Compounds having tyk2 inhibitory activity, pharmaceutical compositions containing the same, and uses thereof

Abstract

The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a compound with TYK2 inhibitory activity, a pharmaceutical composition containing the same, and application thereof. The present application provides a compound with the structure of formula (I), which is an effective inhibitor of TYK2 and can be used for preventing and / or treating diseases and / or disorders responsive to TYK2.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a compound having TYK2 inhibitory activity, a composition comprising the compound, a method for preparing the compound, and the use of the compound in medicine, particularly for the prevention and / or treatment of diseases and / or conditions responding to TYK2 receptor inhibition, such as various diseases including tumors, autoimmune diseases, neurodegenerative diseases, metabolic diseases, and genetic diseases. Background Technology

[0002] Janus kinases, or JAKs, are non-receptor tyrosine kinases that bind to the intracellular portion of cell surface cytokine receptors. The human JAK family currently has four known members: JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2). Each of these members contains a kinase domain and a pseudokinase domain (Trends Pharmacol. Sci. 32 (2011), 25-34). JAK1, JAK2, and TYK2 are expressed in various human tissues, while JAK3 is mainly expressed in hematopoietic cells. A common characteristic of cytokine receptors is that the receptors themselves do not possess kinase activity, but their intracellular domains contain binding sites for the tyrosine kinase JAK. Cytokine binding to receptors leads to JAK activation and phosphorylation of JAK and related receptors. Receptor phosphorylation then initiates STAT recruitment via their SH2 domains, subsequently initiating STAT protein phosphorylation. Then, phosphorylated STAT homodimers or heterodimers translocate to the cell nucleus and bind to specific DNA binding sites, regulating gene transcription and thus causing changes in cell function (J.Med.Chem.,62(2019),8953-8972).

[0003] Different pairs of JAK family members are responsible for transmitting signals of different cytokines and their receptors. For example, TYK2, when paired with JAK2, regulates IL12 and IL23-mediated signaling, and when paired with JAK1, it regulates IFN-α-mediated signaling. Because the JAK / STAT pathway is involved in inflammatory responses, it has become an effective target for treating immune-related diseases (J.Med.Chem., 57(2014), 5023-5038). TYK2, in particular, has received substantial evidence to support its role as a target for autoimmune diseases. Mice deficient in TYK2 can survive and develop normally, whereas JAK1 (Cell, 93(1998), 373-383.) or JAK2 (Cell, 93(1998), 397-409.) deficiency is fatal in mice, while JAK3-deficient mice exhibit severe B-cell and T-cell depletion (Science, 270(1995), 800-802). Furthermore, TYK2 has shown protective effects in various autoimmune disease models (multiple sclerosis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, and psoriasis, etc.) (Brain, 134 (2011), 693-703; Inflammation (London, UK) 7 (2010), 41; Nat. Rev. Rheumatol. 12 (2016), 25-36). TYK2 is also associated with some cancers, such as T-cell acute lymphoblastic leukemia (Cancer Disc. 3 (2013), 564-567).

[0004] Clinically, various antibodies have demonstrated the value of inhibiting pathways involving TYK2 in the treatment of autoimmune diseases. The blocking p40 antibody Ustekinumab, which inhibits the IL-12 and IL-23 pathways, is currently marketed for the treatment of psoriasis, psoriatic arthritis, and Crohn's disease (Drugs, 71 (2011), 1733-1753; N. Engl. J. Med., 375 (2016), 1946-1960), and has recently shown efficacy in patients with systemic lupus erythematosus (SLE) (Lancet, 392 (2018), 1330-1339). The p19 antibody guselkumab, which blocks IL-23 but not IL-12 signaling, has also been shown to be an effective treatment for psoriasis (J. Am. Acad. Dermatol., 76 (2017), 405-417). Some studies have shown that type 1 interferon plays a pathogenic role in SLE, which led to the success of sifalimumab and anifrolumab in phase II clinical trials for the treatment of SLE (Ann. Rheum. Dis., 75 (2016), 1909-1916; Arthritis Rheumatol., 69 (2017), 376-386.).

[0005] With TYK2 as a therapeutic target, obtaining highly selective TYK2 inhibitors holds promise for treating the aforementioned diseases. Currently, the selective TYK2 inhibitor BMS-986165 (J.Med.Chem.,62(2019),8973-8995) and the JAK1 / TYK2 dual inhibitor PF-06700841 (J.Med.Chem.,61(2018),8597-8612) have entered clinical trials; obtaining highly druggable, highly active, and highly selective TYK2 or TYK2 / JAK1 inhibitors has broad application prospects. Summary of the Invention

[0006] In view of the deficiencies of the prior art, the object of the present invention is a compound with TYK2 inhibitory activity, which and its composition can effectively inhibit TYK2 activity, thereby enabling it to be used for the prevention and / or treatment of autoimmune diseases or inflammatory diseases, cancer / tumors, allergies, transplant rejection, neurodegenerative diseases, asthma and other obstructive airway diseases.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] In a first aspect, the present invention provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope label, or isomer thereof:

[0009]

[0010] in,

[0011] n is selected from 0, 1, 2, and 3;

[0012] X1 is selected from N and CH;

[0013] Ring A is selected from C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0014] R 1 Selected from amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl and NH(C) 1-6 Alkyl), the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl and NH(C) 1-6 Alkyl groups are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, and C. 1-3 One or more substituents in the alkyl group are substituted;

[0015] R 2 Selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, NR c R b C(O)R a C(O)NR c R b S(O)R a S(O)2R a C(O)OR a NR d C(O)R a NR d C(O)NR c R b NR d S(O)R a NR d S(O)2R a NR d S(O)NR b R c NR d S(O)2NR b R c and NR dC(O)OR a The alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each independently substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, ynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl groups;

[0016] R 3 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1-6 Alkyl, C 3-6 cycloalkyl, O(C) 1-6 Alkyl), NH(C) 1-6 alkyl), N(C) 1-6 Alkyl)2, C 2-6 alkenyl and C 2-6 alkynyl group, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and C 2-6 Each alkynyl group is independently replaced by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, and hydroxyl;

[0017] If it exists, each R 4 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl groups, O(C) 1-6 Alkyl), O(C) 1-6 deuterated alkyl), NH(C) 1-6 alkyl), N(C) 1-6 Alkyl)2, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl groups, P(O)R5R6, C 6-10 Aryl and C 5-10 Heteroaryl, the C 1-6 Alkyl, C 1-6 Deuterated alkyl groups, O(C) 1-6 Alkyl), O(C) 1-6 (deuterated alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 6-10 Aryl and C 5-10Each heteroaryl group is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, and C. 1-3 One or more substituents in the alkyl group are substituted;

[0018] If it exists, R 5 and R 6 Each is independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, and hydroxyl; or R 5 and R 6 Together with the phosphorus atoms attached to them, they form 5- to 6-membered heterocyclic alkyl groups, which are substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano and hydroxyl.

[0019] R 8 Selected from hydrogen and C 1-6 Alkyl; or R 8 and R 4 Together with ring A, they form 5- to 10-membered heterocycles;

[0020] R a R b R c and R d Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, ynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or any two adjacent or non-adjacent R groups. a R b R c and R d It is connected to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0021] Furthermore, in the above-mentioned compounds having the structure of formula (I) or their pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope labels or isomers, X1 is CH.

[0022] Furthermore, the compounds having the structure of formula (I) above also have the structure of formula (II):

[0023]

[0024] in,

[0025] R 1 R 2 and R 3 As defined in equation (I);

[0026] R 5 and R 6 Each is independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, and hydroxyl; or R 5 and R 6 Together with the phosphorus atoms attached to them, they form 5- to 6-membered heterocyclic alkyl groups, which are substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano and hydroxyl.

[0027] R 7 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1-6 Alkyl, C 3-6 cycloalkyl, O(C) 1-6 Alkyl), NH(C) 1-6 alkyl), N(C) 1-6 Alkyl)2, C 2-6 alkenyl and C 2-6 alkynyl group, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and C 2-6 Each alkynyl group is independently replaced by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, and hydroxyl.

[0028] Furthermore, the compounds having the structure of formula (I) above also have the structure of formula (III):

[0029]

[0030] in,

[0031] R 1 R 2 and R 3 As described in claim 1;

[0032] R 7Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1-6 Alkyl, C 3-6 cycloalkyl, O(C) 1-6 Alkyl), NH(C) 1-6 alkyl), N(C) 1-6 Alkyl)2, C 2-6 alkenyl and C 2-6 alkynyl group, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and C 2-6 Each alkynyl group is independently replaced by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, and hydroxyl.

[0033] 5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope label, or isomer thereof, characterized in that the compound has the structure of formula (IV):

[0034]

[0035] in,

[0036] n is 1 or 2;

[0037] R 1 R 2 and R 3 As defined in equation (I);

[0038] Ring A is selected from the following groups:

[0039]

[0040] R 7 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1-6 Alkyl, C 3-6 cycloalkyl, O(C) 1-6 Alkyl), NH(C) 1-6 alkyl), N(C) 1-6 Alkyl)2, C 2-6 alkenyl and C 2-6 alkynyl group, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and C 2-6 Each alkynyl group is independently replaced by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, and hydroxyl.

[0041] Furthermore, in the compounds having the structure of formula (I), formula (II), or formula (III) or their pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope-labeled derivatives, or isomers, R 1 Selected from amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl and NH(C) 1-6 alkyl).

[0042] Furthermore, among the compounds having the structure of formula (I), formula (II), or formula (III) above, or their pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope-labeled derivatives, or isomers,

[0043] R 2 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, NR c R b C(O)R a C(O)NR c R b S(O)R a S(O)2R a C(O)OR a NR d C(O)R a NR d C(O)NR c R b NR d S(O)R a NR d S(O)2R a NR d S(O)NR b R c NR d S(O)2NR b R c and NR d C(O)OR a Wherein C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-3 alkenyl, C 2-3 Alkyne group, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C 6-10 The aryl group is substituted with one or more substituents in a group of 5 to 10 heteroaryl groups, either substituted or unsubstituted.

[0044] R a R b R c and R d Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 aryl and 5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6Alkyne group, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C 6-10 The aryl group is substituted with one or more substituents from a group consisting of 5 to 10 heteroaryl groups, either substituted or unsubstituted; or any two adjacent or non-adjacent R groups. a R b R c and R d Connect into a C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 The aryl or 5- to 10-membered heteroaryl group is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 It is substituted by one or more substituents of aryl and 5 to 10 heteroaryl groups.

[0045] Furthermore, among the compounds having the structure of formula (I), formula (II), or formula (III) above, or their pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope-labeled derivatives, or isomers,

[0046] R 2 For 1-3 R 11 The following groups, whether substituted or unsubstituted:

[0047]

[0048] R 11 Selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, C 1-3 Alkyl and C 1-3 Alkyl group.

[0049] Secondly, the present invention provides the following compounds or their pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope labels, or isomers:

[0050]

[0051]

[0052] Thirdly, the present invention provides a pharmaceutical composition comprising any of the above-mentioned compounds or their pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope labels or isomers.

[0053] Fourthly, the present invention provides a composition comprising any of the above-described compounds or their pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope labels, isomers, or pharmaceutical compositions thereof, as well as one or more of drugs for treating autoimmune / inflammatory diseases, antitumor / cancer diseases, antiallergic drugs, anti-transplant rejection drugs, anti-neurodegenerative disease drugs, anti-asthma drugs, and other obstructive airway diseases.

[0054] Fifthly, the present invention provides any of the above-described compounds or their pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope labels, isomers, or pharmaceutical compositions thereof, or the use of the above-described compositions in the preparation of medicaments for treating diseases and / or conditions by inhibiting TYK2.

[0055] Furthermore, the aforementioned diseases and / or conditions include autoimmune or inflammatory diseases, cancer / tumor, allergies, transplant rejection, neurodegenerative diseases, asthma, and other obstructive airway diseases.

[0056] Furthermore, the aforementioned autoimmune or inflammatory diseases include enteritis, skin diseases, eye diseases, arthritis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis, autoimmune encephalomyelitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmositis, myositis, primary biliary cirrhosis, hepatitis, primary sclerosing cholangitis, chronic infiltrative hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, ulcerative colitis, membranous glomerulonephritis, and systemic diseases. Systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, polyarthritis dermatomyositis, type I interferon disorders (including Ekadir-Guterres syndrome) and other systemic sclerosis caused by overexpression of type I interferon, Mendelian disease, polyarteritis nodosa, multiple sclerosis, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis and bullous pemphigus, Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, diabetes, and thyroiditis.

[0057] Furthermore, the aforementioned enteritis includes Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, and mastocytosis.

[0058] Furthermore, the aforementioned skin conditions include atopic dermatitis, eczema, psoriasis, scleroderma, pruritus or other itching symptoms, vitiligo, and hair loss.

[0059] Furthermore, the aforementioned eye diseases include keratoconjunctivitis, uveitis (including uveitis associated with Behcet's disease and uveitis caused by the lens), keratitis, herpetic keratitis, keratoconus, muscular dystrophy epithelial keratitis, corneal leukopenia, anterior uveitis, scleritis, Mooren's Graves' eye disease, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca, vesicles, iridocyclitis sarcoidosis, endocrine eye diseases, sympathetic ophthalmia, allergic conjunctivitis, and ocular neovascularization.

[0060] Furthermore, the aforementioned diabetes includes type 1 diabetes and diabetes complications.

[0061] Furthermore, the aforementioned cancers / tumors include gastrointestinal cancers, colon cancers, liver cancers, skin cancers (including mast cell tumors and squamous cell carcinomas), breast cancers, ovarian cancers, prostate cancers, lymphomas, leukemias (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancers, lung cancers, muscle cancers, bone cancers, bladder cancers, brain cancers, melanomas (including oral and metastatic melanomas), Kaposi's sarcoma (including multiple myeloma), myeloproliferative disorders, proliferative diabetic retinopathy, and diseases / tumors associated with angiogenesis.

[0062] Furthermore, the aforementioned neurodegenerative diseases include motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia; neurodegenerative diseases caused by trauma, injury, glutamate neurotoxicity or hypoxia; stroke, myocardial ischemia, renal ischemia, heart disease, cardiac hypertrophy, atherosclerosis and arteriosclerosis, ischemia / reperfusion injury due to organ hypoxia or platelet aggregation.

[0063] Furthermore, the aforementioned allergic reactions include allergic dermatitis in mammals (including allergic diseases in horses, such as bite allergy), summer eczema, horseshoe itching, spasms, airway inflammation, recurrent airway obstruction, airway hyperresponsiveness, and chronic obstructive pulmonary disease.

[0064] Furthermore, the aforementioned asthma and other obstructive airway diseases include chronic or excessive asthma, delayed asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dusty asthma.

[0065] Furthermore, the aforementioned transplant rejections include islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection (e.g., bone marrow, cartilage, cornea, heart, intervertebral disc, islets, kidney, limbs, liver, lung, muscle, myoblasts, nerves, pancreas, skin, small intestine, or trachea), and xenotransplantation.

[0066] The compounds of the present invention having TYK2 inhibitory activity can be used as effective inhibitors of TYK2 and can be used to prevent and / or treat diseases and / or conditions that respond to the TYK2 receptor. Attached Figure Description

[0067] Figure 1 These are the test results for compound A9 in Example 35.

[0068] Figure 2 These are the test results for compound A9 in Example 36.

[0069] Figure 3 These are the test results for compound A9 in Example 37. Detailed Implementation

[0070] In order to provide a clearer understanding of the technical features, objectives and beneficial effects of the present invention, the technical solution of the present invention will now be described in detail below, but it should not be construed as limiting the scope of implementation of the present invention.

[0071] To more clearly describe the content of this invention, the terms involved are defined as follows:

[0072] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, either alone or in combination, especially fluorine, chlorine, or bromine.

[0073] Term "C" 1-6 "Alkyl" refers alone or in combination to a saturated straight-chain or branched alkyl group containing 1 to 6 (particularly 1 to 3) carbon atoms, including (but not limited to) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl, etc. Preferably, "C 1-6 "alkyl" is any one of methyl, ethyl, n-propyl, isopropyl, and tert-butyl. Similarly, the term "C" 1-3 "Alkyl" alone or in combination refers to a saturated straight-chain or branched alkyl group containing 1 to 3 carbon atoms, including methyl, ethyl, propyl, isopropyl, etc.

[0074] Term "C" 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group, either alone or in combination, containing 2 to 6 carbon atoms (especially 2 to 4 carbon atoms) and having at least one unsaturated site (>C=C<), including (but not limited to) vinyl and allyl groups.

[0075] Term "C" 2-6 "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group that contains 2 to 6 carbon atoms (especially 2 to 3 carbon atoms) alone or in combination and has at least one alkynyl (-C≡C-) unsaturated site, including (but not limited to) ethynyl (-C≡CH) and propynyl (-CH2C≡CH).

[0076] The term "OC" 1-6 "alkyl" alone or in combination represents the group "C". 1-6 Alkyl-O-”, where “C” 1-6 "alkyl" indicates as defined above. "O(C)" 1-6 Alkyl groups include (but are not limited to) methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy (-OCH2CH2CH3), isopropoxy (-OCH(CH3)2), n-butoxy (-OCH2CH2CH2CH3), sec-butoxy (-OCH(CH3)CH2CH3), isobutoxy (-OCH2CH(CH3)2), tert-butoxy (-OC(CH3)3), n-pentoxy (-OCH2CH2CH2CH2CH3), and neopentoxy (-OCH2C(CH3)3), etc.

[0077] The term "3- to 8-membered cycloalkyl" refers, alone or in combination, to a saturated or partially unsaturated monocyclic or polycyclic cycloalkyl group having 3 to 8 (particularly 3 to 6) carbon atoms, including (but not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Similarly, the term "C 3-6 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cycloalkyl group having 3 to 6 carbon atoms, either alone or in combination.

[0078] The term "3- to 8-membered heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group comprising 3 to 8 (especially 3 to 6, more particularly 5 to 6) carbon atoms and heteroatoms or heteroatom groups for cyclization, wherein the heteroatoms or heteroatom groups are selected from N, NH, O, C(O), and S(O). m (Where m is 0, 1, or 2). "3- to 8-membered heterocyclic groups" include (but are not limited to) aziridinyl, azirrobutyl, oxobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valproic acid, caprolactam, butyrolactone, valproic acid, or caprolactone, etc. Similarly, the term "3- to 6-membered heterocyclic alkyl" refers to a saturated monocyclic or polycyclic heterocyclic group containing 3 to 6 carbon atoms and heteroatoms or heteroatom groups selected from N, NH, O, C(O), and S(O).m (where m is 0, 1, or 2); the term "5- to 6-membered heterocyclic alkyl" refers to a saturated monocyclic or polycyclic heterocyclic group containing 5 to 6 carbon atoms for cyclization and heteroatoms or heteroatom groups selected from N, NH, O, C(O), and S(O). m (Where m is 0, 1, or 2). Similarly, the term "3- to 6-membered heterocyclic alkenyl" refers to a monocyclic or polycyclic heterocyclic group comprising 3 to 6 carbon atoms and heteroatoms or heteroatom groups for cyclization, and at least one carbon-carbon double bond, wherein the heteroatoms or heteroatom groups are selected from N, NH, O, C(O), and S(O). m (where m is 0, 1, or 2); the term "5- to 8-membered heterocyclic alkenyl" refers to a monocyclic or polycyclic heterocyclic group comprising 5 to 8 carbon atoms and heteroatoms or heteroatom groups for cyclization and at least one carbon-carbon double bond, wherein the heteroatoms or heteroatom groups are selected from N, NH, O, C(O), and S(O). m (where m is 0, 1 or 2).

[0079] The term "aryl" refers to any stable 6- to 10-membered monocyclic or bicyclic aromatic group, including (but not limited to) phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, or biphenyl. The hydrogen atoms on the "aryl" group are each optionally and independently replaced by one or more substituents described in this invention.

[0080] The term "heteroaryl" refers to an aromatic ring group formed by replacing a carbon atom in a ring with at least one heteroatom selected from sulfur, oxygen, or nitrogen. This aromatic ring group can be a 5- to 7-membered monocyclic or a 7- to 12-membered bicyclic group. In this invention, the number of heteroatoms in the heteroaryl group is preferably 1, 2, 3, or 4, such as thiophene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridine-2(1H)-keto, pyridin-4(1H)-keto, pyrroleyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothiophene, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl, etc. The hydrogen atoms on the “heteroaryl” group are each optionally and independently replaced by one or more substituents described in this invention. The term “5- to 10-membered heteroaryl” refers to a heteroaryl ring having 5 to 10 carbon atoms and heteroatoms, wherein the heteroaryl ring is as defined above.

[0081] The term "amino" alone or in combination represents primary amino (-NH2), secondary amino (-NH-) or tertiary amino.

[0082] The term "NH(C)" 1-6 "alkyl)" and the term "N(C)" 1-6"alkyl)2" represents an amino group as defined above, either alone or in combination, wherein the hydrogen atoms of the amino group are respectively surrounded by one and two carbon atoms. 1-6 Alkyl groups are substituted, where "C" is a alkyl group. 1-6 "alkyl" means as defined above.

[0083] The term "pharmaceutically acceptable salt" indicates that the compounds of the present invention exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in SMBerge's description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (Vol. 66: 1-19, 1977). In the present invention, a pharmaceutically acceptable non-toxic acid addition salt refers to a salt formed by the compounds of the present invention with an organic or inorganic acid, including (but not limited to) hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, and malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of this invention with organic or inorganic bases, including (but not limited to) alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts or N-containing organic bases formed with N-groups. + (C 1-6 Alkyl)4 salts, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia, triethylamine, or tetrabutylammonium hydroxide, etc. "Pharmaceutically acceptable salts" can be synthesized by conventional chemical methods.

[0084] The term "ester" is used to refer to organic esters, including monoesters, diesters, triesters, and more commonly polyesters.

[0085] The term "solvent" refers to an association formed by one or more solvent molecules with the compounds of this invention. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[0086] The term "prodrug" refers to a chemical derivative of the compound of the present invention, which is converted into the compound represented by general formula I in vivo through a chemical reaction.

[0087] The term "isotope label" indicates that isotopes include (but are not limited to) [aspects of isotopes]. 2 H, 3 H, 11 C, 13 C, 14 C, 15N, 17 O, 18 O, 18 F, 32 P, 35 S and 36 Cl, etc.

[0088] The term "isomer" encompasses all isomeric forms, including enantiomers, diastereomers, tautomers, and geometric isomers (including cis-trans isomers). Therefore, any single stereochemical isomer of the compound designed in this invention, or a mixture of its enantiomers, diastereomers, tautomers, or geometric isomers (or cis-trans isomers), is within the scope of this invention.

[0089] The term "independently" means that at least two groups (or ring systems) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent X and substituent Y are independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0090] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0091] The term “prevention” refers to the complete or near-complete prevention of the occurrence of a disease or condition (e.g., infection, ischemia, or reperfusion injury) when a patient or subject is susceptible to or at risk of the disease or condition; prevention may also include suppression, i.e., preventing the development of the condition.

[0092] The term “treatment” means: 1) suppressing the disease; for example, suppressing the disease, symptoms or symptom of an individual experiencing or exhibiting the pathology or symptom of the disease (i.e., preventing further development of the pathology and / or symptom); or 2) improving the disease; for example, improving the disease, symptoms or symptom of an individual experiencing or exhibiting the pathology or symptom (i.e., reversing the pathology and / or symptom).

[0093] The term "therapeutic effective amount" refers to the amount of an active compound or agent that researchers, veterinarians, physicians, or other clinicians seek to elicit a biological or medical response in an tissue, system, animal, individual, or human.

[0094] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0095] In the following examples, all solvents and reagents used were of analytical or chemical purity; all solvents were redistilled before use; and all anhydrous solvents were processed according to standard or literature methods.

[0096] Column chromatography silica gel (100-200 mesh) and thin-layer chromatography silica gel (GF254) are products of Qingdao Marine Chemical Plant and Yantai Chemical Plant; unless otherwise specified, petroleum ether (60-90℃) / ethyl acetate (v / v) are used as eluents.

[0097] The colorimetric reagent is an ethanol solution of iodine or phosphomolybdic acid.

[0098] Unless otherwise specified, all extraction solvents were dried over anhydrous Na2SO4.

[0099] 1 HNMR was recorded using a Varian-400 or Vnmrs-300 nuclear magnetic resonance spectrometer, with TMS as an internal standard.

[0100] LC-MS was recorded using an Agilent Technologies 1100 high-performance liquid chromatography-ion trap mass spectrometry (LC-MSDTrap) system with a diode array detector (DAD) at detection wavelengths of 214 nm and 254 nm, and ion trap mass spectrometry (ESI source).

[0101] The HPLC column was an Agela Durashell C18 (4.6 × 50 mm, 3.5 μm); the mobile phase was 0.1% NH4HCO3 aqueous solution: acetonitrile (from 5:95 to 95:5 within 5 minutes); the flow rate was 1.8 mL / min.

[0102] The present invention may use the following abbreviations: BINAP ((±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl); DMSO (dimethyl sulfoxide); DIPEA (diisopropylethylamine); LDA (diisopropylaminolithium); LiHMDS (hexamethyldisiloxane-nitrogen lithium); Pd2(dba)3 (tris(dibenzylacetone)dipalladium); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride); Pd(OAc)2 (palladium acetate); TBAF (tetrabutylamine); Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene).

[0103] Example 1

[0104] Compound A1 is synthesized by the following method:

[0105]

[0106] 1) Synthesis of intermediate A1-1

[0107] 4,6-Dichloronicotinic acid (1.5 g, 7.8 mmol) and N,N'-carbonyldiimidazole (2.5 g, 15.6 mmol) were dissolved in tetrahydrofuran (30 mL) and stirred at room temperature for 30 minutes. Then, N-methyl-N-methoxyamine hydrochloride (921 mg, 9.4 mmol) and DIPEA (2.0 g, 15.6 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated sodium bicarbonate (30 mL), the aqueous phase was extracted with ethyl acetate (60 mL), the organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a yellow oily liquid intermediate A1-1 (1.5 g, 82%).

[0108] 1 H NMR (400MHz, CDCl3): δ8.82(s,1H),8.20(s,1H),3.72(s,3H),3.55(s,3H).

[0109] LC-MS: m / z 234.8 [M+H] + .

[0110] 2) Synthesis of intermediate A1-2

[0111] Intermediate A1-1 (1.3 g, 5.5 mmol), p-methoxybenzylamine (1.5 g, 11 mmol), and one drop of concentrated hydrochloric acid were added to ethanol (15 mL), and the mixture was stirred overnight at 85 °C. The reaction solution was concentrated to dryness, and saturated sodium bicarbonate (20 mL) was added. The mixture was stirred for five minutes, and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give intermediate A1-2 (500 mg, 27%), which is a yellow oily liquid.

[0112] 3) Synthesis of intermediate A1-3

[0113] Intermediate A1-2 (500 mg, 1.5 mmol), cyclopropylformamide (385 mg, 4.5 mmol), Pd2(dba)3 (140 mg, 0.15 mmol), Xantphos (173 mg, 0.30 mmol), and cesium carbonate (980 mg, 3.0 mmol) were added sequentially to 1,4-dioxane (15 mL). Under nitrogen protection, the mixture was heated to 120 °C and stirred overnight. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a yellow solid intermediate A1-3 (580 mg, 87%).

[0114] LC-MS: m / z 384.8 [M+H] + .

[0115] 4) Synthesis of intermediate A1-4

[0116] Intermediate A1-3 (580 mg, 1.5 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen protection, ethyl magnesium bromide (12 mL, 12 mmol) was added dropwise at -10 °C. After stirring for 15 minutes, the mixture was gradually brought to room temperature and stirred overnight. The reaction was quenched by adding saturated ammonium chloride aqueous solution (20 mL), and extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to give intermediate A1-4 (450 mg, 84%), which is a yellow oily liquid.

[0117] 1 H NMR (400MHz, DMSO-d6): δ10.75(s,1H),9.40(s,1H),8.70(s,1H),7.56(s,1H),7.28(s,1H),7.26(s,1H),6.92(s,1H),6.90 (s,1H),4.35-4.28(m,2H),3.73(s,3H),3.00(q,J=7.2Hz,2H),2.04-1.97(m,1H),1.05(t,J=6.8Hz,3H),0.83-0.77(m,4H).

[0118] LC-MS: m / z 354.0 [M+H] + .

[0119] 5) Synthesis of intermediate A1-5

[0120] Intermediate A1-4 (450 mg, 1.3 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added dropwise. The mixture was stirred at 80 °C for 3 hours. The reaction solution was concentrated, and the pH was adjusted to 7-8 by adding saturated sodium bicarbonate aqueous solution (20 mL). The aqueous phase was extracted with ethyl acetate (50 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a yellow solid intermediate A1-5 (220 mg, 74%).

[0121] 1 H NMR (400MHz, DMSO-d6): δ10.62(s,1H),8.63(s,1H),7.45(s,1H),2.95(q,J=7.2Hz,2H),2.04-1.97(m,1H),1.05(t,J=6.8Hz,3H),0.82-0.76(m,4H).

[0122] LC-MS: m / z 233.9 [M+H] + .

[0123] 6) Synthesis of intermediate A1-6

[0124] 6-Methoxypyridine-2-amine (1.1 g, 8.9 mmol) was dissolved in acetonitrile (20 mL), and N-bromosuccinimide (1.6 g, 8.9 mmol) was dissolved in acetonitrile (10 mL) to form a suspension. The suspension was slowly added to the reaction mixture at 0 °C, and the mixture was allowed to return to room temperature and stirred for two hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give intermediate A1-6 (1.4 g, 78%).

[0125] 1 H NMR (400MHz, DMSO-d6): δ7.46 (d, J = 8.0 Hz, 1H), 5.97 (d, J = 8.4 Hz, 1H), 4.36 (s, 2H), 3.90 (s, 3H).

[0126] 7) Synthesis of intermediate A1-7

[0127] Intermediate A1-6 (1.4 g, 6.9 mmol) was dissolved in isopropanol (10 mL), and N,N-dimethylformamide dimethyl acetal (1.6 g, 13.8 mmol) was added. The mixture was refluxed and stirred for two hours, cooled to room temperature, and hydroxylamine hydrochloride (718 mg, 10.4 mmol) was added. The mixture was stirred overnight at 50 °C. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a white solid intermediate A1-8 (1.6 g, 94%).

[0128] 1 H NMR (400MHz, DMSO-d6): δ10.20(s,1H),9.49(d,J=9.6Hz,1H),7.82(d,J=10.0Hz,1H),7.74(d,J=8.0Hz,1H),6.56(d,J=8.0Hz,1H),3.87(s,3H).

[0129] LC-MS: m / z 246.8 [M+H] + .

[0130] 8) Synthesis of intermediate A1-8

[0131] Intermediate A1-7 (600 mg, 2.4 mmol) was dissolved in tetrahydrofuran (6 mL), and trifluoroacetic anhydride (1.0 g, 4.8 mmol) was slowly added under ice-water bath. The mixture was refluxed and stirred for 4 hours. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution. The organic phase was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a white solid intermediate A1-8 (250 mg, 46%).

[0132] 1 H NMR (400MHz, CDCl3): δ8.56 (s, 1H), 7.89 (d, J = 9.2Hz, 1H), 7.63 (d, J = 9.2Hz, 1H), 4.22 (s, 3H).

[0133] LC-MS: m / z 227.9 [M+H] + .

[0134] 9) Synthesis of final product A1

[0135] Intermediate A1-5 (80 mg, 0.35 mmol), intermediate A1-8 (80 mg, 0.34 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), Xantphos (20 mg, 0.035 mmol), and potassium carbonate (97 mg, 0.70 mmol) were added to toluene (6 mL). The mixture was stirred at 160 °C for 4 hours in a microwave reactor. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / petroleum ether = 40 / 1) to give a yellow solid final product A1 (10 mg, 7.5%).

[0136] Example 2

[0137] Compound A2 is synthesized by the following method:

[0138]

[0139] 1) Synthesis of intermediate A2-1

[0140] Ethyl 4,6-dichloronicotinate (5.0 g, 22 mmol) was dissolved in a mixed solution of tetrahydrofuran and methanol (80 mL / 20 mL), and sodium borohydride (8.6 g, 56 mmol) was slowly added under ice-water bath. After reacting for 3 hours, the reaction was quenched by adding 30 mL of saturated ammonium chloride aqueous solution, followed by the addition of ethyl acetate (100 mL × 2) and saturated brine (100 mL), extraction, and drying of the combined organic phases. The mixture was then concentrated under reduced pressure to give crude yellow solid intermediate A2-1 (4.0 g, 92%).

[0141] 1 H NMR (400MHz, CDCl3): δ8.48(s,1H),7.38(s,1H),4.81(s,2H).

[0142] LC-MS: m / z 178.0 [M+H] +

[0143] 2) Synthesis of intermediate A2-2

[0144] Intermediate A2-1 (15 g, 84 mmol) was dissolved in chloroform (10 mL), and manganese dioxide (78 mg, 842 mmol) was added. The mixture was transferred to 75 °C and reacted overnight. The mixture was filtered while hot, the filtrate was concentrated, and the residue was loaded onto a silica gel column for chromatography (petroleum ether / ethyl acetate = 15 / 1) to give a white solid intermediate A2-2 (7.0 g, 47%).

[0145] 1 H NMR (400MHz, CDCl3): δ10.44(s,1H),8.85(s,1H),7.50(s,1H).

[0146] 3) Synthesis of intermediate A2-3

[0147] Intermediate A2-2 (3.0 g, 17 mmol) was dissolved in tetrahydrofuran (30 mL) under N2 protection. 2N-ethylmagnesium bromide (5.6 mL, 22 mmol) was added dropwise at -20 °C. After stirring for 10 minutes, the mixture was transferred to room temperature and reacted for 0.5 hours. The reaction was monitored by TLC and found to be complete. The reaction was quenched by adding saturated ammonium chloride aqueous solution (20 mL), and extracted with saturated brine (20 mL) and ethyl acetate (30 mL × 2). The organic phases were separated, combined, dried, and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give a yellow oily intermediate A2-3 (1.5 g, 42%).

[0148] 1 H NMR (400MHz, CDCl3): δ8.53(s,1H),7.33(s,1H),5.03(s,1H),2.15(br.s,1H),1.87-1.72(m,2H),1.01(t,J=7.2Hz,3H).

[0149] LC-MS: m / z 206.0 [M+H] + .

[0150] 4) Synthesis of intermediate A2-4

[0151] Intermediate A2-3 (4.2 g, 20 mmol) was dissolved in dichloromethane (120 mL), and Dys-Martin reagent (13 g, 31 mmol) was added in portions at room temperature. After reacting for 3 hours, the reaction was quenched by adding saturated sodium bicarbonate aqueous solution (30 mL). The reaction was then carried out by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give a yellow solid intermediate A2-4 (3.3 g, 79%).

[0152] 1 H NMR (400MHz, CDCl3): δ8.54 (s, 1H), 7.45 (s, 1H), 2.98 (q, J = 7.2Hz, 2H), 1.23 (t, J = 7.2Hz, 3H).

[0153] LC-MS: m / z 204.0 [M+H] + .

[0154] 5) Synthesis of intermediate A2-5

[0155] Intermediate A2-4 (2.2 g, 10 mmol), cyclopropylformamide (850 mg, 10 mmol), cesium carbonate (5.2 g, 15 mmol), BINAP (291 mg, 0.32 mmol), and Pd2(dba)3 (330 mg, 0.53 mmol) were added sequentially to 1,4-dioxane (10 mL). The mixture was stirred at 115 °C for 2 hours under N2 protection using a microwave. After dilution with dichloromethane (20 mL), the mixture was filtered, and the filtrate was concentrated. The residue was loaded onto a dry sample and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a yellow solid intermediate A2-5 (1.0 g, 37%).

[0156] 1 H NMR (400MHz, CDCl3): δ8.50(s,1H),8.35(s,1H),8.22(s,1H),3.00(q,J=6.8Hz, 2H),1.56-1.53(m,1H),1.21(t,J=7.Hz,3H),1.14(s,2H),0.96(d,J=5.2Hz,2H).

[0157] LC-MS: m / z 253.1 [M+H] + .

[0158] 6) Synthesis of intermediate A2-6

[0159] 3-Methoxypyridine (2.0 g, 18 mmol) was dissolved in dichloromethane (30 mL). Under ice-water bath conditions, m-chloroperoxybenzoic acid (4.7 g, 27 mmol) was added in portions. The mixture was stirred overnight at room temperature. Saturated sodium sulfite aqueous solution (30 mL) was added, and the mixture was stirred for 30 minutes. Saturated sodium bicarbonate aqueous solution (30 mL) was added, and the mixture was extracted with dichloromethane (60 mL × 10). The extract was then subjected to silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give a yellow solid intermediate A2-6 (1.5 g, 65%).

[0160] 1 H NMR (400MHz, DMSO-d6): δ8.04(s,1H),7.87(d,J=6.0Hz,1H),7.36-7.28(m,1H),7.02(d,J=8.4Hz,1H),3.81(s,3H).

[0161] 7) Synthesis of intermediate A2-7

[0162] Intermediate A2-6 (10 g, 80 mmol) was dissolved in concentrated sulfuric acid (30 mL). Concentrated nitric acid (20 mL) was slowly added dropwise under ice-water bath conditions. After stirring for half an hour, the mixture was transferred to 80 °C and stirred for 3 hours. After cooling to room temperature, the pH was adjusted to 10 with 2NNaOH aqueous solution under ice-water bath conditions. Extraction was performed with dichloromethane (100 mL × 3). The organic phase was dried, concentrated, and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a yellow solid intermediate A2-7 (3.6 g, 26%).

[0163] 1 H NMR (400MHz, DMSO-d6): δ8.46 (s, 1H), 8.05 (d, J = 6.8Hz, 1H), 8.00 (d, J = 6.8Hz, 1H), 3.98 (s, 3H).

[0164] LC-MS: m / z 171.1 [M+H] + .

[0165] 8) Synthesis of intermediate A2-8

[0166] Intermediate A2-7 (5.0 g, 29 mmol) was dissolved in acetic acid (50 mL), and iron powder (9.9 g, 176 mmol) was added at room temperature. The mixture was then refluxed at 100 °C for 3 hours. The solution was first filtered through diatomaceous earth, and the pH of the filtrate was adjusted to 9-10. The solution was then filtered through diatomaceous earth again, and the filtrate was extracted with dichloromethane (50 mL × 4). The organic phase was dried and concentrated to obtain a brown solid intermediate A2-8 (3.6 g, 98%).

[0167] 1H NMR (400MHz, DMSO-d6): δ7.87(s,1H),7.73(d,J=4.4Hz,1H),6.53(d,J=4.4Hz,1H),5.63(s,2H),3.80(s,3H).

[0168] LC-MS: m / z 125.0 [M+H] + .

[0169] 9) Synthesis of intermediate A2-9

[0170] Intermediate A2-8 (3.6 g, 29 mmol) was dissolved in tetrahydrofuran (80 mL). Under N2 protection, 2N-bis(trimethylsilyl)aminolithium (29 mL, 58 mmol) was slowly added in an ice-water bath. After 1 hour, di-tert-butyl dicarbonate (7.0 g, 32 mmol) was slowly added, and the reaction was allowed to proceed for 4 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (50 mL × 3), dried, concentrated, and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid intermediate A2-9 (4.2 g, 64%).

[0171] 1 H NMR (400MHz, CDCl3): δ8.36 (br s, 1H), 8.24 (s, 1H), 8.08 (d, J = 5.2Hz, 1H), 7.83 (d, J = 4.8Hz, 1H), 3.89 (s, 3H), 1.47 (s, 9H).

[0172] LC-MS: m / z 224.9 [M+H] + .

[0173] 10) Synthesis of intermediate A2-10

[0174] Intermediate A2-9 (550 mg, 2.4 mmol) was dissolved in dry acetonitrile (20 mL), and O-(2,4-dinitrophenyl)hydroxylamine (979 mg, 4.9 mmol) was added. The mixture was then transferred to 50 °C and reacted overnight. The reaction solution was concentrated to give a yellow oily crude product A2-10 (1.56 g).

[0175] 11) Synthesis of intermediate A2-11

[0176] Crude A2-10 (1.5 g, 3.7 mmol) was dissolved in N,N-dimethylformamide (10 mL). Potassium carbonate (1.5 g, 11 mmol) was added at room temperature and the mixture was stirred for 1 hour. Ethyl propargylate (360 mg, 3.7 mmol) was then added, and the reaction was allowed to proceed for 24 hours. Ethyl acetate (30 mL) was added, and the mixture was washed with saturated brine (50 mL × 5). The organic phase was separated, dried, and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-3 / 1) to give a gray solid intermediate A2-11 (170 mg, 16%).

[0177] 1 H NMR (400MHz, CDCl3): δ8.36 (s, 1H), 8.29 (d, J = 7.6Hz, 1H), 8.01 (d, J = 7.6Hz, 1H), 7.32(s,1H),4.44-4.30(m,2H),3.89(s,3H),1.55(s,9H),1.40(t,J=7.2Hz,3H).

[0178] 12) Synthesis of intermediate A2-12

[0179] Intermediate A2-11 (170 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1.5 mL) was slowly added at room temperature. The reaction was continued for 2 hours, and the reaction was monitored by TLC until it was complete. The pH was adjusted to 9-10 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were separated and combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give intermediate A2-12 (63 mg, 53%) as a gray solid.

[0180] 1 H NMR (400MHz, CDCl3): δ8.27 (s, 1H), 8.14 (d, J = 7.2Hz, 1H), 6.46 (d, J = 7.2Hz, 1H), 4.42-4.28 (m, 2H), 3.85 (s, 3H), 1.39 (t, J = 7.2Hz, 3H).

[0181] 13) Synthesis of intermediate A2-13

[0182] Intermediate A2-12 (63 mg, 0.27 mmol) was dissolved in 40% H2SO4 (10 mL) aqueous solution and stirred at 80 °C for 4 hours. The pH was adjusted to 10 with 2N sodium hydroxide aqueous solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain a gray solid (34 mg, 77%).

[0183] 1H NMR (400MHz, CDCl3): δ8.12 (d, J = 7.2Hz, 1H), 7.80 (s, 1H), 6.38-6.26 (m, 2H), 3.92 (s, 3H).

[0184] 14) Synthesis of final product A2

[0185] A2-5 (50 mg, 0.20 mmol), A2-13 (30 mg, 0.18 mmol), Pd2(dba)3 (13 mg, 0.01 mmol), BINAP (12 mg, 0.02 mmol), and cesium carbonate (120 mg, 0.36 mmol) were added sequentially to 1,4-dioxane (2 mL). The mixture was stirred at 130 °C for 2 hours under nitrogen protection in a microwave reactor. The reaction mixture was diluted with ethyl acetate (10 mL), filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to obtain a yellow solid final product A2 (20 mg, 27%).

[0186] Example 3

[0187] Compound A3 is synthesized by the following method.

[0188]

[0189] 1) Synthesis of intermediate A3-1

[0190] 4-Bromopyridin-3-ol (1.1 g, 6.3 mmol) was dissolved in concentrated sulfuric acid (10 mL). Concentrated nitric acid (2 mL) was slowly added at -10 °C, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water (50 mL), extracted with ethyl acetate (30 mL × 3), the organic phase was separated, dried, and concentrated to give a yellow solid intermediate A3-1 (1.3 g, 94%).

[0191] 1 H NMR (400MHz, CDCl3): δ10.77 (br s, 1H), 8.05 (d, J = 4.4Hz, 1H), 7.90 (d, J = 4.4Hz, 1H).

[0192] 2) Synthesis of intermediate A3-2

[0193] Intermediate A3-1 (1.2 g, 5.5 mmol) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.5 g, 11 mmol) was slowly added at room temperature. Iodomethane (3.1 g, 22 mmol) was added dropwise at room temperature, and the reaction mixture was stirred at 60 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (100 mL) and washed with saturated brine (30 mL × 5). The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and the residue purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a white solid product (1.0 g, 78%).

[0194] 1 H NMR (400MHz, CDCl3): δ8.09 (d, J = 4.8Hz, 1H), 7.78 (d, J = 5.2Hz, 1H), 4.05 (s, 3H).

[0195] 3) Synthesis of intermediate A3-3

[0196] Intermediate A3-2 (200 mg, 0.86 mmol) was dissolved in a mixed solvent of ethanol / water (10 mL / 5 mL). Ammonium chloride (900 mg, 17 mmol) was added at room temperature, followed by the addition of reduced iron powder (241 mg, 4.3 mmol) in portions at 80 °C. The mixture was stirred at 80 °C for 3 hours and then cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure with 15 mL of saturated sodium bicarbonate solution. The organic phase was separated by extraction with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown oily product A3-3 (140 mg, 80%).

[0197] 1 H NMR (400MHz, CDCl3): δ7.98 (d, J = 5.2 Hz, 1H), 7.18 (d, J = 5.6 Hz, 1H), 5.19 (brs, 2H), 4.21 (s, 3H).

[0198] 4) Synthesis of intermediate A3-4

[0199] Intermediate A3-3 (140 mg, 0.69 mmol) was dissolved in isopropanol (2 mL), and N,N-dimethylformamide dimethyl acetal (204 mg, 1.7 mmol) was added at room temperature. The mixture was stirred at 85 °C for 2 hours. After cooling to room temperature, hydroxylamine hydrochloride (90 mg, 1.3 mmol) was added to the reaction solution. The reaction solution was then stirred at 50 °C overnight. After cooling to room temperature, the reaction solution was filtered to obtain a white solid intermediate A3-4 (110 mg, 65%).

[0200] 1H NMR (400MHz, DMSO-d6): δ10.61(s,1H),8.06(d,J=9.6Hz,1H),7.92-7.76(m,2H),7.21(d,J=5.2Hz,1H),3.84(s,3H).

[0201] 5) Synthesis of intermediate A3-5

[0202] Intermediate A3-4 (300 mg, 1.2 mmol) was dissolved in dry tetrahydrofuran (10 mL). Trifluoroacetic anhydride (1.0 g, 4.8 mmol) was added at room temperature and the mixture was stirred overnight. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (20 mL), and the organic phase was separated by extraction with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a white solid intermediate A3-5 (176 mg, 64%).

[0203] 1 H NMR (400MHz, CDCl3): δ8.28 (s, 1H), 8.22 (d, J = 7.2Hz, 1H), 7.15 (d, J = 6.8Hz, 1H), 4.43 (s, 3H).

[0204] 6) Synthesis of intermediate A3-6

[0205] Intermediate A3-5 (176 mg, 0.78 mmol), tert-butyl carbamate (273 mg, 2.3 mmol), cesium carbonate (500 mg, 1.6 mmol), Xantphos (45 mg, 0.078 mmol), and Pd2(dba)3 (36 mg, 0.039 mmol) were added sequentially to a dry container of 1,4-dioxane (5 mL). After purging with nitrogen, the mixture was stirred at 120 °C for 1 hour in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give an oily liquid intermediate A3-6 (200 mg, 97%).

[0206] 7) Synthesis of intermediate A3-7

[0207] Intermediate A3-6 (200 mg, 0.76 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added at room temperature and stirred for 5 hours. After concentrating the solvent under reduced pressure, the residue was adjusted to pH 8 with saturated sodium bicarbonate. The organic phase was separated by dichloromethane extraction (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give brown oily intermediate A3-7 (110 mg, 89%).

[0208] 1H NMR (400MHz, CDCl3): δ8.15 (d, J = 7.2Hz, 1H), 8.12 (s, 1H), 6.53 (d, J = 6.8Hz, 1H), 4.22 (s, 3H).

[0209] 8) Synthesis of intermediate A3-8

[0210] Intermediates A3-7 (110 mg, 0.67 mmol) and A2-4 (154 mg, 0.76 mmol) were dissolved in dry tetrahydrofuran (10 mL). LiHMDS (2.3 mL, 2.3 mmol) was added dropwise under nitrogen atmosphere and an ice-water bath. After stirring at room temperature for 3 hours, the reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid intermediate A3-8 (32 mg, 14%).

[0211] 9) Synthesis of final product A3

[0212] Intermediate A3-8 (30 mg, 0.10 mmol), cyclopropylformamide (17 mg, 0.20 mmol), cesium carbonate (65 mg, 0.20 mmol), Xantphos (12 mg, 0.020 mmol), and Pd2(dba)3 (10 mg, 0.011 mmol) were added sequentially to dry 1,4-dioxane (2 mL). After purging with nitrogen, the mixture was stirred at 130 °C for 1.5 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to obtain an oily crude product. This crude product was then slurried with ethyl acetate / diethyl ether (5 mL / 5 mL) for 5 hours, filtered, and the white solid final product A3 (20 mg, 53%) was obtained.

[0213] Example 4

[0214] Compound A4 is synthesized by the following method.

[0215]

[0216] 1) Synthesis of intermediate A4-1

[0217] 4-Chloro-1H-pyrrolo[2,3-b]pyridine was dissolved in tetrahydrofuran (5.0 g, 32 mmol). Sodium hydride (1.9 g, 49 mmol, 60%) was added in portions under ice-water bath. After 15 minutes, benzenesulfonyl chloride (6.9 g, 39 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, water (100 ml) was added to quench the reaction, followed by extraction with ethyl acetate (50 ml × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated under vacuum to give a white solid intermediate A4-1 (6.1 g, 64%).

[0218] 1 H NMR (400MHz, CDCl3): δ8.31(d,J=5.2Hz,1H),8.19(d,J=7.6Hz,2H),7.77(d,J=3.6Hz,1H), 7.59(t,J=7.2Hz,1H),7.49(t,J=7.6Hz,2H),7.20(d,J=5.2Hz,1H),6.71(d,J=3.6Hz,1H).

[0219] 2) Synthesis of intermediate A4-2

[0220] Intermediate A4-1 (3.0 g, 10 mmol) and tetramethylammonium nitrate (1.8 g, 13 mmol) were dissolved in dichloromethane (50 mL) and stirred at -10 °C for 5 minutes. Trifluoroacetic acid (18 mL, 13 mmol) was added dropwise, and the mixture was stirred at 0 °C for 30 minutes, then stirred overnight at room temperature. After the reaction was complete, ice water (10 mL) was slowly added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was collected, concentrated, and then dry-coated for silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a white solid intermediate A4-2 (2.8 g, 81%).

[0221] 1 H NMR (400MHz, CDCl3): δ9.00(s,1H),8.28-8.16(m,2H),7.95(s,1H),7.66(s,1H),7.58-7.52(m,2H),6.88(s,1H).

[0222] 3) Synthesis of intermediate A4-3

[0223] Intermediate A4-2 (890 mg, 2.6 mmol) was dissolved in a mixture of methanol and water (20 mL / 7 mL), and potassium carbonate (1.6 g, 11 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the methanol was evaporated to dryness, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give intermediate A4-3 (385 mg, 75%) as a brown solid.

[0224] 1H NMR (400MHz, CDCl3): δ12.36(s,1H),8.69(s,1H),7.56(s,1H),7.05(s,1H),4.40(s,3H).

[0225] 4) Synthesis of intermediate A4-4

[0226] Intermediate A4-3 (140 mg, 0.73 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium hydride (35 mg, 0.87 mmol, purity: 60%) was added and stirred for 5 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (145 mg, 0.87 mmol) was added dropwise at 0 °C. After reacting for 10 minutes, water (15 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phase was collected. The solution was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown oily intermediate A4-4 (75 mg, 32%).

[0227] 1 H NMR (400MHz, DMSO-d6): δ8.75(s,1H),7.75(d,J=3.2Hz,1H),7.14(d,J=3.2Hz,1H), 5.63(s,2H),4.41(s,3H),3.52(t,J=8.0Hz,2H),0.82(t,J=8.0Hz,2H),0.09(s,9H).

[0228] 5) Synthesis of intermediate A4-5

[0229] A4-4 (150 mg, 0.56 mmol) was dissolved in a mixture of ethanol / water (16 mL / 14 mL), and ammonium chloride (187 mg, 3.4 mmol) and reduced iron powder (188 mg, 3.4 mmol) were added. The mixture was refluxed at 85 °C for 2 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give an orange solid intermediate A4-5 (115 mg, 84%).

[0230] 1 H NMR (400MHz, DMSO-d6): δ7.76 (s, 1H), 7.37 (d, J = 3.2Hz, 1H), 6.60 (d, J = 3.2Hz, 1H), 5.47(s,2H),4.14(s,3H),3.47(t,J=8.0Hz,2H),0.80(t,J=8.0Hz,2H),0.10(s,9H).

[0231] LC-MS: m / z 294.2 [M+H] + .

[0232] 6) Synthesis of intermediate A4-6

[0233] Intermediate A4-5 (76 mg, 0.26 mmol) was added to 1,4-dioxane (3 mL) along with A2-5 (60 mg, 0.24 mmol), BINAP (16 mg, 0.026 mmol), Pd2(dba)3 (19 mg, 0.021 mmol), and cesium carbonate (169 mg, 0.52 mmol). The mixture was then reacted under nitrogen protection at 130 °C for 2 hours in a microwave environment. After the reaction was complete, the solvent was concentrated, and the residue was dry-mounted and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow solid intermediate A4-6 (80 mg, 60%).

[0234] 1 H NMR (400MHz, DMSO-d6): δ10.75(s,1H), δ10.43(s,1H), δ8.80(s,1H), δ8.07(s,1 H), δ7.61 (d, J = 3.2Hz, 1H), δ7.40 (s, 1H), δ6.92 (s, 1H), δ5.60 (s, 2H), δ4.21 (s, 3H), δ3.55(t,J=8.0Hz,2H), δ3.10(q,J=7.0Hz,2H), δ1.17(t,J=7.2Hz,1H), δ1. 12(t,J=7.0Hz,3H), δ0.85(t,J=8.0Hz,2H), δ0.74-0.67(m,4H), δ-0.07(s,9H).

[0235] LC-MS (m / z) 510.2 [M+H] + .

[0236] 7) Synthesis of final product A4

[0237] Intermediate A4-6 (80 mg, 0.16 mmol) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (328 mg, 1.3 mmol) was added at room temperature. The mixture was then heated to 65 °C and stirred for 4 hours. After cooling to room temperature, the solvent was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a yellow solid. The solid was then slurried with ethyl acetate / diethyl ether (2 mL / 2 mL) and filtered to obtain the final yellow solid product A4 (8 mg, 13%).

[0238] Example 5

[0239] Compound A5 is synthesized by the following method.

[0240]

[0241] 1) Synthesis of intermediate A5-1

[0242] Intermediate A2-10 (1.5 g, 3.7 mmol) was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (1.5 g, 11 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, ethyl propynate (360 mg, 3.7 mmol) was added, and the reaction was allowed to proceed for 24 hours. Ethyl acetate (30 mL) was added, and the mixture was washed with saturated brine (50 mL × 5). The organic phase was dried, concentrated, and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-3 / 1) to give a gray solid intermediate A5-1 (160 mg, 13%).

[0243] 1 H NMR (400MHz, CDCl3): δ8.73(s,1H),8.25(s,1H),8.02(s,1H),7.23(s,1H),4.47-4.30(m,2H),3.94(s,3H),1.56(s,9H),1.50-1.33(m,3H).

[0244] LC-MS: m / z 335.8 [M+H] + .

[0245] 2) Synthesis of intermediate A5-2

[0246] Intermediate A5-1 (500 mg, 1.5 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (3 mL) was added at room temperature and the mixture was stirred for 3 hours. After concentrating the solvent, the pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a red solid product. This intermediate was dissolved in 40% sulfuric acid aqueous solution (10 mL) and stirred overnight at 80 °C. After cooling to room temperature, the reaction mixture was poured into ice water. The pH was adjusted to 9 with 1 N NaOH aqueous solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a brown solid intermediate A5-2 (160 mg, 65%).

[0247] 3) Synthesis of final product A5

[0248] Intermediates A5-2 (41 mg, 0.25 mmol), A2-5 (71 mg, 0.28 mmol), cesium carbonate (163 mg, 0.50 mmol), BINAP (16 mg, 0.025 mmol), and Pd2(dba)3 (18 mg, 0.020 mmol) were sequentially suspended in dry 1,4-dioxane (2 mL). After purging with nitrogen, the mixture was stirred at 130 °C for 2 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to obtain a yellow solid crude product. This crude product was then slurried with ethyl acetate / diethyl ether (5 mL / 5 mL) for 5 hours, filtered, and the final yellow solid product A5 (45 mg, 47%) was obtained.

[0249] Example 6

[0250] Compound A6 is synthesized by the following method.

[0251]

[0252] 1) Synthesis of intermediate A6-1

[0253] 2-Chloropyridin-3-ol (5.2 g, 40 mmol) was dissolved in N,N-dimethylformamide (60 mL), and potassium carbonate (11 g, 80 mmol) was slowly added at room temperature. Iodomethane (8.5 g, 60 mmol) was added dropwise at room temperature, and the reaction mixture was stirred at 60 °C for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (150 mL) and washed with saturated brine (40 mL × 5). The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and the residue purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a red solid intermediate A6-1 (3.0 g, 53%).

[0254] 1H NMR (400MHz, CDCl3): δ8.02-7.96(m,1H),7.23-7.18(m,2H),3.92(s,3H).

[0255] 2) Synthesis of intermediate A6-2

[0256] Intermediate A6-1 (1.0 g, 7.0 mmol) was dissolved in anhydrous ethanol (15 mL). 98% hydrazine hydrate (15 mL) was added at room temperature, and the mixture was stirred at 115 °C for 36 hours. After cooling to room temperature, the solvent was concentrated, and the residue was extracted with saturated sodium bicarbonate aqueous solution (20 mL), followed by dichloromethane extraction (20 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to obtain a brown oily intermediate. This intermediate was dissolved in trimethyl orthoformate (10 mL), and a catalytic amount of p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol) was added. The mixture was stirred at 110 °C for 1 hour. After cooling to room temperature, the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol / ammonia = 100 / 2 / 0.5) to obtain a brown solid intermediate A6-2 (600 mg, 60%).

[0257] LC-MS: m / z 150.2 [M+H] + .

[0258] 3) Synthesis of intermediate A6-3

[0259] Intermediate A6-2 (586 mg, 3.9 mmol) was dissolved in trifluoroacetic acid (10 mL). Potassium nitrate (1.2 g, 12 mmol) was added at room temperature, and the mixture was stirred overnight at 70 °C. After cooling to room temperature, the solvent was concentrated under reduced pressure. The residue was adjusted to pH 8 with saturated sodium bicarbonate and extracted with dichloromethane (20 mL × 3). The organic phases were separated, combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 3 / 1) to give intermediate A6-3 (70 mg, 9.3%) as a yellow solid.

[0260] 1 H NMR (400MHz, CDCl3): δ8.91 (s, 1H), 7.81 (d, J = 7.6Hz, 1H), 7.42 (d, J = 7.6Hz, 1H), 4.81 (s, 3H).

[0261] 4) Synthesis of intermediate A6-4

[0262] Intermediate A6-3 (50 mg, 0.26 mmol) was dissolved in a mixture of ethanol and water (10 mL / 5 mL). Ammonium chloride (276 mg, 5.2 mmol) was added at room temperature, followed by the addition of reduced iron powder (145 mg, 2.6 mmol) in portions at 80 °C. The mixture was stirred at 80 °C for 3 hours and then cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution (15 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 5). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oily intermediate A6-4 (25 mg, 59%).

[0263] 1 H NMR (400MHz, CDCl3): δ8.61 (s, 1H), 7.71 (d, J = 6.4Hz, 1H), 6.46 (d, J = 6.4Hz, 1H), 4.29 (s, 3H), 4.13 (br s, 2H).

[0264] 5) Synthesis of final product A6

[0265] Intermediates A6-4 (25 mg, 0.15 mmol), A2-5 (42 mg, 0.17 mmol), cesium carbonate (98 mg, 0.30 mmol), BINAP (9.3 mg, 0.015 mmol), and Pd2(dba)3 (14 mg, 0.015 mmol) were sequentially suspended in dry 1,4-dioxane (2 mL). After purging with nitrogen, the mixture was stirred at 130 °C for 2 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to obtain a yellow solid crude product. This crude product was then slurried with ethyl acetate / diethyl ether (5 mL / 5 mL) for 5 hours, filtered, and the final yellow solid product A6 (10 mg, 18%) was obtained.

[0266] Example 7

[0267] Compound A7 is synthesized by the following method.

[0268]

[0269] 1) Synthesis of intermediate A7-1

[0270] 3-Nitro-2-aminophenol (3.0 g, 20 mmol) and potassium carbonate (5.4 g, 39 mmol) were added to N,N-dimethylformamide (6 mL), followed by iodomethane (2 mL). The mixture was stirred at room temperature for two hours. Water (200 mL) was added to the reaction solution, and a solid precipitated out. The solution was filtered to obtain crude red solid intermediate A7-1 (4.0 g).

[0271] 2) Synthesis of intermediate A7-2

[0272] Crude intermediate A7-1 (3.0 g, 18 mmol), iron powder (5.0 g, 90 mmol), and ammonium chloride (5.0 g, 90 mmol) were added to ethanol / water (50 mL / 20 mL) and stirred at 85 °C for 2 hours. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give intermediate A7-2 (2.2 g, 83%) as a yellow solid.

[0273] 1 H NMR (400MHz, CDCl3): δ6.67 (t, J=7.8Hz, 1H), 6.46-6.34 (m, 2H), 3.84 (s, 3H).

[0274] 3) Synthesis of intermediate A7-3

[0275] Intermediate A7-2 (1.0 g, 6.8 mmol) was dissolved in formic acid (10 mL) and stirred at 100 °C for 2 hours. The reaction solution was concentrated, and the pH was adjusted to 7-8 by adding saturated sodium bicarbonate aqueous solution (30 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a white solid intermediate A7-3 (750 mg, 70%).

[0276] 1 H NMR (400MHz, DMSO-d6): δ8.36 (br s, 1H), 8.05 (s, 1H), 7.24 (d, J = 4.0Hz, 1H), 7.17 (t, J = 8.0Hz, 1H), 6.69 (d, J = 8.0Hz, 1H), 3.95 (s, 3H).

[0277] 4) Synthesis of intermediate A7-4

[0278] Intermediate A7-3 (650 mg, 4.4 mmol) was dissolved in trifluoroacetic acid (8 mL), and potassium nitrate (150 mg, 6.6 mmol) was added. The mixture was stirred at 70 °C for 1 hour. The reaction solution was concentrated, and the pH was adjusted to 7-8 by adding saturated sodium bicarbonate aqueous solution (30 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give intermediate A7-4 (750 mg, 77%) as a yellow solid.

[0279] 1H NMR (400MHz, (CD3)2CO): δ8.32 (s, 1H), 7.74 (d, J = 8.8Hz, 1H), 7.32 (d, J = 8.8Hz, 1H), 4.51 (s, 3H).

[0280] 5) Synthesis of intermediate A7-5

[0281] Intermediate A7-4 (260 mg, 1.3 mmol) was dissolved in tetrahydrofuran (15 mL), sodium hydride (39 mg, 1.6 mmol, purity: 60%) was added, and the mixture was stirred for 10 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (269 mg, 1.6 mmol) was added dropwise, and the mixture was stirred for 3 minutes. The reaction was quenched by adding water (35 mL), and the aqueous phase was extracted with ethyl acetate (80 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid intermediate A7-5 (390 mg, 69%).

[0282] 1 H NMR (400MHz, CDCl3): δ7.99 (s, 1H), 7.87 (d, J = 8.4Hz, 1H), 7.16 (d, J = 8.8Hz, 1H), 5. 53(s,2H),4.57(s,3H),3.52(t,J=7.8Hz,2H),0.91(t,J=7.8Hz,2H),-0.04(s,9H).

[0283] 6) Synthesis of intermediate A7-6

[0284] Intermediate A7-5 (390 mg, 1.2 mmol), iron powder (338 mg, 6.0 mmol), and ammonium chloride (320 mg, 6.0 mmol) were added to ethanol / water (35 mL / 15 mL) and stirred at 85 °C for 1 hour. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give intermediate A7-6 (180 mg, 51%) as a yellow solid.

[0285] 7) Synthesis of intermediate A7-7

[0286] Intermediates A7-6 (180 mg, 0.6 mmol) and A2-4 (125 mg, 0.6 mmol) were dissolved in tetrahydrofuran (10 mL). Under nitrogen protection, LiHMDS (1.2 mL) was added dropwise, and the mixture was stirred for 1 hour. The reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give intermediate A7-7 (102 mg, 64%) as a yellow solid.

[0287] 1 H NMR (400MHz, CDCl3): δ10.65(s,1H),8.74(s,1H),7.99-7.90(m,1H),7.19(s,2H),6.64(s,1H),5.53(s,2H),4. 39(s,3H),3.55(t,J=8.0Hz,2H),3.07(q,J=7.2Hz,2H),1.39-1.33(m,3H),0.94(t,J=8.0Hz,2H),-0.03(s,9H).

[0288] 8) Synthesis of intermediate A7-8

[0289] Intermediate A7-7 (102 mg, 0.22 mmol), cyclopropylformamide (125 mg, 0.26 mmol), Pd2(dba)3 (20 mg, 0.020 mmol), xantphos (12 mg, 0.020 mmol), and cesium carbonate (143 mg, 0.44 mmol) were added sequentially to 1,4-dioxane (2 mL). The mixture was stirred in a microwave at 120 °C for 1 hour under nitrogen protection. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a yellow solid intermediate A7-8 (62 mg, 55%).

[0290] 1 H NMR (400MHz, CDCl3): δ10.88(s,1H),9.01(s,1H),8.67(s,1H),7.91(s,1H),7. 76(s,1H),7.32(d,J=8.4Hz,1H),7.20(d,J=8.4Hz,1H),5.50(s,2H),4.38(s,3 H),3.55(t,J=8.0Hz,2H),3.09-2.95(m,2H),1.64-1.51(m,1H),1.28-1.20(m, 3H),1.00-0.95(m,2H),0.93(t,J=8.0Hz,2H),0.86-0.80(m,2H),-0.03(s,9H).

[0291] 9) Synthesis of final product A7

[0292] Intermediate A7-8 (60 mg, 0.12 mmol) was dissolved in tetrahydrofuran (8 mL), and TBAF (1 mL, 1 N) was added. The mixture was stirred at 65 °C for 1 hour. The reaction solution was diluted with ethyl acetate (30 mL), and the organic phase was washed with water (30 mL × 3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give the final product A7 (10 mg, 22%) as a yellow solid.

[0293] Example 8

[0294] Compound A8 is synthesized by the following method.

[0295]

[0296] 1) Synthesis of intermediate A8-1

[0297] 3-Methoxypyridine-2-amine (1.2 g, 10 mmol) was dissolved in anhydrous ethanol (50 mL), and chloroacetaldehyde (1.8 g, 20 mmol) was added at room temperature. The mixture was stirred overnight at 100 °C. After cooling to room temperature, the solvent was concentrated, and the residue was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with dichloromethane (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give a white solid intermediate A8-1 (900 mg, 61%).

[0298] 1 H NMR (400MHz, CDCl3): δ7.77(d,J=6.4Hz,1H),7.57(s,1H),7.55(s,1H),6.74-6.63(m,1H),6.43(d,J=7.2Hz,1H),4.01(s,3H).

[0299] 2) Synthesis of intermediate A8-2

[0300] Intermediate A8-1 (687 mg, 4.6 mmol) was dissolved in anhydrous acetonitrile (20 mL), and N-bromosuccinimide (826 mg, 4.6 mmol) was added at room temperature, followed by stirring for 1 hour. After concentrating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a white solid intermediate A8-2 (700 mg, 70%).

[0301] 1 H NMR (400MHz, CDCl3): δ7.78 (d, J = 6.8 Hz, 1H), 7.57 (s, 1H), 6.91-6.80 (m, 1H), 6.54 (d, J = 7.2 Hz, 1H), 4.03 (s, 3H).

[0302] 3) Synthesis of intermediate A8-3

[0303] Intermediate A8-2 (700 mg, 3.1 mmol) was dissolved in concentrated sulfuric acid (5 mL). Concentrated nitric acid (2 mL) was slowly added at -10 °C, followed by stirring overnight at room temperature. The reaction mixture was poured into ice water (20 mL), and the pH was adjusted to 9 with 1 N NaOH aqueous solution. Extraction was performed with dichloromethane (20 mL × 3), the organic phase was separated, dried, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a yellow solid intermediate A8-3 (300 mg, 36%).

[0304] 1 H NMR (400MHz, CDCl3): δ7.84 (d, J = 7.2 Hz, 1H), 7.76 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 4.61 (s, 3H).

[0305] 4) Synthesis of intermediate A8-4

[0306] Intermediate A8-3 (100 mg, 0.37 mmol) was dissolved in glacial acetic acid (10 mL), and zinc powder (980 mg, 15 mmol) was slowly added at room temperature. The mixture was stirred at 50 °C for 4 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was adjusted to pH 8 with saturated sodium bicarbonate, extracted with dichloromethane (10 mL × 3), and the organic phases were separated, combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give brown oily intermediate A8-4 (25 mg, 42%).

[0307] 1 H NMR (400MHz, CDCl3): δ7.71(br.s,1H),7.44(br.s,1H),7.38(br.s,1H),6.37(br.s,1H),4.17(s,3H),3.94(br s,2H).

[0308] 5) Synthesis of final product A8

[0309] Intermediates A8-4 (25 mg, 0.15 mmol), A2-5 (42 mg, 0.17 mmol), cesium carbonate (98 mg, 0.30 mmol), BINAP (9.3 mg, 0.015 mmol), and Pd2(dba)3 (14 mg, 0.015 mmol) were sequentially suspended in dry 1,4-dioxane (2 mL). After purging with nitrogen, the mixture was stirred at 130 °C for 2 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to obtain a yellow solid crude product. This crude product was then slurried with ethyl acetate / diethyl ether (5 mL / 5 mL) for 5 hours, filtered, and the yellow solid final product A8 (20 mg, 35%) was obtained.

[0310] Example 9

[0311] Compound A9 is synthesized by the following method.

[0312]

[0313] 1) Synthesis of intermediate A9-1

[0314] 4-Bromo-2-fluoro-1-methoxybenzene (2.0 g, 9.8 mmol) was dissolved in dry tetrahydrofuran (20 mL) under nitrogen protection, and LDA (6.3 mL, 12.7 mmol) was slowly added dropwise at -78 °C, with stirring continued for 30 minutes. Dry N,N-dimethylformamide (1.4 g, 18.5 mmol) was then slowly added dropwise, and the mixture was stirred at -78 °C for 2 hours. The reaction mixture was quenched with a saturated ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid intermediate A9-1 (1.6 g, 71%).

[0315] 1 H NMR (400MHz, DMSO-d6): δ10.17(s,1H),7.56(d,J=8.8Hz,1H),7.41(t,J=8.8Hz,1H),3.88(s,3H).

[0316] 2) Synthesis of intermediate A9-2

[0317] Intermediate A9-1 (1.0 g, 4.3 mmol) was dissolved in ethylene glycol dimethyl ether (10 mL), and hydrazine hydrate (4.3 g, 86 mmol) was added. The mixture was stirred overnight at 100 °C. The reaction solution was diluted with water, extracted with ethyl acetate (20 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a white solid intermediate A9-2 (570 mg, 59%).

[0318] 1H NMR (400MHz, DMSO-d6): δ13.70(s,1H),7.97(s,1H),7.22(d,J=8.0Hz,1H),6.78(d,J=8.0Hz,1H),3.94(s,3H).

[0319] 3) Synthesis of intermediate A9-3

[0320] Intermediate A9-2 (400 mg, 1.8 mmol) was dissolved in trifluoroacetic acid (10 mL), and potassium nitrate (179 mg, 1.8 mmol) was added with stirring at room temperature. The mixture was then stirred at 70 °C for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (10 mL), and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. The solution was extracted three times with dichloromethane (10 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a yellow solid intermediate A9-3 (190 mg, 40%).

[0321] 1 H NMR (400MHz, DMSO-d6): δ14.56(s,1H),8.34(s,1H),7.81(s,1H),4.20(s,3H).

[0322] 4) Synthesis of intermediate A9-4

[0323] Intermediate A9-3 (100 mg, 0.37 mmol) was dissolved in ethyl acetate (10 mL), 10% palladium on carbon (100 mg) was added, and triethylamine (37 mg, 0.37 mmol) was added dropwise. The air was replaced with hydrogen, and the reaction was stirred at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain A9-4 (50 mg, 83%).

[0324] 1 H NMR (400MHz, CDCl3): δ7.95 (s, 1H), 7.29 (d, J = 8.4Hz, 1H), 6.67 (d, J = 8.4Hz, 1H), 3.93 (s, 3H).

[0325] 5) Synthesis of final product A9

[0326] Intermediates A9-4 (10 mg, 0.061 mmol), A2-5 (17 mg, 0.067 mmol), BINAP (3.8 mg, 0.0060 mmol), Pd2(dba)3 (5 mg, 0.0050 mmol), and cesium carbonate (40 mg, 0.12 mmol) were added to dry 1,4-dioxane (1 mL), and the mixture was microwaved at 130 °C for 2 hours under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated, and preparative plate chromatography (dichloromethane / methanol = 30 / 1) was performed to obtain a pale yellow solid final product A9 (6 mg, 26%).

[0327] Example 10

[0328] Compound A10 is synthesized by the following method.

[0329]

[0330] 1) Synthesis of intermediate A10-1

[0331] 2,3-Diaminoanisole (1.5 g, 11 mmol) was dissolved in acetic acid (6 mL). Under ice-water bath conditions, 10 mL of an aqueous solution containing sodium nitrite (850 mg, 12 mmol) was added and stirred for 30 minutes. Then, 4 mL of acetic acid was added, and the mixture was stirred at 80 °C for 3 hours. The reaction solution was concentrated, and the pH was adjusted to 7-8 by adding 20 mL of saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a yellow solid intermediate, A10-1 (1.2 g, 92%).

[0332] 1 H NMR (400MHz, CDCl3): δ15.55(s,1H),7.09(s,1H),5.44(s,2H),3.80(s,3H).

[0333] 2) Synthesis of intermediate A10-2

[0334] Intermediate A10-1 (1.2 g, 8 mmol) was dissolved in dichloromethane (20 mL). Under ice-water bath conditions, N-bromosuccinimide (1.4 g, 8 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution (15 mL) was added to the reaction mixture, and the mixture was stirred for 3 minutes. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a white solid intermediate A10-2 (0.9 g, 50%).

[0335] 1H NMR (400MHz, DMSO-d6): δ7.55 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H).

[0336] 3) Synthesis of intermediate A10-3

[0337] Intermediate A10-2 (0.9 g, 4.0 mmol) was dissolved in trifluoroacetic acid (10 mL), and potassium nitrate (0.6 g, 6.0 mmol) was added. The mixture was stirred at 70 °C for 2 hours. The reaction solution was concentrated, and the pH was adjusted to 7-8 by adding saturated sodium bicarbonate aqueous solution (30 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 3) to give intermediate A10-3 (700 mg, 65%) as a yellow solid.

[0338] 1 H NMR (400MHz, DMSO-d6): δ8.94(s,1H),8.23(s,1H),4.60(s,3H).

[0339] 4) Synthesis of intermediate A10-4

[0340] Intermediate A10-3 (700 mg, 2.6 mmol) was dissolved in acetic acid (10 mL), and zinc powder (5.0 g, 78 mmol) was added. The mixture was stirred at 55 °C for 6 hours. The reaction solution was concentrated, and saturated sodium bicarbonate aqueous solution (30 mL) was added. The aqueous phase was extracted with ethyl acetate (60 mL × 3). The organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give intermediate A10-4 (40 mg, 10%) as a yellow solid.

[0341] 1 H NMR (400MHz, DMSO-d6): δ15.22(s,1H),7.45(d,J=8.4Hz,1H),6.83(d,J=8.4Hz,1H),5.21(s,2H),3.81(s,3H).

[0342] 5) Synthesis of final product A10

[0343] Intermediates A10-4 (40 mg, 0.24 mmol), A2-5 (67 mg, 0.26 mmol), Pd2(dba)3 (22 mg, 0.02 mmol), BINAP (12 mg, 0.02 mmol), and cesium carbonate (156 mg, 0.48 mmol) were added sequentially to 1,4-dioxane (2 mL). The mixture was stirred in a microwave at 130 °C for 2 hours under nitrogen protection. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to obtain the yellow solid final product A10 (10 mg, 11%).

[0344] Example 11

[0345] Compound A11 is synthesized by the following method.

[0346]

[0347] 1) Synthesis of intermediate A11-1

[0348] The starting material 2-chloro-5-nitropyridine (3.2 g, 20.1 mmol) was dissolved in isopropanol (20 mL), and hydrazine hydrate (1 mL) was added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, and a solid precipitated out. The solid was filtered and washed with a small amount of isopropanol. The filter cake was dried to obtain crude intermediate A11-1 (3.0 g, 97%), which was directly added to the next step.

[0349] LC-MS: m / z 155.1 [M+H] + .

[0350] 2) Synthesis of intermediate A11-2

[0351] Crude intermediate A11-1 (3.0 g, 19.5 mmol) was dissolved in dichloromethane (20 mL), and trimethyl orthoformate (20 mL) was added. Trifluoroacetic acid (2.5 g, 22.0 mmol) was added dropwise. The mixture was stirred overnight at room temperature. The trifluoroacetic acid was neutralized with saturated sodium bicarbonate solution, and the organic phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give intermediate A11-2 (2.4 g, 75%) as a gray solid.

[0352] 1 H NMR (400MHz, CDCl3): δ9.31 (s, 1H), 9.07 (s, 1H), 8.05 (d, J = 9.2Hz, 1H), 7.92 (d, J = 9.6Hz, 1H).

[0353] 3) Synthesis of intermediate A11-3

[0354] Intermediate A11-2 (2.4 g, 14.6 mmol) was dissolved in a mixture of ethanol / water (40 mL / 20 mL), iron powder (3.7 g, 65.6 mmol) and ammonium chloride (3.7 g, 65.6 mmol) were added, and the mixture was stirred at 85 °C for 2 hours. The reaction solution was diluted with dichloromethane (100 mL), and the iron powder was removed by diatomaceous earth filtration. The filter cake was washed with dichloromethane again, and water (40 mL) was added to the filtrate. The mixture was separated, and the organic phase was extracted with dichloromethane (50 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid intermediate A11-3 (1.3 g, 66%).

[0355] 1 H NMR (400MHz, CDCl3): δ8.19 (s, 1H), 8.04 (s, 1H), 7.58 (d, J = 9.6Hz, 1H), 7.09 (d, J = 9.2Hz, 1H), 3.49 (s, 2H).

[0356] 4) Synthesis of intermediate A11-4

[0357] Intermediate A11-3 (1.3 g, 10.0 mmol) was dissolved in acetonitrile (20 mL). The suspension of N-chlorosuccinimide dissolved in acetonitrile (5 mL) was slowly added to the reaction solution. The mixture was brought back to room temperature and stirred for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain crude intermediate A11-4 (2.1 g) as a pale yellow solid.

[0358] 1 H NMR (400MHz, CDCl3): δ8.29 (s, 1H), 7.60 (d, J = 9.2Hz, 1H), 7.20 (d, J = 9.2Hz, 1H), 3.89 (s, 2H).

[0359] 5) Synthesis of the final product A11

[0360] Crude intermediate A11-4 (80 mg, 0.47 mmol) was dissolved in 1,4-dioxane (5 mL), and A2-5 (58 mg, 0.23 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), XantPhos (25 mg, 0.04 mmol), and cesium carbonate (306 mg, 0.94 mmol) were added. Under nitrogen protection, the mixture was stirred at 130 °C for 2 hours in a microwave reactor. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 80 / 1) to give a pale yellow solid final product A11 (50 mg, 56%).

[0361] Example 12

[0362] Compound A12 is synthesized by the following method.

[0363]

[0364] 1) Synthesis of the final product A12

[0365] Under ice-water bath conditions, sodium hydride (40 mg, 1.0 mmol) was slowly added to 2 mL of methanol dried with molecular sieves. After stirring at room temperature for 10 minutes, A11 (20 mg, 0.05 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The organic phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparing a silica gel plate (dichloromethane / methanol = 50 / 1) to obtain a pale yellow solid final product, A12 (5 mg, 26%).

[0366] Example 13

[0367] Compound A13 is synthesized by the following method.

[0368]

[0369] 1) Synthesis of intermediate A13-1

[0370] The starting material 6-bromo-2-nitrophenol (500 mg, 2.3 mmol) was dissolved in acetone (20 mL), and potassium carbonate (952 mg, 6.9 mmol) was added. The mixture was stirred and refluxed at 70 °C for 1 hour. Iodimethane (980 mg, 6.9 mmol) was slowly added, and the mixture was stirred and refluxed at 70 °C overnight. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated sodium chloride aqueous solution (20 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid intermediate A13-1 (400 mg, 83%).

[0371] 1 H NMR (400MHz, DMSO-d6): δ8.01(d,J=8.0Hz,1H),7.95(d,J=8.0Hz,1H),7.32(t,J=8.0Hz,1H),3.91(s,3H).

[0372] 2) Synthesis of intermediate A13-2

[0373] Intermediate A13-1 (340 mg, 1.5 mmol), dimethylphosphine oxide (160 mg, 2.1 mmol), palladium acetate (33 mg, 0.15 mmol), Xantphos (170 mg, 0.29 mmol), and potassium phosphate (778 mg, 3.7 mmol) were added to 10 mL of dry N,N-dimethylformamide under nitrogen protection and stirred under reflux at 150 °C overnight. The reaction mixture was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give a brownish-black solid intermediate A13-2 (90 mg, 28%).

[0374] 1 H NMR (400MHz, CDCl3): δ11.39(s,1H),8.36-8.26(m,2H),7.21-7.17(m,1H),1.87(s,3H),1.84(s,3H).

[0375] 3) Synthesis of intermediate A13-3

[0376] Intermediate A13-2 (97 mg, 0.45 mmol) was dissolved in acetone (15 mL), potassium carbonate (186 mg, 1.4 mmol) was added, and the mixture was stirred and refluxed at 70 °C for 1 hour. Iodimethane (192 mg, 1.4 mmol) was slowly added, and the mixture was stirred and refluxed at 70 °C overnight. The reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated sodium chloride aqueous solution (20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid intermediate A13-3 (50 mg, 48%).

[0377] 1 H NMR (400MHz, CDCl3): δ8.21 (dd, J=11.2, 8.0Hz, 1H), 8.01 (d, J=8.0Hz, 1H), 7.36-7.33 (m, 1H), 3.94 (s, 3H), 1.84 (s, 3H), 1.81 (s, 3H).

[0378] 4) Synthesis of intermediate A13-4

[0379] Intermediate A13-3 (140 mg, 0.61 mmol) was dissolved in ethanol (10 mL), and 10% palladium on carbon (100 mg) was added. The mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered and concentrated to obtain a pale yellow oily intermediate A13-4 (38 mg, 31%).

[0380] 1H NMR (400MHz, DMSO-d6): δ6.98-6.87(m,2H),6.86-6.78(m,1H),5.11(s,2H),3.74(s,3H),1.65(s,3H),1.62(s,3H).

[0381] LC-MS: m / z 200.2 [M+H] + .

[0382] 5) Synthesis of the final product A13

[0383] Intermediates A13-4 (38 mg, 0.19 mmol), A2-5 (52.9 mg, 0.21 mmol), BINAP (11.8 mg, 0.019 mmol), Pd2(dba)3 (13.9 mg, 0.015 mmol), and cesium carbonate (124 mg, 0.38 mmol) were added to a dry container of 1,4-dioxane (3 mL). The mixture was reacted under nitrogen protection with microwave stirring at 130 °C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated, and the final product was separated by silica gel preparative chromatography (dichloromethane / alcohol / ammonia = 20 / 1 / 1) to give a white solid final product A13 (19 mg, 39%).

[0384] Example 14

[0385] Compound A14 is synthesized by the following method.

[0386]

[0387] 1) Synthesis of intermediate A14-1

[0388] The starting material 4-chloro-2-methoxynitrobenzene (500 mg, 2.7 mmol) was dissolved in dry N,N-dimethylformamide (5 mL), followed by the addition of dimethylphosphine oxide (229 mg, 2.9 mmol), Pd(OAc)₂ (30 mg, 0.13 mmol), K₃PO₄ (623 mg, 2.9 mmol), and Xantphos (92 mg, 0.16 mmol). The mixture was stirred and refluxed at 120 °C for 18 hours under nitrogen protection. The reaction mixture was cooled, diluted with saturated sodium bicarbonate aqueous solution (20 mL), and extracted three times with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a brownish-black solid intermediate A14-1 (118 mg, 19%).

[0389] 1H NMR (400MHz, DMSO-d6): δ7.99(dd,J=7.8,2.0Hz,1H),7.64(d,J=12.0Hz,1H),7.54-7.46(m,1H),3.99(s,3H),1.74(s,3H),1.70(s,3H).

[0390] LC-MS: m / z 230.1 [M+H] + .

[0391] 2) Synthesis of intermediate A14-2

[0392] Intermediate A14-1 (118 mg, 0.51 mmol) was dissolved in ethanol (15 mL), and 10% palladium on carbon (50 mg) was added. The air was replaced with hydrogen, and the mixture was stirred overnight at room temperature. The reaction solution was filtered and concentrated to give a yellow oily intermediate A14-2 (100 mg, 99%).

[0393] 1 H NMR (400MHz, DMSO-d6): δ7.11-6.98(m,2H),6.73-6.65(m,1H),3.80(s,3H),1.57(s,3H),1.53(s,3H).

[0394] 3) Synthesis of the final product A14

[0395] Intermediate A14-2 (50 mg, 0.25 mmol), A2-5 (69.6 mg, 0.27 mmol), BINAP (16 mg, 0.025 mmol), Pd2(dba)3 (18.3 mg, 0.020 mmol), and cesium carbonate (163 mg, 0.5 mmol) were added to dry 1,4-dioxane (3 mL), the air was replaced with nitrogen, and the mixture was microwaved at 130 °C for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the mixture was separated by preparative chromatography (dichloromethane / methanol / ammonia = 20 / 1 / 1) to give a white solid final product A14 (30 mg, 29%).

[0396] Example 15

[0397] Compound A15 is synthesized by the following method.

[0398]

[0399] 1) Synthesis of intermediate A15-1

[0400] 4,6-Dichloronicotinic acid (500 mg, 2.6 mmol) was suspended in dry dichloromethane (15 mL), and a catalytic amount of N,N-dimethylformamide (20 mg) was added dropwise. Oxaloyl chloride (434 mg, 3.4 mmol) was then added dropwise under stirring at room temperature for two hours. The reaction mixture was evaporated to dryness to obtain crude acyl chloride. The freshly prepared crude acyl chloride was dissolved in dry dichloromethane (15 mL), and a methanol solution of ammonia (1.1 mL, 7.9 mmol) was slowly added dropwise under an ice-water bath. The mixture was then slowly brought to room temperature and stirred overnight. The reaction mixture was diluted with water, extracted three times with dichloromethane (10 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a white solid A15-1 (240 mg, 48%).

[0401] 1 H NMR (400MHz, DMSO-d6): δ8.49(s,1H),8.11(s,1H),7.88(s,2H).

[0402] 2) Synthesis of intermediate A15-2

[0403] Intermediates A15-1 (80 mg, 0.42 mmol) and A14-2 (84 mg, 0.42 mmol) were dissolved in dry tetrahydrofuran (6 mL) under nitrogen protection. LiHMDS (1.0 mL, 1.0 mmol) was slowly added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution (15 mL), extracted with ethyl acetate (10 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a brownish-yellow solid intermediate A15-2 (40 mg, 27%).

[0404] 1 H NMR (400MHz, DMSO-d6): δ10.76(s,1H),8.59(s,1H),8.34(s,1H),7.76(s,1H), 7.57(s,1H),7.43(s,2H),7.00(s,1H),3.90(s,3H),1.69(s,3H),1.66(s,3H).

[0405] LC-MS: m / z 354.0 [M+H] + .

[0406] 3) Synthesis of final product A15

[0407] Intermediate A15-2 (140 mg, 0.40 mmol), cyclopropylformamide (43 mg, 0.51 mmol), Xantphos (46.2 mg, 0.080 mmol), Pd2(dba)3 (36.6 mg, 0.040 mmol), and cesium carbonate (258.2 mg, 0.80 mmol) were added to a dry container of 1,4-dioxane (3 mL). The mixture was microwaved at 130 °C for 2 hours under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated, dissolved in methanol, and separated by reversed-phase column chromatography (methanol / water = 2%–70%) to give a white solid product A15 (14 mg, 9.0%).

[0408] Example 16

[0409] Compound A16 is synthesized by the following method.

[0410]

[0411] 1) Synthesis of intermediate A16-1

[0412] 4,6-Dichloronicotinic acid (1.9 g, 10 mmol) and carbonyl diimidazole (3.2 g, 20 mmol) were dissolved in dry tetrahydrofuran (40 mL). After stirring at room temperature for 30 minutes, methylamine hydrochloride (804 mg, 12 mmol) and DIPEA (2.6 g, 22 mmol) were added sequentially. After stirring at room temperature for 3 hours, the mixture was quenched with saturated sodium bicarbonate aqueous solution (20 mL), and then diluted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and the residue was slurried with ethyl acetate / diethyl ether (15 mL / 15 mL) for 3 hours. After filtration, a white solid intermediate A16-1 (1.5 g, 74%) was obtained.

[0413] 1 H NMR (400MHz, CDCl3): δ8.64 (s, 1H), 7.42 (s, 1H), 6.28 (br s, 1H), 3.04 (d, J = 4.8Hz, 3H).

[0414] 2) Synthesis of intermediate A16-2

[0415] Intermediates A14-2 (30 mg, 0.15 mmol) and A16-1 (29 mg, 0.15 mmol) were dissolved in dry tetrahydrofuran (5 mL) under nitrogen protection. LiHMDS (0.40 mL, 0.37 mmol) was slowly added dropwise at room temperature, and the mixture was stirred at room temperature for 4 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (15 mL), extracted with ethyl acetate (10 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol / ammonia = 50 / 1 / 1) to give a pale yellow intermediate A16-2 (20 mg, 37%).

[0416] 1 H NMR (400MHz, CDCl3): δ10.30(s,1H),8.40(s,1H),7.45-7.39(m,2H),7.34(d,J=12.4Hz,1H), 7.17-7.10(m,1H),7.09(s,1H),3.94(s,3H),3.00(d,J=4.0Hz,3H),1.76(s,3H),1.73(s,3H).

[0417] LC-MS: m / z 368.0 [M+H] + .

[0418] 3) Synthesis of the final product A16

[0419] Intermediate A16-2 (20 mg, 0.054 mmol), cyclopropylformamide (6 mg, 0.070 mmol), Xantphos (6.4 mg, 0.011 mmol), Pd2(dba)3 (5 mg, 0.0050 mmol), and cesium carbonate (35 mg, 0.11 mmol) were added to a dry container of 1,4-dioxane (2 mL). The mixture was microwaved at 130 °C for 2 hours under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (dichloromethane / methanol / ammonia = 30 / 1 / 1) to give a white solid final product A16 (12 mg, 54%).

[0420] Example 17

[0421] Compound A17 is synthesized by the following method.

[0422]

[0423] 1) Synthesis of intermediate A17-1

[0424] 4-Chloro-1-methoxy-2-nitrobenzene (1.5 g, 7.9 mmol) was dissolved in methanol (30 mL), and ferric chloride (150 mg, 0.94 mmol) and activated carbon (150 mg, 0.38 mmol) were added. The mixture was heated to reflux, and hydrazine hydrate (3 mL, 47 mmol) was added. The reaction was allowed to proceed for 16 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was evaporated to dryness to obtain a yellow solid intermediate A17-1 (1.0 g, 79%).

[0425] 1 H NMR (400MHz, CDCl3): δ6.68(s,1H),6.67(m,2H),3.83(s,3H).

[0426] 2) Synthesis of intermediate A17-2

[0427] Intermediate A17-1 (700 mg, 4.4 mmol) was dissolved in acetonitrile (15 mL). N-bromosuccinimide (790 mg, 4.4 mmol) was added at 0 °C, and the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was complete, the reaction solution was slowly poured into ice water (100 mL), and saturated sodium bicarbonate solution was added until the pH reached 8. The organic phase was then collected using ethyl acetate (50 mL × 3) and dried over anhydrous sodium sulfate. The solution was loaded onto a silica gel column for chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a white solid intermediate A17-2 (300 mg, 28%).

[0428] 1 H NMR (400MHz, CDCl3): δ6.93(s,1H),6.77(s,1H),3.83(s,3H).

[0429] LC-MS: m / z 238.1 [M+H] + .

[0430] 3) Synthesis of intermediate A17-3

[0431] Intermediate A17-2 (100 mg, 0.42 mmol) was dissolved in 1,4-dioxane (3 mL), and dimethylphosphine oxide (34.64 mg, 0.44 mmol), potassium carbonate (115 mg, 0.85 mmol), Xantphos (25.3 mg, 0.044 mmol), and Pd2(dba)3 (40.3 mg, 0.044 mmol) were added. The mixture was then reacted under nitrogen protection at 125 °C for 3 hours in a microwave oven. After the reaction was complete, the sample was dry-loaded and subjected to silica gel column chromatography (dichloromethane / methanol = 40 / 1) to obtain a yellow solid intermediate A17-3 (50 mg, 51%).

[0432] 4) Synthesis of the final product A17

[0433] Intermediates A17-3 (52 mg, 0.21 mmol) and A2-5 (67.4 mg, 0.27 mmol) were dissolved in 1,4-dioxane (4 mL), and cesium carbonate (139.5 mg, 0.428 mmol), BINAP (13.4 mg, 0.021 mmol), and Pd2(dba)3 (19.6 mg, 0.021 mmol) were added. The mixture was then subjected to nitrogen protection and microwaved at 130 °C for 2 hours. After the reaction was complete, the sample was loaded onto a silica gel column for chromatography (dichloromethane / methanol = 40 / 1). The solvent was evaporated, and the mixture was then stirred overnight with 10 mL of diethyl ether. After filtration and drying, a yellow solid final product, A17 (30 mg, 16%), was obtained.

[0434] Example 18

[0435] Compound A18 is synthesized by the following method.

[0436]

[0437] 1) Synthesis of intermediate A18-1

[0438] 1-Bromo-2,5-difluoro-4-nitrobenzene (1.0 g, 4.2 mmol) was dissolved in methanol (30 mL), and sodium methoxide (340 mg, 1.5 mmol) was added. The mixture was reacted at 45 °C for 2 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and dried under vacuum to give a white solid intermediate A18-1 (900 mg, 86%).

[0439] 1 H NMR (400MHz, CDCl3): δ7.71 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 5.2 Hz, 1H), 3.97 (s, 3H).

[0440] 2) Synthesis of intermediate A18-2

[0441] Intermediate A18-1 (1.1 g, 4.3 mmol) was dissolved in isopropanol (40 mL), and water (10 mL), reduced iron powder (970 mg, 17 mmol), and ammonium chloride (950 mg, 17 mmol) were added. The mixture was reacted at 75 °C for 2 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and then dried under vacuum to give a brown solid intermediate A18-2 (800 mg, 84%).

[0442] 1H NMR (400MHz, CDCl3): δ6.84 (d, J = 6.0 Hz, 1H), 6.50 (d, J = 9.6 Hz, 1H), 3.91 (s, 2H), 3.82 (s, 3H).

[0443] LC-MS: m / z 221.9 [M+H] + .

[0444] 3) Synthesis of intermediate A18-3

[0445] Intermediate A18-2 (100 mg, 0.45 mmol) was dissolved in 1,4-dioxane, and dimethylphosphine oxide (37 mg, 0.48 mmol), potassium carbonate (122 mg, 0.9 mmol), Xantphos (26 mg, 0.045 mmol), and Pd2(dba)3 (21 mg, 0.023 mmol) were added. The mixture was reacted under nitrogen protection at 125 °C for 2 hours in a microwave oven. After the reaction was complete, the solvent was concentrated. The residue was dry-mounted and subjected to silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give a yellow solid intermediate A18-3 (50 mg, 50%).

[0446] 1 H NMR (400MHz, CDCl3): δ7.24-7.20(m,1H),6.40(dd,J=10.6,5.2Hz,1H),3.89(s,3H),1.75(s,3H),1.72(s,3H).

[0447] 4) Synthesis of the final product A18

[0448] Intermediates A18-3 (45 mg, 0.21 mmol) and A2-5 (57 mg, 0.23 mmol) were dissolved in 1,4-dioxane (4 mL), and cesium carbonate (134 mg, 0.41 mmol), BINAP (12 mg, 0.021 mmol), and Pd2(dba)3 (18 mg, 0.021 mmol) were added. The mixture was then subjected to nitrogen protection and microwaved at 130 °C for 2 hours. After the reaction was complete, the sample was loaded onto a silica gel column for chromatography (dichloromethane / methanol = 40 / 1) to obtain a yellow crude solid. The crude solid was then slurried with ether (10 mL) overnight, filtered, and dried to obtain the final yellow solid product A18 (15 mg, 17%).

[0449] Example 19

[0450] Compound A19 is synthesized by the following method.

[0451]

[0452] 1) Synthesis of intermediate A19-1

[0453] 1-Chloro-5-fluoro-2-methyl-5-nitrobenzene (2.5 g, 13 mmol) was dissolved in DMSO (25 mL). Methanol (3 mL) was added at room temperature, followed by potassium carbonate (9.0 g, 65 mmol). The reaction mixture was stirred at 50 °C for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice water (100 mL), filtered, and a yellow solid intermediate A19-1 (2.5 g, 96%) was obtained.

[0454] 1 H NMR (400MHz, CDCl3): δ7.78(s,1H),7.09(s,1H),3.94(s,3H),2.35(s,3H).

[0455] LC-MS: m / z 202.0 [M+H] + .

[0456] 2) Synthesis of intermediate A19-2

[0457] Intermediate A19-1 (1.4 g, 7.0 mmol), dimethylphosphine oxide (1.1 g, 14 mmol), cesium carbonate (3.4 g, 11 mmol), Pd(OAc)₂ (160 mg, 0.70 mmol), and Xantphos (405 mg, 0.70 mmol) were sequentially suspended in dry 1,4-dioxane (15 mL). After purging the air with nitrogen, the mixture was stirred at 150 °C for 1 hour in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a yellow solid intermediate A19-2 (220 mg, 13%).

[0458] 1 H NMR (400MHz, CDCl3): δ7.74(d,J=13.2Hz,1H),7.68(d,J=4.4Hz,1H),4.01(s,3H),2.52(s,3H),1.86(s,3H),1.83(s,3H).

[0459] LC-MS: m / z 244.1 [M+H] + .

[0460] 3) Synthesis of intermediate A19-3

[0461] Intermediate A19-2 (120 mg, 0.29 mmol) was dissolved in anhydrous ethanol (10 mL). 10% palladium on carbon (20 mg) was added, and the mixture was stirred overnight under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated to obtain crude yellow oily intermediate A19-3 (100 mg, 95%), which was used directly in the next step.

[0462] LC-MS: m / z 214.1 [M+H] + .

[0463] 4) Synthesis of final product A19

[0464] Intermediate A19-3 crude product (64 mg, 0.30 mmol), A2-5 (83 mg, 0.33 mmol), cesium carbonate (196 mg, 0.60 mmol), BINAP (19 mg, 0.030 mmol), and Pd2(dba)3 (22 mg, 0.024 mmol) were sequentially suspended in dry 1,4-dioxane (3 mL). After purging with nitrogen, the mixture was stirred at 130 °C for 2 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain a yellow solid crude product. This crude product was then slurried with ethyl acetate / diethyl ether (5 mL / 5 mL) for 5 hours, filtered, and the final yellow solid product A19 (60 mg, 47%) was obtained.

[0465] Example 20

[0466] Compound A20 is synthesized by the following method.

[0467]

[0468] 1) Synthesis of intermediate A20-1

[0469] The starting material 5-bromo-1,3-difluoro-2-nitrobenzene (2.0 g, 8.4 mmol) was dissolved in methanol (15 mL), and potassium hydroxide (504 mg, 9.0 mmol) was added at room temperature. The mixture was stirred and refluxed at 90 °C for 2 hours. The reaction solution was evaporated to dryness, diluted with water (20 mL), and extracted with dichloromethane (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a pale yellow solid intermediate A20-1 (2.0 g, 94%).

[0470] 1 H NMR (400MHz, CDCl3): δ7.03 (d, J = 8.7Hz, 1H), 7.00 (s, 1H), 3.93 (s, 3H).

[0471] 2) Synthesis of intermediate A20-2

[0472] Intermediate A20-1 (200 mg, 0.80 mmol) was dissolved in 3 mL of dry 1,4-dioxane. Then, dimethylphosphine oxide (81 mg, 1.0 mmol), Pd(OAc)₂ (9.0 mg, 0.040 mmol), K₃PO₄ (186 mg, 0.88 mmol), and Xantphos (27 mg, 0.048 mmol) were added sequentially. The mixture was reacted under nitrogen protection with microwave stirring at 130 °C for 2.5 hours. The reaction mixture was cooled, filtered, and the filtrate was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a yellow oily intermediate A20-2 (183 mg, 93%).

[0473] 1 H NMR (400MHz, CDCl3): δ7.42 (d, J = 12.4Hz, 1H), 7.03 (dd, J = 11.8, 8.1Hz, 1H), 4.03 (s, 3H), 1.81 (s, 3H), 1.77 (s, 3H).

[0474] LC-MS: m / z 248.0 [M+H] + .

[0475] 3) Synthesis of intermediate A20-3

[0476] Intermediate A20-2 (183 mg, 0.74 mmol) was dissolved in ethanol (20 mL), and 10% palladium on carbon (100 mg) was added. The air was replaced with hydrogen, and the mixture was stirred overnight at room temperature. The reaction solution was filtered and concentrated to obtain a yellow oily intermediate A20-3 (128 mg, 80%).

[0477] LC-MS: m / z 218.1 [M+H] + .

[0478] 4) Synthesis of final product A20

[0479] Intermediate A20-3 (60 mg, 0.28 mmol), A2-5 (83 mg, 0.33 mmol), BINAP (16.8 mg, 0.027 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), and cesium carbonate (179 mg, 0.55 mmol) were added to a dry container of 1,4-dioxane (3 mL), and the mixture was microwaved at 130 °C for 2 hours under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated, and the mixture was separated by silica gel column chromatography (dichloromethane / methanol / ammonia = 50 / 1 / 0.5) to give a pale yellow solid final product A20 (61 mg, 51%).

[0480] Example 21

[0481] Compound A21 is synthesized by the following method.

[0482]

[0483] 1) Synthesis of intermediate A21-1

[0484] 2-Chloro-4-fluoro-5-nitrobenzoic acid (1.1 g, 5.0 mmol) was dissolved in methanol / N,N-dimethylformamide (30 mL / 5 mL). Sodium methoxide (680 mg, 13 mmol) was added in portions at room temperature, and the mixture was stirred at 100 °C for 4 hours. After cooling to room temperature, the methanol was concentrated under reduced pressure. 1N hydrochloric acid (50 mL) was added to the residue, and the mixture was stirred for 30 minutes. The mixture was filtered to give a yellow solid intermediate A21-1 (1.0 g, 87%).

[0485] 1 H NMR (400MHz, DMSO-d6): δ8.40(s,1H),7.57(s,1H),4.02(s,3H).

[0486] LC-MS: m / z 232.0 [M+H] + .

[0487] 2) Synthesis of intermediate A21-2

[0488] Intermediate A21-1 (1.0 g, 4.3 mmol) was suspended in dichloromethane (25 mL). Oxaloyl chloride (3 mL) was added at room temperature, followed by a catalytic amount of N,N-dimethylformamide (0.020 mL). After stirring at room temperature for 3 hours, the solution became clear. The solvent was concentrated under reduced pressure, and the residue dissolved in dichloromethane (10 mL). 7N ammonia-methanol solution (2 mL) was added at room temperature, and the mixture was stirred for 30 minutes. Filtering yielded a yellow solid intermediate A21-2 (600 mg, 60%).

[0489] 1 H NMR (400MHz, CDCl3): δ8.05(s,1H),8.01(s,1H),7.74(s,1H),7.56(s,1H),4.00(s,3H).

[0490] LC-MS: m / z 231.0 [M+H] + .

[0491] 3) Synthesis of intermediate A21-3

[0492] Intermediate A21-2 (600 mg, 2.8 mmol) was dissolved in anhydrous 1,4-dioxane (10 mL). Trichloromethyl chloroformate (1.7 g, 8.3 mmol) was added at room temperature, and the mixture was stirred at 70 °C for 3 hours in a microwave reactor. After cooling to room temperature, the solvent was concentrated, and the residue was extracted with 20 mL of saturated sodium bicarbonate solution (10 mL × 3) using ethyl acetate. The organic phases were separated and combined, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid intermediate A21-3 (450 mg, 76%).

[0493] 1 H NMR (400MHz, DMSO-d6): δ8.66(s,1H),7.82(s,1H),4.05(s,3H).

[0494] LC-MS: m / z 213.0 [M+H] + .

[0495] 4) Synthesis of intermediate A21-4

[0496] Intermediate A21-3 (380 mg, 1.6 mmol), dimethylphosphine oxide (244 mg, 3.1 mmol), cesium carbonate (782 mg, 2.4 mmol), Pd(OAc)₂ (36 mg, 0.16 mmol), and Xantphos (92 mg, 0.16 mmol) were sequentially suspended in dry 1,4-dioxane (10 mL). After purging the air with nitrogen, the mixture was stirred at 145 °C for 1 hour in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a yellow solid intermediate A21-4 (200 mg, 49%).

[0497] 1 H NMR (400MHz, CDCl3): δ8.23(s,1H),8.16-8.00(m,1H),4.14(s,3H),2.05-1.92(m,6H).

[0498] LC-MS: m / z 255.0 [M+H] + .

[0499] 5) Synthesis of intermediate A21-5

[0500] Intermediate A21-4 (200 mg, 0.79 mmol) was dissolved in tetrahydrofuran / 1,4-dioxane / water (5 mL / 5 mL / 5 mL). Sodium dithionite (690 mg, 3.9 mmol) was added at room temperature, and the mixture was stirred for 4 hours. The solvent was concentrated under reduced pressure, and the residue was adjusted to pH 8 with saturated sodium bicarbonate. The residue was extracted with dichloromethane (15 mL × 3), the organic phases were separated and combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give intermediate A21-5 (60 mg, 34%) as a brown solid.

[0501] 1 H NMR (400MHz, CDCl3): δ7.61 (d, J = 12.4Hz, 1H), 7.00 (s, 1H), 4.30 (br s, 2H), 3.99 (s, 3H), 1.91 (s, 3H), 1.88 (s, 3H).

[0502] LC-MS: m / z 225.1 [M+H] + .

[0503] 6) Synthesis of final product A21

[0504] Intermediate A21-5 (50 mg, 0.22 mmol), A2-5 (61 mg, 0.24 mmol), cesium carbonate (143 mg, 0.44 mmol), BINAP (14 mg, 0.022 mmol), and Pd2(dba)3 (16 mg, 0.018 mmol) were sequentially suspended in dry 1,4-dioxane (3 mL). After purging with nitrogen, the mixture was stirred at 130 °C for 2 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain a yellow solid crude product. This crude product was then slurried with ethyl acetate / diethyl ether (5 mL / 5 mL) for 5 hours, filtered, and the final yellow solid product A21 (60 mg, 62%) was obtained.

[0505] Example 22

[0506] Compound A22 is synthesized by the following method.

[0507]

[0508] 1) Synthesis of intermediate A22-1

[0509] 1-Chloro-2-fluoro-3-methoxybenzene (3.0 g, 18.8 mmol) was dissolved in glacial acetic acid (10 mL), and concentrated nitric acid (4.7 g, 75 mmol) was slowly added at 0 °C, followed by slow dropwise addition of concentrated sulfuric acid (14.7 g, 150 mmol). The reaction mixture was stirred at 0 °C for 6 hours. The reaction solution was poured into water and extracted with ethyl acetate (20 mL × 3). The mixture was washed with water in saturated sodium bicarbonate solution (20 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a pale yellow solid intermediate A22-1 (1.2 g, 32%).

[0510] 1 H NMR (400MHz, CDCl3): δ7.59 (d, J=8.8Hz, 1H), 7.25-7.20 (m, 1H), 4.10 (s, 3H).

[0511] 2) Synthesis of intermediate A22-2

[0512] Intermediate A22-1 (500 mg, 2.4 mmol) was dissolved in 10 mL of dry 1,4-dioxane. Then, dimethylphosphine oxide (266 mg, 3.4 mmol), Pd(OAc)₂ (27.4 mg, 0.12 mmol), K₃PO₄ (568 mg, 2.7 mmol), and Xantphos (84 mg, 0.15 mmol) were added sequentially. The mixture was reacted under nitrogen protection with microwave stirring at 140 °C for 3 hours. The reaction mixture was cooled, filtered, and the filtrate was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a brownish-yellow oily intermediate A22-2 (220 mg, 36%).

[0513] 1 H NMR (400MHz, CDCl3): δ7.79-7.73(m,1H),7.68(d,J=8.1Hz,1H),4.08(s,3H),1.86(s,3H),1.83(s,3H).

[0514] LC-MS: m / z 248.1 [M+H] + .

[0515] 3) Synthesis of intermediate A22-3

[0516] Dissolve A22-2 (220 mg, 0.89 mmol) in ethanol (20 mL), add 10% palladium on carbon (100 mg), replace air with hydrogen, and stir overnight at room temperature. Filter the reaction solution, concentrate, and separate by silica gel column chromatography (dichloromethane / methanol / ammonia = 50 / 1 / 1) to give a pale yellow oily intermediate A22-3 (113 mg, 58%).

[0517] 1 H NMR (400MHz, CDCl3): δ7.43-7.34(m,1H),6.60(d,J=8.2Hz,1H),3.92(s,3H),1.76(s,3H),1.73(s,3H).

[0518] LC-MS: m / z 218.1 [M+H] + .

[0519] 4) Synthesis of final product A22

[0520] Intermediate A22-3 (50 mg, 0.23 mmol), A2-5 (69 mg, 0.28 mmol), BINAP (14 mg, 0.023 mmol), Pd2(dba)3 (17 mg, 0.018 mmol), and cesium carbonate (150 mg, 0.46 mmol) were added to a dry container of 1,4-dioxane (3 mL), and the mixture was microwaved at 130 °C for 2 hours under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (dichloromethane / methanol / ammonia = 50 / 1 / 0.5) to give a pale yellow solid final product A22 (24 mg, 24%).

[0521] Example 23

[0522] Compound A23 is synthesized by the following method.

[0523]

[0524] 1) Synthesis of intermediate A23-1

[0525] 4-Chloro-2-trifluoromethylaniline (3.9 g, 20 mmol) was dissolved in anhydrous acetonitrile (50 mL). N-bromosuccinimide (3.9 g, 22 mmol) was added in portions to the reaction mixture at room temperature, and stirring was continued for 1 hour. The solvent was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown oily intermediate A23-1 (4.5 g, 82%).

[0526] 1 H NMR (400MHz, CDCl3): δ7.59 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 4.69 (brs, 2H).

[0527] 2) Synthesis of intermediate A23-2

[0528] Intermediate A23-1 (2.2 g, 8.0 mmol), pinacol diborate (4.1 g, 16 mmol), potassium acetate (2.0 g, 20 mmol), and Pd(dppf)Cl2 (290 mg, 0.40 mmol) were sequentially suspended in dry 1,4-dioxane (40 mL). The mixture was stirred overnight at 100 °C under nitrogen atmosphere, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give brown oily intermediate A23-2 (2.2 g, 86%).

[0529] 3) Synthesis of intermediate A23-3

[0530] Intermediate A23-2 (2.0 g, 6.6 mmol) was dissolved in THF / H2O (30 mL / 20 mL). Sodium perborate tetrahydrate (5.1 g, 33 mmol) was added in portions at room temperature, and stirring was continued for 1 hour. The solution was diluted with ethyl acetate (50 mL), the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a yellow oily intermediate A23-3 (1.2 g, 86%).

[0531] 4) Synthesis of intermediate A23-4

[0532] Intermediate A23-3 (422 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (414 mg, 3.0 mmol) was added at room temperature, followed by dropwise addition of iodomethane (312 mg, 2.2 mmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate (100 mL), washed with saturated brine (30 mL × 4), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oily intermediate A23-4 (400 mg, 88%).

[0533] 1 H NMR (400MHz, CDCl3): δ7.04 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 1.6 Hz, 1H), 4.39 (brs, 2H), 3.88 (s, 3H).

[0534] LC-MS: m / z 226.0 [M+H] + .

[0535] 5) Synthesis of intermediate A23-5

[0536] Intermediate A23-4 (338 mg, 1.5 mmol), dimethylphosphine oxide (234 mg, 3.0 mmol), potassium carbonate (311 mg, 2.3 mmol), Pd(OAc)₂ (34 mg, 0.15 mmol), and Xantphos (87 mg, 0.15 mmol) were sequentially suspended in dry 1,4-dioxane (10 mL). After purging the air with nitrogen, the mixture was stirred at 145 °C for 1.5 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a yellow solid intermediate A23-5 (250 mg, 62%).

[0537] 1 H NMR (400MHz, CDCl3): δ7.34(d,J=11.6Hz,1H),7.22(d,J=12.4Hz,1H),4.76(br s,2H),3.95(s,3H),1.72(s,3H),1.69(s,3H).

[0538] LC-MS: m / z 268.1 [M+H] + .

[0539] 6) Synthesis of final product A23

[0540] Intermediate A23-5 (53 mg, 0.20 mmol), A2-5 (55 mg, 0.22 mmol), cesium carbonate (130 mg, 0.40 mmol), BINAP (12 mg, 0.020 mmol), and Pd2(dba)3 (15 mg, 0.016 mmol) were sequentially added to dry 1,4-dioxane (3 mL). After purging with nitrogen, the mixture was stirred at 130 °C for 2 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain a yellow solid crude product. This crude product was then slurried with ethyl acetate / diethyl ether (5 mL / 5 mL) for 5 hours, filtered, and the final yellow solid product A23 (20 mg, 21%) was obtained.

[0541] Example 24

[0542] Compound A24 is synthesized by the following method.

[0543]

[0544] 1) Synthesis of intermediate A24-1

[0545] 3-Methoxypyridine-2-amine (620 mg, 5.0 mmol) was dissolved in anhydrous acetonitrile (25 mL). N-bromosuccinimide (980 mg, 5.5 mmol) was added in portions to the reaction mixture at room temperature, and stirring was continued for 1 hour. The solvent was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a white solid intermediate A24-1 (500 mg, 49%).

[0546] 1 H NMR (400MHz, CDCl3): δ7.56 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 5.92 (brs, 2H), 3.79 (s, 3H).

[0547] LC-MS: m / z 203.0 [M+H] + .

[0548] 2) Synthesis of intermediate A24-2

[0549] Intermediate A24-1 (202 mg, 1.0 mmol), dimethylphosphine oxide (156 mg, 2.0 mmol), potassium carbonate (207 mg, 1.5 mmol), Pd(OAc)2 (23 mg, 0.10 mmol), and Xantphos (46 mg, 0.080 mmol) were sequentially suspended in dry 1,4-dioxane (5 mL). After purging the air with nitrogen, the mixture was stirred at 125 °C for 2 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a yellow solid intermediate A24-2 (120 mg, 60%).

[0550] 1 H NMR (400MHz, CDCl3): δ7.80(d,J=6.0Hz,1H),7.29(d,J=11.2Hz,1H),5.09(brs,2H),3.89(s,3H),1.73(s,3H),1.70(s,3H).

[0551] LC-MS: m / z 201.1 [M+H] + .

[0552] 3) Synthesis of the final product A24:

[0553] Intermediates A24-2 (50 mg, 0.25 mmol), A2-5 (69 mg, 0.28 mmol), cesium carbonate (163 mg, 0.50 mmol), BINAP (16 mg, 0.025 mmol), and Pd2(dba)3 (18 mg, 0.020 mmol) were added sequentially to a dry container of 1,4-dioxane (4 mL). After purging with nitrogen, the mixture was stirred at 130 °C for 2 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain a crude yellow solid. This crude solid was then homogenized with ethyl acetate / ether (5 mL / 5 mL) for 5 hours and filtered to obtain the final yellow solid product A24 (50 mg, 48%).

[0554] Example 25

[0555] Compound A25 is synthesized by the following method.

[0556]

[0557] 1) Synthesis of intermediate A25-1

[0558] 2-Methoxypyridine-3-amine (2.5 g, 20 mmol) was dissolved in dry N,N-dimethylformamide (30 mL). Under nitrogen atmosphere at -30 °C, a solution of N-bromosuccinimide (3.9 g, 22 mmol) in N,N-dimethylformamide (3 mL) was added dropwise to the reaction mixture, and stirring was continued for 1 hour. The mixture was diluted with ethyl acetate (100 mL), washed with saturated brine (30 mL × 4), and the organic phase was separated. The solution was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a white solid intermediate A25-1 (3.5 g, 86%).

[0559] 1 H NMR (400MHz, CDCl3): δ6.87 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 3.98 (s, 3H).

[0560] LC-MS: m / z 203.0 [M+H] + .

[0561] 2) Synthesis of intermediate A25-2

[0562] Intermediate A25-1 (202 mg, 1.0 mmol), dimethylphosphine oxide (156 mg, 2.0 mmol), potassium carbonate (207 mg, 1.5 mmol), Pd(OAc)₂ (23 mg, 0.10 mmol), and Xantphos (46 mg, 0.080 mmol) were sequentially suspended in dry 1,4-dioxane (5 mL). After purging the air with nitrogen, the mixture was stirred at 125 °C for 2 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give a yellow solid intermediate A25-2 (180 mg, 90%).

[0563] LC-MS: m / z 201.1 [M+H] + .

[0564] 3) Synthesis of final product A25:

[0565] Intermediate A25-2 (50 mg, 0.25 mmol), A2-5 (69 mg, 0.28 mmol), cesium carbonate (163 mg, 0.50 mmol), BINAP (16 mg, 0.025 mmol), and Pd2(dba)3 (18 mg, 0.020 mmol) were sequentially added to dry 1,4-dioxane (4 mL). After purging with nitrogen, the mixture was stirred at 130 °C for 2 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain a yellow solid crude product. This crude product was then slurried with ethyl acetate / diethyl ether (5 mL / 5 mL) for 5 hours, filtered, and the final yellow solid product A25 (50 mg, 48%) was obtained.

[0566] Example 26

[0567] Compound A26 is synthesized by the following method.

[0568]

[0569] 1) Synthesis of intermediate A26-1

[0570] A mixture of methanol (15 mL) and N,N-dimethylformamide (5 mL) was placed in an ice-water bath. Sodium hydroxide (780 mg, 0.37 mmol, 60% purity) was added in portions, and the mixture was stirred for 10 minutes. Then, 1,3-dichloro-2-methyl-4-nitrobenzene (2.0 g, 0.24 mmol) was slowly added, and the mixture was stirred overnight at 50 °C. After the reaction was complete, the reaction solution was poured into water (20 mL), extracted with dichloromethane (50 mL × 3), and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, concentrated, and the residue was dry-mounted and purified by silica gel column chromatography (petroleum ether / dichloromethane = 50 / 1) to obtain a yellow solid intermediate A26-1 (780 mg, 39%).

[0571] 1 H NMR (400MHz, CDCl3): δ7.64 (d, J = 8.7Hz, 1H), 7.29-7.21 (m, 1H), 3.91 (s, 3H), 2.40 (s, 3H).

[0572] LC-MS: m / z 202.0 [M+H] + .

[0573] 2) Synthesis of intermediate A26-2

[0574] Intermediate A26-1 (726 mg, 0.92 mmol) was dissolved in 1,4-dioxane (3 mL), and dimethylphosphine oxide (563 mg, 1.8 mmol), potassium carbonate (747 mg, 1.8 mmol), Xantphos (208 mg, 0.091 mmol), and Pd2(dba)3 (81 mg, 0.092 mmol) were added. The mixture was then subjected to nitrogen protection and microwaved at 140 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was dry-mounted and purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to obtain a yellow solid intermediate A26-2 (435 mg, 49%).

[0575] 1 H NMR (400MHz, CDCl3): δ7.23-7.22(m,2H),3.92(s,3H),2.67(s,3H),1.83(s,6H).

[0576] LC-MS m / z 244.1 [M+H] + .

[0577] 3) Synthesis of intermediate A26-3

[0578] Intermediate A26-2 (1.08 g, 4.3 mmol) was dissolved in isopropanol (10 mL), and water (4 mL), reduced iron powder (115.4 mg, 2.06 mmol), and ammonium chloride (109.2 mg, 2.06 mmol) were added. The mixture was reacted at 75 °C for 2 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was evaporated to dryness. The residue was extracted with water (50 mL) and ethyl acetate (50 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to give a brown solid intermediate A26-3 (65 mg, 74%).

[0579] 4) Synthesis of final product A26

[0580] Intermediates A26-3 (50 mg, 0.24 mmol) and A2-5 (59 mg, 0.24 mmol) were dissolved in 1,4-dioxane (4 mL), and cesium carbonate (153 mg, 0.47 mmol), BINAP (15 mg, 0.024 mmol), and Pd2(dba)3 (22 mg, 0.024 mmol) were added. The mixture was then subjected to nitrogen protection and microwaved at 130 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was dry-sampled and purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to obtain the crude product. The crude product was then slurried overnight with a mixture of diethyl ether (5 mL) and ethyl acetate (5 mL), filtered, and dried to obtain the yellow solid final product A26 (23 mg, 22%).

[0581] Example 27

[0582] Compound A27 is synthesized by the following method.

[0583]

[0584] 1) Synthesis of intermediate A27-1

[0585] A mixture of concentrated sulfuric acid (6 mL) and concentrated nitric acid (6 mL) was placed at -10 °C, and 1-bromo-3-fluoro-2-(trifluoromethyl)benzene (2.0 g, 6.9 mmol) was slowly added, followed by stirring for 30 minutes. The reaction mixture was poured into ice water (300 mL), and then extracted with dichloromethane (50 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and the residue was loaded onto a silica gel column for chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a yellow solid intermediate A27-1 (1.8 g, 76%).

[0586] 1 H NMR (400MHz, CDCl3): δ7.83 (dd, J=8.4, 4.0Hz, 1H), 7.34 (t, J=9.6Hz, 1H).

[0587] 2) Synthesis of intermediate A27-2

[0588] Intermediate A27-1 (25 mg, 0.086 mmol) was dissolved in methanol (5 mL), and sodium methoxide (18 mg, 0.35 mmol) was added. The mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was concentrated, and the residue was dry-loaded and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a white solid intermediate A27-2 (10 mg, 38%).

[0589] 1 H NMR (400MHz, CDCl3): δ8.13-8.04(m,1H),6.88-6.80(m,1H),3.98(s,3H).

[0590] 3) Synthesis of intermediate A27-3

[0591] Intermediate A27-2 (1.0 g, 3.5 mmol) was dissolved in isopropanol (30 mL), and water (5 mL), reduced iron powder (976 mg, 17.4 mmol), and ammonium chloride (923 mg, 17.4 mmol) were added. The mixture was reacted at 75 °C for 2 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown solid intermediate A27-3 (780 mg, 86%).

[0592] 4) Synthesis of intermediate A27-4

[0593] Intermediate A27-3 (340 mg, 1.2 mmol) was dissolved in 1,4-dioxane (3 mL), and dimethylphosphine oxide (145 mg, 1.8 mmol), potassium carbonate (337 mg, 2.5 mmol), Xantphos (71 mg, 0.12 mmol), and Pd2(dba)3 (57 mg, 0.062 mmol) were added. The mixture was then reacted under nitrogen protection at 140 °C for 2 hours in a microwave oven. The reaction solution was concentrated, and the residue was dry-mounted and subjected to silica gel column chromatography (dichloromethane / methanol = 40 / 1) to obtain a yellow solid intermediate A27-4 (210 mg, 62%).

[0594] LC-MS: m / z 268.1 [M+H] + .

[0595] 5) Synthesis of final product A27

[0596] Intermediates A27-4 (100 mg, 0.37 mmol) and A2-5 (94 mg, 0.37 mmol) were dissolved in 1,4-dioxane (4 mL), and cesium carbonate (241 mg, 0.47 mmol), BINAP (23 mg, 0.037 mmol), and Pd2(dba)3 (33 mg, 0.037 mmol) were added. The mixture was then subjected to nitrogen protection and microwaved at 130 °C for 2 hours. After the reaction was complete, the sample was loaded onto a silica gel column for chromatography (dichloromethane / methanol = 40 / 1) to obtain the crude product. The crude product was slurried overnight with a mixture of diethyl ether (5 mL) and ethyl acetate (5 mL), filtered, and dried to obtain the yellow solid final product A27 (11 mg, 6.3%).

[0597] Example 28

[0598] Compound A28 is synthesized by the following method.

[0599]

[0600] 1) Synthesis of intermediate A28-1

[0601] 2,6-Dichloro-3-nitrobenzene (2.0 g, 9.2 mmol) was dissolved in dry methanol (30 mL), and sodium methoxide (999 mg, 18.5 mmol) was slowly added in portions. The mixture was stirred overnight at room temperature. The reaction solution was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted with dichloromethane (20 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give intermediate A28-1 (420 mg, 21%).

[0602] 1 H NMR (400MHz, CDCl3): δ8.22 (d, J = 9.2 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 4.07 (s, 3H).

[0603] LC-MS: m / z 235.0 [M+Na] + .

[0604] 2) Synthesis of intermediate A28-2

[0605] Intermediate A28-1 (50 mg, 0.23 mmol) was dissolved in glacial acetic acid (5 mL), and iron powder (66 mg, 1.2 mmol) was added with stirring at room temperature. The mixture was stirred at 100 °C for 30 minutes. The solvent was concentrated, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution (20 mL). The mixture was extracted with dichloromethane (20 mL × 3), washed with saturated brine (20 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give crude intermediate A28-2 (44 mg, 99%), a pale yellow solid.

[0606] 1 H NMR (400MHz, CDCl3): δ6.95 (d, J = 9.2 Hz, 1H), 6.76 (d, J = 9.2 Hz, 1H), 3.87 (s, 3H).

[0607] LC-MS: m / z 183.0 [M+H] + .

[0608] 3) Synthesis of intermediate A28-3

[0609] Crude compound A28-2 (100 mg, 0.55 mmol) was dissolved in dry 1,4-dioxane (2 mL), followed by the addition of dimethylphosphine oxide (86 mg, 1.1 mmol), Pd(OAc)₂ (12 mg, 0.055 mmol), potassium carbonate (114 mg, 0.82 mmol), and Xantphos (32 mg, 0.055 mmol). The mixture was reacted under nitrogen protection with microwave stirring at 142 °C for 2.5 hours. The reaction mixture was cooled, filtered, and the filtrate was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a yellow solid A28-3 (61 mg, 50%).

[0610] 1 H NMR (400MHz, CDCl3): δ6.99 (d, J = 9.2 Hz, 1H), 6.85 (dd, J = 9.2, 4.4 Hz, 1H), 5.84 (s, 2H), 3.90 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H).

[0611] LC-MS: m / z 225.1 [M+H] + .

[0612] 4) Synthesis of final product A28

[0613] Intermediate A28-3 (30 mg, 0.13 mmol), A2-5 (40 mg, 0.16 mmol), BINAP (8.0 mg, 0.013 mmol), Pd2(dba)3 (9.0 mg, 0.010 mmol), and cesium carbonate (87 mg, 0.26 mmol) were added to a dry container of 1,4-dioxane (2 mL). The mixture was microwaved at 130 °C for 2 hours under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated, and the product was separated by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give a yellow solid product A28 (22 mg, 37%).

[0614] Example 29

[0615] Compound A29 is synthesized by the following method.

[0616]

[0617] 1) Synthesis of intermediate A29-1

[0618] 2-Chloro-3-methoxyaniline (1.0 g, 6.4 mmol) was dissolved in dry acetonitrile (10 mL), and hydrobromic acid (9N) aqueous solution (6 mL, 57 mmol) was slowly added dropwise. Then, sodium nitrite aqueous solution (524 mg, 7.6 mmol) was added dropwise. After stirring at room temperature for 1 hour, cuprous bromide (1.1 g, 7.6 mmol) was added, and the mixture was stirred at 60 °C for 2 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The solution was washed with saturated brine (20 mL), and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give a colorless oily intermediate A29-1 (600 mg, 43%).

[0619] 1 H NMR (400MHz, DMSO-d6): δ7.23(d,J=8.0Hz,1H),7.09(t,J=8.0Hz,1H),6.87(d,J=8.4Hz,1H),3.90(s,3H).

[0620] 2) Synthesis of intermediate A29-2

[0621] Intermediate A29-1 (100 mg, 0.45 mmol) was dissolved in glacial acetic acid (5 mL), and concentrated nitric acid (0.5 mL) was slowly added at -10 °C, followed by slow dropwise addition of concentrated sulfuric acid (2 mL). The mixture was then slowly brought to room temperature and stirred for 2 hours. The reaction mixture was poured into ice water (20 mL), extracted with ethyl acetate (20 mL × 3), washed with water in saturated sodium bicarbonate solution (20 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give a pale yellow oily liquid A29-2 (36 mg, 30%).

[0622] 1 H NMR (400MHz, CDCl3): δ7.63 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 4.04 (s, 3H).

[0623] 3) Synthesis of intermediate A29-3

[0624] Compound A29-2 (70 mg, 0.26 mmol) was dissolved in dry 1,4-dioxane (2 mL), and dimethylphosphine oxide (26 mg, 0.34 mmol), Pd(OAc)₂ (3.0 mg, 0.013 mmol), potassium phosphate (61 mg, 0.29 mmol), and Xantphos (9.0 mg, 0.016 mmol) were added sequentially. Under nitrogen protection, the mixture was stirred in a microwave at 130 °C for 2.5 h. The reaction mixture was cooled, filtered, and the filtrate was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a yellow solid intermediate A29-3 (47 mg, 69%).

[0625] 1 H NMR (400MHz, CDCl3): δ8.09 (dd, J=11.6, 8.4Hz, 1H), 7.84 (dd, J=8.4, 1.6Hz, 1H), 4.05 (s, 3H), 1.96 (s, 3H), 1.93 (s, 3H).

[0626] LC-MS: m / z 264.0 [M+H] + .

[0627] 4) Synthesis of intermediate A29-4

[0628] Intermediate A29-3 (47 mg, 0.18 mmol) was dissolved in ethanol (10 mL), and 10% palladium on carbon (50 mg) was added. The air was replaced with hydrogen, and the mixture was stirred overnight at room temperature. The reaction solution was filtered, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give colorless oily intermediate A29-4 (28 mg, 68%).

[0629] 1 H NMR (400MHz, CDCl3): δ7.75-7.57(m,1H),6.76(d,J=7.6Hz,1H),4.24(s,2H),3.85(s,3H),1.87(s,3H),1.84(s,3H).

[0630] LC-MS: m / z 234.1 [M+H] + .

[0631] 5) Synthesis of final product A29

[0632] Intermediates A29-4 (28 mg, 0.12 mmol), A2-5 (36 mg, 0.14 mmol), BINAP (7.5 mg, 0.012 mmol), Pd2(dba)3 (9 mg, 0.010 mmol), and cesium carbonate (78 mg, 0.24 mmol) were added to 2 mL of dry 1,4-dioxane. The mixture was microwaved at 130 °C for 2 hours under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give the pale yellow solid final product A29 (12 mg, 23%).

[0633] Example 30

[0634] Compound A30 is synthesized by the following method.

[0635]

[0636] 1) Synthesis of intermediate A30-1

[0637] 2-Bromo-4-fluoro-1-trifluoromethylbenzene (500 mg, 0.2 mmol) was dissolved in concentrated H2SO4 (1 mL), and concentrated HNO3 (0.15 mL) was added dropwise under an ice-water bath. After reacting for 2 hours, the reaction was quenched by adding water (10 mL) under an ice-water bath. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phase was taken and the pH was adjusted to 7-8 by adding saturated NaHCO3 aqueous solution. The organic phase was dried and concentrated to obtain a yellow solid intermediate A30-1 (228 mg, 38%).

[0638] 1 H NMR (400MHz, CDCl3): δ8.45 (d, J = 6.0 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H).

[0639] 2) Synthesis of intermediate A30-2

[0640] Intermediate A30-1 (228 mg, 0.79 mmol) was dissolved in 10 mL of methanol, and sodium methoxide (106 mg, 2.0 mmol) was added. The mixture was reacted at 60 °C for 2 hours. After cooling to room temperature, water (10 mL) was added, and a yellow solid precipitated out. The solid was filtered and dried to obtain yellow intermediate A30-2 (185 mg, 77%).

[0641] 1 H NMR (400MHz, DMSO-d6): δ8.23(s,1H),7.44(s,1H),4.05(s,3H).

[0642] 3) Synthesis of intermediate A30-3

[0643] Intermediate A30-2 (50 mg, 0.17 mmol) was dissolved in ethanol (5 mL), saturated ammonium chloride aqueous solution (1 mL) was added, and iron powder (46 mg, 0.83 mmol) was added. The mixture was reacted at 70 °C for 2 hours. After cooling to room temperature, the mixture was filtered, concentrated under reduced pressure to remove ethanol, and extracted with dichloromethane (20 mL × 3) and saturated NaHCO3 aqueous solution (15 mL × 3). The organic phase was dried, concentrated, and a black oily intermediate A30-3 (40 mg, 76%) was obtained.

[0644] 1 H NMR (400MHz, CDCl3): δ7.01(s,1H),6.99(s,1H),3.93(br s,2H),3.89(s,3H).

[0645] LC-MS: m / z 270.0 [M+H] + .

[0646] 4) Synthesis of intermediate A30-4

[0647] Intermediate A30-3 (50 mg, 0.18 mmol), dimethylphosphine oxide (15 mg, 0.19 mmol), potassium carbonate (51 mg, 0.37 mmol), Xantphos (11 mg, 0.019 mmol), and Pd2(dba)3 (17 mg, 0.019 mmol) were added sequentially to 1,4-dioxane. The mixture was reacted under N2 protection at 125 °C for 2 hours in a microwave environment. After dilution with dichloromethane, the mixture was filtered, the filtrate was concentrated, and the residue was dry-mounted and subjected to silica gel column chromatography (dichloromethane / methanol = 50 / 1) to obtain a gray solid intermediate A30-4 (24 mg, 48%).

[0648] 1H NMR (400MHz, CDCl3): δ7.87(d,J=13.2Hz,1H),7.02(d,J=4.8Hz,1H),4.27(s,2H),3.98(s,3H),1.81(s,3H),1.78(s,3H).

[0649] LC-MS: m / z 268.0 [M+H] + .

[0650] 5) Synthesis of final product A30

[0651] Intermediates A30-4 (40 mg, 0.15 mmol), A2-5 (15 mg, 0.19 mmol), cesium carbonate (96 mg, 0.37 mmol), BINAP (10 mg, 0.018 mmol), and Pd2(dba)3 (17 mg, 0.018 mmol) were added sequentially to 1,4-dioxane. The mixture was reacted under N2 protection at 130 °C for 2 hours under microwave conditions. After dilution with dichloromethane, the mixture was filtered, the filtrate was concentrated, and the solution was loaded onto a dry silica gel column for chromatography (dichloromethane / methanol = 50 / 1) to obtain the gray solid final product A30 (23 mg, 25%).

[0652] Example 31

[0653] Compound A31 is synthesized by the following method.

[0654]

[0655] 1) Synthesis of intermediate A31-1

[0656] Intermediate A5-4 (400 mg, 2.0 mmol) and A14-2 (366 mg, 1.0 mmol) were dissolved in ethanol (5 mL), and 1 drop of concentrated hydrochloric acid was added. The mixture was stirred in a microwave reactor at 120 °C for 3 hours. The pH of the reaction solution was adjusted to 8 by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid intermediate A31-1 (340 mg, 93%).

[0657] 1H NMR (400MHz, CDCl3): δ10.95(s,1H),8.78(s,1H),7.53-7.43(m,2H),7.22-7.13(m,1H),7.06 (s,1H),3.97(s,3H),3.06(q,J=7.2Hz,2H),1.78(s,3H),1.75(s,3H),1.26(t,J=7.2Hz,3H).

[0658] LC-MS: m / z 367.1 [M+H] + .

[0659] 2) Synthesis of final product A31

[0660] Intermediate A31-1 (100 mg, 0.27 mmol), 5-methoxypyridine-2-amine (67 mg, 0.54 mmol), Pd2(dba)3 (27 mg, 0.03 mmol), Xantphos (17 mg, 0.03 mmol), and cesium carbonate (176 mg, 0.54 mmol) were added to 1,4-dioxane (6 mL). Under nitrogen protection, the mixture was stirred overnight at 110 °C. Water (10 mL) was added to the reaction solution, and the organic phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 25 / 1) to give a green oily substance. This substance was then dissolved in dichloromethane (1 mL), and ether (5 mL) was added to precipitate the solid. The solid was filtered, washed with ether, and dried to give the yellow solid final product A31 (28 mg, 23%).

[0661] Similar methods yielded final products A32, A33, A34, A35, and A36.

[0662] Example 32

[0663] Compound A37 is synthesized by the following method.

[0664]

[0665] 1) Synthesis of intermediate A37-1

[0666] 2,6-Dichloroaniline (5.0 g, 31 mmol) was dissolved in chloroform (100 mL), stirred at room temperature, and liquid bromine (6.4 g, 40.3 mmol) was slowly added dropwise, and the mixture was stirred overnight at room temperature. The reaction solution was poured into a saturated sodium thiosulfate aqueous solution (100 mL), extracted with chloroform (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, loaded onto a dry plate, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a white solid intermediate A37-1 (3 g, 40%).

[0667] 1 H NMR (400MHz, CDCl3): δ7.32(s,2H),4.46(s,2H).

[0668] LC-MS: m / z 239.8 [M+H] + .

[0669] 2) Synthesis of intermediate A37-2

[0670] Intermediate A37-1 (1.3 g, 5.4 mmol) was dissolved in dry dichloroethane (50 mL). m-CPBA (4.6 g, 21.6 mmol, purity: 80%) was slowly added in portions at room temperature. After stirring for 1 hour, the mixture was reacted overnight at 70 °C with stirring. The reaction solution was quenched with saturated sodium thiosulfate aqueous solution (50 mL), and then saturated sodium bicarbonate aqueous solution (50 mL) was added and stirred for 1 hour. The mixture was extracted with dichloromethane (50 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1) to give a pale yellow solid intermediate A37-2 (640 mg, 44%).

[0671] 1 H NMR (400MHz, CDCl3): δ7.62 (s, 2H).

[0672] 3) Synthesis of intermediate A37-3

[0673] Intermediate A37-2 (640 mg, 2.4 mmol) was dissolved in dry methanol (40 mL), and sodium methoxide (1 g, 19.0 mmol) was slowly added at room temperature. The mixture was stirred at 65 °C for 24 hours. The reaction solution was concentrated, quenched with saturated ammonium chloride aqueous solution (40 mL), extracted with dichloromethane (50 mL × 3), concentrated, dried over anhydrous sodium sulfate, and separated by dry silica gel column chromatography (petroleum ether / ethyl acetate = 150 / 1) to give a pale yellow solid intermediate A37-3 (400 mg, 64%).

[0674] 1 H NMR (400MHz, CDCl3): δ7.25 (d, J = 1.6 Hz, 1H), 7.11 (d, J = 1.4 Hz, 1H), 3.91 (s, 3H).

[0675] LC-MS: m / z 287.9 ​​[M+H] + .

[0676] 4) Synthesis of intermediate A37-4

[0677] Intermediate A37-3 (70 mg, 0.26 mmol) was dissolved in 2 mL of dry 1,4-dioxane. Then, dimethylphosphine oxide (24.6 mg, 0.31 mmol), Pd(OAc)₂ (5.8 mg, 0.026 mmol), potassium phosphate (61 mg, 0.29 mmol), and Xantphos (15 mg, 0.026 mmol) were added sequentially. The mixture was stirred in a microwave at 120 °C for 2.5 hours under nitrogen protection. The reaction mixture was cooled, filtered, and the filtrate was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a pale yellow intermediate A37-4 (44 mg, 64%).

[0678] 1 H NMR (400MHz, CDCl3): δ7.51 (d, J = 12.2Hz, 1H), 7.21 (d, J = 11.4Hz, 1H), 3.99 (s, 3H), 1.79 (s, 3H), 1.76 (s, 3H).

[0679] LC-MS: m / z 264.0 [M+H] + .

[0680] 5) Synthesis of intermediate A37-5

[0681] Intermediate A37-4 (44 mg, 0.17 mmol) was dissolved in glacial acetic acid (8 mL), and iron powder (93 mg, 1.7 mmol) was added with stirring at room temperature. The mixture was then transferred to 100 °C and stirred for 1 hour. The solvent was concentrated, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution (20 mL). The mixture was extracted with dichloromethane (20 mL × 3), washed with saturated brine (20 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain crude, pale yellow oily intermediate A37-5 (40 mg, 99%).

[0682] 1 H NMR (300MHz, CDCl3): δ7.19-7.05(m,2H),4.49(s,2H),3.92(s,3H),1.71(s,3H),1.67(s,3H).

[0683] LC-MS: m / z 234.0 [M+H] + .

[0684] 6) Synthesis of the final product A37

[0685] Intermediate A37-5 (40 mg, 0.17 mmol), A2-5 (50.4 mg, 0.20 mmol), BINAP (10.6 mg, 0.017 mmol), Pd2(dba)3 (15.6 mg, 0.017 mmol), and cesium carbonate (110 mg, 0.34 mmol) were added to dry 1,4-dioxane (2 mL). The mixture was microwaved at 130 °C for 2 hours under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give a white solid final product A37 (17 mg, 22%).

[0686] Example 33

[0687] Compound A38 is synthesized by the following method.

[0688]

[0689] 1) Synthesis of intermediate A38-1

[0690] 2-Amino-6-bromophenol (1.9 g, 10 mmol) was dissolved in an acetonitrile / water mixture (25 mL / 25 mL). Sodium carbonate (2.4 g, 23 mmol) was slowly added at room temperature, followed by stirring for 10 minutes. Chloroacetyl chloride (1.5 g, 13 mmol) was then slowly added under ice-water bath conditions. The reaction mixture was stirred overnight at 90 °C. After cooling to room temperature, the reaction was quenched by adding a saturated sodium bicarbonate aqueous solution (50 mL). The organic phase was separated by extraction with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was slurried with ethyl acetate / diethyl ether (15 mL / 15 mL) for 3 hours, filtered, and a white solid intermediate A38-1 (1.7 g, 75%) was obtained.

[0691] 1 H NMR (400MHz, DMSO-d6): δ10.85(br s,1H),7.17(s,1H),6.94-6.80(m,2H),4.68(s,2H).

[0692] 2) Synthesis of intermediate A38-2

[0693] Intermediate A38-1 (1.6 g, 7.0 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL). A tetrahydrofuran solution of borane (14 mL, 14 mmol) was added dropwise at room temperature, and the mixture was stirred at 70 °C for 3 hours. After cooling to room temperature, the reaction mixture was poured into methanol (50 mL) and stirred for 30 minutes. After concentrating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a colorless oily intermediate A38-2 (1.4 g, 93%).

[0694] 1 H NMR (400MHz, CDCl3): δ6.88(d,J=7.6Hz,1H),6.67-6.57(m,1H),6.52(d,J=7.6Hz,1H),4.34(m,2H),3.84(br s,1H),3.43(m,2H).

[0695] 3) Synthesis of intermediate A38-3

[0696] Intermediate A38-2 (1.3 g, 6.1 mmol), pinacol diborate (2.3 g, 9.2 mmol), potassium acetate (1.5 g, 15 mmol), and Pd(dppf)Cl2 (440 mg, 0.61 mmol) were sequentially suspended in dry 1,4-dioxane (50 mL). The mixture was stirred at 100 °C under nitrogen for 24 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a yellow solid intermediate A38-3 (900 mg, 57%).

[0697] 4) Synthesis of intermediate A38-4

[0698] Intermediate A38-3 (157 mg, 0.60 mmol), 3-bromo-1-methyl-1,2,4-triazole (81 mg, 0.50 mmol), potassium carbonate (173 mg, 1.3 mmol), and Pd(dppf)Cl2 (35 mg, 0.050 mmol) were sequentially suspended in a mixed solvent of 1,4-dioxane / water (10 mL / 1 mL). The mixture was stirred at 100 °C under nitrogen for 12 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a yellow solid intermediate A38-4 (85 mg, 65%).

[0699] 1 H NMR (400MHz, CDCl3): δ8.07(s,1H),7.30(d,J=7.6Hz,1H),6.88-6.77(m,1H),6.65(d,J=7.6Hz,1H),4.44-4.31(m,2H),3.98(s,3H),3.86(br s,1H),3.56-3.41(m,2H).

[0700] 5) Synthesis of intermediate A38-5

[0701] Intermediates A38-4 (235 mg, 1.1 mmol) and A16-1 (245 mg, 1.2 mmol) were dissolved in dry tetrahydrofuran (15 mL). LiHMDS (4.4 mL, 4.4 mmol) was added dropwise under nitrogen atmosphere and an ice-water bath. After stirring at room temperature for 3 hours, the reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 25 / 1) to give a yellow solid intermediate A38-5 (100 mg, 24%).

[0702] 1 H NMR (400MHz, CDCl3): δ8.73(s,1H),8.13(s,1H),7.70-7.60(m,1H),7.13(s,1H),6.96- 6.89(m,2H),4.41-4.29(m,2H),4.01(s,3H),3.70-3.60(m,2H),2.96(d,J=4.4Hz,3H).

[0703] 6) Synthesis of the final product A38

[0704] Intermediate A38-5 (100 mg, 0.26 mmol), cyclopropylformamide (50 mg, 0.60 mmol), cesium carbonate (170 mg, 0.52 mmol), Xantphos (40 mg, 0.07 mmol), and Pd2(dba)3 (40 mg, 0.04 mmol) were sequentially suspended in dry 1,4-dioxane (3 mL). After purging with nitrogen, the mixture was stirred at 130 °C for 1.5 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain an oily crude product. This crude product was then slurried with ethyl acetate / diethyl ether (5 mL / 5 mL) for 5 hours, filtered, and the white solid final product A38 (65 mg, 58%) was obtained.

[0705] Example 34

[0706] Compound A39 is synthesized by the following method.

[0707]

[0708] 1) Synthesis of intermediate A39-1

[0709] 4-Bromoindoline (1.0 g, 5.1 mmol), pinacol diborate (2.0 g, 7.7 mmol), potassium acetate (1.3 g, 13 mmol), and Pd(dppf)Cl2 (373 mg, 0.51 mmol) were sequentially suspended in dry 1,4-dioxane (50 mL). The mixture was stirred overnight at 100 °C under nitrogen atmosphere, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown oily intermediate A39-1 (400 mg, 32%).

[0710] 1 H NMR (400MHz, CDCl3): δ7.15 (d, J = 7.2Hz, 1H), 7.08-6.96 (m, 1H), 6.74 (d, J = 7.6Hz, 1H), 3.54 (t, J = 8.0Hz, 2H), 3.23 (t, J = 8.0Hz, 2H), 1.33 (s, 12H).

[0711] 2) Synthesis of intermediate A39-2

[0712] Intermediate A39-1 (510 mg, 2.1 mmol), 3-bromo-1-methyl-1,2,4-triazole (335 mg, 2.1 mmol), anhydrous potassium phosphate (1.1 g, 5.3 mmol), and Pd(dppf)Cl2 (77 mg, 0.10 mmol) were sequentially suspended in a 1,4-dioxane / water (20 mL / 2 mL) mixed solvent. The mixture was stirred overnight at 100 °C under nitrogen atmosphere, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give a brown solid intermediate A39-2 (120 mg, 29%).

[0713] 1 H NMR (400MHz, CDCl3): δ8.06 (s, 1H), 7.46 (d, J = 7.2Hz, 1H), 7.15-7.04 (m, 1H), 6 .68(d,J=7.6Hz,1H),3.97(s,3H),3.61(t,J=8.0Hz,2H),3.45(t,J=8.0Hz,2H).

[0714] 3) Synthesis of intermediate A39-3

[0715] Intermediates A39-2 (100 mg, 0.50 mmol) and A16-1 (123 mg, 0.60 mmol) were dissolved in dry tetrahydrofuran (20 mL). LiHMDS (2.0 mL, 2.0 mmol) was added dropwise under nitrogen atmosphere and an ice-water bath. After stirring at room temperature for 3 hours, the reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give a yellow solid intermediate A39-3 (100 mg, 54%).

[0716] 1 H NMR (400MHz, CDCl3): δ8.66(s,1H),8.09(s,1H),7.74(d,J=7.6Hz,1H),7.33(s,1H),6.97(d,J=8.0H z,1H),6.52(s,1H),3.99(s,3H),3.95(t,J=8.0Hz,2H),3.57(t,J=8.0Hz,2H),2.87(d,J=4.4Hz,3H).

[0717] 4) Synthesis of final product A39

[0718] Intermediate A39-3 (37 mg, 0.10 mmol), cyclopropylformamide (11 mg, 0.13 mmol), cesium carbonate (65 mg, 0.20 mmol), Xantphos (12 mg, 0.020 mmol), and Pd2(dba)3 (9.2 mg, 0.010 mmol) were sequentially suspended in dry 1,4-dioxane (3 mL). After purging with nitrogen, the mixture was stirred at 130 °C for 1.5 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain an oily crude product. This crude product was then slurried with ethyl acetate / diethyl ether (5 mL / 5 mL) for 5 hours, filtered, and the white solid final product A39 (13 mg, 31%) was obtained.

[0719] Table 1. Analytical structures and spectroscopic data of compounds A1-A39

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726] Example 35

[0727] In this embodiment, the kinase competitive binding ability of compounds A2, A3, A6, A8, A9, A14, A15, A16 and A24 was tested.

[0728] In the experiments, kinase-labeled T7 phage strains were prepared from E. coli hosts derived from strain BL21. E. coli were cultured to the logarithmic phase, infected with T7 phage, and cultured at 32°C with shaking until lysis. The lysate was centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently detected by qPCR using DNA labeling. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands at room temperature for 30 minutes to generate affinity resins for kinase analysis. The ligand beads were blocked with excess biotin, and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1mM DTT) to remove unbound ligands and reduce nonspecific binding. The binding reaction was assembled by binding the kinase, ligand affinity beads, and testing the compound in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6mM DTT). The test compounds were prepared as a stock solution in 100% DMSO at 111×. Kds were determined using an 11-point 3-fold compound dilution series and three DMSO control points. All compounds used for Kd measurements were distributed in 100% DMSO via acoustic transfer (non-contact distribution). The compounds were then directly diluted to the analytes to a final concentration of 0.9%. All reactions were performed on 384-well polypropylene plates in 0.02 mL volumes. The plates were incubated with shaking at room temperature for 1 hour, and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The affinity beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated with shaking at room temperature for 30 minutes. The kinase concentration in the elution buffer was then determined by qPCR.

[0729] The standard dose-response curve was calculated using the Hill equation with the constant (Kds), and the results are shown in Table 2.

[0730]

[0731] Table 2. Competitive binding effects of compounds with TYK2 JH2 and JAK1 JH1

[0732]

[0733] Conclusion: As shown in Table 2 and Figure 1 As shown, compounds A2, A3, A6, A8, A9, A14, A15, A16, and A24 of the present invention exhibit strong affinity for the TYK2 pseudokinase domain and weak affinity for the JAK1 kinase domain, thus demonstrating good selectivity. Compound A35 shows weak binding affinity to both the TYK2 pseudokinase domain and the JAK1 kinase domain.

[0734] Example 36 Protein Blot Analysis

[0735] Experimental steps:

[0736] 1. Add Jurkat cells (1 million / mL, 2 mL) to a six-well plate.

[0737] 2. Add Tyk2 compound (10 μL) for pretreatment for 2 hours.

[0738] 3. Add IFN-α (100 ng / mL) and treat for 15 minutes.

[0739] 4. Collect cells using EP tubes, centrifuge (13000 rpm) for 1 minute, wash each tube once with pre-chilled PBS (1 mL), then remove the PBS. Add 50 μL of cell lysis buffer (prepared from 20 mM Tris-HCl at pH 7.4, 150 mM NaCl, 10% glycerol, 1 mM Na3VO4, 1% Triton X-100, 25 mM β-glycerol phosphate, and 0.1 mM PMSF) to each tube of cells, incubate on ice for 20 minutes, then centrifuge (13000 rpm, 4°C) for 20 minutes and collect the supernatant.

[0740] 5. Protein concentration was determined using a BSA kit with protein lysis buffer, and the quantification was 2 μg / μL.

[0741] 6. Prepare an 8% protein gel, add 20 μL of protein sample to each well, run the gel at 80V for 45 minutes, and after the protein markers separate, run the gel at 200V until the desired protein bands are separated.

[0742] 7.400mA, 90 minutes, transfer.

[0743] Prepare the required antibody at a ratio of 8.1:1000, incubate the primary antibody on a shaker for 2 hours, then wash with PBST solution on a shaker for 8 minutes, repeating 3 times.

[0744] 9. Incubate the secondary antibody (1:10000 dilution) on a shaker in the dark for 1.5 h, then wash with PBST solution on a shaker for 8 minutes, repeating 3 times.

[0745] 10. Development.

[0746] Conclusion: Figure 2 As shown, compounds A2, A3, A6, A8, A9 and A14 of the present invention can effectively inhibit the phosphorylation of TYK2 protein.

[0747] Example 37 Dual-luciferase experiment

[0748] Experimental steps:

[0749] 1. Seed L929 ISRE cells (5000 cells / well) in 96-well plates and incubate overnight at room temperature.

[0750] 2. Pretreat cells for 2 hours with different concentrations (10 nM, 100 nM, 1000 nM) of the test compound.

[0751] 3. Add IFN-α (100 ng / mL) and treat for 6 hours.

[0752] 4. Remove the upper culture medium, add PBS (100 μL) to wash, and then remove the PBS.

[0753] 5. Add 50 μL of PLB lysis buffer to each well and shake on a shaker for 15 minutes.

[0754] 6. Transfer 30 μL of PLB lysis buffer to a new 96-well white plate, add LAR II reagent (LAR II), and then quickly read the OD value at 450 nm using a plate washer.

[0755] 7. Add Stop & Glo reagent (30 μL), and then quickly read the OD value at 450 nm using a plate washer.

[0756] 8. The final result is the OD value from step 6 divided by the OD value from step 7.

[0757] Table 3. Inhibitory effects of compounds on TYK2

[0758]

[0759] Note: "\" indicates that it has not been tested.

[0760] Conclusion: As shown in Table 3 and Figure 3 As shown, compounds A9, A23, A25, A26, A29, A30 and A32 of the present invention have good inhibitory effects on TYK2.

[0761] Example 38: Test of compound Caco-2

[0762] Experimental steps:

[0763] Preheat HBSS buffer at 1.37℃.

[0764] 2. Take the compound from -20℃ and sonicate it for a few minutes (no less than 1 minute).

[0765] 3. Solvent preparation:

[0766] Donor buffer solution:

[0767] AB direction:

[0768] To prepare HBSS buffer with 0.3% DMSO and 5 μM LY (Lucifer Yellow): Add 150 μL DMSO and 50 μL LY (5 mM) to 50 mL HBSS buffer (pH 7.4).

[0769] HBSS buffer with 0.1% DMSO and 5 μM LY: Add 50 μL DMSO and 50 μL LY (5 mM) to 50 mL HBSS buffer (pH 7.4).

[0770] BA direction:

[0771] HBSS buffer with 0.3% DMSO: Add 150 μL of DMSO to 50 mL of HBSS buffer (pH 7.4).

[0772] HBSS buffer with 0.1% DMSO: Add 50 μL of DMSO to 50 mL of HBSS buffer (pH 7.4).

[0773] 3.2. Receptor buffer solution:

[0774] AB direction: Prepare HBSS buffer by adding 200 μL of 0.4% DMSO solution to 50 mL of HBS buffer (pH 7.4).

[0775] BA direction: Prepare HBSS buffer with 0.4% DMSO and 5μM LY: Add 200μL DMSO and 50μL LY (5mM) to 50mL HBSS buffer.

[0776] Prepare donor solution

[0777]

[0778] 4. Calculate TEER: Remove the cell culture plate from the incubator, wash the cell monolayer with HBSS buffer, and then measure the TEER value at Rm temperature.

[0779] 5. Centrifugation: Centrifuge (4000 rpm) for 5 min before adding the compound solution to the donor chamber.

[0780] 6. Administration: Add the solution according to the volumes listed in the table below (ensure that an additional 100 μL of donor sample can be prepared as T0).

[0781] Add solution volume

[0782] top A--B (Donor Room) 600 μL AB donor solution (100 μL for LY measurement, 100 μL for backup) 400μL Base side plate A--B (Receptor Chamber) 800 μL 0.4% DMSO HBSS 800μL Base side plate B--A (Donor Room) 900 μL BA donor solution (100 μL for backup) 800μL top B--A (Receptor Chamber) 500 μL 0.4% DMSO HBSS + LY (100 μL for LY measurement) 400μL

[0783] 7. Top LY T0 Sample: Determine the LY concentration in the top chamber, and take 100 μL of sample from the top chamber onto an opaque plate as the LY concentration. T0 .

[0784] 8. Preheating: Preheat the top plate and base side plate at 37°C for about 5 minutes, then place the top plate on the base side plate to begin transport.

[0785] 9. Incubation: Keep the plate incubated at 37°C for 90 minutes.

[0786] 10. Prepare the standard curve

[0787] Prepare a 300 μM (20×) compound solution: Add 6 μL of the original sample solution to 194 μL of methanol / water (1:1) solution.

[0788] Prepare the experimental solution using methanol and water (1:1).

[0789] 300 100 400 → 60 60 100 200 → 20 20 100 400 → 4 4 100 400 → 0.8 0.8 100 300 → 0.2 0.2 100 100 → 0.1

[0790] Prepare 1× solution: 3 μL (20×) + 57 μL of 0.4% DMSO HBSS + 60 μL ACN and IS (Osamamethoxam or Imipramine) --- 120 μL (1×).

[0791] 11. Termination of transfer: After incubation for 90 minutes, separate the top plate from the base plate.

[0792] 12. Measure LY: Take 100 μL of sample from the base plate into the opaque plate.

[0793] 13. Measure LY using a fluorometer T0 -LY T90 The concentration.

[0794] 14. Dilute the donor or recipient sample with 0.4% DMSO HBSS and then mix with acetonitrile (Osamamethoxam or Imipramine) containing IS.

[0795] Table 4. Test results of heterocyclic compound Caco-2

[0796]

[0797] Conclusion: Compound A9 of this invention has good permeability and no efflux.

Claims

1. The following compound or a pharmaceutically acceptable salt thereof: 。 2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. A composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 and one or several of an anti-autoimmune disease drug, an anti-tumor drug, an anti-neurodegenerative disease drug, an anti-asthma drug.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the composition according to claim 2 or 3 for the manufacture of a medicament for the treatment of diseases and / or conditions by inhibition of TYK2.

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