RU2797558C2 - Matrix metalloproteinase (mmp) inhibitors and methods of their application - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: compounds based on hydantoin, useful as inhibitors of matrix metalloproteinases (MMPs), in particular macrophage elastase (MMP-12) are described. The invention relates to compounds based on hydantoin of formula (II) or its pharmaceutically acceptable salts, where ring B is pyridinyl or thiophenyl; ring C is phenyl; ring D is phenyl or pyridinyl; X is S; Y is O; Z is CH₂; R₁-R₅, m and n are defined in the claims. The compounds have activity as inhibitors of matrix metalloproteinases (MMPs), in particular macrophage elastase (MMP-12).

EFFECT: pharmaceutical compositions and methods of using the compounds for the inhibition of MMP-12 and the treatment of 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, non-alcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis are also described.

13 cl, 1 dwg, 3 tbl, 3 ex

Description

CROSS-REFERENCE TO RELATED APPLICATION

The present application amends the priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62/671753, filed May 15, 2018, the disclosure of which is incorporated herein by reference.

State of the art invention

Matrix metalloproteinases (MMPs) are a superfamily of enzyme proteinases that are important for the degradation of most extracellular matrix proteins during organogenesis, growth, and normal tissue turnover. MMPs are also believed to play an important role in the uncontrolled destruction of connective tissue, which is associated with several disease processes such as rheumatoid arthritis, osteoarthritis, gastric ulcers, asthma, emphysema, and tumor metastasis. Therefore, inhibition of one or more MMPs may be beneficial in these diseases.

Human macrophage elastase (MMP-12) is a specific MMP. MMP-12 exhibits all the characteristics of other MMPs, but is predominantly produced from macrophages that infiltrate tissues where damage or remodeling occurs and degrade the extracellular matrix. For example, elevated levels of MMP-12 have been observed during the onset of emphysema. In addition, the MMP-12 knockout mouse model showed no development of emphysema after prolonged exposure to cigarette smoke (Hautamkai et al. Science, 1997, 277: 2002-2004). These data suggest that MMP-12 plays a role in the progression of emphysema. The involvement of MMP-12 in the development of chronic asthma has also been suggested based on studies of the MMP-12 deficient asthma model (Warner et al. Am J Pathol. 2004 ; 165(6): 1921-1930). In a FAS-induced acute lung injury model, MMP 12 deficient mice are protected from developing 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 caused by Schistosoma mansoni infection, MMP-12 exhibits profibrotic activity in the lung and liver (Madala et al. J Immunol 2010;184:3955-3963). MMP-12 may also contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF) by degrading extracellular matrix (ECM) proteins, as levels of the type IV collagen fragment BALF generated by MMP-12 are increased in patients with IPF (Sand et al. PLoS One 2013 ; 8:e84934), and human MMP-12 can cleave a number of human ECM proteins in vitro (Owen et al. J Leuk°C Biol 1999;65:137-150). Together, these results suggest that MMP-12 inhibitors may be useful in the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD), emphysema, asthma, acute lung injury, idiopathic pulmonary fibrosis (IPF), liver fibrosis, and non-alcoholic steatohepatitis. (NASH).

et al., World J Gastroenterol. 2012, 18(30):4028-36). Взятые вместе, эти наблюдения позволяют предположить, что MMP-12 может быть мишенью для лечения этих заболеваний.MMP-12 has been shown to be secreted from alveolar macrophages in smokers (Shapiro et al., Journal of Biological Chemistry, 1993, 268:23824), foam cells in atherosclerotic lesions (Matsumoto et al., Am. J. Pathol., 1998, 153:109), and in a rat model with nephritis (Kaneko et al., J. lmmunol., 2003, 170:3377). MMP-12 also plays a role in ischemic heart disease (Jormsjo et al., Circulation Research, 2000, 86: 998). MMP-12 has also been shown to be elevated in patients with inflammatory bowel disease (IBD) as well as in a T cell-mediated colitis model and promote epithelial degradation, and MMP-12-/- mice were protected from TNBS-induced colitis ( Pender et al., Ann NY Acad Sci. 2006, 1072:386-8.). Epithelial and stromal MMP-12, together with MMP-3 and -7, were also elevated in the mucosa of the onset UC sac in children, suggesting that long-term MMP expression in the UC sac in children shares characteristics with IBD (

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.

Given the involvement of MMP-12 in a number of diseases, attempts have been made to obtain inhibitors of MMP-12. A number of MMP-12 inhibitors are known (see, for example, International Patent Application Publication WO 00/40577; European Patent Application Publication EP 1 288 199 A1; US Patent No. 63529761 and US Patent Application Publication No. 2004/0072871; and European patent application EP1394159).

A particular class of MMP inhibitors that have been described are hydantoin derivatives. For example, International Patent Application WO 02/096426 describes hydantoin derivatives with the general formula:

, которые раскрыты как активные в качестве ингибиторов MMP, в частности, в отношении фактор некроза опухолей-альфа-превращающего фермента (ТАСЕ) и аггреканазы. Особенностью раскрытых структур этих производных является спиросвязь между гидантоиновым кольцом и его боковой цепью. В публикации патентной заявки США No. 2004/0067996 и публикации Международной заявки на патент WO 2004/108086 описаны аналогичные производные гидантоина общей формулы:

, which are disclosed as active as MMP inhibitors, in particular against tumor necrosis factor-alpha-converting enzyme (TACE) and aggrecanase. A feature of the disclosed structures of these derivatives is the spiro bond between the hydantoin ring and its side chain. In US Patent Application Publication No. 2004/0067996 and International Patent Application WO 2004/108086 describe similar hydantoin derivatives with the general formula:

, которые также описаны как ингибиторы MMP, в частности, для ТАСЕ и аггреканазы.

, which are also described as MMP inhibitors, in particular for TACE and aggrecanase.

International Patent Publication WO 02/074752 describes the synthesis of MMP inhibitors and International Patent Publication WO 2004/020415 describes MMP-12 inhibitors which are derivatives of hydantoin with the general formula:

и

, соответственно. Некоторые из раскрытых соединений проявляли ингибирующую активность в отношении MMP, в том числе ингибирующую активность в отношении MMP-12.

And

, respectively. Some of the disclosed compounds exhibited MMP inhibitory activity, including MMP-12 inhibitory activity.

More recently, US Patent No. 7179831 described MMP-12 inhibitors, which are derivatives of hydantoin with the general formula:

.

.

Hydantoin derivatives are a useful class of MMP inhibitors. However, there is a need in the art to identify hydantoin derivatives having improved specificity, activity, and pharmacological properties.

SUMMARY OF THE INVENTION

The application satisfies this need by providing hydantoin derivatives with high activity and specificity for MMPs, in particular macrophage elastase (MMP-12).

In a general aspect, the invention relates to a compound of formula (I-b):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

Where:

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;

each of X, Y and Z is independently selected from the group consisting of CH ₂ , O, NR _x and S(O) _q, where R _x represents hydrogen or alkyl;

R ₁ is hydrogen or alkyl;

R ₄ is hydrogen or alkyl;

R ₅ is hydrogen; And

q is 0, 1 or 2,

provided that ring B is not furanyl.

In one embodiment, the application relates to a compound of formula (I):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

Where:

ring B is an optionally substituted aryl or an optionally substituted heteroaryl;

ring C is aryl or heteroaryl;

ring D is aryl or heteroaryl;

each of X, Y and Z is independently selected from the group consisting of CH ₂ , O, NR _x and S(O) _q where R _x is hydrogen or alkyl;

R ₁ is hydrogen or alkyl;

each R ₂ is independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxyl, haloalkyl, alkoxy, alkylthio, amine, amide, alkylamine, aminoalkyl, cyano, hydroxyalkyl, -(CH ₂ ) _p C(O)OR ₆ , and -(CH ₂ ) _p OC(O)R ₆ ;

each R ₃ is independently selected from the group consisting of hydrogen, alkyl and halogen;

R ₄ is hydrogen or alkyl;

R ₅ is hydrogen;

each R ₆ is independently selected from the group consisting of hydrogen and alkyl, where alkyl is unsubstituted or substituted by 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; And

q is 0, 1 or 2,

provided that ring B is not furanyl.

In one embodiment, the application relates to a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring C is phenyl.

In one embodiment, the application relates to a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring D is pyridnyl or phenyl.

In one embodiment, the application relates to a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein ring D is:

.or

.

In one embodiment, the application relates to a compound of formula (I), or its tautomer, stereoisomer, pharmaceutically acceptable salt or solvate, where each of R ₁ , R ₄ and R ₅ represents hydrogen.

In one embodiment, the application relates to a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein X is S; Y is O; and Z is CH ₂ .

In one embodiment, the application relates to a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is a five- or six-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from N, S, and O, where the five- or six-membered monocyclic heteroaryl is optionally substituted with -CH ₃ .

In one embodiment, the application relates to a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein ring B is pyridinyl, thiophenyl, imidazolyl, pyrazolyl, or oxazolyl, where each of pyridinyl, thiophenyl, imidazolyl, pyrazolyl and oxazolyl is optionally substituted with -CH ₃ .

In one embodiment, the application relates to a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyridinyl.

In one embodiment, the application relates to 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):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

Where:

R ₁ is hydrogen, -CH ₃ , or -CH ₂ CH ₃ ;

R ₄ is hydrogen or -CH ₃ ;

R ₅ is hydrogen or -CH ₃ ;

R ₃ is hydrogen, -F, -Cl, or CH ₃ ;

X is S, SO, or SO ₂ ;

Y is O, NH, CH ₂ , or NHCH ₃ ;

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)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.

In one embodiment, the application relates to a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is thiophenyl.

In one embodiment, the application relates to a compound of formula (IV):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

Where:

each of R ₁ , R ₄ and R ₅ represents 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, -OCH3, or -OH; And

n is 0 or 1.

In one embodiment, the 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):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

Where:

R ₁ is hydrogen, -CH ₃ or -CH ₂ CH ₃ ;

R ₄ is hydrogen or -CH ₃ ;

R ₅ is hydrogen or -CH ₃ ;

R ₃ is hydrogen, -F, -Cl or CH ₃ ;

X is S, SO or SO ₂ ;

Y represents O, NH, CH ₂ or NHCH ₃ ;

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)NH ₂ , -C(O) NHCH ₃ , -OCH3, -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , or -CH ₂ CH(CH ₃ ) ₂ ; And

n is 0 or 1.

In one embodiment, the application relates to a compound selected from the group consisting of a compound of formula (VII-a) and a compound of formula (VII-b):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

Where:

each of R ₁ , R ₃ , R ₄ , and R ₅ is hydrogen;

X is S;

Y is O;

ring D is phenyl or pyridinyl;

R ₂ is -CH ₃ , -C(O)NH ₂ , -CH ₂ OH, -OCH ₃ , or -OH; And

n is 0 or 1.

In one embodiment, the application relates to a compound of formula (I-a):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

Where:

ring B is pyridinyl;

Q is CH or N;

R ₁ is hydrogen, -CH ₃ , or -CH ₂ CH ₃ ;

R ₄ is hydrogen or -CH ₃ ;

R ₅ is hydrogen or -CH ₃ ;

R ₂ is selected from the group consisting of -CH ₃ , -C(O)NH ₂ , -CH ₂ OH, -OCH3, or -OH;

X is S; And

Y is O.

In one embodiment, the application relates to a compound selected from the group consisting of the compounds listed in Table 1, or its tautomer, stereoisomer, pharmaceutically acceptable salt or solvate.

In one embodiment, the application relates to a compound selected from the group consisting of the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

In another general aspect, the application relates to a pharmaceutical composition containing a compound according to the application, as described herein, or its tautomer, stereoisomer, pharmaceutically acceptable salt or solvate, and at least one pharmaceutically acceptable carrier.

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

In one embodiment, the application relates to a method for inhibiting macrophage elastase (MMP-12) in a subject in need thereof, comprising administering to the subject a compound or pharmaceutical composition of the application.

In one embodiment, the 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 application.

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.

Also provided herein is a compound of the invention, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate or composition thereof, for use in a method for 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, non-alcoholic steatohepatitis (NASH), arthritis , cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.

Also contemplated herein is the use of a compound of the invention, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate or composition thereof, in the manufacture of a medicament for the inhibition of macrophage elastase (MMP-12) or the treatment of 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, non-alcoholic steatohepatitis (NASH), arthritis, cancer , heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome and nephritis.

In another general aspect, the application relates to a method for preparing a pharmaceutical composition according to the application, including combining the compound according to the application, or its tautomer, stereoisomer, pharmaceutically acceptable salt or solvate, and at least one pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE FIGURES

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

On the figures:

In FIG. 1A-1H show the results of a study of the efficacy of MMP-12 inhibitors in the SD rat kidney fibrosis model by unilateral ureteral occlusion (UUO) described in Example 3; in fig. 1A shows changes in serum urea nitrogen levels at 2 weeks compared to pre-op (pre-op) for each of the experimental groups of SD rats; in fig. 1B shows changes in serum creatine at 2 weeks compared to pre-op (pre-op) for each of the experimental groups of SD rats; in fig. 1C shows images of kidneys after H&E staining at x200 magnification; panel A: right kidney as normal control, panel B: animals treated with vehicle, panel C: animals treated with PC-16 (2 mg/kg/day), panel D: animals treated with PC-16 (6 mg/kg /day), panel E: animals treated with PC-16 (20 mg/kg/day); in fig. 1D shows the assessment of renal tubular injury (I) and the assessment of interstitial inflammation of the kidneys (II) for each of the experimental groups of SD rats; T-test in (I): ***p<0.05 vs. benchmark, $p<0.05 vs. PC-16 (2 mg/kg/day), $$p<0.01 vs. PC-16 (6 mg/kg/day); T-test in (II): **p<0.05 vs. benchmark, ***p<0.001 vs. standard, in Fig. 1E shows histological images of the kidneys after staining with Masson's trichrome at x200 magnification; panels A-E correspond to panels A-E as described in FIG. 1C; in fig. 1F shows the interstitial fibrosis score for renal interstitial fibrosis in the cortex; T-test: **p<0.01 vs. benchmark, ***p<0.001 vs. benchmark, $p<0.05 vs. PC-16 (2 mg/kg/day), $$p<0.01 vs. PC-16 (2 mg/kg/day); in fig. 1G shows collagen I (I) deposition and collagen IV (II) deposition in the cortical region of the left kidney by IHC staining at x200 magnification; panels A-E correspond to panels A-E as described in FIG. 1C; in fig. 1H shows positive staining of collagen I deposition (%) (I) and positive staining of collagen IV deposition (%) (II) in the region of the cortex of the left kidney, as determined by IHC staining in FIG. 1G; one-way analysis of variance: ***p<0.001 vs. normal control; T-test: #p<0.05 vs. reference.

Detailed description of the invention

Various publications, articles and patents are cited or described in the prior art and throughout the description; each of these references is incorporated herein by reference in its entirety. The discussion of documents, acts, materials, devices, articles or the like, which is included in the present description, is intended to provide context for the present invention. Such discussion is not an admission that any or all of these subjects form part of the prior art with respect to any disclosed or claimed inventions.

Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as generally understood by a person skilled in the art to which this invention pertains. Otherwise, some terms used in this document have the meanings specified in the description. All patents, published patent applications, and publications referenced herein are incorporated by reference as if they were set forth in their entirety herein.

It should be noted that the singular forms used in the description and in the appended claims include the plural unless the context clearly dictates otherwise.

Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood as referring to each element in the series. Those skilled in the art will understand, 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 within the scope of the present invention.

Throughout the present description and the following claims, unless the context otherwise requires, the word “comprise” and variations such as “comprises” and “comprising” will be understood to mean the inclusion of the specified integer or step or group of integers or steps, but not the exclusion of any other integer or stage or group of integers or stages. As used herein, the term "comprising" may be replaced by the term "comprising" or "including", and sometimes when used herein, the term "having".

As used herein, "consisting of" excludes any element, step, or ingredient not listed in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the essential and novel features of the claims. Any of the aforementioned terms "comprising", "consisting of", "including" and "having", whenever used herein in the context of an aspect or embodiment of an application, may be replaced by the term "consisting of" or "consisting of on the merits" to change the scope of the disclosure.

When used in the present description, the allied term "and/or" between several of the listed elements is understood to cover both individual and combined options. For example, when two elements are connected by "and/or", the first option refers to the possibility of using the first element without the second. The second option refers to the possibility of using the second element without the first. The third option refers to the possibility of using the first and second element together. Any of these options is intended to be within the scope of the meaning of this term and therefore meet the requirement of the term "and/or" as used herein. It is understood that the possibility of using several options simultaneously is also included in the scope of the meaning of this term and, therefore, meets the requirement of the term "and/or".

Unless otherwise indicated, any numerical value, such as concentration or concentration range, described herein, should be understood as being modified in all cases by the term "about". Thus, the numerical value typically includes ±10% of the quoted value. For example, including "10x" includes 9x and 11x. As used herein, the use of a numeric range explicitly includes all possible subranges, all individual numeric values within that range, including integers within such ranges, and fractions of values, unless the context clearly indicates otherwise.

As used herein, "subject" means any animal, preferably a mammal, most preferably a human, to be or has been treated with a method in accordance with an embodiment of the application. The term "mammal" as used herein includes any mammal. Examples mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHP) such as monkeys or great apes, humans, etc. more preferably person.

The phrase "pharmaceutically acceptable salt(s)", as used herein, refers to those salts of a compound of interest that are safe and effective for topical use in mammals and that have the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in these compounds. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, isonicotinate, carbonate, bicarbonate, acetate, lactate, salicylate, citrate, tartrate, propionate, butyrate salts. , pyruvate, oxalate, malonate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1 ,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Some of the compounds used in the present invention may form pharmaceutically 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 pharmaceutically acceptable salts, see Berge et al., 66 J. Pharm. sci. 1-19 (1977), incorporated herein by reference.

As used herein, the term "alkyl" means a saturated, monovalent, straight or branched hydrocarbon chain. The 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, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like. The alkyl group may have a certain number of carbon atoms. When the numbers are in a subscript after the "C" symbol, the subscript specifies more specifically the number of carbon atoms that a particular alkyl can contain. For example, “C ₁ - C ₁₀ alkyl” or “C _1-10 alkyl” is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ alkyl groups. In addition, for example, "C ₁ -C ₆ alkyl" or "C _1-6 alkyl" means alkyl containing from one to six carbon atoms.

The term "alkoxy" as used herein refers to an -O-alkyl group, where alkyl is as defined above. The alkoxy group is attached to the parent molecule through an oxygen atom. The alkoxy group may have a certain number of carbon atoms. For example, "C ₁ - C ₁₀ alkoxy" or "C _1-10 alkoxy" are intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , and C ₁₀ alkoxy groups. In addition, for example, "C ₁ -C ₆ alkoxy" or "C _1-6 alkoxy" means 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, t-butoxy), pentyloxy (e.g., n-pentyloxy, isopentyloxy, neopentyloxy ) and so on. The alkoxy group may be unsubstituted or substituted with one or more suitable substituents. Similarly, "alkylthio" or "thioalkoxy" is an alkyl group as defined above attached via a sulfur bridge, eg -S-methyl, -S-ethyl, and the like. Representative examples of alkylthio include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , and the like.

As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine. Accordingly, the term "halo" means fluorine, chlorine, bromine and iodine.

"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.

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

The term "carboxy" refers to -COOH.

The term "cyano" refers to -CN.

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 are replaced by an alkyl group. For example, alkylamino includes methylamino (-NHCH ₃ ), dimethylamino (-N(CH ₃ ) ₂ ), -NHCH ₂ CH ₃ , and the like.

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, "C _1-4 aminoalkyl" is intended to include C ₁ , C ₂ , C ₃ , and C ₄ alkyl groups substituted with one or more amino groups. Typical 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 .

As used herein, "amide" refers to -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 .

The terms "hydroxylalkyl" and "hydroxyalkyl" are used interchangeably and refer to an alkyl group substituted with one or more hydroxyl groups. The alkyl may be a branched or straight chain aliphatic hydrocarbon. Examples of hydroxylalkyl include, but are not limited to, hydroxyl methyl (-CH ₂ OH), hydroxyl ethyl (-CH ₂ CH ₂ OH), and the like.

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

As used herein, the term "heteroaryl" includes stable monocyclic and polycyclic aromatic hydrocarbons that include at least one ring member that is a heteroatom such as sulfur, oxygen or nitrogen. The heteroaryl may be monocyclic or polycyclic, for example bicyclic or tricyclic. Each ring of a heteroaryl group containing a heteroatom may contain one or two oxygen 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 atom carbon. For bicyclic heteroaryl groups, the fused rings terminating the bicyclic group may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Heteroaryl groups that are polycyclic, eg bicyclic or tricyclic, must include at least one fully aromatic ring, but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached to any available nitrogen or carbon atom of any ring of the heteroaryl group. Preferably, the term "heteroaryl" refers to 5- or 6-membered monocyclic groups and 9- or 10-membered bicyclic groups that have at least one heteroatom (O, S or N) in at least one of the rings, where the heteroatom The -containing ring preferably has 1, 2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms, selected from O, S and/or N. The heteroaryl group may be unsubstituted or substituted with one or more suitable substituents. The heteroaryl nitrogen heteroatom(s) may be substituted or unsubstituted. The heteroaryl nitrogen and sulfur heteroatom(s) may optionally be oxidized (ie, N→O and S(O) _r , where r is 0, 1, or 2).

Examples of 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. Examples of 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.

According to the convention used in the art:

used in structural formulas herein to represent a bond that is the point of attachment of a moiety or substituent to a core or backbone structure.

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

As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that all normal valences are retained and that the substitution results in a stable compound. When a particular group is "substituted", that group may have one or more substituents, preferably one to five substituents, more preferably one to three substituents, most preferably one to two substituents, independently selected from a list of substituents. The term "independently" when used with respect to substituents means that, when more than one of such substituents is possible, such substituents may be the same or different from each other. Examples of suitable substituents include, but are not limited to, alkyl, halogen, alkoxy, amide, alkithio, amine, alkylamine, aminoalkyl, hydroxyalkyl, hydroxyl, carboxyl, and the like, such as C _1-4 alkyl, C _1-3 alkoxy , -OH, -COOH, -F, -Cl, -C(O)NHCH ₃ , -C(O)N(CH ₃ ) ₂ .

If any variable occurs more than once in any component or compound formula, its definition in each case is independent of its definition in every other case. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may optionally be substituted with up to three R groups, and in each case R is selected independently from the definition of R.

The terms "optional" or "optional" mean that the event or circumstance described subsequently may, but need not, occur, and such description includes the situation in which the event or circumstance occurs or does not occur. For example, "optionally substituted aryl" means that a substituent group may be present, but need not be, and such description includes the situation where the aryl group is substituted with a suitable substituent and the aryl group is not substituted with any substituent.

One skilled in the art will appreciate that, in some embodiments, the compounds of the application may have one or more asymmetric carbon atoms in their structure. As used herein, any chemical formulas with bonds shown as solid lines only, rather than solid wedge or shaded wedge bonds, or otherwise indicated as having a specific configuration (e.g., R or S) around one or more atoms, consider every possible a stereoisomer, or a mixture of two or more stereoisomers. In other words, if the stereochemistry of a structure is not defined, the structure is assumed to encompass all individual stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Enantiomers are stereoisomers that are not superimposed 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 equivalent stereocenters and are not mirror images of each other. Substituent groups (eg, alkyl, heterocyclyl, and the like) may contain stereocenters in the R or S configuration.

Thus, pure stereochemically isomeric forms of the compounds of the invention (ie, single enantiomer or single diastereomer) as well as mixtures thereof, including their racemates, are included within the scope of the invention. When a particular stereoisomer is identified, it means that the stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particular less than 2% and most preferably less than 1% of other stereoisomers. For example, when a compound is, for example, listed as (R), this means that the compound essentially does not contain the (S) isomer. 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.

Pure stereochemically isomeric forms can be obtained by methods known in the art in view of the present disclosure. For example, diastereoisomers can be separated by physical separation methods such as fractional crystallization and chromatographic methods, 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 obtained synthetically from suitable stereochemically pure starting materials or by stereoselective reactions.

The compounds of the application may also form tautomers. The term "tautomer" refers to compounds that are interchangeable forms of a particular compound structure and that differ in the displacement of hydrogen atoms and electrons. Tautomers are structural isomers of chemical compounds that are easily converted into each other, which usually results in the displacement of a proton (hydrogen). Thus, the two structures can be in equilibrium due to the movement of pi electrons and an atom (usually hydrogen). All tautomeric forms and mixtures of tautomers of the compounds of the application are included within the scope of the application.

Compounds according to the application may exist in solvated and unsolvated forms. The term "solvate" means the physical association, for example, by hydrogen bonding, compounds according to the application with one or more solvent molecules. The solvent molecules in the solvate may be in a regular arrangement and/or a random arrangement. The solvate may contain a stoichiometric or non-stoichiometric amount of solvent molecules. "Solvate" includes solvates in solution phase and recoverable solvates. Compounds according to the application can form solvates with water (ie hydrates) or common organic solvents. Examples of solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are widely known in the art.

The scope of the application also includes all isotopes of atoms occurring in the compounds of the application. Isotopes include atoms having the same atomic number but different mass numbers. As a 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 invention can generally be prepared by conventional methods known to those skilled in the art, or by methods analogous to those described herein, using an appropriate isotopically labeled reagent instead of an unlabeled reagent. used in some other way.

As used herein, the name of a compound is intended to encompass all possible isomeric forms (eg, optical isomer, enantiomer, diastereomer, racemate, or racemic mixture), tautomers, and pharmaceutically acceptable salts of the compound.

Connections

In a general aspect, the invention relates to a compound of formula (I-b):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

Where:

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;

each of X, Y and Z is independently selected from the group consisting of CH ₂ , O, NR _x and S(O) _q, where R _x represents hydrogen or alkyl;

R ₁ is hydrogen or alkyl;

R ₄ is hydrogen or alkyl;

R ₅ is hydrogen; And

q is 0, 1 or 2,

provided that ring B is not furanyl.

In one embodiment, a compound of formula (I) is provided:

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

Where:

ring B is an optionally substituted aryl or an optionally substituted heteroaryl;

ring C is aryl or heteroaryl;

ring D is aryl or heteroaryl;

each of X, Y and Z is independently selected from the group consisting of O, CH ₂ , NR _x and S(O) _q where R _x is hydrogen or alkyl;

R ₁ is hydrogen or alkyl;

each R ₂ is independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxyl, haloalkyl, alkoxy, alkylthio, amino, amide, alkylamino, aminoalkyl, cyano, hydroxyalkyl, -(CH ₂ ) _p C(O)OR ₆ , and -(CH ₂ ) _p OC(O)R ₆ ;

each R ₃ is independently selected from the group consisting of hydrogen, alkyl and halogen;

R ₄ is hydrogen or alkyl;

R ₅ is hydrogen;

each R ₆ is independently selected from the group consisting of hydrogen and alkyl, where alkyl is unsubstituted or substituted by one or more groups independently selected from the group consisting of amino, 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; And

q is 0, 1, or 2.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring C is an optionally substituted aryl, preferably an optionally substituted phenyl.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring C is an optionally substituted heteroaryl, preferably an optionally substituted pyridinyl.

In one embodiment, there is provided a compound of formula (I) or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and R ₃ is independently hydrogen, alkyl or halogen, preferably hydrogen, -CH ₃ , -F, or -Cl, more preferably h.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring C is phenyl, m is 1, and R ₃ is hydrogen.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring C is phenyl, m is 1, and R ₃ is fluorine.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring C is phenyl, m is 1, and R ₃ is methyl.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring D is an optionally substituted aryl, preferably an optionally substituted phenyl.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring D is an optionally substituted heteroaryl.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring D is optionally substituted with 1, 2, 3, 4 or 5 substituent groups, preferably 1 or 2 substituent groups independently selected from the group , consisting of alkyl, halogen, haloalkyl, alkoxy, alkylthio, amino, amide, alkylamino, aminoalkyl, cyano, hydroxyalkyl, -(CH ₂ ) _p C(O)OR ₆ and -(CH ₂ ) _p OC(O)R ₆ where p is 0, 1, 2, 3, 4, or 5. A substituent group, if present, may be attached at any position on ring D. Preferably, ring D is substituted with one substituent group.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring D is a monocyclic aryl or monocyclic heteroaryl group substituted with one meta substituent, preferably phenyl or pyridinyl substituted at meta. position, with respect to the bond to variable Z. Particularly preferred substituent groups for ring D include methyl (-CH ₃ ), amide (-C(O)NH ₂ ), methoxy (-OCH3), hydroxyl (-OH), and hydroxylmethyl ( _-CH2OH ).

In a particular embodiment, ring D is phenyl.

In another specific embodiment, ring D is pyridinyl.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R ₂ is C _1-3 alkoxy (e.g., -OCH3, -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ ), C _1-4 alkyl (for example, -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 . Preferably R ₂ is -CH ₃ , -C(O)NH ₂ , -CH ₂ OH, -OCH ₃ or OH.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring D is:

.or

.

In embodiments of the application, the chiral carbon atom of the hydantoin moiety may be unsubstituted (ie, R ₁ is hydrogen) or substituted. In the case of substitution, R ₁ is preferably alkyl. Preferred alkyl groups for substitution of the chiral carbon atom of the hydantoin moiety include C _1-2 alkyl groups such as methyl and ethyl.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, -CH ₃ or -CH ₂ CH ₃ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen.

It is also possible to replace the nitrogen atoms of the hydantoin fragment. According to embodiments of the application, each of R ₄ and R ₅ independently represents hydrogen or alkyl. Preferred alkyl groups include methyl.

In one embodiment, a compound of formula (I) or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof is provided, wherein R ₄ is hydrogen or -CH ₃ and R ₅ is -CH ₃ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein R ₄ and R ₅ are each hydrogen.

According to embodiments of the application, each of X, Y, and Z is independently selected from the group consisting of O, NR _x , CH ₂ , and S(O) _q , where q is 0, 1 or 2 and R _x is hydrogen or alkyl. Thus, each of the linker units X, Y and Z is independently selected from O, S, S(O), SO ₂ , NH, N-alkyl and CH ₂ . Preferably, X, Y, and Z are each independently selected from S, S(O), S(O) ₂ , CH ₂ , and O, more preferably S, CH ₂ , and O.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein X is O, Y is O, and Z is CH ₂ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein X is S, Y is S, and Z is CH ₂ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein X is O, Y is S, and Z is CH ₂ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein X is S, Y is O, and Z is CH ₂ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein Z is O, Y is CH ₂ , and X is S.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein Z is S, Y is CH ₂ , and X is O.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein X is S(O), Y is O, and Z is CH ₂ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein X is S(O) ₂ , Y is O, and Z is CH ₂ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein X is S, Y is NH, and Z is CH ₂ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein X is S, Y is N(CH ₃ ), and Z is CH ₂ .

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

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

In another preferred embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein Z is CH ₂ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is an optionally substituted aryl such as phenyl.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically 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 particular embodiments, Ring B is a 5-membered heteroaryl ring such as imidazolyl, thiophenyl, oxazolyl or pyrazolyl. In other specific embodiments, Ring B is a 6-membered heteroaryl such as pyridinyl or pyridinyl N-oxide. Any positional or regioisomer of the heteroaryl ring may be used, meaning that the hydantoin moiety and linker X may be linked to a heteroaryl at any substitutable carbon atom on the heteroaryl ring. For example, when ring B is a 5-membered heteroaryl ring containing 1 heteroatom, the hydantoin moiety and the X linker can be linked to the 5-membered heteroaryl ring in substitution pattern 2, 3, in substitution pattern 2, 4, in substitution pattern 2, 5, in substitution scheme 3, 4, etc., relative to the heteroatom. As another illustrative example, when ring B is a 6-membered heteroaryl ring containing one heteroatom, the hydantoin moiety and linker X can be linked to the 6-membered heteroaryl ring in substitution pattern 2, 3, in substitution pattern 2, 4, in substitution scheme 2, 5, substitution scheme 2, 6, substitution scheme 3, 4, etc., relative to the heteroatom.

In some embodiments, a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, is provided, wherein Ring B is substituted. Ring B may be substituted on any substituted carbon atom of the aryl or heteroaryl ring, or on any substituted heteroatom, eg nitrogen, of the heteroaryl ring. For example, ring B may be substituted with an alkyl group, eg, methyl, including substitution with a methyl group, eg, at the nitrogen atom of a heteroaryl ring, eg, imidazolyl or pyrazolyl.

In some embodiments, a compound of formula (I) or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof is provided, wherein Ring B is pyridinyl, pyrazolyl, or imidazolyl, wherein pyridinyl, pyrazolyl, or imidazolyl is each optionally substituted with -CH ₃ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein Ring B is pyridinyl optionally substituted with -CH ₃ .

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyridinyl N-oxide.

In some embodiments, where ring B is pyridinyl, a compound of formula (II) is provided:

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has the meanings as defined above for the compounds of formula (I).

In certain embodiments, provided is a compound of formula (II), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein:

ring C is phenyl or pyridinyl;

R ₁ is hydrogen, -CH ₃ or -CH ₂ CH ₃ ;

R ₄ is hydrogen or -CH ₃ ;

R ₅ is hydrogen or -CH ₃ ;

X is S, S(O), or SO ₂ ;

R ₃ is hydrogen, -CH ₃ , -F, or -Cl;

Y is O, NH, CH ₂ , or -NH ₃ ;

Z is CH ₂ ;

ring D is phenyl or pyridinyl; And

R ₂ is 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 ;

m is 1; And

n is 1.

In specific embodiments, a compound of formula (II-a), (II-b), (II-c), or (II-d) is provided:

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein each of the variables is as defined above for a compound of formula (I) or formula (II).

In certain embodiments, provided is a compound of formula of formula (II-a), (II-b), (II-c) or (II-d), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein:

R ₁ is hydrogen, -CH ₃ or -CH ₂ CH ₃ ;

R ₄ is hydrogen or -CH ₃ ;

R ₅ is hydrogen or -CH ₃ ;

X is S, S(O), or SO ₂ ;

R ₃ is hydrogen, -CH ₃ , -F, or -Cl;

Y is O, NH, CH ₂ , or -NH ₃ ;

Z is CH ₂ ;

ring D is phenyl or pyridinyl; And

R ₂ is 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.

In a preferred embodiment where ring B is pyridinyl, a compound of formula (II-b) or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof is provided.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is thiophenyl.

In some embodiments, where ring B is thiophenyl, a compound of formula (IV) is provided:

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has the meanings as defined above for the compounds of formula (I).

In certain embodiments, provided is a compound of formula (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein:

each of R ₁ , R ₄ , and R ₅ is hydrogen;

X is S;

Y is O;

Z is CH ₂ ;

R ₃ is hydrogen;

ring D is phenyl or pyridinyl; And

R ₂ is -CH ₃ , -C(O)NH ₂ , -CH ₂ OH, -OCH3, or -OH; And

n is 1.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is imidazolyl.

In some embodiments where ring B is imidazolyl, a compound of formula (Va) or (Vb) is provided:

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has the meanings as defined above for the compounds of formula (I).

In certain embodiments, provided is a compound of formula (V), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein:

each of R ₁ , R ₄ , and R ₅ is hydrogen;

X is S;

Y is O;

Z is CH ₂ ;

R ₃ is hydrogen;

ring D is phenyl or pyridinyl; And

R ₂ is -CH ₃ , -C(O)NH ₂ , -CH ₂ OH, -OCH3, or -OH; And

n is 1.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyrazolyl.

In some embodiments, where ring B is pyrazolyl, a compound of formula (VI) is provided:

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has the meanings as defined above for the compounds of formula (I).

In certain embodiments, provided is a compound of formula (VI), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein:

each of R ₁ , R ₄ , and R ₅ is hydrogen;

X is S;

Y is O;

Z is CH ₂ ;

R ₃ is hydrogen;

ring D is phenyl or pyridinyl; And

R ₂ is -CH ₃ , -C(O)NH ₂ , -CH ₂ OH, -OCH3, or -OH; And

n is 1.

In one embodiment, there is provided a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein Ring B is oxazolyl.

In some embodiments, where ring B is oxazolyl, a compound of formula (VII) is provided:

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has the meanings as defined above for the compounds of formula (I).

In certain embodiments, provided is a compound of formula (VII), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein:

each of R ₁ , R ₄ , and R ₅ is hydrogen;

X is S;

Y is O;

Z is CH ₂ ;

R ₃ is hydrogen;

ring D is phenyl or pyridinyl; And

R ₂ is -CH ₃ , -C(O)NH ₂ , -CH ₂ OH, -OCH3 or -OH; And

n is 1.

In particular embodiments where ring B is oxazolyl, a compound of formula (VII-a) or a compound of formula (VII-b) is provided:

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has the meanings as defined above for the compounds of formula (I) or formula (VII).

Compounds of particular interest include compounds of formula (I-a):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where Q is CH or N and the remaining variable groups are as defined above for the compound of formula (I).

In one embodiment, there is provided a compound of formula (I-a), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein Q is CH.

In one embodiment, there is provided a compound of formula (I-a), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein Q is N.

In one embodiment, a compound of formula (Ia) or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof is provided, wherein _R2 is alkyl, halo, haloalkyl, alkoxy, alkylthio, amino, amide, alkylamino, aminoalkyl, cyano, hydroxyalkyl, - (CH ₂ ) _p C(O)OR ₆ and -(CH ₂ ) _p OC(O)R ₆ where p is 0, 1, 2, 3, 4, or 5.

In one embodiment, there is provided a compound of formula (Ia), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein R ₂ is 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 . Preferably R ₂ is -CH ₃ , -C(O)NH ₂ , -CH ₂ OH, -OCH ₃ or -OH.

In one embodiment, a compound of formula (Ia) or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof is provided, wherein R ₁ is hydrogen, -CH ₃ , or -CH ₂ CH ₃ . Preferably R ₁ is hydrogen.

In one embodiment, a compound of formula (Ia) or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof is provided, wherein R ₄ is hydrogen.

In one embodiment, a compound of formula (Ia) or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof is provided, wherein R ₅ is hydrogen or —CH ₃ .

In one embodiment, a compound of formula (Ia) or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof is provided, wherein R ₁ , R ₄ , and R ₅ are each hydrogen.

In one embodiment, a compound of formula (Ia) or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof is provided, wherein X is S, S(O), or SO ₂ .

In one embodiment, a compound of formula (Ia) or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof is provided, wherein Y is O, NH, CH ₂ , or N(CH ₃ ).

In one embodiment, there is provided a compound of formula (I-a), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein X is S and Y is O.

In one embodiment, there is provided a compound of formula (I-a), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyridinyl.

In one embodiment, there is provided a compound of formula (I-a), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is thiophenyl.

In one embodiment, there is provided a compound of formula (I-a), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is phenyl.

In one embodiment, there is provided a compound of formula (I-a), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyrazolyl.

In one embodiment, there is provided a compound of formula (I-a), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is imidazolyl.

In one embodiment, there is provided a compound of formula (I-a), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ring B is oxazolyl.

In one embodiment, there is provided a compound of formula (I-a), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein:

ring B is pyridinyl;

Q is CH or N;

each of R ₁ , R ₄ and R ₅ represents hydrogen;

R ₂ is selected from the group consisting of alkyl, amide, hydroxyl, alkoxy and hydroxyalkyl;

X is S; And

Y is O.

Exemplary compounds of the application include, but are not limited to, the compounds listed in Table 1 below and any tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof. The IC ₅₀ values of MMP-12 were determined according to the analysis described in Example 1 below. IC ₅₀ values are presented as follows: A=less than 10 nM, B=10 nM-100 nM, C=100 nM-1000 nM, D=greater than 1000 nM.

Table 1: Compound examples of the application Connection ID Structure Analytical data (LCMS, NMR, etc.) MMP-12
IC ₅₀ (nM) TC1

¹ H-NMR (300 MHz CDCl ₃ ) δ: 7.437 (d, J=5.1 Hz, 1H), 7.304-7.226 (m, 3H), 6.953-6.834 (m, 6H), 5.755 (s, 1H) , 5.033 (s, 2H), 3.923 (t, J=6.5 Hz, 2H), 1.758 (tq, J=7.8 Hz, 2H), 1.036 (t, J=7.4 Hz, 3H); m/z (ESI+) 453.22 (M-); HPLC tR: 8.033 min. C TC2

¹ H-NMR (300 MHz CDCl ₃ ) δ: 7.431 (d, J=5.4 Hz, 2H), 7.301-7.223 (m, 3H), 6.973-6.915 (m, 4H), 6.858-6.826 (m, 2H) 5.751 (s, 1H), 5.026 (s, 2H), 4.020 (kv, J=7.2 Hz, 2H), 1.371 (t, J=7.2 Hz, 3H); m/z (ESI+) 439.16 (M-); HPLC tR: 6.066 min. C TC3

¹ H-NMR (300 MHz DMSO) δ: 7.435 (d, J=5.4 Hz, 1H), 7.306-7.248 (m, 3H), 6.964-6.851 (m, 6H), 5.752 (s, 1H), 5.032 (s, 2H), 4.586 (sqv, J=6.0 Hz, 1H), 1.29 (d, J=6.0 Hz, 6H); m/z (ESI+) 453.22 (M-); HPLC tR: 6.725 min. C TC4

¹ H-NMR (300 MHz DMSO) δ: 8.529 (br s, 1H), 7.574 (d, J=5.1 Hz, 1H), 7.366-7.256 (m, 6H), 6.976 (d, J=8 .7 Hz, 2H) 6.860 (d, J=5.1 Hz, H), 5.647 (s, 1H), 5.225-5.188 (m, 1H), 5.188-5.057 (m, 2H), 4.482 (d, J =5.7 Hz, 2H); m/z (ESI+) 449.43 (M+Na)+; HPLC tR: 3.917 min. A TC5

¹ H-NMR (300 MHz DMSO) δ: 8.547 (br s, 1H), 7.595 (d, J=5.1 Hz, 1H), 7.474-7.260 (m, 6H), 7.010-6.988 (m, 2H ), 6.888 (d, J=5.1 Hz, 1H), 5.556 (s, 1H), 5.198-5.130 (m, 2H), 4.585 (d, J=5.1 Hz, 2H); m/z (ESI+) 449.16 (M+Na)+; HPLC tR: 3.436 min. A TC6

¹ H-NMR (300 MHz DMSO) δ: 10.942 (br s, 1H), 8.545 (s, 1H), 7.88 (d, J=5.4 Hz, 1H), 7.392-7.267 (m, 6H ), 6.981 (d, J=8.7 Hz, 2H) 6.871 (d, J=5.4 Hz, H), 5.663 (s, J=1.2 Hz, 1H), 5.118 (t, J=5 .7 Hz, 1H), 5.065 (s, 2H), 4.486 (d, J=6 Hz, 2H); m/z (ESI+) 449.17 (M+Na)+; HPLC tR: 6.435 min. A TC7

¹ H-NMR (300 MHz CDCl ₃ ) δ: 7.418 (d, J=5.4 Hz, 1H), 7.289-7.261 (m, 2H), 7.185-7.133 (m, 1H), 6.924-6.839 (m, 5H), 6.731-6.701 (m, 1H), 5.743 (s, 1H), 4.988 (s, 2H); m/z (ESI+) 412.00 (M+-); HPLC tR: 6.586 min. A TC8

¹ H-NMR (300 MHz CDCl ₃ ) δ: 10.935 (s, 1H), 8.532 (s, 1H), 8.403 (d, J=5.4 Hz, 1H) 7.576 (d, J=5.4 Hz, 1H), 7.286-7.178 (m, 4H), 6.973 (d, J=8.7 Hz, 2H), 6.861 (d, J=5.4 Hz, 1H), 5.698 (s, 1H), 5.298 (s , 2H), 2.482-2.443 (m, 3H); m/z (ESI+) 412.24 (M+Na)+; HPLC tR: 6.035 min. A PC-1

¹ H NMR (400 MHz, CD ₃ OD) δ 8.297 (d, J=5.2 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.385 (d, J=11, 2 Hz, 2H), 7.237 (dd, J=7.6, 9.6 Hz, 4H), 7.137 (d, J=6.8 Hz, 2H), 7.011 (d, J=9.2 Hz, 1H ), 5.66 (s, 2H), 4.872 (m, 2H), 2.347 (s, 3H); m/z (ESI+) (M+H)+ = 406.25; HPLC tR=7.213 min. B PC-2

¹ H NMR (400 MHz, CD ₃ OD) δ 8.672 (s, 1H), 8.396 (d, J=6.4 Hz, 1H), 7.563 (d, J=8.8 Hz, 2H), 7.281-7.148 (m, 7H), 5.809 (s, 2H), 5.145 (s, 2H), 2.358 (s, 3H); m/z (ESI+) (M+H)+ = 406.15; HPLC tR=6.254 min. B PC-3

¹ H NMR (400 MHz, CD ₃ OD) δ 8.366 (dd, J=0.8, 1.6 Hz, 1H), 7.475 (d, J=9.2 Hz, 1H), 7.447 (d, J= 8.8 Hz, 2H), 7.279-7.218 (m, 4H), 7.143 (s, 1H), 7.052 (d, J=9.2 Hz, 2H), 5.849 (s, 2H), 5.115 (s, 2H ), 2.345 (s, 3H); m/z (ESI+) (M+H)+ = 406.15; HPLC tR=7.317 min. B PC-4

¹ H NMR (400 MHz, CD ₃ OD) δ 7.431 (d, J=8.8 Hz, 3H), 7.247-7.215 (m, 4H), 7.137 (d, J=8.0 Hz, 2H), 7.040 (d, J=8.8 Hz, 2H), 5.792 (s, 2H), 4.824 (s, 2H), 2.343 (s, 3H); m/z (ESI+) (M+H)+ = 406.1; HPLC tR=6.553 min. B PC-5

¹ H NMR (400 MHz, CD ₃ OD) δ 8.818 (d, J=5.2 Hz, 1H), 8.654 (s, 1H), 7.989 (d, J=4.8 Hz, 1H), 7.782 (d , J=8.4 Hz, 2H), 7.260-7.120 (m, 6H), 5.789 (s, 1H), 5.155 (s, 2H), 2.331 (s, 3H); m/z (ESI+) (MH)- = 420; HPLC tR=6.378 min. C PC-6

¹ H NMR (400 MHz, CD ₃ OD) δ 8.785 (d, J=5.2 Hz, 1H), 8.690 (s, 1H), 7.955 (dd, J=8.8, 5.2 Hz, 3H) , 7.248 (s, 2H), 7.213 (d, J=2.8 Hz, 3H), 7.182 (s, 1H), 6.345 (s, 1H), 5.141(s, 2H), 2.335 (s, 3H); m/z (ESI+) (MH)- = 436.1; HPLC tR=6.544 min. C PC-7

¹ H NMR (400 MHz, CD ₃ OD) δ 8.33 (s, 1H), 8.19 (d, J=5.9 Hz, 1H), 7.49-7.41 (m, 4H), 7.37 (d, J=11.9 Hz, 2H), 7.12 (d, J=8.7 Hz, 2H), 6.76 (s, 1H), 5.57 (s, 1H), 5.14 (s, 2H), 4.61 (s, 2H); m/z (ESI+) (M+H)+ = 422.10; HPLC tR=5.271 min. B PC-8

¹ H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.37 (d, J=12.2 Hz, 2H), 8.28 (s, 1H), 7.52- 7.38 (m, 3H), 7.30 (d, J=17.6 Hz, 3H), 7.16 (d, J=7.1 Hz, 2H), 6.65 (s, 1H), 5.49 (s, 1H), 5.24 (s, 1H), 5.14 (s, 2H), 4.50 (s, 2H), 4.11 (s, 1H); m/z (ESI+) (M+H)+ = 422.15; HPLC tR=5.282 min. A PC-9

¹ H NMR (400 MHz, CD ₃ OD) δ 8.33 (s, 1H), 8.18 (s, 1H), 7.46 (d, J=6.3 Hz, 4H), 7.37- 7.27 (m, 2H), 7.15 (d, J=8.7 Hz, 2H), 6.78 (d, J=5.4 Hz, 1H), 5.57 (s, 1H), 5.24 (s, 2H), 4.73 (s, 2H); m/z (ESI+) (M+H)+ = 422.15; HPLC tR=5.383 min. B PC-10

¹ H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.36 (d, J=7.9 Hz, 2H), 8.27 (s, 1H), 7.43 ( d, J=8.8 Hz, 2H), 7.20-7.09 (m, 3H), 6.84 (d, J=11.9 Hz, 2H), 6.74-6.61 (m , 2H), 5.48 (s, 1H), 5.06 (s, 2H); m/z (ESI+) (M+H)+ = 408.10; HPLC tR=5.309 min. A PC-11

¹ H NMR (400 MHz, CD ₃ OD) δ 8.68 (s, 1H), 8.41 (s, 1H), 7.66-7.54 (m, 2H), 7.46 (d, J =18.1Hz, 2H), 7.25(d, J=9.0Hz, 2H), 5.81(s, 1H), 5.34(dd, J=29.1, 12.2Hz , 2H), 5.21 (s, 2H), 3.98 (s, 1H), 3.85 (s, 1H), 2.99 (s, 1H), 2.86 (s, 1H), 2 .29 (s, 1H), 2.03 (s, 1H), 1.29 (s, 3H), 1.03 (t, J=14.5 Hz, 3H), 0.90 (s, 1H) ; m/z (ESI+) (M+H)+ = 521.25; HPLC tR=5.165 min. B PC-12

¹ H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.46-8.34 (m, 2H), 8.27 (s, 1H), 7.50-7.19 (m, 7H), 7.04 (d, J=8.9 Hz, 2H), 5.66 (s, 1H), 5.20-5.10 (m, 3H), 4.57 (d, J=5.4 Hz, 2H); m/z (ESI+) (M+H)+ = 422.00; HPLC tR=5.591 min. A PC-13

¹ H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.46-8.36 (m, 2H), 8.27 (s, 1H), 7.38 (d, J = 8.8 Hz, 3H), 7.36-7.22 (m, 4H), 7.04 (d, J=8.9 Hz, 2H), 5.66 (s, 1H), 5.20 (d, J=5.7 Hz, 1H), 5.09 (s, 2H), 4.49 (d, J=5.8 Hz, 2H); m/z (ESI+) (M+H)+ = 422.05; HPLC tR=5.522 min. A PC-14

¹ H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.45-8.36 (m, 2H), 8.26 (s, 1H), 7.42-7.27 (m, 7H), 7.03 (d, J=8.8 Hz, 2H), 5.66 (s, 1H), 5.18 (t, J=5.7 Hz, 1H), 5.08 (s, 2H), 4.48 (d, J=5.7 Hz, 2H); m/z (ESI+) (M+H)+ = 422.05; HPLC tR=5.483 min. B PC-15

¹ H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.47-8.35 (m, 2H), 8.27 (s, 1H), 7.44-7.28 (m, 3H), 7.15 (t, J=7.7 Hz, 1H), 7.06-6.96 (m, 2H), 6.82 (d, J=8.0 Hz, 2H) , 6.73-6.65 (m, 1H), 5.67 (s, 1H), 5.02 (s, 2H); m/z (ESI+) (M+H)+ = 408.10; HPLC tR=5.607 min. A PC-16

¹ H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.41 (dd, J=22.7, 9.8 Hz, 1H), 8.27 (d, J=5 .4 Hz, 3H), 7.46 (d, J=8.7 Hz, 2H), 7.30 (s, 2H), 7.23 (d, J=4.8 Hz, 1H), 7, 15 (d, J=8.8 Hz, 1H), 6.65 (d, J=5.3 Hz, 1H), 5.74 (s, 1H), 5.49 (s, 2H), 2, 46 (s, 3H); m/z (ESI+) (MH)- = 407.15; HPLC tR=3.792 min. A PC-17

¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.82-8.30 (m, 5H), 8.21 (s, 1H), 7.51 (d, J =8.7 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 6.80 (d, J=5.7 Hz, 1H), 5.69 (s, 1H), 5.56 (s, 1H), 5.28 (s, 1H), 2.44 (s, 3H); m/z (ESI+) (MH)-=405.25; HPLC tR=4.332 min. C PC-18

¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (d, J=5.4 Hz, 3H), 8.25 (s, 1H), 7.42 (dd, J=17.8, 10 .4 Hz, 5H), 7.31 (d, J=5.4 Hz, 1H), 7.05 (d, J=8.6 Hz, 2H), 5.79 (s, 1H), 5, 49 (s, 1H), 5.17 (s, 2H), 2.54 (s, 4H); m/z (ESI+) (M+H)+ = 407.15; HPLC tR=5.028 min. A PC-19

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (dd, J=17.8, 12.6 Hz, 3H), 8.24 (s, 1H), 7.76 (s, 1H), 7.42 (t, J=7.4 Hz, 3H), 7.05 (d, J=8.8 Hz, 2H), 5.79 (s, 1H), 5.13 (s, 2H), 2.37 (d, J=6.4 Hz, 4H); m/z (ESI+) (M+H)+ = 407.15; HPLC tR=4.600 min. C PC-20

¹ H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.71 (d, J=4.5 Hz, 1H), 8.36 (dd, J=39.9, 8 .9 Hz, 3H), 8.10 (s, 1H), 7.67 (s, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.20 (d, J=8 .5 Hz, 3H), 6.72 (d, J=5.6 Hz, 1H), 5.52 (s, 1H), 5.34 (s, 2H); m/z (ESI+) (M+H)+ = 437.1; HPLC tR=4.332 min. D PC-21

¹ H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.97 (d, J=56.5 Hz, 2H), 8.60-8.26 (m, 4H), 7.51 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 6.81 (d, J=5.5 Hz, 1H), 5, 57 (s, 1H), 5.31 (s, 2H); m/z (ESI+) (M+H)+ = 437.1; HPLC tR=4.527 min. D PC-22

¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.64-8.11 (m, 3H), 7.47-6.98 (m, 7H), 6.63 (s, 1H), 5.07 (s, 2H), 2.28 (d, J=4.9 Hz, 3H), 2.26-2.18 (m, 2H), 0.92 (s, 3H); m/z (ESI+) (M+H)+ = 434.15; HPLC tR=5.750 min. A PC-23

¹ H NMR (400 MHz, DMSO-d6) δ 10.82 (d, J=0.8 Hz, 1H), 8.42 (dd, J=29.8, 4.6 Hz, 2H), 8, 21 (s, 1H), 8.00 (d, J=1.7 Hz, 1H), 7.88 (d, J=3.1 Hz, 1H), 7.67 (d, J=2.7 Hz, 1H), 7.51 (d, J=2.8 Hz, 1H), 7.17-6.91 (m, 4H), 6.62 (d, J=1.5 Hz, 1H), 5.33 (d, J=3.2 Hz, 1H), 5.17 (d, J=1.9 Hz, 2H); m/z (ESI+) (M+H)+ = 420.15; HPLC tR=6.453 min. D PC-24

¹ H NMR (400 MHz, CD ₃ OD) δ 9.100 (s, 1H), 8.858 (s, 1H), 8.535 (s, 1H), 8.429 (d, J=6.4 Hz, 1H), 8.256 (s , 1H), 7.498 (d, J=11.6 Hz, 3H), 7.133 (d, J=11.6 Hz, 2H), 5.835 (s, 1H), 5.237 (s, 3H); m/z (ESI+) (M+H)+ = 437.1; HPLC tR=4.778 min. D PC-25

¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.36 (d, J=5.8 Hz, 1H), 7.46 (s, 1H), 7.34 ( d, J=11.5 Hz, 3H), 7.06 (q, J=9.2 Hz, 4H), 6.71 (d, J=5.8 Hz, 1H), 5.40 (s, 1H), 5.11 (s, 2H), 4.62 (s, 2H); m/z (ESI+) (M+H)+ = 406.25; HPLC tR=5.024 min. B PC-26

¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.36 (d, J=5.8 Hz, 1H), 7.30-7.19 (m, 3H), 7.16-6.99 (m, 5H), 6.70 (d, J=5.8 Hz, 1H), 5.40 (s, 1H), 5.06 (s, 2H), 2.35 (s, 3H) ; m/z (ESI+) (M+H)+ = 390.2; HPLC tR=5.780 min. B PC-27

¹ H NMR (400 MHz, CD ₃ OD) δ 8.46 (s, 1H), 8.38 (dd, J=9.4, 5.5 Hz, 2H), 7.42-7.28 (m , 2H), 7.13-7.03 (m, 4H), 6.72 (d, J=5.8 Hz, 1H), 5.49 (s, 1H), 5.40 (s, 1H) , 5.16 (s, 2H), 2.54 (s, 3H); m/z (ESI+) (M+H)+ = 391.3; HPLC tR=3.846 min. B PC-28

¹ H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.37 (d, J=5.1 Hz, 2H), 8.28 (d, J=5.4 Hz, 1H), 7.98 (d, J=12.2 Hz, 1H), 7.84 (d, J=7.8 Hz, 2H), 7.61 (d, J=7.5 Hz, 1H) , 7.51-7.35 (m, 4H), 7.17 (d, J=8.6 Hz, 2H), 6.66 (d, J=5.3 Hz, 1H), 5.49 ( s, 1H), 5.20 (s, 2H); m/z (ESI+) (M+H)+ = 435.15; HPLC tR=4.567 min. A PC-29

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (s, 1H), 8.08 (d, J=5.5 Hz, 1H), 7.79 (s, 1H), 7.64 (d , J=7.7 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.39-7.34 (m, 4H), 6.96 (d, J=8, 5 Hz, 2H), 6.63 (d, J=5.5 Hz, 1H), 5.40 (s, 1H), 5.05 (s, 3H), 2.87 (s, 3H); m/z (ESI+) (M+H)+ = 449.2; HPLC tR=5.091 min. B PC-30

¹ H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.36 (d, J=4.7 Hz, 2H), 8.28 (d, J=5.3 Hz, 1H), 8.16 (d, J=5.3 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H) , 7.03 (d, J=5.1 Hz, 1H), 6.86 (s, 1H), 6.65 (d, J=5.5 Hz, 1H), 5.49 (s, 1H) , 5.19 (s, 2H), 3.84 (s, 3H); m/z (ESI+) (M+H)+ = 423.25; HPLC tR=5.057 min. B PC-31

¹ H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J=3.4 Hz, 2H), 8.28 (d, J=5.4 Hz, 1H), 8.14 (d, J=5.2Hz, 1H), 7.46(d, J=8.2Hz, 2H), 7.15(d, J=8.3Hz, 2H), 7.00(d, J= 5.3Hz, 1H), 6.82(s, 1H), 6.66(d, J=5.4Hz, 1H), 5.49(s, 1H), 5.18(s, 2H) , 4.29 (kv, J=7.0 Hz, 2H), 1.29 (dd, J=7.4, 6.7 Hz, 3H); m/z (ESI+) (M+H)+ = 437.2; HPLC tR=5.204 min. B PC-32

¹ H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J=4.1 Hz, 2H), 8.27 (d, J=5.4 Hz, 1H), 8.13 (d, J=5.3Hz, 1H), 7.46(d, J=8.6Hz, 2H), 7.15(d, J=8.6Hz, 2H), 6.98(d, J= 5.1 Hz, 1H), 6.77 (s, 1H), 6.66 (d, J=5.4 Hz, 1H), 5.49 (s, 1H), 5.23 (dt, J= 12.3, 6.1 Hz, 1H), 5.17 (s, 2H), 1.27 (d, J=6.2 Hz, 6H); m/z (ESI+) (M+H)+ = 451.25; HPLC tR=5.365 min. B PC-33

¹ H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.36 (s, 2H), 8.27 (d, J=5.4 Hz, 1H), 8.13 ( d, J=5.2 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.01 (d, J=5.1Hz, 1H), 6.85(s, 1H), 6.65(d, J=5.4Hz, 1H), 5.49(s, 1H), 5.18(s, 2H), 4.02 (d, J=6.7 Hz, 2H), 2.00 (dt, J=13.4, 6.7 Hz, 1H), 0.94 (d, J=6.7 Hz, 6H) ; m/z (ESI+) (M+H)+ = 465.25; HPLC tR=5.690 min. C PC-34

¹ H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.00 (d, J=1.9 Hz, 1H), 8.81 (d, J=1.8 Hz, 1H), 8.36 (s, 2H), 8.31-8.27 (m, 2H), 8.20 (s, 1H), 7.64 (s, 1H), 7.47 (d, J =8.7 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 6.66 (d, J=5.3 Hz, 1H), 5.49 (s, 1H), 5.26 (s, 2H); m/z (ESI+) (M+H)+ = 436.15; HPLC tR=4.312 min. B PC-35

¹ H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.37 (t, J=22.6 Hz, 3H), 7.47 (d, J=8.6 Hz, 2H), 7.37 (d, J=6.7 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 6.72 (d, J=5.3 Hz, 1H) , 6.36 (s, 1H), 6.19 (d, J=6.7 Hz, 1H), 5.52 (s, 1H), 5.04 (s, 2H); m/z (ESI+) (M+H)+ = 409; HPLC tR=4.665 min. C PC-36

¹ H NMR (400 MHz, CD3OD) δ 8.94 (d, J=2.1 Hz, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.35 (s, 2H) , 8.20 (d, J=5.5 Hz, 1H), 7.51 (s, 2H), 7.21 (s, 2H), 6.79 (d, J=5.5 Hz, 1H) , 5.58 (s, 1H), 5.28 (s, 2H), 2.95 (s, 3H); m/z (ESI+) (M+H)+ = 450.1; HPLC tR=4.221 min. C PC-37

¹ H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J=4.4 Hz, 2H), 8.28 (d, J=5.3 Hz, 1H), 7.97 (s, 1H), 7.89 (d, J=7.8 Hz, 2H), 7.52 (d, J=7.8 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H) , 7.36 (s, 1H), 7.16 (d, J=8.3 Hz, 2H), 6.65 (d, J=5.6 Hz, 1H), 5.49 (s, 1H) . 5.21 (s, 2H); m/z (ESI+) (M+H)+ = 435.1; HPLC tR=5.069 min. C PC-38

¹ H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.64 (d, J=5.3 Hz, 1H), 8.31 (s, 1H), 8.23 ( d, J=5.4 Hz, 1H), 8.16 (s, 1H), 7.67 (s, 1H), 7.58 (d, J=4.7 Hz, 1H), 7.45 ( d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 3H), 6.63 (d, J=5.1 Hz, 1H), 5.40 (s, 3H), 5.36 (s, 1H); m/z (ESI+) (M+H)+ = 436.10; HPLC tR=4.842 min. D PC-39

¹ H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.50 (s, 1H), 8.35-8.31 (m, 1H), 8.20-8.15 (m , 1H), 7.94 (s, 1H), 7.52-7.45 (m, 2H), 7.20-7.13 (m, 2H), 6.77 (d, J=5.5 Hz, 1H), 5.58-5.55(m, 1H), 5.25-5.20(m, 1H), 4.70-4.66(m, 2H), 4.53(s, 1H), 3.34-3.27 (m, 3H), m/z (ESI+) (M+H)+ = 423.20; HPLC tR=1.472 min. C PC-40

¹ H NMR (400 MHz, CD3OD) δ 8.45 (d, J=5.1 Hz, 1H), 8.33 (s, 1H), 8.18 (d, J=5.5 Hz, 1H) , 7.66 (s, 1H), 7.53-7.47 (m, 2H), 7.39 (d, J=4.5 Hz, 1H), 7.15 (d, J=8.9 Hz, 2H), 6.77 (d, J=5.5 Hz, 1H), 5.56 (s, 1H), 5.25 (s, 2H), 4.70 (s, 2H), m/ z(ESI+)(M+H)+ = 423.10; HPLC tR=4.305 min. A PC-41

¹ H NMR (400 MHz, CDCl3) δ 8.50 (d, J=5.1 Hz, 1H), 8.37 (s, 1H), 8.26 (d, J=5.4 Hz, 1H) , 7.45 (d, J=8.5 Hz, 2H), 7.22 (s, 1H), 7.16 (d, J=5.0 Hz, 1H), 7.02 (d, J= 8.4Hz, 2H), 6.69(d, J=5.4Hz, 1H), 6.48(s, 1H), 5.45(s, 1H), 5.08(s, 2H) , 3.11 (s, 3H), 2.58 (s, 3H), m/z (ESI+) (M+H)+ = 421.15; HPLC tR=4.384 min. C PC-42

¹ H NMR (400 MHz, CDCl3) δ 8.53 (d, J=5.2 Hz, 1H), 8.42 (s, 1H), 8.25 (d, J=5.6 Hz, 1H) , 7.47(m, 1H), 7.23(s, 1H), 7.16(m, 1H), 6.98(m, 1H), 6.69(m, 1H), 6.52( m, 1H), 6.11 (m, 1H), 5.54 (s, 1H), 5.08 (s, 2H), 2.60 (s, 3H), 2.28 (s, 3H) , m/z (ESI+) (M+H)+ = 421.10; HPLC tR=4.265 min. B PC-43

¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (s, 1H), 8.23 (d, J=5.5 Hz, 1H), 7.61-7.53 (m, 6H), 7.14 (t, J=7.9 Hz, 1H), 6.87 (d, J=5.5 Hz, 1H), 6.79 (dd, J=17.0, 9.6 Hz, 3H ), 5.61 (s, 1H), 5.12 (s, 2H), 2.30 (s, 3H), m/z (ESI+) (M+H)+ = 406.10; HPLC tR=5.862 min. D PC-44

¹ H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=5.1 Hz, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.47- 7.40 (m, 2H), 7.30 (s, 1H), 7.23 (dd, J=5.2, 1.6 Hz, 1H), 7.18-7.09 (m, 2H) , 6.53 (s, 1H), 5.44 (s, 1H), 5.19 (d, J=6.9 Hz, 2H), 2.46 (d, J=2.2 Hz, 2H) , 2.25 (d, J=2.2 Hz, 3H), m/z (ESI+) (M+H)+ = 407.15; HPLC tR=3.843 min. B PC-45

¹ H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=5.1 Hz, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.47- 7.42 (m, 2H), 7.30 (s, 1H), 7.23 (d, J=4.2 Hz, 1H), 7.18-7.11 (m, 2H), 6.53 (s, 1H), 5.44 (s, 1H), 5.19 (s, 2H), 2.46 (s, 3H), 2.25 (s, 3H), m/z (ESI+) (M +H)+ = 421.10; HPLC tR=3.941 min. B PC-46

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 8.52 (d, J=4.8 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H ), 7.45 (m, 2H), 7.22 (s, 1H), 7.16 (m, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.66 (d , J=5.6 Hz, 1H), 5.08 (s, 2H), 3.14 (s, 3H), 2.75 (s, 3H), 2.59 (s, 3H), 1.93 (s, 3H), m/z (ESI+) (M+H)+ = 449.15; HPLC tR=4.478 min. D PC-47

¹ H NMR (400 MHz, CD ₃ OD) δ 8.71 (m, 2H), 8.46-8.37 (m, 1H), 8.32 (s, 1H), 8.25 (s, 1H ), 7.47 (d, J=8.8 Hz, 3H), 7.10 (d, J=8.8 Hz, 2H), 5.80 (s, 1H), 5.29 (s, 3H ), m/z (ESI+) (M+H)+ = 423.20; HPLC tR=4.554 min. D PC-48

¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 8.19 (d, J=5.6 Hz, 1H), 7.38(m, 1H), 7.36(m, 3H), 7.07(d, J=9.2Hz, 1H), 6.79(d, J=5.6Hz , 1H), 5.57 (s, 1H), 5.23 (s, 2H), 2.56 (s, 3H), 2.32 (s, 3H); m/z (ESI+) (M+H)+ = 421.15; HPLC tR=5.222 min. A PC-49

¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (d, J=5.2 Hz, 1H), 8.37 (s, 1H), 8.24 (d, J=5.6 Hz, 1H), 7.64(m, 1H), 7.38-7.25(m, 4H), 6.83(d, J=5.6Hz, 1H), 5.54(s, 1H) , 5.30 (s, 2H), 2.56 (s, 3H); m/z (ESI+) (M+H)+ = 441.10; HPLC tR=4.186 min. B PC-50

¹ H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.46-8.41 (m, 2H), 8.39 (s, 1H), 8.29 (d, J=5 .3 Hz, 1H), 7.55 (t, J=8.6 Hz, 1H), 7.30 (s, 1H), 7.26-7.15 (m, 2H), 7.06-7 .00 (m, 1H), 6.64 (d, J=5.3 Hz, 1H), 5.53 (s, 1H), 5.21 (s, 2H), 2.47 (s, 3H) ; m/z (ESI+) (M+H)+ = 425.10; HPLC tR=4.416 min. A PC-51

¹ H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.45 (d, J=5.6 Hz, 2H), 8.40 (s, 1H), 8.29 (d, J=5.3Hz, 1H), 7.63(d, J=8.7Hz, 1H), 7.41(d, J=2.7Hz, 1H), 7.30(s, 1H) , 7.23 (d, J=5.0 Hz, 1H), 7.14 (dd, J=8.7, 2.7 Hz, 1H), 6.58 (d, J=5.3 Hz, 1H), 5.53 (d, J=1.1 Hz, 1H), 5.22 (s, 2H), 2.50-2.48 (m, 3H); m/z (ESI+) (M+H)+ = 441.20; HPLC tR=7.101 min. A PC-52

¹ H NMR (400 MHz, DMSO) δ 8.45 (d, J=5.0 Hz, 1H), 8.39 (s, 2H), 8.31 (d, J=5.3 Hz, 1H) , 7.45 (d, J=10.1 Hz, 1H), 7.32 (t, J=8.6 Hz, 3H), 7.23 (d, J=4.2 Hz, 1H), 6 .78 (d, J=5.2 Hz, 1H), 5.50 (s, 1H), 5.26 (s, 2H), 2.47 (s, 4H); m/z (ESI+) (M+H)+ = 425.20; HPLC tR=6.742 min. B PC-53

¹ H NMR (400 MHz, CD ₃ OD) δ 8.66-8.64 (m, 1H), 8.41-8.39 (m, 1H), 8.24-8.23 (m, 1H) , 8.02-8.01(m, 1H), 7.94-7.91(m, 1H), 7.43(m, 3H), 7.11-7.08(m, 2H), 5 .78-5.78 (m, 1H), 5.43-5.42 (m, 2H), 4.82-4.82 (m, 2H); m/z (ESI+) (M+H)+ = 423.05; HPLC tR=4.514 min. B PC-54

¹ H NMR (400 MHz, CD ₃ OD) δ 8.69 (d, J=6.2 Hz, 1H), 8.49 (s, 1H), 8.32 (d, J=5.8 Hz, 1H), 8.01 (s, 1H), 7.94 (d, J=5.4 Hz, 1H), 7.55 (s, 2H), 7.27 (d, J=8.8 Hz, 2H), 6.94 (d, J=5.6 Hz, 1H), 5.48 (s, 3H), 3.08 (s, 3H), 2.90 (s, 3H), 2.81 ( s, 3H); m/z (ESI+) (M+H)+ = 435.10; HPLC tR=4.199 min. D PC-55

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.52 (d, J=5.2 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J=5.4 Hz, 1H ), 7.37 (dd, J=11.8, 8.6 Hz, 4H), 7.24 (s, 1H), 7.18 (d, J=4.9 Hz, 1H), 6.99 (d, J=8.7 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 6.66 (d, J=5.4 Hz, 1H), 6.19 (s , 1H), 5.40 (s, 1H), 5.09 (s, 2H), 4.68 (s, 2H), 3.70 (s, 3H), 2.60 (s, 3H); m/z (ESI+) (M+H)+ = 527.20; HPLC tR=5.118 min. C PC-56

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.309 (d, J=5.2 Hz, 1H), 8.262 (s, 1H), 8.149 (d, J=5.2 Hz, 1H), 7.281- 7.225 (m, 4H), 6.756 (d, J=5.6 Hz, 1H), 6.669 (d, J=8.8 Hz, 2H), 5.517 (s, 1H), 4.393 (s, 2H), 2.487 (s, 3H); m/z (ESI+) (M+H)+ = 406.30, (MH)- = 404.20; HPLC tR=4.831 min. B PC-57

¹ H-NMR (400 MHz DMSO) δ: 10.997 (s, 1H), 8.369 (s, 2H), 8.281 (d, J=5.2 Hz, 2H), 7.399-7.326 (m, 4H), 7.082 ( s, 1H), 7.017 (d, J=5.2 Hz, 1H), 6.665 (d, J=5.2 Hz, 1H), 5.486 (s, 1H), 2.917-2.846 (m, 4H), 2.378 (s, 3H); m/z (ESI+) (M+H)+ = 405.25; HPLC tR=3.645 min. B PC-58

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.577-8.545 (m, 2H), 8.319 (s, 1H), 7.741-7.686 (m, 2H), 7.393 (s, 2H), 7.100 (s, 1H ), 6.873 (s, 2H), 5.703 (s, 1H), 4.923-4.868 (m, 2H), 3.232 (s, 3H), 2.752 (s, 3H); m/z (ESI+) (M+H)+ = 420.25; HPLC tR=3.637 min. B PC-59

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.607 (d, J=5.2 Hz, 1H), 8.376 (d, J=5.2 Hz, 1H), 8.247 (s, 1H), 8.173 ( s, 1H), 7.837 (s, 1H), 7.604-7.596 (m, 1H), 7.430 (d, J=9.2 Hz, 2H), 7.398 (d, J=5.2 Hz, 1H), 7.058 (d, J=8.8 Hz, 2H), 5.772 (s, 1H), 5.447 (s, 1H), 5.237 (s, 2H); m/z (ESI+) (M+H)+ = 436.25, (MH)- = 434.20; HPLC tR=4.762 min. C PC-60

¹ H-NMR (400 MHz DMSO) δ: 10.980 (s, 1H), 8.625 (d, J=4.8 Hz, 1H), 8.345 (s, 1H), 8.269 (d, J=5.2 Hz, 1H), 8.107 (s, 1H), 8.078 (s, 1H), 7.646 (s, 1H), 7.624 (d, J=5.2 Hz, 1H), 7.466 (d, J=8.8 Hz, 2H ), 7.176 (d, J=8.8 Hz, 2H), 6.654 (d, J=5.2 Hz, 1H), 5.472 (s, 1H), 5.326 (s, 1H); m/z (ESI+) (M+H)+ = 436.25, (MH)- = 434.15; HPLC tR=4.966 min. B PC-61

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.581 (d, J=6.4 Hz, 1H), 8.310 (d, J=5.6 Hz, 1H), 8.238 (s, 1H), 7.730 ( s, 1H), 7.715 (s, 1H), 7.393 (d, J=5.6 Hz, 1H), 6.927 (s, 1H), 5.094 (d, J=17.2 Hz, 1H), 4.784 (d , J=17.2 Hz, 1H), 2.77 (s, 3H); m/z (ESI+) (M+H)+ = 408.25, (MH)- = 406.20; HPLC tR=2.054 min. C PC-62

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.475 (s, 1H), 8.417 (d, J=5.6 Hz, 1H), 8.352 (d, J=4.8 Hz, 1H), 7.165 (d , J=8.4 Hz, 2H), 6.977 (d, J=8.4 Hz, 3H), 6.886 (d, J=5.2 Hz, 1H), 6.595 (d, J=5.6 Hz, 1H), 6.087 (s, 1H), 5.346 (s, 1H), 2.916-2.859 (m, 4H), 2.512 (s, 3H); m/z (ESI+) (M+H)+ = 389.25; HPLC tR=3.522 min. C PC-63

¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.146 (br s, 1H), 8.674 (s, 1H), 8.515 (d, J=5.2 Hz, 1H), 8.227 (d, J=5, 2 Hz, 1H), 7.421 (d, J=8.8 Hz, 2H), 7.219 (s, 1H), 7.162 (d, J=4.4 Hz, 1H), 7.017 (d, J=8.8 Hz, 2H), 6.696 (d, J=5.2 Hz, 1H), 6.662 (s, 1H), 5.074 (s, 1H), 2.584 (s, 3H), 2.480-2.426 (m, 1H), 2.343 -2.289 (m, 1H), 1.057 (t, J=7.2 Hz, 3H); m/z (ESI+) (M+H)+ = 435, (MH)- = 430; HPLC tR=3.674 min. A PC-64

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.753 (br s, 1H), 8.502 (d, J=5.2 Hz, 1H), 8.402 (d, J=5.6 Hz, 1H), 8.327 (s, 1H), 7.605 (d, J=5.2 Hz, 2H), 7.295 (d, J=8.8 Hz, 2H), 7.207 (s, 1H), 7.148 (d, J=4.8 Hz, 1H), 6.930 (d, J=8.8 Hz, 2H), 5.036 (s, 2H), 2.583 (s, 3H), 2.296-2.163 (m, 2H), 1.011 (t, J=7, 2 Hz, 3H); m/z (ESI+) (M+H)+ = 435.30, (MH)- = 433.30; HPLC tR=3.924 min. A OC-1

¹ H NMR (400 MHz, CD ₃ OD) δ 7.321 (d, J=9.2 Hz, 3H), 7.260-7.181 (m, 6H), 7.131 (s, 1H), 6.971 (d, J=8, 8 Hz, 2H), 5.738 (s, 2H), 5.030 (s, 2H), 2.338 (s, 3H); m/z (ESI+) (M+H)+ = 405.1; HPLC tR=7.747 min. B OC-2

¹ H NMR (400 MHz, CD ₃ OD) δ 8.007 (d, J=7.2 Hz, 1H), 7.777-7.749 (m, 1H), 7.656-7.581 (m, 2H), 7.531 (dd, J= 7.6, 9.2 Hz, 2H), 7.479 (d, J=7.2 Hz, 1H), 7.235 (m, 2H), 7.198 (s, 1H), 7.151-7.079 (m, 3H), 5.648 (s, 1H), 5.078 (s, 2H), 2.329 (s, 3H); m/z (ESI+) (M+H)+ = 421.1; HPLC tR=6.849 min. C OC-3

¹ H NMR (400 MHz, CD ₃ OD) δ 8.886 (s, 1H), 8.189 (d, J=4 Hz, 1H), 7.424 (d, J=8.8 Hz, 2H), 7.268 (d, J =10.0 Hz, 3H), 7.154-7.103 (m, 3H), 6.769 (d, J=5.6 Hz, 1H), 5.096 (s, 2H), 2.355 (s, 3H); m/z (ESI+) (M+H)+ = 422.2; HPLC tR=5.706 min. B OC-4

¹ H NMR (400 MHz, CD ₃ OD) δ 8.378 (d, J=6.8 Hz, 1H), 8.328 (s, 1H), 8.097 (d, J=6.8 Hz, 1H), 7.995 (d , J=9.2 Hz, 2H), 7.251-7.134 (m, 6H), 6.370 (s, 1H), 5.148 (s, 2H), 2.339 (s, 3H); m/z (ESI+) (MH)-=452.25; HPLC tR=6.255 min. D OC-5

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (s, 1H), 7.24 (dd, J=13.2, 4.1 Hz, 1H), 7.18 (d, J=7, 2 Hz, 2H), 7.12 (s, 1H), 7.08-7.04 (m, 2H), 6.87-6.77 (m, 2H), 6.50 (s, 1H), 5.49 (d, J=0.5 Hz, 1H), 4.93 (s, 2H), 3.83 (s, 3H), 2.33 (s, 3H); m/z (ESI+) (MH)- = 407.15; HPLC tR=7.094 min. B OC-6

¹ H NMR (400 MHz, CD ₃ OD) δ 7.73 (s, 1H), 7.24-7.19 (m, 4H), 7.16 (d, J=7.9 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H), 6.89-6.85 (m, 2H), 5.67 (s, 1H), 4.98 (s, 2H), 3.67 (s, 3H), 2.32 (s, 3H); m/z (ESI+) (M+H)+ = 409.1; HPLC tR=8.891 min. B OC-7

¹ H NMR (400 MHz, CD ₃ OD) δ 8.35 (d, J=5.3 Hz, 1H), 8.23 (s, 1H), 7.39 (d, J=8.9 Hz, 2H), 7.34 (s, 1H), 7.27 (d, J=5.1 Hz, 1H), 6.94 (d, J=8.9 Hz, 2H), 5.11 (s, 2H), 2.51 (s, 3H); m/z (ESI+) (M+H)+ = 397.25; HPLC tR=4.881 min. A OC-8

¹ H-NMR (300 MHz CDCl ₃ ) δ: 7.683 (s, 1H), 7.509 (d, J=8.7 Hz, 2H), 7.288-7.193 (m, 6H), 5.076 (s, 1H), 5.018 (s, 2H), 1.563 (s, 3H); m/z (ESI+) 412.23 (M+Na)+; HPLC tR: 5.234 min. D OC-9

¹ H-NMR (300 MHz CDCl ₃ ) δ: 7.684 (s, 1H), 7.534 (d, J=8.4 Hz, 2H), 7.438-7.348 (m, 4H), 6.997 n(d, J=8 .4 Hz, 2H), 5.085 (s, 2H), 4.800 (br s, 1H), 4.726-4.711 (m, 2H); m/z (ESI+) 418.19 (M+Na)+; HPLC tR: 5.485 min. D OC-10

¹ H-NMR (300 MHz CDCl ₃ ) δ: 7.683 (s, 1H), 7.509 (d, J=8.7 Hz, 2H), 7.288-7.193 (m, 6H), 5.076 (s, 1H), 5.018 (s, 2H), 1.563 (s, 3H); m/z (ESI+) 412.23 (M+Na)+; HPLC tR: 5.234 min. B OC-11

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (d, J=5.1 Hz, 1H), 7.95 (s, 1H), 7.54 (d, J=8.9 Hz, 2H), 7.38 (s, 1H), 7.30 (d, J=4.9 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 5.17 (s, 2H), 5.14 (s, 1H), 2.53 (s, 3H); m/z (ESI+) (M+H)+ = 397.10; HPLC tR=4.623 min. D OC-12

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.337 (d, J=5.2 Hz, 1H), 7.491 (s, 1H), 7.402 (s, 1H), 7.287 (s, 1H), 7.224 ( d, J=4.8 Hz, 1H), 7.136 (d, J=8.8 Hz, 2H), 6.854 (d, J=9.2 Hz, 2H), 5.601 (s, 1H), 5.401 (s , 1H), 5.043 (s, 2H), 3.867 (s, 3H), 2.501 (s, 3H); m/z (ESI+) (M+H)+ = 410.20, (MH)- = 408.20; HPLC tR=4.468 min. A OC-13

¹ H-NMR (400 MHz DMSO) δ: 11.013 (s, 1H), 8.390 (d, J=5.2 Hz, 1H), 8.197 (s, 1H), 7.729 (s, 1H), 7.233 (s, 1H), 7.163 (d, J=8.8 Hz, 3H), 6.892 (d, J=8.8 Hz, 2H), 5.511 (s, 1H), 5.064 (s, 2H), 3.521 (s, 3H ), 2.427 (s, 3H); m/z (ESI+) (M+H)+ = 410.25, (MH)- = 408.15; HPLC tR=5.139 min. A OC-14

¹ H-NMR (400 MHz DMSO) δ: 10.699 (s, 1H), 8.395 (d, J=5.2 Hz, 1H), 8.127 (s, 1H), 7.851 (s, 1H), 7.238 (s, 1H), 7.187 (d, J=8.8 Hz, 2H), 6.950 (d, J=8.8 Hz, 2H), 5.160 (s, 1H), 5.077 (s, 2H), 3.423 (s, 3H ), 2.428 (s, 3H); m/z (ESI+) (M+H)+ = 410.20; HPLC tR=4.608 min. B

Compounds of the application can be obtained in any number of ways, as described in general below and more specifically illustrated by the illustrative examples that follow. For example, compounds of the application can be prepared according to any of the General Schemes 1 to 9. In particular, compounds in which X is S, Y is O, and Z is CH ₂ can be prepared as shown in General Schemes 1- 4 and 9; compounds in which X and Y are each O and Z are CH ₂ can be prepared as shown in General Schemes 5; compounds in which X is S, Y is CH ₂ and Z is O can be prepared as shown in General Schemes 6; compounds in which X is S, Y is NH, and Z is CH ₂ can be prepared as shown in General Schemes 7; and compounds in which X is S and each of Y and Z is CH ₂ can be prepared as shown in General Schemes 8.

General scheme 1 ¹

¹ X is halogen; ring D is an optionally substituted aryl or heteroaryl; R ₃ is independently selected from alkyl hydrogen and halogen; m is an integer from 1 to 4; ring B is an optionally substituted aryl or heteroaryl

A solution of Prom.comp.-A and Prom.comm.-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 and evaporated in high vacuum and the residue is purified by column chromatography for Prom.comp.-C. Prom.comm.-C is then mixed with Prom.comm.-D and potassium carbonate in an organic solvent, and the reaction is monitored by thin layer chromatography (TLC). After the formation of Prom.comp.-E was confirmed by TLC, the reaction mixture was extracted and the organic layer was dried and evaporated under high vacuum. The residue was purified by column chromatography to give Prom.comp.-E. Then Prom.soed.-E is subjected to interaction with (NH ₄ ) ₂ CO ₃ and potassium cyanide (KCN) in aqueous alcohol during the night. The reaction mixture was evaporated to remove the solvent and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to give compounds according to embodiments of the application.

General scheme 2 ¹

¹ X is halogen; ring D is an optionally substituted aryl or heteroaryl; R ₃ is independently selected from alkyl hydrogen and halogen; m is an integer from 1 to 4; ring B is an optionally substituted aryl or heteroaryl

A mixture of Prom.comp.-B in DMSO was stirred overnight with heating under nitrogen. The mixture is then diluted with water and extracted. The organic layer was washed with brine, dried, filtered and concentrated to give Prom.comp.-F. A mixture of Prom.comp.-F, Prom.comm.-D and potassium carbonate was stirred overnight with heating under nitrogen. The mixture is diluted with water and extracted. The organic layer was washed with brine, dried, filtered, concentrated and purified by column chromatography to give Prom.comp.-G. Tripheniphosphine, tetra-n-butylammonium bromide (TBAB) and dilute hydrochloric acid are added to Prom.comp.-G in an organic solvent to form a mixture which is stirred at room temperature. The mixture was concentrated and the residue was purified by column chromatography to give Prom.comp.-H. Prom.comp.-H is reacted with Prom.comp.-A and potassium carbonate, and the mixture is stirred overnight with heating under nitrogen. The mixture was concentrated in vacuo and purified by preparative TLC to give Prom.comp.-E. Then Prom.soed.-E is subjected to interaction with (NH ₄ ) ₂ CO ₃ and potassium cyanide (KCN) in aqueous alcohol during the night. The reaction mixture was evaporated to remove the solvent and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to give compounds according to embodiments of the application.

General scheme 3 ¹

¹ X is halogen; ring D is an optionally substituted aryl or heteroaryl; R ₃ is independently selected from alkyl hydrogen and halogen; m is an integer from 1 to 4; ring B is an optionally substituted aryl or heteroaryl.

A solution of Prom.comp.-A and Prom.comm.-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 was dried and evaporated under high vacuum, and the residue was purified by column chromatography to give Prom.comp.-C. Ethane-1,2-diol and TsOH are added to a mixture of Prom.comp.-C in an organic solvent and the mixture is heated under reflux under nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give Prom.comp.-I. Prom.comp.-I is reacted with Prom.comm.-D, triphenylphosphine and diethyl azodicarboxylate (DEAD) at room temperature with stirring. The reaction is quenched with water and extracted. The organic layer was dried, concentrated under reduced pressure, and the residue was purified by column chromatography to give Prom.comp.-J. A mixture of Prom.comp.-J in acid is stirred with heating. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. Saturated sodium bicarbonate was added to the residue and extracted. The organic layer is washed, dried, and concentrated under reduced pressure to give Prom.comp.-E. Then Prom.soed.-E is subjected to interaction with (NH ₄ ) ₂ CO ₃ and potassium cyanide (KCN) in aqueous alcohol during the night. The reaction mixture was evaporated to remove the solvent and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to give compounds according to embodiments of the application.

General scheme 4 ¹

¹ X is halogen; ring D is an optionally substituted aryl or heteroaryl; R ₃ is independently selected from alkyl hydrogen and halogen; m is an integer from 1 to 4; ring B is an optionally substituted aryl or heteroaryl; R ₁ is alkyl.

LDA was added to Prom.comp.-K at -78°C under nitrogen atmosphere and the mixture was stirred for 1 hour. Then Prom.comp.-L is added dropwise and the mixture is stirred for 1 hour. The reaction is quenched with saturated aqueous ammonium chloride and extracted. The organic layer was washed, dried, concentrated in vacuo, and the residue was purified by column chromatography to give Prom.comp.-M. Prom.comp.-M is oxidized to obtain Prom.comp.-N. Pd(dba) ₂ is added to a mixture of Prom.comp.-N, Prom.comp.-H (obtained as described above in general scheme 2), DPPF and DIEA. The mixture is stirred with heating, then filtered and extracted. The organic phase is dried, concentrated under reduced pressure, and the residue is purified by column chromatography to give Prom.comp.-P. Then Prom.soed.-P is subjected to interaction with (NH ₄ ) ₂ CO ₃ and potassium cyanide (KCN) in aqueous alcohol during the night. The reaction mixture was evaporated to remove the solvent and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to give compounds according to embodiments of the application.

General scheme 5 ¹

¹ X is halogen; ring D is an optionally substituted aryl or heteroaryl; R ₃ is independently selected from alkyl hydrogen and halogen; m is an integer from 1 to 4; ring B is an optionally substituted aryl or heteroaryl.

To a solution of Prom.comp.-D in an organic solvent, Prom.comm.-Q, triphenylphosphine, and DEAD are added at 0°. The mixture is warmed to room temperature and stirred. The mixture is then quenched with water and extracted. The organic layer was washed, dried, concentrated in vacuo and the residue was purified by column chromatography to give Prom.comp.-R. To a solution of Prom.comp.-R in an organic solvent, Prom.comm.-A and potassium carbonate are added. The mixture is stirred with heating, then hydrochloric acid is added to adjust the pH to 6-7. The mixture was extracted, and the organic layer was washed, dried, concentrated under reduced pressure, and the residue was purified by column chromatography to give Prom.comp.-S. Then Prom.soed.-S is subjected to interaction with (NH ₄ ) ₂ CO ₃ and potassium cyanide (KCN) in aqueous alcohol during the night. The reaction mixture was evaporated to remove the solvent and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to give compounds according to embodiments of the application.

General scheme 6 ¹

¹ X is halogen; ring D is an optionally substituted aryl or heteroaryl; R ₃ is independently selected from alkyl hydrogen and halogen; m is an integer from 1 to 4; ring B is an optionally substituted aryl or heteroaryl.

To a solution of Prom.comp.-A in an organic solvent, Prom.comm.-T and potassium carbonate are added at room temperature under a 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, extracted, and the organic layer is washed, dried, concentrated under reduced pressure, and the residue is purified by column chromatography to give Prom. U. TsOH is added to a solution of Prom.comp.-U in an organic solvent. After several minutes of stirring, a solution of ethane-1,2-diol in an organic solvent is added dropwise. The mixture is stirred with heating, and then saturated sodium bicarbonate solution is poured in and extracted. The organic phase is dried, concentrated under reduced pressure and purified by column chromatography to give Prom.comp.-V. Prom.comp.-V restore with LAH, and the reaction is quenched, extracted and the organic layer is dried and concentrated under reduced pressure. The residue was purified by column chromatography to give Prom.comp.-Y. S°Cl ₂ is added to a mixture of Prom.comm.-Y in an organic solvent at 0°C. After stirring for several hours, the pH was adjusted to 7 and the mixture was extracted. The organic layer was dried, concentrated under reduced pressure, and the residue was purified by column chromatography to give Prom.comp.-X. Prom.comp.-X is reacted with Prom.comm.-Y and potassium carbonate at room temperature under a nitrogen atmosphere. The mixture was diluted with water and extracted, and the organic layer was washed, dried, concentrated under reduced pressure, and the residue was purified by column chromatography to give Prom.comp.-Z. A mixture of Prom.comp.-Z in acid is stirred with heating. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. Saturated sodium bicarbonate was added to the residue and extracted. The organic layer is washed, dried, and concentrated under reduced pressure to give Prom.comp.-A1. Prom.compound-A1 is then reacted with (NH ₄ ) ₂ CO ₃ and potassium cyanide (KCN) in aqueous alcohol overnight. The reaction mixture was evaporated to remove the solvent and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to give compounds according to embodiments of the application.

General scheme 7 ¹

¹ X is halogen; ring D is an optionally substituted aryl or heteroaryl; R ₃ is independently selected from alkyl hydrogen and halogen; m is an integer from 1 to 4; ring B is an optionally substituted aryl or heteroaryl.

Triethylamine and DMAP are added to a solution of Prom.comp.-B1 and BOC ₂ O in an organic solvent, and the mixture is stirred at room temperature. The mixture is quenched, extracted and the organic phase is washed, dried, concentrated under reduced pressure and the residue is purified by column chromatography to give Prom.comp.-C1. Prom.comp.-C1 is reacted with Prom.comm.-A and potassium carbonate at room temperature. The mixture is diluted with water, extracted and the organic phase is washed, dried, concentrated under reduced pressure and the residue is purified by column chromatography to give Prom.comp.-D1. TsOH is added to a stirred solution of Prom.comp.-D1 in an organic solvent. After several minutes of stirring, a solution of ethane-1,2-diol in an organic solvent is added dropwise. The mixture is stirred with heating, and then saturated sodium bicarbonate solution is poured in and extracted. The organic phase is dried, concentrated under reduced pressure and purified by column chromatography to give Prom.comp.-E1. Sodium hydride is added to a solution of Prom.comp.-E1 and Prom.comm.-D. The mixture was diluted with water and extracted, and the organic layer was washed, dried, concentrated under reduced pressure, and the residue was purified by column chromatography to give Prom.comp.-F1. A mixture of Prom.comp.-F1 in acid is stirred with heating. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. Saturated sodium bicarbonate was added to the residue and extracted. The organic layer is washed, dried, and concentrated under reduced pressure to give Prom.comp.-G1. Then Prom.soed.-G1 is subjected to interaction with (NH ₄ ) ₂ CO ₃ and potassium cyanide (KCN) in aqueous alcohol during the night. The reaction mixture was evaporated to remove the solvent and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to give compounds according to embodiments of the application.

General scheme 8 ¹

¹ X is halogen; ring D is an optionally substituted aryl or heteroaryl; R ₃ is independently selected from alkyl hydrogen and halogen; m is an integer from 1 to 4; ring B is an optionally substituted aryl or heteroaryl.

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

General scheme 9 ¹

¹ X is halogen; ring D is an optionally substituted aryl or heteroaryl; R ₃ is independently selected from alkyl hydrogen and halogen; m is an integer from 1 to 4; ring B is an optionally substituted aryl or heteroaryl; R is alkyl.

To a solution of Prom.comp.-N1, sodium hydroxide and Prom.comm.-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 Prom.comp.-O1. To a solution of Prom. comp.-O1, potassium carbonate and Prom. comp.-D was added and the mixture was stirred at room temperature. The mixture is extracted, the organic layer is washed, dried, concentrated under reduced pressure, and the residue is purified by column chromatography to give Prom.comp.-P1. DIBAL-H is added to a solution of Prom.comp.-P1 in an anhydrous solvent at 0°C. The mixture was quenched, extracted, the organic layer was washed, dried, concentrated under reduced pressure, and the residue was purified by column chromatography to give Prom.comp.-Q1. Prom. compound-Q1 is oxidized to give Prom. compound-R1. Then Prom.soed.-R1 is subjected to interaction with (NH ₄ ) ₂ CO ₃ and potassium cyanide (KCN) in aqueous alcohol during the night. The reaction mixture was evaporated to remove the solvent and then extracted. The organic layer is dried and evaporated, and the residue is purified by column chromatography to give compounds according to embodiments of the application.

The nitrogen atoms of the hydantoin moiety of the compounds of the application may be alkylated by reacting the compounds prepared according to any of the general schemes above with sodium hydride and alkyl iodide (eg CH ₃ I). Compounds in which one of X, Y and Z is S(O) or SO ₂ can be prepared by reacting compounds prepared according to any of the general schemes above with m-CPBA.

Pharmaceutically acceptable salts of the compounds according to the application can be synthesized from the original compound containing an acidic or basic fragment, by conventional chemical methods. Typically, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the corresponding acid or base in water or in an organic solvent, or a mixture of the two. Examples of suitable organic solvents include, but are not limited to, ether, ethyl acetate, ethanol, isopropanol or acetonitrile.

Compositions

Another aspect of the application relates to a pharmaceutical composition comprising a compound according to the application, as described herein, or its tautomer, stereoisomer, pharmaceutically acceptable salt or solvate.

Compositions according to the application may also include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is non-toxic and should not interfere with the effectiveness of the active ingredient. Pharmaceutically acceptable carriers may include one or more excipients such as binders, disintegrants, swelling agents, suspending agents, emulsifying agents, wetting agents, lubricants, flavors, sweeteners, preservatives, colorants, solubilizers, and coatings. The specific nature of the carrier or other substance may depend on the route of administration, eg, intramuscular, intradermal, subcutaneous, oral, intravenous, dermal, intramucosal (eg, through the intestines), intranasal, or intraperitoneal routes. For liquid injectable preparations, such as suspensions and solutions, suitable carriers and additives include water, glycols, oils, alcohols, preservatives, colorants, and the like. For solid oral preparations, eg powders, capsules, caplets, gelatin capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants, and the like. For nasal spray/inhaler mixtures, the aqueous solution/suspension may include water, glycols, oils, emollients, stabilizers, wetting agents, preservatives, fragrances, flavors, and the like. as suitable carriers and additives.

Compositions for use may be formulated from any material suitable for administration to a subject to facilitate administration and increase efficacy, including, but not limited to, oral (enteral) administration and parenteral injections. Parenteral injections include intravenous injection or infusion, subcutaneous injection, intradermal injection and intramuscular injection. The compositions of the application can also be formulated for other routes of administration, including transdermal, ocular, rectal, long-acting implantation, sublingual, sublingual, oral mucosa bypassing the portal circulation, inhalation or intranasal.

In specific embodiments, the compositions are formulated for oral administration.

Another aspect of the application relates to a method for obtaining a pharmaceutical composition, including combining the compound according to the application, or its tautomer, stereoisomer, pharmaceutically acceptable salt or solvate, with at least one pharmaceutically acceptable carrier. Pharmaceutical compositions can be obtained by any method known in the art in view of the present invention, and experts in this field will be familiar with such methods used to obtain pharmaceutical compositions. For example, a pharmaceutical composition according to the application can be obtained by mixing the compound of the application with one or more pharmaceutically acceptable carriers according to conventional pharmaceutical compounding methods, including, but not limited to, conventional mixing, dissolving, granulating, emulsifying, encapsulating, incorporating, or lyophilizing processes.

Application methods

The application also provides methods for inhibiting matrix metalloproteinase (MMP) and treating diseases mediated by MMP using the compounds of the application and pharmaceutical compositions of the application.

Matrix metalloproteinases (MMPs), also known as matrixins, are a group of enzymes that are collectively responsible for the degradation of most extracellular matrix proteins during organogenesis, growth, and normal tissue turnover. MMPs are calcium dependent zinc endopeptidases and belong to a larger family of proteases known as the metzincin superfamily. MMPs are capable of degrading extracellular matrix proteins, but can also process a range of bioactive molecules and are known to be involved, for example, in cleavage of cell surface receptors, release of apoptotic ligands, and inactivation of chemokines/cytokines. It is also believed that MMPs play an important role in cell behavior such as proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis, and host immune defense. MMPs are inhibited by a specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise 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 (neutrophilic 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 etc.

In a preferred embodiment, the compounds of the invention 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 in humans by the MMP12 gene. In other embodiments, the compounds of the invention are capable of selectively inhibiting MMP-12. The terms "selective", "selectivity" and "selective", when used in relation to the binding or inhibition of the activity of a particular MMP, mean that the compound binds or inhibits the activity of a particular MMP to a greater extent than said compound binds or inhibits the activity of other MMPs. For example, a compound with selectivity for MMP-12 inhibits the activity of MMP-12 more than other MMPs, e.g. MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9 , MMP-10, MMP-13, MMP-14, etc.

In embodiments of the application, a compound that is selective for MMP-12 inhibits MMP-12 activity at least about 10, 100, or 1000 times more than one or more other MMPs, and preferably inhibits MMP-12 activity. at least about 1000 times more than at least one other MMP, such as MMP-1 or MMP-7.

The application also provides methods for treating MMP-12 mediated disease. According to embodiments of the invention, a method of treating an MMP-12 mediated disease comprises administering to a subject a therapeutically effective amount of a compound of the invention, or any tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition of the invention.

As used herein, the terms "treat", "treatment", and "therapy" are intended to mean alleviation or elimination of at least one measurable physical parameter associated with an MMP-12 mediated disease that is not necessarily distinguishable in a subject, but may be distinguishable from the subject. The terms "treat", "treatment", and "therapy" can also refer to regression, prevention of progression, or at least slowing down the progression of an MMP-12 mediated disease. In a specific embodiment, "treat", "treatment" and "therapy" refer to alleviating, preventing the development or onset or reduction in the duration of one or more symptoms associated with an MMP-12 mediated disease. In a specific embodiment, "treat", "treatment" and "therapy" refer to the prevention of recurrence of a disease mediated by MMP-12. In a specific embodiment, "treat", "treatment", and "therapy" refer to increasing the survival of a subject suffering from an MMP-12 mediated disease. In a specific embodiment, "treat", "treatment", and "therapy" refer to the elimination of an MMP-12 mediated disease in a subject.

As used herein, the term "therapeutically effective amount" means the amount of a composition or compound that elicits a biological or drug response in a tissue system or subject that a researcher, veterinarian, clinician, or other condition is seeking, which may include alleviating the symptoms of a disease or disorder to be treated. A therapeutically effective amount may vary depending on a variety of factors such as the subject's physical condition, age, weight, health status, and the like; and the specific disease to be treated. A therapeutically effective amount can be readily determined by one of ordinary skill in the art in view of the present invention.

In specific embodiments of the application, a therapeutically effective amount refers to the amount of the composition or compound according to the application, which is sufficient to inhibit MMP-12 or treat a disease mediated by MMP-12. Diseases mediated by MMP-12 that can be treated in accordance with the methods specified in the 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, non-alcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.

Embodiments

Embodiment 1 is a compound of formula (I-b):

or its tautomer, stereoisomer, pharmaceutically acceptable salts or solvate,

Where:

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;

each of X, Y and Z is independently selected from the group consisting of CH ₂ , O, NR _x and S(O) _q, where R _x represents hydrogen or alkyl;

R ₁ is hydrogen or alkyl;

R ₄ is hydrogen or alkyl;

R ₅ is hydrogen; And

q is 0, 1 or 2,

provided that ring B is not furanyl.

Embodiment 2 is a compound of formula (I):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

Where:

ring B is an optionally substituted aryl or an optionally substituted heteroaryl;

ring C is aryl or heteroaryl;

ring D is aryl or heteroaryl;

each of X, Y and Z is independently selected from the group consisting of O, CH ₂ , NR _x , and S(O) _q, where R _x is hydrogen or alkyl;

R ₁ is hydrogen or alkyl;

each R ₂ is independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxyl, haloalkyl, alkoxy, alkylthio, amine, amide, alkylamine, aminoalkyl, cyano, hydroxyalkyl, -(CH ₂ ) _p C(O)OR ₆ , and -(CH ₂ ) _p °C(O)R ₆ ;

each R ₃ is independently selected from the group consisting of hydrogen, alkyl and halogen;

R ₄ is hydrogen or alkyl;

R ₅ is hydrogen;

each R ₆ is independently selected from the group consisting of hydrogen and alkyl, where alkyl is unsubstituted or substituted by 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; And

q is 0, 1, or 2

provided that ring B is not furanyl.

Embodiment 3 is the compound of Embodiment 1 or Embodiment 2, wherein ring B is a five- or six-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from N, S, and O.

Embodiment 4 is a compound according to any one of Embodiments 1-3, wherein Ring B is pyridinyl, thiophenyl, imidazolyl, pyrazolyl, or oxazolyl.

Embodiment 5 is the compound of Embodiment 4 wherein ring B is pyridinyl.

Embodiment 6 is the compound of Embodiment 5, wherein the compound is a compound of formula (II):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has a value, as defined in the compound of formula (I).

Embodiment 7 is the compound of Embodiment 5, wherein the compound is a compound of formula (II-a), (II-b), (II-c), or (II-d):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has a value, as defined in the compound of formula (I).

Embodiment 8 is the compound of Embodiment 4 wherein Ring B is thiophenyl.

Embodiment 9 is the compound of Embodiment 8, wherein the compound is a compound of formula (IV):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has a value, as defined in the compound of formula (I).

Embodiment 10 is the compound of Embodiment 4 wherein Ring B is imidazolyl.

Embodiment 11 is the compound of Embodiment 10, wherein the compound is a compound of formula (Va) or (Vb):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has a value, as defined in the compound of formula (I).

Embodiment 12 is the compound of Embodiment 4 wherein ring B is pyrazolyl.

Embodiment 13 is the compound of Embodiment 12, wherein the compound is a compound of formula (VI):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has a value, as defined in the compound of formula (I).

Embodiment 14 is the compound of Embodiment 4 wherein ring B is oxazolyl.

Embodiment 15 is the compound of Embodiment 14, wherein the compound is a compound of formula (VII):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has a value, as defined in the compound of formula (I).

Embodiment 16 is the compound of Embodiment 15, wherein the compound is a compound of formula (VII-a) or (VII-b):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

where each of the variables has a value, as defined in the compound of formula (I).

Embodiment 17 is a compound according to any one of Embodiments 1-6 wherein ring C is phenyl.

Embodiment 18 is a compound according to any one of Embodiments 1-6 wherein ring C is pyridinyl.

Embodiment 19 is a compound according to any one of Embodiments 2-18, wherein R ₃ is selected from the group consisting of hydrogen, methyl, fluorine, and chlorine.

Embodiment 20 is a compound according to any one of Embodiments 1-19, wherein ring D is pyridinyl or phenyl.

Embodiment 21 is a compound according to any one of Embodiments 2-20, wherein R ₂ is selected from the group consisting of 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 alkoxy.

Embodiment 22 is a compound according to any one of Embodiments 1-21, wherein Ring D is:

или

.

or

.

Embodiment 23 is a compound according to any one of Embodiments 1-22, where R ₄ is hydrogen.

Embodiment 24 is a compound according to any one of Embodiments 1-22, wherein R ₄ is alkyl.

Embodiment 25 is the compound of Embodiment 24 wherein R ₄ is methyl.

Embodiment 26 is a compound according to any one of Embodiments 1-25, wherein R ₅ is methyl.

Embodiment 27 is a compound according to any one of Embodiments 1-25, where R ₅ is hydrogen.

Embodiment 28 is a compound according to any one of Embodiments 1-27, wherein R ₁ is C _1-4 alkyl.

Embodiment 29 is the compound of Embodiment 28 wherein R ₁ is methyl or ethyl.

Embodiment 30 is a compound according to any one of Embodiments 1-27, wherein R ₁ is hydrogen.

Embodiment 31 is a compound according to any one of Embodiments 1-30, wherein X is S, Y is O, and Z is CH ₂ .

Embodiment 32 is a compound of formula (I-a):

or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof,

Where:

ring B is a 5- or -6-membered heteroaryl;

Z is CH or N;

each of R ₁ and R ₄ represents alkyl or hydrogen;

R ₅ is hydrogen;

R ₂ is selected from the group consisting of alkyl, amide, hydroxyl, alkoxy and hydroxyalkyl; And

X and Y are each independently selected from S and O.

Embodiment 33 is the compound of Embodiment 32 wherein Ring B is pyridinyl, thiophenyl, imidazolyl, pyrazolyl, or oxazolyl.

Embodiment 34 is the compound of Embodiment 32 or Embodiment 33, where R ₁ is hydrogen.

Embodiment 35 is the compound of Embodiment 32 or Embodiment 33, wherein R ₁ is C _1-4 alkyl.

Embodiment 36 is the compound of Embodiment 35 wherein R ₁ is methyl or ethyl.

Embodiment 37 is a compound according to any one of Embodiments 32-36, wherein R ₄ is hydrogen.

Embodiment 38 is a pharmaceutical composition comprising the compound of any one of Embodiments 1-37 and at least one pharmaceutically acceptable carrier.

Embodiment 39 is a method for inhibiting macrophage elastase (MMP-12) in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition according to Embodiment 38.

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

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, non-alcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome and nephritis.

Embodiment 42 is a compound according to any one of Embodiments 1-37, or a pharmaceutical composition according to Embodiment 38 for use in macrophage elastase (MMP-12) inhibition.

Embodiment 43 is a compound according to any one of Embodiments 1-37, or a pharmaceutical composition according to Embodiment 38, for use in the treatment of macrophage elastase mediated disease (MMP-12).

Embodiment 44 is a compound or composition for use according to 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.

Embodiment 45 is the use of the compound of any of Embodiments 1 to 37, or the pharmaceutical composition of Embodiment 38, in the manufacture of a macrophage elastase inhibiting drug (MMP-12).

Embodiment 46 is the use of the compound of any of Embodiments 1 to 37, or the pharmaceutical composition of Embodiment 38, in the manufacture of a medicament for the treatment of macrophage elastase mediated disease (MMP-12).

Embodiment 47 is 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.

Embodiment 48 is a method for preparing the pharmaceutical composition of Embodiment 38, comprising combining a compound or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier.

Examples

The following application examples serve to further illustrate the nature of the application. It is to be understood that the following examples do not limit the application and the scope of the application is to be determined by the appended claims.

Synthesis methods

Unless otherwise indicated, abbreviations for chemical reagents and synthesis conditions have their usual meaning known in the art, namely:

"LDA" means lithium diisopropylamide;

"EA" means ethyl acetate;

“PE” means petroleum ether;

“room temp.” means room temperature;

"THF" means tetrahydrofuran;

"DEAD" means diethyl azodicarboxylate;

"TBAB" means tetrabutylammonium bromide;

"DCM" means dichloromethane;

"HOBT" means hydroxybenzotriazole;

"LAH" means lithium aluminum hydride;

"TLC" means thin layer chromatography;

“prep-TLC” means preparative thin layer chromatography;

"TMS-I" means trimethylsilyl iodide;

"Hexane" means hexanes;

"DMF" means dimethylformamide;

“h” means hours;

"EDCI" means 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

"DMAP" means 4-dimethylaminopyridine;

"Prep-HPLC" means preparative high performance liquid chromatography;

"DHP" means dihydropyran;

“DPPF” means 1,1'-bis(diphenylphosphino)ferrocene; And

"DIEA" means diisopropylethylamine.

Preparation of a 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.

NaOH (0.06 g, 1.5 mmol) was added 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) . The reaction mixture was stirred overnight at room temperature. Water and EA were added to the residue, and extracted twice with EA. The combined organic layer was dried over MgSO ₄ and evaporated under high vacuum 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%).

Synthesis of compounds TC-1, TC-2, TC-3, TC-4, TC-5 and TC-6:

A solution of 3-a (0.2 g, 1.65 mmol), TI-1a (0.40 g, 1.7 mmol), and K ₂ CO ₃ (0.7 g) in ACN was stirred at room temperature for night. The reaction was monitored by TLC (EA/hexane=2/7) to determine when the benzyl bromide spot had disappeared. EA and water were added to the reaction mixture and extracted twice with EA. The combined organic layer was dried over 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%). Intermediates TI-2, TI-3, TI-4, TI-5 and TI-6 were synthesized according to the same procedure, except that starting material 3-12 was replaced with 3-14, 3-15, 3 -16 or 3-17, respectively.

To a solution of TI-1 (0.42 g, 1.18 mmol) in EtOH/H ₂ O (10 ml/5 ml) was added (NH ₄ ) ₂ CO ₃ (1.71 g, 17.8 mmol) and KCN ( 0.15 g, 0.98 mmol). 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 and then extracted twice with EA. The organic layers were combined, dried over MgSO ₄ and evaporated. The residue was purified by flash chromatography with EA/hexane (EA/hexane=1:1) to give TC-1 as a light yellow solid (0.28 g, 38%). Compounds TI-2, TI-3, TI-4, TI-5 and TI-6 were synthesized using a similar procedure, except that intermediate TI-1 was replaced by intermediates TI-2, TI-3, TI- 4, TI-5 or TI-6, respectively.

Obtaining a TC-7 connection:

A solution of 3-18a (0.23 g, 0.76 mmol), TI-1a (0.15 g, 0.64 mmol), and K ₂ CO ₃ (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 extracted twice with EA. The combined organic layer was dried over MgSO ₄ and evaporated under high vacuum. The residue was purified by flash chromatography with EA/hexane (EA/hexane=1:10-1:4) to give TI-7a as a yellow solid (0.17 g, 50%)

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 over night, then the solvent and TFA were removed to obtain a brown oil. NaHCO ₃ and MeOH were added to the brown oil. The solvent was then removed again. The residue was purified by flash chromatography with EA/hexane (EA/hexane=1:4) to give TI-7b as a white solid (0.14 g).

To a solution of TI-1b (0.14 g, 0.41 mmol) in EtOH/H ₂ O (5 ml/2.5 ml) was added (NH ₄ ) ₂ CO ₃ (0.24 g, 2.46 mmol) and KCN (32 mg, 0.41 mmol). 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, and then extracted twice with EA. The organic layers were combined, dried over MgSO ₄ and 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).

Obtaining a TC-8 connection:

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

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

General scheme: Preparation of intermediate compound 4a-1

Synthesis of Intermediate FI-5:

A mixture of compound 2a (68 g, 538.9 mmol, 1.0 eq.) in DMSO (500 ml) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was then diluted with H ₂ O (1000 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give compound FI-5 (67 g, 99%).

Synthesis of Intermediate FI-6:

A mixture of compound FI-5 (5 g, 19.97 mmol, 1.0 eq.), compound 3b (7.39 g, 39.95 mmol, 2 eq.) and K ₂ CO ₃ (11.04 g, 79 .89 mmol, 4.0 eq.) in acetone (100 ml) was stirred at 60°C for 4 h under nitrogen atmosphere. The mixture was then diluted with H ₂ O (1000 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA, 10:1) to give compound FI-6 (8.7 g, 97%).

Synthesis of compound 4a-1:

To a mixture of compound FI-6 (10.7 g, 23.33 mmol, 1.0 eq.) in THF (100 ml) was added PPh ₃ (6.11 g, 23.33 mmol, 1 eq.), TBAB ( 15.04 g, 46.66 mmol, 2 eq) and 5% HCl (5 ml). The mixture was stirred at room temperature for 12 hours under nitrogen. The mixture was then concentrated. The residue was purified by silica gel column chromatography (PE/EA, 2:1) to give compound 4a-1 (6.6 g, 56%).

Getting a PC-1 connection:

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

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

Obtaining PC-2, PC-3 and PC-4 connections:

Compounds PC-2, PC-3, and PC-4 were synthesized using the same procedure as the synthesis of PC-1, except that the starting material 2-chloronicotinaldehyde PS-1 was replaced by 4-chloronicotinaldehyde PS-2, 3-fluoropicolinaldehyde PS-3, or 3-chloroisonicotinaldehyde PS-4, respectively.

Getting the Key Intermediate PI-a.1

To a mixture of 4-chloronicotinaldehyde (2.2 g, 15.54 mmol, 1.0 eq.) and 4-mercaptophenol (2.94 g, 23.31 mmol, 1.5 eq.) in THF (20 ml) was added NaH (1.24 g, 31.08 mmol, 2.0 eq.) at 0° C. and the mixture was stirred at room temperature overnight under nitrogen. The mixture was then concentrated to half the amount of solvent, and then 2.0 N sodium hydroxide was added. HCl 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.

Obtaining PC-7, PC-8 and PC-9 connections:

Ethane-1,2-diol (1.6 g, 260 mmol, 20 eq.) and TsOH (0.112 g, 0.65 mmol, 0.05 eq.). The mixture was heated at reflux for 12 hours under nitrogen. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 2:1) to give compound PI-b.1 (2.9 g, 82%).

To a solution of compound PI-b.1 (200 mg, 0.727 mmol, 1.0 eq.) in THF (10 ml) was added successively 1,4-phenylenedimethanol (50 mg, 3.64 mmol, 5.0 eq.), PPh ₃ (381 mg, 1.454 mmol, 2.0 eq.) and DEAD (253 mg, 1.454 mmol, 2.0 eq.) at 0°C. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then quenched with H ₂ O (10 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound PI-7a (200 mg, 70%).

A mixture of compound PI-7a (140 mg, 0.354 mmol, 1.0 eq.) 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. Saturated NaHCO ₃ solution was added to the residue to adjust pH=8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over 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.

To a mixture of compound PI-7b (150 mg, 0.427 mmol, 1.0 eq.) in MeOH (5 ml) was added KCN (55 mg, 0.854 mmol, 2.0 eq.) and (NH ₄ ) ₂ CO ₃ (164 mg, 1.71 mmol, 4.0 eq.). The mixture was stirred at room temperature for 12 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-7 (38 mg, 21%) as a white solid.

Compounds PC-8 and PC-9 were synthesized following the same procedure, except that 1,4-phenylenedimethanol was replaced by 1,3-phenylenedimethanol or 1,2-phenylenedimethanol, respectively.

Obtaining a PC-10 connection:

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

To a solution of compound PI-b.1 (300 mg, 1.09 mmol, 1.0 eq) in THF (10 ml) was added successively compound PI-10a (905 mg, 5.45 mmol, 5.0 eq) , PPh ₃ (572 mg, 2.18 mmol, 2.0 eq.) and DEAD (380 mg, 2.18 mmol, 2.0 eq.) at 0°C. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then quenched with H ₂ O (10 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound PI-10b (200 mg, 44%).

A mixture of compound PI-10b (200 mg, 0.473 mmol, 1.0 eq.) 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. Saturated NaHCO ₃ solution was added to the residue to adjust pH=8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over 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.

To a mixture of compound PI-10c (150 mg, 0.427 mmol, 1.0 eq.) in MeOH (5 ml) was added KCN (55 mg, 0.854 mmol, 2.0 eq.) and (NH ₄ ) ₂ CO ₃ (164 mg, 1.71 mmol, 4.0 eq.). The mixture was stirred at room temperature for 12 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-10 (55 mg, 30%) as a white solid.

Obtaining a PC-11 connection:

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

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

Obtaining key intermediate PI-a.2.

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

Obtaining PC-12, PC-13 and PC-14 connections:

Ethane-1,2-diol (1.2 g, 19.9 mmol , 20 eq.) and TsOH (86 mg, 0.498 mmol, 0.05 eq.). The mixture was heated at reflux for 12 hours under nitrogen. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound PI-b.2 (2.2 g, 81%).

To a solution of compound PI-b.2 (1.5 g, 5.45 mmol, 1.0 eq.) in THF (50 ml) was added successively 1,4-phenylenedimethanol (2.63 g, 19 mmol, 3.5 eq.), PPh ₃ (2.86 g, 10.9 mmol, 2.0 eq.) and DEAD (1.9 g, 10.9 mmol, 2.0 eq.) at 0°C. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then quenched with H ₂ O (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound PI-14a (1.5 g, 70%).

A mixture of compound PI-14a (500 mg, 1.266 mmol, 1.0 eq.) 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. Saturated NaHCO ₃ solution was added to the residue to adjust pH=8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound PI-14b (280 mg, 63%).

To a mixture of compound PI-14b (150 mg, 0.427 mmol, 1.0 eq.) in EtOH (5 ml) and H ₂ O (2.5 ml) was added KCN (42 mg, 0.641 mmol, 1.5 eq.) and (NH ₄ ) ₂ CO ₃ (410 mg, 4.27 mmol, 10.0 eq.). The mixture was stirred at 50° C. for 5 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-14 (70 mg, 25%) as a white solid.

Compounds PC-12 and PC-13 were synthesized following the same procedure, except that 1,2-phenylenedimethanol was replaced by 1,3-phenylenedimethanol or 1,4-phenylenedimethanol, respectively.

Obtaining a PC-15 connection:

To a solution of compound PI-b.2 (500 mg, 1.82 mmol, 1.0 eq.) in THF (20 ml) was added successively compound PI-10a (1.1 g, 6.37 mmol, 3.5 eq. .), PPh ₃ (954 mg, 3.64 mmol, 2.0 eq.) and DEAD (634 mg, 3.64 mmol, 2.0 eq.) at 0°C. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then quenched with H ₂ O (10 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound PI-15a (460 mg, 60%).

A mixture of compound PI-15a (1 g, 2.364 mmol, 1.0 eq.) 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. Saturated NaHCO ₃ solution was added to the residue to adjust pH=8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound PI-15b (200 mg, 25%).

To a mixture of compound PI-15b (200 mg, 0.593 mmol, 1.0 eq.) in EtOH (6 ml) and H ₂ O (6 ml) was added KCN (58 mg, 0.89 mmol, 1.5 eq.) and (NH ₄ ) ₂ CO ₃ (570 mg, 5.93 mmol, 10.0 eq.). The mixture was stirred at 50° C. for 4 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-HPLC to give PC-15 (58 mg, 24%) as a white solid.

Obtaining PC-16 and PC-17 connections:

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

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

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

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

Obtaining PC-18 and PC-19 connections:

Compounds PC-18 and PC-19 were synthesized following the same procedure as the synthesis of PC-16 except that PI-b.2 was replaced by PI-b.1 as the starting material.

Obtaining PC-20 and PC-21 connections:

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

A mixture of compound PI-20a (500 mg, 1.02 mmol, 1.0 eq.) and HCl (3 M in H ₂ O, 10 ml) in THF (15 ml) was stirred at 70°C for 12 h. the mixture was cooled to room temperature and concentrated under reduced pressure. Saturated NaHCO ₃ was added to the residue to adjust pH=8 and filtered to give compound PI-20b (400 mg, 100%), which was used in the next step without further purification.

₍ NH ₄ ) ₂ CO ₃ (577 mg, 6.01 mmol, 10.0 eq.). The mixture was stirred at 50°C for 5 hours. 0.5 M HCl was added to the mixture to adjust pH=1~2 and stirred for 10 minutes. Then a saturated NaHCO ₃ solution was added to adjust pH=6-7. The mixture was stirred for 1 hour and filtered. The residue was purified by prep-HPLC to give PC-20 (160 mg, 61.3%) as a white solid.

Preparation of PS-4a and PS-4b Intermediates:

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

To a mixture of (2-bromopyridin-4-yl)methanol (25 g, 133.69 mmol, 1.0 eq.) and DHP (22.46 g, 267.38 mmol, 2.0 eq.) in DCM (290 ml) TsOH (2.23 g, 13.37 mmol, 0.1 eq.) was added. The mixture was stirred at room temperature for 15 hours. Analysis of the reaction mixture by TLC showed complete conversion to the desired product. The mixture was then diluted with H ₂ O (100 ml) and extracted with dichloromethane. The organic layer was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 4:1) to give compound PS-4a.1 (34.1 g, 94.1%).

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

A mixture of compound PS-4a.2 (25 g, 79.8 mmol, 1.0 eq.) and HCl (2 M in H ₂ O, 55 ml) in THF (55 ml) was stirred at room temperature for 3 h. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The mixture was then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 2:1) to give compound PS-4a (8 g, 44%).

Intermediate PS-4b was prepared using the same synthetic procedure for PS-4a, except that (2-bromopyridin-4-yl)methanol was replaced with (5-bromopyridin-3-yl)methanol as the starting material.

Obtaining a PC22 connection:

To a mixture of 4-chloropyridine (100 g, 0.667 mol, 1.0 eq.) in dry THF (1 L) was quickly added LDA (2 M in THF, 733.26 ml, 1.467 mol, 2.2 eq.) at - 78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 1 h. Then propionaldehyde (74.1 g, 0.999 mol, 1.5 eq.) was added dropwise and the mixture was stirred for 1 h. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with EA (3 x 500 ml). The organic layer was washed with brine and water, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA, 3:1) to give compound PI-22a (45 g, 48%).

To a mixture of PI-22a (26.3 g, 0.154 mol, 1.0 eq.) in acetone (300 ml) was added CrO ₃ (30.8 g, 0.308 mol, 2.0 eq.). The mixture was stirred at room temperature for 5 hours. The mixture was then 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%).

To a mixture of PI-22b (850 mg, 5.03 mmol, 1.0 eq.), compound 4a-1 (1.27 g, 5.53 mmol, 1.1 eq.), DPPF (42 mg, 0.503 mmol , 0.1 eq.) and DIEA (973 mg, 7.55 mmol, 1.5 eq.) in toluene (10 ml) was added Pd(dba) ₂ (202 mg, 0.352 mmol, 0.07 eq.) in nitrogen atmosphere. The mixture was stirred at 110° C. for 16 hours. The mixture was then filtered and extracted with water and ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound PI-22c (550 mg, 30%).

To a mixture of PI-22c (550 mg, 1.515 mmol, 1.0 eq.) in EtOH (8 ml) and H ₂ O (2 ml) was added KCN (295 mg, 4.55 mmol, 3.0 eq.) and (NH ₄ ) ₂ CO ₃ (720 mg, 7.576 mmol, 5.0 eq.). The mixture was stirred at 50° C. for 3 days. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PC-22 (50 mg, 7%) as a white solid.

Obtaining a PC-23 connection:

To a mixture of 3-(methoxycarbonyl)benzoic acid (5 g, 27.78 mmol, 1.0 eq.) in dry THF (20 ml) was added BH ₃ /THF (1 M in THF, 55 ml, 55.5 mmol, 2.0 equiv.) at 0°C. The mixture was stirred at 30° C. for 16 hours under nitrogen. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound PI-23a (4.2 g, 91%).

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

To a solution of compound PI-23b (2.1 g, 8.14 mmol, 1.0 eq.) in DMF (15 ml) was added 4-chloronicotinaldehyde (1.73 g, 12.2 mmol, 1.5 eq.) and K ₂ CO ₃ (2.25 g, 16.28 mmol, 2.0 eq.). The mixture was stirred at 80° C. for 4 hours under nitrogen. Then 3 M HCl was added to bring the pH=6-7. The mixture was extracted with EA and the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 3:1) to give compound PI-23c (900 mg, 31%).

To a mixture of compound PI-23c (200 mg, 0.551 mmol, 1.0 eq.) in MeOH (5 ml) was added KCN (72 mg, 1.1 mmol, 2.0 eq.) and (NH ₄ ) ₂ CO ₃ (211 mg, 2.2 mmol, 4.0 eq.). The mixture was stirred at room temperature for 12 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give compound PI-23d (100 mg, 42%).

To a mixture of PI-23d (100 mg, 0.23 mmol, 1.0 eq.) in MeOH (5 ml) was added NaOH (80 mg, 2.0 mmol, 10.0 eq.). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated to halve the amount of solvent, and then 1N hydrochloric acid was added. HCl to adjust pH=5. The mixture was filtered to give PC-23 (47 mg, 48%).

Obtaining a PC-24 connection:

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

Obtaining a PC-25 connection:

To a mixture of PI-23c (2.4 g, 6.61 mmol, 1.0 eq.) in toluene (40 ml) was added ethane-1,2-diol (3.7 g, 60 mmol, 10 eq.) and TsOH (56.5 mg, 0.33 mmol, 0.05 eq.). The mixture was heated at reflux for 12 hours under nitrogen. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 2:1) to give compound PI-25a (2.3 g, 85%).

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

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

To a mixture of PI-25c (1.0 g, 2.98 mmol, 1.0 eq.) in _MeOH (20 ml) was added KCN (38 mg, 5.96 mmol, 2.0 eq.) ) ₂ CO ₃ (1.14 g, 11.92 mmol, 4.0 eq.). The mixture was stirred at room temperature for 12 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-25 (215 mg, 18%) as a white solid.

Obtaining PC-26 and PC-27 connections:

To a mixture of 1-(bromomethyl)-3-methylbenzene (5.0 g, 27 mmol, 1.0 eq.) in DMF (150 mL) was added successively 1,4-hydroquinone (5.94 g, 54 mmol, 2.0 0 eq.) and K ₂ CO ₃ (14.9 g, 108 mmol, 4.0 eq.). The mixture was stirred at 80° C. for 3 hours under nitrogen. Then 3 M HCl was added to bring the pH=6-7. The mixture was extracted with EA and the organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 3:1) to give compound PI-26a (2.6 g, 45%).

To a mixture of PI-26a (1.0 g, 4.67 mmol, 1.0 eq.) in DMF (15 ml) were added successively 4-chloronicotinaldehyde (0.99 g, 7 mmol, 1.5 eq.) and K ₂ CO ₃ (1.5 g, 9.34 mmol, 2.0 eq.). The mixture was stirred at 80° C. for 3.5 hours under nitrogen. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The mixture was then diluted with H ₂ O (100 ml) and extracted with EA (3×100 ml). The combined organic layers were washed with saturated aqueous NH ₄ Cl (3×100 ml), brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 1:1) to give compound PI-26b (480 mg, 32%).

To a solution of compound PI-26b (480 mg, 1.5 mmol, 1.0 eq.) in MeOH (10 ml) was added (NH ₄ ) ₂ CO ₃ (578 mg, 6.01 mmol, 4.0 eq.) and KCN (195 mg, 3 mmol, 2.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1-2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=6-7 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ 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 by 4-(bromomethyl)-2-methylpyridine.

Obtaining PC-28 and PC-29 connections:

To a mixture of 3-(chloromethyl)benzoic acid (1.7 g, 9.965 mmol, 1.0 eq.) in DCM (50 ml) was added (COCl) ₂ (1.7 ml, 19.931 mmol, 2.0 eq.) drop by drop at 0°C. The mixture was stirred for 1 hour until the solution became clear. The mixture was then concentrated under reduced pressure. To the mixture of the residue in DCM was added a solution of NH ₃ in THF at -10°C. The mixture was stirred for 0.5 and then concentrated under reduced pressure to give compound PI-28a (1.3 g, 77%)

To a mixture of compound PI-28a (1.0 g, 5.92 mmol, 1.0 eq.) in DMF (50 ml) was added successively compound PI-a.1 (1.36 g, 5.92 mmol, 1. 0 eq.) and K ₂ CO ₃ (2.45 g, 17.76 mmol, 3.0 eq.). The mixture was stirred at room temperature for 16 hours under nitrogen. Then 3 M HCl was added to bring the pH=6-7. The mixture was extracted with EA and the organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound PI-28b (850 mg, 40%).

To a mixture of compound PI-28b (850 mg, 2.33 mmol, 1.0 eq.) in MeOH (10 ml) were added KCN (303 mg, 4.66 mmol, 2.0 eq.) and (NH ₄ ) ₂ CO ₃ (904 mg, 9.33 mmol, 4.0 eq.). The mixture was stirred at 45° C. for 16 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-28 (500 mg, 49%) as a white solid.

Compound PC-29 was synthesized by the same procedure, except that NH ₃ was replaced by MeNH ₂ .

Obtaining PC-30, PC-31, PC-32 and PC-33 connections:

To a mixture of compound 3-8 (750 mg, 3.876 mmol, 1.0 eq.) in DMF (15 ml) were added successively compound PI-a.1 (895 mg, 3.876 mmol, 1.0 eq.) and K ₂ CO ₃ (2.14 g, 15.5 mmol, 4.0 eq.). The mixture was stirred at room temperature for 16 hours under nitrogen. Then 3 M HCl was added to bring the pH=6-7. The mixture was extracted with EA and the organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 1:1) to give compound PI-30 (610 mg, 36%).

To a solution of compound PI-30 (500 mg, 1.419 mmol, 1.0 eq.) in MeOH (6 ml) was added (NH ₄ ) ₂ CO ₃ (545 mg, 5.676 mmol, 4.0 eq.) and KCN (185 mg, 2.838 mmol, 2.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1-2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=6-7 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-30 (350 mg, 58%) as a white solid. 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, respectively.

Obtaining PC-34 and PC-36 connections:

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

Obtaining a PC-35 connection:

To a solution of compound PC-30 (400 mg, 0.95 mmol, 1.0 eq.) in CHCl ₃ (30 ml) was added TMS-I (1.35 ml, 9.5 mmol, 10.0 eq.). The mixture was stirred at 55° C. for 16 hours. 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 PC-35 (350 mg, 90%) as a white solid.

Obtaining a PC-37 connection:

Compound PC-37 was synthesized following the same procedure as the synthesis of compound PC-28, except that intermediate PC-28a was replaced by FI-18a.

Obtaining a PC-38 connection:

To a mixture of methyl 3-(chloromethyl)isonicotinate (800 mg, 4.32 mmol, 1.0 eq.) in DMF (10 mL) was added successively compound PI-b.1 (1.19 g, 4.32 mmol, 1 0 eq.) and CsCO ₃ (4.23 g, 12.97 mmol, 3.0 eq.). The mixture was stirred at room temperature for 16 hours under nitrogen. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The mixture was then diluted with H ₂ O (50 ml) and extracted with EA (3×50 ml). The combined organic layers were washed with saturated aqueous NH ₄ Cl (3×50 ml), brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound PI-38a (300 mg, 16%).

A solution of compound PI-38a (300 mg, 0.708 mmol, 1.0 eq.) in MeOH (10 ml) was purged with gaseous NH ₃ for 10 min at -78°C. The flask was sealed and the mixture was stirred at room temperature for 16 hours. Analysis of the reaction mixture by TLC 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%).

A mixture of compound PI-38b (180 mg, 0.440 mmol, 1.0 eq.) 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. Saturated NaHCO ₃ solution was added to the residue to adjust pH=8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give compound PI-38c (100 mg, 62%).

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

Obtaining PC-39 and PC-40 connections:

To a solution of compound PI-b.1 (738 mg, 2.68 mmol, 1.0 eq.) in THF (20 ml) was added successively the compound PS-4b (615 mg, 2.68 mmol, 1.0 eq.) , PPh ₃ (1.4 g, 5.37 mmol, 2.0 eq.) and DEAD (934 mg, 5.37 mmol, 2.0 eq.) at 0°C. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then quenched with H ₂ O (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound PI-39a (490 mg, 37%).

To a mixture of compound PI-39a (300 mg, 0.617 mmol, 1.0 eq.) in dry THF (10 ml) was added LAH (47 mg, 1.23 mmol, 2.0 eq.) at 0° C. under atmospheric nitrogen. The mixture was stirred at 0°C for 1 h. Analysis of the reaction mixture by TLC showed complete conversion to the desired product. The reaction was quenched with Na ₂ SO ₄ ⋅10 H ₂ O (159 mg, 0.494 mmol, 0.8 eq.) 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%).

A mixture of compound PI-39b (150 mg, 0.379 mmol, 1.0 eq.) 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. Saturated NaHCO ₃ solution was added to the residue to adjust pH=8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give compound PI-39c (110 mg, 82%).

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

Compound PC-40 was synthesized following the same procedure, except that PS-4b was replaced by PS-4a.

Obtaining PC-41, PC-46, PC-54, and PC-55 Connections

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

To a stirred solution of compound PC-41 (100 mg, 0.238 mmol, 1.0 eq.) in DMF (2 ml) was added NaH (12 mg, 0.476 mmol, 2.0 eq.) at 0°C. After 10 minutes, CH ₃ I (68 mg, 0.476 mmol, 2.0 eq.) was added. After additional stirring at 0° C. for 0.5 h, the mixture was allowed to warm 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 phases were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-46 (40 mg, 37%) as a yellow solid.

To a stirred solution of compound PC-41 (300 mg, 0.714 mmol, 1.0 eq.) in DMF (5 ml) was added NaH (17 mg, 0.714 mmol, 1.0 eq.) at 0°C. After 10 minutes, CH ₃ I (101 mg, 0.714 mmol, 1.0 eq.) was added. After additional stirring at 0° C. for 0.5 h, the mixture was allowed to warm 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 phases were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-54 (45 mg, 14%) as a white solid.

To a solution of compound PC-16 (1 g, 2.46 mmol, 1.0 eq.) and 1-(chloromethyl)-4-methoxybenzene (461 mg, 2.96 mmol, 1.2 eq.) in DMF (10 ml) was added NaI (369 mg, 2.46 mol, 1.0 eq.) and K ₂ CO ₃ (679 mg, 4.92 mmol, 2.0 eq.). The mixture was stirred at room temperature for 16 hours. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The mixture was then diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PC-55 (130 mg, 34%) as a pink solid.

Obtaining PC-42, PC-50 and PC-51 connections:

A solution of NaBr (9.5 g, 92.5 mmol, 1.0 eq.) and Br ₂ (5.7 ml, 111 mmol, 1.2 eq.) in MeOH (100 ml). The mixture was stirred at room temperature for 14 hours. Analysis of the reaction mixture by TLC showed complete conversion to the desired product. Water was added to the reaction mixture and extracted with EA (3×100 ml). The organic layer was washed with brine and water, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography to give compound PI-42a (5 g, 33%).

To a mixture of compound PI-42a (5.0 g, 30.3 mmol, 1.0 eq.) in dry THF (50 ml) was added LAH (1.72 g, 45.5 mmol, 1.5 eq.) at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. Analysis of the reaction mixture by TLC showed complete conversion to the desired product. The reaction was quenched with Na ₂ SO ₄ ·10 H ₂ 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%).

To a stirred solution of compound PI-42b (1.0 g, 7.1 mmol, 1.5 eq.) in THF (10 ml) was added NaH (170.4 mg, 7.1 mmol, 1.5 eq.) at 0°C. After 30 minutes, 4-chloronicotinaldehyde (667.4 mg, 4.73 mmol, 1.0 eq.) was added at 0°C. The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with water and extracted with EA (3×10 ml). The combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound PI-42c (1.2 g, 100%).

To a mixture of compound PI-42c (200 mg, 0.82 mmol, 1.0 eq.) and 4-(chloromethyl)-2-methylpyridine (130 mg, 0.902 mmol, 1.1 eq.) in DMF (2 ml) K ₂ CO ₃ (340 mg, 2.46 mmol, 3.0 eq.) was added sequentially. The mixture was stirred at 50° C. for 3 hours under nitrogen. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The mixture was then poured into water and extracted with EA (3×5 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound PI-42d (150 mg, 52%).

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

Obtaining PC-48, PC-49 and PC-52 connections:

Compounds PC-48, PC-49 and PC-52 were synthesized by the same procedure as the synthesis of PC-42, except that the starting material m-cresol was replaced by o-cresol, 2-chlorophenol and 2-fluorophenol, respectively.

Obtaining PC-43 and PC-44 connections:

To a solution of 4-chloronicotinaldehyde (10 g, 70.92 mmol, 1.0 eq.) in DMF (100 ml) was added 4-mercaptobenzoic acid (13.1 g, 85.11 mmol, 1.2 eq.) and K ₂ CO ₃ (29.4 g, 0.213 mol, 3.0 eq.) at room temperature under nitrogen. The mixture was stirred at room temperature for 16 hours. Analysis of the reaction mixture by TLC 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, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-c.1 (11 g, 59%).

To a stirred solution of PI-c.1 (11 g, 42.47 mmol, 1.0 eq.) in THF (100 ml) was added TsOH (731 mg, 4.25 mmol, 0.1 eq.). After 10 minutes, ethane-1,2-diol (13.1 g, 0.212 mol, 5.0 eq.) in THF (50 ml) was added dropwise. The mixture was stirred at 110°C for 16 hours, the Reaction mixture was poured into a saturated solution of NaHCO ₃ (160 ml) and was extracted with EA (3×100 ml). The combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-c.2 (8 g, 62%).

To a mixture of PI-c.2 (8 g, 26.40 mmol, 1.0 eq.) in dry THF (100 ml) was added LAH (2 g, 52.81 mmol, 2.0 eq.) rapidly at 0° C in a nitrogen atmosphere. The mixture was stirred at 0°C for 1 h. Analysis of the reaction mixture by TLC showed complete conversion to the desired product. The reaction was quenched with Na ₂ SO ₄ ·10 H ₂ O (6.8 g, 21.12 mmol, 0.8 eq.) and the mixture was stirred for 0.5 h. The mixture was extracted and then the organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-c.3 (4 g, 52%).

To a mixture of PI-c.3 (1 g, 3.46 mmol, 1.0 eq.) in DCM (10 ml) was added S°Cl ₂ (824 mg, 6.92 mmol, 2.0 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0°C for 4 hours. Analysis of the reaction mixture by TLC showed complete conversion to the desired product. NaHCO ₃ (aq) was added to the reaction mixture to adjust pH >7 and extracted with DCM. Then the organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-c.4 (1 g, 94%).

To a solution of compound PI-c.4 (500 mg, 1.63 mmol, 1.0 eq.) in DMF (5 ml) was added m-cresol (211 mg, 1.95 mmol, 1.2 eq.) and K ₂ CO ₃ (675 mg, 4.89 mmol, 3.0 eq.) at room temperature under nitrogen. The mixture was stirred at room temperature for 16 hours. Analysis of the reaction mixture by TLC 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, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound PI-43a (230 mg, 37%).

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

To a solution of PI-43b (150 mg, 0.448 mmol, 1.0 eq.) in MeOH (3 ml) was added (NH ₄ ) ₂ CO ₃ (172 mg, 1.79 mmol, 4.0 eq.) and KCN ( 58 mg, 0.896 mmol, 2.0 eq.). The mixture was stirred at 40°C for 12 hours. 3 M HCl was added to the reaction mixture to adjust pH=1-2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=6-7 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-43 (40 mg, 22%) as a white solid.

Compound PC-44 was synthesized in the same manner, except that m-cresol was replaced by 2-methylpyridin-4-ol.

Obtaining a PC-45 connection:

To a mixture of 4-hydroxy-6-methylnicotinic acid (10 g, 65.4 mmol, 1.0 eq.) in DCM (100 ml), solution (C°Cl) ₂ (12.35 g, 98.1 mmol, 1.5 eq.) was added dropwise at 0°C. The mixture was stirred for 12 hours. Analysis of the reaction mixture by TLC showed complete conversion to the desired product. The reaction mixture was dried over Na ₂ SO ₄ and concentrated in vacuo to give crude PI-45a (10 g, crude).

A mixture of PI-45a (10 g, 52.9 mmol, 1.0 equiv.) in MeOH (100 ml) was stirred at room temperature for 2 hours. Analysis of the reaction mixture by TLC showed complete conversion to the desired product. The reaction mixture was dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by silica gel chromatography to give crude PI-45b (12 g, 100%).

To a mixture of PI-45b (12.0 g, 64.86 mmol, 1.0 eq) in dry THF (100 mL) was added LAH (3.69 g, 97.3 mmol, 1.5 eq) rapidly at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The reaction was quenched with Na ₂ SO ₄ ·10 H ₂ 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%).

To a stirred solution of PI-45c (6.0 g, 38.2 mmol, 1.0 eq.) in DCM (60 ml) was added Dess-Martin periodinan (32.4 g, 76.4 mmol, 2.0 eq. ). The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with EA (3×60 ml). The combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-45d (2.3 g, 39%).

To a mixture of PI-45d (2.3 g, 14.8 mmol, 1.0 eq.) and 4-mercaptophenol (2.06 g, 16.3 mmol, 1.1 eq.) in DMF (25 ml) in series K ₂ CO ₃ (6.14 g, 44.4 mmol, 3.0 eq.) was added. The mixture was stirred at 50° C. for 3 hours under nitrogen. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The mixture was then poured into water and extracted with EA (3×30 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give PI-45e (1.6 g, 44%).

To a mixture of PI-45e (1.0 g, 4.08 mmol, 1.0 eq.) and 4-(chloromethyl)-2-methylpyridine (633 mg, 4.48 mmol, 1.1 eq.) in DMF ( 10 ml) was successively added K ₂ CO ₃ (1.69 g, 12.24 mmol, 3.0 eq.). The mixture was stirred at 50° C. for 3 hours under nitrogen. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The mixture was then poured into water and extracted with EA (3×10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give PI-45f (700 mg, 49%).

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

Obtaining PC-47 and PC-53 connections:

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

Obtaining a PC-56 connection:

TEA ₍ 25.8 g, 255.6 mmol, 2.0 eq) and DMAP (1.56 g, 12.78 mmol, 0.05 eq) at -0°C. The mixture was stirred at room temperature for 16 hours under nitrogen. The mixture was then quenched with saturated NH ₄ Cl solution. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-56a (8.1 g, 28%).

To a solution of PI-56a (5 g, 22.19 mmol, 1.0 eq.) in DMF (40 ml) was added 4-chloronicotinaldehyde (3.14 g, 22.19 mmol, 1.0 eq.) and K ₂ CO ₃ (9.12 g, 66.57 mmol, 3.0 eq.) at room temperature under nitrogen. The mixture was stirred at room temperature for 16 hours. Analysis of the reaction mixture by TLC 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, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-56b (1.4 g, 19%).

Ethane-1,2-diol (2.25 g, 36.3 mmol, 20 eq.) .) and TsOH (0.02 g, 0.09 mmol, 0.05 eq.). The mixture was heated at reflux for 12 hours under nitrogen. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give PI-56c (0.25 g, 36%).

To a solution of PI-56c (0.2 g, 0.53 mmol, 1.0 eq.) in DMF (5 ml) was added the compound 4-(chloromethyl)-2-methylpyridine (0.09 g, 0.64 mmol, 1.2 eq.) and NaH (14 mg, 0.58 mmol, 1.1 eq., 60%) at room temperature under nitrogen. The mixture was stirred at room temperature for 16 hours. Analysis of the reaction mixture by TLC 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, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-56d (0.13 g, 51%).

A mixture of PI-56d (250 mg, 0.52 mmol, 1.0 eq.) 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 . Saturated NaHCO ₃ solution was added to the residue to adjust pH=8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-56e (110 mg, 63%).

To a solution of PI-56e (110 mg, 0.33 mmol, 1.0 eq.) in MeOH (3 ml) was added (NH ₄ ) ₂ CO ₃ (126 mg, 1.31 mmol, 4.0 eq.) and KCN (43 mg, 0.66 mmol, 2.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=7~8 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-56 (50 mg, 37%) as a white solid.

Obtaining a PC-57 connection:

HCl (80 ml), H ₂ SO ₄ (30 ml) and _{NaNO 2} (6, 6 g, 95.84 mmol, 1.2 eq.) at 0°C. The mixture was stirred at 0° C. for 0.5 h. Urea (0.46 g, 7.99 mmol, 0.1 eq.) was then added. After 15 min, a solution of KI (26.5 g, 159.74 mmol, 2.0 eq.) in H ₂ O (1.5 L) was added dropwise at 0°C. The mixture was stirred at 0° C. for 5 hours. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-57a (7.3 g, 39%).

A mixture of PI-57a (1.8 g, 3.83 mmol, 1.0 eq.) 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 dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-57b (0.9 g, 50%).

To a solution of PI-57b (230 mg, 1 mmol, 1.0 eq.) in DMF (10 ml) was added 4-chloronicotinaldehyde (140 mg, 1 mmol, 1.0 eq.) and K ₂ CO ₃ (276 mg, 2 mmol, 2.0 eq.). The mixture was stirred at room temperature for 16 hours. Water (30 ml) was then added and extracted with ethyl acetate (20 ml x 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-57c (0.3 g, 88%).

To a solution of PI-57c (1 g, 2.9 mmol, 1.0 eq) and 4-ethynyl-2-methylpyridine (0.41 g, 3.5 mmol, 1.2 eq) in TEA (1, 19 g, 0.29 mmol, 0.1 eq.) was added Pd(Ph ₃ P) ₂ Cl ₂ (0.21 g, 0.29 mmol, 0.1 eq.) and CuI (0.06 g, 0 .29 mmol, 0.1 equiv.) in a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours under nitrogen. The mixture was then quenched with saturated NH ₄ Cl solution. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-57d (0.8 g, 83%).

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

To a solution of PI-57e (180 mg, 0.54 mmol, 1.0 eq.) in MeOH (5 ml) was added (NH ₄ ) ₂ CO ₃ (206 mg, 2.15 mmol, 4.0 eq.) and KCN (70 mg, 1.08 mmol, 2.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=7~8 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give PC-57 (60 mg, 27%) as a yellow solid.

Obtaining a PC-58 connection:

A mixture of PI-56d (400 mg, 0.83 mmol, 1.0 eq.) in TFA/DCM (1 ml/3 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Saturated NaHCO ₃ solution was added to the residue to adjust pH=8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give PI-58a (350 mg, 100%), which was used in the next step without further purification.

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

A mixture of PI-58b (210 mg, 0.53 mmol, 1.0 eq.) 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 . Saturated NaHCO ₃ solution was added to the residue to adjust pH=8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give PI-58c (160 mg, 86%), which was used in the next step without further purification.

To a solution of PI-58c (180 mg, 0.52 mmol, 1.0 eq.) in MeOH (3 ml) was added (NH ₄ ) ₂ CO ₃ (198 mg, 2.06 mmol, 4.0 eq.) and KCN (67 mg, 1.03 mmol, 2.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=7~8 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PC-58 (118 mg, 54%) as a yellow solid.

Obtaining a PC-59 connection:

TBSCl (13 .8 g, 91.64 mmol, 2.0 eq) at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was then quenched with saturated NH ₄ Cl solution (100 ml). The mixture was extracted with ethyl acetate (50 mlx3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound PI-59a (7.2 g, 70%).

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

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

To a solution of PI-59c (5.1 g, 20.53 mmol, 1.0 eq.) in ethanol/H2O (100/17 ml) was added NaOH (6.9 g, 172.5 mmol, 8.4 eq. ). The mixture was stirred at 90° C. for 2 hours. The mixture was then cooled to room temperature and 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, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-59d (3.2 g, 99%).

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

To a mixture of PI-59e (0.53 g, 3.48 mmol, 1.0 eq.) in DCM (50 ml) was added SOCl ₂ (0.83 g, 6.96 mmol, 2.0 eq.) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (50 ml) and washed with saturated aqueous NaHCO ₃ , brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give PI-59f (0. 47 g, 79%).

To a solution of PI-59f (470 mg, 2.75 mmol, 1.0 eq.) in DMF (20 ml) was added PI-a.1 (636 mg, 2.75 mmol, 1.0 eq.) and K ₂ CO ₃ (759 mg, 5.5 mmol, 2 eq.). The mixture was stirred at room temperature for 4 hours. The mixture was then diluted with water (50 ml) and extracted with ethyl acetate (30 ml x 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-59g (210 mg, 21%).

To a solution of PI-59g (400 mg, 1.09 mmol, 1.0 eq.) in MeOH (7 ml) was added (NH ₄ ) ₂ CO ₃ (419 mg, 4.38 mmol, 4.0 eq.) and KCN (141 mg, 2.19 mmol, 2.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=7~8 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PC-59 (52 mg, 11%) as a white solid.

Obtaining a PC-60 connection:

To a solution of PI-59f (470 mg, 2.75 mmol, 1.0 eq.) in DMF (20 ml) was added PI-a.2 (636 mg, 2.75 mmol, 1.0 eq.) and K ₂ CO ₃ (759 mg, 5.5 mmol, 2 eq.). The mixture was stirred at room temperature for 4 hours. The mixture was then diluted with water (50 ml) and extracted with ethyl acetate (30 ml x 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-60a (230 mg, 23%).

To a solution of PI-60a (230 mg, 0.63 mmol, 1.0 eq.) in MeOH (6 ml) was added (NH ₄ ) ₂ CO ₃ (241 mg, 2.51 mmol, 4.0 eq.) and KCN (81 mg, 1.26 mmol, 2.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=7~8 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PC-60 (53 mg, 19%) as a yellow solid.

Obtaining a PC-61 connection:

To a solution of 5-bromo-2-hydroxypyridine (5 g, 28.74 mmol, 1.0 eq.) in DMF (100 ml) was added 4-(chloromethyl)-2-methylpyridine (4.07 g, 28.74 mmol , 1.0 eq.) and K ₂ CO ₃ (7.93 g, 57.47 mmol, 2 eq.). The mixture was stirred at room temperature for 4 hours. The mixture was then diluted with water (200 ml) and extracted with ethyl acetate (100 ml x3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-61a (4.1 g, 51%).

To a mixture of PI-61a (1 g, 3.58 mmol, 1.0 eq.), 4-methoxy-α-toluenthiol (607 mg, 3.94 mmol, 1.1 eq.), xantphose (207 mg, 0 .36 mmol, 0.1 eq.) and Cs ₂ CO ₃ (1.75 g, 5.37 mmol, 1.5 eq.) in dioxane (30 ml) were added Pd ₂ (dba) ₃ (230 mg, 0 .25 mmol, 0.07 eq.) under nitrogen atmosphere. The mixture was stirred at 90° C. for 12 hours. The mixture was then filtered and extracted with water (50 ml) and ethyl acetate (30 ml x 3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-61b (0.8 g, 63%).

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

To a solution of PI-61c (600 mg, 2.58 mmol, 1.0 eq.) in THF (20 ml) was added NaH (103 mg, 2.58 mmol, 1 eq., 60%) at 0° C. under atmospheric nitrogen. The mixture was stirred at 0° C. for 1 hour. Then 4-chloronicotinaldehyde (365 mg, 2.58 mmol, 1.0 eq.) was added. The mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (30 ml x 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-61d (250 mg, 29%)

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

Obtaining a PC-62 connection:

To a solution of 4-iodophenol (2.2 g, 10 mmol, 1.0 eq.) and 4-ethynyl-2-methylpyridine (1.29 g, 11 mmol, 1.1 eq.) in DMF (30 ml) was added TEA (3.2 g, 30 mmol, 3 eq.), Pd(Ph ₃ P) ₂ Cl ₂ (1.4 g, 2 mmol, 0.2 eq.) and CuI (0.38 g, 2 mmol, 0.2 equiv.) in a nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours under nitrogen. The mixture was then quenched with saturated NH ₄ Cl solution (50 ml). The mixture was extracted with ethyl acetate (30 ml x 3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-62a (1.05 g, 45%).

To a solution of PI-62a (0.8 g, 3.82 mmol, 1.0 eq.) in DMF (40 ml) was added 4-chloronicotinaldehyde (0.54 g, 3.82 mmol, 1.0 eq.) and K ₂ CO ₃ (1.05 g, 7.64 mmol, 2 eq.). The mixture was stirred at 80° C. for 4 hours. The mixture was then diluted with water (100 ml) and extracted with ethyl acetate (50 mlx3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-62b (0.45 g, 37%).

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

To a solution of PI-62c (1.0 eq.) in MeOH (5 ml) was added (NH ₄ ) ₂ CO ₃ (4.0 eq.) and KCN (2.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=7~8 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give PC-62.

Obtaining a PC-63 connection:

To a mixture of 4-chloropyridine (100 g, 0.667 mol, 1.0 eq.) in dry THF (1 L) was quickly added LDA (2 M in THF, 733.26 ml, 1.467 mol, 2.2 eq.) at - 78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 1 h. Then propionaldehyde (74.1 g, 0.999 mol, 1.5 eq.) was added dropwise and the mixture was stirred for 1 h. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with ethyl acetate (3 x 500 ml). The organic layer was washed with brine and water, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA, 3:1) to give PI-63a (45 g, 48%).

To a mixture of PI-63a (26.3 g, 0.154 mol, 1.0 eq.) in acetone (300 ml) was added CrO ₃ (30.8 g, 0.308 mol, 2.0 eq.). The mixture was stirred at room temperature for 5 hours. The mixture was then 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%)

To a mixture of PI-63b (1 g, 4.67 mmol, 1.0 eq.) and 4-mercaptophenol (590 mg, 4.67 mmol, 1.0 eq.) in DMF (50 ml) was added K ₂ CO ₃ (1.29 g, 9.34 mmol, 2 eq.). The mixture was stirred at room temperature for 16 hours under nitrogen. The mixture was then quenched with H ₂ O (100 ml) and extracted with ethyl acetate (50 ml x3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-63c (1.2 g, 99%).

To a mixture of PI-63c (500 mg, 1.93 mmol, 1.0 eq.) and 4-(chloromethyl)-2-methylpyridine (409 mg, 2.89 mmol, 1.5 eq.) in DMF (20 ml ) was added K ₂ CO ₃ (798 mg, 5.78 mmol, 3 eq.). The mixture was stirred at 70° C. for 4 hours under nitrogen. The mixture was then quenched with H ₂ O (60 ml) and extracted with ethyl acetate (30 ml x 3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-63d (610 mg, 87%).

(NH ₄ ) ₂ CO ₃ (644 mg, 6.71 mmol, 4 0 eq.) and KCN (218 mg, 3.36 mmol, 2.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=7~8 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PC-63 (80 mg, 11%) as a white solid.

Obtaining a PC-64 connection:

To a mixture of 3-chloropyridine (100 g, 0.667 mol, 1.0 eq.) in dry THF (1 L) was added LDA (2 M in THF, 733.26 ml, 1.467 mol, 2.2 eq.) at - 78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 1 h. Then propionaldehyde (74.1 g, 0.999 mol, 1.5 eq.) was added dropwise and the mixture was stirred for 1 h. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with ethyl acetate (3 x 500 ml). The organic layer was washed with brine and water, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA, 3:1) to give PI-64a (45 g, 48%).

To a mixture of PI-64a (26.3 g, 0.154 mol, 1.0 eq.) in acetone (300 ml) was added CrO ₃ (30.8 g, 0.308 mol, 2.0 eq.). The mixture was stirred at room temperature for 5 hours. The mixture was then 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%)

To a mixture of PI-64b (1 g, 4.67 mmol, 1.0 eq.) and 4-mercaptophenol (590 mg, 4.67 mmol, 1.0 eq.) in DMF (50 ml) was added K ₂ CO ₃ (1.29 g, 9.34 mmol, 2 eq.). The mixture was stirred at room temperature for 16 hours under nitrogen. The mixture was then quenched with H ₂ O (100 ml) and extracted with ethyl acetate (50 mlx3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-64c (1.2 g, 99%).

To a mixture of PI-64c (500 mg, 1.93 mmol, 1.0 eq.) and 4-(chloromethyl)-2-methylpyridine (409 mg, 2.89 mmol, 1.5 eq.) in DMF (20 ml ) was added K ₂ CO ₃ (798 mg, 5.78 mmol, 3 eq.). The mixture was stirred at 70° C. for 4 hours under nitrogen. The mixture was then quenched with H ₂ O (60 ml) and extracted with ethyl acetate (30 ml x 3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PI-64d (610 mg, 87%).

(NH ₄ ) ₂ CO ₃ (637 mg, 7.68 mmol, 4 0 eq.) and KCN (248 mg, 3.83 mmol, 2.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=7~8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give PC-64 (242 mg, 29%) as a white solid.

Obtaining compounds OC-1 and OC-2:

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

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

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

Obtaining compounds OC-3 and OC-4:

To a mixture of 4-chloronicotinaldehyde (1 g, 7.1 mmol, 1.0 eq.) in MeOH (6 ml) was added KCN (0.92 mg, 14.2 mmol, 2.0 eq.) and (NH ₄ ) ₂ CO ₃ (2.71 g, 28.2 mmol, 4.0 eq.). The mixture was stirred at room temperature for 12 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give compound OI-3a (1.0 g, 66%) as a white solid.

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

To 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 successively K ₂ CO ₃ (182 mg, 1.31 mmol, 3.0 eq.). The mixture was stirred at 85° C. for 12 hours under nitrogen. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The mixture was then poured into water and extracted with EA (3×5 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give OC-3 (23.6 mg, 13%).

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

Obtaining an OC-5 compound:

To a mixture of 1-methyl-1H-pyrazole (16.4 g, 0.2 mol, 1.0 eq.) in dry THF (150 ml) was added n-BuLi (2.5 M in hexane, 96 ml, 0. 24 mol, 1.2 eq.) at -78° C. under nitrogen. The mixture was stirred at -78°C for 1 h. Then DMF (30.8 ml, 0.4 mol, 2.0 eq.) was added dropwise and the mixture was stirred for 1 h. Analysis of the reaction mixture by TLC showed complete conversion into the target product. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with EA (3 x 500 ml). The organic layer was washed with brine and water, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography to give compound OI-5a (12.7 g, 58%).

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

To a mixture of OI-5b (700 mg, 3.72 mmol, 1.0 eq.), 4a-1 (1.27 g, 4.09 mmol, 1.1 eq.), DPPF (42 mg, 0.503 mmol, 0.1 eq.) and DIEA (942 mg, 7.55 mmol, 1.5 eq.) in toluene (10 ml) was added Pd(dba) ₂ (150 mg, 0.260 mmol, 0.07 eq.) in the atmosphere nitrogen. The mixture was stirred at 110° C. for 16 hours. The mixture was then filtered and extracted with water and ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give OI-5c (120 mg, 10%)

To a mixture of compound OI-5c (140 mg, 0.414 mmol, 1.0 eq.) in MeOH (5 ml) was added KCN (54 mg, 0.828 mmol, 2.0 eq.) and (NH ₄ ) ₂ CO ₃ (159 mg, 1.66 mmol, 4.0 eq.). The mixture was stirred at room temperature for 12 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give compound OC-5 (67 mg, 40%) as a white solid.

Obtaining an OC-6 compound:

A solution of Br ₂ (3, 8 g, 23.77 mmol, 2.3 eq.) in Ac ₂ O (20 ml) at 0° C. under nitrogen. The mixture was stirred at room temperature for 3 hours. Analysis of the reaction mixture by TLC showed complete conversion to the desired product. The reaction was quenched with saturated aqueous NaHCO ₃ and was extracted with EA (3 x 20 ml). The organic layer was washed with brine and water, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography to give OI-6a (0.8 g, 44%).

To a mixture of OI-6a (1 g, 5.71 mmol, 1.0 eq.) and Cs ₂ CO ₃ (1.86 g, 5.71 mmol, 1.0 eq.) in DMF (50 ml) was added successively MeI (0.82 g, 5.71 mmol, 1.0 eq.). The mixture was stirred at room temperature for 3 hours under nitrogen. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The mixture was then poured into water and extracted with EA (3×30 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give OI-6b (0.7 g, 65%).

To a mixture of OI-6b (0.7 g, 3.7 mmol, 1.0 eq.), 4a-1 (1.27 g, 5.56 mmol, 1.5 eq.), CyPF-tBu (CAS: 158923-11-6) (21 mg, 0.04 mmol, 0.01 eq.) and Cs ₂ CO ₃ (942 mg, 7.55 mmol, 2.5 eq.) in DME (10 ml) were added Pd( OAc) ₂ (8 mg, 0.04 mmol, 0.01 eq) under nitrogen atmosphere. The mixture was stirred at 110° C. for 16 hours. The mixture was then filtered and extracted with water and ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give OI-6c (0.28 g, 22%)

To a solution of OI-6c (280 mg, 0.83 mmol, 1.0 eq.) in MeOH (5 ml) was added (NH ₄ ) ₂ CO ₃ (320 mg, 3.31 mmol, 4.0 eq.) and KCN (108 mg, 1.65 mmol, 2.0 eq.). The mixture was stirred at room temperature for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=6~7 and extracted ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give OC-6 (200 mg, 59%) as a white solid.

Preparation of compounds OC-7 and OC-10:

To a solution of ethyloxazole-5-carboxylate (0.28 g, 2.00 mmol) in THF/DMF (2/2 ml) was added Br ₂ (0.13 ml, 2.6 mmol, 1.3 eq.) and LHMDS (2.6 ml 2.6 mmol, 1.3 eq.) to obtain a reaction mixture which was stirred at -60°C for 4 hours. The reaction mixture was extracted with EA and water and the combined organic layer was dried over MgSO ₄ . The residue was purified by flash chromatography with EA/hexane (EA/hexane=1:4) to give OS-a.1 as a yellow oil (0.1 g, 30%).

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

To a solution of compound OS-a.2 (4.2 g, 15.85 mmol, 1.0 eq.) in DMF (40 mL) was added 4-(chloromethyl)-2-methylpyridine (2.2 g, 15.85 mmol, 1.0 eq.) and K ₂ CO ₃ (6.6 g, 47.55 mmol, 3.0 eq.) at room temperature under nitrogen atmosphere. The mixture was stirred at 30° C. for 16 hours. Analysis of the reaction mixture by TLC 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, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound OI-7a (2.5 g, 44%).

To a solution of OI-7a (1.4 g, 3.93 mmol, 1.0 eq.) in anhydrous THF (10 ml) was added DIBAL-H (1 M in hexane, 7.87 ml, 7.87 mmol, 2.0 eq.) dropwise at 0°C. The mixture was stirred at 0° C. for 2 hours under nitrogen. Analysis of the reaction mixture by TLC showed complete conversion to the target product. The mixture was then quenched with saturated Na₂SO₄⋅10H₂O (50 ml). The mixture was extracted with DCM (3×30 ml). The combined organic phases were washed with brine (2×60 ml), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give OI-7b (620 mg, 48%).

To a solution of OI-7b (620 mg, 1.89 mmol, 1.0 eq.) in DCM (5 ml) was added PDC (1.4 g, 3.78 mmol, 2.0 eq.) and K ₂ CO ₃ (782 mg, 5.67 mmol, 3.0 eq.) at room temperature under nitrogen. The mixture was stirred at 40° C. for 16 hours. Analysis of the reaction mixture by TLC 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, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give OI-7c (205 mg, 33%).

To 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 eq.) and KCN ( 82 mg, 1.26 mmol, 2.0 eq.). The mixture was stirred at room temperature for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1-2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=6-7 and extracted ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ 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 way, except that (chloromethyl)-2-methylpyridine was replaced by 1-(bromomethyl)-3-methylbenzene.

Obtaining an OC-8 compound:

Compound OC-8 was synthesized by the same procedure as the synthesis of compound OC-10, except that the starting material ethyloxazole-5-carboxylate was replaced with ethyloxazole-4-carboxylate.

Obtaining an OC-9 compound:

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

Preparation of the OC-11 Compound

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

Obtaining an OC-12 Compound:

To a solution of bis(4-hydroxyphenyl) disulfide (5.0 g, 19.97 mmol, 1.0 eq.) in DMF (100 mL) was added 4-(chloromethyl)-2-methylpyridine (6.22 g, 43. 94 mmol, 2.2 eq.) and K ₂ CO ₃ (8.2 g, 59.91 mmol, 3 eq.). The mixture was stirred at 45° C. for 12 hours. The mixture was then diluted with water (200 ml) and extracted with ethyl acetate (100 ml*3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give OI-12a (3.9 g, 42%).

To a solution of OI-12a (3.9 g, 8.46 mmol, 1.0 eq.) in THF (50 ml) was added PPh ₃ (2.22 g, 8.46 mmol, 1.0 eq.) and concentrated HCl (8.8 ml, 84.6 mmol, 10 eq.). The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water (100 ml) and extracted with ethyl acetate (50 ml x3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound OI-12b (2.1 g, 53%).

To a mixture of OI-12b (296 mg, 1.28 mmol, 1.1 eq.), OI-5b (220 mg, 1.16 mmol, 1.0 eq.), DPPF (10 mg, 0.12 mmol, 0.1 eq.) and DIEA (225 mg, 1.74 mmol, 1.5 eq.) in toluene (10 ml) was added Pd ₂ (dba) ₃ (47 mg, 0.08 mmol, 0.07 eq. ) in a nitrogen atmosphere. The mixture was stirred at 110° C. for 16 hours. The mixture was then filtered and extracted with water and ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give OI-12c (180 mg, 45%)

To a mixture of OI-12c (120 mg, 0.35 mmol, 1.0 eq.) in MeOH (4 ml) was added KCN (46 mg, 0.7 mmol, 2.0 eq.) and (NH ₄ ) ₂ CO ₃ (134 mg, 1.4 mmol, 4.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=7~8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give compound OC-12 (50 mg, 35%) as a white solid.

Getting Compound OC-13:

To a mixture of OI-6b (310 mg, 1.63 mmol, 1.0 eq.), OI-12b (414 mg, 1.79 mmol, 1.1 eq.), DPPF (88 mg, 0.16 mmol, 0.1 eq.) and DIEA (313 mg, 2.43 mmol, 1.5 eq.) in toluene (16 ml) was added Pd ₂ (dba) ₃ (104 mg, 0.11 mmol, 0.07 eq. ) in a nitrogen atmosphere. The mixture was stirred at 110° C. for 16 hours. The mixture was then filtered and extracted with water (50 ml) and ethyl acetate (30 ml x 3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give OI-13a (400 mg, 72%)

To a mixture of OI-13a (370 mg, 1.09 mmol, 1.0 eq.) in MeOH (10 ml) was added KCN (142 mg, 2.18 mmol, 2.0 eq.) and (NH ₄ ) ₂ CO ₃ (418 mg, 4.36 mmol, 4.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=7~8 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give OC-13 (73 mg, 16%) as a white solid.

Obtaining an OC-14 Compound:

To a mixture of 4-imidazolecarboxaldehyde (6 g, 62.44 mmol, 1.0 eq.) in THF (60 ml) was added NaH (3 g, 74.9 mmol, 1.2 eq.) at room temperature. After 10 min, the mixture was cooled to -78°C and MeI (10.5 g, 74.9 mmol, 1.2 eq.) was added. The mixture was then gradually warmed to room temperature and stirred for 18 hours. 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%).

To a solution of OI-14a (4 g, 36.36 mmol, 1.0 eq.) in chloroform (40 ml) was added NBS (7.12 g, 40 mmol, 1.1 eq.). The mixture was stirred at 70°C for 3 hours Then the mixture was cooled to room temperature and diluted with saturated aqueous Na ₂ CO ₃ (50 ml) and DCM (100 ml). The organic layer was washed with brine and water, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography to give OI-14b (333 mg, 4.8%).

To a mixture of OI-14b (333 mg, 1.76 mmol, 1.0 eq.), compound OI-12b (448 mg, 1.94 mmol, 1.1 eq.), DPPF (100 mg, 0.18 mmol , 0.1 eq.) and DIEA (340 mg, 2.64 mmol, 1.5 eq.) in toluene (20 ml) were added Pd ₂ (dba) ₃ (113 mg, 0.12 mmol, 0.07 eq. .) in a nitrogen atmosphere. The mixture was stirred at 110° C. for 16 hours. The mixture was then filtered and extracted with water (50 ml) and ethyl acetate (30 ml x 3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give OI-14c (261 mg, 43%)

To a mixture of OI-14c (261 mg, 0.77 mmol, 1.0 eq.) in MeOH (5 ml) was added KCN (100 mg, 1.53 mmol, 2.0 eq.) and (NH ₄ ) ₂ CO ₃ (295 mg, 3.08 mmol, 4.0 eq.). The mixture was stirred at 45°C for 16 hours. 3 M HCl was added to the reaction mixture to adjust pH=1~2 and stirred at room temperature for 1 hour, then saturated aqueous NaHCO ₃ was added to adjust pH=7~8 and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give OC-14 (183 mg, 58%) as a white solid.

biological testing

Example 1 MMP Inhibition Assays

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

Enzyme and compounds were pre-incubated on a well mixing shaker. After an hour of mixing, a fluorogenic substrate was added to each well. The reaction mixture without enzyme was used as a blank control in the plate. The plate was then loaded into a plate reader to measure fluorescence intensity at excitation/emission wavelengths of 340 nm/440 nm every 10 minutes for at least 1 hour at 37°C. The IC ₅₀ of each compound in MMP-12 inhibition was determined using the reading taken at time point 30 minutes. The results for each compound tested are shown in Table 1.

Example 2 Selectivity Analysis

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. IC ₅₀ compounds for other recombinant human MMPs were determined as described in Example 1 above and are shown in Table 2.

Table 2: Selectivity Profile of MMP-12 Compounds According to Embodiments of the Application

A=less than 10 nM, B=10 nM to 100 nM, C=100 nM to 1000 nM, D=1000 nM to 10000 nM, E=greater than 10000 nM

The results in Table 2 above show that the compounds according to embodiments of the 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.

Example 3 Efficacy Studies of MMP-12 Inhibitors in the SD Rat Kidney Fibrosis Model by Unilateral Ureter Occlusion (UUO)

This study was to evaluate the therapeutic efficacy of the MMP-12 inhibitor, PC-16, in a model of renal fibrosis in unilateral ureteral occlusion (UUO). Male Sprague Dawley (SD) rats (180-220 g, n=71) were used in this study. Animals were randomly divided into 4 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-3, n=10), PC-16 20 mg/kg/day group (group-4, n=9). Animals were anesthetized by inhalation of 2.5% isoflurane. The left ureter was ligated to create a unilateral ureteral occlusion (UUO) model to induce renal fibrosis. Test formulation PC-16 was administered twice a day orally after modeling for 14 days. Peripheral serum was obtained before modeling and at day-15 (one day after the last dose). All animals were euthanized and processed to study the pathology of the left kidney.

Treatment with PC-16 at 20 mg/kg/day somewhat limited the increase in blood urea nitrogen (BUN) compared to the vehicle group, however, all data showed no statistically significant difference compared to the reference group. Serum creatinine levels showed the same changes as in BUN.

Histologically, the left kidney showed significant morphological changes compared to UUO, including pelvic dilatation, renal medulla and cortical atropia and cerebral cortex, tubular epithelial cell flattening and tubular dilation, inflammation, and necrosis. Interstitial fibrosis was clearly observed in the pelvic wall, medulla and cortex. PC-16 treatment showed a clear dose-dependent effect, and the 20 mg/kg/day dose was more effective than the 2 mg/kg/day dose (p<0.01). Semi-quantitative evaluation of interstitial inflammation in the cortex showed a significant reduction with PC-16 treatment and showed a dose-dependent efficacy of PC-16. Semi-quantitative evaluation of interstitial fibrosis in the cortex showed a significant reduction in fibrosis score with PC-16 treatment in all dose groups. In the PC-16 treatment groups, a clear dose-dependent effect was observed.

Analysis of immunohistochemical (IHC) staining in the region of the cortex of the left kidney in animals treated with PC-16 showed a significant reduction in collagen-I deposition at a dose of 20 mg/kg/day (P<0.05) with dose-dependent reduction observed with PC-1 treatment . It also showed a significant reduction in collagen-IV deposition at PC-16 6 mg/kg/day (P < 0.05), PC-16 20 mg/kg/day, with a dose-dependent reduction observed with PC-16 treatment.

In conclusion, UUO caused significant renal cortical damage, inflammation, and interstitial fibrosis within 15 days of simulation. PC-16 treatment had a clear dose-dependent efficacy in limiting kidney damage, interstitial inflammation, or interstitial fibrosis. Analysis of biomarkers associated with fibrosis showed that PC-16 treatment reduced the associated collagen deposition (collagen-I and IV) in the area of the cortex of the injured kidney.

Detailed experimental methods

Animals: Gender: Male, SD rats, 180-220 g, total 71. Certificate: 11400700272659, Beijing Vital River Laboratory Animal Technology Co., Ltd., China. Animal Management: Animals were maintained in a temperature controlled environment with a 12 hour light/12 hour dark cycle and free access to food and water. Experimental procedures were carried out according to IACUC guidelines at the KCI Animal Research Center (SuZhou) Biotech Inc. (KCI). Model creation. A total of 35 male SD rats were used in this study. After anesthesia with inhalation of 2.5% isoflurane, the abdomen of the animal was opened surgically. The left ureter was exposed and ligated adjacent to the bladder to create a UUO model. After confirming the absence of bleeding, the abdominal wall was closed in layers. Animals were kept under a temperature controlled pad (37° C.) to recover from anesthesia and then transferred to housing cages with normal food and water.

Experimental grouping: UUO model animals were divided into 7 groups randomly as vehicle group (group-1, n=8), PC-16 2 mg/kg/day (group-5, n=9), PC-16 6 mg/kg/day (group-6, n=10), PC-16 20 mg/kg/day (group-7, n=9) (Table 4.1). Dosing regimen: All study drugs were designed for oral administration via gastric perfusion. Study formulations were designed to deliver twice daily starting on the same simulation day for 14 days (Table 4.1). Endpoints: 1) Blood collection: all animals in each group were collected peripheral blood and received sera before modeling and on the 15th day (one day after the last injection), stored at -80°C. All animals were euthanized according to KCI SOP. After confirming the death of the animal without respiration and heartbeat, the left kidney was perfused with cold PBS, then with 10% neutral formalin, and collected for further pathology study. 2) Determination of BUN and Serum Creatinine: Serum BUN and creatinine levels were determined using a Hitachi 7060 automatic chemistry analyzer and related test kits. 3) Examination for kidney pathology: 3a) H&E staining and kidney analysis: After pathological SOP KCI, all left kidneys were fixed in 10% formalin for at least 24 hours at room temperature. After fixation, the kidney was cut longitudinally to obtain the largest surface area, and dehydrated in graded ethanol, cleaned with xylene, and embedded in paraffin. Thin sections (3 μm) were placed on glass slides, deparaffinized, rehydrated in distilled water and stained with hematoxylin and eosin (H&E). All stained slides were scanned using a NanoZoomer Digital Pathology Scanner (S210, Hamamaci, Japan). Semi-quantitative assessment of the degree of flattening and dilatation of the tubular epithelium was scored 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. Semi-quantitative assessment of tubular necrosis is scored from 0 to 3 according to the percentage of tubular involvement: score 0=no necrosis; score 1=necrosis <25%; score 2=necrosis 25-50%; score 3=necrosis >50%. Mean tubular flattening, dilatation, and tubular necrosis were presented as total tubular lesions. The semi-quantitative score for interstitial inflammation was scored from 0 to 4 according to the degree of inflammatory cell infiltration: score 0=no inflammatory cells; score 1=slight infiltration of inflammatory cells; score 2=moderate inflammatory cell infiltration; score 3=strong infiltration of inflammatory cells; score 4=extensive inflammatory cell infiltration. 3b) Masson's trichrome stains and analysis: Thin sections (3 μm) were placed on glass slides, deparaffinized, rehydrated in distilled water and stained with Masson's trichrome. All stained slides were scanned using a NanoZoomer Digital Pathology Scanner (S210, Hamamaci, Japan). A semi-quantitative score for cortical interstitial fibrosis with five different fields at x10 magnification is randomly selected from the renal cortex scoring using the following scoring system from 0 to 4 according to the percentage of interstitial fibrosis involved: score 0=no fibrosis; score 1=fibrosis <10%; score 2=fibrosis 10-25%; score 3=fibrosis 25-75%; score 4=fibrosis >75%. 3c) IHC staining and kidney analysis: all left kidneys from each group (eight right kidneys from the reference group) were processed for biomarker analysis using IHC methods such as collagen-I (Abcam, Cat# ab34710), collagen-IV (Abcam, Cat# ab6586). IHC Staining was processed according to the standard IHC protocol in KCI. The stained slides were then scanned with a Hamamatsu NanoZoomer Digital Pathology S210 Slide Scanner and analyzed using software to obtain area of positive staining/area of analysis (%). 4) Statistical analysis: Graphpad, prism 5.0 was used for all statistical analyses, p value <0.05 was considered significant. All data are presented as mean±SEM. Differences between groups were determined using either Bonferroni test of variance or Student's t-test.

Table 4.1: Experimental groups of animals Group N OP CPD Conc. mg/ml Dose ml/kg Dose mg/kg Group-1 9 UUO carrier N/A 10 N/A Group-2 9 UUO PC-16 0.1 mg/ml 10 2 mg/kg/d twice daily Group-3 9 UUO PC-16 0.3 mg/ml 10 6 mg/kg/d twice daily Group-4 9 UUO PC-16 1 mg/ml 10 20 mg/kg/d twice daily

Results:

a) Physiological changes of the animals during the experimental periods: Several animals died during the experimental period, which were considered as a failed model, for example, rupture of the ureter during surgery, which caused peritonitis. The number of dead animals in each group is shown in Table 4.1.

b) Changes in serum BUN and creatinine levels: Serum BUN levels in all animals were increased after UUO on day 15 compared to pre-simulation (p<0.001). Treatment with PC-16 at 20 mg/kg/day showed the same result (Fig. 1A); all data showed no statistically significant difference compared to the reference group. Serum creatinine levels showed the same changes as in BUN (Fig. 1B).

c) Changes in the Lesion of the Left Kidney-Tubular Injury: After 15 days of UUO, the left kidney showed an enlarged pelvic cavity in all animals. The renal cortex presented significant atrophy with varying degrees of tubular epithelial cell flattening, tubular dilation and infiltration with interstitial inflammatory cells, and several foci of tubular necrosis (Fig. 1C). PC-16 treatment presented a clear dose-dependent effect, and the 20 mg/kg/day dose was more effective than the 2 mg/kg/day dose (p<0.01) (FIG. 1D (I)).

d) Changes in Left Kidney Involvement-Interstitial Inflammation: A semi-quantitative assessment of interstitial inflammation in the cortex showed a significant reduction with PC-16 treatment and showed a dose-dependent efficacy of PC-16 (FIG. 1D(II)).

e) Changes in the lesion of the left kidney-Cortical interstitial fibrosis: After 15 days of UUO, the pelvic cavity, medulla region, and cortical region were observed in the left kidney with significant interstitial fibrosis in all animals. Interstitial fibrosis in the cortical region was analyzed and showed varying degrees with the tested CPDs (FIG. 1E). A semi-quantitative assessment of interstitial fibrosis in the cortex showed a significant reduction in fibrosis score with PC-16 treatment at 20 mg/kg/day (p<0.001). A clear dose-dependent effect was observed in the PC-16 treatment groups (FIG. 1F).

f) Pathological analysis of several biomarkers in the left kidney: Collagen-I: analysis of IHC staining in the cortical region of the left kidney in animals treated with PC-16 showed a significant reduction in collagen-I deposition at a dose of 20 mg/kg/day (p<0 .05); tracking dose-dependent decline in PC-16 treatment groups (FIG. 1G(I) and FIG. 1H(I)). Collagen-IV: IHC staining in the cortical region of the left kidney in PC-16-treated animals showed a significant reduction in collagen-IV deposition at 20 mg/kg/day (p<0.05); tracking dose-dependent decline with PC-16 treatment (FIG. 1G(II) and FIG. 1H(II)).

Links

1. US 7179831.

2. WO 02/096426.

3. US 2004/0067996.

4. WO 2004/108086.

5. WO 02/074752.

6. WO 2004/020415.

Claims (79)

1. Compound of formula (II)

(II) or a pharmaceutically acceptable salt thereof, where ring B is pyridinyl or thiophenyl; ring C is phenyl; ring D is phenyl or pyridinyl; X is S; Y is O; Z is CH ₂ ; R ₁ is hydrogen or C _1-6 alkyl; each R ₂ is independently selected from the group consisting of C _1-6 alkyl, hydroxyl, C _1-6 alkoxy, amide, and hydroxyC _1-6 alkyl; each R ₃ is independently selected from the group consisting of hydrogen, C _1-6 alkyl and halogen; R ₄ is hydrogen; R ₅ is hydrogen; m is 1, 2, 3, or 4; And n is 1, 2, 3, 4, or 5. 2. The compound according to claim 1, where each of R ₁ , R ₄ and R ₅ represents hydrogen. 3. A compound according to claim 1 wherein ring B is pyridinyl. 4. A compound according to claim 3, wherein the compound is 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):

or a pharmaceutically acceptable salt thereof, where R ₁ represents hydrogen, -CH ₃ or -CH ₂ CH ₃ ; R ₃ is hydrogen, -F, -Cl, or CH ₃ ; R ₂ is -CH ₃ , -CH ₂ OH, -OH, -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. 5. A compound according to claim 1 wherein ring B is thiophenyl. 6. A compound according to claim 5, wherein the compound is a compound of formula (IV)

or a pharmaceutically acceptable salt thereof, where each of R ₁ , R ₄ and R ₅ represents 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; And n is 0 or 1. 7. The compound according to claim 1, which is a compound of formula (I-a)

or a pharmaceutically acceptable salt thereof, where ring B is pyridinyl; Q is CH or N; R ₁ is hydrogen, -CH ₃ or -CH ₂ CH ₃ ; R ₂ is selected from the group consisting of -CH ₃ , -C(O)NH ₂ , -CH ₂ OH, -OCH ₃ or -OH. 8. The compound according to claim 7, where each of R ₁ , R ₄ and R ₅ represents hydrogen. 9. A compound selected from the group consisting of:

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, or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 9, which is a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition that inhibits macrophage elastase (MMP-12), comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10 and at least one pharmaceutically acceptable carrier. 12. A method for inhibiting macrophage elastase (MMP-12) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to claim 11. 13. 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 claim 11, 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 disease kidney disease (CKD), Alport syndrome and nephritis.

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