Selective PHD1 inhibitor compounds, compositions, and methods of use

Abstract

The present invention provides, in part, compounds and methods for treating diseases mediated by PHD1 activity, such as ischemia-reperfusion injury (including, but not limited to, stroke, myocardial infarction, and acute kidney injury), inflammatory bowel disease, cancer (including colorectal cancer), and liver disease, comprising the compounds of formula (I) and subformulas thereof: [Formula 1] The present invention includes administering to a subject a compound according to the present invention, such as TIFF2025500892000233.tif61170, or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 291,078, filed December 17, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Hypoxia is a state or situation in which the supply of oxygen is insufficient for normal life functions, for example, low arterial blood oxygen supply. Hypoxia can lead to cellular dysfunction and structural tissue damage. Activation of cellular defense mechanisms during hypoxia is mediated by HIF (hypoxia inducible factor) proteins. In response to hypoxic conditions, the level of HIFα increases in most cells due to a decrease in HIFα prolyl hydroxylation. Prolyl hydroxylation of HIFα is accomplished by a family of proteins variously called prolyl hydroxylase domain-containing proteins (PHD1, 2, and 3), also known as HIF prolyl hydroxylases (HPH-3, 2, and 1) or EGLN-2, 1, and 3. PHD proteins are oxygen sensors and regulate the stability of HIF in an oxygen-dependent manner.

[0003] Therefore, compounds that can selectively inhibit one PHD isoform can be particularly useful in new targeted therapy.For example, inhibition of PHD1 can be particularly useful in treating skeletal muscle cell degeneration (US Pat. No. 7,858,593), protecting muscle fibers against ischemia (Aragones et al. (2008) Nat. Genet. 40:170-80), and treating colitis and other forms of inflammatory bowel disease (Tambuwala et al. (2010) Gastroenterology 139:2093-101).Therefore, there is still a need in the art for compounds that are selective inhibitors of PHD1. Summary of the Invention

[0004] The present invention provides, inter alia, a method for treating a disease mediated by PHD1 activity, comprising administering to a subject a compound described herein. In certain embodiments, the disease mediated by PHD1 activity is ischemia-reperfusion injury (e.g., stroke, myocardial infarction, acute kidney injury), inflammatory bowel disease, cancer (e.g., colorectal cancer), liver disease, atherosclerosis, or cardiovascular disease.

[0005] In some embodiments, the subject is administered a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is optionally substituted aryl or optionally substituted heteroaryl; X is CH or N; L is [ka] where n is 0, 1, or 2; R 4a and R 4b are independently H, optionally substituted C1-C6 alkyl, or OH; R 5a and R 5b are independently H, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R 5a and R 5b together with the carbons to which they are attached form an optionally substituted 3- to 5-membered cycloalkyl or heterocycloalkyl; R 1 is H, OH, or NH2, R 2 is H or CN, and R 3 is OH or an optionally substituted ester.

[0006] In some embodiments, the subject is administered a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is optionally substituted aryl or heteroaryl; X is CH or N; L is [ka] where n is 0, 1, or 2; R 2 is H or CN, R 4a and R 4b is independently H, optionally substituted C1-C6 alkyl, or OH; and R 5a and R 5b are independently H, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R 5a and R 5b together with the carbon to which they are attached form an optionally substituted 3-5 membered cycloalkyl or heterocycloalkyl.

[0007] In some embodiments, the subject is administered a compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is optionally substituted aryl or optionally substituted heteroaryl; X is CH or N; R 2 is H or CN, R 4a and R 4b is independently H, optionally substituted C1-C6 alkyl, or OH; and R 5a and R5b are independently H, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R 5a and R 5b together with the carbons to which they are attached form an optionally substituted 3- to 5-membered cycloalkyl or heterocycloalkyl; However, R 4a , R 4b , R 5a , or R 5b At least one of them is not H.

[0008] In some embodiments, A is [ka] where: R 6a , R 6b , and R 6c are independently H, halo, aryl, heteroaryl, CHOR 12 , OR 12 , N.H.R. 12 , CH2R 13 , or SO2R 13 and R 12 , H, R 14 aryl optionally substituted with 15 is a C1-C2 alkyl optionally substituted with R 13 is heterocycloalkyl, R 14 H, halo, OR 16 , or CH2CH2OR 16 and R 15 is cycloalkyl, or aryl optionally substituted with halo, and R 16 is a C1-C3 alkyl optionally substituted with one or more halo.

[0009] In some embodiments, R 13 is pyrrolidine.

[0010] In some embodiments, A is [ka] where: U, V, and T are independently CH or N; R 7a is R 17 C1-C4 alkyl optionally substituted with H, halo, aryl optionally substituted with CF3, CO2R 18 or COR 18 is heteroaryl optionally substituted with R 17 is H, aryl optionally substituted with halo, or heterocycloalkyl; and R 18 is t-butyl.

[0011] In some embodiments, A is [ka] where: U is CH or N; R 7a is R 17 C1-C4 alkyl optionally substituted with H, halo, or CF3, or COR 18 is a heteroaryl or heterocycloalkyl optionally substituted with R 17 is H, aryl optionally substituted with halo, or heterocycloalkyl; and R 18 is t-butyl.

[0012] In some embodiments, A is [ka] where: U, V, and T are independently CH or N; R 7b is R 17 C1-C4 alkyl optionally substituted with H, halo, or CF3, or COR 18 is a heteroaryl or heterocycloalkyl optionally substituted with R 17 is H, aryl optionally substituted with halo, or heterocycloalkyl; and R 18 is t-butyl.

[0013] In some embodiments, A is [ka] where: U is CH or N; R 7b is R 17 C1-C4 alkyl optionally substituted with H, halo, or CF3, or COR 18 is a heteroaryl or heterocycloalkyl optionally substituted with R 17 is H, aryl optionally substituted with halo, or heterocycloalkyl; and R 18 is t-butyl.

[0014] In some embodiments, A is [ka] where: B, D, E, G, and I are independently C, CH, or N; R 8a , R 8b , R 8c , and R 8d are independently H, C1-C3 alkyl, halo, OR 19 , or NHR 20 and R 8e is absent, H, or =O, R 19 is H, aryl optionally substituted with halo, or R 21 is a C1-C3 alkyl optionally substituted with R 20 is SO2CH3, R 21 is aryl optionally substituted with halo, and ------- are optional bonds.

[0015] In some embodiments, A is [ka] where: R 8a is H or methyl, R 8d H, OR 19 , or NHR 20 and R 19 is H, aryl optionally substituted with halo, or R 21 is a C1-C3 alkyl optionally substituted with R 20 is SO2CH3, and R 21 is aryl optionally substituted with halo.

[0016] In some embodiments, A is [ka] where: D is CH or N; I is C, CH, or N; R 8a is H, halo, or C1-C3 alkyl; R 8b is H or C1-C3 alkyl, R 8cis H, ═O, or C1-C3 alkyl; R 8d H, OR 19 , N.H.R. 20 or C1-C3 alkyl; R 19 is H, aryl optionally substituted with halo, or R 21 is a C1-C3 alkyl optionally substituted with R 20 is SO2CH3, R 21 is aryl optionally substituted with halo, and ------ is an optional bond.

[0017] In some embodiments, A is [ka] where: E is CH, CH2, N, or NH; G and B are independently CH or N; R 8e is H, C1-C3 alkyl, or =O, and ------ is an optional bond.

[0018] In some embodiments, A is [ka] where: R 9 is H, C1-C3 alkyl, or phenyl.

[0019] In some embodiments, A is [ka] where: J is C, CH, or N; K is CH, CH2, N, or NH; R 10is H, halo, C1-C4 alkyl, or COR 22 and R 22 is t-butyl, and ------- are optional bonds.

[0020] In some embodiments, A is [ka] where: K is CH or N, and R 10 is H, halo, or C1-C4 alkyl.

[0021] In some embodiments, A is [ka] where: J is CH or N; R 10 is H or CO2R 22 and R 22 is t-butyl.

[0022] In some embodiments, A is [ka] where: R 11a and R 11b are independently H, C1-C3 alkyl, or C1-C3 alkoxy.

[0023] In some embodiments, A is [ka] TIFF2025500892000022.tif208170TIFF2025500892000023.tif98170.

[0024] In another aspect, the present invention also provides novel small molecule inhibitors of PHD1 that are selective relative to PHD2, wherein the compound is any one of compounds 1-62, or a pharma- ceutically acceptable salt thereof. [Table 1] TIFF2025500892000025.tif221170TIFF2025500892000026.tif223170TIFF2025500892 000027.tif203170TIFF2025500892000028.tif236170TIFF2025500892000029.tif41170

[0025] In some embodiments, in compounds 1-62, at least one hydrogen atom is replaced with a deuterium atom.

[0026] In some embodiments, the compounds described herein (e.g., Compounds 1-62), or pharma- ceutically acceptable salts thereof, are useful for treating diseases including ischemia-reperfusion injury (including, but not limited to, stroke, myocardial infarction, and acute kidney injury), inflammatory bowel disease, cancer (including colorectal cancer), and liver disease. [Brief description of the drawings]

[0027] [Figure 1]FIG. 1 is an exemplary schematic showing the principle of the TR-FRET assay of PHD enzymes (PHD1, PHD2, and PHD3). In the presence of 2-oxoglutarate and O2, the PHD enzymes hydroxylate proline 564 of the biotin-tagged HIF-1α peptide, generating biotin-tagged HIF-1α-hydroxyproline, succinate, and CO2. The resulting proximity of the donor fluorophore conjugate, monoclonal antibody anti-6His-Terbium (Tb)-cryptate Gold, bound to the His-tagged VHL protein, EloB, EloC complex (His-VBC), and the acceptor fluorophore, SA-D2 complex, bound to HIF-1α-hydroxyproline, results in a fluorescence resonance energy transfer signal that can be detected and quantified. Detailed Description of the Disclosure

[0028] [Definition] In order that the present invention may be more readily understood, certain terms are first defined below. Additional definitions for these terms and other terms are set forth throughout the specification. Publications and other reference materials referred to herein to describe the background of the invention and to provide additional details regarding its practice are incorporated herein by reference.

[0029] Animal: As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans at any stage of development. In some embodiments, "animal" refers to non-human animals at any stage of development. In certain embodiments, the non-human animals are mammals (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cows, primates, and / or pigs). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or parasites. In some embodiments, animals may be transgenic animals, genetically engineered animals, and / or clones.

[0030] Approximately or about: As used herein, when applied to one or more values ​​of interest, the term "approximately" or "about" refers to a value similar to a stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater or less) of the stated reference value, unless otherwise stated or otherwise clear from the context (except where such value exceeds 100% of possible values).

[0031] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "composition" includes a mixture of two or more such compositions.

[0032] Throughout the description and claims of this specification, the word "comprise" and other forms of the word, such as "comprising" and "comprises", are not intended to exclude, but are not limited to, other additives, components, integers, or steps.

[0033] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and as used herein includes cases where the event or circumstance occurs and cases where it does not occur.

[0034] Improved, increased, or reduced: As used herein, the terms "improved," "increased," or "reduced," or grammatical equivalents, refer to a value compared to a baseline measurement, such as a measurement in the same individual prior to the initiation of a treatment described herein, or a measurement in a control subject (or control subjects) in the absence of a treatment described herein. A "control subject" is a subject who is about the same age as the subject being treated and who is suffering from the same form of the disease as the subject being treated.

[0035] In vitro: As used herein, the term "in vitro" refers to events that take place not within a multicellular organism, but rather in an artificial environment, such as a test tube or reaction vessel, cell culture, etc.

[0036] In vivo: As used herein, the term "in vivo" refers to events that occur within a multicellular organism, such as humans and non-human animals. In the context of cell-based systems, the term may be used to refer to events that occur within living cells (e.g., as opposed to in vitro systems).

[0037] Patient: As used herein, the term "patient" or "subject" refers to any organism to which provided compositions can be administered, for example, for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. Human includes pre- and post-natal forms.

[0038] Pharmaceutically acceptable: As used herein, the term "pharmaceutical acceptable" refers to a material that is suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable thus relates to a material that is not non-biological or otherwise undesirable, i.e., the material can be administered to an individual in conjunction with the associated active compound without producing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

[0039] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describes pharmaceutically acceptable salts in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are the salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanoate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-phenylpropionate salts, such as phenylpropionate, ... + (C 1~4Representative pharmaceutically acceptable salts include amine cations formed, where appropriate, with non-toxic ammonium, quaternary ammonium, and counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates, and arylsulfonates. Additional pharmaceutically acceptable salts include salts formed from the quaternization of amines with suitable electrophiles, e.g., alkyl halides, to form quaternized alkylated amino salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include salts formed from the quaternization of amines with suitable electrophiles, e.g., alkyl halides, to form quaternized alkylated amino salts.

[0040] Subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Human includes prenatal and postnatal forms. In many embodiments, the subject is a human. A subject may be a patient, which refers to a human who visits a health care provider for the purpose of diagnosing or treating a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject may be afflicted with or susceptible to a disease or disorder, but may or may not exhibit symptoms of the disease or disorder.

[0041] Substantially: As used herein, the term "substantially" refers to a qualitative condition that indicates the entire or nearly entire extent or degree of a feature or characteristic of interest. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, proceed to completion and / or perfection or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness that is inherent in many biological and chemical phenomena.

[0042] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount that, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, is sufficient to treat, diagnose, prevent, and / or delay the onset of symptoms of the disease, disorder, and / or condition. One of skill in the art will appreciate that a therapeutically effective amount is typically administered via a dosing regimen comprising at least one unit dose.

[0043] Treatment: As used herein, the terms "treat", "treatment", or "treating" refer to any method used to partially or completely alleviate, ameliorate, reduce, inhibit, prevent, delay onset, reduce severity, and / or reduce incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. Treatment may be administered to subjects who do not show signs of the disease and / or who show only early signs of the disease, for the purpose of reducing the risk of developing pathologies associated with the disease.

[0044] Whenever any of the terms (e.g., alkyl or aryl) or their prefix-roots (e.g., alk- or ar-) appear in the name of a substituent, the name should be interpreted to include those limitations provided herein. For example, the suffix "-ene" on a base indicates that the group is a divalent moiety, e.g., an arylene is a divalent moiety of an aryl, and a heteroarylene is a divalent moiety of a heteroaryl. Similarly, the suffix "-oxy" on a base indicates that the group is attached to the parent molecular structure through an oxygen atom (-O-).

[0045] Aliphatic: As used herein, the term aliphatic refers to any group consisting of C1-C 40 Aliphatic refers to hydrocarbons, including both saturated and unsaturated hydrocarbons. Aliphatic can be linear, branched, or cyclic. For example, C1-C 20 Aliphatic: C1-C 20 Alkyl (e.g., linear or branched C1-C 20 Saturated alkyl), C2-C 20 Alkenyl (e.g., linear or branched C4-C20 Dienyl, linear or branched C6-C 20 trienyl, etc.), and C2-C 20 Alkynyl (e.g., linear or branched C2-C 20 alkynyl). 20 Aliphatic: C3-C 20 Cycloaliphatic (e.g., C3-C 20 Cycloalkyl, C4-C 20 Cycloalkenyl, or C8-C 20 In certain embodiments, an aliphatic group may include one or more cyclic aliphatic groups and / or one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be optionally substituted with one or more substituents, such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester, or amide. An aliphatic group is unsubstituted or substituted with one or more substituents as described herein. For example, an aliphatic group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCOR', -NH2, -NHR', -N(R')2, -SR', or -S02R', where each instance of R' is independently selected from C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the aliphatic is unsubstituted. In some embodiments, the aliphatic does not include any heteroatoms.

[0046] Alkyl: As used herein, the term "alkyl" refers to acyclic straight and branched hydrocarbon groups, such as C1-C 20 "Alkyl" refers to an alkyl group having 1 to 20 carbons, and "C1-C4 alkyl" refers to an alkyl group having 1 to 4 carbons. The alkyl group may be any of C1 to C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, the alkyl group is a C1-C4 alkyl. The alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl tert-pentylhexyl, isohexyl, and the like. The term "lower alkyl" refers to linear or branched alkyl groups of alkyl groups having 1 to 6 carbon atoms. Other alkyl groups will be readily apparent to one of skill in the art given the benefit of this disclosure. The alkyl group may be unsubstituted or substituted with one or more substituents described herein. For example, an alkyl group may be optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of a halogen, -COR', -COH, -COR', -CN, -OH, -OR', -OCOR', -OCOR', -NH, -NHR', -N(R')2, -SR', or -SOR', where each instance of R' is independently selected from C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the alkyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein). In some embodiments, the alkyl group is substituted with an -OH group, sometimes referred to herein as a "hydroxyalkyl" group, where the prefix indicates an -OH group, and "alkyl" is as described herein. In some embodiments, the alkyl group is substituted with an -OR' group.

[0047] Alkylene: As used herein, the term "alkylene" refers to a saturated divalent straight or branched chain hydrocarbon group, exemplified by methylene, ethylene, isopropylene, and the like. Similarly, as used herein, the term "alkenylene" refers to an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon double bonds that may occur at any stable point along the chain, and the term "alkynylene" herein refers to an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon triple bonds that may occur at any stable point along the chain. In certain embodiments, the alkylene, alkenylene, or alkynylene group may contain one or more cyclic aliphatic and / or one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be optionally substituted with one or more substituents, such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester, or amide. For example, an alkylene, alkenylene, or alkynylene may be optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR', -COH, -COR', -CN, -OH, -OR', -OCOR', -OCOR', -NH, -NHR', -N(R')2, -SR', or -SOR', where each instance of R' is independently selected from C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10In some embodiments, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In certain embodiments, the alkylene, alkenylene, or alkynylene is unsubstituted. In certain embodiments, the alkylene, alkenylene, or alkynylene does not include any heteroatoms.

[0048] Alkenyl: As used herein, "alkenyl" refers to any straight or branched hydrocarbon chain having one or more unsaturated carbon-carbon double bonds that may occur at any stable point along the chain, e.g., "C2-C 20 "Alkenyl" refers to an alkenyl group having 2 to 20 carbons. For example, alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like. In some embodiments, an alkenyl contains 1, 2, or 3 carbon-carbon double bonds. In some embodiments, an alkenyl contains a single carbon-carbon double bond. In some embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. An alkenyl group can be unsubstituted or substituted with one or more substituents described herein. For example, an alkenyl group can be optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR', -COH, -COR', -CN, -OH, -OR', -OCOR', -OCOR', -NH, -NHR', -N(R')2, -SR', or -SOR', where each instance of R' is independently selected from C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10In some embodiments, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the alkenyl is unsubstituted. In some embodiments, the alkenyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein). In some embodiments, the alkenyl group is substituted with an -OH group, and is sometimes referred to herein as a "hydroxyalkenyl" group, where the prefix denotes the -OH group and "alkenyl" is as described herein.

[0049] Alkynyl: As used herein, "alkynyl" refers to any hydrocarbon chain, either linear or branched in structure, with one or more carbon-carbon triple bonds occurring at any stable point along the chain, e.g., "C2-C 20 "Alkynyl" refers to an alkynyl group having 2 to 20 carbons. Examples of alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, and the like. In some embodiments, an alkynyl group contains one carbon-carbon triple bond. An alkynyl group can be unsubstituted or substituted with one or more substituents described herein. For example, an alkynyl group can be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR', -COH, -COR', -CN, -OH, -OR', -OCOR', -OCOR', -NH2, -NHR', -N(R')2, -SR', or -SOR', where each instance of R' is independently selected from C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10In some embodiments, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, an alkynyl is unsubstituted. In some embodiments, an alkynyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents described herein).

[0050] Alkoxy: The term "alkoxy" refers to an -O-alkyl group including linear, branched, saturated cyclic structures and combinations thereof, of from 1 to 10 carbon atoms attached to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy, and the like. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbons. In some embodiments, C 1~4 Alkoxy is an alkoxy group that includes both straight and branched chain alkyls of 1 to 4 carbon atoms. Unless otherwise stated herein, an alkoxy group can be optionally substituted with one or more substituents (e.g., as described herein for alkyl). The terms "alkenoxy" and "alkynoxy" mirror the above description of "alkoxy", where the prefix "alk" is replaced with "alkene" or "alkyne", respectively, and the parent terms "alkenyl" or "alkynyl" are as described herein.

[0051] Amide: The term "amide" or "amido" refers to a chemical moiety having the formula -C(O)N(R'), -C(O)N(R')-, -NR'C(O)R', or -NR'C(O)-, where each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), each of which moieties may itself be optionally substituted as described herein, or two R' may be joined to the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring, unless otherwise stated in the specification.

[0052] Amino: The term "amino" or "amine" refers to the group -N(R'), where each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), each of which moieties may itself be optionally substituted as described herein, or two R' may be joined to the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring, unless otherwise stated herein. In embodiments, the amino group is -NHR', where R' is aryl ("arylamino"), heteroaryl ("heteroarylamino"), or alkyl ("alkylamino").

[0053] Aryl: The term "aryl," used alone or as part of a larger moiety, such as in "aralkyl," refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, which ring system has a single point of attachment to the rest of the molecule, at least one ring in the system is aromatic, and each ring in the system contains 4 to 7 ring members. In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl," e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl", e.g., anthracen. "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, in which case the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Exemplary aryls include phenyl, naphthyl, and anthracene.

[0054] Arylalkyl: The term "arylalkyl" refers to a -(alkylene)-aryl radical, where aryl and alkylene are as disclosed herein and are optionally substituted with one or more of the exemplary substituents described herein. An "arylalkyl" group is attached to the parent molecular structure via an alkylene moiety. The term "arylalkoxy" refers to an -O-[arylalkyl] radical (-O-[(alkylene)-aryl]) attached to the parent molecular structure via an oxygen.

[0055] Arylene: As used herein, the term "arylene" refers to an aryl group that is divalent (i.e., has two points of attachment to the molecule). Exemplary arylenes include phenylene (e.g., unsubstituted or substituted phenylene).

[0056] Cyclic: As used herein, the term "cyclic" refers to any covalently closed structure. Cyclic moieties include, for example, carbocycles (e.g., aryl and cycloalkyl), heterocycles (e.g., heteroaryl and heterocycloalkyl), aromatics (e.g., aryl and heteroaryl), and non-aromatic (e.g., cycloalkyl and heterocycloalkyl). In some embodiments, the cyclic moiety is optionally substituted. In some embodiments, the cyclic moiety forms part of a ring system.

[0057] Alicyclic: The term "alicyclic" refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen and can be saturated or partially unsaturated. Fully saturated alicyclic materials can be referred to as "cycloalkyls". Partially unsaturated cycloalkyl groups can be referred to as "cycloalkenyls" if the carbocyclic ring contains at least one double bond, or "cycloalkynyls" if the carbocyclic ring contains at least one triple bond. Alicyclic groups include groups having 3 to 13 ring atoms, such as C 3~13 Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range, for example, "3 to 10 carbon atoms" means that the alicyclic group (e.g., cycloalkyl) may consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., and may contain up to 10 carbon atoms. The term "alicyclic" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic alicyclic groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" refers to C 3~8 In some embodiments, "cycloalkyl" is a C 3~5 Illustrative examples of alicyclic groups include the following moieties: 3~6 Alicyclic groups include, but are not limited to, cycloaliphatic groups (including, but not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like). 3~7 An example of an alicyclic group is norbornyl (C7). 3~8 Examples of alicyclic groups include the above-mentioned C 3~7 Examples include carbocyclyl groups, as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl. 3~13 Examples of alicyclic groups include the above-mentioned C 3~8Examples include carbocyclyl groups, as well as octahydro-1H-indenyl, decahydronaphthalenyl, and spiro[4.5]decanyl.

[0058] Cyano: The term "cyano" refers to the group -CN.

[0059] Deuterium: The term "Deuterium" is also referred to as heavy hydrogen. Deuterium is an isotope of hydrogen with a nucleus composed of one proton and one neutron, which is twice the mass of a normal hydrogen nucleus (one proton). In embodiments, deuterium is also referred to as 2 It may also be specified as H.

[0060] Ester: The term "ester" refers to a group of formula -C(O)OR' or -R'OC(O)-, where R' is selected from alkyl, alkenyl, alkynyl, heteroalkyl (attached via a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocycloalkyl as described herein.

[0061] Halogen or Halo: As used herein, the terms "halogen" or "halo" mean fluorine, chlorine, bromine, or iodine.

[0062] Heteroalkyl: The term "heteroalkyl" refers to a branched or unbranched alkyl, alkenyl, or alkynyl group having 1-14 carbon atoms in addition to 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls include tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. Heteroalkyl groups may optionally contain monocyclic, bicyclic, or tricyclic rings, each ring desirably having 3-6 members. Examples of heteroalkyls include polyethers, such as, for example, methoxymethyl and ethoxyethyl. Thus, the term "heteroalkoxy" refers to an -O-heteroalkyl group, which is attached to the parent molecular structure through an oxygen.

[0063] Heteroalkylene: As used herein, the term "heteroalkylene" refers to a divalent form of the heteroalkyl groups described herein.

[0064] Heteroaryl: As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6-14 ring members, which ring system has a single point of attachment to the remainder of the molecule, at least one ring in the system is aromatic, each ring in the system contains 4-7 ring members, and at least one ring atom is a heteroatom, such as, but not limited to, nitrogen and oxygen. Examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Thus, the term "heteroaryloxy" refers to the group -O-heteroaryl, where the group is attached to the parent molecular structure through an oxygen.

[0065] Heteroarylalkyl: The term "heteroarylalkyl" refers to a -(alkylene)-heteroaryl radical, where heteroaryl and alkylene are as disclosed herein and are optionally substituted with one or more of the exemplary substituents described herein. A "heteroarylalkyl" group is attached to the parent molecular structure via an alkylene moiety. The term "heteroarylalkoxy" refers to an -O-[heteroarylalkyl] radical (-O-[(alkylene)-heteroaryl]) attached to the parent molecular structure via an oxygen.

[0066] Heterocycloalkyl: As used herein, the term "heterocycloalkyl" refers to a non-aromatic ring in which at least one atom is a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. Examples of heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyran ... Heterocycloalkyl groups include pyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, and quinolizinyl. Heterocycloalkyl groups can be substituted or unsubstituted.

[0067] Heterocycle: The term "heterocycle" as used herein refers to heteroaryl and heterocycloalkyl, each of which refers to a group containing 1-4 heteroatoms selected from O, S, and N, with each heterocycle group having 4-10 atoms in its ring system, provided that the ring of the group does not contain two adjacent O or S atoms. As used herein, whenever the number of carbon atoms in a heterocycle is given (e.g., C1-C6 heterocycle), at least one other atom (heteroatom) must be present in the ring. Designations such as "C1-C6 heterocycle" refer only to the number of carbon atoms in the ring, not the total number of atoms in the ring. In some embodiments, it is understood that the heterocycle has additional heteroatoms in the ring. Designations such as "4-6 membered heterocycle" refer to the total number of atoms contained in the ring (i.e., a 4-, 5-, or 6-membered ring in which at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining 2-4 atoms are either carbon atoms or heteroatoms). In some embodiments, in a heterocycle having two or more heteroatoms, the two or more heteroatoms are the same or different from each other. In some embodiments, the heterocycle is optionally substituted. In some embodiments, the bond to the heterocycle occurs at a heteroatom or through a carbon atom. Heterocycloalkyl groups include groups having only four atoms in their ring system, while heteroaryl groups must have at least five atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. In some embodiments, the above groups are derived from the groups listed above and are C- or N-linked, where possible. For example, in some embodiments, the group derived from pyrrole is pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Further, in some embodiments, the group derived from imidazole is imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-linked).Heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, depending on the structure, heterocyclic groups are monoradicals or diradicals (i.e., heterocyclene groups). The heterocycles described herein are substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkylene, mercapto, nitro, amino, and amido moieties.

[0068] Isotope: The term "isotopes" refers to variants of a particular chemical element that have different numbers of neutrons, and therefore different numbers of nucleons. All isotopes of a given element have the same number of protons but different numbers of neutrons in each atom.

[0069] Nitro: The term "nitro" refers to the group --NO.sub.2.

[0070] Sulfonamide: The term “sulfonamide” or “sulfonamido” refers to the following group: —S(═O)2-(R′), —N(R′)-S(═O)2-R′, —S(═O)2-N(R′)-, or —N(R′)-S(═O)2-, where each R ’ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), each of which moieties may itself be optionally substituted as described herein, or two R' can be joined to the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring, unless otherwise stated in the specification.

[0071] Moiety: The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded in or appended to a molecule.

[0072] Molecular groups herein may be substituted or unsubstituted (e.g., as described herein). The term "substituted" means that a particular group or moiety has one or more substituents, where at least one hydrogen present on an atom of a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that upon replacement of the hydrogen results in a stable compound, e.g., a compound that does not spontaneously change, such as by rearrangement, cyclization, elimination, or other reaction. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, it is meant that substitution occurs at any valence-allowed position on the system. In embodiments, the groups described herein are substituted. In embodiments, the groups described herein are unsubstituted. When a particular moiety or group is not explicitly identified as being optionally substituted or substituted with any particular substituent, it is understood that such moiety or group is intended to be unsubstituted.

[0073] A wide variety of substituents are well known, as are their methods of formation and introduction onto various parent groups. Representative substituents include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl, heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino, dialkylamino, alkoxy, hydroxy, halo (e.g., -Cl and -Br), nitro, oximino, -COOR, -COOR- ...50 , -COR 50 , -SO 0-2 R 50 , -SO2NR 50 R 51 , NR 52 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 ) in which R 50、 R 51 and R 52 is the following: hydrogen atoms, as well as branched or linear, substituted or unsubstituted, C 1~6 -Alkyl, C 3~6 -Cycloalkyl, C 4~6 - may be independently selected from heterocycloalkyl, heteroaryl, and aryl groups. Where permitted, R 50 and R 51 can be joined together to form a carbocyclic or heterocyclic ring system.

[0074] In preferred embodiments, the substituents are selected from halogen, -COR', -COH, -COR', -CN, -OH, -OR', -OCOR', -OCOR', -NH, -NHR', -N(R')2, -SR', and -SOR', where each instance of R' is independently selected from C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10In certain embodiments thereof, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 alkyl, or C1-C3 alkyl). Preferably, R' is independently an unsubstituted C1-C3 alkyl.

[0075] Any formula given herein is intended to represent compounds having the structure shown by the structural formula as well as certain variations or forms. In particular, any compound of the formula given herein may have asymmetric centers and therefore may exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, as well as mixtures thereof, are considered to be within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, a particular structure may exist as a geometric isomer (i.e., cis and trans isomers), as a tautomer, or as an atropisomer. Furthermore, any formula given herein is intended to encompass hydrates, solvates, and polymorphs of such compounds, as well as mixtures thereof.

[0076] [Compounds of the present invention] Disclosed herein are compounds that are potent inhibitors of PHD1. In some embodiments, the compounds of the present invention have an enzymatic half maximal inhibitory concentration (IC) of less than 100 μM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 50 μM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 50 μM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 25 μM against PHD1. 50In some embodiments, compounds of the invention have an IC value of less than 20 μM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 15 μM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 10 μM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 5 μM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 1 μM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 500 nM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 200 nM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 100 nM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 50 nM against PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 25 nM for PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 15 nM for PHD1. 50 In some embodiments, compounds of the invention have an IC value of less than 10 nM against PHD1. 50 It has a value.

[0077] In some embodiments, compounds of the invention have an IC50 activity against PHD1 of about 3 nM to about 6000 nM. 50 In some embodiments, the compounds of the present invention have an IC value of about 3 nM to about 5 nM for PHD1. 50 In some embodiments, the compounds of the present invention have an IC value of about 5 nM to about 10 nM for PHD1. 50 In some embodiments, the compounds of the present invention have an IC value of about 10 nM to about 20 nM for PHD1. 50In some embodiments, the compounds of the present invention have an IC value for PHD1 of about 20 nM to about 50 nM. 50 In some embodiments, the compounds of the present invention have an IC value for PHD1 of about 50 nM to about 100 nM. 50 In some embodiments, the compounds of the present invention have an IC value of about 100 nM to about 200 nM for PHD1. 50 In some embodiments, the compounds of the present invention have an IC value for PHD1 of about 200 nM to about 500 nM. 50 In some embodiments, the compounds of the present invention have an IC value for PHD1 of about 500 nM to about 1000 nM. 50 In some embodiments, the compounds of the present invention have an IC value for PHD1 of about 1000 nM to about 2500 nM. 50 In some embodiments, the compounds of the present invention have an IC value for PHD1 of about 2500 nM to about 6000 nM. 50 It has a value.

[0078] In some embodiments, compounds of the present invention have an IC of about 45 nM to about 50,000 nM against PHD2. 50 In some embodiments, the compounds of the present invention have an IC value of 50,000 nM or greater against PHD2. 50 In some embodiments, the compounds of the present invention have an IC value for PHD2 of about 45 nM to about 100 nM. 50 In some embodiments, the compounds of the present invention have an IC value for PHD2 of about 100 nM to about 500 nM. 50 In some embodiments, the compounds of the present invention have an IC value for PHD2 of about 500 nM to about 2000 nM. 50 In some embodiments, the compounds of the present invention have an IC value for PHD2 of about 2000 nM to about 5000 nM. 50 In some embodiments, the compounds of the present invention have an IC value for PHD2 of about 5000 nM to about 15000 nM. 50In some embodiments, the compounds of the present invention have an IC value for PHD2 of about 15,000 nM to about 50,000 nM. 50 It has a value.

[0079] Disclosed herein are compounds that are potent inhibitors of PHD1. In some embodiments, the compounds of the invention have an inhibition constant (Ki) value for PHD1 of less than 0.1 nM. In some embodiments, the compounds of the invention have a Ki value for PHD1 of less than 0.3 nM. In some embodiments, the compounds of the invention have a Ki value for PHD1 of less than 0.5 nM. In some embodiments, the compounds of the invention have a Ki value for PHD1 of less than 0.7 nM. In some embodiments, the compounds of the invention have a Ki value for PHD1 of less than 1.0 nM. In some embodiments, the compounds of the invention have a Ki value for PHD1 of less than 3.0 nM. In some embodiments, the compounds of the invention have a Ki value for PHD1 of less than 5.0 nM. In some embodiments, the compounds of the invention have a Ki value for PHD1 of less than 10.0 nM. In some embodiments, the compounds of the invention have a Ki value for PHD1 of less than 15.0 nM. In some embodiments, the compounds of the invention have a Ki value for PHD1 of less than 20.0 nM. In some embodiments, the compounds of the present invention have a Ki value for PHD1 of less than 25.0 nM. In some embodiments, the compounds of the present invention have a Ki value for PHD1 of less than 30.0 nM. In some embodiments, the compounds of the present invention have a Ki value for PHD1 of less than 50.0 nM. In some embodiments, the compounds of the present invention have a Ki value for PHD1 of less than 75.0 nM.

[0080] In some embodiments, the compounds of the present invention have a Ki value of about 0.05 nM to about 75.0 nM against PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 0.05 nM to about 0.1 nM against PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 0.1 nM to about 0.3 nM against PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 0.3 nM to about 0.5 nM against PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 0.5 nM to about 1.0 nM against PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 1.0 nM to about 3.0 nM against PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 3.0 nM to about 5.0 nM against PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 5.0 nM to about 10.0 nM against PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 5.0 nM to about 10.0 nM for PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 10.0 nM to about 15.0 nM for PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 15.0 nM to about 20.0 nM for PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 20.0 nM to about 30.0 nM for PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 30.0 nM to about 50.0 nM for PHD1. In some embodiments, the compounds of the present invention have a Ki value of about 50.0 nM to about 75.0 nM for PHD1.

[0081] In some embodiments, the compounds of the present invention have a Ki value of about 1.0 nM to about 1100 nM for PHD2. In some embodiments, the compounds of the present invention have a Ki value of 1100 nM or more for PHD2. In some embodiments, the compounds of the present invention have a Ki value of about 1.0 nM to about 5.0 nM for PHD2. In some embodiments, the compounds of the present invention have a Ki value of about 5.0 nM to about 10.0 nM for PHD2. In some embodiments, the compounds of the present invention have a Ki value of about 10.0 nM to about 100.0 nM for PHD2. In some embodiments, the compounds of the present invention have a Ki value of about 100.0 nM to about 1000.0 nM for PHD2. In some embodiments, the compounds of the present invention have a Ki value of about 1000.0 nM to about 5000.0 nM for PHD2. In some embodiments, compounds of the present invention have a Ki value for PHD2 of about 5000.0 nM to about 1100.0 nM.

[0082] Disclosed herein is a series of inhibitors that are potent inhibitors of PHD1, which unexpectedly provide selectivity for PHD1 over PHD2. In some embodiments, PHD1 selectivity is achieved by selectively inhibiting PHD2 over PHD1. IC50 / PHD1 IC50 In some embodiments, PHD1 selectivity is expressed as Ki / PHD1 KiIn some embodiments, the selectivity of PHD1 over PHD2 is about 2 to about 1500 fold. In some embodiments, the selectivity of PHD1 over PHD2 is about 2 to about 10 fold, about 10 to about 20 fold, about 20 to about 50 fold, about 50 to about 100 fold, about 100 to about 200 fold, about 200 to about 500 fold, about 500 to about 1000 fold, about 1000 to about 1500 fold, about 1500 to about 2500 fold, or about 2500 to about 4000 fold. In some embodiments, the selectivity of PHD1 over PHD2 is about 2-fold or more, about 5-fold or more, about 10-fold or more, about 20-fold or more, about 30-fold or more, about 40-fold or more, about 50-fold or more, about 75-fold or more, about 100-fold or more, about 150-fold or more, about 200-fold or more, about 500-fold or more, and about 1000-fold or more, about 1500-fold or more, about 2500-fold or more, or about 3500-fold or more.

[0083] Exemplary compounds are described herein. In particular, these selective inhibitors can be characterized by a substituted alkylene moiety (e.g., alkylene substituted with a hydroxy or cyclic group) linking the amide NH with the carboxyl moiety.

[0084] [Compounds of formulas (I) to (VI)] As used herein, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is optionally substituted aryl or optionally substituted heteroaryl; X is CH or N; L is [ka] where n is 0, 1, or 2; R 4a and R 4b are independently H, optionally substituted C1-C6 alkyl, or OH; R 5a and R 5bare independently H, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R 5a and R 5b together with the carbons to which they are attached form an optionally substituted 3- to 5-membered cycloalkyl or heterocycloalkyl; R 1 is H, OH, or NH2, R 2 is H or CN, and R 3 is OH or an optionally substituted ester.

[0085] In some embodiments, the subject is administered a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is optionally substituted aryl or heteroaryl; X is CH or N; L is [ka] where n is 0, 1, or 2; R 2 is H or CN, R 4a and R 4b is independently H, optionally substituted C1-C6 alkyl, or OH; and R 5a and R 5b are independently H, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R 5a and R 5b together with the carbon to which they are attached form an optionally substituted 3-5 membered cycloalkyl or heterocycloalkyl.

[0086] In some embodiments, n is 0.

[0087] In some embodiments, n is 1.

[0088] In some embodiments, n is 2.

[0089] In some embodiments, R 4a , R 4b , R 5a , and R 5b At least one of them is not H.

[0090] In some embodiments, R 4a and R 4b is independently H or OH.

[0091] In some embodiments, R 4a and R 4b Each of is H. In some embodiments, R 5a and R 5b Each of is an optionally substituted C1-C6 alkyl. In some embodiments, R 5a and R 5b Each of R is an optionally substituted C1-C6 alkoxy. 5a and R 5b taken together with the carbon to which they are attached form a 3-6 membered optionally substituted cycloalkyl. In some embodiments, R 5a and R 5b taken together with the carbons to which they are attached form a 3-6 membered optionally substituted heterocycloalkyl. In some embodiments, R 5a and R 5b One of R is an optionally substituted C1-C6 alkyl (e.g., unsubstituted C1-C6 alkyl) and the other is H. In some embodiments, R 5a and R 5b One of R is OH and the other is H. In some embodiments, R 5a and R 5bThe carbon substituted by R has an S configuration. 5a and R 5b The carbon substituted by has the R configuration.

[0092] In some embodiments, R 4a and R 4b is H, and each of R 5a and R 5b Each of is unsubstituted C1-C6 alkyl (eg, methyl).

[0093] In some embodiments, R 4a and R 4b is H, and each of R 5a and R 5b One of R is unsubstituted C1-C6 alkyl (e.g., methyl) and the other is H. In some embodiments, R 5a and R 5b The carbon substituted by R has an S configuration. 5a and R 5b The carbon substituted by has the R configuration.

[0094] In some embodiments, R 4a and R 4b is H, and each of R 5a and R 5b taken together with the carbons to which they are attached form a 3- to 6-membered unsubstituted cycloalkyl. In some embodiments, R 5a and R 5b together with the carbon to which they are attached form a cyclopropyl. In some embodiments, R 5a and R 5b together with the carbon to which they are attached form a cyclobutyl. In some embodiments, R 5a and R 5b together with the carbon to which they are attached form a cyclopentyl. In some embodiments, R 5a and R 5b together with the carbon to which they are attached to form cyclohexyl.

[0095] In some embodiments, R 5a and R 5b Each of is H. In some embodiments, R 4a and R 4b Each of is an optionally substituted C1-C6 alkyl. In some embodiments, R 4a and R 4b One of R is an optionally substituted C1-C6 alkyl (e.g., unsubstituted C1-C6 alkyl) and the other is H. In some embodiments, R 4a and R 4b One of R is OH and the other is H. In some embodiments, R 4a and R 4b The carbon substituted by R has an S configuration. 4a and R 4b The carbon substituted by has the R configuration.

[0096] In some embodiments, R 4a , R 4b , R 5a , and R 5b Each of is H.

[0097] In some embodiments, L is [ka] It is.

[0098] In some embodiments, L is [ka] It is.

[0099] In some embodiments, the subject is administered a compound of formula (III) [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is optionally substituted aryl or heteroaryl; X is CH or N; R 2 is H or CN, R 4a and R 4b is independently H, optionally substituted C1-C6 alkyl, or OH; and R 5a and R 5b are independently H, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R 5a and R 5b together with the carbon to which they are attached form an optionally substituted 3-5 membered cycloalkyl or heterocycloalkyl.

[0100] In some embodiments, the compound according to formula (I), (II), or (III) has a structure according to formula (IV): [ka] or a pharma- ceutically acceptable salt thereof, wherein A and R 2 is as described anywhere herein.

[0101] In some embodiments, the compound according to Formula (I), (II), or (III) has a structure according to Formula (V): [ka] or a pharma- ceutically acceptable salt thereof, wherein A is as described anywhere herein.

[0102] In some embodiments, the compound according to formula (I), (II), or (III) has a structure according to formula (VI): [ka] or a pharma- ceutically acceptable salt thereof, wherein A is as described anywhere herein.

[0103] In some embodiments, the compound according to Formula (I), (II), or (III) has a structure according to Formula (VII): [ka] or a pharma- ceutically acceptable salt thereof, wherein A is as described anywhere herein.

[0104] In some embodiments, A is an optionally substituted phenyl.

[0105] In some embodiments, A is optionally substituted naphthyl.

[0106] In some embodiments, A is an optionally substituted 5-membered heteroaryl.

[0107] In some embodiments, A is an optionally substituted bicyclic heteroaryl (eg, 7-9 membered heteroaryl).

[0108] In some embodiments, A is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, triazolyl, naphthyl, quinolyl, isoquinolyl, quinoxalyl, phthalazinyl, thiazolyl, thienopyrazolyl (e.g., 1H-thieno[2,3-c]pyrazolyl, benzothiaphen-yl, thienopyridyl (e.g., thieno[3,2-b]pyridyl or thieno[3,2-c]pyridyl), thienopyridazinyl (e.g., thieno[3,2-c]pyridazinyl), tetrahydrothienopyryl, and the like. In some embodiments, A is an optionally substituted group selected from diphenyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridine), and pyrrolopyridine (e.g., 1H-pyrrolyl[2,3-c]pyridine). In some embodiments, A is unsubstituted. In some embodiments, A is substituted with one, two, or three substituents described herein. In some embodiments, A is substituted with one or two halogen groups or an unsubstituted phenyl group.

[0109] In some embodiments, A is [ka] where: R 6a , R 6b , and R 6c are independently H, halo, aryl, heteroaryl, CHOR 12 , OR 12 , N.H.R. 12 , CH2R 13 , or SO2R 13 and R 12 , H, R 14 aryl optionally substituted with 15 is a C1-C2 alkyl optionally substituted with R 13 is heterocycloalkyl, R 14 H, halo, OR 16 , or CH2CH2OR 16 and R 15 is cycloalkyl, or aryl optionally substituted with halo, and R 16 is a C1-C3 alkyl optionally substituted with one or more halo.

[0110] In some embodiments, R 13 is pyrrolidine.

[0111] In some embodiments, R 6a and R 6c Each of is H. In some embodiments, R 6b is halogen. In some embodiments, R 6b is chloro.

[0112] In some embodiments, A is [ka] where: U, V, and T are independently CH or N; R 7a is R 17 C1-C4 alkyl optionally substituted with H, halo, aryl optionally substituted with CF3, CO2R 18 or COR 18 is heteroaryl optionally substituted with R 17 is H, aryl optionally substituted with halo, or heterocycloalkyl; and R 18 is t-butyl.

[0113] In some embodiments, one of U, V, and T is N and two are CH.

[0114] In some embodiments, two of U, V, and T are N and one is CH.

[0115] In some embodiments, R 7a is optionally substituted phenyl. In some embodiments, R 7a is unsubstituted phenyl.

[0116] In some embodiments, A is [ka] where: U is CH or N; R 7a is R 17 C1-C4 alkyl optionally substituted with H, halo, or CF3, or COR 18 is a heteroaryl or heterocycloalkyl optionally substituted with R 17 is H, aryl optionally substituted with halo, or heterocycloalkyl; and R 18is t-butyl.

[0117] In some embodiments, U is CH.

[0118] In some embodiments, U is N.

[0119] In some embodiments, R 7a is optionally substituted phenyl. In some embodiments, R 7a is unsubstituted phenyl.

[0120] In some embodiments, A is [ka] where: U, V, and T are independently CH or N; R 7b is R 17 C1-C4 alkyl optionally substituted with H, halo, or CF3, or COR 18 is a heteroaryl or heterocycloalkyl optionally substituted with R 17 is H, aryl optionally substituted with halo, or heterocycloalkyl; and R 18 is t-butyl.

[0121] In some embodiments, one of U, V, and T is N and two are CH.

[0122] In some embodiments, two of U, V, and T are N and one is CH. In certain embodiments, T and V are N and U is CH.

[0123] In some embodiments, R 7a is optionally substituted phenyl. In some embodiments, R 7a is unsubstituted phenyl.

[0124] In some embodiments, A is [ka] where: U is CH or N; R 7b is R 17 C1-C4 alkyl optionally substituted with H, halo, or CF3, or COR 18 is a heteroaryl or heterocycloalkyl optionally substituted with R 17 is H, aryl optionally substituted with halo, or heterocycloalkyl; and R 18 is t-butyl.

[0125] In some embodiments, R 7a is optionally substituted phenyl. In some embodiments, R 7a is unsubstituted phenyl.

[0126] In some embodiments, A is [ka] where: R 9 is H, C1-C3 alkyl, or aryl.

[0127] In some embodiments, R 9 is H.

[0128] In some embodiments, R 9 is C1-C3 alkyl. In some embodiments, R 9 is methyl.

[0129] In some embodiments, R 9 is aryl. In some embodiments, R 9is phenyl.

[0130] In some embodiments, A is [ka] where: B, D, E, G, and I are independently C, CH, or N; R 8a , R 8b , R 8c , and R 8d are independently H, C1-C3 alkyl, halo, OR 19 , or NHR 20 and R 8e is absent, H, or =O, R 19 is H, aryl optionally substituted with halo, or R 21 is a C1-C3 alkyl optionally substituted with R 20 is SO2CH3, R 21 is aryl optionally substituted with halo, and ------- are optional bonds.

[0131] In some embodiments, ------- is absent, [ka] represents a single bond. In such embodiments, the valences of D, E, G, and / or I may be completed with hydrogen as appropriate. In some embodiments, ------- is absent.

[0132] In some embodiments, ------- is present, [ka] represents a double bond. In some embodiments, each ------ is present.

[0133] In some embodiments, at least one of B, D, E, G, and I is N.

[0134] In some embodiments, no more than two of B, D, E, G, and I are N.

[0135] In some embodiments, each of D, E, G, and I is C or CH.

[0136] In some embodiments, R 8a , R 8b , R 8c , and R 8d Each of is H.

[0137] In some embodiments, A is [ka] where: R 8a is H or methyl, R 8d H, OR 19 , or NHR 20 and R 19 is H, aryl optionally substituted with halo, or R 21 is a C1-C3 alkyl optionally substituted with R 20 is SO2CH3, and R 21 is aryl optionally substituted with halo.

[0138] In some embodiments, R 8a and R 8d Each of is H.

[0139] In some embodiments, A is [ka] where: D is CH or N; I is C, CH, or N; R 8a is H, halo, or C1-C3 alkyl; R 8b is H or C1-C3 alkyl, R 8c is H, ═O, or C1-C3 alkyl; R 8d H, OR 19 , N.H.R. 20 or C1-C3 alkyl; R 19 is H, aryl optionally substituted with halo, or R 21 is a C1-C3 alkyl optionally substituted with R 20 is SO2CH3, R 21 is aryl optionally substituted with halo, and ------ is an optional bond.

[0140] In some embodiments, ------- is absent, [ka] represents a single bond. In such embodiments, I and CR 8c The valence of can be completed with hydrogen if desired.

[0141] In some embodiments, ------- is present, [ka] represents a double bond.

[0142] In some embodiments, I is N. In some embodiments, D is N. In some embodiments, D is CH.

[0143] In some embodiments, D is N. In some embodiments, I is N. In some embodiments, I is C or CH.

[0144] In some embodiments, D is CH and I is C or CH.

[0145] In some embodiments, D and I are both CH.

[0146] In some embodiments, D is N and I is CH.

[0147] In some embodiments, R 8a , R 8b , R 8c , and R 8d Each of is H.

[0148] In some embodiments, A is [ka] where: E is CH, CH2, N, or NH; G and B are independently CH or N; R 8e is H, C1-C3 alkyl, or =O, and ------ is an optional bond.

[0149] In some embodiments, ------- is absent, [ka] represents a single bond. In such embodiments, E and CR 8e The valence of can be completed with hydrogen if desired.

[0150] In some embodiments, ------- is present, [ka] represents a double bond.

[0151] In some embodiments, G is N. In some embodiments, E is CH or CH. In some embodiments, E is N.

[0152] In some embodiments, E is N. In some embodiments, G is CH. In some embodiments, G is N.

[0153] In some embodiments, G is CH and E is CH.

[0154] In some embodiments, R 8e is H.

[0155] In some embodiments, A is [ka] where: J is C, CH, or N; K is CH, CH2, N, or NH; R 10 is H, halo, C1-C4 alkyl, or COR 22 and R 22 is t-butyl, and ------- are optional bonds.

[0156] In some embodiments, ------- is absent, [ka] represents a single bond. In some embodiments, ------- is absent.

[0157] In some embodiments, ------- is present, [ka] represents a double bond. In some embodiments, each ------ is present.

[0158] In some embodiments, J is N. In some embodiments, K is CH or CH. In some embodiments, K is N.

[0159] In some embodiments, K is N. In some embodiments, J is C or CH. In some embodiments, J is N.

[0160] In some embodiments, K is N and J is C.

[0161] In some embodiments, J is N and K is CH2.

[0162] In some embodiments, R 10 is H.

[0163] In some embodiments, R 10 is a halogen.

[0164] In some embodiments, R 10 is C1-C4 alkyl.

[0165] In some embodiments, R 10 CO2R 22 where R 22 is t-butyl.

[0166] In some embodiments, A is [ka] where: K is CH or N, and R 10 is H, halo, or C1-C4 alkyl.

[0167] In some embodiments, K is CH.

[0168] In some embodiments, K is N.

[0169] In some embodiments, R 10 is H.

[0170] In some embodiments, R 10 is a halogen.

[0171] In some embodiments, R 10 is an optionally substituted C1-C4 alkyl.

[0172] In some embodiments, A is [ka] where: J is CH or N; R 10 is H or CO2R 22 and R 22 is t-butyl.

[0173] In some embodiments, J is CH.

[0174] In some embodiments, J is N.

[0175] In some embodiments, R 10 is H.

[0176] In some embodiments, R 10 CO2R 22 It is.

[0177] In some embodiments, R 22 is t-butyl.

[0178] In some embodiments, A is [ka] where: R 11a and R 11bare independently H, C1-C3 alkyl, or C1-C3 alkoxy.

[0179] In some embodiments, R 11a is H.

[0180] In some embodiments, R 11b is H.

[0181] In some embodiments, R 11a is C1-C3 alkyl.

[0182] In some embodiments, R 11b is C1-C3 alkyl.

[0183] In some embodiments, R 11a is C1-C3 alkoxy.

[0184] In some embodiments, R 11b is C1-C3 alkoxy.

[0185] In some embodiments, R 11a and R 11b are both H.

[0186] In some embodiments, A is an optionally substituted 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine. [ka] It is.

[0187] In some embodiments, A is optionally substituted 1-naphthylene. In some embodiments, A is [ka] It is.

[0188] In some embodiments, A is an optionally substituted 2,3-dihydrothieno[3,4-b][1,4]dioxine. In some embodiments, A is [ka] It is.

[0189] In some embodiments, A is any one of substructures A1-A17.

[0190] In some embodiments, A is [ka] The file is TIFF2025500892000067.tif239170.

[0191] [Example compounds] In some embodiments, the PHD1 inhibitor compound is any one of compounds 1-62, or a pharma- ceutically acceptable salt thereof. [Table 2] TIFF2025500892000069.tif232170TIFF2025500892000070.tif234170TIFF2025500892000071.tif234170TIFF2025500892000072.tif117170

[0192] In some embodiments, the PHD1 inhibitor compound is Compound 1. In some embodiments, the PHD1 inhibitor compound is Compound 2. In some embodiments, the PHD1 inhibitor compound is Compound 3. In some embodiments, the PHD1 inhibitor compound is Compound 4. In some embodiments, the PHD1 inhibitor compound is Compound 5. In some embodiments, the PHD1 inhibitor compound is Compound 6. In some embodiments, the PHD1 inhibitor compound is Compound 7. In some embodiments, the PHD1 inhibitor compound is Compound 8. In some embodiments, the PHD1 inhibitor compound is Compound 9. In some embodiments, the PHD1 inhibitor compound is Compound 10. In some embodiments, the PHD1 inhibitor compound is a pharma- ceutically acceptable salt of any one of these compounds.

[0193] In some embodiments, the PHD1 inhibitor compound is compound 11. In some embodiments, the PHD1 inhibitor compound is compound 12. In some embodiments, the PHD1 inhibitor compound is compound 13. In some embodiments, the PHD1 inhibitor compound is compound 14. In some embodiments, the PHD1 inhibitor compound is compound 15. In some embodiments, the PHD1 inhibitor compound is compound 16. In some embodiments, the PHD1 inhibitor compound is compound 17. In some embodiments, the PHD1 inhibitor compound is compound 18. In some embodiments, the PHD1 inhibitor compound is compound 19. In some embodiments, the PHD1 inhibitor compound is compound 20. In some embodiments, the PHD1 inhibitor compound is a pharma- ceutically acceptable salt of any one of these compounds.

[0194] In some embodiments, the PHD1 inhibitor compound is Compound 21. In some embodiments, the PHD1 inhibitor compound is Compound 22. In some embodiments, the PHD1 inhibitor compound is Compound 23. In some embodiments, the PHD1 inhibitor compound is Compound 24. In some embodiments, the PHD1 inhibitor compound is Compound 25. In some embodiments, the PHD1 inhibitor compound is Compound 26. In some embodiments, the PHD1 inhibitor compound is Compound 27. In some embodiments, the PHD1 inhibitor compound is Compound 28. In some embodiments, the PHD1 inhibitor compound is Compound 29. In some embodiments, the PHD1 inhibitor compound is Compound 30. In some embodiments, the PHD1 inhibitor compound is a pharma- ceutically acceptable salt of any one of these compounds.

[0195] In some embodiments, the PHD1 inhibitor compound is compound 31. In some embodiments, the PHD1 inhibitor compound is compound 32. In some embodiments, the PHD1 inhibitor compound is compound 33. In some embodiments, the PHD1 inhibitor compound is compound 34. In some embodiments, the PHD1 inhibitor compound is compound 35. In some embodiments, the PHD1 inhibitor compound is compound 36. In some embodiments, the PHD1 inhibitor compound is compound 37. In some embodiments, the PHD1 inhibitor compound is compound 38. In some embodiments, the PHD1 inhibitor compound is compound 39. In some embodiments, the PHD1 inhibitor compound is compound 40. In some embodiments, the PHD1 inhibitor compound is a pharma- ceutically acceptable salt of any one of these compounds.

[0196] In some embodiments, the PHD1 inhibitor compound is compound 41. In some embodiments, the PHD1 inhibitor compound is compound 42. In some embodiments, the PHD1 inhibitor compound is compound 43. In some embodiments, the PHD1 inhibitor compound is compound 44. In some embodiments, the PHD1 inhibitor compound is compound 45. In some embodiments, the PHD1 inhibitor compound is compound 46. In some embodiments, the PHD1 inhibitor compound is compound 47. In some embodiments, the PHD1 inhibitor compound is compound 48. In some embodiments, the PHD1 inhibitor compound is compound 49. In some embodiments, the PHD1 inhibitor compound is compound 50. In some embodiments, the PHD1 inhibitor compound is a pharma- ceutically acceptable salt of any one of these compounds.

[0197] In some embodiments, the PHD1 inhibitor compound is compound 51. In some embodiments, the PHD1 inhibitor compound is compound 52. In some embodiments, the PHD1 inhibitor compound is compound 53. In some embodiments, the PHD1 inhibitor compound is compound 54. In some embodiments, the PHD1 inhibitor compound is compound 55. In some embodiments, the PHD1 inhibitor compound is compound 56. In some embodiments, the PHD1 inhibitor compound is compound 57. In some embodiments, the PHD1 inhibitor compound is compound 58. In some embodiments, the PHD1 inhibitor compound is compound 59. In some embodiments, the PHD1 inhibitor compound is compound 60. In some embodiments, the PHD1 inhibitor compound is a pharma- ceutically acceptable salt of any one of these compounds.

[0198] In some embodiments, the PHD1 inhibitor compound is compound 61. In some embodiments, the PHD1 inhibitor compound is compound 62. In some embodiments, the PHD1 inhibitor compound is a pharma- ceutically acceptable salt of any one of these compounds.

[0199] Abbreviations and acronyms used herein include the following: [Table 3] TIFF2025500892000074.tif143170[Isotopologue] It should be understood that in the compounds described herein (e.g., compounds of formula (I)-(VII), such as any one of compounds 1-62), the atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that found predominantly in nature. The present invention is intended to include all suitable isotopic variations of the compounds described herein (e.g., compounds of formula (I)-(VII), such as any one of compounds 1-62). For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H). Protium is the predominant hydrogen isotope found in nature. In some embodiments, one or more of the hydrogens of the compounds described herein (e.g., compounds of formula (I)-(VII), such as any one of compounds 1-62) are replaced by deuterium. Enriching with deuterium may provide certain therapeutic advantages, such as increased half-life or reduced dose requirements in vivo, or provide compounds useful as standards for characterization of biological samples. In some embodiments, one or more of the hydrogens of the compounds described herein (e.g., compounds of formula (I)-(VII), such as any one of compounds 1-62) are replaced by tritium. Tritium is radioactive and can provide radiolabeled compounds useful as tracers in metabolic or kinetic studies. Isotopic enrichment of the compounds described herein (e.g., compounds of Formulas (I)-(VII), such as any one of Compounds 1-62) may be accomplished without undue experimentation by conventional techniques known to those of skill in the art, or by processes analogous to those described in the schemes and examples herein using appropriate isotopic enrichment reagents and / or intermediates. The term "isotopologue" refers to a species having the same chemical structure and formula as a particular compound provided herein, except for the position of isotopic substitution and / or the level of isotopic enrichment, such as hydrogen versus deuterium, at one or more positions. Thus, as used herein, the term "compound" encompasses a collection of molecules having the same chemical structure but with isotopic variation between the constituent atoms of the molecule. Thus, it will be apparent to one skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown also contains isotopologues having lesser amounts of hydrogen atoms at one or more of the designated deuterium positions in the structure. The relative amounts of such isotopologues in the compounds provided depend on many factors, including, but not limited to, the isotopic purity of the deuterium reagent used to make the compound, and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound. When a position is designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. 2 When a position is designated as "H" or "deuterium," the position is understood to have deuterium in abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., 2 The term "H" or "deuterium" indicates incorporation of at least 50.1% deuterium). In embodiments, the compounds provided herein may have an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), 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), or at least 6633.3 (99.5% deuterium incorporation) for each deuterium present at a site designated as a potential site for deuterium on the compound.

[0200] [Synthesis of the Compounds of the Present Invention] The compounds described herein (e.g., compounds of Formulas (I)-(VII), such as any one of Compounds 1-62), or pharma- ceutically acceptable salts thereof, can be prepared according to methods known in the art, including the exemplary syntheses of the Examples provided herein, such as those depicted in Schemes A and B.

[0201] [ka] Compounds of formula (I)-(VII), such as any one of compounds 1-62, can be prepared according to Scheme A using commercially available materials. Cross-coupling of (II) and (III) using palladium catalysis gives biaryl compounds of formula (IV). Aromatic nucleophilic displacement of (IV) with sodium methoxide at elevated temperature gives compounds of formula (V). Compound (V) is then exposed to a demethylating reagent such as HBr(aq) or BBr3 at elevated temperature, followed by hydrolysis conditions using a hydroxide base such as NaOH and KOH. Amide compounds (VIII) are synthesized using coupling reactants such as (VI) and CDI, EDCI, or (COCl)2, followed by addition of amino acid (VII) and an amine base such as DIPEA or Et3N. Finally, ester compounds of formula (VIII) are saponified using a suitable base such as NaOH, LiOH, or KOH in a combination of solvents such as THF or dioxane and water.

[0202] Alternatively, compounds of formula (I)-(VII), such as any one of compounds 1-62, are prepared according to Scheme B using commercially available starting materials. An ester of formula (IX) is reacted with an amino acid (VII) and a base such as DIPEA or K2CO3 in a high boiling solvent such as dioxane or DMF at elevated temperature to give a compound of formula (X). Palladium catalyzed cross-coupling of (X) and (XI) gives a biaryl compound of formula (VIII). As in Scheme A, an ester compound of formula (VIII) is saponified using a suitable base such as NaOH, LiOH, or KOH in a combination of solvents such as THF or dioxane and water. [ka]

[0203] Compositions and Methods The present invention provides the use of a compound of formula (I)-(VII), such as any one of compounds 1-62, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of various conditions or disorders described herein. In one embodiment, a pharmaceutical composition is provided comprising at least one compound of formula (I)-(VI) (e.g., any one of compounds 1-62), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier. In various embodiments, the medicament or pharmaceutical composition further comprises, or can be used in combination with, at least one additional therapeutic agent.

[0204] The compounds of the present invention, or medicaments or compositions comprising the compounds or pharma- ceutically acceptable salts thereof, can be used to selectively inhibit the activity of PHD1 relative to other isoforms, such as PHD2 and / or PHD3 enzymes. Selective inhibition of PHD1 may be particularly beneficial in the treatment of ischemia-reperfusion injury (including, but not limited to, stroke, myocardial infarction, and acute kidney injury), inflammatory bowel disease, cancer (including colorectal cancer), and liver disease. In one embodiment, the method of the present invention comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I)-(VII), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more of the compounds of formula (I)-(VII), or a pharma- ceutically acceptable salt thereof.

[0205] The present invention is also directed to a method of inhibiting the activity of PHD1. The PHD1 enzyme is selectively inhibited relative to other PHD isoforms, such as the PHD2 and / or PHD3 enzymes. In one embodiment, the method comprises contacting PHD1 with an effective amount of one or more compounds selected from the group comprising the compounds of formula (I)-(VII), or a pharma- ceutically acceptable salt thereof.

[0206] In an exemplary embodiment, a compound disclosed herein (e.g., a compound of Formula (I)-(VII), such as any one of Compounds 1-62), or a pharma- ceutically acceptable salt thereof, is used to treat chronic kidney disease, polycystic kidney disease, aplastic anemia, autoimmune hemolytic anemia, bone marrow transplant anemia, Churg-Strauss syndrome, Diamond-Blackfan anemia, Fanconi anemia, Felty syndrome, graft-versus-host disease, hematopoietic stem cell transplantation, hemolytic uremic syndrome, myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, myelofibrosis, pancytopenia, pure red cell aplasia, Henoch-Schonlein purpura, refractory anemia with excess blasts, rheumatoid arthritis, , Shwachman syndrome, sickle cell disease, thalassemia major, thalassemia minor, thrombocytopenic purpura, anemic or non-anemic patients undergoing surgery, anemia associated with or secondary to trauma, sideroblastic anemia, anemia secondary to other treatments including reverse transcriptase inhibitors for treating HIV, corticosteroid hormones, cyclic cisplatin or non-cisplatin containing chemotherapeutic agents, vinca alkaloids, mitotic inhibitors, topoisomerase II inhibitors, anthracyclines, alkylating agents; in particular anemia secondary to inflammation, aging and / or chronic disease. PHD1 inhibition may also be used to treat symptoms of anemia including chronic fatigue, pallor, and dizziness.

[0207] In other embodiments, the compounds disclosed herein (e.g., a compound of Formula (I)-(VII), such as any one of Compounds 1-62), or a pharma- ceutically acceptable salt thereof, are useful for treating or preventing diseases of metabolic disorders, including, but not limited to, diabetes and obesity.

[0208] In yet other embodiments, the compounds disclosed herein (e.g., compounds of Formula (I)-(VII), such as any one of Compounds 1-62), or pharma- ceutically acceptable salts thereof, are useful for treating or preventing vascular disorders, including, but not limited to, hypoxia or wound healing-related disorders that require pro-angiogenic mediators for vasculogenesis, angiogenesis, and arteriogenesis.

[0209] In yet other embodiments, the compounds disclosed herein (e.g., compounds of Formula (I)-(VII), such as any one of Compounds 1-62), or pharma- ceutically acceptable salts thereof, are useful for treating or preventing ischemia-reperfusion injury, including, but not limited to, stroke, myocardial infarction, and acute kidney injury.

[0210] In other embodiments, the compounds disclosed herein (e.g., compounds of Formulas (I)-(VII), such as any one of Compounds 1-62), or a pharma- ceutically acceptable salt thereof, are useful for treating inflammatory bowel disease.

[0211] In other embodiments, the compounds disclosed herein (e.g., a compound of Formula (I)-(VII), such as any one of Compounds 1-62), or a pharma- ceutically acceptable salt thereof, are useful in the treatment of cancer, such as colorectal cancer.

[0212] In yet other embodiments, the compounds disclosed herein (e.g., compounds of Formulas (I)-(VII), such as any one of Compounds 1-62), or a pharma- ceutically acceptable salt thereof, are useful for treating liver disease.

[0213] [Pharmaceutical formulations and routes of administration] The compounds and compositions of the present invention, or pharma- ceutically acceptable salts thereof, can be delivered directly or in a pharmaceutical composition or medicament together with a suitable carrier or excipient, as is well known in the art. The therapeutic method of the present invention can include administering an effective amount of the compounds of the present invention, or a pharma- ceutically acceptable salt thereof, 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.

[0214] The effective amount of such compounds, compositions, or pharmaceutical agents can be easily determined by routine experimentation, as can the most effective and convenient route of administration and the most suitable formulation. A variety of formulations and drug delivery systems are available in the art. See, for example, Gennaro, AR, ed. (1995) Remington's Pharmaceutical Sciences, supra.

[0215] Suitable routes of administration may include, for example, oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration. Primary routes of parenteral administration include intravenous, intramuscular, and subcutaneous administration. Secondary routes of administration include intraperitoneal, intraarterial, intraarticular, intracardiac, intracisternal, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration. The indication to be treated and the physical, chemical, and biological properties of the drug determine the type of formulation and route of administration used, and whether local or systemic delivery is preferred.

[0216] Pharmaceutical dosage forms of the compounds of the present invention may be provided in 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, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized preparations. Depending on the route of administration used, special equipment may be required for application or administration of the drug, such as, for example, syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. Pharmaceutical dosage forms are often composed of a drug, excipients, and a container / closure system. One or more excipients, also called inactive ingredients, may be added to the compounds of the present invention to improve or facilitate the manufacture, stability, administration, and safety of the drug, and to provide a means for achieving a desired drug release profile. Thus, the type of excipient added to the drug may depend on various factors, such as, for example, 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 include those listed in the various pharmacopoeias.

[0217] See, for example, the United States Pharmacopoeia (USP), the Japanese Pharmacopoeia (JP), the European Pharmacopoeia (EP), and the British Pharmacopoeia (BP), the U.S. Food and Drug Administration (www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications such as Inactive Ingredient Guide (1996), Ash and Ash, Eds. (2002) Handbook of Pharmaceutical Additives, Synapse Information Resources, Inc., Endicott NY, etc.

[0218] Pharmaceutical dosage forms of the compounds of the present invention can be prepared by any of the methods well known in the art, such as, for example, conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, pulverizing, emulsifying, (nano / micro)encapsulating, encapsulating, or lyophilizing processes. As mentioned above, the compositions of the present invention can contain one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into preparations for pharmaceutical use.

[0219] Appropriate formulations depend on the desired route of administration. For intravenous injection, for example, the composition may be formulated in aqueous solution, using physiologically compatible buffers, including, for example, phosphate, histidine, or citrate to adjust the formulation pH, and isotonicity agents, such as, for example, sodium chloride or dextrose, as necessary. For transmucosal or nasal administration, semi-solid, liquid formulations, or patches, possibly containing a penetration enhancer, may be preferred. Such penetrants are generally known in the art. For oral administration, the compound may be formulated in liquid or solid dosage forms, as immediate or controlled / sustained release formulations. Dosage forms suitable for oral ingestion by a subject include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions. The compound may also be formulated in rectal compositions, such as suppositories or retention enemas, containing, for example, conventional suppository bases, such as cocoa butter or other glycerides.

[0220] Solid oral dosage forms can be obtained using excipients, which may include fillers, disintegrants, binders (dry and wet), dissolution retarders, lubricants, glidants, antiadherents, cation exchange resins, wetting agents, antioxidants, preservatives, colorants, and flavoring agents. These excipients may be of synthetic or natural origin. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated), and waxes. Ethanol and water may serve as granulation aids. In certain cases, coating of tablets, for example, with taste masking film, gastric acid resistant film, or release retarding film, is desirable.Natural and synthetic polymers are often used to coat tablets in combination with coloring agents, sugars, and organic solvents or water, resulting in sugar tablets.When capsules are preferred over tablets, drug powders, suspensions, or solutions thereof can be delivered in compatible hard or soft shell capsules.

[0221] In one embodiment, the compounds of the present invention can be administered locally via skin patches, semi-solid or liquid formulations, such as gels, (micro)emulsions, ointments, solutions, (nano / micro)suspensions, or foams. Penetration of drugs into the skin and underlying tissues can be controlled, for example, using penetration enhancers, using appropriate selection and combination of lipophilic, hydrophilic, and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers, by pH adjustment, and with the use of complexing agents. Other techniques, such as iontophoresis, can be used to control the skin penetration of the compounds of the present invention. Transdermal or topical administration may be preferred, for example, in situations where local delivery with minimal systemic exposure is desired.

[0222] For administration by inhalation or nasal administration, the compound for use according to the present invention is conveniently delivered in the form of a solution, suspension, emulsion, or semi-solid aerosol from a pressurized pack or nebulizer, usually using a propellant such as a halogenated carbon derived from methane and ethane, carbon dioxide, or any other suitable gas.For local aerosol, hydrocarbons such as butane, isobutene, and pentane are useful.For pressurized aerosol, the appropriate dosage unit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges, for example of gelatin, for use in an inhaler or insufflator can be formulated.These typically contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0223] Compounds and compositions formulated for parenteral administration by injection are usually sterile and can be presented in unit dosage form, for example, in ampoules, syringes, injection pens, or multi-dose containers, the latter usually containing preservatives. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents such as buffers, isotonicity agents, viscosity enhancing agents, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives. Depending on the injection site, the vehicle may contain water, synthetic or vegetable oils, and / or organic cosolvents. In certain instances, such as lyophilized products or concentrates, parenteral formulations are reconstituted or diluted prior to administration. Depot formulations providing controlled or sustained release of the compounds of the invention may include injectable suspensions of nano / microparticles or nano / micro or non-particulate crystals. Polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, in addition to others known in the art, can act as controlled / sustained release matrices. Other depot delivery systems may come in the form of implants and pumps that require an incision.

[0224] Carriers suitable for intravenous injection for the compounds of the present invention are well known in the art and include, for example, aqueous solutions containing bases such as sodium hydroxide to form ionized compounds, sucrose or sodium chloride as isotonicity agents, and buffers such as buffers containing phosphate or histidine. Cosolvents such as polyethylene glycol may be added. These aqueous systems are effective in dissolving the compounds of the present invention and make them less toxic when administered systemically. The ratio of components of the solution system may vary widely without compromising solubility and toxicity properties. Furthermore, the identity of the components may vary. For example, low toxicity surfactants such as polysorbates or poloxamers may be used, polyethylene glycol or other cosolvents may be used, biocompatible polymers such as polyvinylpyrrolidone may be added, and other sugars and polyols may be used instead of dextrose.

[0225] The therapeutically effective dose can be initially estimated using various techniques well known in the art. Initial doses used in animal studies may be based on effective concentrations established in cell culture assays. For example, data obtained from animal studies and cell culture assays can be used to determine appropriate dose ranges for human subjects. In certain embodiments, the compounds of the present disclosure are formulated for oral administration. Exemplary doses of the compounds of the present disclosure in pharmaceutical formulations for oral administration are about 0.5 to about 10 mg per kg of subject body weight. In some embodiments, the pharmaceutical formulations include about 0.7 to about 5.0 mg per kg of subject body weight, or about 1.0 to about 2.5 mg per kg of subject body weight. A typical dosing regimen for oral administration is administration of the pharmaceutical formulation for oral administration three times a week, twice a week, once a week, or daily.

[0226] An effective amount or therapeutically effective amount or dose of an agent, such as a compound of the present invention, refers to that amount of the agent or compound that results in the amelioration of symptoms or the prolongation of survival in a subject. The toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the LD50 / ED50 ratio. Agents that exhibit high therapeutic indices are preferred.

[0227] An effective amount or therapeutically effective amount is that amount of a compound or pharmaceutical composition that induces the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or other clinician. The dosage falls specifically within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and / or the route of administration utilized. The exact formulation, route of administration, dosage, and administration interval should be selected according to methods known in the art, taking into account the specifics of the subject's condition.

[0228] Dosage and administration interval can be adjusted individually to provide a plasma level of the active moiety that is sufficient to achieve the desired effect, i.e., the minimum effective concentration (MEC). The MEC varies from compound to compound, but can be estimated, for example, from in vitro data and animal experiments. The dosage required to achieve the MEC depends on individual characteristics and the route of administration. In the case of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0229] The amount of compound or composition administered can depend on a variety of factors, including 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.

[0230] The compounds and compositions may be optionally presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, contain metal or plastic foil, such as a blister pack, or glass or rubber stopper, such as a vial. The pack or dispenser device may be accompanied by instructions for administration. Compositions containing the compounds of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for the treatment of an indicated condition.

[0231] 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 are specifically contemplated. EXAMPLES

[0232] Example 1: Preparation of Compound 1 5-(3-chlorophenyl)-3-hydroxypicolinic acid [ka]

[0233] The above compounds were prepared according to the procedures outlined in US20120309977.

[0234] 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-3-methylbutanoic acid [ka]

[0235] 5-(3-Chlorophenyl)-3-hydroxypicolinic acid (50 mg, 0.20 mmol, 1 equiv) was dissolved in DMSO (0.25 mL) in an oven-dried vial equipped with a magnetic stirrer. 1,1'-carbonyldiimidazole (49 mg, 0.30 mmol, 1.5 equiv) was then added portionwise to the reaction mixture with stirring at room temperature. The vial was sealed and heated to 45°C for 1 h. The reaction mixture was cooled to room temperature and methyl 3-amino-3-methylbutanoate hydrochloride (35 mg, 0.20 mmol, 1 equiv) was added, followed by N,N-diisopropylethylamine (0.13 mL, 0.75 mmol, 3.7 equiv). The reaction mixture was sealed and stirred at room temperature overnight. The reaction mixture was quenched with water (3.5 mL). The vial was then cooled to 0°C and 1M HCl was added dropwise until the pH was 2-3. The reaction mixture was then extracted with dichloromethane (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The crude residue was purified on silica gel (0%-10% methanol in dichloromethane). Methyl 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-3-methylbutanoate (30 mg, 41% yield) was isolated as a white solid. LCMS (ESI+): m / z 363.0 (M+H) +

[0236] 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-3-methylbutanoic acid (compound 1) [ka]

[0237] Methyl 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-3-methylbutanoate (30 mg, 0.08 mmol, 1 equiv) was suspended in THF (1 mL) in a vial equipped with a magnetic stirrer. To the reaction mixture, 1M NaOH (0.25 mL) was added dropwise at room temperature. The reaction progress was monitored by LCMS. Upon complete consumption of the starting material, the reaction mixture was concentrated by rotary evaporation. The crude residue was then suspended in water (4 mL) and acidified to pH 2-3 with 1M HCl. The aqueous solution was extracted with 10% methanol in dichloromethane (3×20 mL). The combined organic layers were filtered through a hydrophobic frit and concentrated by rotary evaporation. The crude residue was purified by preparative HPLC (30%-85% acetonitrile in water). The combined fractions were dried on a lyophilizer to give 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-3-methylbutanoic acid (compound 1) (12 mg, 41% yield). LC-MS (ESI+): m / z 349.0 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 12.35 (s, 1H), 8.61 (s, 1H), 8.48 (d, 1H), 7.88 (s, 1H), 7.78-7.75 (m, 2H), 7.56-7.51 (m, 2H), 2.76 (s, 2H), 1.52 (s, 6H).

[0238] [Example 2: Preparation of Compound 2] (S)-3-Aminobutanoic acid ethyl ester hydrochloride [ka]

[0239] In an oven-dried vial, (S)-3-aminobutanoic acid (500 mg, 4.85 mmol, 1 equiv) was suspended in ethanol (2.2 mL) and the vial was cooled to 0 °C in an ice bath. Thionyl chloride (0.6 mL, 8.24 mmol, 1.7 equiv) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated by rotary evaporation, redissolved in ethanol, and concentrated by rotary evaporation. (S)-ethyl 3-aminobutanoate hydrochloride (813 mg, 100% yield) was isolated as a green oil.

[0240] (S)-3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)butanoic acid [ka]

[0241] (S)-3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)butanoic acid (9 mg, 33% yield) was prepared using the procedure for the synthesis of 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-3-methylbutanoic acid using 5-(3-chlorophenyl)-3-hydroxypicolinic acid (50 mg, 0.20 mmol) and (S)-ethyl 3-aminobutanoate hydrochloride (101 mg, 0.6 mmol). LCMS (ESI+): m / z 335.0 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 9.15 (d, 1H), 8.50 (d, 1H), 7.90 (s, 1H), 7.78-7.75 (m, 1H), 7.76 (d, 1H), 7.56-7.54 (m, 2H), 4.44 (p, 1H), 2.56-2.51 (m, 2H), 1.25 (d, 3H).

[0242] [Example 3: Preparation of Compound 3] (R)-3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)butanoic acid [ka]

[0243] (R)-3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)butanoic acid (35 mg, 90% yield) was prepared using the procedure for the synthesis of 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-3-methylbutanoic acid using 5-(3-chlorophenyl)-3-hydroxypicolinic acid (50 mg, 0.20 mmol) and (S)-ethyl 3-aminobutanoate hydrochloride (101 mg, 0.6 mmol). LCMS (ESI+): m / z 335.0 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 12.26 (s, 1H), 9.13 (d, 1H), 8.48 (d, 1H), 7.89 (s, 1H), 7.77-7.75 (m, 1H), 7.74 (d, 1H), 7.56-7.51 (m, 2H), 4.42 (p, 1H), 2.60 (qd, 2H), 1.23 (d, 3H).

[0244] Example 4: Preparation of Compound 4 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid tert-butyl ester [ka]

[0245] 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-tert-butyl 2,2-dimethylpropanoate (40 mg, 49% yield) was prepared using the procedure for the synthesis of methyl 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-3-methylbutanoate using 5-(3-chlorophenyl)-3-hydroxypicolinic acid (50 mg, 0.20 mmol) and tert-butyl 3-amino-2,2-dimethylpropanoate (35 mg, 0.2 mmol). LCMS (ESI+): m / z 405.0 (M+H). +

[0246] 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0247] In an oven-dried vial, tert-butyl 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoate (40 mg, 0.1 mmol, 1 equiv.) was dissolved in dichloromethane (0.8 mL). Trifluoroacetic acid (0.2 mL) was added dropwise to the reaction mixture. The reaction was allowed to stir at room temperature for 2 h. Reaction progress was monitored by LCMS. Upon completion, the reaction was concentrated by rotary evaporation. The crude residue was purified by preparative HPLC (30% to 85% acetonitrile in water). The combined fractions were dried on a lyophilizer to give 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid (27 mg, 79% yield). LCMS (ESI+): m / z 349.0 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (bs, 2H), 8.81 (t, 1H), 8.52 (d, 1H), 7.90 (s, 1H), 7.79-7.76 (m, 2H), 7.56-7.53 (m, 2H), 3.48 (d, 2H), 1.15 (s, 6H).

[0248] [Example 5: Preparation of Compound 5] 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)propanoic acid [ka]

[0249] 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)propanoic acid (21 mg, 54% yield) was prepared using the procedure for the synthesis of 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-3-methylbutanoic acid using 5-(3-chlorophenyl)-3-hydroxypicolinic acid (50 mg, 0.20 mmol) and ethyl methyl 3-aminopropanoate hydrochloride (84 mg, 0.6 mmol). LCMS (ESI+): m / z 321.0 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 12.34 (s, 1H), 9.18 (t, 1H), 8.49 (d, 1H), 7.90-7.89 (m, 1H), 7.79-7.76 (m, 1H), 7.75 (d, 1H), 7.54-7.53 (m, 1H), 7.53 (d, 1H), 3.54 (q, 2H), 2.57 (t, 2H).

[0250] [Example 6: Preparation of Compound 6] 3-(5-bromo-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid ethyl ester [ka]

[0251] To a mixture of methyl 5-bromo-3-hydroxypicolinate (3.0 g, 12.90 mmol) in dioxane (60 ml) was added ethyl 3-amino-2,2-dimethylpropanoate hydrochloride (2.58 g, 14.20 mmol) and DIPEA (1.84 g, 14.20 mmol). The reaction mixture was stirred at 80° C. overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated to dryness. The crude residue was purified by silica gel column chromatography (EtOAc:Hex=1:40) to give the title compound (2.4 g) as an oil. LCMS (ESI+): m / z 345,347 (M+H +), 1H NMR (300 MHz, CDCl3) δ 12.33 (s, 1H), 8.38 (brs, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.55 (d, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.26 (s, 6H).

[0252] Ethyl 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoate [ka]

[0253] Under nitrogen atmosphere, a mixture of ethyl 3-(5-bromo-3-hydroxypicolinamido)-2,2-dimethylpropanoate (237 mg, 0.69 mmol), K2CO3 (133 mg, 0.96 mmol), (1-phenyl-1H-pyrazol-4-yl)boronic acid (142 mg, 0.76 mmol), and Pd(PPh3)2Cl2 (49 mg, 0.07 mmol) in DMF (4 mL) and water (2 mL) was stirred at 90 °C overnight. After the reaction was completed as shown by TLC analysis, the resulting mixture was diluted with water (80 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over Na2SO4 (10 g), filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc:Hex = 1:20 to 1:8) to give the desired product (205 mg) as a white solid. LCMS (ESI+): m / z 409 (M+H) +; 1H-NMR (300 MHz, CDCl3) δ 12.24 (s, 1H), 8.45 (s, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.24 (s, 1H), 8.05 (s, 1H), 7.73-7.76 (m, 2H), 7.48-7.54 (m, 2H), 7.43 (d, J = 1.8Hz, 1H), 7.33-7.38 (m, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.58 (d, J = 6.6 Hz, 2H), 1.25~1.37 (m, 9H).

[0254] 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0255] To a solution of ethyl 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoate (205 mg, 0.50 mmol) in THF (4 mL) and water (1 mL) was added LiOH·H2O (85 mg, 2.00 mmol) in one portion. After addition, the mixture was stirred at 50 °C overnight. After completion of the reaction as shown by TLC analysis, THF was removed in vacuo. The residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). After separation, the aqueous layer was adjusted to pH 3-4 with dilute HCl solution (1 M) to precipitate a large amount of solid. After filtration, the desired product (145 mg) was isolated as a white solid (145 mg). LCMS (ESI+): m / z 381 (M+H) +; 1H-NMR (300 MHz, CD3OD) δ 8.84 (s, 1H), 8.47 (d, J = 1.8 Hz, 1H ), 8.22 (s, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.62 (d, J = 1.8 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 3.55 (s, 2H), 1.25 (s, 6H).

[0256] Example 7: Preparation of Compound 7 3-(3-hydroxy-5-(1-propyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0257] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LCMS (ESI+): m / z 347 (M+H) + ; 1H-NMR (300 MHz, CD3OD) δ 8.36 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.49 (d, J = 1.8 Hz, 1H), 4.16 (t, J = 6.9 Hz, 2H), 3.54 (s, 2H), 1.87-1.94 (m, 2H), 1.24 (s, 6H), 0.92 (t, J = 7.2 Hz, 3H).

[0258] [Example 8: Preparation of Compound 8] 3-(3-hydroxy-5-(3-phenoxyphenyl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0259] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (3-phenoxyphenyl)boronic acid. LCMS (ESI-): m / z 405 (MH) - ; 1H-NMR (300 MHz, CD3OD) δ 8.35 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.44-7.48 (m, 2H), 7.39 (t, J = 8.1 Hz, 2H), 7.31 (d, J = 1.8 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 7.02-7.07 (m, 3H), 3.56 (s, 2H), 1.25 (s, 6H).

[0260] Example 9: Preparation of Compound 9 3-(5-([1,1'-biphenyl]-3-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0261] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using [1,1'-biphenyl]-3-ylboronic acid. LCMS (ESI+): m / z 391 (M+H) + ; 1H-NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), 7.89 (s, 1H), 7.56-7.70 (m, 6H), 7.47 (t, J = 7.2 Hz, 2H), 7.37 (m, 1H), 3.57 (s, 2H), 1.26 (s, 6H).

[0262] Example 10: Preparation of Compound 10 3-(3-hydroxy-5-(3-(pyrrolidin-1-ylmethyl)phenyl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0263] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidine. LCMS (ESI+): m / z 398 (M+H) + ; 1H-NMR (300 MHz, CD3OD) δ 8.85 (t, J = 6.0 Hz, 1H), 7.80 (s, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.27-7.36 (m, 3H), 4.17 (s, 2H), 3.53 (d, J = 6.0 Hz, 2H), 3.13 (brs, 4H), 2.04 (brs, 4H), 1.32 (s, 6H).

[0264] Example 11: Preparation of Compound 11 3-(5-(3-((3-chlorophenoxy)methyl)phenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0265] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (3-((3-chlorophenoxy)methyl)phenyl)boronic acid. LCMS (ESI+): m / z 455 (M+H) +; 1H-NMR (300 MHz, CDCl3) δ 12.20 (s, 1H), 8.47 (t, J = 6.9 Hz, 1H), 8.33 (d, J = 1.5 Hz, 1H), 7.64 (s, 1H), 7.49-7.57 (m, 4H), 7.19-7.25 (m, 1H), 6.95-7.00 (m, 2H), 6.86-6.89 (m, 1H), 5.11 (s, 2H), 3.64 (d, J = 6.6 Hz, 2H), 1.35 (s, 6H).

[0266] Example 12: Preparation of Compound 12 3-(5-(3-(cyclopropylmethoxy)phenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0267] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (3-(cyclopropylmethoxy)phenyl)boronic acid. LCMS (ESI+): m / z 385 (M+H) + ; 1H-NMR (300 MHz, CDCl3) δ 8.38 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.19-7.24 (m, 2H), 6.97-7.01 (m, 1H), 3.89 (d, J = 6.9 Hz, 2H), 3.56 (s, 2H), 1.28-1.29 (m, 1H), 1.25 (s, 6H), 0.60-0.66 (m, 2H), 0.36~0.40 (m, 2H).

[0268] Example 13: Preparation of compound 13 3-(3-hydroxy-5-(3-((4-(2-methoxyethyl)phenoxy)methyl)phenyl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0269] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (3-((4-(2-methoxyethyl)phenoxy)methyl)phenyl)boronic acid. LCMS (ESI+): m / z 479 (M+H) + ; 1H-NMR (300 MHz, CDCl3) δ 12.18 (s, 1H), 8.45 (t, J = 6.6 Hz, 1H), 8.30 (d, J = 1.8 Hz, 1H), 7.64 (s, 1H), 7.49-7.54 (m, 4H), 7.15 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 5.10 (s, 2H), 3.56-3.65 (m, 4H), 3.36 (s, 3H), 2.84 (t, J = 8.4 Hz, 2H), 1.35 (s, 6H).

[0270] Example 14: Preparation of compound 14 3-(3-hydroxy-5-(2-methylthiazol-5-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0271] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole. LCMS (ESI-): m / z 334 (MH)- ; 1H-NMR (300 MHz, CD3OD) δ 8.36 (d, J = 1.5 Hz, 1H), 8.09 (s, 1H), 7.52 (d, J = 1.5 Hz, 1H), 3.55 (s, 2H), 2.75 (s, 3H), 1.23 (s, 6H).

[0272] Example 15: Preparation of Compound 15 3-(3-hydroxy-5-(3-(pyridin-3-yl)phenyl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0273] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (3-(pyridin-3-yl)phenyl)boronic acid. LCMS (ESI+): m / z 392.2 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 12.45 (s, 1H), 9.03 (dd, 1H), 8.80 (s, 1H), 8.62 (d, 1H), 8.60 (dd, 1H), 8.24-8.21 (m, 1H), 8.13 (t, 1H), 7.88 (d, 1H), 7.86-7.82 (m, 2H), 7.65 (t, 1H), 7.51 (ddd, 1H), 3.49 (d, 2H), 1.16 (s, 6H).

[0274] Example 16: Preparation of Compound 16 3-(3-hydroxy-5-(3-((4-(trifluoromethoxy)phenoxy)methyl)phenyl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0275] The compound was synthesized following the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (3-((4-(trifluoromethoxy)phenoxy)methyl)phenyl)boronic acid. LCMS (ESI+): m / z 505.2 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 12.45 (s, 1H), 8.79 (s, 1H), 8.51 (d, 1H), 7.89 (s, 1H), 7.79-7.76 (m, 1H), 7.72 (d, 1H), 7.55-7.52 (m, 2H), 7.30 (d, 2H), 7.16-7.12 (m, 2H), 5.20 (s, 2H), 3.48 (d, 2H), 1.15 (s, 6H).

[0276] Example 17: Preparation of compound 17 3-(3-hydroxy-5-(naphthalene-2-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0277] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using naphthalen-2-ylboronic acid. LCMS (ESI+): m / z 365.2 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 12.47 (s, 1H), 8.81 (s, 1H), 8.66 (d, 1H), 8.07-7.94 (m, 4H), 7.86 (d, 1H), 7.60-7.56 (m, 2H), 3.50 (d, 2H), 1.16 (s, 6H).

[0278] Example 18: Preparation of Compound 18 3-(3-hydroxy-5-(3-((naphthalene-1-yloxy)methyl)phenyl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0279] The compound was synthesized following the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido-2,2-dimethylpropanoic acid using (3-((naphthalen-1-yloxy)methyl)phenyl)boronic acid. LCMS (ESI+): m / z 471.0 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 12.46 (s, 1H), 8.81 (s, 1H), 8.53 (d, 1H), 8.23 ​​(dd, 1H), 7.98 (s, 1H), 7.88 (dd, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.67 (d, 1H), 7.60-7.41 (m, 5H), 7.12 (d, 1H), 5.39 (s, 2H), 3.48 (d, 2H), 1.15 (s, 6H).

[0280] Example 19: Preparation of Compound 19 3-(3-hydroxy-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0281] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine. LCMS (ESI+): m / z 418.2 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 12.39 (s, 1H), 8.68 (s, 1H), 8.43 (d, 1H), 8.41 (s, 1H), 8.07 (d, 1H), 7.60 (d, 1H), 4.25 (t, 2H), 3.54 (t, 4H), 3.45 (d, 2H), 2.73 (t, 2H), 2.42 (t, 4H), 1.13 (s, 6H).

[0282] Example 20: Preparation of Compound 20 3-(3-hydroxy-5-(naphthalene-1-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0283] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using naphthalen-1-ylboronic acid. LCMS (ESI+): m / z 365.2 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 12.54 (s, 1H), 8.87 (t, 1H), 8.27 (d, 1H), 8.04 (dd, 2H), 7.79 (dd, 1H), 7.64-7.52 (m, 5H), 3.51 (d, 2H), 1.17 (s, 6H).

[0284] Example 21: Preparation of Compound 21 3-(3-hydroxy-5-(3-hydroxyphenyl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0285] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (3-hydroxyphenyl)boronic acid. LCMS (ESI+): m / z 331 (M+H) + ; 1H-NMR (300 MHz, CD3OD) δ 8.35 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 1.8 Hz, 1H), 6.84-6.88 (m, 1H), 3.56 (s, 2H), 1.27 (s, 6H).

[0286] Example 22: Preparation of Compound 22 3-(5-(3-((4-chlorobenzyl)oxy)phenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0287] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (3-((4-chlorobenzyl)oxy)phenyl)boronic acid. LCMS (ESI+): m / z 455 (M+H) +; 1H-NMR (300 MHz, CD3OD) δ 8.37 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.44-7.49 (m, 2H), 7.37-7.41 (m, 3H), 7.26-7.29 (m, 2H), 7.08 (m, 1H), 5.15 (s, 2H), 3.56 (s, 2H), 1.25 (s, 6H).

[0288] Example 23: Preparation of Compound 23 3-(3-hydroxy-5-(6-hydroxynaphthalen-2-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0289] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (6-hydroxynaphthalen-2-yl)boronic acid. LCMS (ESI+): m / z 381 (M+H) + ; 1H-NMR (300 MHz, CD3OD) δ 8.56 (d, J = 1.8 Hz, 1H), 8.13 (s, 1H), 7.71-7.87 (m, 4H), 7.12-7.15 (m, 2H), 3.60 (s, 2H), 1.27 (s, 6H).

[0290] Example 24: Preparation of Compound 24 1-Bromo-3-(4-chlorophenoxy)benzene [ka]

[0291] A mixture of 3-bromophenol (0.50 g, 2.89 mmol), (4-chlorophenyl)boronic acid (0.90 g, 5.78 mmol), Cu(OAc)2·H2O (0.87 g, 4.34 mmol), TEA (1.17 g, 11.56 mmol) and molecular sieves (1 g) in DCM (13 ml) was stirred at room temperature for 3 h. After the reaction was completed as shown by TLC analysis, the reaction mixture was filtered. The filtrate was treated with saturated aqueous NH4Cl solution (15 mL) and extracted with DCM (3×50 mL). The combined organic phase was dried over anhydrous Na2SO4 (30 g), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether) to give the desired product (350 mg) as an oil. GCMS (EI+): 282, 284 (M+).

[0292] (3-(4-chlorophenoxy)phenyl)boronic acid [ka]

[0293] Under nitrogen protection, to a solution of 1-bromo-3-(4-chlorophenoxy)benzene (0.35 g, 1.24 mmol) and B(O-iPr)3 (0.30 g, 1.61 mmol) in dry THF (5 ml) was added n-BuLi (1.35 mmol, 0.54 mL) dropwise over 10 min at -78 °C. After addition, the reaction was stirred at -78 °C for about 1 h and then warmed to room temperature and stirred for an additional 1 h. After the reaction was complete as indicated by TLC, the reaction mixture was quenched with water (5 mL) and treated with dilute hydrochloride solution (2 M, 2 mL). The resulting mixture was stirred at room temperature for about 10 min, after which the reaction mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 (30 g), filtered and concentrated in vacuo. The residue was slurried in hexane (5 mL) and the solid product was filtered to give the title compound (223 mg) as a white solid. LCMS (ESI-): m / z 247 (MH). - .

[0294] 3-(5-(3-(4-chlorophenoxy)phenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0295] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (3-(4-chlorophenoxy)phenyl)boronic acid. LCMS (ESI+): m / z 441 (M+H) + ; 1H-NMR (300 MHz, CDCl3) δ 8.44 (t, J = 6.6 Hz, 1H), 8.26 (s, 1H), 7.41-7.47 (m, 2H), 7.31-7.33 (m, 3H), 7.19 (s, 1H), 6.98-7.06 (m, 3H), 3.62 (d, J = 6.6 Hz, 2H), 1.33 (s, 6H).

[0296] Example 25: Preparation of Compound 25 N-(4-chlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [ka]

[0297] A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.30 g, 1.37 mmol), (4-chlorophenyl)boronic acid (0.24 g, 1.51 mmol), Cu(OAc)2·H2O (0.41 g, 2.05 mmol), TEA (0.55 g, 5.48 mmol) and molecular sieves (1 g) in DCM (30 mL) was stirred at room temperature for 6 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EA:Hex=1:30) to give the desired product (280 mg) as an oil. LCMS (ESI+): m / z 330 (M+H) + , 1H NMR (300 MHz, CDCl3) δ 7.39-7.45 (m, 2H), 7.26-7.31 (m, 1H), 7.17-7.21 (m, 3H), 6.96 (d, J = 8.7 Hz, 2H), 5.68 (brs, 1H), 1.34 (s, 12H).

[0298] 3-(5-(3-((4-chlorophenyl)amino)phenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0299] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using N-(4-chlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. LCMS (ESI+): m / z 440 (M+H) +; 1H-NMR (300 MHz, CD3OD) δ 8.36 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.31-7.39 (m, 2H), 7.22 (d, J = 9.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 3.56 (s, 2H), 1.25 (s, 6H).

[0300] Example 26: Preparation of Compound 26 2-Bromo-6-(4-chlorophenoxy)naphthalene [ka]

[0301] A mixture of 6-bromonaphthalen-2-ol (0.50 g, 2.24 mmol), (4-chlorophenyl)boronic acid (0.53 g, 3.36 mmol), Cu(OAc)2H2O (0.67 g, 3.36 mmol), TEA (0.91 g, 8.96 mmol) and molecular sieves (1 g) in DCM (10 ml) was stirred at room temperature for 4 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether) to give the desired product (286 mg) as a white solid. 1H-NMR(300MHz, CDCl3) δ 7.91(s, 1H), 7.67 (d, J = 6.6 Hz, 1H), 7.44-7.51 (m, 2H), 7.26 (d, J = 6.3 Hz, 2H), 7.17-7.19 (d, J = 6.3 Hz, 2H), 6.92~6.94(d, J=6.3Hz, 2H).

[0302] (6-(4-chlorophenoxy)naphthalene-2-yl)boronic acid [ka]

[0303] Under nitrogen protection, to a mixture of 2-bromo-6-(4-chlorophenoxy)naphthalene (0.20 g, 0.60 mmol) and B(O-iPr)3 (0.15 g, 0.78 mmol) in dry THF (4 mL) was added n-BuLi (0.26 mL, 0.65 mmol) dropwise over 10 min at -78 °C. After the reaction was stirred at -78 °C for 1 h, the mixture was warmed to room temperature and stirred for 1 h. The mixture was quenched with water (5 mL) and dilute hydrochloride solution (2 M, 0.5 mL) was added. After the resulting mixture was stirred at room temperature for 10 min, the reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4 (30 g), filtered and concentrated in vacuo. The residue was slurried in hexane to give the desired product (114 mg) as a white solid, which was used directly in the next step.

[0304] 3-(5-(6-(4-chlorophenoxy)naphthalene-2-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0305] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (6-(4-chlorophenoxy)naphthalen-2-yl)boronic acid. LCMS (ESI+): m / z 491 (M+H) +. 1H-NMR(300MHz, CDCl3) δ 12.21(s, 1H),8.47 (t, J = 6.9 Hz, 1H), 8.43 (s, 1H), 8.03 (s, 1H), 7.90 (d, J = 4.5 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.26-7.37 (m, 4H), 7.04 (d, J = 8.7 Hz, 1H), 3.65 (d, J = 6.9 Hz, 2H), 1.36(s,6H).

[0306] Example 27: Preparation of Compound 27 2-Bromo-6-((4-chlorobenzyl)oxy)naphthalene [ka]

[0307] Under nitrogen protection, to a solution of 6-bromonaphthalen-2-ol (1.0 g, 4.48 mmol) in DMF (10 mL) was added NaH (215 mg, 8.97 mmol) in small portions over 5 min at 0 °C. After addition, the reaction mixture was stirred at 0-4 °C for 30 min. 1-Chloro-4-(chloromethyl)benzene (794 mg, 4.93 mmol) was added dropwise to the reaction over 1 min and the resulting mixture was stirred at 0-4 °C for 1.5 h. After the reaction was complete as indicated by TLC, the reaction was quenched with water (50 mL) and extracted with EtOAc (3 x 150 mL). The combined organic phase was dried over anhydrous Na2SO4 (50 g), filtered and concentrated in vacuo. The residue was slurried in hexane and the solid product was filtered to give the desired product (1.35 g) as a solid. 1H-NMR (300 MHz, CDCl3) δ 7.93(s, 1H),7.58-7.69 (m, 2H), 7.49-7.52 (m, 1H), 7.33-7.44 (m, 4H), 7.15-7.24 (m, 2H), 5.14 (s,2H).

[0308] (6-((4-chlorobenzyl)oxy)naphthalen-2-yl)boronic acid [ka]

[0309] Under nitrogen protection, to a mixture of 2-bromo-6-((4-chlorobenzyl)oxy)naphthalene (140 mg, 0.40 mmol) and B(O-iPr)3 (98 mg, 0.52 mmol) in dry THF (2 mL) was added n-BuLi (0.2 mL, 0.48 mmol) dropwise over 10 min at -78 °C. After stirring the reaction at -78 °C for 1 h, the mixture was warmed to room temperature and stirred for 1 h. The mixture was quenched with water (5 mL) and treated with dilute hydrochloride solution (0.5 mL, 2 M). After stirring at room temperature for 10 min, the reaction mixture was extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4 (20 g), filtered and concentrated in vacuo. The residue was slurried in hexane and the solid product was filtered to give 84 mg of the desired product as a white solid, which was used directly in the next step.

[0310] 3-(5-(6-((4-chlorobenzyl)oxy)naphthalen-2-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0311] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (6-((4-chlorobenzyl)oxy)naphthalen-2-yl)boronic acid. LCMS (ESI+): m / z 505 (M+H) +. 1H-NMR (300MHz, DMSO-d6) δ 12.64 (brs, 1H), 12.49 (brs, 1H), 8.84 (t, J = 5.7 Hz, 1H), 8.65 (d, J = 1.5 Hz, 1H), 8.38 (s, 1H), 7.96 (m, 3H), 7.84 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.7 Hz, 3H), 7.59 (d, J = 8.7 Hz, 3H), 7.32 (dd, J = 9.0, 2.4 Hz, 1H), 5.26 (s, 2H), 3.50 (d, J = 5.7 Hz, 2H), 1.17(s, 6H).

[0312] Example 28: Preparation of Compound 28 2-Bromo-6-(4-chlorophenethoxy)naphthalene [ka]

[0313] The compound was synthesized according to the procedure described for the preparation of 1-bromo-3-(4-chlorophenethoxy)benzene. 1H-NMR (300MHz, CDCl3) δ 7.90(d, J=1.2Hz, 1H), 7.63 (d, J=9Hz, 1H), 7.57 (d, J=8.7Hz, 1H), 7.47 (d, J=8.7Hz, 1H), 7.22-7.35 (m, 4H), 7.13 (d, J=9Hz, 1H), 7.07 (d, J=2.1Hz, 1H), 4.25 (t, J=6.6Hz, 1H), 3.13(t,J=6.6Hz,1H).

[0314] (6-(4-chlorophenethoxy)naphthalen-2-yl)boronic acid [ka]

[0315] The compound was synthesized following the procedure described for the preparation of (3-(4-chlorophenoxy)phenyl)boronic acid using 2-bromo-6-(4-chlorophenoxy)naphthalene. 1H NMR (300MHz, DMSO-d6) δ 8.28(s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.35-7.42 (m, 4H), 7.31 (d, J = 1.8 Hz, 1H), 7.11 (dd, J = 9 Hz, 1.8Hz, 1H), 4.31 (t, J = 6.6 Hz, 2H), 3.11(t,J=6.6Hz,2H).

[0316] 3-(5-(6-(4-chlorophenethoxy)naphthalene-2-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0317] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (6-(4-chlorophenethoxy)naphthalen-2-yl)boronic acid. LCMS (ESI+): m / z 519 (M+H) + . 1H-NMR(300MHz, CDCl3) δ 12.20(s, 1H), 8.43 (d, J = 1.5 Hz, 1H), 7.97 (s, 1H), 7.78 (d, J = 8.4Hz, 2H), 7.63 (d, J = 8.4Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.26-7.32 (m, 4H), 7.10-7.20 (m, 2H), 4.29 (t, J = 6.9 Hz, 2H ), 3.64 (s, 2H), 3.15 (t, J = 6.9 Hz, 2H), 1.36(s,6H).

[0318] Example 29: Preparation of Compound 29 Ethyl 3-(3-hydroxy-5-(3-nitrophenyl)picolinamido)-2,2-dimethylpropanoate [ka]

[0319] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (3-nitrophenyl)boronic acid. LCMS: m / z 388 (M+H) + ; 1H NMR (300 MHz, CDCl3) δ 12.33 (s, 1H), 8.52 (t, J = 6.3 Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.30 (dd, J = 8.1, J =2.1 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.59 (d, J = 6.6 Hz, 2H), 1.27~1.35(m, 9H).

[0320] Ethyl 3-(3-hydroxy-5-(3-aminophenyl)picolinamido)-2,2-dimethylpropanoate [ka]

[0321] A suspension of ethyl 3-(3-hydroxy-5-(3-nitrophenyl)picolinamido)-2,2-dimethylpropanoate (65 mg, 0.17 mmol) and Pd / C (10 mg) in EtOAc (6 mL) was stirred overnight at room temperature under hydrogen atmosphere. After the reaction was complete as indicated by TLC, the suspension was filtered through a pad of Celite and the filter cake was washed with EtOAc (6 mL). The combined filtrate was concentrated to dryness to give the desired product (64 mg) as an oil. LCMS (ESI+): m / z 358 (M+H + ), 1H NMR (300 MHz, CDCl3) δ 12.11 (s, 1H), 8.40 (t, J = 6.3 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.78 (s, 1H), 6.65 (dd, J = 7.8, 2.1 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.81 (brs, 2H), 3.49 (d, J = 6.9 Hz, 2H), 1.23 (d, J = 7.2 Hz, 3H), 1.19 (s, 6H).

[0322] 3-(5-(3-aminophenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0323] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid. LCMS (ESI-): m / z 328 (MH) -. 1H-NMR (300 MHz, CD3OD) δ 8.33 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.00 (t, J = 1.8 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.78 (dd, J = 7.5 Hz, J = 2.1 Hz, 1H), 3.51 (s, 2H), 1.21(s, 6H).

[0324] Example 30: Preparation of Compound 30 3-(5-(3-((4-chlorobenzyl)amino)phenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid ethyl ester [ka]

[0325] To a solution of ethyl 3-(5-(3-aminophenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoate (90 mg, 0.25 mmol) in DCM (8 mL) was added 4-chlorobenzaldehyde (54 mg, 0.38 mmol) and NaBH(OAc)3 (107 mg, 0.50 mmol). The reaction was stirred at room temperature overnight. After the reaction was completed as shown by TLC analysis, the reaction was quenched with water (10 mL) and extracted with DCM (2×50 mL). The combined organic layer was dried over anhydrous Na2SO4 (30 g), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:Hex=1:10 to 1:5) to give the desired product (24 mg) as an oil. LCMS (ESI+): m / z 482 (M+H) + .

[0326] 3-(5-(3-((4-chlorobenzyl)amino)phenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0327] To a solution of ethyl 3-(5-(3-((4-chlorobenzyl)amino)phenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoate (24 mg, 0.05 mmol) in THF (4 mL) and water (1 mL) was added LiOH·H2O (9 mg, 0.20 mmol). The mixture was stirred at 40 °C overnight. After the reaction was complete based on TLC analysis, THF was removed under reduced pressure. The residue was diluted with water (10 mL) and DCM (10 mL). After the layers were separated, the aqueous layer was adjusted to pH 3-4 with dilute HCl solution (1N) and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4 (30 g), filtered and concentrated in vacuo to give the title compound (19 mg) as a yellow solid. LCMS (ESI+): m / z 454 (M+H) + . 1H NMR (300 MHz, CD3OD) δ 8.28 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 7.8 Hz, 1H), 6.84-6.92 (m, 2H), 6.67 (dd, J = 7.8 Hz, J = 2.1 Hz, 1H), 4.37 (s, 2H), 3.56 (s, 2H), 1.25(s, 6H).

[0328] [Example 31: Preparation of Compound 31] 4-Chlorophenethyl 4-methylbenzenesulfonate [ka]

[0329] A solution of 2-(4-chlorophenyl)ethan-1-ol (1.0 g, 6.37 mmol), TsCl (1.22 g, 6.37 mmol) and TEA (1.29 g, 12.74 mmol) in DCM (30 mL) was stirred at room temperature overnight. After the reaction was completed as shown by TLC analysis, the reaction was quenched with water (20 mL) and extracted with DCM (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4 (30 g), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:Hex=1:50-1:10) to give the desired product (1.3 g) as a white solid. 1H-NMR(300MHz, CDCl3) δ 7.65(d, J=8.4Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 4.19 (t, J = 6.6 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H), 2.43(s, 3H).

[0330] 1-Bromo-3-(4-chlorophenethoxy)benzene [ka]

[0331] A solution of 3-bromophenol (167 mg, 0.97 mmol), 4-chlorophenethyl 4-methylbenzenesulfonate (300 mg, 0.97 mmol) and K2CO3 (133 mg, 0.97 mmol) in DMF (5 mL) was stirred at 30 °C for 3.5 h. After the reaction was completed as shown by TLC analysis, the reaction was quenched with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4 (30 g), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:Hex = 1:80) to give the title product (200 mg) as an oil. 1H-NMR (300MHz, CDCl3) δ 7.29-7.30(m, 2H), 7.22-7.27 (m, 2H), 7.03-7.19 (m, 3H), 6.79-6.83 (m, 1H), 4.13 (t, J = 6.6 Hz, 2H), 3.05(t, J=6.6Hz, 2H).

[0332] (3-(4-chlorophenethoxy)phenyl)boronic acid [ka]

[0333] The compound was synthesized according to the procedure described for the preparation of (3-(4-chlorophenoxy)phenyl)boronic acid using 1-bromo-3-(4-chlorophenethoxy)benzene. 1H NMR (300MHz,DMSO-d6) δ 8.05(brs, 2H), 7.20-7.44 (m, 7H), 6.94 (m, 1H), 4.18 (t, J = 6.6 Hz, 2H), 3.03(t,J=6.6Hz, 2H).

[0334] 3-(5-(3-(4-chlorophenethoxy)phenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0335] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (3-(4-chlorophenethoxy)phenyl)boronic acid. LCMS (ESI+): m / z 469 (M+H) + . 1H NMR(300MHz,DMSO-d6) δ 12.75(brs, 1H), 12.45 (s, 1H), 8.80 (brs, 1H), 8.51 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.30-7.42 (m, 7H), 7.03 (d, J = 8.1 Hz, 1H), 4.30 (t, J = 6.6 Hz, 1H), 3.48 (d, J = 6.6 Hz, 1H ), 3.07(t,J=6.6Hz, 1H).

[0336] Example 32: Preparation of Compound 32 3-(5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0337] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate. LC-MS (ESI-): m / z 486 (MH) -, 1H-NMR (300 MHz, DMSO-d6) δ 12.62 (s, 1H), 12.41 (s, 1H), 8.71-8.73 (m, 1H), 8.54 (s, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.13 (s, 1H), 7.64 (d, J = 1.8 Hz, 1H), 4.34-4.48 (m, 1H), 4.02-4.06 (m, 2H), 3.45 (d, J = 6.3 Hz, 2H ), 2.86-3.01 (m, 2H), 1.99-2.07 (m, 2H), 1.76-1.81 (m, 2H), 1.42 (s, 9H), 1.14(s, 6H).

[0338] Example 33: Preparation of Compound 33 3-(5-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0339] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate. LC-MS (ESI-): m / z 474 (MH) -; 1H-NMR (300 MHz, DMSO-d6) δ 12.61 (s, 1H), 12.50 (s, 1H), 8.73-8.78 (m, 1H), 8.43 (d, J = 1.8 Hz, 1H), 7.61 (s, 1H), 7.56 (d, J = 1.5 Hz, 1H), 4.46 (s, 2H), 3.66 (t, J = 5.4 Hz, 2H ), 3.46 (d, J = 6.3 Hz, 2H ), 2.84 (s, 2H), 1.43 (s, 9H), 1.14 (s, 6H).

[0340] Example 34: Preparation of compound 34 3-(5-(1-(2,4-dichlorophenyl)-1H-pyrazol-4-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0341] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 1-(2,4-dichlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LC-MS (ESI+): m / z 449 (M+H) + ; 1H NMR (300 MHz, CD3OD) δ 8.58 (s, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.26 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.54 (dd, J = 2.1 Hz, J = 8.4 Hz, 1H), 3.56 (s, 2H), 1.25 (s, 6H).

[0342] Example 35: Preparation of Compound 35 3-(5-(5-chlorothieno[3,2-b]pyridin-2-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0343] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine. LC-MS (ESI-): m / z 404 (MH) - ; 1H NMR (300 MHz, CD3OD) δ 8.59 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 3.57 (s, 2H), 1.26 (s, 6H).

[0344] Example 36: Preparation of Compound 36 3-(3-hydroxy-5-(2-(hydroxymethyl)-4-(pyrrolidin-1-ylsulfonyl)phenyl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0345] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 5-(pyrrolidin-1-ylsulfonyl)benzo[c][1,2]oxaborol-1(3H)-ol. LC-MS (ESI-): m / z 476 (MH) -; 1H NMR (300 MHz, CD3OD) δ 8.16 (d, J = 1.8 Hz, 1H), 8.09 (s, 1H), 7.84-7.87 (m, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 1.2 Hz, 1H), 4.59 (s, 2H), 3.58 (s, 2H), 3.27-3.34 (m, 4H), 1.77-1.84 (m, 4H), 1.26 (s, 6H).

[0346] Example 37: Preparation of Compound 37 3-(3-hydroxy-5-(1-(3-trifluoromethyl)phenyl)-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0347] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)boronic acid. LC-MS (ESI-): m / z 447 (MH) - ; 1H NMR (300 MHz, DMSO-d6) δ 12.64 (s, 1H), 12.49 (s, 1H), 9.44 (s, 1H), 8.79 (t, J = 6.9 Hz, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.53 (s, 1H), 8.23 ​​(d, J = 7.8 Hz, 2H), 7.79-7.84 (m, 2H), 7.74 (d, J = 7.8 Hz, 1H), 3.48 (d, J = 6.3 Hz, 2H), 1.16 (s, 6H).

[0348] Example 38: Preparation of compound 38 3-(3-hydroxy-5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0349] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine. LC-MS (ESI-): m / z 357 (MH) - ; 1H NMR (300 MHz, CD3OD) δ 8.27 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.36 (d, J = 1.8 Hz, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.55 (s, 2H), 3.01 (t, J = 6.3 Hz, 2H), 2.17-2.05 (m, 2H), 2.00-1.90 (m, 2H), 1.24 (s, 6H).

[0350] Example 39: Preparation of Compound 39 3-(3-hydroxy-5-(4-methylquinolin-6-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0351] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline. LC-MS (ESI+): m / z 380 (M+H) +; 1H NMR (300 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.80 (d, J = 4.2 Hz, 1H), 8.71 (d, J = 1.5 Hz, 1H), 8.47 (s, 1H), 8.13-8.20 (m, 2H), 7.96 (d, J = 1.8 Hz, 1H), 7.44 (d, J = 4.2 Hz, 1H), 3.49 (s, 2H), 2.80 (s, 3H), 1.16 (s, 6H).

[0352] Example 40: Preparation of Compound 40 3-(3-hydroxy-5-(8-methylquinolin-3-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0353] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (8-methylquinolin-3-yl)boronic acid. LC-MS (ESI-): m / z 378 (MH) - ; 1H NMR (300 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.80 (d, J = 4.2 Hz, 1H), 8.71 (d, J = 1.5 Hz, 1H), 8.47 (s, 1H), 8.13-8.20 (m, 2H), 7.96 (d, J = 1.8 Hz, 1H), 7.44 (d, J = 4.2 Hz, 1H), 3.49 (s, 2H), 2.80 (s, 3H), 1.16 (s, 6H).

[0354] [Example 41: Preparation of compound 41] 3-(3-hydroxy-5-(6-methoxynaphthalen-2-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0355] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (6-methoxynaphthalen-2-yl)boronic acid. LC-MS (ESI+): m / z 395 (M+H) + ; 1H NMR (300 MHz, DMSO-d6) δ 12.65 (brs, 1H), 12.49 (brs, 1H), 8.85 (s, 1H), 8.65 (d, J = 1.5 Hz, 1H), 8.37 (s, 1H), 7.98-7.90 (m, 3H), 7.40 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 2.4 Hz, J = 9.0 Hz, 1H), 3.91 (s, 3H), 3.50 (d, J = 5.7 Hz, 2H), 1.16 (s, 6H).

[0356] Example 42: Preparation of Compound 42 3-(3-hydroxy-5-(isoquinolin-6-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0357] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using isoquinolin-6-ylboronic acid. LC-MS (ESI+): m / z 366 (M+H) +; 1H NMR (300 MHz, DMSO-d6) δ 12.63 (s, 1H), 12.53 (s, 1H), 9.40 (s, 1H), 8.88 (t, J = 6.6 Hz, 1H), 8.69 (d, J = 1.8 Hz, 1H), 8.58 (d, J = 5.7 Hz, 1H), 8.48 (s, 1H), 8.28 (d, J = 8.7 Hz, 1H), 8.14 (dd, J = 1.5 Hz, J = 8.7 Hz, 1H), 7.96 - 7.87 (m, 2H), 3.51 (d, J = 6.6 Hz, 2H), 1.17 (s, 6H).

[0358] Example 43: Preparation of Compound 43 3-(3-hydroxy-5-(isoquinolin-7-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0359] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using isoquinolin-7-ylboronic acid. LC-MS (ESI+): m / z 366 (M+H) + ; 1H NMR (300 MHz, DMSO-d6) δ 12.63 (s, 1H), 12.53 (s, 1H), 9.41 (s, 1H), 8.87 (t, J = 6.3 Hz, 1H), 8.65-8.71 (m, 2H), 8.57 (d, J = 5.7 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 6.9 Hz, 2H), 3.51 (d, J = 6.6 Hz, 2H), 1.17 (s, 6H).

[0360] Example 44: Preparation of Compound 44 3-(5-(8-fluoro-2-methylquinolin-7-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0361] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (8-fluoro-2-methylquinolin-7-yl)boronic acid. LC-MS (ESI+): m / z 398 (M+H) + ; 1H NMR (300 MHz, DMSO-d6) δ 12.57 (brs, 2H), 8.92 (s, 1H), 8.51 (s, 1H), 8.39 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.75-7.80 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 3.50(s, 2H), 2.73 (s, 3H), 1.17 (s, 6H).

[0362] Example 45: Preparation of Compound 45 3-(3-hydroxy-5-(2-methylquinolin-6-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0363] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (2-methylquinolin-6-yl)boronic acid. LC-MS (ESI+): m / z 380 (M+H) +; 1H NMR (300 MHz, DMSO-d6) δ 12.63 (s, 1H), 12.51 (s, 1H), 8.86 (t, J = 6.6 Hz, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.17 (dd, J = 1.8 Hz, J = 8.7 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 4.50 (d, J = 8.7 Hz, 1H), 3.50 (d, J = 6.3 Hz, 2H), 2.69 (s, 3H), 1.17 (s, 6H).

[0364] [Example 46: Preparation of compound 46] 3-(3-hydroxy-5-(quinoxalin-6-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0365] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using quinoxalin-6-ylboronic acid. LC-MS (ESI+): m / z 367 (M+H) +; 1H NMR (300 MHz, DMSO-d6) δ 12.63 (s, 1H), 12.53 (s, 1H), 9.02 (dd, J = 1.8 Hz, J = 7.8 Hz, 2H), 8.88 (t, J = 6.6 Hz, 1H), 8.74 (d, J = 1.8 Hz, 1H), 8.57 (d, J = 1.8 Hz, 1H), 8.33 (dd, J = 2.1 Hz, J = 8.7 Hz, 1H), 8.23 ​​(d, J = 8.7 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 3.51 (d, J = 6.6 Hz, 2H), 1.17 (s, 6H).

[0366] Example 47: Preparation of Compound 47 3-(3-hydroxy-5-((trimethylsilyl)ethynyl)picolinamido)-2,2-dimethylpropanoic acid ethyl ester [ka]

[0367] Under nitrogen protection, ethyl 3-(5-bromo-3-hydroxypicolinamido)-2,2-dimethylpropanoate (4.15 g, 12 mmol), TMSA (5.9 g, 60.1 mmol), CuI (916 mg, 4.8 mmol), TEA (3.65 g, 36.1 mmol) and Pd(PPh3)4 in acetonitrile (100 mL) were stirred at 80° C. for 5 h. After the reaction was completed as shown by TLC analysis, the reaction mixture was concentrated to dryness. The residue was purified by silica gel column chromatography to give the title compound (3.9 g) as a red oil. LCMS (ESI+): m / z 363 (M+H) +; 1H-NMR (300 MHz, CDCl3) δ 12.18 (s, 1H), 8.42 (t, J = 6.9 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.55 (d, J = 6.9 Hz, 2H ), 1.30 (t, J = 7.2 Hz, 3H), 1.26 (s, 6H), 0.26 (s, 9H).

[0368] 3-(5-ethynyl-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid ethyl ester [ka]

[0369] A solution of ethyl 3-(3-hydroxy-5-((trimethylsilyl)ethynyl)picolinamido)-2,2-dimethylpropanoate (3.9 g, 10.8 mmol) and TBAF THF solution (38 mL, 38 mmol, 1N) in methanol was stirred at room temperature for 5 h. After the reaction was completed as shown by TLC analysis, the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc (200 mL) and the resulting solution was washed with water (250 mL×4). The organic phase was separated, dried over Na2SO4 (30 g), filtered and concentrated to dryness to give the crude title compound (3.17 g). LCMS (ESI+): m / z 291 (M+H) + ; 1H-NMR (300 MHz, CDCl3) δ 12.23 (s, 1H), 8.44 (t, J = 6.6 Hz, 1H), 8.13 (d, J = 1.5 Hz, 1H), 7.38 (d, J = 1.5 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.55 (d, , J = 6.6 Hz, 2H ), 3.30 (s, 1H), 1.36 (t, J = 7.2 Hz, 3H), 1.28 (s, 6H).

[0370] 3-(5-ethynyl-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid ethyl ester [ka]

[0371] A solution of 1-(3-bromopropyl)-4-chlorobenzene (980 mg, 4.20 mmol) and NaN3 (819 mg, 12.6 mmol) in DMF (20 mL) was stirred at room temperature for 3-4 h. After the reaction was completed as shown by TLC analysis, the reaction mixture was treated with EtOAc (60 mL) followed by precipitation of some inorganic solids. The solids were filtered off and the filtrate was washed with water (300 mL). After separation, the aqueous phase was extracted with EtOAc (80 mL x 2). The combined organic phase was washed with saturated NaCl solution (100 mL), dried over Na2SO4 (30 g) and concentrated to dryness to give the crude title compound (858 mg). 1H-NMR(300MHz, CDCl3) δ 7.26(d, J=8.1Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 3.28 (t, J = 6.6 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H), 1.81~1.95(m, 2H).

[0372] 3-(5-(1-(3-(4-chlorophenyl)propyl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-picolinamido)-2,2-dimethylpropanoic acid ethyl ester [ka]

[0373] A solution of ethyl 3-(5-ethynyl-3-hydroxypicolinamido)-2,2-dimethylpropanoate (127 mg, 0.44 mol), 1-(3-azidopropyl)-4-chlorobenzene (103 mg, 0.53 mmol) and CuI (9 mg, 0.04 mmol) in acetonitrile (8 mL) was stirred at reflux for 2 h. After the reaction was complete as indicated by TLC analysis, the reaction mixture was cooled to room temperature and the insoluble solid was removed by filtration. The filtrate was concentrated to dryness to give the title compound (220 mg) as a pale yellow solid. LCMS (ESI+): m / z 486 (M+H) + .

[0374] 3-(5-(1-(3-(4-chlorophenyl)propyl)-1H-1,2,3-triazol-4-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0375] To a solution of ethyl 3-(5-(1-(3-(4-chlorophenyl)propyl)-1H-1,2,3-triazol-4-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoate (220 mg, 0.45 mmol) in THF / water (8 mL / 2 mL) was added LiOH·HO (77 mg, 1.81 mmol). The resulting mixture was stirred at 40°C for 6 h, after which the reaction was complete as shown by TLC analysis. A large amount of insoluble blue solid precipitated, which was removed by filtration. The filtrate was adjusted to pH 2-3 with dilute HCl solution (1N), precipitating a large amount of yellow solid. The solid was collected by filtration, washed with water, and dried to give the title compound (80 mg) as a solid. LCMS (ESI+): m / z 458 (M+H) +; 1H-NMR (300 MHz, CDCl3) δ 12.23 (s, 1H), 8.57 (d, J = 1.5 Hz, 1H), 8.45 (t, J = 6.6 Hz, 1H), 7.82 (s, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 4.42 (d, J = 6.9 Hz, 2H), 3.62 (d, J = 6.6 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 2.25-2.35 (m, 2H), 1.35 (s, 6H).

[0376] Example 48: Preparation of Compound 48 3-(Benzyloxy)-5-bromopicolinic acid methyl ester [ka]

[0377] To a solution of methyl 5-bromo-3-hydroxypicolinate (2.00 g, 8.60 mmol) in DMF (20 mL) was added BnBr (1.18 g, 10.30 mmol) and Cs2CO3 (2.80 g, 8.60 mmol) in one portion. After the addition, the mixture was stirred at room temperature overnight. After the reaction was complete as shown by TLC, the mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was slurried with hexane (10 mL) for 2 h and filtered to give the desired product (2.31 g) as a white solid. LC-MS (ESI+): m / z 322 (M+H) + ; 1H-NMR (300 MHz, CDCl3) δ 8.35 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8Hz, 1H), 7.35-7.48 (m, 5H), 5.21 (s, 2H), 3.98 (s, 3H).

[0378] 3-(Benzyloxy)-5-(naphthalen-2-yl)picolinic acid methyl ester [ka]

[0379] Under nitrogen protection, a solution of methyl 3-(benzyloxy)-5-bromopicolinate (1.23 g, 3.83 mmol) in DMF (20 mL) was added in one portion to naphthalen-2-ylboronic acid (0.98 g, 5.75 mmol), K2CO3 (1.59 g, 11.50 mmol), and Pd(PPh3)4 (0.31 g, 0.27 mmol). The mixture was stirred at 80 °C overnight. After the reaction was completed as indicated by TLC, the mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica chromatography (EA:PE = 1:20 to 1:5) to give the desired product (1.24 g) as a white solid. LC-MS (ESI+): m / z 370 (M+H) + ; 1H-NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 7.88-8.00 (m, 4H), 7.63-7.66 (m, 2H), 7.53-7.59 (m, 4H), 7.33-7.46 (m, 3H), 5.34 (s, 2H), 4.03 (s, 3H).

[0380] 3-Hydroxy-5-(naphthalen-2-yl)picolinic acid methyl ester [ka]

[0381] A suspension of methyl 3-(benzyloxy)-5-(naphthalen-2-yl)picolinate (1.24 g, 2.50 mmol) and Pd / C (124 mg) in MeOH (20 mL) was stirred overnight at room temperature under hydrogen atmosphere. After the reaction was complete as indicated by TLC, the suspension was filtered through a package of Celite and the filter cake was washed with MeOH (10 mL). The combined filtrate was concentrated to dryness to give the desired product (710 mg) as an oil. LC-MS (ESI+): m / z 280 (M+H + ), 1H NMR (300 MHz, CDCl3) δ 10.74 (s, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.10 (s, 1H), 7.88-7.99 (m, 3H), 7.68-7.74 (m, 2H), 7.54-7.58 (m, 2H), 4.10 (s, 3H).

[0382] 3-Hydroxy-5-(naphthalen-2-yl)picolinic acid [ka]

[0383] To a suspension of methyl 3-hydroxy-5-(naphthalen-2-yl)picolinate (0.57 g, 2.04 mmol) in THF (10 mL) and water (4 mL) was added KOH (1.71 g, 30.6 mmol) in one portion. The mixture was stirred at 110° C. for 6 h. After the reaction was complete as shown by HPLC, the suspension was diluted with water (10 mL) and the pH was adjusted to 3. A large amount of solid was precipitated. The suspension was filtered and dried to give the desired product (500 mg) as a white solid. LC-MS (ESI+): m / z 266 (M+H) + , 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.46 (s, 1H), 7.96-8.09 (m, 5H), 7.59~7.62 (m, 2H).

[0384] 3-(3-hydroxy-5-(naphthalene-2-yl)picolinamido)-2-methylpropanoic acid methyl ester [ka]

[0385] To a solution of 3-hydroxy-5-(naphthalen-2-yl)picolinic acid (0.15 g, 0.57 mmol) in DMF (5 mL) was added 3-amino-2-methylpropanoic acid (87.78 mg, 0.57 mmol), PyBOP (0.85 mg, 1.63 mmol) and TEA (0.13 g, 1.14 mmol) in one portion. The mixture was stirred at room temperature for 3 h. After the reaction was complete as indicated by TLC, the mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with water (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica chromatography (DCM:PE=1:10 to 1:1) to give the desired product (52 mg) as a white solid. LC-MS (ESI+): m / z 365 (M+H) + ; 1H-NMR (300 MHz, CDCl3) δ 12.16 (s, 1H), 8.41-8.45 (m, 2H), 8.07 (s, 1H), 7.88-7.98 (m, 3H), 7.69-7.72 (m, 1H), 7.61 (d, J = 2.1Hz, 1H), 7.52-7.58 (m, 2H), 3.76 (s, 3H), 3.59-3.74 (m, 2H), 2.83-2.89 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H).

[0386] 3-(3-hydroxy-5-(naphthalene-2-yl)picolinamido)-2-methylpropanoic acid [ka]

[0387] To a solution of methyl 3-(3-hydroxy-5-(naphthalen-2-yl)picolinamido)-2-methylpropanoate (50.0 mg, 0.14 mmol) in THF (5 mL) and water (1.25 mL) was added LiOH (70.56 mg, 1.68 mmol) in one portion. The mixture was stirred at 50° C. overnight. After the reaction was complete as shown by TLC, the solution was diluted with water (10 mL) and the pH was adjusted to 3. A large amount of solid precipitated. The suspension was filtered and dried to give the desired product (40 mg) as a white solid. LC-MS (ESI+): m / z 351 (M+H) + ; 1H NMR (300 MHz, CD3OD) δ 8.51 (d, J = 1.5 Hz, 1H), 8.18 (s, 1H), 7.88-7.99 (m, 3H), 7.76-7.80 (m, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.52-7.56 (m, 2H), 3.59 (d, J = 6.6 Hz, 2H), 2.72-2.84 (m, 1H), 1.24 (d, J = 7.2 Hz, 3H).

[0388] Example 49: Preparation of Compound 49 3-(5-(3-chlorophenyl)-3-hydroxypicolinamido)-2-methylpropanoic acid [ka]

[0389] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(naphthalen-2-yl)picolinamido)-2-methylpropanoic acid using (3-chlorophenyl)boronic acid. LC-MS (ESI+): m / z 335 (M+H) +; 1H NMR (300 MHz, CDCl3) δ 12.17 (s, 1H), 8.45-8.47 (m, 1H), 8.26 (d, J = 1.5 Hz, 1H), 7.56 (s, 1H), 7.41-7.46 (m, 4H), 3.58-3.78 (m, 2H), 2.89-2.95 (m, 1H), 1.34 (d, J = 7.2 Hz, 3H).

[0390] Example 50: Preparation of Compound 50 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2-methylpropanoic acid [ka]

[0391] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(naphthalen-2-yl)picolinamido)-2-methylpropanoic acid using (1-phenyl-1H-pyrazol-4-yl)boronic acid. LC-MS (ESI+): m / z 367 (M+H) + ; 1H NMR (300 MHz, CDCl3) δ 12.16 (s, 1H), 8.40 (t, J = 5.7 Hz, 1H), 8.31-8.27 (m, 1H), 8.23 ​​(s, 1H), 8.04 (s, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.50 (t, J = 7.8 Hz, 2H), 7.43 (d, J = 1.8 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 3.77 - 3.68 (m, 1H), 3.68-3.57 (m, 1H), 2.97-2.86 (m, 1H), 1.34 (d, J = 7.2 Hz, 3H).

[0392] [Example 51: Preparation of Compound 51] (Z)-2-(Hydroxyimino)-3-oxobutanoic acid methyl ester [ka]

[0393] To a solution of methyl 3-oxobutanoate (5.00 g, 43.10 mmol) in AcOH (6.3 mL) at 0°C was added an aqueous solution of NaNO2 (2.97 g, 43.10 mmol, H2O: 7.4 mL) over 20 min. The mixture was stirred at 0°C for 1 h. After the starting material was consumed as shown by TLC analysis, the mixture was quenched with water (150 mL) and stirred for 3 h. The aqueous solution was extracted with Et2O (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2) and dried over anhydrous sodium sulfate (10 g). After filtration and concentration, 7.5 g of the desired product was obtained as a pale oil, which was used in the next step without further purification. LCMS (ESI-): m / z 144.2 (MH) - . 1 H-NMR (300MHz, CDCl3) δ 9.53 (brs, 1H), 3.92 (s, 3H), 2.42 (s, 3H).

[0394] (Z)-3-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)imino)but-3-enoic acid methyl ester [ka]

[0395] To a solution of methyl (Z)-2-(hydroxyimino)-3-oxobutanoate (18.60 g, 130.00 mmol) in dry DCM (100 mL) under nitrogen atmosphere was added 2,6-dimethylpyridine (54.90 g, 520.00 mmol) and TBDSOTf (67.70 g, 260.00 mmol) at 0° C. After addition, the mixture was warmed to room temperature and stirred overnight. After the starting material was consumed as indicated by TLC analysis, the solvent was removed by evaporation and the residue was purified by column chromatography (hexane) to give 35.2 g of the desired product as an oil. LCMS (ESI+): m / z 374.2 (M+H) + ; 1H-NMR (300 MHz, CDCl3) δ4.47 (dd, J =11.2, 2.1 Hz, 2H), 3.65 (s, 3H), 0.76 (s, 9H), 0.73 (s, 9H), 0.00 (s, 12H).

[0396] 2-(3-chlorobenzylidene)malononitrile [ka]

[0397] To a solution of 3-chlorobenzaldehyde (10.70 g, 75.80 mmol) and malononitrile (5.00 g, 75.80 mmol) in EtOH (150 mL) at room temperature, KOH (0.42 mg, 7.60 mmol) was added in one portion. The reaction was stirred at room temperature for 2 h, causing a large amount of solid to precipitate. The suspension was filtered through a funnel and the filter cake was washed with EtOH (20 mL x 2) to give 10.7 g of the desired product as a white solid. LCMS (ESI-): m / z 187.2 (MH) - ; 1 H-NMR (300 MHz, CDCl3) δ 7.85-7.81 (m, 2H), 7.73 (s, 1H), 7.64-7.57 (m, 1H), 7.53~7.47 (m, 1H).

[0398] 5-(3-chlorophenyl)-6-cyano-3-hydroxypicolinic acid methyl ester [ka]

[0399] A solution of methyl (Z)-3-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)imino)but-3-enoate (17.9 g, 47.9 mmol) and 2-(3-chlorobenzylidene)malononitrile (3 g, 16.0 mmol) in DMF (50 mL) was heated at 120° C. for 2 h under a nitrogen atmosphere. °C overnight. After the starting material was consumed as shown by TLC analysis, the reaction was cooled to room temperature and quenched with ice water (200 mL). The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (50 mL x 2), dried over anhydrous sodium sulfate (20 g), filtered and concentrated. The residue was purified by flash column purification (EtOAc / PE=1 / 10 to 1 / 3) to give impure product, which was further purified by slurry in Et2O (15 mL) to give 1.7 g of desired product as a brown solid. LCMS (ESI-): m / z 287.1 (MH) - ; 1 H-NMR (300 MHz, CDCl3) δ 11.20 (s, 1H), 7.55 - 7.48 (m, 5H), 4.12 (s, 3H).

[0400] 3-(5-(3-chlorophenyl)-6-cyano-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0401] To a solution of 3-amino-2,2-dimethylpropanoic acid hydrochloride (4.00 g, 26.00 mmol) in DMF (50 mL) under nitrogen atmosphere, MeONa (2.80 g, 52.00 mmol) was added in small portions. After the reaction was stirred at room temperature for 30 minutes, 5-(3-chlorophenyl)-6-cyano-3-hydroxypicolinate methyl ester (1.50 g, 5.20 mmol) was added to the above solution. The mixture was diluted with 150 mL of ethyl acetate and diluted with 10 mL of ethyl acetate. °C for 3 h. After the starting material was consumed as shown by TLC analysis, the mixture was cooled to room temperature and quenched with water (200 mL). The resulting mixture was adjusted to pH 4 with dilute HCl solution (2M) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with water (50 mL x 2) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by column chromatography (EtOAc:Hex=1:5 to 1:2) to give the desired product as a yellow solid. LCMS (ESI+): m / z 373.9 (M+H) + . HPLC purity: 98.9%; 1 H-NMR (300 MHz, CDCl3) δ 12.86 (s, 1H), 8.34 (t, J = 6.3 Hz, 1H), 7.52-7.46 (m, 4H), 7.39 (s, 1H), 3.64 (d, J = 6.6 Hz, 2H), 1.32(s, 6H).

[0402] [Example 52: Preparation of compound 52] 3-(5-(3-((4-chlorophenethyl)amino)phenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0403] The compound was synthesized according to the procedure described for the preparation of 3-(5-(3-((4-chlorobenzyl)amino)phenyl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid. LC-MS: m / z 468 (M+H) +; 1H-NMR (300 MHz, CDCl3) δ 12.2 (brs, 1H), 8.48 (brs, 1H), 8.26 (s, 1H), 7.43 (d, J = 1.2 Hz, 1H), 7.20-7.30 (m, 3H), 7.15 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 7.8 Hz, 1H), 6.74 (s, 1H), 6.65 (d, J = 7.8 Hz, 1H), 3.61 (d, J = 6.0 Hz, 2H), 3.42 (t, J = 6.9 Hz, 2H), 2.91 (t, J = 6.9Hz, 2H), 1.27(s, 6H).

[0404] [Example 53: Preparation of compound 53] 3-(5-bromo-3-(pivaloyloxy)picolinamido)-2,2-dimethylpropanoic acid ethyl ester [ka]

[0405] 0 ° A solution of ethyl 3-(5-bromo-3-hydroxypicolinamido)-2,2-dimethylpropanoate (0.50 g, 1.45 mmol) and TEA (0.29 g, 2.90 mmol) in DCM (30 mL) of C was added dropwise over 5 min to PivCl (0.26 g, 2.17 mmol). The mixture was then stirred at room temperature overnight. After the reaction was complete as indicated by TLC, the reaction was quenched with water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried over anhydrous Na2SO4 (10 g), filtered and concentrated in vacuo to give the desired product (710 mg) as an oil. LC-MS (ESI+): m / z 429 (M+H) + ; 1H-NMR (300 MHz, CDCl3)δ8.49 (d, J = 1.8 Hz, 1H), 8.17 (brs, 1H), 7.63 (d, J = 1.8 Hz, 1H), 4.14-4.21 (q, J = 4.2 Hz, 2H), 3.50 (d, J = 6.6 Hz, 2H), 1.40 (s, 9H), 1.27 (t, J = 5.1 Hz, 3H), 1.23 (s, 6H).

[0406] 2,2-Dimethyl-3-(5-(2-phenylthiazol-5-yl)-3-(pivaloyloxy)picolinamido)propanoic acid ethyl ester [ka]

[0407] A suspension of ethyl 3-(5-bromo-3-(pivaloyloxy)picolinamido)-2,2-dimethylpropanoate (0.11 g, 0.26 mmol), K2CO3 (0.11 mg, 0.77 mmol), 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (82.0 mg, 0.28 mmol), and Pd(PPh3)4 (15.0 mg, 0.013 mmol) in DMF (10 mL) and water (0.5 mL) was added under a nitrogen atmosphere to 65°C. ° C for 2 h. After the reaction was completed as shown by TLC, the resulting mixture was directly concentrated. The residue in EtOAc (20 mL) was stirred at room temperature for 10 min, and then the undissolved solid was filtered off. The filtrate was concentrated and the residue was purified by flash silica chromatography (EA:Hex=1:50-1:30) to give the desired product (55 mg) as an off-white solid. LC-MS (ESI+): m / z 426 (M+H) + .

[0408] 3-(3-hydroxy-5-(2-phenylthiazol-5-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0409] To a solution of ethyl 3-(3-hydroxy-5-(2-phenylthiazol-5-yl)picolinamido)-2,2-dimethylpropanoate (55.0 mg, 0.13 mmol) in THF (4 ml) and water (1 ml) was added LiOH·H2O (22.0 mg, 0.52 mmol) in one portion. The mixture was stirred at 60 °C overnight. After the reaction was complete as shown by TLC, the THF was removed by rotary evaporation. The residue in water (10 mL) was adjusted to pH 3-4 with dilute HCl solution (1N) to precipitate a large amount of solid. The suspension was extracted with ethyl acetate (3 × 5 mL). The combined organic phase was dried over Na2SO4 (10 g), filtered and concentrated. The residue was slurried in hexane to give the desired product (30 mg) as a white solid. LC-MS (ESI-): m / z 396 (MH) - The HPLC purity was 96.9%. 1 H-NMR (300 MHz, CD3OD) δ 8.49 (d, J = 1.8 Hz, 1H), 8.34 (s, 1H), 8.00-8.03 (m, 2H), 7.65 (d, J = 1.8 Hz, 1H), 7.50-7.52 (m, 3H), 3.56 (s, 2H), 1.28(s, 6H).

[0410] Example 54: Preparation of Compound 54 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)propanoic acid [ka]

[0411] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(naphthalen-2-yl)picolinamido)-2-methylpropanoic acid using (1-phenyl-1H-pyrazol-4-yl)boronic acid and 3-aminopropanoic acid. LC-MS (ESI+): m / z 353 (M+H) + ; 1H NMR (300 MHz, DMSO-d6) δ 12.63 (s, 1H), 12.36 (brs, 1H), 9.26 (s, 1H), 9.11 (t, J = 6.0 Hz, 1H), 8.58 (d, J = 1.5 Hz, 1H), 8.45 (s, 1H), 7.89 (t, J = 7.8 Hz, 2H), 7.78 (d, J = 1.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 3.53 (t, J = 6.6 Hz, 2H), 2.58 (t, J = 6.6 Hz, 2H).

[0412] Example 55: Preparation of Compound 55 3-(3-hydroxy-5-(5-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0413] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 5-methoxy-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine. LC-MS (ESI+): m / z 399 (M+H) + ; 1H NMR (300 MHz, CD3OD) δ 8.45 (d, J = 1.8 Hz, 1H), 8.42 (s, 1H), 7.93 (s, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.19 (s, 1H), 3.95 (d, J = 3.6 Hz, 6H), 3.55 (d, J = 8.1 Hz, 2H), 1.28 (s, 6H).

[0414] Example 56: Preparation of Compound 56 3-(5-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0415] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 2-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LC-MS (ESI+): m / z 379 (M+H) + ; 1H NMR (300 MHz, CD3OD) δ 8.43 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 6.57 (s, 1H), 4.36-4.39 (m, 2H), 4.25-4.28 (m, 2H), 3.54 (s, 2H), 1.24 (s, 6H).

[0416] Example 57: Preparation of Compound 57 3-(3-hydroxy-5-(1-oxo-1,2-dihydrophthalazin-6-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0417] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalazin-1(2H)-one. LC-MS (ESI+): m / z 383 (M+H) +; 1H NMR (300 MHz, CD3OD) δ 8.42 (s, 1H), 8.39 (s, 1H), 8.11-8.17 (m, 3H), 7.39 (s, 1H), 3.66 (s, 2H), 1.29 (s, 6H).

[0418] Example 58: Preparation of compound 58 3-(5-(6-ethoxynaphthalene-2-yl)-3-hydroxypicolinamido)-2,2-dimethylpropanoic acid [ka]

[0419] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (6-ethoxynaphthalen-2-yl)boronic acid. LC-MS (ESI+): m / z 409 (M+H) + ; 1H NMR (300 MHz, CDCl3) δ 12.19 (s, 1H), 8.43-8.50 (m, 2H), 7.98 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.64 (dd, J = 1.8 Hz, J = 8.4 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.17-7.21 (m, 1H), 7.13 (d, J = 2.1 Hz, 1H), 4.14-4.21 (q, J = 6.9 Hz, 2H), 3.65 (d, J = 6.6 Hz, 2H), 1.50 (t, J = 6.9 Hz, 3H).

[0420] Example 59: Preparation of Compound 59 3-(3-hydroxy-5-(6-(methylsulfonamido)naphthalen-2-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0421] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (6-(methylsulfonamido)naphthalen-2-yl)boronic acid. LC-MS (ESI+): m / z 458 (M+H) + ; 1H NMR (300 MHz, DMSO-d6) δ 12.63 (s, 1H), 12.49 (s, 1H), 10.14 (s, 1H), 8.84 (t, J = 6.3 Hz, 1H), 8.66 (d, J = 1.8 Hz, 1H), 8.38 (s, 1H), 7.93-8.02 (m, 3H), 7.85 (d, J = 1.8 Hz, 1H), 7.73 (s, 1H), 7.43-7.46 (m, 1H), 3.50 (d, J = 6.6 Hz, 2H), 3.10 (s, 3H), 1.17 (s, 6H).

[0422] Example 60: Preparation of Compound 60 3-(3-hydroxy-5-(1-methylnaphthalen-2-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0423] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using (1-methylnaphthalen-2-yl)boronic acid. LC-MS (ESI+): m / z 379 (M+H) +; 1H NMR (300 MHz, CDCl3) δ 12.24 (s, 1H), 8.51 (t, J = 6.6 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.55-7.59 (m, 1H), 7.38-7.50 (m, 3H), 7.29-7.31 (m, 1H), 3.66 (d, J = 6.9 Hz, 2H), 2.76 (s, 3H), 1.36 (s, 6H).

[0424] [Example 61: Preparation of Compound 61] 3-(3-hydroxy-5-(5-isopropylbenzo[b]thiophen-2-yl)picolinamido)-2,2-dimethylpropanoic acid [ka]

[0425] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)picolinamido)-2,2-dimethylpropanoic acid using 2-(5-isopropylbenzo[b]thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LC-MS (ESI+): m / z 413 (M+H) + ; 1H NMR (300 MHz, CD3OD) δ 8.52 (d, J = 1.5 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 3.55 (s, 2H), 3.01-3.06 (m, 1H), 1.32 (d, J = 6.9 Hz, 6H), 1.29 (s, 6H).

[0426] [Example 62: Preparation of Compound 62] 3-(3-hydroxy-5-(naphthalene-2-yl)picolinamido)propanoic acid [ka]

[0427] The compound was synthesized according to the procedure described for the preparation of 3-(3-hydroxy-5-(naphthalen-2-yl)picolinamido)-2-methylpropanoic acid using 3-aminopropanoic acid. LC-MS (ESI+): m / z 337 (M+H) + ; 1 H NMR (300 MHz, DMSO-d6) δ 12.68 (brs, 1H), 9.23 (s, 1H), 8.64 (d, J = 1.8 Hz, 1H), 7.98-8.08 (m, 4H), 7.85 (d, J = 1.5 Hz, 1H), 7.59 (t, J = 4.8 Hz, 2H), 3.54 (t, J = 6.9 Hz, 2H), 2.56 (t, J = 6.9 Hz, 2H).

[0428] [Example 63: In vitro assay demonstrates selectivity of PHD1 over PHD2.] In vitro assays of exemplary compounds were performed to determine the enzyme 50% inhibitory concentration (IC) of compounds against PHD1 and PHD2. 50 ) and showed increased selectivity of PHD1 over PHD2 as determined by measuring the inhibition constants (Ki).

[0429] Using time-resolved fluorescence resonance energy transfer (TR-FRET) assays, we determined the IC50 inhibitor concentrations (ICs) of full-length human prolyl-4-hydroxylase domain (PHD) inhibitors for PHD1 and PHD2 enzymes. 50) values ​​were determined. The TR-FRET assay was developed based on the specific binding of hydroxylated HIF-1α peptide with the complex formed by VHL, EloB and EloC (VBC) to generate a fluorescent signal. The terbium (Tb)-donor (monoclonal antibody anti-6His-Tb-cryptate gold) and D2-acceptor (streptavidin [SA]-D2) of TR-FRET are linked to the VBC complex and the HIF-1α peptide, respectively. The VBC complex specifically binds to the HIF-1α peptide when hydroxylated, allowing energy transfer from the TR-FRET donor to the acceptor (Figure 1).

[0430] Materials and Methods Unless otherwise noted, all chemicals and materials were of standard laboratory grade and purchased from Sigma-Aldrich (St. Louis, MO, USA).

[0431] [reagent] TR-FRET Reagents Monoclonal antibody anti-6His-Tb-cryptate Gold (cat. no. 61HI2TLA) and streptavidin (SA)-D2 (cat. no. 610SADLA) were purchased from CisBioInternational (Bedford, MA, USA).

[0432] N-terminally biotinylated HIF-1α C35 synthetic peptide, representing amino acids 547–581 and containing the proline 564 PHD2 hydroxylation site, was purchased from California Peptide Research (Salt Lake City, UT, USA).

[0433] Recombinant Proteins VBC complex. His-tagged recombinant VHL protein, EloB, and EloC complex (His-VBC) were provided by Axxam (Milan, Italy). Recombinant human VHL (National Center for Biotechnology Information [NCBI] accession number NP_00542.1) contained a His tag at the C-terminus from amino acids 55 to 213 and was referred to as VHL-His. VHL-His was coexpressed in E. coli with full-length human EloB (NCBI accession number Q15370.1) and full-length human EloC (NCBI accession number Q15369.1) and purified as a His-VBC complex by affinity chromatography on a nickel-nitrilotriacetic acid (Ni-NTA) column. Purity (approximately 80%) was assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).

[0434] PHD1: Recombinant human PHD1 protein (catalog no. 81064, lot no. 24717001) was purchased from Active Motif (Carlsbad, CA, USA). PHD1 was expressed in a baculovirus expression system as a full-length protein (NCBI accession no. NP_542770.2) with an N-terminal FLAG tag (molecular weight 44.9 kDa). Purity (>90%) was assessed by SDS-PAGE.

[0435] PHD2: Full-length human PHD2 enzyme was produced using the baculovirus-infected insect cell (BIIC) expression system by Beryllium (Bedford, MA, USA). The PHD2 construct contained amino acids 1-426 of PHD2 (UniProt Knowledgebase [UniProtKB] / Swiss-Prot accession number Q9GZT9.1) as well as a His-tag and a tobacco etch virus (TEV) protease cleavage site at the N-terminus. The construct was expressed in Sf9 insect cells, purified by Ni-NTA column, and digested with TEV protease to remove the His-tag. The purity of the final cleaved protein was assessed by SDS-PAGE and found to be >94% pure.

[0436] [TR-FRET assay procedure] Compounds were preincubated with PHD enzymes in a reaction volume of 10 μL in white 384-well Optiplate microplates (catalog no. 6007290, PerkinElmer, Waltham, MA, USA). For this, 5 μL of compound was serially diluted in dilution buffer (50 mM HEPES [4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid] pH 7.5, 50 mM sodium chloride [NaCl], 0.01% Tween-20, 0.01% purified bovine serum albumin [BSA]) and mixed with 5 μL of PHD enzyme mix prepared as a 4-fold concentrate in dilution buffer containing PHD enzymes (60 nM PHD1, 20 nM PHD2, 140 nM PHD3), 40 μM ferrous ammonium sulfate (FAS), and 4 mM sodium ascorbate (Na). Plates were incubated for 30 min at room temperature without rotation.

[0437] Five microliters of VBC / anti-6His-Tb-cryptate Gold mix, prepared as a 4-fold concentrate in dilution buffer containing 20 nM His-VBC, 1.32 nM monoclonal antibody anti-6His-Tb-cryptate Gold, was then added. This step was immediately followed by the addition of 5 μL of HIF-1α C35 substrate mix, prepared as a 4-fold concentrate in dilution buffer containing 120 nM biotinylated HIF-1α C35, 132 nM SA-D2, and 4 μM 2-oxoglutarate (2-OG) to reach a final reaction volume of 20 μL.

[0438] The final assay reaction contained 50 mM HEPES, pH 7.5, 50 mM NaCl, 1 μM 2-OG, 10 μM FAS, 1 mM Na-ascorbate, 0.01% Tween-20, 0.01% purified BSA, 30 nM biotinylated HIF-1α C35, 5 nM His-VBC, 0.33 nM monoclonal antibody anti-6His-Tb-cryptate gold, 33 nM SA-D2 and PHD enzymes (15 nM PHD1, 5 nM PHD2, 35 nM PHD3) along with diluted compounds.

[0439] Compound IC 50 For IC measurements, reactions were incubated at room temperature for 10 min and then read on a Perkin Elmer EnVision (Waltham, MA, USA) at an excitation wavelength of 340 nm and emission wavelengths of 615 nm and 665 nm. Data represent the quotient of the signal intensities at 665 nm and 615 nm and are calculated automatically by the Envision Manager software (Perkin Elmer, Waltham, MA, USA). 50 Values ​​(mean, standard deviation, standard error of the mean, geometric mean, and 95% confidence intervals) were determined using a four-parameter curve fit using GraphPad Prism 7.0 (GraphPad, La Jolla, CA, USA) and represent compound concentration plotted against the calculated ratio of 665 nm and 615 nm. TR-FRET assays were performed in triplicate at each concentration of compound.

[0440] The selectivity of compounds for PHD1 versus PHD2 was determined by taking the ratio of Ki in each assay.

[0441] Ki was calculated from IC50 based on the Cheng-Prusoff equation: Ki = IC50 / (1+[2-OG] / Km)

[0442] The final concentration of 2-OG in both the PHD1 and PHD2 assays is 1 uM. The Km of 2-OG in PHD1 was determined to be 12.7 nM, while the Km of 2-OG in PHD2 was determined to be 22.6 nM. Exemplary Compounds [Table 4] TIFF2025500892000176.tif219170TIFF2025500892000177.tif203170TIFF2025500892 000178.tif221170TIFF2025500892000179.tif228170TIFF2025500892000180.tif20917 0TIFF2025500892000181.tif237170TIFF2025500892000182.tif231170TIFF2025500892 000183.tif233170TIFF2025500892000184.tif224170TIFF2025500892000185.tif81170

[0443] From the foregoing, those skilled in the art can easily ascertain the essential characteristics of the present invention, and can make various changes and modifications to the present invention to adapt it to various applications and conditions without departing from the spirit and scope thereof.

[0444] All U.S. or foreign references, patents, or applications cited in this application are hereby incorporated by reference as if set forth in their entirety herein. In the event of any conflict, the material literally disclosed herein will control.

Claims

1. A pharmaceutical composition for use in a method for treating a disease mediated by PHD1 activity, comprising a compound of formula (I): 【Chemistry 1】 (I) or a pharmaceutically acceptable salt thereof, A is optionally substituted aryl or optionally substituted heteroaryl; X is CH or N; L is, 【Chemistry 2】 wherein n is 0, 1, or 2; R ４ａ and R ４ｂ are independently H, optionally substituted C １ ~C ６ alkyl, or OH; R ５ａ and R ５ｂ are independently H, OH, optionally substituted C １ ~C ６ alkyl, or optionally substituted C １ ~C ６ Alkoxy or R ５ａ and R ５ｂ taken together with the carbons to which they are attached form an optionally substituted 3- to 5-membered cycloalkyl or heterocycloalkyl; R １ is H, OH, or NH ２ and R ２ is H or CN, and R ３ is OH, or an optionally substituted ester).

2. A is, 【Transformation 3】 The pharmaceutical composition according to claim 1, wherein R ６ａ , R ６ｂ , and R ６ｃ are independently H, halo, aryl, heteroaryl, CH ２ OR １２ , OR １２ , N.H.R. １２ , C.H. ２ R １３ , or SO ２ R １３ and R １２ is H, R １４ or aryl optionally substituted with R １５ C optionally substituted with １ ~C ２ is alkyl, R １３ is heterocycloalkyl, R １４ H, halo, OR １６ , or CH ２ CH ２ OR １６ and R １５ is cycloalkyl or aryl optionally substituted with halo, and R １６ is C optionally substituted with one or more halo １ ~C ３ alkyl).

3. A is, 【Chemistry 4】 The pharmaceutical composition of claim 1, wherein: U, V, and T are independently CH or N; R ７ａ is R １７ C optionally substituted with １ ~C ４ Alkyl, H, halo, or CF ３ aryl optionally substituted with CO ２ R １８ heterocycloalkyl optionally substituted with ２ R １８ is heteroaryl optionally substituted with R １７ is H, aryl optionally substituted with halo, or heterocycloalkyl, and R １８ is t-butyl).

4. A is, 【Transformation 5】 The pharmaceutical composition according to claim 3, wherein: U is CH or N; R ７ａ is R １７ C optionally substituted with １ ~C ４ Alkyl, H, halo, or CF ３ aryl optionally substituted with, or CO ２ R １８ is a heteroaryl or heterocycloalkyl optionally substituted with R １７ is H, aryl optionally substituted with halo, or heterocycloalkyl, and R １８ is t-butyl).

5. A is, 【Transformation 6】 The pharmaceutical composition of claim 1, wherein: U, V, and T are independently CH or N; R ７ｂ is R １７ C optionally substituted with １ ~C ４ Alkyl, H, halo, or CF ３ aryl optionally substituted with, or CO ２ R １８ is a heteroaryl or heterocycloalkyl optionally substituted with R １７ is H, aryl optionally substituted with halo, or heterocycloalkyl, and R １８ is t-butyl).

6. A is, 【Transformation 7】 The pharmaceutical composition according to claim 5, wherein: U is CH or N; R ７ｂ is R １７ C optionally substituted with １ ~C ４ Alkyl, H, halo, or CF ３ aryl optionally substituted with, or CO ２ R １８ is a heteroaryl or heterocycloalkyl optionally substituted with R １７ is H, aryl optionally substituted with halo, or heterocycloalkyl, and R １８ is t-butyl).

7. A is, 【Transformation 8】 The pharmaceutical composition of claim 1, wherein: B, D, E, G, and I are independently C, CH, or N; R ８ａ , R ８ｂ , R ８ｃ , and R ８ｄ are independently H, C １ ~C ３ Alkyl, halo, OR １９ , or NHR ２０ and R ８ｅ is absent, H, or ═O, R １９ is H, aryl optionally substituted with halo, or R ２１ C optionally substituted with １ ~C ３ is alkyl, R ２０ is SO ２ CH ３ and R ２１ is aryl optionally substituted with halo, and --- is an optional bond).

8. A is, 【Chemistry 9】 The pharmaceutical composition according to claim 7, wherein: R ８ａ is H or methyl, R ８ｄ is H, OR １９ , or NHR ２０ and R １９ is H, aryl optionally substituted with halo, or R ２１ C optionally substituted with １ ~C ３ is alkyl, R ２０ is SO ２ CH ３ and R ２１ is aryl optionally substituted with halo).

9. A is, 【Chemistry 10】 The pharmaceutical composition according to claim 7, wherein: D is CH or N; I is C, CH, or N; R ８ａ is H, or halo, or C １ ~C ３ is alkyl, R ８ｂ is H or C １ ~C ３ is alkyl, R ８ｃ is H, ═O, or C １ ~C ３ is alkyl, R ８ｄ is H, OR １９ , N.H.R. ２０ , or C １ ~C ３ is alkyl, R １９ is H, aryl optionally substituted with halo, or R ２１ C optionally substituted with １ ~C ３ is alkyl, R ２０ is SO ２ CH ３ and R ２１ is aryl optionally substituted with halo, and --- is an optional bond).

10. A is, 【Chemistry 11】 The pharmaceutical composition according to claim 7, wherein: E is CH, CH ２ , N, or NH; G and B are independently CH or N; R ８ｅ is H, C １ ~C ３ alkyl, or =O, and --- is an optional bond).

11. A is, 【Chemistry 12】 The pharmaceutical composition of claim 1, wherein: R ９ is H, C １ ~C ３ alkyl, or phenyl).

12. A is, 【Chemistry 13】 The pharmaceutical composition of claim 1, wherein: J is C, CH, or N; K is CH, CH ２ , N, or NH; R １０ is H, halo, C １ ~C ４ Alkyl or CO ２ R ２２ and R ２２ is t-butyl, and --- is an optional bond).

13. A is, 【Chemistry 14】 The pharmaceutical composition according to claim 12, wherein: K is CH or N, and R １０ is H, halo, or C １ ~C ４ alkyl).

14. A is, 【Chemistry 15】 The pharmaceutical composition according to claim 12, wherein: J is CH or N; R １０ is H or CO ２ R ２２ and R ２２ is t-butyl).

15. A is, 【Chemistry 16】 The pharmaceutical composition of claim 1, wherein: R １１ａ and R １１ｂ are independently H, C １ ~C ３ Alkyl, or C １ ~C ３ alkoxy).

16. A is, 【Chemistry 17】 【change】 The pharmaceutical composition of claim 1, wherein

17. 1. A pharmaceutical composition for use in a method for treating a disease mediated by PHD1 activity, comprising a compound of formula (II): [Chemistry 18] (II) or a pharmaceutically acceptable salt thereof, comprising administering to a subject said pharmaceutical composition: A is an optionally substituted aryl or heteroaryl; X is CH or N; L is, 【Chemistry 19】 wherein n is 0, 1, or 2; R ２ is H or CN, R ４ａ and R ４ｂ are independently H, optionally substituted C １ ~C ６ alkyl, or OH, and R ５ａ and R ５ｂ are independently H, OH, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Alkoxy or R ５ａ and R ５ｂ taken together with the carbon to which they are attached form an optionally substituted 3- to 5-membered cycloalkyl or heterocycloalkyl).

18. A is, 【Chemistry 20】 18. The pharmaceutical composition of claim 17, wherein: R ６ａ , R ６ｂ , and R ６ｃ are independently H, halo, aryl, heteroaryl, CH ２ OR １２ , OR １２ , N.H.R. １２ , C.H. ２ R １３ , or SO ２ R １３ and R １２ is H, R １４ or aryl optionally substituted with R １５ C optionally substituted with １ ~C ２ is alkyl, R １３ is heterocycloalkyl, R １４ H, halo, OR １６ , or CH ２ CH ２ OR １６ and R １５ is cycloalkyl or aryl optionally substituted with halo, and R １６ is C optionally substituted with one or more halo １ ~C ３ alkyl).

19. 18. The pharmaceutical composition of claim 17, wherein A is: 【Chemistry 21】 (In the formula, U, V, and T are independently CH or N; R ７ａ is R １７ C optionally substituted with １ ~C ４ Alkyl, H, halo, or CF ３ aryl optionally substituted with CO ２ R １８ heterocycloalkyl optionally substituted with ２ R １８ is heteroaryl optionally substituted with R １７ is H, aryl optionally substituted with halo, or heterocycloalkyl, and R １８ is t-butyl).

20. A is, 【Chemistry 22】 20. The pharmaceutical composition of claim 19, wherein: U is CH or N; R ７ａ is R １７ C optionally substituted with １ ~C ４ Alkyl, H, halo, or CF ３ aryl optionally substituted with, or CO ２ R １８ is a heteroaryl or heterocycloalkyl optionally substituted with R １７ is H, aryl optionally substituted with halo, or heterocycloalkyl, and R １８ is t-butyl).

21. A is, 【Chemistry 23】 18. The pharmaceutical composition of claim 17, wherein: U, V, and T are independently CH or N; R ７ｂ is R １７ C optionally substituted with １ ~C ４ Alkyl, H, halo, or CF ３ aryl optionally substituted with, or CO ２ R １８ is a heteroaryl or heterocycloalkyl optionally substituted with R １７ is H, aryl optionally substituted with halo, or heterocycloalkyl, and R １８ is t-butyl).

22. A is, 【Chemistry 24】 22. The pharmaceutical composition of claim 21, wherein: U is CH or N; R ７ｂ is R １７ C optionally substituted with １ ~C ４ Alkyl, H, halo, or CF ３ aryl optionally substituted with, or CO ２ R １８ is a heteroaryl or heterocycloalkyl optionally substituted with R １７ is H, aryl optionally substituted with halo, or heterocycloalkyl, and R １８ is t-butyl).

23. 18. The pharmaceutical composition of claim 17, wherein A is: 【Chemistry 25】 (In the formula, B, D, E, G, and I are independently C, CH, or N; R ８ａ , R ８ｂ , R ８ｃ , and R ８ｄ are independently H, C １ ~C ３ Alkyl, halo, OR １９ , or NHR ２０ and R ８ｅ is absent, H, or ═O, R １９ is H, aryl optionally substituted with halo, or R ２１ C optionally substituted with １ ~C ３ is alkyl, R ２０ is SO ２ CH ３ and R ２１ is aryl optionally substituted with halo, and --- is an optional bond).

24. A is, 【Chemistry 26】 24. The pharmaceutical composition of claim 23, wherein: R ８ａ is H or methyl, R ８ｄ is H, OR １９ , or NHR ２０ and R １９ is H, aryl optionally substituted with halo, or R ２１ C optionally substituted with １ ~C ３ is alkyl, R ２０ is SO ２ CH ３ and R ２１ is aryl optionally substituted with halo).

25. A is, 【Chemistry 27】 24. The pharmaceutical composition of claim 23, wherein: D is CH or N; I is C, CH, or N; R ８ａ is H, halo, or C １ ~C ３ is alkyl, R ８ｂ is H or C １ ~C ３ is alkyl, R ８ｃ is H, ═O, or C １ ~C ３ is alkyl, R ８ｄ is H, OR １９ , N.H.R. ２０ , or C １ ~C ３ is alkyl, R １９ is H, aryl optionally substituted with halo, or R ２１ C optionally substituted with １ ~C ３ is alkyl, R ２０ is SO ２ CH ３ and R ２１ is aryl optionally substituted with halo, and --- is an optional bond).

26. A is, 【Chemistry 28】 24. The pharmaceutical composition of claim 23, wherein: E is CH, CH ２ , N, or NH; G and B are independently CH or N; R ８ｅ is H, C １ ~C ３ alkyl, or =O, and --- is an optional bond).

27. A is, 【Chemistry 29】 18. The pharmaceutical composition of claim 17, wherein: R ９ is H, C １ ~C ３ alkyl, or phenyl).

28. 18. The pharmaceutical composition of claim 17, wherein A is: 【Transformation 30】 (In the formula, J is C, CH, or N; K is CH, CH ２ , N, or NH; R １０ is H, halo, C １ ~C ４ Alkyl or CO ２ R ２２ and R ２２ is t-butyl, and --- is an optional bond).

29. A is, 【Chemistry 31】 29. The pharmaceutical composition of claim 28, wherein: K is CH or N, and R １０ is H, halo, or C １ ~C ４ alkyl).

30. A is, 【Chemistry 32】 29. The pharmaceutical composition of claim 28, wherein: J is CH or N; R １０ is H or CO ２ R ２２ and R ２２ is t-butyl).

31. A is, 【Transformation 33】 18. The pharmaceutical composition of claim 17, wherein: R １１ａ and R １１ｂ are independently H, C １ ~C ３ Alkyl, or C １ ~C ３ alkoxy).

32. 18. The pharmaceutical composition of claim 17, wherein A is: 【Transformation 34】 【change】 【change】 。

33. A pharmaceutical composition for use in a method for treating a disease mediated by PHD1 activity, comprising a compound selected from the group consisting of compounds 1 to 62 below, or a pharmaceutically acceptable salt thereof: Table 1 。

34. The pharmaceutical composition according to any one of claims 1 to 33, wherein the disease mediated by PHD1 activity is ischemia-reperfusion injury.

35. 35. The pharmaceutical composition of claim 34, wherein the ischemia-reperfusion injury is selected from stroke, myocardial infarction, and acute kidney injury.

36. The pharmaceutical composition according to any one of claims 1 to 33, wherein the disease mediated by PHD1 activity is irritable bowel disease.

37. The pharmaceutical composition according to any one of claims 1 to 33, wherein the disease mediated by PHD1 activity is cancer.

38. 38. The pharmaceutical composition of claim 37, wherein the cancer is colorectal cancer.

39. The pharmaceutical composition according to any one of claims 1 to 33, wherein the disease mediated by PHD1 activity is a liver disease.

40. The pharmaceutical composition according to any one of claims 1 to 33, wherein the disease mediated by PHD1 activity is atherosclerosis.

41. The pharmaceutical composition according to any one of claims 1 to 33, wherein the disease mediated by PHD1 activity is a cardiovascular disease.

42. A compound selected from the group consisting of compounds 1 to 62 below: Table 2 or a pharmaceutically acceptable salt thereof.

43. 43. The compound of claim 42, wherein at least one hydrogen atom is replaced with a deuterium atom.

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