Targeted IRAK protein inhibition or degradation compound and application thereof

Abstract

The invention relates to a compound for inhibiting or degrading a targeted IRAK protein, a preparation method of the compound and application of the compound in treating or preventing related diseases mediated by the IRAK protein.

Description

Compounds targeting IRAK protein inhibition or degradation and their applications Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a compound targeting IRAK protein for inhibition or degradation, a preparation method thereof, and an application thereof in treating or preventing related diseases mediated by IRAK protein. Background Art

[0002] The interleukin-1 receptor-associated kinase (IRAK) family is a class of specific serine / threonine protein kinases that play an important role in the regulation of innate and adaptive immune responses mediated by the toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) families. The IRAK protein family consists of four isoforms: IRAK1, IRAK2, IRAK3 (IRAK-M), and IRAK4. These four enzymes share similar domain structures, including a conserved N-terminal death domain (DD), a proline / serine / threonine-rich (ProST) domain, a kinase / pseudokinase domain (KD), and, except for IRAK4, a long C-terminal domain (CTD). During inflammatory and immune response signaling, activated TLR / IL-1R recruits the adaptor protein MyD88 through its intracellular TIR domain, leading to the assembly of the Myddosome, a multiprotein complex composed of MyD88, IRAK4, and IRAK2. Within the Myddosome, IRAK4 is activated through trans-autophosphorylation, which then phosphorylates and activates IRAK1 and promotes its dissociation from the complex. Activated IRAK1 forms a complex with the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) and activates TGFβ-activated kinase 1-binding protein 1 (TAK1), which, through a series of intracellular cascades, ultimately activates the downstream NF-κB and MAPK / JNK / p38 signaling pathways, leading to the secretion of proinflammatory cytokines and the proliferation and differentiation of immune cells. In monocytes and macrophages, IRAK3 negatively regulates IRAK signaling by inhibiting the activation of IRAK4 and IRAK1.

[0003] Mutations in MYD88, IRAK4, and IRAK1 have been found in patients with infections, revealing the important role of these proteins in host defense. Studies have shown that patients with autosomal recessive diseases who lack IRAK4 or MyD88 are susceptible to pyogenic bacterial infections, but are still able to resist infections by other types of pathogens, including most bacteria, viruses, fungi, and parasites. IRAK4 is a central kinase at the intersection of the two major signaling pathways of the TLR family and the IL-1R family. Its kinase activity is key to activating the TLR / IL-1R downstream pathway, and is therefore a candidate target for a variety of inflammatory diseases. IRAK4 with kinase domain mutations has shown protective effects on mice in a variety of preclinical inflammatory disease models, including septic shock, systemic lupus erythematosus, acute liver injury, cardiovascular disease, and Alzheimer's disease.

[0004] According to incomplete statistics, there are approximately 40 IRAK4-targeting drugs currently under development worldwide, most of which are in early clinical trials. No IRAK4-targeting drugs are currently on the market. Six are in Phase II clinical trials, two are in Phase I / II clinical trials, ten are in Phase I clinical trials, and 25 are in preclinical trials. The most common indications are autoimmune diseases, including rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, and lupus erythematosus; followed by cancer, including acute myeloid leukemia, myelodysplastic syndrome, and B-cell lymphoma. The most advanced drugs in this field include Pfizer's potent IRAK4 inhibitor PF-06650833, which has completed Phase II clinical trials in rheumatoid arthritis and hidradenitis suppurativa. Results indicate that PF-06650833 has no significant efficacy in either indication. Curis' inhibitor CA-4948 is currently in Phase II clinical trials for multiple oncology indications. It is worth noting that Kymera's IRAK4 degrader KT-474, developed using targeted protein degradation (TPD) technology, has completed Phase I clinical studies for hidradenitis suppurativa and atopic dermatitis and has shown strong anti-inflammatory activity and good safety and tolerability. TPD is an emerging therapeutic strategy that can directly target some proteins that are difficult to target with conventional small molecule drugs by utilizing proteolysis-targeting chimeras (PROTACs). PROTAC is a heterogeneous bifunctional molecule composed of two ligands. One end of the ligand recruits and binds to the target protein (Protein of Interest, POI), and the other end of the ligand recruits and binds to the E3 ubiquitin ligase. PROTAC induces the binding of the target protein and E3, and catalyzes the attachment of the ubiquitination tag to the lysine of the target protein through E3. The ubiquitinated target protein is then recognized and degraded by the 26S subunit of the proteasome in the cell. Currently, due to the lack of available binding pockets and suitable chemicals, approximately 80-85% of the human proteome cannot be drugged. At the same time, established drug targets (such as EGFR-TKI) are prone to drug-resistant mutations, resulting in reduced drug efficacy. Therefore, protein-targeted degradation to make undruggable targets druggable, avoid drug resistance caused by point mutations, and achieve drug development has become a hot topic in new drug research and development. Compared with traditional inhibitors, KT-474, as the first effective, highly selective, and orally bioavailable IRAK4 degrader, has unparalleled unique advantages in inhibiting the TLR / IL-1R signaling pathway.IRAK4 primarily mediates IL-1R / TLR downstream signaling pathways and participates in immune surveillance through two pathways: First, IRAK4 possesses kinase activity, capable of phosphorylating downstream substrate proteins such as IRAK1 and IRF5 / 7; second, IRAK4 functions as a scaffold, participating in the assembly of the multimeric protein complex myddosome. Vollmer et al. found that pharmacological inhibition of IRAK4 autophosphorylation failed to inhibit IL-1-stimulated activation of IRAK1 and the NF-κB / P38 / JNK signaling pathway in IL-1R cells. Qin and Song's study found that inducing expression of an inactive IRAK4 protein with a kinase domain mutation in IRAK4-deficient cells significantly restored the stress response to IL-1, including increased IRAK1 phosphorylation and activation of downstream inflammatory signaling pathways in response to IL-1. Traditional small molecule inhibitors only show moderate efficacy against kinase activity and are unable to disrupt complex formation to completely block the generation of inflammatory response signals. KT-474 can simultaneously block kinase activity and scaffold structure, showing more potent pathway inhibition and anti-inflammatory activity in studies.

[0005] There is still an urgent need to develop more inhibitors and degraders targeting IRAK4.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a compound that targets IRAK protein for inhibition or degradation, a preparation method thereof, and an application thereof in treating or preventing related diseases mediated by IRAK protein.

[0008] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof:

[0009] in,

[0010] Q1, Q2, Q3, Q4 and Q5 are independently selected from C, CH, CH2, N, NH, S or O;

[0011] ---Indicates the presence or absence of a double bond;

[0012] Ring P is an aryl group or a heteroaryl group;

[0013] R1 is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, -OR 1a 、-SR 1a 、-NR 1a R 1b 、-COR 1a 、-SOR 1a 、-SO2R 1a 、-COOR1a 、-CONR 1a R 1b 、-NR 1a COR 1b 、-OCOR 1a 、-S(O)(NR 1a )R 1b 、-SONR 1a R 1b 、-SO2NR 1a R 1b 、-NR 1a SOR 1b 、-NR 1a SO2R 1b , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl and optionally substituted heterocyclyl, wherein R 1a and R 1b are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;

[0014] R2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;

[0015] R3 is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, -OR 3a 、-SR 3a 、-NR 3a R 3b 、-COR 3a 、-SOR 3a 、-SO2R 3a 、-COOR 3a 、-CONR 3a R 3b 、-NR 3a COR 3b 、-OCOR 3a 、-S(O)(NR 3a )R 3b 、-SONR 3a R 3b 、-SO2NR 3a R 3b 、-NR 3a SOR 3b 、-NR 3a SO2R 3b , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein R 3a and R 3bare independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0016] n is 0, 1, 2, 3, 4 or 5.

[0017] In another aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof:

[0018] ALE(II)

[0019] Part A has the following structure:

[0020] in,

[0021] Q1, Q2, Q3, Q4 and Q5 are independently selected from C, CH, CH2, N, NH, S or O;

[0022] ---Indicates the presence or absence of a double bond;

[0023] Ring P is an aryl group or a heteroaryl group;

[0024] R1 is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, -OR 1a 、-SR 1a 、-NR 1a R 1b 、-COR 1a 、-SOR 1a 、-SO2R 1a 、-COOR 1a 、-CONR 1a R 1b 、-NR 1a COR 1b 、-OCOR 1a 、-S(O)(NR 1a )R 1b 、-SONR 1a R 1b 、-SO2NR 1a R 1b 、-NR 1a SOR 1b 、-NR 1a SO2R 1b , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl and optionally substituted heterocyclyl, wherein R 1a and R 1b are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;

[0025] R3 is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, -OR 3a 、-SR 3a 、-NR 3a R 3b 、-COR 3a 、-SOR 3a 、-SO2R 3a 、-COOR 3a 、-CONR 3a R 3b 、-NR 3a COR 3b 、-OCOR 3a 、-S(O)(NR 3a )R 3b 、-SONR 3a R 3b 、-SO2NR 3a R 3b 、-NR 3a SOR 3b 、-NR 3a SO2R 3b , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein R 3a and R 3b are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0026] n is 0, 1, 2, 3, 4 or 5;

[0027] R2' is selected from optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene; and

[0028] The A part is connected to the L part through the ring atom of R2';

[0029] The L section has the following structure:

[0030] -L1-L2-L3-L4-L5- Formula (L)

[0031] in:

[0032] L1, L3 and L5 are independently absent or selected from -Rm-, -Rm-Rn-, -Rm-O-Rn-, -Rm-C(O)-Rn-, -Rm-C(O)O-Rn-, -Rm-OC(O)-Rn-, -Rm-NRx-Rn-, -Rm-C(O)NRx-Rn-, -Rm-NRxC(O)-Rn-, -Rm-S(O)-Rn- n-, -Rm-S(O)NRx-Rn-, -Rm-NRxS(O)-Rn-, -Rm-S(O)2-Rn-, -Rm-S(O)2NRx-Rn-, -R m-NRxS(O)2-Rn-, -Rm-NRxC(O)NRy-Rn-, -Rm-OC(O)NRx-Rn-, -Rm-NRxC(O)O-Rn-, 、-(CH2CH2O) g -or-(OCH2CH2) g -, wherein Rm and Rn are independently selected from a bond, optionally substituted alkylene, optionally substituted alkyleneoxy, optionally substituted cycloalkylene or optionally substituted heterocyclylene, Rx and Ry are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl, and g is an integer from 1 to 20;

[0033] L2 and L4 are independently absent or selected from optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene or optionally substituted heteroarylene; and

[0034] Section E has the following structure:

[0035] Among them, RE 1 is selected from hydrogen, deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl or optionally substituted heterocyclyl, RE 2 is selected from hydrogen, deuterium or halogen, RE L1 is selected from a bond, -CH2-, -NH-, -NCH3-, -O-, -CONH- or -CONCH3-, RE L2 is selected from a bond or -CH2-, and p is 1, 2, 3, 4 or 5;

[0036] RE 1a Selected from -COCH(CH3)OH, -COCH3, -CON(CH3)2, -CO(CH2)2CH(NH2)COOH or -COCH(NH2)(CH2)2COOH, RE 2a Selected from -CH2OCOOC(CH3)3 or -CH2OCOC(CH3)3.

[0037] In another aspect, the present invention provides a method for treating or preventing a disease mediated by an IRAK protein, comprising administering a compound of formula (I) or formula (II) to a patient in need thereof.

[0038] In another aspect, the present invention provides use of a compound of formula (I) or formula (II) in the preparation of a medicament for treating or preventing a disease mediated by an IRAK protein. DETAILED DESCRIPTION

[0039] definition

[0040] As used herein, "substituted" refers to all permissible substituents of the compounds or functional groups described herein. In the broadest sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, but are not limited to, halogen, hydroxyl, or any other organic group containing any number of carbon atoms (e.g., 1-20 carbon atoms), and optionally include one or more heteroatoms, such as oxygen, sulfur, or nitrogen groups, in the form of linear, branched, or cyclic structures. Representative substituents include deuterium, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halogen, nitro, hydroxy, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aryloxy, substituted aryloxy, thiol, substituted thiol, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, substituted cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C3-C 20 Cyclic groups, substituted C3-C 20 Cyclic groups, heterocycles, substituted heterocycles, amino acids, poly(lactic-co-glycolic acid), peptides and polypeptide groups. Such alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halogen, nitro, hydroxy, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aryloxy, substituted aryloxy, thiol, substituted thiol, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, substituted cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C3-C 20Cyclic groups, substituted C3-C 20 Cyclic groups, heterocycles, substituted heterocycles, amino acids, poly(lactic-co-glycolic acid), peptides, and polypeptide groups can be further substituted.

[0041] The heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0042] It is understood that "substitution" or "substituted" includes the implicit proviso that such substitution complies with the permitted valences of the substituted atom and substituent and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, and the like.

[0043] Unless specifically and unambiguously stated otherwise, the term "substituted" refers to a structure, such as a moiety on a compound or larger compound, regardless of how the structure is formed. The structure is not limited to structures made by any particular method.

[0044] As used herein, "aryl" refers to a C5-C 26 As used herein, "aryl" is broadly defined to include 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic or polycyclic aromatic groups, such as benzene, naphthalene, anthracene, phenanthrene, (chrysene), pyrene, corannulene, coronene, etc.

[0045] "Aryl" also includes polycyclic ring systems having two or more rings in which two or more carbon atoms are common to two adjacent rings (i.e., "fused rings"), wherein at least one ring is aromatic, e.g., the other cyclic ring or rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocycle.

[0046] The term "substituted aryl" refers to an aryl group in which one or more hydrogen atoms on one or more aromatic rings are replaced by one or more substituents including, but not limited to, deuterium, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, carbonyl (e.g., ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkaryl, haloalkyl (e.g., CF3, -CH2-CF3, -CCl3), -CN, aryl, heteroaryl, and combinations thereof, which substituents may be further substituted.

[0047] "Heterocycle" and "heterocyclyl" are used interchangeably and refer to a non-aromatic cyclic group consisting of a monocyclic or polycyclic ring (e.g., a bicyclic ring such as a spirocyclic ring, a fused ring, etc.) containing 3-20 ring atoms (e.g., 3-16, 3-14, 3-12, or 3-10 ring atoms, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms), composed of carbon and one to six (e.g., one, two, three, or four) heteroatoms, each of which may be selected from oxygen, sulfur, and nitrogen, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents. By definition, a heterocyclyl group is different from a heteroaryl group. Examples of heterocycles include, but are not limited to, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, tetrahydrofuranyl, dihydrofuran [2,3-b] tetrahydrofuran, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, indolinyl, pyranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, 4H-quinolinyl, quinuclidinyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, tetrahydrothienyl, isoxazolidinyl, isothiazolidinyl, oxazolidinyl, thiazolidinyl, azepanyl, benzazepine. The heterocyclic group may be optionally substituted with one or more substituents as defined herein (e.g., as defined for alkyl and aryl).

[0048] The term "heteroaryl" refers to a C5-C 26The term "heteroaryl" refers to a 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic or polycyclic aromatic ring system or a combination thereof (e.g., 5-24, 5-20, 5-16, 5-12, or 5-10 ring atoms, such as 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms), wherein one or more carbon atoms on one or more aromatic ring structures have been replaced by heteroatoms (e.g., one to six, such as one, two, three, or four heteroatoms). Suitable heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen. As used herein, the broad definition of "heteroaryl" includes 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic aromatic groups, which may include one to four heteroatoms, such as pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, oxadiazolyl, thiadiazolyl, triazinyl, isoxazolyl, isothiazolyl, aza Base, diazepine Heteroaryl groups may also be referred to as "aryl heterocycles" or "heteroaromatic compounds". "Heteroaryl" also includes polycyclic ring systems with two or more rings, wherein two or more carbon atoms are common to two adjacent rings (e.g., "fused rings"), wherein at least one ring is heteroaromatic, and the other ring or rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, heteroaromatic ring, or a combination thereof. Examples of heteroaromatic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzoxadiazolyl, benzothiadiazolyl, benzoquinolinyl, benzoisoquinolinyl, carbazolyl, 4aH-carbazolyl, carbolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl oxadiazole, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyrazolopyrimidine, pyridinyl ... The heteroaryl groups may be substituted or substituents as defined herein.

[0049] The term "substituted heteroaryl" refers to a heteroaryl group in which one or more hydrogen atoms on one or more heteroaryl rings are replaced with one or more substituents, including, but not limited to, deuterium, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, carbonyl (e.g., ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkaryl, haloalkyl (e.g., CF3, -CH2-CF3, -CCl3), -CN, aryl, heteroaryl, and combinations thereof, which substituents may be further substituted.

[0050] As used herein, "alkyl" refers to a saturated aliphatic group that is straight or branched. It can include 1-30, 1-26, 1-20, 1-16, 1-12, 1-8 or 1-6 carbon atoms. Alkyl can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl, etc. The term "alkyl" (or "low alkyl") used throughout the specification, examples and claims is intended to include "unsubstituted alkyl" and "substituted alkyl", the latter referring to one or more substituents replacing the hydrogen on one or more carbons of the hydrocarbon chain. Such substituents include, but are not limited to, deuterium, halogen, hydroxy, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety, which substituents may be further substituted.

[0051] Unless the number of carbon atoms is otherwise specified, "lower alkyl" as used herein refers to an alkyl group as defined above, but having from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, in its backbone structure.

[0052] As used herein, the term "cycloalkyl" refers to a saturated non-aromatic monocyclic or polycyclic hydrocarbon group. It can have 3-30, 3-26, 3-20, 3-16, 3-12, 3-8 or 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0053] "Alkyl" may include one or more substitutions at one or more carbon atoms of the hydrocarbon group. Suitable substituents include, but are not limited to, halogens such as fluorine, chlorine, bromine, or iodine; hydroxy; -NRR', where R and R' are independently hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl, and where the nitrogen atom is optionally quaternized; -SR, where R is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl; -CN; -NO2; -COOH; carboxylates; -COR, -COOR, or CON(R)2, where R is hydrogen, alkyl, or aryl; azide, aralkyl, alkoxy, imino, phosphonate, phosphinate, silyl, ether, sulfonyl, sulfonamido, heterocyclyl, aromatic or heteroaromatic moiety, haloalkyl (e.g., -CF3, -CH2-CF3, -CCl3); CN; -NCOCOCH2CH2; NCOCOCH; -NCS; and combinations thereof.

[0054] Those skilled in the art will appreciate that, if appropriate, the substituted portion of the hydrocarbon chain itself may be substituted. For example, the substituents of substituted alkyl groups may include deuterium, halogen, hydroxyl, sulfhydryl, nitro, thiol, amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamido, sulfamoyl, sulfoxides and sulfonates), and silyl, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), haloalkyl, -CN, etc. Cycloalkyl, heterocyclic, aryl, heteroaryl, etc. may be substituted in the same manner.

[0055] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0056] As used herein, the term "hydroxy" refers to an -OH group.

[0057] As used herein, the term "amino" refers to a -NH2 group.

[0058] As used herein, the term "cyano" refers to a -CN group.

[0059] As used herein, the term "nitro" refers to a -NO2 group.

[0060] As used herein, the term "carbonyl" refers to a -COR group (R is hydrogen or alkyl), particularly a -CHO group.

[0061] As used herein, the term "alkylene" and the like refer to a divalent group in which two hydrogen atoms in a corresponding group, etc. (eg, alkyl) are replaced.

[0062] As used herein, the term "stereoisomer" refers to a compound composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. "Stereoisomers" include enantiomers, diastereomers, and other stereoisomeric forms defined by absolute stereochemistry. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms.

[0063] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and salts with organic carboxylic and sulfonic acids such as acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and naphthalenedisulfonic acid; or salts with conventional bases such as alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), ammonium salts derived from ammonia and organic amines (e.g., diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, methylpiperidine, L-arginine, creatine, choline, L-lysine, ethylenediamine, N,N-dibenzylethylenediamine (benzathine), ethanolamine, meglumine, and tromethamine).

[0064] As used herein, the term "solvate" refers to a complex formed by coordination with a solvent molecule. When the solvent molecule is water, the solvate is a hydrate.

[0065] The compounds described herein may be isotopically labeled, i.e., one or more atoms therein are replaced by atoms having a different atomic mass or mass number. Such isotopically labeled compounds are considered to be within the scope of the present invention. Examples of isotopes that may be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, respectively 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. 36 Cl, 123 I and 125 I.

[0066] The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof:

[0067] in,

[0068] Q1, Q2, Q3, Q4 and Q5 are independently selected from C, CH, CH2, N, NH, S or O;

[0069] ---Indicates the presence or absence of a double bond;

[0070] Ring P is an aryl group or a heteroaryl group;

[0071] R1 is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, -OR 1a 、-SR 1a 、-NR 1a R 1b 、 -COR 1a 、-SOR 1a 、-SO2R 1a 、-COOR 1a 、-CONR 1a R 1b 、-NR 1a COR 1b 、-OCOR 1a 、-S(O)(NR 1a )R 1b 、-SONR 1a R 1b 、-SO2NR 1a R 1b 、-NR 1a SOR 1b 、-NR 1a SO2R 1b , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl and optionally substituted heterocyclyl, wherein R 1a and R 1b are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;

[0072] R2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;

[0073] R3 is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, -OR 3a 、-SR 3a 、-NR 3a R 3b 、-COR 3a 、-SOR 3a、-SO2R 3a 、-COOR 3a 、-CONR 3a R 3b 、-NR 3a COR 3b 、-OCOR 3a 、-S(O)(NR 3a )R 3b 、-SONR 3a R 3b 、-SO2NR 3a R 3b 、-NR 3a SOR 3b 、-NR 3a SO2R 3b , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein R 3a and R 3b are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0074] n is 0, 1, 2, 3, 4 or 5.

[0075] In some embodiments, the ring structure in which Q1-Q5 is located is selected from the following structures:

[0076] In some embodiments, Ring P is a 6-10 membered aryl or heteroaryl. In some embodiments, Ring P is a 6-membered aryl or heteroaryl. In some embodiments, Ring P is a 9-10 membered bicyclic heteroaryl.

[0077] In some embodiments, ring P is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyrazolopyrimidinyl (e.g., derived from pyrazolo[2,3-A]pyrimidinyl) or pyrrolopyridazinyl (e.g. derived from The structure of the pyrrolo[1,2-B]pyridazinyl group).

[0078] In some embodiments, R1 is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, -OR 1a 、 -SR 1a 、-NR 1a R 1b 、-COR 1a 、-SOR 1a 、-SO2R 1a 、-COOR 1a 、-CONR 1aR 1b 、-NR 1a COR 1b 、-OCOR 1a 、-S(O)(NR 1a )R 1b 、-SONR 1a R 1b 、-SO2NR 1a R 1b 、-NR 1a SOR 1b 、-NR 1a SO2R 1b , optionally substituted C 1-12 Alkyl (e.g. C 1-6 alkyl), optionally substituted C 1-12 Alkoxy (e.g. C 1-6 alkoxy), optionally substituted C 3-12 Cycloalkyl (e.g. C 3-6 cycloalkyl) and optionally substituted 3-12 membered heterocyclyl (e.g. 3-6 membered heterocyclyl), wherein R 1a and R 1b are independently selected from hydrogen, deuterium, optionally substituted C 1-12 Alkyl (e.g. C 1-6 alkyl), optionally substituted C 3-12 Cycloalkyl (e.g. C 3-6 cycloalkyl) and optionally substituted 3-12 membered heterocyclyl (e.g., 3-6 membered heterocyclyl).

[0079] In some embodiments, R 1a and R 1b independently selected from: hydrogen; deuterium; unsubstituted alkyl, cycloalkyl or heterocyclyl; and alkyl, cycloalkyl or heterocyclyl substituted by one or more substituents independently selected from: deuterium; halogen; hydroxyl; mercapto; amino; cyano; nitro; aldehyde; carboxyl; -OCO-alkyl; -OCOO-alkyl; and alkyl, alkoxy, cycloalkyl or heterocyclyl optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, aldehyde, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and / or haloheterocyclyl.

[0080] In some embodiments, R1 is selected from unsubstituted alkyl, alkoxy, cycloalkyl, or heterocyclyl; and alkyl, alkoxy, cycloalkyl, or heterocyclyl substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxy, thiol, amino, cyano, nitro, -OR 1c 、-SR 1c 、-NR 1c R 1d 、-COR1c 、-SOR 1c 、-SO2R 1c 、-COOR 1c 、-CONR 1c R 1d 、-NR 1c COR 1d 、-OCOR 1c 、-S(O)(NR 1c )R 1d 、-SONR 1c R 1d 、-SO2NR 1c R 1d 、-NR 1c SOR 1d 、-NR 1c SO2R 1d , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl and optionally substituted heterocyclyl, wherein R 1c and R 1d are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl.

[0081] In some embodiments, R1 is selected from alkyl, alkoxy, cycloalkyl, or heterocyclyl substituted with one or more substituents independently selected from:

[0082] Deuterium; halogen; hydroxyl; thiol; amino; cyano; nitro;

[0083] -OR 1c 、-SR 1c 、-NR 1c R 1d 、-COR 1c 、-SOR 1c 、-SO2R 1c 、-COOR 1c 、-CONR 1c R 1d 、-NR 1c COR 1d 、-OCOR 1c 、-S(O)(NR 1c )R 1d 、-SONR 1c R 1d 、-SO2NR 1c R 1d 、-NR 1c SOR 1d 、-NR 1c SO2R 1d , where R 1c and R 1dindependently selected from: hydrogen; deuterium; unsubstituted alkyl, cycloalkyl or heterocyclyl; and alkyl, cycloalkyl or heterocyclyl substituted with one or more substituents independently selected from: deuterium; halogen; hydroxyl; thiol; amino; cyano; nitro; aldehyde; carboxyl; and alkyl, alkoxy, cycloalkyl or heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and / or haloheterocyclyl; and

[0084] Alkyl, alkoxy, cycloalkyl or heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of deuterium; halogen; hydroxyl; mercapto; amino; cyano; nitro; aldehyde; carboxyl; alkyl; alkoxy; cycloalkyl; heterocyclyl; and alkyl, alkoxy, cycloalkyl or heterocyclyl substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, aldehyde and / or carboxyl.

[0085] In some embodiments, R1 is selected from hydrogen; deuterium; halogen; hydroxyl; thiol; amino; nitro; cyano; alkyl; alkyl substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde and / or carboxyl; alkoxy; alkoxy substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde and / or carboxyl; cycloalkyl; alkyl substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, carboxyl, -OR 1c and / or -NR 1c R 1d substituted cycloalkyl; heterocyclic group; selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, aldehyde, carboxyl, -OR 1c and / or -NR 1c R 1d a heterocyclyl substituted with one or more substituents of 1a 、-SR 1a 、-NR 1a R 1b 、-COR 1a 、-SOR 1a 、-SO2R 1a 、-COOR 1a 、-CONR 1a R 1b 、-NR 1a COR 1b 、-OCOR 1a 、-S(O)(NR 1a )R 1b 、-SONR 1a R1b 、-SO2NR 1a R 1b 、-NR 1a SOR 1b and -NR 1a SO2R 1b , where R 1a and R 1b are independently selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, and alkyl, cycloalkyl or heterocyclyl substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde and / or carboxyl, and R 1c and R 1d Independently selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, and alkyl, cycloalkyl or heterocyclyl substituted with one or more substituents selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, aldehyde and / or carboxyl.

[0086] In some embodiments, R1 is selected from hydrogen, hydroxy, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, cyano, -OR 1c and / or -NR 1c R 1d Substituted cycloalkyl, heterocyclic, -NR 1a R 1b 、-COR 1a 、-CONR 1a R 1b 、-S(O)(NR 1a )R 1b and -SO2NR 1a R 1b , where R 1a and R 1b are independently selected from hydrogen, alkyl, cycloalkyl and alkyl or cycloalkyl substituted with one or more substituents selected from deuterium, halogen, cyano, -OCO-alkyl and / or -OCOO-alkyl, and R 1c and R 1d are independently selected from hydrogen and alkyl.

[0087] In some embodiments, R1 is selected from hydroxy, cyano, methyl, ethyl, propyl (e.g., n-propyl and sec-propyl), tert-butyl, difluoromethyl (-CHF2), hydroxymethyl, hydroxyethyl, hydroxypropyl (e.g., hydroxyisopropyl), methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, trifluoroethoxy, cyclopropyl, azetidinyl, cyclobutyl, cyclobutyl substituted with cyano, hydroxy or -NHCH3, -S(O)(NH)CH3, -SO2NR 1a R 1b 、-NR 1a R 1b 、-COR1a 、-CONR 1a R 1b , where R 1a and R 1b Independently selected from hydrogen, methyl, isopropyl, -CH2CN, -CD3, -CH2CF3, difluoromethyl (-CHF2), -CF3, cyclopropyl, difluorocyclopropyl, -CH2OCOOC(CH3)3, -CH2OCOC(CH3)3.

[0088] In some embodiments, R2 is selected from optionally substituted C 3-12 cycloalkyl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl.

[0089] In some embodiments, R2 is selected from optionally substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, bicyclo[1.1.1]pentyl (e.g. ), bicyclo[2.2.2]octyl (e.g. ) and cubic alkyl groups (e.g. ).

[0090] In some embodiments, R2 is selected from optionally substituted 3-12 membered heterocyclyl containing one to six (eg, one, two, three, or four) heteroatoms independently selected from N, O, and S.

[0091] In some embodiments, R2 is selected from optionally substituted tetrahydropyrrolyl, piperidinyl, piperazinyl, azetidinyl, (1-oxa-8-azaspiro[4.5]decyl) and (7-azaspiro[3.5]nonyl).

[0092] In some embodiments, R2 is selected from optionally substituted phenyl.

[0093] In some embodiments, R2 is selected from optionally substituted 5-6 membered heteroaryl.In some embodiments, R2 is selected from optionally substituted pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl or triazinyl.

[0094] In some embodiments, R2 is selected from unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; and cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, -OR 2a 、-SR 2a 、-NR 2a R 2b 、-COR 2a 、-SOR 2a 、-SO2R2a 、-COOR 2a 、-CONR 2a R 2b 、-NR 2a COR 2b 、-OCOR 2a 、-S(O)(NR 2a )R 2b 、-SONR 2a R 2b 、-SO2NR 2a R 2b 、-NR 2a SOR 2b 、-NR 2a SO2R 2b , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein R 2a and R 2b are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0095] In some embodiments, R 2a and R 2b independently selected from: hydrogen; deuterium; unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents independently selected from: deuterium; halogen; hydroxyl; thiol; amino; cyano; nitro; aldehyde; carboxyl; and alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and / or haloheterocyclyl.

[0096] In some embodiments, R2 is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted with one or more substituents independently selected from:

[0097] Deuterium; halogen; hydroxyl; thiol; amino; cyano; nitro;

[0098] -OR 2a 、-SR 2a 、-NR 2a R 2b 、-COR 2a 、-SOR 2a 、-SO2R 2a 、-COOR 2a 、-CONR 2a R2b 、-NR 2a COR 2b 、 -OCOR 2a 、-S(O)(NR 2a )R 2b 、-SONR 2a R 2b 、-SO2NR 2a R 2b 、-NR 2a SOR 2b 、-NR 2a SO2R 2b , where R 2a and R 2b are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0099] Alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxy, thiol, amino, cyano, nitro, -OR 2c 、-SR 2c 、-NR 2c R 2d 、-COR 2c 、-SOR 2c 、-SO2R 2c 、-COOR 2c 、-CONR 2c R 2d 、-NR 2c COR 2d 、-OCOR 2c 、-S(O)(NR 2c )R 2d 、-SONR 2c R 2d 、-SO2NR 2c R 2d 、-NR 2c SOR 2d 、-NR 2c SO2R 2d , alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, and alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with one or more substituents selected from deuterium, halogen, hydroxy, thiol, amino, cyano, nitro, aldehyde and / or carboxyl, wherein R 2c and R 2dindependently selected from hydrogen; deuterium; unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted by one or more substituents independently selected from the group consisting of deuterium; halogen; hydroxyl; thiol; amino; cyano; nitro; aldehyde; carboxyl; and alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and / or haloheterocyclyl.

[0100] In some embodiments, R2 is selected from:

[0101] Cycloalkyl; Heterocyclyl; Aryl; Heteroaryl;

[0102] is selected from deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, -OR 2a 、-NR 2a R 2b 、-COR 2a 、-COOR 2a 、-CONR 2a R 2b and / or -NR 2a COR 2b One or more substituents substituted cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein R 2a and R 2b independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted with one or more substituents selected from deuterium, halogen, hydroxy, thiol, amino, cyano, nitro, aldehyde, carboxyl, alkyl, and / or haloalkyl;

[0103] Cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with one or more substituents selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, -OR 2c 、-NR 2c R 2d 、-COR 2c 、-COOR 2c 、-CONR 2c R 2d and / or -NR 2c COR 2d An alkyl, cycloalkyl or heterocyclic group substituted with one or more substituents, wherein R 2c and R 2dindependently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted with one or more substituents of deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, carboxyl, alkyl, and / or haloalkyl;

[0104] Cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with one or more substituents selected from the group consisting of alkyl; cycloalkyl; heterocyclyl; and alkyl, cycloalkyl or heterocyclyl substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, thiol, amino, cyano, nitro, aldehyde, carboxyl, alkyl and / or haloalkyl.

[0105] In some embodiments, R2 is selected from: cycloalkyl; heterocyclyl; aryl; heteroaryl; and cycloalkyl, heterocyclyl, aryl, heteroaryl substituted with one or more substituents independently selected from the following: halogen, -OR 2a 、-NR 2a R 2b 、-COR 2a 、-COOR 2a 、-CONR 2a R 2b 、-NR 2a COR 2b , alkyl, cycloalkyl, heterocyclic and selected from halogen, -OR 2c 、-NR 2c R 2d 、-COR 2c 、-COOR 2c 、-CONR 2c R 2d 、-NR 2c COR 2d and / or an alkyl, cycloalkyl or heterocyclic group substituted with one or more substituents of the alkyl group, wherein R 2a and R 2b are independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and alkyl substituted with cycloalkyl or heterocyclyl substituted with alkyl, and R 2c and R 2d Independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and alkyl substituted with cycloalkyl or heterocyclyl substituted with alkyl.

[0106] In some embodiments, R2 is selected from phenyl; pyridinyl; pyrazinyl; pyridazinyl; pyrimidinyl; piperidinyl; cyclobutyl, cyclohexyl; azetidinyl; 1-oxa-8-azaspiro[4.5]decyl; 7-azaspiro[3.5]nonyl; is selected from fluoro, bromo, -OR 2a 、-NR 2a R2b 、-COR 2a 、-COOR 2a 、-CONR 2a R 2b 、-NR 2a COR 2b and / or one or more substituents of piperazinyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl, cyclobutyl, cyclohexyl, wherein R 2a and R 2b selected from hydrogen, methyl, tert-butyl, piperidinyl and methyl substituted by methylpiperidinyl; phenyl substituted by one or more substituents selected from methyl, -OR 2c 、-NR 2c R 2d 、-COR 2c 、-COOR 2c 、-CONR 2c R 2d and / or -NR 2c COR 2d substituted with one or more substituents, methyl or piperazinyl, wherein R 2c and R 2d are independently selected from hydrogen, methyl, phenyl, or methyl substituted by methylpiperidinyl.

[0107] In some embodiments, R3 is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, -OR 3a 、-SR 3a 、-NR 3a R 3b 、-COR 3a 、-SOR 3a 、-SO2R 3a 、-COOR 3a 、-CONR 3a R 3b 、-NR 3a COR 3b 、-OCOR 3a 、-S(O)(NR 3a )R 3b 、-SONR 3a R 3b 、-SO2NR 3a R 3b 、-NR 3a SOR 3b 、-NR 3a SO2R 3b , optionally substituted C 1-12 Alkyl (e.g. C 1-6 alkyl), optionally substituted C 1-12 Alkoxy (e.g. C1-6 alkoxy), optionally substituted C 3-12 Cycloalkyl (e.g. C 3-6 cycloalkyl), optionally substituted 3-12 membered heterocyclyl (e.g., 3-10 membered heterocyclyl), optionally substituted 6-10 membered aryl (e.g., phenyl), and optionally substituted 5-10 membered heteroaryl (e.g., 5-6 membered heteroaryl), wherein R 3a and R 3b are independently selected from hydrogen, deuterium, optionally substituted C 1-12 Alkyl (e.g. C 1-6 alkyl), optionally substituted C 3-12 Cycloalkyl (e.g. C 3-6 cycloalkyl), optionally substituted 3-12 membered heterocyclyl (e.g., 3-10 membered heterocyclyl), optionally substituted 6-10 membered aryl (e.g., phenyl), and optionally substituted 5-10 membered heteroaryl (e.g., 5-6 membered heteroaryl).

[0108] In some embodiments, R 3a and R 3b independently selected from: hydrogen; deuterium; unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted by one or more substituents independently selected from: deuterium; halogen; hydroxyl; thiol; amino; cyano; nitro; aldehyde; carboxyl; and alkyl, alkoxy, cycloalkyl or heterocyclyl optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and / or haloheterocyclyl.

[0109] In some embodiments, R3 is selected from unsubstituted alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, thiol, amino, cyano, nitro, =O, =S, -OR 3c 、-SR 3c 、-NR 3c R 3d 、-COR 3c 、-SOR 3c 、-SO2R 3c 、-COOR 3c 、-CONR 3c R 3d 、-NR 3c COR 3d 、-OCOR 3c 、-S(O)(NR 3c )R 3d 、-SONR3c R 3d 、-SO2NR 3c R 3d 、-NR 3c SOR 3d 、-NR 3c SO2R 3d , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, wherein R 3c and R 3d are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0110] In some embodiments, R3 is selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted with one or more substituents independently selected from:

[0111] Deuterium; halogen; hydroxyl; thiol; amino; cyano; nitro; =O; =S;

[0112] -OR 3c 、-SR 3c 、-NR 3c R 3d 、-COR 3c 、-SOR 3c 、-SO2R 3c 、-COOR 3c 、-CONR 3c R 3d 、-NR 3c COR 3d 、-OCOR 3c 、-S(O)(NR 3c )R 3d 、-SONR 3c R 3d 、-SO2NR 3c R 3d 、-NR 3c SOR 3d 、-NR 3c SO2R 3d , where R 3c and R 3dindependently selected from hydrogen; deuterium; unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with one or more substituents independently selected from deuterium; halogen; hydroxyl; thiol; amino; cyano; nitro; aldehyde; carboxyl; and alkyl, alkoxy, cycloalkyl or heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, halocycloalkyl, heterocyclyl or haloheterocyclyl; and

[0113] Optionally independently selected from deuterium; halogen; hydroxyl; thiol; amino; cyano; nitro; aldehyde; carboxyl; =O; =S; -OR 3e 、-SR 3e 、-NR 3e R 3f 、-COR 3e 、-SOR 3e 、-SO2R 3e 、-COOR 3e 、-CONR 3e R 3f 、-NR 3e COR 3f 、-OCOR 3e 、-S(O)(NR 3e )R 3f 、-SONR 3e R 3f 、-SO2NR 3e R 3f 、-NR 3e SOR 3f 、-NR 3e SO2R 3f , where R 3e and R 3f independently selected from hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl and haloheterocyclyl; alkyl; alkoxy; cycloalkyl; heterocyclyl; and alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with one or more substituents selected from deuterium, halogen, hydroxy, thiol, amino, cyano, nitro, aldehyde and / or carboxyl.

[0114] In some embodiments, R3 is selected from:

[0115] Hydrogen; deuterium; halogen; hydroxyl; thiol; amino; nitro; cyano;

[0116] -OR 3a 、-SR 3a 、-NR 3a R3b 、-COR 3a 、-SOR 3a 、-SO2R 3a 、-COOR 3a 、-CONR 3a R 3b 、-NR 3a COR 3b 、-OCOR 3a 、-S(O)(NR 3a )R 3b 、-SONR 3a R 3b 、-SO2NR 3a R 3b 、-NR 3a SOR 3b 、-NR 3a SO2R 3b , where R 3a and R 3b independently selected from hydrogen and alkyl;

[0117] is selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, -OR 3c 、-SR 3c 、-NR 3c R 3d 、-COR 3c 、-SOR 3c 、-SO2R 3c 、-COOR 3c 、-CONR 3c R 3d 、-NR 3c COR 3d 、-OCOR 3c 、-S(O)(NR 3c )R 3d 、-SONR 3c R 3d 、-SO2NR 3c R 3d 、-NR 3c SOR 3d and / or -NR 3c SO2R 3d An alkyl group substituted with one or more substituents, wherein R 3c and R 3d independently selected from hydrogen and alkyl;

[0118] Alkyl substituted with one or more substituents selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, =O, =S, -OR 3e 、-SR 3e 、-NR3e R 3f 、-COR 3e 、-SOR 3e 、-SO2R 3e 、-COOR 3e 、-CONR 3e R 3f 、-NR 3e COR 3f 、-OCOR 3e 、-S(O)(NR 3e )R 3f 、-SONR 3e R 3f 、-SO2NR 3e R 3f 、-NR 3e SOR 3f 、-NR 3e SO2R 3f and / or a heterocyclic group substituted by one or more substituents of an alkyl group, wherein R 3e and R 3f independently selected from hydrogen and alkyl;

[0119] heterocyclic group;

[0120] is selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, =O, =S, -OR 3c 、-SR 3c 、-NR 3c R 3d 、-COR 3c 、-SOR 3c 、-SO2R 3c 、-COOR 3c 、-CONR 3c R 3d 、-NR 3c COR 3d 、-OCOR 3c 、-S(O)(NR 3c )R 3d 、-SONR 3c R 3d 、-SO2NR 3c R 3d 、-NR 3c SOR 3d 、-NR 3c SO2R 3d and / or a heterocyclic group substituted with one or more substituents of the alkyl group;

[0121] Heterocyclyl substituted by one or more substituents selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, -OR3e 、-SR 3e 、-NR 3e R 3f 、-COR 3e 、-SOR 3e 、-SO2R 3e 、-COOR 3e 、-CONR 3e R 3f 、-NR 3e COR 3f 、-OCOR 3e 、-S(O)(NR 3e )R 3f 、-SONR 3e R 3f 、-SO2NR 3e R 3f 、-NR 3e SOR 3f and / or -NR 3e SO2R 3f an alkyl group substituted with one or more substituents;

[0122] heteroaryl;

[0123] is selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, -OR 3c 、-SR 3c 、-NR 3c R 3d 、-COR 3c 、-SOR 3c 、-SO2R 3c 、-COOR 3c 、-CONR 3c R 3d 、-NR 3c COR 3d 、-OCOR 3c 、-S(O)(NR 3c )R 3d 、-SONR 3c R 3d 、-SO2NR 3c R 3d 、-NR 3c SOR 3d 、-NR 3c SO2R 3d and / or heteroaryl substituted with one or more substituents of the alkyl group; and

[0124] Heteroaryl substituted with one or more substituents selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, -OR 3e 、-SR3e 、-NR 3e R 3f 、-COR 3e 、-SOR 3e 、-SO2R 3e 、-COOR 3e 、-CONR 3e R 3f 、-NR 3e COR 3f 、-OCOR 3e 、-S(O)(NR 3e )R 3f 、-SONR 3e R 3f 、-SO2NR 3e R 3f 、-NR 3e SOR 3f and / or -NR 3e SO2R 3f an alkyl group substituted with one or more substituents;

[0125] where R 3a 、R 3b 、R 3c 、R 3d 、R 3e and R 3f are independently selected from hydrogen and alkyl.

[0126] In some embodiments, R3 is selected from hydrogen; deuterium; halogen; hydroxyl; thiol; amino; nitro; cyano; -OR 3a 、-NR 3a R 3a 、-CONR 3a R 3b ; is selected from halogen, -OR 3c 、-NR 3c R 3d and / or -CONR 3c R 3d Alkyl substituted with one or more substituents selected from the group consisting of halogen, =O, =S, -OR 3e 、-NR 3e R 3f 、-CONR 3e R 3f and / or alkyl substituted with one or more substituents; heterocyclic group; selected from halogen, =O, =S, -OR 3c 、-NR 3c R 3d 、-CONR 3c R 3dand / or alkyl; heterocyclic group substituted by one or more substituents selected from the group consisting of halogen, -OR 3e 、-NR 3e R 3f and / or -CONR 3e R 3f Alkyl substituted with one or more substituents; heteroaryl; selected from halogen, -OR 3c 、-NR 3c R 3d 、-CONR 3c R 3d and / or alkyl substituted with one or more substituents; heteroaryl substituted with one or more substituents selected from the group consisting of halogen, -OR 3e 、-NR 3e R 3f and / or -CONR 3e R 3f an alkyl group substituted with one or more substituents;

[0127] where R 3a 、R 3b 、R 3c 、R 3d 、R 3e and R 3f are independently selected from hydrogen and alkyl.

[0128] In some embodiments, R3 is selected from: nitro; -CONH2; trifluoromethyl; difluoroethyl;

[0129] Methyl substituted by tetrahydropyrimidinyl, triazacyclopentyl, morpholinyl, imidazolidinyl, octahydropyrrolo[3,4-B][1,4]oxazinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, optionally substituted by one or more substituents selected from ═O, ═S, alkyl (e.g., methyl) and / or substituted alkyl (e.g., difluoromethyl, hydroxymethyl, aminomethyl, or dimethylaminomethyl),

[0130] Tetrahydropyrimidinyl; triazacyclopentyl; morpholinyl; imidazolidinyl; octahydropyrrolo[3,4-B][1,4]oxazinyl; 2-oxa-5-azabicyclo[2.2.1]heptyl;

[0131] The following groups substituted by one or more substituents selected from =O, =S, alkyl (e.g. methyl) and / or substituted alkyl (e.g. difluoromethyl, hydroxymethyl, aminomethyl or dimethylaminomethyl): tetrahydropyrimidinyl, morpholinyl, imidazolidinyl, triazacyclopentyl, octahydropyrrolo[3,4-B][1,4]oxazinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, as well as

[0132] pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl and thiadiazole substituted by an amino group.

[0133] In some embodiments, R3 is selected from the following structures:

[0134] In some embodiments, when an R3 substituent is present, the R3 substituent can be substituted at the ortho, meta, or para (eg, meta) position relative to the position of attachment of Ring P to the rest of the molecule.

[0135] In some embodiments, the compound of formula (I) of the present invention has formula (III):

[0136] The ring structure where Q3 and Q4 are located is selected from the following structures:

[0137] wherein the ring P, R1, R2 and R3 in formula (III) are the same as those in formula (I).

[0138] In some embodiments, the present invention relates to a compound of formula (III), or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof:

[0139] in,

[0140] The ring structure where Q3 and Q4 are located is selected from the following structures:

[0141] Ring P is pyridyl, pyrazolopyrimidinyl or pyrrolopyridazinyl;

[0142] R1 is selected from -OR 1a 、-COR 1a 、-CONR 1a R 1b 、-S(O)(NR 1a )R 1b 、-SO2NR 1a R 1b , optionally substituted alkyl, wherein R 1a and R 1bare independently selected from hydrogen, deuterium, optionally substituted alkyl, and optionally substituted cycloalkyl;

[0143] R2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted phenyl, pyridyl, and pyrimidinyl;

[0144] R3 is selected from cyano, optionally substituted alkyl and optionally substituted heteroaryl.

[0145] In some embodiments, R1 is selected from alkyl (eg, methyl, ethyl, propyl (eg, isopropyl)) substituted with one or more substituents independently selected from halogen and hydroxy:

[0146] In some embodiments, R 1a and R 1b Independently selected from: hydrogen; deuterium; alkyl (e.g., methyl, ethyl, propyl (e.g., isopropyl)); cycloalkyl (e.g., cyclopropyl); and alkyl (e.g., methyl, ethyl, propyl (e.g., isopropyl)) and cycloalkyl (e.g., cyclopropyl) substituted with one or more substituents independently selected from: deuterium, halogen (e.g., fluorine), hydroxyl, thiol, amino, cyano, and nitro.

[0147] In some embodiments, R1 is selected from -CONH2, hydroxyisopropyl, hydroxymethyl, hydroxyethyl, methoxy, difluoromethyl, -CONH-(cyclopropyl), -SO2NH2, -S(O)(NH)CH3, -OCH2CF3, -COCH2CF3, -COCH3, -COCD2H, -COCF3, -COCHF2, -CONHCH3, -CONHCH(CH3)2, -SO2NHCH3, -SO2NHCH(CH3)2, -CONH-(difluorocyclopropyl).

[0148] In some embodiments, R2 is selected from optionally substituted cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, or bicyclo[2.2.2]octyl; optionally substituted piperidinyl, azetidinyl, azacyclopentyl, or 1-oxa-8-azaspiro[4.5]decyl or 7-azaspiro[3.5]nonyl; optionally substituted phenyl, pyridinyl, or pyrimidinyl.

[0149] In some embodiments, R2 is selected from unsubstituted cycloalkyl, heterocyclyl, phenyl, pyridyl; and cycloalkyl, heterocyclyl, phenyl, pyridyl substituted with one or more substituents independently selected from the group consisting of deuterium, halogen (e.g., fluorine or bromine), hydroxyl, thiol, amino, cyano, nitro, -OR 2a 、-NR 2a R 2b 、-COR 2a 、-COOR 2a 、-CONR 2aR 2b 、-NR 2a COR 2b 、-OCOR 2a , optionally substituted alkyl and optionally substituted heterocyclic, wherein R 2a and R 2b are independently selected from hydrogen, deuterium, optionally substituted alkyl, and optionally substituted heterocyclyl.

[0150] In some embodiments, R 2a and R 2b Independently selected from hydrogen, deuterium, alkyl (eg, methyl), alkyl substituted by halogen, heterocyclic (eg, piperazinyl), heterocyclic substituted by alkyl.

[0151] In some embodiments, R2 is selected from cycloalkyl, heterocyclyl, phenyl, pyridyl substituted with one or more substituents independently selected from:

[0152] alkyl;

[0153] heterocyclic group;

[0154] Selected-OR 2c 、-NR 2c R 2d 、-COR 2c 、-COOR 2c 、-CONR 2c R 2d and / or -NR 2c COR 2d An alkyl group (eg, methyl) or a heterocyclic group (eg, piperazinyl) substituted with one or more substituents, wherein R 2c and R 2d independently selected from hydrogen, deuterium, alkyl (e.g., methyl), phenyl;

[0155] Heterocyclyl (eg, piperazinyl) substituted by one or more substituents selected from alkyl (eg, methyl).

[0156] In some embodiments, R2 is selected from phenyl; and phenyl substituted with one or more substituents independently selected from: deuterium; halogen (eg, fluorine or bromine); -OR 2a 、-NR 2a R 2b 、-COR 2a 、-COOR 2a 、-CONR 2a R 2b 、-NR 2a COR 2b 、-OCOR 2a , where R 2a and R 2bindependently selected from hydrogen, deuterium, alkyl (e.g., methyl), and heterocyclyl (e.g., piperazinyl); alkyl (e.g., methyl), heterocyclyl (e.g., piperazinyl), and alkyl (e.g., methyl) or heterocyclyl (e.g., piperazinyl) substituted with one or more substituents independently selected from: -OR 2c 、-NR 2c R 2d 、-COR 2c 、-COOR 2c 、-CONR 2c R 2d and / or -NR 2c COR 2d , where R 2c and R 2d Independently selected from hydrogen, deuterium, alkyl (eg methyl), phenyl.

[0157] In some embodiments, R2 is selected from phenyl; and phenyl substituted by one or more substituents independently selected from the group consisting of fluoro, bromo, hydroxy, methoxy, amino, -NHCH3, -N(CH3)2, -NHCOCH3, -COOH, -CONHCH3, -CON(CH3)2, -CO-(N-piperazinyl), -CH2OH, -CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2NHCOCH3, -CH2NCH3COCH3, piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl, and 4-benzoylpiperazinyl.

[0158] In some embodiments, R3 is selected from alkyl (eg, methyl) substituted with halogen (eg, fluorine), such as trifluoromethyl.

[0159] In some embodiments, R3 is selected from a 5-membered heteroaryl group containing one or more nitrogen ring atoms.

[0160] In some embodiments, R3 is selected from:

[0161] In some embodiments, Ring P is pyridyl, and R3 is selected from -CF3.

[0162] In some embodiments, ring P is pyridinyl or pyrazolopyrimidinyl, and R3 is selected from

[0163] In some embodiments, Ring P is pyrrolopyridazinyl, and R3 is cyano.

[0164] In some embodiments, Ring P is pyridyl, R1 is -CONH2, R2 is optionally substituted phenyl, and R3 is selected from -CF3.

[0165] In some embodiments, Ring P is pyridyl, R2 is optionally substituted phenyl, and R3 is selected from:

[0166] In some embodiments, Ring P is pyridyl, R1 is selected from -CONH2, hydroxyisopropyl, hydroxymethyl, hydroxyethyl, methoxy, difluoromethyl, -CONH-(cyclopropyl), -SONH2, -S(O)(NH)CH3, -OCH2CF3, -COCH2CF3, -COCH3, -COCD2H, -COCF3, -COCHF2, -CONHCH3, -CONHCH(CH3)2, -SONHCH3, -SONHCH(CH3)2, -CONH-(difluorocyclopropyl), R2 is phenyl, and R3 is selected from:

[0167] The present invention also provides a compound of formula (II), or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof:

[0168] ALE(II)

[0169] Part A has the following structure:

[0170] in,

[0171] Q1, Q2, Q3, Q4 and Q5 are independently selected from C, CH, CH2, N, NH, S or O;

[0172] ---Indicates the presence or absence of a double bond;

[0173] Ring P is an aryl group or a heteroaryl group;

[0174] R1 is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, -OR 1a 、-SR 1a 、-NR 1a R 1b 、-COR 1a 、-SOR 1a 、-SO2R 1a 、-COOR 1a 、-CONR 1a R 1b 、-NR 1a COR 1b 、-OCOR 1a 、-S(O)(NR 1a )R 1b 、-SONR 1a R 1b 、-SO2NR 1a R 1b、-NR 1a SOR 1b 、-NR 1a SO2R 1b , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl and optionally substituted heterocyclyl, wherein R 1a and R 1b are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;

[0175] R3 is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, -OR 3a 、-SR 3a 、-NR 3a R 3b 、-COR 3a 、-SOR 3a 、-SO2R 3a 、-COOR 3a 、-CONR 3a R 3b 、-NR 3a COR 3b 、-OCOR 3a 、-S(O)(NR 3a )R 3b 、-SONR 3a R 3b 、-SO2NR 3a R 3b 、-NR 3a SOR 3b 、-NR 3a SO2R 3b , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein R 3a and R 3b independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0176] n is 0, 1, 2, 3, 4 or 5;

[0177] R2' is selected from optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene; and

[0178] The A part is connected to the L part through the ring atom of R2';

[0179] The L section has the following structure:

[0180] -L1-L2-L3-L4-L5- Formula (L)

[0181] in:

[0182] L1, L3 and L5 are independently absent or selected from -Rm-, -Rm-Rn-, -Rm-O-Rn-, -Rm-C(O)-Rn-, -Rm-C(O)O-Rn-, -Rm-OC(O)-Rn-, -Rm-NRx-Rn-, -Rm-C(O)NRx-Rn-, -Rm-NRxC(O)-Rn-, -Rm-S(O)-Rn- n-, -Rm-S(O)NRx-Rn-, -Rm-NRxS(O)-Rn-, -Rm-S(O)2-Rn-, -Rm-S(O)2NRx-Rn-, -R m-NRxS(O)2-Rn-, -Rm-NRxC(O)NRy-Rn-, -Rm-OC(O)NRx-Rn-, -Rm-NRxC(O)O-Rn-, 、-(CH2CH2O) g -or-(OCH2CH2) g -, wherein Rm and Rn are independently selected from a bond, optionally substituted alkylene, optionally substituted alkyleneoxy, optionally substituted cycloalkylene or optionally substituted heterocyclylene, Rx and Ry are independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl, and g is an integer from 1 to 20;

[0183] L2 and L4 are independently absent or selected from optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene or optionally substituted heteroarylene; and

[0184] Section E has the following structure:

[0185] Among them, RE 1 is selected from hydrogen, deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl or optionally substituted heterocyclyl, RE 2 is selected from hydrogen, deuterium or halogen, RE L1 is selected from a bond, -CH2-, -NH-, -NCH3-, -O-, -CONH- or -CONCH3-, RE L2 is selected from a bond or -CH2-, and p is 1, 2, 3, 4 or 5.

[0186] RE 1a Selected from -COCH(CH3)OH, -COCH3, -CON(CH3)2, -CO(CH2)2CH(NH2)COOH or -COCH(NH2)(CH2)2COOH, RE 2aSelected from -CH2OCOOC(CH3)3 or -CH2OCOC(CH3)3.

[0187] Section A

[0188] In some embodiments, Q1-Q5 and the rings in which they are located, Ring P, R1 and R3 in Formula (II) are the same as defined in Formula (I) (and Formula (III)).

[0189] In some embodiments, portion A has the following structure:

[0190] In some embodiments, R2' is selected from optionally substituted C 3-12 cycloalkylene, optionally substituted 3- to 12-membered heterocyclylene, optionally substituted 6- to 10-membered arylene, optionally substituted 5- to 10-membered heteroarylene.

[0191] In some embodiments, R2' is selected from optionally substituted cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene, bicyclo[1.1.1]pentylene (eg ), bicyclo[2.2.2]octylene (e.g. ) and cubic alkylene (e.g. ).

[0192] In some embodiments, R2′ is selected from an optionally substituted 3-12 membered heterocyclylene containing one to six (eg, one, two, three, or four) heteroatoms independently selected from N, O, and S.

[0193] In some embodiments, R2' is selected from optionally substituted tetrahydropyrrolylene, piperidinylene, piperazinylene, azetidinylene, 1-oxa-8-azaspiro[4.5]decylene, and 7-azaspiro[3.5]nonylene.

[0194] In some embodiments, R2' is selected from optionally substituted phenylene.

[0195] In some embodiments, R2' is selected from optionally substituted 5-6 membered heteroarylene. In some embodiments, R2' is selected from optionally substituted pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, or triazinylene.

[0196] In some embodiments, R2' is selected from cycloalkylene, heterocyclylene, arylene, or heteroarylene optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, carboxyl, alkyl, alkoxy, and alkyl or alkoxy substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, and / or carboxyl.

[0197] In some embodiments, R2' is selected from phenylene, pyridylene, piperidylene, cyclohexylene, bicyclo[1.1.1]pentylene, bicyclo[2.2.2]octylene, or cubanylene.

[0198] L section

[0199] In some embodiments, Rm and Rn are independently selected from a bond, an optionally substituted C 1-20 Alkylene (e.g. C 1-12 Alkylene or C 1-6 alkylene), optionally substituted C 1-20 Alkyleneoxy (e.g. C 1-12 Alkyleneoxy or C 1-6 alkyleneoxy), optionally substituted C 3-6 cycloalkylene or an optionally substituted 3- to 6-membered heterocyclylene.

[0200] In some embodiments, Rx and Ry are independently selected from hydrogen, deuterium, optionally substituted C 1-20 Alkyl (e.g. C 1-12 Alkyl or C 1-6 alkyl), optionally substituted C 3-6 cycloalkyl or an optionally substituted 3- to 6-membered heterocyclic group.

[0201] In some embodiments, g is an integer from 1-20, or an integer from 1-16, or an integer from 1-12, or an integer from 1-8, or an integer from 1-6, or 1, 2, 3, 4, or 5.

[0202] In some embodiments, Rm and Rn are independently selected from a bond, an alkylene, an alkyleneoxy, a cycloalkylene, a heterocyclylene, and an alkylene, alkyleneoxy, cycloalkylene, or heterocyclylene substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, alkyl, alkoxy, and an alkyl or alkoxy substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, and / or carboxyl.

[0203] In some embodiments, Rx and Ry are independently selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, and alkyl, cycloalkyl, or heterocyclyl substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, alkyl, alkoxy, and alkyl or alkoxy substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, and / or carboxyl.

[0204] In some embodiments, Rm and Rn are independently selected from a bond, methylene, ethylene, propylene, butylene, cyclopropylene, and fluoroC 1-4 Alkylene.

[0205] In some embodiments, Rx and Ry are independently selected from hydrogen, methyl, or cyclopropyl.

[0206] In some embodiments, L1, L3, and L5 are independently selected from: where h is 1, 2, 3, 4, or 5.

[0207] In some embodiments, L2 and L4 are independently absent or selected from optionally substituted C 3-12 cycloalkylene, an optionally substituted 3- to 12-membered heterocyclylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene.

[0208] In some embodiments, L2 and L4 are independently selected from cycloalkylene, heterocyclylene, arylene, heteroarylene, and cycloalkylene, heterocyclylene, arylene, or heteroarylene substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, =0, =S, alkyl, alkoxy, and alkyl or alkoxy substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, and / or carboxyl.

[0209] In some embodiments, L2 and L4 are independently selected from cycloalkylene or halocycloalkylene (eg, fluorinated cycloalkylene).

[0210] In some embodiments, L2 and L4 are independently selected from:

[0211] (For example )

[0212] In some embodiments, L2 and L4 are independently selected from a 3-12 membered heterocyclylene group containing one to six (preferably one, two, three or four) heteroatoms independently selected from N, O and S, which is optionally substituted with one or more substituents selected from halogen (e.g., fluorine), =O and / or alkyl (e.g., methyl).

[0213] In some embodiments, L2 and L4 are independently selected from: (For example ) (For example ) (For example ) (For example )

[0214] In some embodiments, L2 and L4 are independently selected from phenylene, which is optionally substituted with one or more substituents selected from halogen (eg, fluorine) and / or alkyl (eg, methyl).

[0215] In some embodiments, L2 and L4 are independently selected from

[0216] In some embodiments, L2 and L4 are independently selected from 5-6 membered heteroaryl groups containing one, two, three or four heteroatoms independently selected from N, O and S, which are optionally substituted with one or more substituents selected from halogen (e.g., fluorine) and / or alkyl (e.g., methyl). In some embodiments, L2 and L4 are independently selected from pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, which are optionally substituted with one or more substituents selected from halogen (e.g., fluorine) and / or alkyl (e.g., methyl).

[0217] In some embodiments, L2 and L4 are independently selected from:

[0218] In some embodiments, the combination of L2, L3, and L4 in the L portion (with or without L1 and / or L5) or the L portion is selected from:

[0219] In some embodiments, the L moiety is selected from:

[0220] Generally speaking, for part L and each group in part L, the connection point on the left is connected to the remaining molecular parts from part A or in the direction toward part A; the connection point on the right is connected to the remaining molecular parts from part E or in the direction toward part E.

[0221] Section E

[0222] In some embodiments, the E moiety has the following structure:

[0223] In some embodiments, RE 1 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, optionally substituted C 1-20 Alkyl (e.g. C 1-12 Alkyl or C 1-6 alkyl), optionally substituted C 1-20 Alkoxy (e.g. C 1-12 Alkoxy or C 1-6 alkoxy), optionally substituted C 3-6 Cycloalkyl or optionally substituted 3-6 membered heterocyclic group, RE 2 is selected from hydrogen, deuterium or halogen, RE L1 is selected from a bond, -CH2-, -NH-, -NCH3-, -O-, -CONH- or -CONCH3-, RE L2 is selected from a bond or -CH2-, and p is 1, 2, 3, 4 or 5.

[0224] In some embodiments, RE 1 is selected from hydrogen, deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, and alkyl, alkoxy, cycloalkyl or heterocyclyl substituted by one or more substituents selected from deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, alkyl, haloalkyl, alkoxy and / or haloalkoxy.

[0225] In some embodiments, RE 1 is selected from hydrogen, deuterium, fluorine, chlorine, hydroxy, methyl, methoxy, ethoxy, hydroxymethyl, hydroxypropyl (eg hydroxyisopropyl), trifluoromethyl or trifluoromethoxy.

[0226] In some embodiments, RE 2 is selected from hydrogen, deuterium or fluorine.

[0227] In some embodiments, RE 1a Selected from -COCH(CH3)OH, -COCH3, -CON(CH3)2, -CO(CH2)2CH(NH2)COOH or -COCH(NH2)(CH2)2COOH.

[0228] In some embodiments, RE 2a Selected from -CH2OCOOC(CH3)3 or -CH2OCOC(CH3)3.

[0229] In some embodiments, the E moiety is selected from the following structures: (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example ) (For example )

[0230] In some embodiments, the compound of formula (II) has the following structure:

[0231] The ring structure where Q3 and Q4 are located is selected from the following structures:

[0232] wherein the ring P, R1, R2' and R3 in formula (II) are as defined above.

[0233] In some embodiments, the present invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof:

[0234] ALE (II)

[0235] Part A has the following structure:

[0236] The ring structure where Q3 and Q4 are located is selected from the following structures:

[0237] Ring P is pyridyl, pyrazolopyrimidinyl or pyrrolopyridazinyl;

[0238] R1 is selected from -OR 1a 、-COR 1a 、-CONR 1a R 1b 、-S(O)(NR 1a )R 1b 、-SO2NR 1a R 1b , optionally substituted alkyl, wherein R 1a and R 1b are independently selected from hydrogen, deuterium, optionally substituted alkyl, and optionally substituted cycloalkyl;

[0239] R2' is selected from optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted phenylene and pyridylene;

[0240] R3 is selected from cyano, optionally substituted alkyl and optionally substituted heteroaryl;

[0241] And the definitions of L and E are the same as described above (eg, formula (II)).

[0242] In some embodiments, the definitions of Ring P, R1, and R3 in Formula (A') are the same as those described above (eg, Formula (III)).

[0243] In some embodiments, R2' is selected from cycloalkylene, heterocyclylene, phenylene, and pyridylene, optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, carboxyl, and alkyl.

[0244] In some embodiments, R2' is selected from optionally substituted cyclobutylene, cyclopentylene, cyclohexylene, bicyclo[1.1.1]pentylene, or bicyclo[2.2.2]octylene; optionally substituted piperidinylene, azetidinylene, azetidinylene, 1-oxa-8-azaspiro[4.5]decylene, or 7-azaspiro[3.5]nonylene; optionally substituted phenylene or pyridinylene.

[0245] In some embodiments, L1, L3 and L5 are independently absent or selected from -Rm-, -Rm-O-Rn-, -Rm-C(O)-Rn-, -Rm-C(O)O-Rn-, -Rm-OC(O)-Rn-, -Rm-NRx-Rn-, -Rm-C(O)NRx-Rn-, -Rm-NRxC(O)-Rn- or wherein Rm and Rn are independently selected from a bond or optionally substituted alkylene, and Rx is independently selected from hydrogen, deuterium or optionally substituted alkyl.

[0246] In some embodiments, Rm and Rn are independently selected from a bond or an alkylene group (eg, C 1-4 alkylene, such as methylene or ethylene).

[0247] In some embodiments, Rx is independently selected from hydrogen, deuterium, or alkyl (e.g., C 1-4 alkylene groups, such as methylene and ethylene).

[0248] In some embodiments, L2 is selected from optionally substituted heterocyclylene.

[0249] In some embodiments, L2 and L4 are independently selected from 3-12 membered heterocyclylene containing one or two nitrogen heteroatoms, which are optionally substituted with one or more substituents selected from halogen (eg, fluorine) and / or alkyl (eg, methyl).

[0250] In some embodiments, L2 and L4 are independently selected from:

[0251] In some embodiments, L1 is absent or selected from -Rm-, -Rm-O-Rn-, -Rm-C(O)-Rn-, -Rm-C(O)O-Rn-, -Rm-OC(O)-Rn-, -Rm-NRx-Rn-, -Rm-C(O)NRx-Rn-, or -Rm-NRxC(O)-Rn-, wherein Rm and Rn are independently selected from a bond or an alkylene group (e.g., methylene or ethylene), and Rx is independently selected from hydrogen, deuterium, or an alkyl group (e.g., methyl).

[0252] In some embodiments, L1 is absent or selected from -CH2-, -CH2CH2-, -CH2O-, -C(O)-, -CH2C(O)-, -CH2NH-, -NHCH2-, -CH2N(CH3)-, -C(O)NH-.

[0253] In some embodiments, L2 and L4 are independently selected from:

[0254] In some embodiments, L3 is absent or selected from -Rm-, -Rm-O-Rn-, -Rm-C(O)-Rn-, -Rm-C(O)O-Rn-, -Rm-OC(O)-Rn-, -Rm-NRx-Rn-, -Rm-C(O)NRx-Rn-, or -Rm-NRxC(O)-Rn-, wherein Rm and Rn are independently selected from a bond or an alkylene group (e.g., methylene or ethylene), and Rx is independently selected from hydrogen, deuterium, or an alkyl group (e.g., methyl).

[0255] In some embodiments, L3 is absent or selected from -CH2-, -CH2CH2-, -OCH2-, -C(O)-, -C(O)CH2-, -C(O)O-, -NH-, -NHCH2-, -N(CH3)-.

[0256] In some embodiments, L5 is absent or selected from -Rm-, -Rm-C(O)-Rn-, -Rm-NRx-Rn-, or wherein Rm and Rn are independently selected from a bond or an alkylene group (eg, methylene or ethylene), and Rx is independently selected from hydrogen, deuterium, or an alkyl group (eg, methyl).

[0257] In some embodiments, L5 is absent or selected from -CH2-, -C(O)-, -NH-, or

[0258] In some embodiments, L1 is absent or selected from -CH2-, -CH2CH2-, -C(O)-, -NHCH2-, -CH2N(CH3)-, -CH2O-, -C(O)NH-, -CH2C(O)-, -CH2NH-;

[0259] L2 is absent and L4 is selected from the following groups, or L2 is selected from the following groups and L4 is absent:

[0260] L3 is absent or selected from -CH2-, -CH2CH2- or -C(O)-;

[0261] L5 is absent or selected from -CH2-, -NH-, -C(O)-.

[0262] In some embodiments, L1 is selected from -CH2-, -C(O)-;

[0263] L2 is selected from

[0264] L3 is absent or selected from -OCH2-, -CH2CH2-, -NHCH2-;

[0265] L4 does not exist;

[0266] L5 is selected from

[0267] In some embodiments, L1 is absent or selected from -CH2-, -C(O)-, -CH2O-;

[0268] L2 is selected from

[0269] L3 is absent or selected from -CH2-, -CH2CH2-, -NHCH2-, -C(O)O-, -OCH2-, -NH-, -N(CH3)-, -C(O)-, -C(O)CH2-;

[0270] L4 is selected from

[0271] L5 is absent or selected from -C(O)-, -CH2-.

[0272] In some embodiments, L1 is selected from the group consisting of

[0273] L2 is selected from

[0274] L3 is absent or selected from -CH2-, -CH2CH2-, -C(O)-;

[0275] L4 is selected from

[0276] L5 is absent or selected from -C(O)-.

[0277] In some embodiments, L1 is selected from -CH2-, -CH2CH2-, -C(O)-, -C(O)NH-, -CH2NH-, -CH2C(O)-, -CH2O-, -CH2N(CH3)-;

[0278] L2 is selected from

[0279] L3 is absent or selected from -CH2-, -C(O)-;

[0280] L4 does not exist or is selected

[0281] L5 does not exist.

[0282] In specific embodiments of L, L is selected from:

[0283] In some embodiments, the E moiety has the following structure:

[0284] In some embodiments, RE 1 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, alkyl, alkoxy, RE 2 is selected from hydrogen, deuterium or halogen, RE L1 is selected from a bond, -CH2-, -NH-, -NCH3-, -O-, -CONH- or -CONCH3-, RE L2 is selected from a bond, -CH2- or cyclopropylene, and p is 1 or 2.

[0285] In some embodiments, RE 1 is selected from hydrogen, deuterium, halogen (eg fluorine) and methoxy.

[0286] In some embodiments, RE 2 Selected from hydrogen or deuterium.

[0287] In some embodiments, the E moiety has the following structure:

[0288] Among them, RE 1 is selected from hydrogen, deuterium, halogen (such as fluorine), methoxy, RE 2 is selected from hydrogen, deuterium or halogen, RE L1 is selected from a bond, -CH2-, -NH-, -NCH3-, -O-, -CONH- or -CONCH3-, RE L2 is selected from a bond, -CH2-, and p is 1 or 2.

[0289] In some embodiments, the E moiety has the following structure:

[0290] In a specific embodiment of E, E is selected from:

[0291] In some embodiments, the compound of formula (II) has the following structure: ALE (II), wherein

[0292] Part A has the structure of formula (A'), wherein

[0293] The ring structure where Q3 and Q4 are located is selected from:

[0294] Ring P is pyridyl;

[0295] R1 is selected from -CONH2, hydroxyisopropyl, difluoromethyl, -CONH-(cyclopropyl);

[0296] R2' is selected from phenylene, cyclohexylene, bicyclo[1.1.1]pentylene;

[0297] R3 is selected from -CF3.

[0298] The L portion has the following structure: -L1-L2-L3-L4-L5- Formula (L)

[0299] wherein L1 is absent or selected from -CH2-, -C(O)-, -CH2O-;

[0300] L2 is selected from

[0301] L3 is absent or selected from -CH2-, -CH2CH2-, -NHCH2-, -C(O)O-, -OCH2-, -NH-, -N(CH3)-, -C(O)-, -C(O)CH2-;

[0302] L4 is selected from

[0303] L5 is absent or selected from -C(O)-, -CH2-; or

[0304] Specifically, wherein L1 is selected from absent; L2 is selected from L3 is absent or selected from -CH2-, -CH2CH2-, -C(O)-; L4 is selected from L5 is absent or selected from -C(O)-.

[0305] Section E has the following structure:

[0306] Among them, RE 1 is selected from hydrogen, deuterium, halogen (such as fluorine), methoxy, RE 2 is selected from hydrogen, deuterium or halogen, RE L1 is selected from a bond, -CH2-, -NH-, -NCH3-, -O-, -CONH- or -CONCH3-, RE L2 is selected from a bond, -CH2-, and p is 1 or 2; or

[0307] Specifically, E is selected from:

[0308] In some embodiments, the compound of formula (II) has the following structure: ALE (II), wherein

[0309] Part A has the following structure:

[0310] The L portion has the following structure: -L1-L2-L3-L4-L5- Formula (L)

[0311] wherein L1 is absent or selected from -CH2-, -CH2CH2-, -C(O)-, -NHCH2-, -CH2N(CH3)-, -CH2O-, -C(O)NH-, -CH2C(O)-, -CH2NH-;

[0312] L2 is absent and L4 is selected from the following groups, or L2 is selected from the following groups and L4 is absent:

[0313] L3 is absent or selected from -CH2-, -CH2CH2- or -C(O)-;

[0314] L5 is absent or selected from -CH2-, -NH-, -C(O)-.

[0315] E is selected from the following structures: In some embodiments, the compound of formula (II) has the following structure: ALE(II), wherein the A moiety has the following structure: The L portion has the following structure: -L1-L2-L3-L4-L5- Formula (L)

[0316] wherein L1 is selected from -CH2-, -C(O)-;

[0317] L2 is selected from

[0318] L3 is absent or selected from -OCH2-, -CH2CH2-, -NHCH2-;

[0319] L4 does not exist;

[0320] L5 is selected from

[0321] E is selected from the following structures:

[0322] In some embodiments, the compound of formula (II) has the following structure: ALE (II), wherein

[0323] Part A has the following structure:

[0324] The L portion has the following structure: -L1-L2-L3-L4-L5- Formula (L)

[0325] wherein L1 is absent or selected from -CH2-, -C(O)-, -CH2O-;

[0326] L2 is selected from

[0327] L3 is absent or selected from -CH2-, -CH2CH2-, -NHCH2-, -C(O)O-, -OCH2-, -NH-, -N(CH3)-, -C(O)-, -C(O)CH2-;

[0328] L4 is selected from

[0329] L5 is absent or selected from -C(O)-, -CH2-

[0330] E is selected from the following structures:

[0331] In some embodiments, the compound of formula (II) has the following structure: ALE (II), wherein

[0332] Part A has the following structure:

[0333] The L portion has the following structure: -L1-L2-L3-L4-L5- Formula (L)

[0334] Wherein L1 is selected from -CH2-, -CH2CH2-, -C(O)-, -C(O)NH-, -CH2NH-, -CH2C(O)-, -CH2O-, -CH2N(CH3-)

[0335] L2 is selected from

[0336] L3 is absent or selected from -CH2-, -C(O)-

[0337] L4 does not exist or is selected

[0338] L5 does not exist.

[0339] E is selected from the following structures:

[0340] In some embodiments, the compound of Formula I is selected from:

[0341] A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A59, A60, A61, A62, A63, A64, A65, A66, A67, A68, A69, A70, A71, A72, A73, A74, A75, A76, A77, A78, A79, A80, A81, A82, A83, A84, A85, A86, A87, A88, A89, A90, A91, A92, A93, A94, A95, A96, A97, A98, A99, A100, A101, A102, A103, A104, A105, A106, A107, A108, A229, A230, A231, A232, A233, A234, A235, A236, A237, A238, A239, A240, A241, A242, A243, A244, A245, A246, A247, A248, A249, A250, A251, A252, A253, A254, A255, A256, A257, A258, A259, A260, A261, A262, A263, A264, A265, A266, A267, A268, A269, A270, A271, A272, A273, A274, A275, A276, A277, A278, A279, A280, A281, A282, A283, A284, A285, A286, A287, A288, A289, A290, A291, A292, A293, A294, A295, A296, A297, A455, A456, A457, A458, A459, A460, A461, A462, A463, A464, A465, A466, A467, A468, A469, A470, A471, A472, A473。

[0342] In some embodiments, the compounds of formula (II) are selected from:

[0343] A109、A110、A111、A112、A113、A114、A115、A116、A117、A118、A119、A120、A121、A122、A123、A124、A125、A126、A127、A128、A129、A130、A131、A132、A133、A134、A135、A136、A137、A138、A139、A140、A141、A142、A143、A144、A145、A146、A147、A148、A149、A150、A151、A152、A153、A154、A155、A156、A157、A158、A159、A160、A161、A162、A163、A164、A165、A166、A167、A168、A169、A170、A171、A172、A173、A174、A175、A176、A177、A178、A179、A180、A181、A182、A183、A184、A185、A186、A187、A188、A189、A190、A191、A192、A193、A194、A195、A196、A197、A198、A199、A200、A201、A202、A203、A204、A205, A206, A207, A208, A209, A210, A211, A212, A213, A214, A215, A216, A217, A218, A219, A220, A221, A222, A223, A224, A225, A 226, A227, A228, A298, A299, A300, A301, A302, A303, A304, A305, A307, A308, A309, A310, A311, A312, A313, A314, A315, A316, A3 17. A318, A319, A320, A321, A322, A324, A325, A326, A327, A328, A329, A330, A331, A332, A333, A334, A335, A336, A337, A338, A33 9. A340, A341, A343, A348, A349, A350, A351, A352, A353, A354, A355, A356, A357, A358, A359, A360, A361, A362, A363, A364, A365, A366, A367, A368, A369, A370, A371, A372, A373, A374, A377, A378, A379, A380, A383, A384, A385, A386, A387, A388, A389, A390, A 391, A392, A393, A394, A395, A396, A397, A398, A399, A400, A401, A402, A403, A404, A405, A406, A407, A408, A409, A410, A411, A4 12. A413, A414, A415, A416, A417, A418, A419, A420, A421, A422, A423, A424, A425, A426, A427, A428, A429, A430, A431, A432, A43 3. A434, A435, A436, A437, A438, A439, A440, A441, A442, A443, A444, A445, A446, A447, A448, A449, A450, A451, A452, A453, A454.

[0344] The present invention also provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0345] The present invention provides a method for treating or preventing a disease mediated by IRAK protein, comprising administering a compound of formula (I) or formula (II) or a composition of the present invention to a patient in need thereof.

[0346] The present invention provides use of a compound of formula (I) or formula (II) or a composition of the present invention in preparing a medicament for treating or preventing a disease mediated by an IRAK protein.

[0347] In some embodiments, the disease mediated by the IRAK protein is selected from the group consisting of brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, mesothelioma, glioblastoma, neuroblastoma, head and neck cancer, adenoma, adenocarcinoma, melanoma, lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, follicular lymphoma, plasmacytoma or intravascular large B cell lymphoma, diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma (Burkitt lymphoma), lymphoma), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), multiple myeloma, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or injury, hypoxemia, epilepsy, metabolic syndrome, catabolic syndrome, hypertension, type 1 diabetes, type 2 diabetes, obesity, gout, hypercholesterolemia, Hypertriglyceridemia, dyslipidemia, heart disease, chronic heart failure, cardiomegaly, myocarditis, eye disease, eye allergies, conjunctivitis, dry eyes, conjunctivitis, cataracts, glaucoma, retinal disease, endocrine eye disease, nasal disease, sinusitis, allergic rhinitis, viral myocarditis, autoimmune blood disease, hemolytic anemia, aplastic anemia, pure red blood cell anemia, idiopathic thrombocytopenia, myasthenia gravis, Stevens-Johnson syndrome, gastrointestinal disease, gastritis, enteritis, colitis, proctitis, irritable bowel syndrome, Crohn's disease, necrotizing enterocolitis, inflammatory bowel disease, enterocolitis, inflammation associated with gastrointestinal infections (including Clostridium difficile infection), ulcerative colitis, lung disease, pneumonia, acute lung injury, acute respiratory distress syndrome, hyaline membrane disease, chronic obstructive pulmonary disease (COPD), cystic fibrosis, acid-induced lung injury, pulmonary hypertension, asthma Asthma, allergies, bronchiolitis, bronchitis, interstitial pulmonary fibrosis, interstitial lung disease, kidney disease, glomerular disease, chronic kidney disease, diabetic kidney disease, nephritis, glomerulonephritis, leptospirosis, immunoglobulin A nephropathy, renal fibrosis, pyelonephritis, liver disease, hepatitis, chronic hepatitis, alcoholic liver disease, alcoholic fatty liver disease, alcoholic hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), arthritis, systemic juvenile idiopathic arthritis, chronic gouty arthritis, psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis, polychondritis, other inflammatory diseases, cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), lupus nephritis, atopic dermatitis, hidradenitis suppurativa, psoriasis, multiple sclerosis, scleroderma, psoriasis, vitiligo, Sjögren's syndromesyndrome), uveitis, organ transplantation or graft-versus-host disease, vasculitis, cystitis, chronic granulomatous disease, muscular dystrophy, pancreatitis, hereditary periodic fever syndromes, allergic reaction, anaphylaxis, polyneuropathy, inclusion body myositis, thyroiditis, Addison's disease disease), appendicitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, dacryoadenitis, dermatitis, dermatomyositis, polymyositis, encephalitis, endocarditis, endometritis, epididymitis, fasciitis, fibrositis, laryngitis, mastitis, meningitis, myelitis, myositis, liver fibrosis, cardiac fibrosis, oophoritis, orchitis, osteitis, otitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, prostatitis, salpingitis, stomatitis, synovitis, tonsillitis, vaginitis, vulvitis, alopecia areata, erythema multiforme, herpetiform dermatitis, sclerosis, vitiligo, urticaria, pimples, cryptopyrin-associated periodic syndromes, Lyme disease, pelvic inflammatory disease, acute and chronic tissue damage.

[0348] DETAILED DESCRIPTION

[0349] Example

[0350] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0351] Preparation Example 1. Synthesis of Compound A1

[0352] Compound A1-0 (10 g, 54.013 mmol, 1 eq) was dissolved in 150 mL of methanol. Thionyl chloride (8 mL, 110.145 mmol, 2 eq) was added dropwise under an ice bath. The mixture was then stirred at room temperature overnight. Upon completion of the reaction, the solvent was removed by rotary evaporation to afford compound A1-1 (9 g, 52.598 mmol, 98% yield).

[0353] Compound A1-1 (9 g, 52.598 mmol, 1 eq) was diluted in 28% aqueous ammonia (100 ml, 799 mmol, 15 eq) and refluxed in an oil bath at 100°C for 24 h. Upon completion of the reaction, the solution became turbid and yellow. The solvent was removed by rotary evaporation to afford compound A1-2 (7.4 g, 47.406 mmol, 90% yield) as a yellow solid.

[0354] Compound A1-2 (4 g, 25.625 mmol, 1 equivalent) and compound A1-3 (7.16 g, 25.631 mmol, 1 equivalent) were dissolved in 50 ml of DMF, and cesium carbonate (16.7 g, 51.255 mmol, 2 equivalents) was added. The mixture was reacted in an oil bath at 130°C for 16 h. After the reaction was detected to be complete, the mixture was diluted with ethyl acetate and filtered through celite to remove the solid. The mixture was extracted with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and wet-loaded. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain compound A1-4 (2.4 g, 7.072 mmol, 28% yield).

[0355] Compound A1-4 (2.4 g, 7.072 mmol, 1 equivalent) was dissolved in 25 ml of methanol. 5% palladium on carbon (800 mg, 1:0.33) was added and stirred under a hydrogen balloon for 8 h. Upon completion of the reaction, the mixture was filtered through celite and a small layer of silica gel and dried to afford compound A1-5 (830 mg, 2.683 mmol, 38% yield) as a white solid.

[0356] Compound A1-6 (518 mg, 2.710 mmol, 1.01 eq) was dissolved in 10 ml of dry DMF, and DIPEA (2.3 ml, 13.204 mmol, 5 eq) was added. After stirring, HATU (1.224 g, 3.219 mmol, 1.2 eq) was added. After stirring at room temperature for 1 hour, compound A1-5 (830 mg, 2.683 mmol, 1 eq, in 5 ml of DMF) was added and allowed to react at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with a large amount of ethyl acetate, extracted with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, wet loaded, and purified by silica gel column chromatography (dichloromethane:methanol = 250:1) to obtain compound A1 (750 mg, 1.555 mmol, 58% yield). 1 H NMR: (500MHz, DMSO) δ11.70(s,1H),8.47(s,1H),8.41(d,1H,J=7.6Hz),8.37(t,1H,J=7.7Hz),8.18(d,1H,J=7.6Hz),7.68(s, 1H),7.55(s,1H),4.44-4.53(m,1H),4.00-4.14(m,2H),2.81-3.03(m,2H),2.00-2.08(m,2H),1.81-1.92(m,2H),1.42(s,9H).

[0357] Preparation Example 2. Synthesis of Compound A2

[0358] Compound A2-0 (6.1 g, 39.078 mmol, 1 equivalent) was dissolved in 30 ml of methanol, and 5% palladium on carbon (900 mg, 1:0.3) was added. The mixture was stirred under a hydrogen balloon for 8 h. Upon completion of the reaction, the mixture was filtered through Celite and dried. The mixture was then dissolved in a large amount of methanol / dichloromethane and purified by flash column chromatography (dichloromethane:methanol = 4:1) to obtain compound A2-1 (4.4 g, 34.887 mmol, 89% yield).

[0359] Compound A2-2 (6.7 g, 35.058 mmol, 1.005 eq) was dissolved in 30 ml of dry DMF, and DIPEA (30 ml, 172.224 mmol, 5 eq) was added. After stirring, HATU (16 g, 42.079 mmol, 1.2 eq) was added. After stirring at room temperature for 1 hour, compound A2-1 (4.4 g, 34.887 mmol, 1 eq, in 10 ml of DMF) was added and allowed to react at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with a large amount of ethyl acetate, extracted with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and dried by spin drying. After adding dichloromethane, a solid product was precipitated and filtered to obtain compound A2-3 (6.6 g, 22.058 mmol, 63% yield).

[0360] 2,5-Dibromopyrazine (890 mg, 3.741 mmol, 1.12 eq) was placed in a sealed tube and dissolved in 10 ml of DMF. Cesium carbonate (2.7 g, 8.287 mmol, 2.5 eq) was then added dropwise. Compound A2-3 (1 g, 3.342 mmol, 1 eq) was dissolved in 5 ml of DMF and added dropwise to the reaction system. The mixture was reacted in an oil bath at 80°C for 5 h. Upon completion, the reaction was diluted with ethyl acetate, filtered through Celite, and extracted with saturated aqueous NaCl. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (dichloromethane:triethylamine = 500:10, then dichloromethane:methanol:triethylamine = 500:5:10) to afford compound A2 (350 mg, 0.767 mmol, 22% yield). 1 H NMR: (500MHz, DMSO) δ11.74(s,1H),9.16(s,1H),9.08(s,1H),8.82(s,1H),8.43(d,1 H, J=7.6Hz), 8.38 (t, 1H, J=7.6Hz), 8.23 ​​(s, 1H), 8.20 (d, 1H, J=7.6Hz), 7.94 (s, 1H).

[0361] Preparation Example 3. Synthesis of Compound A3

[0362] Compound A1 (120 mg, 0.249 mmol, 1 equivalent) was dissolved in 20 ml of dichloromethane, and TFA (boiling point 72.4°C) (0.25 ml, 3.366 mmol, 12 equivalents) was added. The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, extracted with sodium hydroxide solution and saturated NaCl solution, dried over anhydrous sodium sulfate, and rotary evaporated to obtain compound A3 (93 mg, 0.243 mmol, 97.7% yield) as a white solid. 1 H NMR: (500MHz, DMSO) δ11.72 (s, 1H), 8.41-8.46 (m, 2H), 8.38 (t, 1H, J = 7.6Hz), 8.19 (d, 1H, J = 7.6Hz), 7.66 (s, 1H), 7.57(s,1H),4.29-4.38(m,1H),3.03-3.13(m,2H),2.59-2.64(m,2H),1.97-2.04(m,2H),1.81-1.91(m,2H).

[0363] Preparation Example 4. Synthesis of Compound A4

[0364] Compound A4-0 (3.30 g, 30.5 mmol, 1.00 equivalent) and DMF (33.0 mL) were added to a 100 mL three-necked flask, and compound A4-1 (6.23 g, 30.5 mmol, 3.40 mL, 1.00 equivalent), DMEDA (2.69 g, 30.5 mmol, 3.29 mL, 1.00 equivalent), CuI (2.91 g, 15.2 mmol, 0.50 equivalent) and K 3 PO 4 (19.4 g, 91.5 mmol, 3.00 equivalent) were added under nitrogen at 20-25° C., and the reaction was carried out at 100° C. for 3 hours. LCMS showed that the reaction of compound A4-0 was complete, and the target mass spectrum was detected (RT = 1.748 mins). Filter, collect the filtrate, concentrate, and purify the crude product by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 200*40mm*10μm; mobile phase: [water (TFA)-ACN]; gradient: 20%-50% B, 10 minutes). The mobile phase was extracted twice with 20 mL of ethyl acetate, dried over sodium sulfate, filtered, and concentrated to give compound A4-2 (970 mg, 5.16 mmol, yield 16.9%, purity 98.0%) as a yellow solid.

[0365] 6-(Trifluoromethyl)pyridine-2-carboxylic acid (986 mg, 5.16 mmol, 1.00 equivalent), HATU (2.94 g, 7.74 mmol, 1.50 equivalent), and DCM (10.0 mL) were added to a 100 mL three-necked flask, followed by the addition of DIEA (2.00 g, 15.4 mmol, 2.70 mL, 3.00 equivalent), and the mixture was reacted at 0-10° C. for 0.5 hour. Compound A4-2 (970 mg, 5.16 mmol, 1.00 equivalent) was then added, and the mixture was reacted at 20-25° C. for 15.5 hours. LCMS showed 17.7% of compound A4-2 remaining (RT=0.319 min), and the target mass spectrum was detected (RT=0.478 min). The reaction solution was concentrated to obtain a crude product, which was separated by column chromatography (SiO2, DCM:MeOH = 50:1 to 10:1, product: Rf = 0.75) to obtain compound A4-3 (1.01 g, 2.82 mmol, yield 54.6%, purity 99.7%) as a white solid.

[0366] Compound A4-3 (1.00 g, 2.79 mmol, 1.00 equiv) and dioxane (2.00 mL) were placed in a 100 mL three-necked flask at 20-25°C. HCl (12.0 M, 20.0 mL, 86.0 equiv) was added, and the temperature was raised to 75°C for 3 hours. LCMS showed 11.2% of compound A4-3 remaining (RT = 0.452 min), and the target mass spectrum was detected (RT = 0.253 min). NaHCO3 was added to pH = 7-8, and the mixture was extracted three times with ethyl acetate (50.0 mL). The combined organic phases were washed with saturated brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated to afford compound A4-4 (300 mg, 937 μmol, 33.6% yield, 63.2% purity) as a yellow solid.

[0367] 6-(Trifluoromethyl)pyridine-2-carboxylic acid (179 mg, 937 μmol, 1.20 equiv), HATU (445 mg, 1.17 mmol, 1.50 equiv), and THF (2.00 mL) were added to a 10 mL single-necked vial. DIEA (302 mg, 2.34 mmol, 408 μL, 3.00 equiv) was then added and the mixture was reacted at 0-10°C for 0.5 h. Compound A4-4 (250 mg, 781 μmol, 1.00 equiv) was then added and the mixture was reacted at 25°C for 15.5 h. TLC (dichloromethane:methanol = 8:1) showed that the reaction of compound A4-4 (Rf = 0.70) was complete, yielding a new spot (Rf = 0.45). The filter cake was collected by filtration and dried under vacuum. The solid was slurried with THF (5.00 mL) and filtered. The filter cake was dissolved in water (20.0 mL) and acetonitrile (5.00 mL) and lyophilized to obtain compound A4 (114 mg, 262 μmol, 33.5% yield, 98.5% purity) as a white solid. LCMS: m / z = 376.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ12.22(s,1H)9.00(s,1H)8.36-8.49(m,2H)8.21(d,J=7.4Hz,1H)7.74-7.84(m,3H)7.54-7.62(m,3H)7.38(t,J=7.4Hz,1H).

[0368] Preparation Example 5. Synthesis of Compound A5

[0369] Compound Int1-1 (7.73 g, 40.4 mmol, 1.02 equiv) and DCM (75.0 mL) were added to a 250 mL three-necked flask, and DIEA (10.2 g, 79.2 mmol, 13.8 mL, 2.00 equiv) and HATU (16.5 g, 43.6 mmol, 1.10 equiv) were added at 0-5°C. The mixture was stirred at 0-5°C for 1 hour, and then compound Int1-0 (5.00 g, 39.6 mmol, 1.00 equiv) was added. Stirring was continued at 0-5°C for 1 hour. LCMS showed that the reaction of Int1-0 was complete and the main peak of the product was detected. The mixture was concentrated under reduced pressure, ethyl acetate (500 mL) was added, and the organic phase was washed with saturated brine (500 mL*3). It was dried over sodium sulfate and concentrated. The crude product was slurried with EtOAc / PE = 1 / 5 (200 mL), filtered, and the filter cake was washed with petroleum ether (200 mL) and dried under reduced pressure to obtain compound Int 1 (12.5 g, 38.4 mmol, yield 80.7%, purity 92%) as a yellow solid. LCMS: m / z = 322.1 (M+Na) + .1 H NMR: (400MHz, DMSO) δ13.31(s,1H),11.72(s,1H),8.42-8.39(m,3H),8.43-8.34(m,1H),8.18(d,J=6.4Hz,2H),7.78(d,J=100Hz,1H).

[0370] At 20-25 ° C, ACN (4.00 mL), compound Int1 (200 mg, 668 μmol, 1.00 equiv) and phenylboronic acid (81.5 mg, 668 μmol, 1.00 equiv) were added to a three-necked round-bottom flask. Under an oxygen atmosphere, copper(II) chloride; N,N,N',N'-tetramethylethylenediamine (93.1 mg, 200 μmol, 0.300 equiv) and K2CO3 (184 mg, 1.34 mmol, 2.00 equiv) were added. Under an oxygen atmosphere, the temperature was raised to 75-80 ° C and the reaction was carried out for 16 hours. LCMS showed that compound Int1 was completely reacted and the target mass spectrum was detected. The reaction solution was filtered and the filter cake was washed twice with ACN (0.5 mL). After the filtrate was purified by preparative HPLC (TFA conditions), some fractions were concentrated in vacuo at 45 ° C. NaHCO3 (2.00 g) was added to the concentrate and extracted three times with ethyl acetate (20.0 mL). The combined organic phases were washed with saturated brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was then purified by preparative TLC (ethyl acetate:petroleum ether = 1:1, Rf = 0.44). The scraped silica gel powder was stirred with ACN (30.0 mL) for 30 minutes and concentrated to obtain compound A5 (66.0 mg, 171 μmol, yield 12.8%, purity 97.6%) as a white solid. LCMS: m / z = 376.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.79(s,1H),9.03(s,1H),8.42-8.36(m,1H),8.49-8.36(m,1H),8.25-8.18(m,1H),8.03(br s,1H),7.99(br d,J=8.0Hz,2H),7.77(br s,1H),7.56(t,J=8.0Hz,2H),7.46-7.36(m,1H).

[0371] Preparation Example 6. Synthesis of Compound A6

[0372] At 20-25 ° C, compound Int1 (400 mg, 1.34 mmol, 1.00 equiv), 4-iodophenol (294 mg, 1.34 mmol, 1.00 equiv), DMEDA (118 mg, 1.34 mmol, 144 μL, 1.00 equiv), K3PO4 (851 mg, 4.01 mmol, 3.00 equiv), DMF (1.00 mL) and CuI (127 mg, 668 μmol, 0.50 equiv) were added to a 10 mL single-necked round-bottom flask. Under a nitrogen atmosphere, the temperature was raised to 100 ° C and the reaction was allowed to proceed for 1.5 hours. LCMS showed that 1.76% of compound Int1 remained, and the target mass spectrum was detected. The reaction solution was filtered and the filter cake was washed 3 times with DMF (0.5 mL). The crude product was concentrated in vacuo at 50-55°C and purified by preparative HPLC (TFA conditions), then concentrated in vacuo at 45°C and lyophilized to afford compound A6 (207 mg, 523 μmol, 39.1% yield, 98.8% purity) as a pink solid. LCMS: m / z = 392.0 (M+H) + . 1 H NMR: (400MHz, DMSO-d6)δ11.79(s,1H)9.79(s,1H)8.85(s,1H)8.48-8.38(m,2 H)8.21(dd,J=7.6,1.0Hz,1H)7.93(s,1H)7.78-7.68(m,3H)6.95-6.89(m,2H).

[0373] Preparation Example 7. Synthesis of Compound A7

[0374] At 20-25 ° C, compound Int1 (400 mg, 1.34 mmol, 1.00 equiv), 4-iodoanisole (313 mg, 1.34 mmol, 1.00 equiv), DMEDA (118 mg, 1.34 mmol, 144 μL, 1.00 equiv), K3PO4 (851 mg, 4.01 mmol, 3.00 equiv), DMF (1.00 mL) and CuI (127 mg, 668 μmol, 0.50 equiv) were added to a 10 mL single-necked round-bottom flask. Under a nitrogen atmosphere, the temperature was raised to 100 ° C and the reaction was allowed to proceed for 1.5 hours. LCMS showed that 1.41% of compound Int1 remained, and the target mass spectrum was detected. The reaction solution was filtered and the filter cake was washed 3 times with DMF (0.5 mL). The crude product was concentrated in vacuo at 50-55°C and purified by preparative HPLC (TFA conditions), then concentrated in vacuo at 45°C and lyophilized to afford compound A7 (128 mg, 310 μmol, 23.2% yield, 97.8% purity) as an off-white solid. LCMS: m / z = 406.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6)δ11.79(s,1H).8.93(s,1H)8.48-8.37(m,2H)8.22(dd,J=7.6 ,0.8Hz,1H)7.98(s,1H)7.94-7.86(m,2H)7.73(s,1H)7.15-7.01(m,2H)3.83(s,3H).

[0375] Preparation Example 8. Synthesis of Compound A8

[0376] At 20-25 ° C, compound Int1 (923 mg, 2.49 mmol, 1.00 equivalent), pyridine (394 mg, 4.98 mmol, 402 μ L, 2.00 equivalent) and 4-bromophenylboronic acid (500 mg, 2.49 mmol, 1.00 equivalent) were added to a 40 mL reaction bottle. Under an oxygen atmosphere, [Cu(OH)-(TMEDA)]2Cl2 (347 mg, 747 μ mol, 0.30 equivalent) and ACN (12.0 mL) were added. Under an oxygen atmosphere, the mixture was warmed to 80 ° C and reacted for 16 hours. LCMS showed that 32.8% of compound Int1 remained, and the target mass spectrum was detected. The mixture was concentrated in vacuo at 45 ° C. The crude product was purified by column chromatography (SiO2, dichloromethane:methanol = 10:1, Rf = 0.5), then purified by flash silica gel column chromatography (Welch Ultimate XB-SiOH 250*70*10 μm; mobile phase: [hexane-EtOH]; B%: 6%-30%, 25 min) and lyophilized to obtain compound A8 (55.5 mg, 119 μmol, 4.80% yield, 97.7% purity) as a white solid. LCMS: m / z = 455.7 (M+H) + . 1 H NMR: (400MHz, DMSO-d6)δ11.78(s,1H)9.07(s,1H)8.47-8.37(m,2H)8.13-8.26(m,1H)8.08(s,1H)7.99(d,J=9.0Hz,2H)7.67-7.85(m,3H)3.60(br t,J=6.6Hz,1H).

[0377] Preparation Example 9. Synthesis of Compound A9

[0378] At 20-25 ° C, compound Int1 (2.85 g, 7.69 mmol, 1.00 equiv), K2CO3 (2.12 g, 15.4 mmol, 2.00 equiv) and [Cu(OH)-(TMEDA)]2Cl2 (428 mg, 922 μmol, 0.30 equiv) were added to a 100 mL three-necked reaction flask. Under an oxygen atmosphere, 4-bromophenylboronic acid (1.05 g, 7.69 mmol, 1.00 equiv) and ACN (35.0 mL) were added. Under an oxygen atmosphere, the temperature was raised to 50 ° C and the reaction was allowed to proceed for 16 hours. LCMS showed that 42.7% of compound Int1 remained, and 49.1% of the target mass spectrum was detected. After filtration, the mixture was concentrated under vacuum at 45 ° C. The crude product was purified by preparative HPLC (column: Daisogel C18 250*70 mm*10 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 26%-66%, 15 min) and lyophilized to afford compound A9 (83.5 mg, 205 μmol, yield 2.68%, purity 96.2%) as a gray solid. LCMS: m / z = 390.9 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ12.11-11.48(m,1H)8.76(s,1H)8.47-8.33(m,2H)8.19(d,J=7.4Hz,1H)7.88(br s,1H)7.67(br s,1H)7.56(d,J=8.8Hz,2H)6.68(d,J=8.2Hz,2H)5.38(br s,2H).

[0379] Preparation Example 10. Synthesis of Compound A10

[0380] At 20-25° C., N-methyl-p-bromoaniline (4-bromo-N-methylaniline) (500 mg, 2.69 mmol, 1.00 equiv), DMAP (32.8 mg, 269 μmol, 0.10 equiv), Boc2O (880 mg, 4.03 mmol, 926 μL, 1.50 equiv) and DCM (5.00 mL) were added to 40 mL parallel reaction bottles. The reaction was carried out at 20-25° C. for 14 hours. LCMS showed that 15.5% of N-methyl-p-bromoaniline (4-bromo-N-methylaniline) remained, and the target mass spectrum was detected (RT=0.520 min). The reactant was poured into water (10.0 mL) and extracted four times with dichloromethane (15.0 mL). The combined organic phase was washed with saturated brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated to give compound A10-1 (800 mg, 2.10 mmol, yield 78.0%, purity 75.0%) as a dark brown liquid.

[0381] At 20-25 ° C, compound Int1 (500 mg, 1.67 mmol, 1.00 equivalent), compound A10-1 (638 mg, 1.67 mmol, 1.00 equivalent), DMEDA (147 mg, 1.67 mmol, 180 μL, 1.00 equivalent), K3PO4 (1.06 g, 5.01 mmol, 3.00 equivalent), DMF (10.0 mL) and CuI (159 mg, 836 μmol, 0.50 equivalent) were added to a 100 mL three-necked round-bottom flask. Nitrogen was replaced three times, the temperature was raised to 100 ° C, and the reaction was carried out for 11 hours. LCMS showed that 5.02% of compound Int1 remained, and the target mass spectrum was detected. Filter and extract three times with ethyl acetate (5.00 mL). The crude product was purified by preparative HPLC (TFA conditions), concentrated at 40-45 °C, and lyophilized to give compound A10-2 (50.0 mg, 97.0 μmol, yield 5.81%, purity 97.9%) as a brown solid.

[0382] At 20-25 ° C, compound A10-2 (40.0 mg, 79.3 μmol, 1.00 equivalent) and TFA (271 mg, 2.38 mmol, 177 μL, 30.0 equivalent) were added to 10 mL parallel reaction bottles and reacted at 20-25 ° C for 0.5 hours. LCMS showed that compound A10-2 was completely consumed and the target mass spectrum was detected. After concentration, MeOH (100 mL) and 4.00 g of basic resin were added, reacted at 20-25 ° C for 1 hour, filtered, and concentrated to obtain compound A10 (29.6 mg, 68.5 μmol, yield 86.4%, purity 93.5%) as a yellow solid. LCMS: m / z = 405.1 (M + H) + .1 H NMR: (400MHz, DMSO-d6)δ11.80(s,1H)8.76(s,1H)8.46-8.29(m,2H)8.19(br d,J=3.6Hz,1H)7.87(s,1H)7.58(m,3H)6.59(d,J=9.0Hz,2H)5.97-5.84(m,1H)2.66(d,J=5.0Hz,3H).

[0383] Preparation Example 11. Synthesis of Compound A11

[0384] At 20 ° C, compound Int1 (500 mg, 1.41 mmol, 1.00 equiv), 4-iodo-N,N-dimethylaniline (384 mg, 1.56 mmol, 1.10 equiv), DMEDA (124 mg, 1.41 mmol, 152 μL, 1.00 equiv), K3PO4 (900 mg, 4.24 mmol, 3.00 equiv), CuI (134 mg, 706 μmol, 0.50 equiv) and DMF (20.0 mL) were added to a 10 mL reaction bottle. Under an oxygen atmosphere, the temperature was raised to 60 ° C and the reaction was allowed to proceed for 16 hours. LCMS showed that 12.6% of compound Int1 remained, and the target mass spectrum was detected. The reaction solution was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Welch Ultimate C18 150*25mm*5μm; mobile phase: [water (FA)-ACN]; gradient: 42%-72% B, 12 minutes) and lyophilized to obtain compound A11 (31.7 mg, 75.2 μmol, yield 5.33%, purity 99.3%) as a gray solid. LCMS: m / z = 419.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.80(s,1H),8.84(s,1H),8.54-8.32(m,2H),8.24-8.18(m,1 H),7.90(s,1H),7.74(d,J=9.0Hz,2H),7.68(s,1H),6.68(d,J=9.2Hz,2H),2.96(s,6H).

[0385] Preparation Example 12. Synthesis of Compound A12

[0386] 4-Acetamidophenylboronic acid (300 mg, 848 μmol, 1.00 equiv), compound Int1 (152 mg, 848 μmol, 1.00 equiv) and pyridine (134 mg, 1.70 mmol, 137 μL, 2.00 equiv) and [Cu(OH)-(TMEDA)]2Cl2 (12 mol%) (78.8 mg, 170 μmol, 0.20 equiv) were added to ACN (15.0 mL) and heated to 100°C at 25°C. The mixture was stirred at 100°C under O2 for 12 h. LCMS showed 23.0% of 4-acetamidophenylboronic acid remaining and the desired mass spectrum was detected. The reaction mixture was poured into water (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL*2), and the combined organic phases were washed with brine (100 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by reverse-phase HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (TFA)-ACN]; gradient: 30%-60% B over 10 minutes). The eluate was concentrated in vacuo to remove the ACN, and the aqueous phase was lyophilized to obtain compound A12 (54.6 mg, 124 μmol, yield 14.6%, purity 97.9%) as a yellow solid. LCMS: m / z = 433.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.8(s,1H),10.1(s,1H),8.95(s,1H),8.46-8.38(m,2H),8.21 (d,J=7.4Hz,1H),7.97(s,1H),7.90(d,J=8.6Hz,2H),7.74(d,J=7.8Hz,3H),2.08(s,3H).

[0387] Preparation Example 13. Synthesis of Compound A13

[0388] Compound Int1 (500 mg, 1.41 mmol, 1.00 equiv) and DMF (10.0 mL) were added to a 100 mL vial and, at 20-25° C. under a nitrogen atmosphere, 4-bromobenzoic acid (283 mg, 1.41 mmol, 1.00 equiv), CuI (134 mg, 706 μmol, 0.50 equiv) and DMEDA (124 mg, 1.41 mmol, 151 μL, 1.00 equiv) were injected into the vial. K 3 PO 4 (899 mg, 4.24 mmol, 3.00 equiv) was then added to the vial at 20-25° C. under a nitrogen atmosphere and stirred at 100° C. under a nitrogen atmosphere for 16 hours. LCMS showed 2.01% of Compound Int1 remaining and the desired mass spectrum was detected. The crude product was stirred with ACN (5.00 mL) for 10 minutes at 20-25° C. and filtered. The filter cake was dissolved in 5 mL of water, then adjusted to pH 5-6 with HCl (2.00 M), and filtered to collect the filter cake. The filter cake was dissolved in ACN (2.00 mL), water (10.0 mL) was added, and then lyophilized to obtain compound A13 (266 mg, 634 μmol, 44.9% yield, 100% purity) as a blue solid. LCMS: m / z = 242.0 (M+Na) + . 1 H NMR: (400MHz, DMSO-d6)δ11.80(s,1H)9.08(s,1H)8.47-8.38(m,2H)8.28-8.01(m,6H)7.74(br s,1H).

[0389] Preparation Example 14. Synthesis of Compound A14

[0390] In DCM (5.00 mL) were added Boc2O (836.01 mg, 3.83 mmol, 880 μL, 2.00 equivalents), DMAP (46.8 mg, 383 μmol, 0.200 equivalents) and 4-iodo-N-methylbenzamide (500 mg, 1.92 mmol, 1.00 equivalents) and stirred at 40-45 ° C for 3 hours. Thin layer chromatography (ethyl acetate: petroleum ether = 1: 1) showed that 4-iodo-N-methylbenzamide (Rf = 0.300) was completely consumed and a new spot (Rf = 0.750) was formed. The reaction mixture was added to water (50.0 mL), extracted with METB (50.0 mL * 3), and washed with brine (50.0 mL) to give compound A14-1 (700 mg, crude product) as a yellow solid.

[0391] To a solution of compound A14-1 (408 mg, 1.13 mmol, 1.00 equiv) in DMF (8.00 mL) were added compound Int1 (400 mg, 1.13 mmol, 1.00 equiv), DMEDA (99.5 mg, 1.13 mmol, 121 μL, 1.00 equiv), K 3 PO 4 (719 mg, 3.39 mmol, 3.00 equiv) and CuI (107 mg, 564 μmol, 0.500 equiv) and heated at 20-25° C. under nitrogen. The reaction mixture was stirred at 70° C. under nitrogen for 3 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 8:1) showed that compound A14-1 was completely consumed, forming a new spot (Rf = 0.600). The mixture was washed with water (10 ml) and NaHCO 3 (10 ml). The precipitate was collected. The solid was dissolved in 10 ml of ACN and 20 ml of water. The solution was lyophilized under neutral conditions to obtain crude product A14-2 (400 mg, 751 μmol, yield 66.5%) as a yellow solid. It was used directly in the next step without purification.

[0392] TFA (2.57 g, 22.5 mmol, 1.67 mL, 60.0 equiv) and compound A14-2 (200 mg, 375 μmol, 1.00 equiv) were added to DCM (2.00 mL). The reaction mixture was stirred at 25°C for 1 hour. Thin layer chromatography (petroleum ether:ethyl acetate = 8:1) showed complete consumption of compound A14-2 (Rf = 0.600) with the formation of one new spot (Rf = 0.500). Thin layer chromatography (TLC) showed the reaction was complete. NaHCO3 (10 mL) was added, extracted with DCM (50.0 mL*3), and the combined organic phases were washed with brine (50.0 mL). The mixture was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated at 40°C under reduced pressure to obtain compound A14 (54.7 mg, 125 μmol, 33.4% yield, 99.2% purity) as an off-white solid. LCMS: m / z=432.9 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.79(s,1H),9.13(s,1H),8.59-8.51(m,1H),8.43(br d,J=18.6Hz,2H),8.22(br d,J=7.6Hz,1H),8.15-8.07(m,3H),8.01(br d,J=8.6Hz,2H),7.81(br s,1H),2.81(d,J=4.4Hz,3H).

[0393] Preparation Example 15. Synthesis of Compound A15

[0394] Compound Int1 (700 mg, 1.98 mmol, 1.00 equiv), 4-(N,N-dimethylcarbamoyl)phenylboronic acid (419 mg, 2.17 mmol, 1.10 equiv), pyridine (312 mg, 3.95 mmol, 319.1 μL, 2 equiv), and [Cu(OH)-(TMEDA)]2Cl2 (275 mg, 593 μmol, 0.300 equiv) were added to ACN (14.0 mL). The reaction mixture was stirred at 80°C for 16 hours. LCMS showed approximately 24.4% of Compound Int1 remaining (RT = 0.317 min). Several new peaks appeared on the LCMS, and approximately 22.2% of the title compound was detected (RT = 0.400 min). The product was filtered and concentrated under vacuum at 40°C to obtain a residue. The product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 0:1, Rf = 0.600). The crude product was fermented with THF (2.00 mL) at 25°C for 20 minutes to obtain compound A15 (91.3 mg, 201 μmol, yield 10.1%, purity 98.3%) as a white solid. LCMS: m / z = 447.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6)δ11.80(s,1H),9.09(s,1H),8.43(br d,J=19.0Hz,2H),8.22(d,J=7.6Hz,1H),8.07(d,J=8.4Hz,3H),7.81(s,1H),7.59(d,J=8.6Hz,2H),3.05-2.89(m,6H).

[0395] Preparation Example 16. Synthesis of Compound A16

[0396] At 25°C under oxygen conditions, 4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)phenylboronic acid (726 mg, 2.17 mmol, 1.10 equiv), pyridine (312 mg, 3.95 mmol, 319 μL, 2.00 equiv), [Cu(OH)-(TMEDA)]2Cl2 (275 mg, 593 μmol, 0.300 equiv) and compound Int1 (700 mg, 1.98 mmol, 1.00 equiv) were added to ACN (14.0 mL), and the reaction mixture was stirred at 40°C for 16 hours. LCMS showed that approximately 19.6% of compound Int1 remained (RT = 0.319 min). Several new peaks appeared on the LCMS, and approximately 23.9% of the target compound was detected (RT = 0.464 min). The mixture was filtered and concentrated under vacuum at 40°C to obtain a residue. The product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 1 / 5), followed by secondary purification by thin-layer chromatography (petroleum ether:ethyl acetate = 0:1, Rf = 0.500). The crude product was fermented with THF (5.00 mL) at 25°C for 10 minutes to afford compound A16-1 (180 mg, 296 μmol, 15.0% yield, 96.8% purity) as a white solid.

[0397] In DCM (6.50mL), TFA (601mg, 5.27mmol, 391μL, 20.0 equivalents) and compound A16-1 (160mg, 263μmol, 1.00 equivalents) were added and stirred at 25°C for 3 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 0: 1) showed that compound A16-1 was completely consumed (Rf = 0.500) and a new spot (Rf = 0.150) was formed. Thin layer chromatography (TLC) showed that the reaction was complete. The filtrate was concentrated at 40°C under reduced pressure to obtain crude product A16-2 (160mg, 260μmol, yield 98.9%, purity 98.0%) as a white solid, which was used directly in the next step without purification.

[0398] Compound A16-2 (130 mg, 216 μmol, 1.00 equivalent, TFA) was dissolved in MeOH (10.0 mL) and DCM (10.0 mL), and Amberlyst A26 (4.00 g, 216 μmol, 1.00 equivalent) was added at 25 ° C. and stirred at 25 ° C for 0.5 hours. Thin layer chromatography (dichloromethane: methanol = 1: 2) showed that compound A16-2 (Rf = 0.00) was completely consumed and a new spot (Rf = 0.110) was formed. Thin layer chromatography (TLC) showed that the reaction was complete. Filtered with MeOH (10 ml) at 25 ° C. Filtered and concentrated at 40 ° C under vacuum to obtain a residue. Lyophilized under neutral conditions to obtain compound A16 (79.7 mg, 154 μmol, yield 71.4%, purity 94.3%) as an off-white solid. LCMS: m / z=488.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.79(s,1H),9.08(s,1H),8.43(dd,J=7.2,18.6Hz,2H),8.22(d,J=7.0Hz ,1H),8.07-8.06(m,3H),7.81(s,1H),7.56(d,J=7.8Hz,2H),3.74-3.46(m,4H),2.80-2.60(m,4H).

[0399] Preparation Example 17. Synthesis of Compound A17

[0400] At 20-25 ° C, compound Int1 (591 mg, 1.67 mmol, 1.00 equiv), 2-fluoro-4-iodobenzoic acid (444 mg, 1.67 mmol, 1.00 equiv) and NMP (6.00 mL) were added to a 100 mL three-necked round-bottom flask. At 20-25 ° C and nitrogen conditions, CuI (159 mg, 835 μmol, 0.50 equiv), DMEDA (147 mg, 1.67 mmol, 179 μL, 1.00 equiv) and K3PO4 (1.06 g, 5.01 mmol, 3.00 equiv) were added. The mixture was ventilated and purged with nitrogen three times. Stirred at 100 ° C for 12 hours. LCMS showed that 7.87% of compound Int1 remained (RT = 0.429 min), and 75.7% (RT = 0.549 min) of the target mass spectrum was detected.

[0401] ACN (20.0 mL) was added and filtered. 20.0 mL of water was added to the filter cake, and the pH was adjusted to 5-6 with hydrochloric acid (2N). After filtration, the filter cake was concentrated. The residue was purified by high-performance liquid chromatography (column: Waters xbridge 150*25mm 10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 11%-41%, 10 minutes), and the washings were lyophilized to obtain compound A17 (103 mg, 227 μmol, yield 13.6%, purity 96.6%). LCMS: m / z = 438.0 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.8(s,1H),9.10(s,1H),8.48-8.45(m,1H),8.43-8.37(m,1H),8.22(d,J=8.0Hz,1H),8.12(s,1H),7.92-7.74(m,4H).

[0402] Preparation Example 18. Synthesis of Compound A18

[0403] At 20-25°C, 4-iodobenzyl alcohol (500 mg, 2.14 mmol, 1.00 equiv) and THF (5.00 mL) were added to a 100 mL three-necked round-bottom flask. PMB-Cl (669 mg, 4.27 mmol, 579 μL, 2.00 equiv) and t-BuOK (479 mg, 4.27 mmol, 2.00 equiv) were added at 20-25°C. The mixture was ventilated, purged with N2 three times, and stirred at 25°C for 12 hours. Thin layer chromatography (petroleum ether:ethyl acetate = 1:1) showed that 4-iodobenzyl alcohol (Rf = 0.2) was completely consumed and a new spot (Rf = 0.5) was formed. The reaction solution was poured into 10.0 ml of water, and the aqueous phase was extracted with EtOAc (10.0 mL * 3). The combined organic layers were washed with brine (10.0 mL), dried over Na 2 SO 4 , and concentrated to give compound A18-1 (700 mg, crude) as a white solid.

[0404] At 20-25 ° C, compound Int1 (591 mg, 1.67 mmol, 1.00 equivalent), compound A18-1 (591 mg, 1.67 mmol, 1.00 equivalent) and NMP (10.0 mL) were added to a 100 mL three-necked flask, and CuI (159 mg, 835 μmol, 0.50 equivalent), DMEDA (147 mg, 1.67 mmol, 179 μL, 1.00 equivalent) and K3PO4 (1.06 g, 5.01 mmol, 3.00 equivalent) were added. The nitrogen atmosphere was replaced three times and the temperature was raised to 80 ° C for 12 hours. LCMS showed that 15.9% of compound A18-1 remained (RT = 0.426 min), and 25.9% of the target mass spectrum was detected. The mixture was poured into water, filtered, and the filtrate was concentrated. The crude product was then purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (TFA)-ACN]; gradient: 45%-75% B, over 10 minutes). The eluate was lyophilized to give compound A18-2 (100 mg, 162 μmol, yield 9.71%, purity 85.3%) as a yellow solid.

[0405] At 20-25 ° C, compound A18-2 (100 mg, 190 μmol, 1.00 equivalent) and DCM (4.00 mL) were added to a 100 mL three-necked flask, and TFA (433 mg, 3.81 mmol, 282 μL, 20.0 equivalent) was added, nitrogen was replaced 3 times, and the reaction was carried out at 25 ° C for 2 hours. LCMS showed that the reaction of compound A18-2 was complete, and the target mass spectrum was detected (RT = 0.395 min). After concentration, the crude product was purified by thin layer chromatography (SiO2, petroleum ether: ethyl acetate = 1 / 1, Rf = 0.2). The eluent was concentrated to obtain compound A18 (30.0 mg, 73.6 μmol, yield 38.7%, purity 99.5%) as an off-white solid. LCMS: m / z = 406.1 (M + H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.8(s,1H),9.01(s,1H),8.51-8.35(m,2H),8.22(dd,J=1.2,7.6Hz,1H),8.02(s, 1H),7.95(d,J=8.4Hz,2H),7.76(s,1H),7.49(d,J=8.4Hz,2H),5.30(t,J=5.6Hz,1H),4.56(d,J=5.6Hz,2H).

[0406] Preparation Example 19. Synthesis of Compound A19

[0407] At 25 ° C, compound Int1 (500 mg, 1.41 mmol, 2.00 equiv), 4-(methoxymethoxy)phenylboronic acid (142 mg, 707 μmol, 1.00 equiv), DMF (10.0 mL), DMEDA (62.3 mg, 707 μmol, 76.1 μL, 1.00 equiv), K3PO4 (450 mg, 2.12 mmol, 3.00 equiv) and CuI (67.3 mg, 353 μmol, 0.50 equiv) were added to a reaction flask. The temperature was raised to 100 ° C and stirred under N2 atmosphere for 4 hours. LCMS showed that 49.5% of compound Int1 remained, and the mass spectrum of the target product was detected. The reaction solution was poured into 50.0 ml of water, filtered, and the filter cake was concentrated in vacuo and added to DMF. The mixture was slurried at 100 ° C for 30 minutes to obtain the crude product. The crude product was added to ACN and slurried at 80°C for 30 minutes to obtain compound A19 (45.9 mg, 106 μmol, yield 15.1%, purity 97.2%). LCMS: m / z = 420.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.8(s,1H),9.06(s,1H),8.46-8.40(m,2H),8.21(d,J=7.0Hz,1 H),8.03-7.97(m,3H),7.79(s,1H),7.49(d,J=7.6Hz,2H),4.47(s,2H),3.34-3.34(m,3H).

[0408] Preparation Example 20. Synthesis of Compound A20

[0409] At 20-25°C, THF (20.0 mL) was added to a three-necked reaction flask, followed by the addition of (4-iodophenyl)methylamine. NaHCO3 (2.88 g, 34.3 mmol, 1.34 mL, 4.00 equivalents) was dissolved in H2O (20.0 mL) and added to the reaction flask. Boc2O (2.43 g, 11.2 mmol, 2.56 mL, 1.30 equivalents) was then added. The reaction solution was stirred at 20-25°C for 1 hour. LCMS showed that the reaction of (4-iodophenyl)methylamine was complete, and the target mass spectrum was detected. 20.0 ml of water was added to the reaction solution, extracted three times with ethyl acetate (40 ml), and the organic phase was washed with 15% aqueous citric acid solution (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound A20-1 (4.74 g, crude product).

[0410] At 20-25 ° C, DMF (35.0 mL), compound Int1 (650 mg, 2.00 mmol, 1.00 equivalent), compound A20-1 (705 mg, 2.00 mmol, 1.00 equivalent), DMEDA (528 mg, 6.00 mmol, 645 μL, 3.00 equivalent), CuI (761 mg, 4.00 mmol, 2.00 equivalent) and K3PO4 (1.27 g, 6.00 mmol, 3.00 equivalent) were added to a 100 ml three-necked reaction flask and stirred at 95-100 ° C under a nitrogen atmosphere for 5 hours. LCMS showed that 31.0% of compound A20-1 remained, and the mass spectrum of the target product was detected. 100 ml of water was added to the reaction solution and filtered to obtain a filter cake. The crude product was purified by preparative HPLC to give compound A20-2 (246 mg, 454 μmol, yield 22.7%, purity 93.2%).

[0411] At 20-25°C, HCl / EtOAc (10.0 mL) and compound A20-2 (246 mg, 454 μmol, 1.00 equivalent) were added to a 100 ml three-necked reaction flask and stirred for 1 hour. HPLC showed that compound A20-2 had been completely consumed and a main peak was detected. Filter to obtain a filter cake. Dissolve the filter cake in 10 ml of water and add saturated sodium bicarbonate aqueous solution to adjust the pH to 7-8. Filter to obtain the filter cake, i.e., compound A20. LCMS: m / z = 405.0 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.79(br s,1H),9.00(s,1H),8.49-8.36(m,2H),8.21(br d,J=7.4Hz,1H),8.02-7.87(m,3H),7.75(br s,1H),7.50(br d,J=8.2Hz,2H),3.78(s,2H).

[0412] Preparation Example 21. Synthesis of Compound A21

[0413] At 20-25°C, THF (20.0 mL) and N-methyl-4-bromobenzylamine (2.00 g, 10.0 mmol, 2.00 mL, 1.00 equivalent) were added to a 100 ml three-necked reaction flask. NaHCO3 (3.36 g, 39.9 mmol, 1.56 mL, 4.00 equivalent) was dissolved in water (20.0 mL) and then added to the reaction flask. Boc2O (2.84 g, 13.0 mmol, 2.99 mL, 1.30 equivalent) was then added to the reaction flask. The mixture was stirred for 1 hour at 20-25°C. LCMS showed that N-methyl-4-bromobenzylamine had reacted completely and the target mass spectrum was detected. H2O (20.0 mL) was added to the reaction solution, extracted 3 times with ethyl acetate (50.0 mL), washed with 15% aqueous citric acid solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. After adding n-heptane (10.0 mL), the mixture was stirred at 20-25° C. for 2 hours and filtered to obtain compound A21-1 (3.2 g, crude product).

[0414] At 20-25 ° C, DMF (35.0 mL), compound Int1 (750 mg, 2.31 mmol, 1.00 equivalent), compound A21-1 (699 mg, 2.31 mmol, 1.00 equivalent), DMEDA (406 mg, 4.61 mmol, 496 μL, 2.00 equivalent), CuI (878 mg, 4.61 mmol, 2.00 equivalent) and K3PO4 (1.47 g, 6.92 mmol, 3.00 equivalent) were added to a 100 ml three-necked reaction bottle. Stirred for 16 hours at 95-100 ° C and nitrogen atmosphere. LCMS showed that 27.3% of compound A21-1 remained, and the target mass spectrum was detected. H2O (100 ml) was added to the reaction and filtered to obtain a filter cake. The crude product was purified by preparative HPLC to obtain compound A21-2.

[0415] At 20-25°C, HCl / EtOAc (10.0 mL) and compound A21-2 (494 mg, 921 μmol, 1.00 equivalent) were added to a 100 ml three-necked reaction flask and stirred for 16 hours. LCMS showed that the reaction of compound A21-2 was complete, and the target mass spectrum was detected. The filter cake was filtered and dissolved in H2O (10.0 ml). Saturated sodium bicarbonate aqueous solution was added to adjust the pH to 7-8. The filter cake was filtered to obtain compound A21. LCMS: m / z = 419.0 (M+H) + . 1H NMR: (400MHz, DMSO-d6) δ11.78(s,1H),9.00(s,1H),8.48-8.36(m,2H),8.21(d,J=7.4Hz,1H),8.03-7.87(m,3H),7.75(br s,1H),7.48(br d,J=8.4Hz,2H),3.69(s,2H),2.28(s,3H).

[0416] Preparation Example 22. Synthesis of Compound A22

[0417] At 20-25 ° C and under an oxygen atmosphere, compound Int1 (500 mg, 1.41 mmol, 1.00 equivalent), DMF (8.00 mL), {4-[(N,N'-dimethyl)methylene]}phenylboronic acid (278 mg, 1.55 mmol, 1.10 equivalent) and K2CO3 (390 mg, 2.82 mmol, 2.00 equivalent) were added to the reactor, chloro(hydroxy)copper; N,N,N',N'-tetramethylethylenediamine (196 mg, 423 μmol, 0.30 equivalent) were added to the reaction and stirred at 80 ° C for 16 hours. LCMS indicated that 17.4% of compound Int1 remained, and the target mass spectrum was detected. Concentrated at 50-55 ° C. The crude product was purified by column chromatography and then purified by preparative HPLC (TFA conditions) to obtain compound A22. LCMS: m / z=433.0 (M+H) + . 1 H NMR: (400MHz, DMSO-d6)δ11.79(s,1H)9.00(s,1H)8.36-8.49(m,2H)8.21(d,J=7.6Hz,1H)8.01(br s,1H)7.93(d,J=8.4Hz,2H)7.76(br s,1H)7.45(d,J=8.2Hz,2H)3.44(s,2H)2.17(s,6H).

[0418] Preparation Example 23. Synthesis of Compound A23

[0419] At 20-25 ° C, DMF (5.00 mL), compound A20 (100 mg, 233 μmol, 1.00 equivalent), pyridine (55.4 mg, 701 μmol, 56.5 μL, 3.00 equivalent) and Ac2O (35.7 mg, 350 μmol, 32.9 μL, 1.50 equivalent) were added to a 40.0 ml reaction bottle and stirred for 1 hour. LCMS showed that the reaction of compound A20 was complete and the target mass spectrum was detected. Saturated sodium bicarbonate aqueous solution was added to adjust the pH to 7-8 and filtered to obtain compound A23 (56.5 mg, 121 μmol, yield 51.9%, purity 95.9%). LCMS: m / z=447.2 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.79(s,1H),9.01(s,1H),8.54-8.36(m,3H),8.21(br d,J=7.6Hz,1H),8.03-7.90(m,3H),7.76(br s,1H),7.42(br d,J=8.0Hz,2H),4.31(br d,J=5.2Hz,2H),1.90(s,3H).

[0420] Preparation Example 24. Synthesis of Compound A24

[0421] At 20-25 ° C, DMF (5.00 mL), compound A21 (100 mg, 236 μmol, 1.00 equivalent), pyridine (56.0 mg, 708 μmol, 57.1 μL, 3.00 equivalent) and Ac2O (36.1 mg, 354 μmol, 33.2 μL, 1.50 equivalent) were added to a 40.0 ml reaction bottle. After stirring for 3 hours, LCMS showed that the reaction of compound A21 was complete and the target mass spectrum was detected. Saturated sodium bicarbonate aqueous solution was added to adjust the pH to 7-8 and filtered to obtain compound A24 (96.0 mg, 206 μmol, yield 87.3%, purity 98.9%). LCMS: m / z=461.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.79(s,1H),9.04-8.98(m,1H),8.48-8.37(m,2H),8.21(d,J=7.2Hz,1H),8.04-7.91(m,3H),7.77(br s,1H),7.43-7.35(m,2H),4.64-4.53(m,2H),2.97-2.80(m,3H),2.11-2.06(m,3H).

[0422] Preparation Example 25. Synthesis of Compound A25

[0423] At 20-25° C. and under a nitrogen atmosphere, compound Int1 (1.00 g, 2.82 mmol, 1.00 equiv), DMF (10 mL), tert-butyl 4-(4-iodophenyl)tetrahydro-1(2H)-pyrazinecarboxylate (1.10 g, 2.82 mmol, 1.00 equiv), DMEDA (248 mg, 2.82 mmol, 303 μL, 1.00 equiv), K 3 PO 4 (1.80 g, 8.47 mmol, 3.00 equiv) and CuI (268 mg, 1.41 mmol, 0.50 equiv) were added to a reaction bottle and stirred at 100° C. for 16 hours. LCMS showed that 14.7% of compound Int1 remained, and the target mass spectrum was detected. After filtration and concentration, the crude product was purified by preparative HPLC to give compound A25-1 (400 mg, 706 μmol, yield 25.0%, purity 98.8%).

[0424] At 20-25 ° C, compound A25-1 (400 mg, 706 μmol, 1.00 equivalents), DCM (0.50 mL) and HCl / EtOAc (4.00 M, 4.94 mL, 28.0 equivalents) were added to a 10 ml reaction bottle and stirred for 16 hours. LCMS showed that 63.8% of compound A25-1 remained, and the target mass spectrum was detected. Concentration gave a crude product, which was dissolved with H2O (10.0 mL), and saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7-8, filtered, and the filter cake was washed three times with H2O (4.00 mL). The filter cake was dissolved with H2O (20.0 mL) and ACN (3.00 mL) and lyophilized to give compound A25 (285 mg, 620 μmol, yield 87.8%, purity 100%). LCMS: m / z = 460.2 (M + H) + . 1 H NMR: (400MHz, DMSO-d6)δ11.79(s,1H)8.87(s,1H)8.34-8.52(m,2H)8.14-8.26(m,1H)7.94(br s,1H)7.77(d,J=9.0Hz,2H)7.70(s,1H)7.05(d,J=9.2Hz,2H)3.06-3.15(m,4H)2.80-2.89(m,4H).

[0425] Preparation Example 26. Synthesis of Compound A26

[0426] At 20-25 ° C and nitrogen atmosphere, compound Int1 (500 mg, 1.41 mmol, 1.00 equivalent), 1- (4-bromophenyl) -4-methylpiperazine (360 mg, 1.41 mmol, 1.00 equivalent), DMEDA (124 mg, 1.41 mmol, 151 μL, 1.00 equivalent) and DMF (10.0 mL) were added to a 100 mL three-necked round-bottom flask, and then CuI (134 mg, 706 μmol, 0.5 equivalent) and K3PO4 (899 mg, 4.24 mmol, 3.00 equivalent) were added under nitrogen atmosphere, the temperature was raised to 100 ° C, and the reaction was carried out under nitrogen for 16 hours. LCMS showed that 25.0% of compound Int1 remained, and the target mass spectrum was detected (RT = 0.343 min). The reaction solution was filtered, and the filtrate was collected and concentrated under vacuum. The crude product was purified by reverse-phase HPLC and lyophilized to obtain compound A26 (155 mg, 304 μmol, 21.5% yield, 93.1% purity, TFA) as a white solid. LCMS: m / z = 474.2 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.79 (s, 1H) 9.72-9.98 (m, 1H) 8.93 (s, 1H) 8.32-8.50 (m, 2H) 8.21 (d, J = 7.6Hz, 1H) 7.95 (br s, 1H) 7.87 (br d,J=8.8Hz,2H)7.73(br s,1H)7.17(br d,J=9.0Hz,2H)3.95(br d,J=11.2Hz,2H)3.56-3.60(m,2H)3.18(br s,2H)2.94-3.10(m,2H)2.88(s,3H).

[0427] Preparation Example 27. Synthesis of Compound A27

[0428] At 20-25°C, compound A25 (80.0 mg, 174 μmol, 1.00 equiv), pyridine (27.5 mg, 348 μmol, 28.1 μL, 2.00 equiv) and DMF (4.00 mL) were added to 10 mL parallel reaction bottles. Ac2O (26.6 mg, 261 μmol, 24.5 μL, 1.50 equiv) was then added at 0-5°C. The reaction was continued at 20-25°C for 2 hours. LCMS showed that compound A25 had reacted completely and the target mass spectrum was detected (RT = 0.441 min). The crude product was dissolved in H2O (10.0 mL) and then adjusted to pH 7-8 with saturated NaHCO3. The reaction solution was filtered and washed with H2O (4 mL*3). The filter cake was dissolved in H2O (20.0 mL) and ACN (3.00 mL). The mixture was directly lyophilized to obtain compound A27 (73.9 mg, 147 μmol, yield 84.6%, purity 100%) as a white solid. LCMS: m / z = 502.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6)δ11.79(s,1H)8.90(s,1H)8.36-8.51(m,2H)8.21(d,J=7.6Hz,1H)7.95(br s,1H)7.82(d,J=9.0Hz,2H)7.71(br s,1H)7.11(d,J=9.2Hz,2H)3.60(br s,4H)3.23-3.29(m,2H)3.15-3.22(m,2H)2.06(s,3H).

[0429] Preparation Example 28. Synthesis of Compound A28

[0430] At 20-25°C, compound A25 (140 mg, 304 μmol, 1.00 equiv), pyridine (48.2 mg, 609 μmol, 49.1 μL, 2.00 equiv) and DMF (4.00 mL) were added to 10 mL parallel reaction bottles. Benzoyl benzoate (103 mg, 457 μmol, 86.2 μL, 1.50 equiv) was then added at 0-5°C and reacted at 20-25°C for 2 hours. LCMS showed that compound A25 was completely reacted and the target mass spectrum was detected (RT = 0.496 min). The crude product was dissolved in H2O (10.0 mL) and then adjusted to pH 7-8 with saturated NaHCO3. The reaction solution was filtered and washed with H2O (4.00 mL*3), and the filter cake was dissolved in H2O (20.0 mL) and ACN (3.00 mL). The mixture was directly lyophilized to obtain the crude product. The crude product was stirred with ACN (10.0 mL) at 20-25°C for 10 minutes, and the filter cake was dissolved in H2O (20.0 mL) and ACN (3.00 mL). The mixture was directly lyophilized to obtain compound A28 (74.1 mg, 131 μmol, 43.1% yield, 100% purity) as a white solid. LCMS: m / z = 564.3 (M+H) + . 1 H NMR: (400MHz, DMSO-d6)δ11.78(s,1H)8.89(s,1H)8.36-8.49(m,2H)8.20(d,J=7.6Hz,1H)7.94(s,1H)7.8 2(d,J=9.0Hz,2H)7.70(s,1H)7.38-7.53(m,5H)7.11(d,J=9.0Hz,2H)3.44-3.86(m,4H)3.31-3.27(m,4H).

[0431] Preparation Example 29. Synthesis of Compound A29

[0432] At 20-25° C. and under an oxygen atmosphere, compound Int1 (500 mg, 1.41 mmol, 1.00 equiv), pyridine-3-boronic acid (190 mg, 1.55 mmol, 1.10 equiv), [Cu(OH)-(TMEDA)]2Cl2 (196 mg, 423 μmol, 0.30 equiv), K2CO3 (585 mg, 4.24 mmol, 3.00 equiv) and DMF (15.0 mL) were added to a 10 mL parallel reaction bottle, heated to 100° C., and reacted under an oxygen atmosphere for 12 hours. LCMS showed that 42.8% of compound Int1 remained (RT=1.468 mins), and the target mass spectrum was detected (RT=1.386 mins). The reaction solution was concentrated under vacuum. The crude product was purified by reverse-phase HPLC and lyophilized to obtain compound A29 (104 mg, 272 μmol, 19.2% yield, 97.7% purity) as a yellow solid. LCMS: m / z = 376.9 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ14.02-13.60(m,1H),11.38(s,1H),11.16(s,1H),9.32(br s,1H),8.72(br d,J=8.6Hz,1H),8.64-8.52(m,2H),8.50-8.36(m,2H),8.22(d,J=7.6Hz,1H),7.92(dd,J=5.4,8.4Hz,1H).

[0433] Preparation Example 30. Synthesis of Compound A30

[0434] At 20-25 ° C and an oxygen atmosphere, compound Int1 (300 mg, 848 μmol, 1.00 equivalent), 2-bromopyridine-5-boronic acid (188 mg, 933 μmol, 1.10 equivalent), K2CO3 (351 mg, 2.54 mmol, 3.00 equivalent), [Cu(OH)-(TMEDA)]2Cl2 (118 mg, 254 μmol, 0.30 equivalent) and DMF (20.0 mL) were added to a 40 mL parallel reaction bottle, heated to 80 ° C, and reacted under an oxygen atmosphere for 12 hours. LCMS showed that 23.7% of compound Int1 remained (RT = 0.424 min), and the target mass spectrum was detected (RT = 0.585 min). The reaction solution was concentrated under vacuum. The crude product was purified by reverse-phase high-performance liquid chromatography and lyophilized to obtain compound A30 (86.0 mg, 179 μmol, yield 21.1%, purity 94.9%) as a yellow solid. LCMS: m / z = 456.9 (M+H) + .1 H NMR: (400MHz, DMSO-d6) δ13.68(s,1H),11.44(s,1H),10.74(s,1H),8.90(d,J=2.4Hz,1H),8.54(s,1H),8.46-8.36(m,2H),8.22(br d,J=7.8Hz,2H),7.68(d,J=8.8Hz,1H).

[0435] Preparation Example 31. Synthesis of Compound A31

[0436] At 20-25 ° C and nitrogen atmosphere, compound Int1 (500 mg, 1.54 mmol, 1.00 equiv), 5-iodopyridine-2-carboxylic acid (382 mg, 1.54 mmol, 1.00 equiv), DMEDA (135 mg, 1.54 mmol, 165 μL, 1.00 equiv), K 3 PO 4 (979 mg, 4.61 mmol, 3.00 equiv), CuI (146 mg, 768 μmol, 0.50 equiv) and DMF (10.0 mL) were added to 40 mL parallel reaction bottles, heated to 100 ° C, and reacted under nitrogen atmosphere for 16 hours. LCMS showed that 61% of compound Int1 remained (RT = 0.438 min), and the target mass spectrum was detected (RT = 0.391 min). The reaction solution was cooled to 25 ° C, ACN (50.0 mL) was added, filtered, and the filter cake was collected. The filter cake was added to H2O (50.0 mL), and 2.00 M HCl was added to adjust the pH to 5-6. The filter cake was collected by filtration. The filter cake was dissolved in DMF (50.0 mL) and filtered through celite. After filtration and concentration, the mixture was lyophilized to obtain compound A31 (187 mg, 439 μmol, yield 28.5%, purity 98.7%) as an off-white solid. LCMS: m / z = 421.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.82(s,1H),9.43-9.18(m,2H),8.60(s,1H),8.47-8.39(m,2H),8.23-8.17(m,3H),7.88(s,1H).

[0437] Preparation Example 32. Synthesis of Compound A32

[0438] At 0-25 ° C, tert-butyl (3-hydroxycyclobutyl) carbamate (1.00 g, 5.34 mmol, 1.00 equivalent), TEA (1.62 g, 16.0 mmol, 2.23 mL, 3.00 equivalent) and DCM (10.0 mL) were added to a 100 mL three-necked round-bottom flask, and then MS2O (1.30 g, 7.48 mmol, 1.40 equivalent) and DCM (10 mL) were slowly added. The mixture was replaced with nitrogen 3 times and reacted at 0-25 ° C for 2 hours. LCMS showed that the reaction of compound (3-hydroxycyclobutyl) carbamate was complete, and 53.0% of the target mass spectrum was detected. Concentrated at 45 ° C to give compound A32-1 (1.42 g, crude product) as a light yellow solid.

[0439] At 20-25°C, compound A32-1 (532 mg, 2.01 mmol, 1.20 equiv), compound Int1 (500 mg, 1.67 mmol, 1.00 equiv), Cs2CO3 (2.18 g, 6.68 mmol, 4.00 equiv) and DMF (15.0 mL) were added to a 100 mL three-necked round-bottom flask and heated to 110°C for 12 hours. LCMS showed that 4.25% of compound A32-1 remained, and 51.5% of the target mass spectrum was detected (RT = 0.609 min). Poured into water (30.0 mL), extracted three times with ethyl acetate (60.0 mL), and the combined organic phases were washed with saturated brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated to give compound A32-2 (1.30 g, crude product) as a yellow oil.

[0440] Compound A32-2 (170 mg, 363 μmol, 1.00 equiv), DCM (3.40 mL), and MeOH (3.40 mL) were added to 40 mL parallel reaction vials at 20-25°C. After cooling to 0-5°C, HCl / dioxane (4.00 M, 3.40 mL, 37.5 equiv) was added and the temperature was raised to 20-25°C for 2 hours. TLC (dichloromethane:methanol = 10:1) showed the formation of a new spot (Rf = 0.30). Filtration and concentration afforded compound A32-3 (130 mg, 348 μmol, 91.4% yield, 98.7% purity) as a white solid.

[0441] At 20-25°C, compound A32-3 (130 mg, 353 μmol, 1.00 equiv), DCM (10.0 mL), and MeOH (10.0 mL) were added to a 100 mL three-necked round-bottom flask, followed by the addition of Amberlyst A26 (4.00 g, 1.00 equiv), and the mixture was reacted at 20-25°C for 0.5 h. TLC (dichloromethane:methanol=1:1) showed the formation of a new spot (Rf=0.00). The mixture was filtered, concentrated, diluted with water (30.0 mL), and lyophilized to afford compound A32 (84.9 mg, 226 μmol, 64.1% yield, 98.0% purity) as a white solid. LCMS: m / z=368.9 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.70 (s, 1H) 8.44 (s, 1H) 8.42-8.36 (m, 2H) 8.18 (d, J = 7.4Hz, 1H) 7.73-7.52(m,2H)5.15-4.95(m,1H)3.73-3.64(m,1H)2.71-2.60(m,2H)2.25-2.15(m,2H).

[0442] Preparation Example 33. Synthesis of Compound A33

[0443] At 20-25° C., compound Int1 (500 mg, 1.67 mmol, 1.00 equiv), N-BOC-3-bromocyclobutane (473 mg, 2.01 mmol, 1.20 equiv), Cs CO (1.09 g, 3.34 mmol, 2.00 equiv) and DMF (10.0 mL) were added to a 100 mL three-necked round-bottom flask and the temperature was raised to 60° C. for 12 hours. LCMS showed that compound Int1 was completely consumed, and the target mass spectrum was detected (RT=0.456 min). Pour into water (50.0 mL), extract twice with ethyl acetate (50.0 mL), wash the combined organic phases twice with saturated brine (50.0 mL), dry over sodium sulfate, filter, and purify the crude product by column chromatography and concentrate to give compound A33-1 (480 mg, 1.01 mmol, yield 60.3%, purity 95.4%) as a white solid.

[0444] At 20-25 ° C, compound A33-1 (480 mg, 1.01 mmol, 1.00 equivalent), DCM (10.0 mL) and TFA (1.72 g, 15.12 mmol, 1.12 mL, 15.0 equivalent) were added to 40 mL parallel reaction bottles and reacted at 20-25 ° C for 2 hours. LCMS showed that compound A33-1 was completely consumed and the target mass spectrum was detected (RT = 0.289 min). Filtered and concentrated to give compound A33-2 (490 mg, 990 μmol, yield 98.2%, purity 94.6%, TFA) as a white solid.

[0445] At 20-25°C, compound A33-2 (494 mg, 998 μmol, 1.00 equivalent, TFA), THF (5.00 mL), and MeOH (5.00 mL) were added to a 100 mL three-necked round-bottom flask, followed by the addition of AMBERLYST A26 (5.00 g, 30.9 mmol), and the mixture was reacted at 20-25°C for 0.5 hours. TLC (dichloromethane:methanol=1:1) showed the formation of a new spot (Rf=0.10). Filtration and concentration afforded compound A33 (201 mg, 544 μmol, 54.5% yield, 95.7% purity) as a bright yellow solid. LCMS: m / z=354.9 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.7(s,1H),8.58(s,1H),8.43-8.35(m,2H),8.19(d,J=7.4Hz,1H),7.7 6(s,1H),7.60(s,1H),5.32-5.25(m,1H),3.93(t,J=7.6Hz,2H),3.81-3.77(m,2H),1.35(s,1H).

[0446] Preparation Example 34. Synthesis of Compound A34

[0447] At 20-25° C., N-BOC-3-hydroxypiperidine (1.00 g, 4.97 mmol, 1.00 equivalent), TEA (1.51 g, 14.9 mmol, 2.07 mL, 3.00 equivalent) and DCM (5.00 mL) were added to a 100 mL three-necked round-bottom flask, and Ms O (1.13 g, 6.46 mmol, 1.30 equivalent) dissolved in DCM (5.00 mL) was slowly added, and the mixture was reacted at 0-5° C. for 2.5 hours. LCMS showed that 16.3% of the compound N-BOC-3-hydroxypiperidine remained, and the target mass spectrum was detected (RT = 0.388 min). Pour into water (100.0 mL), extract three times with dichloromethane (30.0 mL), wash the combined organic phase with saturated brine (90.0 mL), dry over sodium sulfate, filter, and concentrate to obtain compound A34-1 (1.37 g, 2.40 mmol, yield 48.4%, purity 49.0%) as a yellow oil.

[0448] At 20-25°C, compound Int1 (856 mg, 2.40 mmol, 1.00 equiv), compound A34-1 (1.37 g, 2.40 mmol, 1.00 equiv), Cs2CO3 (1.57 g, 4.81 mmol, 2.00 equiv) and DMF (27.4 mL) were added to a 100 mL three-necked round-bottom flask, and the temperature was raised to 100°C for reaction for 10 hours. LCMS showed that 29.7% of compound Int1 remained (RT = 0.340 min), and the target mass spectrum was detected (RT = 0.466 min. Poured into water (50.0 mL), extracted 4 times with ethyl acetate (30.0 mL), and the combined organic phases were washed with saturated brine (100.0 mL), dried over sodium sulfate, and filtered. The crude product was purified by column chromatography and concentrated to give compound A34-2 (532 mg, 1.10 mmol, 45.6%, purity 99.4%) as a white solid.

[0449] At 20-25 ° C, compound A34-2 (150 mg, 309 μmol, 1.00 equivalent) and TFA (1.06 g, 9.27 mmol, 689 μL, 30.0 equivalent) were added to 10 mL parallel reaction bottles and reacted at 20-25 ° C for 2 hours. LCMS showed that compound A34-2 was completely consumed and the target mass spectrum was detected (RT = 0.305 min). 5.00 g of basic resin was added, reacted at 20-25 ° C for 1 hour, filtered, and concentrated to obtain compound A34 (125 mg, 311 μmol, yield 77.3%, purity 94.9%) as a white solid. LCMS: m / z = 383.1 (M + H) + . 1H NMR: (400MHz, DMSO-d6) δ11.75-11.69(m,1H)8.49(s,1H)8.43-8.36(m,2H)8.19(d,J=7.4Hz,1H)7.74-7.50(m,2H)4.31-4.19( m,1H)3.23-3.15(m,1H)2.91-2.81(m,2H)2.44-2.32(m,1H)2.20-2.09(m,1H)2.00-1.90(m,1H)1.76-1.69(m,1H)1.59(m,1H).

[0450] Preparation Example 35. Synthesis of Compound A35

[0451] At 20-25 ° C, N-tert-butyloxycarbonyl-1-oxa-8-azaspiro [4.5] decane-3-ol (500 mg, 1.94 mmol, 1.00 equivalent), TEA (589 mg, 5.83 mmol, 811 μL, 3.00 equivalent) and DCM (2.50 mL) were added to a 100 mL three-necked round-bottom flask. Ms2O (473 mg, 2.72 mmol, 1.40 equivalent) dissolved in DCM (2.50 mL) was slowly added and reacted at 0-25 ° C for 1 hour. LCMS showed that the raw material reaction was complete and the target mass spectrum was detected (RT = 0.372 min). After concentration, compound A35-1 (500 mg, crude product) was obtained as a yellow solid.

[0452] At 20-25 ° C, compound Int1 (483 mg, 1.61 mmol, 1.00 equiv), compound A35-1 (500 mg, 1.49 mmol, 1.00 equiv), K2CO3 (669 mg, 4.84 mmol, 3.00 equiv) and DMF (210.0 mL) were added to a 100 mL three-necked round-bottom flask. The temperature was raised to 80 ° C for 1 hour. LC-MS showed that the reaction of compound Int1 was complete and the target mass spectrum was detected (RT = 0.463 min). Poured into water (25.0 mL), extracted three times with ethyl acetate (25.0 mL), and the combined organic phases were washed with NaHCO3 (25.0 mL), dried over sodium sulfate, filtered, and the crude product was purified by preparative HPLC and concentrated to obtain compound A35-2 (400 mg, 736 μmol, yield 45.5%, purity 99.1%) as a yellow solid.

[0453] At 20-25 ° C, compound A35-2 (200 mg, 368.05 μmol, 1.00 equivalent), TFA (839 mg, 7.36 mmol, 546 μL, 20.0 equivalent) and DCM (2.00 mL) were added to 10 mL parallel reaction bottles. Nitrogen was replaced 3 times and the reaction was carried out at 20-25 ° C for 2 hours. LCMS showed that the reaction of compound A35-2 was complete and the target mass spectrum was detected (RT = 0.302 min). The pH was adjusted to 9-10 with NaHCO3, extracted 3 times with dichloromethane (10.0 mL), dried with sodium sulfate, filtered, and concentrated to give compound A35 (85.3 mg, 186 μmol, yield 50.5%, purity 95.6%) as a yellow solid. LCMS: m / z = 439.2 (M + H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.71(s,1H),8.49(s,1H),8.44-8.34(m,2H),8.19( dd,J=1.2,7.6Hz,1H),7.73-7.55(m,2H),5.24-5.09(m,1H),4.23-4.00(m,2H ),2.85(dd,J=3.2,9.2Hz,2H),2.72-2.59(m,2H),2.38(dd,J=8.8,13.2Hz,1H ),2.20(dd,J=5.6,13.2Hz,1H),1.66(t,J=5.2Hz,2H),1.57(t,J=5.2Hz,2H).

[0454] Preparation Example 36. Synthesis of Compound A36

[0455] At 0-5° C., trans-N-4-BOC-aminocyclohexanol (750 mg, 3.48 mmol, 1.00 equiv), TEA (1.06 g, 10.4 mmol, 1.45 mL, 3.00 equiv) and DCM (5.00 mL) were added to a 100 mL three-necked round-bottom flask. Ms O (910 mg, 5.23 mmol, 1.50 equiv) was then added to DCM (5.00 mL) and reacted at 0-5° C. for 1 hour. LCMS showed that 51.2% of trans-N-4-BOC-aminocyclohexanol (RT=0.434 min) was not completely reacted, and the target mass spectrum was detected (RT=0.515 min). Pour into water (30.0 mL), extract twice with ethyl acetate (40.0 mL), wash the combined organic phase with saturated brine (40.0 mL), dry over sodium sulfate, filter, and concentrate to obtain compound A36-1 (1.06 g, 3.38 mmol, yield 96.9%, purity 93.5%) as a yellow solid.

[0456] At 20-25 ° C, compound A36-1 (1.12 g, 3.72 mmol, 1.10 equivalents), compound Int1 (1.06 g, 3.38 mmol, 1.00 equivalents), Cs2CO3 (3.30 g, 10.1 mmol, 3.00 equivalents) and DCM (5.00 mL) were added to a 100 mL three-necked round-bottom flask. The temperature was raised to 80-85 ° C and the reaction was carried out for 12 hours. LCMS showed that 50.1% of compound A36-1 (RT = 0.316 min) was not completely reacted, and the target mass spectrum was detected (RT = 0.456 min). The reaction solution was concentrated, the crude product was purified by preparative HPLC, and lyophilized to obtain compound A36-2 (0.303 g, 604 μmol, yield 17.8%, purity 99.0%) as a white solid.

[0457] At 20-25 ° C, compound A36-2 (288 mg, 574 μmol, 1.00 equivalent), TFA (1.83 g, 16.0 mmol, 1.19 mL, 28.0 equivalent) and DCM (5.00 mL) were added to a 100 mL three-necked round-bottom flask. The reaction was carried out at 20-25 ° C for 2 hours. LCMS showed that the reaction of compound A36-2 was complete, and the target mass spectrum was detected (RT = 0.289 min). 10 ml of saturated sodium bicarbonate aqueous solution was added and stirred at 20 ° C for 10 minutes. Ethyl acetate (20.0 mL) was added and extracted twice. The combined organic phases were washed with saturated brine (15.0 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC and lyophilized to obtain compound A36 (39.2 mg, 97.7 μmol, yield 17.0%, purity 98.8%) as a white solid. LCMS: m / z=397.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.71(s,1H),8.56(s,1H),8.49-8.35(m,2H),8.19(d,J=7.4Hz,1H),7.65-7.5 4(m,2H),4.27-4.21(m,1H),3.05-3.03(m,1H),2.25-2.23(m,2H),1.85-1.76(m,3H),1.64-1.61(m,3H).

[0458] Preparation Example 37. Synthesis of Compound A37

[0459] At 25 ° C and under a nitrogen atmosphere, compound tert-butyl 3-hydroxycyclohexylcarbamate (650 mg, 3.02 mmol, 1.00 equivalent), TEA (916 mg, 9.06 mmol, 1.26 mL, 3.00 equivalent) and DCM (15.0 mL) were added to a 100 mL three-necked round-bottom flask, cooled to 0-5 ° C, and Ms2O (788 mg, 4.53 mmol, 1.50 equivalent) was added under a nitrogen atmosphere. LC-MS showed that tert-butyl 3-hydroxycyclohexylcarbamate reacted completely and the target mass spectrum was detected (RT = 0.488 min). The mixture was concentrated in vacuo, 100 ml of aqueous solution was added, and the mixture was extracted 3 times with ethyl acetate (200 mL * 3). The combined organic phases were washed with saturated brine, dried over sodium sulfate, and filtered. The reaction solution was concentrated to obtain compound A37-1 (890 mg, 2.96 mmol, yield 97.9%, purity 97.5%) as a yellow solid.

[0460] At 25°C, compound Int1 (1.20 g, 3.41 mmol, 1.00 equiv), compound A37-1 (1.00 g, 3.41 mmol, 1.00 equiv), pyridine (312 mg, 3.95 mmol, 319 μL, 2.00 equiv), Cs2CO3 (3.33 g, 10.2 mmol, 3.00 equiv), and DMF (10.0 mL) were added to a 100 mL three-necked round-bottom flask and heated to 80°C for 12 hours. LC-MS showed 57.8% of compound A37-1 remaining (RT = 0.317 min), and 24.57% of the target mass spectrum was detected (RT = 0.454 min). The mixture was concentrated in vacuo, added to the solution with water (50 mL * 3), and extracted three times with ethyl acetate (100 mL * 3). The combined organic phases were washed with saturated brine (100 mL * 2), dried over sodium sulfate, and filtered. The reaction solution was concentrated to obtain compound A37-2 (1.50 g, crude product) as a yellow oil.

[0461] Compound A37-2 (100 mg, 199 μmol, 1.00 equiv), HCl / dioxane (4.00 M, 1.10 mL, 22.1 equiv), and MeOH (2.00 mL) were added to a 100 mL three-necked round-bottom flask at 25°C and reacted for 3 hours. TLC (petroleum ether:ethyl acetate = 0:1) showed complete reaction of compound A37-2 (Rf = 0.600), and a new spot (Rf = 0.200) was detected. The reaction solution was concentrated to afford compound A37-3 (87.0 mg, 197 μmol, 99.0% yield, 98.0% purity, HCl) as a white solid.

[0462] At 25°C, compound A37-3 (87.0 mg, 197 μmol, 1.00 equiv, HCl) was added to MeOH (10.0 mL) and DCM (10.0 mL). Amberlyst A26 (4.00 g, 197 μmol, 1.00 equiv) was then added to a 100 mL three-necked round-bottom flask and reacted at 25°C for 0.5 h. TLC (dichloromethane:methanol = 1:2) showed complete reaction of compound A37-3 (Rf = 0.100), and a new spot (Rf = 0.12) was detected. MeOH (10.0 mL) was added to the reaction solution, which was filtered at 25°C. The crude product was filtered and concentrated under vacuum at 40°C. The product was lyophilized under neutral conditions to afford compound A37 (61.2 mg, 154 μmol, 78.4% yield, 100% purity) as an off-white solid. LCMS: m / z=397.0 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.71(s,1H),8.41(s,3H),8.18(d,J=6.4Hz,1H),7.64-7.53(m,2H), 4.79-4.19(m,1H),2.71-2.66(m,1H),2.18-1.95(m,2H),1.93-1.75(m,2H),1.56-1.49(m,4H).

[0463] Preparation Example 38. Synthesis of Compound A38

[0464] At 20-25°C, methyl 4-hydroxycyclohexanecarboxylate (1.00 g, 6.32 mmol, 1.00 equivalent), TEA (959 mg, 9.48 mmol, 1.32 mL, 1.50 equivalent) and DCM (10.0 mL) were added to a 100 mL three-necked round-bottom flask, and Ms2O (1.43 g, 8.22 mmol, 1.30 equivalent) dissolved in DCM (10.0 mL) was slowly added and reacted at 0°C for 3 hours. TLC (petroleum ether:ethyl acetate = 1:1) showed that methyl 4-hydroxycyclohexanecarboxylate was completely consumed (Rf = 0.40) and a new spot was generated (Rf = 0.50). Concentration gave compound A38-1 (1.30 g, crude product) as a yellow oil.

[0465] At 20-25° C., compound Int1 (1.00 g, 2.83 mmol, 1.00 equiv), Cs CO (1.84 g, 5.65 mmol, 2.00 equiv), A38-1 (802 mg, 3.39 mmol, 1.20 equiv) and DMF (15.0 mL) were added to a 100 mL three-necked round-bottom flask and heated to 80° C. for 12 hours. LCMS showed 21.8% of compound A38-1 remaining, and the target mass spectrum was detected (RT = 0.427 min). Pour into water (50.0 mL), extract twice with ethyl acetate (50.0 mL), wash the solution three times with brine (50.0 mL), dry over sodium sulfate, filter, and purify the crude product by silica gel column chromatography and concentrate to give compound A38-2 (680 mg, 1.42 mmol, yield 50.3%, purity 91.8%) as a white solid.

[0466] At 20-25° C., compound A38-2 (160 mg, 364.14 μmol, 1.00 equiv), THF (2.40 mL), and H O (0.80 mL) were added to a 100 mL three-necked round-bottom flask, the temperature was lowered to 0° C., LiOH.H O (15.3 mg, 364 μmol, 1.00 equiv) and THF (0.30 mL) were added, and the mixture was reacted at 0° C. for 2 hours. LC-MS showed that compound A38-2 was completely consumed, and the target mass spectrum was detected (RT = 0.376 min). The mixture was poured into water (20.0 mL), the pH was adjusted to 4-5, and the mixture was extracted twice with ethyl acetate (20.0 mL). The solution was washed twice with brine (20.0 mL), dried over sodium sulfate, filtered, and the crude product was purified by preparative HPLC and concentrated to afford compound A38 (46.3 mg, 104 μmol, 28.5% yield, 95.3% purity) as a white solid. LCMS: m / z = 426.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ11.7 (s, 1H), 8.42-8.35 (m, 3H), 8.18 (d, J = 7.2Hz, 1H), 7.64 (s, 1H), 7.52(s,1H),4.35-4.31(m,1H),2.60(d,J=4.4Hz,1H),2.08-1.95(m,7H),1.70-1.63(m,2H).

[0467] Preparation Example 39. Synthesis of Compound A39

[0468] 3-Methoxy-4-nitro-1H-pyrazole (1 g, 6.99 mmol, 1.00 equivalent), 4-(4-BOC-1-piperazinyl)phenylboronic acid (2.35 g, 7.69 mmol, 1.10 equivalent), pyridine (1.66 g, 20.9 mmol, 1.69 mL, 3.00 equivalent), and Cu(OAc)2 (152 mg, 838 μmol, 0.12 equivalent) were added to a 10 mL single-necked bottle at 20-25°C, and DMF (10.0 mL) was added. The oxygen was replaced three times, and the reaction was carried out at 20-25°C for 12 hours. LC-MS showed that 57.3% of 3-methoxy-4-nitro-1H-pyrazole remained, and the target mass spectrum was detected. The reaction solution was directly concentrated and slurried with ethyl acetate to obtain compound A39-1 (1.05 g, 2.59 mmol, yield 37.0%, purity 99.5%) as a yellow solid.

[0469] At 20-25 ° C, compound A39-1 (500 mg, 1.23 mmol, 1.00 equivalent), NH4Cl (329 mg, 6.17 mmol, 5.00 equivalent), EtOH (20.0 mL) and H2O (2.00 mL) were added to a 100 mL single-necked bottle, heated to 50 ° C, and reacted for 0.5 hours. Fe (206 mg, 3.70 mmol, 3.00 equivalent) was added and reacted at 85 ° C for 12 hours. LCMS showed that compound A39-1 was completely reacted and the target mass spectrum was detected. The reaction solution was cooled to 25 ° C, diatomaceous earth was added, stirred for 10 minutes, and filtered. The filtrate was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound A39-2 (510 mg, 1.07 mmol, yield 87.0%, purity 78.6%) as a black solid.

[0470] At 20-25 ° C, 6-(trifluoromethyl)pyridine-2-carboxylic acid (193 mg, 1.01 mmol, 1.20 equivalents), HATU (384 mg, 1.01 mmol, 1.20 equivalents), DIPEA (217 mg, 1.68 mmol, 293 μL, 2.00 equivalents) and DCM (10.0 mL) were added to a 100 mL single-necked bottle and reacted at 0-5 ° C for 0.5 hours. Compound A39-2 (400 mg, 841 μmol, 1.00 equivalents) was then added and reacted at 0-5 ° C for 1 hour. LCMS showed that 7.76% of compound A39-2 remained, and the target mass spectrum was detected. The reaction solution was concentrated and the crude product was purified by preparative HPLC to obtain compound A39-3 (288 mg, 310 μmol, yield 36.8%, purity 58.9%) as a black solid.

[0471] Compound A39-3 (288 mg, 310 μmol, 1.00 equiv), TFA (990 mg, 8.69 mmol, 645 μL, 28.0 equiv), and DCM (2.00 mL) were added to a 100 mL single-necked vial at 20-25°C and reacted at 20°C for 12 hours. LCMS showed that the reaction of compound A39-3 was complete, and the target mass spectrum was detected. The reaction solution was concentrated to obtain compound A39-4 (180 mg, crude product) as a yellow solid.

[0472] At 20-25°C, compound A39-4 (180 mg, 403 μmol, 1.00 equiv), MeOH (3.00 mL) and DCM (3.0 mL) were added to a 50 mL single-necked bottle, and Amberlyst A26 (1.00 g, 403 μmol, 1.00 equiv) was added and reacted at 20-25°C for 0.5 hours. The plate showed the remaining compound A39-4, and new spots were detected. The reaction solution was filtered, concentrated, and lyophilized to obtain compound A39 (120 mg, 267 μmol, yield 66.2%, purity 98.7%) as a yellow solid. LCMS: m / z=447 (M+H) + . 1 H NMR: (400MHz, DMSO-d6) δ9.72(s,1H),8.56-8.46(m,1H),8.42-8.30(m,2H),8.18( dd,J=2.2,6.6Hz,1H),7.68-7.46(m,2H),7.12-6.94(m,2H),3.98(s,3H),3.16(br d,J=4.6Hz,1H),3.06-3.02(m,3H),2.86-2.80(m,3H),2.62(br d,J=3.2Hz,1H).

[0473] Preparation Example 40. Synthesis of Compound A40

[0474] At 20-25° C., 3-methoxy-4-nitro-1H-pyrazole (1.00 g, 6.99 mmol, 1.00 equivalent), phenylboronic acid (937 mg, 7.69 mmol, 1.10 equivalent), pyridine (1.66 g, 20.9 mmol, 1.69 mL, 3.00 equivalent) and DMF (17.0 mL) were added to a 100 mL three-necked round-bottom flask, and Cu(OAc) 2 (152 mg, 838 μmol, 0.12 equivalent) was added. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 25° C. for 12 hours. LCMS showed 11.4% of 3-methoxy-4-nitro-1H-pyrazole remained, and the target mass spectrum was detected. The reaction was directly concentrated, and the crude product was purified by preparative HPLC and lyophilized to give compound A40-1 (800 mg, 3.65 mmol, yield 52.2%, purity 100%) as a yellow solid.

[0475] At 20-25 ° C, compound A40-1 (500 mg, 2.28 mmol, 1.00 equivalent), EtOH (20.0 mL) and H2O (2.00 mL) were added to a 100 mL three-necked round-bottom flask, and NH4Cl (610 mg, 11.4 mmol, 5.00 equivalent) was added, the temperature was raised to 50 ° C for 0.5 hours, and Fe (382 mg, 6.84 mmol, 3.00 equivalent) was added, and the temperature was raised to 85 ° C for 12 hours. LCMS showed that the reaction of compound A40-1 was complete and the target mass spectrum was detected. The reaction was cooled to 25 ° C, diatomaceous earth was added to the reaction solution, stirred for 10 minutes, filtered, and the filtrate was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound A40-2 (510 mg, 1.92 mmol, yield 84.0%, purity 71.1%) as a black solid.

[0476] At 0-5 ° C, compound 6-(trifluoromethyl)pyridine-2-carboxylic acid (344 mg, 1.80 mmol, 1.20 equivalents), HATU (628 mg, 1.65 mmol, 1.10 equivalents), DIPEA (388.mg, 3.01 mmol, 523 μL, 2.00 equivalents) and DCM (10.0 mL) were added to a 100 mL three-necked round-bottom flask, and compound A40-2 (400 mg, 1.50 mmol, 1.00 equivalents) was added and reacted at 0-5 ° C for 2 hours. LCMS detected the target mass spectrum. The reaction solution was directly concentrated, the crude product was purified by preparative HPLC, and lyophilized to obtain compound A40 (182 mg, 495 μmol, yield 33.0%, purity 98.6%) as a yellow solid. LCMS: m / z=363 (M+H) + . 1H NMR: (400MHz, DMSO-d6) δ9.76(s,1H),8.68(s,1H),8.42-8.32(m,2H),8.18(dd,J=1.8,6.8 Hz,1H),7.76(d,J=7.8Hz,2H),7.46(dd,J=7.6,8.4Hz,2H),7.26-7.18(m,1H),4.02(s,3H).

[0477] Preparation Example 41. Synthesis of Compound A41

[0478] At 20-25°C, methyl 4-amino-1H-pyrazole-3-carboxylate (8.50 g, 60.2 mmol, 1.00 equiv) and DCM (130 mL) were added to a 250 mL three-necked round-bottom flask, cooled to 0-5°C, and then 6-(trifluoromethyl)pyridine-2-carboxylic acid (11.7 g, 61.4 mmol, 1.02 equiv) and ECD·HCl (13.8 g, 72.2 mmol, 1.20 equiv) were added. The mixture was reacted at 0°C for 1 hour. LCMS showed that the reaction of methyl 4-amino-1H-pyrazole-3-carboxylate was complete, and the target mass spectrum was detected. The reaction solution was concentrated, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound A41-1 (18.3 g, 57.3 mmol, 95.1% yield, 98.4% purity) as a black solid.

[0479] At 20-25 ° C, compound A41-1 (5.00 g, 15.6 mmol, 1.00 equivalent), phenylboronic acid (1.91 g, 15.6 mmol, 1 equivalent) and DMF (50.0 mL) were added to a 250 mL three-necked round-bottom flask, and Cu (OAc) 2 (341 mg, 1.88 mmol, 0.12 equivalent) and K2CO3 (4.33 g, 31.3 mmol, 2.00 equivalent) were added, oxygen was replaced three times, and the temperature was raised to 85 ° C for 12 hours. LCMS showed that 2.33% of compound A41-1 remained, and the target mass spectrum was detected. The reaction solution was cooled to 20-25 ° C and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, water was added to the filtrate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative HPLC to give compound A41-2 (2.00 g, 5.01 mmol, yield 31.9%, purity 97.7%) as a yellow solid.

[0480] At 20-25 ° C, compound A41-2 (1.00 g, 2.50 mmol, 1.00 equivalent) and THF (15.0 mL) were added to a 100 mL three-necked round-bottom flask, cooled to 0-5 ° C, replaced with nitrogen three times, and then added NaBH4 (1.23 g, 32.5 mmol, 13.0 equivalents), and reacted at 65 ° C for 12 hours. LCMS showed that compound A41-2 remained, and the target mass spectrum was detected. The reaction solution was poured into an aqueous ammonium chloride solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain compound A41-3 (400 mg, 1.10 mmol, yield 43.8%, purity 99.4%) as a white solid.

[0481] At 20-25 ° C, compound A41-3 (338 mg, 927 μmol, 1.00 equivalent) and DCM (5.00 mL) were added to a 100 mL three-necked round-bottom flask, and DMP (786 mg, 1.85 mmol, 574 μL, 2.00 equivalent) was added and reacted at 25 ° C for 12 hours. LCMS showed that the reaction of compound A41-3 was complete and the target mass spectrum was detected. The reaction solution was poured into an aqueous solution of sodium thiosulfate, extracted with dichloromethane, washed with sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated to give compound A41-3 (400 mg, 1.10 mmol, yield 43.8%, purity 99.4%) as a white solid.

[0482] At 20-25 ° C, compound A41-3 (325 mg, 733 μmol, 1.00 equivalent) and DCM (10 mL) were added to a 100 mL three-necked round-bottom flask, and DAST (2.36 g, 14.6 mmol, 1.94 mL, 20.0 equivalent) was added and reacted at 25 ° C for 12 hours. LCMS showed that compound A41-3 was completely reacted and the target mass spectrum was detected. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with dichloromethane, washed with sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated. Slurry with methyl tert-butyl ether to obtain compound A41 (96.9 mg, 247 μmol, yield 33.7%, purity 97.6%) as a white solid. LCMS: m / z = 383.1 (M + H) + . 1 H NMR: (400MHz, DMSO-d6) δ10.30(s,1H),8.94(s,1H),8.52-8.36(m,2H),8.23(d ,J=7.6Hz,1H),7.89(d,J=8.0Hz,2H),7.56(t,J=8.0Hz,2H),7.47-7.17(m,2H).

[0483] Preparation Example 42. Synthesis of Compound A42

[0484] At 20-25 ° C, compound A41-1 (5.00 g, 15.6 mmol, 1.00 equivalent), 4- (4-BOC-1-piperazinyl) phenylboronic acid (4.79 g, 15.6 mmol, 1.00 equivalent) and DMF (50.0 mL) were added to a 500 mL three-necked round-bottom flask, and Cu (OAc) 2 (341.27 mg, 1.88 mmol, 0.12 equivalent) and K 2 CO 3 (4.33 g, 31.3 mmol, 2.00 equivalent) were added, and the reaction was carried out at 85 ° C for 12 hours. LCMS showed that 9.90% of compound A41-1 remained, and the target mass spectrum was detected. The reaction solution was poured into water, extracted with ethyl acetate, washed with sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative HPLC to give compound A42-1 (1.30 g, 2.26 mmol, yield 14.4%, purity 100%) as a white solid.

[0485] At 20-25 ° C, compound A42-1 (1.00 g, 1.74 mmol, 1.00 equivalent) and THF (15.0 mL) were added to a 100 mL three-necked round-bottom flask, cooled to 0-5 ° C, replaced with nitrogen three times, and then added NaBH4 (856 mg, 22.6 mmol, 13.0 equivalents) and reacted at 65 ° C for 12 hours. LCMS showed that compound A42-1 was completely reacted and the target mass spectrum was detected. The reaction solution was poured into an aqueous ammonium chloride solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography to obtain compound A42-2 (400 mg, 726 μmol, yield 41.7%, purity 99.3%) as a white solid.

[0486] At 25 ° C, compound A42-2 (334 mg, 606 μmol, 1.00 equivalent) and DCM (1.00 mL) were added to a 100 mL three-necked flask, the nitrogen was replaced 3 times, and DMP (514 mg, 1.21 mmol, 376 μL, 2.00 equivalent) was added and reacted at 25 ° C for 12 hours. LCMS showed that the reaction of compound A42-2 was complete and the target mass spectrum was detected (RT = 0.553 min). Saturated ammonium chloride (20.0 mL) and saturated sodium bicarbonate (20.0 mL) were poured into the solution and extracted 3 times with ethyl acetate (20.0 mL * 3). The organic phase was washed with saturated brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated to obtain compound A42-3 (400 mg, 539 μmol, yield 88.9%, purity 73.5%) as a yellow solid.

[0487] At 20-25 ° C, compound A42-3 (430 mg, 580 μmol, 1.00 equivalent) and DCM (10 mL) were added to a 100 mL three-necked round-bottom flask, and DAST (1.87 g, 11.6 mmol, 1.53 mL, 20.0 equivalent) was added and reacted at 25 ° C for 12 hours. LC-MS showed that compound A42-3 was completely reacted and the target mass spectrum was detected. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with dichloromethane, washed with sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated. Slurry with methyl tert-butyl ether to obtain compound A42-4 (65.0 mg, 114 μmol, yield 21.2%, purity 100%) as a white solid.

[0488] At 20-25 ° C, compound A42-4 (65.0 mg, 114 μmol, 1.00 equivalent) and DCM (2 mL) were added to a 100 mL three-necked round-bottom flask, and TFA (261 mg, 2.29 mmol, 170 μL, 20.0 equivalent) was added and reacted at 25 ° C for 12 hours. LCMS showed that the reaction of compound A42-4 was complete and the target mass spectrum was detected. The reaction solution was poured into an aqueous sodium bicarbonate solution, stirred for 10 minutes, filtered, and concentrated to obtain compound A42 (65.0 mg, 114 μmol, yield 21.2%, purity 100%) as a white solid. LCMS: m / z = 467.1 (M + H) + . 1 H NMR: (400MHz, DMSO-d6) δ10.26(s,1H),8.78(s,1H),8.46-8.37(m,2H),8.23(dd,J=1.2,7.6Hz,1H),7.6 8(d,J=9.2Hz,2H),7.29(t,J=54.0Hz,1H),7.05(d,J=9.2Hz,2H),3.14-3.07(m,4H),2.87-2.81(m,4H).

[0489] Preparation Example 43. Synthesis of Compound A43

[0490] At 20-25° C., DCM (40.0 mL), 6-(trifluoromethyl)pyridine-2-carboxylic acid (2.40 g, 12.5 mmol, 1.00 equivalent), TEA (7.63 g, 75.3 mmol, 10.4 mL, 6.00 equivalent), and HATU (4.78 g, 12.5 mmol, 1.00 equivalent) were added to a 100 mL three-necked round-bottom flask, and the mixture was reacted at 0-5° C. for 0.5 hour. 3-phenyl-1H-pyrazol-5-amine (2.00 g, 12.5 mmol, 1.00 equivalent) was added, and the mixture was reacted at 20-25° C. for 12 hours. LCMS showed that the reaction of 3-phenyl-1H-pyrazol-5-amine was complete, and the target mass spectrum was detected. Filtration and slurrying with dichloromethane gave compound A43-1 (3.10 g, 9.09 mmol, 72.3% yield, 97.4% purity) as a white solid.

[0491] At 20-25 ° C, compound A43-1 (200 mg, 586 μmol, 1.00 equivalent) and DMF (1.50 mL) were added to a 100 mL three-necked round-bottom flask, and sodium difluorochloroacetate (268 mg, 1.76 mmol, 3.00 equivalent) and K2CO3 (243 mg, 1.76 mmol, 3.00 equivalent) were added and reacted at 80-85 ° C for 16 hours. LCMS showed that about 6.2% of compound A43-1 remained, and the target mass spectrum was detected. The reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative HPLC to give compound A43 (146 mg, 392 μmol, yield 66.9%, purity 100%) as a white solid. LCMS: m / z=383.1 (M+H) + . 1 H NMR: (400MHz, DMSO-d6)δ10.94(s,1H)8.42-8.39(m,2H)7.90(d,J=6.8Hz,1H)7.78(t,J=42.4Hz,1H)7.48-7.42(m,3H)7.03(s,1H).

[0492] Preparation Example 44. Synthesis of Compound A44

[0493] Step A: N-methyl-3-(4-nitro-1-phenyl-1H-pyrazol-3-yl)cyclobutane-1-amine

[0494] At room temperature, a solution of 3-(4-nitro-1-phenyl-1H-pyrazol-3-yl)cyclobutane-1-one (200 mg, 0.8 mmol, 1.0 equivalent) in methylamine / methanol (20 mL) was stirred for 15 hours. Then, sodium borohydride (58.8 mg, 1.6 mmol, 2.0 equivalent) was added. The reaction solution was stirred at 25°C under nitrogen for 1 hour. After the reaction was complete, the reaction solution was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound (yellow solid, 218 mg, crude product), which was used directly in the next step without purification.

[0495] Step B: tert-Butyl methyl(3-(4-nitro-1-phenyl-1H-pyrazol-3-yl)cyclobutyl)carbamate

[0496] To a solution of N-methyl-3-(4-nitro-1-phenyl-1H-pyrazol-3-yl)cyclobutane-1-amine (218 mg, 0.8 mmol, 1.0 equiv) in tetrahydrofuran / water (2:1, 30 mL) was added sodium bicarbonate (160 mg, 1.9 mmol, 2.4 equiv) at room temperature, followed by di-tert-butyl dicarbonate (218.6 mg, 1.0 mmol, 1.25 equiv). The reaction was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow solid, 230 mg, 65% yield).

[0497] Step C: tert-Butyl (3-(4-amino-1-phenyl-1H-pyrazol-3-yl)cyclobutyl)(methyl)carbamate

[0498] To a solution of tert-butyl methyl(3-(4-nitro-1-phenyl-1H-pyrazol-3-yl)cyclobutyl)carbamate (230 mg, 0.6 mmol, 1.0 equivalent) in methanol (25 mL) was added 10% palladium on carbon (32.9 mg, 0.3 mmol) at room temperature. The reaction solution was replaced three times under a hydrogen balloon and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford the crude title compound (yellow oil, 170 mg, crude product), which was used directly in the next step without purification.

[0499] Step D: tert-Butyl methyl(3-(1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazol-3-yl)cyclobutyl)carbamate

[0500] To a solution of tert-butyl (3-(4-amino-1-phenyl-1H-pyrazol-3-yl)cyclobutyl)(methyl)carbamate (170 mg, 0.5 mmol, 1.0 equiv) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (95 mg, 0.5 mmol, 1.0 equiv) in N,N-dimethylformamide (15 mL) were added EDCI (142.9 mg, 0.7 mmol, 1.5 equiv), HOBt (100.8 mg, 0.7 mmol, 1.5 equiv), and triethylamine (0.2 mL, 1.5 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the crude title compound (pale yellow solid, 256 mg, crude product).

[0501] Step E: N-(3-(3-(Methylamino)cyclobutyl)-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0502] Tert-butyl methyl(3-(1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazol-3-yl)cyclobutyl)carbamate (256 mg, 0.6 mmol, 1.0 equiv) was stirred in a solution of hydrochloric acid / 1,4-dioxane (4 N, 10 mL) at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (pale yellow solid, 9.6 mg, 4% yield). 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.43-8.34(m,2H),8.31(s,1H),8.24-8.13(m,1H),7.82(d,J=7.8Hz,2H),7.56-7.45(m ,2H),7.36-7.25(m,1H),2.69-2.59(m,2H),2.29(s,3H),2.22-2.11(m,2H),2.09-1.92(m,2H).LC-MS(ESI):m / z=416.3[M+H] + .

[0503] Preparation Example 45. Synthesis of Compound A45

[0504] Step A: Methyl 4-nitro-1-(pyrimidin-5-yl)-1H-pyrazole-3-carboxylate

[0505] To a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (1.00 g, 5.84 mmol, 1.0 equiv) in dichloromethane (20 mL) at room temperature were added pyrimidin-5-ylboronic acid (1.09 g, 8.77 mmol, 1.5 equiv), copper acetate (1.17 g, 5.84 mmol, 1.0 equiv), and pyridine (1.89 mL, 23.4 mmol, 4.0 equiv). The reaction mixture was stirred at room temperature under oxygen for 18 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate diluted with water, and extracted three times with dichloromethane. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (white solid, 580 mg, 40% yield).

[0506] Step B: 4-amino-1-(pyrimidin-5-yl)-1H-pyrazole-3-carboxylic acid methyl ester

[0507] To a solution of methyl 4-nitro-1-(pyrimidin-5-yl)-1H-pyrazole-3-carboxylate (280 mg, 1.12 mmol, 1.0 equiv) in ethanol (9 mL) and water (3 mL) at room temperature were added iron powder (313 mg, 5.62 mmol, 5.0 equiv) and ammonium chloride (60.1 mg, 1.12 mmol, 1.0 equiv). The reaction mixture was stirred at 80°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford the crude title compound (yellow solid, 190 mg, 77% yield), which was used directly in the next step without purification.

[0508] Step C: Methyl 1-(pyrimidin-5-yl)-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-carboxylate

[0509] To a solution of methyl 4-amino-1-(pyrimidin-5-yl)-1H-pyrazole-3-carboxylate (190 mg, 0.88 mmol, 1.0 equiv) in N,N-dimethylformamide (7 mL) at room temperature were added 6-(trifluoromethyl)picolinic acid (165.7 mg, 0.88 mmol, 1.0 equiv), DIEA (336 mg, 2.6 mmol, 3.0 equiv), and HATU (329 mg, 0.88 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature under nitrogen for 18 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 70 mg, 20% yield).

[0510] Step D: 1-(Pyrimidin-5-yl)-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-carboxylic acid

[0511] To a mixed solution of 1-(pyrimidin-5-yl)-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.18 mmol, 1.0 equiv) in methanol (9 mL), tetrahydrofuran (9 mL) and water (3 mL) at 0°C was added lithium hydroxide monohydrate (15 mg, 0.36 mmol, 2.0 equiv). The reaction solution was stirred at room temperature under nitrogen for 18 hours. After the reaction was complete, the reaction solution was adjusted to pH <5 with diluted 1N HCl solution. Filter and dry to obtain the crude title compound (yellow solid, 50 mg, 74% yield), which was used directly in the next step without purification.

[0512] Step E: N-(3-amino-1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0513] To a solution of 1-(pyrimidin-5-yl)-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-carboxylic acid (50 mg, 0.13 mmol, 1.0 equiv) in N,N-dimethylformamide (3 mL) at room temperature were added ammonium chloride (21.2 mg, 0.40 mmol, 3.0 equiv), DIEA (51.3 mg, 0.40 mmol, 3.0 equiv), and HATU (75.4 mg, 0.20 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature under nitrogen for 0.5 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (white solid, 15 mg, 30% yield). 1 H NMR (400MHz, DMSO-d6) δ11.81(s,1H),9.50(s,2H),9.28(s,1H),9.20(s,1H),8.47(d,J=7.7Hz ,1H),8.41(t,J=7.8Hz,1H),8.23(d,J=7.6Hz,1H),8.17(s,1H),7.89(s,1H).LC-MS(ESI):m / z 378[M+H] + .

[0514] Preparation Example 46. Synthesis of Compound A46

[0515] Step A: N-(3-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0516] To a solution of 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.256 mmol, 1.0 equivalent) in tetrahydrofuran (5 mL) was slowly added 3 M methylmagnesium bromide in ether (0.85 mL, 2.56 mmol, 10 equivalents) at 0°C under nitrogen protection. The reaction solution was stirred at room temperature under nitrogen protection for 18 hours. After the reaction was complete, the product was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The mixed organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (white solid, 16.1 mg, 16% yield). 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),8.89(s,1H),8.45(d,J=7.6Hz,1H),8.39(t,J=7.8Hz,1H),8.19(d,J=7.7Hz,1H), 7.80(d,J=7.8Hz,2H),7.49(t,J=7.9Hz,2H),7.29(t,J=7.4Hz,1H),5.98(s,1H),1.59(s,6H).LC / MS(ESI)m / z:391[M+H] + .

[0517] Preparation Example 47. Synthesis of Compound A47

[0518] Step A: Phenylglycine tert-butyl ester

[0519] To a solution of aniline (4.8 g, 51.3 mmol, 1.0 equivalent) and tert-butyl 2-bromoacetate (10.0 g, 51.3 mmol, 1.0 equivalent) in acetonitrile (50.0 mL) was added potassium carbonate (10.6 g, 76.9 mmol, 1.5 equivalents) at room temperature. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (green oil, 10.2 g, 96% yield).

[0520] Step B: 2-(tert-Butyl)4-ethyl 3-amino-1-phenyl-1H-pyrrole-2,4-dicarboxylate

[0521] To a solution of tert-butyl phenylglycine (5.0 g, 24.1 mmol, 1.0 equiv) and methyl (Z)-2-cyano-3-ethoxyacrylate (7.5 g, 48.3 mmol, 2.0 equiv) in toluene (50.0 mL) was added DBU (21.2 g, 84.4 mmol, 3.5 equiv) at room temperature. The reaction mixture was stirred at 120°C under nitrogen for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (white solid, 1.0 g, 13% yield).

[0522] Step C: Ethyl 4-amino-1-phenyl-1H-pyrrole-3-carboxylate

[0523] To 2-(tert-butyl)-4-ethyl 3-amino-1-phenyl-1H-pyrrole-2,4-dicarboxylate (500.0 mg, 1.5 mmol, 1.0 equivalent) was added a 4M HCl solution in 1,4-dioxane (10 mL) at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to afford the crude title compound (white solid, 300 mg, 86% yield), which was used directly in the next step without purification.

[0524] Step D: Ethyl 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrrole-3-carboxylate

[0525] Thionyl chloride (5 mL) was added to 6-(trifluoromethyl)picolinic acid (750 mg, 3.9 mmol, 3.0 equiv) at 0°C. The reaction mixture was stirred at 80°C under nitrogen for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain 6-(trifluoromethyl)picolinoyl chloride (3.0 equiv), which was dissolved in dichloromethane (2.0 mL). To a solution of ethyl 4-amino-1-phenyl-1H-pyrrole-3-carboxylate (300.0 mg, 1.3 mmol, 1.0 equiv) and triethylamine (660.0 mg, 6.5 mmol, 5.0 equiv) in dichloromethane (3.0 mL) at 0°C was added a solution of 6-(trifluoromethyl)picolinoyl chloride (3.0 equiv) in dichloromethane dropwise. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After the reaction was complete, the mixture was diluted with dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (white solid, 300 mg, yield 57%).

[0526] Step E: 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrrole-3-carboxylic acid

[0527] To a solution of ethyl 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrrole-3-carboxylate (300.0 mg, 743.8 μmol, 1.0 equiv) in N,N-dimethylformamide (5.0 mL) was added sodium ethanethiolate (625.6 mg, 7.4 mmol, 10.0 equiv) at room temperature. The reaction mixture was stirred at 100°C under nitrogen for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, the pH was adjusted to 6-7 with a dilute 1N HCl solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (white solid, 200.0 mg, 72% yield).

[0528] Step F: N-(4-amino-1-phenyl-1H-pyrrol-3-yl)-6-(trifluoromethyl)picolinamide

[0529] To a solution of 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrrole-3-carboxylic acid (200.0 mg, 532.9 μmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) at room temperature were added ammonium chloride (43.0 mg, 800.0 μmol, 1.5 equiv), DIEA (344.4 mg, 2.7 nmol, 5.0 equiv), and HATU (304.0 mg, 800.0 μmol, 1.5 equiv). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (white solid, 52.6 mg, 26% yield). 1 H NMR (400MHz, DMSO-d6) δ12.25(s,1H),8.45-8.35(m,2H),8.17(d,J=7.4Hz,1H),8.11(d,J=2.4Hz,1H),8.02 (d,J=2.4Hz,1H),7.75(d,J=26.4Hz,1H),7.62-7.54(m,4H),7.36(dd,J=13.8,6.7Hz,2H).LC-MS(ESI):m / z 375[M+H] + .

[0530] Preparation Example 48. Synthesis of Compound A48

[0531] Step A: Ethyl 5-phenyl-3-(6-(trifluoromethyl)picolinamido)-1H-pyrrole-2-carboxylate

[0532] To a solution of ethyl 3-amino-5-phenyl-1H-pyrrole-2-carboxylate (100 mg, 0.434 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) at room temperature were added 6-(trifluoromethyl)picolinic acid (83.0 mg, 0.434 mmol, 1.0 equiv), DIEA (168 mg, 1.30 mmol, 3.0 equiv), and HATU (165 mg, 0.434 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 130 mg, 74% yield).

[0533] Step B: 5-phenyl-3-(6-(trifluoromethyl)picolinamido)-1H-pyrrole-2-carboxylic acid

[0534] To a mixed solution of ethyl 5-phenyl-3-(6-(trifluoromethyl)picolinamido)-1H-pyrrole-2-carboxylate (130 mg, 0.322 mmol, 1.0 equivalent) in tetrahydrofuran (10 mL) and water (10 mL) was added lithium hydroxide monohydrate (15.4 mg, 0.645 mmol, 2.0 equivalent) at 0°C. The reaction solution was stirred at 40°C for 24 hours. After the reaction was complete, the reaction solution was adjusted to pH 5-6 with a diluted 1N HCl solution. The mixed solution was extracted three times with ethyl acetate, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (white solid, 100 mg, 83% yield), which was used directly in the next step without purification.

[0535] Step C: N-(2-amino-5-phenyl-1H-pyrrol-3-yl)-6-(trifluoromethyl)picolinamide

[0536] To a solution of 5-phenyl-3-(6-(trifluoromethyl)picolinamido)-1H-pyrrole-2-carboxylic acid (100 mg, 0.266 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) at room temperature were added ammonium chloride (42.8 mg, 0.799 mmol, 3.0 equiv), DIEA (103 mg, 0.799 mmol, 3.0 equiv), and HATU (152 mg, 0.400 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature under nitrogen for 12 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (yellow solid, 30.0 mg, 30% yield). 1H NMR (400MHz, CD3OD) δ8.45(d,J=7.8Hz,1H),8.28(t,J=7.8Hz,1H),8.02(d,J=7.2Hz,1H),7.73-7 .68(m,2H),7.48(s,1H),7.44(t,J=7.7Hz,2H),7.32(t,J=7.4Hz,1H).LC-MS(ESI)m / z:375[M+H] + .

[0537] Preparation Example 49. Synthesis of Compound A49

[0538] Step A: tert-Butyl 2-(3-carbamoyl-4-nitro-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0539] tert-Butyl 2-(3-(methoxycarbonyl)-4-nitro-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (2 g, 3.04 mmol, 1.0 equiv) was added to a solution of ammonia in methanol (7N, 50 mL, 12.0 equiv) at room temperature. The reaction mixture was then stirred at 80°C under N2 in a sealed tube for 18 hours. The reaction was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography to give tert-butyl 2-(3-carbamoyl-4-nitro-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.8 g, 69.30%) as a white solid.

[0540] Step B: tert-Butyl 2-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0541] At room temperature, tert-butyl 2-(3-carbamoyl-4-nitro-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (300 mg, 0.79 mmol, 1 eq), ethanol (10 mL), water (2 mL), iron powder (442 mg, 7.91 mmol, 10 eq), and ammonium chloride (423 mg, 7.91 mmol, 10 eq) were stirred at 80°C for 2 hours. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by silica gel column chromatography to afford tert-butyl 2-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (200 mg, 72.39%) as a white solid.

[0542] Step C: tert-Butyl 2-(3-carbamoyl-4-(3-isocyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0543] To a solution of tert-butyl 3-isocyanopyrrolo[1,2-b]pyridazine-7-carboxylate (107 mg, 0.57 mmol, 1 eq), 2-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (200 mg, 0.57 mmol, 1 eq), and DIEA (222 mg, 1.72 mmol, 3 eq) in DMF (5 mL) at 0°C under nitrogen was added HATU (326.44 mg, 0.859 mmol, 1.5 eq). The reaction was stirred under nitrogen for 1 hour. The reaction mixture was added with water, extracted, dried, and concentrated in vacuo. The residue was purified by flash column to give tert-butyl 2-(3-carbamoyl-4-(3-isocyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (200 mg, 67.38% yield) as a colorless oil.

[0544] Step D: N-(3-Carbamoyl-1-(7-azaspiro[3.5]nonan-2-yl)-1H-pyrazol-4-yl)-3-isocyanopyrrolo[1,2-b]pyridazine-7-carboxamide

[0545] Under nitrogen, tert-butyl 2-(3-carbamoyl-4-(3-isocyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (150 mg, 0.412 mmol, 1 equivalent) was added to a 4N HCl / EA solution (5 mL) with stirring in an ice bath. The reaction mixture was stirred under nitrogen for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford N-(3-carbamoyl-1-(7-azaspiro[3.5]nonan-2-yl)-1H-pyrazol-4-yl)-3-isocyanopyrrolo[1,2-b]pyridazine-7-carboxamide (98.7 mg, 61.16% yield) as a yellow solid. 1H NMR (400MHz, DMSO) δ12.12(s,1H),8.97(s,1H),8.71(d,J=2.1Hz,1H),8.48(s,1H),8.39(s,1H),7.74(d,J=4.8Hz,1H),7.60(s,1H),7.49(s, 1H),7.10(d,J=4.8Hz,1H),4.98(p,J=8.3Hz,1H),2.87(dd,J=30.5,4.0Hz,4H),2.42(dd,J=15.3,5.0Hz,2H),2.34-2.28(m,2H),1.74(s,4H).

[0546] Preparation Example 50. Synthesis of Compound A50

[0547] Step A: Methyl 5-phenyl-3-(6-(trifluoromethyl)picolinamido)thiophene-2-carboxylate

[0548] To a solution of methyl 3-amino-5-phenylthiophene-2-carboxylate (500.0 mg, 2.1 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) at room temperature were added 6-(trifluoromethyl)picolinic acid (615.0 mg, 3.2 mmol, 1.5 equiv), HOBT (652.0 mg, 4.3 mmol, 2.0 equiv), EDCI (823.0 mg, 4.3 mmol, 2.0 equiv), and triethylamine (1.1 g, 10.7 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature under nitrogen for 18 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (white solid, 600 mg, 70% yield).

[0549] Step B: 5-phenyl-3-(6-(trifluoromethyl)picolinamido)thiophene-2-carboxylic acid

[0550] To a mixed solution of methyl 5-phenyl-3-(6-(trifluoromethyl)picolinamido)thiophene-2-carboxylate (600.0 mg, 1.47 mmol, 1.0 equiv) in tetrahydrofuran (4 mL) and water (4 mL) at 0°C was added lithium hydroxide (176.4 mg, 7.4 mmol, 5.0 equiv). The reaction solution was stirred at 50°C for 18 hours. After the reaction was complete, the pH was adjusted to 4 with diluted 1N HCl solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (white solid, 300 mg, 69% yield), which was used directly in the next step without purification.

[0551] Step C: N-(2-amino-5-phenylthiophen-3-yl)-6-(trifluoromethyl)picolinamide

[0552] To a solution of 5-phenyl-3-(6-(trifluoromethyl)picolinamido)thiophene-2-carboxylic acid (100.0 mg, 340.1 μmol, 1.0 equiv) and HATU (193.9 mg, 510.2 μmol, 1.5 equiv) in N,N-dimethylformamide (3 mL) at room temperature were added ammonium chloride (36.4 mg, 680.2 μmol, 2.0 equiv) and triethylamine (172.1 mg, 1.7 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (white solid, 8.7 mg, 7% yield). 1 H NMR (400MHz, DMSO-d6) δ13.18(s,1H),8.55(s,1H),8.47(d,J=7.7Hz,1H),8.40(t,J=7.8Hz,1H),8.22(d,J =7.1Hz,1H),7.81(s,2H),7.76-7.69(m,2H),7.52(t,J=7.5Hz,2H),7.45(t,J=7.3Hz,1H).LC-MS(ESI):m / z 392[M+H] + .

[0553] Preparation Example 51. Synthesis of Compound A51

[0554] Step A: 6-(Trifluoromethyl)picolinoyl chloride

[0555] To 6-(trifluoromethyl)picolinic acid (2.0 g, 2.1 mmol, 1.0 equivalent) was added thionyl chloride (20 mL) at 0°C. The reaction mixture was stirred at 80°C under nitrogen for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to afford the crude title compound (yellow solid, 2.0 g, crude product), which was used directly in the next step without purification.

[0556] Step B: Ethyl 5-phenyl-2-(6-(trifluoromethyl)picolinamido)thiophene-3-carboxylate

[0557] To a solution of ethyl 2-amino-5-phenylthiophene-3-carboxylate (172.95 mg, 0.7 mmol, 1.0 equiv) and triethylamine (48.7 mg, 2.0 mmol, 3.0 equiv) in dichloromethane (8.0 mL) was added dropwise a solution of 6-(trifluoromethyl)picolinyl chloride (500.0 mg, crude product) in dichloromethane at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the mixture was diluted with dichloromethane, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (colorless oil, 100 mg, 29% yield).

[0558] Step C: 5-phenyl-2-(6-(trifluoromethyl)picolinamido)thiophene-3-carboxylic acid

[0559] To a mixed solution of ethyl 5-phenyl-2-(6-(trifluoromethyl)picolinamido)thiophene-3-carboxylate (100.0 mg, 0.2 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) and water (1 mL) at 0°C was added lithium hydroxide (75.6 mg, 0.6 mmol, 3.0 equiv). The reaction solution was stirred at 80°C for 16 hours. After the reaction was complete, the pH was adjusted to 4 with a diluted 1N HCl solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (colorless oil, 100 mg, crude product), which was used directly in the next step without purification.

[0560] Step D: N-(3-amino-5-phenylthiophen-2-yl)-6-(trifluoromethyl)picolinamide

[0561] To a solution of 5-phenyl-2-(6-(trifluoromethyl)picolinamido)thiophene-3-carboxylic acid (100.0 mg, 0.02 mmol, 1.0 equiv) and HATU (1 mL) in N,N-dimethylformamide (2 mL) at room temperature were added ammonium chloride (200.0 mg, 0.02 mmol, 1.0 equiv) and triethylamine (1 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (white solid, 11.4 mg, 11% yield). 1H NMR (400MHz, DMSO-d6) δ13.93 (s, 1H), 8.51-8.38 (m, 2H), 8.23 ​​(d, J = 7.5Hz, 1H), 8.00 (s, 1H), 7.96 (s, 1H),7.76(s,1H),7.63(d,J=7.5Hz,2H),7.47(t,J=7.7Hz,2H),7.33(t,J=7.3Hz,1H).LC-MS(ESI):m / z 392[M+H] + .

[0562] Preparation Example 52. Synthesis of Compound A52

[0563] Step A: Ethyl 3-amino-5-phenylfuran-2-carboxylate

[0564] To a solution of 3-phenylpropionitrile (500.0 mg, 2.1 mmol, 1.0 equiv) and ethyl 2-hydroxyacetate (218.63 mg, 2.1 mmol, 1.0 equiv) in N,N-dimethylformamide (20 mL) was added potassium carbonate (438.0 mg, 3.1 mmol, 1.5 equiv) at room temperature. The reaction mixture was stirred at 100°C under nitrogen for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (colorless oil, 450.0 mg, 48% yield).

[0565] Step B: Ethyl 5-phenyl-3-(6-(trifluoromethyl)picolinamido)furan-2-carboxylate

[0566] To a solution of ethyl 3-amino-5-phenylfuran-2-carboxylate (162.4 mg, 0.7 mmol, 1.0 equiv) and DIEA (48.7 mg, 2.0 mmol, 3.0 equiv) in dichloromethane (8.0 mL) was added dropwise 6-(trifluoromethyl)picolinyl chloride (100.0 mg, crude product) at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After the reaction was complete, the mixture was diluted with dichloromethane, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (colorless oil, 80 mg, 29% yield).

[0567] Step C: 5-phenyl-3-(6-(trifluoromethyl)picolinamido)furan-2-carboxylic acid

[0568] To a mixed solution of ethyl 5-phenyl-3-(6-(trifluoromethyl)picolinamido)furan-2-carboxylate (80.0 mg, 0.2 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) and water (1 mL) at 0°C was added sodium hydroxide (75.6 mg, 0.6 mmol, 3.0 equiv). The reaction solution was stirred at 80°C for 16 hours. After the reaction was complete, the pH was adjusted to 4 with a diluted 1N HCl solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (colorless oil, 80.0 mg, crude product), which was used directly in the next step without purification.

[0569] Step D: N-(2-amino-5-phenylfuran-3-yl)-6-(trifluoromethyl)picolinamide

[0570] To a solution of 5-phenyl-3-(6-(trifluoromethyl)picolinamido)furan-2-carboxylic acid (80.0 mg, 20.0 μmol, 1.0 equiv) and HATU (11.4 mg, 30.0 μmol, 1.5 equiv) in N,N-dimethylformamide (2.0 mL) at room temperature were added ammonium chloride (90.0 mg, 0.1 mmol, 1.5 equiv) and DIEA (2.0 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (white solid, 26.6 mg, 33% yield). 1 H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.47(d,J=7.7Hz,1H),8.41(t,J=7.8Hz,1H),8.23(d,J=7.6Hz,1H),8.11(s, 1H), 8.03 (d, J = 7.4Hz, 2H), 7.87 (s, 1H), 7.71 (s, 1H), 7.51 (t, J = 7.5Hz, 2H), 7.42 (t, J = 7.3Hz, 1H). LC-MS (ESI): m / z 376[M+H] + .

[0571] Preparation Example 53. Synthesis of Compound A53

[0572] Step A: 2-Amino-5-phenylfuran-3-carbonitrile

[0573] To a solution of 2-bromo-1-phenylethanol-1-one (2.0 g, 10.0 mmol, 1.0 equivalent) in N,N-dimethylformamide (30.0 mL) at room temperature were added dicyanomethane (0.66 g, 10.0 mmol, 1.0 equivalent) and diethylamine (2.2 g, 30.1 mmol, 3.0 equivalent). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After the reaction was complete, water (100 mL) was added and stirring was continued for 20 minutes. The mixture was filtered, the filter cake was washed twice with water, and dried completely to obtain the crude title compound (yellow solid, 1.0 g, 54% yield), which was used directly in the next step without purification.

[0574] Step B: N-(3-cyano-5-phenylfuran-2-yl)-6-(trifluoromethyl)picolinamide

[0575] To a solution of 2-amino-5-phenylfuran-3-carbonitrile (1.0 g, 5.4 mmol, 1.0 equiv) and DIEA (2.1 g, 16.3 mmol, 3.0 equiv) in dichloromethane (10.0 mL) was added dropwise 6-(trifluoromethyl)pyridine-2-carbonyl chloride (1.7 g, 8.1 mmol, 1.5 equiv) at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 0.5 hours. After completion of the reaction, the mixture was diluted with dichloromethane, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 500.0 mg, 26% yield).

[0576] Step C: N-(3-amino-5-phenylfuran-2-yl)-6-(trifluoromethyl)picolinamide

[0577] Phosphoric acid (20.0 mL) was added to N-(3-cyano-5-phenylfuran-2-yl)-6-(trifluoromethyl)picolinamide (500.0 mg, 1.4 mmol, 1.0 equivalent). The reaction mixture was stirred at 100°C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted three times with dichloromethane. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (yellow solid, 31.5 mg, 6% yield). 1 H NMR(400 MHz, DMSO-d6) δ12.45(s,1H),8.50-8.38(m,2H),8.24(d,J=7.5Hz,1H),7.85(s,1H),7.65(d,J=7. 5Hz,2H),7.56(s,1H),7.49(t,J=7.8Hz,2H),7.40(s,1H),7.34(t,J=7.4Hz,1H).LC-MS(ESI):m / z 376[M+H] + .

[0578] Preparation Example 54. Synthesis of Compound A54

[0579] Step A: Benzyl Benzamidothiocarbate

[0580] To a stirred solution of benzoylthioic acid (500 mg, 3.6 mmol, 1.0 equiv) in chloroform (2 mL) was slowly added a solution of bromomethylbenzene (0.44 mL, 3.6 mmol, 1.0 equiv) in chloroform (3 mL) at room temperature. The reaction mixture was stirred at reflux for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was diluted with ether until a solid precipitated. The filter cake was filtered, washed with cold ether, and dried completely to afford the title compound as a white solid (600 mg, 53% yield).

[0581] Step B: 4-Amino-2-phenyl-1H-imidazole-5-carbonitrile

[0582] To a solution of benzyl benzamidothiocarboxylate (500 mg, 2.2 mmol, 1.0 equiv) in chloroform (5 mL) was added 2-aminomalononitrile (535 mg, 6.6 mmol, 3.0 equiv) and pyridine (0.54 mL, 6.6 mmol, 3.0 equiv) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution and extracted three times with dichloromethane. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 320 mg, 78% yield).

[0583] Step C: N-(4-cyano-2-phenyl-1H-imidazol-5-yl)-6-(trifluoromethyl)picolinamide

[0584] To a solution of 4-amino-2-phenyl-1H-imidazole-5-carbonitrile (320 mg, 1.7 mmol, 1.0 equiv) in dichloromethane (5 mL) were added 6-(trifluoromethyl)pyridine-2-carboxylic acid (498.0 mg, 2.6 mmol, 1.5 equiv), HATU (990.9 mg, 2.6 mmol, 1.5 equiv), and DIEA (673.52 mg, 5.211 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, the reaction solution was diluted with saturated aqueous ammonium chloride and extracted three times with dichloromethane. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 200 mg, 32% yield).

[0585] Step D: N-(4-amino-2-phenyl-1H-imidazol-5-yl)-6-(trifluoromethyl)picolinamide

[0586] To a solution of N-(4-cyano-2-phenyl-1H-imidazol-5-yl)-6-(trifluoromethyl)picolinamide (200 mg, 0.56 mmol, 1.0 equivalent) in acetic acid (10 mL) was added concentrated sulfuric acid (2 mL) at room temperature. The reaction mixture was stirred at 40°C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted three times with dichloromethane. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to yield the title compound (yellow solid, 77 mg, 36% yield). 1 H NMR (400MHz, DMSO-d6) δ12.85(brs,1H),12.06(brs,1H),8.48(d,J=7.7Hz,1H),8.42(t,J=7 .7Hz,1H),8.24(d,J=7.6Hz,1H),8.08(d,J=6.4Hz,2H),7.63-7.27(m,5H).LC-MS(ESI):m / z 376[M+H] + .

[0587] Preparation Example 55. Synthesis of Compound A55

[0588] Step A: Ethyl 4-hydroxy-2-phenylthiazole-5-carboxylate

[0589] To a solution of benzylsulfamide (1 g, 7.29 mmol, 1.0 equiv) in ethanol (20 mL) was added ethyl 2-bromo-3-ethoxy-3-oxopropanoate (1.92 g, 8.02 mmol, 1.1 equiv) at room temperature. The reaction mixture was stirred at 80°C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (yellow solid, 1.6 g, 88% yield).

[0590] Step B: Ethyl 2-phenyl-4-(((trifluoromethyl)sulfonyl)oxy)thiazole-5-carboxylate

[0591] To a solution of ethyl 4-hydroxy-2-phenylthiazole-5-carboxylate (1.6 g, 6.42 mmol, 1.0 equiv) and triethylamine (1.80 mL, 12.84 mmol, 2.0 equiv) in dichloromethane (20 mL) was slowly added trifluoromethanesulfonic anhydride (2.17 g, 7.70 mmol, 1.2 equiv) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution and extracted three times with dichloromethane. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the title compound (white solid, 1.3 g, 53% yield).

[0592] Step C: Ethyl 4-((tert-Butyloxycarbonyl)amino)-2-phenylthiazole-5-carboxylate

[0593] To a solution of ethyl 2-phenyl-4-(((trifluoromethyl)sulfonyl)oxy)thiazole-5-carboxylate (1.3 g, 3.409 mmol, 1.0 equiv) and tert-butyl carbamate (0.80 g, 6.82 mmol, 2.0 equiv) in 1,4-dioxane (20 mL) at room temperature were added Pd(dba) (0.31 g, 0.34 mmol, 0.1 equiv), XantPhos (0.30 g, 0.51 mmol, 0.15 equiv), and cesium carbonate (4.44 g, 13.64 mmol, 4.0 equiv). The reaction mixture was stirred at 80°C under nitrogen for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, added with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (yellow solid, 1 g, 84% yield).

[0594] Step D: 4-((tert-Butyloxycarbonyl)amino)-2-phenylthiazole-5-carboxylic acid

[0595] To a mixed solution of ethyl 4-((tert-butoxycarbonyl)amino)-2-phenylthiazole-5-carboxylate (0.8 g, 2.30 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) and water (5 mL) at 0°C was added lithium hydroxide (0.19 g, 4.59 mmol, 2.0 equiv). The reaction solution was stirred at room temperature under nitrogen for 2 hours. After the reaction was complete, the reaction solution was adjusted to pH 4 with a diluted 4N HCl solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (white solid, 600 mg, crude product), which was used directly in the next step without purification.

[0596] Step E: tert-Butyl (5-carbamoyl-2-phenylthiazol-4-yl)carbamate

[0597] To a solution of 4-((tert-Butyloxycarbonyl)amino)-2-phenylthiazole-5-carboxylic acid (400 mg, 1.25 mmol, 1.0 equiv) and ammonium chloride (334 mg, 6.24 mmol, 5.0 equiv) in dichloromethane (8 mL) was added HATU (569.7 mg, 1.50 mmol, 1.2 equiv) and DIEA (484.1 mg, 3.75 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound as a white solid (230 mg, 58% yield).

[0598] Step F: tert-Butyl (5-cyano-2-phenylthiazol-4-yl)carbamate

[0599] To a solution of tert-butyl (5-carbamoyl-2-phenylthiazol-4-yl)carbamate (160 mg, 0.50 mmol, 1.0 equiv) and triethylamine (0.20 mL, 1.50 mmol, 3.0 equiv) in dichloromethane (5 mL) was slowly added trifluoroacetic anhydride (157.8 mg, 0.75 mmol, 1.5 equiv) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with water and extracted three times with dichloromethane. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the title compound (white solid, 100 mg, 66% yield).

[0600] Step G: 4-amino-2-phenylthiazole-5-carbonitrile

[0601] To tert-butyl (5-cyano-2-phenylthiazol-4-yl)carbamate (100 mg, 0.33 mmol, 1.0 equiv) was added a 4M HCl 1,4-dioxane solution (1 mL, 4 mmol, 12 equiv) at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was concentrated under reduced pressure to afford the crude title compound (white solid, 60 mg, crude product), which was used directly in the next step without purification.

[0602] Step H: 2-phenyl-4-(6-(trifluoromethyl)picolinamido)thiazole-5-carboxamide and 4-amino-2-phenyl-N-(6-(trifluoromethyl)picolinamido)thiazole-5-carboxamide

[0603] To a solution of 4-amino-2-phenylthiazole-5-carbonitrile (60 mg, 0.30 mmol, 1.0 equiv) in tetrahydrofuran (3 mL) at 0°C under nitrogen was added 60 wt% sodium hydride (21.46 mg, 0.89 mmol, 3.0 equiv) in portions. The reaction mixture was stirred at room temperature for 0.5 hours. 6-(trifluoromethyl)picolinoyl chloride (75 mg, 0.36 mmol, 1.2 equiv) was then added to the reaction mixture. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to yield 2-phenyl-4-(6-(trifluoromethyl)picolinamido)thiazole-5-carboxamide (yellow solid, 15.3 mg, 13% yield). 1 H NMR (400MHz, DMSO-d6): δ10.69 (s, 1H), 8.42-8.36 (m, 2H), 8.24 (dd, J = 6.4, 2. 4Hz,1H),7.97-7.94(m,2H),7.64(s,2H),7.60-7.53(m,3H).LC-MS(ESI):m / z 393[M+H] + .; 4-amino-2-phenyl-N-(6-(trifluoromethyl)pyridinoyl)thiazole-5-carboxamide (white solid, 2.7 mg, yield 2%). 1 H NMR (400MHz, DMSO-d6): δ12.74(s,1H),8.46(d,J=7.6Hz,1H),8.40(t,J=7.7Hz,1H),8.2 2(d,J=7.7Hz,1H),8.03-7.99(m,2H),7.92(brs,2H),7.60-7.57(m,3H).LC-MS(ESI):m / z 393[M+H] + .

[0604] Preparation Example 56. Synthesis of Compound A56

[0605] Step A: 5-amino-2-phenylthiazole-4-carboxamide

[0606] To a mixed solution of 2-amino-2-cyanoacetamide (1.0 g, 10.1 mmol, 1.0 equiv) in toluene (20 mL) and N-methylpyrrolidone (20 mL) at room temperature were added benzaldehyde (1.0 mL, 10.1 mmol, 1.0 equiv), cyclooctylsulfane (520.0 mg, 2.0 mmol, 0.2 equiv), and 1-methylimidazole (830.0 mg, 10.1 mmol, 1.0 equiv). The reaction mixture was stirred at 80°C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (white solid, 450 mg, 20% yield).

[0607] Step B: 2-phenyl-5-(6-(trifluoromethyl)picolinamido)thiazole-4-carboxamide

[0608] To a solution of 6-(trifluoromethyl)pyridine-2-carboxylic acid (217.9 mg, 1.14 mmol, 1.0 equiv) in dichloromethane (10 mL) at room temperature were added HATU (433.5 mg, 1.14 mmol, 1.0 equiv) and DIEA (294.7 mg, 2.3 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 0.5 hours. 5-Amino-2-phenylthiazole-4-carboxamide (250.0 mg, 1.14 mmol, 1.0 equiv) was then added to the reaction mixture, and the reaction mixture was stirred at 40°C for 12 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 70 mg, 16% yield). 1 H NMR (400MHz, DMSO-d6) δ13.42 (s, 1H), 8.50-8.41 (m, 2H), 8.26 (d, J = 7.6Hz, 1H) ,8.05(dd,J=7.8,1.3Hz,3H),7.96(s,1H),7.56-7.50(m,3H).LC-MS(ESI):m / z 393[M+H] + .

[0609] Preparation Example 57. Synthesis of Compound A57

[0610] Step A: 2-Nitro-1-phenylethanol-1-one oxime

[0611] To a mixed solution of styrene (5.549 mL, 48.008 mmol, 1.0 equivalent) in dimethyl sulfoxide (100 mL) and water (50 mL) was added tert-butyl nitrite (9.90 g, 96.015 mmol, 2.0 equivalent) at room temperature. The reaction solution was stirred at room temperature under nitrogen for 12 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (yellow oil, 7.0 g, 81% yield).

[0612] Step B: Methyl 2-(((2-nitro-1-phenylethylidene)amino)oxy)-2-oxoacetate

[0613] To a solution of 2-nitro-1-phenylethanol-1-one oxime (3.0 g, 16.6 mmol, 1.0 equivalent) in diethyl ether (100 mL) was added methyl 2-chloro-2-oxoacetate (2.04 g, 16.6 mmol, 1.0 equivalent) at room temperature. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow oil, 4.0 g, 90% yield).

[0614] Step C: Methyl 4-nitro-3-phenylisoxazole-5-carboxylate

[0615] To a solution of methyl 2-(((2-nitro-1-phenylethylidene)amino)oxy)-2-oxoacetate (4.0 g, 15.0 mmol, 1.0 equiv) in dichloromethane (60 mL) was added triethylamine (2.1 mL, 15.0 mmol, 1.0 equiv) at room temperature. The reaction mixture was stirred at 40°C for 48 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with dichloromethane, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow solid, 1.0 g, 27% yield).

[0616] Step D: Methyl 4-nitro-2-phenyloxazole-5-carboxylate

[0617] To a solution of methyl 4-nitro-3-phenylisoxazole-5-carboxylate (50 mg, 0.201 mmol, 1.0 equivalent) in xylene (5 mL) was added anhydrous FeCl3-SiO2 reagent (2 mg, 0.201 mmol, 1.0 equivalent) at room temperature. The reaction mixture was stirred at 155°C in a sealed tube and the reaction was complete. After the reaction was complete, the mixture was cooled to room temperature, diluted with dichloromethane, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow solid, 30 mg, 60% yield).

[0618] Step E: Methyl 4-amino-2-phenyloxazole-5-carboxylate

[0619] To a solution of methyl 4-nitro-2-phenyloxazole-5-carboxylate (300 mg, 1.21 mmol, 1.0 equiv) in methanol (10 mL) and water (2 mL) at room temperature were added iron powder (337 mg, 6.04 mmol, 5.0 equiv) and ammonium chloride (323 mg, 6.04 mmol, 5.0 equiv). The reaction mixture was stirred at 80°C for 2 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound as a white solid (180 mg, 68% yield).

[0620] Step F: Methyl 2-phenyl-4-(6-(trifluoromethyl)picolinamido)oxazole-5-carboxylate

[0621] To a solution of methyl 4-amino-2-phenyloxazole-5-carboxylate (170 mg, 0.779 mmol, 1.0 equiv) in acetonitrile (15 mL) at room temperature were added 6-(trifluoromethyl)picolinic acid (1.49 g, 7.79 mmol, 10 equiv) and N-methylimidazole (1.28 g, 15.6 mmol, 20 equiv). The reaction mixture was stirred at 80°C for 5 minutes. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (2.19 g, 7.79 mmol, 10 equiv) was then added to the reaction mixture. The reaction mixture was stirred at 80°C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into ice water, and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (white solid, 200 mg, 46% yield).

[0622] Step G: 2-phenyl-4-(6-(trifluoromethyl)picolinamido)oxazole-5-carboxamide

[0623] To methyl 2-phenyl-4-(6-(trifluoromethyl)picolinamido)oxazole-5-carboxylate (150 mg, 0.383 mmol, 1.0 equivalent) was added a 2N amine methanol solution (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (white solid, 15.7 mg, 11% yield). 1 HNMR (400MHz, CDCl3) δ11.46(s,1H),8.53(d,J=7.8Hz,1H),8.20(d,J=6.7Hz,2H),8.14( t,J=7.8Hz,1H),7.91(d,J=7.8Hz,1H),7.58-7.47(m,3H),5.97(s,2H).LC-MS(ESI):m / z 377[M+H] + .

[0624] Preparation Example 58. Synthesis of Compound A58

[0625] Step A: 5-amino-2-phenyloxazole-4-carbonitrile

[0626] Benzoyl chloride (1.22 g, 8.686 mmol, 1.1 equiv) was added to a solution of aminomalononitrile p-toluenesulfonate (2 g, 7.896 mmol, 1.0 equiv) in N-methylpyrrolidone (20 mL) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. After completion, the reaction was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 1 g, 68% yield).

[0627] Step B: N-(4-cyano-2-phenyloxazol-5-yl)-6-(trifluoromethyl)picolinamide

[0628] To a solution of 5-amino-2-phenyloxazole-4-carbonitrile (300 mg, 1.620 mmol, 1.0 equivalent) in tetrahydrofuran (5 mL) at 0°C under nitrogen protection was added 60% by weight sodium hydride (129.60 mg, 3.240 mmol, 2.0 equivalent) in portions. The reaction mixture was stirred at room temperature for 0.5 hours. 6-(trifluoromethyl)picolinyl chloride (373.41 mg, 1.782 mmol, 1.1 equivalent) was further added to the above reaction solution. The reaction mixture was stirred at room temperature under nitrogen protection for 2 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow solid, 100 mg, 17% yield).

[0629] Step C: 2-phenyl-5-(6-(trifluoromethyl)picolinamido)oxazole-4-carboxamide

[0630] To N-(4-cyano-2-phenyloxazol-5-yl)-6-(trifluoromethyl)picolinamide (100 mg, 0.279 mmol, 1.0 equivalent) was added acetic acid (4 mL) and concentrated sulfuric acid (2 mL) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was diluted with ice water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (yellow solid, 47.9 mg, 45% yield). 1 H NMR (400MHz, DMSO-d6): δ11.90(s,1H),8.45(dt,J=15.4,7.7Hz,2H),8.27(d,J=7.4H z,1H),8.06-7.97(m,2H),7.76(d,J=38.6Hz,2H),7.63-7.55(m,3H).LC-MS(ESI):m / z 377[M+H] + .

[0631] Preparation Example 59. Synthesis of Compound A59

[0632] Step A: 4-Bromo-3-nitro-1-phenyl-1H-pyrazole

[0633] To a solution of 4-bromo-3-nitro-1H-pyrazole (1.5 g, 7.8 mmol, 1.0 equiv) in tetrahydrofuran (50 mL) at room temperature were added phenylboronic acid (1.05 g, 8.6 mmol, 1.1 equiv), copper acetate (2.34 g, 11.7 mmol, 1.5 equiv), and pyridine (3.2 mL, 39.1 mmol, 5.0 equiv). The reaction mixture was stirred at 40°C under oxygen protection for 18 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate diluted with water, and extracted three times with ethyl acetate. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 800 mg, 38% yield).

[0634] Step B: 4-(Benzylthio)-3-nitro-1-phenyl-1H-pyrazole

[0635] To a solution of 4-bromo-3-nitro-1-phenyl-1H-pyrazole (500 mg, 1.9 mmol, 1.0 equiv) and benzyl mercaptan (278.0 mg, 2.2 mmol, 1.2 equiv) in 1,4-dioxane (10 mL) were added diisopropylethylamine (482.2 mg, 3.8 mmol, 2.0 equiv), 4,5-diphenylphosphine-9,9-dimethylxanthene (215.8 mg, 0.4 mmol, 0.2 equiv), and tris(dibenzylideneacetone)dipalladium (170.8 mg, 0.20 mmol, 0.1 equiv). The reaction mixture was purged with nitrogen three times and stirred at 100°C under nitrogen for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow solid, 350 mg, 60% yield).

[0636] Step C: 3-Nitro-1-phenylpyrazole-4-sulfonyl chloride

[0637] To a solution of 4-(benzylthio)-3-nitro-1-phenyl-1H-pyrazole (350 mg, 1.125 mmol, 1.0 equiv) in dichloromethane (5 mL) at 0°C was added N-chlorosuccinimide (375.3 mg, 2.8 mmol, 2.5 equiv). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (yellow solid, 210 mg, 65% yield).

[0638] Step D: 3-Nitro-1-phenylpyrazole-4-sulfonamide

[0639] To a solution of 3-nitro-1-phenylpyrazole-4-sulfonyl chloride (210 mg, 0.73 mmol, 1.0 equivalent) in dichloromethane (5 mL) was added a 7 M solution of ammonia in methanol (0.3 mL) at 0°C. The reaction was stirred at 30°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to afford the crude title compound (yellow solid, 195 mg, 99% yield), which was used in the next step without purification.

[0640] Step E: tert-Butyl (3-nitro-1-phenyl-1H-pyrazol-4-yl)sulfonyl)carbamate

[0641] To a solution of 3-nitro-1-phenylpyrazole-4-sulfonamide (100 mg, 0.37 mmol, 1.0 equivalent) in tetrahydrofuran (3 mL) at 0°C under nitrogen protection was added 60% by weight sodium hydride (29.9 mg, 0.75 mmol, 2.0 equivalents) in portions. The reaction mixture was stirred at room temperature for 0.5 hours. Di-tert-butyl dicarbonate (122.0 mg, 0.56 mmol, 1.5 equivalents) was further added to the above reaction solution. The reaction mixture was stirred at 50°C under nitrogen protection for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with saturated ammonium chloride solution, and extracted three times with ethyl acetate. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (yellow liquid, 90 mg, 65% yield).

[0642] Step F: tert-Butyl (3-amino-1-phenyl-1H-pyrazol-4-yl)sulfonyl)carbamate

[0643] To a solution of tert-butyl (3-nitro-1-phenyl-1H-pyrazol-4-yl)sulfonyl)carbamate (90.0 mg, 0.25 mmol, 1.0 equiv) in ethanol (5 mL) at room temperature were added zinc powder (159.74 mg, 2.5 mmol, 10 equiv) and ammonium chloride (26.14 mg, 0.5 mmol, 2.0 equiv). The reaction mixture was stirred at 80°C for 3 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the crude title compound (colorless liquid, 70 mg, 84% yield), which was used directly in the next step without purification.

[0644] Step G: tert-Butyl (1-phenyl-3-(6-(trifluoromethyl)picolinamido)-1H-pyrazol-4-yl)sulfonyl)carbamate

[0645] To a solution of 6-(trifluoromethyl)pyridine-2-carboxylic acid (47.44 mg, 0.25 mmol, 1.2 equiv) in dichloromethane (5 mL) at room temperature were added HATU (118.0 mg, 0.31 mmol, 1.5 equiv) and DIEA (80.2 mg, 0.6 mmol, 2.4 equiv). The reaction mixture was stirred at room temperature for 0.5 h. Tert-butyl (3-amino-1-phenyl-1H-pyrazol-4-yl)sulfonyl)carbamate (70 mg, 0.21 mmol, 1.0 equiv) was added to the reaction mixture, and the reaction mixture was stirred at 40°C for 12 h. After the reaction was complete, the reaction mixture was diluted with dichloromethane, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 60 mg, 57% yield).

[0646] Step H: N-(1-phenyl-4-sulfamoyl-1H-pyrazol-3-yl)-6-(trifluoromethyl)picolinamide

[0647] To a solution of tert-butyl (1-phenyl-3-(6-(trifluoromethyl)picolinamido)-1H-pyrazol-4-yl)sulfonyl)carbamate (60 mg, 0.117 mmol, 1.0 equiv) in 1,4-dioxane (1 mL) was added 4M HCl in 1,4-dioxane (1 mL) at 0°C. The reaction mixture was stirred at 30°C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by HPLC to afford the title compound (white solid, 35 mg, 72% yield). 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.98(s,1H),8.52-8.32(m,2H),8.24(d,J=6.6Hz ,1H),7.92(d,J=7.8Hz,2H),7.56(t,J=7.9Hz,2H),7.48-7.30(m,3H).LC-MS(ESI):m / z 412[M+H] + .

[0648] Preparation Example 60. Synthesis of Compound A60

[0649] Step A: 4-(Methylthio)-3-nitro-1-phenyl-1H-pyrazole

[0650] To a solution of 4-bromo-3-nitro-1-phenylpyrazole (850.0 mg, 3.2 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) was added carbamoylthiocarbamate (857.5 mg, 9.6 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 100°C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (yellow solid, 420 mg, 56% yield).

[0651] Step B: Methyl(3-nitro-1-phenylpyrazol-4-yl)(oxo)-λ 6 sulfonamide

[0652] To a solution of 4-(methylthio)-3-nitro-1-phenyl-1H-pyrazole (200.0 mg, 0.85 mmol, 1.0 equiv) in methanol (5 mL) were added iodophenyl diacetic acid (551.1 mg, 1.7 mmol, 2.0 equiv) and acetamide (131.1 mg, 1.7 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, poured into ice water, and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (yellow solid, 96.0 mg, 42% yield).

[0653] Step C: (3-nitro-1-phenyl-1H-pyrazol-4-yl)(oxo)-λ 6 -sulfinyl)carbamic acid tert-butyl ester

[0654] Under nitrogen protection at 0 ° C, methyl (3-nitro-1-phenylpyrazol-4-yl) (oxo)-λ 6 To a solution of sulfanilamide (90.0 mg, 0.34 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added 60 wt% sodium hydride (40.6 mg, 1.0 mmol, 3.0 equiv) in portions. The reaction mixture was stirred at room temperature for 0.5 hours. Di-tert-butyl dicarbonate (147.5 mg, 0.68 mmol, 2.0 equiv) was further added to the above reaction solution. The reaction mixture was stirred at 50°C under nitrogen for 2 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow solid, 95 mg, 76% yield).

[0655] Step D: (3-amino-1-phenyl-1H-pyrazol-4-yl)(methyl)(oxo)-λ 6 -sulfinyl)carbamic acid tert-butyl ester

[0656] At room temperature, to (3-nitro-1-phenyl-1H-pyrazol-4-yl)(oxo)-λ 6 To a solution of tert-butyl (1,4-dimethyl-1,4-thiazolyl)carbamate (95.0 mg, 0.26 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) and water (5 mL) were added zinc powder (169.3 mg, 2.6 mmol, 10.0 equiv) and ammonium chloride (13.8 mg, 0.26 mmol, 1.0 equiv). The reaction mixture was stirred at 80°C for 3 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the crude title compound (yellow solid, 70 mg, crude product), which was used directly in the next step without purification.

[0657] Step D: (Methyl(oxo)(1-phenyl-3-(6-(trifluoromethyl)picolinamido)-1H-pyrazol-4-yl)-λ 6 -sulfinyl)carbamic acid tert-butyl ester

[0658] Under nitrogen protection at 0 ° C, (3-amino-1-phenyl-1H-pyrazol-4-yl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (1-(trifluoromethyl)pyridine-2-carbonyl)carbamate (70.0 mg, 0.21 mmol, 1.0 equiv) in tetrahydrofuran (3 mL) was added 60 wt% sodium hydride (15.0 mg, 0.63 mmol, 3.0 equiv) in portions. The reaction mixture was stirred at room temperature for 0.5 hours. 6-(trifluoromethyl)pyridine-2-carbonyl chloride (52.3 mg, 0.25 mmol, 1.2 equiv) was further added to the above reaction solution. The reaction mixture was stirred at 30°C under nitrogen protection for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate three times. The mixed organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow solid, 105 mg, 99% yield).

[0659] Step F: N-(4-(S-methylsulfonylimino)-1-phenyl-1H-pyrazol-3-yl)-6-(trifluoromethyl)picolinamide

[0660] At 0 ° C, to (methyl (oxo) (1-phenyl-3- (6- (trifluoromethyl) picolinamido) -1H-pyrazol-4-yl) -λ 6To a solution of tert-butyl (1-(2-(2-(4-thiazolyl)sulfinyl)carbamate (105.0 mg, 0.098 mmol)) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (1 mL). The reaction mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (off-white solid, 46.0 mg, 55% yield). 1 H NMR (400MHz, DMSO-d6) δ11.69(s,1H),9.13(s,1H),8.47-8.36(m,2H),8.22(dd,J=7.5,1.2Hz, 1H),7.93(dd,J=8.6,0.9Hz,2H),7.57(m,2H),7.40(t,J=7.4Hz,1H),4.76(s,1H),3.29(s,3H). LC-MS(ESI):m / z 410[M+H] + .

[0661] Preparation Example 61. Synthesis of Compound A61

[0662] Step A: Ethyl 3-amino-1-phenyl-1H-pyrazole-4-carboxylate

[0663] To a solution of ethyl (2Z)-2-cyano-3-ethoxyprop-2-enoate (6.26 g, 36.98 mmol, 1.0 equiv) and phenylhydrazine (4 g, 36.98 mmol, 1.0 equiv) in ethanol (20 mL) was added sodium ethoxide (5.04 g, 73.97 mmol, 2.0 equiv) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was quenched with 4N HCl solution, diluted with water, and extracted three times with ethyl acetate. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (yellow solid, 700 mg, 8% yield).

[0664] Step B: Ethyl 1-phenyl-3-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-4-carboxylate

[0665] To a solution of ethyl 3-amino-1-phenyl-1H-pyrazole-4-carboxylate (100 mg, 0.43 mmol, 1.0 equiv) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (123.9 mg, 0.65 mmol, 1.5 equiv) in tetrahydrofuran (5 mL) was added 50 wt% T3P ethyl acetate solution (550.4 mg, 0.87 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 50°C for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound as a white solid (30 mg, 17% yield).

[0666] Step C: N-(4-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazol-3-yl)-6-(trifluoromethyl)picolinamide

[0667] To a solution of ethyl 1-phenyl-3-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-4-carboxylate (30 mg, 0.07 mmol, 1.0 equivalent) in tetrahydrofuran (5 mL) was slowly added 3 M methylmagnesium bromide in ether (0.1 mL, 0.30 mmol, 4.0 equivalent) at 0°C under nitrogen protection. The reaction solution was stirred at room temperature under nitrogen protection for 3 hours. After the reaction was complete, the product was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The mixed organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (white solid, 20.5 mg, 71% yield). 1 H NMR (400MHz, CD3OD) δ8.49(d,J=7.6Hz,1H),8.31(t,J=7.6Hz,1H),8.13(s,1H),8.06(d,J=7.6Hz,1H),7. 82(d,J=8.0Hz,2H),7.47(t,J=8.0Hz,2H),7.29(t,J=7.2Hz,1H),1.63(s,6H).LC / MS(ESI)m / z:391[M+H] + .

[0668] Preparation Example 62. Synthesis of Compound A62

[0669] Step A: 3-(Benzylthio)-4-nitro-1-phenyl-1H-pyrazole

[0670] To a solution of 3-bromo-4-nitro-1-phenylpyrazole (400 mg, 1.49 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) at 0°C under nitrogen was added 60 wt% sodium hydride (89.5 mg, 2.24 mmol, 1.5 equiv) in portions. The reaction mixture was stirred at room temperature for 0.5 hours. Benzyl mercaptan (204 mg, 1.64 mmol, 1.1 equiv) was then added to the reaction mixture. The reaction mixture was stirred at 70°C under nitrogen for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, quenched with saturated ammonium chloride solution, and extracted three times with ethyl acetate. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow liquid, 390 mg, 84% yield).

[0671] Step B: 3-(Benzylthio)-1-phenyl-1H-pyrazol-4-amine

[0672] To a solution of 3-(benzylthio)-4-nitro-1-phenyl-1H-pyrazole (390 mg, 1.253 mmol, 1.0 equiv) in methanol (10 mL) was added zinc powder (655 mg, 10.0 mmol, 8.0 equiv) and an aqueous solution of ammonium chloride (670 mg, 12.5 mmol, 10 equiv) (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (white solid, 240 mg, 68% yield).

[0673] Step C: N-(3-(Benzylthio)-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0674] To a solution of 6-(trifluoromethyl)pyridine-2-carboxylic acid (179 mg, 0.938 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) at room temperature were added HATU (422 mg, 1.11 mmol, 1.2 equiv) and DIEA (331 mg, 2.56 mmol, 2.7 equiv). The reaction mixture was stirred at room temperature for 0.5 hour. 3-(Benzylthio)-1-phenyl-1H-pyrazol-4-amine (240 mg, 0.853 mmol, 0.9 equiv) was then added to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 240 mg, 62% yield).

[0675] Step D: 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-sulfonyl chloride

[0676] To a mixed solution of N-(3-(benzylthio)-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide (240 mg, 0.528 mmol, 1.0 equiv) in acetonitrile (3 mL), water (1 mL), and acetic acid (3 mL) at 0°C was added N-chlorosuccinimide (564 mg, 4.22 mmol, 8.0 equiv). The reaction mixture was stirred at room temperature under nitrogen for 12 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 220 mg, 96% yield).

[0677] Step E: N-(1-phenyl-3-sulfamoyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0678] To a solution of 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-sulfonyl chloride (170 mg, 0.395 mmol, 1.0 equiv) in acetonitrile (3 mL) at 0°C was added 18% (w / w) aqueous ammonia (1 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into water and extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound as a white solid, 48 mg, 30% yield. 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),9.11(s,1H),8.48(d,J=7.7Hz,1H),8.42(t,J=7.8Hz,1H),8.24(d,J=7 .7Hz,1H),8.02(s,2H),7.92(d,J=8.2Hz,2H),7.59(t,J=7.9Hz,2H),7.45(t,J=7.4Hz,1H).LC-MS(ESI):m / z 412[M+H] + .

[0679] Preparation Example 63. Synthesis of Compound A63

[0680] Step A: 3-(Methylthio)-4-nitro-1-phenyl-1H-pyrazole

[0681] To a solution of 3-bromo-4-nitro-1-phenylpyrazole (500 mg, 1.87 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) was added sodium thiomethoxide (261 mg, 3.73 mmol, 2.0 equiv) in portions at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (yellow solid, 240 mg, 54% yield).

[0682] Step B: Imino(methyl)(4-nitro-1-phenyl-1H-pyrazol-3-yl)-λ 6 -Aminosulfone

[0683] To a solution of 3-(methylthio)-4-nitro-1-phenyl-1H-pyrazole (240 mg, 1.02 mmol, 1.0 equiv) in 1,4-dioxane (3 mL) and methanol (3 mL) was added iodobenzenediacetic acid (661 mg, 2.04 mmol, 2.0 equiv) and ammonium acetate (314 mg, 4.08 mmol, 4.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the product was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow solid, 160 mg, 59% yield).

[0684] Step C: (4-amino-1-phenyl-1H-pyrazol-3-yl)(imino)(methyl)-λ 6 -Aminosulfone

[0685] At room temperature, to imino(methyl)(4-nitro-1-phenyl-1H-pyrazol-3-yl)-λ 6 To a solution of -aminosulfonone (160 mg, 0.601 mmol, 1.0 equiv) in methanol (5 mL) were added zinc powder (314 mg, 4.81 mmol, 8.0 equiv) and an aqueous solution of ammonium chloride (321 mg, 6.01 mmol, 10.0 equiv) (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (white solid, 120 mg, 68% yield).

[0686] Step D: N-(3-(S-methylsulfonylimino)-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0687] To a solution of 6-(trifluoromethyl)pyridine-2-carboxylic acid (89.0 mg, 0.466 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) was added HATU (209 mg, 0.550 mmol, 1.2 equiv) and DIEA (164 mg, 1.27 mmol, 2.7 equiv) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. To the reaction mixture was added (4-amino-1-phenyl-1H-pyrazol-3-yl)(imino)(methyl)-λ 6 -Aminosulfone (100 mg, 0.423 mmol, 0.9 equivalents), the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The mixed organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to obtain the title compound (white solid, 23 mg, 13% yield). 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),9.12(s,1H),8.46(d,J=7.6Hz,1H),8.40(t,J=7.8Hz,1H),8.22(d,J=7.6Hz, 1H),7.95(d,J=8.0Hz,2H),7.58(t,J=7.9Hz,2H),7.45(t,J=7.4Hz,1H),5.22(s,1H),3.36(s,3H).LC-MS(ESI):m / z 410[M+H] + .

[0688] Preparation Example 64. Synthesis of Compound A64

[0689] Step A: 3-Bromo-1-phenyl-1H-pyrazol-4-amine

[0690] To a solution of 3-bromo-4-nitro-1-phenylpyrazole (200 mg, 0.746 mmol, 1.0 equiv) in methanol (8 mL) was added zinc powder (390 mg, 5.97 mmol, 8.0 equiv) and an aqueous solution of ammonium chloride (399 mg, 7.46 mmol, 10.0 equiv) (4 mL) at room temperature. The reaction mixture was stirred at 70°C for 1 hour. After completion, the reaction was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound as a white solid (125 mg, 70% yield).

[0691] Step B: N-(3-Bromo-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0692] To a solution of 6-(trifluoromethyl)pyridine-2-carboxylic acid (125 mg, 0.525 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) at room temperature were added HATU (220 mg, 0.578 mmol, 1.1 equiv) and DIEA (204 mg, 1.58 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature for 0.5 hour. 3-Bromo-1-phenyl-1H-pyrazol-4-amine (125 mg, 0.525 mmol, 1.0 equiv) was then added to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 180 mg, 83% yield).

[0693] Step C: N-(3-cyano-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0694] To a solution of N-(3-bromo-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide (90 mg, 0.219 mmol, 1.0 equiv) in N,N-dimethylacetamide (10 mL) at room temperature were added zinc powder (85.9 mg, 1.31 mmol, 5.0 equiv), zinc cyanide (257 mg, 2.19 mmol, 10.0 equiv), and RuPhos-Pd-G3 (55 mg, 0.066 mmol, 0.3 equiv). The reaction mixture was stirred at 120°C under nitrogen for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, added with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (white solid, 19.4 mg, 25% yield). 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.93(s,1H),8.41(dt,J=15.5,7.8Hz,2H),8.23(d,J=7. 5Hz,1H),7.92(d,J=8.1Hz,2H),7.59(t,J=7.8Hz,2H),7.47(t,J=7.4Hz,1H).LC-MS(ESI):m / z 358[M+H] + .

[0695] Preparation Example 65. Synthesis of Compound A65

[0696] Step A: 4-Nitro-1-phenyl-3-vinyl-1H-pyrazole

[0697] To a solution of 3-bromo-4-nitro-1-phenyl-1H-pyrazole (2 g, 7.46 mmol, 1 eq) and potassium carbonate (3.1 g, 22.4 mmol, 3 eq) in 1,4-dioxane (10 mL) and water (3 mL) at room temperature were added Pd(dppf)Cl2 (545 mg, 0.746 mmol, 0.1 eq) and potassium trifluoro(vinyl)borate (2 g, 14.9 mmol, 2 eq). The reaction mixture was stirred at 90°C under nitrogen for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate. The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 1.5 g, 93% yield).

[0698] Step B: 3-(4-nitro-1-phenyl-1H-pyrazol-3-yl)cyclobutan-1-one

[0699] To a Schlenk tube containing N,N-dimethylacetamide (1.2 mL, 13.4 mmol, 1.2 equiv) and 1,2-dichloroethane (30 mL) was added trifluoromethanesulfonic anhydride (9.83 g, 34.85 mmol, 3.1 equiv) dropwise at room temperature. The mixture was stirred at room temperature for 10 minutes. A solution of 4-nitro-1-phenyl-3-vinyl-1H-pyrazole (2.4 g, 11.2 mmol, 1.0 equiv) and 2,6-lutidine (4.05 mL, 34.85 mmol, 3.1 equiv) in 1,2-dichloroethane (2 mL) was then added. The reaction mixture was stirred at 90°C under nitrogen for 8 hours. The reaction mixture was cooled to room temperature, water (40 mL) was added, and the reaction mixture was stirred at 90°C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow solid, 403 mg, 14% yield).

[0700] Step C: 3-(4-nitro-1-phenyl-1H-pyrazol-3-yl)cyclobutan-1-ol

[0701] To a solution of 3-(4-nitro-1-phenyl-1H-pyrazol-3-yl)cyclobutane-1-one (150 mg, 0.6 mmol, 1.0 equiv) in methanol (2 mL) was added sodium borohydride (44.1 mg, 1.2 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 25°C under nitrogen for 1 hour. After the reaction was complete, the reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (yellow solid, 120 mg, 79% yield).

[0702] Step D: 3-(4-amino-1-phenyl-1H-pyrazol-3-yl)cyclobutan-1-ol

[0703] Under nitrogen protection, 10% palladium on carbon (49.3 mg, 0.5 mmol, 1.0 equivalent) was added to a solution of 3-(4-nitro-1-phenyl-1H-pyrazol-3-yl)cyclobutane-1-ol (120 mg, 0.5 mmol, 1.0 equivalent) in methanol (2 mL) at room temperature. The reaction solution was replaced with hydrogen three times and stirred at 25°C under hydrogen protection for 1 hour. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude title compound (colorless oil, 100 mg, crude product), which was used directly in the next step without purification.

[0704] Step E: N-(3-(3-Hydroxycyclobutyl)-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0705] To a solution of 3-(4-amino-1-phenyl-1H-pyrazol-3-yl)cyclobutan-1-ol (100 mg, 0.4 mmol, 1.0 equiv) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (83.4 mg, 0.4 mmol, 1.0 equiv) in N,N-dimethylformamide (2 mL) at room temperature were added EDCI (125.4 mg, 0.6 mmol, 1.5 equiv), HOBt (88.4 mg, 0.6 mmol, 1.5 equiv), and triethylamine (0.2 mL, 1.3 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (white solid, 30 mg, 17% yield). 1H NMR(400MHz, DMSO-d6)δ9.95(s,1H),8.66(s,1H),8.42-8.33(m,2H),8.20(dd,J=6.8,1.9Hz,1H),7.85-7.78(m,2H),7.51(t,J=8.0Hz,2H) ,7.30(t,J=7.4Hz,1H),5.22(d,J=6.8Hz,1H),4.16-4.06(m,1H),3.10-3.02(m,1H),2.69-2.60(m,2H),2.20-2.09(m,2H).LC-MS(ESI):m / z 403[M+H] + .

[0706] Preparation Example 66. Synthesis of Compound A66

[0707] Step A: 3-Methyl-4-nitro-1-phenyl-1H-pyrazole

[0708] To a solution of 3-bromo-4-nitro-1-phenylpyrazole (500 mg, 1.865 mmol, 1.0 equiv) and methylboronic acid (167.47 mg, 2.798 mmol, 1.5 equiv) in 1,4-dioxane (5 mL) and water (1 mL) at room temperature were added potassium carbonate (773.31 mg, 5.596 mmol, 3.0 equiv) and Pd(dppf)Cl2 (136.48 mg, 0.187 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C under nitrogen for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 150 mg, 39% yield).

[0709] Step B: 3-Methyl-1-phenyl-1H-pyrazol-4-amine

[0710] To a solution of 3-methyl-4-nitro-1-phenyl-1H-pyrazole (150 mg, 0.738 mmol, 1.0 equivalent) in methanol (3 mL) was added 10% palladium on carbon (20 mg) at room temperature. The reaction solution was ventilated three times under a hydrogen balloon and stirred at room temperature for 2 hours under hydrogen. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (yellow solid, 80 mg, 62% yield), which was used directly in the next step without purification.

[0711] Step C: N-(3-methyl-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0712] To a solution of 3-methyl-1-phenyl-1H-pyrazol-4-amine (80 mg, 0.462 mmol, 1.0 equiv) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (132.39 mg, 0.693 mmol, 1.5 equiv) in tetrahydrofuran (3 mL) was added 50 wt% T3P ethyl acetate solution (440.85 mg, 1.386 mmol, 3.0 equiv) and DIEA (179.08 mg, 1.386 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 50°C for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (pink solid, 79.5 mg, 49% yield). 1 H NMR (400MHz, CD3OD) δ8.55(s,1H),8.45(d,J=8.0Hz,1H),8.30(t,J=8.0Hz,1H),8.06(d,J=8.0Hz, 1H),7.74-7.65(m,2H),7.48(t,J=8.0Hz,2H),7.31(d,J=7.2Hz,1H),2.39(s,3H).LC-MS(ESI):m / z 347[M+H] + .

[0713] Preparation Example 67. Synthesis of Compound A67

[0714] Step A: 3-Bromo-4-nitro-1H-pyrazole

[0715] To 3-bromo-1H-pyrazole (5 g, 34.2 mmol, 1.0 equiv) at 0°C was added concentrated sulfuric acid (10 mL), followed by the slow dropwise addition of concentrated nitric acid (2 mL). The reaction mixture was stirred at 0°C for 1 hour. Upon completion of the reaction, the mixture was poured into ice water, filtered, and the filter cake was dried to obtain the crude title compound (yellow solid, 3 g, 46% yield), which was used directly in the next step without purification.

[0716] Step B: 3-Bromo-4-nitro-1-phenyl-1H-pyrazole

[0717] To a solution of 3-bromo-4-nitro-1H-pyrazole (500 mg, 2.61 mmol, 1.0 equiv) in dichloromethane (10 mL) at room temperature were added phenylboronic acid (413 mg, 3.39 mmol, 1.30 equiv), copper acetate (260 mg, 1.302 mmol, 0.50 equiv), and pyridine (0.105 mL, 1.30 mmol, 0.50 equiv). The reaction mixture was stirred at room temperature under oxygen protection for 16 hours. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow solid, 400 mg, 57% yield).

[0718] Step C: 4-Nitro-1-phenyl-3-vinyl-1H-pyrazole

[0719] To a solution of 3-bromo-4-nitro-1-phenyl-1H-pyrazole (200 mg, 0.746 mmol, 1.0 equiv) and potassium vinyl trifluoroborate (85 mg, 0.97 mmol, 1.3 equiv) in 1,4-dioxane (4 mL) and water (1 mL) at room temperature were added potassium carbonate (309 mg, 2.24 mmol, 3.0 equiv) and Pd(dppf)Cl2 (55 mg, 0.075 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C under nitrogen for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 110 mg, 39% yield).

[0720] Step D: 3-Ethyl-1-phenyl-1H-pyrazol-4-amine

[0721] To a solution of 4-nitro-1-phenyl-3-vinyl-1H-pyrazole (110 mg, 0.511 mmol, 1.0 equivalent) in ethyl acetate (10 mL) was added 10% palladium on carbon (10 mg). The reaction solution was evacuated three times under a hydrogen balloon and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (yellow solid, 90 mg, 94% yield), which was used directly in the next step without purification.

[0722] Step E: N-(1-phenyl-3-propyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0723] To a solution of 3-ethyl-1-phenyl-1H-pyrazol-4-amine (90 mg, 0.481 mmol, 1.0 equiv) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (110 mg, 0.577 mmol, 1.5 equiv) in tetrahydrofuran (10 mL) was added a 50 wt% T3P solution in ethyl acetate (379 mg, 1.19 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 50°C for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound as a white solid (54 mg, 30% yield). 1HNMR (400MHz, CDCl3) δ9.68(s,1H),8.68(s,1H),8.48(d,J=7.8Hz,1H),8.14(s,1H),7.89(d,J=7.8Hz,1H),7.72(d,J= 8.0Hz,2H),7.44(t,J=7.9Hz,2H),7.26(d,J=4.4Hz,1H),2.85(q,J=7.6Hz,2H),1.43(t,J=7.6Hz,3H).LC-MS(ESI):m / z 361[M+H] + .

[0724] Preparation Example 68. Synthesis of Compound A68

[0725] Step A: (E)-4-Nitro-1-phenyl-3-(prop-1-en-1-yl)-1H-pyrazole

[0726] To a solution of 3-bromo-4-nitro-1-phenyl-1H-pyrazole (100 mg, 0.373 mmol, 1.0 equiv) and (E)-prop-1-en-1-ylboronic acid (48 mg, 0.559 mmol, 1.5 equiv) in 1,4-dioxane (4 mL) and water (1 mL) at room temperature were added potassium carbonate (103 mg, 0.746 mmol, 2.0 equiv) and Pd(dppf)Cl2 (27 mg, 0.037 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C under nitrogen for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, added with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (white solid, 70 mg, 82% yield).

[0727] Step B: 1-phenyl-3-propyl-1H-pyrazol-4-amine

[0728] To a solution of (E)-4-nitro-1-phenyl-3-(prop-1-en-1-yl)-1H-pyrazole (70 mg, 0.305 mmol, 1.0 equivalent) in methanol (5 mL) was added 10% palladium on carbon (10 mg) at room temperature. The reaction solution was evacuated three times under a hydrogen balloon and stirred at room temperature under hydrogen for 5 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford the crude title compound (brown oil, 50 mg, 81% yield), which was used directly in the next step without purification.

[0729] Step C: N-(1-phenyl-3-propyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0730] To a solution of 1-phenyl-3-propyl-1H-pyrazol-4-amine (50 mg, 0.248 mmol, 1.0 equiv) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (57 mg, 0.298 mmol, 1.20 equiv) in tetrahydrofuran (10 mL) was added a 50 wt% T3P ethyl acetate solution (379 mg, 0.745 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 50°C for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound as a white solid (26.4 mg, 28% yield). 1 H NMR (400MHz, CDCl3) δ9.73(s,1H),8.70(s,1H),8.47(d,J=7.8Hz,1H),8.15(t,J=7.8Hz,1H),7.89(d,J=7.8Hz,1H),7.72(d,J=7.7Hz,2H),7. 45(t,J=7.9Hz,2H),7.32-7.21(t,J=7.7Hz,1H),2.82(t,J=7.5Hz,2H),1.85(dd,J=14.9,7.4Hz,2H),1.09(t,J=7.4Hz,3H).LC-MS(ESI):m / z 375[M+H] + .

[0731] Preparation Example 69. Synthesis of Compound A69

[0732] Step A: 4-Nitro-1-phenyl-3-(prop-1-en-2-yl)-1H-pyrazole

[0733] To a solution of 3-bromo-4-nitro-1-phenyl-1H-pyrazole (200 mg, 0.746 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (163 mg, 0.97 mmol, 1.3 equiv) in 1,4-dioxane (4 mL) and water (1 mL) was added potassium carbonate (309 mg, 2.238 mmol, 3.0 equiv) and Pd(dppf)Cl2 (55 mg, 0.075 mmol, 0.1 equiv) at room temperature. The reaction mixture was stirred at 100°C under nitrogen for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, added with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 100 mg, 58% yield).

[0734] Step B: 3-Isopropyl-1-phenyl-1H-pyrazol-4-amine

[0735] To a solution of 4-nitro-1-phenyl-3-(prop-1-en-2-yl)-1H-pyrazole (100 mg, 0.436 mmol, 1.0 equivalent) in methanol (10 mL) was added 10% palladium on carbon (10 mg) at room temperature. The reaction solution was evacuated three times under a hydrogen balloon and stirred at room temperature for 2 hours under hydrogen. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (brown oil, 80 mg, 91% yield), which was used directly in the next step without purification.

[0736] Step C: N-(3-Isopropyl-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0737] To a solution of 3-isopropyl-1-phenyl-1H-pyrazol-4-amine (80 mg, 0.397 mmol, 1.0 equiv) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (91 mg, 0.477 mmol, 1.20 equiv) in tetrahydrofuran (10 mL) was added a 50 wt% T3P solution in ethyl acetate (379 mg, 1.192 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 50°C for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound as a white solid (26.4 mg, 28% yield). 1 H NMR (400MHz, CD3OD) δ8.59(s,1H),8.46(d,J=8.0Hz,1H),8.31(t,J=8.0Hz,1H),8.07(d,J=8.0Hz,1H),7.74(d,J=8 .4Hz,2H),7.48(t,J=8.0Hz,2H),7.30(t,J=7.6Hz,1H),3.23-3.16(m,1H),1.42(d,J=6.8Hz,6H).LC-MS(ESI):m / z 375[M+H] + .

[0738] Preparation Example 70. Synthesis of Compound A70

[0739] Step A: 3-(tert-Butyl)-4-nitro-1-phenyl-1H-pyrazole

[0740] To a solution of 3-(tert-butyl)-4-nitro-1H-pyrazole (160 mg, 0.946 mmol, 1.00 equiv) and phenylboronic acid (173 mg, 1.419 mmol, 1.50 equiv) in dichloromethane (4 mL) at room temperature were added copper acetate (94.41 mg, 0.473 mmol, 0.50 equiv) and pyridine (74.81 mg, 0.946 mmol, 1.00 equiv). The reaction mixture was stirred at 30°C under oxygen protection for 12 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate diluted with water, and extracted three times with dichloromethane. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (white solid, 200 mg, 86% yield).

[0741] Step B: 3-(tert-Butyl)-1-phenyl-1H-pyrazol-4-amine

[0742] To a solution of 3-(tert-butyl)-4-nitro-1-phenyl-1H-pyrazole (120 mg, 0.489 mmol, 1.00 equiv) in methanol (5 mL) was added 10% palladium on carbon (20 mg) at room temperature. The reaction solution was evacuated three times under a hydrogen balloon and stirred at room temperature for 1 hour under hydrogen. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (yellow solid, 100 mg, crude product), which was used directly in the next step without purification.

[0743] Step C: N-(3-(tert-Butyl)-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0744] To a solution of 3-(tert-butyl)-1-phenyl-1H-pyrazol-4-amine (100 mg, 0.464 mmol, 1.00 equiv) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (133.15 mg, 0.697 mmol, 1.50 equiv) in tetrahydrofuran (2 mL) was added 50 wt% T3P ethyl acetate solution (886.71 mg, 1.393 mmol, 3.00 equiv) at room temperature. The reaction mixture was stirred at 50°C for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by HPLC to afford the title compound as a white solid (106.4 mg, 59% yield). 1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.78(s,1H),8.47-8.34(m,2H), 8.23(dd,J=6.8,2.4Hz,1H),7.82(dd,J=8.4,1.2Hz,2H),7.54-7.45(m,2H),7.29(t,J=7.6Hz,1H),1.43(s,9H).LC-MS(ESI):m / z 389[M+H] + .

[0745] Preparation Example 71. Synthesis of Compound A71

[0746] Step A: 3-Cyclopropyl-4-nitro-1-phenyl-1H-pyrazole

[0747] To a solution of 3-bromo-4-nitro-1-phenyl-1H-pyrazole (200 mg, 0.746 mmol, 1.0 equiv) and cyclopropylboronic acid (128 mg, 1.492 mmol, 2.0 equiv) in 1,4-dioxane (4 mL) and water (1 mL) at room temperature were added potassium carbonate (309 mg, 2.238 mmol, 3.0 equiv) and Pd(dppf)Cl2 (55 mg, 0.075 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C under nitrogen for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (white solid, 100 mg, 58% yield).

[0748] Step B: 3-Cyclopropyl-1-phenyl-1H-pyrazol-4-amine

[0749] To a solution of 3-cyclopropyl-4-nitro-1-phenyl-1H-pyrazole (100 mg, 0.436 mmol, 1.0 equiv) in tetrahydrofuran (3 mL) and water (1 mL) at room temperature were added zinc powder (56 mg, 0.872 mmol, 2.0 equiv) and ammonium chloride (47 mg, 0.872 mmol, 2.0 equiv). The reaction mixture was stirred at 50°C for 2 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford the crude title compound (red oil, 80 mg, 92% yield), which was used directly in the next step without purification.

[0750] Step C: N-(3-cyclopropyl-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0751] To a solution of 3-cyclopropyl-1-phenyl-1H-pyrazol-4-amine (80 mg, 0.401 mmol, 1.0 equiv) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (92 mg, 0.481 mmol, 1.20 equiv) in tetrahydrofuran (10 mL) was added a 50 wt% T3P solution in ethyl acetate (383 mg, 1.203 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 50°C for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound as a white solid (40.1 mg, 27% yield). 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),8.67(s,1H),8.39(q,J=8.0Hz,2H),8.20(d,J=7.1Hz,1H),7.78(d,J=8.1Hz,2H),7.47(t,J=7.8 Hz,2H),7.27(t,J=7.3Hz,1H),2.01(td,J=8.4,4.2Hz,1H),0.94(dd,J=8.2,2.9Hz,2H),0.88(dd,J=9.0,6.2Hz,2H).LC-MS(ESI):m / z 373[M+H] + .

[0752] Preparation Example 72. Synthesis of Compound A72

[0753] Step A: 3-cyclobutyl-4-nitro-1H-pyrazole

[0754] To 3-cyclobutyl-1H-pyrazole (120 mg, 0.984 mmol, 1.0 equivalent) at 0°C was added concentrated sulfuric acid (2 mL), followed by the slow dropwise addition of concentrated nitric acid (1.5 mL). The reaction mixture was stirred at 0°C for 2 hours. Upon completion of the reaction, the mixture was poured into ice water and extracted three times with ethyl acetate. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography to afford the title compound (yellow oil, 120 mg, 73% yield).

[0755] Step B: 3-cyclobutyl-4-nitro-1-phenyl-1H-pyrazole

[0756] To a solution of 3-cyclobutyl-4-nitro-1H-pyrazole (120 mg, 0.732 mmol, 1.0 equiv) and phenylboronic acid (178.6 mg, 1.464 mmol, 2.0 equiv) in dichloromethane (3 mL) at room temperature were added copper acetate (73.1 mg, 0.366 mmol, 0.5 equiv) and pyridine (28 mg, 0.366 mmol, 0.5 equiv). The reaction mixture was stirred at room temperature under oxygen protection for 12 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was diluted with water, and extracted three times with dichloromethane. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (white solid, 130 mg, 74% yield).

[0757] Step C: 3-cyclobutyl-1-phenyl-1H-pyrazol-4-amine

[0758] To a solution of 3-cyclobutyl-4-nitro-1-phenyl-1H-pyrazole (130 mg, 0.534 mmol, 1.0 equiv) in tetrahydrofuran (3 mL) and water (1 mL) was added zinc powder (342 mg, 5.34 mmol, 10.0 equiv) and ammonium chloride (572 mg, 10.7 mmol, 20.0 equiv) at room temperature. The reaction mixture was stirred at 50°C for 3 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (red oil, 130 mg, crude product), which was used directly in the next step without purification.

[0759] Step D: N-(3-cyclobutyl-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0760] To a solution of 3-cyclobutyl-1-phenyl-1H-pyrazol-4-amine (130 mg, 0.610 mmol, 1.0 equiv) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (140 mg, 0.732 mmol, 1.2 equiv) in tetrahydrofuran (10 mL) was added 50 wt% T3P ethyl acetate solution (582 mg, 0.915 mmol, 1.5 equiv) at room temperature. The reaction mixture was stirred at 50°C for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound as a white solid (56.2 mg, 24% yield). 1H NMR (400MHz, DMSO-d6) δ9.93(s,1H),8.69(s,1H),8.42-8.34(m,2H),8.20(dd,J=6.8,2.0Hz,1H),7.83(d,J=7.7Hz,2H),7.49(t, J=8.0Hz,2H),7.28(t,J=7.4Hz,1H),3.77-3.67(m,1H),2.36(td,J=8.8,6.4Hz,4H),2.12-2.01(m,1H),1.97-1.86(m,1H).LC-MS (ESI):m / z 387[M+H] + .

[0761] Preparation Example 73. Synthesis of Compound A73

[0762] Step A: 4-Nitro-1-phenyl-1H-pyrazol-3-ol

[0763] Under nitrogen protection at room temperature, 68% concentrated nitric acid (0.5 mL, 3.12 mmol, 1.0 equivalent) was added to a solution of 1-phenylpyrazole-3-ol (500 mg, 3.12 mmol, 1.0 equivalent) and silica gel powder (1.00 g) in dichloromethane (10 mL). The reaction mixture was stirred at 40 ° C for 18 hours. After the reaction was completed, the filtrate was filtered, the filtrate was quenched with water, and extracted with dichloromethane three times. The organic phase was then mixed, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (yellow solid, 400 mg, 62% yield), which was used directly in the next step without purification.

[0764] Step B: 4-amino-1-phenyl-1H-pyrazol-3-ol

[0765] To a solution of 4-nitro-1-phenyl-1H-pyrazole-3-ol (400 mg, 1.95 mmol, 1.0 equivalent) in methanol (6 mL) and ethyl acetate (6 mL) was added 10% palladium on carbon (180 mg) at room temperature. The reaction solution was ventilated three times under a hydrogen balloon and stirred at room temperature for 6 hours under hydrogen. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (brown solid, 220 mg, 64% yield), which was used directly in the next step without purification.

[0766] Step C: N-(3-Hydroxy-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0767] To a solution of 4-amino-1-phenyl-1H-pyrazol-3-ol (220 mg, 1.26 mmol, 1.0 equiv) and triethylamine (0.698 mL, 5.02 mmol, 4.0 equiv) in dichloromethane (10 mL) was added 6-(trifluoromethyl)picolinyl chloride (289 mg, 1.38 mmol, 1.1 equiv) at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, the reaction solution was quenched with saturated sodium carbonate solution and extracted three times with dichloromethane. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and the residue was separated by column chromatography to yield the title compound (yellow solid, 69.4 mg, 16% yield). 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),9.91(s,1H),8.65(s,1H),8.43-8.36(m,2H),8.20(d,J=7 .3Hz,1H),7.71(d,J=8.4Hz,2H),7.45(t,J=7.9Hz,2H),7.20(t,J=7.3Hz,1H).LC-MS(ESI):m / z 349[M+H] + .

[0768] Preparation Example 74. Synthesis of Compound A74

[0769] Step A: 4-nitro-1-phenyl-1H-pyrazole-3-carboxylic acid methyl ester

[0770] To a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (10.0 g, 58.44 mmol, 1.0 equivalent), phenylboronic acid (14.3 g, 116.88 mmol, 2.0 equivalent), and copper acetate (15.9 g, 87.66 mmol, 1.5 equivalent) in dichloromethane (200 mL) was added pyridine (18.8 mL, 233.77 mmol, 4.0 equivalent) at room temperature. The reaction mixture was stirred at 40°C under oxygen protection for 18 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate diluted with water, and extracted three times with dichloromethane. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the title compound (yellow solid, 8.2 g, 57% yield).

[0771] Step B: 4-amino-1-phenyl-1H-pyrazole-3-carboxylic acid methyl ester

[0772] To a solution of methyl 4-nitro-1-phenyl-1H-pyrazole-3-carboxylate (6.0 g, 24.27 mmol, 1.0 equivalent) in methanol (120 mL) was added 10% palladium on carbon (2.6 g, 2.43 mmol, 0.1 equivalent) at room temperature. The reaction solution was evacuated three times under a hydrogen balloon and stirred at room temperature under hydrogen for 18 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (yellow oil, 5.3 g, 100% yield), which was used directly in the next step without purification.

[0773] Step C: Methyl 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-carboxylate

[0774] At room temperature, EDCI (5.6 g, 29.28 mmol, 1.2 eq) was added to a solution of 4-amino-1-phenyl-1H-pyrazole-3-carboxylic acid methyl ester (5.3 g, 24.40 mmol, 1.0 eq), 6-(trifluoromethyl)picolinic acid (4.7 g, 24.40 mmol, 1.0 eq) and HOBT (4.0 g, 29.28 mmol, 1.2 eq) in N,N-dimethylformamide (120 mL). The reaction mixture was stirred at room temperature under nitrogen for 18 hours. After the reaction was complete, the reaction mixture was diluted with water, and the crude product precipitated. The filter cake was washed with water, slurried with ethyl acetate, filtered again, and completely dried to obtain the crude title compound (gray solid, 6.3 g, 66% yield), which was used directly in the next step without purification.

[0775] Step D: N-(3-(Hydroxymethyl)-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0776] To a solution of 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-carboxylic acid methyl ester (200.0 mg, 0.5 mmol, 1.0 equivalent) in tetrahydrofuran (3 mL) was slowly added lithium diisopropylamide (1.0 mL, 1.0 mmol, 2.0 equivalent) at 0°C under nitrogen protection. The reaction solution was stirred at 0°C under nitrogen protection for 1 hour. After the reaction was complete, the product was quenched with water (0.2 mL) and 30% aqueous sodium hydroxide solution (0.2 mL), diluted with water, and extracted three times with ethyl acetate. The mixed organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (white solid, 40.2 mg, 22% yield). 1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.88(s,1H), 8.46-8.36(m,2H),8.20(d,J=6.8Hz,1H),7.81(d,J=7.8Hz,2H),7.49(t,J=8.0Hz,2H) ,7.29(t,J=7.4Hz,1H),5.87(t,J=4.9Hz,1H),4.82(d,J=4.9Hz,2H).LC-MS(ESI):m / z 363[M+H] + .

[0777] Preparation Example 75. Synthesis of Compound A75

[0778] Step A: N-(3-Formyl-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0779] To a solution of N-(3-(hydroxymethyl)-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide (160.0 mg, 0.4 mmol, 1.0 equiv) in dichloromethane (2 mL) was added DMP (373.1 mg, 0.8 mmol, 2.0 equiv) at 0°C. The reaction mixture was stirred at room temperature for 1 hour under nitrogen. After the reaction was complete, it was quenched with saturated sodium bicarbonate solution and stirred for 0.5 hour. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with water and saturated sodium thiosulfate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound (white solid, 120.0 mg, 75% yield), which was used directly in the next step without purification.

[0780] Step B: N-(3-(1-hydroxyethyl)-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0781] To a solution of N-(3-formyl-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide (120.0 mg, 0.3 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was slowly added 2 M methylmagnesium bromide in ether (1.0 mL, 2.0 mmol, 6.0 equiv) at -78°C under nitrogen. The reaction mixture was stirred at -78°C under nitrogen for 2 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (white solid, 50.6 mg, 40% yield). 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.89(s,1H),8.46-8.34(m,2H),8.19(d,J=7.6Hz,1H),7.81(d,J=7.9Hz,2H),7.49 (t,J=7.9Hz,2H),7.29(t,J=7.4Hz,1H),6.09(d,J=4.3Hz,1H),5.18-5.06(m,1H),1.54(d,J=6.5Hz,3H).LC-MS(ESI):m / z 377[M+H] + .

[0782] Preparation Example 76. Synthesis of Compound A76

[0783] Step A: 1-phenyl-1H-pyrazol-3-ol

[0784] To a solution of 1-phenylpyrazolin-3-one (10 g, 61.6 mmol, 1.0 equiv) in dimethyl sulfoxide (100 mL) was added iodine (0.8 g, 3.1 mmol, 0.05 equiv) at room temperature. The reaction mixture was stirred at 100°C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with saturated sodium thiosulfate solution, and extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (yellow solid, 8.5 g, 86% yield).

[0785] Step B: 3-Ethoxy-1-phenyl-1H-pyrazole

[0786] To a solution of 1-phenyl-1H-pyrazol-3-ol (0.7 g, 4.4 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) at room temperature were added iodoethane (1.0 g, 6.5 mmol, 1.5 equiv) and potassium carbonate (1.2 g, 8.7 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (off-white solid, 660 mg, 80% yield).

[0787] Step C: 3-Ethoxy-4-nitro-1-phenyl-1H-pyrazole

[0788] To a solution of 3-ethoxy-1-phenyl-1H-pyrazole (160 mg, 0.8 mmol, 1.0 equiv) in acetic anhydride (5 mL) was added dropwise 60% nitric acid (0.1 mL, 1.7 mmol, 2.0 equiv) at -20°C. The reaction mixture was stirred at -20°C for 0.5 hours. After the reaction was complete, the reaction mixture was poured into ice water and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (colorless oil, 90 mg, 45% yield).

[0789] Step D: 3-Ethoxy-1-phenyl-1H-pyrazol-4-amine

[0790] To a solution of 3-ethoxy-4-nitro-1-phenyl-1H-pyrazole (600 mg, 2.6 mmol, 1.0 equiv) in methanol (6 mL) was added zinc powder (841 mg, 12.9 mmol, 5.0 equiv) and an aqueous solution of ammonium chloride (1.4 g, 25.7 mmol, 10 equiv) (3 mL) at room temperature. The reaction mixture was stirred at 70°C for 1 hour. After completion, the reaction was filtered and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude title compound (yellow solid, 600 mg, crude product), which was used directly in the next step without purification.

[0791] Step E: N-(3-ethoxy-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0792] To a solution of 6-(trifluoromethyl)picolinic acid (180 mg, 0.9 mmol, 1.0 equiv) and 3-ethoxy-1-phenyl-1H-pyrazol-4-amine (229.7 mg, 1.1 mmol, 1.2 equiv) in N,N-dimethylformamide (5 mL) at room temperature were added DIEA (365.2 mg, 2.8 mmol, 3.0 equiv) and HATU (429.8 mg, 1.1 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to yield the title compound (off-white solid, 63 mg, 18% yield). 1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.67(s,1H),8.44-8.30 (m,2H),8.20(dd,J=6.9,1.9Hz,1H),7.75(d,J=7.8Hz,2H),7.46(t,J=8.0Hz,2H),7 .22(t,J=7.4Hz,1H),4.39(q,J=7.0Hz,2H),1.41(t,J=7.0Hz,3H).LC-MS(ESI):m / z 377[M+H] + .

[0793] Preparation Example 77. Synthesis of Compound A77

[0794] Step A: 4-Nitro-1-phenyl-1H-pyrazol-3-ol

[0795] To a solution of 1-phenyl-1H-pyrazole-3-ol (300 mg, 1.87 mmol, 1.0 equiv) in acetic acid (10 mL) was added 60% nitric acid (983 mg, 4.68 mmol, 2.5 equiv) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, it was quenched with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The mixed organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the title compound (yellow liquid, 260 mg, 68% yield).

[0796] Step B: 4-Nitro-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazole

[0797] To a solution of 4-nitro-1-phenyl-1H-pyrazole-3-ol (800 mg, 3.899 mmol, 1.0 equivalent) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1077 mg, 7.80 mmol, 2.0 equivalents) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.36 g, 5.85 mmol, 1.5 equivalents) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, it was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate. The mixed organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (white liquid, 1.0 g, crude product), which was used directly in the next step without purification.

[0798] Step C: 1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-4-amine

[0799] To a solution of 4-nitro-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazole (500 mg, 1.74 mmol, 1.0 equiv) in methanol (5 mL) was added 5% palladium on carbon (185 mg, 0.174 mmol, 0.1 equiv) at room temperature. The reaction solution was evacuated three times under a hydrogen balloon and stirred at room temperature under hydrogen for 18 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (yellow solid, 370 mg, crude product), which was used directly in the next step without purification.

[0800] Step D: N-(1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0801] To a solution of 1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-4-amine (150 mg, 0.583 mmol, 1.0 equiv) and 6-(trifluoromethyl)picolinic acid (111 mg, 0.583 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) at room temperature were added DIEA (226 mg, 1.75 mmol, 3.0 equiv) and HATU (244 mg, 0.641 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative column chromatography to yield the title compound (white solid, 200 mg, 80% yield). 1 H NMR (400MHz, DMSO-d6) δ9.89 (s, 1H), 8.72 (s, 1H), 8.44-8.33 (m, 2H), 8.20 (dd, J = 6.8, 1.8Hz, 1H), 7.79 (d,J=7.9Hz,2H),7.49(t,J=7.9Hz,2H),7.27(t,J=7.4Hz,1H),5.05(q,J=8.9Hz,2H).LC-MS(ESI):m / z 431[M+H] + .

[0802] Preparation Example 78. Synthesis of Compound A78

[0803] Step A: 3-Isopropoxy-1-phenyl-1H-pyrazole

[0804] To a solution of 1-phenyl-1H-pyrazol-3-ol (1.0 g, 6.24 mmol, 1.0 equiv) in N,N-dimethylformamide (30 mL) were added cesium carbonate (4.07 g, 12.5 mmol, 2.0 equiv) and 2-iodopropane (3.12 mL, 31.2 mmol, 5.0 equiv) at room temperature. The reaction mixture was stirred at 50°C for 18 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (yellow liquid, 1.1 g, 87% yield).

[0805] Step B: 3-Isopropoxy-4-nitro-1-phenyl-1H-pyrazole

[0806] To a solution of 3-isopropoxy-1-phenyl-1H-pyrazole (1.1 g, 5.44 mmol, 1.0 equiv) in acetic anhydride (10 mL) was added concentrated nitric acid (1.58 g, 16.3 mmol, 3.0 equiv) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was poured into ice water and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to yield the title compound (yellow solid, 700 mg, 52% yield).

[0807] Step C: 3-Isopropoxy-1-phenyl-1H-pyrazol-4-amine

[0808] To a solution of 3-isopropoxy-4-nitro-1-phenyl-1H-pyrazole (200 mg, 0.81 mmol, 1.0 equiv) in ethyl acetate (15 mL) was added 5% palladium on carbon (120 mg, 1.13 mmol, 1.4 equiv) at room temperature. The reaction solution was evacuated three times under a hydrogen balloon and stirred at room temperature for 2 hours under hydrogen. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was separated by column chromatography to give the title compound (yellow solid, 100 mg, 57% yield).

[0809] Step D: N-(3-Isopropoxy-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0810] To a solution of 3-isopropoxy-1-phenyl-1H-pyrazol-4-amine (100 mg, 0.46 mmol, 1.0 equiv) and 6-(trifluoromethyl)picolinic acid (88 mg, 0.46 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) at room temperature were added DIEA (178 mg, 1.38 mmol, 3.0 equiv) and HATU (175 mg, 0.46 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature under nitrogen for 0.5 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to yield the title compound (yellow solid, 68 mg, 38% yield). The residue was purified by column chromatography to yield the title compound (yellow solid, 70 mg, 20% yield). 1 H NMR (400MHz, DMSO-d6) δ9.66(s,1H),8.67(s,1H),8.44-8.34(m,2H),8.20(dd,J=6.9,1.9Hz,1H),7.75(d,J=7.9 Hz,2H),7.47(t,J=7.9Hz,2H),7.23(t,J=7.4Hz,1H),5.03-4.94(m,1H),1.41(d,J=6.1Hz,6H).LC-MS(ESI):m / z 391[M+H] + .

[0811] Preparation Example 79. Synthesis of Compound A79

[0812] Step A: 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-carboxylic acid

[0813] To a mixed solution of 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-carboxylic acid methyl ester (1.2 g, 3.07 mmol, 1.0 equivalent) in methanol (50 mL) and water (20 mL) was added lithium hydroxide (220 mg, 9.22 mmol, 3.0 equivalent) at 0°C. The reaction solution was stirred at room temperature for 4 hours. After the reaction was complete, the methanol was removed by concentration under reduced pressure, the mixture was diluted with water, and the pH was adjusted to 4 with a dilute 1N HCl solution until the product was completely precipitated. The crude title compound (white solid, 1.1 g, 95% yield) was obtained by filtration and drying the filter cake. It was used directly in the next step without purification.

[0814] Step B: tert-Butyl 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazol-3-yl)carbamate

[0815] To a solution of 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazole-3-carboxylic acid (900 mg, 2.39 mmol, 1.0 equiv) and triethylamine (1.66 mL, 12.0 mmol, 5.0 equiv) in tert-butanol (50 mL) was added diphenylphosphoryl azide (1316 mg, 4.78 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 90°C under nitrogen for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the tert-butanol, diluted with water, and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and slurried with petroleum ether / ethyl acetate (10 mL, 1 / 20) to afford the title compound as a white solid, 230 mg, 21% yield.

[0816] Step C: N-(3-amino-1-phenyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)picolinamide

[0817] To a solution of tert-butyl 1-phenyl-4-(6-(trifluoromethyl)picolinamido)-1H-pyrazol-3-yl)carbamate (230 mg, 0.51 mmol, 1.0 equiv) in 1,4-dioxane (1 mL) was added a 4M HCl solution in 1,4-dioxane (5 mL) at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with saturat...

Claims

1. A compound of formula (III), or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof: in, The ring structure where Q3 and Q4 are located is selected from the following structures: Ring P is pyridyl, pyrazolopyrimidinyl or pyrrolopyridazinyl; R1 is selected from -OR 1a 、-COR 1a 、-CONR 1a R 1b 、-S(O)(NR 1a )R 1b 、-SO2NR 1a R 1b , optionally substituted alkyl, wherein R 1a and R 1b are independently selected from hydrogen, deuterium, optionally substituted alkyl, and optionally substituted cycloalkyl; R2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted phenyl, pyridyl, and pyrimidinyl; R3 is selected from cyano, optionally substituted alkyl and optionally substituted heteroaryl.

2. A compound of formula (II), or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof: ALE (II) Part A has the following structure: The ring structure where Q3 and Q4 are located is selected from the following structures: Ring P is pyridyl, pyrazolopyrimidinyl or pyrrolopyridazinyl; R1 is selected from -OR 1a 、-COR 1a 、-CONR 1a R 1b 、-S(O)(NR 1a )R 1b 、-SO2NR 1a R 1b , optionally substituted alkyl, wherein R 1a and R 1b are independently selected from hydrogen, deuterium, optionally substituted alkyl, and optionally substituted cycloalkyl; R2' is selected from optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted phenylene and pyridylene; R3 is selected from cyano, optionally substituted alkyl and optionally substituted heteroaryl; and The A part is connected to the L part through the ring atom of R2'; The L section has the following structure: -L1-L2-L3-L4-L5-Formula (L) in: L1, L3 and L5 are independently absent or selected from -Rm-, -Rm-Rn-, -Rm-O-Rn-, -Rm-C(O)-Rn-, -Rm-C(O)O-Rn-, -Rm-OC(O)-Rn-, -Rm-NRx-Rn-, -Rm-C(O)NRx-Rn-, -Rm-NRxC(O)-Rn-, -Rm-S(O)-R n-, -Rm-S(O)NRx-Rn-, -Rm-NRxS(O)-Rn-, -Rm-S(O)2-Rn-, -Rm-S(O)2NRx-Rn-, -R m-NRxS(O)2-Rn-, -Rm-NRxC(O)NRy-Rn-, -Rm-OC(O)NRx-Rn-, -Rm-NRxC(O)O-Rn-, -(CH2CH2O) g -or-(OCH2CH2) g -, wherein Rm and Rn are independently selected from a bond, an optionally substituted alkylene, an optionally substituted alkyleneoxy, an optionally substituted cycloalkylene or an optionally substituted heterocyclylene, Rx and Ry are independently selected from hydrogen, deuterium, an optionally substituted alkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, and g is an integer from 1 to 20; L2 and L4 are independently absent or selected from optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene or optionally substituted heteroarylene; and Section E has the following structure: Among them, RE 1 is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl or optionally substituted heterocyclyl, RE 2 is selected from hydrogen, deuterium or halogen, RE L1 is selected from a bond, -CH2-, -NH-, -NCH3-, -O-, -CONH- or -CONCH3-, RE L2 is selected from a bond or -CH2-, and p is 1, 2, 3, 4 or 5; RE 1a is selected from -COCH(CH3)OH, -COCH3, -CON(CH3)2, -CO(CH2)2CH(NH2)COOH or -COCH(NH2)(CH2)2COOH, RE 2a Selected from -CH2OCOOC(CH3)3 or -CH2OCOC(CH3)3.

3. A compound according to claim 1 or 2, wherein R1 is selected from alkyl (e.g. methyl, ethyl, propyl (e.g. isopropyl)) substituted by one or more substituents independently selected from halogen and hydroxyl:

4. The compound according to claim 1 or 2, wherein R 1a and R 1b Independently selected from: hydrogen; deuterium; alkyl (e.g., methyl, ethyl, propyl (e.g., isopropyl)); cycloalkyl (e.g., cyclopropyl); and alkyl (e.g., methyl, ethyl, propyl (e.g., isopropyl)) and cycloalkyl (e.g., cyclopropyl) substituted with one or more substituents independently selected from the following: deuterium, halogen (e.g., fluorine), hydroxyl, thiol, amino, cyano and nitro.

5. The compound of claim 1, wherein R2 is selected from optionally substituted cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl or bicyclo[2.2.2]octyl; optionally substituted piperidinyl, azetidinyl, azopentyl or 1-oxa-8-azaspiro[4.5]decyl or 7-azaspiro[3.5]nonyl; optionally substituted phenyl, pyridinyl or pyrimidinyl.

6. Compound according to claim 1, wherein R2 is selected from unsubstituted cycloalkyl, heterocyclic radical, phenyl, pyridyl; and cycloalkyl, heterocyclic radical, phenyl, pyridyl substituted by one or more substituents independently selected from the following: deuterium, halogen (e.g., fluorine or bromine), hydroxyl, sulfhydryl, amino, cyano, nitro, -OR 2a 、-NR 2a R 2b 、-COR 2a 、-COOR 2a 、-CONR 2a R 2b 、-NR 2a COR 2b 、-OCOR 2a , optionally substituted alkyl and optionally substituted heterocyclyl, wherein R 2a and R 2b are independently selected from hydrogen, deuterium, optionally substituted alkyl, and optionally substituted heterocyclyl.

7. The compound according to claim 1, wherein R 2a and R 2b Independently selected from hydrogen, deuterium, alkyl (eg methyl), alkyl substituted by halogen, heterocyclic group (eg piperazinyl), heterocyclic group substituted by alkyl.

8. The compound according to claim 1, wherein R2 is selected from cycloalkyl, heterocyclyl, phenyl, pyridyl substituted by one or more substituents independently selected from the following: alkyl; Heterocyclic group; Selected from -OR 2c 、-NR 2c R 2d 、-COR 2c 、-COOR 2c 、-CONR 2c R 2d and / or -NR 2c COR 2d substituted with one or more substituents, alkyl (eg, methyl) or heterocyclic (eg, piperazinyl), wherein R 2c and R 2d are independently selected from hydrogen, deuterium, alkyl (e.g. methyl), phenyl; Heterocyclyl (eg piperazinyl) substituted by one or more substituents selected from alkyl (eg methyl).

9. The compound according to claim 1, wherein R2 is selected from phenyl; and phenyl substituted with one or more substituents independently selected from the following: deuterium; halogen (e.g., fluorine or bromine); -OR 2a 、-NR 2a R 2b 、-COR 2a 、-COOR 2a 、-CONR 2a R 2b 、-NR 2a COR 2b 、-OCOR 2a , where R 2a and R 2b independently selected from hydrogen, deuterium, alkyl (e.g., methyl) and heterocyclyl (e.g., piperazinyl); alkyl (e.g., methyl), heterocyclyl (e.g., piperazinyl) and alkyl (e.g., methyl) or heterocyclyl (e.g., piperazinyl) substituted with one or more substituents independently selected from: -OR 2c 、-NR 2c R 2d 、-COR 2c 、-COOR 2c 、-CONR 2c R 2d and / or -NR 2c COR 2d , where R 2c and R 2d Independently selected from hydrogen, deuterium, alkyl (eg methyl), phenyl.

10. A compound according to claim 1 or 2, wherein R3 is selected from alkyl (eg methyl) substituted by halogen (eg fluorine), such as trifluoromethyl.

11. The compound according to claim 1 or 2, wherein R3 is selected from a 5-membered heteroaryl group containing one or more nitrogen ring atoms.

12. The compound according to claim 2, wherein R2' is selected from cycloalkylene, heterocyclylene, phenylene and pyridylene, optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, aldehyde, carboxyl, alkyl.

13. The compound of claim 2, wherein R2' is selected from optionally substituted cyclobutylene, cyclopentylene, cyclohexylene, bicyclo[1.1.1]pentylene or bicyclo[2.2.2]octylene; optionally substituted piperidinylene, aziridinylene, aziridineylene, 1-oxa-8-azaspiro[4.5]decylene or 7-azaspiro[3.5]nonylene; optionally substituted phenylene or pyridinylene.

14. The compound of claim 2, wherein L1, L3 and L5 are independently absent or selected from -Rm-, -Rm-O-Rn-, -Rm-C(O)-Rn-, -Rm-C(O)O-Rn-, -Rm-OC(O)-Rn-, -Rm-NRx-Rn-, -Rm-C(O)NRx-Rn-, -Rm-NRxC(O)-Rn- or wherein Rm and Rn are independently selected from a bond or an optionally substituted alkylene group, and Rx is independently selected from hydrogen, deuterium or an optionally substituted alkyl group.

15. The compound according to claim 2, wherein Rm and Rn are independently selected from a bond or an alkylene group (eg C 1-4 alkylene, such as methylene or ethylene).

16. The compound according to claim 2, wherein Rx is independently selected from hydrogen, deuterium or alkyl (e.g. C 1-4 alkylene groups, such as methylene and ethylene).

17. The compound according to claim 2, wherein L2 is selected from optionally substituted heterocyclylene.

18. compounds according to claim 2, wherein L2 and L4 are independently selected from 3-12 yuan of heterocyclic radicals containing one or two nitrogen heteroatoms, which are optionally replaced by one or more substituents selected from halogen (e.g. fluorine) and / or alkyl (e.g. methyl).

19. The compound according to claim 2, wherein L2 and L4 are independently selected from:

20. A compound according to claim 2, wherein L1 is absent or selected from -Rm-, -Rm-O-Rn-, -Rm-C(O)-Rn-, -Rm-C(O)O-Rn-, -Rm-OC(O)-Rn-, -Rm-NRx-Rn-, -Rm-C(O)NRx-Rn- or -Rm-NRxC(O)-Rn-, wherein Rm and Rn are independently selected from a bond or an alkylene group (e.g., methylene or ethylene), and Rx is independently selected from hydrogen, deuterium or an alkyl group (e.g., methyl).

21. The compound of claim 2, wherein L1 is absent or selected from -CH2-, -CH2CH2-, -CH2O-, -C(O)-, -CH2C(O)-, -CH2NH-, -NHCH2-, -CH2N(CH3)-, -C(O)NH-.

22. A compound according to claim 2, wherein L3 is absent or selected from -Rm-, -Rm-O-Rn-, -Rm-C(O)-Rn-, -Rm-C(O)O-Rn-, -Rm-OC(O)-Rn-, -Rm-NRx-Rn-, -Rm-C(O)NRx-Rn- or -Rm-NRxC(O)-Rn-, wherein Rm and Rn are independently selected from a bond or an alkylene group (e.g., methylene or ethylene), and Rx is independently selected from hydrogen, deuterium or an alkyl group (e.g., methyl).

23. The compound of claim 2, wherein L3 is absent or selected from -CH2-, -CH2CH2-, -OCH2-, -C(O)-, -C(O)CH2-, -C(O)O-, -NH-, -NHCH2-, -N(CH3)-.

24. The compound according to claim 2, wherein L5 is absent or selected from -Rm-, -Rm-C(O)-Rn-, -Rm-NRx-Rn- or wherein Rm and Rn are independently selected from a bond or an alkylene group (eg, methylene or ethylene), and Rx is independently selected from hydrogen, deuterium, or an alkyl group (eg, methyl).

25. The compound according to claim 2, wherein L5 is absent or selected from -CH2-, -C(O)-, -NH- or 26. The compound according to claim 2, wherein the E moiety has the following structure:

27. The compound according to claim 2, wherein RE 1 is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, alkyl, alkoxy, RE 2 is selected from hydrogen, deuterium or halogen, RE L1 is selected from a bond, -CH2-, -NH-, -NCH3-, -O-, -CONH- or -CONCH3-, RE L2 is selected from a bond, -CH2- or cyclopropylene, and p is 1 or 2.

28. The compound according to claim 2, wherein RE 1 is selected from hydrogen, deuterium, halogen (eg fluorine) and methoxy.

29. The compound according to claim 2, wherein RE 2 Selected from hydrogen or deuterium.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

31. A method for treating or preventing a disease mediated by an IRAK protein, the method comprising administering a compound according to any one of claims 1 to 29 or a composition according to claim 30 to a patient in need thereof.

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