J=7.1Hz,2H),1.50(s,9H),1.35(t,J=7.1Hz,3H).

[0851] Step 2: Synthesis of NPL-96-A2

[0852] Ethyl (E)-3-(5-(tert-butyl)pyrimidin-4-yl)acrylate (300 mg, 1.3 mmol) was dissolved in methanol (8 mL) and water (4 mL). Lithium hydroxide (61 mg, 2.6 mmol) was added with stirring at room temperature and the reaction mixture was reacted for 1.5 hours. After the reaction was complete, 1 N hydrochloric acid solution was added to adjust the pH of the reaction solution to 5. The reaction solution was separated, extracted twice with ethyl acetate, and the organic phase was washed with water and saturated brine. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (E)-3-(5-(tert-butyl)pyrimidin-4-yl)acrylate (NPL-96-A2, 260 mg, 98.5%), a white solid.

[0853] MS(ESI)m / z = 207.1[M+H] +

[0854] Step 3: Synthesis of NPL-100

[0855] Compounds (E)-3-(5-(tert-butyl)pyrimidin-4-yl)acrylic acid (60 mg, 0.3 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (133 mg, 0.4 mmol), and 4-acetamidoaniline (66 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (1 mL), followed by the addition of N,N-diisopropylethylamine (113 mg, 0.9 mmol), and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse phase separation to obtain product (E)-3-(5-(tert-butyl)pyrimidin-4-yl)-N-(4-acetamidophenyl)acrylamide (NPL-100, 25 mg, 25.5%), a yellow solid.

[0856] MS(ESI)m / z = 339.1

[0857] 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),9.92(s,1H),9.08(s,1H),8.85(s,1H),8.06(d,J=14.7 Hz,1H),7.64(d,J=8.8Hz,2H),7.54(d,J=8.7Hz,2H),7.48(s,1H),2.03(s,3H),1.46(s,9H).

[0858] Step 4: Synthesis of NPL-96

[0859] 3-(5-(tert-butyl)pyrimidin-4-yl)-N-(4-acetamidophenyl)acrylamide (110 mg, 0.3 mmol) was dissolved in methanol (20 mL), followed by the addition of palladium on carbon (69 mg, 0.06 mmol, 10% Pd), purging with hydrogen three times, and stirring overnight at room temperature. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse-phase separation to obtain the product 3-(5-(tert-butyl)pyrimidin-4-yl)-N-(4-acetamidophenyl)propionamide (NPL-96, 50 mg, 45.2%), a white solid.

[0860] MS(ESI)m / z = 341.2[M+H] +

[0861] 1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.83(s,1H),8.93(s,1H),8.65(s,1H),7.47(d, J=2.1Hz,4H),3.24(d,J=7.6Hz,2H),2.87(d,J=7.7Hz,2H),2.01(s,3H),1.44(s,9H).

[0862] Synthesis of NPL-102

[0863] Step 1: Synthesis of NPL-102-A1

[0864] 5-Bromo-4-methoxypyrimidine (9.5 g, 50.3 mmol), nickel acetylacetonate (0.7 g, 2.5 mmol), lithium chloride (7.5 g, 175.9 mmol), magnesium chloride (4.8 g, 50.3 mmol), and zinc powder (6.5 g, 100.5 mmol) were dissolved in anhydrous N,N-dimethylacetamide (200 mL) at room temperature. After purging with nitrogen three times, 4-methoxypyridine (5.5 g, 50.3 mmol) and tert-butane bromide (10.3 g, 75.4 mmol) were added dropwise. The mixture was stirred overnight at room temperature. After the reaction was complete, water was added to quench the reaction. The mixture was separated and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: 1%-10% ethyl acetate / petroleum ether) to give 5-tert-butyl-4-methoxypyrimidine (NPL-102-A1, 1.2 g, 14.4%), a colorless oil.

[0865] MS(ESI)m / z = 167.1 [M+H] +

[0866] 1H NMR (400MHz, CDCl3): δ8.62(s,1H),8.34(s,1H),4.01(s,3H),1.35(s,9H).

[0867] Step 2: Synthesis of NPL-102-A2

[0868] 5-tert-butyl-4-methoxypyrimidine (1.2 g, 7.2 mmol) was dissolved in a hydrobromic acid-acetic acid solution (20 mL), sealed in a tube, and stirred overnight at 100 °C. After the reaction was complete, the solution was cooled to room temperature and concentrated under reduced pressure to obtain 5-tert-butyl-4-hydroxypyrimidine (NPL-102-A2, 1.1 g, 97.8%), a yellow oil.

[0869] MS(ESI)m / z = 153.1 [M+H] + by UV spectra

[0870] 1 H NMR (400MHz, CDCl3): δ9.01(s,1H),7.81(s,1H),1.28(s,9H).

[0871] Step 3: Synthesis of NPL-102-A3

[0872] 5-tert-butyl-4-hydroxypyrimidine (1.1 g, 7.1 mmol) was dissolved in acetonitrile (25 mL), and phosphorus oxychloride (10 mL) was added at room temperature. The reaction mixture was stirred overnight in an oil bath at 80 °C. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain 5-tert-butyl-4-chloropyrimidine (NPL-102-A3, 1.2 g, 99.3%), a yellow oil.

[0873] MS(ESI)m / z = 171.0 [M+H] +

[0874] Step 4: Synthesis of NPL-102-A4

[0875] 5-tert-butyl-4-chloropyrimidine (200 mg, 1.18 mmol) and methyl mercaptoacetate (150 mg, 1.42 mmol) were dissolved in tetrahydrofuran (10 mL), purged three times with nitrogen, and sodium hydride (71 mg, 1.77 mmol) was added at 0 °C. The reaction was then stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phase was washed with water. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain methyl 2-((5-tert-butylpyrimidin-4-yl)thio)acetate (NPL-102-A4, 130 mg, 45.8%), a colorless oil.

[0876] MS(ESI)m / z = 241.0[M+H] +

[0877] Step 5: Synthesis of NPL-102-A5

[0878] Crude methyl 2-((5-tert-butylpyrimidin-4-yl)thio)acetic acid (130 mg, 0.54 mmol) was dissolved in methanol (4 mL) and water (2 mL). Lithium hydroxide (25 mg, 1.08 mmol) was added with stirring at room temperature and reacted for 1 hour. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with 1 N hydrochloric acid solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the product 2-((5-tert-butylpyrimidin-4-yl)thio)acetic acid (NPL-102-A5, 120 mg, 98.0%), a yellow solid.

[0879] MS(ESI)m / z=225.0[MH] - .

[0880] Step 3: Synthesis of NPL-102

[0881] 2-((5-tert-butylpyrimidin-4-yl)thio)acetic acid (100 mg, 0.44 mmol), 4-aminophenol (96 mg, 0.88 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (202 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (77 μL, 0.44 mmol) was added with stirring at room temperature and the reaction was carried out for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was directly purified by reverse phase separation (Triart C18, 250*20.0mm.D., S-5um, 12nm, eluent: 20-95% acetonitrile / water (0.1% ammonium bicarbonate)) to obtain the product 2-((5-tert-butylpyrimidin-4-yl)thio)-N-(4-hydroxyphenyl)acetamide (NPL-102, 45mg, 32.1%), a light yellow solid.

[0882] MS(ESI)m / z = 318.1[M+H] +

[0883] 1 H NMR (400MHz, DMSO-d6): δ10.03(s,1H),9.18(s,1H),8.79(s,1H),8.46(s,1H),7.41–7.28(m,2H),6.76–6.62(m,2H),4.16(s,2H),1.46(s,9H).

[0884] The compounds in Table 12 below were prepared using the same method as in the examples described above, either commercially available compounds or intermediate compounds prepared by the methods shown.

[0885] Table 12

[0886] Synthesis of NPL-103

[0887] Step 1: Synthesis of NPL-103-A1

[0888] 5-Bromo-4-aminopyrimidine (5 g, 28.7 mmol) and potassium carbonate (11.9 g, 86.2 mmol) were dissolved in N,N-dimethylformamide (35 mL), followed by the addition of ethyl bromoacetate (7.2 g, 43.1 mmol), and the reaction was carried out overnight at 70 °C. The mixture was cooled to room temperature, the reaction was quenched with water, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give ethyl glycine (5-bromopyrimidine-4-yl)glycine (NPL-103-A1, 1.4 g, 18.7%), a yellow oil.

[0889] MS(ESI)m / z = 260.0[M+H] +

[0890] 1 H NMR (400MHz, CDCl3): δ8.50(s,1H),8.34(s,1H),5.95(s,1H),4.31–4.23(m,4H),1.32(t,J=7.2Hz,3H).

[0891] Step 2: Synthesis of NPL-103-A2

[0892] Compound (5-bromopyrimidin-4-yl)glycine ethyl ester (800 mg, 3.1 mmol), lithium chloride (456 mg, 10.8 mmol), magnesium chloride (293 mg, 3.1 mmol), nickel acetylacetonate (40 mg, 0.2 mmol), and zinc powder (402 mg, 6.2 mmol) were dissolved in N,N-dimethylacetamide (12 mL). The mixture was purged with nitrogen three times. 4-methoxypyridine (336 mg, 3.1 mmol) and tert-butane bromide (0.5 mL, 4.6 mmol) were added with stirring at room temperature. The reaction mixture was stirred overnight at 50 °C. After cooling to room temperature, the reaction was quenched with water, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was reverse-phase prepared to obtain (5-tert-butylpyrimidin-4-yl)glycine ethyl ester (NPL-103-A2, 170 mg, 23.3%), a yellow oily substance.

[0893] MS(ESI)m / z = 238.1[M+H] + .

[0894] Step 3: Synthesis of NPL-103-A3

[0895] Ethyl glycine (5-tert-butylpyrimidin-4-yl) ester (170 mg, 0.7 mmol) was dissolved in methanol (6 mL) and water (3 mL). Lithium hydroxide (70 mg, 1.7 mmol) was added with stirring at room temperature, and the reaction was carried out for 3 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 5 by adding 1 N hydrochloric acid solution. The reaction solution was concentrated under reduced pressure to obtain the product (5-tert-butylpyrimidin-4-yl) glycine (NPL-103-A3, 110 mg, 62.4%), a brown solid, which was directly used in the next step of the reaction.

[0896] MS(ESI)m / z = 210.1[M+H] + .

[0897] Step 4: Synthesis of NPL-103

[0898] Compounds (5-tert-butylpyrimidin-4-yl)glycine (110 mg, 0.5 mmol), 4-aminophenol (86 mg, 0.79 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (240 mg, 0.63 mmol) were dissolved in N,N-dimethylformamide (1 mL). N,N-diisopropylethylamine (68 mg, 0.5 mmol) was added with stirring at room temperature, and the reaction was carried out for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was directly purified to give 2-((5-tert-butylpyrimidin-4-yl)amino)-N-(4-hydroxyphenyl)acetamide (NPL-103, 15 mg, 9.5%), a light pink solid.

[0899] MS(ESI)m / z = 301.2[M+H] + .

[0900] 1 H NMR (400MHz, DMSO-d6) δ9.82(s,1H),9.17(s,1H),8.32(s,1H),8.05(s,1H),7.36(d,J=8. 7Hz, 2H), 6.68 (d, J = 8.7Hz, 2H), 6.47 (t, J = 5.2Hz, 1H), 4.21 (d, J = 5.3Hz, 2H), 1.37 (s, 9H).

[0901] The compounds in Table 13 below were prepared using the same method as in the examples described above, either commercially available compounds or intermediate compounds prepared by the methods shown.

[0902] Table 13

[0903] Synthesis of NPL-106

[0904] Step 1: Synthesis of NPL-106-A1

[0905] Under nitrogen protection, 3-(tert-butyl)pyrazin-2-yltrifluoromethanesulfonate (100 mg, 0.4 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.5 mL), followed by the sequential addition of potassium carbonate (146 mg, 1.1 mmol), (Z)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)but-2-enoate ethyl ester (127 mg, 0.5 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (26 mg, 0.04 mmol). The mixture was purged with nitrogen three times, and the reaction solution was stirred overnight at 80 °C. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain ethyl (E)-3-(3-(tert-butyl)pyrazin-2-yl)but-2-enoate (NPL-106-A1, 80 mg, 91.6%), a colorless oily liquid.

[0906] MS(ESI)m / z = 249.2[M+H] + .

[0907] 1 H NMR (400MHz, CDCl3) δ8.47(d,J=2.2Hz,1H),8.35(d,J=2.2Hz,1H),5.74(d,J=1.3Hz, 1H), 4.22 (q, J = 7.1Hz, 2H), 2.56 (d, J = 1.2Hz, 3H), 1.41 (s, 9H), 1.30 (d, J = 7.1Hz, 3H).

[0908] Step 2: Synthesis of NPL-106-A2

[0909] Ethyl (E)-3-(3-(tert-butyl)pyrazin-2-yl)but-2-enoic acid (80 mg, 0.3 mmol) was dissolved in tetrahydrofuran (3 mL) and water (3 mL), and lithium hydroxide (15 mg, 0.7 mmol) was added and stirred overnight at room temperature. After the reaction was complete, 1 N hydrochloric acid (5 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the product (E)-3-(3-(tert-butyl)pyrazin-2-yl)but-2-enoic acid (NPL-106-A2, 70 mg, 98.6%), a yellow oily liquid, which can be used directly in the next step without purification.

[0910] MS(ESI)m / z = 221.1[M+H] + .

[0911] Step 3: Synthesis of NPL-106-A3

[0912] (E)-3-(3-(tert-butyl)pyrazin-2-yl)but-2-enoic acid (70 mg, 0.3 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (135 mg, 0.4 mmol), and 4-aminophenol (78 mg, 0.4 mmol) were dissolved in dichloromethane (5 mL), followed by the addition of N,N-diisopropylethylamine (114 mg, 0.9 mmol) and stirring for 2 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was directly separated by reverse phase to obtain the product (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-hydroxyphenyl)but-2-enoamide (NPL-106-A3, 30 mg, 32.7%), a light red solid.

[0913] MS(ESI)m / z = 312.1[M+H] + .

[0914] Step 4: Synthesis of NPL-106

[0915] (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-hydroxyphenyl)but-2-enamide (120 mg, 0.4 mmol) was dissolved in methanol (10 mL), palladium on carbon (120 mg, 0.1 mmol) was added, and hydrogen was purged three times. The reaction was stirred overnight at 50 °C and 10 bar under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was purified by reverse preparative separation to obtain NPL-106 (30 mg). NPL-106 was resolved by SFC to obtain products NPL-106-P1 (chiral column retention time: 0.845 min) (2.53 mg, 2.1%) and NPL-174 (chiral column retention time: 1.387 min) (2.69 mg, 2.2%), both white solids.

[0916] NPL-106:

[0917] MS(ESI)m / z = 314.0[M+H] + .

[0918] 1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),9.18(s,1H),8.45(d,J=2.2Hz,1H),8.37(d,J=2.3Hz,1H),7.33(d,J=8.8Hz,2H),6.65(d,J=8.8Hz,2H),3.99–3.90(m,1H),2.69(dd,J=14.5,8.7Hz,1H),2.60(dd,J=14.5,5.4Hz,1H),1.44(s,9H),1.23(d,J=6.5Hz,3H).

[0919] NPL-106-P1:

[0920] MS(ESI)m / z=314.0[M+H] + .

[0921] 1 H NMR(400MHz,DMSO-d6)δ9.73(s,1H),9.18(s,1H),8.45(d,J=2.2Hz,1H),8.37(d,J=2.3Hz,1H),7.33(d,J=8.8Hz,2H),6.65(d,J=8.8Hz,2H),3.99–3.90(m,1H),2.69(dd,J=14.5,8.7Hz,1H),2.60(dd,J=14.5,5.4Hz,1H),1.44(s,9H),1.23(d,J=6.5Hz,3H).

[0922] SFC:t R =0.845min in C-IG-M-30-8MIN.lcm(CHIRALPAK C-IG 5um 4.6*100mm).

[0923] NPL-174:

[0924] MS(ESI)m / z=314.0[M+H] + .

[0925] 1H NMR (400MHz, DMSO-d6) δ9.73(s,1H),9.14(s,1H),8.45(d,J=2.3Hz,1H),8.37(d,J=2.3Hz,1H),7.35–7.32(m,2H),6.67–6.6 4(m,2H),3.98–3.90(m,1H),2.69(dd,J=14.5,8.6Hz,1H),2.60(dd,J=14.5,5.4Hz,1H),1.44(s,9H),1.23(d,J=6.5Hz,3H).

[0926] SFC:t R =1.387min in C-IG-M-30-8MIN.lcm(CHIRALPAK C-IG 5um 4.6*100mm).

[0927] NPL-107 Synthesis

[0928] Step 1: Synthesis of NPL-107-A1

[0929] Methyl methacrylate (4.9 mL, 46.0 mmol) was dissolved in chloroform (60 mL), and bromine (8.8 g, 55.1 mmol) was added dropwise at 0 °C. The reaction was then allowed to proceed at room temperature for 4 hours. After cooling to room temperature, the reaction was quenched with saturated sodium thiosulfate solution. The reaction mixture was separated and extracted with chloroform. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain methyl 2,3-dibromo-2-methylpropionate (NPL-107-A1, 6.0 g, 50%), a colorless oil that could be used directly in the next step without further purification.

[0930] Step 2: Synthesis of NPL-107-A2

[0931] methyl 2,3-dibromo-2-methylpropionate (5.0 g, 19.2 mmol) was dissolved in ultra-dry tetrahydrofuran (100 mL), followed by the addition of 1,8-diazacyclo[5,4,0]undecene-7 (3.2 g, 21.2 mmol). The reaction mixture was stirred at 70 °C for 2 hours. After cooling to room temperature, the reaction was quenched with water (100 mL) and extracted with dichloromethane (250 mL). The organic phases were combined, washed with 1N dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under vacuum. The crude product was purified by silica gel column chromatography to give product (E)-3-bromo-2-methylpropionate (NPL-107-A2, 3 g, 87%), a colorless oil.

[0932] 1H NMR (400MHz, CDCl3) δ7.53 (d, J = 1.3 Hz, 1H), 3.77 (s, 3H), 2.01 (d, J = 1.3 Hz, 3H).

[0933] Step 3: Synthesis of NPL-107-A3

[0934] Compound (E)-3-bromo-2-methyl methacrylate (500 mg, 2.8 mmol) and pinacol diborate (1.1 g, 4.2 mmol) were dissolved in dimethyl sulfoxide (10 mL), followed by the sequential addition of potassium acetate (822 mg, 8.4 mmol) and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (204 mg, 0.3 mmol). The reaction mixture was purged three times with nitrogen and reacted at 80 °C for 18 hours. After cooling to room temperature, the reaction mixture was slowly poured into water and extracted with diethyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give product (E)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) methyl acrylate (NPL-107-A3, 600 mg, 76%), a brown oily substance, which was used directly in the next step without further purification.

[0935] MS(ESI)m / z = 227.1[M+H] + .

[0936] Step 4: Synthesis of NPL-107-A4

[0937] Methyl (E)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)acrylate (360 mg, 1.6 mmol) was dissolved in methanol (30 mL), and potassium hydrogen fluoride (550 mg, 1.6 mmol) was added. Water (15 mL) was then slowly added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solution was concentrated to dryness under vacuum. The crude product was dissolved in hot acetone and then filtered. The filtrate was concentrated under reduced pressure, dissolved in a suitable amount of diethyl ether, and refrigerated for 4 hours to obtain a white precipitate. The precipitate was filtered, washed with ice-cold diethyl ether, and dried under vacuum to give product (E)-trifluoro(3-methoxy-2-methyl-3-oxopropen-1-yl)borate (NPL-107-A4, 250 mg, 94%), a white solid.

[0938] 1 H NMR (400MHz, DMSO-d6) δ6.61 (q, J = 5.0Hz, 1H), 3.58 (s, 3H), 1.81 (s, 3H).

[0939] Step 5: Synthesis of NPL-107-A5

[0940] Compounds 3-(tert-butyl)pyrazin-2-yl trifluoromethanesulfonate (200 mg, 0.7 mmol) and (E)-trifluoro(3-methoxy-2-methyl-3-oxopropen-1-yl)borate (176 mg, 1.1 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), followed by the sequential addition of potassium carbonate (291.3 mg, 2.1 mmol) and 1,1-bis(diphenylphosphine)diferropalladium dichloride (51.43 mg, 0.1 mmol). The reaction mixture was purged three times with nitrogen and reacted overnight at 80 °C. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(3-(tert-butyl)pyrazin-2-yl)-2-methyl methacrylate (NPL-107-A5, 160 mg, 97%), a colorless oil.

[0941] MS(ESI)m / z = 235.1[M+H] + .

[0942] 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=2.3Hz,1H),8.42(d,J=2.3Hz,1H),7.98(d,J=1.1Hz,1H),3.85(s,3H),1.98(d,J=1.4Hz,3H),1.42(s,9H).

[0943] Step 6: Synthesis of NPL-107-A6

[0944] Methyl (E)-3-(3-(tert-butyl)pyrazin-2-yl)-2-methacrylate (160 mg, 0.7 mmol) was dissolved in methanol (9 mL) and water (3 mL), followed by the addition of lithium hydroxide (86 mg, 2.1 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, 1 N hydrochloric acid was added to quench the reaction. The reaction mixture was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give product (E)-3-(3-(tert-butyl)pyrazin-2-yl)-2-methacrylic acid (NPL-107-A6, 140 mg, 93%), a white solid.

[0945] MS(ESI)m / z = 221.1[M+H] + .

[0946] Step 7: Synthesis of NPL-107-A7

[0947] Compound (E)-3-(3-(tert-butyl)pyrazin-2-yl)-2-methacrylic acid (120 mg, 0.5 mmol), 4-aminophenol (89 mg, 0.8 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (249 mg, 0.7 mmol) were dissolved in N,N-dimethylformamide (10 mL). N,N-diisopropylethylamine (0.3 mL, 1.6 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give product (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-hydroxyphenyl)-2-methylacrylamide (NPL-107-A7, 120 mg, 71%), a white solid.

[0948] MS(ESI)m / z = 312.1[M+H] +

[0949] 1 H NMR(400MHz, DMSO-d6)δ9.67(s,1H),8.53(dd,J=21.5,2.3Hz,2H),7.64(s,1H),7.49(d, J=8.9Hz,2H),6.76–6.69(m,2H),6.50–6.38(m,1H),1.99(d,J=1.3Hz,3H),1.38(s,9H).

[0950] Step 8: Synthesis of NPL-107

[0951] Compound (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-hydroxyphenyl)-2-methylacrylamide (120 mg, 0.4 mmol) was dissolved in methanol (10 mL), palladium on carbon (12 mg, 0.01 mmol) was added, and hydrogen was purged three times. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to dryness under vacuum. The crude product was reverse-phase to prepare 3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-hydroxyphenyl)-2-methylpropionamide (NPL-107, 53 mg, 44%), a white solid.

[0952] NPL-107:

[0953] MS(ESI)m / z = 314.2[M+H] +

[0954] 1H NMR (400MHz, DMSO-d6) δ9.65(s,1H),9.09(s,1H),8.37(d,J=2.4Hz,1H),8.34(d,J=2.3Hz,1H),7.32(d,J=8.9Hz,2H), 6.64(d,J=8.9Hz,2H),3.35(dd,J=12.4,5.8Hz,2H),3.03(dd,J=18.6,9.2Hz,1H),1.43(s,9H),1.15(d,J=6.4Hz,3H).

[0955] Synthesis of NPL-111

[0956] Step 1: Synthesis of NPL-111-A1

[0957] Under nitrogen protection, trimethyl sulfoxide (620 mg, 2.8 mmol) was dissolved in dimethyl sulfoxide (12 mL), and sodium hydride (67 mg, 1.7 mmol) was added at 0 °C. The mixture was stirred at room temperature for 0.5 h. Subsequently, compound (E)-3-(3-(tert-butyl)pyrazin-2-yl)ethyl acrylate (300 mg, 1.3 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 h. After the reaction was completed, the reaction solution was added to ice water, diluted with ethyl acetate, separated, and the organic phase was washed with water and saturated brine. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give ethyl 2-(3-(tert-butyl)pyrazin-2-yl)cyclopropane-1-carboxylate (NPL-111-A1, 160 mg, 50.3%), a yellow oily liquid.

[0958] MS(ESI)m / z = 249.1 [M+H] + .

[0959] Step 2: Synthesis of NPL-111-A2

[0960] ethyl 2-(3-(tert-butyl)pyrazin-2-yl)cyclopropane-1-acetic acid (160 mg, 0.6 mmol) was dissolved in methanol (3 mL) and water (1 mL), and lithium hydroxide (54 mg, 1.3 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, 1 N hydrochloric acid (5 mL) was added to adjust the reaction solution to acidity, and then the solution was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product 2-(3-(tert-butyl)pyrazin-2-yl)cyclopropane-1-acetic acid (NPL-111-A2, 140 mg, 98.6%), a yellow oily liquid.

[0961] MS(ESI)m / z = 221.2[M+H] + .

[0962] Step 3: Synthesis of NPL-111

[0963] 2-(3-(tert-butyl)pyrazin-2-yl)cyclopropane-1-acetic acid (130 mg, 0.6 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (337 mg, 0.9 mmol), N,N-diisopropylethylamine (0.3 mL, 1.8 mmol), and 4-aminophenol (77 mg, 0.7 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse phase separation to obtain the product 2-(3-(tert-butyl)pyrazin-2-yl)-N-(4-hydroxyphenyl)cyclopropane-1-carboxamide (NPL-111, 110 mg, 59.9%), a white solid.

[0964] MS(ESI)m / z = 312.1[M+H] +

[0965] 1 H NMR(400MHz,DMSO-d6)δ10.03(s,1H),9.16(s,1H),8.38–8.35(m,2H),7.38–7.33(m,2H),6.70–6.65(m,2H ),2.91–2.85(m,1H),2.38–2.33(m,1H),1.64(ddd,J=8.5,5.8,3.0Hz,1H),1.53–1.49(m,1H),1.45(s,9H).

[0966] Synthesis of NPL-114

[0967] Step 1: Synthesis of NPL-114-A1

[0968] 500 mg (3.5 mmol) of p-fluoronitrobenzene was dissolved in 20 mL of dimethyl sulfoxide, and 777 mg (10.6 mmol) of tert-butylamine was added. The reaction mixture was stirred overnight at 75 °C. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography to give N-(tert-butyl)-4-nitroaniline (NPL-114-A1, 650 mg, 94.4%), a yellow oily liquid.

[0969] MS(ESI)m / z = 195.1 [M+H] + .

[0970] Step 2: Synthesis of NPL-114-A2

[0971] N-(tert-butyl)-4-nitroaniline (600 mg, 3.1 mmol) was dissolved in methanol (10 mL), and palladium on carbon catalyst (164 mg, 1.5 mmol) was added, followed by three purgings with hydrogen. The reaction mixture was stirred overnight under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to dryness. The crude product was purified by silica gel column chromatography to obtain N... 1 -(tert-butyl)-1,4-phenylenediamine (NPL-114-A2, 480 mg, 94.6%), a yellow oily liquid.

[0972] MS(ESI)m / z = 165.1 [M+H] + .

[0973] 1 H NMR (400MHz, CDCl3) δ6.75–6.70(m,2H),6.60–6.56(m,2H),1.19(s,9H).

[0974] Step 3: Synthesis of NPL-114-A3

[0975] N-(tert-butyl)-1,4-phenylenediamine (60 mg, 0.3 mmol) was dissolved in dichloromethane (1 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (166 mg, 0.4 mmol), N,N-diisopropylethylamine (0.1 mL, 0.9 mmol), and (E)-3-(3-(tert-butyl)pyrazin-2-yl)acrylic acid (57 mg, 0.3 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to dryness under vacuum. The crude product was purified by silica gel column chromatography to give (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-(tert-butylamine)phenyl)acrylamide (NPL-114-A3, 60 mg, 58.5%), a yellow oily liquid.

[0976] MS(ESI)m / z = 353.1 [M+H] +

[0977] Step 4: Synthesis of NPL-114

[0978] (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-(tert-butylamine)phenyl)acrylamide (60 mg, 0.2 mmol) was dissolved in methanol (10 mL), and palladium on carbon catalyst (20 mg, 0.02 mmol) was added, followed by three purgings with hydrogen. The reaction mixture was stirred overnight under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to dryness. The crude product was separated by reverse phase to obtain the product 3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-(tert-butylamine)phenyl)propionamide (NPL-114, 20 mg, 33.1%), a yellow oily liquid.

[0979] MS(ESI)m / z = 355.1 [M+H] +

[0980] 1 H NMR (400MHz, DMSO-d6) δ9.63 (s, 1H), 8.40 (d, J = 2.4Hz, 1H), 8.37 (d, J = 2.4Hz, 1H), 7.26 (d, J = 8.9Hz, 2H),6.67–6.64(m,2H),4.70(s,1H),3.28–3.24(m,2H),2.80–2.75(m,2H),1.43(s,9H),1.23(s,9H).

[0981] Synthesis of NPL-115

[0982] Step 1: Synthesis of NPL-115-A1

[0983] Compound (E)-3-(3-(tert-butyl)pyrazin-2-yl)acrylic acid (50 mg, 0.2 mmol) was dissolved in methanol (5 mL), and palladium on carbon catalyst (26 mg, 0.02 mmol) was added, followed by three purgings with hydrogen. The reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under vacuum to obtain the product 3-(3-(tert-butyl)pyrazin-2-yl)propionic acid (NPL-115-A1, 47 mg, 93.1%), a yellow oily liquid, which was used directly in the next reaction.

[0984] MS(ESI)m / z = 209.2[M+H] + .

[0985] Step 2: Synthesis of NPL-115-A3

[0986] 1-Fluoro-4-nitrobenzene (1 g, 7.1 mmol) was dissolved in dimethyl sulfoxide (15 mL), followed by the addition of cyclopropylamine (1.2 g, 21.3 mmol), and the mixture was stirred overnight at 75 °C. After the reaction was complete, the solution was diluted with water and ethyl acetate. The mixture was separated, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give the product N-cyclopropyl-4-nitrobenzene (NPL-115-A3, 1.1 g, 87.1%), a yellow solid, which was used directly in the next reaction.

[0987] MS(ESI)m / z = 179.0 [M+H] + .

[0988] 1 H NMR (400MHz, CDCl3) δ8.10 (d, J = 9.2Hz, 2H), 6.80–6.61 (m, 2H), 4.85 (s, 1H), 2.58–2.48 (m, 1H), 0.90–0.81 (m, 2H), 0.62–0.54 (m, 2H).

[0989] Step 3: Synthesis of NPL-115-A4

[0990] N-cyclopropyl-4-nitroaniline (200 mg, 1.1 mmol) was dissolved in ethyl acetate (8 mL), and palladium on carbon catalyst (119 mg, 0.1 mmol) was added, followed by three purgings with hydrogen. The reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain product N. 1 -Cyclopropylphenyl-1,4-diamine (NPL-115-A4, 160 mg, 96.4%), a deep purple oily liquid, is used directly in the next reaction.

[0991] MS(ESI)m / z = 149.2 [M+H] + .

[0992] Step 4: Synthesis of NPL-115

[0993] 3-(3-(tert-butyl)pyrazin-2-yl)propionic acid (45 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (99 mg, 0.3 mmol), N,N-diisopropylethylamine (14 mg, 0.1 mmol), and N... 1Cyclopropylphenyl-1,4-diamine (64 mg, 0.4 mmol) was reacted and stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by reverse phase to give the product 3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-(cyclopropylamino)phenyl)propionamide (NPL-115, 8 mg, 10.9%), a light purple solid.

[0994] MS(ESI)m / z = 339.1 [M+H] + .

[0995] 1 H NMR (400MHz, DMSO-d6) δ9.61 (s, 1H), 8.40 (d, J = 2.3Hz, 1H), 8.37 (s, 1H), 7.28 (d, J = 8.7Hz, 2H), 6.61 (d, J = 8.8Hz, 2H),5.85(s,1H),3.25(m,2H),2.80–2.74(m,2H),2.26(s,1H),1.43(s,9H),0.67–0.62(m,2H),0.35–0.31(m,2H).

[0996] Synthesis of NPL-116

[0997] Step 1: Synthesis of NPL-116-A1

[0998] At 0 °C, 4-nitroaniline (1.0 g, 7.2 mmol) and triethylamine (3.0 mL, 21.7 mmol) were dissolved in dichloromethane (30 mL), followed by the slow addition of cyclopropionic acid chloride (0.9 g, 8.7 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added at 0 °C to quench the reaction. The reaction mixture was separated and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain N-(4-nitrophenyl)cyclopropionic acid amide (NPL-116-A1, 1.3 g, 87.1%), a yellow solid.

[0999] MS(ESI)m / z = 207.1[M+H] + .

[1000] 1 H NMR (400MHz, CDCl3) δ8.20 (d, J = 9.2Hz, 2H), 7.74–7.66 (m, 2H), 1.59–1.51 (m, 1H), 1.17–1.10 (m, 2H), 0.98–0.89 (m, 2H).

[1001] Step 2: Synthesis of NPL-116-A2

[1002] N-(4-nitrophenyl)cyclopropylformamide (1.1 g, 5.3 mmol) was dissolved in anhydrous ethanol (10 mL) and water (1 mL), followed by the sequential addition of iron powder (1.5 g, 26.7 mmol) and ammonium chloride (1.4 g, 26.7 mmol). The reaction mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product N-(4-aminophenyl)cyclopropylformamide (NPL-116-A2, 750 mg, 79.8%), a white solid.

[1003] MS(ESI)m / z = 177.1 [M+H] + .

[1004] 1 H NMR (400MHz, DMSO-d6) δ9.70(s,1H),7.20(d,J=8.7Hz,2H),6.48(d,J=8.7Hz,2H),4.78(s,2H),1.72–1.62(m,1H),0.72(m,4H).

[1005] Step 3: Synthesis of NPL-116-A3

[1006] N-(4-aminophenyl)cyclopropaneformamide (100 mg, 0.6 mmol) and (E)-3-(3-(tert-butyl)pyrazin-2-yl)acrylic acid (140 mg, 0.7 mmol) were dissolved in dichloromethane (5 mL). Then, N,N-diisopropylethylamine (0.3 mL, 1.7 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (431 mg, 1.1 mmol) were added sequentially at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to quench the reaction. The reaction mixture was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-N-(4-(3-(3-(tert-butyl)pyrazin-2-yl)acrylamido)phenyl)cyclopropaneformamide (NPL-116-A3, 100 mg, 48.3%), a colorless oily liquid.

[1007] MS(ESI)m / z = 365.1 [M+H] +

[1008] Step 4: Synthesis of NPL-116

[1009] (E)-N-(4-(3-(3-(tert-butyl)pyrazin-2-yl)acrylamido)phenyl)cyclopropionic acid amide (100 mg, 0.3 mmol) was dissolved in methanol (10 mL), palladium on carbon (15 mg, 0.01 mmol) was added, and hydrogen was purged three times. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was separated by reverse phase to obtain the product N-(4-(3-(3-(tert-butyl)pyrazin-2-yl)propionic acid amide)cyclopropionic acid amide (NPL-116, 60 mg, 59.7%), a white solid.

[1010] MS(ESI)m / z = 367.1.

[1011] 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),9.93(s,1H),8.39(d,J=2.4Hz,1H),8.37(d,J=2.4Hz,1H),7.48(s,4H ),3.28(t,J=7.4Hz,2H),2.83(t,J=7.4Hz,2H),1.74(dq,J=7.5,5.1Hz,1H),1.44(s,9H),0.81–0.70(m,4H).

[1012] Synthesis of NPL-117

[1013] Step 1: Synthesis of NPL-117-A1

[1014] (E)-3-(3-(tert-butyl)pyrazin-2-yl)acrylic acid (150 mg, 0.7 mmol) was dissolved in dichloromethane (10 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (415 mg, 1.1 mmol), N,N-diisopropylethylamine (0.4 mL, 2.2 mmol), and N-methyl-P-aminoanisole (120 mg, 0.9 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to dryness under vacuum. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-(methoxy)phenyl)-N-methylacrylamide (NPL-117-A1, 150 mg, 63.4%), a yellow oily liquid.

[1015] Step 2: Synthesis of NPL-117-A2

[1016] (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-(methoxy)phenyl)-N-methylacrylamide (150 mg, 0.5 mmol) was dissolved in methanol (5 mL), and palladium on carbon catalyst (49 mg, 0.05 mmol) was added, followed by three purgings with hydrogen. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to dryness. The crude product was purified by silica gel column chromatography to give 3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-(methoxy)phenyl)-N-methylpropionamide (NPL-117-A2, 150 mg, 99.4%), a yellow oily liquid.

[1017] MS(ESI)m / z = 328.1 [M+H] +

[1018] 1 H NMR(400MHz, CDCl3)δ8.24(dd,J=9.1,2.4Hz,2H),7.16–7.11(m,2H),6.93–6.88(m ,2H),3.81(s,3H),3.32–3.27(m,2H),3.24(s,3H),2.59–2.54(m,2H),1.43(s,9H).

[1019] Step 3: Synthesis of NPL-117

[1020] 3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-(methoxy)phenyl)-N-methylpropionamide (150 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (5 mL) at -78 °C under nitrogen protection, and boron tribromide (0.1 mL, 1.0 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, sodium bicarbonate solution was added to quench the reaction, and the mixture was diluted with dichloromethane. The reaction mixture was separated, and the organic phase was washed with water and saturated brine. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure until dry. The crude product was purified by reverse-phase separation to give the product 3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-hydroxyphenyl)-N-methylpropionamide (NPL-117, 60 mg, 41.8%), a yellow solid.

[1021] MS(ESI)m / z = 314.1[M+H] +

[1022] 1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.32(dd,J=5.0,2.3Hz,2H),7.12(d,J=8.7Hz,2H),6 .79(d,J=8.7Hz,2H),3.16–3.12(m,2H),3.08(s,3H),2.46(d,J=7.2Hz,2H),1.37(s,9H).

[1023] Synthesis of NPL-118

[1024] Step 1: Synthesis of NPL-118-A1

[1025] Under nitrogen protection, 4-nitroaniline (330 mg, 2.4 mmol) and neopentanoyl chloride (432 mg, 3.6 mmol) were dissolved in tetrahydrofuran (10 mL). Sodium hydrogen hydride (69 mg, 2.9 mmol) was slowly added to the mixture at 0 °C. The reaction mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, the reaction was quenched by adding saturated ammonium chloride solution at 0 °C, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the product N-(4-nitrophenyl)neopentamide (NPL-118-A1, 500 mg, 94.2%), a yellow solid, which could be used directly in the next step without purification.

[1026] MS(ESI)m / z = 223.1[M+H] +

[1027] Step 2: Synthesis of NPL-118-A2

[1028] N-(4-nitrophenyl)neopentamide (500 mg, 2.3 mmol) was dissolved in methanol (10 mL), palladium on carbon (72 mg, 0.07 mmol) was added, and hydrogen was purged three times. The reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product N-(4-aminophenyl)neopentamide (NPL-118-A2, 330 mg, 76.3%), a yellow solid.

[1029] MS(ESI)m / z = 193.1 [M+H] + .

[1030] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),7.18(d,J=8.6Hz,2H),6.48(d,J=8.6Hz,2H),4.82(s,2H),1.18(s,9H).

[1031] Step 3: Synthesis of NPL-118-A3

[1032] (E)-3-(3-(tert-butyl)pyrazin-2-yl)acrylic acid (70 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (155 mg, 0.4 mmol), N,N-diisopropylethylamine (132 mg, 1 mmol), and N-(4-aminophenyl)neopentamide (78 mg, 0.4 mmol) and stirring overnight. After the reaction was complete, the reaction solution was filtered, and the solid was washed with dichloromethane and then dried under vacuum to give the product (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-neopentamidophenyl)acrylamide (NPL-118-A3, 100 mg, 77.4%), a yellow solid.

[1033] MS(ESI)m / z = 381.1[M+H] + .

[1034] Step 4: Synthesis of NPL-118

[1035] (E)-3-(3-(tert-butyl)pyrazin-2-yl)-N-(4-neopentamylphenyl)acrylamide (100 mg, 0.3 mmol) was dissolved in methanol (10 mL), palladium on carbon (28 mg, 0.03 mmol) was added, and hydrogen was purged three times. The reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was separated by reverse phase to obtain the product N-(4-(3-(3-(tert-butyl)pyrazin-2-yl)propamido)phenyl)neopentamamide (NPL-118, 60 mg, 59.7%), a white solid.

[1036] MS(ESI)m / z = 383.3[M+H] +

[1037] 1 H NMR (400MHz, DMSO-d6) δ9.93(s,1H),9.11(s,1H),8.40(d,J=2.4Hz,1H),8.37(d,J=2.3Hz,1H ),7.53–7.47(m,4H),3.29(t,J=7.4Hz,2H),2.84(t,J=7.4Hz,2H),1.44(s,9H),1.21(s,9H).

[1038] Synthesis of NPL-121

[1039] Step 1: Synthesis of NPL-121-A1

[1040] Compound 2,3-dichloropyrazine (500 mg, 3.4 mmol) and isopropanol (0.3 mL, 4.0 mmol) were dissolved in tetrahydrofuran (10 mL). After purging with nitrogen three times, sodium hydride (97 mg, 4.0 mmol) was added at 0 °C. The reaction mixture was then transferred to an oil bath at 60 °C and stirred for 3 hours. After cooling to room temperature, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was separated, and the aqueous phase was extracted twice with ethyl acetate, while the organic phase was washed with water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product 2-chloro-3-isopropoxypyrazine (NPL-121-A1, 500 mg, 86.3%), a brown oil.

[1041] MS(ESI)m / z = 173.0 [M+H] +

[1042] 1 H NMR (400MHz, CDCl3): δ7.99 (d, J = 2.7Hz, 1H), 7.88 (d, J = 2.7Hz, 1H), 5.33 (dt, J = 12.3, 6.2Hz, 1H), 1.42 (d, J = 6.2Hz, 6H).

[1043] Step 2: Synthesis of NPL-121-A2

[1044] 2-Chloro-3-isopropoxypyrazine (500 mg, 2.9 mmol) and methyl glycolate (391 mg, 4.4 mmol) were dissolved in tetrahydrofuran (10 mL), purged three times with nitrogen, and sodium hydride (140 mg, 3.5 mmol) was added at 0 °C. The reaction mixture was then placed in an oil bath at 80 °C overnight. After cooling to room temperature, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was separated, the aqueous phase was extracted twice with ethyl acetate, and the organic phase was washed with water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography to obtain methyl 2-((3-isopropoxypyrazine-2-yl)oxy)acetate (NPL-121-A2, 160 mg, 24.4%), a brown oil.

[1045] MS(ESI)m / z = 227.0[M+H] + .

[1046] 1H NMR (400MHz, CDCl3): δ7.65(d,J=3.0Hz,1H),7.52(d,J=3.0Hz,1H),5.43–5.33(m,1H),4.94(s,2H),3.76(s,3H),1.42(d,J=6.2Hz,6H).

[1047] Step 3: Synthesis of NPL-121-A3

[1048] methyl 2-((3-isopropoxypyrazin-2-yl)oxy)acetate (160 mg, 0.7 mmol) was dissolved in methanol (6 mL) and water (3 mL). Lithium hydroxide (59 mg, 1.41 mmol) was added with stirring at room temperature, and the mixture was stirred for 1 hour at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 5 by adding 1 N hydrochloric acid solution. The reaction solution was separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product 2-((3-isopropoxypyrazin-2-yl)oxy)acetic acid (NPL-121-A3, 120 mg, 80.0%), a yellow solid.

[1049] MS(ESI)m / z=211.1[MH] - .

[1050] Step 4: Synthesis of NPL-121

[1051] Compounds 2-((3-isopropoxypyrazin-2-yl)oxy)acetic acid (120 mg, 0.6 mmol), 4-aminophenol (84 mg, 0.8 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (260 mg, 0.68 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (98 μL, 0.6 mmol) was added with stirring at room temperature, and the reaction was carried out for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was purified by reverse-phase separation to obtain the product 2-((3-isopropoxypyrazin-2-yl)oxy)-N-(4-hydroxyphenyl)acetamide (NPL-121, 130 mg, 75.2%), a white solid.

[1052] MS(ESI)m / z = 304.1 [M+H] + .

[1053] 1¹H NMR (400MHz, DMSO-d6): δ 9.88 (s, 1H), 9.19 (s, 1H), 7.71 (d, J = 3.0Hz, 1H), 7.62 (d, J = 3.0Hz, 1H), 7.34 (d, J = 8.9Hz, 2H), 6.68 (d, J = 8.9Hz, 2H), 5.36–5.23 (m, 1H), 4.91 (s, 2H), 1.35 (d, J = 6.2Hz, 6H). The compounds in Table 14 below were prepared using the same methods as in the examples described above, either commercially available compounds or the methods for preparing the intermediate compounds shown.

[1054] Table 14

[1055] Synthesis of NPL-123

[1056] Step 1: Synthesis of NPL-123-A1

[1057] 4,5-Dichloropyrimidine (300 mg, 2.01 mmol) and methyl glycolate (272 mg, 3.01 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). After purging with nitrogen three times, sodium hydride (97 mg, 2.42 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phase was washed with water and saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-((5-chloropyrimidin-4-yl)oxy)acetate (NPL-123-A1, 350 mg, 86.1%), a colorless oil, which was used directly in the next reaction.

[1058] MS(ESI)m / z = 203.0[M+H] + .

[1059] 1 H NMR (400MHz, CDCl3: δ8.61(s,1H),8.53(s,1H),5.04(s,2H),3.79(s,3H).

[1060] Step 2: Synthesis of NPL-123-A2

[1061] Crude methyl 2-((5-chloropyrimidin-4-yl)oxy)acetate (350 mg, 1.73 mmol) was dissolved in methanol (4 mL) and water (2 mL). Lithium hydroxide (144 mg, 3.46 mmol) was added with stirring at room temperature, and the reaction was carried out for 1 hour. After the reaction was complete, the pH of the reaction solution was adjusted to 5 by adding 1 N hydrochloric acid solution. The reaction solution was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product 2-((5-chloropyrimidin-4-yl)oxy)acetic acid (NPL-123-A2, 230 mg, 67.8%), a yellow solid, which was directly used in the next reaction step.

[1062] MS(ESI)m / z = 189.0 [M+H] + .

[1063] Step 3: Synthesis of NPL-123

[1064] 2-((5-chloropyrimidin-4-yl)oxy)acetic acid (230 mg, 1.22 mmol), 4-aminophenol (200 mg, 1.83 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (508 mg, 1.46 mmol) were dissolved in N,N-dimethylformamide (4 mL). N,N-diisopropylethylamine (210 μL, 1.22 mmol) was added with stirring at room temperature, and the reaction was carried out for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was directly purified by reverse-phase separation to obtain the product 2-((5-chloropyrimidin-4-yl)oxy)-N-(4-hydroxyphenyl)acetamide (NPL-123, 155 mg, 45.4%), a white solid.

[1065] MS(ESI)m / z = 280.0[M+H] + .

[1066] 1 H NMR (400MHz, DMSO-d6) δ9.98(s,1H),9.20(s,1H),8.75(s,1H),8.71(s,1H),7.33(d,J=8.9Hz,2H),6.74–6.65(m,2H),5.08(s,2H).

[1067] Synthesis of NPL-124

[1068] Step 1: Synthesis of NPL-124-A1

[1069] Compound 3-chloro-N,N-dimethylpyrazin-2-amine (500 mg, 3.2 mmol) and methyl glycolate (572 mg, 6.4 mmol) were dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (508 mg, 12.7 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under vacuum. The crude product was purified by silica gel column chromatography (eluent: 0-20% ethyl acetate / petroleum ether) to give methyl 2-((3-(dimethylamino)pyrazin-2-yl)oxy)acetate (NPL-124-A1, 350 mg, 52.2%), a colorless oil.

[1070] MS(ESI)m / z = 212.1[M+H] +

[1071] 1 H NMR (400MHz, CDCl3) δ7.72(d,J=2.9Hz,1H),7.38(d,J=2.9Hz,1H),4.94(s,2H),3.77(s,3H),3.12(s,6H).

[1072] Step 2: Synthesis of NPL-124-A2

[1073] methyl 2-((3-(dimethylamino)pyrazin-2-yl)oxy)acetate (300 mg, 1.4 mmol) was dissolved in methanol (9 mL) and water (3 mL), followed by the addition of lithium hydroxide (179 mg, 4.3 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, 1 N hydrochloric acid was added to quench the reaction. The reaction mixture was separated, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the product 2-((3-(dimethylamino)pyrazin-2-yl)oxy)acetic acid (NPL-124-A2, 280 mg, 100%), a brown solid.

[1074] MS(ESI)m / z = 198.1 [M+H] +

[1075] 1 H NMR (400MHz, DMSO-d6) δ7.70(d,J=3.0Hz,1H),7.44(d,J=3.0Hz,1H),4.89(s,2H),3.09(s,6H).

[1076] Step 3: Synthesis of NPL-124

[1077] Compounds 2-((3-(dimethylamino)pyrazin-2-yl)oxy)acetic acid (280 mg, 1.4 mmol), 4-aminophenol (186 mg, 1.7 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (810 mg, 2.1 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N,N-diisopropylethylamine (0.7 mL, 4.3 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent in the reaction system was removed by concentration under reduced pressure. The crude product was then purified by reverse-phase separation to obtain the product 2-((3-(dimethylamino)pyrazin-2-yl)oxy)-N-(4-hydroxyphenyl)acetamide (NPL-124, 50 mg, 12.0%), a light brown solid.

[1078] MS(ESI)m / z = 289.2[M+H] +

[1079] 1 H NMR (400MHz, DMSO-d6) δ9.89(s,1H),9.19(s,1H),7.70(d,J=2.9Hz,1H),7.41(d,J= 2.9Hz,1H),7.35(d,J=8.9Hz,2H),6.68(d,J=8.9Hz,2H),4.93(s,2H),3.07(s,6H).

[1080] The compounds in Table 15 below were prepared using the same methods as in the examples described above, either commercially available compounds or intermediate compounds prepared by reference.

[1081] Table 15

[1082] Synthesis of NPL-125

[1083] Step 1: Synthesis of NPL-125-A1

[1084] Compound 2,3-dichloropyrazine (500 mg, 3.4 mmol) was dissolved in water (3 mL), followed by the sequential addition of potassium fluoride (390 mg, 6.7 mmol) and aziridine (192 mg, 3.4 mmol). The reaction was carried out overnight at 100 °C with stirring. After cooling to room temperature, the mixture was diluted with water and dichloromethane. The liquid was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product 2-(aziridine-1-yl)-3-chloropyrazine (NPL-125-A1, 350 mg, 61.5%), a yellow oily liquid.

[1085] MS(ESI)m / z = 169.9 [M+H] + .

[1086] 1 H NMR (400MHz, CDCl3) δ7.95(d,J=2.6Hz,1H),7.61(d,J=2.6Hz,1H),4.34–4.28(m,4H),2.40–2.32(m,2H).

[1087] Step 2: Synthesis of NPL-125-A2

[1088] Under nitrogen protection, methyl 2-hydroxyacetate (319 mg, 3.5 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydrogen (85 mg, 3.5 mmol) was slowly added to the mixture at 0 °C. After 30 minutes, 2-(azacyclobutan-1-yl)-3-chloropyrazine (150 mg, 0.9 mmol) was added, and the reaction mixture was heated to 100 °C and stirred overnight. After the reaction was complete, the reaction was quenched by adding saturated ammonium chloride solution at 0 °C, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 2-((3-(azacyclobutan-1-yl)pyrazin-2-yl)oxy)acetate (NPL-125-A2, 55 mg, 27.9%), a colorless oily solid.

[1089] MS(ESI)m / z = 223.9[M+H] + .

[1090] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=3.1Hz,1H),7.25(s,1H),4.87(s,2H),4.25(t,J=7.5Hz,4H),3.77(s,3H),2.40–2.29(m,2H).

[1091] Step 3: Synthesis of NPL-125-A3

[1092] 2-((3-(azacyclobutan-1-yl)pyrazin-2-yl)oxy)acetic acid methyl ester (230 mg, 1.0 mmol) was dissolved in tetrahydrofuran (3 mL) and water (3 mL), and lithium hydroxide (49 mg, 2.1 mmol) was added and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, 1 N hydrochloric acid (3 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to give the product 2-((3-(azacyclobutan-1-yl)pyrazin-2-yl)oxy)acetic acid (NPL-125-A3, 180 mg, 83.5%), a white solid, which was used directly in the next step.

[1093] MS(ESI)m / z = 209.9[M+H] + .

[1094] Step 4: Synthesis of NPL-125

[1095] 2-((3-(azacyclobutan-1-yl)pyrazin-2-yl)oxy)acetic acid (180 mg, 0.9 mmol) was dissolved in dichloromethane (6 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (393 mg, 1 mmol), N,N-diisopropylethylamine (334 mg, 2.6 mmol), and 4-aminophenol (113 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to reverse phase separation to obtain the product 2-((3-(azacyclobutan-1-yl)pyrazin-2-yl)oxy)-N-(4-hydroxyphenyl)acetamide (NPL-125, 65 mg, 25.2%), a light brown solid.

[1096] MS(ESI)m / z = 301.2[M+H] +

[1097] 1 H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 9.19 (s, 1H), 7.62 (d, J = 3.0Hz, 1H), 7.36–7.32 (m, 2H), 7. 30(d,J=3.0Hz,1H),6.71–6.66(m,2H),4.85(s,2H),4.16(t,J=7.5Hz,4H),2.33–2.25(m,2H).

[1098] The compounds in Table 16 below were prepared using the same method as in the examples described above, either commercially available compounds or intermediate compounds prepared by the method shown.

[1099] Table 16

[1100] Synthesis of NPL-126

[1101] Step 1: Synthesis of NPL-126-A1

[1102] Compound 2,3-dichloropyrazine (2 g, 13.4 mmol) was dissolved in water (6 mL), followed by the addition of potassium fluoride (1.56 g, 26.9 mmol) and pyrrolidine (1.1 mL, 13.4 mmol). The reaction mixture was stirred overnight at 100 °C. After the reaction was complete, dichloromethane was added for dilution. The reaction mixture was separated, the aqueous phase was extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product 2-chloro-3-(pyrrolidine-1-yl)pyrazine (NPL-126-A1, 2 g, 81.1%), a yellow oily liquid.

[1103] MS(ESI)m / z = 184.0 [M+H] + .

[1104] Step 2: Synthesis of NPL-126-A2

[1105] Under nitrogen protection, methyl 2-hydroxyacetate (736 mg, 8.2 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydroxide (327 mg, 8.2 mmol) was slowly added to the mixture at 0 °C. After stirring for 30 minutes, 2-chloro-3-(pyrrolidine-1-yl)pyrazine (500 mg, 2.7 mmol) was added, and the reaction mixture was heated to 100 °C and stirred overnight. After the reaction was complete, the reaction was quenched by adding saturated ammonium chloride solution at 0 °C, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 2-((3-(pyrrolidine-1-yl)pyrazin-2-yl)oxy)acetate (NPL-126-A2, 260 mg, 40.3%), a yellow oily liquid.

[1106] MS(ESI)m / z = 238.0[M+H] + .

[1107] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=2.9Hz,1H),7.20(d,J=2.9Hz,1H),4.87(s,2H),3.77(s,3H),3.73(t,J=6.6Hz,4H),1.97–1.90(m,4H).

[1108] Step 3: Synthesis of NPL-126-A3

[1109] 260 mg (1.1 mmol) of methyl 2-((3-(pyrrolidone-1-yl)pyrazin-2-yl)oxy)acetate was dissolved in methanol (3 mL) and water (3 mL). Lithium hydroxide (52 mg, 2.2 mmol) was added and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, 1 N hydrochloric acid (3 mL) was added to adjust the reaction solution to acidity. The mixture was concentrated under vacuum to obtain the product 2-((3-(pyrrolidone-1-yl)pyrazin-2-yl)oxy)acetic acid (NPL-126-A3, 230 mg, 94%), a yellow solid, which was used directly in the next step.

[1110] MS(ESI)m / z = 224.0[M+H] + .

[1111] Step 4: Synthesis of NPL-126

[1112] 2-((3-(pyrrolidone-1-yl)pyrazin-2-yl)oxy)acetic acid (230 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (470 mg, 1.2 mmol), N,N-diisopropylethylamine (399 mg, 3.1 mmol), pyridine (8 mg, 0.1 mmol), and 4-aminophenol (135 mg, 1.2 mmol). The reaction mixture was stirred overnight at 50 °C. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to reverse phase separation to obtain the product N-(4-hydroxyphenyl)-2-((3-(pyrrolidone-1-yl)pyrazin-2-yl)oxy)acetamide (NPL-126, 12 mg, 3.7%), a light brown solid.

[1113] MS(ESI)m / z = 315.2[M+H] +

[1114] 1 H NMR (400MHz, DMSO-d6) δ9.82 (s, 1H), 9.21 (s, 1H), 7.61 (d, J = 2.9Hz, 1H), 7.38–7.32 (m, 2H), 7. 23(d,J=2.9Hz,1H),6.71–6.66(m,2H),4.87(s,2H),3.67(t,J=6.6Hz,4H),1.90–1.85(m,4H).

[1115] Synthesis of NPL-128

[1116] Step 1: Synthesis of NPL-128-A1

[1117] 2-(dimethylamino)pyridin-3-ol (800 mg, 5.6 mmol) and trifluoromethanesulfonic anhydride (2.4 g, 8.7 mmol) were dissolved in dichloromethane (50 mL) at 0 °C, followed by dropwise addition of N,N-diisopropylethylamine (9.4 mL, 7.0 mmol). The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under vacuum. The crude product was purified by silica gel column chromatography to give 2-(dimethylamino)pyridin-3-yl trifluoromethanesulfonate (NPL-128-A1, 600 mg, 38%), a colorless oil.

[1118] MS(ESI)m / z = 271.0[M+H] +

[1119] 1 H NMR (400MHz, CDCl3) δ8.18(dd,J=4.7,1.3Hz,1H),7.40(dd,J=7.9,1.3Hz,1H),6.75(dd,J=7.9,4.7Hz,1H),3.04(s,6H)

[1120] Step 2: Synthesis of NPL-128-A2

[1121] Compound 2-(dimethylamino)pyridin-3-yl trifluoromethanesulfonate (600 mg, 2.2 mmol) and (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl acrylate (602.4 mg, 2.7 mmol) were dissolved in 1,4-dioxane (9 mL) and water (3 mL), followed by the sequential addition of potassium carbonate (919 mg, 6.7 mmol) and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (162 mg, 0.2 mmol). The reaction mixture was purged three times with nitrogen and reacted overnight at 80 °C. After the reaction was complete, the mixture was cooled to room temperature, slowly poured into water, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under vacuum. The crude product was purified by silica gel column chromatography to obtain (E)-3-(2-(dimethylamino)pyridin-3-yl)ethyl acrylate (NPL-128-A2, 400 mg, 82%), a yellow oily substance.

[1122] MS(ESI)m / z = 221.2[M+H] +

[1123] 1H NMR (400MHz, CDCl3) δ8.22(dd,J=4.8,1.8Hz,1H),7.79(d,J=16.0Hz,1H),7.66(dd,J=7.5,1.5Hz,1H) ,6.86–6.78(m,1H),6.33(d,J=16.0Hz,1H),4.27(q,J=7.1Hz,2H),2.95(s,6H),1.34(t,J=7.1Hz,3H).

[1124] Step 3: Synthesis of NPL-128-A3

[1125] Ethyl (E)-3-(2-(dimethylamino)pyridin-3-yl)acrylate (400 mg, 1.8 mmol) was dissolved in methanol (9 mL) and water (3 mL), followed by the addition of lithium hydroxide (229 mg, 5.5 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, 1 N hydrochloric acid was added to adjust the pH of the reaction mixture to 5. The reaction mixture was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give the product (E)-3-(2-(dimethylamino)pyridin-3-yl)acrylate (NPL-128-A3, 300 mg, 86%), a yellow solid.

[1126] MS(ESI)m / z = 193.1 [M+H] +

[1127] Step 4: Synthesis of NPL-128-A4

[1128] Compounds (E)-3-(2-(dimethylamino)pyridin-3-yl)acrylic acid (300 mg, 1.8 mmol), 4-aminophenol (256 mg, 2.3 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (712 mg, 1.9 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N,N-diisopropylethylamine (0.8 mL, 4.7 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, and the solvent in the reaction system was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography to obtain product (E)-3-(2-(dimethylamino)pyridin-3-yl)-N-(4-hydroxyphenyl)acrylamide (NPL-128-A4, 200 mg, 45%), a brown solid.

[1129] MS(ESI)m / z = 284.1[M+H] +

[1130] Step 5: Synthesis of NPL-128

[1131] Compound (E)-3-(2-(dimethylamino)pyridin-3-yl)-N-(4-hydroxyphenyl)acrylamide (150 mg, 0.5 mmol) was dissolved in methanol (5 mL), and palladium on carbon (28 mg, 0.03 mmol) was added, followed by three purgings with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was reverse-phase to prepare product 3-(2-(dimethylamino)pyridin-3-yl)-N-(4-hydroxyphenyl)propionamide (NPL-128, 60 mg, 40%), a white solid.

[1132] MS(ESI)m / z = 286.1[M+H] +

[1133] 1 H NMR (400MHz, DMSO-d6) δ9.67(s,1H),9.13(s,1H),8.08(dd,J=4.7,1.7Hz,1H),7.52(dd,J=7.4,1.6Hz,1H),7.34(d, J=8.8Hz,2H),6.90(dd,J=7.4,4.8Hz,1H),6.68(t,J=6.0Hz,2H),2.95–2.88(m,2H),2.76(s,6H),2.61–2.55(m,2H).

[1134] Synthesis of NPL-129

[1135] Step 1: Synthesis of NPL-129-A1

[1136] Under nitrogen protection, 3-bromo-2-isopropoxypyridine (1.1 g, 1.4 mmol) was dissolved in 1,4-dioxane (30 mL) and water (10 mL). Then, 3-(4,4,5,5-tetramethyl-[1,3,2]dioxoboron-2-yl)ethyl acrylate (2.3 g, 10.0 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (0.4 g, 0.5 mmol), and potassium carbonate (2.1 g, 15.0 mmol) were added sequentially. After three nitrogen purgings, the reaction mixture was stirred overnight at 80 °C. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain (E)-3-(2-isopropoxypyridine-3-yl)ethyl acrylate (NPL-129-A1, 200 mg, 17.0%), a yellow solid.

[1137] MS(ESI)m / z = 236.1[M+H] +

[1138] 1 H NMR (400MHz, CDCl3) δ8.14(dd,J=4.9,1.8Hz,1H),7.80(d,J=16.1Hz,1H),7.72(dd,J=7.5,1.9Hz,1H),6.86(dd,J=7.4,4.9 Hz,1H),6.60(d,J=16.1Hz,1H),5.49–5.36(m,1H),4.27(q,J=7.1Hz,2H),1.41(s,3H),1.39(s,3H),1.34(t,J=7.1Hz,3H).

[1139] Step 2: Synthesis of NPL-129-A2

[1140] Ethyl (E)-3-(2-isopropoxypyridin-3-yl)acrylate (200 mg, 0.9 mmol) was dissolved in methanol (3 mL) and water (1 mL), and lithium hydroxide (41 mg, 1.7 mmol) was added and the mixture was stirred for 2 hours. After the reaction was completed, 1 N hydrochloric acid (5 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(2-isopropoxypyridin-3-yl)acrylic acid (NPL-129-A2, 170 mg, 96.5%), a white solid.

[1141] MS(ESI)m / z = 208.1[M+H] + .

[1142] Step 3: Synthesis of NPL-129-A3

[1143] The compound (E)-3-(2-isopropoxypyridin-3-yl)acrylic acid (170 mg, 0.8 mmol) was dissolved in N,N-dimethylformamide (4 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (468 mg, 1.2 mmol), N,N-diisopropylethylamine (318 mg, 2.5 mmol), and 4-aminophenol (107 mg, 1.0 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(2-isopropoxypyridin-3-yl)-N-(4-phenol)acrylamide (NPL-129-A3, 170 mg, 69.5%), a yellow oily liquid.

[1144] MS(ESI)m / z = 299.1 [M+H] +

[1145] Step 4: Synthesis of NPL-129

[1146] Compound (E)-3-(2-isopropoxypyridin-3-yl)-N-(4-phenol)acrylamide (160 mg, 0.5 mmol) was dissolved in methanol (3 mL), and palladium on carbon catalyst (57 mg, 0.05 mmol) was added. Hydrogen was purged three times, and the reaction mixture was stirred overnight under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse phase separation to obtain product (E)-3-(2-isopropoxypyridin-3-yl)-N-(4-phenol)propionamide (NPL-129, 60 mg, 37.3%), a white solid.

[1147] MS(ESI)m / z = 301.2[M+H] +

[1148] 1 H NMR (400MHz, DMSO-d6) δ9.61(s,1H),9.12(s,1H),7.98(dd,J=5.0,1.9Hz,1H),7.51(dd,J=7.2,1.8Hz,1H),7.35 -7.30(m,2H),6.85(dd,J=7.2,5.0Hz,1H),6.68–6.64(m,2H),5.31–5.24( m, 1H), 2.79 (t, J = 7.5Hz, 2H), 2.55 (d, J = 8.0Hz, 2H), 1.30 (d, J = 6.2Hz, 6H).

[1149] Synthesis of NPL-130

[1150] Step 1: Synthesis of NPL-130-A1

[1151] Under nitrogen protection, 3-bromo-2-(tert-butoxy)pyridine (500 mg, 2.2 mmol) was dissolved in 1,4-dioxane (12 mL) and water (4 mL). Then, 3-(4,4,5,5-tetramethyl-[1,3,2]dioxoboron-2-yl)ethyl acrylate (983 mg, 4.4 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (42 mg, 0.1 mmol), and potassium carbonate (901 mg, 6.5 mmol) were added sequentially. After three nitrogen purgings, the reaction mixture was stirred overnight at 80 °C. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(2-tert-butoxypyridine-3-yl)ethyl acrylate (NPL-130-A1, 500 mg, 92.3%), a yellow oily liquid.

[1152] MS(ESI)m / z = 250.1[M+H] +

[1153] 1 H NMR (400MHz, CDCl3) δ8.11(dd,J=4.8,1.6Hz,1H),7.78(d,J=16.1Hz,1H),7.69(dd,J=7.4,1.3Hz,1H),6.8 4(dd,J=7.4,4.9Hz,1H),6.57(d,J=16.1Hz,1H),4.26(q,J=7.1Hz,2H),1.65(s,9H),1.33(t,J=7.1Hz,3H).

[1154] Step 2: Synthesis of NPL-130-A2

[1155] Ethyl (E)-3-(2-tert-butoxypyridin-3-yl)acrylate (500 mg, 2.0 mmol) was dissolved in methanol (15 mL) and water (5 mL), and lithium hydroxide (96 mg, 4.0 mmol) was added and the mixture was stirred for 2 hours. After the reaction was completed, 1 N hydrochloric acid (5 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(2-tert-butoxypyridin-3-yl)acrylic acid (NPL-130-A2, 400 mg, 90.1%), a white solid.

[1156] MS(ESI)m / z=220.2[MH] + .

[1157] Step 3: Synthesis of NPL-130-A3

[1158] Compound (E)-3-(2-tert-butoxypyridin-3-yl)acrylic acid (400 mg, 1.8 mmol) was dissolved in N,N-dimethylformamide (9 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1031 mg, 2.7 mmol), N,N-diisopropylethylamine (0.9 mL, 5.4 mmol), and 4-aminophenol (237 mg, 2.2 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with water and diluted with ethyl acetate. The reaction mixture was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(2-tert-butoxypyridin-3-yl)-N-(4-phenol)acrylamide (NPL-130-A3, 260 mg, 46.0%), a yellow solid.

[1159] MS(ESI)m / z = 313.1[M+H] + .

[1160] Step 4: Synthesis of NPL-130

[1161] Compound (E)-3-(2-tert-butoxypyridin-3-yl)-N-(4-phenol)acrylamide (250 mg, 0.8 mmol) was dissolved in methanol (4 mL), and palladium on carbon catalyst (85 mg, 0.1 mmol) was added, followed by three purgings with hydrogen. The reaction mixture was stirred overnight under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse phase separation to obtain product (E)-3-(2-isopropoxypyridin-3-yl)-N-(4-phenol)propionamide (NPL-130, 140 mg, 58.0%), a white solid.

[1162] MS(ESI)m / z = 315.1[M+H] + .

[1163] 1 H NMR (400MHz, DMSO-d6) δ9.61(s,1H),9.13(s,1H),7.95(dd,J=4.8,1.7Hz,1H),7.53–7.45(m,1H),7.34(d,J=8.8Hz ,2H),6.82(dd,J=7.1,5.0Hz,1H),6.67(d,J=8.8Hz,2H),2.76(t,J=7.5Hz,2H),2.54(d,J=7.8Hz,2H),1.56(s,9H).

[1164] Synthesis of NPL-132

[1165] Step 1: Synthesis of NPL-132-A1

[1166] 3-Chloro-N,N-dimethylpyrazine-2-amine (500 mg, 3.2 mmol) and (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)acrylate (861 mg, 3.8 mmol) were dissolved in 1,4-dioxane (30 mL) and water (5 mL), followed by the sequential addition of potassium carbonate (K₂CO₃) (1.3 g, 9.5 mmol) and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (232.1 mg, 0.3 mmol). After purging with nitrogen three times, the reaction mixture was placed at 80 °C for 18 hours. The mixture was cooled to room temperature, and the reaction solution was slowly poured into water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain (E)-3-(3-(dimethylamino)pyrazin-2-yl)ethyl acrylate (NPL-132-A1, 400 mg, 57%), a yellow oily substance.

[1167] MS(ESI)m / z = 222.1[M+H] + .

[1168] 1 H NMR (400MHz, CDCl3) δ8.07(d,J=2.3Hz,1H),8.04(d,J=2.3Hz,1H),7.78(d,J=15.5Hz, 1H), 6.88 (d, J = 15.5Hz, 1H), 4.27 (q, J = 7.1Hz, 2H), 3.02 (s, 6H), 1.33 (t, J = 7.1Hz, 4H).

[1169] Step 2: Synthesis of NPL-132-A2

[1170] Ethyl (E)-3-(3-(dimethylamino)pyrazin-2-yl)acrylate (400 mg, 1.8 mmol) was dissolved in methanol (9 mL) and water (3 mL), followed by the addition of lithium hydroxide (LiOH) (152 mg, 3.6 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, 1 N hydrochloric acid was added to quench the reaction. The reaction mixture was separated and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give the product (E)-3-(3-(dimethylamino)pyrazin-2-yl)acrylate (NPL-132-A2, 310 mg, 89%), a white solid.

[1171] MS(ESI)m / z = 194.1 [M+H] + .

[1172] 1 H NMR (400MHz, DMSO-d6) δ8.16(d,J=2.4Hz,1H),8.10(d,J=2.4Hz,1H),7.60(d,J=15.5Hz,1H),6.70(d,J=15.5Hz,1H),2.94(s,6H).

[1173] Step 3: Synthesis of NPL-132-A3

[1174] Compounds (E)-3-(3-(dimethylamino)pyrazin-2-yl)acrylic acid (120 mg, 0.6 mmol), 4-aminophenol (102 mg, 0.9 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (283 mg, 0.7 mmol) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of N,N-diisopropylethylamine (0.1 mL, 0.6 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was slowly poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(3-(dimethylamino)pyrazin-2-yl)-N-(4-hydroxyphenyl)acrylamide (NPL-132-A3, 60 mg, 34%), a brown oily substance.

[1175] MS(ESI)m / z = 285.1 [M+H] +

[1176] Step 4: Synthesis of NPL-132

[1177] Compound (E)-3-(3-(dimethylamino)pyrazin-2-yl)-N-(4-hydroxyphenyl)acrylamide (60 mg, 0.2 mmol) was dissolved in methanol (5 mL), and palladium on carbon (8.8 mg, 0.01 mmol) was added, followed by three purgings with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was separated by reverse phase to obtain product 3-(3-(dimethylamino)pyrazin-2-yl)-N-(4-hydroxyphenyl)propionamide (25 mg, 41%), a white solid.

[1178] MS(ESI)m / z = 287.2[M+H] +

[1179] 1 H NMR(400MHz,DMSO-d6)δ9.70(s,1H),9.12-9.09(m,1H),8.02(d,J=2.5Hz,1H),8.01(d,J=2.5Hz,1H),7 .34(d,J=8.8Hz,2H),6.65(d,J=8.8Hz,2H),3.07(t,J=7.4Hz,2H),2.86(s,6H),2.75(t,J=7.4Hz,2H).

[1180] Synthesis of NPL-133

[1181] Step 1: Synthesis of NPL-133-A1

[1182] Under nitrogen protection, compound 2-(azacyclobutan-1-yl)-3-chloropyrazine (650 mg, 3.8 mmol) was dissolved in 1,4-dioxane (6 mL) and water (2 mL). Then, potassium carbonate (1.6 g, 11.5 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxborane-2-yl)ethyl acrylate (1.7 g, 7.7 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (280 mg, 0.4 mmol) were added sequentially. The mixture was purged with nitrogen three times, and the reaction solution was stirred overnight at 80 °C. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain (E)-3-(3-(azacyclobutane-1-yl)pyrazin-2-yl)ethyl acrylate (NPL-133-A1, 600 mg, 67.1%), a yellow solid.

[1183] MS(ESI)m / z = 234.0[M+H] +

[1184] 1 H NMR (400MHz, CDCl3) δ8.06(d,J=2.3Hz,1H),7.93(d,J=2.3Hz,1H),7.70(d,J=15.3Hz,1H) ,6.83(d,J=15.3Hz,1H),4.25(t,J=7.5Hz,6H),2.50–2.38(m,2H),1.33(d,J=7.1Hz,3H).

[1185] Step 2: Synthesis of NPL-133-A2

[1186] Ethyl (E)-3-(3-(azacyclobutan-1-yl)pyrazin-2-yl)acrylate (600 mg, 2.6 mmol) was dissolved in methanol (9 mL) and water (9 mL), and lithium hydroxide (123 mg, 5.1 mmol) was added and stirred for 1 hour. After the reaction was completed, 1 N hydrochloric acid (6 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(3-(azacyclobutan-1-yl)pyrazin-2-yl)acrylic acid (NPL-133-A2, 485 mg, 91.9%), a yellow solid.

[1187] MS(ESI)m / z = 206.0[M+H] + .

[1188] Step 3: Synthesis of NPL-133-A3

[1189] Compound (E)-3-(3-(azacyclobutan-1-yl)pyrazin-2-yl)acrylic acid (485 mg, 2.4 mmol), 4-aminophenol (309 mg, 2.8 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.0 g, 2.8 mmol) were dissolved in N,N-dimethylformamide (15 mL), followed by the addition of N,N-diisopropylethylamine (0.5 mL, 2.8 mmol) and stirring for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain product (E)-3-(3-(azacyclobutan-1-yl)pyrazin-2-yl)-N-(4-hydroxyphenyl)acrylamide (NPL-133-A3, 250 mg, 26.8%), a yellow solid.

[1190] MS(ESI)m / z = 297.2[M+H] + .

[1191] Step 4: Synthesis of NPL-133

[1192] Compound (E)-3-(3-(azacyclobutan-1-yl)pyrazin-2-yl)-N-(4-hydroxyphenyl)acrylamide (250 mg, 0.8 mmol) was dissolved in methanol (8 mL), and palladium on carbon catalyst (90 mg, 0.08 mmol) was added, followed by three purgings with hydrogen. The reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse phase separation to obtain product 3-(3-(azacyclobutan-1-yl)pyrazin-2-yl)-N-(4-hydroxyphenyl)propionamide (NPL-133, 70 mg, 27.8%), a white solid.

[1193] MS(ESI)m / z = 299.2[M+H] + .

[1194] 1 H NMR(400MHz, DMSO-d6)δ9.70(s,1H),9.11(s,1H),7.93(d,J=2.7Hz,1H),7.79(d,J=2.7Hz,1H),7.37–7.33(m, 2H),6.68–6.64(m,2H),4.12(t,J=7.5Hz,4H),2.94(t,J=7.3Hz,2H),2.70(t,J=7.4Hz,2H),2.32–2.25(m,2H).

[1195] Synthesis of NPL-134

[1196] Step 1: Synthesis of NPL-134-A1

[1197] Under nitrogen protection, 2-chloro-3-(pyrrolidine-1-yl)pyrazine (500 mg, 2.7 mmol) was dissolved in 1,4-dioxane (9 mL) and water (3 mL). Potassium carbonate (1.1 g, 8.2 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxoboron-2-yl)ethyl acrylate (1.2 g, 5.5 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (199 mg, 0.3 mmol) were added sequentially. The mixture was purged with nitrogen three times, and the reaction solution was stirred overnight at 80 °C. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to give product (E)-3-(3-(pyrrolidine-1-yl)pyrazin-2-yl)ethyl acrylate (NPL-134-A1, 280 mg, 41.6%), a yellow solid.

[1198] MS(ESI)m / z = 248.0[M+H] +

[1199] 1 H NMR (400MHz, CDCl3) δ8.03(d,J=2.3Hz,1H),7.93(d,J=15.3Hz,1H),7.91(d,J=2.3Hz,1H),6.76 (d,J=15.3Hz,1H),4.26(q,J=7.1Hz,2H),3.60(m,4H),1.99–1.95(m,4H),1.32(t,J=7.1Hz,3H).

[1200] Step 2: Synthesis of NPL-134-A2

[1201] Ethyl (E)-3-(3-(pyrrolidone-1-yl)pyrazin-2-yl)acrylate (280 mg, 1.1 mmol) was dissolved in methanol (3 mL) and water (3 mL), and lithium hydroxide (54 mg, 2.3 mmol) was added and stirred for 1 hour. After the reaction was completed, 1 N hydrochloric acid (3 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the product (E)-3-(3-(pyrrolidone-1-yl)pyrazin-2-yl)acrylic acid (NPL-134-A2, 220 mg, 88.6%), a yellow solid, which was used directly in the next step.

[1202] MS(ESI)m / z = 220.0[M+H] + .

[1203] Step 3: Synthesis of NPL-134-A3

[1204] Compound (E)-3-(3-(pyrrolidone-1-yl)pyrazin-2-yl)acrylic acid (220 mg, 1.0 mmol), 4-aminophenol (131 mg, 1.2 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (458 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (8 mL), followed by the addition of N,N-diisopropylethylamine (0.2 mL, 1.2 mmol) and stirring for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain product (E)-N-(4-hydroxyphenyl)-3-(3-(pyrrolidone-1-yl)pyrazin-2-yl)acrylamide (NPL-134-A3, 200 mg, 64.2%), a yellow solid.

[1205] MS(ESI)m / z = 311.0[M+H] + .

[1206] Step 4: Synthesis of NPL-134

[1207] Compound (E)-N-(4-hydroxyphenyl)-3-(3-(pyrrolidone-1-yl)pyrazin-2-yl)acrylamide (200 mg, 0.6 mmol) was dissolved in methanol (10 mL), and palladium on carbon catalyst (69 mg, 0.06 mmol) was added. Hydrogen was purged three times, and the reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse-phase separation to obtain product N-(4-hydroxyphenyl)-3-(3-(pyrrolidone-1-yl)pyrazin-2-yl)propionamide (NPL-134, 75 mg, 37.3%), a white solid.

[1208] MS(ESI)m / z = 313.3[M+H] +

[1209] 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),9.10(s,1H),7.90(d,J=2.6Hz,1H),7.79(d,J=2.6Hz,1H),7.36–7.32(m, 2H),6.68–6.64(m,2H),3.51(t,J=6.6Hz,4H),3.14(t,J=7.4Hz,2H),2.69(t,J=7.4Hz,2H),1.91–1.87(m,4H).

[1210] Synthesis of NPL-136

[1211] Step 1: Synthesis of NPL-136-A1

[1212] Compound 2,3-dichloropyrazine (1 g, 6.7 mmol) and cyclopropylboronic acid (0.6 g, 6.7 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL), followed by the sequential addition of potassium phosphate (4.3 g, 20.1 mmol) and tetrakis(triphenylphosphine)palladium (0.8 g, 0.7 mmol). After three purgings with nitrogen, the reaction was carried out overnight at 80 °C. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (0-3% ethyl acetate / petroleum ether) to give the product 2-cyclopropyl-3-chloropyrazine (NPL-136-A1, 450 mg, 43.4%), a colorless oil.

[1213] 1 H NMR (400MHz, CDCl3) δ8.30(d,J=2.4Hz,1H),8.09(d,J=2.4Hz,1H),2.55–2.47(m,1H),1.15–1.09(m,4H).

[1214] Step 2: Synthesis of NPL-136-A2

[1215] Compound 2-cyclopropyl-3-chloropyrazine (600 mg, 3.9 mmol) and (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl acrylate (1.3 g, 5.8 mmol) were dissolved in 1,4-dioxane (30 mL) and water (5 mL). Potassium carbonate (1.61 g, 11.64 mmol) and bis(triphenylphosphine)ferrocene palladium dichloride (0.28 g, 0.39 mmol) were then added sequentially. After three nitrogen purgings, the mixture was reacted overnight at 80 °C. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(3-cyclopropylpyrazine-2-yl)ethyl acrylate (NPL-136-A2, 370 mg, 43.7%), a pale yellow oil.

[1216] MS(ESI)m / z = 219.1[M+H] + .

[1217] Step 3: Synthesis of NPL-136-A3

[1218] Ethyl (E)-3-(3-cyclopropylpyrazin-2-yl)acrylate (370 mg, 1.7 mmol) was dissolved in methanol (6 mL) and water (3 mL). Lithium hydroxide (140 g, 3.4 mmol) was added with stirring at room temperature, and the reaction was carried out for 1 hour. After the reaction was complete, the pH of the reaction solution was adjusted to 5 by adding 1 N hydrochloric acid solution. The reaction solution was separated, extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (E)-3-(3-cyclopropylpyrazin-2-yl)acrylate (NPL-136-A3, 300 mg, 93.0%), a yellow solid, which was directly used in the next reaction step.

[1219] MS(ESI)m / z = 191.1[M+H] + .

[1220] Step 4: Synthesis of NPL-136-A4

[1221] Compound (E)-3-(3-cyclopropylpyrazin-2-yl)acrylic acid (110 mg, 0.6 mmol), 4-aminophenol (95 mg, 0.9 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (264 mg, 0.7 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (75 mg, 0.6 mmol) was added with stirring at room temperature, and the reaction was carried out for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was directly purified by reverse-phase separation to obtain the product (E)-3-(3-cyclopropylpyrazin-2-yl)-N-(4-hydroxyphenyl)acrylamide (NPL-136-A4, 120 mg, 73.8%), a yellow solid.

[1222] Step 5: Synthesis of NPL-136

[1223] Compound (E)-3-(3-cyclopropylpyrazin-2-yl)-N-(4-hydroxyphenyl)acrylamide (120 mg, 0.4 mmol) was dissolved in methanol (6 mL), and palladium / carbon (40 mg, 0.36 mmol) was added with stirring. After three purgings with hydrogen, the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Subsequently, the crude product was purified by reverse-phase separation to obtain the product 3-(3-cyclopropylpyrazin-2-yl)-N-(4-hydroxyphenyl)propionamide (NPL-136, 60 mg, 58.8%), a white solid.

[1224] MS(ESI)m / z = 284.1[M+H] + .

[1225] 1H NMR (400MHz, DMSO-d6) δ9.74(s,1H),9.15(s,1H),8.27(t,J=2.7Hz,2H),7.35(d,J=8.9Hz,2H),6.67(d,J=8.8Hz,2H), 3.26(t,J=7.4Hz,2H),2.77(t,J=7.4Hz,2H),2.35–2.28(m,1H),1.03(ddd,J=8.0,4.8,2.2Hz,2H),0.99–0.94(m,2H).

[1226] The compounds in Table 17 below were prepared using the same method as in the examples described above, either commercially available compounds or intermediate compounds prepared by the method shown.

[1227] Table 17

[1228] Synthesis of NPL-137

[1229] Step 1: Synthesis of NPL-137-A1

[1230] Compound (E)-3-(3-cyclopropylpyrazin-2-yl)acrylic acid (100 mg, 0.5 mmol), 4-aminophenol (118 mg, 0.8 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (240 mg, 0.6 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (68 mg, 0.5 mmol) was added with stirring at room temperature, and the reaction was carried out for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was directly purified by reverse-phase separation to obtain the product (E)-3-(3-cyclopropylpyrazin-2-yl)-N-(4-acetaminophenyl)acrylamide (NPL-137-A1, 100 mg, 59.0%), a yellow solid.

[1231] MS(ESI)m / z = 323.1[M+H] +

[1232] Step 2: Synthesis of NPL-137

[1233] Compound (E)-3-(3-cyclopropylpyrazin-2-yl)-N-(4-acetaminophenyl)acrylamide (100 mg, 0.3 mmol) was dissolved in methanol (6 mL), and palladium / carbon (33 mg, 0.03 mmol) was added with stirring. After three purgings with hydrogen, the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was directly purified by reverse-phase separation to give the product 3-(3-cyclopropylpyrazin-2-yl)-N-(4-acetaminophenyl)propionamide (NPL-137, 70 mg, 69.6%), a white solid.

[1234] MS(ESI)m / z = 325.1 [M+H] + .

[1235] 1 H NMR(400MHz, DMSO-d6)δ9.94(s,1H),9.84(s,1H),8.28(dd,J=5.6,2.4Hz,2H),7.54–7.42(m,4H),3.27(t, J=7.3Hz,2H),2.81(t,J=7.3Hz,2H),2.37–2.25(m,1H),2.01(s,3H),1.07–1.00(m,2H),0.99–0.92(m,2H).

[1236] Synthesis of NPL-139

[1237] Step 1: Synthesis of NPL-139-A1

[1238] Under nitrogen protection, 2,3-dibromopyrazine (2 g, 8.4 mmol) was dissolved in 1,4-dioxane (30 mL) and water (10 mL). Potassium carbonate (3.5 g, 25.2 mmol), pinacol 1-cyclopentenylborate (1.7 mL, 8.4 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.6 g, 0.8 mmol) were added sequentially. After three nitrogen purgings, the reaction mixture was stirred overnight at 80 °C. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product 2-bromo-3-(cyclopenten-1-yl)pyrazine (NPL-139-A1, 700 mg, 37.0%), a yellow oily liquid.

[1239] MS(ESI)m / z = 225.0[M+H] + .

[1240] 1H NMR (400MHz, CDCl3) δ8.48–8.45(m,1H),8.14(d,J=2.3Hz,1H),6.93–6.82(m,1H),2.95–2.85(m,2H),2.70–2.60(m,2H),2.09–1.98(m,2H).

[1241] Step 2: Synthesis of NPL-139-A2

[1242] Under nitrogen protection, 2-bromo-3-(cyclopenten-1-yl)pyrazine (700 mg, 3.1 mmol) was dissolved in 1,4-dioxane (30 mL) and water (10 mL). Then, ethyl 3-(4,4,5,5-tetramethyl-[1,3,2]dioxoboron-2-yl)acrylate (1406 mg, 6.2 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (228 mg, 0.3 mmol), and potassium carbonate (1289 mg, 9.3 mmol) were added sequentially. After purging with nitrogen three times, the reaction mixture was stirred overnight at 80 °C. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain (E)-3-(3-(cyclopenten-1-yl)pyrazin-2-yl)ethyl acrylate (NPL-139-A2, 300 mg, 65.8%), a yellow oily liquid.

[1243] MS(ESI)m / z = 245.1 [M+H] + .

[1244] 1 H NMR (400MHz, CDCl3) δ8.49(d,J=2.2Hz,1H),8.42(d,J=2.2Hz,1H),8.00(d,J=15.4Hz,1H),7.04(d,J=15.4Hz,1H),6.17–6.11(m,1H), 4.28(q,J=7.1Hz,2H),2.89(ddd,J=9.7,4.6,2.1Hz,2H),2.67(ddt,J=9.9,7.4,2.3Hz,2H),2.11–2.03(m,2H),1.34(t,J=7.1Hz,3H).

[1245] Step 3: Synthesis of NPL-139-A3

[1246] Ethyl (E)-3-(3-(cyclopenten-1-yl)pyrazin-2-yl)acrylate (500 mg, 2.1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL), and lithium hydroxide (98 mg, 4.1 mmol) was added and the mixture was stirred for 12 hours. After the reaction was completed, 1 N hydrochloric acid (10 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(3-(cyclopenten-1-yl)pyrazin-2-yl)acrylic acid (NPL-139-A3, 440 mg, 99.4%), a white solid.

[1247] MS(ESI)m / z = 217.1 [MH] + .

[1248] Step 4: Synthesis of NPL-139-A4

[1249] Compound (E)-3-(3-(cyclopenten-1-yl)pyrazin-2-yl)acrylic acid (250 mg, 1.2 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (659 mg, 1.7 mmol), N,N-diisopropylethylamine (0.6 mL, 3.5 mmol), and 4-aminophenol (189 mg, 1.7 mmol). The mixture was stirred at room temperature for 6 hours. After the reaction was complete, the reaction was quenched with water and diluted with ethyl acetate. The reaction mixture was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(3-(cyclopenten-1-yl)pyrazin-2-yl)-N-(4-phenol)acrylamide (NPL-139-A4, 200 mg, 56.3%), a yellow oily liquid.

[1250] MS(ESI)m / z = 308.1 [M+H] + .

[1251] Step 5: Synthesis of NPL-139

[1252] Compound (E)-3-(3-(cyclopenten-1-yl)pyrazin-2-yl)-N-(4-phenol)acrylamide (200 mg, 0.7 mmol) was dissolved in methanol (5 mL), and palladium on carbon catalyst (70 mg, 0.06 mmol) was added. Hydrogen was purged three times, and the reaction mixture was stirred overnight under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse phase separation to obtain product 3-(3-(cyclopenten-1-yl)pyrazin-2-yl)-N-(4-phenol)propionamide (NPL-139, 30 mg, 14.8%), a white solid.

[1253] MS(ESI)m / z = 312.1[M+H] + .

[1254] 1 H NMR (400MHz, DMSO-d6) δ9.71(s,1H),9.12(s,1H),8.39(d,J=2.4Hz,1H),8.34(d,J=2.4Hz,1H),7.34(d,J=8.8Hz,2H),6.66(d,J=8. 8Hz,2H),3.53–3.45(m,1H),3.16(t,J=7.3Hz,2H),2.75(t,J=7.4Hz,2H),2.03–1.94(m,2H),1.82–1.73(m,4H),1.72–1.62(m,2H).

[1255] Synthesis of NPL-140

[1256] Step 1: Synthesis of NPL-140-A1

[1257] 4-Chloro-6-methylquinazoline (1.0 g, 6.7 mmol) was dissolved in N,N-dimethylformamide (22 mL). Methyl glycolate (605 mg, 6.7 mmol) and sodium hydride (269 mg, 6.7 mmol) were added sequentially at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and the solution was diluted with ethyl acetate. The reaction mixture was separated, and the organic phase was washed with water and saturated brine. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give methyl 2-((6-methylquinazoline-4-yl)oxy)acetate (NPL-140-A1, 620 mg, 59.6%), a yellow solid.

[1258] MS(ESI)m / z = 233.1[M+H] + .

[1259] 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),8.03(s,1H),7.86(d,J=8.6Hz,1H),7.69(dd,J=8.6,1.9Hz,1H),5.15(s,2H),3.81(s,3H),2.55(s,3H).

[1260] Step 2: Synthesis of NPL-140-A2

[1261] 2-((6-methylquinazoline-4-yl)oxy)acetic acid methyl ester (600 mg, 2.6 mmol) was dissolved in methanol (14 mL) and water (7 mL), and lithium hydroxide (217 mg, 5.2 mmol) was added and the mixture was stirred for 4 hours. After the reaction was completed, 1 N hydrochloric acid (10 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product 2-((6-methylquinazoline-4-yl)oxy)acetic acid (NPL-140-A2, 300 mg, 53.2%), a yellow solid.

[1262] MS(ESI)m / z = 219.0 [M+H] + .

[1263] Step 3: Synthesis of NPL-140

[1264] 2-((6-methylquinazoline-4-yl)oxy)acetic acid (80 mg, 0.4 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (209 mg, 0.6 mmol), N,N-diisopropylethylamine (0.2 mL, 1.1 mmol), and 4-aminophenol (48 mg, 0.5 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse-phase separation to obtain the product N-(4-phenol)-2-((6-methylquinazoline-4-yl)oxy)acetamide (NPL-140, 32 mg, 28.2%), a white solid.

[1265] MS(ESI)m / z = 310.1[M+H] + .

[1266] 1 H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.21(s,1H),8.71(s,1H),8.06(s,1H),7.88–7 .81(m,2H),7.36(d,J=8.8Hz,2H),6.70(d,J=8.8Hz,2H),5.17(s,2H),2.55(s,3H).

[1267] Synthesis of NPL-141

[1268] Step 1: Synthesis of NPL-141-A1

[1269] 6-Methylquinoline-4-ol (1.3 g, 8.2 mmol) was dissolved in acetone (60 mL), followed by the sequential addition of potassium carbonate (3.4 g, 24.5 mmol) and ethyl bromoacetate (2.7 g, 16.3 mmol). The mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain ethyl 2-((6-methylquinoline-4-yl)oxy)acetate (NPL-141-A1, 1.9 g, 94.9%), a yellow solid.

[1270] MS(ESI)m / z = 246.2[M+H] + .

[1271] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),7.47(dd,J=8.7,1.9Hz,1H),7.43(d,J=7.7Hz,1H),7.11(d,J=8.6H z,1H),6.29(d,J=7.7Hz,1H),4.75(s,2H),4.25(q,J=7.1Hz,2H),2.46(s,3H),1.25(t,J=7.1Hz,3H).

[1272] Step 2: Synthesis of NPL-141-A2

[1273] 1.0 g (4.1 mmol) of ethyl 2-((6-methylquinoline-4-yl)oxy)acetic acid was dissolved in 10 mL of methanol and 10 mL of water. Lithium hydroxide (200 mg, 8.2 mmol) was added and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, 6 mL of 1 N hydrochloric acid was added to adjust the reaction solution to acidity. The mixture was concentrated under vacuum to give 2-((6-methylquinoline-4-yl)oxy)acetic acid (NPL-141-A2, 800 mg, 90.3%), a yellow solid, which was used directly in the next step of the reaction.

[1274] MS(ESI)m / z = 218.0[M+H] + .

[1275] Step 3: Synthesis of NPL-141

[1276] 2-((6-methylquinoline-4-yl)oxy)acetic acid (180 mg, 0.9 mmol) was dissolved in N,N-dimethylformamide (8 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (NPL-141-A3, 121 mg, 1.1 mmol), N,N-diisopropylethylamine (238 mg, 1.8 mmol), and 4-aminophenol (121 mg, 1.1 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to reverse-phase separation to obtain the product 2-((3-(azacyclobutane-1-yl)pyrazin-2-yl)oxy)-N-(4-hydroxyphenyl)acetamide (15 mg, 5.3%), a white solid.

[1277] MS(ESI)m / z = 309.3[M+H] + .

[1278] 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),9.24(s,1H),7.97(s,1H),7.92(d,J=7.7Hz,1H),7.53(dd,J=8.8,2.0Hz,1 H),7.40(d,J=8.7Hz,1H),7.38–7.34(m,2H),6.72–6.68(m,2H),6.04(d,J=7.7Hz,1H),5.04(s,2H),2.40(s,3H).

[1279] Synthesis of NPL-144

[1280] Step 1: Synthesis of NPL-144

[1281] 2-((6-methylquinazoline-4-yl)oxy)acetic acid (100 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (261 mg, 0.7 mmol), N,N-diisopropylethylamine (0.2 mL, 1.4 mmol), and 4-aminoacetanilide (83 mg, 0.6 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse phase separation to obtain the product N-(4-acetaminophenyl)-2-((6-methylquinazoline-4-yl)oxy)acetamide (NPL-144, 18 mg, 10.8%), a white solid.

[1282] MS(ESI)m / z = 351.3[M+H]+ .

[1283] 1 H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.87(s,1H),8.71(s,1H),8.06(s,1 H),7.88–7.82(m,2H),7.50(s,4H),5.21(s,2H),2.55(s,3H),2.01(s,3H).

[1284] Synthesis of NPL-145

[1285] Step 1: Synthesis of NPL-145

[1286] 2-((6-methylquinoline-4-yl)oxy)acetic acid (200 mg, 0.9 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (420 mg, 1.1 mmol), N,N-diisopropylethylamine (238 mg, 1.8 mmol), and N-(4-aminophenyl)acetamide (166 mg, 1.1 mmol) and stirring overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by reverse phase to give the product N-(4-acetaminophenyl)-2-((6-methylquinoline-4-yl)oxy)acetamide (NPL-145, 35 mg, 10.9%), a white solid.

[1287] MS(ESI)m / z = 350.3[M+H] +

[1288] 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),9.88(s,1H),7.98(s,1H),7.93(d,J=7.7Hz,1H),7.55–7. 47(m,5H),7.41(d,J=8.7Hz,1H),6.05(d,J=7.7Hz,1H),5.08(s,2H),2.40(s,3H),2.01(s,3H).

[1289] Synthesis of NPL-148

[1290] Step 1: Synthesis of NPL-148-A1

[1291] The compound 6-methylquinoline-4-ol (300 mg, 1.9 mmol) was dissolved in acetonitrile (10 mL), and phosphorus tribromooxy (1.6 g, 5.7 mmol) was added. The reaction mixture was stirred overnight at 80 °C. After cooling to room temperature, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was diluted with ethyl acetate, and the reaction mixture was quenched by slowly adding saturated sodium bicarbonate solution. The mixture was separated, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine. After drying with anhydrous sodium sulfate, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the product 4-bromo-6-methylquinoline (NPL-148-A1, 400 mg, 95.6%), a yellow solid.

[1292] MS(ESI)m / z = 221.9[M+H] + .

[1293] 1 H NMR (400MHz, CDCl3) δ8.60(d,J=4.6Hz,1H),7.99(d,J=8.6Hz,1H),7.95(s,1H),7.67(d,J=4.7Hz,1H),7.60(dd,J=8.6,1.8Hz,1H),2.59(s,3H).

[1294] Step 2: Synthesis of NPL-148-A2

[1295] Under nitrogen protection, 4-bromo-6-methylquinoline (400 mg, 1.80 mmol) was dissolved in 1,4-dioxane (6 mL) and water (2 mL), followed by the sequential addition of potassium carbonate (746 mg, 5.4 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxborane-2-yl)ethyl acrylate (814 mg, 3.6 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (132 mg, 0.2 mmol). The mixture was purged with nitrogen three times, and stirred overnight at 80 °C. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain product (E)-3-(6-methylquinoline-4-yl)ethyl acrylate (NPL-148-A2, 300 mg, 69.0%), a yellow solid.

[1296] MS(ESI)m / z = 242.2[M+H] + .

[1297] 1H NMR (400MHz, CDCl3) δ8.86(d,J=4.5Hz,1H),8.41(d,J=15.9Hz,1H),8.04(d,J=8.6Hz,1H),7.91(s,1H),7.60(dd,J=8. 6,1.6Hz,1H),7.50(d,J=4.5Hz,1H),6.63(d,J=15.8Hz,1H),4.34(q,J=7.1Hz,2H),2.59(s,3H),1.39(t,J=7.2Hz,3H).

[1298] Step 3: Synthesis of NPL-148-A3

[1299] Ethyl (E)-3-(6-methylquinoline-4-yl)acrylate (300 mg, 1.2 mmol) was dissolved in tetrahydrofuran (4 mL) and water (4 mL), and lithium hydroxide (60 mg, 2.5 mmol) was added and the mixture was stirred for 3 hours. After the reaction was completed, 1 N hydrochloric acid (3 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the product (E)-3-(6-methylquinoline-4-yl)acrylate (NPL-148-A3, 250 mg, 94.3%), a yellow solid, which was directly used in the next step of the reaction.

[1300] MS(ESI)m / z = 214.2[M+H] + .

[1301] Step 4: Synthesis of NPL-148-A4

[1302] Compound (E)-3-(3-(azacyclobutan-1-yl)pyrazin-2-yl)acrylic acid (250 mg, 1.2 mmol), 4-aminophenol (154 mg, 1.4 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (535 mg, 1.4 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of N,N-diisopropylethylamine (0.6 mL, 3.5 mmol) and stirring overnight. After the reaction was complete, the reaction was quenched with water (10 mL) and diluted with dichloromethane (10 mL). The reaction solution was filtered, the solid was washed with dichloromethane, and dried under vacuum to give product (E)-N-(4-hydroxyphenyl)-3-(6-methylquinoline-4-yl)acrylamide (NPL-148-A4, 140 mg, 39.2%), a yellow solid.

[1303] MS(ESI)m / z = 305.3[M+H] + .

[1304] Step 5: Synthesis of NPL-148

[1305] Compound (E)-N-(4-hydroxyphenyl)-3-(6-methylquinoline-4-yl)acrylamide (140 mg, 0.5 mmol) was dissolved in methanol (5 mL), and palladium on carbon catalyst (49 mg, 0.05 mmol) was added. Hydrogen was purged three times, and the reaction was carried out overnight under a hydrogen atmosphere with stirring. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse-phase separation to obtain the product N-(4-hydroxyphenyl)-3-(6-methylquinoline-4-yl)propionamide (NPL-148, 60 mg, 42.6%), a white solid.

[1306] MS(ESI)m / z = 307.1 [M+H] + .

[1307] 1 H NMR (400MHz, DMSO-d6): δ9.70(s,1H),9.15(s,1H),8.75(d,J=4.5Hz,1H),8.01(s,1H),7.94(d,J=8.6Hz,1H),7.63(dd,J=8.6,1.5 Hz,1H),7.40(d,J=4.5Hz,1H),7.34(d,J=8.8Hz,2H),6.69–6.65(m,2H),3.40(d,J=7.5Hz,2H),2.73(t,J=7.6Hz,2H),2.55(s,3H).

[1308] Synthesis of NPL-149

[1309] Step 1: Synthesis of NPL-149-A1

[1310] Under nitrogen protection, 4-bromo-6-methylisoquinoline (888 mg, 4.0 mmol) was dissolved in 1,4-dioxane (24 mL) and water (8 mL). Then, 3-(4,4,5,5-tetramethyl-[1,3,2]dioxoborane-2-yl)ethyl acrylate (1809 mg, 8.0 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (293 mg, 0.4 mmol), and potassium carbonate (1658 mg, 12.0 mmol) were added sequentially. After three nitrogen purgings, the reaction mixture was stirred overnight at 80 °C. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain product (E)-3-(6-methylisoquinoline-4-yl)ethyl acrylate (NPL-149-A1, 600 mg, 51.8%), a yellow oily liquid.

[1311] MS(ESI)m / z = 242.1[M+H] +

[1312] 1 H NMR (400MHz, CDCl3) δ9.18(s,1H),8.71(s,1H),8.36(d,J=15.9Hz,1H),7.94–7.87(m,2H),7.50(d ,J=8.5Hz,1H),6.59(d,J=15.9Hz,1H),4.33(q,J=7.1Hz,2H),2.61(s,3H),1.39(t,J=7.1Hz,3H).

[1313] Step 2: Synthesis of NPL-149-A2

[1314] Ethyl (E)-3-(6-methylisoquinoline-4-yl)acrylate (600 mg, 2.0 mmol) was dissolved in methanol (15 mL) and water (5 mL), and lithium hydroxide (209 mg, 5.0 mmol) was added and the mixture was stirred for 2 hours. After the reaction was completed, 1 N hydrochloric acid (7 mL) was added to adjust the reaction solution to acidity, and the mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain product (E)-3-(6-methylisoquinoline-4-yl)acrylic acid (NPL-149-A2, 500 mg, 94.3%), a white solid.

[1315] MS(ESI)m / z = 214.0[M+H] -

[1316] Step 3: Synthesis of NPL-149-A3

[1317] Compound (E)-3-(6-methylisoquinoline-4-yl)acrylic acid (500 mg, 2.3 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1137 mg, 3.5 mmol), N,N-diisopropylethylamine (1.2 mL, 7.0 mmol), and 4-aminophenol (307 mg, 2.8 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with water and diluted with ethyl acetate. The reaction mixture was separated and extracted with ethyl acetate. The organic phase was washed with saturated brine, filtered with anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product (E)-3-(6-methylisoquinoline-4-yl)-N-(4-phenol)acrylamide (NPL-149-A3, 200 mg, 28.0%), a yellow solid.

[1318] MS(ESI)m / z = 305.1 [M+H] +

[1319] Step 4: Synthesis of NPL-149

[1320] Compound (E)-3-(6-methylisoquinoline-4-yl)-N-(4-phenol)acrylamide (200 mg, 0.7 mmol) was dissolved in methanol (3 mL), and palladium on carbon catalyst (70 mg, 0.06 mmol) was added. Hydrogen was purged three times, and the reaction mixture was stirred overnight under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was subjected to reverse-phase separation to obtain product 3-(6-methylisoquinoline-4-yl)-N-(4-phenol)propionamide (NPL-149, 20 mg, 9.9%), a white solid.

[1321] MS(ESI)m / z = 307.1 [M+H] +

[1322] 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),9.13(s,1H),9.10(s,1H),8.33(s,1H),8.02(d,J=8.3Hz,1H),7.92(s,1H),7.53(d ,J=8.1Hz,1H),7.33(d,J=8.8Hz,2H),6.67(t,J=6.0Hz,2H),3.29(d,J=7.8Hz,2H),2.68(t,J=7.6Hz,2H),2.56(s,3H).

[1323] Synthesis of NPL-151

[1324] Step 1: Synthesis of NPL-151

[1325] Compounds 2-((3-(1-azacyclobutyl)pyrazin-2-yl)oxy)acetic acid (400 mg, 1.91 mmol), N-(4-aminophenyl)acetamide (363 mg, 2.4 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (582 mg, 1.53 mmol) were dissolved in dichloromethane (5 mL), followed by the addition of N,N-diisopropylethylamine (198 mg, 1.53 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to reverse phase separation to obtain the product N-(4-acetamidophenyl)-2-((3-(1-azacyclobutyl)pyrazin-2-yl)oxy)acetamide (NPL-151, 27 mg, 3.88%), a white solid.

[1326] MS(ESI)m / z = 342.3[M+H] +

[1327] 1 H NMR (400MHz, DMSO-d6) δ10.02 (s, 1H), 9.86 (s, 1H), 7.62 (d, J = 3.0Hz, 1H), 7.48 (s, 4H) ,7.30(d,J=3.0Hz,1H),4.89(s,2H),4.18-4.15(m,4H),2.33-2.28(m,2H),2.01(s,3H)

[1328] Synthesis of NPL-152

[1329] Step 1: Synthesis of NPL-152

[1330] Compounds 2-((3-(pyrrolidone-1-yl)pyrazin-2-yl)oxy)acetic acid (450 mg, 2.0 mmol), N-(4-aminophenyl)acetamide (363 mg, 2.4 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (920 mg, 2.4 mmol) were dissolved in dichloromethane (20 mL), followed by the addition of N,N-diisopropylethylamine (261 mg, 2.0 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase separation to obtain the product N-(4-acetamidophenyl)-2-((3-(pyrrolidone-1-yl)pyrazin-2-yl)oxy)acetamide (NPL-152, 90 mg, 12.7%), a white solid.

[1331] MS(ESI)m / z = 356.3 [M+H] +

[1332] 1 H NMR (400MHz, DMSO-d6) δ10.03 (s, 1H), 9.86 (s, 1H), 7.61 (d, J = 2.9Hz, 1H), 7.49 (s, 4H), 7.23(d,J=2.9Hz,1H),4.90(s,2H),3.69–3.66(m,4H),2.01(s,3H),1.94–1.81(m,4H).

[1333] Synthesis of NPL-153

[1334] Step 1: Synthesis of NPL-153-A1

[1335] Compound (E)-3-(3-(azacyclobutan-1-yl)pyrazin-2-yl)acrylic acid (420 mg, 2.1 mmol), N-(4-aminophenyl)acetamide (246 mg, 1.6 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (623 mg, 1.6 mmol) were dissolved in dichloromethane (5 mL), followed by the addition of N,N-diisopropylethylamine (212 mg, 1.6 mmol) and stirring for 3 hours. After the reaction was complete, water and dichloromethane were added for dilution, at which point a yellow solid precipitated. The mixture...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof: in: Ring A is a heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, and Y1 is selected from aryl; heteroaryl; halogen; C(CH3)3; an amino group substituted with a C1, C2, C3, C4, C5, or C6 alkyl group; a C1, C2, C3, C4, C5, or C6 alkoxy group; a 3, 4, 5, or 6-membered cycloalkyl group and a 3, 4, 5, or 6-membered heterocycloalkyl group, and Y2 is absent; each R is independently selected from halogen, -CN, alkyl, alkoxy, and cycloalkyl. or Y1 and Y2, together with X1 and the carbon atom attached thereto, form a ring C, and ring A and ring C together constitute a benzo[a]aromatic ring, a benzo[hetero]aromatic ring, a benzo[a]cycloalkyl ring, a benzo[a]cycloalkenyl ring, a benzo[a]heterocycloalkyl ring, or a benzo[a]heterocycloalkenyl ring, and ring A and ring C are each independently and optionally substituted by one, two, or three substituents independently selected from halogens; C1, C2, C3, C4, C5, or C6 alkyl; C1, C2, C3, C4, C5, or C6 alkoxy groups and C1, C2, C3, C4, C5, or C6 haloalkyl groups; Ring B is phenyl or benzoxazol-2-one; It can be a single bond or a double bond; Z is selected from CR”R”, O, S, (CR”R”) p "and NR", where "R" is independently selected from H and alkyl; or Z is formed together with the adjacent CR1R2. Structural fragments or cycloalkyl groups; or Z is CR”R” and the two R” together with the carbon atoms attached to them form cycloalkyl groups; When ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is selected from -OH, -NH2, NHR4, NHCOR4 and NHSO2R4, wherein R4 is independently selected from alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, aryl and heteroaryl; when ring B is benzoxazol-2-one, n is 0. X1 is selected from N, NH, NR', CH, CH2, CR' or CHR', wherein R' is selected from halogen, -CN, alkyl and alkoxy, and N is optionally oxidized; R1, R2, and R3 are each independently selected from H and alkyl groups; or R1 and R2 together with the carbon atom attached to them form a cycloalkyl group; m can be 0, 1, 2, 3, or 4; p is 0, 2, 3, 4 or 5. The condition is that the compound of formula (I) is not a 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein: Y1 is selected from C(CH3)3; an amino group substituted with a C1, C2, C3, C4, C5, or C6 alkyl group; a C2, C3, C4, C5, or C6 alkoxy group; a 3, 4, 5, or 6-membered cycloalkyl group and a 3, 4, 5, or 6-membered heterocycloalkyl group, and Y2 is absent, wherein the 3, 4, 5, or 6-membered heterocycloalkyl group contains one or two heteroatoms independently selected from N, O, and S and one N atom is attached to ring A; or Y1 is selected from amino groups substituted with C1, C2, or C3 alkyl groups; C1, C2, or C3 alkoxy groups; 3, 4, 5, or 6-membered cycloalkyl groups and 3, 4, 5, or 6-membered heterocycloalkyl groups, and Y2 is absent, wherein the 3, 4, 5, or 6-membered heterocycloalkyl group contains one or two heteroatoms independently selected from N and O and one N atom is attached to ring A; or the 3, 4, 5, or 6-membered heterocycloalkyl group contains one N atom and the N atom is attached to ring A; or Y1 is selected from C(CH3)3, N(CH3)2, OCH(CH3)2, OC(CH3)3, Cl, 1-azacyclobutane, 1-pyrrolidinyl, Cyclopropyl, cyclobutyl, cyclopentyl, 1-piperazinyl, 4-methyl-1-piperazinyl, and morpholinyl, and Y2 is absent; or Y1 is C(CH3)3, 1-pyrrolidinyl, 1-azacyclobutyl, cyclopentyl, cyclopropyl, N(CH3)2, or OCH(CH3)2, and Y2 is absent; or Y1 is C(CH3)3, 1-pyrrolidinyl, 1-azacyclobutane, cyclopentyl, cyclopropyl, N(CH3)2, or OCH(CH3)2, and Y2 is absent; or Y1 is C(CH3)3, 1-pyrrolidinyl, or 1-azacyclobutane, and Y2 is absent; or Y1 is C(CH3)3 or N(CH3)2, and Y2 does not exist; or Y1 is C(CH3)3, and Y2 does not exist; and / or The ring A is a 5-6 membered heteroaryl, a 5-7 membered cycloalkyl, a 5-7 membered cycloalkenyl, a 5-7 membered heterocycloalkyl, or a 5-7 membered heterocycloalkenyl. The ring A is a 5-6 membered heteroaryl, a 5-7 membered cycloalkyl, a 5-7 membered cycloalkenyl, a 5-7 membered heterocycloalkyl or a 5-7 membered heterocycloalkenyl, wherein each of the 5-6 membered heteroaryl, 5-7 membered heterocycloalkyl or 5-7 membered heterocycloalkenyl independently contains one, two or three heteroatoms independently selected from N, O and S. The ring A is a 5-6-membered heteroaryl, a 5-7-membered cycloalkyl, or a 5-7-membered heterocycloalkyl, wherein the 5-6-membered heteroaryl and the 5-7-membered heterocycloalkyl each independently contain one, two, or three heteroatoms independently selected from N, O, and S; The ring A is a 6-membered heteroaryl, cyclohexyl, or 6-membered heterocycloalkyl, wherein the 6-membered heteroaryl and 6-membered heterocycloalkyl each independently contain one, two, or three N atoms. The ring A is a 5-6 membered heteroaryl or a 5-6 membered cycloalkyl, wherein the 5-6 membered heteroaryl contains one or two N atoms; The ring A is a 6-membered heteroaryl or cyclohexyl group, wherein the 6-membered heteroaryl group contains one or two N atoms; The ring A is a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains one or two N atoms; The ring A is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, or cyclohexyl; or The ring A is pyridyl, pyrazinyl, or pyrimidinyl; or The ring A is Where "*" represents the connection site with Y1, and "**" represents the connection site with Z.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein: The ring A and ring C together constitute a benzo6-10 membered aromatic ring, a benzo5-6 membered heteroaromatic ring, a benzo5-7 membered alkyl ring, a benzo5-7 membered alkenyl ring, a benzo5-7 membered heteroalkyl ring, or a benzo5-7 membered heteroalkyl ring, wherein each of the benzo5-6 membered heteroaromatic ring, the benzo5-7 membered heteroalkyl ring, and the benzo5-7 membered heteroalkyl ring independently contains one, two, or three heteroatoms independently selected from N, O, and S; The ring A and ring C together constitute a benzo6-10 membered aromatic ring, a benzo5-6 membered heteroaromatic ring, a benzo5-6 membered alkyl ring, or a benzo5-6 membered heteroalkyl ring, wherein the benzo5-6 membered heteroaromatic ring and the benzo5-6 membered heteroalkyl ring each independently contain one, two, or three nitrogen atoms; or The ring A and ring C together constitute naphthyl, tetrahydronaphthyl, indolyl, indololinyl, quinolinyl, isoquinolinyl, quinazolinyl, or indanyl; or, the ring A and ring C together constitute quinazolinyl or isoquinolinyl. wherein ring A and ring C are each independently and optionally selected from one, two, or three halogens, C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The ring C is substituted with a haloalkyl group; or the ring C is optionally substituted with one or two substituents independently selected from F, Cl, CH3, C2H5, OCH3, CF3, CH2F, and CHF2; or the ring C is optionally substituted with one CH3 group; or Structural fragments for:

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein: Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom bonded to NR3, and R0 is selected from -OH, NHR4, NHCOR4, and NHSO2R4, where R4 is independently selected from C. 1-6 Alkyl, 3-5 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and 6-10 aryl groups; or R0 is -OH, -NH2, -NHCOR4 and -NHSO2R4, wherein R4 is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; or R0 is -OH, -NHC(CH3)3, -NH-2-oxazolyl, -NH-cyclopropyl, -NHSO2CH3, -NHCOCF3, -NHCOCH3, -NHCOC(CH3)3 or -NHCO-cyclopropyl; or R0 is -OH, -NHCOCH3, -NHCO-cyclopropyl, -NHSO2CH3 or -NH-cyclopropyl; or R0 is -OH, -NHCOCH3 or -NHCO-cyclopropyl; or R0 is -OH or -NHCOCH3; or Ring B is a benzoxazol-2-one linked to NR3 at position 6, and n is 0.

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein: Z is selected from CR”R”, O, S, (CR”R”) p "and NR", where "R" is independently selected from H and C. 1-6 Alkyl group; or Z together with the adjacent CR1R2 to form Structural fragments or 3-5 membered cycloalkyl groups; or Z is CR"R" and the two R" together with the carbon atoms attached to them form 3-5 membered cycloalkyl groups; Z can be CH2, O, S, NH, C(CH3)2, NCH3, CHCH3, or cyclopropyl, or Z can be formed together with the adjacent CR1R2. Structural fragments or Structural fragments; Z can be CH2, O, S, NH, CHCH3, or Z can be formed together with the adjacent CR1R2. Structural fragments or Structural fragments; Z is selected from CR”R”, O, S and NR”, where R” is independently selected from H and C. 1-6 Alkyl group; or Z together with the adjacent CR1R2 to form Structural fragments; Z is selected from CR”R”, O, S and NR”, where R” is independently selected from H and C. 1-3 Alkyl group; or Z together with the adjacent CR1R2 to form Structural fragments; Z is CH2, O, S, or NH; or Z is formed together with the adjacent CR1R2. Structural fragments; Z represents CH2, O, or CHCH3; or Z is CH2 or O; or Structural fragments for 6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein: X1 is selected from N, NH, NR', CH, CH2, CR', or CHR', where R' is selected from halogens, -CN, C 1-6 Alkyl and C 1-6 The alkoxy group, N, is optionally oxidized; X1 is selected from N, CH, or CH2; or X1 is selected from N or CH.

7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein: R1, R2, and R3 are each independently selected from H and C. 1-6 alkyl; R1, R2, and R3 are each independently selected from H and C. 1-3 Alkyl; or R1, R2, and R3 are all H; and / or Each R is independently selected from halogen, -CN, C 1-4 Alkyl and C 1-4 alkoxy; or Each R is independently selected from -F, -CN, and -OCH3; and / or m is 0, 1, 2, or 3; or m is 0 or 1; and / or p is 0 or 2.

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein, Ring A is a 5-6 membered heteroaryl or a 5-6 membered cycloalkyl group, wherein the 5-6 membered heteroaryl group contains one or two nitrogen atoms; Y1 is selected from C(CH3)3; halogen; amino group substituted with C1, C2, C3, C4, C5 or C6 alkyl group; C 1、 C2, C3, C4, C5 or C6 alkoxy; 3, 4, 5 or 6-membered cycloalkyl and 3, 4, 5 or 6-membered heterocycloalkyl, and Y2 is absent, wherein the 3, 4, 5 or 6-membered heterocycloalkyl ring contains one or two heteroatoms independently selected from N, O and S and has one N atom attached to ring A; Alternatively, ring A and ring C together form a benzo6-10 membered aromatic ring, a benzo5-6 membered heteroaromatic ring, a benzo5-6 membered alkyl ring, or a benzo5-6 membered heteroalkyl ring, wherein the benzo5-6 membered heteroaromatic ring and the benzo5-6 membered heteroalkyl ring each independently contain one or two nitrogen atoms; ring C is optionally selected by one, two, or three independently from halogens, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups; Z can be CH2, O, S, NH, C(CH3)2, NCH3, CHCH3, or cyclopropyl, or Z can be formed together with the adjacent CR1R2. Structural fragments or Structural fragments; Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom bonded to NR3, and R0 is selected from -OH, -NH2, NHR4, NHCOR4, and NHSO2R4, where R4 is independently selected from C. 1-6 Alkyl, 3-5 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 6-10 aryl and 5-6 heteroaryl; or ring B is benzoxazol-2-one and n is 0; X1 is selected from N, CH or CH2; R1, R2, and R3 are each independently selected from H and C. 1-6 alkyl; m is 0 or 1, R is halogen, -CN, C 1-4 Alkyl and C 1-4 Alkoxy; or Ring A is a 6-membered heteroaryl or cyclohexyl group, wherein the 6-membered heteroaryl group contains one or two nitrogen atoms; Y1 is selected from C(CH3)3; an amino group substituted with a C1, C2, C3, C4, C5 or C6 alkyl group; a C2, C3, C4, C5 or C6 alkoxy group; a 3, 4, 5 or 6-membered cycloalkyl group and a 3, 4, 5 or 6-membered heterocycloalkyl group, and Y2 is absent, wherein the 3, 4, 5 or 6-membered heterocycloalkyl ring contains one nitrogen atom, and the nitrogen atom is attached to ring A; Alternatively, ring A and ring C together form naphthyl, tetrahydronaphthyl, indolyl, indololinyl, quinolinyl, isoquinolinyl, quinazolinyl, or indanyl; ring C is optionally substituted by one or two substituents independently selected from F, Cl, CH3, C2H5, OCH3, CF3, CH2F, and CHF2; Z can be CH2, O, S, NH, CHCH3, or Z can be formed together with the adjacent CR1R2. Structural fragments or Structural fragments; Ring B is phenyl, n is 1, and R0 is -OH, -NHC(CH3)3, -NH-2-oxazolyl, -NH-cyclopropyl, -NHSO2CH3, -NHCOCF3, -NHCOCH3, -NHCOC(CH3)3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one, n is 0; X1 is selected from N, CH or CH2; R1, R2, and R3 are each independently selected from H and C. 1-3 alkyl; m is 0 or 1, and R is -F, -CN, and -OCH3; or Ring A is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, or cyclohexyl; Y1 is selected from C(CH3)3, N(CH3)2, OCH(CH3)2, OC(CH3)3, Cl, 1-azacyclobutane, 1-pyrrolidinyl, Cyclopropyl, cyclobutyl, cyclopentyl, 1-piperazinyl, 4-methyl-1-piperazinyl, and morpholinyl, and Y2 is absent; or ring A and ring C together constitute naphthyl, tetrahydronaphthyl, indolyl, indololinyl, quinolinyl, isoquinolinyl, quinazolinyl, or indanyl; ring C is optionally substituted by one or two substituents independently selected from F, Cl, CH3, C2H5, OCH3, CF3, CH2F, and CHF2; Z can be CH2, O, S, NH, CHCH3, or Z can be formed together with the adjacent CR1R2. Structural fragments or Structural fragments; Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom bonded to NR3, and R0 is -OH, -NHC(CH3)3, -NH-2-oxazolyl, -NH-cyclopropyl, -NHSO2CH3, -NHCOCF3, -NHCOCH3, -NHCOC(CH3)3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one bonded to NR3 at position 6, n is 0; X1 is selected from N, CH or CH2; R1, R2, and R3 are each independently selected from H and CH3; m is 0 or 1, and R is -F, -CN, and -OCH3; or Ring A is pyridinyl, pyrazinyl, or pyrimidinyl; Y1 is C(CH3)3, 1-pyrrolidinyl, or 1-azacyclobutane, and Y2 is absent; or ring A and ring C together form a quinazolinyl group, with Z attached at position 4 and a methyl group substituted at position 6. Z can be CH2, O, or CHCH3; Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom attached to NR3, and R0 is -OH, -NHCOCH3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one attached to NR3 at position 6, n is 0; X1 is selected from N or CH; R1, R2 and R3 are all H; m is 0; or Ring A is pyridinyl, pyrazinyl, or pyrimidinyl; Y1 is C(CH3)3, 1-pyrrolidinyl, or 1-azacyclobutane, and Y2 is absent; or ring A and ring C together form a quinazolinyl group, with Z attached at position 4 and a methyl group substituted at position 6. Z is CH2 or CHCH3; Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom attached to NR3, and R0 is -OH, -NHCOCH3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one attached to NR3 at position 6, n is 0; X1 is selected from N or CH; R1, R2 and R3 are all H; m is 0; or Ring A is pyridinyl, pyrazinyl, or pyrimidinyl; Y1 is 1-pyrrolidinyl or 1-azacyclobutane, and Y2 is absent; or ring A and ring C together form a quinazolinyl group, with Z attached at position 4 and a methyl group substituted at position 6. Z represents CH2, O, or CHCH3; Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom attached to NR3, and R0 is -OH, -NHCOCH3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one attached to NR3 at position 6, n is 0; X1 is selected from N or CH; R1, R2 and R3 are all H; m is 0; or Structural fragments in equation (I) for or Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is -OH, -NHCOCH3, -NHCO-cyclopropyl, -NHSO2CH3 or -NH-cyclopropyl; or ring B is benzoxazol-2-one, n is 0; Structural fragments for or structural fragments for or Structural fragments in equation (I) In equation (II), (IV), or (V), ring A together with Y1 and Y2 forms one of the following structures: Ring B is phenyl, n is 1, R0 is located at the para position of the phenyl C atom connected to NR3, and R0 is -OH, -NHCOCH3 or -NHCO-cyclopropyl; or ring B is benzoxazol-2-one, n is 0; Structural fragments for or structural fragments for or Ring A is a 6-membered heteroaryl or cyclohexyl group, wherein the 6-membered heteroaryl group contains one or two N atoms, and Y1 is C(CH3)3, and Y2 is absent; R is -F or -CN; or Y1 and Y2, together with X1 and the carbon atom attached thereto, form ring C. Ring A and ring C together constitute a naphthyl, a benzo6-membered heteroaromatic ring, or a benzo5-membered alkyl ring, wherein ring C is optionally selected by one or two independently from C. 1-4 Alkyl and C 1-4 Substituents of haloalkyl groups; Ring B is phenyl or benzoxazol-2-one; Z is O, S, or CH2; or Z is formed together with the adjacent CR1R2. Structural fragments; R0 is -OH, -NHCOCH3 or -NHSO2CH3, and n is 1; X1 is selected from N, CH or CH2; R1, R2 and R3 are all H; m is 0 or 1; or Ring A is a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains one or two N atoms, and Y1 is C(CH3)3, and Y2 is absent; R is -F or -CN; or Y1 and Y2, together with X1 and the carbon atom attached thereto, form a ring C. Ring A and ring C together constitute a naphthyl group, wherein the ring C is optionally surrounded by one carbon atom. 1-4 Alkyl substitution; Ring B is phenyl or benzoxazol-2-one; Z is O or CH2; or Z forms together with the adjacent CR1R2. Structural fragments; R0 is -OH or -NHCOCH3, and n is 1; X1 is selected from N or CH; R1, R2 and R3 are all H; m is 0 or 1; or Ring A is pyridyl, pyrazinyl, or pyrimidinyl, and Y1 is C(CH3)3, while Y2 is absent; Ring B is phenyl or benzoxazol-2-one; Z is either O or CH2; R0 is -OH or -NHCOCH3, and n is 1; X1 is selected from N or CH; R1, R2, and R3 are all H; and m is 0.

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein the compound of formula (I) is a compound of formula (II), (III), (IV), or (V): Z, X1, Y1, Y2, and R1-R3 in equations (II) to (V) are defined according to any one of claims 1 to 8; X2 is selected from N, NH, NR, CH, CH2, CR or CHR, wherein R is selected from halogen, -CN, alkyl, alkoxy and 3-6 membered cycloalkyl, and N is optionally oxidized; X3 is selected from N, NH, NR, CH, CH2, CR or CHR, wherein R is selected from halogen, -CN, alkyl, alkoxy and 3-6 membered cycloalkyl, and N is optionally oxidized; X4 is selected from N, NH, NR, CH, CH2, CR or CHR, wherein R is selected from halogen, -CN, alkyl, alkoxy and 3-6 membered cycloalkyl, and N is optionally oxidized; The condition is that ring A contains a maximum of 3 N atoms; R5 to R8 are each independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy; R9 is -OH, -NHCOR 10 or -NHSO2R 10 , where R 10 Selected independently from C 1-4 Alkyl, C 1-3 Alkoxy, C 1-4 Halogenated alkyl and C 1-3 Haloalkoxy group; or R9 is -OH, -NHC(CH3)3, -NH-2-oxazolyl, -NH-cyclopropyl, -NHSO2CH3, -NHCOCF3, -NHCOCH3, -NHCOC(CH3)3 or -NHCO-cyclopropyl; or R9 is -OH, -NHCOCH3, -NHCO-cyclopropyl, -NHSO2CH3 or -NH-cyclopropyl; or R9 is -OH, -NHCOCH3 or -NHCO-cyclopropyl; or R9 is -OH or -NHCOCH3.

10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein: When ring A is a 6-membered heteroaryl group, X2, X3, and X4 are each independently selected from N, CH, and CR, where each R is independently selected from halogen, -CN, and C. 1-6 Alkyl and C 1-6 The alkoxy group, N is optionally oxidized; or X2, X3 and X4 are each independently selected from N or CH; When ring A is cyclohexyl, X2, X3, and X4 are each independently selected from CH2 and CHR, where each R is independently selected from C. 1-6 Alkyl and 3-6 membered cycloalkyl; When ring A is a 6-membered heterocyclic alkyl group, X2, X3, and X4 are each independently selected from NH, NR, CH2, and CHR, where each R is independently selected from C. 1-6 Alkyl and 3-6 membered cycloalkyl; The condition is that when ring A is a 6-membered heteroaryl or a 6-membered heterocyclic alkyl, ring A contains one or two N atoms.

11. The compound of formula (I) according to claim 9 or 10, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein in formula (II), formula (IV), or formula (V), ring A is pyridinyl, pyrazinyl, pyrazinyl, pyrimidinyl, or cyclohexyl, Y1 is tert-butyl, Y2 is absent, and when A is pyridinyl, the N atom is optionally oxidized.

12. The compound of formula (I) according to any one of claims 9 to 11, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein in formula (II), formula (IV), or formula (V), ring A together with Y1 and Y2 forms one of the following structures: or In equations (II), (IV), and (V), ring A, together with Y1 and Y2, forms one of the following structures: or In equation (II), (IV), or (V), ring A, together with Y1 and Y2, forms one of the following structures: or In equations (II), (IV), and (V), ring A, together with Y1 and Y2, forms one of the following structures:

13. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein in formula (III), ring A is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, or cyclohexyl, Y1 is tert-butyl, Y2 is absent, and when A is pyridyl, the N atom is optionally oxidized.

14. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein in formula (II), (III), (IV), or (V), Y1 and Y2 together with X1 and the carbon atom attached thereto form a ring C, and ring A and ring C together constitute a naphthyl, tetrahydronaphthyl, indoleyl, indolinyl, quinolinyl, isoquinolinyl, quinazolinyl, or indanyl, and optionally one or two of the above groups are selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy and C 1- Substitution of 6-haloalkyl groups.

15. The compound of formula (I) according to claim 9 or 14, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein in formula (II), (III), (IV), or (V), Y1 and Y2 together with X1 and the carbon atom attached thereto form a ring C, and ring A and ring C together form one of the following structures: Each of the structures is independently and optionally selected from one or two halogens, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The haloalkyl group is substituted; optionally, each of the structures is independently substituted by one or two substituents selected from -F, -Cl, -CH3, -C2H5, -OCH3, -CH2F, -CHF2 and -CF3.

16. The compound of formula (I) according to any one of claims 9 and 14-15, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein in formula (II), (III), (IV), or (V), Y1 and Y2 together with X1 and the carbon atom attached thereto form a ring C, and ring A and ring C together form one of the following structures:

17. The compound of formula (I) according to any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein R1 to R3 are all H; and / or R5 to R8 are all H.

18. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein the compound of formula (I) is selected from:

19. The compound of formula (I) according to any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, wherein the compound of formula (I) is not NPL-1 to NPL-37.

20. The compound of formula (I) according to any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, When Z is 0, structural fragment for At that time, structural fragments Not for When Z is 0, structural fragment for At that time, structural fragments Not for and / or When Z is 0, structural fragment for At that time, structural fragments Not for 21. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, and one or more pharmaceutically acceptable excipients.

22. Use of the compound of formula (I) according to any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, or the pharmaceutical composition of claim 21, in the preparation of a medicament for the prevention or treatment of diseases caused by aging or NAD+ deficiency.

23. The use according to claim 22, wherein the diseases caused by aging or decreased NAD+ include chronic demyelinating diseases of the nervous system, amyotrophic lateral sclerosis, Huntington's disease, chronic traumatic encephalopathy and frontotemporal dementia, AIDS-related neurodegeneration, Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, mild to moderate cognitive impairment, obesity, diabetes, type 2 diabetes, diabetic nephropathy, hypertension, COVID-19 coronavirus infection, mitochondrial myopathy, mitochondrial encephalomyopathy, progressive ophthalmoplegia, chronic obstructive pulmonary disease, heart failure, atherosclerosis, coronary artery disease, dyslipidemia, cardiometabolic diseases, diabetic peripheral neuropathy, chronic kidney disease, acute kidney injury, peripheral artery disease, etc. Peripheral diseases, chemotherapy-induced peripheral neuropathy, Friedrich's ataxia, multiple sclerosis, progressive multiple sclerosis, non-alcoholic fatty liver disease, alcoholic liver disease, cystic fibrosis, osteoarthritis, cerebral ischemia, cerebral hemorrhage, ischemic or hemorrhagic stroke, myocardial ischemia, cardiomyopathy, corneal injury, glaucoma, dry eye syndrome, macular degeneration, retinal degeneration, skin-related diseases (such as psoriasis, scleroderma), progeria, reproductive aging-related diseases, and diseases related to muscle aging, injury, or developmental disorders; optionally, reproductive aging-related diseases include oocyte aging-related diseases such as premature ovarian failure, polycystic ovary syndrome, and recurrent miscarriage; optionally, diseases related to muscle aging, injury, or developmental disorders include sarcopenia and Duchenne muscular dystrophy.

24. Use of the compound of formula (I) according to any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, or the pharmaceutical composition of claim 21, in the preparation of a dietary supplement, health product, or pet food health product; optionally, wherein the dietary supplement or health product is used for anti-aging, anti-fatigue, and / or improving menopausal mental state.

25. The use of the compound of formula (I) according to any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, tautomer, enantiomer, diastereomer, or isotopically labeled compound thereof, or the use of the pharmaceutical composition of claim 21 in improving skin symptoms or in the preparation of cosmetics or skin care products or medical aesthetics; optionally, in the cosmetics or skin care products or medical aesthetics, it is used as an anti-wrinkle agent, anti-aging agent, skin protectant, moisturizer, and / or antioxidant.

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