PHD inhibitor compounds, compositions, and methods of use

Abstract

The present invention provides, in part, novel small molecule inhibitors of PHDs having a structure according to Formula (I) and subformulas thereof, or pharmaceutically acceptable salts thereof. The compounds provided herein may be useful in the treatment of diseases including cardiac (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), pulmonary (e.g., pulmonary inflammation, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory (e.g., respiratory infections, acute respiratory distress syndrome), liver (e.g., acute liver failure and liver fibrosis and cirrhosis), and kidney (e.g., acute kidney injury and chronic kidney disease) diseases, inflammatory bowel disease (IBD), ischemia-reperfusion injury (e.g., stroke), and retinopathy of prematurity (ROP). [Formula 1] TIFF2023537611000543.tif35170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 065,642, filed on 14 August 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Hypoxia is a condition or situation in which the supply of oxygen is insufficient for normal daily living functions, such as low arterial oxygen supply. Hypoxia can lead to cellular dysfunction and structural tissue damage. Activation of cellular defense mechanisms during hypoxic states is mediated by HIF (hypoxia-inducible factor) proteins. In response to hypoxia, HIFα levels increase in most cells due to a decrease in HIFα proline hydroxylation. Proline hydroxylation of HIFα is achieved by a family of proteins, variously called prolyl hydroxylase domain-containing proteins (PHD1, 2, and 3), also known as HIF prolyl hydroxylase (HPH-3, 2, and 1) or EGLN-2, 1, and 3. PHD proteins are oxygen sensors and regulate HIF stability in an oxygen-dependent manner. The three PHD isoforms function differently in HIF regulation and may have other non-HIF-related regulatory roles.

[0003] In fact, many studies have shown that stabilizing HIF may suppress tissue inflammation and promote tissue repair. Therefore, compounds that can inhibit the activity of PHD proteins may be particularly beneficial new therapies (Lee et al. (2019) Exp.Mol.Med. 51:68).

[0004] Described herein are novel small molecule PHD inhibitors useful for the treatment of diseases including those of the heart (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung (e.g., pneumonia, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory (e.g., respiratory infections, acute respiratory distress syndrome), liver (e.g., acute liver failure, as well as hepatic fibrosis and cirrhosis), and kidney (e.g., acute kidney injury and chronic kidney disease), inflammatory bowel disease (IBD), ischemic-reperfusion injury (e.g., stroke), and retinopathy of prematurity (ROP). [Overview of the project]

[0005] The present invention provides, in particular, novel small molecule inhibitors of PHD that are useful in treating diseases including, but not limited to, cardiac (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), pulmonary (e.g., pneumonia, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory (e.g., respiratory infections, acute respiratory distress syndrome), hepatic (e.g., acute liver failure, as well as hepatic fibrosis and cirrhosis), and renal (e.g., acute kidney injury and chronic kidney disease) diseases, inflammatory bowel disease (IBD), ischemic-reperfusion injury (e.g., stroke), and retinopathy of prematurity (ROP).

[0006] In one embodiment, a compound having the structure of formula (I), [ka] During the ceremony, R 1 This is C, which is optionally substituted. 1~3 Alkyl, optionally substituted C 3~6 A cycloalkyl or optionally substituted 3-6 member heterocycloalkyl, R 2 C is a hydrogen atom that is optionally substituted with other carbon atoms. 1~3 Alkyl, halogen, CN, or optionally substituted cycloalkyl, R 3is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, carbonyl, ether, thioether, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally substituted aralkyl, optionally substituted alkynyl, or optionally substituted heteroalkynyl, R 4 and R 5 are independently hydrogen, optionally substituted C 1~3 alkyl, or R 4 and R 5 together with the carbon to which they are attached form optionally substituted cycloalkyl or heterocycloalkyl, R 6 is OH or an ester (e.g., OR 18 as described herein), a compound, or a pharmaceutically acceptable salt thereof is provided herein.

[0007] In embodiments, the compound has a structure according to formula (I)

Chemical formula

[0008] In this embodiment, the compound of formula (I) has the structure according to formula (II). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR7 C optionally substituted with halogen, aryl optionally substituted with halogen, or 1~3 alkyl, where R 7 is C optionally substituted with aryl 1~3 alkyl, or R 1 is C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl, R 2 is hydrogen, halogen, CN, or C optionally substituted with one or more halogens 1~3 alkyl, R 3 is hydrogen;

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0009] In this embodiment, R 1 This is C, which is optionally substituted. 1~3 Alkyl and / or R 3 This is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, carbonyl, or ether.

[0010] In this embodiment, R 1 C is optionally substituted with OR7 or aryls optionally substituted with halogens. 1~3 It is alkyl, R 7 C is optionally replaced with an aryl group. 1~3 Alkyl and / or R 3 is hydrogen, [ka] It is selected from the group consisting of the following.

[0011] In this embodiment, R 3 teeth, [ka] That is the case.

[0012] In this embodiment, R 1 is unsubstituted C 1~3 It is alkyl, R 2 is hydrogen, and R 4 and R 5 Each of them is hydrogen, and R 6 It is OH.

[0013] Control mechanism, each R 1 and R 2 is unsubstituted C 1~3 It is alkyl, R 4and R 5 Each of them is hydrogen, and R 6 It is OH.

[0014] In this embodiment, R 2 is unsubstituted C 1~3 It is alkyl, R 3 is hydrogen, and R 4 and R 5 Each of them is hydrogen, and R 6 It is OH.

[0015] In the embodiment, the compound has the structure of formula (III). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each A is independent of N or CR 9 And, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 8 and R 9 These are independently hydrogen, halogen, OR 10 or C, optionally substituted with one or more halogens. 1~3It is alkyl, R 10 C 1~3 It is alkyl or aryl.

[0016] In the embodiment, the compound has the structure of formula (IV). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 8 and R 9 These are independently hydrogen, halogen, OR 10 or C, optionally substituted with one or more halogens. 1~3 It is alkyl, R 10 C 1~3 It is alkyl or aryl.

[0017] In this embodiment, the compound has a structure according to formula (V). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 8 and each R 9 These are independently hydrogen, halogen, OR 10 or C, optionally substituted with one or more halogens. 1~3 It is alkyl, R 10 C 1~3 It is alkyl or aryl.

[0018] In the embodiment, the compound has the structure of formula (VI). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, B is N or CR 11 And, D is N, NH, or CR 11 And, E is N, CR 11 , or CHR 12 And, R 1 is OR7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 11 and R 12 These are independently hydrogen or C 1~3 It is alkyl, The dashed circle indicates the presence or absence of a conjugate system.

[0019] In the embodiment, the compound has a structure according to formula (VII). [ka] or a pharmaceutically acceptable salt thereof.

[0020] In the embodiment, the compound has the structure of formula (VIII). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, B is N or CR 11 And, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 12 is hydrogen or C 1~3 It is alkyl.

[0021] In the embodiment, the compound has a structure according to formula (IX). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each G is independent of N, NH, NR 13 , or CR 14 And, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 It is alkyl, R 7 C is optionally replaced with an aryl group. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens.1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl, R 14 is hydrogen, halogen, cyclopropyl, or C 1~3 It is alkyl.

[0022] In this embodiment, the compound has a structure according to formula (X). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each G is independent of N, NR 13 , or CR 14 And, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 It is alkyl, R 7 C is optionally replaced with an aryl group. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl, R 14 is hydrogen, halogen, cyclopropyl, or C 1~3 It is alkyl.

[0023] In the embodiment, the compound has the structure of formula (XI). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each G is independent of N or NR 13 And, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 It is alkyl, R 7 C is optionally replaced with an aryl group. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 13 This includes cyclopropyl, heteroaryl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls optionally substituted with alkyl groups, heterocycloalkyls optionally substituted with t-butyloxycarbonyl groups, and C molecules optionally substituted with aryl groups optionally substituted with one or more halogens. 1~4 It is alkyl, R 14 is hydrogen, halogen, cyclopropyl, or C 1~3 It is alkyl.

[0024] In the embodiment, the compound has a structure according to formula (XIIa) or formula (XIIb). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R13 This includes cyclopropyl, heteroaryl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls optionally substituted with alkyl groups, heterocycloalkyls optionally substituted with t-butyloxycarbonyl groups, and C molecules optionally substituted with aryl groups optionally substituted with one or more halogens. 1~4 It is alkyl, R 14 is hydrogen, halogen, cyclopropyl, or C 1~3 It is alkyl.

[0025] In the embodiment, the compound has the structure of formula (XIII). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 13 It is either an aryl or heteroaryl compound.

[0026] In the embodiment, the compound has the structure of formula (XIV). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, I is O, S, or CH, J is either N or CH. R 1 is OR 7C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 It is alkyl, R 7 C is optionally replaced with an aryl group. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 15 is hydrogen or C 1~3 It is alkyl, R 19 It is hydrogen or aryl.

[0027] In this embodiment, the compound has the structure of formula (XV). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, I is O, S, or CH, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens.1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 15 is hydrogen or C 1~3 It is alkyl. R 19 It is hydrogen or aryl.

[0028] In the embodiment, the compound has a structure according to formula (XVI). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, X is O, S, or SO2. R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 8 and R 9 These are independently hydrogen, halogen, OR 10or C, optionally substituted with one or more halogens. 1~3 It is alkyl, R 10 C 1~3 It is alkyl or aryl.

[0029] In the embodiment, the compound has a structure according to formula (XVII). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 8 and R 9 These are independently hydrogen, halogen, OR 10 or C, optionally substituted with one or more halogens. 1~3 It is alkyl, R 10 C 1~3 It is alkyl or aryl.

[0030] In the embodiment, the compound has the structure of formula (XVIII). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 8 and R 9 These are independently hydrogen, halogen, OR 10 or C, optionally substituted with one or more halogens. 1~3 It is alkyl, R 10 C 1~3 It is alkyl or aryl.

[0031] In the embodiment, the compound has a structure according to formula (XIX). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl.

[0032] In this embodiment, the compound has a structure according to formula (XX). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens.1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl.

[0033] In this embodiment, the compound has the structure of formula (XXI). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7C is optionally replaced with an aryl group. 1~3 It is alkyl.

[0034] In the embodiment, the compound has the structure of formula (XXII). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1 It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 20 This is an aryl that has been optionally substituted.

[0035] In the embodiment, the compound has the structure of formula (XXIII). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 Alkyl or R 1It is cyclopropyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 7 C is optionally replaced with an aryl group. 1~3 It is alkyl, R 20 This is an aryl that has been optionally substituted.

[0036] In this embodiment, R 3 It is not hydrogen.

[0037] In this embodiment, R 3 These are unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, or trifluoromethylphenyl.

[0038] In this embodiment, R 3 is OR 16 , SR 16 SO2R 16 CH2R 16 CH2CH2R 16 , C≡CR 16 , or C≡CCH2OR 16 And R 16 This is Ariel. 。 In this embodiment, R 16 It is phenyl.

[0039] In this embodiment, R 3 These are pyrrolyl, tetrazolyl, triazolyl, or pyrazolyl compounds optionally substituted with aryl or cycloalkyl groups.

[0040] In this embodiment, R 3 This is piperidinyl or piperazinyl, optionally substituted with an aryl group.

[0041] In this embodiment, R 3 It is either unsubstituted or substituted with cyclopropyl, unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, or trifluoromethylphenyl.

[0042] In this embodiment, R 3 COR 17 And R 17 is an arrow. In this embodiment, R 17 It is phenyl.

[0043] In this embodiment, R 1 is cyclopropyl or substituted C 1~3 It is alkyl.

[0044] In this embodiment, R 1 It is cyclopropyl or difluoromethyl.

[0045] In this embodiment, R 1 C 1~3 It is alkyl. In this embodiment, R 1 is CH2CH3. In the embodiment, R 1 This is CH3. In this embodiment, R 1 C is substituted with halogen-substituted aryl 1~3 It is alkyl. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 C is replaced with OBn 1~3 It is alkyl. In this embodiment, R 1 This is CH2CH2OBn.

[0046] In this embodiment, R 2is hydrogen. In this embodiment, R 2 C 1~3 It is alkyl. In this embodiment, R 2 This is CH3.

[0047] In this embodiment, R 4 is hydrogen, and R 5 is hydrogen. In this embodiment, R 4 is hydrogen, and R 5 C 1~3 It is alkyl. In this embodiment, R 5 is CH3. In this embodiment, R 4 C 1~3 It is alkyl, R 5 C 1~3 It is alkyl. In this embodiment, R 4 It is CH3, and R 5 This is CH3.

[0048] In this embodiment, R 4 and R 5 These, together with the carbon atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl. In the embodiment, the cycloalkyl is cyclopropyl. In the embodiment, the cycloalkyl is cyclobutyl. In the embodiment, the heterocycloalkyl is [ka] That is the case.

[0049] In this embodiment, the compound is one of compounds 1 to 50. [Table 1] TIFF0007832179000040.tif206170TIFF0007832179000041.tif226170TIFF0007832179000042.tif231170TIFF0007832179000043.tif49170 or a pharmaceutically acceptable salt thereof.

[0050] In this embodiment, the compound is one of compounds 51 to 70. [Table 2] TIFF0007832179000045.tif203170 or a pharmaceutically acceptable salt thereof.

[0051] In the embodiment, at least one hydrogen atom is substituted with a deuterium atom in one of the compounds of formula (I) to (XXIII), such as any one of compounds 1 to 70.

[0052] In another embodiment, the present invention is characterized by a pharmaceutical composition comprising any compound described herein (for example, any one of compounds of formula (I) to (XXIII), such as any one of compounds 1 to 70), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0053] In another embodiment, the present invention features a method for treating a disease mediated by PHD activity, comprising administering any of the compounds described herein (for example, any one of compounds (I) to (XXIII), such as any one of compounds 1 to 70) or a pharmaceutically acceptable salt thereof to a subject.

[0054] In this embodiment, the disease mediated by PHD activity is ischemic-reperfusion injury (e.g., stroke, myocardial infarction, or acute kidney injury).

[0055] In this embodiment, the disease mediated by PHD activity is inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease).

[0056] In this embodiment, the disease mediated by PHD activity is cancer (for example, colorectal cancer).

[0057] In this embodiment, the disease mediated by PHD activity is a liver disease.

[0058] In this embodiment, the disease mediated by PHD activity is atherosclerosis.

[0059] In this embodiment, the disease mediated by PHD activity is a cardiovascular disease.

[0060] In this embodiment, the disease mediated by PHD activity is an eye disease or condition (e.g., radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia).

[0061] In this embodiment, the disease mediated by PHD activity is anemia (for example, anemia associated with chronic kidney disease).

[0062] In this embodiment, the disease mediated by PHD activity is chronic kidney disease.

[0063] In this embodiment, the disease mediated by PHD activity is associated with hyperoxia.

[0064] In this embodiment, the disease mediated by PHD activity is retinopathy of prematurity.

[0065] In this embodiment, the disease mediated by PHD activity is bronchopulmonary dysplasia (BPD).

[0066] In this embodiment, the diseases mediated by PHD activity are ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, or cirrhosis.

[0067] In this embodiment, the disease mediated by PHD activity is a respiratory disease, lung disease, respiratory viral infection, or lung viral infection.

[0068] In this embodiment, the respiratory disease is selected from respiratory infection, acute respiratory distress syndrome, pneumonia, and acute lung injury.

[0069] In this embodiment, the lung disease is acute lung injury (ALI), bronchitis, pneumonia, pulmonary fibrosis, asthma, or acute respiratory distress syndrome (ARDS).

[0070] In this embodiment, the disease mediated by PHD activity is injury and / or failure of one or more organs (e.g., acute organ injury or organ failure). [Brief explanation of the drawing]

[0071] [Figure 1] This is an illustrative schematic diagram illustrating the principle of the TR-FRET assay for PHD enzymes (PHD1, PHD2, and PHD3). In the presence of 2-oxoglutaric acid and O2, the PHD enzymes hydroxylate proline 564 of the biotin-tagged HIF-1α peptide, producing biotin-tagged HIF-1α-hydroxyproline, succinic acid, and CO2. The proximity of the resulting donor fluorescent complex, anti-6His-Terbium(Tb)-cryptate Gold, bound to the His-tagged VHL protein, EloB, EloC complex (His-VBC), and the receptor fluorescent complex, SA-D2, bound to HIF-1α-hydroxyproline, yields a fluorescence resonance energy transfer signal that can be detected and quantified. [Modes for carrying out the invention]

[0072] definition To facilitate understanding of the present invention, certain terms are first defined below. Further definitions of the following terms and other terms are provided throughout this specification. Publications and other reference materials referenced herein to provide context for the present invention and to offer additional details regarding its practice are incorporated herein by reference.

[0073] Animals: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to a human at any developmental stage. In some embodiments, “animal” refers to a non-human animal at any developmental stage. In certain embodiments, a non-human animal is a mammal (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cattle, 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 modified animals, and / or clones.

[0074] Approximately or about: As used herein, when applied to one or more values ​​of interest, the terms “approximately” or “about” refer to values ​​similar to the given reference values. In certain embodiments, unless otherwise stated or otherwise evident from the context, the terms “approximately” or “about” refer to a range of values ​​that fall within the range of 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 than or less than) the given reference value (except where such values ​​exceed 100% of the possible values).

[0075] As used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the context otherwise explicitly indicates otherwise. Thus, for example, a reference to "composition" includes mixtures of two or more such compositions.

[0076] Throughout this description and the claims, the word “comprise” and other forms of the word, such as “comprising” and “comprises,” are not intended to exclude, for example, other additives, components, integers, or steps.

[0077] "Optional" or "optionally" means that the event or situation described thereafter may or may not occur, and in this specification, this includes both the event or situation that occurs and the event or situation that does not occur.

[0078] Improvement, Increase, or Reduction: As used herein, the terms “improvement,” “increase,” or “reduction,” or grammatically equivalent terms, refer to a value compared to a baseline measurement, such as a measurement in the same individual before the initiation of the treatment described herein, or a measurement in a control subject (or more control subjects) in the absence of the treatment described herein. A “control subject” is a subject of approximately the same age as the subject being treated and suffering from the same form of disease as the subject being treated.

[0079] In vitro: As used herein, the term “in vitro” refers to an event that occurs in an artificial environment, such as a test tube or reaction vessel or cell culture, rather than within a multicellular organism.

[0080] In vivo: As used herein, the term “in vivo” refers to events occurring within multicellular organisms, such as humans and non-human animals. In the context of cell-based systems, the term may be used to refer to events occurring within living cells (as opposed to, for example, in vitro systems).

[0081] Patient: As used herein, the terms “patient” or “subject” refer to any organism to which the composition provided may be administered, for example, for experimental, diagnostic, preventive, 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 human. Humans include prenatal and postnatal forms.

[0082] Pharmacopoeia-acceptable: As used herein, the term “pharmacopoeia-acceptable” means a substance that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues, with a reasonable benefit-to-risk ratio, without excessive toxicity, irritation, allergic reactions, or other problems or complications.

[0083] pharmaceutically acceptable salts: pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail 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 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 salts of amino groups formed by the use of other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfone. Salts include acid salts, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, and valersates. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N+(C1-4 alkyl) tetrasaltes. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, where appropriate.Quaternary ammonium compounds, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates, and arylsulfonates. Further pharmaceutically acceptable salts include those formed by quaternizing amines using suitable electrophiles, such as alkyl halides, to form quaternized alkylated amino salts.

[0084] Subject: As used herein, the term “subject” means a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, pig, sheep, horse, or primate). Human includes prenatal and postnatal forms. In many embodiments, the subject is a human. The subject may be a patient, referring to a human being presented to a healthcare provider for the diagnosis or treatment of a disease. The term “subject” is used herein interchangeably with “individual” or “patient.” The subject may be afflicted with or susceptible to a disease or disorder, and may or may not exhibit symptoms of the disease or disorder.

[0085] Substantially: As used herein, the term “substantially” refers to a qualitative state indicating the whole or nearly whole range or degree of the characteristics or properties of the subject. Those skilled in the art of biological techniques will understand that biological and chemical phenomena rarely, if any, reach completion and / or proceed completely, or achieve or avoid absolute results. Therefore, the term “substantially” is used herein to capture the inherent lack of completeness in many biological and chemical phenomena.

[0086] Therapeutic dose: As used herein, the term “therapeutic dose” of a therapeutic agent means an amount sufficient to treat, diagnose, prevent, and / or delay the symptoms of a disease, disorder, and / or condition when administered to a subject suffering from or susceptible to such disease, disorder, and / or condition. Those skilled in the art will understand that a therapeutic dose is typically administered via a dosing regimen containing at least one unit dose.

[0087] Treatment: As used herein, the terms “to treat,” “treatment,” or “to treat” refer to any method used to partially or completely alleviate, improve, reduce, inhibit, prevent, delay the onset, reduce the severity, and / or reduce the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. Treatment may be administered to subjects who show no signs of the disease and / or only early signs of the disease, for the purpose of reducing the risk of developing a disease-related condition.

[0088] Aliphatic: As used herein, the term aliphatic means C 1~ C 40 This term refers to hydrocarbons, including both saturated and unsaturated hydrocarbons. Aliphatic hydrocarbons can be linear, branched, or cyclic. For example, C1-C 20 Aliphatic cells are C1-C 20 Alkyl (e.g., linear or branched C1-C) 20 Saturated alkyl, C2~C 20 Alkenyls (e.g., linear or branched C4-C) 20 Dienyl, linear or branched C6-C 20 Trienyl, etc., and C2-C 20 Alkynyl (e.g., linear or branched C2-C) 20 May contain alkynyl) C1~C 20 Aliphatic cells are C3-C 20 Cyclic aliphatic (e.g., C3~C) 20 Cycloalkyl, C4~C 20 Cycloalkenyl, or C8~C 20It may include cycloalkynyls. In certain embodiments, the 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. The aliphatic group is either unsubstituted or substituted with one or more substituents as described herein. For example, the aliphatic group may be substituted with one or more of the halogens, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R' (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents), where each example of R' is independently C1-C 20 Aliphatic (for example, C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 The element is alkyl, or C1-C3 alkyl. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the aliphatic element is unsubstituted. In some embodiments, the aliphatic element does not contain any heteroatoms.

[0089] Alkyl: As used herein, the term "alkyl" means, for example, an acyclic straight-chain and branched hydrocarbon group, for example, "C1-C 20The term "alkyl" refers to an alkyl group having 1 to 20 carbon atoms. Alkyl groups may be linear or branched. Examples of alkyl groups, but not limited to, include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl tert-pentylhexyl, and isohexyl. The term "lower alkyl" means a linear or branched alkyl group having 1 to 6 carbon atoms. Other alkyl groups will be readily apparent to those skilled in the art, given the interests of this disclosure. Alkyl groups may be unsubstituted or substituted with one or more substituents as described herein. For example, the alkyl group may be substituted with one or more of the following (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents): halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', where each example of R' is independently C1-C 20 Aliphatic (for example, C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 The alkyl group is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl group. In some embodiments, the alkyl group is substituted (for example, with one, two, three, four, five, or six substituents as described herein). In some embodiments, the alkyl group is substituted with an -OH group and may also be referred to herein as a "hydroxyalkyl group," where the prefix indicates the -OH group and "alkyl" is as described herein. In some embodiments, the alkyl group is substituted with an -OR' group and may also be referred to herein as an "alkoxy" group.

[0090] Adding the suffix "-en" to a base indicates that the base is a divalent part; for example, arylene is the divalent part of aryl, and heteroarylene is the divalent part of heteroaryl.

[0091] Alkylene: As used herein, the term “alkylene” refers to a saturated divalent linear or branched hydrocarbon group, exemplified by methylene, ethylene, isopropyl, and the like. Similarly, as used herein, the term “alkenylene” refers to an unsaturated divalent linear or branched 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” as used herein refers to an unsaturated divalent linear or branched 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, alkylene, alkenylene, or alkynylene may be substituted with one or more of the following (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents): halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', where each example of R' is independently C1-C 20 Aliphatic (for example, C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10It is an alkyl group (or a C1-C3 alkyl group). In some embodiments, R' is independently an unsubstituted C1-C3 alkyl group. In certain embodiments, the alkylene, alkenylene, or alkynylene is unsubstituted. In certain embodiments, the alkylene, alkenylene, or alkynylene does not contain any heteroatoms.

[0092] Alkenyl: As used herein, “alkenyl” means 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, for example, “C2~C 20 "Alkenyl" refers to an alkenyl group having 2 to 20 carbon atoms. For example, alkenyl groups include propa-2-enyl, buta-2-enyl, buta-3-enyl, 2-methylpropa-2-enyl, hexa-2-enyl, hexa-5-enyl, and 2,3-dimethylbuta-2-enyl. In some embodiments, the alkenyl contains 1, 2, or 3 carbon-carbon double bonds. In some embodiments, the alkenyl contains a single carbon-carbon double bond. In some embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. The alkenyl group may be unsubstituted or substituted with one or more substituents as described herein. For example, the alkenyl group may be substituted with one or more of the following (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents): halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', where each example of R' is independently C1-C 20 Aliphatic (for example, C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10The group is alkyl, or C1-C3 alkyl. 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, which may also be referred to herein as a "hydroxyalkenyl group," with the prefix -OH group, and "alkenyl" as described herein.

[0093] Alkynyl: As used herein, "alkynyl" means any hydrocarbon chain, whether linear or branched, having one or more carbon-carbon triple bonds occurring at any stable point along the chain, for example, "C2-C 20 "Alkynyl" refers to an alkynyl group having 2 to 20 carbon atoms. Examples of alkynyl groups include propa-2-inyl, buta-2-inyl, buta-3-inyl, penta-2-inyl, 3-methylpenta-4-inyl, hexa-2-inyl, and hexa-5-inyl. In some embodiments, the alkynyl contains one carbon-carbon triple bond. The alkynyl group may be unsubstituted or substituted with one or more substituents as described herein. For example, the alkynyl group may be substituted with one or more of the following (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents): halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', where each example of R' is independently C1-C 20 Aliphatic (for example, C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10The alkyl (or C1-C3 alkyl) is used. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the alkynyl is unsubstituted. In some embodiments, the alkynyl is substituted (for example, with one, two, three, four, five, or six substituents as described herein).

[0094] The term "aryl," used alone or as part of a larger term such as "aralkyl," refers to a monocyclic, bicyclic, or tricyclic carbocyclic system having a total of 6 to 14 ring members, the rest of the molecule having a single bond site, at least one ring in the system being aromatic, and each ring in the system containing 4 to 7 ring members. In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl," e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C6 aryl"). 10 "Aryl" (e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring defined above is condensed with one or more carbocyrillic or heterocyclyl groups, and the radical or bond site is on the aryl ring, in which case the number of carbon atoms still specifies the number of carbon atoms in the aryl ring system. Exemplary aryls include phenyl, naphthyl, and anthracene.

[0095] Arylene: As used herein, the term "arylene" refers to a divalent (i.e., having two bonding sites to the molecule) aryl group. Exemplary arylenes include phenylene (e.g., unsubstituted phenylene or substituted phenylene).

[0096] Halogen or halo: As used herein, the terms "halogen" or "halo" mean fluorine, chlorine, bromine, or iodine.

[0097] Amide: The term "amide" or "amide" is derived from the formula -C(O)N(R’ )2, -C(O)N(R ’ )-, -NR ’ C(O)R ’ , -NR ’ C(O)N(R ’ )2-, or -NR ’ This refers to the chemical part containing C(O)-, where each R in the formula ’ These are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded via chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded via ring carbon), and unless otherwise specified herein, each of these parts may be optionally substituted as described herein, or two R' atoms may bond with a nitrogen atom to form a 3, 4, 5, 6, or 7-membered ring.

[0098] Amino: The term "amino" or "amine" refers to the -N(R')2 group, and in the formula, each R ’ R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded via chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via ring carbon), heteroarylalkyl, heterocycloalkyl (bonded via ring carbon), sulfonyl, amide, or carbonyl groups, and unless otherwise specified herein, each of these parts may be optionally substituted as described herein, or two R's may bond with a nitrogen atom to form a 3, 4, 5, 6, or 7-membered ring. In embodiments, the amino group is -NHR', where R' is aryl ("arylamino"), heteroaryl ("heteroarylamino"), amide, or alkyl ("alkylamino").

[0099] Ether: The term "ether" refers to the R'-O-R' group, where each R' is independently selected from alkyl, heteroalkyl (bonded via chain carbon), arylalkyl, heteroarylalkyl, heterocycloalkyl (bonded via ring carbon), cycloalkyl, aryl, and heteroaryl (bonded via ring carbon), and unless otherwise specified herein, each of these parts may be optionally substituted as described herein.

[0100] Ester: The term "ester" refers to an R'-C(=O)OR group, where each R' is independently selected from alkyl, heteroalkyl (bonded via chain carbon), arylalkyl, heteroarylalkyl, heterocycloalkyl (bonded via ring carbon), cycloalkyl, aryl, and heteroaryl (bonded via ring carbon), and unless otherwise specified herein, each of these parts may be optionally substituted as described herein.

[0101] Sulfonyl: The term "sulfonyl" refers to the -S(=O)2R' or -S(=O)2- group, where R is in the formula. ’ The group is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded via chain carbon), amino, cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via ring carbon), heteroarylalkyl, and heterocycloalkyl (bonded via ring carbon), and unless otherwise specified herein, each of these parts may be optionally substituted as described herein. For example, in one embodiment, the sulfonyl group is -SO2R', where R' is an alkyl group substituted with a carbonyl group.

[0102] Sulfinyl: The term "sulfinyl" refers to a chemical part having the formula -S(=O)R', -S(=O)-, or -S(=O)(=NR')-, where R ’The elements are selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded via chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via ring carbon), heteroarylalkyl, and heterocycloalkyl (bonded via ring carbon), and unless otherwise specified herein, each of these elements may be optionally substituted as described herein.

[0103] Carbonyl: The term "carbonyl" refers to a -C(=O)R' or -C(=O)- group, where R is in the formula. ’ The elements are selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded via chain carbon), cycloalkyl, aryl, arylalkyl, amino, hydroxyl, heteroaryl (bonded via ring carbon), heteroarylalkyl, and heterocycloalkyl (bonded via ring carbon), and unless otherwise specified herein, each of these elements may be optionally substituted as described herein.

[0104] Phosphoryl: The term "phosphoryl" refers to the -P(=O)(R')2 or -P(=O)(R')- group, where R is in the formula. ’ The group is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded via chain carbon or heteroatom), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded via ring carbon) groups, and unless otherwise specified herein, each of the groups may be optionally substituted as described herein, or two R' groups may bond with nitrogen atoms to form a 3, 4, 5, 6, or 7-membered ring.

[0105] Heteroalkyl: The term "heteroalkyl" refers to a branched or unbranched alkyl, alkenyl, or alkynyl group having 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P, plus 1 to 14 carbon atoms. Heteroalkyls include tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. Heteroalkyls may optionally contain monocyclic, bicyclic, or tricyclic rings, each preferably having 3 to 6 members. Examples of heteroalkyls include polyethers such as methoxymethyl and ethoxyethyl.

[0106] Heteroalkylene: As used herein, the term "heteroalkylene" refers to the divalent form of the heteroalkyl group described herein.

[0107] Heteroaryl: As used herein, the term “heteroaryl” means a monocyclic, bicyclic, or tricyclic carbocyclic system having a total of 6 to 14 ring members, wherein the rest of the molecule has a single bond site, and where at least one ring in the system is aromatic, each ring in the system contains 4 to 7 ring members, and at least one ring atom is a heteroatom, but is not limited to nitrogen and oxygen.

[0108] Heterocycloalkyl: As used herein, the term “heterocycloalkyl” means a non-aromatic ring in which at least one atom is a heteroatom, such as nitrogen, oxygen, sulfur, or phosphorus, but not limited to these, and the remaining atoms are carbon. Heterocycloalkyl groups may be substituted or unsubstituted.

[0109] Deuterium: The term "Deuterium" ("D" or " 2Deuterium (H) is also called heavy hydrogen. Deuterium is an isotope of hydrogen that has a nucleus consisting of one proton and one neutron, which is twice the mass of the normal hydrogen nucleus (one proton).

[0110] Isotopes: The term "isotope" refers to variants of a particular chemical element that differ in the number of neutrons, and consequently, the number of nucleons. All isotopes of a given element have the same number of protons, but each atom has a different number of neutrons.

[0111] The term "substituted" means that the specified group or part has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is either unsubstituted or substituted by one or more substituents. When the term "substituted" is used to describe a structural system, substitution means that it occurs at any position on the system where any valence is permissible, for example, substitution results in a stable compound (e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reactions). If a particular part or group is optionally substituted with any particular substituent, or is not explicitly recognized as substituted, then such part or group is understood to be intended to be unsubstituted.

[0112] When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl) is substituted with multiple substituents that vary within an explicitly defined range, it is understood that the total number of substituents does not exceed the normal available valencies under existing conditions. It is also understood that hydrogen atoms are assumed to be present to satisfy the remaining valencies of the ring system. Substituents include only combinations of substituents and variables that result in a stable or chemically viable compound. A stable or chemically viable compound is one that, among other factors, possesses sufficient stability to allow its preparation and detection.

[0113] A wide variety of substituents are well known, and methods for their formation and introduction into various parent groups are also well known. Representative substituents, though not limited to, include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, arylalkoxy, arylamino, heteroarylamino, heteroaryl, heteroarylalkoxy, heterocycloalkyl, hydroxyalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino, dialkylamino, amide, cyano, alkoxy, hydroxy, sulfonamide, halo (e.g., -Cl and -Br), nitro, oxyimino, -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 ) are listed, and in the formula, R 50 , R 51 and R 52 The following can be independently selected: hydrogen atoms and branched or straight chains having or not having substituents, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 4~6 Heterocycloalkyl, heteroaryl, and aryl groups. Where permitted, R 50and R 51 These elements can be bonded together to form a carbocyclic or heterocyclic ring system.

[0114] In preferred embodiments, substituents are selected from halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', where each example of R' is independently C1-C 20 Aliphatic (for example, C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. In a particular embodiment, R' is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. Preferably, R' is independently an unsubstituted C1-C3 alkyl group.

[0115] Any formula provided herein is intended to represent compounds having the structure shown by the structural formula, as well as specific variations or forms. In particular, compounds of any formula given herein may have a chiral center and therefore may exist in different enantiomer forms. All optical and stereoisomers of compounds of a general formula, as well as mixtures thereof, are considered to be within the scope of the formula. Therefore, any formula given herein is intended to represent racemates, one or more enantiomer forms, one or more diastereomer forms, one or more atropisomer forms, and mixtures thereof. Furthermore, specific structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. Furthermore, any formula given herein is intended to encompass hydrates, solvates, and polymorphs of such compounds, as well as mixtures thereof.

[0116] The compound of the present invention This specification discloses compounds that are potent inhibitors of PHD. In some embodiments, the compounds of the present invention are used to inhibit any one of PHD1, PHD2, and PHD3 at an enzyme half-maximal inhibitory concentration (IC) of less than 100 μM. 50 ) has a value. In some embodiments, the compound of the present invention has an IC of less than 50 μM for any one of PHD1, PHD2, and PHD3. 50 It has a value. In some embodiments, the compound of the present invention has an IC of less than 25 μM for any one of PHD1, PHD2, and PHD3. 50 It has a value. In some embodiments, the compound of the present invention has an IC of less than 20 μM for any one of PHD1, PHD2, and PHD3. 50 It has a value. In some embodiments, the compound of the present invention has an IC of less than 15 μM relative to any one of PHD1, PHD2, and PHD3. 50 It has a value. In some embodiments, the compound of the present invention has an IC of less than 10 μM relative to any one of PHD1, PHD2, and PHD3. 50 It has a value. In some embodiments, the compound of the present invention has an IC of less than 5 μM relative to any one of PHD1, PHD2, and PHD3. 50 It has a value. In some embodiments, the compound of the present invention has an IC of less than 1 μM for any one of PHD1, PHD2, and PHD3. 50 The compound of the present invention has a value of about 3 nM to about 5 nM relative to any one of PHD1, PHD2, and PHD3. 50 The compound of the present invention has a value of about 5 nM to about 10 nM relative to any one of PHD1, PHD2, and PHD3. 50 It has a value. In some embodiments, the compound of the present invention has an IC of about 10 nM to about 20 nM relative to any one of PHD1, PHD2, and PHD3. 50The compound of the present invention has a value of about 20 nM to about 50 nM relative to any one of PHD1, PHD2, and PHD3. 50 The compound of the present invention has a value of about 50 nM to about 100 nM relative to any one of PHD1, PHD2, and PHD3. 50 The compound of the present invention has a value of about 100 nM to about 200 nM relative to any one of PHD1, PHD2, and PHD3. 50 The compound of the present invention has a value of about 200 nM to about 500 nM relative to any one of PHD1, PHD2, and PHD3. 50 The compound of the present invention has a value of about 500 nM to about 1000 nM relative to any one of PHD1, PHD2, and PHD3. 50 It has a value.

[0117] Typical examples in this class show inhibitory activity against PHD1, PHD2, and PHD3 in vitro.

[0118] Exemplary compounds are described herein.

[0119] Compounds of formulas (I) to (XXIII) In particular, the PHD inhibitors described herein are the 3-hydroxypicolinamide moiety, [ka] It is characterized by the following. Surprisingly, the applicant, R 1 (R 1 We discovered that substitution of the 3-hydroxypicolinamide moiety (not hydrogen) can significantly increase the potency of the inhibitor. Examples of such substitutions include, but are not limited to, substituted or unsubstituted alkyl groups.

[0120] In one embodiment, a compound having the structure of formula (I), [ka] During the ceremony, R 1 This is C, which is optionally substituted. 1~3 Alkyl, optionally substituted C 3~6 A cycloalkyl or optionally substituted 3-6 member heterocycloalkyl, R 2 C is a hydrogen atom that is optionally substituted with other carbon atoms. 1~3 Alkyl, halogen, CN, or optionally substituted cycloalkyl, R 3 This is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, carbonyl, ether, thioether, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally substituted arylalkyl, optionally substituted alkynyl, or optionally substituted heteroalkynyl. R 4 and R 5 These are independently hydrogen, and optionally substituted C 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 6 is an OH or ester (for example, OR as described herein). 18 Compounds or pharmaceutically acceptable salts of the above are provided herein.

[0121] In this embodiment, R 1 is unsubstituted C 1~3 It is alkyl. In this embodiment, R 1 is substitution C 1~3 Alkyl (for example, C containing 1, 2, or 3 substituents) 1~3 It is alkyl.

[0122] In this embodiment, R 1is unsubstituted C 3~6 It is a cycloalkyl (e.g., unsubstituted cyclopropyl). In the embodiment, R 1 is substitution C 3~6 Cycloalkyl (e.g., C containing 1, 2, or 3 substituents) 3~6 It is a cycloalkyl (cycloalkyl) compound.

[0123] In this embodiment, R 1 is an unsubstituted 3-6 member heterocycloalkyl. In the embodiment, R 1 This is a substituted 3- to 6-membered heterocycloalkyl (for example, a 3- to 6-membered heterocycloalkyl containing 1, 2, or 3 substituents).

[0124] In this embodiment, R 2 is hydrogen. In this embodiment, R 2 This is C, which is optionally substituted. 1~3 It is alkyl. In this embodiment, R 2 is unsubstituted C 1~3 It is alkyl. In this embodiment, R 2 is substitution C 1~3 Alkyl (for example, C containing 1, 2, or 3 substituents) 1~3 It is alkyl. In this embodiment, R 2 is a halogen. In this embodiment, R 2 is CN. In this embodiment, R 2 This is a cycloalkyl group that is optionally substituted (e.g., C 3~6 It is a cycloalkyl compound. In this embodiment, R 2 is an unsubstituted cycloalkyl. In the embodiment, R 2 This is a substituted cycloalkyl (for example, a cycloalkyl containing one, two, or three substituents).

[0125] In this embodiment, R 3 is hydrogen. In this embodiment, R 3 is an unsubstituted aryl (e.g., phenyl, naphthalene). In this embodiment, R 3 R is a substituted aryl (e.g., phenyl, naphthalene). In this embodiment, R 3R is an unsubstituted heteroaryl (e.g., quinolone, isoquinoline, pyridine, pyrazole, pyrrole, triazole, tetrazole, oxazole, thiazole). In embodiments, R 3 R is a substituted heteroaryl (e.g., quinolone, isoquinoline, pyridine, pyrazole, pyrrole, triazole, tetrazole, oxazole, thiazole). In the embodiment, R 3 is an unsubstituted cycloalkyl. In the embodiment, R 3 is a substituted cycloalkyl. In this embodiment, R 3 is an unsubstituted heterocycloalkyl (e.g., N-containing heterocycloalkyl). In the embodiment, R 3 is a substituted heterocycloalkyl (e.g., N-containing heterocycloalkyl). In the embodiment, R 3 is a carbonyl group (for example, COR 17 , where R 17 (This is according to any embodiment described herein). In the embodiment, R 3 is ether (for example, OR 16 , where R 16 (This is according to any embodiment described herein). In the embodiment, R 3 is thioether (for example, SR 16 , where R 16 (This is according to any embodiment described herein). In the embodiment, R 3 is an unsubstituted aryl sulfonyl (e.g., phenylsulfonyl). In the embodiment, R 3 is a substituted aryl sulfonyl. In the embodiment, R 3 is an unsubstituted heteroarylsulfonyl. In the embodiment, R 3 is a substituted heteroarylsulfonyl. In the embodiment, R 3 is an unsubstituted arylalkyl (e.g., phenylalkyl). In this embodiment, R 3 is a substituted arylalkyl (e.g., phenylalkyl). In this embodiment, R 3 is an unsubstituted alkynyl. In the embodiment, R 3is a substituted alkynyl (e.g., an aryl-substituted alkynyl). In the embodiment, R 3 is an unsubstituted heteroalkynyl. In the embodiment, R 3 is a substituted heteroalkynyl (e.g., an aryl-substituted heteroalkynyl). In the embodiment, R 3 is OR 16 , SR 16 SO2R 16 CH2R 16 CH2CH2R 16 , C≡CR 16 , or C≡CCH2OR 16 And R 16 That is Ariel.

[0126] In this embodiment, R 4 and R 5 These are independently hydrogen or optionally substituted C 1~3 It is alkyl. In this embodiment, R 4 and R 5 These are independently hydrogen or unsubstituted C 1~3 It is alkyl. In this embodiment, R 4 and R 5 Each of these is hydrogen. In this embodiment, R 4 and R 5 One of them is hydrogen, and the other is unsubstituted C 1~3 It is alkyl. In this embodiment, R 4 and R 5 These are each unsubstituted C 1~3 It is alkyl. In this embodiment, R 4 and R 5 These, together with the carbon to which they are bonded, form optionally substituted cycloalkyls (e.g., C 3~6 Forms a cycloalkyl group. In this embodiment, R 4 and R 5 These, together with the carbon to which they are bonded, form unsubstituted cycloalkyls (e.g., unsubstituted C 3~6 Forms a cycloalkyl group. In this embodiment, R 4 and R 5These, together with the carbon atoms to which they are bonded, form optionally substituted heterocycloalkyl groups (e.g., 3-6 member heterocycloalkyl groups). In the embodiment, R 4 and R 5 These, together with the carbon atoms to which they are bonded, form unsubstituted heterocycloalkyl groups (e.g., unsubstituted 3-6 member heterocycloalkyl groups).

[0127] In this embodiment, R 6 is hydrogen. In this embodiment, R 6 is an ester (for example, OR as described herein). 18 ) is. In this embodiment, R 6 is OR 18 And R 18 C 1~6 It is alkyl.

[0128] In this embodiment, R 1 This is C, which is optionally substituted. 1~3 Alkyl and / or R 3 This is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, carbonyl, or ether.

[0129] In this embodiment, R 1 is unsubstituted C 1~3 It is an alkyl group (e.g., CH3 or CH2CH3). In this embodiment, R 1 This is CH3. In this embodiment, R 2 is hydrogen. In this embodiment, R 4 and R 5 Each of these is hydrogen. In this embodiment, R 6 It is OH.

[0130] Control mechanism, each R 1 and R 2 is unsubstituted C 1~3 It is alkyl. In this embodiment, each R 1 and R 2 This is CH3. In this embodiment, R 4and R 5 Each of these is hydrogen. In this embodiment, R 6 It is OH.

[0131] In this embodiment, R 2 is unsubstituted C 1~3 It is an alkyl group (e.g., CH3 or CH2CH3). In this embodiment, R 2 This is CH3. In this embodiment, R 3 is hydrogen. In this embodiment, R 4 and R 5 Each of these is hydrogen. In this embodiment, R 6 It is OH.

[0132] In this embodiment, the compound has the structure of formula (I). [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 is OR 7 C, optionally substituted with halogens, or aryls optionally substituted with halogens. 1~3 It is alkyl, R 7 C is optionally replaced with an aryl group. 1~3 Alkyl or R 1 This is C, which is optionally substituted. 3~6 A cycloalkyl or optionally substituted 3-6 member heterocycloalkyl, R 2 C is optionally substituted with hydrogen, halogen, CN, or one or more halogens. 1~3 It is alkyl, R 3 teeth, hydrogen; [ka] (In the formula, X is a covalent bond, O, S, SO2, C 1~4 Alkilen, C 2~4 Alkynylene, or C 2~4 It is a heteroalkylene, where each A independently is N or CR. 9And R 8 and R 9 These are independently hydrogen, halogen, OR 10 or C, optionally substituted with one or more halogens. 1~3 It is alkyl, R 10 C 1~3 It is alkyl or aryl; [ka] (In the formula, B is N or CR) 11 And D is N, NH, or CR 11 And E is N, CR 11 , or CHR 12 And R 11 and R 12 These are independently hydrogen or C 1~3 It is an alkyl group, and the dashed circle indicates the presence or absence of a conjugated system. [ka] (In the formula, each G is independently N, NH, NR) 13 , or CR 14 And R 13 C 3~6 Cycloalkyl groups, 3-6 member heterocycloalkyl groups, aryl groups optionally substituted with one or more halogens, and C groups optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl, R 14 is hydrogen, halogen, C 3~6 Cycloalkyl, 3-6 member heterocycloalkyl, or C 1~3 It is alkyl; [ka] (In the formula, I is O, S, or CH, J is N or CH, and R 15 is hydrogen, C 3~6Cycloalkyl, 3-6 member heterocycloalkyl, or C 1~3 It is alkyl, R 19 is hydrogen, C 3~6 It is a cycloalkyl, a 3- to 6-membered heterocycloalkyl, or aryl group; Ure 16 (In the formula, R 16 It is Ariel; [ka] (In the formula, X 1 is N or CH, and R 20 is an aryl that has been optionally substituted; and COR 17 (In the formula, R 17 It is selected from the group consisting of (which are aryls), R 4 and R 5 Independently, C is optionally substituted with hydrogen, one or more halogens. 1~3 Alkyl or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form optionally substituted cycloalkyl or heterocycloalkyl groups. R 6 is OH or OR 18 And R 18 C 1~6 It is alkyl.

[0133] In this embodiment, R 1 is unsubstituted C 1~3 It is alkyl. In this embodiment, R 1 It is either CH3 or CH2CH3.

[0134] In this embodiment, R 1 is substitution C 1~3 It is alkyl. In this embodiment, R 1 C is replaced with OR7. 1~3 It is alkyl. In this embodiment, R 7 is unsubstituted C 1~3 It is alkyl. In this embodiment, R 7 is substitution C1~3 It is alkyl. In this embodiment, R 7 is C substituted with aryl. 1~3 It is alkyl. In the embodiment, the aryl is phenyl. In the embodiment, R 7 is a phenyl-substituted C 1~3 It is alkyl. In this embodiment, R 1 C is replaced with OBn 1~3 It is alkyl. In this embodiment, R 1 This is CH2CH2OBn.

[0135] In this embodiment, R 1 C is a carbon atom substituted with one or more halogens (e.g., F, Cl, Br, or I). 1~3 It is alkyl. In this embodiment, R 1 It is difluoromethyl.

[0136] In this embodiment, R 1 C is substituted with aryls that are optionally substituted with halogens. 1~3 It is alkyl. In the embodiment, the optionally substituted aryl is the optionally substituted phenyl. In the embodiment, the aryl or phenyl is the unsubstituted aryl or unsubstituted phenyl. In the embodiment, the aryl or phenyl is substituted with one or more halogens. In the embodiment, R 1 teeth, [ka] That is the case.

[0137] In this embodiment, R 1 This is C, which is optionally substituted. 3~6 It is a cycloalkyl (for example, optionally substituted cyclopropyl). In the embodiment, R 1 C 3~6 It is a cycloalkyl (e.g., unsubstituted cyclopropyl). In the embodiment, R 1 is substitution C 3~6 Cycloalkyl (e.g., C containing 1, 2, or 3 substituents) 3~6 It is a cycloalkyl (cycloalkyl) compound.

[0138] In an embodiment, R 1 is an optionally substituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1 is an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1 is a substituted 3- to 6-membered heterocycloalkyl (e.g., a 3- to 6-membered heterocycloalkyl containing 1, 2, or 3 substituents).

[0139] In an embodiment, R 2 is hydrogen.

[0140] In an embodiment, R 2 is CN.

[0141] In an embodiment, R 2 is a halogen. In an embodiment, the halogen is F, Cl, Br, or I.

[0142] In an embodiment, R 2 is an unsubstituted C 1~3 alkyl. In an embodiment, R 2 is CH3.

[0143] In an embodiment, R 2 is a C 1~3 alkyl substituted with one or more halogens.

[0144] In an embodiment, R 3 is hydrogen. In an embodiment, R 3 is not hydrogen.

[0145] In an embodiment, R 3 is

Chemical formula

[0146] In an embodiment, R 3 is unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, or trifluoromethylphenyl.

[0147] In an embodiment, R 3 is

Chemical formula

[0148] In an embodiment, R 3 is

Chemical formula

[0149] In this embodiment, R 3 R is a pyrrolyl, tetrazolyl, triazolyl, or pyrazolyl compound optionally substituted with an aryl or cycloalkyl group. In the embodiment, R 3 (For example, pyrrolyl, tetrazolyl, triazolyl, or pyrazolyl) are substituted with cyclopropyl, unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, or trifluoromethylphenyl.

[0150] In this embodiment, R 3 teeth, [ka] And in the formula, I is O, S, or CH, J is either N or CH. R 15 is hydrogen, C 3~6 Cycloalkyl, 3-6 member heterocycloalkyl, or C 1~3 It is alkyl, R 19 is hydrogen, C 3~6 They are cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, or aryl groups.

[0151] In this embodiment, R 3 is OR 16 And R16 is an aryl compound. In this embodiment, the aryl compound is a phenyl compound. In this embodiment, R 3 It is an OPh.

[0152] In this embodiment, R 3 teeth, [ka] And in the formula, X 1 is N or CH, R 20 This is an aryl that has been optionally substituted.

[0153] In this embodiment, R 3 is piperidinyl or piperazinyl, optionally substituted with cyclopropyl or aryl. In embodiments, R 3 (For example, piperidinyl or piperazinyl) is substituted with cyclopropyl, unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, or trifluoromethylphenyl.

[0154] In this embodiment, R 3 COR 17 And R 17 is an aryl compound. In this embodiment, the aryl compound is a phenyl compound. In this embodiment, R 3 This is a COPh.

[0155] In this embodiment, R 3 teeth, [ka] That is the case.

[0156] In this embodiment, R 4 and R 5 Both are hydrogen.

[0157] In this embodiment, R 4 and R 5 One of them is hydrogen, and the other is C1~3 It is alkyl. In this embodiment, C 1~3 The alkyl group is unsubstituted. In this embodiment, C 1~3 The alkyl group is substituted with one or more halogens. In the embodiment, C 1~3 Alkyl groups are CH3.

[0158] In this embodiment, R 4 and R 5 Both are C 1~3 It is alkyl. In this embodiment, C 1~3 The alkyl group is unsubstituted. In this embodiment, C 1~3 The alkyl group is substituted with one or more halogens. In the embodiment, C 1~3 Alkyl groups are CH3.

[0159] In this embodiment, R 4 and R 5 These, together with the carbon atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl. In the embodiment, the cycloalkyl or heterocycloalkyl is unsubstituted. In the embodiment, the cycloalkyl or heterocycloalkyl is unsubstituted (e.g., a cycloalkyl or heterocycloalkyl containing 1, 2, or 3 substituents). In the embodiment, the cycloalkyl or heterocycloalkyl is a 3-membered ring. In the embodiment, the cycloalkyl or heterocycloalkyl is a 4-membered ring. In the embodiment, the heterocycloalkyl is an oxygen-containing heterocycloalkyl. In the embodiment, the cycloalkyl or heterocycloalkyl is cyclopropyl, cyclobutyl, and [ka] It is selected from the group consisting of the following.

[0160] In this embodiment, R 6 It is OH.

[0161] In this embodiment, R 6 is OR 18 And R 18 C 1~6It is alkyl.

[0162] In an embodiment, R 1 is unsubstituted C 1~3 alkyl (e.g., CH3 or CH2CH3). In an embodiment, R 1 is CH3. In an embodiment, R 2 is hydrogen. In an embodiment, R 4 and R 5 are each hydrogen. In an embodiment, R 6 is OH.

[0163] In an embodiment, each R 1 and R 2 is unsubstituted C 1~3 alkyl. In an embodiment, each R 1 and R 2 is CH3. In an embodiment, R 4 and R 5 are each hydrogen. In an embodiment, R 6 is OH.

[0164] In an embodiment, R 2 is unsubstituted C 1~3 alkyl (e.g., CH3 or CH2CH3). In an embodiment, R 2 is CH3. In an embodiment, R 3 is hydrogen. In an embodiment, R 4 and R 5 are each hydrogen. In an embodiment, R 6 is OH.

[0165] In an embodiment, R 1 is C 1~3 alkyl optionally substituted with OR7 or aryl optionally substituted with halogen, R 7 is C 1~3 alkyl optionally substituted with aryl, and / or R 3 is hydrogen,

Chemical formula

[0166] In this embodiment, the compound of formula (I) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 3 , R 4 , and R 5 This is defined as any other part of this specification.

[0167] In the embodiment, the compound of formula (I) or formula (II) has the following structure, [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , and R 5 This is defined as any part thereof, Each A is independent of N or CR 9 And, R 8 and R 9 These are independently hydrogen, halogen, OR 10 or C, optionally substituted with one or more halogens. 1~3 It is alkyl, R 10 C 1~3 It is alkyl or aryl.

[0168] In the embodiment, A is N. In the embodiment, A is CR. 9 In this embodiment, all three A groups are CR 9 In this embodiment, one A is CR 9 In one embodiment, one A is N, and the other two A groups are CR. 9 In this embodiment, all three A groups are N.

[0169] In this embodiment, R 8and R 9 At least one of them is hydrogen. In one embodiment, R 8 and R 9 One of them is hydrogen.

[0170] In this embodiment, R 8 and R 9 None of them are hydrogen.

[0171] In this embodiment, R 8 It is hydrogen.

[0172] In this embodiment, R 8 is a halogen. In the embodiment, the halogen is F, Cl, Br, or I. In the embodiment, R 8 It is Cl.

[0173] In this embodiment, R 8 is OR 10 And R 10 C 1~3 It is alkyl. In this embodiment, R 8 It is OMe.

[0174] In this embodiment, R 8 is OR 10 And R 10 is an aryl compound. In this embodiment, the aryl compound is a phenyl compound. In this embodiment, R 8 It is an OPh.

[0175] In this embodiment, R 8 is unsubstituted C 1~3 It is alkyl. In this embodiment, R 8 C is a C substituted with one or more halogens. 1~3 It is alkyl.

[0176] In this embodiment, R 9 It is hydrogen.

[0177] In this embodiment, R 9 is a halogen. In the embodiment, the halogen is F, Cl, Br, or I. In the embodiment, R9 It is Cl.

[0178] In this embodiment, R 9 is OR 10 And R 10 C 1~3 It is alkyl. In this embodiment, R 9 It is OMe.

[0179] In this embodiment, R 9 is OR 10 And R 10 is an aryl compound. In this embodiment, the aryl compound is a phenyl compound. In this embodiment, R 9 It is an OPh.

[0180] In this embodiment, R 9 is unsubstituted C 1~3 It is alkyl. In this embodiment, R 9 C is a C substituted with one or more halogens. 1~3 It is alkyl. In this embodiment, R 9 This is CH3. In this embodiment, R 9 This is CF3.

[0181] In the embodiment, the compound of formula (I), formula (II), or formula (III) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , R 5 , R 8 and R 9 This is defined as any other part of this specification.

[0182] In the embodiment, the compound of formula (I), formula (II), or formula (III) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R2 , R 4 , R 5 , R 8 and R 9 This is defined as any other part of this specification.

[0183] In the embodiment, [ka] teeth, [ka] In this embodiment, R 9 is halogen, OR 10 or C, optionally substituted with one or more halogens. 1~3 It is alkyl. In this embodiment, R 9 It is a halogen.

[0184] In the embodiment, [ka] teeth, [ka] In this embodiment, R 9 is halogen, OR 10 or C, optionally substituted with one or more halogens. 1~3 It is alkyl. In this embodiment, R 9 It is a halogen.

[0185] In the embodiment, [ka] teeth, [ka] In this embodiment, R 8 is halogen, OR 10 or C, optionally substituted with one or more halogens. 1~3 It is alkyl. In this embodiment, R8 It is a halogen.

[0186] In the embodiment, the compound of formula (I) or formula (II) has the following structure, [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , and R 5 This is defined as any part thereof, B is N or CR 11 And, D is N, NH, or CR 11 And, E is N, CR 11 , or CHR 12 And, R 11 and R 12 These are independently hydrogen or C 1~3 It is alkyl, The dashed circle indicates the presence or absence of a conjugate system.

[0187] In the embodiment, there is a dashed circle, R 3 teeth [ka] In the formula, B is either N or CR. 11 And D is N, or CR 11 And E is N or CR 12 That is the case.

[0188] In this embodiment, D is CR 11 And E is CR 12 Therefore, B is N.

[0189] In this embodiment, B is CR 11 And E is CR 12 Therefore, D is N.

[0190] In this embodiment, both B and D are CR 11Therefore, E is N.

[0191] In this embodiment, both B and D are CR 11 And E is CR 12 That is the case.

[0192] In this embodiment, the dashed circle is absent, R 3 teeth, [ka] In the formula, B is either N or CR. 11 And D is NH, and E is CHR 12 That is the case.

[0193] In this embodiment, B is CR 11 And E is CHR 12 That is the case.

[0194] In this embodiment, R 11 It is hydrogen.

[0195] In this embodiment, R 11 C 1~3 It is alkyl. In this embodiment, R 11 This is CH3.

[0196] In this embodiment, R 12 It is hydrogen.

[0197] In this embodiment, R 12 C 1~3 It is alkyl. In this embodiment, R 12 This is CH3.

[0198] In the embodiment, the compound of formula (I), formula (II), or formula (VI) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula B, D, E, R 1 , R 2 , R 4 , and R 5This is defined as any other part of this specification.

[0199] In the embodiment, [ka] teeth, [ka] That is the case.

[0200] In the embodiment, [ka] teeth, [ka] That is the case.

[0201] In the embodiment, [ka] teeth, [ka] In this embodiment, R 12 is hydrogen or C 1~3 It is alkyl. In this embodiment, R 12 is hydrogen. In this embodiment, R 12 This is CH3.

[0202] In the embodiment, [ka] teeth, [ka] That is the case.

[0203] In the embodiment, the compound of formula (I), formula (II), or formula (VI) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula B, R 1 , R 2 , R 4 , R 5 and R 12 This is defined as any other part of this specification.

[0204] In the embodiment, [ka] teeth, [ka] In this embodiment, R 12 C 1~3 It is alkyl. In this embodiment, R 12 This is CH3.

[0205] In the embodiment, the compound of formula (I) or formula (II) has the following structure, [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , and R 5 This is defined as any part thereof, Each G is independent of N, NH, NR 13 , or CR 14 And, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl, R 14 is hydrogen, halogen, cyclopropyl, or C 1~3It is alkyl.

[0206] In the embodiment, G is N. In the embodiment, G is NH. In the embodiment, G is NR 13 In this embodiment, G is CR 14 That is the case.

[0207] In this embodiment, R 13 It is cyclopropyl.

[0208] In this embodiment, R 13 is an unsubstituted aryl. In this embodiment, R 13 is an aryl substituted with one or more halogens. In this embodiment, R 13 C is one or more optionally substituted C 1~3 Alkyl (for example, C substituted with one or more halogens) 1~3 It is an aryl substituted with an alkyl group. In the embodiment, the aryl is a phenyl group. In the embodiment, R 13 R is an unsubstituted phenyl compound. In this embodiment, R 13 is a phenyl substituted with one or more halogens. In the embodiment, R 13 C is one or more optionally substituted C 1~3 Alkyl (for example, C substituted with one or more halogens) 1~3 It is a phenyl substituted with alkyl. In this embodiment, R 13 The compound is selected from the group consisting of p-trifluoromethylphenyl, m-fluorophenyl, p-fluorophenyl, p-chlorophenyl, 2,4-dichlorophenyl, and 3,5-dichlorophenyl.

[0209] In this embodiment, R 13 is a heteroaryl compound. In the embodiment, the heteroaryl compound is unsubstituted. In the embodiment, the heteroaryl compound is substituted. In the embodiment, the heteroaryl compound is pyridyl. In the embodiment, R 13 These are 2-pyridyl, 3-pyridyl, or 4-pyridyl.

[0210] In this embodiment, R13 is an unsubstituted heterocycloalkyl. In the embodiment, R 13 is a heterocycloalkyl substituted with t-butyloxycarbonyl. In the embodiment, the heterocycloalkyl is a 6-membered heterocycloalkyl. In the embodiment, the heterocycloalkyl is a nitrogen-containing heterocycloalkyl. In the embodiment, the heterocycloalkyl is an oxygen-containing heterocycloalkyl. In the embodiment, R 13 teeth, [ka] That is the case.

[0211] In this embodiment, R 13 is unsubstituted C 1~4 It is alkyl. In this embodiment, R 13 teeth, [ka] That is the case.

[0212] In this embodiment, R 13 is C substituted with aryl. 1~4 It is alkyl. In the embodiment, the aryl is unsubstituted. In the embodiment, the aryl is substituted with one or more halogens. In the embodiment, the aryl is a phenyl group. In the embodiment, the phenyl is unsubstituted phenyl. In the embodiment, the phenyl is substituted with one or more halogens. In the embodiment, R 13 teeth, [ka] That is the case.

[0213] In this embodiment, R 14 It is hydrogen.

[0214] In this embodiment, R 14 is a halogen. In the embodiment, the halogen is F, Cl, Br, or I. In the embodiment, R 14 It is F.

[0215] In this embodiment, R 14 It is cyclopropyl.

[0216] In this embodiment, R 14 C 1~3 It is alkyl. In this embodiment, R 14 This is CH3.

[0217] In the embodiment, [ka] teeth, [ka] That is the case.

[0218] In the embodiment, [ka] teeth, [ka] In this embodiment, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 is an unsubstituted aryl. In this embodiment, R 13 is Ph. In this embodiment, R 13 is an aryl substituted with one or more halogens. In this embodiment, R 13 teeth, [ka] In this embodiment, R 13 It is cyclopropyl.

[0219] In the embodiment, [ka] teeth, [ka] In this embodiment, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 R is an aryl atom optionally substituted with one or more halogens. In this embodiment, R 13 C is substituted with aryls substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 R is an aryl atom optionally substituted with one or more halogens. In this embodiment, R 13 Ph, [ka] That is the case.

[0220] In the embodiment, [ka] teeth, [ka] In this embodiment, [ka] teeth, [ka] In this embodiment, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 is an arrow. In this embodiment, R 13 is Ph. In this embodiment, R 13 Ph, [ka] That is the case.

[0221] In this embodiment, R 14 is hydrogen, halogen, cyclopropyl, or C 1~3 It is alkyl. In this embodiment, R 14 C 1~3 It is an alkyl group (for example, methyl).

[0222] In the embodiment, [ka] teeth, [ka] In this embodiment, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 is an arrow. In this embodiment, R 13 It is Ph.

[0223] In the embodiment, the compound of formula (I), formula (II), or formula (IX) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, wherein G, R 1 , R 2 , R 4 , and R 5 This is defined as any other part of this specification.

[0224] In the embodiment, [ka] teeth, [ka] In this embodiment, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 R is an aryl atom optionally substituted with one or more halogens. In this embodiment, R 13 C is substituted with aryls substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 R is an aryl atom optionally substituted with one or more halogens. In this embodiment, R 13 Ph, [ka] That is the case.

[0225] In the embodiment, the compound of formula (I), formula (II), formula (IX), or formula (X) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , R 5 , and R 14 This is defined as any other part of this specification.

[0226] In the embodiment, the compound of formula (I), formula (II), formula (IX), formula (X), or formula (XI) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , R 5 , R 13 and R 14 This is defined as any other part of this specification.

[0227] In this embodiment, R 14 is halogen or C 1~3 It is alkyl. In this embodiment, R 14 is methyl. In this embodiment, R 14 It is F.

[0228] In this embodiment, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 R is an aryl atom optionally substituted with one or more halogens. In this embodiment, R 13 This is pH, 3-fluorophenyl, or 4-fluorophenyl.

[0229] In this embodiment, R 14 It is hydrogen, [ka] teeth, [ka] In this embodiment, R 14 It is hydrogen, [ka] teeth, [ka] In this embodiment, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 C 1~4 It is alkyl. In this embodiment, R 13 is a heteroaryl. In this embodiment, R 13 is a heterocycloalkyl. In this embodiment, R 13 is an aryl substituted with one or more halogens. In this embodiment, R 13 This is C, which is optionally substituted. 1~3 Alkyl (for example, C substituted with one or more halogens) 1~3 It is an aryl substituted with alkyl. In this embodiment, R 13 Ph, [ka] That is the case.

[0230] In the embodiment, the compound of formula (I), formula (II), formula (IX), formula (X), formula (XI), or formula (XIIa) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 2 , R 4 , R 5 , and R 13 This is defined as any other part of this specification.

[0231] In this embodiment, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 is a heterocycloalkyl substituted with t-butyloxycarbonyl. In the embodiment, R 13 is an arrow. In this embodiment, R 13 is an aryl substituted with one or more halogens. In this embodiment, R 13 This is C, which is optionally substituted. 1~3 Alkyl (for example, C substituted with one or more halogens) 1~3 It is an aryl substituted with alkyl. In this embodiment, R 13 Ph, [ka] That is the case.

[0232] In the embodiment, the compound of formula (I), formula (II), formula (IX), formula (X), or formula (XI) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R1 , R 2 , R 4 , R 5 , and R 13 This is defined as any other part thereof.

[0233] In this embodiment, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 is an unsubstituted aryl. In this embodiment, R 13 It is Ph.

[0234] In the embodiment, the compound of formula (I), formula (II), or formula (IX) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , R 5 , and R 13 This is defined as any other part of this specification.

[0235] In this embodiment, R 13 This includes cyclopropyl, aryls optionally substituted with one or more halogens, and C10s optionally substituted with one or more halogens. 1~3 Aryls, heteroaryls, heterocycloalkyls, and aryls optionally substituted with alkyl groups, t-butyloxycarbonyl groups, or C11s, which are optionally substituted with one or more halogens. 1~4 It is alkyl. In this embodiment, R 13 is an unsubstituted aryl. In this embodiment, R 13 is Ph. In this embodiment, R13 is an aryl substituted with one or more halogens. In this embodiment, R 13 teeth [ka] In this embodiment, R 13 It is cyclopropyl.

[0236] In the embodiment, the compound of formula (I), formula (II), or formula (IX) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , and R 5 This is defined as any other part of this specification.

[0237] In the embodiment, the compound of formula (I) or formula (II) has the following structure, [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , and R 5 This is defined as any part thereof, I is O, S, or CH, J is either N or CH. R 15 is hydrogen or C 1~3 It is alkyl, R 19 It is hydrogen or aryl.

[0238] In this embodiment, I is O. In this embodiment, I is S. In this embodiment, I is CH.

[0239] In the embodiment, J is N. In the embodiment, J is CH.

[0240] In this embodiment, R 15 It is hydrogen.

[0241] In this embodiment, R 15 C 1~3 It is alkyl. In this embodiment, R 15 This is CH3.

[0242] In this embodiment, R 19 It is hydrogen.

[0243] In this embodiment, R 19 is an arrow. In this embodiment, R 19 It is phenyl.

[0244] In the embodiment, the compound of formula (I), (II), or (XIV) has the following structure: [ka] or having a pharmaceutically acceptable salt thereof, in the formula I, R 1 , R 2 , R 4 , R 5 , R 15 and R 19 This is defined as any other part of this specification.

[0245] In the embodiment, [ka] teeth, [ka] In this embodiment, R 19 is an arrow. In this embodiment, R 19 R is phenyl. In this embodiment, R 15 is hydrogen or C 1~3 It is alkyl. In this embodiment, R 15 It is either hydrogen or CH3.

[0246] In the embodiment, [ka] teeth, [ka] In this embodiment, R 19 is an arrow. In this embodiment, R 19 It is phenyl.

[0247] In the embodiment, the compound of formula (I) or formula (II) has the following structure, [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , R 5 , R 8 and R 9 X is as defined anywhere in this specification, where X is O, S, or SO2.

[0248] In the embodiment, X is O. In the embodiment, X is S. In the embodiment, X is SO2.

[0249] In the embodiment, the compound of formula (I) or formula (II) has the following structure, [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , R 5 , R 8 and R 9 This is defined as any other part of this specification.

[0250] In the embodiment, the compound of formula (I) or formula (II) has the following structure, [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1, R 2 , R 4 , R 5 , R 8 and R 9 This is defined as any other part of this specification.

[0251] In the embodiment, the compound of formula (I) or formula (II) has the following structure, [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , and R 5 R is defined as any part thereof, 20 This is an aryl that has been optionally substituted.

[0252] In this embodiment, R 20 R is a substituted aryl (for example, containing one, two, or three substituents). In embodiments, R 20 is an unsubstituted aryl. In the embodiment, the aryl is phenyl. In the embodiment, R 20 It is Ph.

[0253] In the embodiment, the compound of formula (I) or formula (II) has the following structure, [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1 , R 2 , R 4 , and R 5 R is defined as any part thereof, 20 This is an aryl that has been optionally substituted.

[0254] In this embodiment, R 20 R is a substituted aryl (for example, containing one, two, or three substituents). In embodiments, R 20 is an unsubstituted aryl. In the embodiment, the aryl is phenyl. In the embodiment, R20 It is Ph.

[0255] Exemplary compounds In some embodiments, the PHD inhibitor compound is one of compounds 1 to 50, or a pharmaceutically acceptable salt thereof. [Table 3] TIFF0007832179000136.tif213170TIFF0007832179000137.tif202170TIFF0007832179000138.tif214170TIFF0007832179000139.tif215170

[0256] In some embodiments, the PHD inhibitor compound is one of compounds 51 to 70, or a pharmaceutically acceptable salt thereof. [Table 4] TIFF0007832179000141.tif144170

[0257] Isotopologes In the compounds described herein (for example, any one of the compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), it should be understood that atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but different atomic masses or mass numbers from those primarily found in nature. The present invention is intended to encompass all suitable isotopic variations of the compounds described herein (for example, any one of the compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70). For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H), and tritium (3 It contains H). Protium is the primary hydrogen isotope found in nature.

[0258] In some embodiments, one or more hydrogen atoms in the compounds described herein (e.g., any one of the compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70) are substituted with deuterium. Deuterium enrichment may result in specific therapeutic benefits, such as increased half-life in vivo or reduced dose requirements, or provide compounds useful as standards for characterizing biological samples. In some embodiments, one or more hydrogen atoms in the compounds described herein (e.g., any one of the compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70) are substituted with tritium. Because tritium is radioactive, it can provide radiolabeled compounds useful as tracers in metabolic or kinetic studies.

[0259] Isotope enrichment of the compounds disclosed herein (for example, any one of the compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70) can be achieved without excessive experimentation by the prior art well known to those skilled in the art, or by a process similar to that described herein, using appropriate isotope enrichment reagents and / or intermediates.

[0260] The term "isotopolog" 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. Therefore, 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 those skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom also contains a smaller amount of isotopolog with a hydrogen atom at one or more of the specified deuterium positions in its structure. The relative amount of such isotopologs in the provided compounds depends on many factors, but are not limited, including the isotopic purity of the deuterating reagents used to prepare the compound and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound.

[0261] When a position is designated as "H" or "hydrogen," that position is understood to contain hydrogen in its isotopic composition at its natural abundance. When a position is designated as "D" or "deuterium," that position is understood to contain deuterium at an abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the terms "D" or "deuterium" indicate at least 50.1% deuterium incorporation).

[0262] In embodiments, the compounds provided herein may have an isotope enrichment coefficient 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 deuterium site on the compound.

[0263] Synthesis of the Compound of the Present Invention The compounds described herein (for example, any one of the compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70) can be prepared according to methods known in the art, including the exemplary synthesis of the examples provided herein.

[0264] Abbreviations and acronyms used herein include the following: [Table 5] TIFF0007832179000143.tif187170

[0265] Compositions and methods The present invention provides the use of any one compound from formulas (I) to (XXIII), or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical for use in the treatment of various conditions or disorders described herein. In one embodiment, a pharmaceutical composition is provided comprising any one compound from formulas (I) to (XXIII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In various embodiments, the drug or pharmaceutical composition may further comprise or be used in combination with at least one additional therapeutic agent.

[0266] The compounds of the present invention, or agents or compositions containing the compounds, can be used to inhibit the activity of PHD. Inhibition of PHD may be particularly beneficial in the treatment of diseases including cardiac (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), pulmonary (e.g., pneumonia, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, chronic obstructive pulmonary disease), respiratory (e.g., respiratory infections, acute respiratory distress syndrome), hepatic (e.g., acute liver failure, hepatic fibrosis, and cirrhosis), and renal (e.g., acute kidney injury and chronic kidney disease) diseases, inflammatory bowel disease (IBD), ischemic-reperfusion injury (e.g., stroke), and retinopathy of prematurity (ROP).

[0267] In one embodiment, the method of the present invention involves administering to a patient in need a therapeutically effective amount of a pharmaceutical composition containing one of the compounds of formulas (I) to (XXIII), a pharmaceutically acceptable salt thereof, or one or more compounds of formulas (I) to (XXIII).

[0268] The present invention also relates to a method for inhibiting the activity of PHD. In one embodiment, the method involves contacting PHD with an effective amount of one or more compounds selected from the group comprising any one of the compounds of formulas (I) to (XXIII), or pharmaceutically acceptable salts thereof.

[0269] In further embodiments, the compounds disclosed herein (e.g., any one of the compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are 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 blood cell aplasia, Henoch-Schönlein purpura, blast-type refractory anemia, PHD inhibitors are useful in the treatment or prevention of anemia, including the treatment of anemic conditions associated with rheumatoid arthritis, Schwakman syndrome, sickle cell disease, severe thalassemia, mild thalassemia, thrombocytopenic purpura, anemia in anemic or non-anemic patients undergoing surgery, anemia associated with or secondary to trauma, sideroblastic anemia, and anemia secondary to other treatments, including: reverse transcriptase inhibitors for the treatment of HIV, corticosteroid hormones, cyclic cisplatin or non-cisplatin-containing chemotherapeutic agents, vinca alkaloids, mitotic inhibitors, topoisomerase II inhibitors, anthracyclines, alkylating agents; particularly anemia secondary to inflammation, aging, and / or chronic disease. PHD inhibitors may also be used to treat symptoms of anemia, including chronic fatigue, pallor, and dizziness.

[0270] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for the treatment or prevention of metabolic disorders, including but not limited to diabetes and obesity.

[0271] In further embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for the treatment or prevention of vascular disorders. These include, but are not limited to, hypoxic or wound-healing-related disorders requiring angiogenic mediators for vasoconstriction, angiogenesis, and arteriogenesis.

[0272] In further embodiments, compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for the treatment or prevention of ischemia-reperfusion injury. These include, but are not limited to, stroke, myocardial infarction, and acute kidney injury.

[0273] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for the treatment of inflammatory bowel diseases. These include, but are not limited to, ulcerative colitis and Crohn's disease.

[0274] In other embodiments, the compounds disclosed herein (for example, compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for treating cancers such as colorectal cancer.

[0275] In other embodiments, the compounds disclosed herein (for example, compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for the treatment of atherosclerosis.

[0276] In other embodiments, the compounds disclosed herein (for example, compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for the treatment of cardiovascular diseases.

[0277] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for treating diseases or conditions of the eye. These include, but are not limited to, radiation retinopathy, retinopathy of prematurity (ROP), diabetic retinopathy, age-related macular degeneration, and ocular ischemia.

[0278] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for treating diseases associated with hyperoxia.

[0279] In other embodiments, the compounds disclosed herein (for example, compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for the treatment of bronchopulmonary dysplasia (BPD).

[0280] In further embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for the treatment of heart disease. Conditions include, but are not limited to, postoperative myocardial ischemia in pancreatic surgery, myocardial injury after percutaneous coronary intervention (PCI), myocardial injury after non-cardiac surgery, perioperative myocardial ischemia in elective surgery for abdominal aortic aneurysm, myocardial injury after PCI, myocardial injury in patients undergoing coronary artery bypass grafting (CABG), minimally invasive mitral valve (MIMV) repair or replacement, open-heart surgery, chronic heart failure, and adult patients with NYHA class II to IV.

[0281] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful in treating lung diseases such as pneumonia, pneumonia, bronchitis, acute lung injury (ALI), pulmonary hypertension, pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), or chronic obstructive pulmonary disease. Conditions include, but are not limited to, lung injury during selective lobectomy, lung injury during coronary artery bypass grafting (CABG), and lung transplantation.

[0282] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for the treatment of respiratory diseases. These conditions include, but are not limited to, respiratory infections, acute respiratory distress syndrome (ARDS), pneumonia, and acute lung injury.

[0283] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for the treatment of liver diseases. Conditions include, but are not limited to, non-alcoholic steatohepatitis (NASH).

[0284] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for the treatment of kidney disease. Conditions include, but are not limited to, contrast-induced acute kidney injury, chronic kidney disease of stage III to IV undergoing planned coronary angiography, acute kidney injury in patients undergoing heart valve surgery, non-dialysis-dependent chronic kidney disease, chronic kidney disease patients initiating dialysis, and non-dialysis-dependent chronic kidney disease.

[0285] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for treating one or more organ injuries and / or failures (e.g., injuries and / or failures of the lungs, heart, liver, or kidneys). Conditions include, but are not limited to, acute organ injury or organ failure, as well as induced organ dysfunction.

[0286] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, are useful for treating respiratory viral (e.g., coronavirus) infections or lung viral (e.g., coronavirus) infections.

[0287] Furthermore, compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, may be used in combination with additional active ingredients in the treatment of the above conditions. The additional compounds may be co-administered separately with the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70), or pharmaceutically acceptable salts thereof, or may be included together with the additional active ingredients in the pharmaceutical composition according to the present invention. In exemplary embodiments, the additional active ingredients are those known or discovered to be effective in treating PHD enzyme-mediated conditions, disorders, or diseases, or are active against another target associated with a particular condition, disorder, or disease, such as an alternative PHD regulator. Combinations may help increase efficacy (e.g., by including a combination of compounds that enhance the potency or effectiveness of the compounds according to the present invention), reduce one or more side effects, or reduce the required dose of the compounds according to the present invention.

[0288] The compounds of the present invention are used alone or in combination with one or more other active ingredients to formulate the pharmaceutical compositions of the present invention. The pharmaceutical compositions of the present invention comprise (a) an effective amount of any of the compounds disclosed herein (e.g., any one of compounds 1 to 70, or compounds of formulas (I) to (XXIII)), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof, and (b) a pharmaceutically acceptable excipient.

[0289] A "pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable, and otherwise biologically suitable substance for administration to a target, such as an inert substance, that is added to a pharmaceutical composition to facilitate drug administration, or otherwise used as a vehicle, carrier, or diluent, and is compatible with such substance. Examples of excipients include calcium carbonate, calcium phosphate, various types of sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Suitable excipients may also include antioxidants. Such antioxidants can be used in pharmaceutical compositions or storage media to extend the shelf life of the drug.

[0290] Pharmaceutical preparations and routes of administration The compounds and compositions of the present invention can be delivered directly or in pharmaceutical compositions or drug products together with suitable carriers or excipients, as is well known in the art. The therapeutic method of the present invention may include administering an effective amount of the compound of the present invention to a target subject in need. In preferred embodiments, the target is a mammalian subject, and in most preferred embodiments, the target is a human subject.

[0291] The effective dose of such compounds, compositions, or pharmaceuticals can be easily determined by routine experiments, as well as the most effective and convenient route of administration and the most appropriate formulation. Various formulations and drug delivery systems are available in the art. See, for example, Gennaro, AR, ed. (1995) Remington's Pharmaceutical Sciences.

[0292] Appropriate 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, intra-arterial, intra-articular, intracardiac, intracisional, intradermal, intralesional, intraocular, intrapleural, subarachnoid, intrauterine, and intraventricular administration. The type of formulation used, the route of administration, and whether topical or systemic delivery is preferred should be determined by the indication to be treated and the physical, chemical, and biological properties of the drug.

[0293] The 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, sugars, soft or hard-shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized formulations. Depending on the route of administration used, special equipment such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks may be required for the application or administration of the drug. Pharmaceutical dosage forms often consist of the drug, excipients, and a container / sealing system. Adding one or more excipients, also called inactive components, to the compounds of the present invention can improve or enhance the manufacture, stability, administration, and safety of the drug and provide a means to achieve a desired drug release profile. Therefore, the type of excipient added to the drug may depend on various factors, such as the physical and chemical properties of the drug, the route of administration, and the manufacturing procedure. Pharmaceutically acceptable excipients include those available in the art and listed in various pharmacopoeias. See, for example, the United States Pharmacopeia (USP), the Japanese Pharmacopoeia (JP), the European Pharmacopoeia (EP), the British Pharmacopoeia (BP), and the U.S. Food and Drug Administration.

[0294] (Administrative (www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications, e.g., Inactive Ingredient Guide (1996), Ash and Ash, Eds. (2002) Handbook of Pharmaceutical Additives, Synapse Information Resources, Inc., Endicott NY, etc.)

[0149] Pharmaceutical dosage forms of the compounds of the present invention may be produced by any of the methods well known in the art, such as conventional mixing, sieving, dissolution, melting, granulation, sugar formulation, tableting, suspension, extrusion, spray drying, powdering, emulsification, (nano / micro)encapsulation, encapsulation, or freeze-drying processes. As described above, the compositions of the present invention may contain one or more physiologically acceptable inactive components that facilitate the processing of the active molecule into preparations for pharmaceutical use.

[0295] Appropriate formulation depends on the desired route of administration. For intravenous injection, for example, the composition may be formulated in aqueous solution as needed, using physiologically compatible buffers, such as phosphates, histidine, or citrates, to adjust the formulation pH, and isotonic agents such as sodium chloride or dextrose. For transmucosal or nasal administration, semi-solid, liquid formulations, or patches, possibly containing an osmotic enhancer, are preferred. Such osmotic enhancers are commonly 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. Suitable dosage forms for oral intake by the subject include tablets, pills, sugars, hard and soft-shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions. The compound may also be formulated into rectal compositions such as suppositories or retained enemas, containing conventional suppository bases such as cocoa butter or other glycerides.

[0296] Solid oral dosage forms can be obtained using excipients, which may include fillers, disintegrants, binders (drying and wetting), dissolution retarders, lubricants, flow promoters, antiadherants, 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 (cured), and waxes. Ethanol and water may serve as granulation aids. In certain cases, for example, coating tablets with taste-masking films, acid-resistant films, or release-delay films is desirable. Natural and synthetic polymers are often used in combination with colorants, sugars, and organic solvents or water to coat tablets, resulting in the production of sugar tablets. When capsules are preferred over tablets, drug powders, suspensions, or solutions thereof can be delivered in suitable hard or soft-shell capsules.

[0297] In one embodiment, the compounds of the present invention can be administered topically via skin patches, semi-solids, or liquid formulations, such as gels, (micro)emulsions, ointments, solutions, (nano / micro)suspensions, or foams. The penetration of the drug into the skin and subcutaneous tissues can be regulated by the use of complexing agents, by pH adjustment, by appropriate selection and combination of lipophilic, hydrophilic, and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, and emulsifiers, for example, by using penetration enhancers. Skin penetration of the compounds of the present invention can be regulated using other techniques, such as iontophoresis. Transdermal or topical administration is preferred, for example, in situations where topical delivery with minimal systemic exposure is desirable.

[0298] For administration by inhalation or nasal administration, the compounds for use according to the present invention are conveniently delivered in the form of solutions, suspensions, emulsions, or semi-solid aerosols from a pressurized pack or nebulizer, usually using a propellant such as a halide carbon derived from methane and ethane, carbon dioxide, or any other suitable gas. For topical aerosols, hydrocarbons such as butane, isobutene, and pentane are useful. In the case of pressurized aerosols, the appropriate dosage unit can be determined by providing a valve for delivering a measured amount. Capsules and cartridges, for example, of gelatin, may be formulated for use in inhalers or air delivery devices. These typically contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0299] Compounds and compositions formulated for parenteral administration by injection are typically sterile and can be presented in unit dosage forms, e.g., ampoules, syringes, injection pens, or multi-dose containers, the latter typically containing preservatives. Compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain compounding agents such as buffers, isotonic agents, viscosity enhancers, 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 oil, and / or organic cosolvents. In certain examples, such as lyophilized products or concentrates, parenteral formulations are reconstituted or diluted before administration. Depot formulations providing controlled or sustained release of the compounds of the present invention may comprise 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 those well known in the art, can act as controlled / sustained-release matrices. Other depot delivery systems may be presented in the form of implants and pumps that require incisions.

[0300] Suitable carriers for intravenous injection of the compounds of the present invention are well known in the art and include, for example, aqueous solutions containing a base such as sodium hydroxide for forming the ionized compound, sucrose or sodium chloride as an isotonic agent, and a buffer, such as a buffer containing phosphate or histidine. A co-solvent, such as polyethylene glycol, may be added. These aqueous systems are effective in dissolving the compounds of the present invention and provide low toxicity upon systemic administration. The ratios of the components of the solution system can be changed considerably without impairing the solubility and toxicity properties. Furthermore, the identity of the components can be changed. For example, low-toxicity surfactants such as polysorbate or poloxamer may be used, polyethylene glycol or other co-solvents may be used, biocompatible polymers such as polyvinylpyrrolidone may be added, or other sugars and polyols may be used instead of dextrose.

[0301] The therapeutically effective dose can be initially estimated using various techniques known in the art. The initial dose used in animal studies may be based on the effective concentration established in cell culture assays. For example, data obtained from animal studies and cell culture assays can be used to determine an appropriate dose range for human subjects. In certain embodiments, the compounds of the Disclosure are formulated for oral administration. Exemplary doses of the compounds of the Disclosure in pharmaceutical formulations for oral administration are about 0.5 to about 10 mg per kg of body weight of the subject. In some embodiments, the pharmaceutical formulation contains about 0.7 to about 5.0 mg per kg of body weight of the subject, or about 1.0 to about 2.5 mg per kg of body weight of the subject. Typical administration regimens for oral administration are administration of the pharmaceutical formulation for oral administration three times a week, twice a week, once a week, or daily.

[0302] The effective amount or therapeutic amount or dose of a drug, for example, a compound of the present invention, refers to the amount of the drug or compound that results in improvement of symptoms or extension 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 (lethal dose for 50% of the population) and ED50 (therapeutic effective dose for 50% of the population). The dose-to-toxicity ratio is the therapeutic index, which can be expressed as the LD50 / ED50 ratio. Drugs exhibiting a high therapeutic index are preferred.

[0303] The effective dose or therapeutic effective dose is the amount of compound or pharmaceutical composition that elicits a biological or medical response in a tissue, system, animal, or human, as determined by researchers, veterinarians, physicians, or other clinicians. The dose, in particular, falls within the range of circulating concentrations containing little to no toxicity ED50. The dose may vary within this range depending on the dosage form used and / or the route of administration utilized. The exact formulation, route of administration, dose, and administration interval should be selected according to methods known in the art, taking into account the details of the condition of the subject.

[0304] Dosage and administration intervals can be individually adjusted to provide the plasma level of the active portion sufficient to achieve the desired effect, i.e., the minimum effective concentration (MEC). The MEC varies for each compound but can be estimated, for example, from in vitro data and animal studies. The dose required to achieve the MEC depends on the individual characteristics and route of administration. In the case of topical administration or selective uptake, the effective topical concentration of the drug may not be related to the plasma concentration.

[0305] The amount of compound or composition administered may depend on various factors, including the sex, age, and weight of the person being treated, the severity of their suffering, the method of administration, and the judgment of the prescribing physician.

[0306] The compound and composition may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such packs or devices may include, for example, metal or plastic foil such as blister packs, or glass or rubber stoppers such as vials. The packs or dispenser devices may be accompanied by instructions for administration. Compositions containing the compound of the present invention, formulated in a suitable pharmaceutical carrier, may also be prepared, placed in appropriate containers, and labeled for the treatment of a specified condition.

[0307] These and other embodiments of the present invention will be readily conceivable and specifically contemplated by those skilled in the art in light of the disclosure herein. [Examples]

[0308] General method Most of the chemicals were purchased from Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other vendors.

[0309] 1 1H NMR or 19 The 1F NMR spectrum was recorded using a Bruker AVIII 400 or Bruker AVIII 500.

[0310] LCMS measurements were performed on an Agilent 1200 HPLC / 6100 SQ system under the following conditions:

[0311] Method A: Mobile phase: A: Water (0.01% TFA) B: Acetonitrile (0.01% TFA) Gradient phase: Increase from 5% B to 95% B within 1.4 minutes, and to 95% B in 1.6 minutes (total run time: 3 minutes); Flow rate: 2.3 mL / min; Column: SunFire C18, 4.6*50 mm, 3.5 μm; Column temperature: 50°C. Detector: ADC ELSD, DAD (214 nm and 254 nm), ES-API.

[0312] Method B: Mobile phase: A: Water (10 mM NH4HCO3) B: Acetonitrile; Gradient phase: 5% to 95% B in less than 1.5 min, 95% B in 1.5 min (total run time: 3 min); Flow rate: 2.0 mL / min; Column: XBridge C18, 4.6*50 mm, 3.5 μm; Column temperature: 40 °C. Detector: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).

[0313] General scheme for the synthesis of the compound of formula (I) The compound of formula (I) is prepared according to scheme A using commercially available materials. The reaction of a halogenated pyridine (compound a) with an oxidizing agent yields the N-oxidepyridine compound of compound (b). Cyanation of compound (b) provides compound (c). Cross-coupling of compound (c) with a boronic acid yields compound (e). Halogen substitution of compound (e) using benzyl alcohol provides compound (f). Nitrile hydrolysis of compound (f), followed by amide formation with an amino ester, yields the amide (compound (i)). Deprotection of the benzyl group provides the compound of formula (I), and subsequent saponification of the ester provides compound (j). [ka]

[0314] Synthesis of Exemplary Compounds Example 1: Preparation of Compound 1 3,5-Dichloro-4-methylpyridine 1-oxide [ka]

[0315] To a solution of 3,5-dichloro-4-methylpyridine (5.0 g, 30.8 mmol) in dichloromethane (70.0 mL), 3-chloroperoxybenzoic acid (8.12 g, 40.11 mmol, 85%) was added at 0°C. The mixture was stirred at room temperature for 18.0 hours, and potassium carbonate (4.42 g, 32.0 mmol) was added. The mixture was stirred for a further 1 hour, and the insoluble solid was filtered. The filtrate was concentrated to obtain 3,5-dichloro-4-methylpyridine 1-oxide (4.7 g, 26.4 mmol, yield 85.1%) as a white solid. LC-MS: m / z = 178.1 [M + H] + The retention time was 1.47 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0316] 3,5-Dichloro-4-methylpicolinonitrile [ka]

[0317] A mixture of 3,5-dichloro-4-methylpyridine 1-oxide (5.0 g, 28.4 mmol), trimethylsilyl cyanide (5.0 g, 40.3 mmol), and triethylamine (4.28 g, 42.3 mmol) in acetonitrile (90.0 mL) was stirred at 85°C for 24.0 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 3,5-dichloro-4-methylpicolinonitrile (4.96 g, 26.8 mmol, yield 94.5%) as a yellow oil. LC-MS: m / z = 187.2 [M + H] + , retention time 1.74 min (Method A).

[0318] 3-Chloro-5-(3-fluorophenyl)-4-methylpicolinonitrile [ka]

[0319] To a solution of 3,5-dichloro-4-methylpicolinonitrile (500 mg, 2.67 mmol), (3-fluorophenyl)boronic acid (374 mg, 2.67 mmol), and potassium carbonate (443 mg, 3.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78 mg, 0.11 mmol) in N,N-dimethylformamide / water (5.0 mL / 0.5 mL) was added. The mixture was stirred under nitrogen at 45°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-chloro-5-(3-fluorophenyl)-4-methylpicolinonitrile (400 mg, 1.63 mmol, yield 61%) as a yellow solid. LC-MS: m / z=247.1[M+H]+, retention time=1.83 min (Method A).

[0320] 3-(benzyloxy)-5-(3-fluorophenyl)-4-methylpicolinonitrile [ka]

[0321] To a solution of 3-chloro-5-(3-fluorophenyl)-4-methylpicolinonitrile (400.0 mg, 1.62 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (78 mg, 1.94 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (210 mg, 1.94 mmol) was added. The solution was stirred at 0°C for 1.0 hour and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 3-(benzyloxy)-5-(3-fluorophenyl)-4-methylpicolinonitrile (378 mg, 1.18 mmol, yield 73%) as a yellow solid. LC-MS: m / z=319.1[M+H]+, retention time=2.21 min (Method A).

[0322] 3-(benzyloxy)-5-(3-fluorophenyl)-4-methylpicolinic acid [ka]

[0323] A solution of 3-(benzyloxy)-5-(3-fluorophenyl)-4-methylpicolinonitrile (378 mg, 1.19 mmol) in ethanol (10.0 mL) was mixed with 5.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 5.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-5-(3-fluorophenyl)-4-methylpicolinic acid (340 mg, 1.01 mmol, yield 85%) as a white solid. LC-MS: m / z = 338.1 [M + H] + The retention time was 2.00 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0324] Ethyl (3-(benzyloxy)-5-(3-fluorophenyl)-4-methylpicolinoyl)glycinate [ka]

[0325] A mixture of 3-(benzyloxy)-5-(3-fluorophenyl)-4-methylpicolinic acid (170 mg, 0.50 mmol), ethyl glycinate hydrochloride (70 mg, 0.50 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (288 mg, 0.55 mmol), and triethylamine (254 mg, 2.52 mmol) in dichloromethane (5.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ethyl (3-(benzyloxy)-5-(3-fluorophenyl)-4-methylpicolinoyl)glycinate (200 mg, 0.47 mmol, yield 94%) as a white solid. LC-MS: m / z = 423.1 [M + H] + , retention time 2.15 min (Method A).

[0326] Ethyl (5-(3-fluorophenyl)-3-hydroxy-4-methylpicolinoyl)glycinate [ka]

[0327] A mixture of ethyl (3-(benzyloxy)-5-(3-fluorophenyl)-4-methylpicolinoyl)glycinate (200 mg, 0.47 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under a hydrogen atmosphere for 18.0 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycinate (150 mg, 0.45 mmol, yield 95%) as a yellow solid. LC-MS: m / z = 333.1 [M + H] + The retention time was 2.19 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0328] (5-(3-fluorophenyl)-3-hydroxy-4-methylpicolinoyl)glycine [ka]

[0329] To a solution of ethyl (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycinate (150 mg, 0.45 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL), lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain (5-(3-fluorophenyl)-3-hydroxy-4-methylpicolinoyl)glycine (24.0 mg, 0.06 mmol, yield 13%) as a white solid. LC-MS: m / z = 305.1 [M + H] + , retention time 4.37 min (Method A). 1 HNMR(400MHz,DMSO-d6)δ12.81(s,1H),9.38(t,J=5.9Hz,1H),8.06(s,1H),7.57 (dd,J=14.1,7.8Hz,1H),7.42-7.16(m,3H),4.01(d,J=6.1Hz,2H),2.16(s,3H).

[0330] Example 2: Preparation of Compound 2 3-Chloro-5-(3-methoxyphenyl)-4-methylpicolinonitrile [ka]

[0331] 3,5-Dichloro-4-methylpicolinonitrile (600 mg, 3.21 mmol), (3-methoxyphenyl)boronic acid (487.7 mg, 3.21 mmol), and potassium carbonate (531.34 mg, 3.85 mmol) were mixed with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (117.27 mg, 0.05 mmol) in N,N-dimethylformamide / water (2.0 mL / 0.2 mL). The mixture was stirred under nitrogen at 45°C for 12.0 hours and then cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-chloro-5-(3-methoxyphenyl)-4-methylpicolinonitrile (500 mg, 1.94 mmol, yield 61%) as a yellow solid. LC-MS: m / z = 259 [M+H] + , retention time 2.13 min (Method B).

[0332] 3-(benzyloxy)-5-(3-methoxyphenyl)-4-methylpicolinonitrile [ka]

[0333] To a solution of 3-chloro-5-(3-methoxyphenyl)-4-methylpicolinonitrile (500 mg, 1.94 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (100.8 mg, 2.52 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (172.1 mg, 2.52 mmol) was added. The solution was stirred at room temperature for 2.0 hours and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 3-(benzyloxy)-5-(3-methoxyphenyl)-4-methylpicolinonitrile (350 mg, 1.06 mmol, yield 54.6%) as a yellow solid. LC-MS: m / z = 331.0 [M + H] + , retention time 1.91 min (Method A).

[0334] 3-(benzyloxy)-5-(3-methoxyphenyl)-4-methylpicolinic acid [ka]

[0335] A solution of 3-(benzyloxy)-5-(3-methoxyphenyl)-4-methylpicolinonitrile (350 mg, 1.06 mmol in ethanol (10.0 mL)) was mixed with 5.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 3.0 hours, then cooled and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-5-(3-methoxyphenyl)-4-methylpicolinic acid (350 mg, 1.0 mmol, yield 94.61%) as a white solid. LC-MS: m / z = 350.0 [M + H] + The retention time was 1.38 minutes (Method B). The product was sufficiently pure and used directly in the next step.

[0336] Ethyl (3-(benzyloxy)-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycinate [ka]

[0337] A mixture of 3-(benzyloxy)-5-(3-methoxyphenyl)-4-methylpicolinic acid (180 mg, 0.52 mmol), ethyl glycinate hydrochloride (86.0 mg, 0.62 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (321.8 mg, 0.62 mmol), and triethylamine (260.5 mg, 2.58 mmol) in dichloromethane (5.0 mL) was stirred at room temperature for 12.0 hours. The reaction product was then prepared. The mixture was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ethyl (3-(benzyloxy)-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycinate (180 mg, 0.41 mmol, yield 79.76%) as a white solid. LC-MS: m / z = 435.0 [M + H] + , retention time 2.18 min (Method B).

[0338] Ethyl (3-hydroxy-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycinate [ka]

[0339] A mixture of ethyl (3-(benzyloxy)-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycinate (180 mg, 0.42 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred overnight under a hydrogen atmosphere. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (3-hydroxy-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycinate (180 mg, crude) as a yellow solid. LC-MS: m / z = 345.0 [M + H]+, retention time 1.88 min (Method A). The product was sufficiently pure and used directly in the next step.

[0340] (3-Hydroxy-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycine [ka]

[0341] To a solution of ethyl (3-hydroxy-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycinate (160 mg, 0.47 mmol) in tetrahydrofuran / water (10.0 mL / 4.0 mL), sodium hydroxide (160 mg, 4.0 mmol) was added. The mixture was stirred at 40°C for 12.0 hours and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain (3-hydroxy-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycine (62 mg, 0.20 mmol, yield 42%) as a white solid. LC-MS: m / z = 317.0 [M + H] + , retention time 4.40 min (Method A). 1 HNMR(400MHz,DMSO-d6)δ12.78(s,1H),9.37(t,J=6.0Hz,1H),8.05(s,1H),7.44(dd,J=10.1,6.1Hz,1H), 7.03(dt,J=7.4,3.8Hz,1H),6.99(dd,J=3.7,1.9Hz,2H),4.02(t,J=7.9Hz,2H),3.82(s,3H),2.17(s,3H).

[0342] Example 3: Preparation of Compound 3 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline [ka]

[0343] To a solution of 6-bromoisoquinoline (1.04 g, 5.0 mmol), bis(pinacolate)diborone (2.54 g, 10.0 mmol), and potassium acetate (1.96 g, 20.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (365 mg, 0.5 mmol) was added in 1,4-dioxane (15.0 mL). The mixture was stirred under nitrogen at 90°C for 2.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (0.79 g, 3.1 mmol, yield 62%) as a white solid. LC-MS: m / z = 256.0 [M + H] + , retention time 1.41 min (Method B).

[0344] 3-Chloro-5(isoquinoline-6-yl)-4-methylpicolinonitrile [ka]

[0345] To a solution of 3,5-dichloro-4-methylpicolinonitrile (400 mg, 2.16 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (550 mg, 2.16 mmol), and potassium carbonate (358 mg, 2.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (146 mg, 0.2 mmol) was added in N,N-dimethylformamide / water (5.0 mL / 0.5 mL). The mixture was stirred overnight at 45°C under nitrogen and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 3-chloro-5-(isoquinoline-6-yl)-4-methylpicolinonitrile (500 mg, 1.79 mmol, yield 83%) as a yellow solid. LC-MS: m / z = 280.0 [M + H] + , retention time 1.58 min (Method B).

[0346] 5-(isoquinoline-6-yl)-3-((4-methoxybenzyl)oxy)-4-methylpicolinonitrile [ka]

[0347] To a solution of 3-chloro-5-(isoquinoline-6-yl)-4-methylpicolinonitrile (500.0 mg, 1.79 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (86 mg, 2.15 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then (4-methoxyphenyl)methanol (296 mg, 2.15 mmol) was added. The solution was stirred at 0°C for 1.0 hour and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 5-(isoquinoline-6-yl)-3-((4-methoxybenzyl)oxy)-4-methylpicolinonitrile (250 mg, 0.66 mmol, yield 37%) as a yellow solid. LC-MS: m / z=382.1[M+H]+, retention time=2.21 min (Method A).

[0348] 3-Hydroxy-5(isoquinoline-6-yl)-4-methylpicolinic acid [ka]

[0349] A solution of 5-(isoquinoline-6-yl)-3-((4-methoxybenzyl)oxy)-4-methylpicolinonitrile (250 mg, 0.66 mmol) in ethanol (10.0 mL) was mixed with 30% aqueous sodium hydroxide solution (4.0 mL). The mixture was stirred at 100°C for 5.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinic acid (250 mg, crude) as a white solid. LC-MS: m / z = 401.1 [M + H] + The retention time was 2.00 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0350] Ethyl (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinoyl)glycinate [ka]

[0351] A mixture of 3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinic acid (250 mg, 0.62 mmol), ethyl glycinate hydrochloride (87 mg, 0.62 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (390 mg, 0.75 mmol), and triethylamine (254 mg, 2.52 mmol) in dichloromethane (5.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ethyl (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinoyl)glycinate (140 mg, 0.38 mmol, yield 43%) as a white solid. LC-MS: m / z = 366.1 [M + H] + , retention time 2.15 min (Method A).

[0352] (3-Hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinoyl)glycine [ka]

[0353] To a solution of ethyl (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinoyl)glycinate (140 mg, 0.38 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL), lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to obtain (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinoyl)glycine (72.6 mg, 0.22 mmol, yield 56%) as a white solid. LC-MS: m / z = 338.1 [M + H] + , retention time 2.28 min (Method A). 1 HNMR(500MHz,DMSO-d6)δ12.88(s,1H),9.71(s,1H),9.45(t,J=6.0Hz,1H),8.68(d,J=6.1Hz,1H),8.47(d,J=8.5Hz,1 H),8.27(s,1H),8.24(d,J=6.1Hz,1H),8.19(s,1H),7.95(dd,J=8.5,1.4Hz,1H),4.04(d,J=6.1Hz,2H),2.20(s,3H).

[0354] Example 4: Preparation of Compound 4 3-Chloro-4-methyl-5(1-phenyl-1H-pyrazole-4-yl)picolinonitrile [ka]

[0355] To a solution of 3,5-dichloro-4-methylpyridine-2-carbonitrile (550 mg, 2.96 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (800 mg, 2.96 mmol), and potassium carbonate (490 mg, 3.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (86.5 mg, 0.12 mmol) in N,N-dimethylformamide / water (10.0 mL / 1.0 mL) was added. The mixture was stirred under nitrogen at 50°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-chloro-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinonitrile (400 mg, 1.36 mmol, yield 46%) as a yellow solid. LC-MS: m / z = 295.3 [M + H]+, retention time = 1.909 min (Method A).

[0356] 3-(benzyloxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinonitrile [ka]

[0357] To a solution of 3-chloro-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinonitrile (600.0 mg, 2.04 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (90 mg, 2.24 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (220.2 mg, 2.04 mmol) was added. The solution was stirred at 0°C for 1.0 hour and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 3-(benzyloxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinonitrile (300 mg, 0.82 mmol, yield 40.2%) as a yellow solid. LC-MS: m / z = 367.1 [M + H]+, retention time = 2.20 min (Method A).

[0358] 3-(benzyloxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinic acid [ka]

[0359] A solution of 3-(benzyloxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinonitrile (300 mg, 0.82 mmol) in ethanol (5.0 mL) was mixed with 5.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 5.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinic acid (290 mg, 0.75 mmol, yield 91.4%) as a white solid. LC-MS: m / z = 386.4 [M + H] + The retention time was 1.74 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0360] Ethyl (3-(benzyloxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycinate [ka]

[0361] A mixture of 3-(benzyloxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinic acid (290 mg, 0.75 mmol), ethyl glycinate hydrochloride (104 mg, 0.75 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (430 mg, 0.83 mmol), and triethylamine (380 mg, 3.75 mmol) in dichloromethane (8.0 mL) was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ethyl (3-(benzyloxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl) glycinate (200 mg, 0.42 mmol, yield 56.5%) as a yellow solid. LC-MS: m / z = 471.1 [M+H] + , retention time 2.13 min (Method A).

[0362] Ethyl (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycinate [ka]

[0363] A mixture of ethyl (3-(benzyloxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl) glycinate (200 mg, 0.42 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under a hydrogen atmosphere for 18 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl) glycinate (150 mg, 0.39 mmol, yield 94%) as a white solid. LC-MS: m / z = 381.0 [M + H] + The retention time was 2.16 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0364] (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine [ka]

[0365] A solution of ethyl (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycinate (150 mg, 0.39 mmol) in tetrahydrofuran / water (6.0 mL / 3.0 mL) was mixed with lithium hydroxide monohydrate (164 mg, 4.0 mmol). The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine (121.6 mg, 0.35 mmol, yield 88.5%) as a white solid. LC-MS: m / z = 353.1 [M + H] + , retention time 4.534 minutes (Method A). 1HNMR(500MHz,DMSO-d6)δ12.80(s,1H),9.32(t,J=6.1Hz,1H),8.94(s,1H),8.33(s,1H),8.19(s,1H),7 .94(d,J=7.8Hz,2H),7.55(t,J=7.9Hz,2H),7.37(t,J=7.4Hz,1H),4.01(d,J=6.1Hz,2H),2.38(s,3H).

[0366] Example 5: Preparation of Compound 5 2-Methyl-6(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline [ka]

[0367] To a solution of 6-bromo-2-methylquinoline (2.0 g, 9.01 mmol), bis(pinacolate)diborone (2.6 g, 10.28 mmol), and potassium acetate (2.65 g, 27 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (660 mg, 0.9 mmol) in 1,4-dioxane (15.0 mL) was added. The mixture was stirred under nitrogen at 100 °C for 2.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. Crude 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (2.1 g, 7.81 mmol, yield 87.5%) was obtained. LC-MS: m / z = 270.2 [M + H] + The retention time was 2.08 minutes (Method B). The product was used directly in the next step.

[0368] 3-Chloro-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile [ka]

[0369] To a solution of 3,5-dichloro-4-methylpyridine-2-carbonitrile (1.2 g, 6.42 mmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (1.73 g, 6.42 mmol), and potassium carbonate (1.16 g, 7.70 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (234.5 mg, 0.32 mmol) was added in N,N-dimethylformamide / water (10.0 mL / 1.0 mL). The mixture was stirred overnight at 45°C under nitrogen and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 3-chloro-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile (900 mg, 3.07 mmol, yield 47.9%) as a yellow solid. LC-MS: m / z = 294.0 [M + H] + , retention time 1.61 min (Method A).

[0370] 3-((4-methoxybenzyl)oxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile [ka]

[0371] To a solution of 3-chloro-5-(isoquinoline-6-yl)-4-methylpicolinonitrile (500 mg, 1.71 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (95.6 mg, 2.39 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then (4-methoxyphenyl)methanol (329.7 mg, 2.39 mmol) was added. The solution was stirred at 0°C for 2.0 hours and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-((4-methoxybenzyl)oxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile (400 mg, 1.01 mmol, yield 59.2%) as a yellow solid. LC-MS: m / z = 396.0 [M+H] + , retention time 1.49 min (Method A).

[0372] 3-Hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid [ka]

[0373] A solution of 3-((4-methoxybenzyl)oxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile (400 mg, 0.47 mmol) in ethanol (10.0 mL) was mixed with 30% aqueous sodium hydroxide solution (4.0 mL). The mixture was stirred at 100°C for 5.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid (400 mg, crude) as a white solid. LC-MS: m / z = 295.2 [M + H] + The retention time was 1.15 minutes (Method B). The product was sufficiently pure and used directly in the next step.

[0374] Ethyl (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinoyl)glycinate [ka]

[0375] A mixture of 3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid (200.0 mg, 0.68 mmol), ethyl glycinate hydrochloride (113.5 mg, 0.82 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (424.5 mg, 0.82 mmol), and triethylamine (343.5 mg, 3.40 mmol) in dichloromethane (10.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain ethyl (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinoyl)glycinate (120 mg, 0.32 mmol, yield 47.1%) as a white solid. LC-MS: m / z = 380.1 [M + H] + , retention time 1.60 min (Method A).

[0376] (3-Hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinoyl)glycine [ka]

[0377] To a solution of ethyl (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinoyl)glycinate (120 mg, 0.33 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL), lithium hydroxide monohydrate (140 mg, 3.3 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to obtain (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinoyl)glycine (5.9 mg, 0.017 mmol, 5.09%) as a white solid. LC-MS: m / z = 352.1 [M + H] + , retention time 2.05 min (Method B). 1 HNMR(400MHz,DMSO-d6)δ9.04(s,1H),8.32(d,J=8.4Hz,1H),8.15(s,1H),8.03(d,J=8.8Hz,2H) ,7.78(d,J=8.6Hz,1H),7.50(d,J=8.4Hz,1H),3.72(d,J=4.3Hz,2H),2.70(s,3H),2.20(s,3H).

[0378] Example 6: Preparation of Compound 6 tert-butyl 4-(4-(5-chloro-6-cyano-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate [ka]

[0379] To a solution of 3,5-dichloro-4-methylpyridine-2-carbonitrile (561 mg, 3.0 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (1.13 mg, 3.0 mmol), and potassium carbonate (497 mg, 3.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (110 mg, 0.15 mmol) was added in N,N-dimethylformamide / water (10.0 mL / 1.0 mL). The mixture was stirred under nitrogen at 50°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain tert-butyl 4-(4-(5-chloro-6-cyano-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (400 mg, 1.0 mmol, yield 33%) as a yellow solid. LC-MS: m / z = 346.2 [M-56] + , retention time = 2.078 min (method A).

[0380] tert-butyl 4-(4-(5-(benzyloxy)-6-cyano-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate [ka]

[0381] To a solution of tert-butyl 4-(4-(5-chloro-6-cyano-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (600 mg, 1.49 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (72 mg, 1.79 mmol, 60% w / w dispersion in mineral oil) was added at 0°C under nitrogen. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (194 mg, 1.79 mmol) was added. The solution was stirred at 0°C for 1.0 hour and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain tert-butyl 4-(4-(5-(benzyloxy)-6-cyano-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (330 mg, 0.70 mmol, yield 46%) as a yellow solid. LC-MS: m / z = 474.0 [M + H] + , retention time = 2.21 min (method A).

[0382] 3-(benzyloxy)-5-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazole-4-yl)-4-methylpicolinic acid [ka]

[0383] To a solution of tert-butyl 4-(4-(5-(benzyloxy)-6-cyano-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (330 mg, 0.70 mmol) in ethanol (15.0 mL), 5.0 mL of 30% aqueous sodium hydroxide solution was added. The mixture was stirred at 100°C for 1.0 hour, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH = 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-5-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazole-4-yl)-4-methylpicolinic acid (330 mg, 0.33 mmol, yield 96%) as a white solid. LC-MS: m / z = 493.2 [M + H] + The retention time was 1.97 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0384] tert-butyl4-(4-(5-(benzyloxy)-6-((2-ethoxy-2-oxoethyl)carbamoyl)-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate [ka]

[0385] A mixture of 3-(benzyloxy)-5-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazole-4-yl)-4-methylpicolinic acid (165 mg, 0.33 mmol), ethyl glycinate hydrochloride (47 mg, 0.33 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (192 mg, 0.37 mmol), and triethylamine (167 mg, 1.67 mmol) in dichloromethane (10.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl 4-(4-(5-(benzyloxy)-6-((2-ethoxy-2-oxoethyl)carbamoyl)-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (165 mg, 0.29 mmol, yield 85%) as a white solid. LC-MS: m / z = 578.0 [M + H] + , retention time 2.14 min (Method A).

[0386] tert-butyl4-(4-(6-((2-ethoxy-2-oxoethyl)carbamoyl)-5-hydroxy-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate [ka]

[0387] A mixture of tert-butyl 4-(4-(5-(benzyloxy)-6-((2-ethoxy-2-oxoethyl)carbamoyl)-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (165 mg, 0.29 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under a hydrogen atmosphere for 18.0 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain tert-butyl 4-(4-(6-((2-ethoxy-2-oxoethyl)carbamoyl)-5-hydroxy-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (135 mg, 0.27 mmol, yield 97%) as a yellow solid. LC-MS: m / z = 460.1 [M + H] + The retention time was 2.19 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0388] (5-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazole-4-yl)-3-hydroxy-4-methylpicolinoyl)glycine [ka]

[0389] To a solution of tert-butyl 4-(4-(6-((2-ethoxy-2-oxoethyl)carbamoyl)-5-hydroxy-4-methylpyridine-3-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (135 mg, 0.27 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL), lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH=3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, dried, and (5-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazole-4-yl)-3-hydroxy-4-methylpicoli Noylglycine (85.5 mg, 0.18 mmol, 67% yield) was obtained as a white solid.

[0390] L C-MS: m / z = 502.1 [M + H] + , retention time 5.33 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ12.75(s,1H),9.62-9.10(m,1H),8.28(s,1H),8.23(s,1H) ,7.88(s,1H),4.56-4.30(m,1H),4.15-4.03(m,2H),4.00(d,J=6.1Hz,2H),2.93(br s, 2H), 2.29 (d, J=8.5Hz, 3H), 2.14-2.00 (m, 2H), 1.92-1.77 (m, 2H), 1.43 (s, 9H).

[0391] Example 7: Preparation of Compound 7 2-Phenyl-5(tributylstannyl)thiazole [ka]

[0392] To a solution of 2-phenylthiazole (10.0 g, 62.03 mmol) in anhydrous tetrahydrofuran (200.0 mL), n-butyllithium (30.98 mL, 77.54 mmol, 2.5 M in hexane) was added under nitrogen at -78°C. The mixture was stirred at -78°C for 30 minutes, and then chlorotributyltin (20.8 mL, 71.34 mmol) was added. The mixture was heated to 0°C and stirred for a further 1 hour. The reaction product was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 2-phenyl-5-(tributylstannyl)thiazole (27.7 g, 61.6 mmol, 99% yield) as a yellow solid. LC-MS: m / z = 451.2 [M + H] + , retention time 2.30 min (Method A).

[0393] 3-Chloro-4-methyl-5-(2-phenylthiazole-5-yl)picolinonitrile [ka]

[0394] To a solution of 3,5-dibromo-4,6-dimethylpicolinonitrile (2.9 g, 15.55 mmol), 2-phenyl-5-(tributylstannyl)thiazole (5.0 g, 11.10 mmol), cesium fluoride (5.06 g, 33.31 mmol), and copper iodide (423 mg, 2.22 mmol) in N,N-dimethylformamide (20.0 mL), tetrakis(triphenylphosphine)palladium (1.28 g, 1.11 mmol) was added. The mixture was stirred under nitrogen at 40°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-chloro-4-methyl-5-(2-phenylthiazole-5-yl)picolinonitrile (150 mg, 0.48 mmol, yield 10%) as a green solid. LC-MS: m / z = 312.1 [M + H] + , retention time = 1.909 min (method A).

[0395] 3-Hydroxy-4-methyl-5-(2-phenylthiazole-5-yl)picolinonitrile [ka]

[0396] Benzyl alcohol (780 mg, 7.22 mmol) was added to a solution of 3-chloro-4-methyl-5-(2-phenylthiazole-5-yl)picolinonitrile (1.50 g, 4.81 mmol) and potassium carbonate (2.0 g, 14.43 mmol) in N,N-dimethylacetamide (10.0 mL). The mixture was stirred at 120 °C for 2 days (2.0 d) and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC to obtain 3-hydroxy-4-methyl-5-(2-phenylthiazole-5-yl)picolinonitrile (200 mg, 0.68 mmol, yield 14%) as a white solid. LC-MS: m / z = 294.1 [M + H] + , retention time = 1.40 min (method A).

[0397] 3-Hydroxy-4-methyl-5-(2-phenylthiazole-5-yl)picolinic acid [ka]

[0398] A solution of 3-hydroxy-4-methyl-5-(2-phenylthiazole-5-yl)picolinonitrile (200 mg, 0.68 mmol) in ethanol (10.0 mL) was mixed with 30% aqueous sodium hydroxide solution (3.0 mL). The mixture was stirred at 100°C for 3.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-hydroxy-4-methyl-5-(2-phenylthiazole-5-yl)picolinic acid (200 mg, 0.64 mmol, yield 94%) as a white solid. LC-MS: m / z = 313.4 [M + H] + The retention time was 1.74 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0399] Ethyl (3-hydroxy-4-methyl-5-(2-phenylthiazole-5-yl)picolinoyl)glycinate [ka]

[0400] A mixture of 3-hydroxy-4-methyl-5-(2-phenylthiazole-5-yl)picolinic acid (200 mg, 0.64 mmol), ethyl glycinate hydrochloride (150 mg, 1.08 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (420 mg, 0.77 mmol), and triethylamine (380 mg, 3.75 mmol) in dichloromethane (20.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain ethyl (3-hydroxy-4-methyl-5-(2-phenylthiazole-5-yl)picolinoyl)glycinate (140 mg, 0.35 mmol, yield 55%) as a white solid. LC-MS: m / z = 398.1 [M + H] + , retention time 2.13 min (Method A).

[0401] (3-Hydroxy-4-methyl-5-(2-phenylthiazole-5-yl)picolinoyl)glycine [ka]

[0402] A solution of ethyl (3-hydroxy-4-methyl-5-(2-phenylthiazole-5-yl)picolinoyl)glycinate (140 mg, 0.35 mmol) in tetrahydrofuran / water (8.0 mL / 4.0 mL) was mixed with lithium hydroxide monohydrate (164 mg, 4.0 mmol). The mixture was stirred overnight at 40°C and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain (3-hydroxy-4-methyl-5-(2-phenylthiazole-5-yl)picolinoyl)glycine (106.6 mg, yield 82%) as a white solid. LC-MS: m / z = 370.0 [M + H] + , retention time 4.92 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ12.91(s,1H),9.41(t,J=6.1Hz,1H),8.31(s,1H),8.21( s, 1H), 8.12-7.87 (m, 2H), 7.78-7.38 (m, 3H), 4.02 (d, J=6.1Hz, 2H), 2.38 (s, 3H).

[0403] Example 8: Preparation of Compound 8 4,4,5,5-Tetramethyl-2-(3-phenoxyphenyl)-1,3,2-dioxaborolane [ka]

[0404] To a solution of 1-bromo-3-phenoxybenzene (1.5 g, 6.02 mmol), bis(pinacolate)diborone (3.06 g, 12.04 mmol), and potassium acetate (2.36 g, 24.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (438 mg, 0.6 mmol) in 1,4-dioxane (15.0 mL) was added. The mixture was stirred under nitrogen at 90°C for 2.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. Crude 4,4,5,5-tetramethyl-2-(3-phenoxyphenyl)-1,3,2-dioxaborolane (1.0 g, 3.37 mmol, yield 56.1%) was obtained. LC-MS: m / z = 297.0 [M + H] + The product was used directly in the next step after a retention time of 2.41 minutes (Method B).

[0405] 3-Chloro-4-methyl-5-(3-phenoxyphenyl)picolinonitrile [ka]

[0406] To a solution of 3,5-dichloro-4-methylpyridine-2-carbonitrile (626 mg, 3.37 mmol), 4,4,5,5-tetramethyl-2-(3-phenoxyphenyl)-1,3,2-dioxaborolane (1.0 g, 3.37 mmol), and potassium carbonate (697 mg, 5.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (123 mg, 0.17 mmol) was added in N,N-dimethylformamide / water (10.0 mL / 1.0 mL). The mixture was stirred overnight at 50°C under nitrogen and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 3-chloro-4-methyl-5-(3-phenoxyphenyl)picolinonitrile (450 mg, 1.41 mmol, yield 41.7%) as a yellow solid. LC-MS: m / z = 321.0 [M+H] + , retention time 2.30 min (Method A).

[0407] 3-(benzyloxy)-4-methyl-5-(3-phenoxyphenyl)picolinonitrile [ka]

[0408] To a solution of 3-chloro-4-methyl-5-(3-phenoxyphenyl)picolinonitrile (450 mg, 1.41 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (113 mg, 2.82 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (152 mg, 1.41 mmol) was added. The solution was stirred at 0°C for 1.0 hour and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-(benzyloxy)-4-methyl-5-(3-phenoxyphenyl)picolinonitrile (350 mg, 0.89 mmol, yield 63.3%) as a yellow solid. LC-MS: m / z = 352.0 [M + H] + , retention time 1.70 min (Method A).

[0409] 3-(benzyloxy)-4-methyl-5-(3-phenoxyphenyl)picolinic acid [ka]

[0410] A solution of 3-(benzyloxy)-4-methyl-5-(3-phenoxyphenyl)picolinonitrile (350 mg, 0.89 mmol) in ethanol (10.0 mL) was mixed with 4.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred overnight at 100°C, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-4-methyl-5-(3-phenoxyphenyl)picolinic acid (300 mg, 0.73 mmol, yield 82.0%) as a white solid. LC-MS: m / z = 393.0 (M + H) + The retention time was 2.35 minutes (Method B). The product was sufficiently pure and used directly in the next step.

[0411] Ethyl (3-(benzyloxy)-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycinate [ka]

[0412] A mixture of 3-(benzyloxy)-4-methyl-5-(3-phenoxyphenyl)picolinic acid (300 mg, 0.73 mmol), ethyl glycinate hydrochloride (152 mg, 1.09 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (456 mg, 0.88 mmol), and triethylamine (370 mg, 3.65 mmol) in dichloromethane (10.0 mL) was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain ethyl (3-(benzyloxy)-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycinate (210 mg, 0.42 mmol, yield 58.0%) as a white solid. LC-MS: m / z = 497.0 (M + H) + , retention time 2.26 min (Method A).

[0413] Ethyl (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycinate [ka]

[0414] A mixture of ethyl (3-(benzyloxy)-4-methyl-5-(3-phenoxyphenyl)picolinoyl) glycinate (210 mg, 0.42 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred at 40°C for 5.0 hours under a hydrogen atmosphere. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)picolinoyl) glycinate (140 mg, 0.34 mmol, yield 81%) as a yellow solid. LC-MS: m / z = 407.0 (M + H) + The retention time was 2.32 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0415] (3-Hydroxy-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycine [ka]

[0416] A solution of ethyl (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycinate (140 mg, 0.34 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL) was mixed with lithium hydroxide monohydrate (164 mg, 4.0 mmol). The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to obtain (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycine (38.7 mg, 0.10 mmol, yield 30%) as a white solid. LC-MS: m / z = 379.0 [M + H] + , retention time 5.76 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ12.82(s,1H),9.46-9.14(m,1H),8.05(s,1H),7.53(t,J=8.0Hz,1H) ,7.47-7.38(m,2H),7.25-7.14(m,2H),7.13-7.04(m,4H),3.96(d,J=6.0Hz,2H),2.16(s,3H).

[0417] Example 9: Preparation of Compound 9 5-Chloro-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonitrile [ka]

[0418] To a solution of 3,5-dichloro-4-methylpyridine-2-carbonitrile (500.00 mg, 2.67 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (730.03 mg, 2.67 mmol), and potassium carbonate (443.41 mg, 3.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78.25 mg, 0.11 mmol) in N,N-dimethylformamide / water (10.0 mL / 1.0 mL) was added. The mixture was stirred overnight at 50°C under nitrogen and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 5-chloro-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonitrile (577 mg, 1.94 mmol, yield 72%) as a yellow solid. LC-MS: m / z = 298 [M+H] + , retention time 2.052 minutes (Method A).

[0419] 5-(benzyloxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonitrile [ka]

[0420] To a solution of 5-chloro-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonitrile (500.00 mg, 1.68 mmol) in N,N-dimethylformamide (20.0 mL), sodium hydride (80.8 mg, 2.02 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (217.97 mg, 2.02 mmol, 0.21 mL) was added. The solution was stirred at 0°C for 50 minutes and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 5-(benzyloxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonitrile (306 mg, yield 49%). LC-MS: m / z = 370 [M+H] + , retention time 2.190 min (method B).

[0421] 5-(benzyloxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxylic acid [ka]

[0422] A solution of 5-(benzyloxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonitrile (306.00 mg, 0.83 mmol) in ethanol (10.0 mL) was mixed with 4.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 3.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 5-(benzyloxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxylic acid (353 mg, crude) as a white solid. LC-MS: m / z = 389 [M + H] + The retention time was 1.977 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0423] Ethyl (5-(benzyloxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycinate [ka]

[0424] 5-(benzyloxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxylic acid (300.00 mg, 0.77 mmol) in dichloromethane (20.0 mL), glycy N'e A mixture of tyl hydrochloride (107.83 mg, 0.77 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (442.21 mg, 0.85 mmol), and triethylamine (390.85 mg, 3.86 mmol, 0.54 mL) was stirred overnight at room temperature. 。 The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain ethyl (5-(benzyloxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycinate (257 mg, 0.54 mmol, 70% yield). LC-MS: m / z = 474 [M+H] + , retention time 1.810 min (method A).

[0425] Ethyl (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycinate [ka]

[0426] A mixture of ethyl (5-(benzyloxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl) glycinate (230.00 mg, 0.49 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl) glycinate (230 mg, crude) as a yellow solid. LC-MS: m / z = 384 [M + H] + The retention time was 2.116 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0427] (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine [ka]

[0428] To a solution of ethyl (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycinate (200.00 mg, 0.52 mmol) in methanol / water (10.0 mL / 2.0 mL), lithium hydroxide monohydrate (219 mg, 5.22 mmol) was added. The mixture was stirred overnight at 40°C and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to obtain (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine (formate) (48.2 mg, 0.14 mmol, yield 26%) as a yellow solid. LC-MS: m / z = 356 [M + H] + , retention time 4.420 min (method A). 1H NMR(500MHz,DMSO-d6)δ12.88(br,2H),9.43(t,J=6.0Hz,1H),8.90(d,J=1.5Hz,1H),8.24(dd, J=8.5Hz,J=2.0Hz,1H),8.16(s,1H),8.07(d,J=7.5Hz,1H),4.01(d,J=6.0Hz,2H),2.18(s,3H).

[0429] Example 10: Preparation of Compound 10 5-Chloro-4-methyl-[3,3'-bipyridine]-6-carbonitrile [ka]

[0430] To a solution of 3,5-dichloro-4-methylpyridine-2-carbonitrile (500 mg, 2.67 mmol), pyridine-3-ylboronic acid (329 mg, 2.67 mmol), and potassium carbonate (443 mg, 3.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78 mg, 0.11 mmol) in N,N-dimethylformamide / water (5.0 mL / 0.5 mL) was added. The mixture was stirred overnight at 45°C under nitrogen and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 5-chloro-4-methyl-[3,3'-bipyridine]-6-carbonitrile (300 mg, 1.31 mmol, yield 49%) as a yellow solid. LC-MS: m / z = 230.1 [M + H] + , retention time = 1.83 min (method A).

[0431] 5-(benzyloxy)-4-methyl-[3,3'-bipyridine]-6-carbonitrile [ka]

[0432] To a solution of 5-chloro-4-methyl-[3,3'-bipyridine]-6-carbonitrile (300.0 mg, 1.31 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (78 mg, 1.94 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (152 mg, 1.41 mmol) was added. The solution was stirred at 0°C for 1.0 hour and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 5-(benzyloxy)-4-methyl-[3,3'-bipyridine]-6-carbonitrile (300 mg, 0.99 mmol, yield 76%) as a yellow solid. LC-MS: m / z = 302.1 [M + H] + , retention time = 2.21 min (method A).

[0433] 5-(benzyloxy)-4-methyl-[3,3'-bipyridine]-6-carboxylic acid [ka]

[0434] A solution of 5-(benzyloxy)-4-methyl-[3,3'-bipyridine]-6-carbonitrile (300 mg, 0.99 mmol) in ethanol (10.0 mL) was mixed with 4.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 3.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 5-(benzyloxy)-4-methyl-[3,3'-bipyridine]-6-carboxylic acid (300 mg, 0.94 mmol, yield 94%) as a white solid. LC-MS: m / z = 321.1 [M + H] + The retention time was 2.00 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0435] Ethyl (5-(benzyloxy)-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycinate [ka]

[0436] A mixture of 5-(benzyloxy)-4-methyl-[3,3'-bipyridine]-6-carboxylic acid (300 mg, 0.94 mmol), ethyl glycinate hydrochloride (144 mg, 1.03 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (536 mg, 1.03 mmol), and triethylamine (473 mg, 4.68 mmol) in dichloromethane (10.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ethyl (5-(benzyloxy)-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycinate (240 mg, 0.59 mmol, yield 63%) as a white solid. LC-MS: m / z = 406.1 [M + H] + , retention time 2.15 min (Method A).

[0437] Ethyl (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycinate [ka]

[0438] A mixture of ethyl (5-(benzyloxy)-4-methyl-[3,3'-bipyridine]-6-carbonyl) glycinate (240 mg, 0.59 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred at room temperature under a hydrogen atmosphere for 18.0 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl) glycinate (185 mg, 0.59 mmol, 99% yield) as a white solid. LC-MS: m / z = 316.1 [M + H] + The retention time was 2.19 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0439] (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine [ka]

[0440] A solution of ethyl (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycinate (185 mg, 0.59 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL) was mixed with lithium hydroxide monohydrate (164 mg, 4.0 mmol). The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to obtain (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine (formate) (34.0 mg, 0.118 mmol, yield 20%) as a white solid. LC-MS: m / z = 288.1 [M + H] + , retention time 2.20 min (method A). 1 HNMR(400MHz,DMSO-d6)δ12.83(s,2H),9.41(t,J=6.1Hz,1H),8.84-8.50(m,2H),8.13(s,1 H),8.10(s,1H),8.04-7.81(m,1H),7.73-7.41(m,1H),4.01(d,J=6.1Hz,2H),2.17(s,3H).

[0441] Example 11: Preparation of Compound 11 5-Chloro-4-methyl-[3,4'-bipyridine]-6-carbonitrile [ka]

[0442] To a solution of 3,5-dichloro-4-methylpyridine-2-carbonitrile (500.00 mg, 2.67 mmol), pyridine-4-ylboronic acid (328.63 mg, 2.67 mmol), and potassium carbonate (443.41 mg, 3.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78.25 mg, 0.11 mmol) in N,N-dimethylformamide / water (10.0 mL / 1.0 mL) was added. The mixture was stirred under nitrogen at 50°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 5-chloro-4-methyl-[3,4'-bipyridine]-6-carbonitrile (292 mg, 1.27 mmol, yield 48%). LC-MS: m / z = 230 [M+H] + , retention time 1.599 minutes (Method A).

[0443] 5-(benzyloxy)-4-methyl-[3,4'-bipyridine]-6-carbonitrile [ka]

[0444] To a solution of 5-chloro-4-methyl-[3,4'-bipyridine]-6-carbonitrile (250.00 mg, 1.09 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (52.3 mg, 1.31 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (141.25 mg, 1.31 mmol, 0.14 mL) was added. The solution was stirred at 0°C for 50 minutes and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 5-(benzyloxy)-4-methyl-[3,4'-bipyridine]-6-carbonitrile (86 mg, 0.29 mmol, yield 26%). LC-MS: m / z = 302[M+H] + , retention time 1.895 minutes (Method B).

[0445] 5-Hydroxy-4-methyl-[3,4'-bipyridine]-6-carboxylic acid [ka]

[0446] A solution of 35-(benzyloxy)-4-methyl-[3,4'-bipyridine]-6-carbonitrile (86.00 mg, 0.29 mmol) in ethanol (5.0 mL) was mixed with 4.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 3.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carboxylic acid (160 mg, crude) as a white solid. LC-MS: m / z = 231 [M + H] + The retention time was 1.020 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0447] Ethyl (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycinate [ka]

[0448] A mixture of 5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carboxylic acid (130.00 mg, 0.56 mmol), ethyl glycinate hydrochloride (78.82 mg, 0.56 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (323.24 mg, 0.62 mmol), and triethylamine (285.70 mg, 2.82 mmol, 0.4 mL) in dichloromethane (10.0 mL) is heated at room temperature. The mixture was stirred overnight. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 2) to obtain ethyl (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycinate (36 mg, 0.114 mmol, 20% yield). LC-MS: m / z = 316 [M+H] + , retention time 1.586 min (Method A).

[0449] (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycine [ka]

[0450] To a solution of ethyl (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycinate (30.00 mg, 0.10 mmol) in methyl / water (4.0 mL / 1.0 mL), lithium hydroxide monohydrate (22.79 mg, 0.95 mmol) was added. The mixture was stirred at 40°C for 16.0 hours and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycine (13.2 mg, yield 46%) as a white solid. LC-MS: m / z = 288 [M + H] + , retention time 2.159 minutes (Method A). 1 H NMR(500MHz,DMSO-d6)δ12.85(br,2H),9.42(s,1H),8.72(dd,J=4.5Hz,J=1.5Hz,2H ),8.08(s,1H),7.51(dd,J=4.0Hz,J=1.5Hz,2H),4.01(d,J=6.0Hz,2H),2.17(s,3H).

[0451] Example 12: Preparation of Compound 12 5'-Chloro-4'-methyl-[2,3'-bipyridine]-6'-Carbonitrile [ka]

[0452] To a solution of 3,5-dibromo-4,6-dimethylpicolinonitrile (1.86 g, 10 mmol), 2-(tributylstannyl)pyridine (4.42 g, 12 mmol), cesium fluoride (302 mg, 2.0 mmol), and copper iodide (380 mg, 2.0 mmol) in N,N-dimethylformamide (15.0 mL), tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) was added. The mixture was stirred under nitrogen at 50 °C for 16.0 hours and then cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 5'-chloro-4'-methyl-[2,3'-bipyridine]-6'-carbonitrile (460 mg, 2.0 mmol, yield 20%) as a yellow solid. LC-MS: m / z = 230.0 [M+H] + , retention time = 1.704 min (method A).

[0453] 5'-(benzyloxy)-4'-methyl-[2,3'-bipyridine]-6'-carbonitrile [ka]

[0454] To a solution of 5'-chloro-4'-methyl-[2,3'-bipyridine]-6'-carbonitrile (160.0 mg, 0.70 mmol) in N,N-dimethylformamide (5.0 mL), sodium hydride (33 mg, 0.84 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (90 mg, 0.84 mmol) was added. The solution was stirred at 0°C for 1 hour and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain 5'-(benzyloxy)-4'-methyl-[2,3'-bipyridine]-6'-carbonitrile (120 mg, 0.40 mmol, yield 57%) as a yellow solid. LC-MS: m / z = 302.1 [M + H] + , retention time = 2.21 min (method A).

[0455] 5'-Hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carboxylic acid [ka]

[0456] A solution of 5'-(benzyloxy)-4'-methyl-[2,3'-bipyridine]-6'-carbonitrile (120 mg, 0.40 mmol) in ethanol (10.0 mL) was mixed with 30% aqueous sodium hydroxide solution (4.0 mL). The mixture was stirred at 100°C for 5.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carboxylic acid (140 mg, crude) as a white solid. LC-MS: m / z = 321.1 [M + H] + The retention time was 2.00 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0457] Ethyl (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycinate [ka]

[0458] A mixture of 5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carboxylic acid (140 mg, 0.44 mmol), ethyl glycinate hydrochloride (61 mg, 0.44 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (250 mg, 0.48 mmol), and triethylamine (254 mg, 2.52 mmol) in dichloromethane (5.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain ethyl (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycinate (50 mg, 0.16 mmol, yield 26%) as a white solid. LC-MS: m / z = 406.1 [M + H] + , retention time 2.15 min (Method A).

[0459] (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycine [ka]

[0460] To a solution of ethyl (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycinate (50 mg, 0.16 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL), lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to obtain (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycine (9.6 mg, yield 21%) as a white solid. LC-MS: m / z = 288.0 [M + H] + , retention time 2.54 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ12.82(s,2H),9.42(t,J=6.0Hz,1H),8.76(d,J=4.3Hz,1H),8.21(s,1H),7.99(td ,J=7.8,1.7Hz,1H),7.68(d,J=7.8Hz,1H),7.50(dd,J=6.8,4.9Hz,1H),4.02(d,J=6.2Hz,2H),2.24(s,3H).

[0461] Example 13: Preparation of Compound 13 3-Chloro-5-(3-chlorophenyl)-4-methylpicolinonitrile [ka]

[0462] To a solution of 3,5-dichloro-4-methylpicolinonitrile (500 mg, 2.67 mmol), (3-chlorophenyl)boronic acid (418 mg, 2.67 mmol), and potassium carbonate (443 mg, 3.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78 mg, 0.11 mmol) in N,N-dimethylformamide / water (5.0 mL / 0.5 mL) was added. The mixture was stirred under nitrogen at 45°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-chloro-5-(3-chlorophenyl)-4-methylpicolinonitrile (640 mg, 2.43 mmol, yield 91%) as a yellow solid. LC-MS: m / z = 264.1 [M + H] + , retention time = 1.83 min (method A).

[0463] 3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinonitrile [ka]

[0464] To a solution of 3-chloro-5-(3-chlorophenyl)-4-methylpicolinonitrile (3.2 g, 12.16 mmol) in N,N-dimethylformamide (40.0 mL), sodium hydride (584 mg, 14.60 mmol in mineral oil, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (1.58 g, 14.60 mmol) was added. The solution was stirred at 0°C for 1.0 hour and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinonitrile (3.2 g, 9.56 mmol, yield 80%) as a yellow solid. LC-MS: m / z = 335.1 [M + H] + , retention time = 2.21 min (method A).

[0465] 3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinic acid [ka]

[0466] A solution of 3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinonitrile (3.2 g, 9.56 mmol) in ethanol (60.0 mL) was mixed with 20.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 5.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinic acid (2.1 g, 5.96 mmol, yield 64%) as a white solid. LC-MS: m / z = 354.1 [M + H] + The retention time was 2.00 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0467] Methyl 2-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)-2-methylpropanoate [ka]

[0468] A mixture of 3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinic acid (100 mg, 0.28 mmol), 2-amino-2-methylpropanoate methyl hydrochloride (44 mg, 0.28 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (162 mg, 0.31 mmol), and triethylamine (143 mg, 1.41 mmol) in dichloromethane (5.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain methyl 2-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)-2-methylpropanoate (110 mg, 0.24 mmol, yield 87%) as a white solid. LC-MS: m / z = 453.1 [M+H] + , retention time 2.15 min (Method A).

[0469] Methyl 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)-2-methylpropanoate [ka]

[0470] A mixture of methyl 2-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)-2-methylpropanoate (500 mg, 1.10 mmol) and 10% palladium carbon (50.0 mg) in tetrahydrofuran (10.0 mL) was stirred under a hydrogen atmosphere for 18.0 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain methyl 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)-2-methylpropanoate (240 mg, 0.66 mmol, yield 60%) as a white solid. LC-MS: m / z = 363.1 [M + H] + The retention time was 2.19 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0471] 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)-2-methylpropanoic acid [ka]

[0472] A solution of methyl 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)-2-methylpropanoate (240 mg, 0.66 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL) was mixed with lithium hydroxide monohydrate (164 mg, 4.0 mmol). The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)-2-methylpropanoic acid (176.3 mg, 0.51 mmol, yield 77%) as a white solid. LC-MS: m / z = 349.0 [M + H] + , retention time 5.36 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ12.93(br s,1H),12.70(s,1H),9.07(s,1H),8.04(s,1H),7.67-7.45(m,3H),7.47-7.18(m,1H),2.14(s,3H),1.59(s,6H).

[0473] Example 14: Preparation of Compound 14 Ethyl 1-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)cyclopropane-1-carboxylate [ka]

[0474] A mixture of 3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinic acid (intermediate from Example 13) (100 mg, 0.28 mmol), 1-aminocyclopropane-1-carboxylate ethyl hydrochloride (43 mg, 0.28 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (162 mg, 0.31 mmol), and triethylamine (143 mg, 1.41 mmol) in dichloromethane (5.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ethyl 1-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)cyclopropane-1-carboxylate (110 mg, 0.24 mmol, yield 85%) as a white solid. LC-MS: m / z = 465.1 [M+H] + , retention time 2.15 min (Method A).

[0475] Ethyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)cyclopropane-1-carboxylate [ka]

[0476] A mixture of ethyl 1-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)cyclopropane-1-carboxylate (500 mg, 1.08 mmol) and 10% palladium carbon (50.0 mg) in tetrahydrofuran (10.0 mL) was stirred under a hydrogen atmosphere for 18.0 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)cyclopropane-1-carboxylate (250 mg, 0.67 mmol, yield 62%) as a white solid. LC-MS: m / z = 375.1 [M + H] + The retention time was 2.19 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0477] 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)cyclopropane-1-carboxylic acid [ka]

[0478] To a solution of ethyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)cyclopropane-1-carboxylate (250 mg, 0.67 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL), lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)cyclopropane-1-carboxylic acid (133.0 mg, 0.38 mmol, yield 58%) as a white solid. LC-MS: m / z = 347.0 [M + H] + , retention time 4.93 minutes (Method A). 1HNMR(400MHz,DMSO-d6)δ12.93(s,1H),12.57(s,1H),9.71(s,1H),8.02(s,1H),7.67-7.46(m, 3H),7.45-7.36(m,1H),2.14(s,3H),1.44(dd,J=7.8,4.6Hz,2H),1.25(dd,J=7.9,4.6Hz,2H).

[0479] Example 15: Preparation of Compound 15 Methyl 1-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)cyclobutane-1-carboxylate [ka]

[0480] A mixture of 3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinic acid (intermediate from Example 13) (400 mg, 1.13 mmol), 1-aminocyclobutane-1-carboxylate methyl hydrochloride (187 mg, 1.13 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (647 mg, 1.24 mmol), and triethylamine (571 mg, 5.65 mmol) in dichloromethane (15.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain methyl 1-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)cyclobutane-1-carboxylate (500 mg, 1.08 mmol, yield 95%) as a white solid. LC-MS: m / z = 465.1 [M+H] + , retention time 2.15 min (Method A).

[0481] Methyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)cyclobutane-1-carboxylate [ka]

[0482] A mixture of methyl 1-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)cyclobutane-1-carboxylate (500 mg, 1.08 mmol) and 10% palladium-on-carbon (50.0 mg) in tetrahydrofuran (10.0 mL) was stirred under a hydrogen atmosphere for 18.0 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain methyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)cyclobutane-1-carboxylate (250 mg, 0.67 mmol, yield 62%) as a white solid. LC-MS: m / z = 375.1 [M + H] + The retention time was 2.19 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0483] 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)cyclobutane-1-carboxylic acid [ka]

[0484] A solution of methyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)cyclobutane-1-carboxylate (250 mg, 0.67 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL) was mixed with lithium hydroxide monohydrate (164 mg, 4.0 mmol). The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)cyclobutane-1-carboxylic acid (93.0 mg, 0.26 mmol, yield 39%) as a white solid. LC-MS: m / z = 361.0 [M + H] + , retention time 5.37 minutes (Method A). 1HNMR(400MHz,DMSO-d6)δδ12.80(s,1H),12.69(br s,1H),9.63(s,1H),8.05(s,1H),7.75-7.44(m,3H),7.49-7.26(m,1H),2.76-2.38(m,6H),2.14(s,3H),2.03-1.85(m,2H).

[0485] Example 16: Preparation of Compound 16 Methyl 3-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)oxetane-3-carboxylate [ka]

[0486] A mixture of 3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinic acid (intermediate from Example 13) (450 mg, 1.27 mmol), methyl 3-aminooxetane-3-carboxylic acid hydrochloride (213 mg, 1.27 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (728 mg, 1.40 mmol), and triethylamine (571 mg, 5.65 mmol) in dichloromethane (15.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain methyl 3-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)oxetane-3-carboxylate (500 mg, 1.07 mmol, yield 84%) as a white solid. LC-MS: m / z = 467.1 [M+H] + , retention time 2.15 min (Method A).

[0487] Methyl 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)oxetane-3-carboxylate [ka]

[0488] A mixture of methyl 3-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamide)oxetane-3-carboxylate (500 mg, 1.07 mmol) and 10% palladium carbon (50.0 mg) in tetrahydrofuran (10.0 mL) was stirred under a hydrogen atmosphere for 18 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain methyl 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)oxetane-3-carboxylate (300 mg, 0.80 mmol, yield 74%) as a white solid. LC-MS: m / z = 377.1 [M + H] + The retention time was 2.19 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0489] 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)oxetane-3-carboxylic acid [ka]

[0490] To a solution of methyl 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)oxetane-3-carboxylate (300 mg, 0.80 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL), lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamide)oxetane-3-carboxylic acid (71.4 mg, 0.20 mmol, yield 25%) as a white solid. LC-MS: m / z = 363.0 [M + H] + , retention time 4.85 minutes (Method A). 1HNMR (400MHz, DMSO-d6) δ12.53(s,1H),10.18(s,1H),8.08(s,1H),7.58-7.53(m,3H),7.45-7.37(m,1H),4.94-4.80(m,4H),2.14(s,3H).

[0491] Example 17: Preparation of Compound 17 3-(benzyloxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile [ka]

[0492] To a solution of 3-chloro-4-methyl-5-(3-phenoxyphenyl)picolinonitrile (intermediate from Example 8) (700 mg, 2.39 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (114.80 mg, 2.87 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (309.6 mg, 2.87 mmol) was added. The solution was stirred at 0°C for 1.0 hour and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 3-(benzyloxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile (400 mg, 1.09 mmol, yield 45.87%). LC-MS: m / z = 366.0 [M + H] + , retention time 1.72 min (Method A).

[0493] 3-(benzyloxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid [ka]

[0494] A solution of 3-(benzyloxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile (400 mg, 1.09 mmol) in ethanol (10.0 mL) was mixed with 8.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 3.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid (350 mg, 0.91 mmol, yield 75.32%) as a white solid. LC-MS: m / z = 385.0 [M + H] + The retention time was 1.51 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0495] Ethyl (3-(benzyloxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinoyl)glycinate [ka]

[0496] A mixture of 3-(benzyloxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid (350 mg, 0.91 mmol), ethyl glycinate hydrochloride (73.84 mg, 0.53 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (276.25 mg, 0.53 mmol), and triethylamine (223.57 mg, 2.21 mmol) in dichloromethane (5.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain ethyl (3-(benzyloxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinoyl) glycinate (150 mg, 0.32 mmol, yield 72.69%) as a white solid. LC-MS: m / z = 470.0 [M+H] + , retention time 2.04 min (Method B).

[0497] Ethyl (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)picolinoyl)glycinate [ka]

[0498] A mixture of ethyl (3-(benzyloxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinoyl) glycinate (150 mg, 0.32 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)picolinoyl) glycinate (120 mg, 0.31 mmol, yield 97.91%) as a yellow solid. LC-MS: m / z = 384.3 [M + H]+, retention time 2.27 min (Method B). The product was sufficiently pure and used directly in the next step.

[0499] (3-Hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)picolinoyl)glycine [ka]

[0500] A solution of ethyl (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)picolinoyl)glycinate (100 mg, 0.26 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL) was mixed with lithium hydroxide monohydrate (164 mg, 4.0 mmol). The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to obtain (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)picolinoyl)glycine (formate) (17.9 mg, 0.05 mmol, 19.39%) as a white solid. LC-MS: m / z = 356.1 [M + H] + , retention time 3.91 min (Method A). 1 HNMR(400MHz,DMSO-d6)δ12.73(s,1H),9.17(s,1H),8.17(s,1H),7.97(s,1H),6.94(d,J=6.3Hz,2H),6.56(d,J=8.7Hz,1H),5.93(br s,1H),3.95(d,J=5.5Hz,2H),2.82-2.60(m,3H),2.58-2.53(m,1H),2.18(s,3H),1.93-1.81(m,1H),1.56-1.37(m,1H),1.17(d,J=6.1Hz,3H).

[0501] Example 18: Preparation of Compound 18 2-(4-bromo-1H-pyrazole-1-yl)pyridine [ka]

[0502] To a solution of 2-(1H-pyrazole-1-yl)pyridine (1.0 g, 6.89 mmol) in acetic acid (20 mL), bromine (3302.54 mg, 20.67 mmol, 1.06 mL) was added dropwise. The mixture was stirred at room temperature for 30 minutes. The reaction product was diluted with water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated. Crude 2-(4-bromo-1H-pyrazole-1-yl)pyridine (1.35 g, crude product) was obtained as a yellow solid. LC-MS: m / z = 224 [M + H] + The retention time was 1.941 minutes (Method B). The product was used directly in the next step.

[0503] 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)pyridine [ka]

[0504] To a solution of 2-(4-bromo-1H-pyrazole-1-yl)pyridine (1.2 g, 5.36 mmol), bis(pinacolate)diborone (6.8 g, 26.78 mmol), and potassium acetate (2.63 g, 26.78 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (391.88 mg, 0.54 mmol) in 1,4-dioxane (15.0 mL) was added. The mixture was stirred under nitrogen at 90°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)pyridine (1.38 g, 5.09 mmol, 95% yield). LC-MS: m / z = 272 [M + H] + , retention time 2.000 min (method B).

[0505] 3-Chloro-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinonitrile [ka]

[0506] A solution of 3,5-dichloro-4-methylpicolinonitrile (862.2 mg, 4.61 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)pyridine (1.25 g, 4.61 mmol), and potassium carbonate (764.6 mg, 5.53 mmol) is prepared by adding [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (134.9 mg, 0.18 mg) in N,N-dimethylformamide / water (10.0 mL / 1.0 mL). Ol was added. The mixture was stirred under nitrogen at 45°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 3-chloro-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinonitrile (342 mg, 1.16 mmol, yield 25%). LC-MS: m / z = 296 [M + H] + , retention time 2.090 minutes (Method A).

[0507] 3-(benzyloxy)-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinonitrile [ka]

[0508] To a solution of 3-chloro-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinonitrile (300.0 mg, 1.01 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (48.8 mg, 1.22 mmol, 60% w / w dispersion in mineral oil) was added at 0°C under nitrogen. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (131.6 mg, 1.22 mmol, 0.127 mL) was added. The solution was stirred at 0°C for 50 minutes and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 3-(benzyloxy)-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinonitrile (82 mg, 0.22 mmol, yield 22%). LC-MS: m / z = 368 [M+H] + , retention time 2.138 min (Method B).

[0509] 3-(benzyloxy)-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinic acid [ka]

[0510] A solution of 3-(benzyloxy)-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinonitrile (70.0 mg, 0.19 mmol) in ethanol (3.0 mL) was mixed with 1.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 5.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinic acid (72 mg, crude) as a white solid. LC-MS: m / z = 387 [M + H] + The retention time was 1.290 minutes (Method B). The product was sufficiently pure and used directly in the next step.

[0511] Ethyl (3-(benzyloxy)-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinoyl)glycinate [ka]

[0512] A mixture of 3-(benzyloxy)-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinic acid (60.0 mg, 0.16 mmol), ethyl glycinate hydrochloride (26.41 mg, 0.19 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (88.89 mg, 0.17 mmol), and triethylamine (78.56 mg, 0.78 mmol) in dichloromethane (5.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 2) to obtain ethyl (3-(benzyloxy)-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinoyl)glycinate (70 mg, 0.15 mmol, yield 93%). LC-MS: m / z = 472 [M+H] + , retention time 2.028 min (Method B).

[0513] Ethyl (3-hydroxy-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinoyl)glycinate [ka]

[0514] A mixture of ethyl (3-(benzyloxy)-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinoyl) glycinate (60.0 mg, 0.13 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under a hydrogen atmosphere for 5.0 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (3-hydroxy-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinoyl) glycinate (50 mg, crude product) as a white solid. LC-MS: m / z = 382 [M + H] + The retention time was 2.127 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0515] (3-Hydroxy-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinoyl)glycine [ka]

[0516] To a solution of ethyl (3-hydroxy-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinoyl)glycinate (50.0 mg, 0.13 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL), lithium hydroxide monohydrate (55.0 mg, 1.31 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to obtain (3-hydroxy-4-methyl-5-(1-(pyridine-2-yl)-1H-pyrazole-4-yl)picolinoyl)glycine (formate) (28.5 mg, 0.08 mmol, yield 62%) as a white solid. LC-MS: m / z = 354 [M + H] + , retention time 4.255 minutes (Method A). 1H NMR(500MHz,DMSO-d6)δ12.84(br,1H),9.27(br,1H),9.01(s,1H),8.53(d,J=4.0Hz,1H),8.35 (s,1H),8.27(s,1H),8.08-8.00(m,2H),7.44-7.41(m,1H),3.97(d,J=6.0Hz,2H),2.37(s,3H).

[0517] Example 19: Preparation of Compound 19 4-bromo-1-(4-fluorophenyl)-1H-pyrazole [ka]

[0518] A mixture of 4-bromo-1H-pyrazole (1.47 g, 10.0 mmol), 1-fluoro-4-iodobenzene (2.44 g, 11.0 mmol), cesium carbonate (6.50 g, 20.0 mmol), copper iodide (380 mg, 2.0 mmol), and N,N'-dimethyl-1,2-ethanediamine (176 mg, 2.0 mmol) in acetonitrile (20.0 mL) was stirred overnight at 80°C in a sealed tube. The solution was cooled to room temperature and filtered. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 4-bromo-1-(4-fluorophenyl)-1H-pyrazole (1.30 g, 5.39 mmol, yield 53.9%) as a yellow solid. LC-MS: m / z = 243.0 [M + H] + , retention time 2.01 min (Method A).

[0519] 1-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka]

[0520] To a solution of 4-bromo-1-(4-fluorophenyl)-1H-pyrazole (1.30 g, 5.39 mmol), bis(pinacolate)diborone (1.21 g, 4.78 mmol), and potassium acetate (2.11 g, 21.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (395 mg, 0.54 mmol) in 1,4-dioxane (15.0 mL) was added. The mixture was stirred under nitrogen at 90°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 1-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.21 g, 4.20 mmol, yield 77.9%). LC-MS: m / z = 289.1 [M+H] + , retention time 2.14 min (Method A).

[0521] 3-Chloro-5(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinonitrile [ka]

[0522] To a solution of 3,5-dichloro-4-methylpyronitrile (785 mg, 4.20 mmol), 1-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.21 g, 4.20 mmol), and potassium carbonate (869.4 mg, 6.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (307 mg, 0.42 mmol) was added in N,N-dimethylformamide / water (10.0 mL / 1.0 mL). The mixture was stirred under nitrogen at 50°C for 16.0 hours and then cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinonitrile (180 mg, 0.58 mmol, yield 13.8%). LC-MS: m / z = 313.0 [M + H] + , retention time 2.13 min (Method A).

[0523] 3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinonitrile [ka]

[0524] To a solution of 3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinonitrile (180 mg, 0.58 mmol) in N,N-dimethylformamide (5.0 mL), sodium hydride (27.8 mg, 0.70 mmol, 60% w / w dispersion in mineral oil) was added at 0°C under nitrogen. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (62.6 mg, 0.58 mmol) was added. The solution was stirred at 0°C for 1.0 hour and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinonitrile (35 mg, 0.09 mmol, yield 15.7%). LC-MS: m / z = 385.1 [M+H] + , retention time 2.194 minutes (Method A).

[0525] 3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinic acid [ka]

[0526] A solution of 3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinonitrile (35 mg, 0.09 mmol) in ethanol (3.0 mL) was mixed with 1.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 5.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinic acid (32 mg, crude) as a white solid. LC-MS: m / z = 404.1 [M + H] + The retention time was 2.014 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0527] Ethyl (3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate [ka]

[0528] A mixture of 3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinic acid (32 mg, crude), ethyl glycinate hydrochloride (13.9 mg, 0.1 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (62.4 mg, 0.12 mmol), and triethylamine (50.5 mg, 0.5 mmol) in dichloromethane (5.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ethyl (3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate (40 mg, 0.08 mmol, yield 91%). LC-MS: m / z = 489.1 [M+H] + , retention time 2.128 min (Method A).

[0529] Ethyl (5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-3-hydroxy-4-methylpicolinoyl)glycinate [ka]

[0530] A mixture of ethyl (3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate (40 mg, 0.08 mmol) and 10% palladium carbon (10.0 mg) in tetrahydrofuran (5.0 mL) was stirred overnight under a hydrogen atmosphere. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-3-hydroxy-4-methylpicolinoyl)glycinate (30 mg, 0.08 mmol, yield 100%) as a yellow solid. LC-MS: m / z = 399.0 [M + H] + The retention time was 2.15 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0531] (5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-3-hydroxy-4-methylpicolinoyl)glycine [ka]

[0532] To a solution of ethyl (5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-3-hydroxy-4-methylpicolinoyl)glycinate (30 mg, 0.08 mmol) in tetrahydrofuran / water (5.0 mL / 1.0 mL), lithium hydroxide monohydrate (42 mg, 1.0 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain (5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-3-hydroxy-4-methylpicolinoyl)glycine (20.1 mg, 0.05 mmol, yield 67.9%) as a white solid. LC-MS: m / z = 371.0 [M + H] + , retention time 4.641 min (method A). 1H NMR(500MHz,DMSO-d6)δ12.88(s,1H),9.21(s,1H),8.91(s,1H),8.32(s,1H),8.20 (s,1H),8.07-7.84(m,2H),7.53-7.28(m,2H),3.92(d,J=5.7Hz,2H),2.37(s,3H).

[0533] Example 20: Preparation of Compound 20 4-Bromo-1-isopropyl-1H-pyrazole [ka]

[0534] To a solution of 4-bromo-1H-pyrazole (1.47 g, 10.0 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (480 mg, 12.0 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 20 minutes, and then 2-iodopropane (1.7 g, 10.0 mmol) was added. The solution was stirred at room temperature for 18.0 hours and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 4-bromo-1-isopropyl-1H-pyrazole (1.47 g, 7.8 mmol, yield 78%). LC-MS: m / z = 189.0 [M + H] + , retention time 1.90 min (Method B).

[0535] 1-Isopropyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka]

[0536] To a solution of 4-bromo-1-isopropyl-1H-pyrazole (1.47 g, 7.8 mmol), bis(pinacolate)diborone (3.96 g, 15.6 mmol), and potassium acetate (3.06 g, 31.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (570 mg, 0.78 mmol) in 1,4-dioxane (15.0 mL) was added. The mixture was stirred under nitrogen at 90°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.18 g, 5.0 mmol, yield 64.1%). LC-MS: m / z = 237.0 [M+H] + , retention time 1.96 min (Method B).

[0537] 3-Chloro-5(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile [ka]

[0538] To a solution of 3,5-dichloro-4-methylpicolinonitrile (1.5 g, 8.02 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.9 g, 8.02 mmol), and potassium carbonate (1.3 g, 9.63 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (235 mg, 0.32 mmol) was added in N,N-dimethylformamide / water (15.0 mL / 1.5 mL). The mixture was stirred overnight at 50°C under nitrogen and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-chloro-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (580 mg, 2.22 mmol, yield 29%) as a yellow solid. LC-MS: m / z = 261.1 [M + H]+, retention time = 1.83 min (Method A).

[0539] 3-(benzyloxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile [ka]

[0540] To a solution of 3-chloro-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (580.0 mg, 2.22 mmol) in N,N-dimethylformamide (5.0 mL), sodium hydride (108 mg, 2.67 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (288 mg, 2.67 mmol) was added. The solution was stirred at 0°C for 50 minutes and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 3-(benzyloxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (180 mg, 0.54 mmol, yield 24%) as a yellow solid. LC-MS: m / z=333.1[M+H]+, retention time=2.21 min (Method A).

[0541] 3-(benzyloxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinic acid [ka]

[0542] A solution of 3-(benzyloxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (180 mg, 0.54 mmol) in ethanol (5.0 mL) was mixed with 1.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 5.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinic acid (100 mg, 0.28 mmol, yield 53%) as a white solid. LC-MS: m / z = 352.1 [M + H] + The retention time was 2.00 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0543] Ethyl (3-(benzyloxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate [ka]

[0544] A mixture of 3-(benzyloxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinic acid (100 mg, 0.28 mmol), ethyl glycinate hydrochloride (40 mg, 0.28 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (178 mg, 0.34 mmol), and triethylamine (254 mg, 2.52 mmol) in dichloromethane (5.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ethyl (3-(benzyloxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate (100 mg, 0.18 mmol, yield 81%) as a white solid. LC-MS: m / z = 437.1 [M+H] + , retention time 2.15 min (Method A).

[0545] Ethyl (3-hydroxy-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate [ka]

[0546] A mixture of ethyl (3-(benzyloxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl) glycinate (100 mg, 0.18 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under a hydrogen atmosphere for 18 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (3-hydroxy-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl) glycinate (80 mg, crude) as a yellow solid. LC-MS: m / z = 347.1 [M + H] + The retention time was 2.19 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0547] (3-Hydroxy-5-(1-Isopropyl-1H-Pyrazole-4-yl)-4-methylpicolinoyl)glycine [ka]

[0548] To a solution of ethyl (3-hydroxy-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate (80 mg, crude) in tetrahydrofuran / water (8.0 mL / 2.0 mL), lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain (3-hydroxy-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine (45.7 mg, yield 62%) as a white solid. LC-MS: m / z = 319.1 [M + H] + , retention time 3.81 min (Method A). 1HNMR(400MHz,DMSO-d6)δδ12.75(s,1H),9.24(t,J=6.0Hz,1H),8.23(s,2H),7.86(s,1H) ,4.58(dt,J=13.3,6.6Hz,1H),3.99(d,J=6.1Hz,2H),2.31(s,3H),1.48(d,J=6.7Hz,6H).

[0549] Example 21: Preparation of Compound 21 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole [ka]

[0550] To a solution of 4-bromo-1H-pyrazole (1.47 g, 10.0 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (480 mg, 12.0 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 20 minutes, and then tetrahydro-2H-pyran-4-ylmethanesulfonate (1.8 g, 10.0 mmol) was added. The solution was stirred at 10°C for 2.0 hours and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (1.16 g, 5.0 mmol, 50% yield). LC-MS: m / z = 231.0 [M + H] + , retention time 1.76 min (Method B).

[0551] 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka]

[0552] To a solution of 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (2.8 g, 12.10 mmol), bis(pinacolate)diborone (3.7 g, 14.50 mmol), and potassium acetate (3.6 g, 36.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (443 mg, 0.61 mmol) in 1,4-dioxane (15.0 mL) was added. The mixture was stirred under nitrogen at 90°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5 g, 8.99 mmol, yield 74%) as a white solid. LC-MS: m / z = 279.1 [M + H]+, retention time = 1.83 min (Method A).

[0553] 3-Chloro-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinonitrile [ka]

[0554] To a solution of 3,5-dichloro-4-methylpicolinonitrile (1.51 g, 8.09 mmol), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.25 g, 8.09 mmol), and potassium carbonate (1.34 g, 9.71 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (237 mg, 0.32 mmol) was added in N,N-dimethylformamide / water (6.0 mL / 0.6 mL). The mixture was stirred under nitrogen at 50°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-chloro-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinonitrile (1.0 g, 3.31 mmol, yield 37%) as a yellow solid. LC-MS: m / z = 303.1 [M + H]+, retention time = 1.83 min (Method A).

[0555] 3-(benzyloxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinonitrile [ka]

[0556] To a solution of 3-chloro-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinonitrile (900.0 mg, 2.97 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (143 mg, 3.57 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (386 mg, 3.57 mmol) was added. The solution was stirred at 0°C for 1.0 hour and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 3-(benzyloxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinonitrile (100 mg, 0.27 mmol, yield 8%) as a yellow solid. LC-MS: m / z = 375.1 [M + H]+, retention time = 2.21 min (Method A).

[0557] 3-(benzyloxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinic acid [ka]

[0558] A solution of 3-(benzyloxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinonitrile (100 mg, 0.27 mmol) in ethanol (5.0 mL) was mixed with 1.5 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 5.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinic acid (90 mg, 0.23 mmol, yield 86%) as a white solid. LC-MS: m / z = 394.1 [M + H] +The retention time was 2.00 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0559] Ethyl (3-(benzyloxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinoyl)glycinate [ka]

[0560] A mixture of 3-(benzyloxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinic acid (90 mg, 0.23 mmol), ethyl glycinate hydrochloride (32 mg, 0.23 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (143 mg, 0.27 mmol), and triethylamine (254 mg, 2.52 mmol) in dichloromethane (5.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ethyl (3-(benzyloxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinoyl) glycinate (90 mg, 0.19 mmol, yield 82%) as a white solid. LC-MS: m / z = 479.1 [M + H] + , retention time 2.15 min (Method A).

[0561] Ethyl (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinoyl)glycinate [ka]

[0562] A mixture of ethyl (3-(benzyloxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinoyl) glycinate (90 mg, 0.19 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under a hydrogen atmosphere for 18 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinoyl) glycinate (70 mg, 0.18 mmol, yield 96%) as a yellow solid. LC-MS: m / z = 389.1 [M + H] + The retention time was 2.19 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0563] (3-Hydroxy-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinoyl)glycine [ka]

[0564] To a solution of ethyl (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinoyl)glycinate (70 mg, 0.18 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL), lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to obtain (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)picolinoyl)glycine (10.8 mg, 0.03 mmol, yield 17%) as a white solid. LC-MS: m / z = 361.1 [M + H] + , retention time 3.45 minutes (Method A). 1HNMR(500MHz,DMSO-d6)δ12.76(s,2H),9.25(t,J=6.0Hz,1H),8.28(s,1H),8.23(s,1H),7.89(s, 1H),4.69-4.32(m,1H),3.98(d,J=6.2Hz,4H),3.58-3.43(m,3H),2.31(s,3H),2.07-1.93(m,4H).

[0565] Example 22: Preparation of Compound 22 4-Bromo-1-isobutyl-1H-pyrazole [ka]

[0566] Potassium carbonate (2.82 g, 20.41 mmol) was added to a solution of 4-bromo-1H-pyrazole (1.0 g, 6.80 mmol) and 1-bromo-2-methylpropane (1118.68 mg, 8.16 mmol) in N,N-dimethylformamide (10.0 mL). The mixture was stirred at 90°C for 18.0 hours and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 4-bromo-1-isopropyl-1H-pyrazole (1.15 g, 5.69 mmol, yield 83%). LC-MS: m / z = 203 [M + H] + , retention time 1.861 min (Method B).

[0567] 1-Isobutyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka]

[0568] To a solution of 4-bromo-1-isobutyl-1H-pyrazole (1.1 g, 5.42 mmol), bis(pinacolate)diborone (6.88 g, 27.08 mmol), and potassium acetate (1.59 g, 16.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (396 mg, 0.54 mmol) in 1,4-dioxane (15.0 mL) was added. The mixture was stirred under nitrogen at 90°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 4.39 mmol, yield 81%). LC-MS: m / z = 251 [M + H] + , retention time 2.047 minutes (Method A).

[0569] 3-Chloro-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile [ka]

[0570] To a solution of 3,5-dichloro-4-methylpicolinonitrile (411.2 mg, 2.20 mmol), 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (550.0 mg, 2.20 mmol), and potassium carbonate (364.7 mg, 2.64 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (64.4 mg, 0.09 mmol) was added in N,N-dimethylformamide / water (10.0 mL / 1.0 mL). The mixture was stirred overnight at 50°C under nitrogen and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 3-chloro-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (732 mg, 2.67 mmol, yield 87%). LC-MS: m / z = 275 [M+H] + , retention time 2.065 minutes (Method A).

[0571] 3-(benzyloxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile [ka]

[0572] To a solution of 3-chloro-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (650.00 mg, 2.37 mmol) in N,N-dimethylformamide (10.0 mL), sodium hydride (113.6 mg, 2.84 mmol, 60% w / w dispersion in mineral oil) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 10 minutes, and then benzyl alcohol (307.0 mg, 2.84 mmol, 0.3 mL) was added. The solution was stirred at 0°C for 50 minutes and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 3-(benzyloxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (105 mg, 0.30 mmol, yield 13%). LC-MS: m / z = 347 [M+H] + , retention time 2.089 minutes (Method B).

[0573] 3-(benzyloxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinic acid [ka]

[0574] A solution of 3-(benzyloxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (95.0 mg, 0.27 mmol) in ethanol (3.0 mL) was mixed with 1.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 5.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-(benzyloxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinic acid (90 mg, crude) as a white solid. LC-MS: m / z = 366 [M + H] + The retention time was 1.391 minutes (Method B). The product was sufficiently pure and used directly in the next step.

[0575] Ethyl (3-(benzyloxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate [ka]

[0576] A mixture of 3-(benzyloxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinic acid (90.00 mg, 0.25 mmol), ethyl glycinate hydrochloride (41.7 mg, 0.30 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (140.98 mg, 0.27 mmol), and triethylamine (124.6 mg, 1.23 mmol) in dichloromethane (10.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ethyl (3-(benzyloxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate (30 mg, 0.067 mmol, yield 27%). LC-MS: m / z = 451 [M+H] + , retention time 2.008 min (Method B).

[0577] Ethyl (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate [ka]

[0578] A mixture of ethyl (3-(benzyloxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate (25.0 mg, 0.06 mmol) and 10% palladium carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under a hydrogen atmosphere for 18.0 hours. The insoluble solid was filtered, and the filtrate was concentrated to obtain ethyl (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate (30.0 mg, crude product) as a yellow solid. LC-MS: m / z = 361 [M + H] + The retention time was 1.966 minutes (Method B). The product was sufficiently pure and used directly in the next step.

[0579] (3-Hydroxy-5-(1-Isobutyl-1H-Pyrazole-4-yl)-4-methylpicolinoyl)glycine [ka]

[0580] To a solution of ethyl (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycinate (25.00 mg, 0.07 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL), lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added. The mixture was stirred overnight and concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was purified by reverse-phase preparative HPLC to obtain (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine (formate) (6.4 mg, 0.02 mmol, yield 27%) as a yellow solid. LC-MS: m / z = 333 [M + H] + , retention time 4.188 min (Method A). 1H NMR(400MHz,DMSO-d6)δ12.75(s,1H),9.27-9.25(m,1H),8.22(s,1H),8.20(s,1H),7.87(s,1 H),4.00(s,2H),3.98(d,J=2.4Hz,2H),2.30(s,3H),2.19-2.15(m,1H),0.88(d,J=6.8Hz,6H).

[0581] Example 23: Preparation of Compound 23 Methyl 3-oxohepta-6-enoate [ka]

[0582] To a suspension of sodium hydride (1.89 g, 47.30 mmol, 60% w / w dispersion in mineral oil) in anhydrous tetrahydrofuran (120 mL), methyl 3-oxobutanoate (3.23 g, 27.82 mmol) was added at 0°C. The solution was stirred at 0°C for 30 minutes, and n-butyllithium (17.8 mL, 44.52 mmol, 2.5 M in n-hexane) was added. After stirring for 30 minutes, 3-bromopropa-1-ene (3.70 g, 30.61 mmol) was added. The reaction mixture was heated to 20°C and stirred for a further 2.0 hours. The reaction product was quenched by adding saturated ammonium aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 100 / 3) to obtain methyl 3-oxohepta-6-enoate (2.74 g, 17.6 mmol, yield 63%) as a yellow oily substance. LC-MS: m / z = 157 [M+H] + , retention time 1.446 min (Method B).

[0583] Methyl 4-(2-(benzyloxy)ethyl)-3-oxohepta-6-enoate [ka]

[0584] To a solution of methyl 3-oxohepta-6-enoate (800.0 mg, 5.12 mmol) in anhydrous tetrahydrofuran (15.0 mL), fresh lithium diisopropylamide (11.2 mmol, 5.63 mL, 2.0 M in n-hexane) was added at 0°C. The mixture was stirred at 0°C for 15 minutes, and ((2-bromoethoxy)methyl)benzene (1.32 g, 6.15 mmol) was added. The mixture was heated to 20°C and stirred for 3.0 hours. The reaction product was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain methyl 4-(2-(benzyloxy)ethyl)-3-oxohepta-6-enoate (729 mg, 2.51 mmol, yield 49%) as a yellow oily substance. LC-MS: m / z = 313 [M + Na] + , retention time 2.080 min (method A).

[0585] Methyl 2,2-diazide-4-(2-(benzyloxy)ethyl)-3-oxohepta-6-enoate [ka]

[0586] A mixture of methyl 4-(2-(benzyloxy)ethyl)-3-oxohepta-6-enoate (700.0 mg, 2.41 mmol), sodium azide (626.9 mg, 9.64 mmol), sodium bicarbonate (607.6 mg, 7.23 mmol), and iodine (1.25 g, 4.94 mmol) in dimethyl sulfoxide / water (30.0 mL / 15.0 mL) was stirred at room temperature for 16.0 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain methyl 2,2-diazide-4-(2-(benzyloxy)ethyl)-3-oxohepta-6-enoate (330 mg, 0.89 mmol, yield 37%). LC-MS: m / z = 395 [M+Na] + , retention time 2.314 min (Method A).

[0587] Methyl 4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methyl picolinate [ka]

[0588] A mixture of methyl 2,2-diazide-4-(2-(benzyloxy)ethyl)-3-oxohepta-6-enoate (300.0 mg, 0.81 mmol) in toluene (5.0 mL) was stirred in a sealed tube at 110°C for 16.0 hours. The solution was cooled and concentrated to dryness. The resulting residue was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain methyl 4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methyl picolinate (65 mg, 0.22 mmol, yield 27%). LC-MS: m / z = 302 [M + H] + , retention time 1.991 min (Method A).

[0589] 4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methylpicolinic acid [ka]

[0590] To a solution of methyl 4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methyl picolinate (60.0 mg, 0.20 mmol) in methanol / water (4.0 mL / 1.0 mL), lithium hydroxide monohydrate (83.6 mg, 1.99 mmol) was added. The mixture was stirred overnight and concentrated to remove methanol. The resulting aqueous solution was acidified by adding 10% hydrochloric acid (5.0 mL) and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Crude 4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methyl picolinate (55 mg, 0.19 mmol, yield 96%) was obtained as a yellow solid. LC-MS: m / z = 288 [M + H] + The retention time was 1.626 minutes (Method A). The crude product was used in the next step.

[0591] Ethyl (4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methylpicolinoyl)glycinate [ka]

[0592] A mixture of 4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methyl picolinic acid (50.00 mg, 0.17 mmol), ethyl glycinate hydrochloride (21.53 mg, 0.21 mmol), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (99.62 mg, 0.19 mmol), and triethylamine (88.05 mg, 0.87 mmol) in dichloromethane (10.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain ethyl (4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methylpicolinoyl)glycinate (48 mg, 0.13 mmol, yield 76%) as a white solid. LC-MS: m / z = 373 [M+H] + , retention time 2.179 minutes (Method A).

[0593] (4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methylpicolinoyl)glycine [ka]

[0594] To a solution of ethyl (4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methylpicolinoyl)glycinate (48.0 mg, 0.13 mmol) in methanol / water (4.0 mL / 1.0 mL), lithium hydroxide monohydrate (54.2 mg, 1.29 mmol) was added. The mixture was stirred overnight and concentrated to remove methanol. The resulting aqueous solution was acidified to pH=3-4 with 10% hydrochloric acid. The precipitate was purified by reverse-phase preparative HPLC to obtain (4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methylpicolinoyl)glycine (formate) (29.7 mg, 0.09 mmol, yield 66%) as a red solid. LC-MS: m / z=345[M+H] + , retention time 4.596 minutes (Method A). 1H NMR(500MHz,DMSO-d6)δ12.75(br,1H),12.40(s,1H),9.11(t,J=6.0Hz,1H),7.34-7.31(m,3H),7.28-7. 25(m,3H),4.48(s,2H),3.99(d,J=6.0Hz,2H),3.69(t,J=6.5Hz,2H),2.87(t,J=6.5Hz,2H),2.42(s,3H).

[0595] Example 24: Preparation of Compound 24 Methyl 4-(4-fluorobenzyl)-3-oxohepta-6-enoate [ka]

[0596] To a solution of methyl 3-oxohepta-6-enoate (intermediate from Example 22) (500.0 mg, 3.20 mmol) in anhydrous tetrahydrofuran (20.0 mL), fresh lithium diisopropylamide (7.04 mmol, 3.52 mL, 2.0 M in n-hexane) was added at 0°C. The mixture was stirred at 0°C for 30 minutes, and 1-(bromomethyl)-4-fluorobenzene (726.2 mg, 3.84 mmol) was added. The mixture was heated to 20°C and stirred for 3.0 hours. The reaction product was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain methyl 4-(4-fluorobenzyl)-3-oxohepta-6-enoate (650 mg, 2.46 mmol, yield 77%) as a yellow oily substance. LC-MS: m / z = 265 [M + H] + , retention time 1.934 minutes (Method B).

[0597] Methyl 2,2-diazide-4-(4-fluorobenzyl)-3-oxohepta-6-enoate [ka]

[0598] A mixture of methyl 4-(4-fluorobenzyl)-3-oxohepta-6-enoate (500.0 mg, 1.89 mmol), sodium azide (369.2 mg, 5.68 mmol), sodium bicarbonate (476.7 mg, 5.68 mmol), and iodine (984.3 mg, 3.88 mmol) in dimethyl sulfoxide / water (20.0 mL / 10.0 mL) was stirred at room temperature for 16.0 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain methyl 2,2-diazide-4-(4-fluorobenzyl)-3-oxohepta-6-enoate (310 mg, 0.89 mmol, yield 47%) as a yellow solid. LC-MS: m / z = 369 [M + Na] + , retention time 2.279 minutes (Method A).

[0599] Methyl 4-(4-fluorobenzyl)-3-hydroxy-6-methyl picolinate [ka]

[0600] A mixture of methyl 2,2-diazide-4-(4-fluorobenzyl)-3-oxohepta-6-enoate (300.0 mg, 0.87 mmol) in toluene (5.0 mL) was stirred in a sealed tube at 110°C for 2.0 hours. The solution was cooled and concentrated to dryness. The resulting residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 3) to obtain methyl 4-(4-fluorobenzyl)-3-hydroxy-6-methyl picolinate (64 mg, 0.23 mmol, yield 27%) as a yellow oil. LC-MS: m / z = 276 [M + H] + , retention time 2.006 min (Method A).

[0601] 4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinic acid [ka]

[0602] To a solution of methyl 4-(4-fluorobenzyl)-3-hydroxy-6-methyl picolinate (60.0 mg, 0.22 mmol) in methanol / water (4.0 mL / 1.0 mL), lithium hydroxide monohydrate (91.5 mg, 2.18 mmol) was added. The mixture was stirred overnight and concentrated to remove methanol. The resulting aqueous solution was acidified by adding 10% hydrochloric acid (5.0 mL) and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Crude 4-(4-fluorobenzyl)-3-hydroxy-6-methyl picolinate (34 mg, 0.13 mmol, yield 59%) was obtained as a yellow solid. LC-MS: m / z = 262 [M + H] + The retention time was 1.626 minutes (Method A). The crude product was used in the next step.

[0603] Ethyl (4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinoyl)glycinate [ka]

[0604] A mixture of 4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinic acid (30.0 mg, 0.11 mmol), ethyl glycinate hydrochloride (14.21 mg, 0.14 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (65.73 mg, 0.13 mmol), and triethylamine (58.10 mg, 0.57 mmol) in dichloromethane (3.0 mL) was stirred overnight at room temperature. The reaction product was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 85 / 15) to obtain ethyl (4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinoyl)glycinate (26 mg, 0.08 mmol, yield 68%) as a yellow solid. LC-MS: m / z = 347 [M + H] + , retention time 2.180 min (method A).

[0605] (4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinoyl)glycine [ka]

[0606] To a solution of ethyl (4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinoyl)glycinate (26.00 mg, 0.08 mmol) in methanol / water (4.0 mL / 1.0 mL), lithium hydroxide monohydrate (31.53 mg, 0.75 mmol) was added. The mixture was stirred overnight and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was purified by reverse-phase preparative HPLC to obtain (4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinoyl)glycine (formate) (11.2 mg, 0.04 mmol, yield 47%) as a white solid. LC-MS: m / z = 319 [M + H] + , retention time 4.616 min (Method A). 1H NMR(400MHz,DMSO-d6)δ12.85(br,1H),12.47(s,1H),9.15-9.11(m,1H),7.32-7. 25(m,3H),7.11(t,J=8.8Hz,2H),3.98(d,J=6.4Hz,2H),3.93(s,2H),2.41(s,3H).

[0607] Example 25: Preparation of Compound 25 3,5-dibromo-2,4-dimethylpyridine 1-oxide [ka]

[0608] To a solution of 3,5-dibromo-2,4-dimethylpyridine (400 mg, 1.51 mmol) in dichloromethane (10.0 mL), 3-chloroperoxybenzoic acid (400 mg, 1.96 mmol, 85%) was added at 0°C. The mixture was stirred at room temperature for 18.0 hours, and potassium carbonate (400 mg, 3.20 mmol) was added. The mixture was stirred for a further 1 hour, and the insoluble solid was filtered. The filtrate was concentrated to obtain 3,5-dibromo-2,4-dimethylpyridine 1-oxide (400 mg, 1.43 mmol, yield 94%) as a white solid. LC-MS: m / z = 281.1 [M + H] + The retention time was 1.47 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0609] 3,5-Dibromo-4,6-dimethylpicolinonitrile [ka]

[0610] A mixture of 3,5-dibromo-2,4-dimethylpyridine 1-oxide (400 mg, 1.42 mmol), trimethylsilyl cyanide (2.0 mL), and triethylamine (2.0 mL) in acetonitrile (10.0 mL) was stirred at 85°C for 24.0 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 3,5-dibromo-4,6-dimethylpicolinonitrile (240 mg, 0.69 mmol, yield 46%) as a yellow oil. LC-MS: m / z = 291.2 [M + H] + , retention time 1.74 min (Method A).

[0611] 3-Bromo-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinonitrile [ka]

[0612] To a solution of 3,5-dibromo-4,6-dimethylpicolinonitrile (600 mg, 2.07 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (559 mg, 2.07 mmol), and potassium carbonate (343 mg, 2.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (239 mg, 0.21 mmol) was added in N,N-dimethylformamide / water (3.0 mL / 0.3 mL). The mixture was stirred under nitrogen at 45°C for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-bromo-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinonitrile (95 mg, 0.27 mmol, yield 32%) as a yellow solid. LC-MS: m / z = 354.3 [M + H]+, retention time = 1.909 min (Method A).

[0613] 3-Hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinonitrile [ka]

[0614] A mixture of 3-bromo-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinonitrile (90.0 mg, 0.25 mmol), potassium carbonate (106 mg, 0.76 mmol), and benzyl alcohol (270 mg, 2.5 mmol) in N,N-dimethylacetamide (3.0 mL) was stirred at 120 °C for 72.0 hours. The mixture was cooled and evaporated to dry. The resulting residue was purified by reverse-phase preparative HPLC to obtain 3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinonitrile (20 mg, 0.07 mmol, yield 27%) as a white solid. LC-MS: m / z = 291.1 [M + H]+, retention time = 1.40 min (Method A).

[0615] 3-Hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinic acid [ka]

[0616] A solution of 3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinonitrile (20 mg, 0.07 mmol) in ethanol (5.0 mL) was mixed with 1.0 mL of 30% aqueous sodium hydroxide solution. The mixture was stirred at 100°C for 3.0 hours, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid solution. The precipitate was filtered and dried to obtain 3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinic acid (25 mg, crude) as a white solid. LC-MS: m / z = 310.4 [M + H] + The retention time was 1.74 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0617] Ethyl (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycinate [ka]

[0618] A mixture of 3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinic acid (25 mg, 0.08 mmol), ethyl glycinate hydrochloride (17 mg, 0.12 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (50 mg, 0.10 mmol), and triethylamine (380 mg, 3.75 mmol) in dichloromethane (8.0 mL) was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain ethyl (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl) glycinate (20 mg, 0.05 mmol, yield 63%) as a white solid. LC-MS: m / z = 395.1 [M + H] + , retention time 2.13 min (Method A).

[0619] (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine [ka]

[0620] To a solution of ethyl (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycinate (20 mg, 0.05 mmol) in methanol / water (6.0 mL / 3.0 mL), lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added. The mixture was stirred overnight and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine (6.4 mg, 0.017 mmol, yield 36%) as a white solid. LC-MS: m / z = 367.0 [M + H] + , retention time 4.81 min (Method A).1 HNMR(400MHz,DMSO-d6)δ12.49(s,1H),9.18(t,J=6.0Hz,1H),8.73(s,1H),8.01-7.81(m,3H), 7.54(t,J=7.9Hz,2H),7.35(t,J=7.4Hz,1H),4.02(d,J=6.1Hz,2H),2.39(s,3H),2.12(s,3H).

[0621] Example 26: Preparation of Compound 26 3,5-Dichloro-4-methylpyridine 1-oxide [ka]

[0622] To a solution of 3,5-dichloro-4-methylpyridine (9.4 g, 57.7 mmol) in DCM (150 mL) at room temperature, m-CPBA (12.9 g, 74.7 mmol) was gradually added over 2 minutes. The reaction mixture was stirred overnight at room temperature. After the reaction was complete as shown by TLC analysis, K2CO3 (12 g, 87 mmol) was added all at once to the reaction mixture, and the mixture was stirred at room temperature for approximately 2 hours. The resulting suspension was filtered, and the filtrate was concentrated to dryness. The residue was slurryed in a mixed solvent (PE:SiO=50:1, 50 mL) to obtain 7.4 g of the title compound. LC-MS (ESI+): m / z 178 (M+H) + ,

[0623] 3,5-Dichloro-4-methylpicolinonitrile [ka]

[0624] To a solution of 3,5-dichloro-4-methylpyridine 1-oxide (8 g, 44.94 mmol) in MeCN (150 mL) at room temperature, TMS-CN (9 g, 89.88 mmol) and TEA (9.4 mL) were added. The reaction was refluxed overnight. After the reaction was complete as shown by TLC analysis, the reaction was quenched with brine (150 mL) and extracted with EA (150 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ (60 g), filtered, and concentrated under vacuum. The residue was purified by silica column chromatography (PE:SiO₂ = 10:1) to obtain 6.8 g of the title compound. 1 H-NMR (300MHz, CDCl3) δ8.52(s,1H),2.57(s,3H)).

[0625] 3-Chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile [ka]

[0626] Under nitrogen protection, a mixture of 3,5-dichloro-4-methylpicolinonitrile (3.72 g, 20 mmol), B2Pin2 (7.62 g, 30 mmol), Pd(dppf)Cl2 (1.4 g, 2 mmol), and KOAc (5.88 g, 60 mmol) in dioxane (100 mL) was stirred overnight at 100 °C. After the reaction was complete as shown by TLC, the resulting suspension was filtered. The filter cake was washed with HCl (200 mL), and the combined filtrate was concentrated to dryness. The resulting residue was dissolved in aqueous NaOH solution (60 mL, 1 N) and stirred for half an hour. The aqueous solution was washed with HCl (100 mL). After separation, the organic phase was treated again with aqueous NaOH solution (30 mL, 1 N). After separation, the combined aqueous phase was acidified to pH=4-5 with dilute HCl solution (2 N), and a large amount of solid precipitated. The suspension was filtered to obtain 407 mg of the title compound. 1 H-NMR (300MHz, CDCl3) δ8.68 (s, 1H), 2.61 (s, 3H), 1.34 (s, 12H).

[0627] 3-Chloro-4-methyl-5-(2-phenyloxazol-5-yl)picolinonitrile [ka]

[0628] Under nitrogen protection, a mixture of 3-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (270 mg, 0.97 mmol), 5-bromo-2-phenyloxazole (280 mg, 1.2 mmol), Pd(PPh3)4 (138 mg, 0.12 mmol), and K3PO4·H2O (958 g, 3.6 mmol) in dioxane (7 mL) and H2O (0.4 mL) was stirred overnight at 100 °C. After the reaction was complete as shown by TLC analysis, the reaction product was quenched with H2O (10 mL) and extracted with DCM (25 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4 (30 g), filtered, and concentrated under vacuum. The residue was purified by silica column chromatography (DCM) to obtain 250 mg of the title compound. LC-MS (ESI+): m / z 296 (M+H) + ,

[0629] 3-(benzyloxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinonitrile [ka]

[0630] To a solution of 3-chloro-4-methyl-5-(2-phenyloxazole-5-yl)picolinonitrile (250 mg, 0.85 mmol) in THF (12.5 mL) at room temperature, BnOH (184 mg, 1.7 mmol) and t-BuOK (184 mg, 1.7 mmol) were added. The reaction mixture was stirred at 40 °C for 3 hours. After the reaction was complete as shown by TLC analysis, the reaction mixture was quenched with H₂O (20 mL) and extracted with DCM (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ (5 g), filtered, and concentrated under vacuum. The residue was purified by silica column chromatography (PE / Â=5 / 1) to obtain 157 mg of the title compound. LC-MS (ESI+): m / z 368 (M+H) + , 1 H-NMR (300MHz, CDCl3) δ 8.84 (s, 1H), 8.14-8.11 (m, 2H), 7.54-7.50 (m, 6H), 7.44-7.26 (m, 3H), 2.25 (s, 2H), 2.44 (s, 3H).

[0631] 3-(benzyloxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinic acid [ka]

[0632] At room temperature, a solution of 3-(benzyloxy)-4-methyl-5-(2-phenyloxazole-5-yl)picolinonitrile (167 mg, 0.45 mmol) in EtOH (15 mL) was mixed with an aqueous NaOH solution (1.6 mL, 30 wt%). The reaction was stirred overnight at reflux temperature. After the reaction was complete, as shown by LC-MS analysis, the reaction was cooled to room temperature and acidified to pH 4-5 with dilute HCl solution. A large amount of solid precipitated. The suspension was filtered to obtain 158 mg of the title compound. LC-MS (ESI+): m / z 387 (M+H) + ,

[0633] Methyl (3-(benzyloxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycinate [ka]

[0634] To a solution of 3-(benzyloxy)-4-methyl-5-(2-phenyloxazole-5-yl)picolinic acid (158 mg, 0.41 mmol) in DMF (5 mL) at room temperature, methyl glycinate hydrochloride (62 mg, 0.49 mmol), DIEA (212 mg, 1.64 mmol), and HATU (234 mg, 0.45 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete as shown by TLC analysis, the reaction mixture was quenched with H2O (20 mL) and extracted with DCM (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4 (5 g), filtered, and concentrated under vacuum. The residue was purified by silica column chromatography (PE / DCM = 1 / 1) to obtain 115 mg of the title compound. LC-MS (ESI+): m / z 458 (M+H) + , 1 H-NMR(300MHz,CDCl3)δ8.77(s,1H),8.37(brs,1H),8.14-8.11(m,2H),7.55-7.49(m ,6H),7.42-7.35(m,3H),5.13(s,2H),4.29(d,J=6Hz,2H),3.81(s,3H),2.44(s,3H).

[0635] Methyl (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycinate [ka]

[0636] At room temperature, methyl (3-(benzyloxy)-4-methyl-5-(2-phenyloxazole-5-yl)picolinoyl) glycinate (167 mg, 0.45 mmol) was dissolved in MeOH (6 mL) and DCM (3 mL), to which Pd / C (10 wt%, 34 mg) was added. The reaction mixture was stirred for 45 minutes under hydrogen atmosphere pressure from a balloon. After the reaction was complete as shown by TLC analysis, the reaction mixture was filtered through a Celite package. The filtrate was concentrated under vacuum to obtain 80 mg of the title compound. 1 H-NMR (300MHz, CDCl3) δ12.27(s,1H),8.47(s,2H),8.14-8.11(m,2H),7.51(d,J=3.6Hz,4H),4.27(d,J=6Hz,2H),3.83(s,3H),2.50(s,3H).

[0637] (3-Hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine [ka]

[0638] To a solution of methyl (3-hydroxy-4-methyl-5-(2-phenyloxazole-5-yl)picolinoyl) glycinate (80 mg, 0.22 mmol) in THF (5 mL) and H2O (2 mL) at room temperature, LiOH·H2O (92 mg, 2.2 mmol) was added. The reaction was stirred at 50°C for 2 hours. After the reaction was complete as shown by TLC analysis, the reaction was acidified to pH 4-5 with dilute HCl solution (1 N). A large amount of solid precipitated. The suspension was filtered to obtain 45 mg of the title compound. HPLC purity was 99.1%, LC-MS (ESI+): m / z 354(M+H) + , 1 H-NMR(300MHz,DMSO-d6)δ12.95(s,1H),12.85(brs,1H),9.38(t,J=6.0Hz,1H),8.61(s,1 H),8.15-8.12(m,2H),7.95(s,1H),7.64-7.58(m,3H),4.03(d,J=6.0Hz,2H),2.67(s,3H).

[0639] Example 27: Preparation of Compound 27 5-Chloro-4,6'-dimethyl-[3,3'-bipyridine]-6-carbonitrile [ka]

[0640] The compound was synthesized using 5-bromo-2-methylpyridine according to the preparation procedure for 3-chloro-4-methyl-5-(2-phenyloxazole-5-yl)picolinonitrile. LC-MS(ESI+): m / z 244(M+H) + .

[0641] 5-(benzyloxy)-4,6'-dimethyl-[3,3'-bipyridine]-6-carbonitrile [ka]

[0642] The compound was synthesized according to the preparation procedure for 3-(benzyloxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinonitrile. LC-MS(ESI+): m / z 316(M+H) + , 1 H-NMR(300MHz,CDCl3)δ8.45(d,J=1.8Hz,1H),8.30(s,1H),7.55-7.48(m,3H) ,7.55-7.42(m,3H),7.37-7.28(m,1H),5.28(s,2H),2.65(s,3H),2.17(s,3H).

[0643] 5-(benzyloxy)-4,6'-dimethyl-[3,3'-bipyridine]-6-carboxylic acid [ka]

[0644] The compound was synthesized according to the preparation procedure for 3-(benzyloxy)-4-methyl-5-(2-phenyloxazole-5-yl)picolinic acid. LC-MS(ESI+):m / z335(M+H) + , 1 H-NMR (300MHz, DMSO-d6) δ13.45(brs,1H),8.53(d,J=1.8Hz,1H),8.28(s,1H),7.81(dd,J=7.8,2.1Hz,1H),5.03(s,2H),2.55(s,3H),2.15(s,3H).

[0645] Methyl(5-(benzyloxy)-4,6'-dimethyl-[3,3'-bipyridine]-6-carbonyl)glycinate [ka]

[0646] The compound was synthesized according to the preparation procedure for methyl(3-(benzyloxy)-4-methyl-5-(2-phenyloxazole-5-yl)picolinoyl)glycinate. LC-MS(ESI+):m / z406(M+H) + ,

[0647] Methyl(5-hydroxy-4,6'-dimethyl-[3,3'-bipyridine]-6-carbonyl)glycinate [ka]

[0648] The compound was synthesized according to the preparation procedure for methyl(3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycinate. LC-MS(ESI+):m / z316(M+H) + , 1H-NMR(300MHz,CDCl3)δ12.16(s,1H),8.49(d,J=1.8Hz,2H),7.96(s,1H),7.56(dd,J=8.1 Hz,2.1Hz,1H),7.29(s,1H),4.26(d,J=5.7Hz,2H),3.82(s,3H),2.64(s,3H),2.23(s,3H).

[0649] (5-hydroxy-4,6'-dimethyl-[3,3'-bipyridine]-6-carbonyl)glycine [ka]

[0650] The compound was synthesized according to the preparation procedure for (3-hydroxy-4-methyl-5-(2-phenyloxazole-5-yl)picolinoyl)glycine. LC-MS(ESI+):m / z302(M+H) + , 1 H-NMR(300MHz,DMSO-d6)δ12.80(s,1H),9.38(t,J=6Hz,1H),8.53(d,J=1.8Hz,1H),7.8 2-7.79(m,1H),7.42(d,J=8.1Hz,1H),4.01(d,J=6.6Hz,2H),2.55(s,3H),2.16(s,3H).

[0651] Example 28: Preparation of Compound 28 [ka] The compound was synthesized according to the preparation procedure for (3-hydroxy-4-methyl-5-(2-phenyloxazole-5-yl)picolinoyl)glycine. LC-MS(ESI+):m / z338(M+H) + , 1H-NMR(300MHz,DMSO-d6)δ12.86(s,1H),12.80(brs,1H),9.45(t,J=6.Hz,1H),9.00(d,J=2.1Hz,1H),8.53(s,1 H),8.23(s,1H),8.10(t,J=8.1Hz,2H),7.88-7.73(m,1H),7.71-7.68(m,1H),4.03(d,J=6Hz,2H),2.50(s,3H).

[0652] Example 29: Preparation of Compound 29 [ka] The compound was synthesized according to the preparation procedure for (3-hydroxy-4-methyl-5-(2-phenyloxazole-5-yl)picolinoyl)glycine. LC-MS(ESI+):m / z302(M+H) + , 1 H-NMR(300MHz,DMSO-d6)δ12.80(s,1H),9.39(t,J=6.5Hz,1H),8.55(dd,J=4.9,1.8Hz,1H),7.99(s,1H), 7.62(dd,J=7.6,1.8Hz,1H),7.36(dd,J=7.7,4.9Hz,1H),4.00(d,J=6.0Hz,2H),2.25(s,3H),1.96(s,3H).

[0653] Example 30: Preparation of Compound 30 [ka] The compound was synthesized according to the preparation procedure for (3-hydroxy-4-methyl-5-(2-phenyloxazole-5-yl)picolinoyl)glycine. LC-MS(ESI+):m / z367(M+H) + , 1H-NMR(300MHz,DMSO-d6)δ12.88(brs,1H),12.78(s,1H),9.17(d,J=7.7Hz,1H),8.92(s,1H),8.32(s,1H),8.18(s,1H),7.9 4(d,J=8.0Hz,2H),7.55(t,J=7.8Hz,2H),7.37(t,J=7.4Hz,1H),4.51(t,J=7.2Hz,1H),2.37(s,3H),1.47(d,J=7.2Hz,3H).

[0654] Example 31: Preparation of Compound 31 [ka] The compound was synthesized according to the preparation procedure for (3-hydroxy-4-methyl-5-(2-phenyloxazole-5-yl)picolinoyl)glycine. LC-MS(ESI+):m / z367(M+H) + , 1 H-NMR(300MHz,DMSO-d6)δ12.90(brs,1H),12.77(s,1H),9.17(d,J=7.6Hz,1H),8.93(s,1H),8.33(s,1H),8.18(s,1H),7.9 4(d,J=8.0Hz,2H),7.55(t,J=7.8Hz,2H),7.37(t,J=7.4Hz,1H),4.51(t,J=7.4Hz,1H),2.37(s,3H),1.47(d,J=7.2Hz,3H).

[0655] Example 32: Preparation of Compound 32 3,5-Dichloro-4-methylpyridine 1-oxide [ka]

[0656] 3,5-Dichloro-4-methylpyridine (5 g, 30.86 mmol) was dissolved in DCM (70 mL) and cooled to 0°C. m-CPBA (7.85 g, 40.11 mmol) was added lotwise at 0°C. The reaction mixture was stirred overnight at room temperature. LC-MS showed complete conversion to the desired product (MS / 178). K2CO3 (4.427 g, 32.08 mmol) was added. The turbid reaction mixture was stirred for 1 hour. The white precipitate was filtered through a Celite pad, and the filter cake was rinsed with DCM (50 mL). The filtrate was concentrated to obtain a white solid (5.0 g). LC-MS (ESI+): m / z 179.0 (M+H) + .

[0657] 3,5-Dichloro-4-methylpicolinonitrile [ka]

[0658] A mixture of 3,5-dichloro-4-methylpyridine 1-oxide (5 g, 28.087 mmol), TMS-cyanide (5 g, 50.38 mmol), and triethylamine (5.8 mL, 42.29 mmol) in acetonitrile (90 mL) was heated under reflux (85 °C) for 7 hours. The reaction mixture was cooled to room temperature and stirred overnight. The reaction mixture was quenched with aqueous NaHCO3 solution (50 mL). The mixture was diluted with ethyl acetate (100 mL). The layers were separated, the organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (12 g column, 0-100% ethyl acetate in hexane) to obtain a light brown liquid (4.09 g). LC-MS (ESI+): m / z 186.0 (M+H) + .

[0659] 3-Chloro-5-(3-chlorophenyl)-4-methylpicolinonitrile [ka]

[0660] Pd(dppf)Cl2 (0.178 g, 0.243 mmol) was added to a stirred mixture of 3,5-dichloro-4-methylpyridine-2-carbonitrile (1.2 g, 6.416 mmol), (3-chlorophenyl)boronic acid (1 g, 6.416 mmol), and K2CO3 (1.06 g, 7.699 mmol) in DMF (10 mL) and 1 mL of water at room temperature. The resulting mixture was heated at 45°C under nitrogen for 17 hours. TLC (in hexane with 30% ethyl acetate) showed that 90% of the starting material had been consumed. The reaction mixture was diluted with water (20 mL) and ethyl acetate (30 mL) and stirred well. The layers were separated, and the organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (24 g column, 0-50% ethyl acetate in hexane) to obtain the white solid product. ¹H-NMR showed a mixture of 3:8 positional isomers. The mixture was subjected to the following reaction: LC-MS (ESI+): m / z 263.0 (M+H) + .

[0661] 3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinonitrile [ka]

[0662] 4-chloro-6-(3-chlorophenyl)-5-methylpyridine-3-carbonitrile (1.35 g, 5.130 mmol) was dissolved in DMF (10 mL), and the reaction mixture was cooled to 0°C. NaH (60% suspension in mineral oil, 246 mg, 6.156 mmol) was added. After 3 minutes, benzyl alcohol (0.637 mL, 6.156 mmol) was added dropwise at 0°C. The reaction was stirred at 0°C. After 50 minutes, TLC (in hexane with 10% ethyl acetate) showed 90% conversion. The reaction product was quenched with water (20 mL). The mixture was extracted with ethyl acetate (30 mL). The organic layer was dried over Na₂SO₄ and concentrated. The crude product was purified by column chromatography (20 g, in hexane with 0-40% ethyl acetate) to separate the two positional isomers (from the previous reaction). Major product (1.16 g, 67%). The major product showed strong NOE between 8.40 ppm and 7.57-7.42 ppm, indicating it is the desired product. LC-MS (ESI+): m / z 335.0 (M+H) + .

[0663] 3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinic acid [ka]

[0664] A mixture of 4-benzyloxy-6-(3-chlorophenyl)-5-methylpyridine-3-carbonitrile (1.1 g, 3.3 mmol) in ethanol (11 mL) and a 30% aqueous NaOH solution (14 mL) was heated at 100°C for 3 hours. LC-MS showed complete conversion to the desired high polarity. The reaction mixture was cooled to room temperature. The ethanol was evaporated under reduced pressure. The aqueous residue was acidified with concentrated HCl (pH approximately 2), and the pale brown solid was pulverized. The solid was separated by filtration, washed with water, and dried in air to obtain a pale brown solid (1.2 g, 100%). The crude material was used in the following reaction. LC-MS (ESI+): m / z 354.0 (M+H) + .

[0665] Ethyl (3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinoyl)glycinate [ka]

[0666] PyBOP (323 mg, 0.621 mmol) and triethylamine (0.39 mL, 2.862 mmol) were added at room temperature to a stirred mixture of 4-benzyloxy-6-(3-chlorophenyl)-5-methylpyridine-3-carboxylic acid (200 mg, 0.565 mmol) and 2-aminoethyl acetate hydrochloride (79 mg, 0.565 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 2 hours. LC-MS showed that the starting materials were completely consumed. The reaction product was concentrated directly. The crude product was purified by column chromatography (0-100% ethyl acetate in hexane) to obtain a white solid (201 mg, 81%). LC-MS (ESI+): m / z 439.0 (M+H) + .

[0667] Ethyl (5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinoyl)glycinate [ka]

[0668] A stirred mixture of ethyl 2-[[4-benzyloxy-6-(3-chlorophenyl)-5-methylpyridine-3-carbonyl]amino]acetate (201 mg, 0.458 mmol) and 10% Pd-carbon (5 mg) in methanol (1 mL) and ethyl acetate (1 mL) was degassed with hydrogen for 2 minutes and then stirred at room temperature under a hydrogen atmosphere for 12 hours. LC-MS showed complete conversion to the desired product. The reaction mixture was filtered through a Celite pad and rinsed with ethyl acetate (15 mL). The filtrate was concentrated. The crude product (151 mg, 0.429 mmol) was subjected to the next reaction without further purification. LC-MS (ESI+): m / z 349.0 (M+H) + .

[0669] (5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinoyl)glycine [ka]

[0670] 0.5 mL of 1N NaOH aqueous solution was added to a stirred solution of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxy-4-methylpyridine-2-carbonyl]amino]acetate (132 mg, 0.378 mmol) in THF (1.5 mL) and methanol (1.5 mL) at room temperature. The reaction mixture was stirred at 40°C for 1.5 hours. The reaction mixture was directly concentrated to remove THF and methanol. The residue was acidified with 0.6 mL of 1N HCl aqueous solution. The precipitate was filtered, washed with water, and dried in air. The crude product was purified by preparative HPLC (30-80% MeCN in water over 25 minutes). LC-MS(ESI+):m / z321.0(M+H)+, 1H NMR(400MHz,DMSO)δ12.79(s,2H),9.38(t,J=6.1Hz,1H),8.04(d,J=4.7Hz,1 H),7.60-7.46(m,3H),7.46-7.35(m,1H),4.00(d,J=6.2Hz,2H),2.14(s,3H).

[0671] Example 33: Preparation of Compound 33 3-Chloro-4-methyl-5-(naphthalene-2-yl)picolinonitrile [ka]

[0672] Pd(dppf)Cl2 (0.032 g, 0.0248 mmol) was added at room temperature to a stirred mixture of 3,5-dichloro-4-methylpyridine-2-carbonitrile (0.4 g, 2.14 mmol), 2-naphthylboronic acid (368 mg, 2.14 mmol), and K2CO3 (354 mg, 2.57 mmol) in DMF (8 mL) an...

Claims

1. Compound of formula (I): 【Chemistry 1】 (In the formula, R １ This includes unsubstituted C1-3 alkyl groups; halogens, unsubstituted aryl groups, aryl groups substituted with one or more halogens, or C1-7 substituted groups. １～３ Alkyl; or unsubstituted cyclopropyl, R ２ C is hydrogen; unsubstituted C1-3 alkyl; C substituted with one or more halogens. １～３ Alkyl; halogen; CN; or unsubstituted cycloalkyl, R ３ teeth, hydrogen; 【Chemistry 2】 (wherein X is a covalent bond, O, S, SO₂, C1-4 alkylene, C2-4 alkylylene, or C2-4 heteroalkylylene, each A is independently N or CR₁, R₂ and R₁ are independently hydrogen, halogen, OR₁₀, unsubstituted C1-3 alkyl, or C1-3 alkyl substituted with one or more halogens, and R₁₀ is a C1-3 alkyl or aryl); 【Transformation 3】 (wherein B is N or CR11, D is N, NH, or CR11, E is N, CR11, or CHR12, and R11 and R12 are independently hydrogen or C1-3 alkyl, and in the formula, the dashed circle represents the presence or absence of a conjugated system); 【Chemistry 4】 (wherein each G is independently N, NH, NR13, or CR14, where R13 is cyclopropyl, a 3- to 6-membered heterocycloalkyl, an unsubstituted aryl, an aryl substituted with one or more halogens, an aryl substituted with one or more unsubstituted C1- to C3 alkyls, an aryl substituted with one or more halogen-substituted C1- to C3 alkyls, a heteroaryl, a heterocycloalkyl substituted with t-butyloxycarbonyl, an unsubstituted C1- to C4 alkyl, a C1- to C4 alkyl substituted with an unsubstituted aryl, or a C1- to C4 alkyl substituted with one or more halogens, and R14 is hydrogen, a halogen, cyclopropyl, or a C1- to C3 alkyl); 【Transformation 5】 (wherein I is O, S, or CH, J is N or CH, R 15 is hydrogen, cyclopropyl, or C1-3 alkyl, and R 19 is hydrogen, cyclopropyl, or aryl); OR 16 (wherein R 16 is an aryl); 【Transformation 6】 (wherein X1 is N or CH, and R20 is an unsubstituted aryl); and Selected from the group consisting of COR 17 (wherein R 17 is an aryl), R ４ and R ５ are each independently hydrogen, unsubstituted C1-3 alkyl, or C １～３ alkyl substituted with one or more halogens, or R ４ and R ５ together with the carbon to which they are attached form unsubstituted cycloalkyl or unsubstituted heterocycloalkyl, R ６ is an OH or an ester, and R7 is an unsubstituted C1-3 alkyl or an aryl-substituted C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

2. Structure according to formula (I): 【Transformation 7】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl and R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ３ teeth, hydrogen; 【Transformation 8】 (In the formula, X is a covalent bond, O, S, or SO2, and each A is independently N or CR) ９ And R ８ and R ９ These are independently hydrogen, halogen, OR １０ , unsubstituted C1-3 alkyl, or C substituted with one or more halogens １～３ It is alkyl and R １０ C １～３ (It is alkyl or aryl); 【Chemistry 9】 (In the formula, B is N or CR) １１ And D is N, NH, or CR １１ And E is N, CR １１ , or CHR １２ And R １１ and R １２ These are independently hydrogen or C １～３ It is an alkyl group, and in the formula, the dashed circle represents the presence or absence of a conjugated system); 【Chemistry 10】 (In the formula, each G is independently N, NH, NR １３ , or CR １４ And R １３ These include cyclopropyl, 3-6 member heterocycloalkyl, unsubstituted aryl, aryl substituted with one or more halogens, aryl substituted with one or more unsubstituted C1-3 alkyls, and one or more halogen-substituted C1-3 alkyls. １～３ Alkyl-substituted aryls, heteroaryls, t-butyloxycarbonyl-substituted heterocycloalkyls, unsubstituted C1-4 alkyls, unsubstituted aryl-substituted C1-4 alkyls, or aryl-substituted C1-4 alkyls with one or more halogens １～４ It is alkyl and R １４ is hydrogen, halogen, cyclopropyl, or C １～３ (It is alkyl); 【Chemistry 11】 (In the formula, I is O, S, or CH, J is N or CH, and R １５ is hydrogen, cyclopropyl, or C １～３ It is alkyl and R １９ (wherein it is hydrogen, cyclopropyl, or aryl); OR １６ (In the formula, R １６ (is Ariel); 【Chemistry 12】 (In the formula, X １ is N or CH, and R ２０ (is an unsubstituted aryl); and COR １７ (In the formula, R １７ It is selected from the group consisting of (which are aryls), R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form an unsubstituted cycloalkyl or unsubstituted heterocycloalkyl, and R ６ is OH or OR １８ And R １８ C １～６ A compound according to claim 1, having (being alkyl), or a pharmaceutically acceptable salt thereof.

3. Structure according to formula (II): 【Chemistry 13】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl and R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ３ teeth, hydrogen; 【Chemistry 14】 (In the formula, X represents a covalent bond, O, S, SO) ２ , C １～４ Alkylene, C ２～４ Alkynylene, or C ２～４ It is a heteroalkylene, and each A independently corresponds to N or CR ９ And R ８ and R ９ These are independently hydrogen, halogen, OR １０ , unsubstituted C1-3 alkyl, or C substituted with one or more halogens １～３ It is alkyl and R １０ C １～３ (It is alkyl or aryl); 【Chemistry 15】 (In the formula, B is N or CR) １１ And D is N, NH, or CR １１ And E is N, CR １１ , or CHR １２ And R １１ and R １２ These are independently hydrogen or C １～３ It is an alkyl group, and in the formula, the dashed circle represents the presence or absence of a conjugated system); 【Chemistry 16】 (wherein each G is independently N, NR １３ , or CR １４ , and R １３ is cyclopropyl, 3- to 6-membered heterocycloalkyl, unsubstituted aryl, aryl substituted with one or more halogens, aryl substituted with one or more unsubstituted C1-3 alkyls, aryl substituted with one or more halogens and one or more C １～３ alkyls, heteroaryl, unsubstituted heterocycloalkyl, heterocycloalkyl substituted with t-butyloxycarbonyl, unsubstituted C1-4 alkyl, C1-4 alkyl substituted with unsubstituted aryl, or C １～４ alkyl substituted with aryl substituted with one or more halogens, and R １４ is hydrogen, halogen, cyclopropyl, or C １～３ alkyl); 【Chemistry 17】 (In the formula, I is O, S, or CH, J is N or CH, and R １５ is hydrogen, cyclopropyl, or C １～３ It is alkyl and R １９ (wherein it is hydrogen, cyclopropyl, or aryl); OR １６ wherein R １６ is aryl); [Chemistry 18] (In the formula, X １ is N or CH, and R ２０ (is an unsubstituted aryl); and COR １７ (In the formula, R １７ It is selected from the group consisting of (which are aryls), and R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ The compound according to claim 1, having (these carbon atoms, together with the carbon atoms to which they are bonded, form an unsubstituted cycloalkyl or heterocycloalkyl group), or a pharmaceutically acceptable salt thereof.

4. R １ However, C1-3 alkyl, OR7, halogen, unsubstituted aryl, or halogen-substituted aryl C １～３ It is alkyl, and R7 is an unsubstituted C1-3 alkyl or an aryl-substituted C1-3 alkyl, and / or R ３ However, hydrogen, 【Chemistry 19】 (wherein X is a covalent bond or O, each A is independently N or CR9, R8 and R9 are independently hydrogen, halogen, OR10, unsubstituted C1-3 alkyl, or C1-3 alkyl substituted with one or more halogens, and R10 is C1-3 alkyl or aryl); 【Chemistry 20】 (wherein B is N or CR11, D is N, NH, or CR11, E is N, CR11, or CHR12, and R11 and R12 are independently hydrogen or C1-3 alkyl, and in the formula, the dashed circle represents the presence or absence of a conjugated system); 【Chemistry 21】 (wherein each G is independently N, NH, NR13, or CR14, where R13 is cyclopropyl, a 3- to 6-membered heterocycloalkyl, an unsubstituted aryl, an aryl substituted with one or more halogens, an aryl substituted with one or more unsubstituted C1- to C3 alkyls, an aryl substituted with one or more halogen-substituted C1- to C3 alkyls, a heteroaryl, a heterocycloalkyl substituted with t-butyloxycarbonyl, an unsubstituted C1- to C4 alkyl, a C1- to C4 alkyl substituted with an unsubstituted aryl, or a C1- to C4 alkyl substituted with one or more halogens, and R14 is hydrogen, a halogen, cyclopropyl, or a C1- to C3 alkyl); 【Chemistry 22】 (wherein I is O, S, or CH, J is N or CH, R 15 is hydrogen, cyclopropyl, or C1-3 alkyl, and R 19 is hydrogen, cyclopropyl, or aryl); OR 16 (wherein R 16 is an aryl); 【Chemistry 23】 (wherein X1 is N or CH, and R20 is an unsubstituted aryl); and A compound according to claim 1, selected from the group consisting of COR 17 (wherein R 17 is an aryl compound).

5. Structures based on one of the following formulas: Formula (III), 【Chemistry 24】 (In the formula, Each A is independent of N or CR ９ And, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, R ８ and R ９ These are independently hydrogen, halogen, OR １０ , unsubstituted C1-3 alkyl, or C substituted with one or more halogens １～３ It is alkyl, and R １０ C １～３ (It is alkyl or aryl); Formula (IV), 【Chemistry 25】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, R ８ and R ９ These are independently hydrogen, halogen, OR １０ , unsubstituted C1-3 alkyl, or C substituted with one or more halogens １～３ It is alkyl, and R １０ C １～３ (Alkyl or aryl); and Formula (V), 【Chemistry 26】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, R ８ and each R ９ These are independently hydrogen, halogen, OR １０ , unsubstituted C1-3 alkyl, or C substituted with one or more halogens １～３ It is alkyl, and R １０ C １～３ (It is alkyl or aryl.) A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. Structure according to formula (VI): 【Chemistry 27】 (In the formula, B is N or CR １１ And, D is N, NH, or CR １１ And, E is N, CR １１ , or CHR １２ And, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, R １１ and R １２ These are independently hydrogen or C １～３ It is alkyl, and A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having (in the formula, the dashed circle represents the presence or absence of a conjugated system).

7. Structure according to formula (VII): 【Chemistry 28】 , or Structure according to formula (VIII): 【Chemistry 29】 (In the formula, B is N or CR １１ And, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ It is alkyl, or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, and R １２ is hydrogen or C １～３ The compound according to claim 6, having (being alkyl), or a pharmaceutically acceptable salt thereof.

8. Structure by formula (IX): 【Transformation 30】 (In the formula, Each G is independent of N, NH, NR １３ , or CR １４ And, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl and R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R １３ This includes cyclopropyl, unsubstituted aryl, aryl substituted with one or more halogens, aryl substituted with one or more unsubstituted C1-3 alkyls, and C1-3 alkyls. １～３ Alkyl-substituted aryls, heteroaryls, unsubstituted heterocycloalkyls, t-butyloxycarbonyl-substituted heterocycloalkyls, unsubstituted C1-4 alkyls, unsubstituted aryl-substituted C1-4 alkyls, or aryl-substituted C1-4 alkyls with one or more halogens １～４ It is alkyl, and R １４ is hydrogen, halogen, cyclopropyl, or C １～３ A compound according to claim 1, having (being alkyl), or a pharmaceutically acceptable salt thereof.

9. Structures based on one of the following formulas: Formula (X), 【Chemistry 31】 (In the formula, Each G is independent of N, NR １３ , or CR １４ And, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl and R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R １３ This includes cyclopropyl, unsubstituted aryl, aryl substituted with one or more halogens, aryl substituted with one or more unsubstituted C1-3 alkyls, and C1-3 alkyls. １～３ Alkyl-substituted aryls, heteroaryls, unsubstituted heterocycloalkyls, t-butyloxycarbonyl-substituted heterocycloalkyls, unsubstituted C1-4 alkyls, unsubstituted aryl-substituted C1-4 alkyls, or aryl-substituted C1-4 alkyls with one or more halogens １～４ It is alkyl, and R １４ is hydrogen, halogen, cyclopropyl, or C １～３ (It is alkyl); Formula (XI), 【Chemistry 32】 (In the formula, Each G is independent of N or NR １３ And, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl and R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R １３ This includes cyclopropyl, heteroaryl, unsubstituted aryl, aryl substituted with one or more halogens, aryl substituted with one or more unsubstituted C1-3 alkyls, and C1-3 alkyls. １～３ Alkyl-substituted aryls, unsubstituted heterocycloalkyls, t-butyloxycarbonyl-substituted heterocycloalkyls, unsubstituted C1-4 alkyls, unsubstituted aryl-substituted C1-4 alkyls, or aryl-substituted C1-4 alkyls with one or more halogens １～４ It is alkyl, and R １４ is hydrogen, halogen, cyclopropyl, or C １～３ (It is alkyl); Formula (XIIa) or formula (XIIb), 【Transformation 33】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, R １３ This includes cyclopropyl, heteroaryl, unsubstituted aryl, aryl substituted with one or more halogens, aryl substituted with one or more unsubstituted C1-3 alkyls, and C1-3 alkyls. １～３ Alkyl-substituted aryls, unsubstituted heterocycloalkyls, t-butyloxycarbonyl-substituted heterocycloalkyls, unsubstituted C1-4 alkyls, unsubstituted aryl-substituted C1-4 alkyls, or aryl-substituted C1-4 alkyls with one or more halogens １～４ It is alkyl, and R １４ is hydrogen, halogen, cyclopropyl, or C １～３ (It is alkyl); Equation (XIII), 【Transformation 34】 (In the formula, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups, and R １３ (is aryl or heteroaryl); Formula (XIX), 【Chemistry 35】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, and R １３ This includes cyclopropyl, unsubstituted aryl, aryl substituted with one or more halogens, aryl substituted with one or more unsubstituted C1-3 alkyls, and C1-3 alkyls. １～３ Alkyl-substituted aryls, heteroaryls, unsubstituted heterocycloalkyls, t-butyloxycarbonyl-substituted heterocycloalkyls, unsubstituted C1-4 alkyls, unsubstituted aryl-substituted C1-4 alkyls, or aryl-substituted C1-4 alkyls with one or more halogens １～４ (It is alkyl); Formula (XX), 【Transformation 36】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, and R １３ This includes cyclopropyl, unsubstituted aryl, aryl substituted with one or more halogens, aryl substituted with one or more unsubstituted C1-3 alkyls, and C1-3 alkyls. １～３ Alkyl-substituted aryls, heteroaryls, unsubstituted heterocycloalkyls, t-butyloxycarbonyl-substituted heterocycloalkyls, unsubstituted C1-4 alkyls, unsubstituted aryl-substituted C1-4 alkyls, or aryl-substituted C1-4 alkyls with one or more halogens １～４ (It is alkyl); and Formula (XXI), 【Chemistry 37】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups, and R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ (It is alkyl.) A compound according to claim 8, or a pharmaceutically acceptable salt thereof.

10. Structure according to formula (XIV): 【Transformation 38】 (In the formula, I is O, S, or CH, J is either N or CH. R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl and R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R １５ is hydrogen or C １～３ It is alkyl, and R １９ The compound according to claim 1, having (wherein is hydrogen or an aryl atom), or a pharmaceutically acceptable salt thereof.

11. Structure by formula (XV): 【Chemistry 39】 (In the formula, I is O, S, or CH, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, R １５ is hydrogen or C １～３ It is alkyl, and R １９ The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein (where is hydrogen or an aryl atom).

12. Structure by formula (XVI): 【Chemistry 40】 (In the formula, X is O, S, or SO ２ And, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, R ８ and R ９ These are independently hydrogen, halogen, OR １０ , unsubstituted C1-3 alkyl, or C substituted with one or more halogens １～３ It is alkyl, and R １０ C １～３ A compound according to claim 1, having (being alkyl or aryl), or a pharmaceutically acceptable salt thereof.

13. Structure according to formula (XVII): 【Chemistry 41】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, R ８ and R ９ These are independently hydrogen, halogen, OR １０ , unsubstituted C1-3 alkyl, or C substituted with one or more halogens １～３ It is alkyl, and R １０ C １～３ A compound according to claim 1, having (being alkyl or aryl), or a pharmaceutically acceptable salt thereof.

14. Structure according to formula (XVIII): 【Chemistry 42】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, R ８ and R ９ These are independently hydrogen, halogen, OR １０ , unsubstituted C1-3 alkyl, or C substituted with one or more halogens １～３ It is alkyl, and R １０ C １～３ A compound according to claim 1, having (being alkyl or aryl), or a pharmaceutically acceptable salt thereof.

15. Structure by formula (XXII): 【Chemistry 43】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, and R ２０ The compound according to claim 1, having (where is an unsubstituted aryl), or a pharmaceutically acceptable salt thereof.

16. Structure according to formula (XXIII): 【Chemistry 44】 (In the formula, R １ is an unsubstituted C1-3 alkyl, or OR ７ C substituted with halogens, unsubstituted aryls, or halogen-substituted aryls １～３ It is alkyl, or R １ It is cyclopropyl, R ２ This includes hydrogen, halogens, CN, unsubstituted C1-3 alkyls, or C substituted with one or more halogens. １～３ It is alkyl, R ４ and R ５ These are independently hydrogen, unsubstituted C1-3 alkyl, or C substituted with one or more halogens. １～３ Alkyl or R ４ and R ５ These, together with the carbon atoms to which they are bonded, form unsubstituted cycloalkyl or heterocycloalkyl groups. R ７ This refers to unsubstituted C1-3 alkyl or aryl-substituted C １～３ It is alkyl, and R ２０ The compound according to claim 1, having (where is an unsubstituted aryl), or a pharmaceutically acceptable salt thereof.

17. Structure of any one of the compounds 1 to 50 in the table below: Table 1 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

18. Structure of any one of compounds 51-70 in the table below: Table 2 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. The pharmaceutical composition according to claim 19, for use in a method for treating a disease mediated by PHD activity.

21. The pharmaceutical composition according to claim 20, wherein the disease mediated by the PHD activity is ischemic reperfusion injury, inflammatory bowel disease, cancer, liver disease, atherosclerosis, cardiovascular disease, eye disease or condition, anemia, chronic kidney disease, hyperoxia-related disease, respiratory disease, lung disease, respiratory viral infection, or pulmonary viral infection, or the disease is injury and / or failure of one or more organs.

22. The ischemic reperfusion injury is selected from stroke, myocardial infarction, and acute kidney injury. The aforementioned inflammatory bowel disease is ulcerative colitis or Crohn's disease. The aforementioned cancer is colorectal cancer. The aforementioned eye disease or condition is selected from radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia. The aforementioned anemia is anemia associated with chronic kidney disease. The disease associated with the aforementioned hyperoxia is retinopathy of prematurity or bronchopulmonary dysplasia (BPD). The aforementioned respiratory disease is selected from respiratory infection, acute respiratory distress syndrome, pneumonia, and acute lung injury. The lung disease is acute lung injury (ALI), bronchitis, pneumonia, pulmonary fibrosis, asthma, or acute respiratory distress syndrome (ARDS), or The injury and / or failure of one or more organs is acute organ injury or organ failure. The pharmaceutical composition according to claim 21.

23. The pharmaceutical composition according to claim 20, wherein the disease is selected from ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, and liver cirrhosis.