Matrix metalloproteinase (MMP) inhibitors and methods of use thereof

Abstract

To provide hydantoin derivatives improved in specificity, potency and pharmacological properties as MMP inhibitors.SOLUTION: The invention provides hydantoin-based compounds, e.g., represented by the formula (I), useful as inhibitors of matrix metalloproteinases (MMPs), particularly macrophage elastase (MMP-12). Also provided are related compositions and methods of using compounds for inhibiting MMP-12 and treating diseases mediated by MMP-12, such as asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 671,753, filed May 15, 2018, the disclosure of which is incorporated herein by reference. [Background technology]

[0002] Matrix metalloproteinases (MMPs) are a superfamily of proteinase enzymes that are important for the degradation of the outermost extracellular matrix proteins during organogenesis, growth and normal tissue turnover.MMPs are also considered to be important in the uncontrolled destruction of connective tissue, which is related to several disease processes, such as rheumatoid arthritis, osteoarthritis, gastric ulcer formation, asthma, emphysema and tumor metastasis.Therefore, the inhibition of one or more MMPs may be beneficial in these diseases.

[0003] Human macrophage elastase (MMP-12) is a unique MMP. MMP-12 exhibits all the characteristics of other MMPs, but is preferentially produced by macrophages that infiltrate tissues where injury or remodeling occurs, and degrades the extracellular matrix. For example, enhanced levels of MMP-12 are observed during the development of emphysema. Furthermore, MMP-12 knockout mouse models have been shown to not develop emphysema after long-term exposure to cigarette smoke (Hautamkai et al., Science, 1997, vol. 277:2002-2004). These data suggest that MMP-12 plays a role in the disease progression of emphysema. Based on studies in an MMP12-deficient model of asthma, the involvement of MMP-12 in the development of chronic asthma has also been suggested (Warner et al., Am J Pathol. 2004; vol. 165(6):1921-1930). In a Fas-induced model of acute lung injury, MMP-12-deficient mice are protected from the development of pulmonary fibrosis (Matute-Bello et al., Am J Respir Cell Mol Biol. 2007;37(2):210-221). In a model of lung and liver fibrosis induced by Schistosoma mansoni infection, MMP-12 has profibrogenic activity in the lung and liver (Madala et al. J Immunol 2010;184:3955-3963). MMP-12 may also contribute to idiopathic pulmonary fibrosis (IPF) pathogenesis by cleaving extracellular matrix (ECM) proteins, as BALF levels of type IV collagen fragments generated by MMP-12 are increased in patients with IPF (Sand et al., PLoS One 2013; 8: e84934), and human MMP-12 can cleave several human ECM proteins in vitro (Owen et al., J Leukoc Biol 1999; 65: 137-150). Taken together, these results suggest that inhibitors of MMP-12 may be useful in the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), emphysema, asthma, acute lung injury, idiopathic pulmonary fibrosis (IPF), liver fibrosis, and nonalcoholic steatohepatitis (NASH).

[0004] MMP-12 has been shown to be secreted by alveolar macrophages in smokers (Shapiro et al., Journal of Biological Chemistry, 1993, 268:23824), in atherosclerotic lesions (Matsumoto et al., Am. J. Pathol., 1998, 153:109) and in foam cells in a rat model of nephritis (Kaneko et al., J. Immunol., 2003, 170:3377). MMP-12 also plays a role in coronary artery disease (Jormsjo et al., Circulation Research, 2000, 86:998). MMP-12 has also been shown to be upregulated and contribute to epithelial degradation in patients with inflammatory bowel disease (IBD) and in T cell-mediated models of colitis, and MMP-12- / - mice were protected from TNBS-induced colitis (Pender et al., Ann NY Acad Sci. 2006, 1072:386-8). Epithelial and interstitial MMP-12, along with MMP-3 and MMP-7, are also upregulated in pouch mucosa of childhood-onset UC, suggesting that long-term expression of MMPs in pediatric UC pouches shares characteristics with IBD (Makitalo et al., World J Gastroenterol. 2012, 18(30):4028-36). Taken together, these observations suggest that MMP-12 may be a target for the treatment of these diseases.

[0005] Considering the involvement of MMP-12 in some diseases, attempts have been made to prepare MMP-12 inhibitors.Some MMP-12 inhibitors are known (see, for example, International Patent Application Publication No. WO00 / 40577, European Patent Application Publication No. EP1288199A1, U.S. Patent No. 6,352,9761 and U.S. Patent Application Publication No. 2004 / 0072871, and European Patent Application Publication No. EP1394159).

[0006] A particular class of MMP inhibitors described are hydantoin derivatives. For example, International Patent Application Publication No. WO 02 / 096426 describes hydantoin derivatives of the following general formula:

[0007] [ka] which are disclosed to be active as MMP inhibitors, particularly against tumor necrosis factor-alpha converting enzyme (TACE) and aggrecanase. A feature of the disclosed structures of these derivatives is a spiro-linking group between the hydantoin ring and its side chain. U.S. Patent Application Publication No. 2004 / 0067996 and International Patent Application Publication No. WO2004 / 108086 disclose similar hydantoin derivatives of the following general formula:

[0008] [ka] which is also described as active as an MMP inhibitor, especially against TACE and aggrecanase.

[0009] International Patent Application Publication No. WO 02 / 074752 describes the synthesis of MMP inhibitors, and International Patent Application Publication No. WO 2004 / 020415 discloses MMP-12 inhibitors, each of which is a hydantoin derivative of the following general formula:

[0010] [ka] Some of the disclosed compounds exhibited MMP inhibitory activity, including MMP-12 inhibitory activity.

[0011] More recently, inhibitors of MMP-12 have been described in U.S. Pat. No. 7,179,831, which include hydantoin derivatives of the general formula:

[0012] [ka] It is. Summary of the Invention [Problem to be solved by the invention]

[0013] Hydantoin derivatives are a useful class of MMP inhibitors, however, there is a need in the art to identify hydantoin derivatives with improved specificity, potency and pharmacological properties. [Means for solving the problem]

[0014] The present application meets the above-mentioned needs by providing hydantoin derivatives that have high activity and specificity against MMPs, particularly macrophage elastase (MMP-12).

[0015] In a general aspect, the present application relates to a compound of formula (Ib):

[0016] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, Ring B is an optionally substituted aryl or an optionally substituted heteroaryl; Ring C is an optionally substituted aryl or an optionally substituted heteroaryl; Ring D is an optionally substituted aryl or an optionally substituted heteroaryl; X, Y and Z are each CH 2 , O, N.R. x and S(O) q R x is hydrogen or alkyl, R 1 is hydrogen or alkyl, R 4 is hydrogen or alkyl, R 5 is hydrogen, q is 0, 1 or 2; provided that ring B is not furanyl. Regarding.

[0017] In an embodiment, the present application provides a compound of formula (I):

[0018] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, Ring B is an optionally substituted aryl or an optionally substituted heteroaryl; Ring C is aryl or heteroaryl; Ring D is aryl or heteroaryl; X, Y and Z are each CH 2 , O, N.R. x and S(O) q R x is hydrogen or alkyl, R 1 is hydrogen or alkyl, R 2 are respectively hydrogen, alkyl, halogen, hydroxyl, haloalkyl, alkoxy, alkylthio, amine, amide, alkylamine, aminoalkyl, cyano, hydroxyalkyl, -(CH 2 ) p C(O)OR 6 and -(CH 2 ) p O.C.(O)R 6 are independently selected from the group consisting of: R 3 are each independently selected from the group consisting of hydrogen, alkyl, and halo; R 4 is hydrogen or alkyl, R 5 is hydrogen, R 6are each independently selected from the group consisting of hydrogen and alkyl, wherein alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of amine, hydroxyl, halogen, and alkoxy; m is 1, 2, 3 or 4; n is 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4 or 5; q is 0, 1 or 2; provided that ring B is not furanyl. Regarding.

[0019] In an embodiment, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring C is phenyl.

[0020] In an embodiment, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring D is pyridinyl or phenyl.

[0021] In an embodiment, the present application relates to a compound wherein ring D is

[0022] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof.

[0023] In an embodiment, the present application provides 1 , R 4 and R 5 are each hydrogen, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0024] In an embodiment, the present application provides a compound wherein X is S, Y is O, and Z is CH 2 or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof.

[0025] In an embodiment, the present application provides a method for the preparation of a 5- or 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from N, S, and O, the 5- or 6-membered monocyclic heteroaryl being selected from -CH 3 or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, optionally substituted by

[0026] In an embodiment, the present application provides a method for the preparation of a compound according to the present invention, wherein Ring B is pyridinyl, thiophenyl, imidazolyl, pyrazolyl, or oxazolyl, wherein pyridinyl, thiophenyl, imidazolyl, pyrazolyl, and oxazolyl are each independently -CH 3 or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, wherein

[0027] In an embodiment, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is pyridinyl.

[0028] In an embodiment, the present application provides a compound selected from the group consisting of a compound of formula (II-a), a compound of formula (II-b), a compound of formula (II-c) and a compound of formula (II-d):

[0029] [ka] JPEG0007656669000009.jpg34170 or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof (In the formula, R 1 is hydrogen, -CH 3 or -CH 2 CH 3 and R 4 is hydrogen or -CH 3 and R 5 is hydrogen or -CH 3 and R 3 is hydrogen, -F, -Cl or CH 3 and X is S, SO or SO 2 and Y is O, NH, CH 2 or NHCH 3 and Ring D is pyridinyl or phenyl; R 2 -CH 3 , -CH 2 OH, -OH, CH 2 OC(O)CH(NH 2 )CH(CH 3 ) 2 , -COOH, -C(O)NH 2 , -C(O)NHCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 or -CH 2 CH(CH 3 ) 2 and n is 0 or 1. Regarding.

[0030] In an embodiment, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is thiophenyl.

[0031] In an embodiment, the present application relates to a compound of formula (IV):

[0032] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, R 1 , R 4 and R 5 are hydrogen, X is S, Y is O, R 3 is hydrogen, Ring D is phenyl or pyridinyl; R 2 is -CH 3 , -C(O)NH 2 , -CH 2 OH, -OCH 3 or -OH, n is 0 or 1. Regarding.

[0033] In an embodiment, the present application relates to a compound selected from the group consisting of a compound of formula (Va), a compound of formula (Vb) and a compound of formula (VI):

[0034] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, R 1 is hydrogen, -CH 3 or -CH 2 CH 3 and R 4 is hydrogen or -CH 3 and R 5 is hydrogen or -CH 3 and R 3 is hydrogen, -F, -Cl or CH 3 and X is S, SO or SO 2 and Y is O, NH, CH 2 or NHCH 3 and Ring D is pyridinyl or phenyl; R 2 is -CH 3 , -CH 2 OH, -OH, CH 2 OC(O)CH(NH 2 )CH(CH 3 ) 2 , -COOH, -C(O)NH2 , -C(O)NHCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 or -CH 2 CH(CH 3 ) 2 and n is 0 or 1. Regarding.

[0035] In an embodiment, the present application provides a compound selected from the group consisting of compounds of formula (VII-a) and compounds of formula (VII-b):

[0036] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, R 1 , R 3 , R 4 and R 5 are hydrogen, X is S, Y is O, Ring D is phenyl or pyridinyl; R 2 -CH 3 , -C(O)NH 2 , -CH 2 OH, -OCH 3 or -OH, n is 0 or 1. Regarding.

[0037] In an embodiment, the present application provides a compound of formula (Ia):

[0038] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, Ring B is pyridinyl; Q is CH or N; R 1 is hydrogen, -CH 3 or -CH 2 CH 3 and R 4 is hydrogen or -CH 3 and R 5 is hydrogen or -CH 3 and R 2 -CH 3 , -C(O)NH 2 , -CH 2 OH, -OCH 3 or -OH; X is S, Y is O Regarding.

[0039] In an embodiment, the present application relates to a compound selected from the group consisting of the compounds listed in Table 1, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0040] In an embodiment, the present application relates to a compound selected from the group consisting of the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof.

[0041] In another general aspect, the application relates to a pharmaceutical composition comprising a compound of the application described herein or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, and at least one pharma- ceutically acceptable carrier.

[0042] Other general aspects of the application relate to methods of inhibiting macrophage elastase (MMP-12) in a subject in need thereof, and methods of treating diseases mediated by macrophage elastase (MMP-12) in a subject in need thereof.

[0043] In embodiments, the present application relates to a method of inhibiting macrophage elastase (MMP-12) in a subject in need thereof, comprising administering to the subject a compound or pharmaceutical composition of the present application.

[0044] In embodiments, the present application relates to a method of treating a disease mediated by macrophage elastase (MMP-12) in a subject in need thereof, comprising administering to the subject a compound or pharmaceutical composition of the present application.

[0045] In some embodiments, the disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, and idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, non-alcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.

[0046] Also provided herein is a compound of the present application or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, or a composition of the present application, for use in a method of inhibiting macrophage elastase (MMP-12) or treating a disease mediated by macrophage elastase (MMP-12). In some embodiments, the disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, and idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.

[0047] Also provided herein is the use of a compound of the present application or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, or a composition of the present application, in the manufacture of a medicament for inhibiting macrophage elastase (MMP-12) or treating a disease mediated by macrophage elastase (MMP-12).Preferably, the disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, and idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.

[0048] In yet another general aspect, the application relates to a method of preparing a pharmaceutical composition of the application, the method comprising combining a compound of the application or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, and at least one pharma- ceutically acceptable carrier.

[0049] The foregoing summary, as well as the following detailed description, will be better understood when read in conjunction with the accompanying drawings. It should be understood that the invention is not limited to the precise embodiments shown in the drawings. [Brief description of the drawings]

[0050] 1A to 1H are graphs illustrating the results of an investigation into the efficacy of an MMP-12 inhibitor on a renal fibrosis model caused by unilateral ureteral obstruction (UUO) in SD rats, as described in Example 3. [Figure 1A] 1 is a graph showing the change in serum BUN at 2 weeks compared to before surgery (pre-OP) for each of the experimental SD rat groups. [Figure 1B] 1 is a graph showing the change in serum creatine at 2 weeks compared to pre-surgery (pre-OP) for each of the experimental SD rat groups. [Figure 1C]Histological images of kidneys from H&E staining at ×200 magnification. Panel A: right kidney as normal control, Panel B: vehicle-treated animals, Panel C: PC-16-treated animals (2 mg / kg / day), Panel D: PC-16-treated animals (6 mg / kg / day), Panel E: PC-16-treated animals (20 mg / kg / day). [Figure 1D] Graphs showing renal tubular injury score (I) and renal interstitial inflammation score (II) for each of the experimental SD rat groups. T-test in (I): ***p<0.05 vs. model, $p<0.05 vs. PC-16 (2 mg / kg / day), $$p<0.01 vs. PC-16 (6 mg / kg / day); T-test in (II): **p<0.05 vs. model, ***p<0.001 vs. model. [Figure 1E] Histological images of kidneys from Masson's Trichrome staining at a magnification of ×200. Panels A-E correspond to panels A-E described in FIG. 1C. [Figure 1F] Figure 14. Interstitial fibrosis score for renal interstitial fibrosis in the cortex. T-test: **p<0.01 vs. model, ***p<0.001 vs. model, $p<0.05 vs. PC-16 (2 mg / kg / day), $$p<0.01 vs. PC-16 (2 mg / kg / day). [Figure 1G] Figure 1 shows collagen I (I) and collagen IV (II) deposits in the cortical region of the left kidney by IHC staining at ×200 magnification, Panels A-E correspond to Panels A-E described in Figure 1C. [Figure 1H] Figure 1C shows the percentage of positive staining for collagen I deposition (I) and percentage of positive staining for collagen IV deposition (II) in the cortical region of the left kidney as determined from the IHC staining in Figure 1G. One-way ANOVA: ***p<0.001 vs. normal control; T-test: #p<0.05 vs. model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] In the background and throughout the specification, various publications, articles and patents are cited or described. Each of these references is incorporated herein by reference in its entirety. The discussion of documents, acts, materials, devices, articles and the like included in the specification is for the purpose of providing background related to the present invention. Such discussion is not an admission that any or all of the subject matter forms part of the prior art with respect to any invention(s) disclosed or claimed.

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Unless otherwise specified, certain terms used herein have the meanings described herein. All patents, published patent applications, and publications cited herein are incorporated by reference as if fully set forth herein.

[0053] It must be noted that as used in this specification and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0054] Unless otherwise indicated, the term "at least" preceding a series of elements should be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

[0055] Throughout this specification and the claims that follow, unless the context otherwise requires, the word "comprise", as well as variations such as "comprises" and "comprising", will be understood to mean the inclusion of a specified integer or step or group of integers or steps, but not the exclusion of any other integers or steps or group of integers or steps. The term "comprising", as used herein, can be replaced by the terms "containing" or "including", or, sometimes, as used herein, by the term "having".

[0056] "Consisting of," as used herein, excludes any element, step, or ingredient not specified in the claim element. "Consisting essentially of," as used herein, does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any of the above terms "comprising," "containing," "including," and "having," whenever used herein in the context of an aspect or embodiment of this application, may be replaced by the term "consisting of" or "consisting essentially of" to modify the scope of the disclosure.

[0057] As used herein, the connecting term "and / or" between multiple cited elements is understood to include both individual and combined options. For example, when two elements are connected by "and / or", the first option refers to the first element being applied without the second element. The second option refers to the second element being applied without the first element. The third option refers to the first and second elements being applied together. Any one of these options is understood to fall within the meaning and thus satisfy the requirements of the term "and / or" as used herein. It is also understood that more than one of these options can be applied simultaneously and still fall within the meaning and thus satisfy the requirements of the term "and / or".

[0058] Unless otherwise specified, any numerical value, such as a concentration or concentration range described herein, should be understood in all cases to be modified by the term "about". Thus, numerical values ​​generally include ±10% of the cited value. For example, a reference to "10 times" includes 9 times and 11 times. As used herein, unless the context clearly indicates otherwise, the use of numerical ranges expressly includes all individual numerical values ​​within such ranges, including all possible subranges, integers within such ranges and fractions of these values.

[0059] As used herein, "subject" refers to any animal, preferably a mammal, most preferably a human, that will be or has been treated by a method according to an embodiment of the present application. The term "mammal" as used herein includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs), such as monkeys or apes, humans, and more preferably humans.

[0060] The phrase "pharmaceutically acceptable salts" as used herein means salts of a subject compound that are safe and effective for topical use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the specified compound. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, carbonate, bicarbonate, acetate, lactate, salicylate, citrate, tartrate, propionate, butyrate, pyruvate, oxalate, malonate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronic acid, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts. Certain compounds used in this application can form pharma- ceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolamine salts. For a review of pharma- ceutically acceptable salts, see Berge et al., Vol. 66, J. Pharm. Sci. pp. 1-19 (1977), incorporated herein by reference.

[0061] As used herein, the term "alkyl" refers to a univalent unbranched or branched saturated hydrocarbon chain. An alkyl group may be unsubstituted or substituted with one or more suitable substituents. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group may have a specified number of carbon atoms. When a number appears in a subscript after the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular alkyl may contain. For example, "C 1 ~C 10 Alkyl" or "C 1~10 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 It is intended to include alkyl groups. 1 ~C 6 Alkyl" or "C 1~6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

[0062] The term "alkoxy" as used herein refers to an -O-alkyl group, where alkyl is as defined above. An alkoxy group is attached to the parent molecule through an oxygen atom. An alkoxy group can have a specified number of carbon atoms. For example, "C 1 ~C 10 Alkoxy" or "C 1~10 Alkoxy" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10Alkoxy groups are intended to be included. 1 ~C 6 Alkoxy" or "C 1~6 "Alkoxy" refers to an alkoxy having 1 to 6 carbon atoms. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy, isopropoxy), butoxy (e.g., n-butoxy, isobutoxy, tert-butoxy), pentyloxy (e.g., n-pentyloxy, isopentyloxy, neopentyloxy), and the like. An alkoxy group can be unsubstituted or substituted with one or more suitable substituents. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above attached through a sulfur bridge, such as, for example, -S-methyl, -S-ethyl, and the like. Representative examples of alkylthio include, but are not limited to, -SCH 3 , -SCH 2 CH 3 etc.

[0063] As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine. Correspondingly, the term "halo" means fluoro, chloro, bromo and iodo.

[0064] "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more halogen atoms. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0065] The terms "hydroxy" and "hydroxyl" may be used interchangeably and refer to --OH.

[0066] The term "carboxy" refers to --COOH.

[0067] The term "cyano" refers to --CN.

[0068] The term "amino" refers to -NH 2 The term "alkylamino" refers to an amino group in which one or both of the hydrogen atoms attached to the nitrogen have been replaced by an alkyl group. For example, alkylamino includes methylamino (-NHCH 3 ), dimethylamino (-N(CH 3 ) 2 ), -NHCH 2 CH 3 etc.

[0069] The term "aminoalkyl," as used herein, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more amino groups. For example, 1~4 "Aminoalkyl" refers to a C alkyl group substituted with one or more amino groups. 1 , C 2 , C 3 and C 4 Representative examples of aminoalkyl groups include, but are not limited to, -CH 2 NH 2 , -CH 2 CH 2 NH 2 and -CH 2 CH(NH 2 )CH 3 Includes:

[0070] As used herein, "amide" refers to a -C(O)N(R) 2 where each R is independently an alkyl group or hydrogen. Examples of amides include, but are not limited to, -C(O)NH 2 , -C(O)NHCH 3 and -C(O)N(CH 3 ) 2 Includes:

[0071] The terms "hydroxylalkyl" and "hydroxyalkyl" are used interchangeably and refer to an alkyl group substituted with one or more hydroxyl groups. The alkyl can be a branched or straight chain aliphatic hydrocarbon. Examples of hydroxylalkyl include, but are not limited to, hydroxylmethyl (-CH 2 OH), hydroxyethyl (-CH 2 CH 2 OH) and others.

[0072] The term "aryl" as used herein refers to any carbon-based aromatic group-containing group, including, but not limited to, phenyl, naphthyl, anthracenyl, phenanthranyl, and the like. Aryl moieties are well known and are described, for example, in Lewis, RJ (ed.), Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). Aryl groups can be unsubstituted or substituted with one or more suitable substituents. Aryl groups can be single ring structures (i.e., monocyclic) or can include multiple ring structures (i.e., polycyclic) that are fused ring structures. Preferably, the aryl group is a monocyclic aryl group, such as phenyl.

[0073] As used herein, the term "heteroaryl" includes stable monocyclic and polycyclic aromatic hydrocarbons containing at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. Heteroaryls can be monocyclic or polycyclic, such as bicyclic or tricyclic. Each ring of a heteroatom-containing heteroaryl group can contain one or two oxygen atoms, or sulfur atoms, and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring has at least one carbon atom. In the case of bicyclic heteroaryl groups, the fused rings completing the bicyclic group can contain only carbon atoms and can be saturated, partially saturated, or unsaturated. Heteroaryl groups that are polycyclic, e.g., bicyclic or tricyclic, must contain at least one fully aromatic ring, but the other fused ring(s) can be aromatic or non-aromatic. The heteroaryl group can be attached at any available nitrogen or at a carbon atom of any ring of the heteroaryl group. Preferably, the term "heteroaryl" refers to 5- or 6-membered monocyclic and 9- or 10-membered bicyclic groups having at least one heteroatom (O, S or N) in at least one of the rings, the heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms selected from O, S and / or N. Heteroaryl groups may be unsubstituted or substituted with one or more suitable substituents. The nitrogen heteroatom of a heteroaryl may be substituted or unsubstituted. The nitrogen and sulfur heteroatoms of a heteroaryl may be optionally oxidized (i.e., N→O and S(O)). r and r is 0, 1 or 2.

[0074] Exemplary monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Exemplary bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl.

[0075] According to the convention used in the art:

[0076] [ka] is used in structural formulas herein to depict the bond that serves as the point of attachment of a moiety or substituent to a core structure or backbone structure.

[0077] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring.

[0078] As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that all normal valences are maintained and the replacement results in a stable compound. When a particular group is "substituted", the group can have one or more substituents, preferably 1-5 substituents, more preferably 1-3 substituents, and most preferably 1-2 substituents, independently selected from a list of substituents. The term "independently", when used in reference to a substituent, means that when more than one of such substituents is possible, such substituents can be the same or different from each other. Examples of suitable substituents include, but are not limited to, alkyl, halogen, alkoxy, amido, alkylthio, amine, alkylamine, aminoalkyl, hydroxyalkyl, hydroxyl, carboxyl, and the like, e.g., C 1~4 Alkyl, C 1~3 Alkoxy, -OH, -COOH, -F, -Cl, -C(O)NHCH 3 , -C(O)N(CH 3 ) 2 Includes:

[0079] With respect to compounds, when any variable occurs more than one time in any constituent or formula, its definition at each occurrence is independent of its definition at all other occurrences. Thus, for example, if a group is shown to be substituted with 0 to 3 R groups, then said group may be optionally substituted with up to 3 R groups, and R at each occurrence is independently selected from the definition of R.

[0080] The term "optional" or "optionally" means that the subsequently described event or circumstance can, but does not necessarily, occur, and such a description includes situations in which the event or circumstance occurs or does not occur. For example, "optionally substituted aryl" means that substituents can, but do not necessarily, be present, and such a description includes situations in which the aryl group is substituted with suitable substituents and situations in which the aryl group is not substituted with any substituents.

[0081] Those skilled in the art will recognize that in certain embodiments, the compounds of the present application may have one or more asymmetric carbon atoms in their structure. As used herein, any chemical formula containing bonds that are shown as solid lines only, rather than solid or dotted wedge bonds, or otherwise shown as having a particular configuration (e.g., R or S) around one or more atoms, contemplates any possible stereoisomer or mixture of two or more stereoisomers. In other words, if the stereochemistry of a structure is not specified, the structure is intended to encompass all of the individual stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers. "Enantiomers" are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images, and occur when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of one another. Substituents (e.g., alkyl, heterocyclyl, etc.) can contain stereocenters in either the R or S configuration.

[0082] Thus, stereochemically pure isomers (i.e., single enantiomers or diastereomers) of the compounds of the present invention, and mixtures thereof, including their racemates, are included within the scope of the present invention. When a particular stereoisomer is specified, this means that the stereoisomer is substantially free, i.e., with less than 50%, preferably less than 20%, more preferably less than 5%, particularly less than 2%, and most preferably less than 1% of other stereoisomers. For example, when a compound is specified as, for example, (R), this means that the compound is substantially free of (S) isomers. The compounds of the application described herein can be used as racemic mixtures, enantiomerically or diastereomerically enriched mixtures, or as enantiomerically or diastereomerically pure individual stereoisomers.

[0083] Stereochemically pure isomers can be obtained by techniques known in the art in light of the present disclosure. For example, diastereoisomers can be separated by physical separation methods, such as fractional crystallization and chromatographic techniques, and enantiomers can be separated from each other by selective crystallization of diastereomeric salts with optically active acids or bases, or by chiral chromatography. Pure stereoisomers can also be prepared by synthesis from appropriate stereochemically pure starting materials, or by using stereoselective reactions.

[0084] The compounds of the present application can also form tautomers. The term "tautomer" refers to compounds that are interconvertible forms of a particular compound's structure, with different displacements of hydrogen atoms and electrons. Tautomers are constitutional isomers of chemical compounds that readily interconvert, usually resulting in the rearrangement of protons (hydrogen). Thus, two structures can be in equilibrium through the shifting of pi electrons and atoms (usually hydrogen). All tautomers of the compounds of the present application and their mixtures are included within the scope of the present application.

[0085] The compounds of the present application may exist in solvated and nonsolvated forms. The term "solvate" refers to a physical association of the compounds of the present application with one or more solvent molecules, for example, by hydrogen bonding. The solvent molecules in a solvate may exist in an ordered and / or non-ordered arrangement. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolable solvates. The compounds of the present application may form solvates with water (i.e., hydrates) or common organic solvents. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.

[0086] Similarly, all isotopes of atoms occurring in the compounds of this application are included within the scope of this application. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described herein, using the appropriate isotopically labeled reagent in place of the non-labeled reagent used otherwise.

[0087] As used herein, compound names are intended to encompass all possible isomers (e.g., optical isomers, enantiomers, diastereomers, racemates or racemic mixtures), tautomers, and pharma- ceutically acceptable salts of the compound that may exist.

[0088] compound In a general aspect, the present application relates to a compound of formula (Ib):

[0089] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, Ring B is an optionally substituted aryl or an optionally substituted heteroaryl; Ring C is an optionally substituted aryl or an optionally substituted heteroaryl; Ring D is an optionally substituted aryl or an optionally substituted heteroaryl; X, Y and Z are each CH 2 , O, N.R. x and S(O) q R x is hydrogen or alkyl, R 1 is hydrogen or alkyl, R 4is hydrogen or alkyl, R 5 is hydrogen, q is 0, 1 or 2; provided that ring B is not furanyl. Regarding.

[0090] In an embodiment, the compound of formula (I):

[0091] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, Ring B is an optionally substituted aryl or an optionally substituted heteroaryl; Ring C is aryl or heteroaryl; Ring D is aryl or heteroaryl; X, Y and Z are O, CH 2 , N.R. x and S(O) q R x is hydrogen or alkyl, R 1 is hydrogen or alkyl, R 2 are respectively hydrogen, alkyl, halo, hydroxyl, haloalkyl, alkoxy, alkylthio, amino, amido, alkylamino, aminoalkyl, cyano, hydroxyalkyl, -(CH 2 ) p C(O)OR 6 and -(CH 2 ) p O.C.(O)R 6 are independently selected from the group consisting of: R 3 are each independently selected from the group consisting of hydrogen, alkyl, and halo; R 4 is hydrogen or alkyl, R 5 is hydrogen, R6 are each independently selected from the group consisting of hydrogen and alkyl, wherein alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of amino, hydroxyl, halo, and alkoxy; m is 1, 2, 3 or 4; n is 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4 or 5; q is 0, 1 or 2. is provided.

[0092] In embodiments, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, wherein Ring C is optionally substituted aryl, preferably optionally substituted phenyl.

[0093] In embodiments, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, wherein Ring C is optionally substituted heteroaryl, preferably optionally substituted pyridinyl.

[0094] In an embodiment, m is 1 and R 3 are independently hydrogen, alkyl or halo, preferably hydrogen, -CH 3 , -F or -Cl, more preferably H, or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof.

[0095] In an embodiment, Ring C is phenyl, m is 1, and R 3 is hydrogen, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0096] In an embodiment, Ring C is phenyl, m is 1, and R 3 is fluoro; or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0097] In an embodiment, Ring C is phenyl, m is 1, and R 3 is methyl, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0098] In an embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, wherein Ring D is optionally substituted aryl, preferably optionally substituted phenyl.

[0099] In embodiments, there is provided a compound of Formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring D is optionally substituted heteroaryl.

[0100] In an embodiment, Ring D is selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, alkylthio, amino, amido, alkylamino, aminoalkyl, cyano, hydroxyalkyl, -(CH 2 ) p C(O)OR 6 and -(CH 2 ) p O.C.(O)R 6 and p is 0, 1, 2, 3, 4 or 5. The substituents, when present, may be attached at any position of Ring D. Preferably, Ring D is substituted by one substituent.

[0101] In embodiments, compounds of formula (I) are provided in which Ring D is a monocyclic aryl or heteroaryl group substituted with one substituent at the meta position relative to the bond to variable Z, preferably phenyl or pyridinyl substituted at the meta position, or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. In particular, preferred substituents for Ring D include methyl (-CH 3 ), amide (-C(O)NH 2 ), methoxy (-OCH 3 ), hydroxyl (-OH) and hydroxylmethyl (-CH 2 OH) is included.

[0102] In certain embodiments, Ring D is phenyl.

[0103] In another particular embodiment, Ring D is pyridinyl.

[0104] In an embodiment, n is 1 and R 2 But, C 1~3 Alkoxy (e.g., -OCH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ), C 1~4 Alkyl (e.g., -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 ), -CH 2 OH, -OH, -COOH, -C(O)NH 2 , -C(O)NHCH 3 or -CH 2 OC(O)CH(NH 2 )CH(CH 3 ) 2 , -C(O)NH 2 , -C(O)NHCH 3or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. Preferably, R 2 -CH 3 , -C(O)NH 2 , -CH 2 OH, -OCH 3 Or OH.

[0105] In an embodiment, Ring D is

[0106] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0107] According to an embodiment of the present application, the asymmetric carbon atom of the hydantoin moiety can be unsubstituted (i.e., R 1 is hydrogen), or may be substituted. When substituted, R 1 The substituent is preferably alkyl. Preferred alkyl groups for substitution of the asymmetric carbon atom of the hydantoin moiety are C 1~2 Alkyl groups include, for example, methyl and ethyl.

[0108] In embodiments, R 1 is hydrogen, -CH 3 or -CH 2 CH 3 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0109] In embodiments, R 1 is hydrogen, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0110] Substitution of the nitrogen atom of the hydantoin moiety is also possible. According to an embodiment of the present application, R 4 and R 5are each independently hydrogen or alkyl. Preferred alkyl groups include methyl.

[0111] In embodiments, R 4 is hydrogen or -CH 3 and R 5 Ga-CH 3 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0112] In embodiments, R 4 and R 5 are each hydrogen, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0113] According to an embodiment of the present application, X, Y and Z are each O, NR x , C.H. 2 and S(O) q q is 0, 1 or 2; R x is hydrogen or alkyl. Thus, the linker units X, Y and Z are O, S, S(O), SO 2 , NH, N-alkyl and CH 2 Preferably, X, Y and Z are independently selected from S, S(O), S(O), 2 , C.H. 2 and O, more preferably S, CH 2 and O.

[0114] In an embodiment, X is O, Y is O and Z is CH 2 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0115] In an embodiment, X is S, Y is S and Z is CH 2 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0116] In an embodiment, X is O, Y is S and Z is CH 2 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0117] In an embodiment, X is S, Y is O and Z is CH 2 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0118] In an embodiment, Z is O and Y is CH 2 and X is S, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0119] In an embodiment, Z is S and Y is CH 2 and X is O, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0120] In an embodiment, X is S(O), Y is O and Z is CH 2 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0121] In an embodiment, X is S(O) 2 and Y is O and Z is CH 2 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0122] In an embodiment, X is S, Y is NH and Z is CH 2 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0123] In an embodiment, X is S and Y is N(CH 3 ) and Z is CH 2or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0124] In a preferred embodiment, there is provided a compound of formula (I), wherein one of X and Y is S and the other is O, or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof.

[0125] In a more preferred embodiment, there is provided a compound of formula (I) wherein X is S and Y is O, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0126] In another preferred embodiment, Z is CH 2 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0127] In embodiments, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, wherein Ring B is optionally substituted aryl, such as phenyl.

[0128] In an embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein ring B is an optionally substituted heteroaryl. Preferably, ring B is an optionally substituted 5- or 6-membered heteroaryl having 1-2 heteroatoms selected from N, S, and O. In a particular embodiment, ring B is a 5-membered heteroaryl ring, such as imidazolyl, thiophenyl, oxazolyl, or pyrazolyl. In another particular embodiment, ring B is a 6-membered heteroaryl, such as pyridinyl or pyridinyl N-oxide. Any positional or regioisomer of the heteroaryl ring can be used, meaning that the hydantoin moiety and the X linker can be attached to the heteroaryl at any substitutable carbon atom on the heteroaryl ring. For example, if ring B is a 5-membered heteroaryl ring containing one heteroatom, the hydantoin moiety and the X linker may be attached to the 5-membered heteroaryl ring in a 2,3-substitution pattern, a 2,4-substitution pattern, a 2,5-substitution pattern, a 3,4-substitution pattern, etc., about the heteroatom. As another illustrative example, if ring B is a 6-membered heteroaryl ring containing one heteroatom, the hydantoin moiety and the X linker may be attached to the 6-membered heteroaryl ring in a 2,3-substitution pattern, a 2,4-substitution pattern, a 2,5-substitution pattern, a 2,6-substitution pattern, a 3,4-substitution pattern, etc., about the heteroatom.

[0129] In some embodiments, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, in which ring B is substituted. Ring B may be substituted on any substitutable carbon atom of an aryl or heteroaryl ring, or on any substitutable heteroatom, such as a nitrogen atom, of a heteroaryl ring. For example, ring B may be substituted by an alkyl group, such as methyl, including, for example, by a methyl group on the nitrogen atom of a heteroaryl ring, such as imidazolyl or pyrazolyl.

[0130] In some embodiments, Ring B is pyridinyl, pyrazolyl, or imidazolyl, each of which is -CH 3 or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof.

[0131] In an embodiment, Ring B is -CH 3 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0132] In embodiments, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is a pyridinyl N-oxide.

[0133] In some embodiments, the compound of formula (II) wherein Ring B is pyridinyl:

[0134] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined above for compounds of formula (I), is provided.

[0135] In certain embodiments, Ring C is phenyl or pyridinyl; R 1 is hydrogen, -CH 3 or -CH 2 CH 3 and R 4 is hydrogen or -CH 3 and R 5 is hydrogen or -CH 3 and X is S, S(O) or SO 2 and R 3is hydrogen, -CH 3 , -F or -Cl; Y is O, NH, CH 2 or -NH 3 and Z is CH 2 and Ring D is phenyl or pyridinyl; R 2 But, C 1~3 Alkoxy, C 1~4 Alkyl, -CH 2 OH, -OH, -COOH, -C(O)NH 2 , -C(O)NHCH 3 or -CH 2 OC(O)CH(NH 2 )CH(CH 3 ) 2 and m is 1, n is 1, Provided is a compound of formula (II) or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof:

[0136] In certain embodiments, a compound of formula (II-a), (II-b), (II-c) or (II-d):

[0137] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein each of the variables is as defined above for a compound of Formula (I) or Formula (II).

[0138] In certain embodiments, R 1 is hydrogen, -CH 3 or -CH 2 CH 3 and R 4 is hydrogen or -CH 3 and R 5 is hydrogen or -CH 3 and X is S, S(O) or SO 2 and R 3 is hydrogen, -CH 3 , -F or -Cl; Y is O, NH, CH 2 or -NH 3 and Z is CH 2 and Ring D is phenyl or pyridinyl; R 2 But, C 1~3 Alkoxy, C 1~4 Alkyl, -CH 2 OH, -OH, -COOH, -C(O)NH 2 , -C(O)NHCH 3 or -CH 2 OC(O)CH(NH 2 )CH(CH 3 ) 2 and n is 1, Provided are compounds of formula (II-a), (II-b), (II-c) or (II-d), or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof:

[0139] In a preferred embodiment, there is provided a compound of formula (II-b), or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, wherein Ring B is pyridinyl.

[0140] In embodiments, there is provided a compound of Formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is thiophenyl.

[0141] In some embodiments, the compound of formula (IV) wherein ring B is thiophenyl:

[0142] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined above for compounds of formula (I), is provided.

[0143] In certain embodiments, R 1 , R 4 and R 5 are hydrogen, X is S, Y is O; Z is CH 2 and R 3 is hydrogen, Ring D is phenyl or pyridinyl; R 2 But -CH 3 , -C(O)NH 2 , -CH 2 OH, -OCH 3 or -OH, n is 1, Provided is a compound of formula (IV) or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof:

[0144] In an embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is imidazolyl.

[0145] In some embodiments, the compound of Formula (Va) or (Vb) wherein Ring B is imidazolyl:

[0146] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined above for compounds of formula (I), is provided.

[0147] In certain embodiments, R 1 , R 4 and R 5are hydrogen, X is S, Y is O; Z is CH 2 and R 3 is hydrogen, Ring D is phenyl or pyridinyl; R 2 But -CH 3 , -C(O)NH 2 , -CH 2 OH, -OCH 3 or -OH, n is 1, Provided is a compound of formula (V), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof:

[0148] In an embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is pyrazolyl.

[0149] In some embodiments, the compound of formula (VI) wherein Ring B is pyrazolyl:

[0150] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined above for compounds of formula (I), is provided.

[0151] In certain embodiments, R 1 , R 4 and R 5 are hydrogen, X is S, Y is O; Z is CH 2 and R 3 is hydrogen, Ring D is phenyl or pyridinyl; R2 But -CH 3 , -C(O)NH 2 , -CH 2 OH, -OCH 3 or -OH, n is 1, Provided is a compound of formula (VI) or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof:

[0152] In an embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is oxazolyl.

[0153] In some embodiments, the compound of formula (VII) wherein Ring B is oxazolyl:

[0154] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined above for compounds of formula (I), is provided.

[0155] In certain embodiments, R 1 , R 4 and R 5 are hydrogen, X is S, Y is O; Z is CH 2 and R 3 is hydrogen, Ring D is phenyl or pyridinyl; R 2 But -CH 3 , -C(O)NH 2 , -CH 2 OH, -OCH 3 or -OH, n is 1, Provided is a compound of formula (VII) or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof:

[0156] In certain embodiments, the compound of formula (VII-a) or the compound of formula (VII-b) wherein Ring B is oxazolyl:

[0157] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined above for a compound of formula (I) or formula (VII). is provided.

[0158] Compounds of particular interest are compounds of formula (Ia):

[0159] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein Q is CH or N, and the remainder of the variable groups are as defined above for compounds of formula (I). Includes.

[0160] In embodiments, there is provided a compound of formula (Ia), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Q is CH.

[0161] In embodiments, there is provided a compound of Formula (Ia), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Q is N.

[0162] In embodiments, R 2 is alkyl, halogen, haloalkyl, alkoxy, alkylthio, amino, amido, alkylamino, aminoalkyl, cyano, hydroxyalkyl, -(CH 2 ) pC(O)OR 6 and -(CH 2 ) p O.C.(O)R 6 and p is 0, 1, 2, 3, 4 or 5, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0163] In embodiments, R 2 But, C 1~3 Alkoxy (e.g., -OCH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ), C 1~4 Alkyl (e.g., -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 ), -CH 2 OH, -OH, -COOH, -C(O)NH 2 , -C(O)NHCH 3 or -CH 2 OC(O)CH(NH 2 )CH(CH 3 ) 2 , -C(O)NH 2 , -C(O)NHCH 3 or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. Preferably, R 2 is -CH 3 , -C(O)NH 2 , -CH 2 OH, -OCH 3 Or -OH.

[0164] In embodiments, R 1 is hydrogen, -CH 3 or -CH 2 CH 3or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. Preferably, R 1 is hydrogen.

[0165] In embodiments, R 4 is hydrogen, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0166] In embodiments, R 5 is hydrogen or -CH 3 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0167] In embodiments, R 1 , R 4 and R 5 are each hydrogen, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0168] In an embodiment, X is S, S(O) or SO 2 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0169] In embodiments, Y is O, NH, CH 2 or N(CH 3 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0170] In embodiments, there is provided a compound of formula (Ia), wherein X is S and Y is O, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0171] In embodiments, there is provided a compound of Formula (Ia), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is pyridinyl.

[0172] In embodiments, there is provided a compound of Formula (Ia), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is thiophenyl.

[0173] In embodiments, there is provided a compound of Formula (Ia), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is phenyl.

[0174] In embodiments, there is provided a compound of Formula (Ia), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is pyrazolyl.

[0175] In an embodiment, there is provided a compound of formula (Ia), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is imidazolyl.

[0176] In embodiments, there is provided a compound of Formula (Ia), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is oxazolyl.

[0177] In an embodiment, Ring B is pyridinyl; Q is CH or N; R 1 , R 4 and R 5 are hydrogen, R 2 is selected from the group consisting of alkyl, amido, hydroxyl, alkoxy, and hydroxylalkyl; X is S, Y is O; Provided is a compound of formula (Ia), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof:

[0178] Exemplary compounds of the present application include, but are not limited to, the compounds listed in Table 1 below, and any tautomers, stereoisomers, pharma- ceutically acceptable salts or solvates thereof. 50 Values ​​were determined according to the assay described in Example 1 below. IC 50 Values ​​are reported as follows: A=less than 10 nM, B=10 nM-100 nM, C=100 nM-1000 nM, D=greater than 1000 nM.

[0179] [Table 1] JPEG0007656669000027.jpg253170JPEG0007656669000028.jpg255168JPEG0007656669 000029.jpg255162JPEG0007656669000030.jpg255162JPEG0007656669000031.jpg25516 0JPEG0007656669000032.jpg255168JPEG0007656669000033.jpg255162JPEG0007656669 000034.jpg243170JPEG0007656669000035.jpg255162JPEG0007656669000036.jpg25516 2JPEG0007656669000037.jpg255164JPEG0007656669000038.jpg239170JPEG0007656669 000039.jpg253170JPEG0007656669000040.jpg255162JPEG0007656669000041.jpg25516 5JPEG0007656669000042.jpg255162JPEG0007656669000043.jpg251170JPEG0007656669 000044.jpg255168JPEG0007656669000045.jpg255161JPEG0007656669000046.jpg38170

[0180] The compounds of the present application can be prepared by any number of methods generally described below, and more particularly illustrated by the illustrative examples that follow herein below. For example, the compounds of the present application can be prepared by any one of general schemes 1-9. In particular, compounds of the present application can be prepared by any one of general schemes 1-9, in which X is S, Y is O, and Z is CH 2 Compounds in which X and Y are each O and Z is CH can be prepared as shown in general schemes 1-4 and 9. 2 Compounds in which X is S and Y is CH can be prepared as shown in General Scheme 5. 2 and Z is O can be prepared as shown in General Scheme 6. 2 Compounds in which X is S and Y and Z are each CH 2 Compounds which are can be prepared as shown in general Scheme 8.

[0181] [ka] 1 X is halo. Ring D is an optionally substituted aryl or heteroaryl. R 3 is independently selected from hydrogen, alkyl, and halo. m is an integer from 1 to 4. Ring B is an optionally substituted aryl or heteroaryl.

[0182] A solution of intermediate A and intermediate B is prepared in an organic solvent, and sodium hydroxide is added to the solution to form a reaction mixture. The reaction mixture is stirred overnight and then mixed with water and an organic solvent for extraction. The organic layer is dried, the solvent is evaporated under high vacuum, and the residue is purified by column chromatography to obtain intermediate C. Intermediate C is then mixed with intermediate D and potassium carbonate in an organic solvent, and the reaction is monitored by thin layer chromatography (TLC). Once the formation of intermediate E is confirmed by TLC, the reaction mixture is extracted, the organic layer is dried, and the solvent is evaporated under high vacuum. The residue is purified by column chromatography to obtain intermediate E. Intermediate E is then purified by column chromatography to obtain intermediate E by eluting with (NH 4 ) 2 CO 3 and potassium cyanide (KCN) overnight. The reaction mixture is evaporated to remove the solvent, and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to obtain a compound according to an embodiment of the present application.

[0183] [ka] 1 X is halo. Ring D is an optionally substituted aryl or heteroaryl. R 3 is independently selected from hydrogen, alkyl, and halo. m is an integer from 1 to 4. Ring B is an optionally substituted aryl or heteroaryl.

[0184] A mixture of intermediate B in DMSO is stirred overnight with heating under nitrogen atmosphere. The mixture is then diluted with water and extracted. The organic layer is washed with brine, dried, filtered and concentrated to obtain intermediate F. A mixture of intermediate F, intermediate D and potassium carbonate is stirred with heating under nitrogen atmosphere. The mixture is diluted with water and extracted. The organic layer is washed with brine, dried, filtered, concentrated and purified by column chromatography to obtain intermediate G. Triphenylphosphine, tetra-n-butylammonium bromide (TBAB) and dilute hydrochloric acid are added to intermediate G in an organic solvent to form a mixture which is stirred at room temperature. The mixture is concentrated and the residue is purified by column chromatography to obtain intermediate H. Intermediate H is reacted with intermediate A and potassium carbonate and the mixture is stirred overnight with heating under nitrogen atmosphere. The mixture is concentrated under vacuum and purified by preparative TLC to obtain intermediate E. Intermediate E is then purified by column chromatography using (NH 4 ) 2 CO 3 and potassium cyanide (KCN) overnight. The reaction mixture is evaporated to remove the solvent, and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to obtain a compound according to an embodiment of the present application.

[0185] [ka] 1 X is halo. Ring D is an optionally substituted aryl or heteroaryl. R 3 is independently selected from hydrogen, alkyl, and halo. m is an integer from 1 to 4. Ring B is an optionally substituted aryl or heteroaryl.

[0186] A solution of intermediate A and intermediate B in an organic solvent is prepared, and sodium hydroxide is added to the solution to form a reaction mixture. The reaction mixture is stirred overnight, then mixed with water and an organic solvent and extracted. The organic layer is dried, the solvent is evaporated under high vacuum, and the residue is purified by column chromatography to obtain intermediate C. Ethane-1,2-diol and TsOH are added to a mixture of intermediate C in an organic solvent, and the mixture is heated under reflux under nitrogen. The mixture is concentrated under reduced pressure, and the residue is purified by column chromatography to obtain intermediate I. Intermediate I is reacted with intermediate D, triphenylphosphine, and diethyl azodicarboxylate (DEAD) under stirring at room temperature. The reaction is quenched with water and extracted. The organic layer is dried, concentrated under reduced pressure, and the residue is purified by column chromatography to obtain intermediate J. A mixture of intermediate J in acid is stirred under heating. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is added with saturated sodium bicarbonate and extracted. The organic layer is washed, dried and concentrated under reduced pressure to give intermediate E. Intermediate E is then reacted with (NH 4 ) 2 CO 3 and potassium cyanide (KCN) overnight. The reaction mixture is evaporated to remove the solvent, and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to obtain a compound according to an embodiment of the present application.

[0187] [ka] 1 X is halo. Ring D is an optionally substituted aryl or heteroaryl. R 3 is independently selected from hydrogen, alkyl and halo. m is an integer from 1 to 4. Ring B is an optionally substituted aryl or heteroaryl. R 1 is alkyl.

[0188] To the mixture of intermediate K, LDA is added at −78° C. under nitrogen atmosphere, and the mixture is stirred for 1 h. Intermediate L is then added dropwise, and the mixture is stirred for 1 h. The reaction is quenched and extracted with a saturated aqueous solution of ammonium chloride. The organic layer is washed, dried, and concentrated under vacuum, and the residue is purified by column chromatography to give intermediate M. Intermediate M is oxidized to give intermediate N. A mixture of intermediate N, intermediate H (prepared as above in General Scheme 2), DPPF, and DIEA is treated with Pd(dba) 2 The mixture is stirred under heating, then filtered and extracted. The organic phase is dried and concentrated under reduced pressure, and the residue is purified by column chromatography to obtain intermediate P. Intermediate P is then purified by elution with (NH 4 ) 2 CO 3 and potassium cyanide (KCN) overnight. The reaction mixture is evaporated to remove the solvent, and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to obtain a compound according to an embodiment of the present application.

[0189] [ka] 1 X is halo. Ring D is an optionally substituted aryl or heteroaryl. R 3 is independently selected from hydrogen, alkyl, and halo. m is an integer from 1 to 4. Ring B is an optionally substituted aryl or heteroaryl.

[0190] To a solution of intermediate D in an organic solvent, intermediate Q, triphenylphosphine and DEAD are added at 0° C. The mixture is warmed to room temperature and stirred. The mixture is then quenched with water and extracted. The organic layer is washed, dried and concentrated under vacuum and the residue is purified by column chromatography to obtain intermediate R. To a solution of intermediate R in an organic solvent, intermediate A and potassium carbonate are added. The mixture is stirred under heating and then hydrochloric acid is added to adjust the pH to 6-7. The mixture is extracted, the organic layer is washed, dried and concentrated under reduced pressure and the residue is purified by column chromatography to obtain intermediate S. Intermediate S is then eluted with (NH 4 ) 2 CO 3 and potassium cyanide (KCN) overnight. The reaction mixture is evaporated to remove the solvent, and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to obtain a compound according to an embodiment of the present application.

[0191] [ka] 1 X is halo. Ring D is an optionally substituted aryl or heteroaryl. R 3 is independently selected from hydrogen, alkyl, and halo. m is an integer from 1 to 4. Ring B is an optionally substituted aryl or heteroaryl.

[0192] To a solution of intermediate A in an organic solvent, intermediate T and potassium carbonate are added at room temperature under nitrogen atmosphere. The mixture is stirred at room temperature, and after TLC analysis of the mixture shows conversion to the desired product, the mixture is diluted with water and extracted, the organic layer is washed, dried, concentrated under reduced pressure, and the residue is purified by column chromatography to obtain intermediate U. To a solution of intermediate U in an organic solvent, TsOH is added. After stirring for a few minutes, a solution of ethane-1,2-diol in an organic solvent is added dropwise. The mixture is stirred under heating, then poured into saturated sodium bicarbonate solution and extracted. The organic phase is dried, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate V. Intermediate V is reduced with LAH, the reaction is quenched and extracted, the organic layer is dried, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain intermediate Y. To a mixture of intermediate Y in an organic solvent, SOCl is added at 0 °C. 2 After stirring for several hours, the pH is adjusted to pH 7 and the mixture is extracted. The organic layer is dried and concentrated under reduced pressure, and the residue is purified by column chromatography to obtain intermediate X. Intermediate X is reacted with intermediate Y and potassium carbonate at room temperature under nitrogen atmosphere. The mixture is diluted with water and extracted, the organic layer is washed, dried, concentrated under reduced pressure, and the residue is purified by column chromatography to obtain intermediate Z. A mixture of intermediate Z in acid is stirred under heating. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is added with saturated sodium bicarbonate and extracted. The organic layer is washed, dried, and concentrated under reduced pressure to obtain intermediate A1. Intermediate A1 is then reacted with (NH 4 ) 2 CO 3 and potassium cyanide (KCN) overnight. The reaction mixture is evaporated to remove the solvent, and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to obtain a compound according to an embodiment of the present application.

[0193] [ka] 1X is halo. Ring D is an optionally substituted aryl or heteroaryl. R 3 is independently selected from hydrogen, alkyl, and halo. m is an integer from 1 to 4. Ring B is an optionally substituted aryl or heteroaryl.

[0194] Intermediate B1 and BOC in organic solvent 2 To a solution of O, triethylamine and DMAP are added and the mixture is stirred at room temperature. The mixture is quenched and extracted, the organic phase is washed and dried, concentrated under reduced pressure, and the residue is purified by column chromatography to obtain intermediate C1. At room temperature, intermediate C1 is reacted with intermediate A and potassium carbonate. The mixture is diluted with water and extracted, the organic phase is washed and dried, concentrated under reduced pressure, and the residue is purified by column chromatography to obtain intermediate D1. TsOH is added to a stirred solution of intermediate D1 in an organic solvent. After stirring for a few minutes, a solution of ethane-1,2-diol in an organic solvent is added dropwise. The mixture is stirred under heat and then poured into a saturated sodium bicarbonate solution and extracted. The organic phase is dried, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate E1. Sodium hydride is added to a solution of intermediate E1 and intermediate D. The mixture is diluted with water and extracted, the organic phase is washed and dried, concentrated under reduced pressure, and the residue is purified by column chromatography to obtain intermediate F1. A mixture of intermediate F1 in acid is stirred under heating. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is extracted with saturated sodium bicarbonate. The organic layer is washed, dried and concentrated under reduced pressure to give intermediate G1. Intermediate G1 is then reacted with (NH 4 ) 2 CO 3 and potassium cyanide (KCN) overnight. The reaction mixture is evaporated to remove the solvent, and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to obtain a compound according to an embodiment of the present application.

[0195] [ka] 1 X is halo. Ring D is an optionally substituted aryl or heteroaryl. R 3 is independently selected from hydrogen, alkyl, and halo. m is an integer from 1 to 4. Ring B is an optionally substituted aryl or heteroaryl.

[0196] A solution of intermediate B1 was added to hydrochloric acid (HCl), sulfuric acid (H 2 SO 4 ) and NaNO 2 is added successively and the mixture is stirred. Then urea is added. After stirring for a few minutes, an aqueous solution of KI is added dropwise and the mixture is stirred at 0° C. The mixture is extracted, the organic layer is washed and evaporated, and the residue is purified by column chromatography to give intermediate H1. A mixture of intermediate H1 in alcohol is stirred for a few hours at room temperature, then the mixture is concentrated under reduced pressure, extracted, and purified by column chromatography to give intermediate I1. To a solution of intermediate I1, intermediate A and potassium carbonate are added and the mixture is stirred at room temperature. Then water is added and the mixture is extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to give intermediate J1. To a solution of intermediate J1 and intermediate K1 in triethylamine, under nitrogen atmosphere, a palladium complex suitable for palladium-catalyzed coupling reaction and CuI are added. The mixture is stirred at room temperature and then quenched with saturated ammonium chloride solution. The mixture is extracted, the organic layer is washed and dried, and concentrated under reduced pressure to give intermediate L1. To a solution of intermediate L1 in alcohol is added Pd / C, and the mixture is stirred under hydrogen atmosphere at room temperature. The mixture is filtered and the filtrate is concentrated to give intermediate M1. Intermediate M1 is then reacted with (NH 4 ) 2 CO 3 and potassium cyanide (KCN) overnight. The reaction mixture is evaporated to remove the solvent, and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to obtain a compound according to an embodiment of the present application.

[0197] [ka] 1 X is halo. Ring D is an optionally substituted aryl or heteroaryl. R 3 is independently selected from hydrogen, alkyl, and halo. m is an integer from 1 to 4. Ring B is an optionally substituted aryl or heteroaryl. R is alkyl.

[0198] To a solution of intermediate N1, sodium hydroxide and intermediate B are added and the mixture is stirred overnight. The reaction mixture is extracted, the organic layer is dried and the residue is purified by flash chromatography to give intermediate O1. To a solution of intermediate O1, potassium carbonate and intermediate D are added and the mixture is stirred at room temperature. The mixture is extracted, the organic layer is washed and dried, concentrated under reduced pressure and the residue is purified by column chromatography to give intermediate P1. To a solution of intermediate P1 in anhydrous solvent is added DIBAL-H at 0° C. The mixture is quenched and extracted, the organic layer is washed and dried, concentrated under reduced pressure and the residue is purified by column chromatography to give intermediate Q1. Intermediate Q1 is oxidized to give intermediate R1. Intermediate R1 is then oxidized with (NH 4 ) 2 CO 3 and potassium cyanide (KCN) overnight. The reaction mixture is evaporated to remove the solvent, and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to obtain a compound according to an embodiment of the present application.

[0199] The nitrogen atom of the hydantoin portion of the compounds of the present application can be substituted by reacting a compound prepared according to any one of the general schemes above with sodium hydride and an alkyl iodide (e.g., CH 3 I) can be alkylated by reacting with X, Y and Z with S(O) or SO 2Compounds which are can be prepared by reacting a compound prepared according to any one of the general schemes above with m-CPBA.

[0200] Pharmaceutically acceptable salts of the compounds of the present application can be synthesized from parent compounds containing an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in their free acid or free base form with a stoichiometric amount of the appropriate acid or base in water or in an organic solvent, or in a mixture of the two. Examples of suitable organic solvents include, but are not limited to, ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.

[0201] composition Another aspect of the present application pertains to pharmaceutical compositions comprising a compound of the present application as described herein, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

[0202] The compositions of the present application may also include a pharma- ceutically acceptable carrier. The pharma- ceutically acceptable carrier should be non-toxic and not interfere with the effectiveness of the active ingredient. The pharma- ceutically acceptable carrier may include one or more excipients, such as binders, disintegrating agents, swelling agents, suspending agents, emulsifying agents, wetting agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, solubilizing agents, and coating agents. The exact nature of the carrier or other material may depend on the route of administration, such as intramuscular, intradermal, subcutaneous, oral, intravenous, transdermal, transmucosal (e.g., gastrointestinal), intranasal, or intraperitoneal routes. For liquid injection preparations, such as suspensions and solutions, suitable carriers and excipients include water, glycols, oils, alcohols, preservatives, coloring agents, and the like. For solid oral preparations such as powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. For nasal sprays / inhalation mixtures, aqueous solutions / suspensions can include water, glycols, oils, emollients, stabilizers, wetting agents, preservatives, fragrances, flavorings, etc. as suitable carriers and additives.

[0203] The compositions of the present application can be formulated in any substance suitable for administration to a subject to facilitate administration and improve efficacy, including, but not limited to, oral (intestinal) administration and parenteral injection. Parenteral injection includes intravenous injection or infusion, subcutaneous injection, intradermal injection, and intramuscular injection. The compositions of the present application can also be formulated for other routes of administration, including transmucosal, ocular, rectal, long-acting implants, sublingual administration under the tongue, via the oral mucosa bypassing the portal circulation, by inhalation, or intranasal.

[0204] In certain embodiments, the compositions are formulated for oral administration.

[0205] Yet another aspect of the present application relates to a method for preparing a pharmaceutical composition, comprising combining a compound of the present application, or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, with at least one pharma- ceutically acceptable carrier. The pharmaceutical composition, in view of the present disclosure, can be prepared by any method known in the art, and a person skilled in the art will be familiar with such techniques used to prepare pharmaceutical compositions. For example, the pharmaceutical composition according to the present application can be prepared by mixing the compound of the present application with one or more pharma- ceutically acceptable carriers in accordance with conventional pharmaceutical compounding techniques, including, but not limited to, conventional mixing, dissolving, granulating, emulsifying, encapsulating, entrapping or lyophilizing.

[0206] How to use The present application also provides methods of inhibiting matrix metalloproteinases (MMPs) and treating diseases mediated by MMPs using the compounds of the present application and the pharmaceutical compositions of the present application.

[0207] Matrix metalloproteinases (MMPs), also known as matrixins, are a group of enzymes that are coordinately responsible for the degradation of the outermost extracellular matrix proteins during organogenesis, growth and normal tissue turnover. MMPs are calcium-dependent zinc-containing endopeptidases and belong to a larger family of proteases known as the metzincin superfamily. Although MMPs can degrade extracellular matrix proteins, they can also process several bioactive molecules, for example, they are known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands and chemokine / cytokine inactivation. MMPs are also thought to play a major role in cell behavior, for example, cell proliferation, migration (adhesion / dispersion), differentiation, angiogenesis, apoptosis and host defense. MMPs are inhibited by certain endogenous tissue inhibitors of metalloproteinases (TIMPs), which include a family of four protease inhibitors: TIMP-1, TIMP-2, TIMP-3 and TIMP-4. Examples of MMPs include, but are not limited to, MMP-1 (interstitial collagenase), MMP-2 (gelatinase-A), MMP-3 (stromelysin 1), MMP-7 (matrilysin), MMP-8 (neutrophil collagenase), MMP-9 (gelatinase-B), MMP-10 (stromelysin 2), MMP-11 (stromelysin 3), MMP-12 (macrophage elastase), MMP-13 (collagenase 3), MMP-14 (MT1-MMP), and the like.

[0208] In a preferred embodiment, the compounds of the present application are capable of inhibiting macrophage elastase (MMP-12) and / or treating diseases mediated by MMP-12. MMP-12, also known as macrophage metalloelastase (MME) or macrophage elastase (ME), is encoded by the MMP12 gene in humans. In other embodiments, the compounds of the present application are capable of selectively inhibiting MMP-12. The terms "selective," "selectivity," and "selectively," when used in reference to binding to or inhibiting the activity of a particular MMP, mean that the compound binds to or inhibits the activity of the particular MMP to a greater extent than a compound binds to or inhibits the activity of other MMPs. For example, a compound that has selectivity for MMP-12 inhibits the activity of MMP-12 to a greater extent than other MMPs, e.g., MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-13, MMP-14, etc.

[0209] According to embodiments of the present application, a compound that is selective for MMP-12 inhibits the activity of MMP-12 at least about 10-fold, 100-fold, or 1000-fold more than one or more other MMPs, and preferably inhibits the activity of MMP-12 at least about 1000-fold more than at least one other MMP, e.g., MMP-1 or MMP-7.

[0210] The present application also provides a method for treating a disease mediated by MMP-12. According to an embodiment of the present invention, the method for treating a disease mediated by MMP-12 comprises administering to a subject a therapeutically effective amount of a compound of the present application, or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present application.

[0211] As used herein, the terms "treat", "treating" and "treatment" are all intended to refer to an improvement or reversal of at least one measurable physical parameter associated with an MMP-12-mediated disease that is discernible in a subject, although not necessarily discernible in the subject. The terms "treat", "treating" and "treatment" can also refer to inducing regression, preventing the progression, or at least slowing the progression of an MMP-12-mediated disease. In certain embodiments, "treat", "treating" and "treatment" refer to alleviating, preventing, or shortening the duration of the development or onset of one or more symptoms associated with an MMP-12-mediated disease. In certain embodiments, "treat", "treating" and "treatment" refer to preventing the recurrence of an MMP-12-mediated disease. In certain embodiments, "treat", "treating" and "treatment" refer to increasing the survival of a subject having an MMP-12-mediated disease. In certain embodiments, "treat", "treating" and "treatment" refer to the elimination of an MMP-12-mediated disease in a subject.

[0212] As used herein, a "therapeutically effective amount" refers to an amount of a composition or compound that induces a biological or medical response in a tissue system or subject as desired by a researcher, veterinarian, physician, or other condition, which may include alleviating the symptoms of the disease or disorder being treated. Therapeutically effective amounts may vary depending on a variety of factors, such as the subject's physical condition, age, weight, health, etc., and the particular disease being treated. Therapeutically effective amounts can be readily determined by one of skill in the art in light of the present disclosure.

[0213] In certain embodiments of the present application, a therapeutically effective amount refers to an amount of the composition or compound of the present application sufficient to inhibit MMP-12 or treat a disease mediated by MMP-12. Diseases mediated by MMP-12 that can be treated by the methods of the present application include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.

[0214] Embodiment Embodiment 1 relates to a compound of formula (Ib):

[0215] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, Ring B is an optionally substituted aryl or an optionally substituted heteroaryl; Ring C is an optionally substituted aryl or an optionally substituted heteroaryl; Ring D is an optionally substituted aryl or an optionally substituted heteroaryl; X, Y and Z are each CH 2 , O, N.R. x and S(O) q R x is hydrogen or alkyl, R 1 is hydrogen or alkyl, R 4 is hydrogen or alkyl, R 5 is hydrogen, q is 0, 1 or 2; provided that ring B is not furanyl. It is.

[0216] Embodiment 2 is a compound of formula (I):

[0217] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, Ring B is an optionally substituted aryl or an optionally substituted heteroaryl; Ring C is aryl or heteroaryl; Ring D is aryl or heteroaryl; X, Y and Z are O, CH 2 , N.R. x and S(O) q R x is hydrogen or alkyl, R 1 is hydrogen or alkyl, R 2 are respectively hydrogen, alkyl, halogen, hydroxyl, haloalkyl, alkoxy, alkylthio, amine, amide, alkylamine, aminoalkyl, cyano, hydroxyalkyl, -(CH 2 ) p C(O)OR 6 and -(CH 2 ) p O.C.(O)R 6 are independently selected from the group consisting of: R 3 are each independently selected from the group consisting of hydrogen, alkyl, and halogen; R 4 is hydrogen or alkyl, R 5 is hydrogen, R 6 are each independently selected from the group consisting of hydrogen and alkyl, wherein alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of amine, hydroxyl, halogen, and alkoxy; m is 1, 2, 3 or 4; n is 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4 or 5; q is 0, 1 or 2; provided that ring B is not furanyl. It is.

[0218] Embodiment 3 is a compound of embodiment 1 or embodiment 2, wherein Ring B is a 5- or 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from N, S, and O.

[0219] Embodiment 4 is a compound of any one of embodiments 1-3, wherein Ring B is pyridinyl, thiophenyl, imidazolyl, pyrazolyl, or oxazolyl.

[0220] Embodiment 5 is a compound of embodiment 4, wherein Ring B is pyridinyl.

[0221] Embodiment 6 relates to a compound of formula (II):

[0222] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined for compounds of formula (I). The compound of embodiment 5 is

[0223] Embodiment 7 relates to a compound of formula (II-a), (II-b), (II-c) or (II-d):

[0224] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined for compounds of formula (I). The compound of embodiment 5 is

[0225] Embodiment 8 is a compound of embodiment 4, wherein Ring B is thiophenyl.

[0226] Embodiment 9 relates to a compound of formula (IV):

[0227] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined for compounds of formula (I). The compound of embodiment 8 is

[0228] Embodiment 10 is a compound of embodiment 4, wherein Ring B is imidazolyl.

[0229] Embodiment 11 relates to a compound of formula (Va) or (Vb):

[0230] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined for compounds of formula (I). The compound of embodiment 10 is

[0231] Embodiment 12 is a compound of embodiment 4, wherein Ring B is pyrazolyl.

[0232] Embodiment 13 relates to a compound of formula (VI):

[0233] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined for compounds of formula (I). 13. The compound of embodiment 12, wherein

[0234] Embodiment 14 is a compound of embodiment 4, wherein Ring B is oxazolyl.

[0235] Embodiment 15 is Compound of formula (VII):

[0236] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined for compounds of formula (I). 15. The compound of embodiment 14, wherein

[0237] Embodiment 16 relates to a compound of formula (VII-a) or (VII-b):

[0238] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. wherein each variable is as defined for compounds of formula (I). 16. The compound of embodiment 15, wherein

[0239] Embodiment 17 is a compound of any one of embodiments 1-6, wherein Ring C is phenyl.

[0240] Embodiment 18 is a compound of any one of embodiments 1-6, wherein Ring C is pyridinyl.

[0241] Embodiment 19 is a compound comprising R 3 is selected from the group consisting of hydrogen, methyl, fluoro and chloro.

[0242] Embodiment 20 is a compound of any one of embodiments 1-19, wherein Ring D is pyridinyl or phenyl.

[0243] Embodiment 21 is a compound comprising R 2 Methyl, -CH 2 OH, hydroxyl, -OC(O)CH(NH 2 )CH(CH 3 ) 2 , -COOH, -CH 2 OC(O)CH(NH 2 )CH(CH 3 ) 2 , -C(O)NH 2 , -C(O)NH(CH 3 ) and C 1~4 21. The compound of any one of embodiments 2-20, wherein the compound is selected from the group consisting of: alkoxy.

[0244] Embodiment 22 is an embodiment in which Ring D is

[0245] [ka] The compound of any one of embodiments 1-21, wherein

[0246] Embodiment 23 is a compound comprising R 4 is hydrogen.

[0247] Embodiment 24 is a method for producing a compound according to the present invention 4 A compound of any one of embodiments 1-22, wherein is alkyl.

[0248] Embodiment 25 is a method for producing a compound according to the present invention 4 is methyl.

[0249] Embodiment 26 is a method for producing a compound according to the present invention 5 is methyl.

[0250] Embodiment 27 is a method for producing a compound according to the present invention 5is hydrogen.

[0251] Embodiment 28 is a compound comprising R 1 C 1~4 A compound of any one of embodiments 1-27, wherein R is alkyl.

[0252] Embodiment 29 is a method for producing a compound according to the present invention 1 is methyl or ethyl.

[0253] Embodiment 30 is a method for producing a compound according to the present invention 1 A compound of any one of embodiments 1-27, wherein is hydrogen.

[0254] Embodiment 31 is an embodiment in which X is S, Y is O and Z is CH 2 The compound of any one of embodiments 1-30, wherein

[0255] Embodiment 32 relates to a compound of formula (Ia):

[0256] [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, Ring B is a 5- or 6-membered heteroaryl; Z is CH or N; R 1 and R 4 are each alkyl or hydrogen; R 5 is hydrogen, R 2 is selected from the group consisting of alkyl, amido, hydroxyl, alkoxy, and hydroxylalkyl; X and Y are each independently selected from S and O. It is.

[0257] Embodiment 33 is a compound of embodiment 32, wherein Ring B is pyridinyl, thiophenyl, imidazolyl, pyrazolyl, or oxazolyl.

[0258] Embodiment 34 is directed to R 1 is hydrogen.

[0259] Embodiment 35 is directed to R 1 C 1~4 A compound of embodiment 32 or embodiment 33, wherein R is alkyl.

[0260] Embodiment 36 is directed to R 1 is methyl or ethyl.

[0261] Embodiment 37 is a method for producing a compound according to the present invention 4 A compound of any one of embodiments 32-36, wherein is hydrogen.

[0262] Embodiment 38 is a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 37 and at least one pharma- ceutically acceptable carrier.

[0263] Embodiment 39 is a method of inhibiting macrophage elastase (MMP-12) in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of embodiment 38.

[0264] Embodiment 40 is a method of treating a disease mediated by macrophage elastase (MMP-12) in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of embodiment 38.

[0265] Embodiment 41 is the method of embodiment 40, wherein the disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.

[0266] Embodiment 42 is a compound of any one of embodiments 1-37 or a pharmaceutical composition of embodiment 38 for use in inhibiting macrophage elastase (MMP-12).

[0267] Embodiment 43 is a compound of any one of embodiments 1 to 37 or a pharmaceutical composition of embodiment 38 for use in treating a disease mediated by macrophage elastase (MMP-12).

[0268] Embodiment 44 is a compound or composition for use of embodiment 43, wherein the disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, non-alcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.

[0269] Embodiment 45 is the use of a compound of any one of embodiments 1 to 37 or a pharmaceutical composition of embodiment 38 in the manufacture of a medicament for inhibiting macrophage elastase (MMP-12).

[0270] Embodiment 46 is the use of a compound of any one of embodiments 1 to 37 or a pharmaceutical composition of embodiment 38 in the manufacture of a medicament for treating a disease mediated by macrophage elastase (MMP-12).

[0271] Embodiment 47 is the use of embodiment 46, wherein the disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, non-alcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.

[0272] Embodiment 48 is a method of preparing the pharmaceutical composition of embodiment 38, comprising combining a compound or a pharma- ceutically acceptable salt thereof with at least one pharma- ceutically acceptable carrier.

[0273] [Example] The following examples of the present application are intended to further illustrate the nature of the present application. It should be understood that the following examples do not limit the present application, and the scope of the present application should be determined by the appended claims.

[0274] Method of synthesis Unless otherwise indicated, abbreviations for chemical reagents and synthetic conditions have their ordinary meanings known in the art, as follows: "LDA" refers to lithium diisopropylamide. "EA" refers to ethyl acetate. "PE" refers to petroleum ether. "rt" and "rt" refer to room temperature. "THF" refers to tetrahydrofuran. "DEAD" refers to diethyl azodicarboxylate. "TBAB" refers to tetrabutylammonium bromide. "DCM" refers to dichloromethane; "HOBT" refers to hydroxybenzotriazole. "LAH" refers to lithium aluminum hydride. "TLC" refers to thin layer chromatography. "Prep TLC" refers to preparative thin layer chromatography. "TMS-I" refers to trimethylsilyl iodide. "Hex" refers to hexane. "DMF" refers to dimethylformamide. "h" refers to hours. "EDCI" refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. "DMAP" refers to 4-dimethylaminopyridine. "Prep HPLC" refers to preparative high performance liquid chromatography. "DHP" refers to dihydropyran. "DPPF" refers to 1,1'-bis(diphenylphosphino)ferrocene. "DIEA" refers to diisopropylethylamine.

[0275] Preparation of Key Intermediate TI-1 for the Synthesis of Compounds TC-1, TC-2, TC-3, TC-4, TC-5, TC-6, TC-7 and TC-8

[0276] [ka]

[0277] To a solution of 3-bromothiophene-2-carbaldehyde (10 g, 52.5 mmol) and 4-mercaptophenol (6.3 g, 50 mmol) in THF (255 mL) was added NaOH (0.06 g, 1.5 mmol). The reaction mixture was stirred at room temperature overnight. Water and EA were added to the residue and extracted twice with EA. The combined organic layers were washed with MgSO 4 After drying under high vacuum, the solvent was evaporated to give a yellow solid. The residue was purified by flash chromatography with DCM / MeOH (DCM / MeOH=1:50) to give TI-1a as a light yellow solid (9.2 g, 75%).

[0278] Synthesis of Compounds TC-1, TC-2, TC-3, TC-4, TC-5 and TC-6

[0279] [ka]

[0280] 3-a (0.2g, 1.65mmol), TI-1a (0.40g, 1.7mmol) and K 2 CO 3 A solution of (0.7 g) in ACN was stirred at room temperature overnight. The reaction was monitored by TLC (EA / Hex=2 / 7) to determine the time when the benzyl bromide spot disappeared. EA and water were added to the reaction mixture, and it was extracted twice with EA. The combined organic layer was washed with MgSO 4 The residue was purified by flash chromatography with EA / hexane (EA / hexane=1:3) to give intermediate TI-1 as a light yellow solid (0.41 g, 55%). Thus, intermediates TI-2, TI-3, TI-4, TI-5 and TI-6 were synthesized following the same procedure, except that starting material 3-12 was replaced with 3-14, 3-15, 3-16 or 3-17.

[0281] TI-1 (0.42 g, 1.18 mmol) in EtOH / H 2 In a 10 mL / 5 mL solution of (NH 4 ) 2 CO 3 (1.71 g, 17.8 mmol) and KCN (0.15 g, 0.98 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solution was evaporated to remove most of the solvent. Water was added to the mixture, which was then extracted twice with EA. The organic layers were combined and washed with MgSO 4 The mixture was dried by filtration and the solvent was evaporated. The residue was purified by flash chromatography using EA / hexane (EA / hexane=1:1) to obtain TC-1 as a light yellow solid (0.28 g, 38%). Thus, compounds TI-2, TI-3, TI-4, TI-5 and TI-6 were synthesized using the same procedure, except that intermediate TI-1 was replaced by intermediate TI-2, TI-3, TI-4, TI-5 or TI-6.

[0282] Preparation of compound TC-7:

[0283] [ka]

[0284] 3-18a (0.23 g, 0.76 mmol), TI-1a (0.15 g, 0.64 mmol) and K 2 CO 3 A solution of (0.35 g, 2.56 mmol) in ACN (4 mL) was stirred at room temperature overnight. Water and EA were added to the reaction mixture, and it was extracted twice with EA. The combined organic layer was washed with MgSO 4 The mixture was dried by filtration and the solvent was evaporated under high vacuum. The residue was purified by flash chromatography with EA / Hex (EA / Hex=1:10 to 1:4) to give TI-7a as a yellow solid (0.17 g, 50%).

[0285] To a solution of TI-7a (1.03 g) in DCM (25 mL) was added TFA (1 mL) dropwise at room temperature. The reaction mixture was stirred overnight, then the solvent and TFA were removed to give a brown oil. The brown oil was treated with NaHCO 3 and MeOH were added. Then the solvent was removed again. The residue was purified by flash chromatography with EA / Hex (EA / Hex=1:4) to give TI-7b as a white solid (0.14 g).

[0286] EtOH / H 2 To a solution of TI-1b (0.14 g, 0.41 mmol) in 2O (5 mL / 2.5 mL), (NH 4 ) 2 CO 3 (0.24 g, 2.46 mmol) and KCN (32 mg, 0.41 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solution was evaporated to remove most of the solvent. Water and EA were added to the mixture, which was then extracted twice with EA. The organic layers were combined and washed with MgSO 4The mixture was dried by filtration and the solvent was evaporated under high vacuum. The residue was purified by flash chromatography with DCM / MeOH (DCM / MeOH=20:1) to give TC-7 as an oily compound (51 mg).

[0287] Preparation of compound TC-8:

[0288] [ka]

[0289] TI-1a (0.9 g, 3.81 mmol, 1 equiv.), 4-chloromethyl-2-methylpyridine (mg, 1.19 mmol, 1 equiv.) and K 2 CO 3 A solution of (1.58 g, 3 equiv.) in ACN (70 ml) was stirred and heated to 50° C. The mixture was monitored by TLC. The solvent was removed by rotary evaporation. EA and water were added to the residue, and the aqueous layer was quenched with EA twice. The crude product was purified by silica gel (DCM / EA=1 / 4) to give TI-8 as a pale yellow solid (1.02 g, 76%).

[0290] To a solution of TI-8 (200 mg, 0.4 mmol, 1 equiv) was added KCN (0.057 mg, 1.5 equiv) and ammonium carbonate (0.844 g, 15 equiv) in EtOH / DI water (2 / 1) (10 ml). The mixture was monitored by TLC. The solvent was removed by rotary evaporation. EA and water were added to the residue, and the aqueous layer was quenched twice with EA. The crude product was purified on silica gel (DCM / MeOH=30 / 2) to give TC-8 as a yellow solid (45 mg, 18%).

[0291] General scheme: Preparation of intermediate 4a-1

[0292] [ka]

[0293] Synthesis of intermediate FI-5: A mixture of compound 2a (68 g, 538.9 mmol, 1.0 equiv) in DMSO (500 mL) was stirred overnight at 80° C. under a nitrogen atmosphere. This mixture was then subjected to H 2 The mixture was diluted with 200 mL of HO (1000 mL) and extracted with ethyl acetate. The organic layer was washed with brine and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give compound FI-5 (67 g, 99%).

[0294] Synthesis of intermediate FI-6 Compound FI-5 (5 g, 19.97 mmol, 1.0 equiv.), compound 3b (7.39 g, 39.95 mmol, 2 equiv.) and K in acetone (100 mL). 2 CO 3 (11.04 g, 79.89 mmol, 4.0 equiv.) was stirred at 60° C. for 4 h under nitrogen atmosphere. The mixture was then diluted with H 2 The mixture was diluted with 200 mL of HO (1000 mL) and extracted with ethyl acetate. The organic layer was washed with brine and 2 SO 4 The residue was purified by column chromatography on silica gel (PE / EA, 10:1) to give compound FI-6 (8.7 g, 97%).

[0295] Synthesis of compound 4a-1: To a mixture of compound FI-6 (10.7 g, 23.33 mmol, 1.0 equiv.) in THF (100 mL), PPh 3 (6.11 g, 23.33 mmol, 1 equiv), TBAB (15.04 g, 46.66 mmol, 2 equiv) and 5% HCl (5 mL) were added. The mixture was stirred at room temperature under nitrogen atmosphere for 12 h. Then, the mixture was concentrated. The residue was purified by column chromatography on silica gel (PE / EA, 2:1) to give compound 4a-1 (6.6 g, 56%).

[0296] Preparation of compound PC-1:

[0297] [ka]

[0298] To a mixture of compound 4a-1 (0.5 g, 2.17 mmol, 1.0 equiv.) in ACN (15 mL) was added compound 2-chloronicotinaldehyde (0.307 g, 2.17 mmol, 1.0 equiv.) and K 2 CO 3 (0.906 g, 6.52 mmol, 3.0 equiv.) was added. The mixture was stirred at 85° C. overnight under nitrogen atmosphere. The mixture was then concentrated in vacuo. The residue was purified by preparative TLC to give compound PI-1 (500 mg, 69%).

[0299] To a mixture of compound PI-1 (450 mg, 1.34 mmol, 1.0 equiv.) in MeOH (30 mL) was added KCN (174 mg, 2.68 mmol, 2.0 equiv.) and (NH 4 ) 2 CO 3 (516 mg, 5.3 mmol, 4.0 equiv.) was added. The mixture was stirred at 40° C. overnight under nitrogen atmosphere. The mixture was then concentrated in vacuo. The residue was purified by preparative TLC to give compound PC-1 (44 mg, 10%).

[0300] Preparation of compounds PC-2, PC-3 and PC-4:

[0301] [ka]

[0302] Thus, compounds PC-2, PC-3 and PC-4 were synthesized using the same procedure as for the synthesis of PC-1, except that the starting material 2-chloronicotinaldehyde PS-1 was replaced with 4-chloro-nicotinaldehyde PS-2, 3-fluoropicolinaldehyde PS-3 or 3-chloroisonicotinaldehyde PS-4.

[0303] Preparation of key intermediate PI-a.1

[0304] [ka]

[0305] To a mixture of 4-chloronicotinaldehyde (2.2 g, 15.54 mmol, 1.0 equiv.) and 4-mercaptophenol (2.94 g, 23.31 mmol, 1.5 equiv.) in THF (20 mL) was added NaH (1.24 g, 31.08 mmol, 2.0 equiv.) at 0° C., and the mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was then concentrated to half the solvent, and then 2.0 N HCl was added to adjust pH=6, and filtered to give compound PI-a.1 (950 mg, 26%), which was used in the next step without further purification.

[0306] Preparation of compounds PC-7, PC-8 and PC-9:

[0307] [ka]

[0308] To a mixture of compound PI-a.1 (3.0 g, 12.99 mmol, 1.0 equiv.) in toluene (100 mL), ethane-1,2-diol (1.6 g, 260 mmol, 20 equiv.) and TsOH (0.112 g, 0.65 mmol, 0.05 equiv.) were added sequentially. The mixture was heated under reflux for 12 h under nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EA, 2:1) to give compound PI-b.1 (2.9 g, 82%).

[0309] A solution of compound PI-b.1 (200 mg, 0.727 mmol, 1.0 equiv.) in THF (10 mL) was added at 0 °C with 1,4-phenylenedimethanol (50 mg, 3.64 mmol, 5.0 equiv.), PPh 3 (381 mg, 1.454 mmol, 2.0 equiv.) and DEAD (253 mg, 1.454 mmol, 2.0 equiv.) were added sequentially. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then diluted with H2 The mixture was quenched with 2×O (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give compound PI-7a (200 mg, 70%).

[0310] A mixture of compound PI-7a (140 mg, 0.354 mmol, 1.0 equiv) in HCl / THF (2.0 M, 3 mL / 3 mL) was stirred at 70° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 and concentrated under reduced pressure to give compound PI-7b (130 mg, 100%), which was used in the next step without further purification.

[0311] To a mixture of compound PI-7b (150 mg, 0.427 mmol, 1.0 equiv.) in MeOH (5 mL) was added KCN (55 mg, 0.854 mmol, 2.0 equiv.) and (NH 4 ) 2 CO 3 (164 mg, 1.71 mmol, 4.0 equiv.) was added. The mixture was stirred at room temperature for 12 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound PC-7 (38 mg, 21%) as a white solid.

[0312] Thus, compounds PC-8 and PC-9 were synthesized by the same procedure, except that 1,4-phenylenedimethanol was replaced with 1,3-phenylenedimethanol or 1,2-phenylenedimethanol.

[0313] Preparation of compound PC-10:

[0314] [ka]

[0315] Ac 2 A mixture of 3-(hydroxymethyl)phenol (180 mL, 1.9 mol, 4.0 equiv) in 2O (360 mL, 9.54 mol, 21.2 equiv) was stirred at 60° C. for 1 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and then KOH (42.3 g, 0.45 mol, 1.0 equiv) was added. The mixture was then stirred at room temperature for 16 h. The mixture was extracted with EA (3×150 mL) and water, and the combined organic layers were then washed with H 2 O (3 x 100 mL) and saturated NaHCO 3 Solution (2 x 100 mL) and Na 2 SO 4 The mixture was dried at rt and concentrated under reduced pressure to give compound PI-10a (60 g, 26%).

[0316] Compound PI-b.1 (300 mg, 1.09 mmol, 1.0 equivalent) in THF (10 mL) was added at 0° C. to a solution of compound PI-10a (905 mg, 5.45 mmol, 5.0 equivalent), PPh 3 (572 mg, 2.18 mmol, 2.0 equiv.) and DEAD (380 mg, 2.18 mmol, 2.0 equiv.) were added sequentially. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then diluted with H 2 The mixture was quenched with 2×O (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give compound PI-10b (200 mg, 44%).

[0317] A mixture of compound PI-10b (200 mg, 0.473 mmol, 1.0 equiv) in HCl / THF (2.0 M, 3 mL / 3 mL) was stirred at 70° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO 3The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 and concentrated under reduced pressure to give compound PI-10c (150 mg, 91%), which was used in the next step without further purification.

[0318] To a mixture of compound PI-10c (150 mg, 0.427 mmol, 1.0 equiv.) in MeOH (5 mL) was added KCN (55 mg, 0.854 mmol, 2.0 equiv.) and (NH 4 ) 2 CO 3 (164 mg, 1.71 mmol, 4.0 equiv.) was added. The mixture was stirred at room temperature for 12 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound PC-10 (55 mg, 30%) as a white solid.

[0319] Preparation of compound PC-11:

[0320] [ka]

[0321] To a solution of compound PC-8 (1.0 g, 2.37 mmol, 1.0 equiv.) in DCM (50 mL), (tert-butoxycarbonyl)-D-valine (1.02 g, 2.61 mol, 1.1 equiv.), EDCI (0.53 g, 2.84 mol, 1.2 equiv.) and DMAP (0.056 g, 0.47 mol, 0.2 equiv.) were added successively. The mixture was stirred at 25° C. for 24 h. Then, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH, 10:1) to give compound PI-11 (496 mg, 35%) as a yellow solid.

[0322] To a solution of compound PI-11 (0.5 g, 0.8 mmol, 1.0 equiv) in EA (20 mL) was added HCl (4.5 M in EA, 20 mL). The mixture was stirred at room temperature for 12 h. The mixture was then concentrated under reduced pressure to give PC-11 (430 mg, 96%) as a white solid.

[0323] Preparation of key intermediate PI-a.2

[0324] [ka]

[0325] A mixture of 3-fluoroisonicotinaldehyde (2.9 g, 23.2 mmol, 1.0 equiv.) in DMF (150 mL) was treated with 4-mercaptophenol (5.85 g, 46.4 mmol, 2.0 equiv.) and K 2 CO 3 (12.8 g, 92.8 mmol, 4.0 equiv.) was added in succession. The mixture was stirred at room temperature under nitrogen atmosphere for 16 h. Then, 3M HCl was added to adjust pH=6-7. The mixture was extracted with EA, and the organic layer was washed with brine and concentrated to Na 2 SO 4 The residue was purified by column chromatography on silica gel to give compound PI-a.2 (1.6 g, 30%).

[0326] Preparation of compounds PC-12, PC-13 and PC-14:

[0327] [ka]

[0328] To a mixture of compound PI-a.2 (2.3 g, 9.96 mmol, 1.0 equiv.) in toluene (100 mL), ethane-1,2-diol (1.2 g, 19.9 mmol, 20 equiv.) and TsOH (86 mg, 0.498 mmol, 0.05 equiv.) were added sequentially. The mixture was heated under reflux for 12 h under nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound PI-b.2 (2.2 g, 81%).

[0329] A solution of compound PI-b.2 (1.5 g, 5.45 mmol, 1.0 equiv.) in THF (50 mL) was added at 0 °C with 1,4-phenylenedimethanol (2.63 g, 19 mmol, 3.5 equiv.), PPh 3 (2.86 g, 10.9 mmol, 2.0 equiv.) and DEAD (1.9 g, 10.9 mmol, 2.0 equiv.) were added sequentially. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then diluted with H 2 The mixture was quenched with 2×O (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give compound PI-14a (1.5 g, 70%).

[0330] A mixture of compound PI-14a (500 mg, 1.266 mmol, 1.0 equiv) in HCl / THF (3.0 M, 35 mL / 35 mL) was stirred at 70° C. for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give compound PI-14b (280 mg, 63%).

[0331] EtOH (5 mL) and H 2To a mixture of compound PI-14b (150 mg, 0.427 mmol, 1.0 equiv.) in 2.5 mL of O was added KCN (42 mg, 0.641 mmol, 1.5 equiv.) and (NH 4 ) 2 CO 3 (410 mg, 4.27 mmol, 10.0 equiv.) was added. The mixture was stirred at 50° C. for 5 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound PC-14 (70 mg, 25%) as a white solid.

[0332] Thus, compounds PC-12 and PC-13 were synthesized by the same procedure, except that 1,2-phenylenedimethanol was replaced with 1,3-phenylenedimethanol or 1,4-phenylenedimethanol.

[0333] Preparation of compound PC-15:

[0334] [ka]

[0335] Compound PI-b.2 (500 mg, 1.82 mmol, 1.0 equiv.) in THF (20 mL) was added at 0° C. to a solution of compound PI-10a (1.1 g, 6.37 mmol, 3.5 equiv.), PPh 3 (954 mg, 3.64 mmol, 2.0 equiv.) and DEAD (634 mg, 3.64 mmol, 2.0 equiv.) were added sequentially. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then diluted with H 2 The mixture was quenched with 2×O (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give compound PI-15a (460 mg, 60%).

[0336] A mixture of compound PI-15a (1 g, 2.364 mmol, 1.0 equiv) in HCl / THF (3.0 M, 25 mL / 25 mL) was stirred at 70° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give compound PI-15b (200 mg, 25%).

[0337] EtOH (6 mL) and H 2 To a mixture of compound PI-15b (200 mg, 0.593 mmol, 1.0 equiv.) in 20O (6 mL), KCN (58 mg, 0.89 mmol, 1.5 equiv.) and (NH 4 ) 2 CO 3 (570 mg, 5.93 mmol, 10.0 equiv.) was added. The mixture was stirred at 50° C. for 4 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative HPLC to give compound PC-15 (58 mg, 24%) as a white solid.

[0338] Preparation of compounds PC-16 and PC-17:

[0339] [ka]

[0340] A solution of compound PI-b.2 (1.2 g, 4.363 mmol, 1.0 equiv.) in THF (20 mL) was added at 0° C. with (2-methylpyridin-4-yl)methanol (2.68 g, 21.8 mmol, 5.0 equiv.), PPh 3(2.29 g, 8.73 mmol, 2.0 equiv.) and DEAD (1.5 g, 8.73 mmol, 2.0 equiv.) were added sequentially. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then diluted with H 2 The mixture was quenched with 2×O (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give compound PI-16a (1.4 g, 84%).

[0341] A mixture of compound PI-16a (1.4 g, 3.684 mmol, 1.0 equiv) in HCl / THF (2.0 M, 30 mL / 30 mL) was stirred at 70° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 and concentrated under reduced pressure to give compound PI-16b (760 mg, 61%), which was used in the next step without further purification.

[0342] To a mixture of compound PI-16b (760 mg, 2.262 mmol, 1.0 equiv.) in MeOH (10 mL) was added KCN (294 mg, 4.524 mmol, 2.0 equiv.) and (NH 4 ) 2 CO 3 (869 mg, 9.048 mmol, 4.0 equiv.) was added. The mixture was stirred at room temperature for 12 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give compound PC-16 (130 mg, 14%) as a white solid.

[0343] Compound PC-17 was synthesized by the same procedure as in the synthesis of compound PC-16, except that (2-methylpyridin-4-yl)methanol was replaced by (5-methylpyridin-3-yl)methanol.

[0344] Preparation of compounds PC-18 and PC-19:

[0345] [ka]

[0346] Compounds PC-18 and PC-19 were synthesized by the same procedure as in the synthesis of PC-16, except that PI-b.2 was replaced with PI-b.1 as the starting material.

[0347] Preparation of Compounds PC-20 and PC-21:

[0348] [ka]

[0349] Compound PI-b.1 (1.2 g, 4.36 mmol, 1.0 equivalent) in THF (10 mL) was added at 0° C. to a solution of compound PS-4a (2.0 g, 8.73 mmol, 2.0 equivalent), PPh 3 (3.4 g, 13.0 mmol, 3.0 equiv.) and DEAD (2.3 g, 13.0 mmol, 3.0 equiv.) were added sequentially. The mixture was allowed to warm to room temperature and stirred for 20 h. The mixture was then diluted with H 2 The mixture was quenched with O (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel (PE / EA, 1:1) to give compound PI-20a (2.0 g, 95%) as a white solid.

[0350] Compound PI-20a (500 mg, 1.02 mmol, 1.0 equiv.) and HCl (H 2A mixture of 3M in 2048 (10 mL) was stirred at 70° C. for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 The solution was added, adjusted to pH=8 and filtered to give compound PI-20b (400 mg, 100%), which was used in the next step without further purification.

[0351] EtOH (12 mL) and H 2 To a solution of compound PI-20b (220 mg, 0.601 mmol, 1.0 equiv) and KCN (117 mg, 1.803 mmol, 3.0 equiv) in 20O (6 mL), was added (NH 4 ) 2 CO 3 (577 mg, 6.01 mmol, 10.0 equiv.) was added. The mixture was stirred at 50° C. for 5 h. 0.5 M HCl was added to the mixture to adjust the pH to 1-2 and stirred for 10 min. Then, saturated NaHCO 3 The solution was added to adjust the pH to 6-7. The mixture was stirred for 1 h and filtered. The residue was purified by preparative HPLC to give PC-20 (160 mg, 61.3%) as a white solid.

[0352] Preparation of intermediates PS-4a and PS-4b:

[0353] [ka]

[0354] Ac 2 A mixture of formic acid (180 mL, 1.9 mol, 4.0 equiv) in 2O (360 mL, 9.54 mol, 21.2 equiv) was stirred at 60° C. for 1 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and then diluted with PhOH (42.3 g, 0.45 mol, 1.0 equiv) and NaHCO 3 (76.5 g, 0.91 mol, 2.0 equiv.) was added. The mixture was then stirred at room temperature for 16 h. The mixture was extracted with EA (3×150 mL) and water, and the combined organic layers were then washed with H 2 O (3 x 100 mL) and saturated NaHCO3 Solution (2 x 100 mL) and Na 2 SO 4 The mixture was dried at rt and concentrated under reduced pressure to give compound PS-4.1 (60 g, 26%).

[0355] To a mixture of (2-bromopyridin-4-yl)methanol (25 g, 133.69 mmol, 1.0 equiv.) and DHP (22.46 g, 267.38 mmol, 2.0 equiv.) in DCM (290 mL) was added TsOH (2.23 g, 13.37 mmol, 0.1 equiv.). The mixture was stirred at room temperature for 15 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then purified by H 2 The mixture was diluted with 200 mL of HO and extracted with dichloromethane. The organic layer was washed with brine (100 mL) and diluted with anhydrous NaCl. 2 SO 4 The residue was purified by column chromatography on silica gel (PE / EA, 4:1) to give compound PS-4a.1 (34.1 g, 94.1%).

[0356] Compound PS-4a.1 (30g, 110.7mmol, 1.0eq), Compound PS-4.1 (33.7g, 276.75mmol, 2.5eq), Et in ACN (700mL) 3 N (28g, 276.75mmol, 2.5eq) and P(t-Bu) 3 HBF 4 (3.85 g, 13.284 mmol, 0.12 equiv.) was added to a mixture of Pd(OAc) 2 (743.9 mg, 3.321 mmol, 0.03 equiv.) was added. The mixture was stirred at 80° C. for 15 h. Then, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EA, 1:1) to give compound PS-4a.2 (11 g, 32%).

[0357] Compound PS-4a.2 (25 g, 79.8 mmol, 1.0 equiv.) in THF (55 mL) and HCl ( 2A mixture of 2M in 200, 55 mL) was stirred at room temperature for 3 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then diluted with Na 2 SO 4 The residue was purified by column chromatography on silica gel (PE / EA, 2:1) to give compound PS-4a (8 g, 44%).

[0358] Intermediate PS-4b was prepared by the same procedure as in the synthesis of PS-4a, except (2-bromopyridin-4-yl)methanol was replaced with (5-bromopyridin-3-yl)methanol as the starting material.

[0359] Preparation of compound PC22:

[0360] [ka]

[0361] To a mixture of 4-chloropyridine (100 g, 0.667 mol, 1.0 equiv) in dry THF (1 L) was added LDA (2 M in THF, 733.26 mL, 1.467 mol, 2.2 equiv) quickly at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 1 h. Propionaldehyde (74.1 g, 0.999 mol, 1.5 equiv) was then added dropwise and the mixture was stirred for 1 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was purified by NH 4 The mixture was quenched with a saturated aqueous solution of Cl and extracted with EA (3×500 mL). The organic layer was washed with brine and water and added Na 2 SO 4 The residue was purified by column chromatography on silica gel (PE:EA, 3:1) to give compound PI-22a (45 g, 48%).

[0362] To a mixture of PI-22a (26.3 g, 0.154 mol, 1.0 equiv.) in acetone (300 mL), CrO 3(30.8 g, 0.308 mol, 2.0 equiv.) was added. The mixture was stirred at room temperature for 5 hours. Then, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound PI-22b (16.0 g, 62%).

[0363] A mixture of PI-22b (850 mg, 5.03 mmol, 1.0 equiv.), compound 4a-1 (1.27 g, 5.53 mmol, 1.1 equiv.), DPPF (42 mg, 0.503 mmol, 0.1 equiv.) and DIEA (973 mg, 7.55 mmol, 1.5 equiv.) in toluene (10 mL) was added to the reaction system under nitrogen atmosphere with Pd(dba) 2 (202 mg, 0.352 mmol, 0.07 equiv.) was added. The mixture was stirred at 110° C. for 16 h. The mixture was then filtered and extracted with water and ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give compound PI-22c (550 mg, 30%).

[0364] EtOH (8 mL) and H 2 To a mixture of PI-22c (550 mg, 1.515 mmol, 1.0 equiv) in 2 mL of HO was added KCN (295 mg, 4.55 mmol, 3.0 equiv) and (NH 4 ) 2 CO 3 (720 mg, 7.576 mmol, 5.0 equiv.) was added. The mixture was stirred at 50° C. for 3 days. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give compound PC-22 (50 mg, 7%) as a white solid.

[0365] Preparation of compound PC-23:

[0366] [ka]

[0367] A mixture of 3-(methoxycarbonyl)benzoic acid (5 g, 27.78 mmol, 1.0 equiv) in dry THF (20 mL) was treated with BH 3 / THF (1M in THF, 55 mL, 55.5 mmol, 2.0 equiv.) was added. The mixture was stirred at 30° C. under nitrogen atmosphere for 16 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give compound PI-23a (4.2 g, 91%).

[0368] A solution of PI-23a (4.1 g, 24.7 mmol, 1.0 equiv.) in THF (100 mL) was added at 0 °C with 1,4-hydroquinone (5.4 g, 49.4 mmol, 2.0 equiv.) and PPh 3 (13.0 g, 49.4 mmol, 2.0 equiv.) and DEAD (8.6 g, 49.4 mmol, 2.0 equiv.) were added sequentially. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then diluted with H 2 The mixture was quenched with O (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel (PE / EA, 2:1) to give compound PI-23b (2.1 g, 33%).

[0369] A solution of compound PI-23b (2.1 g, 8.14 mmol, 1.0 equiv.) in DMF (15 mL) was added with 4-chloronicotinaldehyde (1.73 g, 12.2 mmol, 1.5 equiv.) and K 2 CO 3 (2.25 g, 16.28 mmol, 2.0 equiv.) was added. The mixture was stirred at 80° C. for 4 h under nitrogen atmosphere. Then, 3M HCl was added to adjust the pH to 6-7. The mixture was extracted with EA, and the organic layer was washed with brine to remove Na2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE / EA, 3:1) to give compound PI-23c (900 mg, 31%).

[0370] To a mixture of compound PI-23c (200 mg, 0.551 mmol, 1.0 equiv.) in MeOH (5 mL) was added KCN (72 mg, 1.1 mmol, 2.0 equiv.) and (NH 4 ) 2 CO 3 (211 mg, 2.2 mmol, 4.0 equiv.) was added. The mixture was stirred at room temperature for 12 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound PI-23d (100 mg, 42%).

[0371] To a mixture of PI-23d (100 mg, 0.23 mmol, 1.0 equiv) in MeOH (5 mL) was added NaOH (80 mg, 2.0 mmol, 10.0 equiv). The mixture was stirred at room temperature for 3 h. The mixture was concentrated to half the solvent, and then 1N HCl was added to adjust the pH to 5. The mixture was filtered to give PC-23 (47 mg, 48%).

[0372] Preparation of compound PC-24:

[0373] [ka]

[0374] Compound PC-24 was synthesized by the same procedure as in the synthesis of PC-22, except that the starting material PI-b.1 was replaced with PI-b.2.

[0375] Preparation of compound PC-25:

[0376] [ka]

[0377] To a mixture of PI-23c (2.4 g, 6.61 mmol, 1.0 equiv.) in toluene (40 mL), ethane-1,2-diol (3.7 g, 60 mmol, 10 equiv.) and TsOH (56.5 mg, 0.33 mmol, 0.05 equiv.) were added sequentially. The mixture was heated under reflux for 12 h under nitrogen atmosphere. Then, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EA, 2:1) to give compound PI-25a (2.3 g, 85%).

[0378] To a mixture of PI-25a (2.3 g, 25.65 mmol, 1.0 equiv.) in dry THF (100 mL) was added DIBAL-H (1.0 M in toluene, 14.1 mL, 14.1 mmol, 2.5 equiv.) dropwise at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 1 h. Then, Na 2 SO 4 10H 2 O (6.6 g, 20.5 mmol, 0.8 equiv) was added dropwise and the mixture was stirred for 0.5 h. The reaction was cooled to NH 4 The mixture was quenched with a saturated aqueous solution of Cl and extracted with EtOAc (3×100 mL). The organic layer was washed with brine and water and added with Na 2 SO 4 The residue was purified by column chromatography on silica gel (PE:EA, 3:1) to give compound PI-25b (1.1 g, 51%).

[0379] A mixture of PI-25b (1.1 g, 2.902 mmol, 1.0 equiv) in HCl / THF (2.0 M, 20 mL / 20 mL) was stirred at 70° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4and concentrated under reduced pressure to give compound PI-25c (1.0 g, 100%), which was used in the next step without further purification.

[0380] To a mixture of compound PI-25c (1.0 g, 2.98 mmol, 1.0 equiv.) in MeOH (20 mL) was added KCN (38 mg, 5.96 mmol, 2.0 equiv.) and (NH 4 ) 2 CO 3 (1.14 g, 11.92 mmol, 4.0 equiv.) was added. The mixture was stirred at room temperature for 12 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound PC-25 (215 mg, 18%) as a white solid.

[0381] Preparation of Compounds PC-26 and PC-27:

[0382] [ka]

[0383] A mixture of 1-(bromomethyl)-3-methylbenzene (5.0 g, 27 mmol, 1.0 equiv.) in DMF (150 mL) was treated with 1,4-hydroquinone (5.94 g, 54 mmol, 2.0 equiv.) and K 2 CO 3 (14.9 g, 108 mmol, 4.0 equiv.) was added in succession. The mixture was stirred at 80° C. under nitrogen atmosphere for 3 h. Then, 3M HCl was added to adjust the pH to 6-7. The mixture was extracted with EA, and the organic layer was washed with brine and concentrated to give Na 2 SO 4 The residue was purified by column chromatography on silica gel (PE / EA, 3:1) to give compound PI-26a (2.6 g, 45%).

[0384] To a mixture of PI-26a (1.0 g, 4.67 mmol, 1.0 equiv.) in DMF (15 mL) was added 4-chloronicotinaldehyde (0.99 g, 7 mmol, 1.5 equiv.) and K 2 CO 3 (1.5 g, 9.34 mmol, 2.0 equiv.) was added in portions. The mixture was stirred at 80° C. under nitrogen atmosphere for 3.5 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then subjected to H 2 The mixture was diluted with O (100 mL) and extracted with EA (3×100 mL). The combined organic layers were washed with NH 4 Wash with a saturated aqueous solution of Cl (3×100 mL), brine, and anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel (PE / EA, 1:1) to give compound PI-26b (480 mg, 32%).

[0385] To a solution of compound PI-26b (480 mg, 1.5 mmol, 1.0 equiv.) in MeOH (10 mL), (NH 4 ) 2 CO 3 (578 mg, 6.01 mmol, 4.0 equiv) and KCN (195 mg, 3 mmol, 2.0 equiv) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The pH was adjusted to 6-7 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na 2 SO 4 The mixture was dried by hexane and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-26 (208.1 mg, 44%) as a white solid. Compound PC-27 was synthesized in the same manner, except that the starting material 1-(bromomethyl)-3-methylbenzene was replaced with 4-(bromomethyl)-2-methylpyridine.

[0386] Preparation of Compounds PC-28 and PC-29:

[0387] [ka]

[0388] To a mixture of 3-(chloromethyl)benzoic acid (1.7 g, 9.965 mmol, 1.0 equiv) in DCM (50 mL) was added (COCl) at 0 °C. 2 (1.7 mL, 19.931 mmol, 2.0 equiv) was added dropwise. The mixture was stirred for 1 h during which the solution became cloudy. The mixture was then concentrated under reduced pressure. A mixture of the residue in DCM was diluted with NH 3 A solution of was added. The mixture was stirred for 0.5 h and then concentrated under reduced pressure to give compound PI-28a (1.3 g, 77%).

[0389] A mixture of compound PI-28a (1.0 g, 5.92 mmol, 1.0 equiv.) in DMF (50 mL) was diluted with compound PI-a.1 (1.36 g, 5.92 mmol, 1.0 equiv.) and K 2 CO 3 (2.45 g, 17.76 mmol, 3.0 equiv) was added in succession. The mixture was stirred at room temperature under nitrogen atmosphere for 16 h. Then, 3M HCl was added to adjust the pH to 6-7. The mixture was extracted with EA, and the organic layer was washed with brine and concentrated to give Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel to give compound PI-28b (850 mg, 40%).

[0390] To a mixture of compound PI-28b (850 mg, 2.33 mmol, 1.0 equiv.) in MeOH (10 mL) was added KCN (303 mg, 4.66 mmol, 2.0 equiv.) and (NH 4 ) 2 CO 3 (904 mg, 9.33 mmol, 4.0 equiv.) was added. The mixture was stirred at 45° C. for 16 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4The residue was purified by preparative TLC to give compound PC-28 (500 mg, 49%) as a white solid.

[0391] NH 3 MeNH 2 Compound PC-29 was synthesized using the same procedure, except for replacing with.

[0392] Preparation of compounds PC-30, PC-31, PC-32 and PC-33:

[0393] [ka]

[0394] To a mixture of compound 3-8 (750 mg, 3.876 mmol, 1.0 equiv.) in DMF (15 mL) was added compound PI-a.1 (895 mg, 3.876 mmol, 1.0 equiv.) and K 2 CO 3 (2.14 g, 15.5 mmol, 4.0 equiv.) was added in succession. The mixture was stirred at room temperature under nitrogen atmosphere for 16 h. Then, 3M HCl was added to adjust the pH to 6-7. The mixture was extracted with EA, and the organic layer was washed with brine and concentrated to give Na 2 SO 4 The residue was purified by column chromatography on silica gel (PE / EA, 1:1) to give compound PI-30 (610 mg, 36%).

[0395] To a solution of compound PI-30 (500 mg, 1.419 mmol, 1.0 equiv.) in MeOH (6 mL), (NH 4 ) 2 CO 3 (545 mg, 5.676 mmol, 4.0 equiv.) and KCN (185 mg, 2.838 mmol, 2.0 equiv.) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3The pH was adjusted to 6-7 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na 2 SO 4 The mixture was dried by hexane and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-30 (350 mg, 58%) as a white solid. Thus, compounds PC-31, PC-32 and PC-33 were synthesized in the same manner, except that intermediate 3-8 was replaced with 3-9, 3-11 and 3-10.

[0396] Preparation of Compounds PC-34 and PC-36:

[0397] [ka]

[0398] Compounds PC-34 and PC-36 were synthesized following the same procedure as in the synthesis of compounds PC-28 and PC-29, except that the starting material 3-(chloromethyl)benzoic acid was replaced with 5-(chloromethyl)nicotinic acid.

[0399] Preparation of compound PC-35:

[0400] [ka]

[0401] Compound PC-30 (400 mg, 0.95 mmol, 1.0 equiv.) in CHCl 3 To the (30 mL) solution was added TMS-I (1.35 mL, 9.5 mmol, 10.0 equiv). The mixture was stirred at 55° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (EA:MeOH, 10:1) to give compound PC-35 (350 mg, 90%) as a white solid.

[0402] Preparation of compound PC-37:

[0403] [ka]

[0404] Compound PC-37 was synthesized following the same procedure as in the synthesis of PC-28, except intermediate PC-28a was replaced with FI-18a.

[0405] Preparation of compound PC-38:

[0406] [ka]

[0407] A mixture of methyl 3-(chloromethyl)isonicotinate (800 mg, 4.32 mmol, 1.0 equiv.) in DMF (10 mL) was diluted with compound PI-b.1 (1.19 g, 4.32 mmol, 1.0 equiv.) and CsCO. 3 (4.23 g, 12.97 mmol, 3.0 equiv.) was added in portions. The mixture was stirred at room temperature under nitrogen for 16 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then diluted with H 2 The mixture was diluted with O (50 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with NH 4 Wash with a saturated aqueous solution of Cl (3×50 mL), brine, and anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give compound PI-38a (300 mg, 16%).

[0408] A solution of compound PI-38a (300 mg, 0.708 mmol, 1.0 equiv.) in MeOH (10 mL) was treated with NH 3 Gas was purged for 10 minutes. The flask was sealed and the mixture was stirred at room temperature for 16 hours. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give compound PI-38b (180 mg, 62%).

[0409] A mixture of compound PI-38b (180 mg, 0.440 mmol, 1.0 equiv) in HCl / THF (3.0 M, 2 mL / 2 mL) was stirred at 70° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound PI-38c (100 mg, 62%).

[0410] To a solution of compound PI-38c (90 mg, 0.247 mmol, 1.0 equiv.) in MeOH (5 mL), (NH 4 ) 2 CO 3 (94 mg, 0.986 mmol, 4.0 equiv.) and KCN (32 mg, 0.493 mmol, 2.0 equiv.) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The pH was adjusted to 6-7 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give PC-38 (55 mg, 51%) as a white solid.

[0411] Preparation of compounds PC-39 and PC-40:

[0412] [ka]

[0413] Compound PI-b.1 (738 mg, 2.68 mmol, 1.0 equiv.) in THF (20 mL) was added at 0° C. to a solution of compound PS-4b (615 mg, 2.68 mmol, 1.0 equiv.), PPh 3(1.4 g, 5.37 mmol, 2.0 equiv.) and DEAD (934 mg, 5.37 mmol, 2.0 equiv.) were added sequentially. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then diluted with H 2 The mixture was quenched with 2×O (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give compound PI-39a (490 mg, 37%).

[0414] To a mixture of compound PI-39a (300 mg, 0.617 mmol, 1.0 equiv) in dry THF (10 mL) was added LAH (47 mg, 1.23 mmol, 2.0 equiv) quickly at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 1 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was purified by HPLC with Na 2 SO 4 10H 2 O (159 mg, 0.494 mmol, 0.8 equiv.) and the mixture was stirred for 0.5 h. The mixture was then filtered and the organic layer was concentrated in vacuo. The residue was purified by preparative TLC to give compound PI-39b (150 mg, 61%).

[0415] A mixture of compound PI-39b (150 mg, 0.379 mmol, 1.0 equiv) in HCl / THF (3.0 M, 4 mL / 4 mL) was stirred at 70° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound PI-39c (110 mg, 82%).

[0416] To a solution of compound PI-39c (110 mg, 0.313 mmol, 1.0 equiv.) in MeOH (5 mL), (NH 4) 2 CO 3 (120 mg, 1.25 mmol, 4.0 equiv.) and KCN (40 mg, 0.625 mmol, 2.0 equiv.) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The pH was adjusted to 6-7 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound PC-39 (49 mg, 37%) as a white solid.

[0417] Compound PC-40 was synthesized by the same procedure, except that PS-4b was replaced with PS-4a.

[0418] Preparation of compounds PC-41, PC-46, PC-54 and PC-55:

[0419] [ka]

[0420] To a mixture of compound PC-16 (250 mg, 0.616 mmol, 1.0 equiv) in THF (2 mL), CH 2 N 2 (1M in ether, 3 mL, 3.08 mmol, 5.0 equiv.) was added. The mixture was stirred at room temperature for 3 h. The mixture was then concentrated under reduced pressure to give compound PC-41 (80 mg, 30%) as a white solid.

[0421] To a stirred solution of compound PC-41 (100 mg, 0.238 mmol, 1.0 equiv) in DMF (2 mL) was added NaH (12 mg, 0.476 mmol, 2.0 equiv) at 0 °C. After 10 min, CH 3I (68 mg, 0.476 mmol, 2.0 equiv) was added. After further stirring at 0° C. for 0.5 h, the mixture was warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with water and extracted with EA (3×50 mL). The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound PC-46 (40 mg, 37%) as a yellow solid.

[0422] To a stirred solution of compound PC-41 (300 mg, 0.714 mmol, 1.0 equiv) in DMF (5 mL) was added NaH (17 mg, 0.714 mmol, 1.0 equiv) at 0 °C. After 10 min, CH 3 I (101 mg, 0.714 mmol, 1.0 equiv) was added. After further stirring at 0° C. for 0.5 h, the mixture was warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with water and extracted with EA (3×50 mL). The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound PC-54 (45 mg, 14%) as a white solid.

[0423] A solution of compound PC-16 (1 g, 2.46 mmol, 1.0 equiv.) and 1-(chloromethyl)-4-methoxybenzene (461 mg, 2.96 mmol, 1.2 equiv.) in DMF (10 mL) was added to the reaction mixture containing NaI (369 mg, 2.46 mol, 1.0 equiv.) and K 2 CO 3 (679 mg, 4.92 mmol, 2.0 equiv) was added. The mixture was stirred at room temperature for 16 h. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then diluted with water and extracted with DCM. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give compound PC-55 (130 mg, 34%) as a pink solid.

[0424] Preparation of compounds PC-42, PC-50 and PC-51:

[0425] [ka]

[0426] A mixture of m-cresol (10 g, 92.5 mmol, 1.0 equiv.) and NaSCN (22.5 g, 277.6 mmol, 3.0 equiv.) in MeOH (100 mL) was treated with NaBr (9.5 g, 92.5 mmol, 1.0 equiv.) and Br 2 A solution of (5.7 mL, 111 mmol, 1.2 equiv) in MeOH (100 mL) was added dropwise. The mixture was stirred at room temperature for 14 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. Water was added to the reaction and extracted with EA (3×100 mL). The organic layer was washed with brine and water and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo, and the residue was purified by column chromatography on silica gel to give compound PI-42a (5 g, 33%).

[0427] To a mixture of compound PI-42a (5.0 g, 30.3 mmol, 1.0 equiv.) in dry THF (50 mL) was added LAH (1.72 g, 45.5 mmol, 1.5 equiv.) quickly at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 3 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was purified by HPLC with Na 2 SO 4 10H 2 The mixture was quenched with O and stirred at 0° C. for 0.5 h. The mixture was then filtered and the organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography to give compound PI-42b (2.9 g, 68%).

[0428] To a stirred solution of compound PI-42b (1.0 g, 7.1 mmol, 1.5 equiv) in THF (10 mL) was added NaH (170.4 mg, 7.1 mmol, 1.5 equiv) at 0° C. After 30 min, 4-chloronicotinaldehyde (667.4 mg, 4.73 mmol, 1.0 equiv) was added at 0° C. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with water and extracted with EA (3×10 mL). The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give compound PI-42c (1.2 g, 100%).

[0429] A mixture of compound PI-42c (200 mg, 0.82 mmol, 1.0 equiv.) and 4-(chloromethyl)-2-methylpyridine (130 mg, 0.902 mmol, 1.1 equiv.) in DMF (2 mL) was added with K 2 CO 3 (340 mg, 2.46 mmol, 3.0 equiv) were added stepwise. The mixture was stirred under nitrogen atmosphere at 50° C. for 3 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then poured into water and extracted with EA (3×5 mL). The combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give compound PI-42d (150 mg, 52%).

[0430] To a solution of compound PI-42d (190 mg, 0.54 mmol, 1.0 equiv.) in MeOH (2 mL), (NH 4 ) 2 CO 3 (208.45 mg, 2.17 mmol, 4.0 equiv.) and KCN (70.2 mg, 1.08 mmol, 2.0 equiv.) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3The pH was adjusted to 6-7 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na 2 SO 4 The mixture was dried by hexane and concentrated under reduced pressure. The residue was purified by preparative TLC to give compound PC-42 (200 mg, 88%) as a white solid. Thus, compounds PC-50 and PC-51 were synthesized in the same manner, except that starting material m-cresol was replaced with 3-fluorophenol and 3-chlorophenol.

[0431] Preparation of compounds PC-48, PC-49 and PC-52:

[0432] [ka]

[0433] Thus, compounds PC-48, PC-49 and PC-52 were synthesized by the same procedure as in the synthesis of PC-42, except that the starting material m-cresol was replaced with o-cresol, 2-chlorophenol and 2-fluorophenol.

[0434] Preparation of Compounds PC-43 and PC-44:

[0435] [ka]

[0436] A solution of 4-chloronicotinaldehyde (10 g, 70.92 mmol, 1.0 equiv.) in DMF (100 mL) was added with 4-mercaptobenzoic acid (13.1 g, 85.11 mmol, 1.2 equiv.) and K 2 CO 3 (29.4 g, 0.213 mol, 3.0 equiv.) was added. The mixture was stirred at room temperature for 16 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and washed with anhydrous Na 2 SO 4The residue was purified by silica gel chromatography to give PI-c.1 (11 g, 59%).

[0437] To a stirred solution of PI-c.1 (11 g, 42.47 mmol, 1.0 equiv) in THF (100 mL) was added TsOH (731 mg, 4.25 mmol, 0.1 equiv). After 10 min, ethane-1,2-diol (13.1 g, 0.212 mol, 5.0 equiv) in THF (50 mL) was added dropwise. The mixture was stirred at 110 °C for 16 h. The reaction mixture was diluted with saturated NaHCO 3 The combined organic phase was poured into anhydrous NaCl solution (160 mL) and extracted with EA (3×100 mL). 2 SO 4 The residue was purified by silica gel chromatography to give PI-c.2 (8 g, 62%).

[0438] To a mixture of PI-c.2 (8 g, 26.40 mmol, 1.0 equiv.) in dry THF (100 mL) was added LAH (2 g, 52.81 mmol, 2.0 equiv.) quickly at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 1 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was purified by HPLC with Na 2 SO 4 10H 2 The mixture was quenched with 2,4-dimethylformamide (6.8 g, 21.12 mmol, 0.8 equiv.) and the mixture was stirred for 0.5 h. The mixture was extracted and the organic layer was then washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-c.3 (4 g, 52%).

[0439] A mixture of PI-c.3 (1 g, 3.46 mmol, 1.0 equiv) in DCM (10 mL) was treated with SOCl under nitrogen atmosphere at 0 °C. 2(824 mg, 6.92 mmol, 2.0 equiv) was added. The mixture was stirred at 0° C. for 4 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was treated with NaHCO 3 (aqueous) was added, the pH was adjusted to >7, and the organic layer was extracted with DCM. 2 SO 4 The residue was purified by silica gel chromatography to give PI-c.4 (1 g, 94%).

[0440] A solution of compound PI-c.4 (500 mg, 1.63 mmol, 1.0 equiv.) in DMF (5 mL) was treated with m-cresol (211 mg, 1.95 mmol, 1.2 equiv.) and K 2 CO 3 (675 mg, 4.89 mmol, 3.0 equiv) was added. The mixture was stirred at room temperature for 16 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give compound PI-43a (230 mg, 37%).

[0441] A mixture of PI-43a (230 mg, 0.607 mmol, 1.0 equiv) in HCl / THF (3.0 M, 2 mL / 2 mL) was stirred at 70° C. for 14 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-43b (150 mg, 73%).

[0442] A solution of PI-43b (150 mg, 0.448 mmol, 1.0 eq.) in MeOH (3 mL) was added with (NH4 ) 2 CO 3 (172 mg, 1.79 mmol, 4.0 equiv.) and KCN (58 mg, 0.896 mmol, 2.0 equiv.) were added. The mixture was stirred at 40° C. for 12 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The pH was adjusted to 6-7 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound PC-43 (40 mg, 22%) as a white solid.

[0443] Compound PC-44 was synthesized in the same manner, except m-cresol was replaced with 2-methylpyridin-4-ol.

[0444] Preparation of compound PC-45:

[0445] [ka]

[0446] To a mixture of 4-hydroxy-6-methylnicotinic acid (10 g, 65.4 mmol, 1.0 equiv) in DCM (100 mL) was added (COCl) at 0 °C. 2 A solution of (12.35 g, 98.1 mmol, 1.5 equiv) was added dropwise. The mixture was stirred for 12 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was purified by distillation with Na 2 SO 4 The mixture was dried at rt and concentrated in vacuo to give crude PI-45a (10 g, crude).

[0447] A mixture of PI-45a (10 g, 52.9 mmol, 1.0 equiv) in MeOH (100 mL) was stirred at room temperature for 2 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was purified by hexane distillation with Na 2 SO 4The residue was purified by silica gel chromatography to give crude PI-45b (12 g, 100%).

[0448] To a mixture of PI-45b (12.0 g, 64.86 mmol, 1.0 equiv) in dry THF (100 mL) was added LAH (3.69 g, 97.3 mmol, 1.5 equiv) quickly at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 3 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was purified by HPLC with Na 2 SO 4 10H 2 The mixture was quenched with O and stirred at 0° C. for 0.5 h. The mixture was then filtered and the organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography to give PI-45c (6.0 g, 59%).

[0449] To a stirred solution of PI-45c (6.0 g, 38.2 mmol, 1.0 equiv) in DCM (60 mL) was added Dess-Martin periodinane (32.4 g, 76.4 mmol, 2.0 equiv). The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with EA (3×60 mL). The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-45d (2.3 g, 39%).

[0450] A mixture of PI-45d (2.3 g, 14.8 mmol, 1.0 equiv.) and 4-mercaptophenol (2.06 g, 16.3 mmol, 1.1 equiv.) in DMF (25 mL) was diluted with K 2 CO 3 (6.14 g, 44.4 mmol, 3.0 equiv) was added in portions. The mixture was stirred under nitrogen atmosphere at 50° C. for 3 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then poured into water and extracted with EA (3×30 mL). The combined organic layers were washed with brine and washed with anhydrous Na 2 SO4 The residue was purified by column chromatography on silica gel to give PI-45e (1.6 g, 44%).

[0451] A mixture of PI-45e (1.0 g, 4.08 mmol, 1.0 equiv) and 4-(chloromethyl)-2-methylpyridine (633 mg, 4.48 mmol, 1.1 equiv) in DMF (10 mL) was diluted with K 2 CO 3 (1.69 g, 12.24 mmol, 3.0 equiv) was added stepwise. The mixture was stirred under nitrogen atmosphere at 50° C. for 3 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then poured into water and extracted with EA (3×10 mL). The combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give PI-45f (700 mg, 49%).

[0452] To a solution of PI-45f (700 mg, 2.0 mmol, 1.0 equiv) in MeOH (1 mL), (NH 4 ) 2 CO 3 (767.8 mg, 8.0 mmol, 4.0 equiv) and KCN (260 mg, 4.0 mmol, 2.0 equiv) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The pH was adjusted to 6-7 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give PC-45 (512 mg, 61%) as a white solid.

[0453] Preparation of compounds PC-47 and PC-53:

[0454] [ka]

[0455] Compounds PC-47 and PC-53 were synthesized by the same procedure as the synthesis of PC-39 and PC-40, except that the starting material PI-b.1 was replaced with PI-b.2.

[0456] Preparation of compound PC-56:

[0457] [ka]

[0458] 4-Aminothiophenol (16 g, 127.8 mmol, 1.0 equiv.) and Boc 2 To a solution of 2H2O (55.2 g, 255.6 mmol, 2.0 equiv.) in DCM (200 mL) was added TEA (25.8 g, 255.6 mmol, 2.0 equiv.) and DMAP (1.56 g, 12.78 mmol, 0.05 equiv.) at 0° C. The mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was then diluted with saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-56a (8.1 g, 28%).

[0459] A solution of PI-56a (5 g, 22.19 mmol, 1.0 equiv.) in DMF (40 mL) was added with 4-chloronicotinaldehyde (3.14 g, 22.19 mmol, 1.0 equiv.) and K 2 CO 3 (9.12 g, 66.57 mmol, 3.0 equiv.) was added. The mixture was stirred at room temperature for 16 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and washed with anhydrous Na 2 SO 4The residue was purified by silica gel chromatography to give PI-56b (1.4 g, 19%).

[0460] To a mixture of PI-56b (0.6 g, 1.82 mmol, 1.0 equiv) in toluene (50 mL) was added ethane-1,2-diol (2.25 g, 36.3 mmol, 20 equiv) and TsOH (0.02 g, 0.09 mmol, 0.05 equiv) successively. The mixture was heated under reflux for 12 h under nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give PI-56c (0.25 g, 36%).

[0461] To a solution of PI-56c (0.2 g, 0.53 mmol, 1.0 equiv.) in DMF (5 mL) was added compound 4-(chloromethyl)-2-methylpyridine (0.09 g, 0.64 mmol, 1.2 equiv.) and NaH (14 mg, 0.58 mmol, 1.1 equiv., 60%) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and purified with anhydrous NaH. 2 SO 4 The residue was purified by silica gel chromatography to give PI-56d (0.13 g, 51%).

[0462] A mixture of PI-56d (250 mg, 0.52 mmol, 1.0 equiv) in HCl / THF (2.0 M, 3 mL / 3 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-56e (110 mg, 63%).

[0463] To a solution of PI-56e (110 mg, 0.33 mmol, 1.0 equiv) in MeOH (3 mL), (NH 4 ) 2 CO 3 (126 mg, 1.31 mmol, 4.0 equiv.) and KCN (43 mg, 0.66 mmol, 2.0 equiv.) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The mixture was added with a saturated aqueous solution of 1,000 ml of ethyl acetate, adjusted to pH 7-8, and extracted with ethyl acetate. The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give PC-56 (50 mg, 37%) as a white solid.

[0464] Preparation of compound PC-57:

[0465] [ka]

[0466] 4-Aminothiophenol (10 g, 79.87 mmol, 1.0 equiv.) 2 To a solution of 200 mL of HCl (80 mL) at 0 °C, 2 SO 4 (30 mL) and NaNO 2 (6.6 g, 95.84 mmol, 1.2 equiv.) was added in portions. The mixture was stirred at 0° C. for 0.5 h. Then, urea (0.46 g, 7.99 mmol, 0.1 equiv.) was added. After 15 min, H 2 A solution of KI (26.5 g, 159.74 mmol, 2.0 equiv) in 2O (1.5 L) was added dropwise at 0° C. The mixture was stirred at 0° C. for 5 h. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-57a (7.3 g, 39%).

[0467] A mixture of PI-57a (1.8 g, 3.83 mmol, 1.0 equiv) in MeOH (40 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with water and brine. The organic layer was extracted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-57b (0.9 g, 50%).

[0468] A solution of PI-57b (230 mg, 1 mmol, 1.0 equiv.) in DMF (10 mL) was added with 4-chloronicotinaldehyde (140 mg, 1 mmol, 1.0 equiv.) and K 2 CO 3 (276 mg, 2 mmol, 2.0 equiv.) was added. The mixture was stirred at room temperature for 16 h. Then, water (30 mL) was added and extracted with ethyl acetate (20 mL×3). The organic layer was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-57c (0.3 g, 88%).

[0469] A solution of PI-57c (1 g, 2.9 mmol, 1.0 equiv.) and 4-ethynyl-2-methylpyridine (0.41 g, 3.5 mmol, 1.2 equiv.) in TEA (1.19 g, 0.29 mmol, 0.1 equiv.) was added to Pd(Ph 3 P) 2 Cl 2 (0.21 g, 0.29 mmol, 0.1 equiv.) and CuI (0.06 g, 0.29 mmol, 0.1 equiv.) were added. The mixture was stirred at room temperature under nitrogen for 16 h. The mixture was then diluted with saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-57d (0.8 g, 83%).

[0470] To a solution of PI-57d (0.2 g, 0.61 mmol, 1.0 equiv) in methanol (10 mL) was added Pd / C (20 mg). The mixture was stirred at room temperature under hydrogen atmosphere (20 psi) for 16 h. The mixture was filtered and the filtrate was concentrated to give PI-57e (170 mg, 84%) without further purification.

[0471] To a solution of PI-57e (180 mg, 0.54 mmol, 1.0 equiv) in MeOH (5 mL), (NH 4 ) 2 CO 3 (206 mg, 2.15 mmol, 4.0 equiv) and KCN (70 mg, 1.08 mmol, 2.0 equiv) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The mixture was added with a saturated aqueous solution of 1,000 ml of ethyl acetate, adjusted to pH 7-8, and extracted with ethyl acetate. The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give PC-57 (60 mg, 27%) as a yellow solid.

[0472] Preparation of compound PC-58:

[0473] [ka]

[0474] A mixture of PI-56d (400 mg, 0.83 mmol, 1.0 equiv) in TFA / DCM (1 mL / 3 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4Drying by HCl and concentration under reduced pressure afforded PI-58a (350 mg, 100%), which was used in the next step without further purification.

[0475] A mixture of PI-58a (360 mg, 0.95 mmol, 1.0 equiv) in formic acid (80%, 3 ml) and formaldehyde solution (40%, 1 ml) was prepared. The mixture was heated at 100° C. for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-58b (210 mg, 56%).

[0476] A mixture of PI-58b (210 mg, 0.53 mmol, 1.0 equiv) in HCl / THF (2.0 M, 3 mL / 3 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated NaHCO 3 The solution was added, the pH was adjusted to 8, and extracted with ethyl acetate. The organic layer was washed with brine and anhydrous Na 2 SO 4 Drying by HCl and concentration under reduced pressure afforded PI-58c (160 mg, 86%), which was used in the next step without further purification.

[0477] To a solution of PI-58c (180 mg, 0.52 mmol, 1.0 equiv) in MeOH (3 mL), (NH 4 ) 2 CO 3 (198 mg, 2.06 mmol, 4.0 equiv) and KCN (67 mg, 1.03 mmol, 2.0 equiv) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The mixture was added with a saturated aqueous solution of 1,000 ml of ethyl acetate, adjusted to pH 7-8, and extracted with ethyl acetate. The organic layer was washed with brine and diluted with anhydrous Na 2 SO4 The residue was purified by silica gel chromatography to give PC-58 (118 mg, 54%) as a yellow solid.

[0478] Preparation of compound PC-59:

[0479] [ka]

[0480] To a solution of compound 4-pyridinemethanol (5 g, 45.82 mmol, 1.0 equiv.) and imidazole (7.97 g, 137.45 mmol, 3.0 equiv.) in DCM (100 mL) was added TBSCl (13.8 g, 91.64 mmol, 2.0 equiv.) at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was then diluted with saturated NH 4 The mixture was quenched with Cl solution (100 mL). The mixture was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give compound PI-59a (7.2 g, 70%).

[0481] To a solution of compound PI-59a (10 g, 44.76 mmol, 1.0 equiv.) in DCM (150 mL) was added m-CPBA (11.58 g, 67.14 mmol, 1.5 equiv.) at room temperature. The mixture was stirred at room temperature for 16 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then quenched with a saturated aqueous solution of sodium sulfite. The organic layer was washed with brine and purified with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give compound PI-59b (8.1 g, 75%).

[0482] To a mixture of compound PI-59b (10.3 g, 43.4 mmol, 1.0 equiv.) in TEA (40 mL) was added trimethylsilyl cyanide (13 g, 130.4 mmol, 3 equiv.). The mixture was heated at 90° C. for 3 h under nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-59c (5.1 g, 47%).

[0483] To a solution of PI-59c (5.1 g, 20.53 mmol, 1.0 equiv) in ethanol / HO (100 / 17 mL) was added NaOH (6.9 g, 172.5 mmol, 8.4 equiv). The mixture was stirred at 90 °C for 2 h. The mixture was then cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate. The aqueous layer was acidified to pH = 4-5 and extracted with ethyl acetate. The organic layer was washed with brine and purified with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-59d (3.2 g, 99%).

[0484] To a solution of PI-59d (2.2 g, 14.36 mmol, 1.0 equiv) in DMF (100 mL), NH 4 Cl (1.54 g, 28.73 mmol, 2.0 equiv), HATU (5.46 g, 14.36 mmol, 1.0 equiv) and DIEA (5.57 g, 43.08 mmol, 3.0 equiv) were added successively. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with brine, water and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-59e (0.6 g, 27%).

[0485] A mixture of PI-59e (0.53 g, 3.48 mmol, 1.0 equiv) in DCM (50 mL) was treated with SOCl under nitrogen atmosphere at 0 °C. 2(0.83 g, 6.96 mmol, 2.0 equiv) was added dropwise. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (50 mL) and NaHCO 3 Wash with a saturated aqueous solution of NaCl, brine, and anhydrous Na 2 SO 4 The mixture was dried by FT-IR and concentrated under reduced pressure to give PI-59f (0.47 g, 79%).

[0486] A solution of PI-59f (470 mg, 2.75 mmol, 1.0 equiv.) in DMF (20 mL) was mixed with PI-a.1 (636 mg, 2.75 mmol, 1.0 equiv.) and K 2 CO 3 (759 mg, 5.5 mmol, 2 equiv.) was added. The mixture was stirred at room temperature for 4 h. Then, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-59g (210 mg, 21%).

[0487] To a solution of PI-59g (400 mg, 1.09 mmol, 1.0 equiv) in MeOH (7 mL), (NH 4 ) 2 CO 3 (419 mg, 4.38 mmol, 4.0 equiv) and KCN (141 mg, 2.19 mmol, 2.0 equiv) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The mixture was added with a saturated aqueous solution of 1,000 ml of ethyl acetate, adjusted to pH 7-8, and extracted with ethyl acetate. The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PC-59 (52 mg, 11%) as a white solid.

[0488] Preparation of compound PC-60:

[0489] [ka]

[0490] A solution of PI-59f (470 mg, 2.75 mmol, 1.0 equiv.) in DMF (20 mL) was mixed with PI-a.2 (636 mg, 2.75 mmol, 1.0 equiv.) and K 2 CO 3 (759 mg, 5.5 mmol, 2 equiv.) was added. The mixture was stirred at room temperature for 4 h. Then, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-60a (230 mg, 23%).

[0491] To a solution of PI-60a (230 mg, 0.63 mmol, 1.0 equiv) in MeOH (6 mL), (NH 4 ) 2 CO 3 (241 mg, 2.51 mmol, 4.0 equiv.) and KCN (81 mg, 1.26 mmol, 2.0 equiv.) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The mixture was added with a saturated aqueous solution of 1,000 ml of ethyl acetate, adjusted to pH 7-8, and extracted with ethyl acetate. The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PC-60 (53 mg, 19%) as a yellow solid.

[0492] Preparation of compound PC-61:

[0493] [ka]

[0494] A solution of 5-bromo-2-hydroxypyridine (5 g, 28.74 mmol, 1.0 equiv.) in DMF (100 mL) was added with 4-(chloromethyl)-2-methylpyridine (4.07 g, 28.74 mmol, 1.0 equiv.) and K 2 CO 3 (7.93 g, 57.47 mmol, 2 equiv.) was added. The mixture was stirred at room temperature for 4 h. Then, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL×3). The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-61a (4.1 g, 51%).

[0495] PI-61a (1 g, 3.58 mmol, 1.0 equiv.), 4-methoxy-α-toluenethiol (607 mg, 3.94 mmol, 1.1 equiv.), Xantphos (207 mg, 0.36 mmol, 0.1 equiv.) and Cs in dioxane (30 mL). 2 CO 3 (1.75 g, 5.37 mmol, 1.5 equiv.) was added to a mixture of Pd 2 (dba) 3 (230 mg, 0.25 mmol, 0.07 equiv) was added. The mixture was stirred at 90° C. for 12 h. Then, the mixture was filtered and extracted with water (50 mL) and ethyl acetate (30 mL×3). The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-61b (0.8 g, 63%).

[0496] PI-61b (1 g, 2.83 mmol, 1.0 equiv) was dissolved in TFA (20 mL) and stirred under nitrogen atmosphere at 90° C. for 16 h. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-61c (0.5 g, 76%).

[0497] To a solution of PI-61c (600 mg, 2.58 mmol, 1.0 equiv) in THF (20 mL) was added NaH (103 mg, 2.58 mmol, 1 equiv, 60%) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 1 h. Then, 4-chloronicotinaldehyde (365 mg, 2.58 mmol, 1.0 equiv) was added. The mixture was stirred at room temperature for 12 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine and purified with anhydrous NaH. 2 SO 4 The residue was purified by silica gel chromatography to give PI-61d (250 mg, 29%).

[0498] To a solution of PI-61d (200 mg, 0.59 mmol, 1.0 equiv) in MeOH (5 mL), (NH 4 ) 2 CO 3 (227 mg, 2.37 mmol, 4.0 equiv.) and KCN (77 mg, 1.19 mmol, 2.0 equiv.) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The mixture was added with a saturated aqueous solution of 1,000 ml of ethyl acetate, adjusted to pH 7-8, and extracted with ethyl acetate. The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give PC-61 (104 mg, 43%) as a white solid.

[0499] Preparation of compound PC-62:

[0500] [ka]

[0501] A solution of 4-iodophenol (2.2 g, 10 mmol, 1.0 equiv.) and 4-ethynyl-2-methylpyridine (1.29 g, 11 mmol, 1.1 equiv.) in DMF (30 mL) was added to the reaction mixture under nitrogen atmosphere with TEA (3.2 g, 30 mmol, 3 equiv.), Pd(P 3 P) 2 Cl 2 (1.4 g, 2 mmol, 0.2 equiv.) and CuI (0.38 g, 2 mmol, 0.2 equiv.) were added. The mixture was stirred at room temperature under nitrogen for 3 h. The mixture was then diluted with saturated NH 4 The mixture was quenched with Cl (50 mL) solution. The mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-62a (1.05 g, 45%).

[0502] A solution of PI-62a (0.8 g, 3.82 mmol, 1.0 equiv.) in DMF (40 mL) was added with 4-chloronicotinaldehyde (0.54 g, 3.82 mmol, 1.0 equiv.) and K 2 CO 3 (1.05 g, 7.64 mmol, 2 equiv.) was added. The mixture was stirred at 80° C. for 4 h. Then, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-62b (0.45 g, 37%).

[0503] To a solution of PI-62b (1.0 equiv.) in methanol (10 mL) is added Pd / C (20 mg). The mixture is stirred under hydrogen atmosphere (20 psi) at room temperature for 16 h. The mixture is filtered and the filtrate is concentrated to give PI-62c without further purification.

[0504] To a solution of PI-62c (1.0 equiv.) in MeOH (5 mL), (NH 4) 2 CO 3 (4.0 equiv.) and KCN (2.0 equiv.). The mixture is stirred at 45° C. for 16 h. The reaction is adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The organic layer was washed with brine and extracted with ethyl acetate. 2 SO 4 The mixture is dried by hexane and concentrated under reduced pressure to give PC-62.

[0505] Preparation of compound PC-63:

[0506] [ka]

[0507] To a mixture of 4-chloropyridine (100 g, 0.667 mol, 1.0 equiv) in dry THF (1 L) was added LDA (2 M in THF, 733.26 mL, 1.467 mol, 2.2 equiv) quickly at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 1 h. Propionaldehyde (74.1 g, 0.999 mol, 1.5 equiv) was then added dropwise and the mixture was stirred for 1 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was purified by NH 4 The mixture was quenched with a saturated aqueous solution of Cl and extracted with ethyl acetate (3×500 mL). The organic layer was washed with brine and water and added with Na 2 SO 4 The residue was purified by column chromatography on silica gel (PE:EA, 3:1) to give PI-63a (45 g, 48%).

[0508] To a mixture of PI-63a (26.3 g, 0.154 mol, 1.0 equiv.) in acetone (300 mL), CrO 3(30.8 g, 0.308 mol, 2.0 equiv.) was added. The mixture was stirred at room temperature for 5 h. Then, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-63b (16.0 g, 62%).

[0509] A mixture of PI-63b (1 g, 4.67 mmol, 1.0 equiv.) and 4-mercaptophenol (590 mg, 4.67 mmol, 1.0 equiv.) in DMF (50 mL) was diluted with K 2 CO 3 (1.29 g, 9.34 mmol, 2 equiv.) was added. The mixture was stirred at room temperature under nitrogen for 16 h. The mixture was then diluted with H 2 The mixture was quenched with 200 mL of ethyl acetate (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-63c (1.2 g, 99%).

[0510] A mixture of PI-63c (500 mg, 1.93 mmol, 1.0 equiv) and 4-(chloromethyl)-2-methylpyridine (409 mg, 2.89 mmol, 1.5 equiv) in DMF (20 mL) was diluted with K 2 CO 3 (798 mg, 5.78 mmol, 3 equiv.) was added. The mixture was stirred at 70° C. under nitrogen atmosphere for 4 h. The mixture was then diluted with H 2 The mixture was quenched with 20 mL of ethyl acetate (60 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-63d (610 mg, 87%).

[0511] To a solution of PI-63d (610 mg, 1.68 mmol, 1.0 equiv) in MeOH / HO (12 mL, 5 / 1) was added (NH 4 ) 2 CO3 (644 mg, 6.71 mmol, 4.0 equiv.) and KCN (218 mg, 3.36 mmol, 2.0 equiv.) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The mixture was added with a saturated aqueous solution of 1,000 ml of ethyl acetate, adjusted to pH 7-8, and extracted with ethyl acetate. The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give PC-63 (80 mg, 11%) as a white solid.

[0512] Preparation of compound PC-64:

[0513] [ka]

[0514] To a mixture of 3-chloropyridine (100 g, 0.667 mol, 1.0 equiv) in dry THF (1 L) was added LDA (2 M in THF, 733.26 mL, 1.467 mol, 2.2 equiv) quickly at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 1 h. Propionaldehyde (74.1 g, 0.999 mol, 1.5 equiv) was then added dropwise and the mixture was stirred for 1 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was purified by NH 4 The mixture was quenched with a saturated aqueous solution of Cl and extracted with ethyl acetate (3×500 mL). The organic layer was washed with brine and water and added with Na 2 SO 4 The residue was purified by column chromatography on silica gel (PE:EA, 3:1) to give PI-64a (45 g, 48%).

[0515] To a mixture of PI-64a (26.3 g, 0.154 mol, 1.0 equiv.) in acetone (300 mL), CrO 3(30.8 g, 0.308 mol, 2.0 equiv.) was added. The mixture was stirred at room temperature for 5 h. Then, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-64b (16.0 g, 62%).

[0516] A mixture of PI-64b (1 g, 4.67 mmol, 1.0 equiv.) and 4-mercaptophenol (590 mg, 4.67 mmol, 1.0 equiv.) in DMF (50 mL) was diluted with K 2 CO 3 (1.29 g, 9.34 mmol, 2 equiv.) was added. The mixture was stirred at room temperature under nitrogen for 16 h. The mixture was then diluted with H 2 The mixture was quenched with 200 mL of ethyl acetate (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-64c (1.2 g, 99%).

[0517] A mixture of PI-64c (500 mg, 1.93 mmol, 1.0 equiv) and 4-(chloromethyl)-2-methylpyridine (409 mg, 2.89 mmol, 1.5 equiv) in DMF (20 mL) was diluted with K 2 CO 3 (798 mg, 5.78 mmol, 3 equiv.) was added. The mixture was stirred at 70° C. under nitrogen atmosphere for 4 h. The mixture was then diluted with H 2 The mixture was quenched with 20 mL of ethyl acetate (60 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PI-64d (610 mg, 87%).

[0518] To a solution of PI-64d (700 mg, 1.92 mmol, 1.0 equiv) in MeOH / HO (12 mL, 5 / 1) was added (NH 4 ) 2 CO3 (637 mg, 7.68 mmol, 4.0 equiv) and KCN (248 mg, 3.83 mmol, 2.0 equiv) were added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The pH was adjusted to 7-8 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give PC-64 (242 mg, 29%) as a white solid.

[0519] Preparation of compounds OC-1 and OC-2:

[0520] [ka]

[0521] To a mixture of compound 4a-1 (0.5 g, 2.17 mmol, 1.0 equiv.) in ACN (15 mL) was added 2-fluorobenzaldehyde (0.271 g, 2.17 mmol, 1.0 equiv.) and K 2 CO 3 (0.906 g, 6.52 mmol, 3.0 equiv.) was added. The mixture was stirred at 85° C. overnight under nitrogen atmosphere. The mixture was then concentrated in vacuo. The residue was purified by preparative TLC to give compound OI-1 (490 mg, 68%).

[0522] To a mixture of compound OI-1 (200 mg, 0.6 mmol, 1.0 equiv.) in MeOH (10 mL), KCN (78 mg, 1.2 mmol, 2.0 equiv.) and (NH 4 ) 2 CO 3 (230 mg, 2.4 mmol, 4.0 equiv.) was added. The mixture was stirred overnight at 40° C. under nitrogen atmosphere. The mixture was then concentrated in vacuo to give compound OC-1 (200 mg, 82%).

[0523] To a mixture of compound OC-1 (15 mg, 0.037 mmol, 1.0 equiv.) in dioxane (1 mL) was added m-CPBA (6.4 mg, 0.037 mmol, 1.0 equiv.). The mixture was stirred at room temperature for 12 h. The mixture was then diluted with EA and saturated NaHCO 3 The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give compound OC-2 (9.6 mg, 62%).

[0524] Preparation of compounds OC-3 and OC-4:

[0525] [ka]

[0526] A mixture of 4-chloronicotinaldehyde (1 g, 7.1 mmol, 1.0 equiv.) in MeOH (6 mL) was treated with KCN (0.92 mg, 14.2 mmol, 2.0 equiv.) and (NH 4 ) 2 CO 3 (2.71 g, 28.2 mmol, 4.0 equiv.) was added. The mixture was stirred at room temperature for 12 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound OI-3a (1.0 g, 66%) as a white solid.

[0527] To a mixture of OI-3a (1.0 g, 4.73 mmol, 1.0 equiv) in dioxane (10 mL) was added m-CPBA (0.82 g, 4.73 mmol, 1.0 equiv). The mixture was stirred at room temperature for 12 h. The mixture was then diluted with EA and saturated NaHCO 3 The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give OI-3b (200 mg, 19%).

[0528] A mixture of OI-3b (100 mg, 0.43 mmol, 1.0 equiv.) and compound 4a-1 (99 mg, 0.43 mmol, 1 equiv.) in ACN (2 mL) was added with K 2 CO 3 (182 mg, 1.31 mmol, 3.0 equiv) were added stepwise. The mixture was stirred at 85° C. under nitrogen atmosphere for 12 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then poured into water and extracted with EA (3×5 mL). The combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give OC-3 (23.6 mg, 13%).

[0529] To a mixture of compound OC-3 (20 mg, 0.05 mmol, 1.0 equiv.) in dioxane (1 mL) was added m-CPBA (8.5 mg, 0.05 mmol, 1.0 equiv.). The mixture was stirred at room temperature for 12 h. The mixture was then diluted with EA and saturated NaHCO 3 The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give OC-4 (8 mg, 40%).

[0530] Preparation of compound OC-5:

[0531] [ka]

[0532] To a mixture of 1-methyl-1H-pyrazole (16.4 g, 0.2 mol, 1.0 equiv) in dry THF (150 mL) was added n-BuLi (2.5 M in hexanes, 96 mL, 0.24 mol, 1.2 equiv) at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 1 h. DMF (30.8 mL, 0.4 mol, 2.0 equiv) was then added dropwise and the mixture was stirred for 1 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was purified by NH4 The mixture was quenched with a saturated aqueous solution of Cl and extracted with EA (3×500 mL). The organic layer was washed with brine and water and added with Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo, and the residue was purified by column chromatography on silica gel to give compound OI-5a (12.7 g, 58%).

[0533] To a mixture of compound OI-5a (2 g, 18.2 mmol, 1.0 equiv.) in DMF (20 mL) was added NBS (4.86 g, 27.3 mmol, 1.5 equiv.). The mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was then filtered and extracted with water and ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried by hexane and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give compound OI-5b (2.3 g, 67%).

[0534] A mixture of OI-5b (700 mg, 3.72 mmol, 1.0 equiv), 4a-1 (1.27 g, 4.09 mmol, 1.1 equiv), DPPF (42 mg, 0.503 mmol, 0.1 equiv) and DIEA (942 mg, 7.55 mmol, 1.5 equiv) in toluene (10 mL) was treated with Pd(dba) 2 (150 mg, 0.260 mmol, 0.07 equiv.) was added. The mixture was stirred at 110° C. for 16 h. The mixture was then filtered and extracted with water and ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give OI-5c (120 mg, 10%).

[0535] To a mixture of compound OI-5c (140 mg, 0.414 mmol, 1.0 equiv.) in MeOH (5 mL), KCN (54 mg, 0.828 mmol, 2.0 equiv.) and (NH 4 ) 2 CO 3(159 mg, 1.66 mmol, 4.0 equiv.) was added. The mixture was stirred at room temperature for 12 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound OC-5 (67 mg, 40%) as a white solid.

[0536] Preparation of compound OC-6:

[0537] [ka]

[0538] A mixture of 4-imidazolecarboxaldehyde (1 g, 10.4 mmol, 1.0 equiv.) and NaOAc (14.15 g, 104 mmol, 10 equiv.) in AcOH (100 mL) was treated with Br at 0 °C under nitrogen. 2 (3.8 g, 23.77 mmol, 2.3 equiv.) of Ac 2 A solution of 200 mL of HO was added dropwise. The mixture was stirred at room temperature for 3 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The reaction was diluted with saturated NaHCO 3 The mixture was quenched with aqueous EA and extracted with EA (3×20 mL). The organic layer was washed with brine and water and added Na 2 SO 4 The mixture was dried over 1000 ml and concentrated in vacuo, and the residue was purified by column chromatography to give OI-6a (0.8 g, 44%).

[0539] OI-6a (1 g, 5.71 mmol, 1.0 equiv.) and Cs in DMF (50 mL) 2 CO 3(1.86 g, 5.71 mmol, 1.0 equiv.) was added successively to a mixture of MeI (0.82 g, 5.71 mmol, 1.0 equiv.). The mixture was stirred at room temperature under nitrogen for 3 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then poured into water and extracted with EA (3×30 mL). The combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel to give OI-6b (0.7 g, 65%).

[0540] OI-6b (0.7g, 3.7mmol, 1.0eq), 4a-1 (1.27g, 5.56mmol, 1.5eq), CyPF-tBu (CAS:158923-11-6) (21mg, 0.04mmol, 0.01eq) and Cs in DME (10mL) 2 CO 3 (942 mg, 7.55 mmol, 2.5 equiv.) was added to a mixture of Pd(OAc) 2 (8 mg, 0.04 mmol, 0.01 equiv.) was added. The mixture was stirred at 110° C. for 16 h. The mixture was then filtered and extracted with water and ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give OI-6c (0.28 g, 22%).

[0541] To a solution of OI-6c (280 mg, 0.83 mmol, 1.0 equiv) in MeOH (5 mL), (NH 4 ) 2 CO 3 (320 mg, 3.31 mmol, 4.0 equiv) and KCN (108 mg, 1.65 mmol, 2.0 equiv) were added. The mixture was stirred at room temperature for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The pH was adjusted to 6-7 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na2 SO 4 The residue was purified by silica gel chromatography to give OC-6 (200 mg, 59%) as a white solid.

[0542] Preparation of compounds OC-7 and OC-10:

[0543] [ka]

[0544] A solution of ethyl oxazole-5-carboxylate (0.28 g, 2.00 mmol) in THF / DMF (2 / 2 mL) was added to Br 2 (0.13 mL, 2.6 mmol, 1.3 equiv) and LHMDS (2.6 mL, 2.6 mmol, 1.3 equiv) were added to give a reaction mixture which was stirred at -60 °C for 4 h. The reaction mixture was extracted with EA and water, and the combined organic layers were washed with MgSO 4 The residue was purified by flash chromatography with EA / Hex (EA / Hex=1:4) to give OS-a.1 as a yellow oil (0.1 g, 30%).

[0545] To a solution of OS-a.1 (0.3 g, 1.36 mmol) in THF (10 mL), NaOH (81 mg, 2.05 mmol, 1.5 equiv.) and 4-mercaptophenol (0.17 g, 1.36 mmol, 1 equiv.) were added and stirred overnight. The reaction mixture was extracted with EA and water, and the combined organic layer was diluted with MgSO 4 The residue was purified by flash chromatography with EA / Hex (EA / Hex=1:2) to give OS-a.2 as a yellow solid (0.25 g, 71%).

[0546] A solution of compound OS-a.2 (4.2 g, 15.85 mmol, 1.0 equiv.) in DMF (40 mL) was added with 4-(chloromethyl)-2-methylpyridine (2.2 g, 15.85 mmol, 1.0 equiv.) and K 2 CO 3(6.6 g, 47.55 mmol, 3.0 equiv.) was added. The mixture was stirred at 30° C. for 16 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and purified by anhydrous Na 2 SO 4 The mixture was dried by hexane and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give compound OI-7a (2.5 g, 44%).

[0547] To a solution of OI-7a (1.4 g, 3.93 mmol, 1.0 equiv) in anhydrous THF (10 mL) at 0° C. was added DIBAL-H (1 M in hexanes, 7.87 mL, 7.87 mmol, 2.0 equiv) dropwise. The mixture was stirred at 0° C. for 2 h under nitrogen atmosphere. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then washed with saturated Na 2 SO 4 10H 2 The mixture was quenched with 2×O solution (50 mL). The mixture was extracted with DCM (3×30 mL). The combined organic phase was washed with brine (2×60 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give OI-7b (620 mg, 48%).

[0548] A solution of OI-7b (620 mg, 1.89 mmol, 1.0 equiv.) in DCM (5 mL) was treated with PDC (1.4 g, 3.78 mmol, 2.0 equiv.) and K 2 CO 3 (782 mg, 5.67 mmol, 3.0 equiv) was added. The mixture was stirred at 40° C. for 16 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then diluted with water and extracted with DCM. The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give OI-7c (205 mg, 33%).

[0549] A solution of OI-7c (205 mg, 0.629 mmol, 1.0 eq.) in MeOH (3 mL) was added (NH 4 ) 2 CO 3 (241 mg, 2.52 mmol, 4.0 equiv.) and KCN (82 mg, 1.26 mmol, 2.0 equiv.) were added. The mixture was stirred at room temperature for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The pH was adjusted to 6-7 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na 2 SO 4 The mixture was dried by hexanes and concentrated under reduced pressure. The residue was purified by preparative TLC to give OC-7 (41 mg, 16%) as a white solid. Compound OC-10 was synthesized in the same manner, except that (chloromethyl)-2-methylpyridine was replaced with 1-(bromomethyl)-3-methylbenzene.

[0550] Preparation of compound OC-8:

[0551] [ka]

[0552] Compound OC-8 was synthesized by the same procedure as in the synthesis of compound OC-10, except that the starting material ethyl oxazole-5-carboxylate was replaced with ethyl oxazole-4-carboxylate.

[0553] Preparation of compound OC-9:

[0554] [ka]

[0555] Compound OC-9 was synthesized by the same procedure as in the synthesis of OC-8, except that the starting material 1-(bromomethyl)-3-methylbenzene was replaced with (3-(bromomethyl)phenyl)methanol.

[0556] Preparation of compound OC-11

[0557] [ka]

[0558] Compound OC-11 was synthesized by the same procedure as in the synthesis of OC-8, except that the starting material 1-(bromomethyl)-3-methylbenzene was replaced with 4-(chloromethyl)-2-methylpyridine.

[0559] Preparation of compound OC-12:

[0560] [ka]

[0561] A solution of bis(4-hydroxyphenyl) disulfide (5.0 g, 19.97 mmol, 1.0 equiv.) in DMF (100 mL) was added with 4-(chloromethyl)-2-methylpyridine (6.22 g, 43.94 mmol, 2.2 equiv.) and K 2 CO 3 (8.2 g, 59.91 mmol, 3 equiv.) was added. The mixture was stirred at 45° C. for 12 h. Then, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL×3). The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give OI-12a (3.9 g, 42%).

[0562] To a solution of OI-12a (3.9 g, 8.46 mmol, 1.0 equiv.) in THF (50 mL), PPh 3(2.22 g, 8.46 mmol, 1.0 equiv) and concentrated HCl (8.8 mL, 84.6 mmol, 10 equiv) were added. The mixture was stirred at room temperature for 16 h. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried by hexane and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give compound OI-12b (2.1 g, 53%).

[0563] A mixture of OI-12b (296 mg, 1.28 mmol, 1.1 equiv.), OI-5b (220 mg, 1.16 mmol, 1.0 equiv.), DPPF (10 mg, 0.12 mmol, 0.1 equiv.) and DIEA (225 mg, 1.74 mmol, 1.5 equiv.) in toluene (10 mL) was added to Pd 2 (dba) 3 (47 mg, 0.08 mmol, 0.07 equiv) was added. The mixture was stirred at 110° C. for 16 h. The mixture was then filtered and extracted with water and ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give OI-12c (180 mg, 45%).

[0564] To a mixture of OI-12c (120 mg, 0.35 mmol, 1.0 equiv) in MeOH (4 mL) was added KCN (46 mg, 0.7 mmol, 2.0 equiv) and (NH 4 ) 2 CO 3 (134 mg, 1.4 mmol, 4.0 equiv.) was added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The mixture was added with a saturated aqueous solution of 1,000 ml of ethyl acetate, adjusted to pH 7-8, and extracted with ethyl acetate. The organic layer was washed with brine and diluted with anhydrous Na 2 SO 4The residue was purified by preparative TLC to give compound OC-12 (50 mg, 35%) as a white solid.

[0565] Preparation of compound OC-13:

[0566] [ka]

[0567] A mixture of OI-6b (310 mg, 1.63 mmol, 1.0 equiv.), OI-12b (414 mg, 1.79 mmol, 1.1 equiv.), DPPF (88 mg, 0.16 mmol, 0.1 equiv.) and DIEA (313 mg, 2.43 mmol, 1.5 equiv.) in toluene (16 mL) was added to Pd 2 (dba) 3 (104 mg, 0.11 mmol, 0.07 equiv) was added. The mixture was stirred at 110° C. for 16 h. Then, the mixture was filtered and extracted with water (50 mL) and ethyl acetate (30 mL×3). The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give OI-13a (400 mg, 72%).

[0568] To a mixture of OI-13a (370 mg, 1.09 mmol, 1.0 equiv) in MeOH (10 mL) was added KCN (142 mg, 2.18 mmol, 2.0 equiv) and (NH 4 ) 2 CO 3 (418 mg, 4.36 mmol, 4.0 equiv.) was added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The pH was adjusted to 7-8 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na 2 SO 4The residue was purified by preparative TLC to give OC-13 (73 mg, 16%) as a white solid.

[0569] Preparation of compound OC-14:

[0570] [ka]

[0571] To a mixture of 4-imidazolecarboxaldehyde (6 g, 62.44 mmol, 1.0 equiv) in THF (60 mL) was added NaH (3 g, 74.9 mmol, 1.2 equiv) at room temperature. After 10 min, the mixture was cooled to -78 °C and MeI (10.5 g, 74.9 mmol, 1.2 equiv) was added. The mixture was then allowed to warm gradually to room temperature and stirred for 18 h. The reaction was quenched with methanol (10 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give OI-14a (4 g, 58%).

[0572] To a solution of OI-14a (4 g, 36.36 mmol, 1.0 equiv.) in chloroform (40 mL) was added NBS (7.12 g, 40 mmol, 1.1 equiv.). The mixture was stirred at 70° C. for 3 h. The mixture was then cooled to room temperature and Na 2 CO 3 The organic layer was washed with brine and water and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo, and the residue was purified by column chromatography on silica gel to give OI-14b (333 mg, 4.8%).

[0573] A mixture of OI-14b (333 mg, 1.76 mmol, 1.0 equiv.), compound OI-12b (448 mg, 1.94 mmol, 1.1 equiv.), DPPF (100 mg, 0.18 mmol, 0.1 equiv.) and DIEA (340 mg, 2.64 mmol, 1.5 equiv.) in toluene (20 mL) was treated with Pd2 (dba) 3 (113 mg, 0.12 mmol, 0.07 equiv) was added. The mixture was stirred at 110° C. for 16 h. Then, the mixture was filtered and extracted with water (50 mL) and ethyl acetate (30 mL×3). The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give OI-14c (261 mg, 43%).

[0574] To a mixture of OI-14c (261 mg, 0.77 mmol, 1.0 equiv) in MeOH (5 mL) was added KCN (100 mg, 1.53 mmol, 2.0 equiv) and (NH 4 ) 2 CO 3 (295 mg, 3.08 mmol, 4.0 equiv.) was added. The mixture was stirred at 45° C. for 16 h. The reaction was adjusted to pH=1-2 with 3M HCl and stirred at room temperature for 1 h, then NaHCO 3 The pH was adjusted to 7-8 by adding a saturated aqueous solution of ethyl acetate, and the organic layer was washed with brine and then extracted with anhydrous Na 2 SO 4 The residue was purified by preparative TLC to give compound OC-14 (183 mg, 58%) as a white solid.

[0575] Biological testing

[0576] [Example 1] MMP inhibition assay The inhibitory effect of compounds on the rate of cleavage of a fluorescent MMP substrate (Enzo, BML-P128) by recombinant human MMP-12 catalytic domain (Enzo, BML-SE138) was performed by methods known in the art. Briefly, all reagents were added sequentially by pipetting to each well of a 96-well black opaque plate, and the final reaction contained 4 nM recombinant human MMP-12 catalytic domain, 4 μM fluorescent MMP substrate, and 10 mM CaCl. 2The plates contained dilutions of test compounds at various concentrations (0.15 nM to 10,000 nM) in HEPES buffer (pH 7.5) containing 0.01% Brij® 35 (polyoxyethylene (23) lauryl ether) and 0.1 mg / ml BSA.

[0577] The enzyme and compounds were pre-incubated on a shaker and mixed in the wells. After mixing for 1 hour, a fluorescent substrate was added to each well. A reaction without enzyme was used as a blank control in the plate. The plate was then fed into a plate reader and the fluorescence intensity was measured at excitation / emission wavelengths of 340 nm / 440 nm every 10 minutes for at least 1 hour at 37°C. The IC of each compound in inhibiting MMP-12 was calculated. 50 was determined using readings taken at the 30 minute time point. The results for each compound tested are shown in Table 1.

[0578] [Example 2] Selectivity Assays MMP selectivity assays were performed using other recombinant human MMPs, including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-13 and MMP-14. The IC of the compounds with respect to other recombinant human MMPs was 50 was determined as described above in Example 1 and is shown in Table 2.

[0579] [Table 2]

[0580] The results in Table 2 above show that compounds according to embodiments of the present application have high selectivity for MMP-12 over other MMPs, including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-13 and MMP-14.

[0581] [Example 3] Efficacy of MMP-12 inhibitors in a unilateral ureteral obstruction (UUO)-induced renal fibrosis model in SD rats This study was conducted to evaluate the therapeutic efficacy of PC-16, an MMP-12 inhibitor, on a unilateral ureteral obstruction (UUO)-induced renal fibrosis model. Male Sprague Dawley (SD) rats (180-220 g, n=71) were used in this study. The animals were randomly divided into four groups: vehicle group (group-1, n=8), PC-16 2 mg / kg / day group (group-2, n=9), PC-16 6 mg / kg / day group (group-3, n=10), and PC-16 20 mg / kg / day group (group-4, n=9). The animals were anesthetized with 2.5% isoflurane inhelation. The left ureter was ligated to create a unilateral ureteral obstruction (UUO) model to induce renal fibrosis. Test article PC-16 was administered twice daily via oral delivery after modeling for 14 days. Peripheral blood serum was prepared before modeling and on day 15 (1 day after the last administration). All animals were euthanized and processed for left kidney pathology examination.

[0582] PC-16 treatment at a dose of 20 mg / kg / day slightly limited the blood urea nitrogen (BUN) improvement compared with the vehicle group, but all the data showed no statistically significant difference compared with the model group. Serum creatinine level showed a similar change as BUN.

[0583] Histologically, the left kidney showed significant morphological changes compared to UUO, including pelvic expansion, atropsy of the renal medulla and cortex, tubular epithelial cell flattening and tubular dilatation, inflammation, and necrosis. Interstitial fibrosis was clearly observed in the pelvic wall, medulla, and cortex. PC-16 treatment showed a clear dose-dependent effect, with the 20 mg / kg / day dose being more effective than the 2 mg / kg / day dose (p<0.01). Semiquantitative assessment of interstitial inflammation in the cortex showed a significant reduction with PC-16 treatment, indicating a dose-dependent efficacy of PC-16. Semiquantitative assessment of interstitial fibrosis in the cortex showed a significant reduction in fibrosis scores with PC-16 treatment in all dose groups. There was a clear dose-dependent effect in the PC-16 treatment groups.

[0584] Analysis of immunohistochemical (IHC) staining in the cortical region of the left kidney in animals treated with PC-16 showed a significant decrease in collagen I deposition at a dose of 20 mg / kg / day (P<0.05), with a transduction of dose-dependent decrease with PC-16 treatment. The above immunohistochemical staining also showed a significant decrease in collagen IV deposition at a dose of PC-16 6 mg / kg / day (P<0.05), with a trend of dose-dependent decrease with PC-16 treatment at a dose of PC-16 20 mg / kg / day.

[0585] In conclusion, UUO induced severe renal cortical injury, inflammation and interstitial fibrosis within 15 days of modeling. PC-16 treatment showed a clear dose-dependent efficacy on either renal injury, interstitial inflammation or interstitial fibrosis. Fibrosis-related biomarker analysis showed that PC-16 treatment reduced associated collagen deposition (collagen I and IV) in the cortical region of the injured kidney.

[0586] Detailed experimental method Animals: Gender: Male SD rats, 180-220g, total 71 animals. Certificate: 11400700272659, Beijing Vital River Laboratory Animal Technology Co., Ltd., China. Animal holding: Animals were maintained in a temperature-controlled environment with a 12-h light / 12-h dark cycle and had free access to food and water. Experimental procedures were performed in accordance with IACUC guidelines at KCI (SuZhou) Biotech Inc. (KCI) Animal Research Facility. Model generation: A total of 35 male SD rats were used in this study. After anesthesia with 2.5% isoflurane inhalation, the abdomen of the animals was surgically opened. The left ureter was exposed and ligated proximal to the bladder to create the UUO model. After confirming the absence of bleeding, the abdominal wall was closed in layers. The animals were maintained under a temperature-controlled pad (37°C) during recovery from anesthesia and then transferred to holding cages with regular food and water.

[0587] Experimental Grouping: UUO modeling animals were randomly divided into seven groups: Vehicle (Group-1, n=8), PC-16 2mg / kg / day (Group-5, n=9), PC-16 6mg / kg / day (Group-6, n=10), PC-16 20mg / kg / day (Group-7, n=9) (Table 4.1). Dosing Regimen: All test articles were designed for oral administration by gastric perfusion. Test articles were designed to be delivered twice a day for 14 days, starting on the same day as modeling (Table 4.1). Endpoints: 1) Blood Collection: Peripheral blood was collected from all animals in each group, and serum was prepared before modeling and on the 15th day (1 day after the last administration) and stored at -80°C. All animals were euthanized according to KCI SOP. After confirming the absence of respiration and heartbeat (bite) and the death of the animals, the left kidney was perfused with cold PBS, followed by 10% neutral formalin, and collected for further pathological examination. 2) Detection of serum BUN and creatinine: Serum BUN and creatinine levels were detected using a Hitachi 7060 automatic biochemistry analyzer and related test kits. 3) Renal pathological examination: 3a) Renal H&E staining and analysis: Following KCI pathological SOP, all of the left kidneys were fixed in 10% formalin at room temperature for at least 24 hours. After fixation, the kidneys were cut longitudinally to obtain the maximum surface, dehydrated in graded ethanol, washed in xylene, and embedded in paraffin. Thin sections (3 μm) were mounted on glass slides, dewaxed, rehydrated in distilled water, and stained with hematoxylin and eosin (H&E). All stained slides were scanned by a NanoZoomer digital pathology (S210, Hamamaci, Japan) scanner. Semiquantitative assessment of the degree of tubular epithelial flattening and dilatation was graded from 0 to 5 according to the percentage of tubular involvement: score 0 = no damage; score 1 = 1-10% damage; score 2 = 10-25% damage; score 3 = 25-50% damage; score 4 = 50-75% damage; score 5 = 75-100% damage. Semiquantitative assessment of tubular necrosis was graded from 0 to 3 according to the percentage of tubular involvement: score 0 = no necrosis; score 1 = <25% necrosis; score 2 = 25-50% necrosis; score 3 = >50% necrosis.The mean of tubular flattening and dilation and necrosis was shown as total tubular damage. Semiquantitative assessment of interstitial inflammation was graded from 0 to 4 according to the degree of inflammatory cell infiltration: score 0 = no inflammatory cells; score 1 = mild inflammatory cell infiltration; score 2 = moderate inflammatory cell infiltration; score 3 = severe inflammatory cell infiltration; score 4 = extensive inflammatory cell infiltration. 3b) Kidney Masson's Trichrome Staining and Analysis: Thin sections (3 μm) were mounted on glass slides, dewaxed, rehydrated in distilled water and stained with Masson's Trichrome. All stained slides were scanned by NanoZoomer Digital Pathology (S210, Hamamaci, Japan) scanner. Semiquantitative assessment of cortical interstitial fibrosis by 5 different fields at ×10 magnification randomly selected from the kidney cortex was estimated according to the percentage of interstitial fibrosis involvement as 0 to 4 using the following scoring system: score 0 = no fibrosis formation. Score 1 = <10% fibrosis. Score 2 = 10-25% fibrosis. Score 3 = 25-75% fibrosis. Score 4 = >75% fibrosis. 3c) Kidney IHC staining and analysis: All left kidneys from each group (8 right kidneys from model group) were processed for biomarker analysis using IHC methods, e.g., collagen I (Abcam, Cat. No. ab34710), collagen IV (Abcam, Cat. No. ab6586). IHC staining was processed according to standard protocols for IHC at KCI. All stained slides were then scanned by a Hamamatsu NanoZoomer Digital Pathology S210 slide scanner and analyzed using software to obtain positive staining area / analysis area (%). 4) Statistical analysis: Graphpad, prism 5.0 was used for all statistical analyses, and P value <0.05 was considered significant. All data were reported as mean ± standard error. Differences between groups were determined using ANOVA tests with either Bonferroni tests or Student's T tests.

[0588] [Table 3]

[0589] result: a) Physiological changes of animals during the experiment: Several animals died during the experiment, which was considered to be due to model malfunctions, such as rupture of the ureter during surgery that induced peritonitis. The number of animals that died in each group is shown in Table 4.1. b) Changes in serum BUN and creatinine: After UUO, on the 15th day, serum BUN of all animals was improved compared to before modeling (P<0.001). PC-16 treatment at a dose of 20 mg / kg / day showed the same results (Fig. 1A). All data showed no statistically significant difference compared to the model group. Serum creatinine levels showed similar changes, similar to BUN (Fig. 1B). c) Changes in left kidney injury - tubular injury: 15 days after UUO, the left kidney showed dilation of the pelvic cavity in all animals. The renal cortex showed significant atrophy with various degrees of tubular epithelial cell flattening, tubular dilation and infiltration of interstitial inflammatory cells and few foci of tubular necrosis (Figure 1C). PC-16 treatment showed a clear dose-dependent effect, with a dose of 20 mg / kg / day being more effective than a dose of 2 mg / kg / day (p<0.01) (Figure 1D(I)). d) Changes in left kidney injury - interstitial inflammation: Semiquantitative assessment of interstitial inflammation in the cortex showed a significant reduction with PC-16 treatment, indicating a dose-dependent efficacy of PC-16 (Figure 1D(II)). e) Changes in left kidney injury - cortical interstitial fibrosis: 15 days after UUO, the left kidney showed severe interstitial fibrosis in the pelvic cavity, medullary and cortical regions in all animals. Interstitial fibrosis in the cortical region was analyzed and showed different degrees in the case of treatment with the tested CPDs (Figure 1E). Semiquantitative evaluation of interstitial fibrosis in the cortex showed a significant reduction in fibrosis score in the case of treatment with PC-16 at a dose of 20 mg / kg / day (p<0.001). There was a clear dose-dependent effect in the PC-16 treatment group (Figure 1F). f) Pathological analysis of multiple biomarkers in the left kidney: Collagen I: Analysis of IHC staining in the cortical region of the left kidney for animals treated with PC-16 showed a significant reduction in collagen I deposition at a dose of 20 mg / kg / day (p<0.05). Trans-dose-dependent reduction in the PC-16 treatment group (Figure 1G(I) and Figure 1H(I)). Collagen IV: Analysis of IHC staining in the cortical region of the left kidney for animals treated with PC-16 showed a significant reduction in collagen IV deposition at a dose of 20 mg / kg / day (p<0.05). Trans-dose-dependent reduction with PC-16 treatment (Figure 1G(II) and Figure 1H(II)). References 1. US 7179831 2. WO 02 / 096426 3. US 2004 / 0067996 4. WO 2004 / 108086 5. WO 02 / 074752 6. WO 2004 / 020415 (Additional Note) (Appendix 1) Compounds of formula (I): [ka] or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, Ring B is an optionally substituted aryl or an optionally substituted heteroaryl; Ring C is aryl or heteroaryl; Ring D is aryl or heteroaryl; X, Y and Z are O, CH 2 , N.R. x and S(O) q R x is hydrogen or alkyl, R 1 is hydrogen or alkyl, R 2 are respectively hydrogen, alkyl, halo, hydroxyl, haloalkyl, alkoxy, alkylthio, amino, amido, alkylamine, aminoalkyl, cyano, hydroxyalkyl, -(CH2 ) p C(O)OR 6 and -(CH 2 ) p O.C.(O)R 6 are independently selected from the group consisting of: R 3 are each independently selected from the group consisting of hydrogen, alkyl, and halo; R 4 is hydrogen or alkyl, R 5 is hydrogen, R 6 are each independently selected from the group consisting of hydrogen and alkyl, wherein alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of amino, hydroxyl, halo, and alkoxy; m is 1, 2, 3 or 4; n is 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4 or 5; q is 0, 1 or 2; With the proviso that ring B is not furanyl). (Appendix 2) The compound according to claim 1, wherein Ring C is phenyl. (Appendix 3) The compound according to claim 1, wherein Ring D is pyridinyl or phenyl. (Appendix 4) Ring D is

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Claims

1. Compounds of formula (I): 【Chemistry 1】 or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof. (In the formula, Ring B is phenyl or pyridinyl N-oxide, each of which is optionally substituted with -CH3; Ring C is aryl or heteroaryl; Ring D is aryl or heteroaryl; X is O or S; Y and Z are O, CH 2 , N.R. x and S(O) q R x is hydrogen or alkyl, R 1 is hydrogen or alkyl, R 2 are respectively hydrogen, alkyl, halo, hydroxyl, haloalkyl, alkoxy, alkylthio, amino, amido, alkylamine, aminoalkyl, cyano, hydroxyalkyl, -(CH 2 ) p C(O)OR 6 and -(CH 2 ) p O.C.(O)R 6 are independently selected from the group consisting of: R 3 are each independently selected from the group consisting of hydrogen, alkyl, and halo; R 4 is hydrogen or alkyl, R 5 is hydrogen, R 6 are each independently selected from the group consisting of hydrogen and alkyl, wherein alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of amino, hydroxyl, halo, and alkoxy; m is 1, 2, 3 or 4; n is 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4 or 5; and q is 0, 1 or 2.

2. 2. The compound of claim 1, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring C is phenyl.

3. 2. The compound of claim 1, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring D is pyridinyl or phenyl.

4. 2. The compound of claim 1, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is phenyl.

5. 2. The compound of claim 1, or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Ring B is a pyridinyl N-oxide. 【Request 6】 【Chemical 2】 or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

7. 7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a tautomer, stereoisomer, pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, for inhibiting macrophage elastase (MMP-12).

9. 8. The pharmaceutical composition according to claim 7, for treating a disease mediated by macrophage elastase (MMP-12), wherein the disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, non-alcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome and nephritis.

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