PHD inhibitor compounds, compositions, and uses

Abstract

PHD inhibitor compounds are provided.SOLUTION: Novel small molecule inhibitors of PHD are provided. In one aspect, a compound having a structure according to Formula (A), or a pharmaceutically acceptable salt thereof, is provided. The compounds provided herein may be useful for the treatment of diseases including diseases of the heart (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver (e.g., acute liver failure, hepatic fibrosis, and cirrhosis), and kidney (e.g., acute kidney injury and chronic kidney disease).SELECTED DRAWING: None

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 992,585, filed March 20, 2020. This application claims priority to the same patent application Ser. No. 09 / 109,599, filed on Oct. 1, 2007, which is incorporated herein by reference in its entirety. Be absorbed.

[0002] Hypoxia is a condition in which the supply of oxygen is inadequate for normal vital functions, e.g., arterial oxygen supply is low. Hypoxia is a condition or state in which there is little or no oxygen available to the body. Hypoxia can lead to cellular dysfunction and structural tissue damage. The activation of cellular defense mechanisms during hypoxia may be linked to the activation of HIF (hypoxia-inducible factor ) protein. Decreased HIFα prolyl hydroxylation in response to hypoxia. This increases the level of HIFα in most cells. The ligation is mediated by prolyl hydroxylase domain-containing proteins (PHD1, 2, and 3) and Variously called HIF prolyl hydroxylases (HPH-3, 2, and 1) or E This is accomplished by a family of proteins also known as GLN-2, 1, and 3. PHD proteins are oxygen sensors that regulate HIF stability in an oxygen-dependent manner. The two PHD isoforms function differently in regulating HIF and other non-HIF-related may play a role in regulating

[0003] In fact, many studies have shown that stabilizing HIF attenuates tissue inflammation and promotes tissue repair. Therefore, it is possible to inhibit the activity of PHD proteins. Compounds with this property may be particularly beneficial in new therapies (Lee et al. (2019) )Exp.Mol.Med.51:68)

[0004] Cardiac (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), pulmonary (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver (e.g., acute liver failure) , liver fibrosis, and cirrhosis), and kidney (e.g., acute kidney injury and chronic kidney disease) Described herein are novel small molecule PHD inhibitors that have utility in treating diseases, including can be. Summary of the Invention

[0005] The present invention provides, inter alia, novel small molecule inhibitors of PHDs, which are useful in treating heart (e.g., ischemic heart) heart disease, congestive heart failure, and valvular heart disease), pulmonary (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis) liver (e.g., acute liver failure, liver fibrosis, and cirrhosis) ), and diseases of the kidney (e.g., acute kidney injury and chronic kidney disease) These compounds have utility in treating diseases that are not readily apparent.

[0006] In one aspect, a compound having a structure according to formula (A): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ar 1 is phenyl or a 6-membered nitrogen-containing heteroaryl, Aryl is a C alkyl group optionally substituted with halogen, CN, OH, or one or more halogens. 1-3 Alkyl, or C 1-3 optionally substituted with alkoxy; R 2 is H or C alkyl, Ar 2 is a halogen, OH, amine, or C 1-36-membered optionally alkyl-substituted is a nitrogen-containing heteroaryl; R 4 is hydrogen or C 1-4 is alkyl, Formula (A) excludes the following compounds: [ka]

[0007] In some embodiments, R 2 is H.

[0008] In some embodiments, R 2 is C 1-3 It is alkyl.

[0009] In some embodiments, Ar 1 teeth, [ka] where: X, Y, and Z are independently CH or N, wherein N is optionally oxidized; Each R 1 are independently hydrogen, halogen, CN, OH, optionally substituted with one or more halogens; Replaced C 1-3 Alkyl, and C 1-3 alkoxy; m is 1, 2, 3, or 4.

[0010] In some embodiments, Ar 1 is substituted phenyl. In some embodiments, Ar 1 teeth , at least one R 1 wherein R 1 is CN or a halogen.

[0011] In some embodiments, Ar 1 is C optionally substituted with one or more halogens 1- 3 one or two R independently selected from alkyl, halogen, CN, or OH 1 The group is substituted.

[0012] In some embodiments, Ar 1 is a pyridyl N-oxide, or C 1-3 Al At least one R is koxy or halogen 1 pyridyl optionally substituted by be.

[0013] In some embodiments, each R 1 are independently hydrogen, halogen, CN, OH, one or more C optionally substituted with several halogens 1-3 Alkyl, and C 1-3 consisting of alkoxy is selected from the group.

[0014] In some embodiments, Ar 2 teeth, [ka] where: A and B are independently CH or N, wherein N is optionally oxidized; Each R 3 are independently hydrogen, halogen, OH, amine, and C 1-3 alkyl is selected from n is 0, 1, or 2.

[0015] In some embodiments, Ar 2 is a group which is pyridyl or pyrazinyl, unsubstituted or halogen, C 1-3 It includes substituents that are alkyl, or OH.

[0016] In some embodiments, each R 3 are independently hydrogen, halogen, OH, amine, and C1 -3 alkyl.

[0017] In some embodiments, R 4 is H. In some embodiments, R 4 is C 1-4 Al It's a kill.

[0018] In embodiments, the compound of formula (A) is [ka] isn't it.

[0019] In embodiments, compounds of Formula (A) exclude the following compounds: [ka]

[0020] In embodiments, the compound of Formula (A) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0021] In embodiments, X, Y, Z, A, and B are independently CH or N, wherein: N is optionally oxidized, m is 1, 2, 3, or 4, and n is 0, 1, or 2; Each R 1 are independently hydrogen, halogen, CN, OH, optionally substituted with one or more halogens; Replaced C 1-3 Alkyl, and C 1-3 alkoxy; R 2 teeth hydrogen or C alkyl, and each R 3 are independently hydrogen, halogen, OH, amine , and C 1-3 alkyl; R 4is halogen or C 1-4 Al It's a kill.

[0022] In embodiments, the compound of Formula (A) or Formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, X, Y, and Z are independently CH or N, where N is any optionally oxidized, m is 1, 2, 3, or 4, n is 0, 1, or 2, and each R 1 are independently hydrogen, halogen, CN, OH, optionally substituted with one or more halogens TaC 1-3 Alkyl, and C 1-3 alkoxy; R 2 Is hydrogen or C alkyl, and each R 3 are independently hydrogen, halogen, OH, amine, and and C 1-3 alkyl; R 4 is halogen or C 1-4 With alkyl be.

[0024] In embodiments, the compound of formula (I) is [ka] isn't it.

[0025] In embodiments, compounds of formula (I) exclude the following compounds: [ka]

[0026] In embodiments, the compound of Formula (A) or Formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, A and B are independently CH or N, where N is optionally an acid. m is 1, 2, 3, or 4, n is 0, 1, or 2, and each R 1 is independent and hydrogen, halogen, CN, OH, C1 optionally substituted with one or more halogens. -3 Alkyl, and C 1-3 alkoxy; R 2 is hydrogen or C 1-3 alkyl, and each R 3 are independently hydrogen, halogen, OH, amine, and C1 -3 alkyl; R 4 is halogen or C 1-4 It is alkyl.

[0028] In embodiments, the compound of formula (Ib) is [ka] isn't it.

[0029] In embodiments, compounds of Formula (Ib) exclude the following compounds: [ka]

[0030] In embodiments, the compound of Formula (A) or Formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0031] In embodiments, X, Y, Z, A, and B are independently CH or N, wherein: N is optionally oxidized, m is 1, 2, 3, or 4, and n is 0, 1, or 2; Each R 1 are independently hydrogen, halogen, CN, OH, optionally substituted with one or more halogens; Replaced C 1-3 Alkyl, and C 1-3 alkoxy, and each R 3 are independently hydrogen, halogen, OH, amine, and C 1-3 From the group consisting of alkyl Selected, R 4 is halogen or C 1-4 It is alkyl.

[0032] In embodiments, the compound of Formula (A) or Formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, m is 1, 2, 3, or 4, and n is 0, 1, or 2. , each R 1 are independently hydrogen, halogen, CN, OH, optionally one or more halogens Substituted C 1-3 Alkyl, and C 1-3 alkoxy; R 2 is hydrogen or C alkyl, and each R 3 are independently hydrogen, halogen, OH, amine N, and C 1-3 alkyl; R 4 is halogen or C 1-4 a It's Rukiru.

[0034] In embodiments, the compound of formula (II) is [ka] isn't it.

[0035] In embodiments, compounds of formula (II) exclude the following compounds: [ka]

[0036] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, m is 1, 2, 3, or 4, and n is 0, 1, or 2. , each R 1 are independently hydrogen, halogen, CN, OH, optionally one or more halogens Substituted C 1-3 Alkyl, and C 1-3 alkoxy; R 2 is hydrogen or C alkyl, and each R 3 are independently hydrogen, halogen, OH, amine N, and C 1-3 alkyl.

[0038] In embodiments, the compound of formula (IIa) is [ka] isn't it.

[0039] In embodiments, compounds of Formula (IIa) exclude the following compounds: [ka]

[0040] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, m is 1, 2, 3, or 4, and each R 1 are independently hydrogen, halo halogen, CN, OH, C optionally substituted with one or more halogens 1-3 Alkyl, and C 1-3 alkoxy; R 2 is hydrogen or C1-3 alkyl and R 4 is hydrogen or C 1-4 It is alkyl.

[0042] In embodiments, the compound of formula (IIb) is [ka] isn't it.

[0043] In embodiments, compounds of Formula (IIb) exclude the following compounds: [ka]

[0044] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, m is 1, 2, 3, or 4, and each R 1 are independently hydrogen, halo halogen, CN, OH, C optionally substituted with one or more halogens1-3 Alkyl, and C 1-3 alkoxy; R 2 is hydrogen or C1-3 alkyl is.

[0046] In embodiments, the compound of formula (IIc) is [ka] isn't it.

[0047] In embodiments, compounds of Formula (IIc) exclude the following compounds: [ka]

[0048] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, m is 1, 2, 3, or 4, and n is 0, 1, or 2. , each R 1 are independently hydrogen, halogen, CN, OH, optionally one or more halogens Substituted C 1-3 Alkyl, and C 1-3 alkoxy, and each R 3 are independently hydrogen, halogen, OH, amine, and C 1-3 From the group consisting of alkyl be selected.

[0050] In embodiments, the compound of formula (IId) is [ka] isn't it.

[0051] In embodiments, compounds of Formula (IId) exclude the following compounds: [ka]

[0052] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, m is 1, 2, 3, or 4, and each R 1 are independently hydrogen, halo halogen, CN, OH, C optionally substituted with one or more halogens 1-3 Alkyl, and C 1-3 alkoxy; R 2 is hydrogen or C1-3 alkyl and each R 3 are independently hydrogen, halogen, OH, amine, and C 1-3 Alkyl or and R is selected from the group consisting of 4 is halogen or C 1-4 It is alkyl.

[0054] In embodiments, the compound of formula (IIe) is [ka] isn't it.

[0055] In embodiments, compounds of Formula (IIe) exclude the following compounds: [ka]

[0056] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, m is 1, 2, 3, or 4, and each R 1 are independently hydrogen, halo halogen, CN, OH, C optionally substituted with one or more halogens 1-3 Alkyl, and C 1-3 alkoxy is selected from the group consisting of:

[0058] In embodiments, the compound of formula (IIf) is [ka] isn't it.

[0059] In embodiments, compounds of Formula (IIf) exclude the following compounds: [ka]

[0060] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, m is 1, 2, 3, or 4, and n is 0, 1, or 2. , each R 1 are independently hydrogen, halogen, CN, OH, optionally one or more halogens Substituted C 1-3 Alkyl, and C 1-3 alkoxy, and each R 3 are independently hydrogen, halogen, OH, amine, and C 1-3 From the group consisting of alkyl Selected, R 4 is halogen or C 1-4 It is alkyl.

[0062] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, m is 1, 2, 3, or 4, and n is 0, 1, or 2. , each R 1 are independently hydrogen, halogen, CN, OH, optionally one or more halogens Substituted C 1-3 Alkyl, and C 1-3 alkoxy; R 2 is hydrogen or C alkyl, and each R 3 are independently hydrogen, halogen, OH, amine N, and C 1-3 alkyl; R 4 is halogen or C 1-4 a Rukill and R 5 is CN or a halogen.

[0064] In embodiments, the compound of formula (III) is [ka] isn't it.

[0065] In embodiments, compounds of formula (III) exclude the following compounds: [ka]

[0066] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, m is 1, 2, 3, or 4, and n is 0, 1, or 2. , each R 1 are independently hydrogen, halogen, CN, OH, optionally one or more halogens Substituted C 1-3 Alkyl, and C 1-3 alkoxy; R 2 is hydrogen or C alkyl, and each R 3 are independently hydrogen, halogen, OH, amine N, and C 1-3 alkyl; R 5 is CN or halogen .

[0068] In embodiments, the compound of formula (IIIa) is [ka] isn't it.

[0069] In embodiments, compounds of Formula (IIIa) exclude the following compounds: [ka]

[0070] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, m is 1, 2, 3, or 4, and each R 1 are independently hydrogen, halo halogen, CN, OH, C optionally substituted with one or more halogens 1-3 Alkyl, and C 1-3 alkoxy; R 2 is hydrogen or C1-3 alkyl and R 4 is hydrogen or C 1-4 alkyl, and R 5 is CN or a halogen.

[0072] In embodiments, the compound of formula (IIIb) is [ka] isn't it.

[0073] In embodiments, compounds of Formula (IIIb) exclude the following compounds: [ka]

[0074] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, m is 1, 2, 3, or 4, and each R 1 are independently hydrogen, halo halogen, CN, OH, C optionally substituted with one or more halogens 1-3 Alkyl, and C 1-3 alkoxy; R2 is hydrogen or C1-3 alkyl and R 5 is CN or a halogen.

[0076] In embodiments, the compound of formula (IIIc) is [ka] isn't it.

[0077] In embodiments, compounds of Formula (IIIc) exclude the following compounds: [ka]

[0078] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, m is 1, 2, 3, or 4, and n is 0, 1, or 2. , each R 1 are independently hydrogen, halogen, CN, OH, optionally one or more halogens Substituted C 1-3 Alkyl, and C 1-3 alkoxy, and each R 3 are independently hydrogen, halogen, OH, amine, and C 1-3 From the group consisting of alkyl Selected, R 5 is CN or a halogen.

[0080] In embodiments, the compound of formula (IIId) is [ka] isn't it.

[0081] In embodiments, compounds of Formula (IIId) exclude the following compounds: [ka]

[0082] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) is Lower structure [ka] or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, m is 1, 2, 3, or 4, and each R 1 are independently hydrogen, halo halogen, CN, OH, C optionally substituted with one or more halogens 1-3 Alkyl, and C 1-3 alkoxy; R 4 is hydrogen or C 1-4 Alkyl and R 5 is CN or a halogen.

[0084] In embodiments, the compound of formula (IIIe) is [ka] isn't it.

[0085] In embodiments, compounds of Formula (IIIe) exclude the following compounds: [ka]

[0086] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, m is 1, 2, 3, or 4, and each R 1 are independently hydrogen, halo halogen, CN, OH, C optionally substituted with one or more halogens 1-3 Alkyl, and C 1-3 alkoxy; R 5 is CN or a halogen.

[0088] In embodiments, the compound of formula (IIIf) is [ka] isn't it.

[0089] In embodiments, compounds of Formula (IIIf) exclude the following compounds: [ka]

[0090] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, m is 1, 2, 3, or 4, and n is 0, 1, or 2. , each R 1 are independently hydrogen, halogen, CN, OH, optionally one or more halogens Substituted C 1-3 Alkyl, and C 1-3 alkoxy, and each R 3 are independently hydrogen, halogen, OH, amine, and C 1-3 From the group consisting of alkyl Selected, R 4 is hydrogen or C 1-4 alkyl, and R 5 is CN or halogen .

[0092] In some embodiments, X is CH. In some embodiments, X is N, where N is any is oxidized by

[0093] In embodiments, Y is CH. In embodiments, Y is N.

[0094] In embodiments, Z is CH. In embodiments, Z is N.

[0095] In embodiments, A is CH. In embodiments, A is N.

[0096] In embodiments, B is CH. In embodiments, B is N.

[0097] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0098] In some embodiments, n is 0. In some embodiments, n is 1. In the embodiment, n is 2.

[0099] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is CN. In some embodiments, R 1 is OH.

[0100] In some embodiments, R 1is halogen. In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br.

[0101] In some embodiments, R 1 is C optionally substituted with one or more halogens 1-3 In some embodiments, R 1 is C 1-3 alkyl. So, R 1 is methyl. In some embodiments, R 1 is ethyl. So, R 1 is CF3.

[0102] In some embodiments, R 1 is C 1-3 In some embodiments, R 1 teeth It is methoxy.

[0103] In some embodiments, R 2 is hydrogen.

[0104] In some embodiments, R2 is C 1-3 In some embodiments, R2 is methyl. It's chill.

[0105] In some embodiments, R 3 is hydrogen.

[0106] In some embodiments, R 3 is halogen. In some embodiments, R 3 is F.

[0107] In some embodiments, R 3 is OH.

[0108] In some embodiments, R 3 is an amine. In some embodiments, R 3 is NH2 .

[0109] In some embodiments, R 3 is C 1-3 In some embodiments, R 3 Hame It's chill.

[0110] In some embodiments, R 4 is hydrogen.

[0111] In some embodiments, R 4 is C 1-4 In some embodiments, R 4 Hame In some embodiments, R 4 is ethyl. In some embodiments, R 4 Yes In some embodiments, R 4 is tert-butyl.

[0112] In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In an embodiment of the present invention, R 5 is Br.

[0113] In some embodiments, R 5 is CN.

[0114] In some embodiments, the compound is any one of compounds 1-44, or a pharmaceutically acceptable salt thereof. Acceptable salts. [Table 1] TIFF2026021443000060.tif219170TIFF2026021443000061.tif170170

[0115] In some embodiments, compounds of formula (A) and (I), such as any one of compounds 1-44, ) to (III), or a pharmaceutically acceptable salt thereof, The hydrogen atoms are replaced with deuterium atoms.

[0116] In another aspect, the present invention provides any of the compounds described herein (e.g., Compounds 1-4). 4), or a compound of formula (A) and (I)-(III), and a pharmaceutically acceptable excipient. do.

[0117] In another aspect, the present invention provides a method for treating a disease mediated by PHD activity. The method includes the step of: Compounds of formula (A) and (I) to (III), such as any one of the compounds of formula (A) and (I) to (III), or pharmaceutical compositions thereof The method includes administering to a subject a commercially acceptable salt thereof.

[0118] In embodiments, the disease mediated by PHD activity is ischemia-reperfusion injury (e.g., , stroke, myocardial infarction, or acute kidney injury).

[0119] In embodiments, the disease mediated by PHD activity is inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease).

[0120] In embodiments, the disease mediated by PHD activity is cancer (e.g., colorectal cancer, cancer).

[0121] In embodiments, the disease mediated by PHD activity is a liver disease.

[0122] In embodiments, the disease mediated by PHD activity is atherosclerosis. is.

[0123] In embodiments, the disease mediated by PHD activity is a cardiovascular disease.

[0124] In some embodiments, the disease mediated by PHD activity is an ocular disease or condition (e.g., (e.g., radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia) be.

[0125] In embodiments, the disease mediated by PHD activity is anemia (e.g., chronic kidney disease, disease-related anemia).

[0126] In embodiments, the disease mediated by PHD activity is associated with hyperoxia. .

[0127] In embodiments, the disease mediated by PHD activity is retinopathy of prematurity.

[0128] In embodiments, the disease mediated by PHD activity is bronchopulmonary dysplasia (BP). D).

[0129] In embodiments, the disease mediated by PHD activity is ischemic heart disease, valvular heart disease, or disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD) , acute liver failure, liver fibrosis, or cirrhosis. [Brief explanation of the drawings]

[0130] [Figure 1]Figure 1 is an exemplary schematic diagram illustrating the principle of the TR-FRET assay for PHD enzymes (PHD1, PHD2, and PHD3). In the presence of 2-oxoglutarate and O, PHD enzymes hydroxylate proline 564 of the biotin-tagged HIF-1α peptide, resulting in the production of biotin-tagged HIF-1α-hydroxyproline, succinate, and CO. The donor fluorophore conjugate, monoclonal antibody anti-6His-terbium (Tb)-cryptate gold, bound to His-tagged VHL protein, EloB, and EloC complexes (His-VBC), and the acceptor fluorophore, SA-D2 conjugate, bound to HIF-1α-hydroxyproline, result in a fluorescence resonance energy transfer (FER) signal that can be detected and quantified. DETAILED DESCRIPTION OF THE INVENTION

[0131] definition In order that the present invention may be more readily understood, certain terms are first defined below. Additional definitions of the following terms and other terms are set forth throughout the specification. Publications referenced herein to explain and provide further details regarding its implementation and other references incorporated herein by reference.

[0132] Animal: As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to a human being at any stage of development. In certain embodiments, "animal" refers to non-human animals at any stage of development. The non-human animals include mammals (e.g., rodents, mice, rats, rabbits, monkeys, dogs, In some embodiments, the mammal is a mammal, such as a cat, a sheep, a cow, a primate, and / or a pig. Animals include mammals, birds, reptiles, amphibians, fish, insects, and / or parasites In some embodiments, the animal is a transgenic animal. , genetically engineered animals, and / or clones.

[0133] Approximately or about: As used herein, refers to one or more values ​​of interest. The term "approximately" or "about" as used herein refers to a value similar to the specified reference value. In embodiments, the terms "approximately" or "about" are used unless otherwise indicated or in context. Unless otherwise apparent from the context (unless such number exceeds 100% of the possible values), 25%, 20%, 1 in either direction (greater or less than) the reference value being measured 9%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9 %, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the value Indicates the range.

[0134] As used in this specification and the appended claims, the singular forms "a," "an ... "An" and "the" are used interchangeably unless the context clearly indicates otherwise. Thus, for example, the term "a composition" includes two or more It includes mixtures of such compositions.

[0135] Throughout the description and claims of this specification, the word "comprises" may be used. The words "comprising" and "comprise" Other forms of the word, such as "(s)" mean including, but not limited to, for example, other It is not intended to exclude additives, components, integers, or steps.

[0136] "Any" or "optionally" means that the subsequently described event or circumstance may occur. There may or may not be any events or circumstances in the description, and the events or circumstances may or may not occur. It means to be included.

[0137] Improve, increase, or reduce: As used herein, "improve," "Increase" or "Decrease" or grammatical synonyms refer to baseline measurements, e.g. For example, measurements in the same individual before initiation of the treatments described herein, or Values ​​are shown relative to measurements in a control subject(s) in the absence of treatment. A "control subject" is a subject suffering from the same form of disease as the subject being treated, and The subject is approximately the same age as the elephant.

[0138] In vitro: As used herein, the term "in vitro" refers to within a multicellular organism. events that occur in artificial environments, such as in test tubes, reaction vessels, or cell culture media, rather than in laboratory experiments. Refers to...

[0139] In vivo: As used herein, the term "in vivo" refers to both human and non-human Refers to events that occur within multicellular organisms, such as animals. In the context of cell-based systems, the term is used to refer to events occurring within living cells (as opposed to, for example, in vitro systems) obtain.

[0140] Patient: As used herein, the term "patient" or "subject" refers to a subject provided The compositions are administered, for example, for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mice, rats, rabbits, etc.) mammals, such as primates, non-human primates, and / or humans. In certain embodiments, the patient is a human, including prenatal and postnatal forms.

[0141] Pharmaceutically acceptable: The term "pharmaceutically acceptable" as used herein means If, within the scope of sound medical judgment, there is a risk of excessive toxicity, irritation, allergic response, or other problems, or suitable for use in contact with human and animal tissue without complications. It refers to substances that are suitable for a reasonable benefit / risk ratio.

[0142] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, , S.M. Berge et al., J. Pharmaceuti. Cal Sciences (1977) 66:1-19. Compounds of the Invention Pharmaceutically acceptable salts of include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include those derived from the groups: hydrochloride, bromide, with inorganic acids such as hydrochloric, phosphoric, sulfuric, and perchloric acids, or with acetic, oxalic, Organic acids such as maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid are used. or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, etc. , ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate , borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane Propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, humectant Salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptane acid salt, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobic acid salt Salts include hydroxybenzoates, ... acid salts, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates Sulfate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenanthate Nylpropionate, phosphate, picrate, pivalate, propionate, stearyl Phosphate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, Salts derived from appropriate bases include alkali gold salts, undecanoates, valerates, etc. Examples include metal salts, alkaline earth metal salts, ammonium salts, and N+(C1-4 alkyl)4 salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, Further pharmaceutically acceptable salts include ammonium, potassium, calcium, magnesium, etc. Salts include, where appropriate, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates Non-toxic compounds formed using counterions such as salts, sulfonates, and arylsulfonates ammonium cations, quaternary ammonium cations, and amine cations. Further pharmaceutically acceptable salts may be prepared by reacting the amines with suitable electrophiles, e.g., quaternized alkylated amines. Salts formed from the quaternization of amines using alkyl halides to form the salts Includes.

[0143] Subject: As used herein, the term "subject" refers to a human or any non-human animal. animals (e.g., mice, rats, rabbits, dogs, cats, cows, pigs, sheep, horses, or Humans refer to both prenatal and postnatal forms. In many embodiments, In the present invention, the subject is a human. The subject may be a patient, receiving medical care for the diagnosis or treatment of a disease. The term "subject" is used herein to refer to an "individual" or "patient." A subject may be suffering from or susceptible to a disease or disorder. However, they may or may not present with symptoms of a disease or disorder.

[0144] Substantially: As used herein, the term "substantially" means that the desired characteristics or It refers to the qualitative state of exhibiting the full or nearly full range or degree of a characteristic or property. If so, biological and chemical phenomena are completed and / or brought to completion. or that absolute results are rarely, if ever, achieved or avoided. It will be understood that the term "substantially" is therefore often used herein. It is used to capture the potential lack of completion inherent in biological and chemical phenomena.

[0145] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" of a therapeutic agent is used to describe a therapeutically effective amount of a therapeutic agent for a disease. administered to a subject suffering from or susceptible to a disorder, and / or condition Sometimes to treat the symptoms of, diagnose, or prevent the disease, disorder, and / or condition; and / or delay the onset of the therapeutic effect. An effective amount is typically administered by a dosing regimen comprising at least one unit dose. Understand that.

[0146] Treating: As used herein, "treat," "treatment," or "treatment" refers to The term "having" refers to one or more symptoms of a particular disease, disorder, and / or condition. Partially or completely alleviate, improve, mitigate, suppress, or prevent a condition or characteristic delaying its onset, reducing its severity, and / or reducing its incidence Treatment refers to any method used to treat a disease in subjects who do not exhibit signs of disease and and / or induce the development of pathology associated with a disease in a subject who exhibits only early signs of the disease. It can be administered to reduce the risk of

[0147] Aliphatic: As used herein, the term aliphatic refers to C1-C 40 Hydrocarbons Aliphatic hydrocarbons include both saturated and unsaturated hydrocarbons. can be cyclic, for example, C1-C 20 Aliphatic includes C1-C 20 Alkyl (e.g., Linear or branched C1-C 20 saturated alkyl), C2-C 20 Alkenyl (e.g., Linear or branched C4-C 20 Dienyl, linear or branched C6-C 20 Trienyl etc. ), and C2-C 20 Alkynyl (e.g., linear or branched C-C 20 Alkini C1-C 20 Aliphatic includes C3-C 20 Cycloaliphatic (e.g., C3- C 20 Cycloalkyl, C4-C 20 Cycloalkenyl, or C8-C 20 Cycloal In certain embodiments, the aliphatic may include one or more cycloaliphatic and and / or one or more heteroatoms, such as oxygen, nitrogen, or sulfur, Optionally, alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ethoxy, ethoxylated, Aliphatic groups may be unsubstituted or substituted with one or more substituents such as esters, amides, or the like. or substituted with one or more substituents described herein, for example: Aliphatic groups include halogens, -COR', -CO2H, -CO2R', -CN, -OH, and -OR. ', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR' or one or more (e.g., 1, 2, 3, 4, 5, or 6) of -SO2R' wherein each instance of R' is independently substituted with C-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Al In some embodiments, R' is independently Unsubstituted alkyl (e.g., unsubstituted C-C 20 Alkyl, C1-C 15 Alkyl, C1- C 10 alkyl, or C1-C3 alkyl). In some embodiments, R' is In some embodiments, the aliphatic is an unsubstituted C1-C3 alkyl. In some embodiments, the aliphatic does not contain any heteroatoms.

[0148] Alkyl: As used herein, the term "alkyl" refers to non-cyclic straight-chain and and branched hydrocarbon groups, e.g., "C1-C 20 "Alkyl" is a group of 1 to 20 carbon atoms The alkyl group may be linear or branched. Examples of methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, s ec-butyl, tert-butyl, pentyl, isopentyl, tert-pentylhexyl Examples of "lower alkyl" include, but are not limited to, hexyl, isohexyl, and the like. The term refers to straight or branched alkyl, alkyl groups having 1 to 6 carbon atoms. Other alkyl groups will be readily apparent to those of skill in the art given the benefit of this disclosure. Alkyl groups can be unsubstituted or can have one or more substituents as described herein. For example, the alkyl group may be substituted with halogen, -COR', -CO2H, -CO2 R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR ', -N(R')2, -SR', or -SO2R' (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents), wherein R Each instance of ' is independently 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C1 5 alkyl, C1-C 10 alkyl, or C1-C3 alkyl). In embodiments, R' is independently unsubstituted alkyl (e.g., unsubstituted C-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 alkyl, or C1-C3 alkyl). In some embodiments, R' is independently unsubstituted C1-C3 alkyl. In embodiments, alkyl is any of the 1, 2, 3, 4, 5, or 6 alkyl groups described herein. In some embodiments, the alkyl group is substituted with an —OH group. and may also be referred to herein as a "hydroxyalkyl" group, where the prefix - denotes an OH group, and "alkyl" is as defined herein. In some embodiments, the alkyl is substituted with an -OR' group, which may also be referred to herein as an "alkoxy" group. do.

[0149] When the suffix "-ene" is added to a group, it becomes a divalent moiety. For example, aryl Heteroarylene is a divalent moiety of an aryl, and heteroarylene is a divalent moiety of a heteroaryl. be.

[0150] Alkylene: As used herein, the term “alkylene” refers to a saturated divalent straight chain or represents a branched chain hydrocarbon group, exemplified by methylene, ethylene, isopropylene, etc. Similarly, the term "alkenylene" as used herein refers to any stable alkyl group along the chain. unsaturated divalent straight chain or As used herein, the term "alkynylene" refers to a hydrocarbon group having a cyclic or branched chain. It is an unsaturated compound having one or more unsaturated carbon-carbon triple bonds that can occur at any stable point. represents a saturated divalent straight or branched chain hydrocarbon group. In certain embodiments, an alkylene group, The alkenylene or alkynylene group may comprise one or more cycloaliphatic and / or It may contain one or more heteroatoms such as oxygen, nitrogen, or sulfur, and may be an alkyl, halo, or , alkoxyl, hydroxy, amino, aryl, ether, ester, or amide It may be optionally substituted with one or more substituents, such as alkylene, alkene, The alkynylene or alkynylene is substituted with halogen, -COR', -CO2H, -CO2R', - CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N (R')2, -SR', or -SO2R' (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents), wherein each instance of R′ are independent, C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Archi Le, C1-C 10 alkyl, or C1-C3 alkyl). R' is independently an unsubstituted alkyl (e.g., an unsubstituted C-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 alkyl, or C1-C3 alkyl). In embodiments, R' is independently unsubstituted C1-C3 alkyl. , alkylene, alkenylene, or alkynylene is unsubstituted. The alkylene, alkenylene, or alkynylene does not contain any heteroatoms. .

[0151] Alkenyl: As used herein, "alkenyl" refers to any stable alkyl group along the chain. Any linear or branched chain having one or more unsaturated carbon-carbon double bonds that may occur at any point. means a branched hydrocarbon chain, e.g., "C2-C 20 "Alkenyl" means a group consisting of 2 to 20 alkyl groups. It refers to an alkenyl group having carbon atoms. For example, alkenyl groups include prop-2-enyl, butylenyl, and butylenyl. 2-Tenyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl Some examples include hex-5-enyl, hex-5-enyl, and 2,3-dimethylbut-2-enyl. In some embodiments, the alkenyl contains 1, 2, or 3 carbon-carbon double bonds. In some embodiments, the alkenyl contains a single carbon-carbon double bond. In this form, multiple double bonds (e.g., two or three) are conjugated. , which may be unsubstituted or substituted with one or more substituents described herein. For example, an alkenyl group can be substituted with halogen, -COR', -CO2H, -CO2R', -CN , -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R ')2, -SR', or -SO2R' (e.g., 1, 2, 3, and 4, 5, or 6 independently selected substituents), wherein each instance of R' is independently Stand up, C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 alkyl, or C1-C3 alkyl). In some embodiments, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 alkyl, or C1-C3 alkyl). In some embodiments, R' is independently unsubstituted C1-C3 alkyl. In some embodiments, alkenyl is unsubstituted (e.g., as described herein). Substituted with 1, 2, 3, 4, 5, or 6 substituents as described in the document. In one embodiment, the alkenyl group is substituted with an —OH group, and is referred to herein as a “hydroxyalkynyl group.” "Alkenyl" may also be referred to as an "alkenyl" group, where the prefix denotes an -OH group. As stated in the book.

[0152] Alkynyl: As used herein, "alkynyl" refers to any stable alkyl group along the chain. A linear or branched arrangement having one or more carbon-carbon triple bonds occurring at different points. means any hydrocarbon chain in any position, e.g., "C2-C 20 "Alkynyl" is 2 It refers to an alkynyl group having up to 20 carbon atoms. Examples of alkynyl groups include prop-2-ynyl. but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl -ynyl, hex-2-ynyl, hex-5-ynyl, etc. In certain embodiments, an alkynyl group contains one carbon-carbon triple bond. An alkynyl group is unsubstituted. It may be substituted with one or more substituents as described herein. The alkynyl group is a halogen atom, -COR', -CO2H, -CO2R', -CN, -OH, - OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -S R', or -SO2R' (e.g., 1, 2, 3, 4, 5, or is optionally substituted with six independently selected substituents, wherein each instance of R' is independently selected from C1 -C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 alkyl, or C1-C3 alkyl). In some embodiments, R' is independently and unsubstituted alkyl (e.g., unsubstituted C-C 20 Alkyl, C1-C 15 Alkyl, C 1-C 10 alkyl, or C1-C3 alkyl). In some embodiments, R ' is independently unsubstituted C1-C3 alkyl. In some embodiments, alkynyl In some embodiments, alkynyl is unsubstituted (e.g., as described herein). substituted with 1, 2, 3, 4, 5, or 6 substituents as defined above.

[0153] Aryl: alone or as part of a larger moiety, as in "aralkyl." The term "aryl" as used herein refers to monocyclic, bicyclic, or aryl rings having a total of 6 to 14 ring members. or a tricyclic carbocyclic ring structure, wherein said ring structure is in a single bond with the rest of the molecule. having a point of attachment, at least one ring in the system is aromatic, and wherein Each ring in the system contains 4 to 7 ring members. In some embodiments, the aryl group is having 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In this embodiment, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., 1 naphthyl, such as -naphthyl and 2-naphthyl. In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 aryl"; for example, anthracyl (ant "Aryl" also includes ring systems, in which case the ring systems are as defined above. The aryl ring is fused to one or more carbocyclic or heterocyclyl groups, in which case In the example, the bonding radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms followed by the number of carbon atoms in the aryl ring system. Examples of aryl are phenyl, naphthyl, , and anthracene.

[0154] Arylene: As used herein, the term “arylene” refers to a divalent Refers to an aryl group (i.e., has two points of attachment to the molecule). Examples of arylene are: Examples include phenylene (eg, unsubstituted phenylene or substituted phenylene).

[0155] Halogen or Halo: As used herein, the terms “halogen” or “halo” mean , fluorine, chlorine, bromine, or iodine.

[0156] Amide: The term "amide" or "amido" refers to a compound of the formula -C(O)N(R ’ )2, -C(O)N(R ’ )-, -NR ’ C(O)R ’ , -NR ’ C (O)N(R ’ )2-, or -NR ’ refers to a chemical moiety having the formula C(O)—, where each R ’ are independently selected from hydrogen, alkyl, alkenyl, alkyl, and alkyl-alkyl groups, unless otherwise specified in the specification. aryl, heteroalkyl (attached via a chain carbon), cycloalkyl, aryl, aryla alkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heteroaryl and cycloalkyl (attached via a ring carbon), each of which is by itself a member of the present invention. It may be optionally substituted as described herein, or two R's may be combined with a nitrogen atom. can be joined to form a 3-, 4-, 5-, 6-, or 7-membered ring.

[0157] Amino: The term “amino” or “amine” refers to the group —N(R′) 2 , where: Each R ’ are independently selected from hydrogen, alkyl, alkenyl, and alkyl groups, unless otherwise specified in the specification. Alkynyl, heteroalkyl (bonded through a carbon chain), cycloalkyl, aryl, aryl Heteroaryl (bonded through a ring carbon), heteroarylalkyl, heteroaryl selected from cycloalkyl (attached via a ring carbon), sulfonyl, or carbonyl groups; , each of which may itself be optionally substituted as described herein, or Two R's may be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. In embodiments, the amino group is —NHR′, where R′ is aryl (aryl). arylamino), heteroaryl (heteroarylarylamino), or alkyl ( alkylamino).

[0158] Sulfonyl: The term "sulfonyl" refers to -S(=O)R', or -S(=O) 2-group, where R ’ Unless otherwise specified in the specification, alkynyl, heteroalkyl (attached via a chain carbon), cycloalkyl, aryl aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl and heterocycloalkyl (attached via a ring carbon), each of which may be independently The isomer may be optionally substituted as described herein.

[0159] Sulfinyl: The term "sulfinyl" refers to a group of the formula -S(=O)R', -S(=O)- or —S(═O)(═NR′)—, where R ’ is described in this specification. Unless otherwise specified, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl ( (bonded via a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded via a ring carbon) and bonded together), each of which may itself be optionally selected as described herein. It can be substituted.

[0160] Carbonyl: The term "carbonyl" refers to -C(=O)R', or -C(=O)- refers to a group, wherein R ’ Unless otherwise specified in this specification, alkyl, alkynyl, heteroalkyl (attached via a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via a ring carbon), heteroarylalkyl, heterocycloalkyl (attached via a ring carbon), each of which may itself be selected from: It may be optionally substituted as described herein.

[0161] Phosphoryl: The term "phosphoryl" refers to -P(=O)(R')2, or -P(= O)(R')- group, where R ’ Unless otherwise specified herein, alkyl, alkenyl, alkynyl, heteroalkyl (through the chain carbon or heteroatom) (bonded via a ring carbon atom), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via a ring carbon atom), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon) and bonded) groups, each of which may itself be any of the groups described herein. or two R's may be combined with the nitrogen atom to form 3, 4, 5, 6, Or it can form a seven-membered ring.

[0162] Heteroalkyl: The term "heteroalkyl" refers to any heteroalkyl group selected from the group consisting of N, O, S, and P. and 1 to 14 carbon atoms, in addition to 1, 2, 3, or 4 heteroatoms independently selected from means a branched or unbranched alkyl, alkenyl, or alkynyl group having the formula Heteroalkyls are useful for tertiary amines, secondary amines, ethers, thioethers, amides, thio Amides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphatides Heteroalkyl groups include sulforamidates, sulfonamides, and disulfides. Optionally, it may contain monocyclic, bicyclic, or tricyclic rings, each ring preferably having 3 to 6 members. Examples of heteroalkyl include polyethers such as methoxymethyl and ethoxyethyl. Includes ether.

[0163] Heteroalkylene: As used herein, the term “heteroalkylene” refers to Represents a divalent form of the heteroalkyl groups described herein.

[0164] Heteroaryl: As used herein, the term "heteroaryl" refers to a heteroaryl having a total of six to ten refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having four ring members, said ring systems being , has a single point of attachment to the rest of the molecule, at least one ring in the system is aromatic, and the system Each ring contains 4 to 7 ring members, and at least one ring atom is a nitrogen atom or an oxygen atom. are, but are not limited to, heteroatoms.

[0165] Heterocycloalkyl: As used herein, the term "heterocycloalkyl" refers to a heterocycloalkyl , wherein at least one atom is nitrogen, oxygen, sulfur, or phosphorus, such as, but not limited to, A heterocyclic ring is a non-aromatic ring in which the ring is a heteroatom and the remaining atoms are carbon. The alkyl group can be substituted or unsubstituted.

[0166] Deuterium: "Deuterium" ("D" or "2 The term "H") Also called deuterium (heavy hydrogen), deuterium has one proton and isotope of hydrogen with a nucleus consisting of one neutron and one neutron, which is the mass of a normal hydrogen nucleus (one proton).

[0167] Isotopes: The term "isotopes" refers to variations of a particular chemical element that differ in the number of neutrons and therefore the number of nucleons. All isotopes of a given component have the same number of protons, but each atom The atoms have different numbers of neutrons.

[0168] The term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or or more than one substituent. When used to describe a structural system, substitution may occur at any valence-allowed position on the system. For example, substitutions are meant to result in stable compounds (e.g., rearrangements, cyclizations, removals, or (Compounds that do not spontaneously undergo transformation by other reactions, etc.) When a moiety or group is explicitly stated to be optionally substituted or substituted with any specified substituent, It is understood that unless expressly stated, such moiety or group is intended to be unsubstituted. It is understood.

[0169] a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl) is substituted with a different number of substituents within an explicitly defined range, the total number of substituents is It is understood that the valence of the atom will not exceed the normally available valence under the existing conditions. It is also understood that is presumed to be present to satisfy the remaining valences of the ring system. is a combination of substituents and variables that results in stable or chemically feasible compounds. A stable or chemically feasible compound is one that is compatible with other factors. Among these are compounds that are sufficiently stable to allow their preparation and detection.

[0170] A wide variety of substituents are well known, as are methods for their formation and introduction onto various parent groups. Representative substituents include alkyl, cycloalkyl, alkenyl, cycloalkane, and cycloalkyl groups. Nyl, alkynyl, arylalkyl, alkylaryl, aryl, arylalkoxy arylamino, heteroarylamino, heteroaryl, heteroarylalkoxy cycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, haloalkyl, thio Alkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indo alkyl, mono-, di-, and trihaloalkyl, mono-, di-, and trihaloalkoxy si, amino, alkylamino, dialkylamino, amido, cyano, alkoxy, hydro oxy, sulfonamido, halo (e.g., -Cl and -Br), nitro, oximino, -COOR 50 , -COR 50 , -SO 0-2 R 50 , -SO2NR 50 R 51 , N.R. 5 2 SO2R 50 , =C(R 50 R 51 ), =N-OR 50 , =N-CN, =C(halo)2 , =S, =O, -CON(R 50 R 51 ), -OCOR 50 , -OCON(R 50 R 51 ), -N(R 52 )CO(R 50 ), -N(R 52 )COOR 50 , and -N(R 52 )CON(R 50 (R 51 ), but are not limited to, wherein R 50 , R 5 1 , and R 52 may be independently selected from: a hydrogen atom, and a branched or Straight chain C 1-6 -Alkyl, C 3-6 -cycloalkyl, C 4-6 -heterocycloalkoxy aryl, heteroaryl, and aryl groups (substituted or unsubstituted). Where permitted, R 50 and R 51 may be joined together to form a carbocyclic or heterocyclic ring system can be done.

[0171] In a preferred embodiment, the substituents are halogen, -COR', -CO2H, -CO2R' , -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', and -SO2R', wherein each instance of R' is independently Then, C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C 1-C 10 alkyl, or C1-C3 alkyl). In certain embodiments, R' is Independently, unsubstituted alkyl (e.g., unsubstituted C-C 20Alkyl, C1-C 15 Archi Le, C1-C 10 alkyl, or C1-C3 alkyl). Preferably, R' is independently and unsubstituted C1-C3 alkyl.

[0172] Any formula provided herein refers to a compound having the structure shown by the structural formula, if It is intended to represent any particular variation or form of the invention. Compounds of any formula may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds of the general formula, and mixtures thereof are considered within the scope of the formula. Thus, any formula provided herein may be used in combination with a racemic , one or more enantiomers, one or more diastereomeric forms, one or more It is intended to represent a number of atropisomeric forms, and mixtures thereof. The structure of In addition, any of the compounds provided herein may exist as isomers or as atropisomers. The formula encompasses hydrates, solvates, and polymorphs of such compounds, and mixtures thereof. It is intended that

[0173] Compounds of the Invention Disclosed herein are compounds that are potent inhibitors of PHD. In some embodiments, The compound of the present invention has a function to inhibit any one of PHD1, PHD2, and PHD3. The enzymatic half-maximal inhibitory concentration (IC) was less than 100 μM. 50 ) values. The compound of the present invention has a function of one of PHD1, PHD2, and PHD3. IC<50 μM50 In some embodiments, the compounds of the present invention have the value , less than 25 μM I for any one of PHD1, PHD2, and PHD3 C 50 In some embodiments, the compounds of the present invention have PHD1, PHD2, and an IC of less than 20 μM against any one of PHD3 50 It has value. In some embodiments, the compounds of the present invention are selected from the group consisting of PHD1, PHD2, and PHD3. IC<15 μM for either 50 In some embodiments, the The compound of the invention has a 1:1 ratio to any one of PHD1, PHD2, and PHD3. IC less than 0 μM 50 In some embodiments, the compounds of the present invention have a PHD IC<5 μM for any one of PHD1, PHD2, and PHD3 50 Value In some embodiments, the compounds of the present invention have PHD1, PHD2, and PH IC less than 1 μM for any one of D3 50 Some implementations In this embodiment, the compound of the present invention is a compound that inhibits any one of PHD1, PHD2, and PHD3. IC of approximately 3 nM to approximately 5 nM 50 In some embodiments, the present invention The compound was administered at approximately 5 nM to any one of PHD1, PHD2, and PHD3. ~10 nM IC 50 In some embodiments, the compounds of the present invention have a pH Approximately 10 nM to approximately 20 nM for any one of D1, PHD2, and PHD3 IC 50 In some embodiments, the compounds of the present invention have PHD1, PHD IC of approximately 20 nM to approximately 50 nM against either PHD2 or PHD3 50 value In some embodiments, the compounds of the present invention have PHD1, PHD2, and P IC of approximately 50 nM to approximately 100 nM against any one of HD3 50 It has a value. In some embodiments, the compounds of the present invention inhibit the activity of PHD1, PHD2, and PHD3. IC of approximately 100 nM to approximately 200 nM for any one of these 50 Has value. Some In this embodiment, the compounds of the invention are capable of inhibiting any of PHD1, PHD2, and PHD3. IC of approximately 200nM to approximately 500nM for each 50 Some implementations In this embodiment, the compound of the present invention is a compound that inhibits any one of PHD1, PHD2, and PHD3. IC of approximately 500 nM to approximately 1000 nM 50 It has a value.

[0174] Representative examples from this class are expressed in vitro in PHD1, PHD2, and PHD3. It exhibits inhibitory activity against

[0175] Exemplary compounds are described herein. In particular, these selective inhibitors are compounds that bind to two aromatic Characterize the pyrazole moiety (e.g., 5-hydroxy-substituted pyrazole) that links the aromatic moieties. It is possible.

[0176] Compounds of formula (A) and (I) to (III) In one aspect, a compound having a structure according to formula (A): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ar 1is phenyl or a 6-membered nitrogen-containing heteroaryl, Aryl is a C alkyl group optionally substituted with halogen, CN, OH, or one or more halogens. 1-3 Alkyl, or C 1-3 optionally substituted with alkoxy; R 2 is H or C1-3 alkyl, Ar 2 is a halogen, OH, amine, or C 1-3 6-membered optionally alkyl-substituted is a nitrogen-containing heteroaryl; R 4 is hydrogen or C 1-4 It is alkyl.

[0177] In embodiments of the formulas described herein (e.g., Formula (A)), compounds (e.g., of Formula ( A) is a compound of [ka] isn't it.

[0178] In embodiments of the formulas described herein (e.g., Formula (A)), compounds (e.g., of Formula ( A) Compounds) exclude the following compounds: [ka]

[0179] In some embodiments, R 2 is H.

[0180] In some embodiments, R 2 is C alkyl. In some embodiments, R 2 is C H3. In some embodiments, R 2 is CH2CH3. In some embodiments, R 2 is CH2CH2CH3. In some embodiments, R2 is CH(CH3)2.

[0181] In some embodiments, R 4 is H.

[0182] In some embodiments, R 4 is C alkyl. In some embodiments, R 4 is C H3. In some embodiments, R 4 is CH2CH3. In some embodiments, R 4 is CH2CH2CH3. In some embodiments, R 4 is CH(CH3)2. In some embodiments, R 4 is CH2CH2CH2CH3. In some embodiments, R 4 is CH(CH3)(CH2CH3). In some embodiments, R 4 is C(CH3) It is 3.

[0183] In some embodiments, Ar 1 is unsubstituted aryl. In some embodiments, Ar 1 is substituted aryl. In some embodiments, Ar 1 is unsubstituted phenyl. In the embodiment, Ar 1 is a substituted phenyl.

[0184] In some embodiments, Ar 1 is an unsubstituted 6-membered nitrogen-containing heteroaryl. In the embodiment, Ar 1 is a substituted 6-membered nitrogen-containing heteroaryl.

[0185] In some embodiments, Ar 1 is a halogen, CN, OH, one or more halogens Optionally substituted C 1-3 Alkyl, and C1-3 one or more selected from alkoxy is substituted with multiple groups. In some embodiments, Ar 1 is substituted with one substituent In some embodiments, Ar 1 is substituted with two substituents. In this state, Ar 1 is substituted with three substituents. In some embodiments, Ar 1 is 4 is substituted with substituents.

[0186] In some embodiments, Ar 1 is one or more R 1 groups, and each R 1 is hydrogen, ha halogen, CN, OH, C optionally substituted with one or more halogens 1-3 Alkyl, and C 1-3 In some embodiments, Ar is independently selected from alkoxy. 1 is m R represented by 1 R includes the amount of groups, and m is 1, 2, 3, or 4. 1 exists In this case, R 1 can replace a hydrogen in the parent molecular structure. 1 is present and is a non-hydrogen moiety, R 1 represents a substituent. In some embodiments, R 1 is halogen, CN, OH, CN or C optionally substituted with one or more halogens 1-3 Alkyl, and C 1-3 alkoxy.

[0187] Therefore, for any value of m described herein, hydrogen is present in the molecule at a stable compounds (e.g., molecules that spontaneously undergo recombination, such as by rearrangement, cyclization, elimination, or other reaction) (a compound that does not undergo transformation) 1 The constituent atoms of It is understood that Ar may be present as needed. 1 , R 1 , and m's exemplary implementation Embodiments are described herein.

[0188] In some embodiments, Ar 1 teeth, [ka] where: X, Y, and Z are independently CH or N, wherein N is optionally oxidized; Each R 1 are independently hydrogen, halogen, CN, OH, optionally substituted with one or more halogens; Replaced C 1-3 Alkyl, and C 1-3 alkoxy; m is 1, 2, 3, or 4.

[0189] In some embodiments, R 1 is not hydrogen. In some embodiments, R 1 There is non-aqueous If it is an elementary part, R 1 represents a substituent.

[0190] In some embodiments, the value of m is based on the number of nitrogen atoms present in the ring. In an embodiment, when two and only two of X, Y and Z are N, m is 1, 2 In some embodiments, when X, Y, and Z are each N, m is 1, or 3. Or 2.

[0191] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0192] In some embodiments, X, Y and Z are all N and m is 1 or 2. In this embodiment, m is 1 and any remaining unsubstituted carbon ring atoms are In some embodiments, m is 2.

[0193] In some embodiments, one of X, Y, and Z is CH and the others are N wherein N is optionally oxidized and m is 1, 2, or 3. In some embodiments, , m is 1, and any remaining unsubstituted carbon ring atoms are bonded to hydrogen to satisfy valences. In some embodiments, m is 2 and any remaining unsubstituted carbocyclic atoms are considered to be The atoms are considered to be bonded to hydrogen atoms to satisfy valence. is 3.

[0194] In some embodiments, two of X, Y, and Z are CH and the others are N wherein N is optionally oxidized and m is 1, 2, 3, or 4. In the formula, m is 1 and any remaining unsubstituted carbon ring atoms are bonded to hydrogen to satisfy the valence. In some embodiments, m is 2 and any remaining unsubstituted carbon atom is considered to be bonded to the The ring atoms are considered to be bonded to hydrogens to satisfy valence. , m is 3, and any remaining unsubstituted carbon ring atoms are bonded to hydrogen to satisfy valences. In some embodiments, m is 4.

[0195] In some embodiments, Ar 1 The N atom in the

[0196] In some embodiments, Ar1 The N atom in the

[0197] In some embodiments, Ar 1 is substituted phenyl. In some embodiments, Ar 1 teeth , at least one R 1 wherein R 1 is CN or a halogen.

[0198] In some embodiments, Ar 1 is C optionally substituted with one or more halogens 1- 3 one or two R independently selected from alkyl, halogen, CN, or OH 1 The group is substituted.

[0199] In some embodiments, Ar 1 is a pyridyl N-oxide, or C 1-3 Al At least one R is koxy or halogen 1 pyridyl optionally substituted by be.

[0200] In some embodiments, R 1 is always hydrogen.

[0201] In some embodiments, R 1 is always CN.

[0202] In some embodiments, R 1 is OH every time.

[0203] In some embodiments, R 1 is a halogen. In some embodiments, the halogen is In some embodiments, the halogen is Cl. In some embodiments, the halogen is Br. The first one is I.

[0204] In some embodiments, R 1 Every time, C 1-3 It is alkyl.

[0205] In some embodiments, R 1 is always a non-substituted C 1-3 In some embodiments, is R 1 is CH3 each time. In some embodiments, R 1 is CH2CH3 every time .

[0206] In some embodiments, R 1 is always replaced by C 1-3 In some embodiments, the alkyl group is substituted or unsubstituted. , R 1 Each time, C is substituted with one or more halogens. 1-3 It is an alkyl. In embodiments, the halogen is F. In some embodiments, the halogen is Cl. In some embodiments, the halogen is Br. In some embodiments, the halogen is I.

[0207] In some embodiments, R 1 is always CF3.

[0208] In some embodiments, R 1 Every time, C 1-3 In some embodiments, R 1 is OMe every time.

[0209] In some embodiments, Ar 1 teeth, [ka] is selected from.

[0210] In some embodiments, Ar 1 teeth, [ka] is selected from.

[0211] In some embodiments, Ar 1 teeth, [ka] is selected from.

[0212] In some embodiments, Ar 1 teeth, [ka] is selected from.

[0213] In some embodiments, Ar 1 teeth, [ka] is selected from.

[0214] In some embodiments, Ar 1 teeth, [ka] is selected from.

[0215] In some embodiments, Ar 2 is an unsubstituted 6-membered nitrogen-containing heteroaryl.

[0216] In some embodiments, Ar 2 is a halogen, OH, amine, or C 1-3 With alkyl In some embodiments, Ar is a substituted 6-membered nitrogen-containing heteroaryl. 2 This specification In some embodiments, Ar is substituted by one of the substituents described in the document. 2 is Honmei It is substituted by two substituents as described in the specification.

[0217] In some embodiments, Ar2 teeth, [ka] where: A and B are independently CH or N, wherein N is optionally oxidized; Each R 3 are independently hydrogen, halogen, OH, amine, and C 1-3 alkyl is selected from n is 0, 1, or 2.

[0218] In some embodiments, the value of n is based on the number of nitrogen atoms present in the ring. In an embodiment, when one and only one of A and B is N, n is 0, 1, or 2. In some embodiments, A and B are both N, and n is 0 or 1. is.

[0219] In some embodiments, n is 0. In some embodiments, n is 1. In the embodiment, n is 2.

[0220] In some embodiments, A and B are both N, where N is optionally oxidized, and n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1 is.

[0221] In some embodiments, one of A and B is CH and the other is N. wherein N is optionally oxidized and n is 0, 1, or 2. In some embodiments, n is In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0222] In embodiments, A and B are both CH and n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In the embodiment, n is 2.

[0223] In some embodiments, Ar 2 The N atom in the

[0224] In some embodiments, Ar 2 The N atom in the

[0225] In some embodiments, R 3 is always hydrogen.

[0226] In some embodiments, R 3 is OH every time.

[0227] In some embodiments, R 3 is a halogen. In some embodiments, the halogen is In embodiments, the halogen is Cl. In embodiments, the halogen is is Br. In some embodiments, the halogen is I.

[0228] In some embodiments, R 3 is an amine each time. 3 Every time, It is NH2.

[0229] In some embodiments, R 3 Every time, C 1-3 It is alkyl.

[0230] In some embodiments, R 3 is always a non-substituted C 1-3 In some embodiments, is R 3 is CH3 every time.

[0231] In some embodiments, Ar 2 is selected from the group consisting of: [ka]

[0232] In embodiments, the compound of Formula (A) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein A, B, X, Y, Z, R 1 , R 2 , R 3 , and R 4 is as defined elsewhere herein.

[0233] In embodiments of the formulas described herein (e.g., Formula (I)), compounds (e.g., compounds of formula ( I) Compound) is [ka] isn't it.

[0234] In embodiments of the formulas described herein (e.g., Formula (I)), compounds (e.g., compounds of formula ( Compounds I) exclude the following compounds: [ka]

[0235] In embodiments, the compound of Formula (A) or Formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R 1 , R 2 , R 3 , and R 4 is as defined elsewhere herein.

[0236] In embodiments of the formulas described herein (e.g., Formula (Ia)), the compound (e.g., Compound (Ia) [ka] isn't it.

[0237] In embodiments of the formulas described herein (e.g., Formula (Ia)), the compound (e.g., Compounds of (Ia)) exclude the following compounds: [ka]

[0238] In embodiments, the compound of Formula (A) or Formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 is Honmei As defined elsewhere in the specification.

[0239] In embodiments of the formulas described herein (e.g., Formula (Ib)), compounds (e.g., of Formula Compound (Ib) [ka] isn't it.

[0240] In embodiments of the formulas described herein (e.g., Formula (Ib)), compounds (e.g., of Formula Compounds of (Ib)) exclude the following compounds: [ka]

[0241] In embodiments, the compound of Formula (A) or Formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein A, B, X, Y, Z, R 1 , R 3 , and BiR 4 is as defined elsewhere herein.

[0242] In embodiments, the compound of Formula (A) or Formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 is Honmei As defined elsewhere in the specification.

[0243] In embodiments of the formulas described herein (e.g., Formula (II)), the compound (e.g., (II) Compound [ka] isn't it.

[0244] In embodiments of the formulas described herein (e.g., Formula (II)), the compound (e.g., Compounds (II)) exclude the following compounds: [ka]

[0245] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R1 , R 2 , and R 3 is the As defined elsewhere.

[0246] In embodiments of the formulas described herein (e.g., Formula (IIa)), the compound (e.g., The compound of formula (IIa) [ka] isn't it.

[0247] In embodiments of the formulas described herein (e.g., Formula (IIa)), the compound (e.g., Compounds of formula (IIa) exclude the following compounds: [ka]

[0248] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 4 is the As defined elsewhere.

[0249] In embodiments of the formulas described herein (e.g., Formula (IIb)), the compound (e.g., The compound of formula (IIb) [ka] isn't it.

[0250] In embodiments of the formulas described herein (e.g., Formula (IIb)), the compound (e.g., Compounds of formula (IIb)) exclude the following compounds: [ka]

[0251] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 is somewhere in this specification As defined.

[0252] In embodiments of the formulas described herein (e.g., Formula (IIc)), the compound (e.g., The compound of formula (IIc) [ka] isn't it.

[0253] In embodiments of the formulas described herein (e.g., Formula (IIc)), the compound (e.g., Compounds of formula (IIc)) exclude the following compounds: [ka]

[0254] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 is somewhere in this specification As defined.

[0255] In embodiments of the formulas described herein (e.g., Formula (IId)), the compound (e.g., Compounds of formula (IId) [ka] isn't it.

[0256] In embodiments of the formulas described herein (e.g., Formula (IId)), the compound (e.g., Compounds of formula (IId)) exclude the following compounds: [ka]

[0257] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 4 is somewhere in this specification As defined.

[0258] In embodiments of the formulas described herein (e.g., Formula (IIe)), the compound (e.g., Compounds of formula (IIe) [ka] isn't it.

[0259] In embodiments of the formulas described herein (e.g., Formula (IIe)), the compound (e.g., Compounds of formula (IIe)) exclude the following compounds: [ka]

[0260] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is defined elsewhere in this specification That's right.

[0261] In embodiments of the formulas described herein (e.g., Formula (IIf)), the compound (e.g., The compound of formula (IIf) [ka] isn't it.

[0262] In embodiments of the formulas described herein (e.g., Formula (IIf)), the compound (e.g., Compounds of formula (IIf) exclude the following compounds: [ka]

[0263] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , and R 4 is the As defined elsewhere.

[0264] In embodiments, the compound of Formula (A), Formula (I), or Formula (II) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 is Honmei As defined elsewhere in the specification. R 5 is CN or a halogen,

[0265] In some embodiments, R 5 is CN.

[0266] In some embodiments, R 5 is a halogen. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl. In some embodiments, the halogen is Br. In some embodiments, the halogen is I.

[0267] In embodiments of the formulas described herein (e.g., Formula (III)), the compound (e.g., The compound of formula (III) [ka] isn't it.

[0268] In embodiments of the formulas described herein (e.g., Formula (III)), the compound (e.g., Compounds of formula (III) exclude the following compounds: [ka]

[0269] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 and R 5 teeth, As defined elsewhere herein.

[0270] In embodiments of the formulas described herein (e.g., Formula (IIIa)), the compound (e.g., , a compound of formula (IIIa)) [ka] isn't it.

[0271] In embodiments of the formulas described herein (e.g., Formula (IIIa)), the compound (e.g., , compounds of formula (IIIa)) excludes the following compounds: [ka]

[0272] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , and R 5 is Honmei As defined elsewhere in the specification.

[0273] In embodiments of the formulas described herein (e.g., Formula (IIIb)), the compound (e.g., , a compound of formula (IIIb)) [ka] isn't it.

[0274] In embodiments of the formulas described herein (e.g., Formula (IIIb)), the compound (e.g., , compounds of formula (IIIb)) excludes the following compounds: [ka]

[0275] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 5 is the As defined elsewhere.

[0276] In embodiments of the formulas described herein (e.g., Formula (IIIc)), the compound (e.g., , a compound of formula (IIIc)) [ka] isn't it.

[0277] In embodiments of the formulas described herein (e.g., Formula (IIIc)), the compound (e.g., , compounds of formula (IIIc)) excludes the following compounds: [ka]

[0278] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , and R 5 is the As defined elsewhere.

[0279] In embodiments of the formulas described herein (e.g., Formula (IIId)), the compound (e.g., , a compound of formula (IIId)) [ka] isn't it.

[0280] In embodiments of the formulas described herein (e.g., Formula (IIId)), the compound (e.g., , compounds of formula (IIId)) excludes the following compounds: [ka]

[0281] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 4 , and R 5 is the As defined elsewhere.

[0282] In embodiments of the formulas described herein (e.g., Formula (IIIe)), the compound (e.g., , compounds of formula (IIIe)) [ka] isn't it.

[0283] In embodiments of the formulas described herein (e.g., Formula (IIIe)), the compound (e.g., , compounds of formula (IIIe)) excludes the following compounds: [ka]

[0284] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 5 is somewhere in this specification As defined.

[0285] In embodiments of the formulas described herein (e.g., Formula (IIIf)), the compound (e.g., , a compound of formula (IIIf)) [ka] isn't it.

[0286] In embodiments of the formulas described herein (e.g., Formula (IIIf)), the compound (e.g., , compounds of formula (IIIf)) excludes the following compounds: [ka]

[0287] In embodiments, a compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , and R 5 is Honmei As defined elsewhere in the specification.

[0288] Exemplary Compounds In some embodiments, the PHD inhibitor compound is any one of compounds 1-44. or a pharmaceutically acceptable salt thereof. [Table 2] TIFF2026021443000129.tif221170TIFF2026021443000130.tif223170TIFF2026021443000131.tif47170

[0289] Isotopic substitution Compounds described herein (e.g., compounds of formula, such as any one of Compounds 1-44) In the compound (A) and any one of (I) to (III), the atom is or one or more of the atoms may have the same atomic number. have atomic masses or mass numbers that differ from those found primarily in nature It should be understood that certain isotopes with different quantities may be artificially enriched. is a compound of the compounds described herein (e.g., any one of Compounds 1 to 44). All of the compounds of formula (A) and any one of (I) to (III) Suitable isotopic variations are intended to be included. For example, different isotopic forms of hydrogen (H) are Protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H). Protium is , the predominant hydrogen isotope found in nature.

[0290] In some embodiments, the compounds described herein (e.g., compounds 1-44) A compound of any one of formula (A) and (I) to (III), such as any one of the compounds One or more of the hydrogen atoms in the nucleus are replaced by deuterium. may offer certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements. or may provide compounds useful as standards for characterization of biological samples. In some embodiments, the compounds described herein (e.g., compounds 1-44) Any one of the compounds of formula (A) and (I) to (III) One or more of the hydrogen atoms in Radiolabeled compounds that are radioactive and therefore useful as tracers in metabolic or kinetic studies can provide things.

[0291] Compounds disclosed herein (e.g., compounds of formula, such as any one of Compounds 1-44) The isotopic enrichment of (A) and any one of (I) to (III) can be carried out by a method known in the art. by conventional techniques known to those skilled in the art, or by using suitable isotopically enriched reagents and / or medium. In processes similar to those described in the schemes and examples herein, intermediates were used. Thus, this can be accomplished without undue experimentation.

[0292] The term "isotopically substituted" refers to the position and / or position(s) of an isotopic substitution. The level of isotopic enrichment at a given position, e.g., hydrogen versus deuterium, is not limited to the specific isotopic enrichment levels provided herein. Therefore, as used herein, In this case, the term "compound" refers to a compound having the same chemical structure but with different isotopes between the constituent atoms of the molecule. Therefore, the specific molecules containing the deuterium atom shown are included in the set of molecules that also contain the deuterium atom. The compound represented by the chemical structure has one of the designated deuterium positions in the structure. or may contain smaller amounts of isotopic substitutions having multiple hydrogen atoms, It will be apparent to one skilled in the art that the relative amounts of such isotopic substitution in the compounds provided the isotopic purity of the deuterated reagents used to make the compounds, and the purity of the compounds prepared. These include, but are not limited to, the efficiency of deuterium incorporation in the various synthetic steps used to The actual time is not fixed and depends on many factors.

[0293] When a position is designated as "H" or "hydrogen," the position is designated as the hydrogen atom of that natural abundance isotope. When a position is designated as "D" or "deuterium", it is understood to have hydrogen in its composition. positions have deuterium at an abundance that is at least 3340 times the natural abundance of deuterium. It is understood that this is 0.015% (i.e., the term "D" or "deuterium" indicates at least 50.1% deuterium incorporation).

[0294] In embodiments, the compounds provided herein have a β-glucan value of at least 3500 (52.5 % deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4 500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least At least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466. 7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), and for deuteration on compounds with at least 6633.3 (99.5% deuterium incorporation) has an isotopic enrichment factor for each deuterium present at a site designated as a potential site of obtain.

[0295] Synthesis of Compounds of the Invention Compounds described herein (e.g., compounds of formula, such as any one of Compounds 1-44) A and any one of compounds I to III) can be synthesized as shown in Scheme A. Such synthesis can be achieved by methods known in the art, including the exemplary synthesis of the examples provided herein. It can be prepared accordingly.

[0296] The purity of the compounds and their synthetic intermediates can be determined by one of the methods described below. The results were determined by reverse phase HPLC using:

[0297] Method A: Mobile phase: A: Water (0.01% TFA) B: Acetonitrile (0.01% TFA Gradient phase: increase from 5% B to 95% B within 1.4 min, then 95% B in 1.6 min (total run Time: 3 min; Flow rate: 2.3 mL / min; Column: SunFire C18, 4.6*50 mm, 3.5 μm; Column temperature: 50 °C. Detector: ADC ELSD, DAD (214n m and 254 nm), ES-API.

[0298] Method B: Mobile phase: A: Water (10 mM NH4HCO3) B: Acetonitrile; 1.5 min 5% to 95% B within 1.5 min, 95% B in 1.5 min (total run time: 3 min); flow rate: 2.0 mL / min; Column: XBridge C18, 4.6*50mm, 3.5um; Column temperature: 40°C. Detectors: ADC ELSD, DAD (214nm and 254nm), MSD ( ES-API). Abbreviations and acronyms used herein include the following: [Table 3] Scheme A [ka]

[0299] Compounds of formula (IId) are prepared according to Scheme A using commercially available materials. Compound IId) is prepared according to Scheme A using commercially available materials. Reaction of the ester with N,N-dimethylformamide dimethyl acetal gives the compound of formula (C): By cyclization of (C) and hydrazide (D), an enamine compound of formula (IId ) is obtained.

[0300] Compositions and Methods The present invention provides pharmaceutical compositions for use in the treatment of various conditions or disorders described herein. A compound of any one of formulas (A) and (I) to (III) for the production thereof, The present invention provides the use of pharmaceutically acceptable salts thereof. At least one compound of any one of the above, or a pharmaceutically acceptable salt thereof, and a pharmaceutical and a physiologically acceptable excipient or carrier. Alternatively, the medicament or pharmaceutical composition may further comprise at least one additional therapeutic agent, or may be used in combination therewith.

[0301] The compounds of the present invention, or pharmaceutical or composition containing the compounds, can be used to inhibit the activity of PHDs. Inhibition of PHD can be beneficial in the treatment of cardiac (e.g., ischemic heart disease, congestive heart failure) diseases. , and valvular heart disease), pulmonary (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease) lung disease), liver (e.g., acute liver failure, liver fibrosis, and cirrhosis), and kidney (e.g., For example, they may be particularly useful in the treatment of diseases, including those of acute kidney injury and chronic kidney disease. In one embodiment, the method of the present invention comprises administering a therapeutically effective amount of a compound of Formula (A) and (I)-(III). any one of the compounds of formula (A) and (B), or a pharmaceutically acceptable salt thereof, A pharmaceutical composition containing one or more compounds of any one of (I) to (III). , including administering it to a patient in need thereof.

[0302] The present invention is also directed to a method of inhibiting the activity of a PHD. In one embodiment, the method comprises: PHD, an effective amount of a compound of any one of formulas (A) and (I) to (III), or a pharmaceutically acceptable salt thereof. This includes making someone do something.

[0303] In yet other embodiments, the compounds disclosed herein (e.g., compounds 1-44) A compound of any one of formula (A) and (I) to (III), such as any one of the compounds or a pharmaceutically acceptable salt thereof is used to treat anemic conditions associated with chronic kidney disease, polycystic kidney disease, Disease, aplastic anemia, autoimmune hemolytic anemia, bone marrow transplant anemia, Churg-Strauss disease syndrome, Diamond-Blackfan anemia, Fanconi anemia, Felty syndrome, transplantation Graft-versus-host disease, hematopoietic stem cell transplantation, hemolytic uremic syndrome, myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria Globinuria, myelofibrosis, pancytopenia, pure red cell aplasia, Schönlein-Henoch purpura , refractory anemia with excess blasts, rheumatoid arthritis, Shwachman syndrome, sickle cell disease, severe Thalassemia, mild thalassemia, thrombocytopenic purpura, anemic or non-anemic patients undergoing surgery Patients with hematologic anemia, anemia related to or secondary to trauma, sideroblastic anemia, and anemia secondary to other treatments, including: Anemia: Reverse transcriptase inhibitors, corticosteroid hormones, and cyclic Cisplatin or non-cisplatin-containing chemotherapy agents, vinca alkaloids, mitotic inhibitors agents, topoisomerase II inhibitors, anthracyclines, alkylating agents, especially inflammatory, Treatment or prevention of anemia, including treatment of anemia associated with aging and / or secondary to chronic disease PHD1 inhibition can treat symptoms of anemia, including chronic fatigue, paleness, and dizziness. It can also be used to treat

[0304] In other embodiments, any of the compounds disclosed herein (e.g., any of Compounds 1-44) any one of the compounds of formula (A) and (I) to (III)), or a pharmaceutically acceptable salt thereof. The tolerable salts are useful in the treatment of metabolic disorders, including but not limited to diabetes and obesity. Or it is useful for prevention.

[0305] In yet other embodiments, the compounds disclosed herein (e.g., compounds 1-44) Compounds of formula (A) and (I) to (III), such as any one of the compounds of formula (A) and (I) to (III), or pharmaceutical compositions thereof The physiologically acceptable salts are useful in the treatment or prevention of vascular disorders. These include angiogenesis, Hypoxia or hypoxia requires pro-angiogenic mediators for angiogenesis and arteriogenesis. These include, but are not limited to, wound healing-related disorders.

[0306] In yet other embodiments, the compounds disclosed herein (e.g., compounds 1-44) Compounds of formula (A) and (I) to (III), such as any one of the compounds of formula (A) and (I) to (III), or pharmaceutical compositions thereof The environmentally acceptable salts are useful in the treatment or prevention of ischemia-reperfusion injury. These include, but are not limited to, stroke, myocardial infarction, and acute kidney injury.

[0307] In other embodiments, any of the compounds disclosed herein (e.g., any of Compounds 1-44) any one of the compounds of formula (A) and (I) to (III)), or a pharmaceutically acceptable salt thereof. Tolerable salts are useful in the treatment of inflammatory bowel diseases. These include ulcerative colitis and clostridium erythropoietin. Examples of such diseases include, but are not limited to, Crohn's disease.

[0308] In other embodiments, any of the compounds disclosed herein (e.g., any of Compounds 1-44) any one of the compounds of formula (A) and (I) to (III)), or a pharmaceutically acceptable salt thereof. The acceptable salts are useful in the treatment of cancers such as colorectal cancer.

[0309] In other embodiments, any of the compounds disclosed herein (e.g., any of Compounds 1-44) any one of the compounds of formula (A) and (I) to (III)), or a pharmaceutically acceptable salt thereof. The acceptable salts are useful in the treatment of atherosclerosis.

[0310] In other embodiments, any of the compounds disclosed herein (e.g., any of Compounds 1-44) any one of the compounds of formula (A) and (I) to (III)), or a pharmaceutically acceptable salt thereof. The acceptable salts are useful in the treatment of cardiovascular disease.

[0311] In other embodiments, any of the compounds disclosed herein (e.g., any of Compounds 1-44) any one of the compounds of formula (A) and (I) to (III)), or a pharmaceutically acceptable salt thereof. Tolerable salts are useful in the treatment of ocular diseases or conditions. These include radiation retinopathy, ocular glaucoma, and ocular thrombocytopenia. Including, but not limited to, neonatal retinopathy, diabetic retinopathy, age-related macular degeneration, and ocular ischemia It will not be done.

[0312] In other embodiments, any of the compounds disclosed herein (e.g., any of Compounds 1-44) any one of the compounds of formula (A) and (I) to (III)), or a pharmaceutically acceptable salt thereof. The acceptable salts are useful in treating disorders associated with hyperoxia.

[0313] In other embodiments, any of the compounds disclosed herein (e.g., any of Compounds 1-44) any one of the compounds of formula (A) and (I) to (III)), or a pharmaceutically acceptable salt thereof. The acceptable salts are useful in the treatment of bronchopulmonary dysplasia (BPD).

[0314] In yet other embodiments, the compounds disclosed herein (e.g., compounds 1-44) a compound of formula (I) to (III), such as any one of These salts are useful in the treatment of heart diseases. Myocardial injury after percutaneous coronary intervention (PCI), myocardial injury after noncardiac surgery, abdominal Perioperative myocardial ischemia in elective aortic aneurysm surgery, myocardial injury after PCI, and coronary artery bypass grafting Myocardial injury in patients undergoing coronary artery bypass grafting (CABG), minimally invasive mitral valve repair (MIMV) or Adult patients undergoing open-heart surgery, chronic heart failure, NYHA class II to IV These include, but are not limited to:

[0315] In other embodiments, any of the compounds disclosed herein (e.g., any of Compounds 1-44) any one of the compounds of formula (A) and (I) to (III)), or a pharmaceutically acceptable salt thereof. Tolerable salts are useful in the treatment of pulmonary diseases, including lung injury during elective lobectomy. These include, but are not limited to, lung injury during CABG surgery, and lung transplantation.

[0316] In other embodiments, any of the compounds disclosed herein (e.g., any of Compounds 1-44) any one of the compounds of formula (A) and (I) to (III)), or a pharmaceutically acceptable salt thereof. Tolerable salts are useful in the treatment of liver diseases, including non-alcoholic steatohepatitis (NASH). Nonalcoholic Bone Marrow Stem Cell Disorders (NASH) are some of the conditions that can cause ulcerative colitis.

[0317] In other embodiments, any of the compounds disclosed herein (e.g., any of Compounds 1-44) any one of the compounds of formula (A) and (I) to (III)), or a pharmaceutically acceptable salt thereof. The tolerable salts are useful in the treatment of renal diseases, including contrast-induced acute kidney injury, Patients with stage III-IV chronic kidney disease undergoing scheduled coronary angiography, patients undergoing valvular heart surgery acute kidney injury in patients undergoing dialysis, non-dialysis-dependent chronic kidney disease, and chronic kidney disease initiating dialysis Patients with renal disease, including but not limited to, non-dialysis dependent chronic kidney disease.

[0318] In addition, the compounds disclosed herein (e.g., any one of Compounds 1-44) a compound of any one of formulas (A) and (I) to (III), or The pharmaceutically acceptable salts may be used in combination with additional active ingredients in the treatment of the above conditions. Additional compounds can be used in combination with the compounds disclosed herein (e.g., compounds 1-44). Any one of the formulas (A) and (I) to (III) or a pharmaceutically acceptable salt thereof, or In an exemplary embodiment, the additional active ingredient may be included in a pharmaceutical composition according to the present invention. The active ingredient is effective in treating a condition, disorder, or disease mediated by PHD enzymes. known or discovered or alternative PHD modulators, etc. or an active ingredient that is active against another target associated with a particular condition, disorder, or disease. The combination may enhance the efficacy (e.g., potency or effectiveness of the compounds according to the invention). (by including in the combination a compound that enhances the efficacy of the compound) to reduce one or more side effects. or may serve to reduce the required dose of the compound according to the invention.

[0319] The compounds of the present invention may be used alone or in combination to formulate the pharmaceutical compositions of the present invention. The pharmaceutical compositions of the present invention comprise: (a) an effective amount of of the formula (e.g., any one of compounds 1-44) disclosed herein. A) and any one of (I) to (III)), or a pharmaceutically acceptable salt thereof a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof; b) a pharmaceutically acceptable excipient.

[0320] A "pharmaceutically acceptable excipient" is a substance added to a pharmacological composition or used to administer a drug. used as a vehicle, carrier, or diluent that facilitates and is compatible with the administration of , inert substances, etc., that are non-toxic, biologically tolerable, and otherwise biocompatible upon administration to a subject. Examples of excipients include calcium carbonate and calcium phosphate. , various sugar and starch types, cellulose derivatives, gelatin, vegetable oils, and poly Suitable excipients may also include antioxidants. Such antioxidants can be used in pharmaceutical compositions or storage media to extend the shelf life of pharmaceutical products. This can be done.

[0321] Pharmaceutical Formulations and Routes of Administration The compounds and compositions of the present invention can be administered directly or via administration to a suitable support, as is well known in the art. The therapeutic method of the present invention may be delivered in a pharmaceutical composition or medicament together with a carrier or excipient. The method can include administering an effective amount of a compound of the present invention to a subject in need thereof. In a preferred embodiment, the subject is a mammalian subject, and in a most preferred embodiment, The subject is a human subject.

[0322] The effective amount of such a compound, composition, or agent will depend on the most effective and convenient route of administration, and The most suitable formulation can be readily determined by routine experimentation. Drug delivery systems are available in the art, see, e.g., Gennaro, AR ,ed.(1995)Remington's Pharmaceutical Sci See ences (see above).

[0323] Suitable routes of administration include, for example, oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral. The main routes of parenteral administration include intravenous, intramuscular, and subcutaneous administration. Secondary routes of administration include intraperitoneal, intra-arterial, intra-articular, intracardiac, intravesical, These include intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intracerebroventricular administration. The indications for use depend on the physical, chemical, and biological properties of the drug, as well as the formulation used. Determine the type and route of administration, and whether local or systemic delivery is preferred .

[0324] Pharmaceutical dosage forms of the compounds of the present invention may be immediate release, controlled release, sustained release, or targeted drug delivery systems. Commonly used dosage forms include, for example, solutions and suspensions, (Micro)emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, vaginal pessaries, implants, amorphous or crystalline powders, Depending on the route of administration used, for example, , syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks Special devices, such as a syringe, may be required for application or administration of the drug. Pharmaceutical dosage forms are often , consisting of the drug, excipients, and container / closure system. Or multiple excipients may be added to the compounds of the present invention to aid in drug manufacturing, stability, administration, and and to achieve a desired drug release profile. Therefore, the types of excipients added to the drug can be varied, e.g. It depends on various factors, such as the physical and chemical properties of the drug, the route of administration, and the manufacturing procedure. Pharmaceutically acceptable excipients are available in the art and are described in various pharmacopeias. For example, the United States Pharmacopoeia (USP), the Japanese Pharmacopoeia (JP), the European Pharmacopoeia Pharmacopoeia (EP), and British Pharmacopoeia (BP); the US Food and Drug Administration g.

[0325] Administration(www.fda.gov)Center for D Publications from the Center for Comprehensive Evaluation and Research (CEDR), e.g. For example, Inactive Ingredient Guide (1996), Ash and d Ash, Eds. (2002) Handbook of Pharmaceutic al Additives,Synapse Information Resources See, for example, Chem. Chem. Soc., Inc., Endicott, NY. The pharmaceutical formulations of the compounds can be prepared, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, or other processes. Tableting, suspension, extrusion, spray drying, micronization, emulsification, (nano / micro)encapsulation The composition may be prepared by any of the methods well known in the art, such as by encapsulation, encapsulation, or freeze-drying processes. As mentioned above, the compositions of the present invention can be used to process active molecules into preparations for pharmaceutical use. The composition may contain one or more physiologically acceptable inactive ingredients that facilitate the administration of the composition.

[0326] Suitable formulations depend on the desired route of administration. For intravenous injection, for example, the composition may be , for example, phosphate, histidine, or quercetin to adjust the formulation pH, as needed. Physiologically compatible buffers, including phosphates, and, for example, sodium chloride or dextran. It may be formulated in an aqueous solution using an isotonic agent such as sucrose. For administration, semi-solid, liquid formulations, or patches may be preferred, and in some cases, permeable formulations may be used. Such penetrants are generally known in the art. The compounds may be administered in liquid or solid dosage forms and in immediate or controlled / sustained release formulations. Suitable dosage forms for oral ingestion by a subject include tablets, pills, dragees, Hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emasculations Compounds also include, for example, cocoa butter or other glycerides. The active ingredient may also be formulated in rectal compositions such as suppositories or retention enemas containing conventional suppository bases.

[0327] The solid oral dosage form can be obtained using excipients, which can include fillers, disintegrants, binders, and the like. Mixing agents (dry and wet), dissolution retarders, lubricants, glidants, anti-adherents, cation exchangers These excipients may include resins, humectants, antioxidants, preservatives, colorants, and flavoring agents. The excipients may be of synthetic or natural origin. Examples of such excipients include cellulose derivatives. , citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate Sodium / Sodium, Mannitol, Polyethylene Glycol, Polyvinylpyrrolidone, Ke Acid salts, silicon dioxide, sodium benzoate, sorbitol, starch, stearin Acids or their salts, sugars (i.e., dextrose, sucrose, lactose, etc.), Mucilage, tragacanth mucilage, vegetable oils (hydrogenated), and waxes. and water may act as a granulation aid. In certain cases, for example, taste masking agents may be used. Coating tablets with a gastric acid-resistant film, a gastric acid-resistant film, or a release-retarding film is preferred. Natural and synthetic polymers in combination with colorants, sugars, and organic solvents or water are It is often used to coat tablets, resulting in sugar-coated capsules. If preferred over tablets, the drug powder, suspension, or solution may be packaged in a compatible hard or may be delivered in a soft shell capsule.

[0328] In one embodiment, the compounds of the present invention are administered in a skin patch, semi-solid, or liquid formulation, e.g., Gels, (micro)emulsions, ointments, solutions, (nano / micro)suspensions, or foams The drug may be administered locally, such as through the body. Penetration of the drug into the skin and underlying tissues may be achieved by, e.g. , use of penetration enhancers, water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants Appropriate selection and combination of lipophilic, hydrophilic, and amphiphilic excipients, including agents and emulsifiers This can be adjusted by pH adjustment, as well as the use of complexing agents. The following techniques may be used to modulate the penetration of the compounds of the present invention into the skin. For example, it is preferred in situations where local delivery with minimal systemic exposure is desired.

[0329] For administration by inhalation or nasal administration, the compounds for use according to the invention are , typically halocarbons derived from, for example, methane and ethane, carbon dioxide, or any Dissolved liquid from a pressurized pack or nebulizer with the use of a propellant such as any other suitable gas. It is conveniently delivered in the form of a liquid, suspension, emulsion, or semi-solid aerosol. For aerosols, hydrocarbons such as butane, isobutene, and pentane are useful. In the case of a pressurized aerosol, a suitable dosage unit will provide a valve to deliver a metered amount. For example, gelatin for use in an inhaler or insufflator can be determined by Capsules and cartridges of the compound may be formulated. These typically contain a powder of the compound. The mix contains a suitable powder base such as lactose or starch.

[0330] Compounds and compositions formulated for parenteral administration by injection are usually sterile. and presented in unit dosage form, e.g., ampoules, syringes, injection pens, or multi-dose containers. The compositions may be prepared as suspensions in oily or aqueous vehicles, the latter usually containing preservatives. The composition may take the form of a liquid, solution, or emulsion, and may contain buffering agents, tonicity adjusting agents, viscosity enhancing agents, interfacial agents, etc. Active agents, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and It may contain formulating agents such as preservatives. Depending on the injection site, the vehicle may be water, synthetic oils, or other suitable solvents. The lyophilized product or concentrate may contain vegetable oil, and / or organic co-solvents. In certain cases, such as those having a steroid or anti-inflammatory agent, parenteral formulations are reconstituted or diluted prior to administration. Depot formulations providing controlled or sustained release of the compounds of the invention include nano / microparticles, or may contain injectable suspensions of nano / micro or non-micronized crystals. Poly(lactic acid), Polymers such as poly(glycolic acid), or copolymers thereof, are well known in the art. In addition to other known depot delivery systems, these may act as controlled / sustained release matrices. The system may be presented in the form of an implant and a pump that requires an incision.

[0331] Suitable carriers for intravenous injection of the compounds of the present invention are well known in the art, and include, for example, For example, an aqueous solution containing a base such as sodium hydroxide to form an ionizable compound; Sucrose or sodium chloride as an isotonic agent, and buffering agents, such as phosphate or The buffers include those containing histidine. A cosolvent such as polyethylene glycol may be added. These aqueous systems are effective in dissolving the compounds of the invention and are suitable for systemic administration. The proportions of the components in the solution system can be adjusted to destroy the solubility and toxicity characteristics. Furthermore, the identity of the constituents may vary. Low-toxicity surfactants such as resolvates or poloxamers are used in combination with polyethylene glycol or or other cosolvents, biocompatible polymers such as polyvinylpyrrolidone, etc. may be added. Other sugars and polyols may be used in place of dextrose.

[0332] A therapeutically effective dose can be estimated initially using a variety of techniques known in the art. The initial dose used in drug testing may be based on the effective concentration established in cell culture assays. Dosage ranges appropriate for human subjects may be obtained, for example, from animal studies and cell culture assays. In certain embodiments, the compounds of the present disclosure may be determined using the data obtained. is formulated for oral administration. Compounds of the present disclosure in pharmaceutical formulations for oral administration An exemplary dose is about 0.5 to about 10 mg / kg of subject body weight. The pharmaceutical formulation may be administered at a dose of about 0.7 to about 5.0 mg / kg of body weight of a subject, or alternatively at a dose of about 1.0 A typical dosing regimen for oral administration includes: Administration of a pharmaceutical formulation for oral administration three times a week, twice a week, once a week, or daily.

[0333] An effective or therapeutically effective amount or dose of an agent, e.g., a compound of the present invention, is determined by measuring the amount of the agent in a subject. It refers to the amount of a drug or compound that results in improvement of symptoms or prolongation of survival in a patient. The potency and therapeutic efficacy can be measured, for example, by the LD50 (the dose lethal to 50% of the population) and Cell cultures were analyzed by determining the ED50 (the dose therapeutically effective in 50% of the population). Toxicity vs. therapeutic efficacy can be determined by standard pharmaceutical procedures in cultures or experimental animals. The dose ratio of LD50 to ED50 is the therapeutic index, and it can be expressed as the ratio LD50 / ED50. Agents that exhibit long therapeutic indices are preferred.

[0334] An effective or therapeutically effective amount may be determined by a researcher, veterinarian, physician, or other clinician. compounds or compounds that induce a biological or medical response in tissues, systems, animals, or humans The amount of pharmaceutical composition to be administered is particularly in the range of circulating doses that contain an ED50 with little or no toxicity. The dosage will vary depending on the dosage form used and / or the route of administration utilized. The exact formulation, route of administration, dosage, and interval between doses can vary within this range depending on the patient. The selection must be made according to methods known in the art, taking into account the specifics of the subject's condition. do not have.

[0335] Dosage and interval should be determined based on plasma levels of the active moiety that are sufficient to achieve the desired effect. That is, it can be individually adjusted to provide a minimum effective concentration (MEC). It varies from compound to compound but can be estimated, for example, from in vitro data and animal studies. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In the case of selective administration or uptake, the effective local concentration of a drug is not related to the plasma concentration. There may be cases where this is the case.

[0336] The amount of compound or composition administered will depend on the sex, age, and weight of the subject being treated. The severity of the affliction, the manner of administration, and the judgment of the prescribing physician may depend on various factors.

[0337] The compounds and compositions are optionally presented in one or more unit dosage forms containing the active ingredient. The formulation may be presented in a pack or dispenser device containing the formulation. The device may, for example, be enclosed in a metal or plastic foil, such as a blister pack or may contain glass and rubber stoppers such as those found in vials. The dispenser device may be accompanied by instructions for administration. Compositions containing formulated compounds of the invention may also be prepared, placed in an appropriate container, and packaged as directed. The drug may be labeled for the treatment of a specific condition.

[0338] These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in light of the disclosure herein. and specifically intended. [Example]

[0339] Synthesis of exemplary compounds Example 1: Preparation of Compound 1 6-Chloronicotinic acid tert-butyl ester [ka]

[0340] 6-Chloronicotinic acid (5.0 g, 6.37 mL) in tetrahydrofuran (50.0 mL) A solution of 4-dimethylaminopyridine (0.39 g, 0.64 mmol) and 4-dimethylaminopyridine (0.39 g, 0.64 mmol) Di-tert-butyl dicarbonate (10.41 g, 47.77 mmol) was added to The reaction mixture was stirred at reflux for 4 hours and concentrated. The residue was purified by flash chromatography. The compound was purified by distillation with petroleum ether / ethyl acetate=10 / 1 to give 6-chloronicotinic acid. tert-Butyl ester (5.5 g, 81.12% yield) was obtained as a yellow solid. LC-MS: m / z=214.0(M+H) + , retention time 1.83 min (Method A).

[0341] 6-Hydrazinylnicotinic acid tert-butyl ester [ka]

[0342] tert-Butyl 6-chloronicotinate (5.5 g, 25.82 mmol) of hydrazine hydrate (6.46 g, 129.11 mmol) , 85% in water) was added. The mixture was stirred at 100°C for 2 hours and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine and concentrated over sodium sulfate. The residue was triturated with petroleum ether, filtered and purified to give 6-hydrazinyl nicotine. tert-Butyl phosphate (5.0 g, 92.76% yield) was obtained as a yellow solid. S: m / z = 210.0 (M+H) + , retention time 1.19 min (Method A).

[0343] Ethyl (E)-3-(dimethylamino)-2-(p-tolyl)acrylate [ka]

[0344] Ethyl 2-(p-tolyl)acetate () in N,N-dimethylformamide (10.0 mL) A solution of 1.00 g (5.61 mmol) of N,N-dimethylformamide diethylacetate was added. Tar (3.34 g, 28.05 mmol, 3.73 mL) was added. The reaction mixture was stirred for 10 The mixture was stirred at 0°C for 3 hours and cooled to 0°C. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give (E)- Ethyl 3-(dimethylamino)-2-(p-tolyl)acrylate (1.1 g, 4.71 m mol, yield 84%). LC-MS: m / z = 234.0 [M+H] + , retention time 2.064 min (Method B). The product was sufficiently pure to be used directly in the next step.

[0345] 6-(5-hydroxy-4-(p-tolyl)-1H-pyrazol-1-yl)nicotine tert-butyl acetate [ka]

[0346] (E)-3-(dimethylamino)-2-(p-tolyl) in ethanol (10.0 mL) ) Ethyl acrylate (50.00 mg, 2.14 mmol) and 6-hydrazinyl nicotinamide To a solution of tert-butyl phosphate (448.4 mg, 2.14 mmol), p-toluene Sulfonic acid monohydrate (40 mg, 0.21 mmol) was added. The reaction was heated at 90° C. for 16 h. The mixture was stirred for 1 hour and cooled to allow the solid to precipitate. The crude solid was purified by flash chromatography (Di Purification with chloromethane / ethyl acetate=10 / 1 gave 6-(5-hydroxy-4- (p-Tolyl)-1H-pyrazol-1-yl)nicotinic acid tert-butyl ester (393m g, 1.11 mmol, 52% yield) as a yellow solid. LC-MS: m / z=35 2.0[M+H] + , retention time 6.78 min (Method A). 1 H NMR (400 MHz, DM SO-d6)δ12.86(s,1H),8.92(s,1H),8.80-8.15( m,3H),7.78(s,2H),7.17(d,J=8.0Hz,2H),2.29 (s,3H),1.58(s,9H).

[0347] Example 2: Preparation of Compound 2 (E)-2-(4-bromophenyl)-3-(dimethylamino)acrylate ethyl ester [ka]

[0348] 2-(4-Bromophenyl)acetic acid in N,N-dimethylformamide (20.0 mL) A solution of ethyl acetate (1.01 g, 4.15 mmol) in N,N-dimethylformamide was Cetyl acetal (2.47 g, 20.7 mmol) was added, and the mixture was heated at 100°C for 16 hours. The mixture was stirred for a period of time and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give (E)-2-(4-bromo-2-methylpropional). ethyl 3-(dimethylamino)-4-(chlorophenyl)acrylate (980 mg, 3.32 mm ol, 80% yield) was obtained as a yellow oil. LC-MS: m / z=298.0 [M+H] + , retention time 1.710 min (Method B). The product was sufficiently pure to be used directly in the next step. Used.

[0349] 6-(4-(4-bromophenyl)-5-hydroxy-1H-pyrazol-1-yl) tert-Butyl nicotinate [ka]

[0350] (E)-2-(4-bromophenyl)-3-(dimethylamino)methyl Ethyl (amino)acrylate (300.0 mg, 1.01 mmol) and 6-hydrazine To a solution of tert-butyl nicotinate (210.5 mg, 1.01 mmol), p- Toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) was added. The mixture was heated to 80°C. The mixture was stirred at rt for 16 h and cooled to precipitate a solid. The crude product was purified by flash chromatography. The compound was purified by filtration (dichloromethane / methanol = 100 / 3) to give 6-(4-(4-bromo-2-methyl-2-propanol). (bromophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid tert- Butyl (286 mg, 0.69 mmol, 68% yield) was obtained as a yellow solid. S: m / z = 416.0 (M+H) + , retention time 6.76 minutes (Method A). 1 HNMR(4 00MHz,DMSO-d6)δ13.13(br,1H),8.91(s,1H),8 .80-8.25(m,3H),7.89(br,2H),7.53(d,J=8.0H z,2H), 1.58(s,9H).

[0351] Example 3: Preparation of Compound 3 6-(4-(4-bromophenyl)-5-hydroxy-1H-pyrazol-1-yl) Nicotinic acid [ka]

[0352] 6-(4-(4-bromophenyl)-5-hydroxybenzoate) in dichloromethane (10.0 mL) tert-Butyl nicotinate (80.00mg, 0 To a solution of 0.19 mmol of acetic acid was added trifluoroacetic acid (0.5 mL). The mixture was heated at room temperature. The mixture was stirred at rt overnight and concentrated. The residue was triturated with ethyl acetate, filtered, and the 6-(4-(4-bromo- (bromophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (67mg , 0.18 mmol, 97% yield) was obtained as a yellow solid. LC-MS: m / z=360 .0(M+H) + , retention time 4.995 minutes (Method A). 1 H NMR (400 MHz, DM SO-d6)δ13.29(br,2H),8.96(s,1H),8.51-8.44 (m,3H),7.89(d,J=7.5Hz,2H),7.53(d,J=8.5Hz ,2H).

[0353] Example 4: Preparation of Compound 4 Ethyl (E)-3-(dimethylamino)-2-(4-chlorophenyl)acrylate [ka]

[0354] 2-(4-chlorophenyl)acetic acid in N,N-dimethylformamide (25.0 mL) A solution of ethyl acetate (5.0 g, 25.25 mmol) in N,N-dimethylformamide was Cetyl acetal (12.0 g, 101.01 mmol) was added. The mixture was heated at 100°C for 1 hour. Stir overnight and cool to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. Organic layer was washed with brine, dried over sodium sulfate and concentrated to give (E)-3-(dimethylamino)methylpropional. Ethyl (4-chlorophenyl)-2-(4-aminophenyl)acrylate (3.5 g, 14.04 mm ol, yield 55.60%) was obtained as a colorless oil. LC-MS: m / z = 254.1 [M +H] + , retention time 2.030 min (Method A). The product was sufficiently pure to proceed to the next step. Used directly.

[0355] 6-(4-(4-chlorophenyl)-5-hydroxy-1H-pyrazol-1-yl) tert-Butyl nicotinate [ka]

[0356] (E)-3-(dimethylamino)-2-(4-chlorophenyl ... Ethyl (phenyl)acrylate (0.83 mg, 3.95 mmol) and 6-hydrazinium A solution of tert-butyl trunicotinate (1.00 g, 3.95 mmol) was added to p-toluenesulfonate. To the mixture was added benzophenone sulfonic acid monohydrate (150 mg, 0.79 mmol). The mixture was refluxed for 1 The mixture was stirred for 2 hours and cooled to precipitate a solid, which was filtered, washed with ethanol, and dried. 6-(4-(4-chlorophenyl)-5-hydroxy-1H-pyrazole-1-yl) tert-Butyl nicotinate (800.0 mg, 2.16 mmol, yield 54.79 %) was obtained as a white solid. LC-MS: m / z=372.1 (M+H) + , retention time 6 .645 minutes (Method A). 1 HNMR (400 MHz, DMSO-d6) δ 9.04-8. 86(m,1H),8.62-8.33(m,3H),7.95(d,J=7.2Hz, 2H), 7.41(d,J=8.6Hz,2H),1.58(s,9H).

[0357] Example 5: Preparation of Compound 5 6-(4-(4-chlorophenyl)-5-hydroxy-1H-pyrazol-1-yl) Nicotinic acid [ka]

[0358] 6-(4-(4-chlorophenyl)-5-hydroxybenzoate) in dichloromethane (10.0 mL) tert-Butyl nicotinate (200.00 mg, To a solution of 4-(4-hydroxybenzoic acid) (0.54 mmol), trifluoroacetic acid (5.0 mL) was added. The mixture was stirred at 0° C. for 2 hours and concentrated. The residue was triturated with ethyl acetate, filtered, and purified to give 6-(4-(4 -chlorophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (74 0.0 mg, 0.24 mmol, 43.52% yield) was obtained as a white solid. LC-MS: m / z=316.0(M+H) + , retention time 4.718 min (Method A). 1 HNMR (40 0MHz,DMSO-d6)δ13.23(s,1H),8.97(s,1H),8.6 7-8.47(m,3H),8.04-7.97(m,2H),7.41(d,J=3. 8Hz,2H).

[0359] Example 6: Preparation of Compound 6 Ethyl (E)-3-(dimethylamino)-2-(4-fluorophenyl)acrylate [ka]

[0360] 2-(4-Fluorophenyl)acetic acid in N,N-dimethylformamide (5.0 mL) A solution of ethyl acetate (2.0 g, 10.98 mmol) in N,N-dimethylformamide was Cetyl acetal (8.07 g, 54.8 mmol) was added, and the mixture was stirred at 100°C overnight. The mixture was stirred and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was Wash with brine, dry over sodium sulfate and concentrate to give (E)-3-(dimethylamino)- Ethyl (amino)-2-(4-fluorophenyl)acrylate (2.0 g, 8.45 mmol , 77% yield) was obtained as a colorless oil. LC-MS: m / z=238.0 [M+H] + , Retention time 1.89 min (Method B). The product was sufficiently pure to be used directly in the next step. .

[0361] 6-(4-(4-fluorophenyl)-5-hydroxy-1H-pyrazol-1-yl ) tert-butyl nicotinate [ka]

[0362] (E)-3-(dimethylamino)-2-(4-fluorophenyl)-2-(4-methyl-2-propanol) in ethanol (5.0 mL) Ethyl (phenyl)acrylate (567.0 mg, 2.39 mmol) and 6-hydrazinium To a solution of tert-butyl nicotinate (500.0 mg, 2.39 mmol), p- Toluenesulfonic acid monohydrate (91.2 mg, 0.48 mmol) was added. The mixture was stirred at reflux for 12 hours, cooled, and a solid precipitated. The solid was filtered and washed with ethanol. , dried, and 6-(4-(4-fluorophenyl)-5-hydroxy-1H-pyrazoline tert-Butyl (1-phenyl)nicotinate (350.0 mg, 0.98 mmol, yield 41%) as a white solid. LC-MS: m / z=356.0 (M+H) + , when held for 6.23 minutes (method A). 1 HNMR (400MHz, DMSO-d6) δ 8.91 (s ,1H),8.41(s,3H),7.93(s,2H),7.19(s,2H),1. 57(s,9H).

[0363] Example 7: Preparation of Compound 7 6-(4-(4-fluorophenyl)-5-hydroxy-1H-pyrazol-1-yl ) Nicotinic acid [ka]

[0364] 6-(4-(4-fluorophenyl)-5-hydroxybenzoate) in dichloromethane (5.0 mL) tert-Butyl nicotinate (150.0 mg, 0 To a solution of 1.42 mmol of acetic acid (2.0 mL) was added trifluoroacetic acid (2.0 mL). The mixture was stirred at RT for 2 h and concentrated. The residue was triturated with ethyl acetate, filtered, and the resulting mixture was 6-(4-(4- Fluorophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (10 3.2 mg, 0.34 mmol, 81% yield) was obtained as a white solid. LC-MS: m / z=300.0(M+H) + , retention time 4.23 min (Method A). 1 HNMR (400MH z,DMSO-d6)δ8.95(s,1H),8.45(s,3H),7.94(s, 2H), 7.20-7.17(m,2H).

[0365] Example 8: Preparation of Compound 8 2-(4-cyano-2-methylphenyl)acetic acid ethyl ester [ka]

[0366] 4-Bromo-3-methylbenzonitrile (5.0 g, 25.6 mmol), dimalonate Ethyl (27 g, 168 mmol), tris(dibenzylideneacetone)dipalladium ( 0) (0.24 g, 0.26 mmol), tri-tert-butylphosphine tetrafluoro oroborate (0.08 g, 0.26 mmol), potassium carbonate (5.3 g, 38.4 m A mixture of 16 mol) and potassium bicarbonate (3.84 g, 38.4 mmol) was The mixture was stirred for 12 hours at 0° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was dissolved in ethanol. Purification by cross-linking chromatography (petroleum ether / ethyl acetate = 1 / 1) gave 2 Ethyl 4-cyano-2-methylphenylacetate (2.0 g, 31.7% yield) was obtained as a yellow LC-MS: m / z 204.1 (M+H) + .

[0367] (E)-2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylic acid Ethyl acetate [ka]

[0368] 2-(4-cyano-2-methyl-2-propanol) in N,N-dimethylformamide (10.0 mL) A solution of ethyl (phenyl)acetate (1.0 g, 5.0 mmol) in N,N-dimethylformamide was added. Mitodiethyl acetal (2.9 g, 25.0 mmol) was added. The mixture was heated at 100°C. Stirred overnight and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography. Purification by chromatography (dichloromethane / methanol=98 / 2) gave (E)- 2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylate ethyl ester ( 600 mg (47.2% yield) was obtained as a yellow oil. LC-MS: m / z 259.0 (M+H) + .

[0369] 6-Chloronicotinic acid tert-butyl ester [ka]

[0370] 6-chloronicotinic acid (5.0 g, 6.37 mmol) in THF (50.0 mL) and 4-dimethylaminopyridine (0.39 g, 0.64 mmol), rt-Butyl dicarbonate (10.41 g, 47.77 mmol) was added to the reaction mixture. The mixture was refluxed for 4 hours and concentrated. The residue was purified by flash chromatography (petroleum ether Purification was carried out using a solvent mixture containing ethanol / ethyl acetate (10 / 1) to obtain tert-butyl 6-chloronicotinate. (5.5 g, 81.12% yield) was obtained as a yellow solid. LC-MS: m / z 214. 0(M+H) + .

[0371] 6-Hydrazinylnicotinic acid tert-butyl ester [ka]

[0372] tert-Butyl 6-chloronicotinate (5.5 g, 25.82 mmol) of hydrazine hydrate (6.46 g, 129.11 mmol) , 85% in water) was added. The mixture was stirred at 100°C for 2 hours and concentrated. The residue was dissolved in ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and The residue was triturated with petroleum ether, filtered and purified to give 6-hydrazinylnicotinic acid tert-butyl ester. t-Butyl ester (5.0 g, 92.76% yield) was obtained as a yellow solid. LC-MS: m / z 210.0(M+H) + .

[0373] 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazole (1-yl)nicotinic acid tert-butyl ester [ka]

[0374] (E)-2-(4-cyano-2-methylphenyl)- in ethanol (10.0 mL) Ethyl 3-(dimethylamino)acrylate (260 mg, 1.0 mmol) and 6-hydroxybenzoate To a solution of tert-butyl nicotinate (200 mg, 1.0 mmol), 4- Methylbenzenesulfonic acid (34.4 mg, 0.2 mmol) was added. The mixture was refluxed. The mixture was stirred at room temperature for 12 hours and cooled to precipitate a solid. The solid was filtered, washed with ethanol, and dried. After drying, 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyridinyl (190 mg, 50% yield) tert-butyl nicotinate (1-isothiazol-1-yl) was obtained as a white solid LC-MS: m / z 377.0 (M+H) + .

[0375] Example 9: Preparation of Compound 9 Ethyl-3-acetoxy-2-(4-cyanophenyl)but-2-enoate [ka]

[0376] 2-(4-cyanophenyl)- ... ) ethyl acetate (3.50 g, 18.50 mmol) and LHMDS (28.00 mL, 27.75 mmol) was added dropwise over 20 minutes. The reaction was warmed to 0°C and The reaction was then cooled again to -30°C and the solution was diluted with THF (8 mL A solution of acetyl chloride (2.18 g, 27.75 mmol) in HCl was added dropwise over 15 min. The reaction was gradually warmed to room temperature and stirred for 4 hours. The reaction was complete by TLC. After stirring, the mixture was quenched with cold aqueous NH4Cl (50 mL) and added to EtOAc (3× The combined organic layers were dried over anhydrous NaSO (30 g) and extracted with 100 ml of ethyl acetate (80 ml). The residue was purified by silica column chromatography (EA:Hex= 1:50 to 1:5) to give the desired product (1.9 g) as a yellow oil. .1 H NMR δ ppm(300MHz,CDCl3)7.68(dd,J=6.6 ,1.8Hz,2H),7.41(dd,J=6.6,1.8Hz,2H),4.11- 4.18(q,J=6.9Hz,2H),2.25(s,3H),1.88(s,3H) ,1.20(t,J=6.9Hz,3H).

[0377] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazole -1-yl)nicotinic acid [ka]

[0378] Ethyl 2-(4-cyanophenyl)-3-oxobutanoate ( 0.30 g, 1.38 mmol) was added to a mixture of 4-hydrazinylbenzoic acid (1.06 g, 6.91 mmol) was added. The mixture was stirred at 100°C overnight. The reaction was monitored by TLC. After completion, the reaction was quenched with water (20 mL), causing a large amount of solid to precipitate. The solid was dissolved in TEA (5 eq), water (20 mL), and MeOH (20 mL). The solution was extracted with EtOAc (3 x 10 mL) and the aqueous phase was adjusted to pH 3 with diluted HCl solution. A large amount of solid precipitated. The solid was collected by filtration and dried to give the desired product ( 128 mg) was obtained as a yellow solid. LC-MS (ESI+): m / z 321 (M+H ) + ;HPLC purity is 97.3%; 1 H NMR (300 MHz, DMSO-d6) δ ppm 13.25(brs,2H),8.95(d,J=1.5Hz,1H),8. 56(d,J=8.7Hz,1H),8.41(dd,J=8.7Hz,1H),7.8 9(d,J=8.1Hz,2H),7.81(d,J=8.1Hz,2H),2.51( s,3H).

[0379] Example 10: Preparation of Compound 10 6-Hydrazinylnicotinic acid tert-butyl ester [ka]

[0380] tert-Butyl 6-chloronicotinate (0.2 mL) in 1,4-dioxane (10 mL) hydrazine (0.35g, 5.62mmol) was added to a solution of 100mg of ethanol (0.0g, 0.94mmol). The mixture was stirred at 80° C. overnight. After the reaction was complete by TLC analysis, The product was concentrated in vacuo. The residue was purified by preparative HPLC to give 180 mg of the title compound (1 80 mg) was obtained as an oil. 1 H NMR (300 MHz, CDCl3) δ ppm 8 .71(d,J=1.8Hz,1H),8.01(dd,J=8.1,1.8Hz,1H ),6.70(d,J=8.7Hz,1H),6.24(brs,1H),3.90(b rs,2H),1.60(s,9H).

[0381] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazole (1-yl)nicotinic acid tert-butyl ester [ka]

[0382] The compound was synthesized by 6-(4-(4 -cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nico LC-MS (ESI-): m / z 375 (MH ) - ;HPLC purity 96.3%; 1 H NMR (300 MHz, CDCl3) δ p pm 13.10(brs,1H),8.88(d,J=2.1Hz,1H),8.42 (dd,J=8.7,2.1Hz,1H),7.96(d,J=8.7Hz,1H),7 .69(s,4H),2.46(s,3H),1.63(s,9H).

[0383] Example 11: Preparation of Compound 11 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazole (1-yl)nicotinic acid methyl ester [ka]

[0384] The compound was converted to 6-(4-(4-cyanopropyl)-2-methyl-2-propanol using methyl 6-hydrazinylnicotinate. Preparation of (phenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid It was synthesized according to the manufacturer's procedure. LC-MS: m / z = 335 (M+H) + ;1H NMR( 300MHz,DMSO-d6)δ ppm 13.11(s,1H),8.95(d, J=1.6Hz,1H),8.58(d,J=8.8Hz,1H),8.43(dd,J =7.0,2.3Hz,1H),7.90(dd,J=17.6,8.3Hz,2H), 7.79(dd,J=14.5,8.4Hz,2H),3.90(s,3H),2.48 (s,3H).

[0385] Example 12: Preparation of Compound 12 Di-tert-butyl 2-(4-cyano-2,5-difluorophenyl)malonate [ka]

[0386] Under a nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil) in anhydrous DMF (100 mL) A solution of di-tert-butyl malonate (5.09 g, 127.31 mmol) was added to the solution at 0°C. Cetyl (8.26 g, 31.19 mmol) was added dropwise over 15 minutes. After stirring at 0°C for 15 minutes, 2,4,5-trifluorobenzonitrile (5.00 g, The mixture was stirred at 0°C for 15 minutes, followed by The mixture was stirred at 60°C overnight. After the reaction was complete by TLC analysis, the mixture was diluted with saturated NH The mixture was quenched with 1H2O (800 mL) and extracted with EtOAc (200 mL x 3). The organic phase was washed with water (100 mL × 2) and dried over anhydrous Na2SO4 (50 g). The resulting mixture was filtered and concentrated in vacuo to give 12.60 g of the crude title compound as a yellow oil. Used in the next step without further purification. LC-MS (ESI+): m / z 23 9(M-(t-Bu)2) + .

[0387] 2-(4-cyano-2,5-difluorophenyl)acetic acid [ka]

[0388] 2-(4-cyano-2,5-difluorophenyl)malonic acid dihydrate in DCM (35 mL) To a solution of 12.30 g (34.80 mmol) of 1,4-tert-butyl ether (35 mL) was added TFA ( ) was added in one portion. The reaction was stirred at room temperature overnight. After the reaction was complete by TLC analysis, The mixture was concentrated in vacuo. Toluene (50 mL) was added to the residue, stirred, and concentrated again. After drying, 6.07 g of the crude title compound was obtained as a white solid, which could be further purified. This was used in the next step without further purification. LC-MS (ESI+): m / z 216 (M+H+H2O) + .

[0389] 2-(4-cyano-2,5-difluorophenyl)acetic acid methyl ester [ka]

[0390] 2-(4-cyano-2,5-difluorophenyl)acetic acid ( A solution of 4.00 g (20.29 mmol) of HCl was added to 4.0 mL of SOCl2 at room temperature for 5 min. The reaction was stirred at 70° C. for 3 hours. The reaction was complete by TLC analysis. After that, 80% of the reaction solvent was removed by evaporation. The residue was quenched with ice water (180 mL). The combined organic phase was washed with anhydrous Na2SO4 (50 g), filtered and concentrated in vacuo to give 4.30 g of the crude title compound in a yellow solid. This was obtained as an oil which was used in the next step without further purification. +): m / z 230 (M+H+HO) + .

[0391] (E)-2-(4-cyano-2,5-difluorophenyl)-3-(dimethylamino) Methyl acrylate [ka]

[0392] The compound was purified using methyl 2-(4-cyano-2,5-difluorophenyl)acetate, (E)-2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylic acid The compound was synthesized according to the procedure for the preparation of ethyl methyl ester. LC-MS (ESI+): m / z 267 (M+H ) + .

[0393] 6-(4-(4-cyano-2,5-difluorophenyl)-5-hydroxy-1H-pyridinyl (Isopropyl-1-yl)nicotinic acid [ka]

[0394] The compound was prepared by the procedure of (E)-2-(4-cyano-2,5-difluorophenyl)-3-(dimethylamino)phenyl. 6-(4-(4-cyano-2-methylphenyl)methyl acrylate was used to )-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid according to the procedure LC-MS(ESI-):m / z 341(MH) - , HPLC purity is 95.4 %, 1 H NMR(300MHz,DMSO-d6)δ ppm 13.41(brs, 1H),8.96(d,J=2.1Hz,1H),8.58-8.42(m,3H),8 .31(d,J=3.0Hz,1H),7.93(dd,J=10.8,5.4Hz,1 H).

[0395] Example 13: Preparation of Compound 13 2-(3-fluoro-4-hydroxyphenyl)acetic acid methyl ester [ka]

[0396] 2-(3-fluoro-4-hydroxyphenyl)acetic acid (2. To a mixture of 1000 mg of HCl (11.76 mmol), concentrated H2SO4 (0.2 mL) was added. The mixture was stirred at 65° C. for 2 hours. After the reaction was complete by TLC, the mixture was washed with water (40 mL The mixture was quenched with HCl (2×50 mL) and extracted with EtOAc (3×50 mL). The combined organic phase was dried and Filtration and direct concentration gave the title product (2.49 g) as an oil. 1 H NMR(30 0MHz, CDCl3)δ ppm 7.03(d,J=1.5Hz,1H),6.91 (dd,J=3.9,1.5Hz,2H),3.70(s,3H),3.54(s,2H ).

[0397] 2-(3-fluoro-4-(((trifluoromethyl)sulfonyl)oxy)phenyl ) Methyl acetate [ka]

[0398] 2-(3-fluoro-4-hydroxyphenyl)-2-(4-hydroxyphenyl)-2-(2-(3-fluoro-4-hydroxyphenyl)-2-(2 ... To a mixture of methyl acetone (2.49 g, 13.50 mmol) and trifluoromethyl acetone (2.49 g, 13.50 mmol) was added at 0°C. Tanesulfonic anhydride (5.71 g, 20.25 mmol) was added dropwise over 15 minutes. TEA (4.10 g, 40.50 mmol) was added to the reaction over a period of 10 minutes. The reaction was stirred at 0° C. for 4 hours. After the reaction was complete by TLC, the mixture The reaction mixture was quenched with aqueous NaHCO3 (30 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 (50 g), filtered and concentrated in vacuo. The residue was purified by silica column chromatography (EA:n-Hex=1:20). This gave the desired product (2.18 g) as a yellow oil. 1H NMR (300 MHz) ,CDCl3)δ ppm 7.30(d,J=8.1Hz,1H),7.24(dd, J=3.3,1.11Hz,1H),7.13(d,J=8.1Hz,1H),3.73 (s,3H),3.65(s,2H).

[0399] 2-(4-cyano-3-fluorophenyl)acetic acid methyl ester [ka]

[0400] 2-(3-fluoro-4-((trifluoromethyl)-2-(2-chloro-2-methyl-4-oxo ... (Fluoromethyl)sulfonyl)oxy)phenyl)methyl acetate (2.18g, 6.90mm ol), Zn(CN)2 (0.49 g, 4.14 mmol) and Pd(PP h3) 4 (0.80 g, 0.69 mmol) was added. The reaction was stirred at 80 °C for 4 h. After the reaction was complete by TLC, the mixture was quenched with water (50 mL) and EtOAc was added. The combined organic layers were washed with water (2×20 mL) and extracted with anhydrous N The residue was dried over a2SO4 (50 g), filtered and concentrated in vacuo. Purify by chromatography (EA:Hex=1:40 to 1:8) to obtain the desired product. The product (1.27 g) was obtained as a yellow oil. 1 H NMR (300 MHz, CDCl3) δ ppm 7.59(t,J=7.5Hz,1H),7.20(d,J=8.7Hz,2 H), 3.73(s,3H), 3.70(s,2H).

[0401] (E)-2-(4-cyano-3-fluorophenyl)-3-(dimethylamino)acryl Methyl phosphate [ka]

[0402] The compound was prepared by the reaction of (E) with methyl 2-(4-cyano-3-fluorophenyl)acetate. Ethyl 2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylate It was synthesized according to the preparation procedure of LC-MS (ESI+): m / z 249 (M+H) + .

[0403] 6-(4-(4-cyano-3-fluorophenyl)-5-hydroxy-1H-pyrazoline (1-yl)nicotinic acid [ka]

[0404] The compound was prepared by the procedure of (E)-2-(4-cyano-3-fluorophenyl)-3-(dimethylamino)-2-methylpropional. 6-(4-(4-cyano-2-methylphenyl)-5-methyl-2-propanol)-4-methyl-2-propanol-2-one was prepared using methyl acrylate. -hydroxy-1H-pyrazol-1-yl)nicotinic acid was synthesized according to the procedure for the preparation of 1H-hydroxy-1H-pyrazol-1-ylnicotinic acid. LC-MS(ESI-):m / z 323(M−H) - ; 1 H-NMR (300 MHz, DMSO-d6)δ ppm 13.32(brs,1H),8.77(d,J=1.2 Hz,1H),8.55(s,1H),8.34(d,J=8.4Hz,1H),8.2 6(dd,J=8.4,2.1Hz,1H),7.88(d,J=12.3Hz,1H) ,7.78(d,J=8.1Hz,1H),7.65(t,J=7.5Hz,1H).

[0405] Example 14: Preparation of Compound 14 5-Fluoro-6-hydrazinyl nicotinic acid [ka]

[0406] 6-Chloro-5-fluoronicotinic acid (0.46 g, 2.59 mL) in THF (22 mL) To a solution of 0.81 g (12.95 mmol), N2H4H2O (0.81 g, 12.95 mmol) was added over 1 min. The mixture was stirred at 65° C. overnight, after which a large amount of solid precipitated. The suspension was filtered and the solid was slurried in MeOH (3 mL) for 1 h. After filtration, 440 mg of the desired product was obtained as a white solid. LC-MS (ESI+): m / z 172( M+H) + .

[0407] 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl) -5-Fluoronicotinic acid [ka]

[0408] The compound was prepared by subjecting 5-fluoro-6-hydrazinyl nicotinic acid and (E)-2-(4-cyano-2-methyl-2-propanol)-2-one to acetone synthesis. 6-(4-(4-phenyl)-3-(dimethylamino) methyl acrylate was used to Cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid LC-MS (ESI+): m / z 325 (M+H) + ; 1 H-NMR(300MHz,DMSO-d6)δ ppm 8.78(s,1H) ,8.08(d,J=9.9Hz,1H),7.90(d,J=8.4Hz,2H),7 .84(s,1H),7.46(d,J=8.4Hz,2H),7.12(brs,2H ).

[0409] Example 15: Preparation of Compound 15 2-(4-chlorophenyl)-3-oxobutanoic acid methyl ester [ka]

[0410] Methyl 2-(4-chlorophenyl)acetate in anhydrous THF (50 mL) under nitrogen atmosphere A solution of (1.00 g, 5.41 mmol) was added to LHMDS (8.1 mL, 8. 11 mmol) was added dropwise over 10 min. The resulting mixture was heated at -40 °C for 1 After stirring for 1 hour, 1-(1H-imidazol-1-yl)ethan-1-one (0.89 g (8.11 mmol) was added portionwise over 10 minutes. After the addition, the mixture was allowed to warm to room temperature. After the reaction was complete as indicated by TLC analysis, the residue was dissolved in water ( The mixture was diluted with 50 mL of ethyl acetate and extracted with 50 mL of ethyl acetate. The desired product (1.6 g) was obtained by drying over 2SO4 (30 g), filtering, and concentrating to dryness to give the desired product (1.6 g) as an oil. LC-MS (ESI+): m / z 249 (M+Na) + .

[0411] 6-(4-(4-chlorophenyl)-5-hydroxy-1H-pyrazol-1-yl) Nicotinic acid [ka]

[0412] The compound was converted to 6- (4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazole-1- LC-MS (ESI+): m / z 33 0(M+H) + ; 1 H-NMR(300MHz,DMSO-d6)δ ppm 12.7 7-13.27(m,2H),8.95(d,J=1.5Hz,1H),8.55(br s,1H),8.41(dd,J=9.0Hz,J=2.1Hz,1H),7.66(d ,J=8.4Hz,2H),7.44(d,J=8.4Hz,2H),2.42(s,3 H).

[0413] Example 16: Preparation of Compound 16 2-(4-(benzyloxy)-3-methylphenyl)acetic acid methyl ester [ka]

[0414] Methyl 2-(4-hydroxy-3-methylphenyl)acetate (3 To a solution of 1000 mg, 1.70 mmol of benzyl bromide (292 mg, 1.70 mmol) ) and Cs2CO3 (1.66 g, 5.10 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete by TLC analysis, the mixture was quenched with water (50 mL). The combined organic layer was washed with anhydrous Na2SO4 ( The mixture was dried over 300 ml of ethyl acetate, filtered and concentrated in vacuo. The residue was purified by silica column chromatography. The product was purified by filtration (PE: EtOAc = 100:1 to 50:1) to give 498 mg of the title compound. The compound was obtained. 1 H NMR(300MHz,CDCl3)δ ppm 7.29-7. 45(m,5H),7.03-7.08(m,2H),6.82(d,J=8.1Hz, 1H),5.06(s,2H),3.68(s,3H),3.54(s,2H),2.2 7(s,3H).

[0415] (Z)-2-(4-(benzyloxy)-3-methylphenyl)-3-(dimethylamino) Methyl acrylate [ka]

[0416] The compound was synthesized using methyl 2-(4-(benzyloxy)-3-methylphenyl)acetate. (E)-2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylate The compound was synthesized according to the procedure for the preparation of ethyl benzoate. LC-MS (ESI+): m / z 326 (M +H + ).

[0417] 6-(4-(4-(benzyloxy)-3-methylphenyl)-5-hydroxy-1H -pyrazol-1-yl)nicotinic acid [ka]

[0418] The compound was (Z)-2-(4-(benzyloxy)-3-methylphenyl)-3-(diphenyl)-2-methyl-4-(4-benzyloxy)-3-methylphenyl. 6-(4-(4-cyano-2-methylphenyl)methylamino)acrylate was used to Preparation of (5-hydroxy-1H-pyrazol-1-yl)nicotinic acid according to the procedure Synthesized. LC-MS(ESI+):m / z 402(M+H + ).

[0419] 6-(5-hydroxy-4-(4-hydroxy-3-methylphenyl)-1H-pyrazoline (1-yl)nicotinic acid [ka]

[0420] 6-(4-(4-benzyloxy)-3-methylphenyl)-2 ... (1H-pyrazol-1-yl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (60 mg, 0.12 A solution of 10 mmol) and Pd / C (10 mg) was heated under a hydrogen atmosphere from a balloon for 7 h. After the reaction was complete as indicated by TLC analysis, the suspension was poured onto a celite pad. The mixture was filtered through a filter cake and the filter cake was washed with MeOH (5 mL). Concentration and purification by preparative HPLC gave 9 mg of the title compound as a solid. S(ESI-): m / z 310(MH - ), 1 H NMR (300 MHz, CD3O D)δ ppm 8.94(s,1H),8.45(d,J=8.7Hz,1H),8. 11(d,J=8.7Hz,1H),7.90(s,1H),7.48(s,1H),7 .41(d,J=8.7Hz,1H),6.75(s,1H),6.65(d,J=6. 9Hz,1H),2.22(s,3H).

[0421] Example 17: Preparation of Compound 17 (Z)-2-(6-chloropyridin-3-yl)-3-(dimethylamino)acrylic acid ethyl [ka]

[0422] The compound was converted to (E)-2 using ethyl 2-(6-chloropyridin-3-yl)acetate. Preparation of ethyl 4-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylate It was synthesized according to the manufacturer's procedure. LC-MS (ESI+): m / z 241 (M+H + ), 1 H NMR(300MHz,CDCl3)ppm8.18(d,J=2.4Hz,1H),7 .66(s,1H),7.51(dd,J=2.4,8.1Hz,1H),7.26(d ,J=8.4Hz,1H),3.64(s,3H),2.75(s,6H).

[0423] 6-(4-(6-chloropyridin-3-yl)-5-hydroxy-1H-pyrazole- 1-yl)nicotinic acid [ka]

[0424] The compound was prepared as follows: (Z)-2-(6-chloropyridin-3-yl)-3-(dimethylamino) Ethyl acrylate was used to prepare 6-(4-(4-cyano-2-methylphenyl)-5-hydroxybenzoates. It was synthesized according to the procedure for the preparation of (hydroxy-1H-pyrazol-1-yl)nicotinic acid. -MS(ESI+): m / z 317 (M+H + ), 1 H NMR (300 MHz, DMS O-d6)δ13.44(brs,2H),8.94(d,J=16.8Hz,2H), 8.67(s,1H),8.55(s,1H),8.44-8.48(m,1H),8. 38(d,J=7.8Hz,1H),7.51(d,J=8.4Hz,1H).

[0425] Example 18: Preparation of Compound 18 6-Hydrazinyl-4-methylnicotinic acid [ka]

[0426] 6-Fluoro-4-methylnicotinic acid (0.50 g, 3.23 mL) in THF (50 ml) To a solution of 1.00 mmol of hydrazine (2.00 g, 32.26 mmol) was added hydrazine (2.00 g, 32.26 mmol). The mixture was stirred at 66° C. for 2 hours. After the reaction was complete as shown by LC-MS, The mixture was diluted with ethanol (6 mL) to precipitate a large amount of solid. After filtration, 725 mg of The desired product was obtained. LC-MS (ESI+): m / z 168 (M+H + ), 1 HNM R(300MHz,DMSO-d6)δ8.44(s,1H),7.56(brs,1H ),6.43(s,1H),5.90(brs,2H),2.44(s,3H)

[0427] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazole -1-yl)-4-methylnicotinic acid [ka]

[0428] 6-hydrazinyl-4-methylnicotinic acid (0.30 g, 1.8 mL) in acetic acid (20 mL) 0 mmol) was added to a solution of ethyl 2-(4-cyanophenyl)-3-oxobutanoate (0. 43 g, 1.98 mmol) was added. The reaction was stirred at 100° C. overnight. LC-MS analysis After the reaction was complete, as indicated by precipitation, the mixture was cooled to room temperature and a large amount of solid precipitated. After filtration, the filter cake was further purified by preparative HPLC to give 36 mg of the desired product. The product was obtained. LC-MS (ESI+): m / z 335 (M+H + ), 1 H-NMR(3 00MHz,DMSO-d6)δ12.97-13.21(brs,2H),8.87( s,1H),8.45(brs,1H),8.01(d,J=8.1Hz,2H),7. 82(d,J=8.1Hz,2H),2.78(s,3H),2.52(s,3H).

[0429] Example 19: Preparation of Compound 19 6-Hydrazinyl-2-methylnicotinic acid [ka]

[0430] The compound was converted to 6-hydrazinyl-4- It was synthesized according to the procedure for preparing methyl nicotinic acid. 1 H-NMR (300 MHz, DO) δ7.63(d,J=8.7Hz,1H),6.55(d,J=8.7Hz,1H),2 .37(s,3H).

[0431] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazole -1-yl)-2-methylnicotinic acid [ka]

[0432] The compound was synthesized by 6-(4-(4-cyclohexyl)-2-methyl-nicotinic acid synthesis using 6-hydrazinyl-2-methylnicotinic acid. (aminophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-4-methyl Synthesized according to the procedure for preparing nicotinic acid. LC-MS (ESI+): m / z 335 (M+H) + ; 1 H-NMR(300MHz,DMSO-d6)δ12.95(brs, 1H),8.28-8.35(m,2H),7.89(d,J=8.7Hz,2H),7 .79(d,J=8.7Hz,2H),2.80(s,3H),2.58(s,3H).

[0433] Example 20: Preparation of Compound 20 Ethyl 2-(5-chloropyridin-2-yl)-3-oxobutanoate [ka]

[0434] 2-(5-chloropyridin-2-yl)acetic acid in anhydrous THF (15 mL) under N2 atmosphere A mixture of ethyl acetate (500 mg, 2.5 mmol) and LHMDS (5.0 mmol) was added at -55 °C. L, 5.0 mmol) was added dropwise over 20 minutes. The reaction was stirred at 0° C. for 1 hour. , 1-(1H-imidazol-1-yl)ethan-1-one (4 A solution of 12 mg, 3.75 mmol) was added dropwise over 15 min at -55°C. The reaction was allowed to warm slowly to room temperature and stirred at room temperature for 1 hour. TLC analysis indicated After the reaction was complete, the mixture was quenched with aqueous NH4Cl solution (50 mL) and The combined organic phase was extracted with tOAc (3 x 20 mL). The residue was purified by silica column chromatography (E The title compound (152 mg) was obtained as a solid by purification with HCl (HCl:Hex=1:100). LC-MS (ESI+): m / z 242 (M+H) + .

[0435] 6-(4-(5-chloropyridin-2-yl)-5-hydroxy-3-methyl-1H- Pyrazol-1-yl)nicotinic acid [ka]

[0436] The compound was synthesized using ethyl 2-(5-chloropyridin-2-yl)-3-oxobutanoate. 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazoline LC-MS (ESI+): m / z331(M+H) + ; 1 H NMR (300 MHz, DMSO-d6) δ 13.20 (brs,2H),8.95(d,J=1.8Hz,1H),8.53-8.61(m, 1H),8.52(s,1H),8.41(dd,J=8.7Hz,J=2.1Hz,1 H),8.32(d,J=5.1Hz,1H),7.87(dd,J=8.7Hz,J= 2.7Hz,1H),2.62(s,3H).

[0437] Example 21: Preparation of Compound 21 2-(4-bromo-2-methoxyphenyl)acetic acid methyl ester [ka]

[0438] 2-(4-Bromo-2-methoxyphenyl)acetic acid (2.00 ml) in MeOH (35 ml) g, 8.16 mmol) was added with SOCl2 (6 mL, 82.71 mmol) at room temperature. The mixture was stirred at 55° C. overnight. After the reaction was complete as indicated by analysis, the reaction mixture was directly concentrated to dryness. It was diluted with aqueous NaHCO3 (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was dried over Na2SO4, filtered and concentrated to give the desired product (2.0 5g) was obtained as a yellow oil. LC-MS (ESI+): m / z 281 (M+Na) + ; 1 H-NMR(300MHz,CDCl3)δ7.02-7.08(m,2H),7. 00(s,1H),3.93(s,3H),3.81(s,3H),3.57(s,2H ).

[0439] 2-(4-cyano-2-methoxyphenyl)acetic acid methyl ester [ka]

[0440] Under nitrogen protection, 2-(4-bromo-2-methoxyphenyl)acetic acid was dissolved in DMF (20 ml). To a solution of methyl nitrate (3.02 g, 11.66 mmol), Zn(CN)2 (2.74 g, 23.32 mmol), Pd2(dba)3 (0.11 g, 0.12 mmol) and S -Phos (0.48 g, 1.17 mmol) was added. The reaction was stirred at 110 °C for 4 h. After the reaction was complete as indicated by TLC analysis, the reaction was filtered and the solution was dissolved. The undissolved solid was removed. The filtrate was concentrated directly to dryness. The residue was purified by flash silica gel chromatography. The desired product was obtained by purifying the product by chromatography (EtOAc / PE = 1 / 50 to 1 / 10). The product (2.04 g) was obtained as a white solid. LC-MS (ESI+): m / z 206( M+H) + ; 1 H-NMR(300MHz,CDCl3)δ7.23-7.30(m,3 H),3.86(s,3H),3.71(s,3H),3.67(s,2H).

[0441] (Z)-2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acryl Methyl phosphate [ka]

[0442] 2-(4-cyano-2-methoxyphenyl)acetic acid methyl in DMF-DMA (27.4 g) A solution of ethyl acetate (0.94 g, 4.57 mmol) was stirred at 100° C. overnight. TLC analysis After the reaction was completed as indicated by The combined organic phase was dried over Na2SO4 and filtered. The mixture was stirred for 1 hour and concentrated to give the desired product (1.23 g) as a brown oil. +): m / z 261 (M+H) + ;

[0443] 6-(4-(4-cyano-2-methoxyphenyl)-5-hydroxy-1H-pyrazoline (1-yl)nicotinic acid [ka]

[0444] (Z)-2-(4-cyano-2-methoxyphenyl)-3 in i-PrOH (6 mL) -(dimethylamino)methyl acrylate (0.32 g, 1.24 mmol) in a suspension 6-hydrazinylnicotinic acid (0.19 g, 1.24 mmol) and HCl (1.25 mL, 1M, 1.24mmol) was added. The reaction was stirred at room temperature for 6 hours, after which a large amount of A solid was allowed to precipitate. The suspension was filtered. The filter cake was diluted with i-PrOH (6 mL), water (1 The resulting mixture was stirred at 50° C. overnight. Dilute HCl solution (1 M, 5 mL) was added to the reaction and the reaction was stirred at room temperature for a further 20 minutes. Stirring was continued for 1 minute. A large amount of solid precipitated. After filtration, the filter cake was diluted with methanol (5 mL ) overnight. After filtration and drying, 185 mg of the title compound was obtained. MS(ESI+): m / z 335(MH)- ; 1 H-NMR (300 MHz, DMS O-d6)δ13.5(brs,1H),8.97(s,1H),8.56-8.68( brs,2H),8.45-8.47(m,2H),7.44-7.49(m,2H), 3.96(s,3H).

[0445] 6-(4-(4-cyano-2-hydroxyphenyl)-5-hydroxy-1H-pyrazoline (1-yl)nicotinic acid [ka]

[0446] Under nitrogen protection, 6-(4-(4-cyano-2-methoxyphenyl)-2-(2-methyl-2-propanol)-2-one was dissolved in DMF (8 mL). )-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (0.15g, 0.45 A solution of 100 mmol of EtSNa (0.11 g, 1.34 mmol) was added in one portion to EtSNa (0.11 g, 1.34 mmol). The reaction was stirred at 150° C. for 48 hours. The reaction was complete as indicated by TLC analysis. The mixture was then diluted with water (80 mL) and the pH was adjusted to 2 with diluted HCl solution. After filtration, the solid was purified by preparative HPLC purification to give 20 mg of the above solid. The title compound was obtained as a yellow solid. LC-MS(ESI+): m / z 321(M−H) - ; 1 H-NMR(300MHz,CD3OD)δ9.10(s,1H),8.30-8. 50(m,2H),8.20(m,1H),7.82(m,1H),7.12(m,1H ), 7.02(s,1H)

[0447] Example 22: Preparation of Compound 22 1-chloro-2-methoxy-4-methylbenzene [ka]

[0448] 2-Chloro-5-methylphenol (1 g, 6.99 mmol) in DMF (4 mL) To the solution, K2CO3 (2.4 g, 17.48 mmol) and MeI (1.04 g, 7 0.34 mmol) was added. The reaction was stirred at room temperature for approximately 6 hours. TLC analysis showed After the reaction was complete as shown, the reaction was diluted with water (20 mL) and The combined organic phase was washed with water (10 mL), dried over Na2SO4, and Drying and concentration to dryness gave 1.05 g of the desired crude product. GC-MS (EI+): 1 56; 1 H-NMR(300MHz, CDCl3)δ7.22(d,J=8.1Hz,1 H),6.69-6.74(m,2H),3.88(s,3H),2.33(s,3H) .

[0449] 4-(Bromomethyl)-1-chloro-2-methoxybenzene [ka]

[0450] 1-Chloro-2-methoxy-4-methylbenzene (20. A solution of NBS (26.24 g, 0.15 mol) and B PO (1.62 g, 6.7 mmol) was added, and the resulting mixture was stirred at 80° C. overnight. After the reaction was complete by TLC analysis, the mixture was filtered and the filtrate was washed with diluted HCl solution ( The combined organic layer was diluted with DCM (200 mL x 3). Wash with saturated NaHCO3 solution (40 mL), dry with Na2SO4 (60 g), and filter The crude product was purified by silica column chromatography. Further purification was carried out by filtration (PE / EtOAc = 100 / :1 to 60 / :1) to give 32. 6 g of the title compound was obtained. 1 H-NMR (300 MHz, CDCl3) δ 7.32 (d J=8.1Hz,1H),6.90-6.96(m,2H),4.54(s,2H),3 .93(s,3H).

[0451] 2-(4-chloro-3-methoxyphenyl)acetonitrile [ka]

[0452] 4-(Bromomethyl)-1-chloropropanediol in EtOH (50 mL) and H2O (10 mL) A solution of 10 g of 2-methoxybenzene (42.7 mmol) was added to a solution of 10 g of NaCN (3.14 g, 64.05 mmol) was added in one portion, and the resulting mixture was stirred at 80° C. overnight. After the reaction was complete by TLC analysis, the reaction was diluted with water (100 mL) and The combined organic phase was extracted with saturated NaHCO3 solution (50 mL) and and brine (50 mL), dried and concentrated to give 7.58 g of crude product. The crude product was purified by column chromatography (PE: EtOAc = 60 / 1 to 15 / 1). Purification thus gave 5.58 g of the title compound. 1 H-NMR (300 MHz, CDC l3)δ7.34(d,J=8.1Hz,1H),6.83-6.88(m,2H),3 .91(s,3H), 3.73(s,2H).

[0453] 2-(4-chloro-3-methoxyphenyl)acetic acid [ka]

[0454] 2-(4-chloro-3-methoxybenzoate) in ethanol (120 mL) and water (40 mL) To a solution of phenyl)acetonitrile (5.58 g, 31 mmol), KOH (8.68 g (155 mol) was added in one portion. The reaction was stirred at reflux for approximately 3 hours. After the reaction was complete as shown, the reaction was concentrated to remove most of the ethanol. The residue was adjusted to pH 3 with diluted HCl solution and extracted with EtOAc (200 mL x 3). The combined organic phase was washed with water (30 mL), dried and concentrated to dryness to give 7.2 9 g of crude product was obtained. 1 H-NMR (300 MHz, DMSO-d6) δ 12.40 ( brs,1H),7.34(d,J=7.8Hz,1H),7.05(d,J=1.5H z,1H),6.84(d,J=7.8,1.5Hz,1H),3.92(s,3H), 3.72(s,2H).

[0455] 2-(4-chloro-3-methoxyphenyl)acetic acid methyl ester [ka]

[0456] 2-(4-chloro-3-methoxyphenyl)acetic acid (7. A solution of concentrated H2SO4 (3.578 g, 36.45 mmol) mol) was added in one portion. The reaction was stirred at 70°C for 2 hours. TLC analysis showed After the reaction was complete, the reaction was cooled to room temperature and concentrated to remove most of the methanol. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL x 2). The organic layer was dried and concentrated. The residue was purified by column chromatography (PE / EtOA). c=60 / 1 to 20 / 1) to give 4.68 g of the title compound. 1 HN MR(300MHz,CDCl3)δ7.29(d,J=8.1Hz,1H),6.86 (d,J=1.5Hz,1H),6.80(d,J=7.8,1.5Hz,1H),3. 90(s,3H),3.72(s,3H),3.60(s,2H).

[0457] (Z)-2-(4-chloro-3-methoxyphenyl)-3-(dimethylamino)acryl Methyl phosphate [ka]

[0458] The compound was converted to (Z) using methyl 2-(4-chloro-3-methoxyphenyl)acetate. Methyl-2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate LC-MS (ESI+): m / z 270 (M+H) + ;

[0459] 6-(4-(4-chloro-3-methoxyphenyl)-5-hydroxy-1H-pyrazoline (1-yl)nicotinic acid [ka]

[0460] The compound was prepared by the procedure of (Z)-2-(4-chloro-3-methoxyphenyl)-3-(dimethylamino)-2-methylpropional. 6-(4-(4-cyano-2-methoxyphenyl)-)- 5-Hydroxy-1H-pyrazol-1-yl)nicotinic acid was synthesized according to the procedure LC-MS(ESI+):m / z 346(M+H) + ;

[0461] 6-(4-(4-chloro-3-hydroxyphenyl)-5-hydroxy-1H-pyrazoline (1-yl)nicotinic acid [ka]

[0462] The compound was 6-(4-(4-chloro-3-methoxyphenyl)-5-hydroxy-1H -pyrazol-1-yl)nicotinic acid to produce 6-(4-(4-cyano-2-hydrogen methyl)- Preparation procedure for (5-hydroxyphenyl)-1H-pyrazol-1-yl)nicotinic acid LC-MS (ESI+): m / z 332 (M+H) + ; 1 H-NM R(300MHz,CDCl3)δ13.30(brs,1H),10.07(s,1H ),8.95(s,1H),8.42-8.52(m,2H),8.33(s,1H), 7.70(s,1H),7.25(s,2H).

[0463] Example 23: Preparation of Compound 23 2-(4-bromo-3-fluorophenyl)acetic acid methyl ester [ka]

[0464] The compound was converted to 2-(4-bromo-2-fluoro)acetic acid using 2-(4-bromo-3-fluoro)acetic acid. The compound was synthesized according to the procedure for the preparation of methyl (-methoxyphenyl)acetate.1 H-NMR (300M Hz, CDCl3)δ7.49(t,J=8.1Hz,1H),7.08(d,J=9. 0Hz,1H),6.95(d,J=8.1Hz,1H),3.71(s,3H),3. 59(s,2H).

[0465] 2-(4-cyano-3-fluorophenyl)acetic acid methyl ester [ka]

[0466] The compound was converted to 2-( It was synthesized according to the procedure for the preparation of methyl (4-cyano-2-methoxyphenyl)acetate. 1 HN MR(300MHz,CDCl3)δ7.59(t,J=8.1Hz,1H),7.19 (d,J=8.7Hz,2H),3.73(s,3H),3.70(s,2H).

[0467] 2-(4-cyano-3-fluorophenyl)-3-oxobutanoic acid methyl ester [ka]

[0468] Under nitrogen protection, 2-(4-cyano-3-fluorophenyl)acetic acid was dissolved in THF (15 mL). A solution of methyl hydroxybenzoate (363 mg, 1.88 mmol) in LiHMDS (2.9 m mol, 2.9 mL) was added dropwise over 10 minutes. After stirring at 4°C for 30 min, 1-acetylimidazole (249 mg) in THF (5 mL) was added. A solution of 2.25 mmol) was added dropwise to the reaction over a period of 10 minutes. The mixture was left stirring at -78°C for 1 hour. The reaction was complete as indicated by TLC analysis. After completion, the reaction was quenched with saturated NH4Cl solution (20 mL) and The combined organic phase was dried and concentrated to dryness to give 410 mg of crude title compound. The compound was obtained and used in the next step without further purification. LC-MS (ESI-): m / z 234(MH) - ;

[0469] 6-(4-(4-cyano-3-fluorophenyl)-5-hydroxy-3-methyl-1 H-pyrazol-1-yl)nicotinic acid [ka]

[0470] The compound was prepared by adding methyl 2-(4-cyano-3-fluorophenyl)-3-oxobutanoate. 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyridinyl) The compound was synthesized according to the procedure for the preparation of (4-methyl-1-benzothiazolinone-1-yl)-4-methylnicotinic acid. (ESI+): m / z 337 (M+H + ), 1 H NMR (300 MHz, DMSO- d6)δ8.99(d,J=1.5Hz,1H),8.34(m,1H),8.26(d ,J=8.1Hz,2H),7.86(d,J=11.7Hz,1H),7.68(m, 1H), 7.57(m,1H), 2.44(s,3H).

[0471] Example 24: Preparation of Compound 24 3-Methyl-4-vinylbenzonitrile [ka]

[0472] Under nitrogen protection, 4-bromo-3-methylbenzene was dissolved in THF / water (250 mL / 25 mL). zonitrile (5 g, 25.51 mmol) and potassium vinyltrifluoroborate ( A solution of Cs2CO3 (6.84 g, 51.02 mmol) was added to (1.8 g, 2.55 mmol) and Pd(dppf)Cl2 (1.8 g, 2.55 mmol) were added. The resulting mixture was stirred at 70° C. overnight. The reaction was complete as indicated by TLC analysis. After stirring, the reaction was quenched with water (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried and concentrated. The residue was purified by column chromatography (PE : EtOAc = 20 / 1 to 10 / 1) to give 3.2 g of the title compound as a pale yellow GC-MS (EI+): m / z 143 (M + ).

[0473] 2-(4-cyano-2-methylphenyl)acetic acid [ka]

[0474] 3-Methyl-4-vinylbenzonitrile in DME (200 mL) and water (48 mL) To a solution of 1,2-dichloroisothiazolinone (3.2 g, 22.38 mmol), I2 (0.57 g, 2.24 mmol) The resulting mixture was stirred at room temperature with Oxone (27.52 g, 44.76 m mol) was added portionwise over 10 minutes. After the addition, the reaction was stirred at room temperature overnight. After the reaction was complete as indicated by LC analysis, the suspension was filtered to remove any undissolved The heavy solids were removed and the filtrate was concentrated in vacuo to remove most of the organic solvent. The mixture was diluted with Na2S2O3 (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was dried and concentrated, and the residue was stirred in n-hexane (30 mL) for 30 minutes. The n-hexane slurry and filtration purification were repeated twice, and then 3. 56 g of crude product was obtained, which was used directly in the next step without further purification.

[0475] 2-(4-cyano-2-methylphenyl)acetic acid methyl ester [ka]

[0476] The compound was converted to 2-(4-bromo-2-methyl)acetic acid using 2-(4-bromo-2- It was synthesized according to the procedure for the preparation of methyl (methoxyphenyl)acetate. 1 H NMR (300 M z, CDCl3)δ7.45-7.48(m,2H),7.30(d,J=8.1Hz, 1H), 3.71 (s, 3H), 3.69 (s, 2H), 2.34 (s, 3H).

[0477] 2-(4-cyano-2-methylphenyl)-3-oxobutanoic acid methyl ester [ka]

[0478] The compound was purified by 2-(4-cyano-2-methylphenyl)methyl acetate. Synthesized according to the procedure for the preparation of methyl (-cyano-3-fluorophenyl)-3-oxobutanoate LC-MS(ESI+): m / z 232(M+H) + ;

[0479] 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-3-methyl-1H -pyrazol-1-yl)nicotinic acid [ka]

[0480] The compound was purified using methyl 2-(4-cyano-2-methylphenyl)-3-oxobutanoate. 6-(4-(4-cyano-3-fluorophenyl)-5-hydroxy-3-methyl (1H-pyrazol-1-yl)nicotinic acid was synthesized according to the procedure described above. LC-MS (ESI+): m / z 332 (M+H) + ; 1 H-NMR (300 MHz, DMSO- d6)δ12.91(brs,2H),8.95(s,1H),8.52(d,J=8. 7Hz,1H),8.39(d,J=8.7Hz,1H),8.23(s,1H),7. 80(s,1H),6.78(s,1H).

[0481] Example 25: Preparation of Compound 25 2-(4-Bromo-2-fluorophenyl)acetic acid methyl ester [ka]

[0482] The compound was converted to 2-(4-chlorophenyl)acetic acid using 2-(4-bromo-2-fluorophenyl)acetic acid. The compound was synthesized according to the procedure for the preparation of methyl (3-methyl-3-methoxyphenyl)acetate. 1 H NMR( 300MHz, CDCl3)δ7.24-7.27(m,2H),7.14(t,J=8 .4Hz,1H),3.71(s,3H),3.63(s,2H).

[0483] 2-(4-cyano-2-fluorophenyl)acetic acid methyl ester [ka]

[0484] The compound was converted to 2-( It was synthesized according to the procedure for the preparation of methyl 4-cyano-3-fluorophenyl)acetate. 1 HN MR(300MHz,CDCl3)δ7.86(dd,J=8.7,1.2Hz,1H) ,7.70(d,J=8.1Hz,1H),7.60(t,J=7.5Hz,1H),3 .87(s,2H), 3.64(s,3H).

[0485] 2-(4-cyano-2-fluorophenyl)-3-oxobutanoic acid methyl ester [ka]

[0486] The compound was converted to 2-( Synthesize according to the procedure for the preparation of methyl 4-cyano-3-fluorophenyl-3-oxobutanoate. LC-MS(ESI+):m / z 258(M+Na) + .

[0487] 6-(4-(4-cyano-2-fluorophenyl)-5-hydroxy-3-methyl-1 H-pyrazol-1-yl)nicotinic acid [ka]

[0488] The compound was prepared by adding methyl 2-(4-cyano-2-fluorophenyl)-3-oxobutanoate. Using 6-(4-(4-cyano-3-fluorophenyl)-5-hydroxy-3-methylphenyl)- This compound was synthesized according to the procedure for the preparation of (ethyl-1H-pyrazol-1-yl)nicotinic acid. S(ESI+): m / z 339 (M+H + ), 1H NMR (300 MHz, DMSO -d6)δ13.22(brs,1H),8.94(d,J=1.8Hz,1H),8. 59(d,J=9.3Hz,1H),8.38(d,J=9.3Hz,1H),7.69 -7.94(m,3H),2.23(s,3H).

[0489] Example 26: Preparation of Compound 26 2-(4-chloro-3-fluorophenyl)acetic acid methyl ester [ka]

[0490] The compound was converted to 2-(4-chlorophenyl)acetic acid using 2-(4-chloro-3-fluorophenyl)acetic acid. The compound was synthesized according to the procedure for the preparation of methyl (3-methyl-3-methoxyphenyl)acetate. 1 H NMR( 300MHz, CDCl3)δ7.34(t,J=7.8Hz,1H),7.10(dd ,J=8.1,1.8Hz,1H),7.01(d,J=8.1Hz,1H),3.71 (s,3H),3.6(s,2H).

[0491] 2-(4-chloro-3-fluorophenyl)-3-oxobutanoic acid methyl ester [ka]

[0492] The compound was converted to 2-( Synthesize according to the procedure for the preparation of methyl 4-cyano-2-fluorophenyl-3-oxobutanoate. LC-MS(ESI+):m / z 267(M+Na) + ;

[0493] 6-(4-(4-chloro-3-fluorophenyl)-5-hydroxy-3-methyl-1 H-pyrazol-1-yl)nicotinic acid [ka]

[0494] The compound was prepared by adding methyl 2-(4-chloro-3-fluorophenyl)-3-oxobutanoate. Using 6-(4-(4-cyano-2-fluorophenyl)-5-hydroxy-3-methylphenyl)- This compound was synthesized according to the procedure for the preparation of (ethyl-1H-pyrazol-1-yl)nicotinic acid. S(ESI+): m / z 348(M+Na) + ; 1 H-NMR (300 MHz, DMS O-d6)δ13.30(brs,1H),13.01(brs,1H),8.95(s ,1H),8.56(brs,1H),8.41(dd,J=9.0,2.1Hz,1H ),7.74(d,J=11.7Hz,1H),7.55-7.58(m,2H),2. 47(s,3H).

[0495] Example 27: Preparation of Compound 27 4-Amino-6-hydrazinylnicotinic acid [ka]

[0496] The compound was converted to 6-hydrazinyl-4- Synthesized according to the procedure for the preparation of methyl nicotinic acid. LC-MS (ESI+): m / z 16 9(M+H) + ;

[0497] 4-amino-6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H -pyrazol-1-yl)nicotinic acid [ka]

[0498] The compound was synthesized by 6-(4-(4-cyclohexyl)-4-amino-6-hydrazinyl nicotinic acid synthesis. (3-fluorophenyl)-5-hydroxy-3-methyl-1H-pyrazole-1- LC-MS (ESI+): m / z 33 6(M+H) + ; 1 H-NMR(300MHz,DMSO-d6)δ8.63(s,1H ),8.08(s,2H),7.88(d,J=8.4Hz,2H),7.76(d,J =8.4Hz,2H),7.37(brs,1H),2.39(s,3H).

[0499] Example 28: Preparation of Compound 28 6-(4-(4-chloro-2-fluorophenyl)-5-hydroxy-3-methyl-1 H-pyrazol-1-yl)nicotinic acid [ka]

[0500] The compound was 6-(4-(4-chloro-3-fluorophenyl)-5-hydroxy-3- It was synthesized according to the procedure for the preparation of methyl-1H-pyrazol-1-yl)nicotinic acid. MS(ESI+):m / z 348(M+Na) + ; 1 H-NMR (300 MHz, DM SO-d6)δ13.36(brs,1H),12.82(brs,1H),8.95( d,J=1.5Hz,1H),8.58(brs,1H),8.40(m,1H),7. 48-7.56 (m, 2H), 7.33 (m, 1H), 2.21 (s, 3H).

[0501] Example 29: Preparation of Compound 29 2-Methyl-4-vinylbenzonitrile [ka]

[0502] The compound was converted to 3-methyl-4-vinyl using 4-bromo-2-methylbenzonitrile. It was synthesized according to the procedure for the preparation of benzonitrile. 1 H NMR (300 MHz, CDCl 3)δ7.55(d,J=7.8Hz,1H),7.26-7.32(m,2H),6. 70(m,1H),5.85(d,J=17.4Hz,1H),5.42(d,J=10 .8Hz,1),2.54(s,3H).

[0503] 2-(4-cyano-3-methylphenyl)acetic acid methyl ester [ka]

[0504] The compound was synthesized by the reaction of 2-(4-cyano-2-methylbenzonitrile with 2-methyl-4-vinylbenzonitrile. (-methylphenyl)methyl acetate was synthesized according to the procedure. 1 H NMR (300 M z,CDCl3)δ7.56(d,J=7.8Hz,1H),7.18-7.25(m, 2H),3.71(s,3H),3.64(s,2H),2.54(s,3H).

[0505] 2-(4-cyano-3-methylphenyl)-3-oxobutanoic acid methyl ester [ka]

[0506] The compound was purified by 2-(4-cyano-3-methylphenyl)methyl acetate. Synthesized according to the procedure for the preparation of methyl (-cyano-3-fluorophenyl)-3-oxobutanoate LC-MS(ESI-):m / z 230(MH) - ;

[0507] 6-(4-(4-cyano-3-methylphenyl)-5-hydroxy-3-methyl-1H -pyrazol-1-yl)nicotinic acid [ka]

[0508] The compound was purified using methyl 2-(4-cyano-3-methylphenyl)-3-oxobutanoate. 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-2-yl)- The compound was synthesized according to the procedure for the preparation of (1-azol-1-yl)-4-methylnicotinic acid. ESI+): m / z 333 (MH) - ; 1 H-NMR (300 MHz, CD3OD) δ8.96(s,1H),8.40(d,J=8.7,2.1Hz,1H),8.39( d,J=8.7Hz,1H),7.71(s,1H),7.58-7.66(m,2H) ,2.55(s,3H),2.45(s,3H).

[0509] Example 30: Preparation of Compound 30 2-(4-bromo-2-chlorophenyl)acetic acid methyl ester [ka]

[0510] The compound was converted to 2-(4-bromo-2-fluorophenyl)acetic acid using 2-(4-bromo-2-fluorophenyl)acetic acid. The compound was synthesized according to the procedure for the preparation of methyl bromo-2-fluorophenyl)acetate. 1 H-NMR( 300MHz, CDCl3)δ7.55(d,J=1.8Hz,1H),7.37(dd ,J=8.1,1.8Hz,1H),7.16(d,J=1.8Hz,1H),3.71 (s,3H),3.67(s,2H).

[0511] 2-(2-chloro-4-cyanophenyl)acetic acid methyl ester [ka]

[0512] The compound was purified by 2-(4-bromo-2-chlorophenyl)methyl acetate. This was synthesized according to the procedure for the preparation of methyl (2-cyano-2-fluorophenyl)acetate. GC-MS (EI+): m / z 209.

[0513] (Z)-2-(2-chloro-4-cyanophenyl)-3-(dimethylamino)acrylic acid Methyl acetate [ka]

[0514] The compound was converted to (Z)- 2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate methyl ester It was synthesized according to the preparation procedure of LC-MS (ESI+): m / z 265 (M+H) +

[0515] 6-(4-(2-chloro-4-cyanophenyl)-5-hydroxy-1H-pyrazole -1-yl)nicotinic acid [ka]

[0516] The compound was prepared as follows: (Z)-2-(2-chloro-4-cyanophenyl)-3-(dimethylamino) ) methyl acrylate to obtain 6-(4-(4-cyano-2-methoxyphenyl)-5 -hydroxy-1H-pyrazol-1-yl)nicotinic acid was synthesized according to the procedure for the preparation of 1H-hydroxy-1H-pyrazol-1-ylnicotinic acid. LC-MS(ESI+):m / z 341(M+H) + ; 1 H-NMR (300 MHz, DMSO-d6)δ13.42(brs,2H),8.97(s,1H),8.44-8 .60(m,3H),8.28(d,J=8.1Hz,1H),8.06(s,1H), 7.81(d,J=8.1Hz,1H).

[0517] Example 31: Preparation of Compound 31 3,5-Dimethyl-4-vinylbenzonitrile [ka]

[0518] The compound was converted to 3-methyl-4-bromobenzonitrile using 4-bromo-3,5-dimethylbenzonitrile. -vinylbenzonitrile was synthesized according to the procedure for its preparation. 1 H-NMR (300 MHz, C DCl3)δ7.32(s,2H),6.64(m,1H),5.54(dd,J=11 .7,1.5Hz,1H),5.32(dd,J=17.7,1.5Hz,1H),2. 32(s,6H).

[0519] 2-(4-cyano-2,6-dimethylphenyl)acetic acid methyl ester [ka]

[0520] The compound was synthesized by 2-(4-cyano)-2-methyl-4-methylbenzonitrile using 3,5-dimethyl-4-vinylbenzonitrile. It was synthesized according to the procedure for the preparation of methyl 2-methylphenyl)acetate. 1 H-NMR (30 0MHz, CDCl3)δ7.33(s,2H),3.72(s,2H),3.70(s ,3H),2.35(s,6H).

[0521] (Z)-2-(4-cyano-2,6-dimethylphenyl)-3-(dimethylamino)a Methyl acrylate [ka]

[0522] The compound was purified by 2-(4-cyano-2,6-dimethylphenyl)methyl acetate ( Z)-2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylic acid It was synthesized according to the procedure for the preparation of methyl. 1 H-NMR (300 MHz, CDCl3) δ7. 62(s,1H),7.28(s,2H),3.59(s,3H),2.64(s,6H ),2.20(s,6H).

[0523] 6-(4-(4-cyano-2,6-dimethylphenyl)-5-hydroxy-1H-pyrazol-2-yl (1-(2-isopropyl)nicotinic acid [ka]

[0524] The compound was designated as (Z)-2-(4-cyano-2,6-dimethylphenyl)-3-(dimethylphenyl). 6-(4-(4-cyano-2-methoxyphenyl)-amino)methyl acrylate was used to )-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid according to the procedure LC-MS(ESI+):m / z 335(M+H) + ;1 H-NMR (300M Hz,CD3OD)δ8.03(s,1H),8.52(m,2H),7.75(s,1 H),7.40-7.47(m,2H),2.30(s,6H).

[0525] Example 32: Preparation of Compound 32 2-(4-Methoxy-3-methylphenyl)acetic acid methyl ester [ka]

[0526] The compound was converted to 2-(4-bromophenyl)acetic acid using 2-(4-methoxy-3-methylphenyl)acetic acid. This was synthesized according to the procedure for the preparation of methyl bromo-2-methoxyphenyl)acetate. 1 H-NMR( 300MHz,CD3OD)δ7.05-7.07(m,2H),6.77(d,J=7 .8Hz,1H),3.81(1,3H),3.76(s,3H),3.54(s,2H ),2.20(s,3H).

[0527] 2-(4-Methoxy-3-methylphenyl)-3-oxobutanoic acid methyl ester [ka]

[0528] The compound was purified by 2-(4-methoxy-3-methylphenyl)methyl acetate. Synthesize according to the procedure for the preparation of methyl 4-cyano-3-fluorophenyl-3-oxobutanoate. LC-MS(ESI+): m / z 259(M+Na) + ;

[0529] 6-(5-hydroxy-4-(4-methoxy-3-methylphenyl)-3-methyl-1 H-pyrazol-1-yl)nicotinic acid [ka]

[0530] The compound was prepared by adding methyl 2-(4-methoxy-3-methylphenyl)-3-oxobutanoate. Using 6-(4-(4-cyano-3-fluorophenyl)-5-hydroxy-3-methylphenyl)- This compound was synthesized according to the procedure for the preparation of (ethyl-1H-pyrazol-1-yl)nicotinic acid. S(ESI+): m / z 340(M+H) + ; 1 H-NMR (300 MHz, DMSO -d6)δ13.30(brs,1H),12.35(brs,1H),8.93(s, 1H),8.58(s,1H),8.39(d,J=6.9Hz,1H),7.34-7 .36(m,2H),6.96(d,J=9.0Hz,1H),3.80(s,3H), 2.35(s,3H),2.18(s,3H).

[0531] Example 33: Preparation of Compound 33 Diethyl 2-(2-bromo-4-cyanophenyl)malonate [ka]

[0532] Under nitrogen protection, a solution of diethyl malonate (2 g, 12.5 mmol) in DMF was added with 0 NaH (600 mg, 15 mmol) was added portionwise over 5 min at 0°C. After stirring at 4°C for 30 minutes, 3-bromo-4-fluorobenzonitrile (2.08 g, 10 (mmol) was added to the reaction in one portion and the reaction was stirred at 80°C for 1.5 hours. After the reaction was complete as indicated by the arrow, the reaction was quenched with water (20 mL) and diluted The pH was adjusted to 5 with diluted HCl solution. The resulting mixture was then diluted with EtOAc (50 mL The combined organic phase was washed with water (20 mL) and brine (20 mL). The residue was purified by column chromatography (PE / EtOA). c=20 / 1 to 10 / 1) to give 1.8 g of the title compound. (ESI+): m / z 340, 342 (M+H) + . 1 H-NMR (300 MHz, C DCl3)δ7.90(s,2H),7.64(s,2H),5.24(s,1H),4 .21-4.32(m,4H),1.29(t,J=7.2Hz,6H).

[0533] 2-(2-bromo-4-cyanophenyl)acetic acid ethyl ester [ka]

[0534] Diethyl 2-(2-bromo-4-cyanophenyl)malonate in DMSO (20 mL) (1.8 g, 5.3 mmol) in water (96 mg, 5.3 mmol) (339 mg, 8 mmol) was added in one portion. The resulting mixture was stirred at 120° C. overnight. After the reaction was complete as indicated by TLC analysis, the reaction was quenched with water (20 mL). The pH was adjusted to 6 with diluted HCl solution and extracted with EtOAc (20 mL × 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried and concentrated. The residue was purified by column chromatography (PE / EtOAc = 20 / 1 to 10 / 1). Further purification gave 780 mg of the title compound. 1 H-NMR (300 MHz, CDCl 3) δ7.87(s,1H),7.59(d,J=7.8Hz,1H),7.42(d, J=7.8Hz,1H),4.20(q,J=6.9Hz,2H),3.84(s,2H ), 1.27(t,J=6.9Hz,3H)

[0535] 2-(4-cyano-2-vinylphenyl)acetic acid ethyl ester [ka]

[0536] The compound was converted to 3-methylphenyl using ethyl 2-(2-bromo-4-cyanophenyl)acetate. The compound was synthesized according to the procedure for the preparation of 4-vinylbenzonitrile. 1 H NMR (300 M z,CDCl3)δ7.7(s,1H),7.52(d,J=7.8Hz,1H),7. 33(d,J=7.8Hz,1H),6.89(m,1H),5.70(d,J=17. 4Hz,1H),5.42(d,J=10.8Hz,1),4.15(q,J=7.2H z,1H),3.73(s,3H),1.24(q,J=7.2Hz,1H).

[0537] 2-(4-cyano-2-ethylphenyl)acetic acid ethyl ester [ka]

[0538] Methyl 2-(4-cyano-2-vinylphenyl)acetate (5 mL) in methanol (10 mL) To a solution of Pd / C (60 mg, 2.6 mmol) was added Pd / C (56 mg). The mixture was stirred under a hydrogen atmosphere from a boiler for approximately 1 hour. The reaction was as shown by TLC analysis. After completion of the procedure, the suspension was filtered through a package of Celite and the filter cake was diluted with methanol. (10 mL) The filtrate was concentrated to dryness to give 540 mg of the crude title compound. 1 H-NMR(300MHz,CDCl3)δ7.61(s,1H),7.49(d,J =8.1Hz,1H),7.31(d,J=8.1Hz,1H),4.16(q,J=7 .2Hz,2H),3.69(s,2H),2.68(q,J=7.5Hz,2H),1 .21-1.28(m,6H).

[0539] (Z)-2-(4-cyano-2-ethylphenyl)-3-(dimethylamino)acrylic acid Ethyl acetate [ka]

[0540] The compound was converted to (Z)- 2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate methyl ester It was synthesized according to the preparation procedure of 1 H-NMR (300 MHz, CDCl3) δ 7.60 ( s,1H),7.49(s,1H),7.41(d,J=8.1Hz,1H),7.23 (m,1H),4.12(q,J=6.9Hz,2H),3.60(s,3H),2.6 7(s,6H), 1.14(t,J=6.9Hz,3H)

[0541] 6-(4-(4-cyano-2-ethylphenyl)-5-hydroxy-1H-pyrazole -1-yl)nicotinic acid [ka]

[0542] The compound was (Z)-2-(4-cyano-2-ethylphenyl)-3-(dimethylamino) ) Ethyl acrylate was used to produce 6-(4-(4-cyano-2-methoxyphenyl)-5 -hydroxy-1H-pyrazol-1-yl)nicotinic acid was synthesized according to the procedure for the preparation of 1H-hydroxy-1H-pyrazol-1-ylnicotinic acid. LC-MS(ESI+):m / z 335(M+H) + ; 1 H-NMR (300 MHz, DMSO-d6)δ8.97(s,1H),8.52(m,2H),8.12(s,1H ),7.75(s,1H),7.60-7.69(m,2H),2.78(q,J=7. 5Hz,2H), 1.17(q,J=7.5Hz,3H)

[0543] Example 34: Preparation of Compound 34 5-Hydrazinylpyrazine-2-carboxylic acid [ka]

[0544] The compound was converted to 6-hydrazinyl-4- Synthesized according to the procedure for the preparation of methyl nicotinic acid. LC-MS (ESI+): m / z 15 5(M+H) + ;

[0545] 5-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazole -1-yl)pyrazine-2-carboxylic acid [ka]

[0546] The compound was converted to 6-(4-(4- Cyano-3-fluorophenyl)-5-hydroxy-3-methyl-1H-pyrazole-1 LC-MS (ESI+): m / z 3 22(M+H) + ; 1 H-NMR(300MHz,DMSO-d6)δ9.80(s,1 H),9.04(s,1H),7.91(d,J=8.4Hz,2H),7.83(d, J = 8.4 Hz, 2H), 2.51 (s, 3H).

[0547] Example 35: Preparation of Compound 35 2-(2-Methoxypyridin-4-yl)acetic acid ethyl ester [ka]

[0548] 2-Methoxy-4-methylpyridine (2 To a solution of 0.0 g, 16.2 mmol) of lithium diisopropylamide (16.0 mL, 32.0 mmol, 2.0 M in n-heptane) was added under nitrogen at -78°C. The mixture was stirred at -78°C for 10 minutes, and diethyl carbonate (3.78 g, 32.0 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2.0 hours. The reaction was quenched with water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to give ethyl 2-(2-methoxypyridin-4-yl)acetate (2.0 g 10.2 mmol, 63.4% yield) was obtained as a yellow oil. LC-MS: m / z=1 96.1(M+H) + , retention time 1.97 min (Method A).

[0549] (E)-3-(dimethylamino)-2-(2-methoxypyridin-4-yl)acrylic acid Ethyl acetate [ka]

[0550] 2-(2-methoxypyridine-4- To a solution of ethyl (methyl)acetate (1.95 g, 10 mmol) was added N,N-dimethylformamide. Diethyl acetal (5.95 g, 50 mmol) was added, and the mixture was heated at 100° C. for 12 hours. The mixture was stirred for 0.5 hours and cooled. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer The residue was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purify by rush chromatography (dichloromethane / methanol = 98 / 2) , (E)-3-(dimethylamino)-2-(2-methoxypyridin-4-yl)acrylic Ethyl methyl acetate (1.1 g, 4.4 mmol, 44% yield) was obtained as a colorless oil. S: m / z = 251.0 [M+H] + , retention time 1.68 min (Method B).

[0551] 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazole (1-yl)nicotinic acid tert-butyl ester [ka]

[0552] (E)-3-(dimethylamino)-2-(2-methoxyphenyl)-2-(2-methyl-2-propanol) in ethanol (5.0 mL) Ethyl (pyridin-4-yl)acrylate (0.25 g, 1.0 mmol) and 6-hydroxybenzoate A solution of tert-butyl azidinylnicotinate (0.21 g, 1.0 mmol) was added to the p- Benzene sulfonic acid monohydrate (19 mg, 0.1 mmol) was added, and the mixture was heated to reflux temperature. The mixture was stirred at rt for 12.0 h and cooled to precipitate a solid, which was filtered and washed with ethanol. , dried, and 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H -pyrazol-1-yl) tert-butyl nicotinate (210 mg, 0.57 mmol (57% yield) was obtained as a white solid. LC-MS: m / z=369.0 (M+H) + , Retention time 4.38 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ 13 .53(m,1H),8.91(s,1H),8.39-8.67(m,2H),8.0 4-8.06(d,J=5.0Hz,1H),7.39-7.50(m,2H),3.8 6(m,3H),1.58(s,9H).

[0553] Example 36: Preparation of Compound 36 6-Hydrazinylnicotinic acid ethyl ester [ka]

[0554] Ethyl 6-chloronicotinate (1.0 g, 5. 40 mmol) in water. %) was added. The mixture was stirred at reflux temperature overnight. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine and diluted with sodium sulfate. The mixture was dried over ice and concentrated. The crude product was obtained as a yellow oil (600 mg, 3.31 mmHg). ol, yield 61.4%). LC-MS:m / z=182.1(M+H) + , retention time 0. 37 min (Method A). The product was sufficiently pure to be used directly in the next step.

[0555] 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl) Ethyl nicotinate [ka]

[0556] (E)-2-(4-cyanophenyl)-3-(dimethylamino)methylpropional in ethanol (5.0 mL) Methyl (amino)acrylate (300 mg, 1.30 mmol) and 6-hydrazinyl A solution of ethyl cocoate (235 mg, 1.30 mmol) was added to p-toluenesulfonic acid monobasic solution. hydrate (25 mg, 0.13 mmol) was added. The reaction was stirred at 90° C. overnight and cooled. The solid was filtered, washed with ethanol, dried and purified to give 6-(4- (4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid ester The ethyl acetate (51 mg, 0.15 mmol, 11.7% yield) was obtained as a yellow solid. S: m / z = 335.1 [M+H] + , retention time 5.05 min (Method A). 1 HNMR(4 00MHz,DMSO-d6)δ13.58(s,1H),8.97(s,1H),8. 70-8.47(m,3H),8.15(s,2H),7.79-7.77(m,2H) ,4.39-4.34(m,2H),1.37-1.22(m,3H).

[0557] Example 37: Preparation of Compound 37 6-Chloronicotinic acid isopropyl ester [ka]

[0558] 6-Chloronicotinic acid (3.0 g, 19.2 mmHg) in dichloromethane (50.0 mL) To a solution of 1.2g (3.42g, 21.1mmol), carbonyldiimidazole (3.42g, 21.1mmol) was added at room temperature. The mixture was stirred for 1.0 hour, and isopropyl alcohol (3.78 g, 32.0 m mol) was added. Dichloromethane was removed under vacuum. A catalytic amount of isopropoxide was added. Sodium (164 mg, 2.0 mmol) was added and the mixture was heated at 90° C. for 1.0 h. The solution was concentrated in vacuo, and the resulting residue was slurried with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 6-chloronicotinamide. Isopropyl tungstate (3.4 g, 17.1 mmol, 89% yield) was obtained as a yellow solid. LC-MS: m / z=200.0 [M+H] + , retention time 2.04 min (Method A). Generate The material was sufficiently pure to be used directly in the next step.

[0559] 6-Hydrazinylnicotinic acid isopropyl ester [ka]

[0560] Isopropyl 6-chloronicotinate (1.0 g, 5. 03 mmol) in 85% water with hydrazine hydrate (1.0 g, 20.1 mmol). ) was added. The mixture was stirred at 80°C overnight. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine and concentrated over sodium sulfate. The residue was triturated with petroleum ether, filtered and purified to give 6-hydrazinyl nicotine. Isopropyl phosphate (800 mg, 4.1 mmol, 81.6% yield) was obtained as a yellow solid. LC-MS: m / z = 196.0 (M+H) + , retention time 0.39 min (Method A).

[0561] 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl) Isopropyl nicotinate [ka]

[0562] (E)-2-(4-cyanophenyl)-3-(dimethylamino)methylpropional in ethanol (5.0 mL) Methyl (amino)acrylate (300 mg, 1.30 mmol) and 6-hydrazinyl A solution of isopropyl cocoate (254 mg, 1.30 mmol) was added to p-toluenesulfonyl Phosphoric acid monohydrate (25 mg, 0.13 mmol) was added and the reaction was stirred at 90° C. overnight. The solid was filtered, washed with ethanol, and dried to give 6- (4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinamide Isopropyl phosphate (53 mg, 0.15 mmol, 11.7% yield) was obtained as a yellow solid. LC-MS: m / z = 349.0 [M+H] + , retention time 5.44 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.55(s,1H),8.95(s, 1H),8.69(s,1H),8.53-8.44(m,2H),8.14-8.12 (m,2H),8.79-8.77(m,2H),5.21-5.15(m,1H),1 .36-1.34(m,6H).

[0563] Example 38: Preparation of Compound 38 6-Chloronicotinic acid tert-butyl ester [ka]

[0564] 6-Chloronicotinic acid (5.0 g, 6.37 mL) in tetrahydrofuran (50.0 mL) A solution of 4-dimethylaminopyridine (0.39 g, 0.64 mmol) and 4-dimethylaminopyridine (0.39 g, 0.64 mmol) Di-tert-butyl dicarbonate (10.41 g, 47.77 mmol) was added to The reaction mixture was refluxed for 4.0 hours and concentrated. The residue was purified by flash chromatography. The compound was purified by distillation with petroleum ether / ethyl acetate=10 / 1 to give 6-chloronicotinic acid. tert-Butyl ester (5.5 g, 81.12% yield) was obtained as a yellow solid. LC-MS: m / z=214.0(M+H) + , retention time 1.83 min (Method A).

[0565] 6-Hydrazinylnicotinic acid tert-butyl ester [ka]

[0566] tert-Butyl 6-chloronicotinate (5.5 g, 25.82 mmol) of hydrazine hydrate (6.46 g, 129.11 mmol) , 85% in water) was added. The mixture was stirred at 100° C. for 2.0 hours. The mixture was cooled and Concentrate to dryness. Partition the residue between ethyl acetate and water. Wash the organic phase with brine. The residue was triturated with petroleum ether, filtered and concentrated to give a 1,000 ml solution of 1,000 ml of hexane, dried over sodium sulfate and concentrated. tert-Butyl 6-hydrazinylnicotinate (5.0 g, 92.76% yield) was obtained as a yellow solid. LC-MS: m / z=210.0 (M+H) + , retention time 1.19 minutes Law A).

[0567] 2-(4-cyanophenyl)acetic acid methyl ester [ka]

[0568] 2-(4-cyanophenyl)acetic acid (5.0 g, 31. To a mixture of 10.0 mmol) was added hydrochloric acid in methanol (20.0 mL, 3.0 M) at 0 °C. The mixture was stirred at 70°C for 3.0 hours and cooled to precipitate a solid. The solid was filtered and Washed with methanol and dried to obtain methyl 2-(4-cyanophenyl)acetate (5.0 g, 28.4 mmol, 92% yield) was obtained as a yellow solid. LC-MS: m / z=176. 0[M+H] + , retention time 1.54 min (Method A).

[0569] (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl ester [ka]

[0570] 2-(4-cyanophenyl)acetic acid in N,N-dimethylformamide (25.0 mL) To a solution of methyl (5.0 g, 28.5 mmol) in N,N-dimethylformamide diethyl The mixture was heated at 100° C. for 1 hour. Stirred for 6.0 hours and cooled. Ethyl acetate and water were added to the solution and the layers were separated. The layer was washed with brine, dried over sodium sulfate and concentrated to give (E)-2-(4- Cyanophenyl)-3-(dimethylamino)acrylmethyl (5.20g, 25.4mmol 1, 89% yield) was obtained as a yellow solid. LC-MS: m / z=231.0 [M+H]+ , retention time 1.70 min (Method A). The product was sufficiently pure to be used directly in the next step. Ta.

[0571] 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl) tert-Butyl nicotinate [ka]

[0572] (E)-2-(4-cyanophenyl)-3-(dimethylamino)methyl (amino)methyl acrylate (2.0 g, 8.70 mmol) and 6-hydrazinyl A solution of tert-butyl cocoate (1.82 g, 8.70 mmol) was added to p-toluenesulfonate. Sulfonic acid monohydrate (171 mg, 0.9 mmol) was added. The reaction was heated to 90° C. for 16 h. The mixture was stirred for 0.0 hours and cooled to precipitate a solid, which was filtered, washed with ethanol, and dried. 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1- (yl) tert-Butyl nicotinate (2.3 g, 6.35 mmol, 73% yield) was obtained as a yellow Obtained as a solid. LC-MS: m / z=363.1 (M+H) + , retention time 5.82 minutes ( Method A). 1 HNMR(400MHz,DMSO-d6)δ13.58(s,1H),8 .92(s,1H),8.69(s,1H),8.51(s,1H),8.44-8.4 1(m,1H),8.15-8.13(m,2H),7.81-7.78(m,2H), 1.58(s,9H).

[0573] Example 39: Preparation of Compound 39 2-(4-chloro-2-methoxyphenyl)acetic acid methyl ester [ka]

[0574] The compound was converted to 2-(4-bromophenyl)acetic acid using 2-(4-chloro-2-methoxyphenyl)acetic acid. The compound was synthesized according to the procedure for the preparation of methyl bromo-2-methoxyphenylacetate. LC-MS (E SI+): m / z 237 (M+Na) + ; 1 H-NMR (300 MHz, CDCl3) δ7.10(d,J=8.1Hz,1H),6.85-6.92(m,2H),3.86 (s,3H),3.71(s,3H),3.67(s,2H).

[0575] (Z)-2-(4-chloro-2-methoxyphenyl)-3-(dimethylamino)acryl Methyl phosphate [ka]

[0576] The compound was converted to (Z) using methyl 2-(4-chloro-2-methoxyphenyl)acetate. Methyl-2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate LC-MS (ESI+): m / z 270 (M+H) + .

[0577] 6-(4-(4-chloro-2-methoxyphenyl)-5-hydroxy-1H-pyrazoline (1-yl)nicotinic acid [ka]

[0578] The compound was prepared by the procedure of (Z)-2-(4-chloro-2-methoxyphenyl)-3-(dimethylamino)-2-methylpropional. 6-(4-(4-cyano-2-methoxyphenyl)-)- 5-Hydroxy-1H-pyrazol-1-yl)nicotinic acid was synthesized according to the procedure LC-MS(ESI+):m / z 346(M+H) + ;

[0579] 6-(4-(4-chloro-2-hydroxyphenyl)-5-hydroxy-1H-pyrazoline (1-yl)nicotinic acid [ka]

[0580] The compound was 6-(4-(4-chloro-2-methoxyphenyl)-5-hydroxy-1H -pyrazol-1-yl)nicotinic acid to produce 6-(4-(4-cyano-2-hydrogen methyl)- Preparation procedure for (5-hydroxyphenyl)-1H-pyrazol-1-yl)nicotinic acid LC-MS (ESI+): m / z 332 (M+H) + ; 1 H-NM R(300MHz,DMSO-d6)δ12.91(brs,2H),8.95(s,1 H),8.52(d,J=8.7Hz,1H),8.39(d,J=8.7Hz,1H) ,8.23(s,1H),7.80(s,1H),6.78(s,2H).

[0581] Example 40: Preparation of Compound 40 Diethyl 2-(4-cyano-2-(trifluoromethyl)phenyl)malonate [ka]

[0582] Under nitrogen protection, 3-(ethylperoxy)-3-oxopropanol was dissolved in DMF (100 ml). A solution of ethyl pantothenate (10.20 g, 63.50 mmol) was added to Cs2CO3 (45.5 The reaction mixture was stirred at 70°C for 10 minutes, after which 4-fluorouracil was added to the reaction mixture. Fluoro-3-(trifluoromethyl)benzonitrile (12.00 g, 63.50 mmol) l) was added to the reaction mixture. The resulting mixture was stirred at 70°C for 2 hours. After the reaction was complete as shown, the reaction was quenched with water (300 mL) and EtOAc ( The combined organic phase was washed with water (50 mL) and extracted with NaSO. 4, filtered and concentrated to give the desired product (20.8 g) as an oil. 1 H- NMR(300MHz,CDCl3)δ7.99(s,1H),7.86-7.92(m ,2H),5.11(s,1H),4.20-4.33(m,4H),1.28(t,J =7.2Hz,6H).

[0583] 2-(4-cyano-2-(trifluoromethyl)phenyl)acetic acid ethyl ester [ka]

[0584] 2-(4-cyano-2-(trifluoromethyl)phenyl)- ... ) A solution of diethyl malonate (15.00 g, 45.60 mmol) was added to LiCl (2.9 To the mixture was added 100 ml of toluene (0.0 g, 68.40 mmol) and water (0.80 mL, 45.6 mmol). The mixture was stirred at 120° C. overnight. After the reaction was complete as indicated by TLC, The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with water (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography (EA / PE=1 / 25) to give the desired product. The product (8.28 g) was obtained as a white solid. 1 H-NMR (300 MHz, CDCl3 )δ7.97(d,J=1.8Hz,1H),7.83(d,J=7.8Hz,1H), 7.57(d,J=7.8Hz,1H),4.18(q,J=7.2Hz,2H),3. 88(s,2H),1.26(t,J=7.2Hz,3H).

[0585] (Z)-2-(4-cyano-2-(trifluoromethyl)phenyl)-3-(dimethyl Ethyl aminoacrylate [ka]

[0586] Ethyl 2-(4-cyano-2-(trifluoromethyl)phenyl)acetate (4 A solution of 1.00 g (15.56 mmol) and DME-DMA (15 mL) was heated at 150 °C. After the reaction was complete as indicated by TLC, the mixture was diluted with water (10 The combined organic layer was diluted with 100 mL of EtOAc (150 mL × 3) and extracted with Na The residue was purified by silica chromatography (EA / PE =1 / 9) to give the desired product (3.2 g) as a brown oil. 1 HN MR(300MHz,CDCl3)δ7.94(s,1H),7.75(d,J=7.8 Hz,1H),7.59(s,1H),7.46(d,J=7.8Hz,1H),3.9 5-4.08(m,2H),2.66(brs,6H),1.10(t,J=7.2Hz ,3H).

[0587] 6-(4-(4-cyano-2-(trifluoromethyl)phenyl)-5-hydroxy- 1H-pyrazol-1-yl)nicotinic acid [ka]

[0588] (Z)-2-(4-cyano-2-trifluoromethyl) in i-PrOH (38 mL) Ethyl (phenyl)-3-(dimethylamino)acrylate (1.00 g, 3.20 mmol ) solution, 6-hydrazinylnicotinic acid (0.59 g, 0.38 mmol) and diluted A solution of distilled HCl (38 mL, 1 M) was added. The reaction was stirred at room temperature for 24 hours. LC After the reaction was complete as indicated by MS analysis, DIEA (15 equiv.) was added and mixed. The mixture was stirred at room temperature for 2 days, and the pH of the mixture was adjusted to 3, after which a large amount of solid was precipitated. After filtration and slurry purification, 90 mg of the desired product was obtained as a solid. HPLC purity was 93.1%. LC-MS (ESI+): m / z 375 (M+H) + ; 1 HN MR(300MHz,DMSO-d6)δ8.98(s,1H),8.47-8.57( m,2H),8.34(s,1H),8.17(d,J=8.4Hz,1H),7.97 -8.02(m,2H).

[0589] Example 41: Preparation of Compound 41 Ethyl 3-oxo-2-(pyridin-4-yl)butanoate [ka]

[0590] The compound was converted to 2- Preparation of methyl (4-cyano-2-fluorophenyl)-3-oxobutanoate according to the procedure Synthesized. LC-MS(ESI+):m / z 208(M+H) +

[0591] 6-(5-hydroxy-3-methyl-4-(pyridin-4-yl)-1H-pyrazole -1-yl)nicotinic acid [ka]

[0592] The compound was converted to 6- (4-(4-cyano-3-fluorophenyl)-5-hydroxy-3-methyl-1H-pyridin (Isopropyl-1-benzoyl)nicotinic acid was synthesized according to the procedure described above. LC-MS (ESI+) : m / z 297(M+H) + ; 1 H-NMR (300MHz, CD3OD) δ 9.00 (s,1H),8.24-8.33(m,4H),7.84(d,J=6.0Hz,2H ), 2.44(s,3H)

[0593] 4-(1-(5-carboxypyridin-2-yl)-5-hydroxy-3-methyl-1 H-pyrazol-4-yl)pyridine 1-oxide [ka]

[0594] 6-(5-hydroxy-3-methyl-4-(pyridin-4-yl)methyl)-2-(2-methyl-4-pyridin-4-yl ... (1H-pyrazol-1-yl)nicotinic acid (190 mg, 0.64 mmol) To the resulting mixture, m-CPBA (166 mg, 0.96 mmol) was added in one portion at room temperature. The mixture was stirred at room temperature for about 2 hours. After the reaction was complete as indicated by HPLC analysis, The reaction mixture was directly purified by preparative HPLC to give 50 mg of the title compound. (ESI+): m / z 313 (M+H) + ; 1 H-NMR (300 MHz, CD3OD) )δ9.03(d,J=2.1Hz,1H),8.61(d,J=6.3Hz,1H), 8.45(m,1H),8.07(d,J=8.7Hz,1H),7.92(d,J=6 .3Hz,1H),2.07(s,3H).

[0595] Example 42: Preparation of Compound 42 2-(3-bromo-4-chlorophenyl)acetic acid methyl ester [ka]

[0596] The compound was converted to 2-(4-bromophenyl)acetic acid using 2-(3-bromo-4-chlorophenyl)acetic acid. It was synthesized according to the procedure for the preparation of methyl 2-methoxyphenyl)acetate. 1 H-NMR(3 00MHz, CDCl3)δ7.55(d,J=1.8Hz,1H),7.40(d,J =8.1Hz,1H),7.17(dd,J=8.1,1.8Hz,1H),3.71( s,3H),3.58(s,2H).

[0597] 2-(4-chloro-3-cyanophenyl)acetic acid methyl ester [ka]

[0598] The compound was converted to 2-(4-bromophenyl)methyl acetate using 2-(3-bromo-4-chlorophenyl)acetate. The compound was synthesized according to the procedure for the preparation of methyl (-cyano-2-fluorophenyl)acetate. 1 H-NM R(300MHz,CDCl3)δ7.61(s,1H),7.48(s,2H),3. 73(s,3H),3.64(s,2H).

[0599] 2-(4-chloro-3-cyanophenyl)-3-oxobutanoic acid methyl ester [ka]

[0600] The compound was purified by 2-(4-chloro-3-cyanophenyl)methyl acetate. Synthesized according to the procedure for the preparation of methyl (-cyano-3-fluorophenyl)-3-oxobutanoate The crude product was used directly in the next step without further treatment.

[0601] 6-(4-(4-chloro-3-cyanophenyl)-5-hydroxy-3-methyl-1H -pyrazol-1-yl)nicotinic acid [ka]

[0602] The compound was purified using methyl 2-(4-chloro-3-cyanophenyl)-3-oxobutanoate. 6-(4-(4-cyano-3-fluorophenyl)-5-hydroxy-3-methyl (1H-pyrazol-1-yl)nicotinic acid was synthesized according to the procedure described above. LC-MS (ESI+): m / z 355 (M+H) + ; 1 H-NMR (300 MHz, DMSO- d6)δ8.95(s,1H),8.57(d,J=6.9Hz,1H),8.43(m ,1H),8.22(s,1H),8.03(d,J=9.0Hz,1H),7.75( d, J = 9.0 Hz, 1H), 1.91 (s, 3H).

[0603] Example 43: Preparation of Compound 43 2-(6-oxo-1,6-dihydropyridin-3-yl)acetic acid: [ka]

[0604] 2-(6-chloropyridine-3-yl)pyridine in glacial acetic acid (13.0 mL) and water (3.0 mL) A mixture of 1.0 g (6.4 mmol) methyl-2-benzothiazolinone (2.0 g, 1.0 mmol) and 2.0 mmol of methyl-2-benzothiazolinone (2.0 g, 1.0 mmol) was heated in a sealed tube at 150 °C for 3.0 days. The solution was cooled and evaporated to give a residue. The residue was re-evaporated from toluene to give 2-(6-oxo-1,6-dihydropyridin-3-yl)acetic acid (1.1 g, crude) was added to brown rice. Obtained as a colored solid. LC-MS: m / z=154.1 [M+H] + , retention time 1.63 minutes (Method A). The crude product was used in the next step.

[0605] 2-(6-oxo-1,6-dihydropyridin-3-yl)methyl acetate: [ka]

[0606] 2-(6-oxo-1,6-dihydropyridine-3- To a solution of (methyl)acetic acid (1.1 g, crude) was added concentrated sulfuric acid (0.5 mL). The mixture was heated at room temperature. The mixture was stirred for 15 hours and concentrated. The residue was diluted with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. 2-(6-oxo-1,6-dihydropyridin-3-yl)methyl acetate (800 mg 4.79 mmol, 74.8% yield) was obtained as a white solid. LC-MS: m / z=1 68.1[M+H] + , retention time 1.35 min (Method A).

[0607] 2-(6-Methoxypyridin-3yl)acetic acid methyl ester [ka]

[0608] 2-(6-oxo-1,6-dihydropyridinone) in anhydrous tetrahydrofuran (20.0 mL) Lysin-3-yl)methyl acetate (450 mg, 2.69 mmol) and cesium carbonate ( A solution of 1.05 g, 3.23 mmol) of iodomethane (580 mg, 4.20 mmol) l) was added. The mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was Purification by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) gave 2 -(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetate methyl ester and 2-(6-methoxypyridin-3-yl)methyl acetate (400 mg, 2.21 mmol, The mixture was obtained as a yellow oil in a yield of 82.1%. LC-MS: m / z = 182.1 ( M+H) + , retention time 1.33 min (Method A).

[0609] (E)-3-(dimethylamino)-2-(6-methoxypyridin-3-yl)acrylic acid Methyl acetate [ka]

[0610] 2-(1-methyl-6-oxo-1-methylpropional) in N,N-dimethylformamide (5.0 mL) ,6-Dihydropyridin-3-yl) methyl acetate and 2-(6-methoxypyridine-3 To a solution of methyl (-yl)acetate (400 mg, 2.21 mmol), N,N-dimethylformamide was added To the mixture was added methylamide diethyl acetal (1.63 g, 11.1 mmol). Stirred overnight at 100° C. and cooled. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give (E)-3-( Dimethylamino)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl (E)-3-(dimethylamino)-2-(6-methoxypyridine) methyl acrylate and (E)-3-(dimethylamino)-2-(6-methoxypyridine) methyl acrylate Methyl acrylate (400 mg, 1.69 mmol, 76.7% yield) A mixture of the above was obtained as a yellow oil. LC-MS: m / z=237.1 [M+H] + , when held Time 1.08 min, 1.51 min (Method B). The mixture was used in the next step.

[0611] 6-(5-hydroxy-4-(6-methoxypyridin-3-yl)-1H-pyrazole (1-yl)nicotinic acid tert-butyl ester [ka]

[0612] (E)-3-(dimethylamino)-2-(1-methyl-) in ethanol (5.0 mL) 6-oxo-1,6-dihydropyridin-3-yl)acrylate methyl and (E)-3 -(dimethylamino)-2-(6-methoxypyridin-3-yl)acrylate methyl (3 A mixture of 50 mg of HCl (1.48 mmol) was stirred in a sealed tube at 90°C for 16.0 hours and then cooled. The insoluble solid was filtered off and the filtrate was concentrated to dryness. The two isomers were separated by reverse phase preparative H It was isolated by PLC as a white solid. Lysin-3-yl)-1H-pyrazol-1-yl)nicotinic acid tert-butyl ester (76 mg, 0.21 mmol, yield 27.9%). LC-MS:m / z=369.0[M+H ] + , retention time 2.29 minutes (Method A). 1 H NMR (500 MHz, DMSO-d6) δ 12.97(br,1H),8.91(d,J=1.5Hz,1H),8.70(s,1 H),8.47-8.39(m,2H),8.19-8.14(m,1H),6.85- 6.83 (m, 1H), 3.85 (s, 3H), 1.58 (s, 9H).

[0613] 6-(5-hydroxy-4-(6-methoxypyridin-3-yl)-1H-pyrazole -1-yl)nicotinic acid [ka]

[0614] 6-(5-hydroxy-4-(6-methoxypyridinium chloride) in dichloromethane (6.0 mL) (3-yl)-1H-pyrazol-1-yl) tert-butyl nicotinate (76mg To a solution of 1,2-dimethyl-3,4-trifluoroacetic acid (3.0 mL) was added the mixture. The mixture was stirred at room temperature overnight and concentrated. The residue was triturated with ethyl acetate, filtered, and purified to give 6-(5-hydroxybenzoate). 4-(6-methoxypyridin-3-yl)-1H-pyrazol-1-yl)nico The resulting carboxylic acid (5.4 mg, 0.017 mmol, 8.2% yield) was obtained as a white solid. -MS: m / z=313.0 [M+H] + , retention time 3.73 minutes (Method A).1 H NMR (400MHz,DMSO-d6)δ13.47(br,1H),13.06(br,1 H),8.96(s,1H),8.73-8.44(m,4H),8.21-8.18( m, 1H), 6.84 (d, J=8.8Hz, 1H), 3.85 (s, 3H).

[0615] Example 44: Preparation of Compound 44 Diethyl 2-(3-chloro-4-cyanophenyl)malonate [ka]

[0616] The compound was converted to 2-(2-bromo- It was synthesized according to the procedure for the preparation of diethyl 4-cyanophenylmalonate. 1 H-NMR(3 00MHz, CDCl3)δ7.68(d,J=8.1Hz,1H),7.61(d,J =1.2Hz,1H),7.45(dd,J=8.1,1.2Hz,1H),4.63( s,1H),4.30(q,J=6.9Hz,4H),1.26(t,J=6.9Hz, 6H).

[0617] 2-(3-chloro-4-cyanophenyl)acetic acid ethyl ester [ka]

[0618] The compound was 2-(3-chloro-4-cyanophenyl)diethyl malonate. The compound was synthesized according to the procedure for the preparation of ethyl 2-bromo-4-cyanophenylacetate. 1 H- NMR(300MHz, CDCl3)δ7.63(d,J=8.1Hz,1H),7.4 7(d,J=1.2Hz,1H),7.27(dd,J=8.1,1.2Hz,1H), 4.22(q,J=6.9Hz,2H),3.66(s,2H),1.26(t,J=6 .9Hz,3H).

[0619] (E)-3-Acetoxy-2-(3-chloro-4-cyanophenyl)but-2-enoic acid ethyl [ka]

[0620] The compound was converted to 6-(4 -(4-cyano-2-fluorophenyl)-5-hydroxy-3-methyl-1H-pyrazo LC-MS (ESI+): m / z 330(M+Na) + .

[0621] 6-(4-(3-chloro-4-cyanophenyl)-5-hydroxy-3-methyl-1H -pyrazol-1-yl)nicotinic acid [ka]

[0622] The compound was prepared as (E)-3-acetoxy-2-(3-chloro-4-cyanophenyl)buta- Ethyl 2-enoate was used to prepare 6-(4-(4-cyano-3-fluorophenyl)-5- Preparation of Hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid according to the procedure Synthesized. LC-MS(ESI+):m / z 355(M+H) + ; 1 H-NMR (30 0MHz,DMSO-d6)δ13.35(brs,2H),8.95(s,1H),8 .57(d,J=9.0Hz,1H),8.42(d,J=9.0,1.8Hz,1H) ,8.14(s,1H),7.92(d,J=8.4Hz,1H),7.82(d,J= 8.4Hz,1H),2.53(s,3H).

[0623] Example 45: In vitro assay demonstrates PHD inhibition Enzymatic half-maximal inhibitory concentration (IC 50 ) values ​​were determined on selected compounds of the present invention.

[0624] Using time-resolved fluorescence resonance energy transfer (TR-FRET) assay, full-length human Prolyl-4-hydroxylase domain (PHD) enzymes, PHD1, PHD2, and The half-maximal inhibitory concentration (IC) of PHD inhibitors against PHD3 50 The TR value was determined. The FRET assay utilizes hydroxylated HIF-1α peptides, which generate a fluorescent signal. The specific interaction of the complex formed by VHL, EloB, and EloC (VBC) with The terbium (Tb)-donor (antimonoclonal) of TR-FRET was developed based on the specific binding. monoclonal antibody, anti-6His-Tb-cryptate gold) and D2-acceptor ( Streptavidin [SA]-D2) binds to the VBC complex and HIF-1α peptide, respectively. The VBC complex binds specifically to the HIF-1α peptide when hydroxylated. , allowing energy transfer from the TR-FRET donor to the acceptor (Figure 1).

[0625] material and method Unless otherwise noted, all chemicals and materials were of standard laboratory grade. It was purchased from Sigma-Aldrich (St. Louis, MO, USA).

[0626] reagent TR-FRET Reagents Monoclonal antibody, anti-6His-Tb-cryptate gold (Cat. No. 61H I2TLA) and streptavidin (SA)-D2 (Cat. no. 610SADLA ) from CisBio International (Bedford, MA, USA) I bought it from

[0627] Represents amino acids 547-581, including the proline 564 PHD2 hydroxylation site N-terminally biotinylated HIF-1α C35 synthetic peptide was purified from California Pep Purchased from Tide Research (Salt Lake City, UT, USA) did.

[0628] Recombinant proteins VBC complex His-tagged recombinant VHL protein, EloB, and EloC complex (His-VBC ) was supplied by Axxam (Milan, Italy). National Center for Biotechnology Inform ation [NCBI] accession number NP_00542.1) is located between amino acids 55 and The VHL-His gene contains a His tag at the C-terminus of 213 and is called VHL-His. Full-length human EloB (NCBI accession number Q15370.1) and full-length human Co-expressed with EloC (NCBI accession number Q15369.1) in E. coli The His-VBC complex was then purified by precipitation onto a nickel-nitrilotriacetic acid (Ni-NTA) column. The purity (approximately 80%) was confirmed by affinity chromatography using sodium dodecyl sulfate. The results were evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE).

[0629] PHD1 Recombinant human PHD1 protein (Cat. No. 81064, Lot No. 2471700 1) was purchased from Active Motif (Carlsbad, CA, USA). PHD1 was expressed as a full-length protein with an N-terminal FLAG tag (molecular weight 44.9 kDa). (NCBI accession number NP_542770.2) as a baculovirus expression system Purity (>90%) was assessed by SDS-PAGE.

[0630] PHD2 The full-length human PHD2 enzyme was synthesized in Beryllium (Bedford, MA, USA). The PHD2 construct was produced using a baculovirus-infected insect cell (BIIC) expression system. The material is amino acids 1 to 426 of PHD2 (UniProt Knowledgebase [ UniProtKB] / Swiss-Prot accession number Q9GZT9.1), and a His tag and tobacco etch virus (TEV) protease cleavage site at the N-terminus The construct was expressed in Sf9 insect cells and purified by Ni-NTA column. The His tag was removed by digestion with TEV protease. was assessed by SDS-PAGE and found to be greater than 94% pure.

[0631] PHD3 Recombinant human PHD3 protein (molecular weight 31.1 kDa) was used in Active Motif This was purchased from Sigma-Aldrich (Carlsbad, CA, USA) with an N-terminal 6-His tag ( Catalog No. 81033, Lot No. 24417001) along with the full-length protein ( It was expressed in E. coli under the NCBI accession number NP_071356.1. Purity was assessed by SDS-PAGE and found to be >75% pure.

[0632] PHD inhibitors. Small molecule PHD inhibitors were synthesized and their identities confirmed as described herein .

[0633] TR-FRET assay procedure PHD inhibitor compounds were plated in white 384-well Optiplate microplates (catalyzed Log No. 6007290, Perkin Elmer, Waltham, MA, USA) The mixture was pre-incubated with PHD enzyme in a 10 μL reaction volume. PHD inhibitor compounds were diluted in dilution buffer (50 mM HEPES [4-(2-hydroxyethyl) )-1-piperazineethanesulfonic acid] pH 7.5, 50 mM sodium chloride [NaC l], 0.01% Tween-20, 0.01% purified bovine serum albumin [BSA] ) and prepared as a 4x concentrate in dilution buffer containing PHD enzyme. PHD enzyme mix (60 nM PHD1, 20 nM PHD2, 140 nM PHD 3), 40 μM ferrous ammonium sulfate (FAS), 4 mM sodium ascorbate The plate was incubated at room temperature without rotation for 30 minutes. Ta.

[0634] Then, 20 nM His-VBC, 1.32 nM monoclonal antibody, anti-6His prepared as a 4-fold concentrate in dilution buffer containing -Tb-cryptate gold, 5 Add microliters of VBC / anti-6His-Tb-cryptate gold mix. Immediately after this step, 120 nM biotin-labeled HIF-1α C35, 132 nM of SA-D2 in dilution buffer containing 4 μM 2-oxoglutarate (2-OG) Add 5 μL of HIF-1α C35 substrate mix, prepared as a 4x concentrate, and incubate for 2 A final reaction volume of 0 μL was reached.

[0635] The final assay reaction consisted of 50 mM HEPES, pH 7.5, 50 mM NaCl, 1 10 μM 2-OG, 10 μM FAS, 1 mM Na ascorbate, 0.01% Twe en-20, 0.01% purified BSA, 30 nM biotin-labeled HIF-1α C35, 5 nM His-VBC, 0.33 nM monoclonal antibody, anti-6His-Tb-Cl acetate gold, 33 nM SA-D2, and PHD enzymes (15 nM PHD1, 5 100 nM PHD2, or 35 nM PHD3) along with diluted compounds.

[0636] IC of PHD inhibitor compounds 50 For measurements, the reaction was incubated at room temperature for 10 minutes. and then at an excitation wavelength of 340 nm and emission wavelengths of 615 nm and 665 nm. He is the head of Perkin Elmer EnVision (Waltham, MA, USA). The data was read using Envision Manager software (Perk in Elmer, Waltham, MA, USA) It represents the quotient of the signal intensities at 5 nm and 615 nm. 50 Values ​​(mean, standard deviation, average Standard error, geometric mean, and 95% confidence interval) were calculated using GraphPad Prism 7. 0 (GraphPad, La Jolla, CA, USA) to generate a 4-parameter song. Determined using a line fit and plotted against the calculated ratio of 665 nm and 615 nm The TR-FRET assay was performed in triplicate at each compound concentration. It was repeated three times independently.

[0637] Ki is calculated based on the following Cheng-Prusoff equation: 50 It was calculated from. Ki = IC50 / (1+[2-OG] / Km)

[0638] The final concentration of 2-OG in both the PHD1 and PHD2 assays was 1 u The Km of 2-OG for PHD1 was determined to be 12.7 nM, while the Km of 2-OG for PHD1 was determined to be 12.7 nM. The Km of 2-OG for D2 was determined to be 22.6 nM. Exemplary Compounds [Table 4] TIFF2026021443000277.tif245170TIFF2026021443000278.tif244170TIFF2026021443 000279.tif245170TIFF2026021443000280.tif245170TIFF2026021443000281.tif59170

[0639] From the present description, one skilled in the art can easily ascertain the essential characteristics of the present invention and understand its purpose. and variations of the present invention may be made to adapt it to various uses and conditions without departing from its scope. Various changes and modifications may be made.

[0640] All U.S. or foreign references, patents, or applications cited in this application are expressly incorporated herein by reference. No. 6,023,499, all of which are incorporated herein by reference in their entireties as if set forth herein. In the event of any discrepancy, the material literally disclosed herein will prevail. The present application provides the following aspects of the invention. (Aspect 1) A compound of formula A, (chemical 1) TIFF2026021443000282.tif25170 or a pharmaceutically acceptable salt thereof, wherein: Ar 1 is phenyl or a 6-membered nitrogen-containing heteroaryl, Heteroaryl is optionally substituted with halogen, CN, OH, one or more halogens. TaC 1-3 Alkyl, or C 1-3 optionally substituted with alkoxy; R 2 is H or C alkyl, Ar 2 is a halogen, OH, amine, or C 1-3 6-membered optionally alkyl-substituted is a nitrogen-containing heteroaryl of the formula R 4 is hydrogen or C 1-4 is alkyl, Formula (A) represents the following compound: (Case 2) A compound of Formula A or a pharmaceutically acceptable salt thereof, excluding TIFF2026021443000283.tif108170. (Aspect 2) Ar 1 teeth, (3) TIFF2026021443000284.tif19170, wherein: X, Y, and Z are independently CH or N, wherein N is optionally oxidized; Each R 1 are independently hydrogen, halogen, CN, OH, optionally one or more halogens Substituted C 1-3 Alkyl, and C 1-3 alkoxy; The compound of embodiment 1, wherein m is 1, 2, 3, or 4. (Aspect 3) Ar 1 at least one R is CN or halogen 1 Phenylene substituted by 3. The compound of claim 1 or 2, wherein (Aspect 4) Ar 1 C optionally substituted with one or more halogens 1-3 Alkyl, halogen one or two R independently selected from , CN, or OH; 1 substituted with a group, The compound described in Example 3. (Aspect 5) Ar 1 is a pyridyl N-oxide, or C 1-3 Alkoxy or halogen At least one R 1 In one embodiment, pyridyl is optionally substituted by The compound described in (Aspect 6) Ar 2 but, (C4) TIFF2026021443000285.tif24170, wherein: A and B are independently CH or N, wherein N is optionally oxidized; Each R 3 are independently hydrogen, halogen, OH, amine, and C 1-3 consisting of alkyl selected from the group The compound according to any one of embodiments 1 to 5, wherein n is 0, 1, or 2. (Aspect 7) Ar 2 is a pyridyl or pyrazinyl group, said group being unsubstituted or or halogen, C 1-3 Any of embodiments 1-6, including a substituent that is alkyl, or OH. 3. The compound according to claim 1. (Aspect 8) R 2The compound of any one of embodiments 1-7, wherein is H or CH3. (Aspect 9) R 4 The compound according to any one of embodiments 1 to 8, wherein is H. (Aspect 10) R 4 But C 1-4 The compound according to any one of embodiments 1 to 8, wherein the compound is alkyl. (Aspect 11) A structure according to formula (I): (C5) TIFF2026021443000286.tif28170 or a pharmaceutically acceptable salt thereof, wherein: X, Y, Z, A, and B are independently CH or N, wherein N is optionally oxidized; m is 1, 2, 3, or 4; n is 0, 1, or 2; Each R 1 are independently hydrogen, halogen, CN, OH, optionally one or more halogens Substituted C 1-3 Alkyl, and C 1-3 alkoxy; R 2 is hydrogen or C1-3 alkyl, Each R 3 are independently hydrogen, halogen, OH, amine, and C 1-3 consisting of alkyl selected from the group R 4 is hydrogen or C 1-4 The compound according to embodiment 1, wherein the aryl group is alkyl. (Aspect 12) The structure of formula (Ia): (6) 12. The compound of embodiment 11, having TIFF2026021443000287.tif29170 or a pharmaceutically acceptable salt thereof. (Aspect 13) A structure of formula (Ib): (C7) 12. The compound of embodiment 11, having TIFF2026021443000288.tif33170, or a pharmaceutically acceptable salt thereof. (Aspect 14) The structure of formula (Ic): (C8) 12. The compound of embodiment 11, having TIFF2026021443000289.tif33170 or a pharmaceutically acceptable salt thereof. (Aspect 15) A structure according to formula (II): (9) TIFF2026021443000290.tif37170 or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, 3, or 4; n is 0, 1, or 2; R 1 are independently each time hydrogen, halogen, CN, OH, one or more halogens, or C replaced by 1-3 Alkyl, and C 1-3 alkoxy; R 2 is hydrogen or C1-3 alkyl, R 3 are each independently hydrogen, halogen, OH, amine, or C 1-3 From alkyl is selected from the group R 4 is hydrogen or C 1-4 The compound according to embodiment 1, wherein the aryl group is alkyl. (Aspect 16) The structure of formula (IIa): (C10) 16. The compound of embodiment 15, having TIFF2026021443000291.tif41170, or a pharmaceutically acceptable salt thereof. (Aspect 17) The structure of formula (IIb): (Chem.11) 16. The compound of embodiment 15, having TIFF2026021443000292.tif36170, or a pharmaceutically acceptable salt thereof. (Aspect 18) The structure of formula (IIc): (C12) 16. The compound of embodiment 15, having TIFF2026021443000293.tif33170, or a pharmaceutically acceptable salt thereof. (Aspect 19) The structure of formula (IId): (C13) 16. The compound of embodiment 15, having TIFF2026021443000294.tif33170, or a pharmaceutically acceptable salt thereof. (Aspect 20) The structure of formula (IIe): (C14) 16. The compound of embodiment 15, having TIFF2026021443000295.tif33170, or a pharmaceutically acceptable salt thereof. (Aspect 21) The structure of formula (IIf): (C15) 16. The compound of embodiment 15, having TIFF2026021443000296.tif30170, or a pharmaceutically acceptable salt thereof. (Aspect 22) The structure of formula (IIg): (C16) 16. The compound of embodiment 15, having TIFF2026021443000297.tif32170, or a pharmaceutically acceptable salt thereof. (Aspect 23) A structure according to formula III: (C17) TIFF2026021443000298.tif32170 or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, 3, or 4; n is 0, 1, or 2; R 1 are independently each time hydrogen, halogen, OH, and optionally one or more halogens. C replaced by 1-3 is selected from the group consisting of alkyl, R 2 is hydrogen or C1-3 alkyl, R 3 are each independently hydrogen, halogen, OH, amine, and C 1-3 From alkyl is selected from the group R 4 is hydrogen or C 1-4 is alkyl, R 5 is CN or halogen. (Aspect 24) The structure of formula (IIIa): (C18) 24. The compound of embodiment 23, having TIFF2026021443000299.tif41170, or a pharmaceutically acceptable salt thereof. (Aspect 25) The structure of formula (IIIb): (C19) 24. The compound of embodiment 23, having TIFF2026021443000300.tif42170, or a pharmaceutically acceptable salt thereof. (Aspect 26) The structure of formula (IIIc): (20) 24. The compound of embodiment 23, having TIFF2026021443000301.tif42170, or a pharmaceutically acceptable salt thereof. (Aspect 27) The structure of formula (IIId): (21) 24. The compound of embodiment 23, having TIFF2026021443000302.tif40170, or a pharmaceutically acceptable salt thereof. (Aspect 28) The structure of formula (IIIe): (22) 24. The compound of embodiment 23, having TIFF2026021443000303.tif36170, or a pharmaceutically acceptable salt thereof. (Aspect 29) A structure of formula (IIIf): (23) 24. The compound of embodiment 23, having TIFF2026021443000304.tif35170, or a pharmaceutically acceptable salt thereof. (Aspect 30) A structure of formula III(g): (24) 24. The compound of embodiment 23, having TIFF2026021443000305.tif29170, or a pharmaceutically acceptable salt thereof. (Aspect 31) The compound of embodiment 11, 12, or 14, wherein X is CH. (Aspect 32) The compound of embodiment 11, 12, or 14, wherein X is N. (Aspect 33) 33. The compound according to embodiment 32, wherein N is optionally oxidized. (Aspect 34) The compound of embodiment 11, 12, or 14, wherein Y is CH. (Aspect 35) The compound of embodiment 11, 12, or 14, wherein Y is N. (Aspect 36) The compound of embodiment 11, 12, or 14, wherein Z is CH. (Aspect 37) The compound of embodiment 11, 12, or 14, wherein Z is N. (Aspect 38) The compound of embodiment 11, 12, or 14, wherein A is CH. (Aspect 39) The compound of embodiment 11, 12, or 14, wherein A is N. (Aspect 40) The compound of embodiment 11, 12, or 14, wherein B is CH. (Aspect 41) The compound of embodiment 11, 12, or 14, wherein B is N. (Aspect 42) The compound according to any one of embodiments 11 to 30, wherein m is 1. (Aspect 43) The compound according to any one of embodiments 11 to 30, wherein m is 2. (Aspect 44) The compound according to any one of embodiments 11 to 30, wherein m is 3. (Aspect 45) A compound according to any one of aspects 11 to 22, wherein m is 4. (Aspect 46) any one of embodiments 11 to 16, 19, 22 to 24, 27, and 30, wherein n is 0; The compound described. (Aspect 47) any one of embodiments 11 to 16, 19, 22 to 24, 27, and 30, wherein n is 1; The compound described. (Aspect 48) any one of embodiments 11 to 16, 19, 22 to 24, 27, and 30, wherein n is 2; The compound described. (Aspect 49) R 1 The compound according to any one of embodiments 11 to 30, wherein is hydrogen. (Aspect 50) R 1 The compound according to any one of embodiments 11 to 30, wherein is halogen. (Aspect 51) R 1 is F. (Aspect 52) R 1 51. The compound according to embodiment 50, wherein is Cl. (Aspect 53) R 1 51. The compound according to embodiment 50, wherein is Br. (Aspect 54) R 1 The compound of any one of embodiments 11-30, wherein is CN. (Aspect 55) R 1 The compound according to any one of embodiments 11 to 30, wherein is OH. (Aspect 56) R 1 C optionally substituted with one or more halogens 1-3 alkyl, The compound according to any one of 11 to 30. (Aspect 57) R 1 But C 1-3 57. The compound according to embodiment 56, wherein the aryl group is alkyl. (Aspect 58) R 1 57. The compound according to embodiment 56, wherein is methyl. (Aspect 59) R 1 57. The compound according to embodiment 56, wherein is ethyl. (Aspect 60) R 1 57. The compound of embodiment 56, wherein (Aspect 61) R 1 But C 1-3 The compound according to any one of embodiments 11 to 30, which is alkoxy. (Aspect 62) R 1 62. The compound according to embodiment 61, wherein is methoxy. (Aspect 63) R 2 The compound according to any one of embodiments 11-18 and 23-26, wherein is hydrogen. (Aspect 64) R 2 But C 1-3 any one of embodiments 11 to 18 and 23 to 26, wherein The compound described. (Aspect 65) R 2 65. The compound according to embodiment 64, wherein is methyl. (Aspect 66) R 3 is hydrogen. Item 1. The compound according to item 1. (Aspect 67) R 3 Any of embodiments 11-16, 19, 22-24, 27, and 30, wherein 3. The compound according to claim 1. (Aspect 68) R 3 57. The compound according to embodiment 56, wherein (Aspect 69) R 3 Any one of embodiments 11-16, 19, 22-24, 27, and 30, wherein Item 1. The compound according to item 1. (Aspect 70) R 3 Any of embodiments 11-16, 19, 22-24, 27, and 30, wherein The compound according to claim 1. (Aspect 71) R 3 71. The compound of embodiment 70, wherein (Aspect 72) R 3 But C 1-3 alkyl, in embodiments 11 to 16, 19, 22 to 24, 27 and 3. 10. The compound according to any one of claims 1 to 8. (Aspect 73) R 3 73. The compound of embodiment 72, wherein is methyl. (Aspect 74) R 4 Any of embodiments 11-15, 17, 20, 22, 25, 28, and 30, wherein The compound according to any one of claims 1 to 4. (Aspect 75) R 4 But C 1-4 alkyl, embodiments 11 to 15, 17, 20, 22, 25, and 30. The compound according to any one of claims 1 to 30. (Aspect 76) R 4 76. The compound according to embodiment 75, wherein is methyl. (Aspect 77) R 4 76. The compound according to embodiment 75, wherein is ethyl. (Aspect 78) R 4 76. The compound according to embodiment 75, wherein is isopropyl. (Aspect 79) R 4 76. The compound according to embodiment 75, wherein is tert-butyl. (Aspect 80) R 5The compound according to any one of aspects 23 to 30, wherein is F. (Aspect 81) R 5 The compound according to any one of aspects 23 to 30, wherein is Cl. (Aspect 82) R 5 The compound according to any one of embodiments 23 to 30, wherein is Br. (Aspect 83) R 5 The compound of any one of embodiments 23-30, wherein is CN. (Aspect 84) (Table 1) TIFF2026021443000306.tif238170TIFF2026021443000307.tif239170TIFF2026021443000308.tif97170, or a pharmaceutically acceptable salt thereof. (Aspect 85) 85. Any one of embodiments 1 to 84, wherein at least one hydrogen atom is replaced with a deuterium atom. The compound described herein or a pharmaceutically acceptable salt thereof. (Aspect 86) A compound according to any one of aspects 1 to 85 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable excipient. (Aspect 87) 86. A method for treating a disease mediated by PHD activity, comprising administering to a subject a compound of claim 1, a compound of claim 2, a compound of claim 3, a compound of claim 4, a compound of claim 5, a compound of claim 6, a compound of claim 7, a compound of claim 8, a compound of claim 9, a compound of claim 10, a compound of claim 11, a compound of claim 12, a compound of claim 13, a compound of claim 14, a A method comprising administering to a subject a compound described in any one of claims 1 to 4. (Aspect 88) 88. The method of claim 87, wherein the disease mediated by PHD activity is ischemia-reperfusion injury. method. (Aspect 89) Embodiment 8, wherein the ischemia-reperfusion injury is selected from stroke, myocardial infarction, and acute kidney injury. 8. The method according to claim 8. (Aspect 90) 88. The method of claim 87, wherein the disease mediated by PHD activity is inflammatory bowel disease. Law. (Aspect 91) 91. The method of embodiment 90, wherein the inflammatory bowel disease is ulcerative colitis. (Aspect 92) 91. The method of embodiment 90, wherein the inflammatory bowel disease is Crohn's disease. (Aspect 93) 88. The method of embodiment 87, wherein the disease mediated by PHD activity is cancer. (Aspect 94) 94. The method of embodiment 93, wherein the cancer is colorectal cancer. (Aspect 95) 88. The method of embodiment 87, wherein the disease mediated by PHD activity is a liver disease. (Aspect 96) 87. The disease mediated by PHD activity is atherosclerosis. The method described below. (Aspect 97) 88. The method of embodiment 87, wherein the disease mediated by PHD activity is a cardiovascular disease. . (Aspect 98) 88. The method of claim 87, wherein the disease mediated by PHD activity is an ocular disease or condition. How to post. (Aspect 99) The ocular disease or condition is radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macula, 99. The method of embodiment 98, wherein the ocular ischemia is selected from the group consisting of ocular degeneration and ocular ischemia. (Aspect 100) 88. The method of embodiment 87, wherein the disease is anemia. (Aspect 101) 101. The method of embodiment 100, wherein the anemia is anemia associated with chronic kidney disease. (Aspect 102) 88. The method of embodiment 87, wherein the disease is chronic kidney disease. (Aspect 103) 88. The method of embodiment 87, wherein the disease is associated with hyperoxia. (Aspect 104) 104. The method of embodiment 103, wherein the disease is retinopathy of prematurity. (Aspect 105) 104. The method of embodiment 103, wherein the disease is bronchopulmonary dysplasia (BPD). (Aspect 106) The disease is ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary Select from hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, and liver cirrhosis 88. The method of embodiment 87, wherein

Claims

1. A compound of formula A, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: Ar １ is phenyl, said phenyl being selected from the group consisting of one or more of halogen, CN, OH, C optionally substituted with halogen １－３ Alkyl, or C １－３ Alkoxy substituted 、 R ２ is H or C １ - ３ is alkyl, Ar ２ is a halogen, OH, amine, or C １－３ 6-membered optionally substituted with alkyl is a nitrogen-containing heteroaryl of the formula R ４ is hydrogen or C １－４ alkyl, and Formula (A) represents the following compound: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, excluding:

2. Ar １ at least one R is CN or halogen １ Phenylene substituted by The compound of claim 1, wherein

3. Ar １ C optionally substituted with one or more halogens １－３ Alkyl, halogen one or two R independently selected from , CN, or OH; １ substituted with a group, The compound according to claim 2.

4. Ar ２ but, 【Transformation 3】 wherein: A and B are independently CH or N, wherein N is optionally oxidized; Each R ３ are independently hydrogen, halogen, OH, amine, and C １－３ consisting of alkyl selected from the group The compound of any one of claims 1 to 3, wherein n is 0, 1, or 2.

5. Ar ２ is a pyridyl or pyrazinyl group, said group being unsubstituted or or halogen, C １－３ Any of claims 1 to 4, containing a substituent that is alkyl, or OH. The compound according to any one of claims 1 to 4.

6. R ２ is H or CH ３ The compound according to any one of claims 1 to 5,

7. R ４ The compound of any one of claims 1 to 6, wherein is H.

8. R ４ But C １－４ The compound of any one of claims 1 to 6, which is alkyl.

9. The structure of formula (Ib): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein: R １ is independently each time halogen, CN, OH, optionally substituted with one or more halogens C １－３ Alkyl, and C １－３ alkoxy; A and B are independently CH or N, wherein N is optionally oxidized; and Each R ３ are independently hydrogen, halogen, OH, amine, and C １－３ consisting of alkyl 2. The compound of claim 1 selected from the group:

10. A structure according to formula (II): 【Transformation 5】 or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, 3, or 4; n is 0, 1, or 2; R １ is independently each time halogen, CN, OH, optionally substituted with one or more halogens C １－３ Alkyl, and C １－３ alkoxy; R ２ is hydrogen or C １ - ３ is alkyl, R ３ are each independently hydrogen, halogen, OH, amine, or C １－３ From alkyl and R ４ is hydrogen or C １－４ The compound of claim 1 , wherein the aryl group is alkyl.

11. The structure of formula (IIa): 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

12. The structure of formula (IIb): 【Transformation 7】 or a pharmaceutically acceptable salt thereof.

13. The structure of formula (IIc): 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

14. The structure of formula (IId): 【Chemistry 9】 or a pharmaceutically acceptable salt thereof.

15. The structure of formula (IIe): 【Chemistry 10】 or a pharmaceutically acceptable salt thereof.

16. A structure of formula (IIf): 【Chemistry 11】 or a pharmaceutically acceptable salt thereof.

17. The structure of formula (IIg): 【Chemistry 12】 or a pharmaceutically acceptable salt thereof.

18. A structure according to formula III: 【Chemistry 13】 or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, 3, or 4; n is 0, 1, or 2; R １ is independently each time a halogen, OH, and optionally substituted with one or more halogens C １－３ is selected from the group consisting of alkyl, R ２ is hydrogen or C １ - ３ is alkyl, R ３ are each independently hydrogen, halogen, OH, amine, and C １－３ From alkyl is selected from the group R ４ is hydrogen or C １－４ is alkyl, R ５ is CN or a halogen.

19. The structure of formula (IIIa): 【Chemistry 14】 19. The compound of claim 18, wherein:

20. The structure of formula (IIIb): 【Chemistry 15】 19. The compound of claim 18, wherein:

21. The structure of formula (IIIc): 【Chemistry 16】 19. The compound of claim 18, wherein:

22. The structure of formula (IIId): 【Chemistry 17】 19. The compound of claim 18, wherein:

23. The structure of formula (IIIe): [Chemistry 18] 19. The compound of claim 18, wherein:

24. The structure of formula (IIIf): 【Chemistry 19】 19. The compound of claim 18, wherein:

25. A structure of formula III(g): 【Chemistry 20】 19. The compound of claim 18, wherein:

26. The compound of any one of claims 9 to 25, wherein m is 1.

27. The compound of any one of claims 9 to 25, wherein m is 2.

28. The compound of any one of claims 9 to 25, wherein m is 3.

29. The compound according to any one of claims 9 to 17, wherein m is 4.

30. Any one of claims 9 to 11, 14, 17 to 19, 22 and 25, wherein n is 0. The compound described.

31. Any one of claims 9 to 11, 14, 17 to 19, 22 and 25, wherein n is 1. The compound described.

32. Any one of claims 9 to 11, 14, 17 to 19, 22 and 25, wherein n is 2. The compound described.

33. R １ The compound of any one of claims 9 to 25, wherein is halogen.

34. R １ 34. The compound of claim 33, wherein is F.

35. R １ 34. The compound of claim 33, wherein is Cl.

36. R １ 34. The compound of claim 33, wherein is Br.

37. R １ The compound of any one of claims 9 to 25, wherein is CN.

38. R １ The compound of any one of claims 9 to 25, wherein is OH.

39. R １ C optionally substituted with one or more halogens １－３ alkyl, Item 26. The compound according to any one of items 9 to 25.

40. R １ But C １－３ 40. The compound of claim 39, which is alkyl.

41. R １ 40. The compound of claim 39, wherein is methyl.

42. R １ 40. The compound of claim 39, wherein is ethyl.

43. R １ is CF ３ 40. The compound of claim 39, wherein:

44. R １ But C １－３ The compound of any one of claims 9 to 25, which is alkoxy.

45. R １ 45. The compound of claim 44, wherein is methoxy.

46. R ２ The compound of any one of claims 9 to 13 and 18 to 21, wherein is hydrogen.

47. R ２ But C １－３ 22. The method according to claim 9, wherein the aryl group is alkyl. The compound described.

48. R ２ 48. The compound of claim 47, wherein is methyl.

49. R ３ is hydrogen. Item 1. The compound according to item 1.

50. R ３ Any one of claims 9 to 11, 14, 17 to 19, 22 and 25, wherein 3. The compound according to claim 1.

51. R ３ 40. The compound of claim 39, wherein is F.

52. R ３ is OH, Item 1. The compound according to item 1.

53. R ３ Any one of claims 11, 14, 17-19, 22 and 25, wherein is an amine. The compound described in

54. R ３ NH ２ 54. The compound of claim 53, wherein:

55. R ３ But C １－３ Claims 9 to 11, 14, 17 to 19, 22 and 2 are alkyl.

5. The compound according to any one of claims 1 to 4.

56. R ３ 56. The compound of claim 55, wherein is methyl.

57. R ４ is hydrogen. The compound according to any one of claims 1 to 4.

58. R ４ But C １－４ 9, 10, 12, 15, 17, 20, 23, wherein the alkyl is and 25. The compound according to any one of claims 1 to 25.

59. R ４ 59. The compound of claim 58, wherein is methyl.

60. R ４ 59. The compound of claim 58, wherein is ethyl.

61. R ４ 59. The compound of claim 58, wherein is isopropyl.

62. R ４ 59. The compound of claim 58, wherein is tert-butyl.

63. R ５ The compound of any one of claims 18 to 25, wherein is F.

64. R ５ The compound of any one of claims 18 to 25, wherein is Cl.

65. R ５ The compound of any one of claims 18 to 25, wherein is Br.

66. R ５ The compound of any one of claims 18 to 25, wherein is CN. 【Request Item 67】 【Table 1】 or a pharmaceutically acceptable salt thereof. 。 【Request Item 68】 【Table 2】 or a pharmaceutically acceptable salt thereof. thing. 【Request Item 69】 【Chemistry 21】 or a pharmaceutically acceptable salt thereof. 【Request Item 70】 【Chemistry 22】 or a pharmaceutically acceptable salt thereof. 【Request Item 71】 【Chemistry 23】 or a pharmaceutically acceptable salt thereof. 【Request Item 72】 【Chemistry 24】 or a pharmaceutically acceptable salt thereof. 【Request Item 73】 【Chemistry 25】 or a pharmaceutically acceptable salt thereof. 【Request Item 74】 【Chemistry 26】 or a pharmaceutically acceptable salt thereof. 【Request Item 75】 【Chemistry 27】 or a pharmaceutically acceptable salt thereof. 【Request Item 76】 【Table 3】 or a pharmaceutically acceptable salt thereof. thing.

77. 77. Any one of claims 1 to 76, wherein at least one hydrogen atom is replaced with a deuterium atom. or a pharmaceutically acceptable salt thereof.

78. 78. A compound according to any one of claims 1 to 77, or a pharmaceutically acceptable salt thereof. , pharmaceutical compositions.

79. A compound according to any one of claims 1 to 77, mediated by PHD activity. A pharmaceutical composition for treating a disease.

80. 80. The method of claim 79, wherein the disease mediated by PHD activity is ischemia-reperfusion injury. A pharmaceutical composition comprising:

81. 2. The method of claim 1 , wherein the ischemia-reperfusion injury is selected from stroke, myocardial infarction, and acute kidney injury.

80. The pharmaceutical composition described in 80.

82. 80. The method of claim 79, wherein the disease mediated by PHD activity is inflammatory bowel disease. Pharmaceutical compositions.

83. 83. The pharmaceutical composition of claim 82, wherein the inflammatory bowel disease is ulcerative colitis.

84. 83. The pharmaceutical composition of claim 82, wherein the inflammatory bowel disease is Crohn's disease.

85. 80. The pharmaceutical composition of claim 79, wherein the disease mediated by PHD activity is cancer. thing.

86. 86. The pharmaceutical composition of claim 85, wherein the cancer is colorectal cancer.

87. 80. The pharmaceutical composition of claim 79, wherein the disease mediated by PHD activity is a liver disease. Finished product.

88. 8. The method of claim 7, wherein the disease mediated by PHD activity is atherosclerosis.

9. The pharmaceutical composition described in 9.

89. 80. The method of claim 79, wherein the disease mediated by PHD activity is a cardiovascular disease. Pharmaceutical composition.

90. 80. The method of claim 79, wherein the disease mediated by PHD activity is an ocular disease or condition. The pharmaceutical composition described.

91. The ocular disease or condition is radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macula, 91. The pharmaceutical composition of claim 90, wherein the ocular ischemia is selected from the group consisting of ocular degeneration and ocular ischemia.

92. 80. The pharmaceutical composition of claim 79, wherein the disease is anemia.

93. 93. The pharmaceutical composition of claim 92, wherein the anemia is anemia associated with chronic kidney disease.

94. 80. The pharmaceutical composition of claim 79, wherein the disease is chronic kidney disease.

95. 80. The pharmaceutical composition of claim 79, wherein the disease is associated with hyperoxia.

96. 96. The pharmaceutical composition of claim 95, wherein the disease is retinopathy of prematurity.

97. 96. The pharmaceutical composition of claim 95, wherein the disease is bronchopulmonary dysplasia (BPD).

98. The disease is ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary Select from hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, and liver cirrhosis 80. The pharmaceutical composition of claim 79,

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