Heteroaromatic inhibitors of astacin proteinases

Abstract

To provide a compound useful as inhibitors of astacin metalloproteinases, in particular procollagen C-proteinase (PCP) enzymes, meprins, ovastacin and / or nematode astacins; more particularly human or mammalian meprin α, meprin β, BMP-1, ovastacin and / or DPY-31 from nematodes.SOLUTION: The present invention relates to novel hydroxamic acid derivatives with the following structure; pharmaceutical compositions comprising such compounds; methods for treatment or prophylaxis of diseases or conditions, especially such that are related to the metalloproteinases; and compounds and pharmaceutical compositions for use in such methods.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to astacin metalloproteinases, particularly procollagen C-proteinases. (PCP) enzymes, meprin, ovastacin, and / or nematode astacin; more particularly, human or mammalian meprin α, meprin β, BMP-1, ovastatin, and / or DP derived from nematodes. Novel hydroxamic acid derivatives useful as inhibitors of Y-31; compounds containing such compounds Pharmaceutical compositions; diseases or disorders, especially those associated with said metalloproteinases Methods of treatment or prevention; and compounds and pharmaceutical compositions for use in such methods Pertaining to things. [Background technology]

[0002] (Background technology) Proteinases from the astacin family are a wide variety of enzymes occurring in lower and higher organisms. Astacin represents a group of metalloproteinases. Astacin is a protein of the metzincin superfamily. A subfamily of enzymes, all of which share a conserved zinc bond in their active site. The conserved methionine-containing turn (Met-turn) that backs the zinc site and share a very similar three-dimensional structure of the catalytic domain of the ts Med.(2008), 29(5): 309-328). In the human organism, at least one member of the astacin family four enzymes: bone morphogenetic protein 1 (BMP-1), two meprins (meprin α and meprin β), Additionally, nematode parasites such as Trichinella spiralis and hookworms are known to inhibit the growth of nematodes. They secrete a variety of astacins found throughout the taxon (Nemathelminthes).

[0003] BMP-1 and meprin are involved in collagen formation and therefore in the pathological formation of connective tissue. It plays a role in a variety of related diseases, such as fibrotic diseases including pulmonary fibrosis and keloids. Furthermore, meprin has been shown to be effective in treating various types of cancer, Alzheimer's disease, It has been described to be associated with acute renal failure and chronic inflammatory bowel disease. Inhibitors of this disorder are novel candidates for the treatment of such diseases.

[0004] Similarly, ovastatin plays a role in reproduction. When an oocyte is fertilized, it causes a pellucida Zygospermia (ZPH) occurs, which is induced by ovastacin activity and is associated with polyspermy. Provides mechanical protection to the fertilized egg by establishing a barrier to ensure normal embryo development. However, if such hardening occurs too early or in the absence of fertilization, Infertility can occur even in this case. Therefore, inhibition of ovastacin may affect the realization of having a child. to address unmet needs and / or in the context of in vitro fertilization and reproductive medicine This may be a novel approach.

[0005] Furthermore, a number of astacin proteases have been identified in C. elegans. Nematode infections are particularly prevalent in livestock farming. Furthermore, nematode parasites contribute to many tropical diseases. Inhibition of the enzyme prevents the formation of the outer protective layer, resulting in reduced growth or death of the nematodes. Therefore, inhibitors of such nematode astacins may be novel therapeutic agents for the treatment of parasitic infections. It is an insecticide.

[0006] (Metzincin and Astacin families) As mentioned above, astacin is a multi-domain metalloproteinase with pleiotropic functions in metabolism. A family of peptidases. They are either secreted or membrane-anchored and By being synthesized as an active zymogen and colocalizing with protein inhibitors Distinct family members contain an N-terminal signal peptide and a promoter. -segment, zinc-dependent catalytic domain, further downstream extracellular domain, transmembrane anchor , and a cytosolic domain. The catalytic domain of the precursor is structurally characterized, with an active site groove separating the N-terminal subdomain. Contains a compact, ~200-residue zinc-dependent region that can be divided into a C-terminal and a D-terminal subdomain Astacin has been shown to possess an extended zinc-binding motif. [ka] This motif contains three metal ligands and places astacin in the metzincin family. In unbound mature astacin, the conserved chiral residue is The tyrosine arcs upon binding of a substrate or inhibitor in a "tyrosine switch" action. Another characteristic feature of the astacin catalytic domain is that it acts as an additional zinc ligand that moves along the sigma. The main structural elements are three large α-helices and a five-stranded β-sheet, as well as two or three The N-terminal pro-segment is variable in length and somewhat structured. This is mediated by an aspartic acid buried in a conserved motif (FXGD). It inhibits the catalytic zinc by an "aspartate switch" mechanism known as the pro-segment. Removal of the ATP-binding domain exposes a deep and elongated active site groove, which generally corresponds to the specificity pocket. The ATP-dependent cleavage of the ATP-dependent cleavage pathway (S1') shows a preference for aspartic acid residues in the ATP-dependent cleavage pathway (Gomis-Ruth et al., Biol. Chem. (2012), 393: 1027-1041).

[0007] In addition to the astacin family, further metalloproteinases within the metzincin superfamily are The proteinase family includes the enzymes described in Sterchi et al., Mol Aspects Med. (2008), 29(5): 30 ADAM ("A Disintegrin and Metalloproteinase"), as shown in Figure 1 of 9-328. enzymes, such as ADAM metallopeptidase, also known as TACE (tumor necrosis factor-alpha converting enzyme) ADAM17 (Adaptive Amino Acid Modulation Mechanism 17); and ADAM10 (i.e., α-secretase) and MMPs ("matrix membrane proteins"). "Thyroproteinases," e.g., MMP1 collagenase; MMP2 gelatinase; MMP9; and MMP13 ) is included.

[0008] For example, TACE (ADAM17) inhibitors are known. However, the effectiveness of these compounds is unclear. Many of them are non-selective and have a strong inhibitory effect on matrix metalloproteinases, especially MMP-1. The inhibition of the inhibitor is achieved by metalloplasty, as described in WO 2008 / 142376 A1. It has been hypothesized that protease inhibitors cause joint pain in clinical trials. Among them, bicyclosulfonyl acid (BCSA) compounds are disclosed, all of which share a common structure: As a structural motif, 2-(1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazolinone) (1,1-dioxo-2-phenyl-2,3-dihydro-1H-isothiazolo[4,5-b]piperidinyl-3-yl)acetic acid, Lysin-3-yl)acetic acid, 2-(1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[b]thiophene The compounds in question share the same structure: All have an SO2 group at the 1-position within the five-membered ring of the bicyclic system. All five-membered ring-forming moieties in the formula system are partially saturated, i.e., puckered. The compounds disclosed in the patents inhibit TACE (ADAM) rather than astacin metalloproteinase. It is an inhibitor of ATP (proteinase inhibitors).

[0009] In the human and mouse genomes, the genes encoding astacin proteases include BM These include P-1, tll1, tll2, mep1a, mep1b, and astl. The first three are called tolloi. d subgroup, which encodes the protein BMP-1 and its major splice barrier. These two proteins are procollagen C-protease and Also known as mep1a and mep1b, these genes are important for extracellular matrix assembly. They encode the multidomain proteins meprin α and meprin β, respectively. A further subgroup of astacins is the oba The so-called hatching, represented by only one member of the mammalian family, called the stachys Finally, the genomes of lower invertebrates, and in particular nematodes, contain more abundant enzymes than mammalian genomes. contain more astacin genes than nematodes (e.g., Caenorhabditis elegans In Caenorhabditis elegans, the maximum number is approximately 40 (Gomis-Ruth et al., Biol. Chem. (2012), 393: 1027-1041).

[0010] (Meprin) Specifically, both meprin α and β are members of the astacin family and metzincin superfamily. They correspond to the zinc-dependent metalloproteases of the β-glucan family, which share a similar domain structure. The human enzymes share 45% sequence homology with each other. Meprin α is a type 1 transmembrane protein with protease activity, whereas meprin α is a type 1 transmembrane protein that acts as a transporter in the secretory pathway. Both enzymes are highly expressed in kidney and intestinal epithelial cells. They are expressed as proenzymes with high expression rates in intestinal leukocytes, skin, and certain cancer cells. It is shown by the cell.

[0011] Meprins exhibit distinct substrate specificity, preferring acidic amino acids at the P1'-position (Becker-Paul (See Mol. Cell Proteomics (2011), doi: 10.1074 / mcp.M111.009233). Several in vitro proteins, including peptide hormones, and cytokines In vitro substrates of meprin β have been identified. Phosphorus 17, peptide YY, kinetensin, osteopontin, interleukin 1β, APP, MU C2 mucin and the cystic fibrosis transmembrane conductance regulator E-cadherin. On the other hand, known in vitro substrates of meprin α include bombesin, neurotensin, and substance A. P, angiotensin I, luteinizing hormone-releasing hormone, valosin, vasoactive intestinal peptide peptide, bradykinin, α-melanocyte stimulating hormone, MCP-1, and occludin Known in vitro substrates for both meprin β and α include, for example, gastrin-releasing peptide and The in vivo functions of meprins remain unclear. However, its role in collagen assembly, inflammation, intestinal immune response, and neurodegeneration has not been fully elucidated. The evidence is growing.

[0012] The absence of meprin β and α in mice or the use of actinonin (a meprin inhibitor) Use has been shown to prevent kidney damage and cystitis (Bylander et al., American Journal of Renal physiology (2008), 294(3): F480-90; Yura et al., American Journal of Physiology. Renal Physiology (2009), 296(1): F135-44). Purines β and α are known to cause, for example, nephritis, kidney damage, renal ischemic injury, ischemic acute tubular necrosis, acute These findings appear to be involved in the pathogenesis and / or progression of chronic renal failure and cystitis.

[0013] Both enzymes are C- and N-procollagen proteinases and are known to inhibit collagen synthesis. It has been shown that ATP induces ATP maturation and assembly (Biasin et al., The Journal of pathology (2014), 233(1): 7-17; Prox et al., Matrix biology (2015), 44-46: 7-13) In fibrotic diseases (keloids, pulmonary hypertension), overexpression of the enzyme was found in these studies. Therefore, meprin β and α are useful for, for example, treating fibrosis and fibrotic diseases (e.g., keloids). It has been implicated in the pathogenesis and / or progression of interstitial lung disease (ILD) and pulmonary hypertension (PE). It seems so.

[0014] Meprin β acts as a β-secretase for the amyloid precursor protein, It has been shown that amyloid-β (Aβ) peptides are formed in vitro (Bien et al., The Journal of Neurology, 2013). Urnal of Biological Chemistry (2012), 287(40): 33304-33313). Aβ peptides, found in large amounts in the brains of affected individuals, are central to the pathogenesis of the disease. This study revealed that, in contrast to BACE I, meprin β inhibits N-terminal truncated Aβ. and therefore may be involved in the generation of potentially more toxic Aβ species. Therefore, meprin β may be involved in, for example, the onset and / or progression of Alzheimer's disease. appears to be involved in disease progression.

[0015] Meprin α is a susceptibility gene for IBD (Crohn's disease, ulcerative colitis), and Meprin β has pro-inflammatory activity, whereas its absence increases chronic inflammation. has been shown to provide some protection from injury (Banerjee et al., Am. J. Physiol. Gastrointest. Liver Physiol.(2011), 300(2): G273-82). Purines β and α are involved in, for example, chronic inflammation, Crohn's disease, ulcerative colitis, and inflammatory bowel disease (IBD). Meprin α appears to be involved in the pathogenesis and / or progression of BD. Pro-angiogenic activity and non-polarized secretion, resulting in increased invasiveness of colorectal cancer, have been described. (Lottaz et al., PloS one(2011), 6(11): e26450). Therefore, meprin α is a potential therapeutic agent for cancer, In particular, it has been implicated in the development and / or progression of colorectal cancer.

[0016] Several broad metalloproteases have been reported with regard to their inhibitory activity against meprin α and β. The enzymes and MMP inhibitors have been elucidated (Broder et al., The Biochemical Journal (2013)). 13), 450: 253-264). Some compounds showed inhibition of meprin α, but not all of the compounds showed inhibition. The inhibition of meprin β was much lower (showing an inhibition constant in the micromolar range). either lacked acceptable drug-like properties (Madoux et al., Biopolymers (2014), 1 02(5): 396-406). The phosphinic acid inhibitor of meprin β (PMI) was developed as described in Broder C et al. Characterization of meprin α and meprin β, metalloproteases within the protease web (August 2013; PhD thesis; Universitatsbibliothek Kiel; accession number urn:nbn:de:gb v:8-diss-146034; pp. 29, 53).

[0017] (PCP enzyme; BMP-1) The bone morphogenetic protein BMP-1 specifically targets the carboxyl pro-domain of fibrillar collagen. Procoproteinases, a small group of closely related zinc metalloproteinases, have the ability to cleave It belongs to the class of enzymes known as PCP (Proteinase C-proteinase) (Turtle et al., Expert Opin., Ther. Pa tents(2004), 14(8): 1185-1197). PCP is a zinc metalloprotein of the astacin family. Astacin, a digestive enzyme from crayfish, is a member of this family. BMP-1 is one of the smallest members of the family of proteases. It shares sequence homology with α- and β-glucan-binding domains and, like all members of this family, has a conserved zinc-binding domain. chief [ka] The astacin active site domain consists of a large N-terminal domain and a C-terminal domain. The active site zinc is located in the groove between the two nucleotides. The consensus sequence includes three histidine residues and a tyrosine residue. The glutamic acid in the consensus sequence is coordinated with the substrate cleavage site. It acts as a general base on the zinc-bound water molecule, which is a nucleophile that attacks the easily accessible amide bond.

[0018] BMP-1 is the smallest of the PCP isoforms. In addition to BMP-1, there are four closely related Related mammalian PCPs: mTLD, TLL-1 and -2, and BMP-1 / His enzymes have been identified. All of these enzymes share high sequence homology in the catalytic astacin-like domain, and several There also appears to be redundancy in some functions. PCPs are primarily involved in fibrosis and wound healing. Its procollagen-containing activity and collagen remodeling, processes required for healing PCP inhibition as an anti-fibrotic approach is well known for its association with diseases that promote fibrosis. The concept is that blocking PCP activity does not, in itself, reduce procollagen formation. PCP is believed to interfere with the formation of highly structured collagen fibrils. Even without cleavage by collagen, procollagen remains soluble up to 0.5-1.0 mg / ml. PCP inhibition is not readily incorporated into the matrix. Collagen precipitation, which is more susceptible to rapid degradation by metalloproteinases (MMPs), Therefore, inhibition of PCP enzymes, especially BMP-1, may be beneficial in preventing fibrosis / scar formation. and has been established as a therapeutic approach for the treatment of related diseases and disorders. (Turtle et al., Expert Opin. Ther. Patents (2004), 14(8): 1185-1197).

[0019] Scar formation is part of the natural healing response to tissue or organ injury. The process consists of blood coagulation, inflammatory response, tissue formation, and tissue remodeling. The remodeled tissue is called a scar. Under ideal wound healing conditions, the fibrotic response results in minimal scarring or fibrotic tissue. It creates scar tissue, leaving the majority of functional tissue intact, thereby allowing organ function Fibrotic diseases are characterized by the hyperproliferation of fibroblasts and the formation of dense fibers that penetrate tissues. It is characterized by excessive deposition of collagen that appears in the arteries. The resulting fibrous tissue blocks the arteries. , which immobilizes joints, stiffens internal organs, and interferes with the body's ability to function normally. It remains the leading cause of death worldwide, accounting for over 45% of all deaths in the United States, but There are currently no adequate treatments for any fibrotic disease (Turtle et al., Expert Op in. Ther. Patents(2004), 14(8): 1185-1197).

[0020] Fibrosis is usually not a primary pathological event but rather occurs as a result of trauma, infection, inflammation, or surgical procedures. This is secondary to the placement of a genotype, which may occur for unknown reasons and may have a genetic component. Fibrosis may also have an autoimmune component. Therefore, fibrosis can occur in any organ. Hepatitis (liver cirrhosis), high blood pressure and myocardial infarction (heart failure), asthma and pulmonary hypertension (pulmonary fibrosis), Dermatitis (fibrotic skin and internal organs), diabetes (nephropathy), atherosclerosis (fibrotic blood) In addition, hypertrophic skin scarring and keloids are associated with many disease states, including ulcerative colitis and ulcerative colitis. May result in disability and disfigurement and may cause stroke and spinal Acute CNS scar formation after traumatic injury, such as spinal cord injury, presents a major barrier to neural regeneration. The development of obstructive fibrosis of the intragraft lumen is a common manifestation of chronic allograft rejection. The process of fibrosis and wound healing, regardless of its etiology, is in fact embryonic. However, the underlying mechanisms are not entirely In adults, wound healing is often accompanied by scar formation, whereas fetal wound healing is Healing occurs with minimal or no scarring. Severe, often life-threatening chronic wrinkles In addition to fibrotic disorders, acute fibrotic diseases such as post-operative scarring and cutaneous scarring require anti-inflammatory drugs. Fibrosis is a significant potential market. Millions of surgical procedures are performed each year. Surgical scars The formation can complicate medical procedures and limit recovery, and the need for treatment is often cosmetic. Far beyond its intended use: Fibrosis resulting from gynecological procedures can lead to infertility Fibrosis after ophthalmic surgery can lead to blindness; fibrosis after angioplasty can lead to recurrence. and fibrosis after joint surgery can severely limit range of motion. Finally, PCP inhibitors have been shown to be effective in preventing squamous cell carcinoma (SCC), particularly skin cancer. It also prevents local invasion, recurrence, and metastasis of malignant keratinocytes, a common form of In summary, inhibitors that are selective for PCPs such as BMP-1 are hypothesized to be useful. is ideal for healing excessive collagen deposition associated with pathological fibrotic and related disorders. (Turtle et al., Expert Opin. Ther. Patents (2004), 14(8): 11 85-1197).

[0021] However, nonspecific inhibition of MMPs may not result in the musculoskeletal stiffness side effects seen in human clinical trials. It is also known that the effects of ) 14(8): 1185-1197, p. 1190). Therefore, MMPs such as MMP2 and MMP9 are preferred. There is a need for selective PCPs, particularly BMP-1 inhibitors, that are more selective than BMP-1 inhibitors.

[0022] (Hatching enzyme; Ovastacin) Ovastacin's inhibition has been reported to be directly related to mammalian gamete fusion. It is therefore highly relevant to reproductive biology and fertility control (Stocker et al., Biol. Chem. (2014), 395(10): 1195-1199). The glycoprotein matrix surrounding mammalian oocytes The zona pellucida, which is the primary membrane of the ovary, hardens after the first sperm penetration, thus protecting the embryo until implantation and Prevents fertilization (polyspermy). Final hardening of the zona pellucida occurs when the sperm penetrate the oocyte's cortical granules. This is mediated by a metalloprotease called ovastacin, which is released from the Therefore, trace amounts of ovastacin leak from unfertilized eggs and induce zona pellucida hardening even in the absence of sperm. These small amounts of proteases are inactivated by the plasma protein fetuin-B. Once the sperm penetrate the egg, the cortex Vesicle-derived ovastacin neutralizes fetuin-B and initiates zona pellucida sclerosis. The molecular mechanism of regulation is the interaction of fetuin-B and the cortical granule protease ovastatin. It was discovered that ovastasin interacts with fetuses in a highly specific manner on the surface of egg cells. The proposed mechanism for the interaction of IFN-B is that in wild-type mouse oocytes, The small amount of ovastasin leaking from unfertilized eggs is inhibited by fetuin-B. Based on the observation that the penetrating sperm induces cortical degranulation, which releases large amounts of sperm from the cortical granules. The release of ovastacin reverses fetuin-B inhibition in the zona pellucida. This cleaves ZP2, resulting in the hardening of the zona pellucida, thus providing mechanical protection for the zygote and preventing polyspermy. In contrast, in fetuB- / - mice, which lack fetuin-B, unfertilized eggs The small amount of ovastacin that leaks out from the vesicles is not inhibited by fetuin-B. Zona pellucida sclerosis (ZPH) can occur in the absence of fertilization, and premature ZPH can prevent oocytes from becoming fertilized. (See Stocker et al., Biol. Chem. (2014), 395(10): 1195-1199; see Figure 1 therein).

[0023] Premature release of ovastacin causes infertility in fetuin-B-deficient female mice It has also been suggested that fetuin-B (a natural ovastatin inhibitor) during IVF may be a factor influencing the development of ovarian cancer. The addition partially blocked ZPH and improved fertility (Korschgen et al., Molecular Human Rep production(2017), 23(9): 607-616).

[0024] Therefore, the development of novel inhibitors of ovastacin is useful for the treatment of mammalian infertility and infertility. This can contribute to improved in vitro fertilization.

[0025] (Nematode astacin) Nematode astacin is crucial for the development of nematodes (roundworms), and Stepek et al. As described by the National Journal for Parasitology (2015), 45: 345-355, It has specific roles in hatching, molting, and cuticle synthesis. Thus, gastrointestinal (GI) nematodes are a chronic disease in livestock and humans that has a major economic impact on the sheep industry. It causes sexually wasting infections worldwide, resulting in loss of appetite, weight loss, wool, meat, This leads to reduced milk production and death. Current treatment involves the use of anthelmintics. However, multiple resistance to the three major classes of anthelmintics is now occurring in animal parasites. In recent years, only a limited number of new drugs with novel modes of action have become available. There is no evidence that effective control is possible, thereby limiting the prospects for effective control.

[0026] All nematodes are surrounded by an outer protective structure called the cuticle. It functions as a skeleton and provides protection from the external environment during development, and therefore its role in the survival of the nematode. The synthesis of this structure is a complex multi-step process involving numerous enzymes. The cuticle is mainly composed of collagen, which is found in the free-living nematode C. elegans. and parasitic nematodes, such as Teladorsagia kyrcumkin, the major GI nematode of sheep. Teladorsagia circumcincta and Haemonchus contortus The process of cuticle biosynthesis has been studied in detail in C. elegans. Many of the most important cuticle synthesis enzymes and proteases are also present in parasitic nematodes, suggesting that the Kura biosynthetic process may be similar between C. elegans and its parasitic counterpart. Protease enzymes are essential for the continued development and survival of the nematode within the host. The following major classes: aspartic proteases, cysteine ​​proteases, metalloproteases They are classified into proteases, threonine proteases, and serine proteases. Synmetalloprotease enzymes play essential roles in cuticle biosynthesis in C. elegans These enzymes share two conserved motifs in the N-terminal astacin domain: zinc Zinc metalloendopeptidase characterized by a binding active site and a methionine turn (SxMHY) Binding of zinc in the active site is essential for the catalytic activity of the enzyme; Between the three histidine residues in the binding motif and the tyrosine and water molecules in the methionine turn It is pentacoordinated in a trigonal bipyramidal molecular structure. Its functional role is host tissue penetration by infectious L3s (Williamson et al., Infect. Immun. (2006), 74: 961-967), cuticle formation and molting (Gamble et al., J. Parasitol. (1 989), 82: 197-202; Stepek et al., Int. J. Parasitol.(2010), 40: 533-542; Stepek et al., Parasitology (2011), 138: 237-248), as well as digestion (Gallego et al., Parasitology (2011), 138: 237-248). ol. Int.(2005), 54: 123-133).

[0027] There are 39 nematode astasin (NAS) metalloproteinases expressed in C. elegans ( Stepek et al., International Journal for Parasitology (2015), 45: 345-355). All Legance NASs have similar domain arrangements. Among them, DPY-31 (also known as NAS-35 ) is a chondrocyte-derived protein that forms mature collagen by its cleavage of the C-terminal domain of procollagen. and the vertebrate procollagen, which is important for the assembly of collagen fibrils during bone formation. C. elegans C-proteinase has similarity to bone morphogenetic protein 1 (BMP-1). In D. cerevisiae, DPY-31 is involved in most of the life cycle, especially during embryonic and larval stages. It is expressed in subcutaneous cells, as well as rectal and vulvar epithelial cells (Novelli et al., Genetics (2004) 168, 1259-1273). Procollagen in the DPY-31(e2770) mutant is partially procollagenized. They remain in a sessed state and are unable to form mature collagen (Novelli et al. Genetics (2006), 172, 2253-2267). Therefore, DPY-31 is a C. elegans It plays a vital role in the culla formation and molting process.

[0028] 74% identity was found between DPY-31 from C. elegans and DPY-31 from T. circumcincta. Not only are there 70% identities between C. elegans and H. contortus, but there are also 89% identities between C. elegans and H. contortus. Identity between proteins from T. kyrcumincta and H. contortus The existence of DPY-31 orthologues across the phylum Nematoda supports this role in nematode development. This confirms the conserved and crucial role of proteases. A number of compounds specifically developed to target PCP have been synthesized using recombinant C. elegans DPY-31. and therefore a novel drug to combat important nematode infections. (Stepek et al., International Journal of Journal for Parasitology (2015), 45: 345-355). Finally, France et al. & Medicinal Chemistry Letters (2015), 25: 5752-5755) reported that the parasitic gastrointestinal tract of sheep Malayan silk from the human filarial nematode, which is also active against DPY-31 from the worm T. kirkumkincuta Several inhibitors of DPY-31 from Brugia malayi have been reported.

[0029] Therefore, zinc-dependent metzincin metalloproteases of the astacin family, Specifically, procollagen C-proteinase (PCP) enzymes, meprin, ovastacin, and / or nematode proteins, even more particularly human or mammalian BMP-1, meprin alpha , meprin β, and / or ovastacin, and C. elegans DPY-31 are highly relevant therapeutics. can be considered targets and have a high potential for the development of new treatments for diseases and disorders associated with them. The demand exists.

[0030] (compound) US 4,146,721 describes pyrazole-4-acetic acid compounds, such as substituted pyrazole-4-acetic acids, Esters, amides, nitrites, and pharmaceutically acceptable salts thereof are disclosed. and methods for preparing these compounds are disclosed. These compounds are useful analgesics, anti-inflammatory agents. It is an antipyretic and antipyretic.

[0031] WO 2006114263 A1 describes a novel type of peptide deformylase (PDF) inhibitor. and therefore of great interest as new antibiotics, especially imidazo[1,2-a] Pyridine derivatives are disclosed.

[0032] In the article by E. Adiguzel et al. (JOURNAL OF MOLECULAR STRUCTURE. Vol. 1127, pp. 403-412) , Synthesis and characterization of two new hydroxamic acid derivatives and their metal complexes, especially keto / Studies on the enol E / Z and its hydroxamate / hydroxymate forms have been published. There are.

[0033] (Problem to be solved by the present invention) In view of the above, the present invention provides metalloproteinases of the astacin family; in particular Procollagen C-proteinase (PCP) enzymes, meprin, ovastatin, and / or fibronectin insect astacin; more particularly human or mammalian meprin alpha (e.g., human meprin alpha, h meprin α), meprin β (e.g., human meprin β, hmeprin β), BMP-1 (e.g., human BMP-1, hBMP-1), ovastacin (e.g., human ovastacin, hovastacin), and / or DPY-31 derived from C. elegans (e.g., DPY-31 derived from T. circumcinctum (tcDPY-31) and H. contortus) inhibiting DPY-31 from S. typhi (hcDPY-31) and Brugia malayi (bmDPY-31) The present invention aims at the object of providing compounds and / or pharmaceutical compositions that can

[0034] Preferably, to reduce potential side effects, the inhibitor and / or pharmaceutical composition , ADAMs (e.g., ADAM10 and ADAM17 (TACE)) and MMPs (e.g., MMP2, MMP9, and MMP13) It should be selective for further members of the metzincin superfamily, including Preferably, the inhibitor is hmeprin α, hmeprin β, hBMP-1, hovastatin , tcDPY-31, hcDPY-31, and bmDPY-31. More preferably, the inhibitor should have acceptable drug-like properties. You should.

[0035] A further object is to provide a method for the treatment of any of the foregoing objects that is suitable for administration to a subject in need thereof. The present invention provides pharmaceutical compositions containing the inhibitors.

[0036] A further object is to provide methods for producing such compounds.

[0037] Further objects are methods for the treatment or prevention of the human or animal body, and compounds for use in such methods. The present invention provides a compound or pharmaceutical composition for use in

[0038] A further object is to inhibit one of the aforementioned astacin family metalloproteinases. or more than one related disease or disorder, or the disease or disorder and (ii) providing a method for treating or preventing a disease or condition in a subject at risk. The disease is caused by hMeprin α, hMeprin β, hBMP-1, hOvastacin, tcDPY-31, hcDPY-31, and and bmDPY-31.

[0039] Further objectives include the treatment of Alzheimer's disease; nephritis; renal injury; renal ischemic injury; ischemic acute tubular necrosis. Death; acute renal failure; cystitis; inflammatory bowel disease (IBD); Crohn's disease; ulcerative colitis; chronic inflammation; colitis; fibrosis; fibrotic disease; keloid; pulmonary hypertension; interstitial lung disease (ILD); cancer; and colorectal cancer. suffers from or is at risk of developing the selected disease or disorder and / or for use in a method for treating or preventing a subject having The objective of the present invention is to provide a compound.

[0040] Further objects include the treatment of fibrosis; acute fibrotic disorders and diseases; chronic fibrotic disorders and diseases; and organ-related diseases. fibrosis and / or hepatitis, cirrhosis, hypertension, myocardial infarction, heart failure, asthma, pulmonary hypertension Hypertension, scleroderma, fibrotic skin and internal organs, diabetes, diabetic nephropathy, atherosclerosis and associated diseases and disorders selected from fibrotic blood vessels; hypertrophic skin scarring; keloids; Pulmonary fibrosis; acute CNS scarring after traumatic injury; nerve regeneration after stroke or spinal cord injury; intragraft Obstructive fibrosis of the lumen structure; chronic allograft rejection; impaired wound healing; postoperative scar formation; Skin scarring; fibrosis due to gynecological procedures; fibrosis after ophthalmic surgery; lines after angioplasty fibrosis; fibrosis after joint surgery; local invasion of malignant keratinocytes or squamous cell carcinoma (SCC), recurrence and prevention of metastasis of a disease or disorder. and / or methods for treating or preventing a disease in a subject at risk of developing the disease. and providing compounds for use in the method.

[0041] Further objects are methods for treating or preventing infertility in mammals and in vitro methods for treating or preventing infertility in mammals. Therapeutic methods of use for fertility (IVF) treatments and / or for use in such methods The object of the present invention is to provide a compound for the purpose of

[0042] A further objective is to investigate the nematode infection caused by Teladorsagia kyrcuminecta. infections caused by Haemonchus contortus; and Malayan filamentous or suffering from a disease or illness selected from infectious diseases caused by insects a method for treating or preventing a subject at risk of developing said disease or disorder; and / or and to provide compounds for use in such methods. Summary of the Invention

[0043] (Summary of the Invention) As a solution to the problem formulated above, the present invention provides compounds according to formula I below, the individual enantiomers thereof, the individual diastereoisomers thereof, the hydrates thereof, the solvates thereof, The present invention provides a crystalline form, its individual tautomers, or pharmaceutically acceptable salts thereof. [ka] (In the formula: A is, [ka] are independently selected from; B is [ka] are independently selected from; C is [ka] independently selected from -O-, and -S-; F, if present, [ka] are independently selected from; G, if present, [ka] are independently selected from; H, if present, [ka] are independently selected from; I, if present, [ka] are independently selected from; where F, G, H, and I are present: D is [ka] and E is [ka] are independently selected from The ring formed by D, E, F, G, H, and I is R 2 By the p-substituent represented by substituted, where p is 0, 1, 2, 3, or 4; Otherwise, if F, G, H, and I are not present: D is [ka] are independently selected from E is [ka] where p is 0, 1, 2, 3, 4, or 5; L 1 and L 2 each independently represents alkyl, aryl, arylalkyl, heterocyclyl, is selected from the group consisting of heteroaryl, cycloalkyl, and cycloalkenyl, So, L 1 and L 2 can come together to form a ring; Each X is C(R a )R b , N.R. a and O; X and L 2 can be joined together to form a ring, wherein the ring is optionally may be condensed to a hydroxyl group; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, or 5; Each R 1 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH2, alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, and hydroxy; Each R 2is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH2, alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, and further substituted by one or more groups independently selected from , hydroxyl, and heteroaryl. can be exchanged; Each R 3 is hydrogen, as well as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, and cycloalkyl groups. Alkenyl, aryl, arylalkyl, heterocyclyl, heterocyclic, fused to aryl and independently selected from the group consisting of cyclohexyl, ... Each of these is an amino, halogen, cyano, hydroxy, carboxy, -C(O)O(a) alkyl), -C(O)NH2, -C(O)NH(alkyl), alkylsulfonate, functional groups having acidic hydrogen, Alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Aryl, arylalkyl, heterocyclyl, heteroaryl, and heteroaryla and each of which may be substituted with one or more groups independently selected from alkyl, , halogen, carboxy, cyano, alkyl, alkoxy, and hydroxy; and R a and R b are each independently hydrogen, deuterium, and C 1-3 alkyl) .

[0044] The present invention further provides a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable excipient. Pharmaceutical compositions are provided.

[0045] The present invention also provides methods for producing the above compounds.

[0046] The present invention further provides a method for the treatment or prophylaxis of the human or animal body by surgery or therapy. A compound or pharmaceutical composition as defined above for use as well as said compound or pharmaceutical administering a therapeutically effective amount of the composition to a subject in need thereof. Methods for treating or preventing the human or animal body by therapy are provided.

[0047] The present invention further comprises: (a) Alzheimer's disease; nephritis; kidney injury; renal ischemic injury; ischemic acute tubular necrosis; acute renal failure; Cystitis; Inflammatory Bowel Disease (IBD); Crohn's Disease; Ulcerative Colitis; Chronic Inflammation; Colitis; Fibrosis; Fibrotic Disease Disease; Keloid; Pulmonary hypertension; Interstitial lung disease (ILD); Cancer; Colorectal cancer; (b) Fibrosis; acute fibrotic disorders and diseases; chronic fibrotic disorders and diseases; fibrosis occurring in organs and and / or hepatitis, cirrhosis, hypertension, myocardial infarction, heart failure, asthma, pulmonary hypertension, scleroderma, fibrosis from damaged skin and internal organs, diabetes, diabetic nephropathy, atherosclerosis, and fibrotic blood vessels Concomitant diseases and conditions selected from the following: hypertrophic skin scarring; keloids; pulmonary fibrosis; post-traumatic injury Acute CNS scar formation; nerve regeneration after stroke or spinal cord injury; occlusive fibers in lumenal structures within the graft Chronic allograft rejection; Wound healing disorders; Postoperative scarring; Skin scarring; Gynecology Fibrosis due to surgical procedures; fibrosis after ophthalmic surgery; fibrosis after angioplasty; fibrosis after joint surgery prevention of local invasion, recurrence, and metastasis of malignant keratinocyte or squamous cell carcinoma (SCC); (c) mammalian infertility; therapeutic use for mammalian in vitro fertilization (IVF) procedures; (d) Nematode infection; infection caused by Teladorsagia kyrcumincta; hemo infection caused by B. contortus; and by Brugia malayi Infections caused as defined above for use in a method for the treatment or prevention of diseases and disorders selected from: The present invention provides a compound or pharmaceutical composition that is [Brief explanation of the drawings]

[0048] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figure 1 shows a structural alignment of astacin-proteinases: hmeprin α (homology model, template pdb:4GWN), hmeprin β (X-ray, pdb:4GWN), hovastacin (homology model, template pdb:3LQB), Teladorsagia circumcincta DPY-31 (tcDPY-31, homology model, template pdb:6BTO), Haemonchus contortus DPY-31 (hcDPY-31, homology model, template pdb:6BTO), and hBMP-1 (X-ray, pdb:6BTO). [Figure 2] Figure 2 shows the active site diagrams of aligned proteinases (hmeprin α (homology model, template pdb: 4GWN), hmeprin β (X-ray, pdb: 4GWN), and hovastacin (homology model, template pdb: 3LQB). The essential side chains for inhibitor binding are indicated. [Figure 3]Figure 3 shows the active site diagrams of aligned proteinases (hmeprin α (homology model, template pdb:4GWN), hmeprin β (X-ray, pdb:4GWN)), Teladorsagia circumcinctus DPY-31 (tcDPY-31, homology model, template pdb:6BTO), and Haemonchus contortus DPY-31 (hcDPY-31, homology model, template pdb:6BTO). The essential side chains for inhibitor binding are indicated. [Figure 4] Figure 4 shows the active site diagrams of aligned proteinases (hmeprin α (homology model, template pdb:4GWN), hmeprin β (X-ray, pdb:4GWN), and hBMP-1 (X-ray, pdb:6BTO). The essential side chains for inhibitor binding are indicated. [Figure 5] Figure 5 shows the CLUSTAL O(1.2.4) multiple sequence alignment of hmeprin α, hmeprin β, hovastacin, tcDPY-31, and hcDPY-31. DETAILED DESCRIPTION OF THE INVENTION

[0049] (Detailed Description of the Invention) Therapeutic Goals, Inhibitory Activities, and Effects Achieved by the Invention As evidenced by the experimental results presented herein (see Table 2), the inventors have demonstrated that the compounds of formula I The compounds by [the present invention] have been shown to have potent inhibitors of various astacin-containing metalloproteinases, particularly meprin alpha. Furthermore, it was found that the inhibitory activity against meprin β was high. As is evident from the results, the compound also has an inhibitory effect on astacin metalloproteinase. While showing selectivity, at the same time, ADAMs (e.g., ADAM10 and ADAM17 (TACE)) and MMPs (e.g., , MMP2, MMP9, and MMP13) to further members of the metzincin superfamily. It has significantly lower activity against steroids, thereby reducing the risk of potential side effects.

[0050] Furthermore, as can be seen from the sequence alignment shown in Figure 5, Further enzymes, such as hOvastacin, tcDPY-31, and hcDPY-31, are Identical Zn in the active site 2+ The binding sequence, the same specificity pocket (S1'), and the zinc site from the back They share a highly conserved methionine-containing turn (Met-turn, SxMHY) that supports the ATP-dependent ATPase. Furthermore, meprin α, meprin β, ovastacin, tcDPY-31, and hcDPY-31 were all The three-dimensional structure of the ATP-binding domain (shown in Figure 1) and, in particular, those involved in inhibitor binding. The active sites of (shown in Figures 2-4) are remarkably similar.

[0051] Furthermore, early studies have demonstrated the secretion of procollagen C-proteinases (e.g., BMP-1). It is known as a highly effective inhibitor of meprin (actinonin) The compounds that can be used are those that inhibit nematode DPY-31 enzymes, such as tcDPY-31 and hcDPY-31 (Stepek et al., Int. J. Med. Soc. 1999, 144:131-132, 2001). International Journal for Parasitology (2015), 45: 345-355) and tcDPY-31 and bmDPY-3 1 (France et al., Bioorganic & Medicinal Chemistry Letters (2015), 25: 5752-5755) It has also been shown to be effective against

[0052] Considering the above evidence and the experimental results presented herein, all of the present compounds are aspartame-containing compounds. Metalloproteinases of the tacin family; in particular, procollagen C-proteinase (PCP) enzymes, meprins, ovastacins, and / or nematode astacins; more particularly human or mammalian Mammalian meprin α (e.g., human meprin α, h meprin α), meprin β (e.g., human meprin β, hmeprin β), BMP-1 (e.g., human BMP-1, hBMP-1), ovastacin (e.g., , human ovastacin, hovastacin), and / or DPY-31 from nematodes (e.g., T. kirkii DPY-31 from Mucinctus (tcDPY-31), DPY-31 from H. contortus (hcDPY-31), and It is useful as an inhibitor of DPY-31 derived from Dirofilaria immitis (bmDPY-31).

[0053] The present invention relates to a new class of compounds whose physicochemical properties differ from those known from the prior art. The present invention provides inhibitors of tertiary amines, such as tertiary amine inhibitors. The activity and pharmacokinetic properties of the compound are thereby affected, which may result in, for example, increased activity against the target enzyme. Furthermore, the compounds have a planar aromatic or heteroaromatic center. The structural features of the compounds described herein are characterized by the presence of a ring system. are distinct from any previously described inhibitors of protease or related enzymes. .

[0054] (compound) Specifically, the present disclosure provides the following aspects: <1> ~ <31> The present invention provides a compound according to any one of the following:

[0055] <1> Compounds according to formula I below, their individual enantiomers, their individual diastereoisomers , its hydrate, its solvate, its crystalline form, its individual tautomer, or a pharmaceutical composition thereof Acceptable salts [ka] (In the formula: A is, [ka] are independently selected from; B is [ka] are independently selected from; C is [ka] independently selected from -O-, and -S-; F, if present, [ka] are independently selected from; G, if present, [ka] are independently selected from; H, if present, [ka] are independently selected from; I, if present, [ka] are independently selected from; where F, G, H, and I are present: D is [ka] and E is [ka] are independently selected from The ring formed by D, E, F, G, H, and I is R 2By the p-substituent represented by It has been replaced, where p is 0, 1, 2, 3, or 4; Otherwise, if F, G, H, and I are not present: D is [ka] are independently selected from E is [ka] where p is 0, 1, 2, 3, 4, or 5; L 1 and L 2 each independently represents alkyl, aryl, arylalkyl, heterocyclyl, is selected from the group consisting of heteroaryl, cycloalkyl, and cycloalkenyl, So, L 1 and L 2 can be taken together to form a ring; preferably, L 1 and L 2 is, each independently, aryl, heterocyclyl, heteroaryl, cycloalkyl, and cycloa wherein L is selected from the group consisting of: 1 and L 2 come together to form a ring and can; Each X is C(R a )R b , N.R. a and O; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, or 5; Each R 1 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH2, alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, and hydroxy; Each R 2 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH2, alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, and further substituted by one or more groups independently selected from , hydroxyl, and heteroaryl. can be exchanged; Each R 3 is hydrogen, as well as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, and cycloalkyl groups. Alkenyl, aryl, arylalkyl, heterocyclyl, heterocyclic, fused to aryl and independently selected from the group consisting of cyclohexyl, ... Each of these is an amino, halogen, cyano, hydroxy, carboxy, -C(O)O(a) alkyl), -C(O)NH2, -C(O)NH(alkyl), alkylsulfonate, functional groups having acidic hydrogen, Alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Aryl, arylalkyl, heterocyclyl, heteroaryl, and heteroaryla and each of which may be substituted with one or more groups independently selected from alkyl, , halogen, carboxy, cyano, alkyl, alkoxy, and hydroxy; and R a and R b are each independently hydrogen, deuterium, and C 1-3 alkyl) .

[0056] <2> A compound according to embodiment 1 (wherein, unless otherwise specified: The aryl is independently a monocyclic C 6-10 , bicyclic C 6-10 , monocyclic C6, and bicyclic C6 aryl selected from the group consisting of: The heterocyclyl has 1 to 4 ring heteroatoms independently selected from N, S, and O, each of which is Monocyclic C 2-11 , monocyclic C 2-8 , monocyclic C 3-5 , bicyclic C 2-11 , bicyclic C 2-8 , and bicyclic C 3-5 heterocyclic groups; The heteroaryl has 1 to 3 ring heteroatoms independently selected from N, S, and O. Monocyclic C 2-11 , monocyclic C 2-8 , monocyclic C 3-5 , bicyclic C 2-11 , bicyclic C 2-8 , and bicyclic C 3-5 selected from the group consisting of aromatic heterocyclic groups; The alkyl or alk may each independently be linear or branched, open-chain or cyclic. Get, C 1-12 , C 1-6 , C 1-3 , C 1-2 and a C1 alkyl group; The alkenyls may be independently selected from a group consisting of at least two alkyl groups, each of which may be linear or branched, open chain or cyclic. Contains at least one C=C bond, C 2-12 , C 2-4 , C 2-3 and C2 groups; The alkynyls may independently be at least one of which may be linear or branched, open chain or cyclic. Contains at least one C≡C bond, C 2-12 , C 2-6 , C 2-4 , C 2-3 and a C2 group be; The cycloalkyl is independently a monocyclic C 3-12 , monocyclic C 3-6 , bicyclic C 3-12 , and bicyclic C3 -6 alkyl groups; The cycloalkenyl independently contains at least one C=C bond. 3-12 , C 4-6 , and C 5-6 selected from the group consisting of carbocyclic groups; wherein each of the above groups is selected from halogen, carboxy, cyano, methoxy, and hydroxy. and (iii) may be substituted with one or more groups selected from the group consisting of:

[0057] <3> A compound according to embodiment 1 or 2 (wherein, unless otherwise specified: The aryl is independently a monocyclic or bicyclic C 6-10 , preferably a C6 aryl group; The heterocyclyl contains 1 to 4 ring heteroatoms independently selected from N, S, and O. Monocyclic or bicyclic C 2-11 , preferably C 2-8 , more preferably C 3-5 Heterocyclic group the law of nature; The heteroaryl contains 1 to 3 ring heteroatoms independently selected from N, S, and O. Monocyclic or bicyclic C 2-11 , preferably C 2-8 , more preferably C 3-5 Aromatic heterocycles It is a base; The alkyl or alk may be independently linear or branched, open chain or cyclic C 1-12 , preferably , C 1-6 , more preferably C 1-3 , and even more preferably C 1-2 is an alkyl group; The alkenyl may be linear or branched, open chain or branched, independently containing at least one C=C bond. cyclic C 2-12 , preferably C 2-4 , more preferably C 2-3 and even more preferably a C2 group. can be; The alkynyl may be linear or branched, open chain or branched, independently containing at least one C≡C bond. is cyclic C 2-12 , preferably C 2-6 , more preferably C 2-4 , and even more preferably C 2-3 It is a base; The cycloalkyl is independently selected from C 3-12 , preferably C 3-6 , monocyclic or bicyclic alkyl It is a base; The cycloalkenyl independently contains at least one C=C bond. 3-12 , preferably , C 4-6 , more preferably C 5-6 is a carbocyclic group; wherein each of the above groups is selected from halogen, carboxy, cyano, methoxy, and hydroxy. and (iii) may be substituted with one or more groups selected from the group consisting of:

[0058] <4> Formula Ia below: [ka] A compound according to any one of embodiments 1 to 3, represented by:

[0059] <5> If F, G, H, and I are absent, the ring fragment [ka] But the following structure: [ka] 5. The compound according to any one of embodiments 1 to 4, represented by one of:

[0060] <6> ring fragment [ka] but, [ka] When represented by: R 3 is hydrogen, as well as optionally substituted alkyl, optionally substituted alkenyl, optionally Substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl aryl, substituted aryl, optionally substituted arylalkyl, optionally substituted heptyl Tetracyclyl, optionally substituted heteroaryl, and optionally substituted heteroaryl Alkyl (where optionally substituted or substituted means optionally substituted or amino, respectively). No, halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)NH2, -C(O)N H(alkyl), alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkynyl and wherein the alkyl, alkyl group is independently selected from alkyl, heterocyclyl, heteroaryl, and heteroarylalkyl. each of which is selected from the group consisting of halogen, carboxyl, methyl ... one or more independently selected from carboxy, cyano, alkyl, alkoxy, and hydroxy; which may be further substituted by groups of A compound according to any one of aspects 1 to 5.

[0061] <7> R 3 Amino, chloro, fluoro, bromo, iodo, cyano, hydroxy, carboxy C 1-6 one or more groups independently selected from alkyl, C1-C6 alkoxy, and hydroxy; A compound according to any one of aspects 1 to 6, wherein the compound is aryl substituted with aryl.

[0062] <8> Formula Ib below: [ka] A compound according to any one of embodiments 1 to 7, represented by:

[0063] <9> Ring fragments F, G, H, and I, if present [ka] But the following structure: [ka] The compound according to any one of embodiments 1 to 8, represented by one of:

[0064] <10> ring fragment [ka] but, [ka] If represented by At least one of m and p is greater than 0; A compound according to any one of aspects 1 to 9.

[0065] <11> A compound according to any of embodiments 8 to 10, wherein n=1.

[0066] <12> According to any one of aspects 1 to 11, at least one of m and p is greater than 0. A compound.

[0067] <13> R 1 and R 2 are the same or different and each independently represent chloro, fluoro, bromo, Bromo, iodo, cyano, C1-C6 alkoxy, C1-C6 alkyl, fluoro(C 1-6 alkyl), Ruolo (C 1-6 alkoxy), as well as hydroxy, carboxy, -SO3H, -P(O)(OH)2, -C(O)-N H-OH, tetrazol-5-yl, -SO3H, -P(O)(OH)2, -C(O)-NH-OH, and tetrazol-5-yl any one of Aspects 1 to 12, wherein the functional group is selected from the group consisting of functional groups having an acidic hydrogen selected from the group consisting of: A compound made by

[0068] <14> L 1 (R 1 ) m and L 2 (R 2 ) p are the same or different and each independently have the following structure: : [ka] (where: (i)R o , R o ', R m , R m ', and R p At least one of the following is hydroxy, carboxy, -SO3 -H, -P(O)(OH)2, -C(O)-NH-OH, and tetrazol-5-yl the remaining one is H or R according to any one of the preceding embodiments. 1 too Or R 2 and / or (ii)R o , R o ', R m , R m ', and R p At least two of the are part of a 5- to 8-membered heterocycle. the other is H or any of the above embodiments. R by one of them 1 Or R 2 (either as defined for represented by A compound according to any of aspects 1 to 13.

[0069] <15> L 1 (R 1 ) m and L 2 (R 2 ) p are the same or different and each independently represent 2-carboxy 3-chlorophenyl, 3-chlorophenyl, 4-carboxyphenyl, 3-chlorophenyl, 4 ... phenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-methylphenyl, 4-carboxyphenyl 4-chlorophenyl, 4-cyanophenyl, 4-fluorophenyl, 4-methoxyphenyl phenyl, 3,4-dimethoxyphenyl, 4-methylphenyl, 3-carboxy-4-methoxyphenyl 3-fluoro-4-methoxyphenyl, 4-chloro-2-fluoro-3-hydroxyphenyl, 5- Chloro-3-fluoro-4-hydroxyphenyl, 3-chloro-5-fluoro-4-hydroxyphenyl , 3,5-dichloro-4-hydroxyphenyl, 2,6-difluoro-4-methoxyphenyl, 2,3-dihydroxyphenyl 1,4-benzodioxin-6-yl, 1,3-benzodioxol-5-yl, 3-(trifluoromethyl) methyl)-1H-pyrazol-4-yl, 3-(1H-tetrazol-5-yl)phenyl, 2-carboxysilyl cyclohexyl, 3-carboxycyclohexyl, 3-carboxycyclohexyl, and (1,3- benzodioxol-5-yl)methyl; preferably 3-carboxyphenyl, 3- Chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-methyl phenyl, 4-carboxyphenyl, 4-chlorophenyl, 4-cyanophenyl, 4-fluorophenyl Phenyl, 4-methoxyphenyl, 4-methylphenyl, 3-carboxy-4-methoxyphenyl , 3-fluoro-4-methoxyphenyl, 4-chloro-2-fluoro-3-hydroxyphenyl, 3-chloro 3,5-dichloro-4-hydroxyphenyl, 2,6-dichloro-5-fluoro-4-hydroxyphenyl Fluoro-4-methoxyphenyl, 2,3-dihydro-1,4-benzodioxin-6-yl, and 1,3- 15. A compound according to any of embodiments 1 to 14 selected from the group consisting of benzodioxol-5-yl thing.

[0070] <16> L 1 (R 1 ) m and L 2 (R 2 ) p 16. The compound according to any of aspects 1 to 15, wherein:

[0071] <17> L 1 (R 1 ) m and L 2 (R 2 )p 16. The compound according to any of embodiments 1 to 15, wherein:

[0072] <18> Each R 3 are independently hydrogen and C 1-6 Alkyl, carboxy (C 1-6 alkyl), amine No (C 1-6 alkyl), cyano (C 1-6 alkyl), C 2-6 Alkynyl, C 3-6 Cycloalkyl, cycloalkyl Boxy (C 6-10 aryl), C 1-6 Alkoxy (C 6-10 aryl), cyano (C 6-10 aryl), ha Ro (C 6-10 aryl), hydroxy (C 6-10 aryl), C 1-6 Alkoxy (C 2-8 Heteroaryl) , cyano(C 2-8 Heteroaryl), halo(C 2-8 Heteroaryl), C 3-5 Heteroaryl (C 6-10 aryl), hydroxy (C 2-8 heteroaryl), carboxy (C 2-8 heteroaryl), (C 6-1 0aryl)methyl, (C 1-6 Alkoxy (C 6-10 aryl))methyl, (hydroxy(C 6-10 Ally (carboxy(C 6-10 aryl))methyl, (C 1-6 Alkoxy (C 2-8 Heteroary (C 2-8 Heteroaryl (C 6-10 aryl))methyl, (hydroxy(C 2-8 Heteroa aryl))methyl, and (carboxy(C 2-8heteroaryl))methyl , each of which is chloro, fluoro, bromo, iodo, carboxy, cyano, C 1-6 Al and further substituted by one or more groups independently selected from alkyl, C1-C6 alkoxy, and hydroxy. A compound according to any of embodiments 1 to 17, which may be substituted.

[0073] <19> Each R 3 are independently selected from hydrogen, methyl, ethyl, 2-propyl, 1-propyl, phenyl nyl, 2-aminoethyl, propargyl, cyclopropyl, -CH2COOH, -CH2CN, phenyl, 3-carboxyphenyl, 3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3- Methoxyphenyl, 3-methylphenyl, 4-carboxyphenyl, 4-chlorophenyl, 4-chlorophenyl anhydrophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, 3-carbo 4-chloro-2-fluoro-3-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, 4-chloro-2-fluoro-3-hydroxyphenyl hydroxyphenyl, 3-chloro-5-fluoro-4-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl 2,6-difluoro-4-methoxyphenyl, 1,3-benzodioxol-5-yl , benzyl, (3-carboxyphenyl)methyl, (3-chlorophenyl)methyl, (3-cyanophenyl)methyl (phenyl)methyl, (3-fluorophenyl)methyl, (3-methoxyphenyl)methyl, (3-methyl (phenyl)methyl, (4-carboxyphenyl)methyl, (4-chlorophenyl)methyl, (4-cyanophenyl)methyl (4-fluorophenyl)methyl, (4-methoxyphenyl)methyl, (4-methylphenyl)methyl (3-carboxy-4-methoxyphenyl)methyl, (3-fluoro-4-meth (4-chloro-2-fluoro-3-hydroxyphenyl)methyl, (3-chloro -5-fluoro-4-hydroxyphenyl)methyl, (3,5-dichloro-4-hydroxyphenyl)methyl (2,6-difluoro-4-methoxyphenyl)methyl, (2,3-dihydro-1,4-benzodioxy from the group consisting of (1,3-benzodioxol-6-yl)methyl, and (1,3-benzodioxol-5-yl)methyl, and and / or para-methyl-benzoic acid and meta-methyl-benzoic acid, A compound according to any of the methods 1 to 18.

[0074] <20> C is, [ka] -O-, and -S-; D is, [ka] is selected from R 3C and R 3D are the same or different from one another and each independently represent one of the above embodiments. R by either one 3 selected from the groups defined for A compound according to any of aspects 1 to 19.

[0075] <21> R 3C and R 3D 21. The compound according to embodiment 20, wherein:

[0076] <22> Each X is C(R a )R b where C(R a )R b One of the groups is NR a Substituted by a group n is 1 or 2; m is 0, 1, 2, or 3; and p is 0, 1, 2, or 3. and; L 1 is phenyl; L 2 is phenyl; R 1 are independently Cl, F, OH, CN, OCH 3, and COOH, and / or two R 1 The 1,3-benzodioxole ring also contains the or forms part of a 2,3-dihydro-1,4-benzodioxin ring; R 2 Independently, Cl, F, OH , CN, OCH3, and COOH, and / or two R 2 The groups together form a 1,3-benzodioxo R forms part of the benzoyl ring or 2,3-dihydro-1,4-benzodioxin ring; 3 But hydrogen, ethyl, ethyl, propargyl, cyclopropyl, 2-aminoethyl, -CH2COOH, -CH2CN, phenyl, unsubstituted phenyl, and 3-carboxyphenyl and 4-carboxyphenyl. and R is selected from the group consisting of substituted phenyl, a and R b is hydrogen. Compounds by.

[0077] <23> X is C(R a )R b n is 1; and at least one of m and p is greater than 0. , a compound according to any of aspects 1 to 22.

[0078] <24> Each X is C(R a )R b n is 1 or 2; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; L 1 is phenyl; L 2 is cyclohexyl; R1 is COOH , R 2 is COOH; R 3 is hydrogen; and R a and R b is hydrogen. Compounds by.

[0079] <25> Each X is C(R a )R b where C(R a )R b One of the groups is NR a Substituted by a group n is 1 or 2; m is 0, 1, 2, or 3; and p is 0, 1, 2, or 3. and; L 1 is phenyl; L 2 is phenyl; R 1 are independently Cl, F, OH, CN, OCH 3, and COOH, and / or two R 1 The 1,3-benzodioxole ring also contains the or forms part of a 2,3-dihydro-1,4-benzodioxine ring; preferably, R 1 is hydrogen R 2 is a bioisosteric replacement for the acidic group, preferably R 3 is tetrazole; R 3 is hydrogen, methyl, ethyl, propargyl, cyclopropyl, 2-aminoethyl, -CH2COOH , -CHCN, benzyl, unsubstituted phenyl, and 3-carboxyphenyl and 4-carboxyphenyl. phenyl; preferably, R 3 is hydrogen; and R a Reach BiR b 22. The compound according to any of embodiments 1-21, wherein is hydrogen.

[0080] <26> Compounds having a structure selected from Table 2, their individual enantiomers, their individual dimers, Astereoisomers, hydrates thereof, solvates thereof, crystalline forms thereof, individual tautomers thereof, or a pharmaceutically acceptable salt thereof.

[0081] <27> A pharmaceutical composition comprising a compound according to any of aspects 1 to 25 and a pharmaceutically acceptable excipient. thing.

[0082] <28> A compound according to any of aspects 1 to 26 for use in a method of treatment of the human or animal body. 27. A combination or pharmaceutical composition according to embodiment 26.

[0083] <29> Alzheimer's disease; nephritis; kidney damage; renal ischemic injury; ischemic acute tubular necrosis; acute renal failure; Cystitis; Inflammatory Bowel Disease (IBD); Crohn's Disease; Ulcerative Colitis; Chronic Inflammation; Colitis; Fibrosis; Fibrotic Disease Diseases selected from the group consisting of: keloid; pulmonary hypertension; interstitial lung disease (ILD); cancer; and colorectal cancer. A compound or compound according to any of aspects 1 to 26 for use in a method for the treatment or prevention of a disease. 27. A pharmaceutical composition according to embodiment 26.

[0084] <30> Fibrosis; acute fibrotic disorders and diseases; chronic fibrotic disorders and diseases; fibrosis occurring in organs, and / or hepatitis, cirrhosis, high blood pressure, myocardial infarction, heart failure, asthma, pulmonary hypertension, scleroderma, fibrosis fibrotic skin and internal organs, diabetes, diabetic nephropathy, atherosclerosis, and fibrotic blood Concomitant diseases and conditions selected from the following: vascular; hypertrophic skin scarring; keloids; pulmonary fibrosis; traumatic injuries acute CNS scar formation after stroke or spinal cord injury; nerve regeneration after stroke or spinal cord injury; obstruction of lumen structures within the graft Fibrosis; chronic allograft rejection; wound healing disorders; postoperative scarring; skin scarring; women Fibrosis due to chemical procedures; fibrosis after ophthalmic surgery; fibrosis after angioplasty; fibrosis after joint surgery Fibrosis; prevention of local invasion, recurrence, and metastasis of malignant keratinocyte or squamous cell carcinoma (SCC) A method for treating or preventing a disease or disorder selected from the group consisting of: A compound according to any one of the compounds or pharmaceutical compositions according to aspect 27.

[0085] <31> Method for treating or preventing disorders and diseases selected from infertility in mammals, and mammals 27. The method of claim 1, wherein the compound of claim 1 is a compound selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28. A compound according to any one of claims 1 to 27 or a pharmaceutical composition according to claim 27.

[0086] <32> Nematode infection; infection caused by Teladorsagia kyrcumkinkuta; hemo infection caused by B. contortus; and by Brugia malayi For use in a method for treating or preventing diseases and illnesses selected from infectious diseases caused by A compound according to any one of aspects 1 to 26 or a pharmaceutical composition according to aspect 27.

[0087] Aspects <1> In a preferred embodiment, the present disclosure provides compounds of formula I below, their individual energies enantiomers, individual diastereoisomers thereof, hydrates thereof, solvates thereof, crystalline forms thereof , its individual tautomers, or pharmaceutically acceptable salts thereof. [ka] (In the formula: A is, [ka] are independently selected from; B is [ka] are independently selected from; C is [ka] independently selected from -O-, and -S-; F, if present, [ka] are independently selected from; G, if present, [ka] are independently selected from; H, if present, [ka] are independently selected from; I, if present, [ka] are independently selected from; where F, G, H, and I are present: D is [ka] and E is [ka] are independently selected from The ring formed by D, E, F, G, H, and I is R 2 By the p-substituent represented by It has been replaced, where p is 0, 1, 2, 3, or 4; Otherwise, if F, G, H, and I are not present: D is [ka] are independently selected from E is [ka] where p is 0, 1, 2, 3, 4, or 5; L 1 and L 2 each independently represents alkyl, aryl, arylalkyl, heterocyclyl, is selected from the group consisting of heteroaryl, cycloalkyl, and cycloalkenyl, So, L 1 and L 2 can come together to form a ring; Each X is C(R a )R b , N.R. a and O; X and L 2 can be joined together to form a ring, wherein the ring is optionally may be condensed to a hydroxyl group; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, or 5; Each R 1 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH2, alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, and hydroxy; Each R 2 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH2, alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, , hydroxy, and heteroaryl; can be; Each R 3 are independently selected from hydrogen and alkyl, alkenyl, alkynyl, cycloalkynyl, aryl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, fused to aryl selected from the group consisting of heterocyclyl, heteroaryl, and heteroarylalkyl; and each of the groups is selected from the group consisting of amino, halogen, cyano, hydroxy, carboxy, -C(O)O(a), alkyl), -C(O)NH2, -C(O)NH(alkyl), alkylsulfonate, functional groups having acidic hydrogen, Alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Aryl, arylalkyl, heterocyclyl, heteroaryl, and heteroaryla and each of which may be substituted with one or more groups independently selected from alkyl, , halogen, carboxy, cyano, alkyl, alkoxy, and hydroxy; and R a and R b are each independently hydrogen, deuterium, and C 1-3 alkyl, Where, unless otherwise specified: The aryl is independently a monocyclic or bicyclic C 6-10, preferably a C6 aryl group; The heterocyclyl contains 1 to 4 ring heteroatoms independently selected from N, S, and O. Monocyclic or bicyclic C 2-11 , preferably C 2-8 , more preferably C 3-5 Heterocyclic group the law of nature; The heteroaryl contains 1 to 3 ring heteroatoms independently selected from N, S, and O. Monocyclic or bicyclic C 2-11 , preferably C 2-8 , more preferably C 3-5 Aromatic heterocycles It is a base; The alkyl or alk may be independently linear or branched, open chain or cyclic C 1-12 , preferably , C 1-6 , more preferably C 1-3 , and even more preferably C 1-2 is an alkyl group; The alkenyl may be linear or branched, open chain or branched, independently containing at least one C=C bond. cyclic C 2-12 , preferably C 2-4 , more preferably C 2-3 and even more preferably a C2 group. can be; The alkynyl may be linear or branched, open chain or branched, independently containing at least one C≡C bond. is cyclic C 2-12 , preferably C 2-6 , more preferably C 2-4 , and even more preferably C 2-3 It is a base; The cycloalkyl is independently selected from C 3-12 , preferably C 3-6 , monocyclic or bicyclic alkyl It is a base; The cycloalkenyl independently contains at least one C=C bond. 3-12 , preferably , C 4-6, more preferably C 5-6 is a carbocyclic group; wherein each of the above groups is selected from halogen, carboxy, cyano, methoxy, and hydroxy. and may be substituted by one or more groups selected from wherein the ring fragment [ka] but, [ka] When represented by: R 3 represents hydrogen, as well as optionally substituted alkyl, optionally substituted alkenyl, optionally Substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl aryl, substituted aryl, optionally substituted arylalkyl, optionally substituted heptyl Tetracyclyl, optionally substituted heteroaryl, and optionally substituted heteroaryl Alkyl (wherein optionally substituted or substituted) is, respectively, amino, halogen, Cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)NH2, -C(O)NH(alkyl), Alkyl sulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkoxy quinyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclo and one or more groups independently selected from aryl, heteroaryl, and heteroarylalkyl. each of which is selected from the group consisting of halogen, one or more independently selected from carboxy, cyano, alkyl, alkoxy, and hydroxy; may be further substituted by the above groups; the ring fragment [ka] but, [ka] where m and p are both 0 and n, and the ring fragment [ka] but, [ka] where m is greater than 0).

[0088] In a further preferred embodiment, the following compounds a) to d) are selected from the group consisting of compounds of formula (I): Excluded: Compound a): [ka] 1-Phenyl-3-(p-chlorophenyl)-pyrazol-4-yl-methylhydroxamic acid; Compound b): [ka] 1,3,5-triphenyl-pyrazol-4-yl-methyl-hydroxamic acid; Compound c): [ka] N-Hydroxy-2-(5-methyl-2-phenyl-imidazo[1,2-a]pyridin-3-yl-amino)-acetate toamide; and Compound d): [ka] (2-Phenyl-benzimidazol-1-yl)-methylhydroxamic acid.

[0089] Compounds a) and b) are disclosed in US Pat. No. 4,146,721.

[0090] Compound c) is disclosed in WO 2006114263 A1.

[0091] Compound d) was prepared according to the method described in E. Adiguzel et al. (JOURNAL OF MOLECULAR STRUCTURE. Vol. 1127, pp. 403-409). (page 412).

[0092] More preferably, compounds a) to d) are used in methods for treating or preventing the diseases and disorders described herein. The compounds of formula (I) are not excluded from the scope as far as their use in the method is concerned.

[0093] (definition) As used herein, the symbols [ka] can be connected to three additional atoms 2 Represents carbon atoms and each molecule Any orientation within the child structure, e.g. [ka] and the double bond is to be understood to mean the respective planar ring system (ABC This must be part of the symbol DE or ABCDEFGHI. [ka] applies analogously to the 2 Each carbon atom is The groups H, L can be connected to two further atoms of the planar ring system. 2 (R 2 ) p , and R 3are substituents of the respective planar ring systems (ABCDE or ABCDEFGHI). As used herein, the symbols [ka] can be connected to two additional atoms 2 Represents a nitrogen atom and each moiety Any orientation within the child structure, e.g. [ka] and the double bond is to be understood to mean the respective planar ring system (ABC DE or ABCDEFGHI). As used herein, the symbols [ka] can be connected to three additional atoms 3 Represents a nitrogen atom and each moiety It should be understood that this includes any orientation within the structure. [ka] applies analogously to the 3 The nitrogen atoms are The group R 3 Yes, respectively The point is that the substituents are planar ring systems.

[0094] As used herein, unless specifically limited, the term "alkyl" includes C 1-12 Alkyl groups, preferably C 1-8 Alkyl groups, such as C 1-6 Alkyl groups, such as C 1-4 Al The alkyl group may be linear or branched. Examples of alkyl groups include methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl), butyl (e.g., n-butyl, iso-butyl, sec-butyl, and tert-butyl), pentabutyl, ethyl (e.g., n-pentyl), hexyl (e.g., n-hexyl), heptyl (e.g., n-heptyl), The term "alkyl" includes aryl, aryl (e.g., n-octyl), and octyl (e.g., n-octyl). The term "cycloalkyl" includes, but is not limited to, cycloalkyl groups. Ri, C 3-10 Cycloalkyl groups (i.e., 3 to 10 ring carbon atoms), more preferably C 3-8 S chloroalkyl groups, e.g., C 3-6 means a cycloalkyl group. Exemplary cycloalkyl groups Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexyl. The most preferred number of ring carbon atoms is 3 to 6. .

[0095] The term "heteroalkyl" means, unless specifically limited, one or more carbon atoms, preferably Preferably, one, two, or three of the alkyl groups are substituted with heteroatoms selected from N, S, and O. refers to the alkyl group.

[0096] The terms "carbocyclyl" and "carbocyclic" are all used unless specifically limited. is a carbon atom and has 3 to 12 ring carbon atoms, preferably 3 to 10 carbon atoms, and More preferably, it refers to any ring system containing 3 to 8 carbon atoms. , saturated or partially unsaturated, but does not contain an aromatic ring. Examples of carbocyclyl groups include , monocyclic, bicyclic, and tricyclic ring systems, particularly monocyclic and bicyclic ring systems. Bicyclic groups include bridged ring systems (e.g., bicyclo[2.2.1]heptenyl). Specific examples of carbocyclyl groups are cycloalkyl groups. Further examples of carbocyclyl groups are is a cycloalkenyl group.

[0097] Unless specifically limited, the term "aryl" includes C 6-12 Aryl groups, preferably , C 6-10 Aryl groups, more preferably C 6-8 The aryl group is at least Each of these compounds contains one aromatic ring (e.g., one, two, or three rings). An example of a typical aryl group is phenyl. Typical aryl groups with two aromatic rings are: An example is naphthyl.

[0098] The terms "heterocyclyl" and "heterocycle" refer to one or more heterocyclic rings, unless specifically limited. wherein one, two, or three of the ring atoms are replaced by a heteroatom selected from N, S, and O. Specific examples of heterocyclyl groups include those having one or more (e.g., one , 2, or 3, particularly 1 or 2, especially 1) ring atoms are selected from N, S, and O. cycloalkyl groups substituted with heteroatoms, such as cyclopentyl or more particularly cyclopentyl; Exemplary heterocyclyl groups containing one heteroatom include: Examples include pyrrolidine, tetrahydrofuran, and piperidine, and Exemplary heterocyclyl groups containing include morpholine and piperazine More particular examples of heterocyclyl groups include those having one or more (e.g., 1, 2, or 3, particularly 1 or Two, especially one, ring atoms are replaced by heteroatoms selected from N, S, and O. Examples of such groups are dihydroxybenzoates, ... dropyranyl (eg, 3,4-dihydro-2H-pyran-2-yl-).

[0099] The term "heteroaryl" refers to one or more (e.g., 1, 2, 3, or 4, preferably 1, 2, or 3) ring atoms are selected from N, S, and O. an aryl residue substituted at or in place of a hetero atom selected from N, S, and O; and one or more (e.g., 1, 2, 3, or 4, preferably 1, 2, or 3) ring atoms. A heteroaryl group is a 5-membered aromatic ring. Represents a specific subtype within the general class of groups. Exemplary monocyclic groups having one heteroatom Cyclic heteroaryl groups include: five-membered rings (e.g., pyrrole, furan, thiophene); and 6-membered rings (e.g., pyridine, e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl) Exemplary monocyclic heteroaryl groups having two heteroatoms include: Five-membered rings (e.g., pyrazole, oxazole, isoxazole, thiazole, isothiazoline) Azoles, imidazoles, for example, imidazol-1-yl, imidazol-2-yl imidazo 6-membered rings (e.g., pyridazine, pyrimidine, pyrazine). Exemplary monocyclic heteroaryl groups having heteroatoms include: 1,2,3-triazole and Exemplary monocyclic heteroaryls having four heteroatoms include 1,2,4-triazoles. Exemplary bicyclic heteroaryl groups include tetrazole. Indoles (e.g., indol-6-yl), benzofurans, benzthiophenes hene), quinoline, isoquinoline, indazole, benzimidazole, benzothiazoline Examples include benzodiazepines, quinazolines, and purines.

[0100] "Alkoxyaryl", "carboxyaryl", "cyanoaryl", "Hydroaryl" The terms "aryl," "hydroxyaryl," and "heteroarylaryl" are used interchangeably. Unless specifically limited, each of the aryl groups may be selected from at least one of alkoxy, carboxy, cyano, It refers to aryl residues substituted with halo, hydroxy, and heteroaryl groups. do.

[0101] "Alkoxyheteroaryl", "carboxyheteroaryl", "cyanoheteroaryl" The terms "haloheteroaryl," "haloheteroaryl," and "hydroxyheteroaryl" are used interchangeably. Unless specifically limited, each of them contains at least one alkoxy, carboxy, cyano , halo, and hydroxy groups.

[0102] For example, the word "alk" in the words "alkoxy" and "haloalkyl" should be interpreted in accordance with the definition of "alkyl." Exemplary alkoxy groups include: , methoxy, ethoxy, propoxy (e.g., n-propoxy), butoxy (e.g., n-butoxy), oxy), pentoxy (e.g., n-pentoxy), hexoxy (e.g., n-hexoxy), heptoxy Examples of alkoxy include butoxy (eg, n-heptoxy), and octoxy (eg, n-octoxy). Exemplary haloalkyl groups include fluoroalkyl, such as CF3; exemplary Haloalkoxy groups include fluoroalkyl, such as OCF3.

[0103] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine. Contains element (I).

[0104] As used herein, the term "hydrogen" or "H" refers to all isotopes of hydrogen, in particular Protium ( 1 H) and deuterium ( 2 H, D).

[0105] The term "optionally substituted" includes any of the following: amino, halogen, cyano, hydroxy, carbo Oxy, -C(O)O(alkyl), -C(O)NH2, -C(O)NH(alkyl), alkylsulfono, acidic hydrogen functional groups having alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl groups, chloroalkenyl, aryl, arylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl, wherein the group each of which is selected from halogen, carboxy, cyano, alkyl, alkoxy, and hydroxy. may be further substituted with one or more independently selected groups; In each occurrence, the aryl is a C6 aryl group; the heterocyclyl is N, S, and O; the heteroaryl is a heterocyclic group containing 1 to 4 ring heteroatoms selected from C containing 1 to 3 ring heteroatoms selected from N, S, and O 3-5 is an aromatic heterocyclic group; The alkyl or alk is C 1-2alkyl group; the alkenyl group is the alkynyl is a C group containing at least one C≡C bond; 2-3 It is a base; The cycloalkyl is C 3-6 , monocyclic, or bicyclic alkyl groups; the cycloalkenyl is a C containing at least one C=C bond 5-6 It is a carbocyclic group.

[0106] As used herein, the term "comprising" means three options: "comprising," "consisting of," and "essentially consisting of" "consisting essentially of" is included.

[0107] (stereoisomer) All possible stereoisomers of the claimed compounds are included in the present invention. When a compound has at least one chiral center, it may be divided into enantiomers accordingly. When the compound possesses two or more chiral centers, it may further be present as a diastereomeric chiral center. All such isomers and mixtures thereof are within the scope of the present invention. It should be understood that the process for the preparation of the compounds according to the invention is encompassed within the scope of the present invention. If the process gives rise to a mixture of stereoisomers, these isomers can be separated by conventional techniques, e.g., preparative chromatography. The compound can be prepared in racemic form. or the individual enantiomers can be obtained either by enantiospecific synthesis or by resolution. The compounds can be prepared, for example, by standard techniques, e.g. Optically active acids, such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l- By salt formation with tartaric acid followed by fractional crystallization and regeneration of the free base, or by optically active salts. Groups such as quinine, quinidine, quinotoxin, syncotoxin, (S)-phenylethyl Amines, (1R,2S)-ephedrine, (R)-phenylglycinol, (S)-2-aminobutanol by salt formation of the diastereomeric pair followed by fractional crystallization and regeneration of the free acid. The compound can be resolved into its component enantiomers by Formation of esters or amides followed by chromatographic separation and removal of the chiral auxiliary Alternatively, the compounds can be resolved using a chiral HPLC column. It is possible.

[0108] (polymorphic crystal forms, solvates, hydrates) Furthermore, some of the individual crystalline forms of the compounds may exist as polymorphs; Therefore, it is intended to be included in the present invention. Furthermore, some of the compounds may be soluble in water. It can form solvates (i.e., hydrates) of benzophenone or solvates with common organic solvents. and such solvates are intended to be encompassed within the scope of this invention. It may also be obtained in the form of its hydrates, including its salts, or other solvents used for its crystallization. It is also possible to include a compound in the form of a salt, hydrate, or solvate thereof. Given the close relationship, whenever a compound is mentioned in this context, such Corresponding salts, solvates or polymorphs are also intended, where possible or appropriate under the circumstances. It is illustrated.

[0109] (tautomer) As used herein, the term "tautomer" refers to an approximation of adjacent single and double bonds. The tautomerization process is reversible. The compounds may undergo any possible tautomerization that is within the scope of the physical properties of the compounds. This can be done.

[0110] (Pharmaceutically acceptable salts) As used herein, the term "pharmaceutically acceptable" means a compound that is suitable for human use. For example, the term "pharmaceutically acceptable" includes both veterinary and non-veterinary uses. and compounds that are acceptable in human medicine and health care. do.

[0111] Salts, hydrates and solvates of compounds of formula I which are suitable for use in medicine, and These physiologically functional derivatives are those in which the counter ions or associated solvents are pharmaceutically acceptable. However, salts, hydrates, and other compounds having pharmaceutically unacceptable counterions or associated solvents are not permitted. and solvates thereof are within the scope of the present invention, and may be used in combination with other compounds and pharmaceutical preparations thereof. For use as intermediates in the preparation of acceptable salts, hydrates, and solvates be.

[0112] Suitable salts according to the present invention include salts of both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed with hydrochloric acid. , hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, tri Fluoroacetic acid, triphenylacetic acid, sulfamic acid, sulfanilic acid, succinic acid, oxalic acid Acid, fumaric acid, maleic acid, malic acid, mandelic acid, glutamic acid, aspartic acid, xaloacetic acid, methanesulfonic acid, ethanesulfonic acid, arylsulfonic acids (e.g., p-thiazolinone, benzenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, or naphthalenedisulfonic acid acid), salicylic acid, glutaric acid, gluconic acid, tricarballylic acid, cinnamic acid, substituted Cinnamic acids (e.g., phenyl, methyl, methoxy, including 4-methyl and 4-methoxycinnamic acids) or halo-substituted cinnamic acids), ascorbic acid, oleic acid, naphthoic acid, hydroxynaphthoic acid acids (e.g., 1- or 3-hydroxy-2-naphthoic acid), naphthalene acrylic acids (e.g., naphtha benzoic acid, 4-methoxybenzoic acid, 2- or 4-hydroxybenzoic acid, 4-chlorobenzoic acid benzoic acid, 4-phenylbenzoic acid, benzeneacrylic acid (e.g., 1,4-benzenediacrylic acid) acid), isethionic acid, perchloric acid, propionic acid, glycolic acid, hydroxyethanesulfonic acid Succinic acid, pamoic acid, cyclohexanesulfamic acid, salicylic acid, saccharinic acid, and thiazolinone. Pharmaceutically acceptable base salts include those formed from trifluoroacetic acid. , ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth salts metal salts, such as calcium and magnesium salts; organic bases, such as dicyclohexane; Examples include salts with silamine and N-methyl-D-glucamine.

[0113] All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are encompassed by the scope of the present invention. It is intended to be included.

[0114] (Pharmaceutical composition) The pharmaceutical composition according to the present invention comprises the compound described above and a pharmaceutically acceptable excipient.

[0115] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical composition containing the claimed compounds as a therapeutic agent. and products containing a therapeutically effective amount thereof, and products obtained directly or indirectly from the combination of the claimed compounds. As used herein, "excipient" is intended to encompass any product in which The term "prescription" is used for galenical preparations, e.g., liquid preparations such as suspensions, elixirs, and solutions. For oral preparations; and / or for formulations such as powders, capsules, gelcaps, and tablets. Refers to carriers, binders, disintegrants, and / or further suitable additives for solid oral preparations. Carriers that may be added to the product include necessary and inert pharmaceutical excipients, including: Suitable suspending agents, lubricants, flavorings, sweeteners, preservatives, coating agents, granulating agents, colorants, and These include, but are not limited to, colorants and coloring agents.

[0116] (therapeutic use) The present disclosure provides compounds for use in methods of treatment of the human or animal body, such as compounds described above. Aspects <1> ~ <24> and / or the pharmaceutical composition described above. provides a method of treating the human or animal body, wherein the method comprises administering to a subject in need thereof The method includes administering a therapeutically effective amount of the compound or composition to a subject.

[0117] The present disclosure provides methods for treating or preventing diseases and disorders associated with meprin alpha and / or meprin beta. The compounds and / or pharmaceutical compositions described herein for use in the methods, e.g. The above aspects <1> ~ <24> and the treatment or administration of such diseases and disorders. Further provided are methods of prevention, wherein the method comprises administering the compound or compounds to a subject in need thereof. As explained in the Background section above, meprin Such diseases and disorders associated with meprin α and / or meprin β include Alzheimer's disease; Nephritis; kidney injury; renal ischemic injury; ischemic acute tubular necrosis; acute renal failure; cystitis; inflammatory bowel disease (I BD); Crohn's disease; Ulcerative colitis; Chronic inflammation; Colitis; Fibrosis; Fibrotic disease; Keloid; Pulmonary hypertension interstitial lung disease (ILD); cancer; and colorectal cancer.

[0118] The present disclosure provides compounds for use in methods of treating or preventing diseases and disorders associated with BMP-1. , the compounds and / or pharmaceutical compositions described herein, e.g., in the above aspects <1> ~ <24> Noi and methods for treating or preventing such diseases and disorders, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound or composition. As explained in the Background section above, such diseases and conditions associated with BMP-1 and diseases include fibrosis; acute fibrotic disorders and diseases; chronic fibrotic disorders and diseases; and diseases occurring in organs. fibrosis and / or hepatitis, cirrhosis, hypertension, myocardial infarction, heart failure, asthma, pulmonary hypertension, Scleroderma, fibrotic skin and internal organs, diabetes, diabetic nephropathy, atherosclerosis, and Concomitant diseases and conditions selected from fibrotic blood vessels; hypertrophic skin scarring; keloids; pulmonary fibrosis acute CNS scar formation after traumatic injury; nerve regeneration after stroke or spinal cord injury; lumen within grafts Obstructive fibrosis of structures; chronic allograft rejection; impaired wound healing; postoperative scar formation; skin scars scar formation; fibrosis due to gynecological procedures; fibrosis after ophthalmic surgery; fibrosis after angioplasty; Fibrosis after nodal surgery; and local invasion and recurrence of malignant keratinocyte or squamous cell carcinoma (SCC) and prevention of metastasis.

[0119] The present disclosure provides a method for treating or preventing diseases and disorders associated with ovastacin. The compounds and / or pharmaceutical compositions described herein for, for example, <1> ~<2 and methods for treating or preventing such diseases and disorders. wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound or composition. As explained in the Background section above, ovastacin and its associated Such diseases and disorders include mammalian infertility; and mammalian in vitro fertilization (IVF) procedures. Typical candidates for such treatment are those suffering from infertility. The subject may be a mammal who is suffering from or suspected of suffering from infertility. Preferably, the subject is a female. More preferably, the subject is a human female. WHO-IC According to the MART Revised Glossary, infertility in humans is defined as "the absence of conventional contraception for 12 months or more." A disorder of the reproductive system defined by the inability to achieve clinical pregnancy after a period of sexual intercourse Furthermore, the compounds may be used in vivo, for example, to stimulate fertilization. It can be administered to women undergoing assisted reproductive treatment, such as in vitro fertilization. The method may, for example, administer a therapeutically effective amount of the compound or composition to a subject undergoing such treatment. and / or administering to the oocyte a composition comprising a compound described herein. and increasing the fertility rate of a subject undergoing assisted reproductive therapy or procedure by in vitro contacting the subject with It can be used as a method for improving

[0120] The term "in vitro fertilization (IVF)" refers to the process of retrieving eggs and combining them with sperm in vitro. The egg is then fertilized in the uterus, and once division has progressed to a certain extent, it is inserted into the uterine cavity. This can refer to methods including ovulation induction, egg collection, in vitro fertilization and culture. This may include the process of embryo adoption, as well as embryo transfer.

[0121] As used herein, the term "subject" refers to an animal, preferably a mammal, most preferably a More specifically, it refers to humans.

[0122] As used herein, the term "therapeutically effective amount" refers to a dose that reduces the symptoms of the disease or disorder being treated. tissue systems sought by researchers, veterinarians, physicians, or other clinicians, including the alleviation of symptoms It refers to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a subject, animal, or human. Taste. [Example]

[0123] (Example) Explanation of synthesis method Scheme 1 [ka] (Method i:) Each 1,3-diaryl-1,3-propanedione or azole derivative or benzo-fused N- The heterocycle (1 equiv.) was dissolved in DMF (c=0.5 M), cooled to 0°C, and treated with sodium hydride (1.2 equiv.). After 30 minutes, methyl bromoacetate or another suitable alkyl halide (1.1 equivalents) The mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched by the addition of water. The mixture was stirred for 1 hour at room temperature for 1 hour and extracted with EtOAc (3 x 30 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica, heptane / EtOAc gradient).

[0124] (Method ii:) Each 1,3-diaryl-1,3-propanedione (1 equivalent) was dissolved in dichloromethane (c = 0.2 M). The mixture was cooled to 0°C and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.2 equivalents). After 15 minutes, methyl acrylate (2 equivalents) dissolved in DCM was added dropwise over 15 minutes. After the addition of 100 ml of HCl, the reaction was allowed to warm to room temperature and stirred for 48 hours. The organic layer was separated and the aqueous phase was extracted with EtOAc (3 x 25 ml). The mixture was dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica, Purification was carried out using a hexanes / EtOAc gradient.

[0125] (Method iii:) The compound obtained by either method I or ii (1 equivalent) was dissolved in a mixture of EtOH / THF (2:1, v / v, c =0.07M). Hydrazine monohydrate (5 eq) was added and the mixture was stirred at room temperature. Once the starting material was completely consumed (~4 to 5 hours), the volatiles were evaporated. The residue was washed with water. It was dissolved, acidified with dilute aqueous HCl and extracted with EtOAc (3 x 25 ml). The mixture was dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica, Purification was carried out using a hexanes / EtOAc gradient.

[0126] (Method iv:) The compound obtained by either method I or ii (1 equivalent) was dissolved in an EtOH / water mixture (3:2, v / v, c= Hydroxylamine hydrochloride (1 eq.) was added and the mixture was heated in a microwave oven. The mixture was then heated at 110° C. for 20 minutes. After cooling, the mixture was poured into ice water and extracted with DCM (2×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was flash chromatographed. The residue was purified by column chromatography (silica, heptane / EtOAc gradient).

[0127] (method v:) Each ester derivative (1 equivalent) was dissolved in MeOH (5 ml) and added with NaOCH3 (6 equivalents) and hydrochloric acid. The mixture was heated in a microwave at 80° C. for 10 minutes. The volatiles were evaporated. The residue was dissolved in water and acidified with dilute aqueous HCl. Extraction with tOAc (3 x 25 ml) was performed. The combined organic layers were dried over Na2SO4 and evaporated. The residue was It was purified by semi-preparative HPLC.

[0128] Example 1: 2-(3,5-diphenyl-1H-pyrazol-4-yl)ethanehydroxamic acid The compound was synthesized according to methods i, iii, and v above. Yield (last step): 83 mg (40%); ESI-MS: m / z 294.5[M+H] + HPLC (gradient 1): rt 12.03 min (>99%); [ka] A mixture of cis-trans isomers.

[0129] Example 2: 2-(3,5-diphenylisoxazol-4-yl)ethanehydroxamic acid The compound was synthesized according to methods i, iv, and v above. Yield (last step): 32 mg (35%); ESI-MS: m / z 295.1[M+H] + , 317.2[M+Na] + HPLC (gradient 1): rt 14.56 min (>99%); [ka]

[0130] Example 3: 3-(3,5-diphenyl-1H-pyrazol-4-yl)propanehydroxamic acid The compound was synthesized according to methods ii, iii, and v above. Yield (last step): 58 mg (19%) ESI-MS: m / z 308.4[M+H] + HPLC (gradient 1): rt 15.52 min (96.8%); [ka]

[0131] Example 4: 3-(3,5-diphenylisoxazol-4-yl)propanehydroxamic acid The compound was synthesized according to methods ii, iv, and v above. Yield (last step): 11 mg (22%); ESI-MS: m / z 309.4[M+H] + , 331.4[M+Na] + HPLC (gradient 1): rt 14.93 min (>99%); [ka]

[0132] Scheme 2 [ka] (Method vi:) The respective diarylpyrazole (1 equivalent) obtained by method iii above, or another suitable A suitable azole derivative was dissolved in acetonitrile (c = 1.7 M) and added with DBU (0.5 equivalents) and methyl azide. The mixture was stirred at room temperature overnight. The volatiles were evaporated and The residue was dissolved in EtOAc. Water was added and the aqueous layer was extracted with EtOAc (3 x 25 ml). The organic layer was dried over Na2SO4 and evaporated. The residue was used without further purification. I was able to do it.

[0133] Example 5: 2-(3,5-diphenylpyrazol-1-yl)ethanehydroxamic acid The compound was synthesized according to methods iii, i, and v above. Yield (last step): 141 mg (57%) ESI-MS: m / z 294.4[M+H] + HPLC (gradient 1): rt 15.63 min (97.5%); [ka] A mixture of cis-trans isomers.

[0134] Example 6: 3-(3,5-diphenylpyrazol-1-yl)propanehydroxamic acid The compound was synthesized according to methods iii, vi, and v above. Yield (last step): 171 mg (66% ); ESI-MS: m / z 308.4[M+H] + HPLC (gradient 1): rt 17.68 min (>99%); [ka] A mixture of cis-trans isomers.

[0135] Scheme 3 [ka] (Method vii:) Each benzamide derivative (1 equivalent) and 2-fluoro-pyridine (1.1 equivalents) were mixed in an argon solution. The mixture was cooled in an ice bath and the trifluoromethyl ... Methanesulfonic anhydride (1.1 equiv.) was added slowly via syringe. The mixture was stirred at 0°C for 45 minutes. After further stirring, the respective benzhydrazides were added. After 45 minutes at room temperature, the mixture was The mixture was heated in a microwave at 140°C for 2 hours. After cooling, saturated aqueous NaHCO3 was added and the mixture was diluted with DCM (3 x 25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography. Purification was performed by chromatography (silica, CHCl3 / MeOH gradient).

[0136] Example 7: 2-(3,5-diphenyl-1,2,4-triazol-4-yl)ethanehydroxamic acid The compound was synthesized according to methods vii and v above. Yield (last step): 45 mg (53%); ESI- MS: m / z 295.3[M+H] + HPLC (gradient 1): rt 7.73 min (98.2%); [ka] A mixture of cis-trans isomers.

[0137] Example 8: 3-(3,5-diphenyl-1,2,4-triazol-4-yl)propanehydroxamic acid The compound was synthesized according to methods vii and v above. Yield (last step): 39 mg (37%); ESI- MS: m / z 309.4[M+H] + HPLC (gradient 1): rt 8.59 min (97.0%); [ka] A mixture of cis-trans isomers.

[0138] Scheme 4 [ka] (Method viii:) Each 1,4-butanedione (1 equivalent) was dissolved in THF / toluene (1:1 v / v, c=0.1 M). The appropriate benzyl-protected amino acid derivative (1.5 equivalents) and para-toluenesulfonic acid (0.07 equivalents) were The mixture was heated to reflux for 48 hours. The volatiles were evaporated and the residue was redissolved in water. The mixture was then slightly basified with aqueous NaHCO3 and extracted with EtOAc (3 x 25 ml). The organic layer was evaporated and purified by flash chromatography (silica, heptane / EtOAc gradient). Made.

[0139] (Method ix:) Each benzyl-protected hydroxamic acid derivative was dissolved in MeOH / THF (1:1 v / v, 10 ml). Palladium on carbon was added and the vial was purged with hydrogen. After 4 hours at 4 bar, the mixture It was filtered through celite and evaporated, and the residue was purified by semi-preparative HPLC.

[0140] Example 9: 2-(2,5-diphenylpyrrol-1-yl)ethanehydroxamic acid The compound was synthesized according to methods viii and ix above. Yield (last step): 25 mg (37%); ES I-MS: m / z 293.2[M+H] + HPLC (gradient 1): rt 15.84 min (97.7%); [ka] A mixture of cis-trans isomers.

[0141] Example 10: 3-(2,5-diphenylpyrrol-1-yl)propanehydroxamic acid The compound was synthesized according to methods viii and ix above. Yield (last step): 9 mg (4%); ESI- MS: m / z 307.4[M+H] +, 329.4[M+Na] + HPLC (gradient 1): rt 16.27 min (>99%); [ka] A mixture of cis-trans isomers.

[0142] Scheme 5 [ka] (method x:) Each 4-oxo-4-phenylbutanoate (1 equivalent) was dissolved in toluene (c=0.2 M). Tosylhydrazide (1 equivalent) was added and the mixture was stirred at 80°C for 2 hours. (1 equiv.), Cu(OAc)2 (1 equiv.), and pivalic acid (2 equiv.) were added and the mixture was heated to 100 °C overnight. The volatiles were evaporated and the residue was purified by flash chromatography (silica, heptane / dichloromethane). Purification was carried out using an ethyl ether gradient.

[0143] Example 11: 2-(3,5-diphenyltriazol-4-yl)ethanehydroxamic acid The compound was synthesized according to methods x and v above. Yield (last step): 23 mg (32%); ESI-MS : m / z 295.1[M+H] + HPLC (gradient 1): rt 10.43 min (>99%); [ka] A mixture of cis-trans isomers.

[0144] Scheme 6 [ka] (Method xi:) A suspension of potassium ethyl malonate (1.5 equiv.), MgCl2 (anhydrous, 1 equiv.) in THF (c = 0.6 M) was The mixture was stirred at 50°C for 6 hours under a nitrogen atmosphere. The azole (1.5 equiv.) was added to a solution of Boc-Phg-OH (1 equiv.) in THF (c=0.6 M) at 0°C under an argon atmosphere. The mixture was stirred at room temperature for 2 hours. The ethanol solution was added via syringe and the mixture was stirred vigorously at room temperature overnight. The residue was dissolved in water and adjusted to pH 3 with dilute aqueous HCl. The aqueous layer was diluted with EtOAc (3x The combined organic layers were dried over Na2SO4 and evaporated. The residue was The residue was purified by column chromatography (silica, heptane / EtOAc gradient). ) and the mixture was stirred at room temperature until TLC showed complete conversion of the starting material. The volatiles were evaporated and the residue was used without further purification.

[0145] (Method xii:) The compound obtained from method xi was dissolved in EtOH (c=0.4 M). Triethylamine (1.5 equiv.) and phenyl isothiocyanate (1.2 equivalents) were added to the solution and the mixture was heated to 50°C for 4 hours. The reaction mixture was then concentrated to dryness in vacuo. The residue was suspended in toluene (c=0.4 M). The mixture was heated to 120°C for 4 hours. After cooling to room temperature, The volatiles were evaporated and the residue was dissolved in water, and the aqueous layer was extracted with EtOAc (3 x 25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography. (silica, heptane / EtOAc gradient).

[0146] (Method xiii:) The cyclic thiourea obtained from method xii was suspended in glacial acetic acid (c = 0.3 M). H2O2 (30%, 4 equivalents) Amount of 10% K2CO3 solution (10 ml) was added dropwise and the mixture was stirred at room temperature for 5 minutes. The reaction was cooled to 0 °C and 10% K2CO3 solution (10 ml) was added. The mixture was quenched with 1N NaOH solution to pH 9. The mixture was then diluted with EtOAc (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was Purified by chromatography (silica, heptane / EtOAc gradient).

[0147] Example 12: 2-(3,5-diphenylimidazol-4-yl)ethanehydroxamic acid Compounds were synthesized according to methods xi, xii, xiii, and v above. Yield (last step): 34 mg (39%); ESI-MS: m / z 294.1[M+H] + HPLC (gradient 1): rt 6.51 min (>99%); [ka] A mixture of cis-trans isomers.

[0148] Scheme 7 [ka] (Method xiv:) Ortho-phenylenediamine or a substituted analogue (1 equivalent) was dissolved in acetonitrile (c = 0.2 M). Each aldehyde (1 equivalent), 30% hydrogen peroxide (4 equivalents), and ammonium nitrate were added. Sodium (0.1 equiv.) was added and the mixture was heated to 50° C. under microwave irradiation for 12 min. The effervescent material was evaporated and the residue was dissolved in water and extracted with EtOAc (3 x 25 ml). The layer was dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica, C Purification was carried out using a HCl3 / MeOH gradient.

[0149] (Method xv:) Each 2-phenylbenzimidazole obtained by method xiv (1 equivalent) was reacted with acetonitrile. It was dissolved in nitrite (2 ml), methyl acrylate (1.1 equivalents) and K2CO3 (1 equivalent) were added, and The mixture was heated under reflux for 6 hours. The volatiles were evaporated and the mixture was dissolved in a small amount of EtOAc. was added and the mixture was extracted with EtOAc (3 x 25 ml). The combined organic layers were dried over Na2SO4 and The residue was purified by flash chromatography (silica, heptane / EtOAc gradient). Purified.

[0150] Example 13: 2-(2-phenylbenzimidazol-1-yl)ethanehydroxamic acid The compound was synthesized according to methods xiv, i, and v above. Yield (last step): 88 mg (66%); ESI-MS: m / z 268.3[M+H] + HPLC (gradient 1): rt 5.96 min (>99%); [ka] A mixture of cis-trans isomers.

[0151] Example 14: 3-(2-phenylbenzimidazol-1-yl)propanehydroxamic acid Compounds were synthesized according to methods xiv, xv, and v above. Yield (last step): 33 mg (37%) ESI-MS: m / z 282.4[M+H] + HPLC (gradient 1): rt 6.61 min (95.7%); [ka] A mixture of cis-trans isomers.

[0152] Example 15: 2-[2-(4-methoxyphenyl)benzimidazol-1-yl]ethanehydroxam acid) The compound was synthesized according to methods xiv, i, and v above. Yield (last step): 55 mg (36%); ESI-MS: m / z 298.1[M+H] + HPLC (gradient 1): rt 6.88 min (98.2%); [ka] A mixture of cis-trans isomers.

[0153] Example 16: 2-[2-(4-chloro-2-fluoro-3-hydroxy-phenyl)benzimidazole-1 -yl]ethanehydroxamic acid) The compound was synthesized according to methods xiv, i, and v above, with final deprotection of the phenol using BBr This was achieved by treatment with 3 (1M in DCM, 5 equiv.). Yield (last step): 24 mg (51%); ESI-M S: m / z 336.5[M+H] + HPLC (gradient 1): rt 7.31 min (>99%); [ka] A mixture of cis-trans isomers.

[0154] Scheme 8 [ka] (Method xvi:) Each 1-fluoro-2-nitrobenzene derivative (1 equivalent), amino acid tert-butyl ester A suspension of 1 equivalent of ethanol and 2 equivalents of NaHCO3 was added to EtOH (c = 0.3 M). The mixture was heated under microwave irradiation. The mixture was heated to 120°C under reduced pressure for 20 minutes. After cooling to room temperature, the mixture was transferred to a flask and diluted with EtOH (5 ml). The mixture was diluted with HCl. The respective aldehyde and Na2S2O4 were added in small portions. The mixture was left to simmer overnight. Heat to reflux. Volatiles were evaporated. The residue was dissolved in a small amount of water and saturated aqueous NaHCO3 was added and the mixture was extracted with EtOAc (3 x 25 ml). The combined organic layers were dried over Na2SO4 and The residue was purified by flash chromatography (silica, heptane / EtOAc gradient). Purified.

[0155] (Method xvii:) The compound obtained by either method i or xvi (1 equivalent) was dissolved in 5M dioxane (50 equivalents). HCl and cooled on ice. The mixture was allowed to warm to room temperature and stirred overnight. Volatiles The was evaporated and used without further purification.

[0156] (Method xviii:) Each 2-(2-phenyl-1H-benzimidazol-1-yl) compound obtained by method xvii Acetic acid (1 equivalent) was dissolved in dimethylformamide (c=0.2 M). TBTU (1 equivalent) and DIPEA (2 equivalents) were added. Amount) was added and the mixture was stirred at room temperature. After a few minutes, O-benzylhydroxylamine hydrochloride ( 1 equivalent) and DIPEA (2 equivalents) were added and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with water. The mixture was cooled and extracted with EtOAc (3 x 25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica, CHCl3 / MeOH gradient). The resulting product was dissolved in DCM (c=0.1 M) in a sealed flask under an argon atmosphere. The mixture was cooled to 0 °C and treated with BBr3 (1 M in DCM, 10-13 equiv.) for final deprotection. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water and cooled on ice. The organic layer was extracted with EtOAc (3 x 25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by semi-preparative HPLC.

[0157] Example 17: 2-[1-[2-(hydroxyamino)-2-oxo-ethyl]benzimidazol-2-yl] benzoic acid) Compounds were synthesized according to methods xiv, i, xvii, and xviii above. Yield (last step): 1 .5mg(2%); ESI-MS: m / z 312.1[M+H] + HPLC (gradient 1): rt 5.17 min (>99%); [ka] A mixture of cis-trans isomers.

[0158] Example 18: 3-[1-[2-(hydroxyamino)-2-oxo-ethyl]benzimidazol-2-yl] benzoic acid) Compounds were synthesized according to methods xiv, i, xvii, and xviii above. Yield (last step): 5 mg (3%); ESI-MS: m / z 312 [M+H] + HPLC (gradient 1): rt 6.13 min (>99%); [ka] A mixture of cis-trans isomers.

[0159] Example 19: 4-[1-[2-(hydroxyamino)-2-oxo-ethyl]benzimidazol-2-yl] benzoic acid) Compounds were synthesized according to methods xiv, i, xvii, and xviii above. Yield (last step): 4 mg (4%); ESI-MS: m / z 312 [M+H] + HPLC (gradient 1): rt 6.37 min (>99%); [ka] A mixture of cis-trans isomers.

[0160] Example 20: 2-(4-chloro-2-fluoro-3-hydroxy-phenyl)-1-[2-(hydroxyamino) -2-oxo-ethyl]benzimidazole-4-carboxylic acid) Compounds were synthesized according to methods xvi, xvii, and xviii above. Yield (last step): 32 mg (39%); ESI-MS: m / z 380[M+H] + HPLC (gradient 1): rt 7.44 min (91.4%); [ka] A mixture of cis-trans isomers.

[0161] Example 21: 2-(4-chloro-2-fluoro-3-hydroxy-phenyl)-1-[2-(hydroxyamino) -2-oxo-ethyl]benzimidazole-5-carboxylic acid) Compounds were synthesized according to methods xvi, xvii, and xviii above. Yield (last step): 35 mg (26%); ESI-MS: m / z 380[M+H] + HPLC (gradient 1): rt 8.48 min (>99%); [ka] A mixture of cis-trans isomers.

[0162] Example 22: 2-(4-chloro-2-fluoro-3-hydroxy-phenyl)-3-[2-(hydroxyamino) -2-oxo-ethyl]benzimidazole-5-carboxylic acid) Compounds were synthesized according to methods xvi, xvii, and xviii above. Yield (last step): 49 mg (43%); ESI-MS: m / z 379.9[M+H] + HPLC (gradient 1): rt 8.75 min (>99%); [ka] A mixture of cis-trans isomers.

[0163] Scheme 9 [ka] (Method xiv * :) Pyridine-2,3-diamine or a substituted analogue (1 equivalent) was dissolved in water (1 M) and the respective aldehyde The mixture was treated with HCl (1 equiv.) and heated to reflux overnight. After cooling, the mixture was basified with aqueous NaHCO3. The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica, CHCl3 / MeOH gradient).

[0164] (Method xix:) Each amino acid ester (1 equivalent) was dissolved in dimethylformamide (c=1.0 M). -chloro-3-nitropyridine derivative (1 equivalent) and triethylamine (2.5 equivalents) were added and mixed. The mixture was heated in a microwave to 120° C. for 20 min. After cooling, water was added and the mixture was washed with EtOAc (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was further purified. It was used without

[0165] (Method xx:) The nitropyridine derivative obtained by method xix was dissolved in DMF / EtOH (1:1 v / v, c=0.15M). The respective aldehyde (1 equivalent) and NaSO (3 equivalents) were added, and the mixture was heated at 80 °C for 22 The mixture was stirred for 1 hour. The volatiles were evaporated and the residue was dissolved in a small amount of water. The mixture was diluted with EtOAc ( The combined organic layers were dried over Na2SO4 and evaporated. The residue was The residue was purified by column chromatography (silica, heptane / EtOAc 1:1).

[0166] Example 23: 2-(2-phenylimidazo[4,5-b]pyridin-3-yl)ethane-hydroxamic acid The compound was synthesized according to methods xix, xx, and v above. Yield (last step): 35 mg (39%) ESI-MS: m / z 269.1[M+H] + HPLC (gradient 1): rt 6.75 min (>99%); [ka] A mixture of cis-trans isomers.

[0167] Example 24: 2-(2-phenylimidazo[4,5-b]pyridin-1-yl)ethane-hydroxamic acid Compounds were prepared by the method xiv above. * , i, and v. Yield (last step): 38 mg (20%) ESI-MS: m / z 269.1[M+H] + HPLC (gradient 1): rt 6.61 min (>99%); [ka] A mixture of cis-trans isomers.

[0168] Scheme 10 [ka] Example 25: 2-(2-phenylindol-1-yl)ethanehydroxamic acid The compound was synthesized according to methods i and v above. Yield (last step): 91 mg (34%); ESI-MS : m / z 267.3[M+H] + HPLC (gradient 1): rt 15.81 min (>99%); [ka] A mixture of cis-trans isomers.

[0169] Example 26: 3-(2-phenylindol-1-yl)propanehydroxamic acid The compound was synthesized according to methods vi and v above. Yield (last step): 33 mg (18%); ESI-M S: m / z 281.2[M+H] + HPLC (gradient 1): rt 15.22 min (>99%); [ka] A mixture of cis-trans isomers.

[0170] Scheme 11 [ka] (Method xxi:) Each benzoylpropionic acid (1 equivalent) was dissolved in acetic acid (c=0.33M). Add hydrazine (1.2 equivalents), para-toluenesulfonic acid (1.1 equivalents), and ZnCl (1 equivalent), The mixture was heated in a microwave at 180° C. for 40 min. After cooling, water was added and the mixture was diluted with EtOAc (3 x 25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was Purification was achieved by cross-chromatography (silica, heptane / EtOAc gradient).

[0171] (Method xxii:) Each indole derivative obtained by method xxi was dissolved in methanol (5 ml), The mixture was heated to reflux for 4 hours. The volatiles were evaporated and dichloromethane was added. The organic layer was dried over Na2SO4 and washed carefully with saturated aqueous NaHCO3. Evaporated and the residue was used without further purification.

[0172] Example 27: 2-(2-phenyl-1H-indol-3-yl)ethanehydroxamic acid Compounds were synthesized according to methods xxi, xxii, and v above. Yield (last step): 14 mg (15 %); ESI-MS: m / z 267.2[M+H] + , 206.1 [M-CH2NO2] + HPLC (gradient 1): rt 11.97 min (>99%) ; [ka] A mixture of cis-trans isomers.

[0173] Scheme 12 [ka] (Method xxiii:) Aminopyridine (1 equivalent) and the respective aldehyde (1.2 equivalents) were dissolved in toluene (c=0.2M). Molecular sieves (3 Å, 200 mg) were added and the mixture was heated to 120° C. for 14 hours. After cooling, Cu(OAc)2 × H2O (0.1 equivalent) and ethyl propiolate (1 equivalent) were added and the mixture was heated to 120°C. The mixture was then filtered through Celite and the volatiles were evaporated. The residue was purified by flash chromatography (silica, CHCl3 / MeOH gradient).

[0174] Example 28: 2-[2-(4-chloro-2-fluoro-3-hydroxy-phenyl)imidazo-[1,2-a]pyridine ethanehydroxamic acid) The compound was synthesized according to methods xxiii and v above, and final deprotection of the phenol was carried out to BBr3(D This was achieved by treatment with 1M CM, 5 eq. Yield (last step): 7 mg (13%); ESI-MS: m / z 336.2[M+H] + HPLC (gradient 1): rt 6.75 min (>99%); [ka] A mixture of cis-trans isomers.

[0175] Scheme 13 [ka] (Method xxiv:) 2-Aminopyridine or a substituted analog (1 equivalent) was dissolved in MeOH (c=0.4 M). Methyl isocyanoacetate (1 equivalent) was added and the mixture was stirred at ambient temperature for 10 minutes. After adding 1 equivalent of HCl, the reaction mixture was heated at 100° C. for 30 minutes under microwave irradiation. Cold diethyl ether was added and the resulting precipitate was collected by filtration without further purification. I used it without any problems.

[0176] Example 29: 2-[(2-phenylimidazo[1,2-a]pyridin-3-yl)amino]-ethanehydroxane nicotinic acid) The compound was synthesized according to methods xxiv and v above. Yield (last step): 32 mg (6%); ESI- MS: m / z 283.2[M+H] + HPLC (gradient 2): rt 6.91 min (>99%); [ka] A mixture of cis-trans isomers.

[0177] Example 30: 4-[3-[[2-(hydroxyamino)-2-oxo-ethyl]amino]-imidazo[1,2-a]piperidin Lysin-2-yl]benzoic acid) The compound was synthesized according to methods xxiv and v above. Yield (last step): 67 mg (11%); ESI -MS: m / z 327.2[M+H] + HPLC (gradient 2): rt 6.69 min (93.4%); [ka]

[0178] Example 31: 3-[3-[[2-(hydroxyamino)-2-oxo-ethyl]amino]-imidazo[1,2-a]piperidin Lysin-2-yl]benzoic acid) The compound was synthesized according to methods xxiv and v above. Yield (last step): 39 mg (10%); ESI -MS: m / z 327.2[M+H] + HPLC (gradient 2): rt 7.15 min (98.9%); [ka]

[0179] Example 32: 2-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)imidazo-[1,2-a]pyri 3-[(2- ... The compound was synthesized according to methods xxiv and v above. Yield (last step): 36 mg (10%); ESI -MS: m / z 327.2[M+H] + HPLC (gradient 2): rt 8.19 min (96.8%); [ka] A mixture of cis-trans isomers.

[0180] Example 33: 3-[[2-(hydroxyamino)-2-oxo-ethyl]amino]-2-phenyl-imidazo[ 1,2-a]pyridine-8-carboxylic acid) The compound was synthesized according to methods xxiv and v above. Yield (last step): 16 mg (11%); ESI -MS: m / z 327.4[M+H] + HPLC (gradient 1): rt 5.81 min (98.0%); [ka]

[0181] Scheme 14 [ka] (Method xxv:) Each azabenzene (1 equivalent), [Cp * Contains RhCl2]2 (0.05 equivalents) and Cu(OAc)2 (2 equivalents). The vial containing the dimethylformamide (c=0.2 M) and methylformamide were sealed and purged with argon. Ethyl acrylate (1.2 equiv.) was added and the mixture was stirred at 130° C. overnight. The reaction was quenched with water. The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica, heptane / EtOAc gradient).

[0182] Example 34: 2-(2-phenylindazol-3-yl)ethanehydroxamic acid The compound was synthesized according to methods xxv and v above. Yield (last step): 18 mg (56%); ESI- MS: m / z 268.1[M+H] + HPLC (gradient 1): rt 9.49 min (>99%); [ka] A mixture of cis-trans isomers.

[0183] Scheme 15 [ka] (Method xxvi:) 2-(3,5-diphenyl-1H-pyrazol-4-yl)-N-trityloxy-acetamide (1 equivalent) Each boronic acid (2 equivalents), triethylamine ( 2 equiv.), Cu(OAc)2 (1.5 equiv.), and molecular sieves were added until TLC showed complete conversion of the starting material. The mixture was vigorously stirred at room temperature. The mixture was filtered through Celite and evaporated. The residue was purified by flash chromatography (silica, heptane / EtOAc gradient). The resulting product was treated with TFA / DCM (1:1 v / v, 10 ml) and triisopropylsilane (180 μl), Stirred at room temperature for 1-2 hours. Volatiles were evaporated and the residue was purified by semi-preparative HPLC.

[0184] Example 35: 2-(1-methyl-3,5-diphenyl-pyrazol-4-yl)ethanehydroxamic acid The compound was synthesized according to methods i and v above. Yield (last step): 96 mg (45%); ESI-MS : m / z 308.2[M+H] + HPLC (gradient 1): rt 11.55 min (>99%); [ka] A mixture of cis-trans isomers.

[0185] Example 36: 2-(1,3,5-triphenylpyrazol-4-yl)ethanehydroxamic acid The compound was synthesized according to method xxvi above. Yield (last step): 50 mg (14%); ESI-MS: m / z 370.3[M+H] + HPLC (gradient 1): rt 15.63 min (>99%); [ka] A mixture of cis-trans isomers.

[0186] Example 37: 4-[4-[2-(hydroxyamino)-2-oxo-ethyl]-3,5-diphenyl-pyrazole -1-yl]benzoic acid) The compound was synthesized according to methods i and v above. Yield (last step): 55 mg (13%); ESI-MS : m / z 414.2[M+H] + HPLC (gradient 1): rt 13.08 min (>99%); [ka] A mixture of cis-trans isomers.

[0187] Example 38: 3-[4-[2-(hydroxyamino)-2-oxo-ethyl]-3,5-diphenyl-pyrazole -1-yl]benzoic acid) The compound was synthesized according to methods i and v above. Yield (last step): 45 mg (11%); ESI-MS : m / z 414.3[M+H] + HPLC (gradient 1): rt 13.09 min (>99%); [ka] A mixture of cis-trans isomers.

[0188] Example 39: 2-(1-benzyl-3,5-diphenyl-pyrazol-4-yl)ethanehydroxamic acid The compound was synthesized according to methods i and v above. Yield (last step): 81 mg (35%); ESI-MS : m / z 383.4[M+H] + HPLC (gradient 1): rt 15.63 min (>99%); [ka] A mixture of cis-trans isomers.

[0189] Example 40: 4-[[4-(2-(hydroxyamino)-2-oxo-ethyl]-3,5-diphenyl-1H-pyrazoline [1-(2-methyl-1-yl)methyl]benzoic acid The compound was synthesized according to methods i and v above. Yield (last step): 130 mg (32%); ESI-M S: m / z 428.2[M+H] + HPLC (gradient 1): rt 12.69 min (>99%); [ka] A mixture of cis-trans isomers.

[0190] Example 41: 3-[[4-[2-(hydroxyamino)-2-oxo-ethyl]-3,5-diphenyl-1H-pyrazoline [1-(2-methyl-1-yl)methyl]benzoic acid The compound was synthesized according to methods i and v above. Yield (last step): 16 mg (5%); ESI-MS: m / z 428.2[M+H] + HPLC (gradient 1): rt 12.88 min (>99%); [ka] A mixture of cis-trans isomers.

[0191] Example 42: 2-[1-(4-chloro-2-fluoro-3-hydroxybenzyl)-3,5-diphenyl-1H-pyridinyl] 4-[4-(4-hydroxybenzoyl)ethanehydroxamic acid] The compound was synthesized according to methods i and v above, followed by 3 equivalents of BBr3 in DCM (5 ml). The phenol was deprotected. Yield (last step): 142 mg (54%); ESI-MS: m / z 452.2 [M+H] + HPLC (gradient 1): rt 14.75 min (98.4%); [ka] A mixture of cis-trans isomers.

[0192] Example 43: 2-[1-(1,3-benzodioxol-5-ylmethyl)-3,5-diphenyl-1H-pyrazoline [4-(4-yl)ethanehydroxamic acid] The compound was synthesized according to methods i and v above. Yield (last step): 161 mg (53%); ESI-M S: m / z 428.4[M+H] + HPLC (gradient 1): rt 15.33 min (>99%); [ka] A mixture of cis-trans isomers.

[0193] Scheme 16 [ka] (Method xxvii:) Each acetophenone derivative (1 equivalent) was added to anhydrous toluene in a septum-sealed flask. The solution was cooled to -60°C. DMPU (3.6 equiv.) and LiHMDS (in THF) were added. 1M, 1.2 equivalents) was added via syringe under an argon atmosphere at -60°C. Stirring was continued for 30 minutes. Then, methyl bromoacetate or other suitable alkyl halide (1.5 equivalents) was added dropwise. The mixture was stirred for a further 10 minutes, then allowed to warm to room temperature and stirred for a further 5 hours. The organic material was evaporated and the residue was dissolved in a small amount of water. The aqueous layer was washed with dilute aqueous HCl. The mixture was acidified and extracted with EtOAc (3 x 25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica, heptane / diethyl ether gradient). ) and purified.

[0194] (Method xxviii:) Each tert-butyl ester derivative obtained by method xxvii was diluted with TFA / DCM (1:1) at 0°C. The mixture was treated with 10 ml of hexane and stirred for 2 hours. The volatiles were evaporated and the residue was purified by flash chromatography. Purification was carried out by chromatography (silica, heptane / EtOAc gradient).

[0195] (Method xxviii * :) Each methyl ester derivative was dissolved in THF / water (3:1, c=0.4 M). * H2O(2 units Amount of HCl was added and the mixture was stirred at room temperature overnight. The volatiles were evaporated and the residue was dissolved in water. The mixture was then acidified with dilute aqueous HCl and extracted with EtOAc (3 x 25 ml). The combined organic layers were washed with Na It was dried over SO4 and evaporated, and the residue was used without further purification.

[0196] (Method xxix:) Each 4-oxo-4-phenylbutanoic acid derivative (1 equivalent) was dissolved in dimethylformamide (c = 0.2 TBTU (1 eq.) and DIPEA (2 eq.) were added and the mixture was stirred at room temperature. After 1 minute, O-benzylhydroxylamine hydrochloride (1 equivalent) and DIPEA (2 equivalents) were added and the mixture was The mixture was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with EtOAc (3 x 25 ml). The organic layer was dried over Na2SO4 and evaporated. The residue was purified by flash chromatography ( Purification was carried out by column chromatography (heptane / EtOAc gradient).

[0197] (method xxx:) Each N-benzyloxy-4-oxo-4-phenylbutane obtained by method xxix The imido derivative (1 equivalent) was dissolved in anhydrous toluene (c = 0.4 M) in a flask sealed with a septum. The solution was cooled to 0°C under argon. LiHMDS (1 M in THF, 2.1 equiv.) was added via syringe. The mixture was stirred for 5 minutes after the rapid addition of each acyl chloride derivative (0.5 equiv.) The mixture was allowed to warm to room temperature until TLC showed complete conversion of the acyl chloride. The mixture was stirred vigorously. AcOH (2 ml) was added to the mixture. EtOH (10 ml) and THF (5 ml) were added. Add to form a homogeneous mixture, then add N2H4 * H2O (34.3 equiv.) was added. The mixture The reaction was heated to 50° C. and monitored by TLC. The volatiles were evaporated and the residue was dissolved in water. The combined organic layer was dissolved in HCl, acidified with dilute aqueous HCl, and extracted with EtOAc (3 x 25 ml). The layer was dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica, C Purification was carried out using a HCl3 / MeOH gradient.

[0198] (method xxx * :) Each carboxylic acid derivative (0.5 equivalents) was dissolved in anhydrous THF (c=0.3 M). CDI was added to the solution under air. The mixture was stirred at room temperature for 1 hour. In a separate flask, Each N-benzyloxy-4-oxo-4-phenylbutanamide derivative obtained by ix The compound (1 equivalent) was dissolved in anhydrous toluene (c=0.4 M) and sealed with a septum. The solution was then cooled under argon. The mixture was cooled to 0° C. at RT. LiHMDS (1 M in THF, 2.1 equiv.) was added quickly via syringe and the mixture was stirred for 5 min. Each activated carboxylic acid derivative (0.5 equivalents) was added in one portion and the mixture was stirred for 1 minute. The mixture was heated until TLC showed complete conversion of the carboxylic acid derivative. AcOH (2 ml) was added to the mixture. EtOH (10 ml) and THF (5 ml) were added to A homogeneous mixture was formed, after which hydrazine monohydrate (34.3 equivalents) was added. The reaction was heated to 50° C. and monitored by TLC. The volatiles were evaporated and the residue was dissolved in water. The combined organic layer was dissolved in HCl, acidified with dilute aqueous HCl, and extracted with EtOAc (3 x 25 ml). The layer was dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica, C Purification was carried out using a HCl3 / MeOH gradient.

[0199] (method xxxi:) Method xxx or xxx * The compound obtained by The mixture was cooled to 0°C and treated with BB for final deprotection. The reaction was treated with r3 (1M in DCM, 3-15 equiv.). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with water and cooled on ice. The aqueous layer was extracted with EtOAc (3 x 25 ml). The combined organic layer was The layer was dried over Na2SO4 and evaporated, and the residue was purified by semi-preparative HPLC.

[0200] Example 44: 2-(3-methyl-5-phenyl-1H-pyrazol-4-yl)ethanehydroxamic acid The compounds were synthesized according to methods xxix and xxx above to give the final benzyl-protected hydroxamic acid Partial deprotection was achieved according to method xxxi. Yield (last step): 22 mg (27%); ESI-MS: m / z 232.2[M+H] + HPLC (gradient 1): rt 6.56 min (>99%); [ka] A mixture of cis-trans isomers.

[0201] Example 45: 2-(3-cyclopentyl-5-phenyl-1H-pyrazol-4-yl)ethanehydroxamate nicotinic acid) The compounds were synthesized according to methods xxix and xxx above to give the final benzyl-protected hydroxamic acid Partial deprotection was achieved according to method xxxi. Yield (last step): 49 mg (31%); ESI-MS: m / z 286.2[M+H] + HPLC (gradient 1): rt 9.07 min (>99%); [ka] A mixture of cis-trans isomers.

[0202] Example 46: 2-(3-benzyl-5-phenyl-1H-pyrazol-4-yl)ethanehydroxamic acid The compounds were synthesized according to methods xxix and xxx above to give the final benzyl-protected hydroxamic acid Partial deprotection was achieved according to method xxxi. Yield (last step): 24 mg (30%); ESI-MS: m / z 308.3[M+H] + HPLC (gradient 1): rt 10.43 min (>99%); [ka] A mixture of cis-trans isomers.

[0203] Example 47: 2-[3-(3-methoxyphenyl)-5-phenyl-1H-pyrazol-4-yl]ethanehydride loxamic acid) The compounds were synthesized according to methods xxix and xxx above to give the final benzyl-protected hydroxamic acid Partial deprotection was achieved according to method ix. Yield (last step): 145 mg (82%); ESI-MS: m / z 3 24.3[M+H] + HPLC (gradient 1): rt 10.69 min (98.1%); [ka] A mixture of cis-trans isomers.

[0204] Example 48: 2-[3-(4-methoxyphenyl)-5-phenyl-1H-pyrazol-4-yl]ethanehydride loxamic acid) The compounds were synthesized according to methods xxix and xxx above to give the final benzyl-protected hydroxamic acid Partial deprotection was achieved according to method ix. Yield (last step): 114 mg (48%); ESI-MS: m / z 3 24.3[M+H] + HPLC (gradient 1): rt 10.37 min (97.8%); [ka] A mixture of cis-trans isomers.

[0205] Example 49: 2-[3-(3,4-dimethoxyphenyl)-5-phenyl-1H-pyrazol-4-yl]ethane Hydroxamic Acid) The compounds were synthesized according to methods xxix and xxx above to give the final benzyl-protected hydroxamic acid Partial deprotection was achieved according to method ix. Yield (last step): 49 mg (52%); ESI-MS: m / z 35 4.3[M+H] + HPLC (gradient 1): rt 9.95 min (98.6%); [ka] A mixture of cis-trans isomers.

[0206] Example 50: 2-[3-(1,3-benzodioxol-5-yl)-5-phenyl-1H-pyrazol-4-yl] Ethanehydroxamic acid) The compounds were synthesized according to methods xxix and xxx above to give the final benzyl-protected hydroxamic acid Partial deprotection was achieved according to method ix. Yield (last step): 45 mg (41%); ESI-MS: m / z 33 8.2[M+H] + HPLC (gradient 1): rt 10.40 min (98.1%); [ka] A mixture of cis-trans isomers.

[0207] Example 51: 3-[4-[2-(hydroxyamino)-2-oxo-ethyl]-5-phenyl-1H-pyrazole- 3-yl]benzoic acid) The compounds were synthesized according to methods xxix and xxx above, and the methyl ester and benzyl protected hydroxybenzoates were obtained. Final deprotection of the doxamic acid was achieved according to method xxxi. Yield (last step): 5 mg (6 %); ESI-MS: m / z 338.2[M+H] + HPLC (gradient 1): rt 9.39 min (95.8%); [ka] A mixture of cis-trans isomers.

[0208] Example 52: 4-[4-[2-(hydroxyamino)-2-oxo-ethyl]-5-phenyl-1H-pyrazole- 3-yl]benzoic acid) Compounds were treated according to methods xxix and xxx above. * This was achieved by adding the methyl ester and benzyl protected hydroxybenzoates. Final deprotection of the doxamic acid was achieved according to Method xxxi. Yield (last step): 16 mg (5 %); ESI-MS: m / z 338.3[M+H] + HPLC (gradient 1): rt 9.41 min (95.5%); [ka] A mixture of cis-trans isomers.

[0209] Example 53: 2-[3-(4-chloro-2-fluoro-3-hydroxy-phenyl)-5-phenyl-1H-pyrazoline [4-(4-yl)ethanehydroxamic acid] Compounds were treated according to methods xxix and xxx above. * The phenol and benzyl-protected hydrochloride are prepared according to the following procedure: Final deprotection of the xamic acid was achieved according to Method xxxi. Yield (last step): 28 mg (45%) ESI-MS: m / z 362.2[M+H] + HPLC (gradient 1): rt 10.32 min (97.0%); [ka] A mixture of cis-trans isomers.

[0210] Example 54: 2-[3-(3-chloro-5-fluoro-4-hydroxy-phenyl)-5-phenyl-1H-pyrazoline [4-(4-yl)ethanehydroxamic acid] Compounds were treated according to methods xxix and xxx above. * The phenol and benzyl-protected hydrochloride are prepared according to the following procedure: Final deprotection of the xamic acid was achieved according to Method xxxi. Yield (last step): 13 mg (17%) ESI-MS: m / z 362.3[M+H] + HPLC (gradient 1): rt 10.51 min (95.9%); [ka] A mixture of cis-trans isomers.

[0211] Example 55: 2-[3-(3-cyanophenyl)-5-phenyl-1H-pyrazol-4-yl]ethanehydrochloride xamic acid) Compounds were treated according to methods xxix and xxx above. * The final benzyl-protected hydroxamic acid was obtained according to Partial deprotection was achieved according to method xxxi. Yield (last step): 25 mg (39%); ESI-MS: m / z 319.2[M+H] + HPLC (gradient 1): rt 10.48 min (95.6%); [ka] A mixture of cis-trans isomers.

[0212] Example 56: 2-[3-(4-cyanophenyl)-5-phenyl-1H-pyrazol-4-yl]ethanehydrochloride xamic acid) Compounds were treated according to methods xxix and xxx above. * The final benzyl-protected hydroxamic acid was obtained according to Partial deprotection was achieved according to method xxxi. Yield (last step): 27 mg (42%); ESI-MS: m / z 74.1 C2H4NO2·fragment, 319.2[M+H] + HPLC (gradient 1): rt 10.56 min (>99%); [ka] A mixture of cis-trans isomers.

[0213] Example 57: 2-[3,5-bis(1,3-benzodioxol-5-yl)-1H-pyrazol-4-yl]ethanoate hydroxamic acid) The compound is subjected to the above methods xxvii and xxviii. * , xxix, and xxx, and benzyl-protected hydroxybenzoates are prepared according to the methods described above. Final deprotection of the doxamic acid was achieved according to method ix. Yield (last step): 29 mg (13 %); ESI-MS: m / z 382.3[M+H] + HPLC (gradient 1): rt 10.72 min (95.4%); [ka] A mixture of cis-trans isomers.

[0214] Example 58: 3-[3-(3-carboxyphenyl)-4-[2-(hydroxyamino)-2-oxo-ethyl]- 1H-pyrazol-5-yl]benzoic acid) Compounds xxvii, xxviii, xxix, and xxx are prepared by the methods described above. * The methyl ester was synthesized according to and final deprotection of the benzyl-protected hydroxamic acid was achieved according to Method xxxi. Last step): 3mg(3%); ESI-MS: m / z 382.3[M+H] + HPLC (gradient 1): rt 8.67 min (93.0%); [ka] A mixture of cis-trans isomers.

[0215] Example 59: 4-[3-(4-carboxyphenyl)-4-[2-(hydroxyamino)-2-oxo-ethyl]- 1H-pyrazol-5-yl]benzoic acid) Compounds xxvii, xxviii, xxix, and xxx are prepared by the methods described above. * The methyl ester was synthesized according to and final deprotection of the benzyl-protected hydroxamic acid was achieved according to Method xxxi. Last step): 3mg(5%); ESI-MS: m / z 382.2[M+H] + HPLC (gradient 1): rt 8.43 min (90.2%); [ka]

[0216] Example 60: 2-[3,5-bis(4-chloro-2-fluoro-3-hydroxy-phenyl)-1H-pyrazole- 4-yl]ethanehydroxamic acid) Compounds xxvii, xxviii, xxix, and xxx are prepared by the methods described above. * Phenol and Final deprotection of the benzyl-protected hydroxamic acid was achieved according to Method xxxi. process): 4mg(11%); ESI-MS: m / z 430.3[M+H] + HPLC (gradient 1): rt 10.40 min (96.8%); [ka] A mixture of cis-trans isomers.

[0217] Example 61: 3-[3-(1,3-benzodioxol-5-yl)-4-[2-(hydroxyamino)-2-oxo -ethyl]-1H-pyrazol-5-yl)benzoic acid Compounds xxvii, xxviii, xxix, and xxx are prepared by the methods described above. * The methyl ester was synthesized according to and final deprotection of the benzyl-protected hydroxamic acid by method xxviii * and ix. Yield (last step): 90 mg (69%); ESI-MS: m / z 382.3 [M+H] + , 404.3[M+Na] + ; HPLC(gradient) Distribution 1): rt 9.63 minutes (>99%); [ka] A mixture of cis-trans isomers.

[0218] Example 62: 4-[3-(1,3-benzodioxol-5-yl)-4-[2-(hydroxyamino)-2-oxo -ethyl]-1H-pyrazol-5-yl)benzoic acid Compounds xxvii, xxviii, xxix, and xxx are prepared by the methods described above. * The methyl ester was synthesized according to and final deprotection of the benzyl-protected hydroxamic acid by method xxviii * and ix. Yield (last step): 8 mg (10%); ESI-MS: m / z 382.2 [M+H]+ HPLC (gradient 1): rt 9.68 min (>99%); [ka] A mixture of cis-trans isomers.

[0219] Example 63: 3-[5-(4-chloro-2-fluoro-3-hydroxyphenyl)-4-[2-(hydroxyamino)methyl]-4-[(2- ... (2-oxo-ethyl)-1H-pyrazol-3-yl]benzoic acid Compounds xxvii, xxviii, xxix, and xxx are prepared by the methods described above. * It is synthesized according to the Final deprotection of the benzyl ester and benzyl protected hydroxamic acid is achieved according to Method xxxi. Yield (last step): 4 mg (16%); ESI-MS: m / z 406.3 [M+H] + ; HPLC (gradient 1): rt 9. 55 minutes (95.3%); [ka] A mixture of cis-trans isomers.

[0220] Example 64: 3-[5-(3-chloro-5-fluoro-4-hydroxyphenyl)-4-[2-(hydroxyamino)methyl]-4-[(2- ... (2-oxo-ethyl)-1H-pyrazol-3-yl]benzoic acid Compounds xxvii, xxviii, xxix, and xxx are prepared by the methods described above. * It is synthesized according to the Final deprotection of the benzyl ester and benzyl protected hydroxamic acid is achieved according to Method xxxi. Yield (last step): 18 mg (26%); ESI-MS: m / z 406.3 [M+H] + ; HPLC (gradient 1): rt 9 .55 minutes (97.6%); [ka] A mixture of cis-trans isomers.

[0221] Example 65: 4-[5-(4-chloro-2-fluoro-3-hydroxyphenyl)-4-[2-(hydroxyamino)methyl]-4-[(4-chloro-2-fluoro-3-hydroxyphenyl)-4-[(2- ... (2-oxo-ethyl)-1H-pyrazol-3-yl]benzoic acid Compounds xxvii, xxviii, xxix, and xxx are prepared by the methods described above. * It is synthesized according to the Final deprotection of the benzyl ester and benzyl protected hydroxamic acid is achieved according to Method xxxi. Yield (last step): 4 mg (5%); ESI-MS: m / z 406.3 [M+H] + HPLC (gradient 1): rt 9.6 3 minutes (>99%); [ka] A mixture of cis-trans isomers.

[0222] Example 66: 3-[3-(4-carboxyphenyl)-4-[2-(hydroxyamino)-2-oxo-ethyl]- 1H-pyrazol-5-yl]benzoic acid) Compounds xxvii, xxviii, xxix, and xxx are prepared by the methods described above. * The methyl ester was synthesized according to and final deprotection of the benzyl-protected hydroxamic acid was achieved according to Method xxxi. Last step): 3mg(7%); ESI-MS: m / z 382.3[M+H] + HPLC (gradient 1): rt 8.64 min (>99%); [ka] A mixture of cis-trans isomers.

[0223] Example 67: 3-phenyl-1,4-dihydroindeno[1,2-c]pyrazole-4-carbohydroxam acid) The compounds were synthesized according to methods xxix and xxx above to give the final benzyl-protected hydroxamic acid Partial deprotection was achieved according to method xxxi. Yield (last step): 37 mg (11%); ESI-MS: m / z 292.3[M+H] + HPLC (gradient 1): rt 9.92 min (96.5%); [ka] A mixture of cis-trans isomers.

[0224] Example 68: 3-phenyl-4,5-dihydro-1H-benzo[g]indazole-4-carbohydroxam acid) The compounds were synthesized according to methods xxix and xxx above to give the final benzyl-protected hydroxamic acid Partial deprotection was achieved according to method xxxi. Yield (last step): 4 mg (11%); ESI-MS: m / z 3 06.2[M+H] + HPLC (gradient 1): rt 10.59 min (97.9%); [ka]

[0225] Example 69: 2-[3-(3-hydroxyisoxazol-5-yl)-5-phenyl-1H-pyrazole-4 -yl]ethanehydroxamic acid) Compounds were treated according to methods xxix and xxx above. * and benzyl-protected hydroxyisoxa Final deprotection of the zole and benzyl protected hydroxamic acids was achieved according to Method xxxi. Yield (last step): 10 mg (16%); ESI-MS: m / z 301.3 [M+H]+ HPLC (gradient 1): rt 8.37 min (> 99%); [ka] A mixture of cis-trans isomers.

[0226] Example 70: 2-[5-phenyl-3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrazol-4-yl [4-[4-(4-yl)-2-ethoxy]ethanehydroxamic acid) Compounds were treated according to methods xxix and xxx above. * tert-butyl-protected pyrazole and Final deprotection of the benzyl-protected hydroxamic acid was achieved according to Method xxxi. Process): 26mg(31%); ESI-MS: m / z 352.2[M+H] + HPLC (gradient 1): rt 9.84 min (97.9%); [ka] A mixture of cis-trans isomers.

[0227] Example 71: 2-[5-phenyl-3-[3-(1H-tetrazol-5-yl)phenyl]-1H-pyrazole-4- yl]ethanehydroxamic acid) Compounds were treated according to methods xxix and xxx above. * PMB-protected tetrazole and benzyl Final deprotection of the protected hydroxamic acid was achieved according to method xxxi. Yield (last step): 38mg(32%); ESI-MS: m / z 362.1[M+H] + HPLC (gradient 1): rt 9.47 min (>99%); [ka] A mixture of cis-trans isomers.

[0228] Example 72: 3-[1-[(4-chloro-2-fluoro-3-hydroxyphenyl)methyl]-3,5-diphenyl 4-pyrazol-4-yl]propanehydroxamic acid The compound was synthesized according to methods i and v above, with final deprotection of the phenol being carried out with BBr3 (in DCM). 1M, 3 eq.). Yield (last step): 56 mg (21%); ESI-MS: m / z 466.2[M+H] + HPLC (gradient 1): rt 15.28 min (>99%); [ka]

[0229] Example 73: (1S,2R)-2-[4-[2-(hydroxyamino)-2-oxoethyl]-5-phenyl-1H-pyra [3-(2-(2-phenyl-3-yl)cyclohexanecarboxylic acid)] Compounds can be prepared by methods xxix and xxx using the respective anhydrides mentioned above. * Benzyl Final deprotection of the protected hydroxamic acid was achieved according to method xxxi. Yield (last step): 2mg(2%); ESI-MS: m / z 344.2[M+H] + HPLC (gradient 1): rt 9.01 min (91.8%); [ka] A mixture of cis-trans isomers.

[0230] Example 74: 3-[4-[2-(hydroxyamino)-2-oxo-ethyl]-5-phenyl-1H-pyrazole- 3-yl]cyclohexanecarboxylic acid) Compounds were treated according to methods xxix and xxx above. * This was achieved by adding the methyl ester and benzyl protected hydroxybenzoates. Final deprotection of the doxamic acid was achieved according to method xxxi. Yield (last step): 10 mg (8 %); ESI-MS: m / z 344.3[M+H] + HPLC (gradient 1): rt 8.64 min (96.5%); [ka] A mixture of cis-trans isomers.

[0231] Example 75: cis-4-[4-[2-(hydroxyamino)-2-oxo-ethyl]-5-phenyl-1H-pyrazoline [3-yl]cyclohexanecarboxylic acid) Compounds were treated according to methods xxix and xxx above. * This was achieved by adding the methyl ester and benzyl protected hydroxybenzoates. Final deprotection of the doxamic acid was achieved according to method xxxi. Yield (last step): 10 mg (1 3%); ESI-MS: m / z 344.2[M+H] + HPLC (gradient 1): rt 8.67 min (26.4%) and 8.80 min (73.6%) double peak; [ka] A mixture of cis-trans isomers.

[0232] Example 76: trans-4-[4-[2-(hydroxyamino)-2-oxo-ethyl]-5-phenyl-1H-pyra [3-(2-(2-phenyl-3-yl)cyclohexanecarboxylic acid)] Compounds were treated according to methods xxix and xxx above. * This was achieved by adding the methyl ester and benzyl protected hydroxybenzoates. Final deprotection of the doxamic acid was achieved according to method xxxi. Yield (last step): 8 mg (12 %); ESI-MS: m / z 344.3[M+H] +HPLC (gradient 1): rt 8.69 min (>99%); [ka] A mixture of cis-trans isomers.

[0233] Example 77: cis-3-[3-(4-carboxycyclohexyl)-4-[2-(hydroxyamino)-2-oxo- [iso-ethyl]-1H-pyrazol-5-yl]benzoic acid Compounds xxvii, xxviii, xxix, and xxx are prepared by the methods described above. * The methyl ester was synthesized according to and final deprotection of the benzyl-protected hydroxamic acid was achieved according to Method xxxi. Last step): 2mg(1%); ESI-MS: m / z 388.4[M+H] + HPLC (gradient 1): rt 8.00 min (95.2%); [ka] A mixture of cis-trans isomers.

[0234] Example 78: trans-3-[3-(4-carboxycyclohexyl)-4-[2-(hydroxyamino)-2-(hydroxypropyl)]-2-(hydroxypropyl)-4-[2-(hydroxypropyl)]-2-(hydroxypropyl) ... 1H-pyrazol-5-yl]benzoic acid) Compounds xxvii, xxviii, xxix, and xxx are prepared by the methods described above. * The methyl ester was synthesized according to and final deprotection of the benzyl-protected hydroxamic acid was achieved according to Method xxxi. Last step): 2mg(1%); ESI-MS: m / z 388.3[M+H] + HPLC (gradient 1): rt 7.95 min (>99%); [ka] A mixture of cis-trans isomers.

[0235] (Analysis method) (HPLC:) The analytical HPLC system consisted of a LUNA RP 18 (5 μm) analytical column (length: 125 mm, diameter: 4 mm); and Merck-Hitman using a diode array detector (DAD) with λ = 214 nm as the reporting wavelength. The instrument consisted of a chromatograph (model LaChrom). Compounds were analyzed using a flow rate gradient of 1 mL / min. Here, the eluent (A) is acetonitrile and the eluent (B) is water, both of which contain 0.04% ( v / v) trifluoroacetic acid and one of the following gradients was applied: Gradient 1: 0 min - 5 min → 5% (A), 5 min - 15 min → 5 - 60% (A), 15 min - 20 min → 60 - 95%, (A) 20 min ~30 min 95%(A) Gradient 2: 0-15 min: 5-50% (A), 15-20 min: 50-95% (A), 20-23 min: 95% (A)

[0236] The purity of all compounds reported is determined by the percentage of peak area at 214 nm. It was decided that

[0237] (Mass spectrometry, NMR-spectroscopy:) ESI-mass spectra were obtained using a SCIEX API 1200 mass spectrometer (Perkin Elmer) or an expression CMS ( Acquired using Advion. 1 H NMR spectra were recorded on an Agilent DD2 400-MHz mass spectrometer. Chemical shifts (δ) are expressed in parts per million (ppm) downfield from tetramethylsilane. Splitting patterns are denoted as follows: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), m (multiplet), and br (broad signal).

[0238] I. Enzyme Assays Determination of enzyme activity was based on the cleavage of an internally quenched peptide substrate. A typical assay in a total volume of 250 μl measured in a well plate contains 100 μl of buffer 50 μl of enzyme at a final concentration of 5e-8M to 2e-10M, 50 μl of substrate (0.15 to 80 μM in buffer, 0.5 125 μl of the inhibitor solution (1% DMSO in buffer) and 50 μl of the inhibitor solution (1% DMSO in buffer). For an assay volume of 1 l (black 96 half-area well plate), all volumes were halved. The enzyme activity of DAM was measured by centrifugation using 20 μl of inhibitor, 20 μl of buffer, 10 μl of enzyme, and 10 μl of of substrate in a total assay volume of 60 μl in 384-well plates. Table 1. Peptide substrates and assay conditions used to determine enzyme activity (Abz = 2-aminobenzoyl) Dnp=2,4-dinitrophenyl; Mca=7-methoxycoumarin; Dap=2,3-diaminopropyl onic acid; hmeprin = human meprin; hMMP = human matrix metalloproteinase, hADAM = human death integrins and metalloproteases) [Table 1]

[0239] I C 50 Values ​​were determined by Method A and / or B. IC in Method A 50 Regarding the value, enzyme activity The effect of 12 inhibitor concentrations ranging from 0 to 5e-5M on the activity was compared with one standard substrate concentration (10μL). M) was examined. IC in Method B 50 The value ranges from 0 to 1e-5M for enzyme activity. The effect of 14 inhibitor concentrations on meprin α was investigated at a substrate concentration of 8 μM and meprin β. was investigated in the presence of a substrate concentration of 20 μM. The initial velocity was determined and converted to concentration units to give The standard curve was obtained after complete conversion of various substrate concentrations under assay conditions. Based on Ki (app) The values ​​were determined using the Morrison equation. All measurements were performed using a fluorescent platelet count. The reaction was carried out at 30°C using a FLUOstar OPTIMA reader (BMG Labtech). The reaction rate parameters were: The reaction rates were determined at least in duplicate on separate days. The excitation / emission wavelengths were 340 / 420 nm. Data were evaluated using GraFit software (version 7.0.3, Erithacus Software).

[0240] Prior to measurement, MMP was purified by APMA (p-aminoacetic acid phenyl ester) according to the manufacturer's instructions (R&D systems). It was activated by treatment with mercury.

[0241] II. Inhibition of Meprin α and β The following compounds according to the invention were synthesized using the general procedure described above: IC of inhibition of meprin β and α measured using 50 The values ​​are shown in the table below .I C 50 is the average IC measured as above 50 Values ​​(geometric means of independent experiments; geometric SD coefficients are (given in brackets). Table 2. Compounds and their inhibitory activity against meprin α and β [Table 2] TIFF2025165966000165.tif222170TIFF2025165966000166.tif209170TIFF2025165966000167.tif206170TIFF2025165966000168.tif23717 0TIFF2025165966000169.tif233170TIFF2025165966000170.tif218170TIFF2025165966000171.tif236170TIFF2025165966000172.tif21917 0TIFF2025165966000173.tif208170TIFF2025165966000174.tif206170TIFF2025165966000175.tif221170TIFF2025165966000176.tif22617 0TIFF2025165966000177.tif218170TIFF2025165966000178.tif233170TIFF2025165966000179.tif225170TIFF2025165966000180.tif56170 * Geometric means of independent experiments (geometric SD coefficients in parentheses). A IC determined by using Method A 50 value B IC determined by using Method B 50 value

[0242] III. Inhibition of Selected Other Metalloproteases Table 3. Other metalloproteinases in the presence of 10 and 200 μM of selected inhibitor compounds. Residual enzyme activity of ase [Table 3]

Claims

1. Compounds according to formula I below, their individual enantiomers, their individual diastereoisomers , its hydrate, its solvate, its crystalline form, its individual tautomer, or a pharmaceutical composition thereof Acceptable salts 【Chemistry 1】 (In the formula: A is, 【Chemistry 2】 are independently selected from; B is 【Transformation 3】 are independently selected from; C is 【Chemistry 4】 independently selected from -O-, and -S-; F, if present, 【Transformation 5】 are independently selected from; G, if present, 【Transformation 6】 are independently selected from; H, if present, 【Transformation 7】 are independently selected from; I, if present, 【Transformation 8】 are independently selected from; where F, G, H, and I are present: D is 【Chemistry 9】 and E is 【Chemistry 10】 are independently selected from The ring formed by D, E, F, G, H, and I is R 2 By the p-substituent represented by It has been replaced, where p is 0, 1, 2, 3, or 4; Otherwise, if F, G, H, and I are not present: D is 【Chemistry 11】 are independently selected from E is 【Chemistry 12】 where p is 0, 1, 2, 3, 4, or 5; L 1 and L 2 each independently represents alkyl, aryl, arylalkyl, heterocyclyl, is selected from the group consisting of heteroaryl, cycloalkyl, and cycloalkenyl, So, L 1 and L 2 can come together to form a ring; Each X is C(R a )R b , N.R. a and O; X and L 2 can be joined together to form a ring, wherein the ring is optionally may be condensed to a hydroxyl group; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, or 5; Each R 1 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH 2 , alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, and hydroxy; Each R 2 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH 2 , alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, , hydroxy, and heteroaryl; can be; Each R 3 is hydrogen, as well as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, and cycloalkyl groups. Alkenyl, aryl, arylalkyl, heterocyclyl, heterocyclic, fused to aryl and independently selected from the group consisting of cyclohexyl, ... Each of these is an amino, halogen, cyano, hydroxy, carboxy, -C(O)O(a) -C(O)NH 2 , -C(O)NH(alkyl), alkylsulfono, functional group having acidic hydrogen, Alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Aryl, arylalkyl, heterocyclyl, heteroaryl, and heteroaryla and each of which may be substituted with one or more groups independently selected from alkyl, , halogen, carboxy, cyano, alkyl, alkoxy, and hydroxy; and R a and R b are each independently hydrogen, deuterium, and C 1-3 alkyl, Where, unless otherwise specified: The aryl is independently a monocyclic or bicyclic C 6-10 , preferably C 6 is an aryl group; The heterocyclyl contains 1 to 4 ring heteroatoms independently selected from N, S, and O. Monocyclic or bicyclic C 2-11 , preferably C 2-8 , more preferably C 3-5 Heterocyclic group the law of nature; The heteroaryl contains 1 to 3 ring heteroatoms independently selected from N, S, and O. Monocyclic or bicyclic C 2-11 , preferably C 2-8 , more preferably C 3-5 Aromatic heterocycles It is a base; The alkyl or alk may be independently linear or branched, open chain or cyclic C 1-12 , preferably , C 1-6 , more preferably C 1-3 , and even more preferably C 1-2 is an alkyl group; The alkenyl may be linear or branched, open chain or branched, independently containing at least one C=C bond. cyclic C 2-12 , preferably C 2-4 , more preferably C 2-3 , and even more preferably C 2 Based on can be; The alkynyl may be linear or branched, open chain or branched, independently containing at least one C≡C bond. is cyclic C 2-12 , preferably C 2-6 , more preferably C 2-4 , and even more preferably C 2-3 It is a base; The cycloalkyl is independently selected from C 3-12 , preferably C 3-6 , monocyclic or bicyclic alkyl It is a base; The cycloalkenyl independently contains at least one C=C bond. 3-12 , preferably , C 4-6 , more preferably C 5-6 is a carbocyclic group; wherein each of the above groups is selected from halogen, carboxy, cyano, methoxy, and hydroxy. and may be substituted by one or more groups selected from wherein the ring fragment 【Chemistry 13】 but, 【Chemistry 14】 When represented by: R 3 represents hydrogen, as well as optionally substituted alkyl, optionally substituted alkenyl, optionally Substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl aryl, substituted aryl, optionally substituted arylalkyl, optionally substituted heptyl Tetracyclyl, optionally substituted heteroaryl, and optionally substituted heteroaryl Alkyl (where optionally substituted or substituted means optionally substituted or amino, respectively). No, halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)NH 2 , -C(O)N H(alkyl), alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkynyl and wherein the alkyl, alkyl group is independently selected from alkyl, heterocyclyl, heteroaryl, and heteroarylalkyl. each of which is selected from the group consisting of halogen, carboxyl, methyl ... one or more independently selected from carboxy, cyano, alkyl, alkoxy, and hydroxy; can be further substituted by groups of the ring fragment 【Chemistry 15】 but, 【Chemistry 16】 where m and p are both 0 and n, and the ring fragment 【Chemistry 17】 but, [Chemistry 18] where m is greater than 0).

2. L 1 and L 2 each independently represents an aryl, heterocyclyl, heteroaryl, cycloalkyl and cycloalkenyl, wherein L 1 and L 2 But together , capable of forming a ring; Each X is C(R a )R b , N.R. a and O; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, or 5; R 1 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)NH(alkoxy) Kill), -C(O)-NH 2 , alkylsulfono, functional groups having acidic hydrogen, alkoxy, alkyl , alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryla from the group consisting of alkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups; each of said groups is selected from halogen, carboxy, cyano, alkoxy, and hydroxy. and may be further substituted by one or more groups independently selected from: Each R 2 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH 2 , alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, and hydroxy. 、 Each R 3 is hydrogen, and alkyl, alkenyl, alkynyl, cycloalkyl, cyclo Alkenyl, aryl, arylalkyl, heterocyclyl, heteroaryl, and heterocyclic and each of the aryl and aryl groups is independently selected from the group consisting of amino, halogen, and aryl. , cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)NH 2 , -C(O)NH(alkyl) , alkylsulfonate, functional groups having acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic one or more groups independently selected from acryl, heteroaryl, and heteroarylalkyl; each of which may be substituted by halogen, carboxy, cyano, alkoxy, and further substituted by one or more groups independently selected from alkyl, alkoxy, and hydroxy. can be done, The compound of claim 1.

3. Formulas Ia and Ib below: 【Chemistry 19】 3. The compound of claim 1 or 2, represented by one of:

4. If F, G, H, and I are absent, the ring fragment 【Chemistry 20】 But the following structure: 【Chemistry 21】 4. The compound of any one of claims 1, 2, or 3, represented by one of:

5. Ring fragments F, G, H, and I, if present 【Chemistry 22】 But the following structure: 【Chemistry 23】 5. The compound of any one of claims 1 to 4, represented by one of:

6. R 1 and R 2 are the same or different and each independently represent chloro, fluoro, bro Mo, Iodine, Cyano, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, Fluoro(C 1-6 alkyl), full Oro (C 1-6 Alkoxy), as well as hydroxy, carboxy, -SO 3 H, -P(O)(OH) 2 , -C(O)-NH- OH, tetrazol-5-yl, -SO 3 H, -P(O)(OH) 2 , -C(O)-NH-OH, and tetrazol-5-yl Any one of claims 1 to 5, wherein the functional group having an acidic hydrogen is selected from the group consisting of:

3. The compound according to claim 1.

7. L 1 (R 1 ) m and L 2 (R 2 ) p are the same or different, and: (a) independently, each having the following structure: 【Chemistry 24】 (where: (i)R o , R o ', R m , R m ', and R p At least one of the groups is hydroxy, carboxy, or -SO 3 H, -P(O)(OH) 2 , —C(O)—NH—OH, and tetrazol-5-yl the remaining one is H or R 1 too Or R 2 and / or (ii)R o , R o ', R m , R m ', and R p at least two of which are part of a 5- to 8-membered heterocycle the other is H or any of claims 1 to 6. or R according to any one of the preceding claims. 1 Or R 2 (either as defined for and / or (b) each independently 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl , 3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3- Methylphenyl, 4-carboxyphenyl, 4-chlorophenyl, 4-cyanophenyl, 4-fluorophenyl 4-Methoxyphenyl, 3,4-Dimethoxyphenyl, 4-Methylphenyl, 3-Carboxyphenyl carboxy-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-chloro-2-fluoro- 3-Hydroxyphenyl, 5-chloro-3-fluoro-4-hydroxyphenyl, 3-chloro-5-fluoro 3,5-dichloro-4-hydroxyphenyl, 2,6-difluoro-4- Methoxyphenyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 1,3-benzodioxo 3-(trifluoromethyl)-1H-pyrazol-5-yl, 3-(trifluoromethyl)-1H-pyrazol-4-yl, 3-(1H-tetrazol-5-yl) phenyl, 2-carboxycyclohexyl, 3-carboxycyclohexyl, 3-carboxy (1,3-benzodioxol-5-yl)methyl) can be, The compound of any one of claims 1 to 6.

8. Each R 3 but, (a) hydrogen, and each of these is chloro, fluoro, bromo, iodo, carboxy, cyano , C 1-6 Alkyl, C 1 -C 6 alkoxy, and hydroxy, can be further substituted by C 1-6 Alkyl, carboxy (C 1-6 alkyl), amino (C 1-6 alkyl), cyano (C 1-6 alkyl), C 2-6 Alkynyl, C 3-6 Cycloalkyl, carbo Kishi (C 6-10 aryl), C 1-6 Alkoxy (C 6-10 aryl), cyano (C 6-10 aryl), halo( C 6-10 aryl), hydroxy (C 6-10 aryl), C 1-6 Alkoxy (C 2-8 heteroaryl), Cyano(C 2-8 Heteroaryl), halo(C 2-8 Heteroaryl), C 3-5 Heteroaryl (C 6-10 a Reel), Hydroxy (C 2-8 heteroaryl), carboxy (C 2-8 heteroaryl), (C 6-10 aryl)methyl, (C 1-6 Alkoxy (C 6-10 aryl))methyl, (hydroxy(C 6-10 Ally (carboxy(C 6-10 aryl))methyl, (C 1-6 Alkoxy (C 2-8 Heteroary (C 2-8 Heteroaryl-(C 6-10 aryl))methyl, (hydroxy(C 2-8 Heteroa aryl))methyl, and (carboxy(C 2-8 heteroaryl))methyl; and / or (b) Hydrogen, methyl, ethyl, 2-propyl, 1-propyl, phenyl, 2-aminoethyl , propargyl, cyclopropyl, -CH 2 COOH, -CH 2 CN, phenyl, 3-carboxyphenyl , 3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3- Methylphenyl, 4-carboxyphenyl, 4-chlorophenyl, 4-cyanophenyl, 4-fluorophenyl 4-methoxyphenyl, 4-methylphenyl, 3-carboxy-4-methoxyphenyl 3-fluoro-4-methoxyphenyl, 4-chloro-2-fluoro-3-hydroxyphenyl, 3 -chloro-5-fluoro-4-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl, 2,6- Difluoro-4-methoxyphenyl, 1,3-benzodioxol-5-yl, benzyl, (3-calcium (3-chlorophenyl)methyl, (3-cyanophenyl)methyl, (3-fluorophenyl)methyl (3-fluorophenyl)methyl, (3-methoxyphenyl)methyl, (3-methylphenyl)methyl, (4- (carboxyphenyl)methyl, (4-chlorophenyl)methyl, (4-cyanophenyl)methyl, ( (4-fluorophenyl)methyl, (4-methoxyphenyl)methyl, (4-methylphenyl)methyl , (3-carboxy-4-methoxyphenyl)methyl, (3-fluoro-4-methoxyphenyl)methyl , (4-chloro-2-fluoro-3-hydroxyphenyl)methyl, (3-chloro-5-fluoro-4-hydroxyphenyl)methyl (3,5-dichloro-4-hydroxyphenyl)methyl, (2,6-difluoro (2,3-dihydro-1,4-benzodioxin-6-yl)methyl, (2,3-dihydro-1,4-benzodioxin-6-yl)methyl, (1,3-benzodioxol-5-yl)methyl, para-methyl-benzoic acid, and meta-methyl-benzoic acid The group consisting of benzoic acids 8. The compound of any one of claims 1 to 7, independently selected from:

9. Each X is C(R a )R b where C(R a )R b One of the groups is NR a substituted by a group can be; n is 1 or 2; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; L 1 is phenyl; L 2 is phenyl; R 1 are independently Cl, F, OH, CN, OCH 3 and COOH, and / or two R 1 The base Together, the 1,3-benzodioxole ring or 2,3-dihydro-1,4-benzodioxine ring moiety Form; R 2 are independently Cl, F, OH, CN, OCH 3 and COOH, and / or two R 2 The base Together, the 1,3-benzodioxole ring or 2,3-dihydro-1,4-benzodioxine ring moiety Form; R 3 is hydrogen, methyl, ethyl, propargyl, cyclopropyl, 2-aminoethyl, -CH 2 COOH, -CH 2 CN, benzyl, unsubstituted phenyl, and 3-carboxyphenyl and 4-carboxyphenyl substituted phenyl selected from phenyl; and R a and R b is hydrogen, A compound according to any one of claims 1 to 8.

10. X is C(R a )R b and; n is 1; and At least one of m and p is greater than 0; 20. The compound of any one of claims 1 to 19.

11. Each X is C(R a )R b and; n is 1 or 2; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; L 1 is phenyl; L 2 is cyclohexyl; R 1 is COOH, R 2 is COOH; R 3 is hydrogen; and R a and R b is hydrogen, A compound according to any one of claims 1 to 8.

12. Each X is C(R a )R b where C(R a )R b One of the groups is NR a substituted by a group can be; n is 1 or 2; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; L 1 is phenyl; L 2 is phenyl; R 1 are independently Cl, F, OH, CN, OCH 3 and COOH, and / or two R 1 The base Together, the 1,3-benzodioxole ring or 2,3-dihydro-1,4-benzodioxine ring moiety Preferably, R 1 is hydrogen; R 2 is a bioisosteric replacement for the acidic group, preferably R 3 is tetrazole; R 3 is hydrogen, methyl, ethyl, propargyl, cyclopropyl, 2-aminoethyl, -CH 2 COOH, -CH 2 CN, benzyl, unsubstituted phenyl, and 3-carboxyphenyl and 4-carboxyphenyl phenyl; preferably, R 3 is hydrogen; and R a and R b is hydrogen, A compound according to any one of claims 1 to 8. 【Request Item 13】 【Chemistry 25】 【change】 【change】 13. The compound of any one of claims 1 to 12, selected from the group consisting of: 【Request Item 14】 【Chemistry 26】 【change】 【change】 【change】 13. The compound of any one of claims 1 to 12, selected from the group consisting of:

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient. Pharmaceutical composition.

16. A method according to any one of claims 1 to 14 for use in a method of treatment of the human or animal body. or the pharmaceutical composition of claim 15.

17. (a) Alzheimer's disease; nephritis; kidney injury; renal ischemic injury; ischemic acute tubular necrosis; acute renal failure ;Cystitis;Inflammatory Bowel Disease (IBD);Crohn's Disease;Ulcerative Colitis;Chronic Inflammation;Colitis;Fibrosis;Fibrotic Disease; Keloid; Pulmonary hypertension; Interstitial lung disease (ILD); Cancer; Colorectal cancer; (b) Fibrosis; acute fibrotic disorders and diseases; chronic fibrotic disorders and diseases; fibrosis occurring in organs and For / or hepatitis, cirrhosis, hypertension, myocardial infarction, heart failure, asthma, pulmonary hypertension, scleroderma, fibrosis Degenerated skin and internal organs, diabetes, diabetic nephropathy, atherosclerosis, and fibrotic blood vessels Concomitant diseases and conditions selected from: hypertrophic skin scarring; keloids; pulmonary fibrosis; and post-traumatic injury acute CNS scar formation; nerve regeneration after stroke or spinal cord injury; occlusive lines of lumenal structures within the graft Fibrosis; chronic allograft rejection; wound healing disorders; postoperative scarring; skin scarring; gynecology Fibrosis due to medical procedures; fibrosis after ophthalmic surgery; fibrosis after angioplasty; fibrosis after joint surgery fibrosis; prevention of local invasion, recurrence, and metastasis of malignant keratinocyte or squamous cell carcinoma (SCC); (c) mammalian infertility; therapeutic use for mammalian in vitro fertilization (IVF) procedures; (d) Nematode infection; infection caused by Teladorsagia kyrcumkinctus; infection caused by Moncus contortus; and by Brugia malayi Infections caused 1. For use in a method for treating or preventing diseases and disorders selected from: A compound according to formula I, its individual enantiomers, its individual diastereoisomers, its water a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutical or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient. 【Chemistry 27】 (In the formula: A is, 【Chemistry 28】 are independently selected from; B is 【Chemistry 29】 are independently selected from; C is 【Transformation 30】 independently selected from -O-, and -S-; F, if present, 【Chemistry 31】 are independently selected from; G, if present, 【Chemistry 32】 are independently selected from; H, if present, 【Transformation 33】 are independently selected from; I, if present, 【Transformation 34】 are independently selected from; where F, G, H, and I are present: D is 【Chemistry 35】 and E is 【Transformation 36】 are independently selected from The ring formed by D, E, F, G, H, and I is R 2 By the p-substituent represented by It has been replaced, where p is 0, 1, 2, 3, or 4; Otherwise, if F, G, H, and I are not present: D is 【Chemistry 37】 are independently selected from E is 【Transformation 38】 where p is 0, 1, 2, 3, 4, or 5; L 1 and L 2 each independently represents alkyl, aryl, arylalkyl, heterocyclyl, is selected from the group consisting of heteroaryl, cycloalkyl, and cycloalkenyl, So, L 1 and L 2 can come together to form a ring; Each X is C(R a )R b , N.R. a and O; X and L 2 can be joined together to form a ring, wherein the ring is optionally may be condensed to a hydroxyl group; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, or 5; Each R 1 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH 2 , alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, and hydroxy; Each R 2 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH 2 , alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, and further substituted by one or more groups independently selected from , hydroxyl, and heteroaryl. can be exchanged; Each R 3 is hydrogen, as well as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, and cycloalkyl groups. Alkenyl, aryl, arylalkyl, heterocyclyl, heterocyclic, fused to aryl and independently selected from the group consisting of cyclohexyl, ... Each of these is an amino, halogen, cyano, hydroxy, carboxy, -C(O)O(a) -C(O)NH 2 , -C(O)NH(alkyl), alkylsulfono, functional group having acidic hydrogen, Alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Aryl, arylalkyl, heterocyclyl, heteroaryl, and heteroaryla and each of which may be substituted with one or more groups independently selected from alkyl, , halogen, carboxy, cyano, alkyl, alkoxy, and hydroxy; and R a and R b are each independently hydrogen, deuterium, and C 1-3 alkyl) 。

18. L 1 and L 2 each independently represents an aryl, heterocyclyl, heteroaryl, cycloalkyl and cycloalkenyl, wherein L 1 and L 2 But together , capable of forming a ring; Each X is C(R a )R b , N.R. a and O; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, or 5; Each R 1 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH 2 , alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, and hydroxy; Each R 2 is halogen, cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)N H(alkyl), -C(O)-NH 2 , alkylsulfonate, functional groups with acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl heteroaryl, heteroarylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups each of which is independently selected from the group consisting of halogen, carboxy, cyano, alkoxy, and hydroxyl. tree; Each R 3 is hydrogen, and alkyl, alkenyl, alkynyl, cycloalkyl, cyclo Alkenyl, aryl, arylalkyl, heterocyclyl, heteroaryl, and heterocyclic and each of the aryl and aryl groups is independently selected from the group consisting of amino, halogen, and aryl. , cyano, hydroxy, carboxy, -C(O)O(alkyl), -C(O)NH 2 , -C(O)NH(alkyl) , alkylsulfonate, functional groups having acidic hydrogen, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic one or more groups independently selected from acryl, heteroaryl, and heteroarylalkyl; and each of said groups may be substituted by halogen, carboxy, cyano, alkyl, and further substituted by one or more groups independently selected from alkyl, alkoxy, and hydroxy. and R a and R b are each independently hydrogen, deuterium, and C 1-3 selected from alkyl, 18. A compound or pharmaceutical composition for use according to claim 17.

19. For use in the method of claim 17, 【Chemistry 39】 【change】 a compound selected from the group consisting of: tautomers thereof, hydrates thereof, solvates thereof, crystalline forms thereof, individual tautomers thereof, or Pharmaceutically acceptable salts thereof, or compounds containing the compounds and pharmaceutically acceptable excipients Pharmaceutical compositions.

20. For use in the method of claim 17, 【Chemistry 40】 【change】 【change】 a compound selected from the group consisting of: tautomers thereof, hydrates thereof, solvates thereof, crystalline forms thereof, individual tautomers thereof, or Pharmaceutically acceptable salts thereof, or compounds containing the compounds and pharmaceutically acceptable excipients Pharmaceutical compositions.

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