Phd inhibitor compounds, compositions, and methods of use

Abstract

The present invention provides, in part, novel small molecule PHD inhibitors having a structure according to Formula (I) or a subformula thereof: or a pharmaceutically acceptable salt thereof. The compounds provided herein can be useful in treating diseases including cardiac diseases (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), pulmonary diseases (e.g., pulmonary inflammation, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory diseases (e.g., respiratory tract infection, acute respiratory distress syndrome), liver diseases (e.g., acute liver failure and liver fibrosis, and cirrhosis), and kidney diseases (e.g., acute kidney injury and chronic kidney disease), inflammatory bowel disease (IBD), ischemic reperfusion injury (e.g., stroke), and retinopathy of prematurity (ROP).

Description

[0001] Cross-referencing related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 065,642, filed August 14, 2020, which is incorporated herein by reference in its entirety. Background Technology

[0003] Hypoxia is a condition or state in which the oxygen supply is insufficient for normal life functions, such as in the presence of low arterial oxygen supply. Hypoxia can lead to functional and structural damage to cells. Activation of cellular defense mechanisms during hypoxia is mediated by HIF (hypoxia-inducible factor) proteins. In response to hypoxia, the HIFα content increases in most cells due to reduced HIFα prolyl hydroxylation. Prolyl hydroxylation of HIFα is accomplished by a family of proteins, commonly referred to as proteins containing prolyl hydroxylase domains (PHD1, PHD2, and PHD3), also known as HIF prolyl hydroxylases (HPH-3, HPH-2, and HPH-1) or EGLN-2, EGLN-1, and EGLN-3. PHD proteins are oxygen sensors and regulate HIF stability in an oxygen-dependent manner. The three PHD isotypes function differently in the regulation of their HIF and may also have other non-HIF-related regulatory roles.

[0004] In fact, many studies have shown that stabilization of HIF can reduce tissue inflammation and promote tissue repair. Therefore, compounds that can inhibit the activity of PHD proteins could be particularly beneficial new therapies (Lee et al. (2019) Exp. Molecular Medicine 51:68).

[0005] This article describes novel small-molecule PHD inhibitors that are indicated for the treatment of diseases including: heart diseases (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung diseases (e.g., lung inflammation, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory diseases (e.g., respiratory infections, acute respiratory distress syndrome), liver diseases (e.g., acute liver failure and liver fibrosis, and cirrhosis), kidney diseases (e.g., acute kidney injury and chronic kidney disease), inflammatory bowel disease (IBD), ischemic-reperfusion injury (e.g., stroke), and retinopathy of prematurity (ROP). Summary of the Invention

[0006] Furthermore, this invention provides novel small molecule inhibitors of PHD, which are suitable for treating diseases including, but not limited to, the following: heart diseases (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung diseases (e.g., lung inflammation, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory diseases (e.g., respiratory infections, acute respiratory distress syndrome), liver diseases (e.g., acute liver failure and liver fibrosis, i.e., cirrhosis), and kidney diseases (e.g., acute kidney injury and chronic kidney disease), inflammatory bowel disease (IBD), ischemic-reperfusion injury (e.g., stroke), and retinopathy of prematurity (ROP).

[0007] On the one hand, this article provides compounds having a structure according to formula (I).

[0008]

[0009] Or its pharmaceutically acceptable salt, wherein:

[0010] R 1 C is arbitrarily replaced 1-3 Alkyl groups, optionally substituted C 3-6 Cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl;

[0011] R 2 Hydrogen, optionally substituted C 1-3 Alkyl, halogen, CN, or optionally substituted cycloalkyl;

[0012] R 3 The group can be 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 alkynyl.

[0013] R 4 and R 5 C is independently hydrogen, optionally substituted 1-3 Alkyl, or R 4 and R 5 Together with the carbon atom to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups; and

[0014] R 6 For OH or ester (e.g., OR as described herein) 18 ).

[0015] In the implementation scheme, the compound has a structure according to formula (I).

[0016]

[0017] Or its pharmaceutically acceptable salt, wherein:

[0018] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl group, wherein R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl, or R 1 C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl;

[0019] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0020] R 3 Choose from the following groups:

[0021] hydrogen;

[0022] Where X represents covalent bonds, O, S, SO2, and C. 1-4 Alkylene, C 2-4 alkyne or C 2-4 Hypo-yne group; each A is independently N or CR 9 R 8 and R 9 Independent of hydrogen, halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl, and R 10 C 1-3 Alkyl or aryl;

[0023] Where B is N or CR 11 D is N, NH or CR 11 E represents N and CR 11 or CHR 12 And R 11 and R 12 Independently hydrogen or C 1-3 Alkyl groups, wherein the dashed circle indicates the presence or absence of a conjugated system;

[0024] Each G is independently N, NH, NR. 13 or CR 14 ;R 13 C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups.1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl, and R 14 For hydrogen, halogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C 1-3 alkyl;

[0025] Where I represents O, S, or CH, J represents N or CH, and R represents... 15 For hydrogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C 1-3 Alkyl, and R 19 For hydrogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl or aryl;

[0026] OR 16 , where R 16 It is aryl;

[0027] Where X 1 It is N or CH, and R 20 For aryl groups that are optionally substituted; and

[0028] COR 17 , where R 17 It is aryl;

[0029] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon atom to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups; and

[0030] R 6 For OH or OR 18 , where R 18 C 1-6 alkyl.

[0031] In the embodiments, the compound of formula (I) has a structure according to formula (II).

[0032]

[0033] Or its pharmaceutically acceptable salt, wherein:

[0034] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3Alkyl group, wherein R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl, or R 1 C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl;

[0035] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0036] R 3 Choose from the following groups:

[0037] hydrogen;

[0038] Where X represents covalent bonds, O, S, SO2, and C. 1-4 Alkylene, C 2-4 alkyne or C 2-4 Hypo-yne group; each A is independently N or CR 9 R 8 and R 9 Independent of hydrogen, halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl, and R 10 C 1-3 Alkyl or aryl;

[0039] Where B is N or CR 11 D is N, NH or CR 11 E represents N and CR 11 or CHR 12 And R 11 and R 12 Independently hydrogen or C 1-3 Alkyl groups, wherein the dashed circle indicates the presence or absence of a conjugated system;

[0040] Each G is independently N, NR 13 CR 14 R 13 C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl, and R 14 For hydrogen, halogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C 1-3alkyl;

[0041] Where I represents O, S, or CH, J represents N or CH, and R represents... 15 For hydrogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C 1-3 Alkyl, and R 19 For hydrogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl or aryl;

[0042] OR 16 , where R 16 It is aryl;

[0043] Where X 1 It is N or CH, and R 20 For aryl groups that are optionally substituted; and

[0044] COR 17 , where R 17 It is aryl;

[0045] and

[0046] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups.

[0047] In the implementation plan, R 1 C is arbitrarily replaced 1-3 Alkyl groups; and / or

[0048] R 3 It can be hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, carbonyl, or ether.

[0049] In the implementation plan, R 1 For optional OR 7 C or aryl (which may be substituted with halogen) 1-3 Alkyl group, wherein R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl groups; and / or

[0050] R 3 Choose free hydrogen, A group that is formed.

[0051] In the implementation plan, R 3 for

[0052] In the implementation plan, R 1 For the unreplaced C 1-3 Alkyl, R 2 For hydrogen, R 4 and R 5 Each is hydrogen, and R 6 It is OH.

[0053] In the implementation plan, each R 1 and R 2 For the unreplaced C 1-3 Alkyl, R 4 and R 5 Each is hydrogen, and R 6 It is OH.

[0054] In the implementation plan, R 2 For the unreplaced C 1-3 Alkyl, R 3 For hydrogen, R 4 and R 5 Each is hydrogen, and R 6 It is OH.

[0055] In the implementation scheme, the compound has a structure according to formula (III).

[0056]

[0057] Or its pharmaceutically acceptable salt, wherein

[0058] Each A is independently either N or CR 9 ;

[0059] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0060] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0061] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0062] R7 C, which is optionally substituted with an aryl group 1-3 alkyl;

[0063] R 8 and R 9 Independent of hydrogen, halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl; and

[0064] R 10 C 1-3 Alkyl or aryl.

[0065] In the implementation scheme, the compound has a structure according to formula (IV).

[0066]

[0067] Or its pharmaceutically acceptable salt, wherein

[0068] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0069] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0070] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0071] R 7 C, which is optionally substituted with an aryl group 1-3 alkyl;

[0072] R 8 and R 9 Independent of hydrogen, halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl; and

[0073] R 10 C 1-3 Alkyl or aryl.

[0074] In the implementation scheme, the compound has a structure according to formula (V).

[0075]

[0076] Or its pharmaceutically acceptable salt, wherein:

[0077] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0078] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0079] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0080] R 7 C, which is optionally substituted with an aryl group 1-3 alkyl;

[0081] R 8 and each R 9 Independent of hydrogen, halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl; and

[0082] R 10 C 1-3 Alkyl or aryl.

[0083] In the implementation scheme, the compound has a structure according to formula (VI).

[0084]

[0085] Or its pharmaceutically acceptable salt, wherein

[0086] B is N or CR 11 ;

[0087] D is N, NH or CR 11 ;

[0088] E represents N and CR 11 or CHR 12 ;

[0089] R 1 For optional OR 7C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0090] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0091] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0092] R 7 C, which is optionally substituted with an aryl group 1-3 alkyl;

[0093] R 11 and R 12 Independently hydrogen or C 1-3 Alkyl; and

[0094] The dashed circle indicates the presence or absence of a conjugate system.

[0095] In the implementation scheme, the compound has a structure according to formula (VII).

[0096]

[0097] Or its pharmaceutically acceptable salt.

[0098] In the implementation scheme, the compound has a structure according to formula (VIII).

[0099]

[0100] Or its pharmaceutically acceptable salt, wherein:

[0101] B is N or CR 11 ;

[0102] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0103] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0104] R4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0105] R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl; and

[0106] R 12 It is hydrogen or C 1-3 alkyl.

[0107] In the implementation scheme, the compound has a structure according to formula (IX).

[0108]

[0109] Or its pharmaceutically acceptable salt, wherein:

[0110] Each G is independently N, NH, NR 13 or CR 14 ;

[0111] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl group, wherein R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl, or R 1 It is cyclopropyl;

[0112] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0113] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0114] R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl; and

[0115] R 14 It is hydrogen, halogen, cyclopropyl or C 1-3 alkyl.

[0116] In the implementation scheme, the compound has a structure according to formula (X).

[0117]

[0118] Or its pharmaceutically acceptable salt, wherein:

[0119] Each G is independently for N, NR 13 or CR 14 ;

[0120] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl group, wherein R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl, or R 1 It is cyclopropyl;

[0121] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0122] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0123] R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl; and

[0124] R 14 It is hydrogen, halogen, cyclopropyl or C 1-3 alkyl.

[0125] In the implementation scheme, the compound has a structure according to formula (XI).

[0126]

[0127] Or its pharmaceutically acceptable salt, wherein

[0128] Each G is independently either N or NR. 13 ;

[0129] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl group, wherein R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl, or R 1 It is cyclopropyl;

[0130] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0131] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0132] R 13 Cyclopropyl, heteroaryl, aryl optionally substituted with one or more halogens, C optionally substituted with one or more C-aryl groups 1-3 Alkyl-substituted aryl groups, heterocyclic alkyl groups optionally substituted with tert-butoxycarbonyl groups, and C-aryl groups optionally substituted with aryl groups (which are optionally substituted with one or more halogens) 1-4 Alkyl; and

[0133] R 14 It is hydrogen, halogen, cyclopropyl or C 1-3 alkyl.

[0134] In the embodiments, the compound has a structure according to formula (XIIa) or formula (XIIb).

[0135]

[0136] Or its pharmaceutically acceptable salt, wherein:

[0137] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0138] R 2It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0139] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0140] R 7 C, which is optionally substituted with an aryl group 1-3 alkyl;

[0141] R 13 Cyclopropyl, heteroaryl, aryl optionally substituted with one or more halogens, C optionally substituted with one or more C-aryl groups 1-3 Alkyl-substituted aryl groups, heterocyclic alkyl groups optionally substituted with tert-butoxycarbonyl groups, and C-aryl groups optionally substituted with aryl groups (which are optionally substituted with one or more halogens) 1-4 Alkyl; and

[0142] R 14 It is hydrogen, halogen, cyclopropyl or C 1-3 alkyl.

[0143] In the embodiment, the compound has a structure according to formula (XIII).

[0144]

[0145] Or its pharmaceutically acceptable salt, wherein:

[0146] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0147] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon atom to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups; and

[0148] R 13 It is aryl or heteroaryl.

[0149] In the embodiments, the compound has a structure according to formula (XIV).

[0150]

[0151] Or its pharmaceutically acceptable salt, wherein:

[0152] I represents O, S, or CH;

[0153] J is either N or CH;

[0154] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl group, wherein R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl, or R 1 It is cyclopropyl;

[0155] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0156] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0157] R 15 It is hydrogen or C 1-3 Alkyl; and

[0158] R 19 It is hydrogen or aryl.

[0159] In the embodiments, the compound has a structure according to formula (XV).

[0160]

[0161] Or its pharmaceutically acceptable salt, wherein:

[0162] I represents O, S, or CH;

[0163] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0164] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0165] R 4 and R5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0166] R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl; and

[0167] R 15 It is hydrogen or C 1-3 alkyl.

[0168] R 19 It is hydrogen or aryl.

[0169] In the embodiments, the compound has a structure according to formula (XVI).

[0170]

[0171] Or its pharmaceutically acceptable salt, wherein

[0172] X is O, S, or SO2;

[0173] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0174] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0175] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0176] R 7 C, which is optionally substituted with an aryl group 1-3 alkyl;

[0177] R 8 and R 9 Independent of hydrogen, halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl; and

[0178] R10 C 1-3 Alkyl or aryl.

[0179] In the embodiments, the compound has a structure according to formula (XVII).

[0180]

[0181] Or its pharmaceutically acceptable salt, wherein

[0182] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0183] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0184] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0185] R 7 C, which is optionally substituted with an aryl group 1-3 alkyl;

[0186] R 8 and R 9 Independent of hydrogen, halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl; and

[0187] R 10 C 1-3 Alkyl or aryl.

[0188] In the embodiment, the compound has a structure according to formula (XVIII).

[0189]

[0190] Or its pharmaceutically acceptable salt, wherein

[0191] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0192] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0193] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0194] R 7 C, which is optionally substituted with an aryl group 1-3 alkyl;

[0195] R 8 and R 9 Independent of hydrogen, halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl; and

[0196] R 10 C 1-3 Alkyl or aryl.

[0197] In the embodiments, the compound has a structure according to formula (XIX).

[0198]

[0199] Or its pharmaceutically acceptable salt, wherein:

[0200] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0201] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0202] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0203] R 7 C, which is optionally substituted with an aryl group1-3 Alkyl; and

[0204] R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 alkyl.

[0205] In the implementation scheme, the compound has a structure according to formula (XX).

[0206]

[0207] Or its pharmaceutically acceptable salt, wherein:

[0208] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0209] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0210] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0211] R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl; and

[0212] R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 alkyl.

[0213] In the implementation scheme, the compound has a structure according to formula (XXI).

[0214]

[0215] Or its pharmaceutically acceptable salt, wherein:

[0216] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0217] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0218] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon atom to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups; and

[0219] R 7 C, which is optionally substituted with an aryl group 1-3 alkyl.

[0220] In the implementation scheme, the compound has a structure according to formula (XXII).

[0221]

[0222] Or its pharmaceutically acceptable salt, wherein:

[0223] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0224] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0225] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0226] R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl; and

[0227] R20 The aryl group is optionally substituted.

[0228] In the implementation scheme, the compound has a structure according to formula (XXIII).

[0229]

[0230] Or its pharmaceutically acceptable salt, wherein:

[0231] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl, or R 1 It is cyclopropyl;

[0232] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0233] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5 Together with the carbon to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups;

[0234] R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl; and

[0235] R 20 The aryl group is optionally substituted.

[0236] In the implementation plan, R 3 It is not hydrogen.

[0237] In the implementation plan, R 3 It is an unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, or trifluoromethylphenyl.

[0238] In the implementation plan, R 3 OR 16 SR 16 SO2R 16 CH2R 16 CH2CH2R 16 C≡CR 16 Or C≡CCH2OR 16 And R 16 It is aryl. In the implementation scheme, R 16 It is a phenyl group.

[0239] In the implementation plan, R 3 It is pyrrole, tetrazolyl, triazolyl or pyrazolyl, optionally substituted with aryl or cycloalkyl.

[0240] In the implementation plan, R 3 It is piperidinyl or piperazine, optionally substituted with aryl.

[0241] In the implementation plan, R 3 It is either unsubstituted or substituted with cyclopropyl, unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl or trifluoromethylphenyl.

[0242] In the implementation plan, R 3 For COR 17 And R 17 It is aryl. In the implementation scheme, R 17 It is a phenyl group.

[0243] In the implementation plan, R 1 Cyclopropyl or substituted C 1-3 alkyl.

[0244] In the implementation plan, R 1 It is cyclopropyl or difluoromethyl.

[0245] In the implementation plan, R 1 C 1-3 Alkyl group. In the implementation scheme, R 1 It is CH2CH3. In the implementation scheme, R 1 For CH3. In the implementation scheme, R 1 C is replaced by an aryl group (which is substituted by a halogen). 1-3 Alkyl group. In the implementation scheme, R 1 for In the implementation plan, R 1 C replaced by OBn 1-3 Alkyl group. In the implementation scheme, R 1 It is CH2CH2 OBn.

[0246] In the implementation plan, R 2 It is hydrogen. In the implementation scheme, R 2 C 1-3 Alkyl group. In the implementation scheme, R 2 It is CH3.

[0247] In the implementation plan, R 4 It is hydrogen and R 5 It is hydrogen. In the implementation scheme, R 4 It is hydrogen and R 5 C 1-3 Alkyl group. In the implementation scheme, R 5For CH3. In the implementation scheme, R 4 C 1-3 Alkyl and R 5 C 1-3 Alkyl group. In the implementation scheme, R 4 It is CH3 and R 5 It is CH3.

[0248] In the implementation plan, R 4 and R 5 Together with the carbon atom it is attached to, it forms a cycloalkyl or heterocycloalkyl group. In an embodiment, the cycloalkyl group is cyclopropyl. In an embodiment, the cycloalkyl group is cyclobutyl. In an embodiment, the heterocycloalkyl group is...

[0249] In the implementation scheme, the compound is any one of compounds 1 to 50:

[0250]

[0251]

[0252]

[0253]

[0254] Or its pharmaceutically acceptable salt.

[0255] In the implementation scheme, the compound is any one of compounds 51 to 70.

[0256]

[0257]

[0258] Or its pharmaceutically acceptable salt.

[0259] In the embodiments, in the compounds of formula (I) to (XXIII) (e.g., any one of compounds 1 to 70), at least one hydrogen atom is replaced by a deuterium atom.

[0260] In another aspect, the present invention is characterized by a pharmaceutical composition comprising any compound described herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0261] In another aspect, the present invention is characterized by a method of treating a disease mediated by PHD activity, comprising administering to a subject any of the compounds described herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70) or a pharmaceutically acceptable salt thereof.

[0262] In the implementation scheme, the disease mediated by PHD activity is ischemia-reperfusion injury (e.g., stroke, myocardial infarction, or acute kidney injury).

[0263] In the implementation scheme, the disease mediated by PHD activity is inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease).

[0264] In the implementation scheme, the disease mediated by PHD activity is cancer (e.g., colorectal cancer).

[0265] In the implementation plan, the disease mediated by PHD activity is liver disease.

[0266] In the implementation plan, the disease mediated by PHD activity is atherosclerosis.

[0267] In the implementation plan, the disease mediated by PHD activity is cardiovascular disease.

[0268] In the implementation scheme, 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).

[0269] In the implementation scheme, the disease mediated by PHD activity is anemia (e.g., anemia associated with chronic kidney disease).

[0270] In the implementation plan, the disease mediated by PHD activity is chronic kidney disease.

[0271] In the implementation plan, diseases mediated by PHD activity are associated with hyperoxia.

[0272] In the implementation plan, the disease mediated by PHD activity is retinopathy of prematurity.

[0273] In the implementation plan, the disease mediated by PHD activity is bronchopulmonary dysplasia (BPD).

[0274] In the implementation plan, 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, and cirrhosis.

[0275] In the implementation plan, the diseases mediated by PHD activity are respiratory diseases, lung diseases, respiratory viral infections, or lung viral infections.

[0276] In the implementation plan, respiratory diseases are selected from respiratory infections, acute respiratory distress syndrome, lung inflammation, pneumonia, and acute lung injury.

[0277] In the implementation plan, lung diseases are acute lung injury (ALI), bronchitis, pneumonia, pulmonary fibrosis, asthma, or acute respiratory distress syndrome (ARDS).

[0278] In the implementation scheme, the disease mediated by PHD activity is damage and / or failure of one or more organs (e.g., acute organ damage or organ failure). Attached Figure Description

[0279] Figure 1 This is an exemplary schematic diagram illustrating the TR-FRET assay principle of PHD enzymes (PHD1, PHD2, and PHD3). In the presence of 2-oxoglutarate and O2, the PHD enzymes hydroxylate the proline 564 of the biotin-labeled HIF-1α peptide, thereby producing biotin-labeled HIF-1α-hydroxyproline, succinate, and CO2. The close proximity of the donor fluorophore complex (monoclonal antibody anti-6His-Terbium(Tb)-cryptate Gold) bound to the His-labeled VHL protein / EloB / EloC complex (His-VBC) and the acceptor fluorophore bound to HIF-1α-hydroxyproline (SA-D2 complex) produces a detectable and quantifiable fluorescence resonance energy transfer signal. Detailed Implementation

[0280] definition

[0281] To facilitate understanding of this invention, certain terms are defined below. Additional definitions for these terms, along with others, are set forth throughout the specification. Publications and other references cited herein to describe the background of the invention and to provide additional details on its practice are incorporated herein by reference.

[0282] Animal: As used herein, the term "animal" means any member of the animal kingdom. In some embodiments, "animal" means a human being at any developmental stage. In some embodiments, "animal" means a non-human animal at any developmental stage. In some 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 worms. In some embodiments, an animal may be a transgenic animal, a genetically engineered animal, and / or a clone.

[0283] Approximately or about: As used herein, the term “approximately” or “about” applied to one or more values ​​of interest means a value similar to the reference value. In some embodiments, unless otherwise stated or otherwise obvious from the context (except where the value would exceed 100% of the possible value), the term “approximately” or “about” means a range of values ​​in either direction (greater than or less than) that are 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the reference value.

[0284] As used in the specification and appended claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” may include a plural of indicators. Thus, for example, reference to “a composition” includes a mixture of two or more such compositions.

[0285] Throughout the description and claims of this specification, the word "comprise" and other forms of the word, such as "comprising" and "comprises," mean "including but not limited to" and are not intended to exclude, for example, other additives, components, integers, or steps.

[0286] "Optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes instances where the event or situation occurs and instances where the event or situation does not occur.

[0287] Improvement, increase, or decrease: As used herein, the terms “improvement,” “increase,” or “decrease,” or their grammatical equivalents, refer to a value relative to a baseline measurement, such as a measurement in the same individual prior to the initiation of the treatment described herein, or a measurement in a control subject (or multiple control subjects) in the absence of the treatment described herein. A “control subject” is a subject who has the same form of disease as the treated subject and whose age is approximately the same as that of the treated subject.

[0288] In vitro: As used herein, the term “in vitro” refers to events that occur in an artificial environment, such as in a test tube or reactor, in cell culture, etc., rather than in a multicellular organism.

[0289] In vivo: As used herein, the term "in vivo" refers to events occurring in a multicellular organism, such as humans and non-human animals. In the context of cell-based systems, the term may be used to refer to events occurring within living cells (as opposed to, for example, in vitro systems).

[0290] Patient: As used herein, the terms "patient" or "subject" refer to any organism to which the provided composition may be administered, for example, for experimental, diagnostic, preventative, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. Humans include both prenatal and postnatal forms.

[0291] Pharmaceutically acceptable: As used herein, the term “pharmaceutically acceptable” means a substance that, to the extent of reasonable medical judgment, is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0292] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. described pharmaceutically acceptable salts in detail in the Journal of Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are those 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 formed by other methods used in the art, such as ion exchange, and containing an amino group. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, sodium p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N+(C1-4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium salts. Quaternary ammonium salts and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, sulfonate, and arylsulfonate ions are also acceptable. Other pharmaceutically acceptable salts include those formed by quaternizing amines with suitable electrophilic agents (e.g., alkyl halides) to form quaternized alkylated amino salts.

[0293] Subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Humans include both prenatal and postnatal forms. In many embodiments, the subject is a human. A subject can be a patient, which refers to a human presented to a healthcare provider for the diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject may have a disease or condition or be susceptible to a disease or condition, but may or may not exhibit symptoms of said disease or condition.

[0294] Essentially: As used herein, the term “essentially” refers to a qualitative condition that exhibits the total or near-total range or degree of the characteristic or property of interest. Those skilled in the art of biology will understand that biological and chemical phenomena rarely complete and / or begin to complete or achieve or avoid absolute results. Therefore, the term “essentially” is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0295] Therapeutic effective amount: As used herein, the term "therapeutic effective amount" means an amount sufficient to treat, diagnose, prevent, and / or delay the onset of symptoms of a disease, condition, and / or symptom when administered to a subject who has or is susceptible to the disease, condition, and / or symptom. Those skilled in the art will understand that a therapeutic effective amount is typically administered via a dosing regimen comprising at least one unit dose.

[0296] Treatment: As used herein, the terms “treat,” “treatment,” or “treating” mean any method used to partially or completely alleviate, improve, reduce, suppress, prevent, delay the onset of, reduce the severity of one or more symptoms or features of a particular disease, condition, and / or symptom, and / or symptom, and / or reduce their incidence. Treatment may be administered to subjects who do not exhibit signs of disease and / or only exhibit early signs of disease, in order to reduce the risk of developing disease-related pathology.

[0297] Aliphatic: As used in this article, the term aliphatic refers to C 1- C 40 Hydrocarbons, including both saturated and unsaturated hydrocarbons. Aliphatic hydrocarbons can be straight-chain, branched, or cyclic. For example, C1-C... 20 Aliphatic can include C1-C 20 Alkyl groups (e.g., straight-chain or branched C1-C) 20 saturated alkyl), C2-C 20 Alkenyl (e.g., straight-chain or branched C4-C) 20 Dieneyl, straight-chain or branched C6-C 20 Trienyl groups, etc., and C2-C 20 Alkyne groups (e.g., straight-chain or branched C2-C) 20 Alkyne group). C1-C 20 Aliphatic ali ... 20 Cyclic aliphatic (e.g., C3-C) 20 cycloalkyl, C4-C 20 Cycloalkenyl or C8-C 20(Cycloalkynyl). In some 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 optionally be substituted with one or more substituents, such as alkyl, halogen, alkoxy, hydroxyl, 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 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', wherein each instance of R' is independently C1-C1. 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl or C1-C3 alkyl). In some embodiments, R' is independently an unsubstituted alkyl group (e.g., an unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl or C1-C3 alkyl). In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the aliphatic group is unsubstituted. In some embodiments, the aliphatic group does not include any heteroatoms.

[0298] Alkyl: As used herein, the term "alkyl" means non-cyclic straight-chain and branched hydrocarbon groups, such as "C1-C". 20 "Alkyl" refers to an alkyl group having 1 to 20 carbon atoms. Alkyl groups can be straight-chain or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentylhexyl, isohexyl, etc. The term "low carbon number alkyl" means an alkyl group having 1 to 6 carbon atoms, whether straight-chain or branched. Other alkyl groups will be apparent to those skilled in the art in view of the benefits of this disclosure. Alkyl groups can be unsubstituted or substituted with one or more substituents as described herein. For example, an alkyl group can 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', wherein each instance of R' is independently C1-C. 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C10 Alkyl or C1-C3 alkyl). In some embodiments, R' is independently an unsubstituted alkyl group (e.g., an unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl or C1-C3 alkyl. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the alkyl group is substituted (e.g., substituted by 1, 2, 3, 4, 5, or 6 substituents as described herein). In some embodiments, the alkyl group is substituted with a -OH group and may also be referred to herein as "hydroxyalkyl", wherein the prefix indicates a -OH group and "alkyl" is as described herein. In some embodiments, the alkyl group is substituted with a -OR' group and may also be referred to herein as "alkoxy".

[0299] Adding the suffix "-ene" to a group indicates that the group is a divalent moiety. For example, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0300] Alkylene: As used herein, the term "alkylene" refers to a saturated divalent straight-chain or branched hydrocarbon group, and exemplified by methylene, ethylene, isopropylene, etc. Similarly, as used herein, the term "alkenylene" refers to an unsaturated divalent straight-chain or branched hydrocarbon group having one or more unsaturated carbon-carbon double bonds, which may be present at any stable point along the chain, and the term "alkynylene" herein refers to an unsaturated divalent straight-chain or branched hydrocarbon group having one or more unsaturated carbon-carbon triple bonds, which may be present at any stable point along the chain. In some embodiments, alkylene, alkenylene, or alkynylene may comprise one or more cyclic aliphatic and / or one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may optionally be substituted with one or more substituents, such as alkyl, halogen, alkoxy, hydroxyl, amino, aryl, ether, ester, or amide. For example, an alkylene, alkenylene, or ynylene 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', wherein each instance of R' is independently C1-C. 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl or C1-C3 alkyl). In some embodiments, R' is independently an unsubstituted alkyl group (e.g., an unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C15 Alkyl, C1-C 10 Alkyl or C1-C3 alkyl). In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the alkylene, alkenyl, or ynylene groups are unsubstituted. In some embodiments, the alkylene, alkenyl, or ynylene groups do not include any heteroatoms.

[0301] Alkynyl: As used herein, "alkenyl" means any straight or branched hydrocarbon chain having one or more unsaturated carbon-carbon double bonds, which may be present at any stability point along the chain, such as "C2-C". 20 "Alkenyl" refers to an alkenyl group having 2 to 20 carbons. Examples of alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, etc. In some embodiments, the alkenyl group comprises 1, 2, or 3 carbon-carbon double bonds. In some embodiments, the alkenyl group comprises a single carbon-carbon double bond. In some embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. The alkenyl group may not be... The alkenyl group may be substituted or replaced by one or more substituents as described herein. For example, the alkenyl group may be substituted by 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', wherein each instance of R' is independently C1-C. 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl or C1-C3 alkyl). In some embodiments, R' is independently an unsubstituted alkyl group (e.g., an unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl or C1-C3 alkyl). In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the alkenyl group is unsubstituted. In some embodiments, the alkenyl group is substituted (e.g., substituted by 1, 2, 3, 4, 5, or 6 substituents as described herein). In some embodiments, the alkenyl group is substituted with a -OH group and may also be referred to herein as "hydroxyalkenyl," wherein the prefix indicates a -OH group and "alkenyl" is as described herein.

[0302] Alkynyl: As used herein, "alkynyl" means any hydrocarbon chain having a straight-chain or branched configuration with one or more carbon-carbon triple bonds, said carbon-carbon triple bonds being present at any stable point along the chain, for example, "C2-C".20 "Alynyl" refers to an alkynyl group having 2 to 20 carbon atoms. Examples of alkynyl groups include prop-2-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-2-alkynyl, 3-methylpent-4-alkynyl, hex-2-alkynyl, hex-5-alkynyl, etc. In some embodiments, the alkynyl group comprises a 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', wherein each instance of R' is independently C1-C. 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl or C1-C3 alkyl). In some embodiments, R' is independently an unsubstituted alkyl group (e.g., an unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl or C1-C3 alkyl. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the alkynyl group is unsubstituted. In some embodiments, the alkynyl group is substituted (e.g., substituted by 1, 2, 3, 4, 5 or 6 substituents as described herein).

[0303] Aryl: The term "aryl" used alone or as part of a larger portion such as "araneyl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein the ring system has a single attachment point to the rest of the molecule, at least one ring in the system is aromatic, and each ring in the system contains four to seven ring members. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has ten 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., anthracene). "Aryl" also includes ring systems in which, as defined above, the aryl ring is fused with one or more carbocyclic or heterocyclic groups, wherein the groups or attachment sites are on the aryl ring, and in such instances, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Exemplary aryl groups include phenyl, naphthyl, and anthracene.

[0304] arylene: As used herein, the term "arylene" refers to a divalent aryl group (i.e., having two attachment sites with the molecule). Exemplary arylenes include phenylene (e.g., unsubstituted or substituted phenylene).

[0305] Halogen or halogen group: As used herein, the term “halogen” or “halogen group” means fluorine, chlorine, bromine or iodine.

[0306] Amide: The term “amide” or “amide group” means having the formula -C(O)N(R')2, -C(O)N(R')-, -NR'C(O)R', -NR'C(O)N(R')2- or -NR'C(O)-, wherein each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (by carbon-chain linkage), cycloalkyl, aryl, arylalkyl, heteroaryl (by carbon-ring linkage), heteroarylalkyl or heterocycloalkyl (by carbon-ring linkage), and unless otherwise stated in the specification, each part may optionally be substituted as described herein, or the two R' may be combined with a nitrogen atom to form a 3-, 4-, 5-, 6- or 7-membered ring.

[0307] Amine: The term “amino” or “amine” refers to a -N(R')2 group, wherein each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (by carbon-chain linkage), cycloalkyl, aryl, arylalkyl, heteroaryl (by carbon-ring linkage), heteroarylalkyl, heterocycloalkyl (by carbon-ring linkage), sulfonyl, amide, or carbonyl. Unless otherwise stated in the specification, each part may optionally be substituted as described herein, or both R' may be combined with a nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. In some embodiments, the amino group is -NHR', wherein R' is an aryl (“arylamino”), heteroaryl (“heteroarylamino”), amide, or alkyl (“alkylamino”).

[0308] Ether: The term “ether” refers to an R'-O-R' group, wherein each R' is independently selected from alkyl, heteroalkyl (by chain carbon bond), arylalkyl, heteroarylalkyl (by cyclic carbon bond), cycloalkyl, aryl, heteroaryl (by cyclic carbon bond), and each part may optionally be substituted as described herein unless otherwise stated in the specification.

[0309] Ester: The term “ester” refers to an R'-C(=O)OR group, wherein each R' is independently selected from alkyl, heteroalkyl (by chain carbon bond), arylalkyl, heteroarylalkyl, heterocycloalkyl (by ring carbon bond), cycloalkyl, aryl, heteroaryl (by ring carbon bond), and each part may optionally be substituted as described herein unless otherwise stated in the specification.

[0310] Sulfonyl group: The term "sulfonyl group" refers to a -S(=O)2R' or -S(=O)2- group, wherein R' is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (by carbon-chain bonding), amino, cycloalkyl, aryl, aralkyl, heteroaryl (by carbon-ring bonding), heteroarylalkyl, heterocycloalkyl (by carbon-ring bonding), and each part may optionally be substituted as described herein unless otherwise stated in the specification. For example, in one embodiment, the sulfonyl group is -SO2R', wherein R' is an alkyl group substituted with a carbonyl group.

[0311] Sulphinyl group: The term “sulphinyl group” refers to a chemical part having the formula -S(=O)R', -S(=O)- or -S(=O)(=NR')-, wherein R' is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (by carbon-chain linkage), cycloalkyl, aryl, aralkyl, heteroaryl (by carbon-ring linkage), heteroarylalkyl, heterocycloalkyl (by carbon-ring linkage), and each part may optionally be substituted as described herein unless otherwise stated in the specification.

[0312] Carbonyl: The term “carbonyl” refers to a -C(=O)R’ or -C(=O)- group, wherein R’ is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (by carbon-chain linkage), cycloalkyl, aryl, aralkyl, amino, hydroxyl, heteroaryl (by carbon-ring linkage), heteroarylalkyl, heterocycloalkyl (by carbon-ring linkage), and each part may optionally be substituted as described herein unless otherwise stated in the specification.

[0313] Phosphoryl group: The term “phosphoryl group” refers to a -P(=O)(R')2 or -P(=O)(R')- group, wherein R' is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (by carbon atom or by heteroatom), cycloalkyl, aryl, aralkyl, heteroaryl (by carbon atom), heteroarylalkyl or heterocycloalkyl (by carbon atom), unless otherwise stated in the specification, each part may optionally be as described herein, or the two R' may be combined with a nitrogen atom to form a 3-, 4-, 5-, 6- or 7-membered ring.

[0314] Heteroalkyl: The term "heteroalkyl" means a branched or unbranched alkyl, alkenyl, or alkynyl group having 1 to 14 carbon atoms in addition to 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyl groups include tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphate diesters, aminophosphates, sulfonamides, and disulfides. Heteroalkyl groups may optionally include monocyclic, bicyclic, or tricyclic rings, wherein each ring ideally has three to six members. Examples of heteroalkyl groups include polyethers, such as methoxymethyl and ethoxyethyl.

[0315] Heteroalkyl: As used herein, the term “heteroalkyl” refers to the divalent form of heteroalkyl as described herein.

[0316] Heteroaryl: As used herein, the term “heteroaryl” refers to a monocyclic, bicyclic, or tricyclic carbocyclic system having a total of six to fourteen ring members, wherein the ring system has a single connection point with the rest of the molecule, wherein at least one ring in the system is aromatic, wherein each ring in the system contains four to seven ring members, and wherein at least one ring atom is a heteroatom, such as, but not limited to, nitrogen and oxygen.

[0317] Heterocyclic alkyl: As used herein, the term "heterocyclic alkyl" is a non-aromatic ring in which at least one atom is a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atom is carbon. Heterocyclic alkyl may be substituted or unsubstituted.

[0318] Deuterium: The term "deuterium" ("D" or "...") 2 H”) is also called deuterium. Deuterium is an isotope of hydrogen, in which the nucleus consists of one proton and one neutron, and has twice the mass of the nucleus of a normal hydrogen atom (one proton).

[0319] Isotopes: The term "isotope" refers to variants of a particular chemical element that differ in the number of protons, and therefore the number of nucleons. All isotopes of a given element have the same number of protons in each atom but different numbers of neutrons.

[0320] The term "substituted" means that a specific group or part contains one or more substituents. The term "unsubstituted" means that the specified group does not contain any 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 in the system where the valence is allowed, such as substitution producing a stable compound (e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reactions). Where a specified part or group is not explicitly stated to be optionally substituted or substituted by any specified substituent, it should be understood that such part or group is intended to be unsubstituted.

[0321] When a ring system (e.g., cycloalkyl, heterocyclic, aryl, or heteroaryl) is substituted by multiple substituents varying within a well-defined range, it should be understood that the total number of substituents does not exceed the normally usable valence under existing conditions. It should also be understood that the presence of hydrogen atoms to fill the remaining valence of the ring system is assumed. Substituted groups only encompass combinations of substituents and variations that produce stable or chemically viable compounds. A stable or chemically viable compound is one that, among other things, possesses stability sufficient to allow its preparation and detection.

[0322] Various substituents are well known, and methods for forming substituents and introducing them into various parent groups are also well known. Representative substituents include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aralkyl, alkylaryl, aryl, arylalkoxy, arylamino, heteroarylamino, heteroaryl, heteroarylalkoxy, heterocycloalkyl, hydroxyalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxylalkyl, imidazolylalkyl, indolylalkyl, monohaloalkyl, dihaloalkyl and trihaloalkyl, monohaloalkoxy, dihaloalkoxy and trihaloalkoxy, amino, alkylamino, dialkylamino, amide, cyano, alkoxy, hydroxy, sulfonamide, halogen (e.g., -Cl and -Br), nitro, hydroxyimino, -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 ), where R 50 R 51 and R 52 It can be independently selected from the following: hydrogen atoms and branched or straight-chain C atoms. 1-6 Alkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic alkyl, heteroaryl, and aryl groups, with or without substituents. Where permissible, R 50 and R 51 They can connect together to form carbon rings or heterocyclic systems.

[0323] In a preferred embodiment, the substituent is selected from halogens, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', and -SO2R', wherein each instance of R' is independently C1-C.20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl or C1-C3 alkyl). In some embodiments, R' is independently an unsubstituted alkyl group (e.g., an unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl or C1-C3 alkyl). Preferably, R' is independently an unsubstituted C1-C3 alkyl.

[0324] Any formula given herein is intended to represent compounds having the structure described in the structural formula, as well as certain variations or forms. Specifically, compounds of any formula given herein may have an asymmetric center and thus exist in different enantiomeric forms. All optical and stereoisomers of the general formula compound, as well as mixtures thereof, are considered to be within the scope of the stated formula. Therefore, any formula given herein is intended to represent racemic mixtures, one or more enantiomeric forms, one or more diastereomeric forms, one or more transisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as transisomers. Additionally, any formula given herein is intended to include hydrates, solvates, and polymorphs of such compounds, as well as mixtures thereof.

[0325] The compounds of the present invention

[0326] This document discloses compounds as potent inhibitors of PHD. In some embodiments, the compounds of the present invention have an enzyme half-maximal inhibitory concentration (IC50) of less than 100 μM against any of PHD1, PHD2, and PHD3. 50 ( ) value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2 and PHD3 having an IC value of less than 50 μM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of less than 25 μM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any of PHD1, PHD2, and PHD3 having an IC value of less than 20 μM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of less than 15 μM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of less than 10 μM. 50Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of less than 5 μM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of less than 1 μM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of about 3 nM to about 5 nM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of about 5 nM to about 10 nM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of about 10 nM to about 20 nM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of about 20 nM to about 50 nM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of about 50 nM to about 100 nM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of about 100 nM to about 200 nM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of about 200 nM to about 500 nM. 50 Value. In some embodiments, the compounds of the present invention are targeted at any one of PHD1, PHD2, and PHD3 having an IC value of about 500 nM to about 1000 nM. 50 value.

[0327] Representative examples from the aforementioned categories demonstrate inhibitory activity against PHD1, PHD2, and PHD3 in vitro.

[0328] This article describes exemplary compounds.

[0329] Compounds of formulas (I) to (XXIII)

[0330] Specifically, the PHD inhibitors described in this article are characterized by the 3-hydroxypyridine carboxamide moiety. The applicant unexpectedly discovered R 1 The 3-hydroxypyridine carboxamide moiety (R) at the site 1 Substitution (excluding hydrogen) can significantly increase the potency of inhibitors. Examples of such substitutions include, but are not limited to, substituted or unsubstituted alkyl groups.

[0331] On the one hand, this article provides compounds having a structure according to formula (I):

[0332]

[0333] Or its pharmaceutically acceptable salt, wherein:

[0334] R 1 C is arbitrarily replaced 1-3 Alkyl groups, optionally substituted C 3-6 Cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl;

[0335] R 2 Hydrogen, optionally substituted C 1-3 Alkyl, halogen, CN, or optionally substituted cycloalkyl;

[0336] R 3 The group can be 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 alkynyl.

[0337] R 4 and R 5 C is independently hydrogen, optionally substituted 1-3 Alkyl, or R 4 and R 5 Together with the carbon atom to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups; and

[0338] R 6 For OH or ester (e.g., OR as described herein) 18 ).

[0339] In the implementation plan, R 1 It is the unreplaced C 1-3 Alkyl group. In the implementation scheme, R 1 The C that was replaced 1-3 Alkyl groups (e.g., C164 ... 1-3 alkyl).

[0340] In the implementation plan, R 1 It is the unreplaced C 3-6 Cycloalkyl (e.g., unsubstituted cyclopropyl). In the embodiments, R 1 The C that was replaced 3-6 Cycloalkyl groups (e.g., C1646-C ... 3-6 (cycloalkyl).

[0341] In the implementation plan, R 1 It is an unsubstituted 3- to 6-membered heterocyclic alkyl group. In the embodiments, R 1 It is a substituted 3- to 6-membered heterocyclic alkyl group (e.g., a 3- to 6-membered heterocyclic alkyl group including 1, 2 or 3 substituents).

[0342] In the implementation plan, R 2 It is hydrogen. In the implementation scheme, R 2 C is arbitrarily replaced 1-3 Alkyl group. In the implementation scheme, R 2 It is the unreplaced C 1-3 Alkyl group. In the implementation scheme, R 2 The C that was replaced 1-3 Alkyl groups (e.g., C164 ... 1-3 Alkyl). In the implementation scheme, R 2 It is a halogen. In the implementation plan, R 2 For CN. In the implementation plan, R 2 It is an optionally substituted cycloalkyl group (e.g., C10, C20, C30, C40 3-6 (Cycloalkyl). In the implementation scheme, R 2 It is an unsubstituted cycloalkyl group. In the implementation scheme, R 2 It is a substituted cycloalkyl group (e.g., a cycloalkyl group including 1, 2 or 3 substituents).

[0343] In the implementation plan, R 3 It is hydrogen. In the implementation scheme, R 3 It is an unsubstituted aryl group (e.g., phenyl, naphthalene). In the embodiments, R 3 It is a substituted aryl group (e.g., phenyl, naphthalene). In the embodiments, R 3 It is an unsubstituted heteroaryl group (e.g., quinolone, isoquinoline, pyridine, pyrazole, pyrrole, triazole, tetraazole, oxazole, thiazole). In the embodiments, R 3 It is a substituted heteroaryl group (e.g., quinolone, isoquinoline, pyridine, pyrazole, pyrrole, triazole, tetraazole, oxazole, thiazole). In the embodiments, R 3 It is an unsubstituted cycloalkyl group. In the implementation scheme, R 3 It is a substituted cycloalkyl group. In the implementation, R 3 It is an unsubstituted heterocyclic alkyl group (e.g., an N-containing heterocyclic alkyl group). In the embodiments, R 3 It is a substituted heterocyclic alkyl group (e.g., an N-containing heterocyclic alkyl group). In the embodiments, R 3 It is a carbonyl group (e.g., COR). 17 , where R 17(This is based on any implementation described herein). In the implementation, R 3 It is an ether (e.g., OR) 16 , where R 16 (This is based on any implementation described herein). In the implementation, R 3 For sulfides (e.g., SR) 16 , where R 16 (This is based on any implementation described herein). In the implementation, R 3 It is an unsubstituted aryl sulfonyl group (e.g., benzenesulfonyl). In the embodiments, R 3 It is a substituted arylsulfonyl group. In the embodiments, R 3 It is an unsubstituted heteroarylsulfonyl group. In the embodiments, R 3 It is a substituted heteroarylsulfonyl group. In the embodiments, R 3 It is an unsubstituted aralkyl group (e.g., a phenylalkyl group). In the embodiments, R 3 It is a substituted aralkyl group (e.g., a phenylalkyl group). In the embodiments, R 3 It is an unsubstituted alkynyl group. In the implementation scheme, R 3 It is a substituted alkynyl group (e.g., an aryl-substituted alkynyl group). In the embodiments, R 3 It is an unsubstituted heteroyne group. In the implementation scheme, R 3 It is a substituted pyrynyl group (e.g., a pyrynyl group substituted with an aryl group). In the embodiments, R 3 OR 16 SR 16 SO2R 16 CH2R 16 CH2CH2R 16 C≡CR 16 Or C≡CCH2OR 16 And R 16 It is an aryl group.

[0344] In the implementation plan, R 4 and R 5 Independently hydrogen or optionally substituted C 1-3 Alkyl group. In the implementation scheme, R 4 and R 5 Independently hydrogen or unsubstituted C 1-3 Alkyl group. In the implementation scheme, R 4 and R 5 Each is hydrogen. In the implementation plan, R 4 and R 5 One is hydrogen and the other is unsubstituted C. 1-3 Alkyl group. In the implementation scheme, R 4 and R5 Each is an unreplaced C 1-3 Alkyl group. In the implementation scheme, R 4 and R 5 Together with the carbon to which it is attached, it forms an optionally substituted cycloalkyl group (e.g., C10). 3-6 (Cycloalkyl). In the implementation scheme, R 4 and R 5 Together with the carbon it is attached to, it forms an unsubstituted cycloalkyl group (e.g., an unsubstituted C10). 3-6 (Cycloalkyl). In the implementation scheme, R 4 and R 5 Together with the carbon atom it is attached to, it forms an optionally substituted heterocyclic alkyl group (e.g., a 3- to 6-membered heterocyclic alkyl group). In an embodiment, R 4 and R 5 Together with the carbon to which it is attached, it forms an unsubstituted heterocyclic alkyl group (e.g., an unsubstituted 3- to 6-membered heterocyclic alkyl group).

[0345] In the implementation plan, R 6 It is hydrogen. In the implementation scheme, R 6 For esters (e.g., OR as described herein) 18 In the implementation plan, R 6 OR 18 , where R 18 C 1-6 alkyl.

[0346] In the implementation plan, R 1 C is arbitrarily replaced 1-3 Alkyl; and / or R 3 It can be hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, carbonyl, or ether.

[0347] In the implementation plan, R 1 For the unreplaced C 1-3 Alkyl group (e.g., CH3 or CH2CH3). In the embodiments, R 1 For CH3. In the implementation scheme, R 2 It is hydrogen. In the implementation scheme, R 4 and R 5 Each is hydrogen. In the implementation plan, R 6 It is OH.

[0348] In the implementation plan, each R 1 and R 2 For the unreplaced C 1-3 Alkyl group. In the implementation scheme, each R 1 and R 2 For CH3. In the implementation scheme, R4 and R 5 Each is hydrogen. In the implementation plan, R 6 It is OH.

[0349] In the implementation plan, R 2 For the unreplaced C 1-3 Alkyl group (e.g., CH3 or CH2CH3). In the embodiments, R 2 For CH3. In the implementation scheme, R 3 It is hydrogen. In the implementation scheme, R 4 and R 5 Each is hydrogen. In the implementation plan, R 6 It is OH.

[0350] In the implementation scheme, the compound has a structure according to formula (I),

[0351]

[0352] Or its pharmaceutically acceptable salt, wherein

[0353] R 1 For optional OR 7 C substituted with halogen or aryl (which may optionally be substituted with halogen) 1-3 Alkyl group, wherein R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl, or R 1 C is arbitrarily replaced 3-6 Cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl;

[0354] R 2 It is hydrogen, halogen, CN, or C optionally substituted with one or more halogens. 1-3 alkyl;

[0355] R 3 Choose from the following groups:

[0356] hydrogen;

[0357] Where X represents covalent bonds, O, S, SO2, and C. 1-4 Alkylene, C 2-4 alkyne or C 2-4 Hypo-yne group; each A is independently N or CR 9 R 8 and R 9 Independent of hydrogen, halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl, and R 10 C 1-3 Alkyl or aryl;

[0358] Where B is N or CR 11 D is N, NH or CR 11 E represents N and CR 11 or CHR 12 And R 11 and R 12 Independently hydrogen or C 1-3 Alkyl groups, wherein the dashed circle indicates the presence or absence of a conjugated system;

[0359] Each G is independently N, NH, NR. 13 or CR 14 ;R 13 C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl, and R 14 For hydrogen, halogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C 1-3 alkyl;

[0360] Where I represents O, S, or CH, J represents N or CH, and R represents... 15 For hydrogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C 1-3 Alkyl, and R 19 For hydrogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl or aryl;

[0361] OR 16 , where R 16 It is aryl;

[0362] Where X 1 It is N or CH, and R 20 For aryl groups that are optionally substituted; and

[0363] COR 17 , where R 17 It is aryl;

[0364] R 4 and R 5 C that is independently hydrogen, optionally substituted with one or more halogens 1-3 Alkyl, or R 4 and R 5Together with the carbon atom to which it is attached, it forms optionally substituted cycloalkyl or heterocycloalkyl groups; and

[0365] R 6 For OH or OR 18 , where R 18 C 1-6 alkyl.

[0366] In the implementation plan, R 1 It is the unreplaced C 1-3 Alkyl group. In the implementation scheme, R 1 It is CH3 or CH2CH3.

[0367] In the implementation plan, R 1 C that was replaced 1-3 Alkyl group. In the implementation scheme, R 1 For OR 7 Replacement C 1-3 Alkyl group. In the implementation scheme, R 7 For the unreplaced C 1-3 Alkyl group. In the implementation scheme, R 7 C that was replaced 1-3 Alkyl group. In the implementation scheme, R 7 C replaced by aryl 1-3 Alkyl group. In the embodiments, the aryl group is phenyl. In the embodiments, R 7 C substituted with phenyl 1-3 Alkyl group. In the implementation scheme, R 1 C replaced by OBn 1-3 Alkyl group. In the implementation scheme, R 1 It is CH2CH2OBn.

[0368] In the implementation plan, R 1 It is a C that has been substituted with one or more halogens (e.g., F, Cl, Br, or I). 1-3 Alkyl group. In the implementation scheme, R 1 It is difluoromethyl.

[0369] In the implementation plan, R 1 It is a C that is substituted with an aryl group (which is optionally substituted with a halogen). 1-3 Alkyl group. In embodiments, the optionally substituted aryl group is an optionally substituted phenyl group. In embodiments, the aryl or phenyl group is an unsubstituted aryl or unsubstituted phenyl group. In embodiments, the aryl or phenyl group is substituted with one or more halogens. In embodiments, R 1 for

[0370] In the implementation plan, R 1 C is arbitrarily replaced 3-6Cycloalkyl (e.g., optionally substituted cyclopropyl). In embodiments, R 1 C 3-6 Cycloalkyl (e.g., unsubstituted cyclopropyl). In the embodiments, R 1 C that was replaced 3-6 Cycloalkyl groups (e.g., C1646-C ... 3-6 (cycloalkyl).

[0371] In the implementation plan, R 1 It is an optionally substituted 3- to 6-membered heterocyclic alkyl group. In the embodiments, R 1 It is an unsubstituted 3- to 6-membered heterocyclic alkyl group. In the embodiments, R 1 It is a substituted 3- to 6-membered heterocyclic alkyl group (e.g., a 3- to 6-membered heterocyclic alkyl group including 1, 2 or 3 substituents).

[0372] In the implementation plan, R 2 It is hydrogen.

[0373] In the implementation plan, R 2 For CN.

[0374] In the implementation plan, R 2 It is a halogen. In the implementation scheme, the halogen is F, Cl, Br, or I.

[0375] In the implementation plan, R 2 It is the unreplaced C 1-3 Alkyl group. In the implementation scheme, R 2 It is CH3.

[0376] In the implementation plan, R 2 C substituted by one or more halogens 1-3 alkyl.

[0377] In the implementation plan, R 3 It is hydrogen. In the implementation scheme, R 3 It's not hydrogen.

[0378] In the implementation plan, R 3 for in

[0379] X represents a covalent bond, O, S, SO2, or C. 1-4 Alkylene, C 2-4 alkyne or C 2-4 Hypo-heyne group;

[0380] Each A is independently either N or CR 9 ;

[0381] R 8 and R 9Independent of hydrogen, halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl; and

[0382] R 10 C 1-3 Alkyl or aryl.

[0383] In the implementation plan, R 3 It is an unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, or trifluoromethylphenyl.

[0384] In the implementation plan, R 3 for in

[0385] B is N or CR 11 ;

[0386] D is N, NH or CR 11 ;

[0387] E represents N and CR 11 or CHR 12 ;and

[0388] R 11 and R 12 Independently hydrogen or C 1-3 Alkyl; and wherein

[0389] The dashed circle indicates the presence or absence of a conjugate system.

[0390] In the implementation plan, R 3 for in

[0391] Each G is independently N, NH, NR 13 or CR 14 ;

[0392] R 13 C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl; and

[0393] R 14 For hydrogen, halogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C 1-3 alkyl.

[0394] In the implementation plan, R 3It is pyrrole, tetrazolyl, triazolyl, or pyrazolyl, optionally substituted with aryl or cycloalkyl. In embodiments, R 3 (For example, pyrrole, tetrazolyl, triazolyl or pyrazolyl) is substituted with cyclopropyl, unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl or trifluoromethylphenyl.

[0395] In the implementation plan, R 3 for in

[0396] I represents O, S, or CH;

[0397] J is either N or CH;

[0398] R 15 For hydrogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl or C 1-3 Alkyl; and

[0399] R 19 For hydrogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl or aryl.

[0400] In the implementation plan, R 3 OR 16 , where R 16 It is an aryl group. In the embodiments, the aryl group is phenyl. In the embodiments, R 3 For OPh.

[0401] In the implementation plan, R 3 for in

[0402] X 1 It is N or CH; and

[0403] R 20 The aryl group is optionally substituted.

[0404] In the implementation plan, R 3 It is piperidinyl or piperazine, optionally substituted with cyclopropyl or aryl. In embodiments, R 3 (For example, piperidinyl or piperazine) is substituted with cyclopropyl, unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl or trifluoromethylphenyl.

[0405] In the implementation plan, R 3 It is COR 17 , where R 17 It is an aryl group. In the embodiments, the aryl group is phenyl. In the embodiments, R 3 It is COPh.

[0406] In the implementation plan, R 3for

[0407] In the implementation plan, R 4 and R 5 Both are hydrogen.

[0408] In the implementation plan, R 4 and R 5 One of them is hydrogen, and the other is C. 1-3 Alkyl group. In the embodiments, C 1-3 The alkyl group is not substituted. In the embodiments, C 1-3 The alkyl group is replaced by one or more halogens. In the embodiments, C 1-3 Alkyl groups are CH3.

[0409] In the implementation plan, R 4 and R 5 All are C 1-3 Alkyl group. In the embodiments, C 1-3 The alkyl group is not substituted. In the embodiments, C 1-3 The alkyl group is replaced by one or more halogens. In the embodiments, C 1-3 Alkyl groups are CH3.

[0410] In the implementation plan, R 4 and R 5 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocycloalkyl group. In embodiments, the cycloalkyl or heterocycloalkyl group is unsubstituted. In embodiments, the cycloalkyl or heterocycloalkyl group is unsubstituted (e.g., a cycloalkyl or heterocycloalkyl group comprising 1, 2, or 3 substituents). In embodiments, the cycloalkyl or heterocycloalkyl group is a 3-membered ring. In embodiments, the cycloalkyl or heterocycloalkyl group is a 4-membered ring. In embodiments, the heterocycloalkyl group is an oxygen-containing heterocycloalkyl group. In embodiments, the cycloalkyl or heterocycloalkyl group is selected from cyclopropyl, cyclobutyl, and... A group that is formed.

[0411] In the implementation plan, R 6 It is OH.

[0412] In the implementation plan, R 6 Is it OR 18 , where R 18 It is C 1-6 alkyl.

[0413] In the implementation plan, R 1 For the unreplaced C 1-3 Alkyl group (e.g., CH3 or CH2CH3). In the embodiments, R 1 For CH3. In the implementation scheme, R 2 It is hydrogen. In the implementation scheme, R 4and R 5 Each is hydrogen. In the implementation plan, R 6 It is OH.

[0414] In the implementation plan, each R 1 and R 2 For the unreplaced C 1-3 Alkyl group. In the implementation scheme, each R 1 and R 2 For CH3. In the implementation scheme, R 4 and R 5 Each is hydrogen. In the implementation plan, R 6 It is OH.

[0415] In the implementation plan, R 2 For the unreplaced C 1-3 Alkyl group (e.g., CH3 or CH2CH3). In the embodiments, R 2 For CH3. In the implementation scheme, R 3 It is hydrogen. In the implementation scheme, R 4 and R 5 Each is hydrogen. In the implementation plan, R 6 It is OH.

[0416] In the implementation plan, R 1 For optional OR 7 C or aryl (which may be substituted with halogen) 1-3 Alkyl group, wherein R 7 C, which is optionally substituted with an aryl group 1-3 Alkyl; and / or R 3 Choose from the following groups: hydrogen,

[0417] In the implementation scheme, the compound of formula (I) has the following structure,

[0418] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 R 4 and R 5 As defined anywhere in this document.

[0419] In the embodiments, the compounds of formula (I) or formula (II) have the following structures,

[0420] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 and R 5As defined anywhere in this document, and where

[0421] Each A is independently either N or CR 9 ;

[0422] R 8 and R 9 Independent of hydrogen, halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl; and

[0423] R 10 C 1-3 Alkyl or aryl.

[0424] In the implementation scheme, A represents N. In the implementation scheme, A represents CR. 9 In the implementation scheme, all three A groups are CR. 9 In the implementation plan, one A is CR. 9 Furthermore, the other two A groups are N. In an embodiment, one A group is N, and the other two A groups are CR. 9 In the implementation scheme, all three A groups are N.

[0425] In the implementation plan, R 8 and R 9 At least one of them is hydrogen. In the implementation, R 8 and R 9 One of them is hydrogen.

[0426] In the implementation plan, R 8 and R 9 None of them are hydrogen.

[0427] In the implementation plan, R 8 It is hydrogen.

[0428] In the implementation plan, R 8 It is a halogen. In the embodiments, the halogen is F, Cl, Br, or I. In the embodiments, R 8 It is Cl.

[0429] In the implementation plan, R 8 OR 10 , where R 10 C 1-3 Alkyl group. In the implementation scheme, R 8 For OMe.

[0430] In the implementation plan, R 8 Is it OR 10 , where R 10 It is an aryl group. In the embodiments, the aryl group is phenyl. In the embodiments, R 8 It's OPh.

[0431] In the implementation plan, R 8 For the unreplaced C 1-3 Alkyl group. In the implementation scheme, R 8 C substituted by one or more halogens 1-3 alkyl.

[0432] In the implementation plan, R 9 It is hydrogen.

[0433] In the implementation plan, R 9 It is a halogen. In the embodiments, the halogen is F, Cl, Br, or I. In the embodiments, R 9 It is Cl.

[0434] In the implementation plan, R 9 OR 10 , where R 10 C 1-3 Alkyl group. In the implementation scheme, R 9 For OMe.

[0435] In the implementation plan, R 9 Is it OR 10 , where R 10 It is an aryl group. In the embodiments, the aryl group is phenyl. In the embodiments, R 9 It's OPh.

[0436] In the implementation plan, R 9 For the unreplaced C 1-3 Alkyl group. In the implementation scheme, R 9 C substituted by one or more halogens 1-3 Alkyl group. In the implementation scheme, R 9 For CH3. In the implementation scheme, R 9 It is CF3.

[0437] In the embodiments, the compounds of formula (I), formula (II), or formula (III) have the following structures,

[0438] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 R 5 R 8 and R 9 As defined anywhere in this document.

[0439] In the embodiments, the compounds of formula (I), formula (II), or formula (III) have the following structures,

[0440] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 R 5 R 8 and R 9 As defined anywhere in this document.

[0441] In the implementation plan, yes In the implementation plan, R 9 For halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl group. In the implementation scheme, R 9 It is halogen.

[0442] In the implementation plan, yes In the implementation plan, R 9 For halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl group. In the implementation scheme, R 9 It is a halogen.

[0443] In the implementation plan, yes In the implementation plan, R 8 For halogen, OR 10 C, or optionally substituted with one or more halogens 1-3 Alkyl group. In the implementation scheme, R 8 It is a halogen.

[0444] In the embodiments, the compounds of formula (I) or formula (II) have the following structures,

[0445] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 and R 5 As defined anywhere in this document, and where

[0446] B is N or CR 11 ;

[0447] D is N, NH or CR 11 ;

[0448] E represents N and CR 11 or CHR 12 ;and

[0449] R 11 and R 12 Independently hydrogen or C 1-3 Alkyl; and

[0450] The dashed circle indicates the presence or absence of a conjugate system.

[0451] In the implementation scheme, the dashed circle exists and R 3 for Where B is N or CR 11 D is N, or CR 11 And E is N or CR 12 .

[0452] In the implementation plan, D represents CR. 11 E is CR 12 And B is N.

[0453] In the implementation plan, B is CR. 11 E is CR 12 And D is N.

[0454] In the implementation plan, both B and D are CR. 11 And E is N.

[0455] In the implementation plan, both B and D are CR. 11 And E is CR 12 .

[0456] In the implementation plan, the dashed circle does not exist, and R 3 for Where B is N or CR 11 D is NH; and E is CHR. 12 .

[0457] In the implementation plan, B is CR. 11 And E is CHR 12 .

[0458] In the implementation plan, R 11 It is hydrogen.

[0459] In the implementation plan, R 11 C 1-3 Alkyl group. In the implementation scheme, R 11 It is CH3.

[0460] In the implementation plan, R 12 It is hydrogen.

[0461] In the implementation plan, R 12 C 1-3 Alkyl group. In the implementation scheme, R 12 It is CH3.

[0462] In the embodiments, the compounds of formula (I), formula (II), or formula (VI) have the following structures,

[0463] Or its pharmaceutically acceptable salts, wherein B, D, E, R 1 R 2 R 4 and R 5 As defined anywhere in this document.

[0464] In the implementation plan, yes

[0465] In the implementation plan, yes

[0466] In the implementation plan, yes In the implementation plan, R 12 It is hydrogen or C 1-3 Alkyl group. In the implementation scheme, R 12 It is hydrogen. In the implementation scheme, R 12 It is CH3.

[0467] In the implementation plan, yes

[0468] In the embodiments, the compounds of formula (I), formula (II), or formula (VI) have the following structures,

[0469] Or its pharmaceutically acceptable salts, wherein B, R 1 R 2 R 4 R 5 and R 12 As defined anywhere in this document.

[0470] In the implementation plan, yes In the implementation plan, R 12 C 1-3 Alkyl group. In the implementation scheme, R 12 It is CH3.

[0471] In the embodiments, the compounds of formula (I) or formula (II) have the following structures,

[0472] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 and R 5 As defined anywhere in this document, and where

[0473] Each G is independently N, NH, NR 13or CR 14 ;

[0474] R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl; and

[0475] R 14 It is hydrogen, halogen, cyclopropyl or C 1-3 alkyl.

[0476] In the implementation scheme, G is N. In the implementation scheme, G is NH. In the implementation scheme, G is NR. 13 In the implementation plan, G is CR 14 .

[0477] In the implementation plan, R 13 It is cyclopropyl.

[0478] In the implementation plan, R 13 The aryl group is unsubstituted. In the implementation scheme, R 13 The aryl group is substituted with one or more halogens. In the embodiments, R 13 For C that is optionally replaced by one or more 1-3 Alkyl groups (e.g., C substituted with one or more halogens) 1-3 An alkyl-substituted aryl group. In the embodiments, the aryl group is phenyl. In the embodiments, R... 13 It is an unsubstituted phenyl group. In the implementation scheme, R 13 R is a phenyl group substituted with one or more halogens. In the embodiments, R 13 For C that is optionally replaced by one or more 1-3 Alkyl groups (e.g., C substituted with one or more halogens) 1-3 Alkyl-substituted phenyl. In the embodiments, R 13 Choose from the group consisting of: p-trifluoromethylphenyl, m-fluorophenyl, p-fluorophenyl, p-chlorophenyl, 2,4-dichlorophenyl, and 3,5-dichlorophenyl.

[0479] In the implementation plan, R 13 It is a heteroaryl group. In some embodiments, the heteroaryl group is not substituted. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group is pyridyl. In some embodiments, R 13 It is 2-pyridinyl, 3-pyridinyl or 4-pyridinyl.

[0480] In the implementation plan, R13 It is an unsubstituted heterocyclic alkyl group. In the embodiments, R 13 The heterocyclic alkyl group is substituted with a tert-butoxycarbonyl group. In an embodiment, the heterocyclic alkyl group is a 6-membered heterocyclic alkyl group. In an embodiment, the heterocyclic alkyl group is a nitrogen-containing heterocyclic alkyl group. In an embodiment, the heterocyclic alkyl group is an oxygen-containing heterocyclic alkyl group. In an embodiment, R... 13 for

[0481] In the implementation plan, R 13 For the unreplaced C 1-4 Alkyl group. In the implementation scheme, R 13 for

[0482] In the implementation plan, R 13 C replaced by aryl 1-4 Alkyl group. In embodiments, the aryl group is unsubstituted. In embodiments, the aryl group is substituted with one or more halogens. In embodiments, the aryl group is phenyl. In embodiments, the phenyl group is an unsubstituted phenyl group. In embodiments, the phenyl group is substituted with one or more halogens. In embodiments, R... 13 for

[0483] In the implementation plan, R 14 It is hydrogen.

[0484] In the implementation plan, R 14 It is a halogen. In the embodiments, the halogen is F, Cl, Br, or I. In the embodiments, R 14 It is F.

[0485] In the implementation plan, R 14 It is cyclopropyl.

[0486] In the implementation plan, R 14 C 1-3 Alkyl group. In the implementation scheme, R 14 It is CH3.

[0487] In the implementation plan, yes

[0488] In the implementation plan, yes In the implementation plan, R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl group. In the implementation scheme, R 13 The aryl group is unsubstituted. In the implementation scheme, R 13 For Ph. In the implementation plan, R 13 The aryl group is substituted with one or more halogens. In the embodiments, R 13 for In the implementation plan, R 13 It is cyclopropyl.

[0489] In the implementation plan, yes In the implementation plan, R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl group. In the implementation scheme, R 13 The aryl group is optionally substituted with one or more halogens. In the embodiments, R 13 C is replaced by an aryl group (which is substituted by one or more halogens). 1-4 Alkyl group. In the implementation scheme, R 13 The aryl group is optionally substituted with one or more halogens. In the embodiments, R 13 Ph,

[0490]

[0491] In the implementation plan, yes In the implementation plan, yes In the implementation plan, R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl group. In the implementation scheme, R 13 It is aryl. In the implementation scheme, R 13 For Ph. In the implementation plan, R 13 Ph, 2-Pyridyl,

[0492] In the implementation plan, R 14 It is hydrogen, halogen, cyclopropyl or C 1-3 Alkyl group. In the implementation scheme, R 14 C 1-3 Alkyl (e.g., methyl).

[0493] In the implementation plan, yes In the implementation plan, R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl group. In the implementation scheme, R 13 It is aryl. In the implementation scheme, R 13 Ph.

[0494] In the embodiments, the compounds of formula (I), formula (II), or formula (IX) have the following structures,

[0495] Or a pharmaceutically acceptable salt thereof, wherein G, R 1 R 2 R 4 and R 5 As defined anywhere in this document.

[0496] In the implementation plan, yes In the implementation plan, R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl group. In the implementation scheme, R 13 The aryl group is optionally substituted with one or more halogens. In the embodiments, R 13 C is replaced by an aryl group (which is substituted by one or more halogens). 1-4 Alkyl group. In the implementation scheme, R 13 The aryl group is optionally substituted with one or more halogens. In the embodiments, R 13 Ph,

[0497]

[0498] In the embodiments, the compounds of formula (I), formula (II), formula (IX) or formula (X) have the following structures,

[0499] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 R 5 and R 14 As defined anywhere in this document.

[0500] In the embodiments, the compounds of formula (I), formula (II), formula (IX), formula (X) or formula (XI) have the following structures,

[0501]

[0502] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 R 5 R 13 and R 14 As defined anywhere in this document.

[0503] In the implementation plan, R 14 Halogen or C 1-3 Alkyl group. In the implementation scheme, R 14 It is methyl. In the embodiment, R is... 14 It is F.

[0504] In the implementation plan, R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl group. In the implementation scheme, R 13 The aryl group is optionally substituted with one or more halogens. In the embodiments, R 13 It can be Ph, 3-fluorophenyl, or 4-fluorophenyl.

[0505] In the implementation plan, R 14 It is hydrogen and for In the implementation plan, R 14 It is hydrogen and for In the implementation plan, R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl group. In the implementation scheme, R 13 C 1-4 Alkyl group. In the implementation scheme, R 13 It is a heteroaryl group. In the implementation scheme, R 13 It is a heterocyclic alkyl group. In the embodiment, R... 13 The aryl group is substituted with one or more halogens. In the embodiments, R 13 C is arbitrarily replaced 1-3 Alkyl groups (e.g., C substituted with one or more halogens) 1-3 Alkyl-substituted aryl group. In the embodiments, R 13 Ph, 2-Pyridyl,

[0506] In the embodiments, the compounds of formula (I), formula (II), formula (IX), formula (X), formula (XI), or formula (XIIa) have the following structures.

[0507] Or a pharmaceutically acceptable salt thereof, wherein R 2 R 4 R 5 and R 13 As defined anywhere in this document.

[0508] In the implementation plan, R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl group. In the implementation scheme, R 13 It is a heterocyclic alkyl group substituted with a tert-butoxycarbonyl group. In the embodiments, R 13 It is aryl. In the implementation scheme, R 13 The aryl group is substituted with one or more halogens. In the embodiments, R 13 C is arbitrarily replaced 1-3 Alkyl groups (e.g., C substituted with one or more halogens) 1-3 Alkyl-substituted aryl group. In the embodiments, R 13 Ph, 2-Pyridyl,

[0509] In the embodiments, the compounds of formula (I), formula (II), formula (IX), formula (X) or formula (XI) have the following structures,

[0510] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 R 5 and R 13 As defined anywhere in this document.

[0511] In the implementation plan, R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl group. In the implementation scheme, R 13 The aryl group is unsubstituted. In the implementation scheme, R 13 Ph.

[0512] In the embodiments, the compounds of formula (I), formula (II), or formula (IX) have the following structures,

[0513] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 R 5 and R 13 As defined anywhere in this document.

[0514] In the implementation plan, R 13 Cyclopropyl, aryl group optionally substituted with one or more halogens, C group optionally substituted with one or more C groups. 1-3 Alkyl-substituted aryl, heteroaryl, heterocyclic alkyl optionally substituted with tert-butoxycarbonyl, C-substituted aryl (which is optionally substituted with one or more halogens) 1-4 Alkyl group. In the implementation scheme, R 13 The aryl group is unsubstituted. In the implementation scheme, R 13 For Ph. In the implementation plan, R 13 The aryl group is substituted with one or more halogens. In the embodiments, R 13 for In the implementation plan, R 13 It is cyclopropyl.

[0515] In the embodiments, the compounds of formula (I), formula (II), or formula (IX) have the following structures,

[0516] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 and R 5 As defined anywhere in this document.

[0517] In the embodiments, the compounds of formula (I) or formula (II) have the following structures,

[0518] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 and R 5 As defined anywhere in this document, and where

[0519] I represents O, S, or CH;

[0520] J is either N or CH;

[0521] R 15 It is hydrogen or C 1-3 Alkyl; and

[0522] R 19 It is hydrogen or aryl.

[0523] In the implementation scheme, I represents O. In the implementation scheme, I represents S. In the implementation scheme, I represents CH.

[0524] In the implementation scheme, J is N. In the implementation scheme, J is CH.

[0525] In the implementation plan, R 15 It is hydrogen.

[0526] In the implementation plan, R 15 C 1-3 Alkyl group. In the implementation scheme, R 15 It is CH3.

[0527] In the implementation plan, R 19 It is hydrogen.

[0528] In the implementation plan, R 19 It is aryl. In the implementation scheme, R 19 It is a phenyl group.

[0529] In the embodiments, the compounds of formula (I), (II), or (XIV) have the following structures,

[0530] Or a pharmaceutically acceptable salt thereof, wherein I, R 1 R 2 R 4 R5 R 15 and R 19 As defined anywhere in this document.

[0531] In the implementation plan, yes In the implementation plan, R 19 It is aryl. In the implementation scheme, R 19 It is phenyl. In the embodiment, R is... 15 It is hydrogen or C 1-3 Alkyl group. In the implementation scheme, R 15 It is hydrogen or CH3.

[0532] In the implementation plan, yes In the implementation plan, R 19 It is aryl. In the implementation scheme, R 19 It is a phenyl group.

[0533] In the embodiments, the compounds of formula (I) or formula (II) have the following structures,

[0534] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 R 5 R 8 and R 9 As defined anywhere in this document, and where X is O, S, or SO2.

[0535] In the implementation scheme, X is O. In the implementation scheme, X is S. In the implementation scheme, X is SO2.

[0536] In the embodiments, the compounds of formula (I) or formula (II) have the following structures,

[0537] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 R 5 R 8 and R 9 As defined anywhere in this document.

[0538] In the embodiments, the compounds of formula (I) or formula (II) have the following structures,

[0539] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 R 5 R8 and R 9 As defined anywhere in this document.

[0540] In the embodiments, the compounds of formula (I) or formula (II) have the following structures,

[0541] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 and R 5 As defined anywhere in this document, and where R 20 The aryl group is optionally substituted.

[0542] In the implementation plan, R 20 The substituted aryl group (e.g., including 1, 2, or 3 substituents). In the embodiments, R 20 The aryl group is an unsubstituted aryl group. In the embodiments, the aryl group is phenyl. In the embodiments, R... 20 Ph.

[0543] In the embodiments, the compounds of formula (I) or formula (II) have the following structures,

[0544] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 4 and R 5 As defined anywhere in this document, and where R 20 The aryl group is optionally substituted.

[0545] In the implementation plan, R 20 The substituted aryl group (e.g., including 1, 2, or 3 substituents). In the embodiments, R 20 The aryl group is an unsubstituted aryl group. In the embodiments, the aryl group is phenyl. In the embodiments, R... 20 Ph.

[0546] Exemplary compounds

[0547] In some implementations, the PHD inhibitor compound is any one of compounds 1 to 50 or a pharmaceutically acceptable salt thereof.

[0548]

[0549]

[0550]

[0551]

[0552] In some implementations, the PHD inhibitor compound is any one of compounds 51 to 70 or a pharmaceutically acceptable salt thereof.

[0553]

[0554]

[0555] isotope

[0556] It should be understood that in the compounds described herein (e.g., compounds of any of formulas (I) to (XXIII), such as any of compounds 1 to 70), atoms may exhibit their natural isotopic abundances, 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 found primarily in nature. The present invention is intended to include all suitable isotopic variations of the compounds described herein (e.g., compounds of any of formulas (I) to (XXIII), such as any of compounds 1 to 70). For example, different isotopic forms of hydrogen (H) include protium (… 1 H), deuterium ( 2 H) and tritium ( 3 H). Protium is the main hydrogen isotope found in nature.

[0557] In some embodiments, one or more hydrogen atoms of the compounds described herein (e.g., compounds of any of formulas (I) to (XXIII), such as any of compounds 1 to 70) are replaced with deuterium. Enrichment of deuterium can provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or can provide compounds that can be used as standards for characterizing biological samples. In some embodiments, one or more hydrogen atoms of the compounds described herein (e.g., compounds of any of formulas (I) to (XXIII), such as any of compounds 1 to 70) are replaced with tritium. Tritium is radioactive and therefore can provide radiolabeled compounds that can be used as tracers in metabolic or kinetic studies.

[0558] Isotopic enrichment of the compounds disclosed herein (e.g., compounds of any of the formulas (I) to (XXIII), such as any of compounds 1 to 70) can be achieved without excessive experimentation using conventional techniques well known to those skilled in the art or using appropriate isotopic enrichment reagents and / or intermediates with processes similar to those described in the procedures and examples herein.

[0559] The term "isotope" refers to a species having the same chemical structure and formula as the specific compounds provided herein, except for isotopic substitution sites and / or isotopic enrichment levels at one or more sites, such as hydrogen versus deuterium. Thus, as used herein, the term "compound" encompasses a collection of molecules having the same chemical structure but also exhibiting isotopic variations among the constituent atoms of the molecule. Therefore, it will be apparent to those skilled in the art that a compound represented by a specific chemical structure containing the indicated deuterium atom will also contain a smaller amount of isotopes having hydrogen atoms at one or more designated deuterium sites in said structure. The relative amount of such isotopes in the provided compounds depends on a number of factors, including, but not limited to, the isotopic purity of the deuterating agent used to prepare the compound and the efficiency of deuteration incorporation in the various synthetic steps used to prepare the compound.

[0560] When a position is designated as “H” or “hydrogen”, the position should be understood as having hydrogen in its natural abundance isotopic composition. When a position is designated as “D” or “deuterium”, the position is understood as having a deuterium abundance of at least 3340 times greater than the natural abundance of deuterium, wherein the natural abundance of deuterium is 0.015% (i.e., the term “D” or “deuterium” indicates at least 50.1% deuterium doping).

[0561] In the implementation scheme, the isotopic enrichment factor of the compound provided herein for each deuterium at the site designated as a potential deuteration site on the compound may be at least 3500 (52.5% deuterium doping), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0562] Synthesis of the compounds of the present invention

[0563] The compounds described herein (e.g., compounds of any of the formulas (I) to (XXIII), such as any of compounds 1 to 70) can be prepared according to methods known in the art, including exemplary synthesis of the examples provided herein.

[0564] The abbreviations and acronyms used in this article include the following:

[0565]

[0566]

[0567]

[0568] Compositions and methods

[0569] This invention provides the use of compounds of any one of formulas (I) to (XXIII) or pharmaceutically acceptable salts thereof for the manufacture of medicaments for treating a variety of conditions or ailments as described herein. In one embodiment, a pharmaceutical composition is provided comprising at least one compound of any one of formulas (I) to (XXIII) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In various embodiments, the medicament or pharmaceutical composition may further comprise or be used in combination with at least one additional therapeutic agent.

[0570] The compounds of the present invention, or drugs or compositions comprising said compounds, can be used to inhibit the activity of PHD. Inhibition of PHD has specific benefits in treating diseases including: heart diseases (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung diseases (e.g., lung inflammation, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory diseases (e.g., respiratory infections, acute respiratory distress syndrome), liver diseases (e.g., acute liver failure and liver fibrosis, and cirrhosis), and kidney diseases (e.g., acute kidney injury and chronic kidney disease), inflammatory bowel disease (IBD), ischemic-reperfusion injury (e.g., stroke), and retinopathy of prematurity (ROP).

[0571] In one embodiment, the method of the present invention includes administering to a patient in need a therapeutically effective amount of a compound of any one of formulas (I) to (XXIII) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds of any one of formulas (I) to (XXIII).

[0572] The present invention also relates to a method for inhibiting PHD activity. In one embodiment, the method comprises contacting PHD with an effective amount of one or more compounds selected from the group consisting of a compound comprising any one of formulas (I) to (XXIII) or a pharmaceutically acceptable salt thereof.

[0573] In other embodiments, the compounds disclosed herein (e.g., compounds of any of formulas (I) to (XXIII), such as any one of compounds 1 to 70) or pharmaceutically acceptable salts thereof are suitable for the treatment or prevention of anemia, including the treatment of anemia symptoms associated with: chronic kidney disease, polycystic kidney disease, aplastic anemia, autoimmune hemolytic anemia, bone marrow transplant anemia, Churg-Strauss syndrome, Diamond Blackfan anemia, Fanconi's anemia, Felty syndrome, graft-versus-host disease, hematopoietic stem cell transplantation, hemolytic uremic syndrome, myelodysplastic syndrome, nocturnal paroxysmal hemoglobinuria, myelofibroma, pancytopenia, pure red cell aplasia, and allergic purpura. Schoenlein-Henoch anemia, refractory anemia with excessive blasts, rheumatoid arthritis, Shwachman syndrome, sickle cell disease, severe thalassemia, mild thalassemia, thrombocytopenic purpura, anemia or non-anemia in patients who have undergone surgery, anemia related to or secondary to trauma, sideroblastic anemia, and anemia secondary to other treatments, including: reverse transcriptase inhibitors used to treat HIV, corticosteroids, cyclocisplatin or cisplatin-free chemotherapy drugs, vinca alkaloids, mitotic inhibitors, topoisomerase II inhibitors, anthracyclines, alkylating agents, especially anemia secondary to inflammation, aging, and / or chronic diseases. PHD suppression can also be used to treat symptoms of anemia, including chronic fatigue, pallor, and dizziness.

[0574] 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 suitable for the treatment or prevention of metabolic disorders, including but not limited to diabetes and obesity.

[0575] 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 suitable for the treatment or prevention of vascular disorders. These include, but are not limited to, hypoxia or wound healing-related diseases that require pro-angiogenic mediators for angiogenesis, angiogenesis, and arterial formation.

[0576] 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 suitable for the treatment or prevention of local ischemia-reperfusion injury. These include, but are not limited to, stroke, myocardial infarction, and acute kidney injury.

[0577] 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 suitable for treating inflammatory bowel disease. These include, but are not limited to, ulcerative colitis and Crohn's disease.

[0578] 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 their pharmaceutically acceptable salts are suitable for treating cancers, such as colorectal cancer.

[0579] 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 their pharmaceutically acceptable salts are suitable for treating atherosclerosis.

[0580] 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 their pharmaceutically acceptable salts are suitable for treating cardiovascular diseases.

[0581] 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 suitable for treating ocular diseases or conditions. These include, but are not limited to, radiation retinopathy, retinopathy of prematurity (ROP), diabetic retinopathy, age-related macular degeneration, and ocular ischemia.

[0582] 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 their pharmaceutically acceptable salts are suitable for treating diseases associated with hyperoxia.

[0583] 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 suitable for the treatment of bronchopulmonary dysplasia (BPD).

[0584] 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 their pharmaceutically acceptable salts are suitable for treating heart disease. The conditions include, but are not limited to, myocardial ischemia following pancreatic surgery, myocardial injury following percutaneous coronary intervention (PCI), myocardial injury following non-cardiac surgery, perioperative myocardial ischemia following elective abdominal aortic aneurysm surgery, myocardial injury following PCI, myocardial injury in patients undergoing coronary artery bypass grafting (CABG) surgery, minimally invasive mitral valve (MIMV) repair or replacement, adult patients undergoing open-heart surgery, and chronic heart failure, NYHA class II-IV.

[0585] 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 suitable for treating lung diseases such as lung inflammation, pneumonia, bronchitis, acute lung injury (ALI), pulmonary hypertension, pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), or chronic obstructive pulmonary disease. The conditions include, but are not limited to, lung injury during elective lobectomy, lung injury during coronary artery bypass grafting (CABG), and lung transplantation.

[0586] 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 suitable for treating respiratory diseases. These diseases include, but are not limited to, respiratory infections, acute respiratory distress syndrome (ARDS), lung inflammation, pneumonia, and acute lung injury.

[0587] 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 suitable for treating liver diseases. These conditions include, but are not limited to, non-alcoholic steatohepatitis (NASH).

[0588] 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 suitable for treating kidney disease. The conditions include, but are not limited to, contrast-induced acute kidney injury, stage III to IV chronic kidney disease undergoing planned coronary angiography, acute kidney injury in patients undergoing heart valve surgery, non-dialysis-dependent chronic kidney disease, patients with chronic kidney disease initiating dialysis, and non-dialysis-dependent chronic kidney disease.

[0589] 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 suitable for treating damage and / or failure of one or more organs (e.g., damage and / or failure of the lungs, heart, liver, or kidneys). The conditions include, but are not limited to, acute organ injury or organ failure and induced organ dysfunction.

[0590] 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 suitable for treating respiratory viral (e.g., coronavirus) infections or pulmonary viral (e.g., coronavirus) infections.

[0591] Additionally, the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70) or their pharmaceutically acceptable salts may be combined with additional active ingredients for the treatment of the aforementioned symptoms. These additional compounds may be administered separately from the compounds disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70) or their pharmaceutically acceptable salts, or may be included together with additional active ingredients in the pharmaceutical compositions according to the invention. In one exemplary embodiment, the additional active ingredient is one known or found to be effective in treating symptoms, conditions, or diseases mediated by PHD enzymes, or active against another target associated with a particular symptom, condition, or disease, such as alternative PHD modulators. Such combinations may be used to increase efficacy (e.g., by including compounds that enhance the potency or effectiveness of the compounds according to the invention in the combination), reduce one or more side effects, or reduce the required dosage of the compounds according to the invention.

[0592] The compounds of the present invention may be 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 a compound disclosed herein (e.g., compounds of formulas (I) to (XXIII), such as any one of compounds 1 to 70) or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and (b) a pharmaceutically acceptable excipient.

[0593] "Pharmaceutically acceptable excipients" are substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as inert substances, and that are added to or otherwise used as a mediator, carrier, or diluent to facilitate the administration of the drug. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, 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.

[0594] Drug formulation and route of administration

[0595] As is well known in the art, the compounds and compositions of the present invention can be delivered directly or in a pharmaceutical composition or agent together with a suitable carrier or excipient. Treatment methods of the present invention may include administering an effective amount of the compounds of the present invention to a subject in need. In a preferred embodiment, the subject is a mammalian subject, and in a most preferred embodiment, the subject is a human subject.

[0596] The effective amount of such compounds, compositions, or agents can be readily determined through routine experiments, such as determining the most effective and convenient route of administration and the most suitable formulation. Various formulations and drug delivery systems are available in the art. See, for example, Gennaro, AR, ed. (1995), Remington's Pharmaceutical Sciences, ibid.

[0597] Suitable routes of administration may include, for example, oral, rectal, local, 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-articular, intra-articular, intracardiac, intracisional, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration. The indication for treatment and the physical, chemical, and biological properties of the drug determine the type of formulation and route of administration, as well as whether local or systemic delivery is preferred.

[0598] The pharmaceutical dosage forms of the compounds of the present invention can be provided in the form of 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, sugar-coated pills, soft or hard-shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized formulations. Depending on the route of administration used, special devices may be required to apply or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. Pharmaceutical dosage forms typically consist of the drug, excipients, and a container / closure system. One or more excipients, also known as inactive ingredients, may be added to the compounds of the present invention to improve or facilitate the manufacture, stability, administration, and safety of the drug, and may provide a method for achieving a desired drug release profile. Therefore, the type of excipient to be added to the drug can depend on various factors, such as the physical and chemical properties of the drug, the route of administration, and the manufacturing process. Pharmaceutically acceptable excipients are available in the art and include those listed in various pharmacopoeias. See, for example, the United States Pharmacopeia (USP), the Japanese Pharmacopoeia (JP), the European Pharmacopoeia (EP), and the British Pharmacopoeia (BP); the U.S. Food and Drug Administration.

[0599] (www.fda.gov) Publications from the Center for Drug Evaluation and Research (CEDR), such as the Inactive Ingredient Guide (1996); Ash and Ash ed. (2002) Handbook of Pharmaceutical Additives, Synapse Information Resources, Inc., Endicott NY; etc.

[0600] The pharmaceutical dosage forms of the compounds of the present invention can be manufactured by any method well known in the art, such as conventional mixing, sieving, dissolving, melting, granulation, sugar-coated pellet preparation, tableting, suspension, extrusion, spray drying, grinding, emulsification, (nano / micro) encapsulation, embedding, or lyophilization. As described above, the compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate the processing of active molecules into formulations for pharmaceutical use.

[0601] The appropriate formulation depends on the desired route of administration. For example, for intravenous injection, the composition may be formulated in an aqueous solution, using physiologically compatible buffers, such as phosphates, histidine, or citrates, to adjust the pH of the formulation, and tonics, such as sodium chloride or glucose, if necessary. For transmucosal or nasal administration, semi-solid, liquid formulations, or patches may be preferred and may contain penetration enhancers. Such penetration enhancers are generally known in the art. For oral administration, the compound may be formulated into liquid or solid dosage forms, as well as immediate-release or controlled-release / sustained-release formulations. Suitable dosage forms for oral ingestion by subjects include tablets, pills, sugar-coated pills, hard and soft-shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions. These compounds may also be formulated into rectal compositions (such as suppositories or retention enemas), for example, containing a conventional suppository base (such as cocoa butter or other glycerides).

[0602] Solid oral dosage forms can be obtained using excipients, which may include fillers, disintegrants, binders (dry and wet), dissolution delayers, lubricants, flow aids, anti-adhesion agents, cation exchange resins, wetting agents, antioxidants, preservatives, colorants, and flavoring agents. These excipients can be synthetic or naturally derived. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silica, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., glucose, sucrose, lactose, etc.), talc, tragacanth gum, hydrogenated vegetable oils, and waxes. Ethanol and water can be used as granulation aids. In some cases, coating tablets with, for example, a taste-masking film, an acid-resistant film, or a release-blocking film is desirable. Natural and synthetic polymers, combined with colorants, sugars, and organic solvents or water, are commonly used to coat tablets, resulting in sugar-coated pills. When capsules are preferred over tablets, drug powders, their suspensions, or solutions can be delivered in compatible hard or soft-shell capsules.

[0603] In one embodiment, the compounds of the present invention can be applied topically, such as through skin patches, semi-solid or liquid formulations, such as gels, (micro)emulsions, ointments, solutions, (nano / micro)suspensions, or foams. Drug penetration into the skin and underlying tissues can be achieved, for example, using penetration enhancers; appropriate selection and combinations of lipophilic, hydrophilic, and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers; pH adjustment; and the use of complexing agents. Other techniques, such as those used in iontophoresis, can be used to modulate the skin penetration of the compounds of the present invention. For example, percutaneous or topical application is preferred where local delivery with minimal systemic exposure is desired.

[0604] For inhalation or nasal application, the compounds used according to the invention are conveniently delivered from pressurized packages or nebulizers in the form of solutions, suspensions, emulsions, or semi-solid aerosols, typically using propellants such as carbon halogens derived from methane and ethane, carbon dioxide, or any other suitable gas. For topical aerosols, hydrocarbons such as butane, isobutene, and pentane are suitable. In the case of pressurized aerosols, the appropriate dosage unit can be determined by providing a valve for delivering the amount of the dose. Capsules and cartridges, such as gelatin, can be formulated for inhalers or blowpipes. These typically contain a mixture of the compound and a suitable powder matrix such as lactose or starch.

[0605] Compounds and compositions formulated for parenteral administration via injection are typically sterile and may be present in unit dosage forms, such as ampoules, syringes, injection pens, or multi-dose containers, which typically contain preservatives. Compositions may take the form of oily or aqueous media such as suspensions, solutions, or emulsions, and may contain conditioning agents such as buffers, tonics, viscosity enhancers, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives. Depending on the injection site, the media may contain water, synthetic or vegetable oils, and / or organic cosolvents. In some cases, such as when using lyophilized products or concentrates, parenteral formulations will be reconstituted or diluted prior to administration. Depot formulations providing controlled-release or sustained-release of the compounds of the present invention may comprise injectable suspensions of nano / micron particles or nano / micron or non-micronized crystals. Polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof may be used as controlled-release / sustained-release matrices, among others, in addition to those well known in the art. Other depot delivery systems may be presented in the form of implants requiring incisions and pumps.

[0606] Suitable carriers for intravenous injection of the compounds of the present invention are well known in the art and include aqueous solutions containing an alkali, such as sodium hydroxide, to form ionized compounds; sucrose or sodium chloride as a tonic agent; and buffers, such as buffers containing phosphate or histidine. Cosolvents, such as polyethylene glycol, may be added. These aqueous systems are effective in dissolving the compounds of the present invention and produce low toxicity when administered systemically. The proportions of the components in the solution system can vary significantly without compromising its solubility and toxicity properties. Furthermore, the identity of the components can be varied. For example, low-toxicity surfactants such as polysorbate or poloxamer can be used, as can polyethylene glycol or other cosolvents; biocompatible polymers such as polyvinylpyrrolidone can be added; and other sugars and polyols can replace glucose.

[0607] The therapeutically effective dose can be initially estimated using various techniques well known in the art. The initial dose used in animal studies can be based on effective concentrations established in cell culture assays. For example, data obtained from animal studies and cell culture assays can be used to determine a dose range suitable for human subjects. In some embodiments, the compounds of this disclosure are formulated for oral administration. An exemplary dose of the compounds of this disclosure in a pharmaceutical formulation for oral administration is about 0.5 to about 10 mg / kg of subject body weight. In some embodiments, the pharmaceutical formulation comprises about 0.7 to about 5.0 mg / kg of subject body weight, or alternatively, about 1.0 to about 2.5 mg / kg of subject body weight. Typical dosing regimens for oral administration are three times a week, twice a week, once a week, or daily administration of the pharmaceutical formulation for oral administration.

[0608] A pharmaceutical agent, such as the effective amount or therapeutically effective amount or dose of the compounds of the present invention, refers to the amount of a pharmaceutical agent or compound that results in symptom improvement or prolonged survival in a subject. The toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or laboratory animals, for example by determining the LD50 (the dose that is lethal to 50% of the population) and ED50 (the dose that is therapeutically effective to 50% of the population). The dose ratio of toxicity to therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Pharmaceutical agents exhibiting a high therapeutic index are preferred.

[0609] An effective or therapeutically effective dose is the amount of a compound or pharmaceutical composition that researchers, veterinarians, physicians, or other clinicians are seeking to elicit a biological or medical response in tissues, systems, animals, or humans. Specifically, the dose falls within a range of circulating concentrations, including the ED50, indicating minimal or no toxicity. The dose may vary within this range depending on the dosage form used and / or the route of administration employed. Given the specific circumstances of the subject's condition, precise formulations, routes of administration, doses, and dose intervals should be selected according to methods known in the art.

[0610] Dosage and intervals can be individually adjusted to provide a plasma concentration of the active ingredient sufficient to achieve the desired effect; that is, the minimum effective concentration (MEC). The MEC will vary for each compound but can be estimated from, for example, in vitro data and animal studies. The dose required to achieve the MEC will depend on individual characteristics and the route of administration. In cases of local application or selective uptake, the effective local concentration of the drug may be independent of plasma concentration.

[0611] The amount of compound or composition applied can depend on a variety of factors, including the sex, age and weight of the subject to be treated, the severity of the pain, the method of administration, and the judgment of the prescribing physician.

[0612] If desired, the compounds and compositions of the present invention can be presented in packaging or dispenser devices, which may contain one or more unit dosage forms containing the active ingredient. Such packaging or devices may, for example, comprise metal or plastic foil, such as blister packs; or glass and rubber stoppers, such as vials. The packaging or dispenser device may be accompanied by instructions for use. Compositions comprising the compounds of the present invention formulated in a compatible drug carrier can also be prepared, placed in suitable containers, and labeled for the treatment of specified conditions.

[0613] Given the disclosure herein, those skilled in the art will readily conceive of and consider these and other embodiments of the invention.

[0614] example

[0615] General methods

[0616] Most of the chemicals were purchased from Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other suppliers.

[0617] 1 H NMR or 19 F NMR spectra were recorded on a Bruker AVⅢ400 or Bruker AVⅢ500.

[0618] LCMS measurements were performed on an Agilent 1200HPLC / 6100SQ system under the following conditions:

[0619] Method A: Mobile phase: A: Water (0.01% TFA) B: Acetonitrile (0.01% TFA); Gradient phase: 5% B increased to 95% B within 1.4 min, then 95% B within 1.6 min (total run time: 3 min); Flow rate: 2.3 mL / min; Column: SunFire C18, 4.6*50 mm, 3.5 μm; Column temperature: 50 °C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), ES-API.

[0620] Method B: Mobile phase: A: Water (10mM NH4HCO3) B: Acetonitrile; Gradient phase: from 5% to 95% B in 1.5 min, then 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; Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).

[0621] General scheme for synthesizing compounds of formula (I)

[0622] According to scheme A, compound (I) is prepared using commercially available materials. The reaction of halogenated pyridine (compound a) with an oxidizing agent yields an N-oxide pyridine compound (b). Cyanidation of compound (b) provides compound (c). Cross-coupling of compound (c) with boric acid yields compound (e). Halogen substitution of compound (e) with benzyl alcohol provides compound (f). Hydrolysis of the nitrile of compound (f), followed by formation of an amide with an amino ester, yields amide (compound (i)). Deprotection of benzyl provides compound (I), and subsequent saponification of its ester provides compound (j).

[0623] Scheme A: Synthesis of compound (I)

[0624]

[0625] Synthesis of exemplary compounds

[0626] Example 1: Preparation of Compound 1

[0627] 3,5-Dichloro-4-methylpyridine 1-oxide

[0628]

[0629] 3-Chloroperoxybenzoic acid (8.12 g, 40.11 mmol, 85%) was added to a solution of 3,5-dichloro-4-methylpyridine (5.0 g, 30.8 mmol) in dichloromethane (70.0 mL) at 0 °C. The mixture was stirred at room temperature for 18.0 h and potassium carbonate (4.42 g, 32.0 mmol) was added. The mixture was stirred for another 1 h and the insoluble solid was filtered off. The filtrate was concentrated to give 3,5-dichloro-4-methylpyridine 1-oxide as a white solid (4.7 g, 26.4 mmol, 85.1% yield). LC-MS: m / z = 178.1 [M+H] + The residence time was 1.47 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0630] 3,5-Dichloro-4-methylpicolinonitrile

[0631]

[0632] A mixture of 3,5-dichloro-4-methylpyridine 1-oxide (5.0 g, 28.4 mmol), trimethylsilane 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 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 3,5-dichloro-4-methylpicolinonitrile (4.96 g, 26.8 mmol, 94.5% yield) as a yellow oil. LC-MS: m / z = 187.2 [M+H] + The residence time was 1.74 min (Method A).

[0633] 3-Chloro-5-(3-fluorophenyl)-4-methylpicolinonitrile

[0634]

[0635] N,N-dimethylformamide / water (5.0 mL / 0.5 mL) was added 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). The mixture was stirred at 45 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 3-chloro-5-(3-fluorophenyl)-4-methylpicolinonitrile (400 mg, 1.63 mmol, 61% yield) as a yellow solid. LC-MS: m / z = 247.1[M+H]+, residence time = 1.83 min (Method A).

[0636] 3-(benzoxy)-5-(3-fluorophenyl)-4-methylpicolinonitrile

[0637]

[0638] Sodium hydride (78 mg, 1.94 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 3-chloro-5-(3-fluorophenyl)-4-methylpicolinonitrile (400.0 mg, 1.62 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (210 mg, 1.94 mmol). The solution was stirred at 0 °C for 1.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-(benzoxy)-5-(3-fluorophenyl)-4-methylpicolinonitrile (378 mg, 1.18 mmol, 73% yield) as a yellow solid. LC-MS: m / z = 319.1[M+H]+, residence time = 2.21 min (Method A).

[0639] 3-(benzoxy)-5-(3-fluorophenyl)-4-methylpicolinic acid

[0640]

[0641] A solution of 3-(benzoxy)-5-(3-fluorophenyl)-4-methylpicolinonitrile (378 mg, 1.19 mmol) in ethanol (10.0 mL) was added to a solution of 3-(benzoxy)-5-(3-fluorophenyl)-4-methylpicolinonitrile (378 mg, 1.19 mmol) in ethanol (10.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-5-(3-fluorophenyl)-4-methylpicolinic acid (340 mg, 1.01 mmol, 85% yield) as a white solid. LC-MS: m / z = 338.1 [M+H] + The residence time was 2.00 min (Method A). The product was sufficiently pure and used directly in the next step.

[0642] (3-(benzooxy)-5-(3-fluorophenyl)-4-methylpicolinoyl)glycine ethyl ester

[0643]

[0644] A mixture of 3-(benzoxy)-5-(3-fluorophenyl)-4-methylpicolinic acid (170 mg, 0.50 mmol), glycine ethyl ester hydrochloride (70 mg, 0.50 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give ethyl (3-(benzoxy)-5-(3-fluorophenyl)-4-methylpicolinoyl)glycine (200 mg, 0.47 mmol, 94% yield) as a white solid. LC-MS: m / z = 423.1 [M+H] + The residence time was 2.15 min (Method A).

[0645] (5-(3-fluorophenyl)-3-hydroxy-4-methylpicolinoyl)glycine ethyl ester

[0646]

[0647] A mixture of ethyl (3-(benzoxy)-5-(3-fluorophenyl)-4-methylpicolinoyl)glycine (200 mg, 0.47 mmol) and 10% palladium / carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 18.0 h under a hydrogen atmosphere. The insoluble solid was filtered off and the filtrate was concentrated to give ethyl (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinoyl)glycine (150 mg, 0.45 mmol, 95% yield) as a yellow solid. LC-MS: m / z = 333.1 [M+H] + The residence time was 2.19 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0648] (5-(3-fluorophenyl)-3-hydroxy-4-methylpicolinoyl)glycine

[0649]

[0650] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine ethyl ester (150 mg, 0.45 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give (5-(3-fluorophenyl)-3-hydroxy-4-methylpicolinoyl)glycine (24.0 mg, 0.06 mmol, 13% yield) as a white solid. LC-MS: m / z = 305.1 [M+H] + The residence time was 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).

[0651] Example 2: Preparation of Compound 2

[0652] 3-Chloro-5-(3-methoxyphenyl)-4-methylpicolinonitrile

[0653]

[0654] To a solution of 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), N,N-dimethylformamide / water (2.0 mL / 0.2 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (117.27 mg, 0.05 mmol) was added. The mixture was stirred at 45 °C under nitrogen for 12.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 3-chloro-5-(3-methoxyphenyl)-4-methylpicolinonitrile (500 mg, 1.94 mmol, 61% yield) as a yellow solid. LC-MS: m / z = 259 [M+H] + The residence time was 2.13 min (Method B).

[0655] 3-(benzoxy)-5-(3-methoxyphenyl)-4-methylpicolinonitrile

[0656]

[0657] Sodium hydride (100.8 mg, 2.52 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 3-chloro-5-(3-methoxyphenyl)-4-carboxynitrile (500 mg, 1.94 mmol) in N,N-dimethylformamide (10.0 mL) under nitrogen atmosphere at 0 °C. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (172.1 mg, 2.52 mmol). The solution was stirred at room temperature for 2.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-(benzyloxy)-5-(3-methoxyphenyl)-4-methylpicolinonitrile (350 mg, 1.06 mmol, 54.6% yield) as a yellow solid. LC-MS: m / z = 331.0 [M+H] + The residence time was 1.91 min (Method A).

[0658] 3-(benzoxy)-5-(3-methoxyphenyl)-4-methylpicolinic acid

[0659]

[0660] A solution of 3-(benzoxy)-5-(3-methoxyphenyl)-4-methylpicolinonitrile (350 mg, 1.06 mmol) in ethanol (10.0 mL) was added to a solution of 3-(benzoxy)-5-(3-methoxyphenyl)-4-methylpicolinonitrile (350 mg, 1.0 mmol, 94.61% yield). 30% hydrochloric acid aqueous solution (5.0 mL) was added to the solution. The mixture was stirred at 100 °C for 3.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-5-(3-methoxyphenyl)-4-methylpicolinic acid (350 mg, 1.0 mmol, 94.61% yield) as a white solid. LC-MS: m / z = 350.0 [M+H] + The residence time was 1.38 min (Method B). The product was sufficiently pure and could be used directly in the next step.

[0661] (3-(benzooxy)-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycine ethyl ester

[0662]

[0663] A mixture of 3-(benzoxy)-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycine ethyl ester hydrochloride (86.0 mg, 0.62 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 h. 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give ethyl (3-(benzoxy)-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycine (180 mg, 0.41 mmol, 79.76% yield) as a white solid. LC-MS: m / z = 435.0 [M+H] + The residence time was 2.18 min (Method B).

[0664] (3-hydroxy-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycine ethyl ester

[0665]

[0666] A mixture of ethyl (3-(benzoxy)-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycine (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 off and the filtrate was concentrated to give ethyl (3-hydroxy-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycine (180 mg, crude product) 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.

[0667] (3-hydroxy-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycine

[0668]

[0669] Sodium hydroxide (160 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycine (160 mg, 0.47 mmol) in tetrahydrofuran / water (10.0 mL / 4.0 mL). The mixture was stirred at 40 °C for 12.0 h and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give (3-hydroxy-5-(3-methoxyphenyl)-4-methylpicolinoyl)glycine (62 mg, 0.20 mmol, 42% yield) as a white solid. LC-MS: m / z = 317.0 [M+H] + The residence time was 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).

[0670] Example 3: Preparation of Compound 3

[0671] 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)isoquinoline

[0672]

[0673] 1,4-Dioxane (15.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (365 mg, 0.5 mmol) was added to a solution of 6-bromoisoquinoline (1.04 g, 5.0 mmol), bis(pinacol)diboron (2.54 g, 10.0 mmol), and potassium acetate (1.96 g, 20.0 mmol). The mixture was stirred at 90 °C under nitrogen for 2.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)isoquinoline (0.79 g, 3.1 mmol, 62% yield) as a white solid. LC-MS: m / z = 256.0 [M+H] + The residence time was 1.41 min (Method B).

[0674] 3-Chloro-5-(isoquinoline-6-yl)-4-methylpicolinonitrile

[0675]

[0676] To a solution of 3,5-dichloro-4-methylpicolinonitrile (400 mg, 2.16 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)isoquinoline (550 mg, 2.16 mmol), and potassium carbonate (358 mg, 2.59 mmol), N,N-dimethylformamide / water (5.0 mL / 0.5 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (146 mg, 0.2 mmol) 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 3-chloro-5-(isoquinolin-6-yl)-4-methylpicolinonitrile (500 mg, 1.79 mmol, 83% yield) as a yellow solid. LC-MS: m / z = 280.0 [M+H] + The residence time was 1.58 min (Method B).

[0677] 5-(isoquinoline-6-yl)-3-((4-methoxybenzyl)oxy)-4-methylpicolinonitrile

[0678]

[0679] Sodium hydride (86 mg, 2.15 mmol, 60% w / w dispersion in mineral oil) was added 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) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of (4-methoxyphenyl)methanol (296 mg, 2.15 mmol). The solution was stirred at 0 °C for 1.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 5-(isoquinoline-6-yl)-3-((4-methoxyphenylmethyl)oxy)-4-methylpicolinonitrile (250 mg, 0.66 mmol, 37% yield) as a yellow solid. LC-MS: m / z = 382.1[M+H]+, residence time = 2.21 min (Method A).

[0680] 3-Hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinic acid

[0681]

[0682] A solution of 5-(isoquinoline-6-yl)-3-((4-methoxybenzyl)oxy)-4-methylpicolinonitrile (250 mg, 0.66 mmol) in ethanol (10.0 mL) was added to a 30% aqueous sodium hydroxide solution (4.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinic acid (250 mg, crude substance) as a white solid. LC-MS: m / z = 401.1 [M+H] + The residence time was 2.00 min (Method A). The product was sufficiently pure and used directly in the next step.

[0683] (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinoyl)glycine ethyl ester

[0684]

[0685] A mixture of 3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinic acid (250 mg, 0.62 mmol), glycine ethyl ester hydrochloride (87 mg, 0.62 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinoyl)glycine ethyl ester (140 mg, 0.38 mmol, 43% yield) as a white solid. LC-MS: m / z = 366.1 [M+H] + The residence time was 2.15 min (Method A).

[0686] (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinoyl)glycine

[0687]

[0688] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinoyl)glycine (140 mg, 0.38 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse preparative HPLC to give (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpicolinoyl)glycine (72.6 mg, 0.22 mmol, 56% yield) as a white solid. LC-MS: m / z = 338.1 [M+H] + The residence time was 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).

[0689] Example 4: Preparation of Compound 4

[0690] 3-Chloro-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinonitrile

[0691]

[0692] To a solution of 3,5-dichloro-4-methylpyridin-2-carboxynitrile (550 mg, 2.96 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1H-pyrazole (800 mg, 2.96 mmol), and potassium carbonate (490 mg, 3.55 mmol), N,N-dimethylformamide / water (10.0 mL / 1.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (86.5 mg, 0.12 mmol) was added. The mixture was stirred at 50 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 3-chloro-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinenone (400 mg, 1.36 mmol, 46% yield) as a yellow solid. LC-MS: m / z = 295.3 [M+H]+, retention time = 1.909 min (Method A).

[0693] 3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinonitrile

[0694]

[0695] Sodium hydride (90 mg, 2.24 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 3-chloro-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinonitrile (600.0 mg, 2.04 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (220.2 mg, 2.04 mmol). The solution was stirred at 0 °C for 1.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinonitrile (300 mg, 0.82 mmol, 40.2% yield) as a yellow solid. LC-MS: m / z = 367.1[M+H]+, residence time = 2.20 min (Method A).

[0696] 3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinic acid

[0697]

[0698] A solution of 3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinonitrile (300 mg, 0.82 mmol) in ethanol (5.0 mL) was added to a solution of 3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinic acid (5.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinic acid (290 mg, 0.75 mmol, 91.4% yield) as a white solid. LC-MS: m / z = 386.4 [M+H] + The residence time was 1.74 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0699] (3-(benzooxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinyl)glycine ethyl ester

[0700]

[0701] A mixture of 3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinic acid (290 mg, 0.75 mmol), glycine ethyl ester hydrochloride (104 mg, 0.75 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give ethyl glycine (3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinoyl) as a yellow solid (200 mg, 0.42 mmol, 56.5% yield). LC-MS: m / z = 471.1 [M+H] + The residence time was 2.13 min (Method A).

[0702] (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine ethyl ester

[0703]

[0704] A mixture of (3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine ethyl ester (200 mg, 0.42 mmol) and 10% palladium / carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 18 h under a hydrogen atmosphere. The insoluble solid was filtered off and the filtrate was concentrated to give (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine ethyl ester (150 mg, 0.39 mmol, 94% yield) as a white solid. LC-MS: m / z = 381.0 [M+H] + The residence time was 2.16 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0705] (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine

[0706]

[0707] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine ethyl ester (150 mg, 0.39 mmol) in tetrahydrofuran / water (6.0 mL / 3.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine as a white solid (121.6 mg, 0.35 mmol, 88.5% yield). LC-MS: m / z = 353.1 [M+H] + The residence time was 4.534 min (Method A). 1 HNMR(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).

[0708] Example 5: Preparation of Compound 5

[0709] 2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline

[0710]

[0711] 1,4-Dioxane (15.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (660 mg, 0.9 mmol) was added to a solution of 6-bromo-2-methylquinoline (2.0 g, 9.01 mmol), bis(pinacol)diboron (2.6 g, 10.28 mmol), and potassium acetate (2.65 g, 27 mmol). The mixture was stirred at 100 °C under nitrogen for 2.0 h 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-dioxaborpentane-2-yl)quinoline (2.1 g, 7.81 mmol, 87.5% yield) was given. LC-MS: m / z = 270.2 [M+H] + The residence time was 2.08 min (Method B). The product was used directly in the next step.

[0712] 3-Chloro-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile

[0713]

[0714] To a solution of 3,5-dichloro-4-methylpyridin-2-carboxynitrile (1.2 g, 6.42 mmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)quinoline (1.73 g, 6.42 mmol), and potassium carbonate (1.16 g, 7.70 mmol), N,N-dimethylformamide / water (10.0 mL / 1.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (234.5 mg, 0.32 mmol) 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 3-chloro-4-methyl-5-(2-methylquinolin-6-yl)picolinonitrile (900 mg, 3.07 mmol, 47.9% yield) as a yellow solid. LC-MS: m / z = 294.0 [M+H] + The residence time was 1.61 min (Method A).

[0715] 3-((4-methoxybenzyl)oxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile

[0716]

[0717] Sodium hydride (95.6 mg, 2.39 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 3-chloro-5-(isoquinoline-6-yl)-4-methylpicolinonitrile (500 mg, 1.71 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of (4-methoxyphenyl)methanol (329.7 mg, 2.39 mmol). The solution was stirred at 0 °C for 2.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 3-((4-methoxyphenylmethyl)oxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile (400 mg, 1.01 mmol, 59.2% yield) as a yellow solid. LC-MS: m / z = 396.0 [M+H] + The residence time was 1.49 min (Method A).

[0718] 3-Hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid

[0719]

[0720] 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 added to a solution of 3-((4-methoxybenzyl)oxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid (400 mg, crude product) in ethanol (10.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid (400 mg, crude product) as a white solid. LC-MS: m / z = 295.2 [M+H] + The residence time was 1.15 min (Method B). The product was sufficiently pure and could be used directly in the next step.

[0721] (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolineloyl)glycine ethyl ester

[0722]

[0723] A mixture of 3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid (200.0 mg, 0.68 mmol), glycine ethyl ester hydrochloride (113.5 mg, 0.82 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 2) to give (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinoyl)glycine ethyl ester (120 mg, 0.32 mmol, 47.1% yield) as a white solid. LC-MS: m / z = 380.1 [M+H] + The residence time was 1.60 min (Method A).

[0724] (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolinoyl)glycine

[0725]

[0726] Lithium hydroxide monohydrate (140 mg, 3.3 mmol) was added to a solution of ethyl (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolineloyl)glycine (120 mg, 0.33 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse preparative HPLC to give (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)picolineloyl)glycine (5.9 mg, 0.017 mmol, 5.09%) as a white solid. LC-MS: m / z = 352.1 [M+H] + The residence time was 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).

[0727] Example 6: Preparation of Compound 6

[0728] 4-(4-(5-chloro-6-cyano-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0729]

[0730] To a solution of 3,5-dichloro-4-methylpyridin-2-carboxylonitrile (561 mg, 3.0 mmol), tert-butyl piperidine-1-carboxylate (1.13 mmol, 3.0 mmol), and potassium carbonate (497 mg, 3.6 mmol), N,N-dimethylformamide / water (10.0 mL / 1.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (110 mg, 0.15 mmol) was added. The mixture was stirred at 50 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl 4-(4-(5-chloro-6-cyano-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylate (400 mg, 1.0 mmol, 33% yield) as a yellow solid. LC-MS: m / z = 346.2 [M-56] + The dwell time was 2.078 min (Method A).

[0731] 4-(4-(5-(benzyloxy)-6-cyano-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0732]

[0733] Sodium hydride (72 mg, 1.79 mmol, in mineral oil, 60% w / w dispersion) was added to a solution of 4-(4-(5-chloro-6-cyano-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (600 mg, 1.49 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (194 mg, 1.79 mmol). The solution was stirred at 0 °C for 1.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl 4-(4-(5-(benzyloxy)-6-cyano-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (330 mg, 0.70 mmol, 46% yield) as a yellow solid. LC-MS: m / z = 474.0 [M+H] + The dwell time was 2.21 min (Method A).

[0734] 3-(benzoxy)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-methylpicolinic acid

[0735]

[0736] A solution of tert-butyl piperidine-1-carboxylate (330 mg, 0.70 mmol) in ethanol (15.0 mL) was added to a solution of tert-butyl piperidine-1-carboxylate (5.0 mL). The mixture was stirred at 100 °C for 1.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazole-4-yl)-4-methylpicolinic acid (330 mg, 0.33 mmol, 96% yield) as a white solid. LC-MS: m / z = 493.2 [M+H] + The residence time was 1.97 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0737] 4-(4-(5-(benzyloxy)-6-((2-ethoxy-2-oxoethyl)carbamoyl)-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0738]

[0739] A mixture of 3-(benzoxy)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-methylpicolinic acid (165 mg, 0.33 mmol), glycine ethyl ester hydrochloride (47 mg, 0.33 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl 4-(4-(5-(benzoxy)-6-((2-ethoxy-2-oxoethyl)carbamoyl)-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid (165 mg, 0.29 mmol, 85% yield) as a white solid. LC-MS: m / z = 578.0 [M+H] + The residence time was 2.14 min (Method A).

[0740] 4-(4-(6-((2-ethoxy-2-oxoethyl)carbamoyl)-5-hydroxy-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0741]

[0742] A mixture of 4-(4-(5-(benzyloxy)-6-((2-ethoxy-2-oxoethyl)carbamoyl)-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (165 mg, 0.29 mmol) and 10% palladium / carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 18.0 h under a hydrogen atmosphere. The insoluble solid was filtered off and the concentrated filtrate was used to give a yellow solid of 4-(4-(6-((2-ethoxy-2-oxoethyl)carbamoyl)-5-hydroxy-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (135 mg, 0.27 mmol, 97% yield LC-MS: m / z = 460.1 [M+H]). + The residence time was 2.19 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0743] (5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpicolinoyl)glycine

[0744]

[0745] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of 4-(4-(6-(((2-ethoxy-2-oxoethyl)carbamoyl)-5-hydroxy-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (135 mg, 0.27 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give a white solid of (5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpicorinyl

[0746] Glycine (85.5 mg, 0.18 mmol, 67% yield). LC-MS: m / z = 502.1 [M+H] + The residence time was 5.33 min (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).

[0747] Example 7: Preparation of Compound 7

[0748] 2-Phenylacetyl-5-(tributyltinyl)thiazole

[0749]

[0750] To a solution of 2-phenylthiazolium (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 at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 30 minutes, followed by the addition of tributyltin chloride (20.8 mL, 71.34 mmol). The mixture was then heated to 0 °C. ℃The mixture was stirred for another hour. The reactants were 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 rapid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 2-phenyl-5-(tributyltinyl)thiazole as a yellow solid (27.7 g, 61.6 mmol, 99% yield). LC-MS: m / z = 451.2 [M+H] + The residence time was 2.30 min (Method A).

[0751] 3-Chloro-4-methyl-5-(2-phenylthiazo-5-yl)picolinonitrile

[0752]

[0753] Tetra(triphenylphosphine)palladium (1.28 g, 1.11 mmol) was added to a solution of 3,5-dibromo-4,6-dimethylpicolinonitrile (2.9 g, 15.55 mmol), 2-phenyl-5-(tributyltinyl)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). The mixture was stirred at 40 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 3-chloro-4-methyl-5-(2-phenylthiazolyl-5-yl)picolinenone (150 mg, 0.48 mmol, 10% yield) as a green solid. LC-MS: m / z = 312.1 [M+H] + The residence time was 1.909 min (Method A).

[0754] 3-Hydroxy-4-methyl-5-(2-phenylthiazolyl-5-yl)picolinonitrile

[0755]

[0756] Benzyl alcohol (780 mg, 7.22 mmol) was added to a solution of 3-chloro-4-methyl-5-(2-phenylthiazolyl-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 2.0 days 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 preparative HPLC to give 3-hydroxy-4-methyl-5-(2-phenylthiazolyl-5-yl)picolinonitrile (200 mg, 0.68 mmol, 14% yield) as a white solid. LC-MS: m / z = 294.1 [M+H] + The dwell time is 1.40 min (Method A).

[0757] 3-Hydroxy-4-methyl-5-(2-phenylthiazo-5-yl)picolinic acid

[0758]

[0759] A solution of 200 mg (0.68 mmol) of 3-hydroxy-4-methyl-5-(2-phenylthiazolyl-5-yl)picolinonitrile in 10.0 mL of ethanol was added to a 30% aqueous solution of sodium hydroxide (3.0 mL). The mixture was stirred at 100 °C for 3.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 200 mg (0.64 mmol, 94% yield) of 3-hydroxy-4-methyl-5-(2-phenylthiazolyl-5-yl)picolinic acid as a white solid. LC-MS: m / z = 313.4 [M+H] + The residence time was 1.74 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0760] (3-hydroxy-4-methyl-5-(2-phenylthiazo-5-yl)picolinoyl)glycine ethyl ester

[0761]

[0762] A mixture of 3-hydroxy-4-methyl-5-(2-phenylthiazol-5-yl)picolinic acid (200 mg, 0.64 mmol), glycine ethyl ester hydrochloride (150 mg, 1.08 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 2) to give ethyl glycine (3-hydroxy-4-methyl-5-(2-phenylthiazol-5-yl)picolinoyl) as a white solid (140 mg, 0.35 mmol, 55% yield). LC-MS: m / z = 398.1 [M+H] + The residence time was 2.13 min (Method A).

[0763] (3-hydroxy-4-methyl-5-(2-phenylthiazo-5-yl)picolinoyl)glycine

[0764]

[0765] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of (3-hydroxy-4-methyl-5-(2-phenylthiazol-5-yl)picolinoyl)glycine ethyl ester (140 mg, 0.35 mmol) in tetrahydrofuran / water (8.0 mL / 4.0 mL). The mixture was stirred overnight at 40 °C and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give (3-hydroxy-4-methyl-5-(2-phenylthiazol-5-yl)picolinoyl)glycine (106.6 mg, 82% yield) as a white solid. LC-MS: m / z = 370.0 [M+H] + The residence time was 4.92 min (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).

[0766] Example 8: Preparation of Compound 8

[0767] 4,4,5,5-Tetramethyl-2-(3-phenoxyphenyl)-1,3,2-dioxaborane

[0768]

[0769] 1,4-Dioxane (15.0 mL) containing [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (438 mg, 0.6 mmol) was added to a solution of 1-bromo-3-phenoxybenzene (1.5 g, 6.02 mmol), bis(pinacol)diboron (3.06 g, 12.04 mmol), and potassium acetate (2.36 g, 24.1 mmol). The mixture was stirred at 90 °C under nitrogen for 2.0 h 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-dioxaborane (1.0 g, 3.37 mmol, 56.1% yield) was given. LC-MS: m / z = 297.0 [M+H] + The residence time was 2.41 min (Method B). The product was used directly in the next step.

[0770] 3-Chloro-4-methyl-5-(3-phenoxyphenyl)picolinonitrile

[0771]

[0772] To a solution of 3,5-dichloro-4-methylpyridin-2-carboxynitrile (626 mg, 3.37 mmol), 4,4,5,5-tetramethyl-2-(3-phenoxyphenyl)-1,3,2-dioxaborane (1.0 g, 3.37 mmol), and potassium carbonate (697 mg, 5.05 mmol), N,N-dimethylformamide / water (10.0 mL / 1.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (123 mg, 0.17 mmol) 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-chloro-4-methyl-5-(3-phenoxyphenyl)picolinonitrile as a yellow solid (450 mg, 1.41 mmol, 41.7% yield). LC-MS: m / z = 321.0 [M+H] + The residence time was 2.30 min (Method A).

[0773] 3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)picolinonitrile

[0774]

[0775] Sodium hydride (113 mg, 2.82 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 3-chloro-4-methyl-5-(3-phenoxyphenyl)picolinonitrile (450 mg, 1.41 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (152 mg, 1.41 mmol). The solution was stirred at 0 °C for 1.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)picolinonitrile (350 mg, 0.89 mmol, 63.3% yield) as a yellow solid. LC-MS: m / z = 352.0 [M+H] + The residence time was 1.70 min (Method A).

[0776] 3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)picolinic acid

[0777]

[0778] A solution of 3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)picolinonitrile (350 mg, 0.89 mmol) in ethanol (10.0 mL) was added to a solution of 3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)picolinonitrile (4.0 mL). 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. The precipitate was filtered and dried to give 3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)picolinic acid (300 mg, 0.73 mmol, 82.0% yield) as a white solid. LC-MS: m / z = 393.0 (M+H) + The residence time was 2.35 min (Method B). The product was sufficiently pure and could be used directly in the next step.

[0779] (3-(benzooxy)-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycine ethyl ester

[0780]

[0781] A mixture of 3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)picolinic acid (300 mg, 0.73 mmol), glycine ethyl ester hydrochloride (152 mg, 1.09 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 2) to give ethyl (3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycine (210 mg, 0.42 mmol, 58.0% yield) as a white solid. LC-MS: m / z = 497.0(M+H) + The residence time was 2.26 min (Method A).

[0782] (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycine ethyl ester

[0783]

[0784] A mixture of ethyl (3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycine (210 mg, 0.42 mmol) and 10% palladium / carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred at 40 °C under a hydrogen atmosphere for 5.0 h. The insoluble solid was filtered off and the filtrate was concentrated to give ethyl (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycine (140 mg, 0.34 mmol, 81% yield) as a yellow solid. LC-MS: m / z = 407.0 (M+H) + The residence time was 2.32 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0785] (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycine

[0786]

[0787] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycine (140 mg, 0.34 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse preparative HPLC to give (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)picolinoyl)glycine (38.7 mg, 0.10 mmol, 30% yield) as a white solid. LC-MS: m / z = 379.0 [M+H] + The residence time was 5.76 min (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).

[0788] Example 9: Preparation of Compound 9

[0789] 5-Chloro-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxynitrile

[0790]

[0791] To a solution of 3,5-dichloro-4-methylpyridin-2-carboxynitrile (500.00 mg, 2.67 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-2-(trifluoromethyl)pyridine (730.03 mg, 2.67 mmol), and potassium carbonate (443.41 mg, 3.21 mmol), N,N-dimethylformamide / water (10.0 mL / 1.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (78.25 mg, 0.11 mmol) 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 rapid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 5-chloro-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxynitrile (577 mg, 1.94 mmol, 72% yield) as a yellow solid. LC-MS: m / z = 298 [M+H]+ The residence time was 2.052 min (Method A).

[0792] 5-(benzoxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxynitrile

[0793]

[0794] Sodium hydride (80.8 mg, 2.02 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 5-chloro-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxynitrile (500.00 mg, 1.68 mmol) in N,N-dimethylformamide (20.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, and then benzyl alcohol (217.97 mg, 2.02 mmol, 0.21 mL) was added. The solution was stirred at 0 °C for 50 min 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 rapid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 5-(benzoxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxynitrile (306 mg, 49% yield). LC-MS: m / z = 370 [M+H] + The residence time was 2.190 min (Method B).

[0795] 5-(benzoxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxylic acid

[0796]

[0797] A solution of 5-(benzoxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxynitrile (306.00 mg, 0.83 mmol) in ethanol (10.0 mL) was added to a solution of 30% sodium hydroxide aqueous solution (4.0 mL). The mixture was stirred at 100 °C for 3.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 5-(benzoxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxylic acid (353 mg, crude substance) as a white solid. LC-MS: m / z = 389 [M+H] + The residence time was 1.977 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0798] (5-(benzooxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine ethyl ester

[0799]

[0800] A mixture of 5-(benzoxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxylic acid (300.00 mg, 0.77 mmol), glycine ethyl ester hydrochloride (107.83 mg, 0.77 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate (442.21 mg, 0.85 mmol), and triethylamine (390.85 mg, 3.86 mmol, 0.54 mL) in dichloromethane (20.0 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give ethyl glycine (5-(benzoxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl) ester (257 mg, 0.54 mmol, 70% yield). LC-MS: m / z = 474 [M+H] + The residence time was 1.8-10 min (Method A).

[0801] (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine ethyl ester

[0802]

[0803] A mixture of (5-(benzoxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine ethyl ester (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 off and the filtrate was concentrated to give (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine ethyl ester (230 mg, crude product) as a yellow solid. LC-MS: m / z = 384 [M+H] + The residence time was 2.116 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0804] (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine

[0805]

[0806] Lithium hydroxide monohydrate (219 mg, 5.22 mmol) was added to a solution of (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine ethyl ester (200.00 mg, 0.52 mmol) in methanol / water (10.0 mL / 2.0 mL). The mixture was stirred overnight at 40 °C and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse preparative HPLC to give (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine (formate) as a yellow solid (48.2 mg, 0.14 mmol, 26% yield). LC-MS: m / z = 356 [M+H] + The residence time was 4.420 min (Method A). 1 H 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).

[0807] Example 10: Preparation of Compound 10

[0808] 5-Chloro-4-methyl-[3,3'-bipyridine]-6-carboxynitrile

[0809]

[0810] N,N-dimethylformamide / water (5.0 mL / 0.5 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (78 mg, 0.11 mmol) was added to a solution of 3,5-dichloro-4-methylpyridin-2-carboxynitrile (500 mg, 2.67 mmol), pyridin-3-ylboronic acid (329 mg, 2.67 mmol), and potassium carbonate (443 mg, 3.21 mmol). 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 5-chloro-4-methyl-[3,3'-bipyridine]-6-carboxynitrile (300 mg, 1.31 mmol, 49% yield) as a yellow solid. LC-MS: m / z = 230.1 [M+H] + The dwell time was 1.83 min (Method A).

[0811] 5-(benzoxy)-4-methyl-[3,3'-bipyridine]-6-carboxynitrile

[0812]

[0813] Sodium hydride (78 mg, 1.94 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 5-chloro-4-methyl-[3,3'-bipyridine]-6-carboxynitrile (300.0 mg, 1.31 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (152 mg, 1.41 mmol). The solution was stirred at 0 °C for 1.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 5-(benzyloxy)-4-methyl-[3,3'-bipyridine]-6-carboxynitrile (300 mg, 0.99 mmol, 76% yield) as a yellow solid. LC-MS: m / z = 302.1 [M+H] + The dwell time was 2.21 min (Method A).

[0814] 5-(benzoxy)-4-methyl-[3,3'-bipyridine]-6-carboxylic acid

[0815]

[0816] A solution of 5-(benzoxy)-4-methyl-[3,3'-bipyridine]-6-carboxynitrile (300 mg, 0.99 mmol) in ethanol (10.0 mL) was added to a solution of 5-(benzoxy)-4-methyl-[3,3'-bipyridine]-6-carboxylic acid (300 mg, 0.94 mmol, 94% yield). 30% hydrochloric acid solution was added to the solution. The mixture was stirred at 100 °C for 3.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 5-(benzoxy)-4-methyl-[3,3'-bipyridine]-6-carboxylic acid (300 mg, 0.94 mmol, 94% yield) as a white solid. LC-MS: m / z = 321.1 [M+H] + The residence time was 2.00 min (Method A). The product was sufficiently pure and used directly in the next step.

[0817] (5-(benzooxy)-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine ethyl ester

[0818]

[0819] A mixture of 5-(benzoxy)-4-methyl-[3,3'-bipyridine]-6-carboxylic acid (300 mg, 0.94 mmol), glycine ethyl ester hydrochloride (144 mg, 1.03 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give (5-(benzoxy)-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine ethyl ester (240 mg, 0.59 mmol, 63% yield) as a white solid. LC-MS: m / z = 406.1 [M+H] + The residence time was 2.15 min (Method A).

[0820] (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine ethyl ester

[0821]

[0822] A mixture of (5-(benzoxy)-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine ethyl ester (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 h. The insoluble solid was filtered off and the filtrate was concentrated to give (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine ethyl ester (185 mg, 0.59 mmol, 99% yield) as a yellow solid. LC-MS: m / z = 316.1 [M+H] + The residence time was 2.19 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0823] (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine

[0824]

[0825] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine ethyl ester (185 mg, 0.59 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse preparative HPLC to give (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine (formate) as a white solid (34.0 mg, 0.118 mmol, 20% yield). LC-MS: m / z = 288.1 [M+H] + The residence time was 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).

[0826] Example 11: Preparation of Compound 11

[0827] 5-Chloro-4-methyl-[3,4'-bipyridine]-6-carboxynitrile

[0828]

[0829] To a solution of 3,5-dichloro-4-methylpyridin-2-carboxynitrile (500.00 mg, 2.67 mmol), pyridin-4-ylboronic acid (328.63 mg, 2.67 mmol), and potassium carbonate (443.41 mg, 3.21 mmol), N,N-dimethylformamide / water (10.0 mL / 1.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (78.25 mg, 0.11 mmol) was added. The mixture was stirred at 50 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 5-chloro-4-methyl-[3,4'-bipyridine]-6-carboxynitrile (292 mg, 1.27 mmol, 48% yield). LC-MS: m / z = 230 [M+H] + The residence time was 1.599 min (Method A).

[0830] 5-(benzoxy)-4-methyl-[3,4'-bipyridine]-6-carboxynitrile

[0831]

[0832] Sodium hydride (52.3 mg, 1.31 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 5-chloro-4-methyl-[3,4'-bipyridine]-6-carboxynitrile (250.00 mg, 1.09 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, and then benzyl alcohol (141.25 mg, 1.31 mmol, 0.14 mL) was added. The solution was stirred at 0 °C for 50 min 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 5-(benzyloxy)-4-methyl-[3,4'-bipyridine]-6-carboxynitrile (86 mg, 0.29 mmol, 26% yield). LC-MS: m / z = 302 [M+H] + The residence time was 1.895 min (Method B).

[0833] 5-Hydroxy-4-methyl-[3,4'-bipyridine]-6-carboxylic acid

[0834]

[0835] A solution of 35-(benzoxy)-4-methyl-[3,4'-bipyridine]-6-carboxynitrile (86.00 mg, 0.29 mmol) in ethanol (5.0 mL) was added to a 30% aqueous sodium hydroxide solution (4.0 mL). The mixture was stirred at 100 °C for 3.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 160 mg of crude 5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carboxylic acid as a white solid. LC-MS: m / z = 231 [M+H] + The residence time was 1.020 min (Method A). The product was sufficiently pure and used directly in the next step.

[0836] (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycine ethyl ester

[0837]

[0838] A mixture of 5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carboxylic acid (130.00 mg, 0.56 mmol), glycine ethyl ester hydrochloride (78.82 mg, 0.56 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate (323.24 mg, 0.62 mmol), and triethylamine (285.70 mg, 2.82 mmol, 0.4 mL) 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 2) to give (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycine ethyl ester (36 mg, 0.114 mmol, 20% yield). LC-MS: m / z = 316 [M+H] + The residence time was 1.586 min (Method A).

[0839] (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycine

[0840]

[0841] Lithium hydroxide monohydrate (22.79 mg, 0.95 mmol) was added to a solution of ethyl (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycine (30.00 mg, 0.10 mmol) in methanol / water (4.0 mL / 1.0 mL). The mixture was stirred at 40 °C for 16.0 h and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycine (13.2 mg, 46% yield) as a white solid. LC-MS: m / z = 288 [M+H] + The residence time was 2.159 min (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).

[0842] Example 12: Preparation of Compound 12

[0843] 5'-Chloro-4'-methyl-[2,3'-bipyridine]-6'-carboxynitrile

[0844]

[0845] Tetra(triphenylphosphine)palladium (116 mg, 0.1 mmol) was added to a solution of 3,5-dibromo-4,6-dimethylpicolinonitrile (1.86 g, 10 mmol), 2-(tributyltinyl)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). The mixture was stirred at 50 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 5'-chloro-4'-methyl-[2,3'-bipyridine]-6'-carboxynitrile (460 mg, 2.0 mmol, 20% yield) as a yellow solid. LC-MS: m / z = 230.0 [M+H] + The dwell time was 1.704 min (Method A).

[0846] 5'-(benzoxy)-4'-methyl-[2,3'-bipyridine]-6'-carboxynitrile

[0847]

[0848] Sodium hydride (33 mg, 0.84 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 5'-chloro-4'-methyl-[2,3'-bipyridine]-6'-carboxynitrile (160.0 mg, 0.70 mmol) in N,N-dimethylformamide (5.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (90 mg, 0.84 mmol). The solution was stirred at 0 °C for 1 h 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 2) to give 5'-(benzoxy)-4'-methyl-[2,3'-bipyridine]-6'-carboxynitrile (120 mg, 0.40 mmol, 57% yield) as a yellow solid. LC-MS: m / z = 302.1 [M+H] + The dwell time was 2.21 min (Method A).

[0849] 5'-Hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carboxylic acid

[0850]

[0851] A solution of 5'-(benzoxy)-4'-methyl-[2,3'-bipyridine]-6'-carboxynitrile (120 mg, 0.40 mmol) in ethanol (10.0 mL) was added to a 30% aqueous sodium hydroxide solution (4.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carboxylic acid (140 mg, crude substance) as a white solid. LC-MS: m / z = 321.1 [M+H] + The residence time was 2.00 min (Method A). The product was sufficiently pure and used directly in the next step.

[0852] (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycine ethyl ester

[0853]

[0854] A mixture of 5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carboxylic acid (140 mg, 0.44 mmol), glycine ethyl ester hydrochloride (61 mg, 0.44 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 2) to give (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycine ethyl ester (50 mg, 0.16 mmol, 26% yield) as a white solid. LC-MS: m / z = 406.1 [M+H] + The residence time was 2.15 min (Method A).

[0855] (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycine

[0856]

[0857] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (50 mg, 0.16 mmol) of (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycine in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse preparative HPLC to give (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycine (9.6 mg, 21% yield) as a white solid. LC-MS: m / z = 288.0 [M+H] + The residence time was 2.54 min (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).

[0858] Example 13: Preparation of Compound 13

[0859] 3-Chloro-5-(3-chlorophenyl)-4-methylpicolinonitrile

[0860]

[0861] N,N-dimethylformamide / water (5.0 mL / 0.5 mL) was added to a solution of 3,5-dichloro-4-methylpicolinonitrile (500 mg, 2.67 mmol), (3-fluorophenyl)boronic acid (418 mg, 2.67 mmol), and potassium carbonate (443 mg, 3.21 mmol). The mixture was stirred at 45 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 3-chloro-5-(3-chlorophenyl)-4-carboxynitrile picolinonitrile (640 mg, 2.43 mmol, 91% yield) as a yellow solid. LC-MS: m / z = 264.1 [M+H] + The dwell time was 1.83 min (Method A).

[0862] 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinonitrile

[0863]

[0864] Sodium hydride (584 mg, 14.60 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 3-chloro-5-(3-chlorophenyl)-4-carboxynitrile (3.2 g, 12.16 mmol) in N,N-dimethylformamide (40.0 mL) under nitrogen atmosphere at 0 °C. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (1.58 g, 14.60 mmol). The solution was stirred at 0 °C for 1.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-(benzoxy)-5-(3-fluorophenyl)-4-methylpicolinonitrile (3.2 g, 9.56 mmol, 80% yield) as a yellow solid. LC-MS: m / z = 335.1 [M+H] + The dwell time was 2.21 min (Method A).

[0865] 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinic acid

[0866]

[0867] A solution of 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinonitrile (3.2 g, 9.56 mmol) in ethanol (60.0 mL) was added to a solution of 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinic acid (20.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinic acid (2.1 g, 5.96 mmol, 64% yield) as a white solid. LC-MS: m / z = 354.1 [M+H] + The residence time was 2.00 min (Method A). The product was sufficiently pure and used directly in the next step.

[0868] 2-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpyridinamide)-2-methylpropionate methyl ester

[0869]

[0870] A mixture of 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinic acid (100 mg, 0.28 mmol), methyl 2-amino-2-methylpropionate hydrochloride (44 mg, 0.28 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give methyl 2-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinamido)-2-methylpropionate (110 mg, 0.24 mmol, 87% yield) as a white solid. LC-MS: m / z = 453.1 [M+H] + The residence time was 2.15 min (Method A).

[0871] 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)-2-methylpropionate

[0872]

[0873] A mixture of methyl 2-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinamido)-2-methylpropionate (500 mg, 1.10 mmol) and 10% palladium / carbon (50.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 18.0 h under a hydrogen atmosphere. The insoluble solid was filtered off and the filtrate was concentrated to give methyl 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)-2-methylpropionate (240 mg, 0.66 mmol, 60% yield) as a white solid. LC-MS: m / z = 363.1 [M+H] + The residence time was 2.19 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0874] 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)-2-methylpropionic acid

[0875]

[0876] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of methyl 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)-2-methylpropionic acid (240 mg, 0.66 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)-2-methylpropionic acid (176.3 mg, 0.51 mmol, 77% yield) as a white solid. LC-MS: m / z = 349.0 [M+H] + The residence time was 5.36 min (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).

[0877] Example 14: Preparation of Compound 14

[0878] 1-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamido)cyclopropane-1-carboxylic acid ethyl ester

[0879]

[0880] A mixture of 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinic acid (an intermediate from Example 13) (100 mg, 0.28 mmol), ethyl 1-aminocyclopropane-1-carboxylate hydrochloride (43 mg, 0.28 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give ethyl 1-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamido)cyclopropane-1-carboxylate (110 mg, 0.24 mmol, 85% yield) as a white solid. LC-MS: m / z = 465.1 [M+H] + The residence time was 2.15 min (Method A).

[0881] 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)cyclopropane-1-carboxylic acid ethyl ester

[0882]

[0883] A mixture of 1-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamido)cyclopropane-1-carboxylate (500 mg, 1.08 mmol) and 10% palladium / carbon (50.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 18.0 h under a hydrogen atmosphere. The insoluble solid was filtered off and the filtrate was concentrated to give 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)cyclopropane-1-carboxylate (250 mg, 0.67 mmol, 62% yield) as a white solid. LC-MS: m / z = 375.1 [M+H] + The residence time was 2.19 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0884] 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)cyclopropane-1-carboxylic acid

[0885]

[0886] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)cyclopropane-1-carboxylic acid (250 mg, 0.67 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)cyclopropane-1-carboxylic acid (133.0 mg, 0.38 mmol, 58% yield) as a white solid. LC-MS: m / z = 347.0 [M+H] + The residence time was 4.93 min (Method A). 1 HNMR(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).

[0887] Example 15: Preparation of Compound 15

[0888] methyl 1-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinamido)cyclobutane-1-carboxylate

[0889]

[0890] A mixture of 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinic acid (an intermediate from Example 13) (400 mg, 1.13 mmol), methyl 1-aminocyclobutane-1-carboxylate hydrochloride (187 mg, 1.13 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give methyl 1-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamido)cyclobutane-1-carboxylate (500 mg, 1.08 mmol, 95% yield) as a white solid. LC-MS: m / z = 465.1 [M+H] + The residence time was 2.15 min (Method A).

[0891] methyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)cyclobutane-1-carboxylate

[0892]

[0893] A mixture of methyl 1-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinamido)cyclobutane-1-carboxylate (500 mg, 1.08 mmol) and 10% palladium / carbon (50.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 18.0 h under a hydrogen atmosphere. The insoluble solid was filtered off and the filtrate was concentrated to give methyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)cyclobutane-1-carboxylate (250 mg, 0.67 mmol, 62% yield) as a white solid. LC-MS: m / z = 375.1 [M+H] + The residence time was 2.19 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0894] 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)cyclobutane-1-carboxylic acid

[0895]

[0896] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of methyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)cyclobutane-1-carboxylic acid (250 mg, 0.67 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)cyclobutane-1-carboxylic acid (93.0 mg, 0.26 mmol, 39% yield) as a white solid. LC-MS: m / z = 361.0 [M+H] + The residence time was 5.37 min (Method A). 1 HNMR(400MHz,DMSO-d6)δδ12.80(s,1H),12.69(brs,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).

[0897] Example 16: Preparation of Compound 16

[0898] 3-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinamido)oxetane-3-carboxylic acid methyl ester

[0899]

[0900] A mixture of 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinic acid (an intermediate from Example 13) (450 mg, 1.27 mmol), methyl 3-aminooxetane-3-carboxylate hydrochloride (213 mg, 1.27 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give methyl 3-(3-(benzyloxy)-5-(3-chlorophenyl)-4-methylpicolinamido)oxetane-3-carboxylate as a white solid (500 mg, 1.07 mmol, 84% yield). LC-MS: m / z = 467.1 [M+H] +The residence time was 2.15 min (Method A).

[0901] methyl 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)oxetane-3-carboxylate

[0902]

[0903] A mixture of methyl 3-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinamido)oxetane-3-carboxylate (500 mg, 1.07 mmol) and 10% palladium / carbon (50.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 18 h under a hydrogen atmosphere. The insoluble solid was filtered off and the filtrate was concentrated to give methyl 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)oxetane-3-carboxylate (300 mg, 0.80 mmol, 74% yield) as a white solid. LC-MS: m / z = 377.1 [M+H] + The residence time was 2.19 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0904] 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)oxetane-3-carboxylic acid

[0905]

[0906] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of methyl 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)oxetane-3-carboxylic acid (300 mg, 0.80 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinamido)oxetane-3-carboxylic acid (71.4 mg, 0.20 mmol, 25% yield) as a white solid. LC-MS: m / z = 363.0 [M+H] + The residence time was 4.85 min (Method A). 1 HNMR (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).

[0907] Example 17: Preparation of Compound 17

[0908] 3-(benzoxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile

[0909]

[0910] Sodium hydride (114.80 mg, 2.87 mmol, in 60% w / w dispersion in mineral oil) was added to a solution of 3-chloro-4-methyl-5-(3-phenoxyphenyl)picolinonitrile (an intermediate from Example 8) (700 mg, 2.39 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (309.6 mg, 2.87 mmol). The solution was stirred at 0 °C for 1.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 3-(benzoxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile (400 mg, 1.09 mmol, 45.87% yield). LC-MS: m / z = 366.0 [M+H] + The residence time was 1.72 min (Method A).

[0911] 3-(benzoxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid

[0912]

[0913] A solution of 3-(benzoxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile (400 mg, 1.09 mmol) in ethanol (10.0 mL) was added to a solution of 3-(benzoxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinonitrile (8.0 mL). The mixture was stirred at 100 °C for 3.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid (350 mg, 0.91 mmol, 75.32% yield) as a white solid. LC-MS: m / z = 385.0 [M+H] + The residence time was 1.51 min (Method A). The product was sufficiently pure and used directly in the next step.

[0914] (3-(benzooxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinoyl)glycine ethyl ester

[0915]

[0916] A mixture of 3-(benzoxy)-4-methyl-5-(2-methylquinoline-6-yl)picolinic acid (350 mg, 0.91 mmol), glycine ethyl ester hydrochloride (73.84 mg, 0.53 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 2) to give ethyl (3-(benzoxy)-4-methyl-5-(2-methylquinolin-6-yl)picolinoyl)glycine (150 mg, 0.32 mmol, 72.69% yield) as a white solid. LC-MS: m / z = 470.0 [M+H] + The residence time was 2.04 min (Method B).

[0917] (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)picolinoyl)glycine ethyl ester

[0918]

[0919] A mixture of (3-(benzoxy)-4-methyl-5-(2-methylquinoline-6-yl)picolineyl)glycine ethyl ester (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 off and the filtrate was concentrated to give (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)picolineyl)glycine ethyl ester (120 mg, 0.31 mmol, 97.91% yield) 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.

[0920] (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)picolinoyl)glycine

[0921]

[0922] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)picolineyl)glycine ethyl ester (100 mg, 0.26 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse preparative HPLC to give (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)picolineyl)glycine (formate) (17.9 mg, 0.05 mmol, 19.39%) as a white solid. LC-MS: m / z = 356.1 [M+H] + The residence time was 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).

[0923] Example 18: Preparation of Compound 18

[0924] 2-(4-bromo-1H-pyrazol-1-yl)pyridine

[0925]

[0926] Bromine (3302.54 mg, 20.67 mmol, 1.06 mL) was added dropwise to a solution of 2-(1H-pyrazol-1-yl)pyridine (1.0 g, 6.89 mmol) in acetic acid (20 mL). The mixture was stirred at room temperature for 30 min. The reactants were 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-pyrazol-1-yl)pyridine (1.35 g, crude) was obtained as a yellow solid. LC-MS: m / z = 224 [M+H] + The residence time was 1.941 min (Method B). The product was used directly in the next step.

[0927] 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)pyridine

[0928]

[0929] 1,4-Dioxane (15.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (391.88 mg, 0.54 mmol) was added to a solution of 2-(4-bromo-1H-pyrazol-1-yl)pyridine (1.2 g, 5.36 mmol), bis(pinacol)diboron (6.8 g, 26.78 mmol), and potassium acetate (2.63 g, 26.78 mmol). The mixture was stirred at 90 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)pyridine (1.38 g, 5.09 mmol, 95% yield). LC-MS: m / z = 272 [M+H] + The residence time was 2,000 min (Method B).

[0930] 3-Chloro-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinonitrile

[0931]

[0932] To a solution of 3,5-dichloro-4-methylpicolinonitrile (862.2 mg, 4.61 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)pyridine (1.25 g, 4.61 mmol), and potassium carbonate (764.6 mg, 5.53 mmol), N,N-dimethylformamide / water (10.0 mL / 1.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (134.9 mg, 0.18 mmol) was added. The mixture was stirred at 45 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 3-chloro-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinenone (342 mg, 1.16 mmol, 25% yield). LC-MS: m / z = 296 [M+H] +The residence time was 2.090 min (Method A).

[0933] 3-(benzoxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinonitrile

[0934]

[0935] Sodium hydride (48.8 mg, 1.22 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 3-chloro-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picoline nitrile (300.0 mg, 1.01 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, and then benzyl alcohol (131.6 mg, 1.22 mmol, 0.127 mL) was added. The solution was stirred at 0 °C for 50 min 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 rapid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 3-(benzyloxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinenone (82 mg, 0.22 mmol, 22% yield). LC-MS: m / z = 368 [M+H] + The residence time was 2.138 min (Method B).

[0936] 3-(benzoxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinic acid

[0937]

[0938] A solution of 3-(benzoxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinone (70.0 mg, 0.19 mmol) in ethanol (3.0 mL) was added to a solution of 3-(benzoxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinone (72 mg, crude product) as a white solid. LC-MS: m / z = 387 [M+H] + The residence time was 1.290 min (Method B). The product was sufficiently pure and could be used directly in the next step.

[0939] (3-(benzooxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinyl)glycine ethyl ester

[0940]

[0941] A mixture of 3-(benzoxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinic acid (60.0 mg, 0.16 mmol), glycine ethyl ester hydrochloride (26.41 mg, 0.19 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 2) to give ethyl glycine (3-(benzoxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolineloyl)glycine (70 mg, 0.15 mmol, 93% yield). LC-MS: m / z = 472 [M+H] + The residence time was 2.028 min (Method B).

[0942] (3-hydroxy-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinoyl)glycine ethyl ester

[0943]

[0944] A mixture of (3-(benzyloxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinoyl)glycine ethyl ester (60.0 mg, 0.13 mmol) and 10% palladium / carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 5.0 h under a hydrogen atmosphere. The insoluble solid was filtered off and the filtrate was concentrated to give (3-hydroxy-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinoyl)glycine ethyl ester (50 mg, crude product) as a white solid. LC-MS: m / z = 382 [M+H] + The residence time was 2.127 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0945] (3-hydroxy-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinyl)glycine

[0946]

[0947] Lithium hydroxide monohydrate (55.0 mg, 1.31 mmol) was added to a solution of (3-hydroxy-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinoyl)glycine ethyl ester (50.0 mg, 0.13 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse preparative HPLC to give (3-hydroxy-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinoyl)glycine (formate) as a white solid (28.5 mg, 0.08 mmol, 62% yield). LC-MS: m / z = 354 [M+H] + The residence time was 4.255 min (Method A). 1 H 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).

[0948] Example 19: Preparation of Compound 19

[0949] 4-Bromo-1-(4-Fluorophenyl)-1H-pyrazole

[0950]

[0951] 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-ethylenediamine (176 mg, 2.0 mmol) in acetonitrile (20.0 mL) was stirred overnight at 80 °C in a sealed test 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 rapid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 4-bromo-1-(4-fluorophenyl)-1H-pyrazole (1.30 g, 5.39 mmol, 53.9% yield) as a yellow solid. LC-MS: m / z = 243.0 [M+H] +The residence time was 2.01 min (Method A).

[0952] 1-(4-Fluorophenyl)-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborone-2-yl)-1H-pyrazole

[0953]

[0954] 1,4-Dioxane (15.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (395 mg, 0.54 mmol) was added to a solution of 4-bromo-1-(4-fluorophenyl)-1H-pyrazole (1.30 g, 5.39 mmol), bis(pinacol)diboron (1.21 g, 4.78 mmol), and potassium acetate (2.11 g, 21.6 mmol). The mixture was stirred at 90 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 1-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.21 g, 4.20 mmol, 77.9% yield). LC-MS: m / z = 289.1 [M+H] + The residence time was 2.14 min (Method A).

[0955] 3-Chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinonitrile

[0956]

[0957] To a solution of 3,5-dichloro-4-methylpicolinonitrile (785 mg, 4.20 mmol), 1-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)-1H-pyrazole (1.21 g, 4.20 mmol), and potassium carbonate (869.4 mg, 6.30 mmol), N,N-dimethylformamide / water (10.0 mL / 1.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (307 mg, 0.42 mmol) was added. The mixture was stirred at 50 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinonitrile (180 mg, 0.58 mmol, 13.8% yield). LC-MS: m / z = 313.0 [M+H] + The residence time was 2.13 min (Method A).

[0958] 3-(benzoxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinonitrile

[0959]

[0960] Sodium hydride (27.8 mg, 0.70 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinonitrile (180 mg, 0.58 mmol) in N,N-dimethylformamide (5.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (62.6 mg, 0.58 mmol). The solution was stirred at 0 °C for 1.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 3-(benzoxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinonitrile (35 mg, 0.09 mmol, 15.7% yield). LC-MS: m / z = 385.1 [M+H] + The residence time was 2.194 min (Method A).

[0961] 3-(benzoxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinic acid

[0962]

[0963] A solution of 3-(benzoxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinonitrile (35 mg, 0.09 mmol) in ethanol (3.0 mL) was added to a solution of 3-(benzoxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinonitrile (35 mg, 0.09 mmol) in ethanol (3.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinic acid (32 mg, crude substance) as a white solid. LC-MS: m / z = 404.1 [M+H] + The residence time was 2.014 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0964] (3-(benzooxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinoyl)glycine ethyl ester

[0965]

[0966] A mixture of 3-(benzoxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinic acid (32 mg, crude), glycine ethyl ester hydrochloride (13.9 mg, 0.1 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give ethyl (3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinoyl)glycine (40 mg, 0.08 mmol, 91% yield). LC-MS: m / z = 489.1 [M+H] + The residence time was 2.128 min (Method A).

[0967] (5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpicolinoyl)glycine ethyl ester

[0968]

[0969] A mixture of (3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpicolinoyl)glycine ethyl ester (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 off and the filtrate was concentrated to give (5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpicolinoyl)glycine ethyl ester (30 mg, 0.08 mmol, 100% yield) as a yellow solid. LC-MS: m / z = 399.0 [M+H] + The residence time was 2.15 min (Method A). The product was sufficiently pure and used directly in the next step.

[0970] (5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpicolinoyl)glycine

[0971]

[0972] Lithium hydroxide monohydrate (42 mg, 1.0 mmol) was added to a solution of (5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpicolinoyl)glycine ethyl ester (30 mg, 0.08 mmol) in tetrahydrofuran / water (5.0 mL / 1.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give (5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpicolinoyl)glycine as a white solid (20.1 mg, 0.05 mmol, 67.9% yield). LC-MS: m / z = 371.0 [M+H] + The residence time was 4.641 min (Method A). 1 H 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).

[0973] Example 20: Preparation of Compound 20

[0974] 4-Bromo-1-isopropyl-1H-pyrazole

[0975]

[0976] Sodium hydride (480 mg, 12.0 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 4-bromo-1H-pyrazole (1.47 g, 10.0 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 20 min, followed by the addition of 2-iodopropane (1.7 g, 10.0 mmol). The solution was stirred at room temperature for 18.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 4-bromo-1-isopropyl-1H-pyrazole (1.47 g, 7.8 mmol, 78% yield). LC-MS: m / z = 189.0 [M+H] + The residence time was 1.90 min (Method B).

[0977] 1-Isopropyl-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborone-2-yl)-1H-pyrazole

[0978]

[0979] 1,4-Dioxane (15.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (570 mg, 0.78 mmol) was added to a solution of 4-bromo-1-isopropyl-1H-pyrazole (1.47 g, 7.8 mmol), bis(pinacol)diboron (3.96 g, 15.6 mmol), and potassium acetate (3.06 g, 31.2 mmol). The mixture was stirred at 90 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1H-pyrazole (1.18 g, 5.0 mmol, 64.1% yield). LC-MS: m / z = 237.0 [M+H] + The residence time was 1.96 min (Method B).

[0980] 3-Chloro-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpicolinonitrile

[0981]

[0982] 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-dioxaborpentane-2-yl)-1H-pyrazole (1.9 g, 8.02 mmol), and potassium carbonate (1.3 g, 9.63 mmol), N,N-dimethylformamide / water (15.0 mL / 1.5 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (235 mg, 0.32 mmol) 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 3-chloro-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpicolinonitrile (580 mg, 2.22 mmol, 29% yield) as a yellow solid. LC-MS: m / z = 261.1 [M+H]+, retention time = 1.83 min (Method A).

[0983] 3-(benzoxy)-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpicolinonitrile

[0984]

[0985] Sodium hydride (108 mg, 2.67 mmol, 60% w / w dispersion in mineral oil) was added 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) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (288 mg, 2.67 mmol). The solution was stirred at 0 °C for 50 min 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-(benzoxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (180 mg, 0.54 mmol, 24% yield) as a yellow solid. LC-MS: m / z = 333.1[M+H]+, residence time = 2.21 min (Method A).

[0986] 3-(benzoxy)-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpicolinic acid

[0987]

[0988] A solution of 3-(benzoxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (180 mg, 0.54 mmol) in ethanol (5.0 mL) was added to a solution of 3-(benzoxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (180 mg, 0.28 mmol, 53% yield). 30% sodium hydroxide aqueous solution (1.0 mL) was added to the solution. The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinic acid (100 mg, 0.28 mmol, 53% yield) as a white solid. LC-MS: m / z = 352.1 [M+H] + The residence time was 2.00 min (Method A). The product was sufficiently pure and used directly in the next step.

[0989] (3-(benzooxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine ethyl ester

[0990]

[0991] A mixture of 3-(benzoxy)-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpicolinic acid (100 mg, 0.28 mmol), glycine ethyl ester hydrochloride (40 mg, 0.28 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give ethyl (3-(benzyloxy)-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpicolinoyl)glycine (100 mg, 0.18 mmol, 81% yield) as a white solid. LC-MS: m / z = 437.1 [M+H] + The residence time was 2.15 min (Method A).

[0992] (3-hydroxy-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine ethyl ester

[0993]

[0994] A mixture of (3-(benzyloxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine ethyl ester (100 mg, 0.18 mmol) and 10% palladium / carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 18 h under a hydrogen atmosphere. The insoluble solid was filtered off and the filtrate was concentrated to give (3-hydroxy-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine ethyl ester (80 mg, crude product) as a yellow solid. LC-MS: m / z = 347.1 [M+H] + The residence time was 2.19 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[0995] (3-hydroxy-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpicolinoyl)glycine

[0996]

[0997] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of (3-hydroxy-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine ethyl ester (80 mg, crude) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give (3-hydroxy-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine (45.7 mg, 62% yield) as a white solid. LC-MS: m / z = 319.1 [M+H] + The residence time was 3.81 min (Method A). 1 HNMR(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).

[0998] Example 21: Preparation of Compound 21

[0999] 4-Bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole

[1000]

[1001] Sodium hydride (480 mg, 12.0 mmol, 60% w / w dispersion in mineral oil) was added to a solution of 4-bromo-1H-pyrazole (1.47 g, 10.0 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 20 min, followed by the addition of tetrahydro-2H-pyran-4-yl methanesulfonate (1.8 g, 10.0 mmol). The solution was stirred at 10 °C for 2.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 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] + The residence time was 1.76 min (Method B).

[1002] 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-1H-pyrazole

[1003]

[1004] 1,4-Dioxane (15.0 mL) containing [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (443 mg, 0.61 mmol) was added to a solution of 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (2.8 g, 12.10 mmol), bis(pinacol)diborone (3.7 g, 14.50 mmol), and potassium acetate (3.6 g, 36.30 mmol). The mixture was stirred at 90 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole as a white solid (2.5 g, 8.99 mmol, 74% yield). LC-MS: m / z = 279.1 [M+H]+, retention time = 1.83 min (Method A).

[1005] 3-Chloro-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinonitrile

[1006]

[1007] 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-dioxaborpentan-2-yl)-1H-pyrazole (2.25 g, 8.09 mmol), and potassium carbonate (1.34 g, 9.71 mmol), N,N-dimethylformamide / water (6.0 mL / 0.6 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (237 mg, 0.32 mmol) was added. The mixture was stirred at 50 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 3-chloro-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinenone (1.0 g, 3.31 mmol, 37% yield) as a yellow solid. LC-MS: m / z = 303.1 [M+H]+, retention time = 1.83 min (Method A).

[1008] 3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinonitrile

[1009]

[1010] Sodium hydride (143 mg, 3.57 mmol, in mineral oil, 60% w / w dispersion) was added to a solution of 3-chloro-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinenil (900.0 mg, 2.97 mmol) in N,N-dimethylformamide (10.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (386 mg, 3.57 mmol). The solution was stirred at 0 °C for 1.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinenone (100 mg, 0.27 mmol, 8% yield) as a yellow solid. LC-MS: m / z = 375.1 [M+H]+, retention time = 2.21 min (Method A).

[1011] 3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinic acid

[1012]

[1013] A solution of 3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinone (100 mg, 0.27 mmol) in ethanol (5.0 mL) was added to a solution of 3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinone (90 mg, 0.23 mmol, 86% yield) as a white solid. LC-MS: m / z = 394.1 [M+H] + The residence time was 2.00 min (Method A). The product was sufficiently pure and used directly in the next step.

[1014] (3-(benzooxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinyl)glycine ethyl ester

[1015]

[1016] A mixture of 3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinic acid (90 mg, 0.23 mmol), glycine ethyl ester hydrochloride (32 mg, 0.23 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give ethyl (3-(benzyloxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinyl)glycine (90 mg, 0.19 mmol, 82% yield) as a white solid. LC-MS: m / z = 479.1 [M+H] + The residence time was 2.15 min (Method A).

[1017] (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinyl)glycine ethyl ester

[1018]

[1019] A mixture of (3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinoyl)glycine ethyl ester (90 mg, 0.19 mmol) and 10% palladium / carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 18 h under a hydrogen atmosphere. The insoluble solid was filtered off and the filtrate was concentrated to give (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinoyl)glycine ethyl ester (70 mg, 0.18 mmol, 96% yield) as a yellow solid. LC-MS: m / z = 389.1 [M+H] + The residence time was 2.19 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[1020] (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinyl)glycine

[1021]

[1022] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolineyl)glycine ethyl ester (70 mg, 0.18 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse preparative HPLC to give (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolineyl) as a white solid (10.8 mg, 0.03 mmol, 17% yield). LC-MS: m / z = 361.1 [M+H] + The residence time was 3.45 min (Method A). 1 HNMR(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).

[1023] Example 22: Preparation of compound 22

[1024] 4-Bromo-1-isobutyl-1H-pyrazole

[1025]

[1026] 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 h 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 rapid chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 4-bromo-1-isobutyl-1H-pyrazole (1.15 g, 5.69 mmol, 83% yield). LC-MS: m / z = 203 [M+H] + The residence time was 1.861 min (Method B).

[1027] 1-Isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-1H-pyrazole

[1028]

[1029] 1,4-Dioxane (15.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (396 mg, 0.54 mmol) was added to a solution of 4-bromo-1-isobutyl-1H-pyrazole (1.1 g, 5.42 mmol), bis(pinacol)diboron (6.88 g, 27.08 mmol), and potassium acetate (1.59 g, 16.25 mmol). The mixture was stirred at 90 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1H-pyrazole (1.1 g, 4.39 mmol, 81% yield). LC-MS: m / z = 251 [M+H] + The residence time was 2.047 min (Method A).

[1030] 3-Chloro-5-(1-isobutyl-1H-pyrazol-4-yl)-4-methylpicolinonitrile

[1031]

[1032] 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-dioxaborpentan-2-yl)-1H-pyrazole (550.0 mg, 2.20 mmol), and potassium carbonate (364.7 mg, 2.64 mmol), N,N-dimethylformamide / water (10.0 mL / 1.0 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (64.4 mg, 0.09 mmol) 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 crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-chloro-5-(1-isobutyl-1H-pyrazol-4-yl)-4-methylpicolinonitrile (732 mg, 2.67 mmol, 87% yield). LC-MS: m / z = 275 [M+H] + The residence time was 2.065 min (Method A).

[1033] 3-(benzoxy)-5-(1-isobutyl-1H-pyrazol-4-yl)-4-methylpicolinonitrile

[1034]

[1035] Sodium hydride (113.6 mg, 2.84 mmol, 60% w / w dispersion in mineral oil) was added 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) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, and then benzyl alcohol (307.0 mg, 2.84 mmol, 0.3 mL) was added. The solution was stirred at 0 °C for 50 min 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 rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-(benzoxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (105 mg, 0.30 mmol, 13% yield). LC-MS: m / z = 347 [M+H] + The residence time was 2.089 min (Method B).

[1036] 3-(benzoxy)-5-(1-isobutyl-1H-pyrazol-4-yl)-4-methylpicolinic acid

[1037]

[1038] A solution of 3-(benzoxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinonitrile (95.0 mg, 0.27 mmol) in ethanol (3.0 mL) was added to a 1.0 mL solution of 30% sodium hydroxide. The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 90 mg of crude 3-(benzoxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinic acid as a white solid. LC-MS: m / z = 366 [M+H] + The residence time was 1.391 min (Method B). The product was sufficiently pure and could be used directly in the next step.

[1039] (3-(benzooxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine ethyl ester

[1040]

[1041] A mixture of 3-(benzoxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinic acid (90.00 mg, 0.25 mmol), glycine ethyl ester hydrochloride (41.7 mg, 0.30 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give ethyl (3-(benzyloxy)-5-(1-isobutyl-1H-pyrazol-4-yl)-4-methylpicolinoyl)glycine (30 mg, 0.067 mmol, 27% yield). LC-MS: m / z = 451 [M+H] + The residence time was 2.008 min (Method B).

[1042] (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine ethyl ester

[1043]

[1044] A mixture of (3-(benzyloxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine ethyl ester (25.0 mg, 0.06 mmol) and 10% palladium / carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 18.0 h under a hydrogen atmosphere. The insoluble solid was filtered off and the filtrate was concentrated to give (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine ethyl ester (30.0 mg, crude product) as a yellow solid. LC-MS: m / z = 361 [M+H] + The residence time was 1.966 min (Method B). The product was sufficiently pure and could be used directly in the next step.

[1045] (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine

[1046]

[1047] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine ethyl ester (25.00 mg, 0.07 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was purified by reverse preparative HPLC to give (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpicolinoyl)glycine (formate) as a yellow solid (6.4 mg, 0.02 mmol, 27% yield). LC-MS: m / z = 333 [M+H] + The residence time was 4.188 min (Method A). 1 H 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).

[1048] Example 23: Preparation of compound 23

[1049] methyl 3-oxohep-6-enoate

[1050]

[1051] Methyl 3-oxobutyrate (3.23 g, 27.82 mmol) was added to a suspension of sodium hydride (1.89 g, 47.30 mmol, 60% w / w dispersion in mineral oil) in anhydrous tetrahydrofuran (120 mL) at 0 °C. The solution was stirred at 0 °C for 30 min and n-butyllithium (17.8 mL, 44.52 mmol, 2.5 M in n-hexane) was added. After stirring for 30 min, 3-bromopropyl-1-ene (3.70 g, 30.61 mmol) was added. The reaction mixture was heated to 20 °C and stirred for another 2.0 h. The reaction mixture was quenched by adding saturated ammonium chloride 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 rapid chromatography (petroleum ether / ethyl acetate = 100 / 3) to give methyl 3-oxohepyl-6-enoate as a yellow oil (2.74 g, 17.6 mmol, 63% yield). LC-MS: m / z = 157 [M+H] + The residence time was 1.446 min (Method B).

[1052] 4-(2-(benzooxy)ethyl)-3-oxohep-6-enoic acid methyl ester

[1053]

[1054] Fresh lithium diisopropylamine (11.2 mmol, 5.63 mL, 2.0 M in n-hexane) was added to a solution of methyl 3-oxohepyl-6-enoate (800.0 mg, 5.12 mmol) in anhydrous tetrahydrofuran (15.0 mL) at 0 °C. The mixture was stirred at 0 °C for 15 min and ((2-bromomethoxy)methyl)benzene (1.32 g, 6.15 mmol) was added. The mixture was heated to 20 °C and stirred for 3.0 h. The reaction mixture 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 rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 4-(2-(benzyloxy)ethyl)-3-oxohepyl-6-enoate (729 mg, 2.51 mmol, 49% yield) as a yellow oil. LC-MS: m / z = 313[M+H] + The residence time was 2.080 min (Method A).

[1055] 2,2-Diazido-4-(2-(benzooxy)ethyl)-3-oxohep-6-enoic acid methyl ester

[1056]

[1057] A mixture of methyl 4-(2-(benzoxy)ethyl)-3-oxohept-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 h. 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 rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 2,2-diazido-4-(2-(benzoxy)ethyl)-3-oxohept-6-enoate (330 mg, 0.89 mmol, 37% yield). LC-MS: m / z = 395 [M + Na] + The residence time was 2.314 min (Method A).

[1058] 4-(2-(benzooxy)ethyl)-3-hydroxy-6-methylpicolinate methyl ester

[1059]

[1060] The mixture of methyl 2,2-diazido-4-(2-(benzooxy)ethyl)-3-oxohep-6-enoate (300.0 mg, 0.81 mmol) in toluene (5.0 mL) was heated in 110 mL of water. ℃ The solution was stirred in a sealed test tube for 16.0 h. The solution was cooled and concentrated to dryness. The resulting residue was purified by rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give methyl 4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methylpicolinate (65 mg, 0.22 mmol, 27% yield). LC-MS: m / z = 302 [M+H] + The residence time was 1.991 min (Method A).

[1061] 4-(2-(benzyloxy)ethyl)-3-hydroxy-6-methylpicolinic acid

[1062]

[1063] Lithium hydroxide monohydrate (83.6 mg, 1.99 mmol) was added to a solution of methyl 4-(2-(benzoxy)ethyl)-3-hydroxy-6-methylpicolinate (60.0 mg, 0.20 mmol) in methanol / water (4.0 mL / 1.0 mL). 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-(benzoxy)ethyl)-3-hydroxy-6-methylpicolinate (55 mg, 0.19 mmol, 96% yield) was given as a yellow solid. LC-MS: m / z = 288 [M+H] + The residence time was 1.626 min (Method A). The crude product was used in the next step.

[1064] (4-(2-(benzooxy)ethyl)-3-hydroxy-6-methylpicolinoyl)glycine ethyl ester

[1065]

[1066] A mixture of 4-(2-(benzoxy)ethyl)-3-hydroxy-6-methylpicolinic acid (50.00 mg, 0.17 mmol), glycine ethyl ester hydrochloride (21.53 mg, 0.21 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 4 / 1) to give (4-(2-(benzoxy)ethyl)-3-hydroxy-6-methylpicolinoyl)glycine ethyl ester (48 mg, 0.13 mmol, 76% yield) as a white solid. LC-MS: m / z = 373 [M+H] + The residence time was 2.179 min (Method A).

[1067] (4-(2-(benzooxy)ethyl)-3-hydroxy-6-methylpicolinoyl)glycine

[1068]

[1069] Lithium hydroxide monohydrate (54.2 mg, 1.29 mmol) was added to a solution of (4-(2-(benzoxy)ethyl)-3-hydroxy-6-methylpicolinoyl)glycine ethyl ester (48.0 mg, 0.13 mmol) in methanol / water (4.0 mL / 1.0 mL). The mixture was stirred overnight and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was purified by reverse preparative HPLC to give (4-(2-(benzoxy)ethyl)-3-hydroxy-6-methylpicolinoyl)glycine (formate) as a red solid (29.7 mg, 0.09 mmol, 66% yield). LC-MS: m / z = 345 [M+H] + The residence time was 4.596 min (Method A). 1 H 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).

[1070] Example 24: Preparation of compound 24

[1071] 4-(4-fluorobenzyl)-3-oxohep-6-enoic acid methyl ester

[1072]

[1073] Fresh lithium diisopropylamine (7.04 mmol, 3.52 mL, 2.0 M in n-hexane) was added to a solution of methyl 3-oxohepyl-6-enoate (an intermediate from Example 22) (500.0 mg, 3.20 mmol) in anhydrous tetrahydrofuran (20.0 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min 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 h. The reaction mixture 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 rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 4-(4-fluorobenzyl)-3-oxohepyl-6-enoate (650 mg, 2.46 mmol, 77% yield) as a yellow oil. LC-MS: m / z = 265 [M+H] + The residence time was 1.934 min (Method B).

[1074] 2,2-Diazido-4-(4-fluorobenzyl)-3-oxohep-6-enoic acid methyl ester

[1075]

[1076] A mixture of methyl 4-(4-fluorobenzyl)-3-oxohept-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 h. 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 rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 2,2-diazido-4-(4-fluorobenzyl)-3-oxohept-6-enoate (310 mg, 0.89 mmol, 47% yield) as a yellow solid. LC-MS: m / z = 369 [M + Na] + The residence time was 2.279 min (Method A).

[1077] 4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinate methyl ester

[1078]

[1079] The mixture of methyl 2,2-diazido-4-(4-fluorobenzyl)-3-oxohep-6-enoate (300.0 mg, 0.87 mmol) in toluene (5.0 mL) was heated in 110 mL of water. ℃ The solution was stirred in a sealed test tube for 2.0 h. The solution was cooled and concentrated to dryness. The residue was purified by rapid chromatography (petroleum ether / ethyl acetate = 10 / 3) to give methyl 4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinate (64 mg, 0.23 mmol, 27% yield) as a yellow oil. LC-MS: m / z = 276 [M+H] + The residence time was 2.006 min (Method A).

[1080] 4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinic acid

[1081]

[1082] Lithium hydroxide monohydrate (91.5 mg, 2.18 mmol) was added to a solution of methyl 4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinate (60.0 mg, 0.22 mmol) in methanol / water (4.0 mL / 1.0 mL). 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. The crude substance, 4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinate (34 mg, 0.13 mmol, 59% yield), was a yellow solid. LC-MS: m / z = 262 [M+H] + The residence time was 1.626 min (Method A). The crude product was used in the next step.

[1083] (4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinoyl)glycine ethyl ester

[1084]

[1085] A mixture of 4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinic acid (30.0 mg, 0.11 mmol), glycine ethyl ester hydrochloride (14.21 mg, 0.14 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 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 rapid chromatography (petroleum ether / ethyl acetate = 85 / 15) to give ethyl (4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinoyl)glycine (26 mg, 0.08 mmol, 68% yield) as a yellow solid. LC-MS: m / z = 347 [M+H] + The residence time was 2.180 min (Method A).

[1086] (4-(4-fluorophenylmethyl)-3-hydroxy-6-methylpicolinoyl)glycine

[1087]

[1088] Lithium hydroxide monohydrate (31.53 mg, 0.75 mmol) was added to a solution of (4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinoyl)glycine ethyl ester (26.00 mg, 0.08 mmol) in methanol / water (4.0 mL / 1.0 mL). The mixture was stirred overnight and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was purified by reverse preparative HPLC to give (4-(4-fluorobenzyl)-3-hydroxy-6-methylpicolinoyl)glycine (formate) as a white solid (11.2 mg, 0.04 mmol, 47% yield). LC-MS: m / z = 319 [M+H] + The residence time was 4.616 min (Method A). 1 H 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).

[1089] Example 25: Preparation of Compound 25

[1090] 3,5-Dibromo-2,4-dimethylpyridine 1-oxide

[1091]

[1092] 3-Chloroperoxybenzoic acid (400 mg, 1.96 mmol, 85%) was added to a solution of 3,5-dibromo-2,4-dimethylpyridine (400 mg, 1.51 mmol) in dichloromethane (10.0 mL) at 0 °C. The mixture was stirred at room temperature for 18.0 h and potassium carbonate (400 mg, 3.20 mmol) was added. The mixture was stirred for another 1 h and the insoluble solid was filtered off. The filtrate was concentrated to give 3,5-dibromo-2,4-dimethylpyridine 1-oxide (400 mg, 1.43 mmol, 94% yield) as a white solid. LC-MS: m / z = 281.1 [M+H] + The residence time was 1.47 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[1093] 3,5-Dibromo-4,6-dimethylpicolinonitrile

[1094]

[1095] A mixture of 3,5-dibromo-2,4-dimethylpyridine 1-oxide (400 mg, 1.42 mmol), trimethylsilane cyanide (2.0 mL), and triethylamine (2.0 mL) in acetonitrile (10.0 mL) was heated at 85 °C. ℃ The mixture was stirred for 24.0 h. It was diluted with water and extracted with ethyl acetate. The organic layer was washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 3,5-dibromo-4,6-dimethylpicolinonitrile (240 mg, 0.69 mmol, 46% yield) as a yellow oil. LC-MS: m / z = 291.2 [M+H] + The residence time was 1.74 min (Method A).

[1096] 3-Bromo-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinonitrile

[1097]

[1098] 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-dioxaborpentan-2-yl)-1H-pyrazole (559 mg, 2.07 mmol), and potassium carbonate (343 mg, 2.48 mmol), N,N-dimethylformamide / water (3.0 mL / 0.3 mL) containing [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (239 mg, 0.21 mmol) was added. The mixture was stirred at 45 °C under nitrogen for 16.0 h 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 rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 3-bromo-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinenone (95 mg, 0.27 mmol, 32% yield) as a yellow solid. LC-MS: m / z = 354.3 [M+H]+, retention time = 1.909 min (Method A).

[1099] 3-Hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinonitrile

[1100]

[1101] A mixture of 3-bromo-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-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 h. The mixture was cooled and evaporated to dryness. The resulting residue was purified by reverse preparative HPLC to give 3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinonitrile (20 mg, 0.07 mmol, 27% yield) as a white solid. LC-MS: m / z = 291.1 [M+H]+, residence time = 1.40 min (Method A).

[1102] 3-Hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinic acid

[1103]

[1104] A solution of 3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinonitrile (20 mg, 0.07 mmol) in ethanol (5.0 mL) was added to a 1.0 mL solution of 30% sodium hydroxide. The mixture was stirred at 100 °C for 3.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 25 mg of crude 3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinic acid as a white solid. LC-MS: m / z = 310.4 [M+H] + The residence time was 1.74 min (Method A). The product was sufficiently pure and could be used directly in the next step.

[1105] (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine ethyl ester

[1106]

[1107] A mixture of 3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinic acid (25 mg, 0.08 mmol), glycine ethyl ester hydrochloride (17 mg, 0.12 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphonium 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 rapid chromatography (petroleum ether / ethyl acetate = 1 / 2) to give (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine ethyl ester (20 mg, 0.05 mmol, 63% yield) as a white solid. LC-MS: m / z = 395.1 [M+H] + The residence time was 2.13 min (Method A).

[1108] (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)picolinoyl)glycine

[1109]

[1110] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine (20 mg, 0.05 mmol) in methanol / water (6.0 mL / 3.0 mL). The mixture was stirred overnight and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3 to 4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazole-4-yl)picolinoyl)glycine (6.4 mg, 0.017 mmol, 36% yield) as a white solid. LC-MS: m / z = 367.0 [M+H] + The residence time was 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).

[1111] Example 26: Preparation of Compound 26

[1112] 3,5-Dichloro-4-methylpyridine 1-oxide

[1113]

[1114] m-CPBA (12.9 g, 74.7 mmol) was added dropwise to a solution of 3,5-dichloro-4-methylpyridine (9.4 g, 57.7 mmol) in DCM (150 mL) over 2 min at room temperature. The reaction mixture was stirred overnight at room temperature. After the reaction was complete as indicated by TLC analysis, K₂CO₃ (12 g, 87 mmol) was added to the reaction mixture in a single addition and the mixture was stirred for approximately 2 h at room temperature. After filtering the resulting suspension, the filtrate was concentrated to dryness. The residue was slurried in a mixed solvent (PE:EtOAc = 50:1, 50 mL) to give 7.4 g of the title compound. LC-MS (ESI+): m / z 178 (M+H) + ;

[1115] 3,5-Dichloro-4-methylpicolinonitrile

[1116]

[1117] TMS-CN (9 g, 89.88 mmol) and TEA (9.4 mL) were added to a solution of 3,5-dichloro-4-methylpyridine 1-oxide (8 g, 44.94 mmol) in MeCN (150 mL) at room temperature. The reaction mixture was refluxed overnight. After the reaction was completed as indicated by TLC analysis, the mixture was quenched with brine (150 mL) and extracted with EA (150 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄ (60 g), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1) to give 6.8 g of the title compound. 1 H-NMR (300MHz, CDCl3) δ8.52(s,1H),2.57(s,3H)).

[1118] 3-Chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)picolinonitrile

[1119]

[1120] 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 indicated by TLC, the resulting suspension was filtered. The filter cake was washed with EtOAc (200 mL), and the combined filtrates were concentrated to dryness. The resulting residue was dissolved in an aqueous solution of NaOH (60 mL, 1 N) and stirred for half an hour. The aqueous solution was washed with EtOAc (100 mL). After separation, the organic phase was treated again with an aqueous solution of NaOH (30 mL, 1 N). After separation, the combined aqueous phases were acidified with diluted HCl solution (2 N) to pH 4 to 5, and a large amount of solid precipitated. The suspension was filtered to give 407 mg of the title compound. 1 H-NMR (300MHz, CDCl3) δ8.68(s,1H),2.61(s,3H),1.34(s,12H).

[1121] 3-Chloro-4-methyl-5-(2-phenyloxazol-5-yl)picolinonitrile

[1122]

[1123] Under nitrogen protection, a mixture of 3-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)picorinonitrile (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 completed as indicated by TLC analysis, the reactants were quenched with H2O (10 mL) and extracted with DCM (25 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 (30 g), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM) to give 250 mg of the title compound. LC-MS (ESI+): m / z 296 (M+H) + ;

[1124] 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinonitrile

[1125]

[1126] BnOH (184 mg, 1.7 mmol) and t-BuOK (184 mg, 1.7 mmol) were added to a solution of 3-chloro-4-methyl-5-(2-phenyloxazol-5-yl)picolinonitrile (250 mg, 0.85 mmol) in THF (12.5 mL) at room temperature. The reaction mixture was stirred at 40 °C for 3 h. After the reaction was complete as indicated by TLC analysis, the mixture was quenched with H₂O (20 mL) and extracted with DCM (10 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄ (5 g), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EtOAc = 5 / 1) to give 157 mg of the title compound. LC-MS (ESI+): m / z 368 (M+H) + ; 1 H-NMR (300MHz, CDCl3) δ8.84(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).

[1127] 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinic acid

[1128]

[1129] A solution of 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinonitrile (167 mg, 0.45 mmol) in EtOH (15 mL) was added to a solution of NaOH (1.6 mL, 30 wt%) at room temperature. The reaction mixture was stirred overnight at reflux. After the reaction was complete as indicated by LC-MS analysis, the mixture was cooled to RT and acidified to pH 4-5 with diluted HCl solution. A large amount of solid precipitated. The suspension was filtered to give 158 mg of the title compound. LC-MS (ESI+): m / z 387 (M+H) + ;

[1130] (3-(benzooxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine methyl ester

[1131]

[1132] Glycine methyl ester hydrochloride (62 mg, 0.49 mmol), DIEA (212 mg, 1.64 mmol), and HATU (234 mg, 0.45 mmol) were added to a solution of 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinic acid (158 mg, 0.41 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. After the reaction was complete as indicated by TLC analysis, the mixture was quenched with H2O (20 mL) and extracted with DCM (10 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 (5 g), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / DCM = 1 / 1) to give 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).

[1133] (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine methyl ester

[1134]

[1135] Pd / C (10 wt%, 34 mg) was added to a solution of (167 mg, 0.45 mmol) methyl glycine in MeOH (6 mL) and DCM (3 mL) at room temperature. The reaction mixture was stirred for 45 min under atmospheric pressure with a hydrogen gas chamber. After the reaction was completed as indicated by TLC analysis, the reaction mixture was filtered through a diatomaceous earth bag. The filtrate was concentrated under vacuum to give 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).

[1136] (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine

[1137]

[1138] LiOH·H₂O (92 mg, 2.2 mmol) was added to a solution of (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine methyl ester (80 mg, 0.22 mmol) in THF (5 mL) and H₂O (2 mL) at room temperature. The reaction mixture was stirred at 50 °C for 2 hours. After the reaction was complete as indicated by TLC analysis, the reaction mixture was acidified to pH 4 to 5 with diluted HCl solution (1 N). A large amount of solid precipitated. The suspension was filtered to give 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).

[1139] Example 27: Preparation of Compound 27

[1140] 5-Chloro-4,6'-dimethyl-[3,3'-bipyridine]-6-carboxynitrile

[1141]

[1142] The compound was synthesized using 5-bromo-2-methylpyridine according to the procedure used to prepare 3-chloro-4-methyl-5-(2-phenyloxazol-5-yl)picolinonitrile. LC-MS (ESI+): m / z 244 (M+H) + .

[1143] 5-(benzoxy)-4,6'-dimethyl-[3,3'-bipyridine]-6-carboxynitrile

[1144]

[1145] The compound was synthesized according to the procedure used to prepare 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinenitrile. LC-MS (ESI+): m / z 316 (M+H) + ; 1H-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).

[1146] 5-(benzoxy)-4,6'-dimethyl-[3,3'-bipyridine]-6-carboxylic acid

[1147]

[1148] The compound was synthesized according to the procedure used to prepare 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinic acid. LC-MS (ESI+): m / z 335 (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).

[1149] (5-(benzooxy)-4,6'-dimethyl-[3,3'-bipyridine]-6-carbonyl)glycine methyl ester

[1150]

[1151] The compound was synthesized according to the procedure used to prepare (3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine methyl ester. LC-MS (ESI+): m / z 406 (M+H) + ;

[1152] (5-hydroxy-4,6'-dimethyl-[3,3'-bipyridine]-6-carbonyl)glycine methyl ester

[1153]

[1154] The compound was synthesized according to the procedure used to prepare (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine methyl ester. LC-MS (ESI+): m / z 316 (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).

[1155] (5-hydroxy-4,6'-dimethyl-[3,3'-bipyridine]-6-carbonyl)glycine

[1156]

[1157] The compound was synthesized according to the procedure used to prepare (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine. LC-MS (ESI+): m / z 302 (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).

[1158] Example 28: Preparation of Compound 28

[1159]

[1160] The compound was synthesized according to the procedure used to prepare (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine. LC-MS (ESI+): m / z 338 (M+H) + ; 1 H-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).

[1161] Example 29: Preparation of Compound 29

[1162]

[1163] The compound was synthesized according to the procedure used to prepare (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine. LC-MS (ESI+): m / z 302 (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, 1.8 Hz, 1H), 7.36 (dd, J = 7.7, 4.9 Hz, 1H), 4.00 (d, J = 6.0 Hz, 2H), 2.25 (s, 3H), 1.96 (s, 3H).

[1164] Example 30: Preparation of Compound 30

[1165]

[1166] The compound was synthesized according to the procedure used to prepare (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine. LC-MS (ESI+): m / z 367 (M+H) + ; 1 H-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).

[1167] Example 31: Preparation of compound 31

[1168]

[1169] The compound was synthesized according to the procedure used to prepare (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)picolinoyl)glycine. LC-MS (ESI+): m / z 367 (M+H) + ; 1H-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).

[1170] Example 32: Preparation of compound 32

[1171] 3,5-Dichloro-4-methylpyridine 1-oxide

[1172]

[1173] 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 in portions at 0 °C. The reaction mixture was stirred overnight at room temperature. LC-MS indicated completion of conversion to the desired product (MS / 178). K₂CO₃ (4.427 g, 32.08 mmol) was added. The turbid reaction mixture was stirred for 1 h. The white precipitate was filtered through a diatomaceous earth mat, and the filter cake was washed with DCM (50 mL). The filtrate was concentrated to give a white solid (5.0 g). LC-MS (ESI+): m / z 179.0 (M+H) + .

[1174] 3,5-Dichloro-4-methylpicolinonitrile

[1175]

[1176] 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 to reflux (85 °C). ℃ The reaction mixture was stirred for 7 hours. The mixture was then cooled to room temperature and stirred overnight. The reaction mixture was quenched with 50 mL of NaHCO3 aqueous solution. The mixture was diluted with 100 mL of ethyl acetate. The layers were separated; the organic layer was washed with 50 mL of brine, dried over Na2SO4, and concentrated. The crude material was purified by column chromatography (12 g column, 0-100% ethyl acetate / hexane) to give a light brown liquid (4.09 g). LC-MS (ESI+): m / z 186.0 (M+H) + .

[1177] 3-Chloro-5-(3-chlorophenyl)-4-methylpicolinonitrile

[1178]

[1179] Pd(dppf)Cl2 (0.178 g, 0.243 mmol) was added to a stirred mixture of 3,5-dichloro-4-methylpyridin-2-carboxynitrile (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 to 45°C under nitrogen. ℃ The reaction mixture was allowed to stand for 17 hours. TLC (30% EtOAc / hexane) indicated 90% consumption of the starting material. The reaction mixture was diluted with water (20 mL) and ethyl acetate (30 mL) and stirred thoroughly. 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 / hexane) to give a white solid. ¹H-NMR indicated a 3:8 regiomeric mixture. The mixture was then subjected to the next reaction. LC-MS (ESI+): m / z 263.0 (M+H) + .

[1180] 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinonitrile

[1181]

[1182] 4-Chloro-6-(3-chlorophenyl)-5-methylpyridin-3-carboxynitrile (1.35 g, 5.130 mmol) was dissolved in DMF (10 mL), and the reaction mixture was cooled to 0 °C. ℃ Add NaH (60% suspension in mineral oil, 246 mg, 6.156 mmol). After 3 minutes, add benzyl alcohol (0.637 mL, 6.156 mmol) dropwise at 0 °C. Stir the red reaction mixture at 0 °C. After 50 min, TLC (10% ethyl acetate / hexane) showed 90% conversion. Quench the reaction mixture with water (20 mL). Extract the mixture with ethyl acetate (30 mL). Dry the organic layer with Na2SO4 and concentrate. Purify the crude material by column chromatography (20 g, 0-40% ethyl acetate / hexane) to separate two regiomeric isomers (from the aforementioned reaction). Major product (1.16 g, 67%). The major product showed a strong NOE between 8.40 ppm and 7.57-7.42 ppm, indicating the desired product. LC-MS (ESI+): m / z 335.0 (M+H) + .

[1183] 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpicolinic acid

[1184]

[1185] A mixture of 1.1 g (3.3 mmol) of 4-benzoxy-6-(3-chlorophenyl)-5-methylpyridin-3-carboxynitrile (1.1 g, 3.3 mmol) in ethanol (11 mL) and 30% NaOH aqueous solution (14 mL) was heated to 100 °C for 3 h. LC-MS indicated complete conversion to the desired high polarity. The reactants were cooled to room temperature. Ethanol was evaporated under reduced pressure. The aqueous residue was acidified with concentrated HCl (pH approximately 2), yielding a light brown solid. The solid was separated by filtration, washed with water, and dried in air to give a light brown solid (1.2 g, 100%). The crude material was used in the next reaction. LC-MS (ESI+): m / z 354.0 (M+H) + .

[1186] (3-(benzooxy)-5-(3-chlorophenyl)-4-methylpicolinoyl)glycine ethyl ester

[1187]

[1188] PyBOP (323 mg, 0.621 mmol) and triethylamine (0.39 mL, 2.862 mmol) were added to a stirred mixture of 4-benzoxy-6-(3-chlorophenyl)-5-methylpyridine-3-carboxylic acid (200 mg, 0.565 mmol) and ethyl 2-aminoacetic acid; ethyl hydrochloride (79 mg, 0.565 mmol) was added to a DCM (5 mL) container at room temperature. The resulting mixture was stirred at room temperature for 2 h. LC-MS indicated complete depletion of the starting material. The reactants were directly concentrated. The crude product was purified by column chromatography (0-100% ethyl acetate / hexane) to give a white solid (201 mg, 81%). LC-MS (ESI+): m / z 439.0 (M+H) + .

[1189] (5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinoyl)glycine ethyl ester

[1190]

[1191] A mixture of ethyl 2-[[4-benzyloxy-6-(3-chlorophenyl)-5-methylpyridine-3-carbonyl]amino]ethyl 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 min, followed by stirring at room temperature under a hydrogen atmosphere for 12 h. LC-MS indicated complete conversion to the desired product. The reaction mixture was filtered through a diatomaceous earth filter and washed with ethyl acetate (15 mL). The filtrate was concentrated. The crude product (151 mg, 0.429 mmol) was used for the next reaction without further purification. LC-MS (ESI+): m / z 349.0 (M+H) + .

[1192] (5-(3-chlorophenyl)-3-hydroxy-4-methylpicolinoyl)glycine

[1193]

[1194] At room temperature, 0.5 mL of 1 N NaOH aqueous solution was added to a stirred solution of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxy-4-methylpyridine-2-carbonyl]amino]ethyl acetate (132 mg, 0.378 mmol) in THF (1.5 mL) and methanol (1.5 mL). The reaction mixture was stirred at 40 °C for 1.5 h. The reaction mixture was directly concentrated to remove THF and methanol. The residue was acidified with 0.6 mL of 1 N HCl aqueous solution. The precipitate was filtered, washed with water, and dried in air. The crude substance was purified by preparative HPLC (30–80% MeCN / water, over 25 min). LC-MS(ESI+):m / z 321.0(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).

[1195] Example 33: Preparat...

Claims

1. A compound of formula (IX): (IX) Or its pharmaceutically acceptable salt, wherein: Each G is independently N, NH, NR 13 or CR 14 ; R 1 For unreplaced C 1-3 Alkyl or OR 7 , halogen or halogen-substituted phenyl C 1-3 Alkyl group, wherein R 7 For unreplaced C 1-3 Alkyl groups or C groups substituted with unsubstituted phenyl groups 1-3 Alkyl, or R 1 It is cyclopropyl; R 2 Hydrogen, halogen, CN, unsubstituted C 1-3 Alkyl groups or C atoms substituted with one or more halogens 1-3 alkyl; R 4 and R 5 Independently hydrogen or unsubstituted C 1-3 alkyl; R 13 Cyclopropyl, unsubstituted phenyl, C-shaped with one or more halogens or unsubstituted C 1-3 Alkyl-substituted phenyl, pyridyl, unsubstituted 6-membered heterocyclic alkyl, 6-membered heterocyclic alkyl substituted with tert-butoxycarbonyl, unsubstituted C 1-4 Alkyl groups, C groups substituted with unsubstituted phenyl groups 1-4 C-aryl groups or phenyl groups substituted with one or more halogens 1-4 Alkyl; and R 14 It is hydrogen, halogen, cyclopropyl or unsubstituted C 1-3 alkyl.

2. The compound according to claim 1, having a structure according to formula (X). （X） Or its pharmaceutically acceptable salt, wherein: Each G is independently for N, NR 13 or CR 14 ; R 1 For unreplaced C 1-3 Alkyl or OR 7 , halogen or halogen-substituted phenyl C 1-3 Alkyl group, wherein R 7 For unreplaced C 1-3 Alkyl groups or C groups substituted with unsubstituted phenyl groups 1-3 Alkyl, or R 1 It is cyclopropyl; R 2 Hydrogen, halogen, CN, unsubstituted C 1-3 Alkyl groups or C atoms substituted with one or more halogens 1-3 alkyl; R 4 and R 5 Independently hydrogen or unsubstituted C 1-3 alkyl; R 13 Cyclopropyl, unsubstituted phenyl, C-shaped with one or more halogens or unsubstituted C 1-3 Alkyl-substituted phenyl, pyridyl, unsubstituted 6-membered heterocyclic alkyl, 6-membered heterocyclic alkyl substituted with tert-butoxycarbonyl, unsubstituted C 1-4 Alkyl groups, C groups substituted with unsubstituted phenyl groups 1-4 C-aryl groups or phenyl groups substituted with one or more halogens 1-4 Alkyl; and R 14 It is hydrogen, halogen, cyclopropyl or unsubstituted C 1-3 alkyl.

3. The compound according to claim 1, having a structure according to formula (XI). (XI) Or its pharmaceutically acceptable salt, wherein Each G is independently either N or NR. 13 ; R 1 For unreplaced C 1-3 Alkyl or OR 7 , halogen or halogen-substituted phenyl C 1-3 Alkyl group, wherein R 7 For unreplaced C 1-3 Alkyl groups or C groups substituted with unsubstituted phenyl groups 1-3 Alkyl, or R 1 It is cyclopropyl; R 2 Hydrogen, halogen, CN, unsubstituted C 1-3 Alkyl groups or C atoms substituted with one or more halogens 1-3 alkyl; R 4 and R 5 Independently hydrogen or unsubstituted C 1-3 alkyl; R 13 It is cyclopropyl, pyridyl, unsubstituted phenyl, or C substituted with one or more halogens or unsubstituted C. 1-3 Alkyl-substituted phenyl groups, unsubstituted 6-membered heterocyclic alkyl groups, 6-membered heterocyclic alkyl groups substituted with tert-butoxycarbonyl groups, and unsubstituted C66 groups. 1-4 Alkyl groups, C groups substituted with unsubstituted phenyl groups 1-4 C-aryl groups or phenyl groups substituted with one or more halogens 1-4 Alkyl; and R 14 It is hydrogen, halogen, cyclopropyl or unsubstituted C 1-3 alkyl.

4. The compound according to claim 1, having a structure according to formula (XIIa) or formula (XIIb). (XIIa)(XIIb) Or its pharmaceutically acceptable salt, wherein: R 1 For unreplaced C 1-3 Alkyl or OR 7 , halogen or halogen-substituted phenyl C 1-3 Alkyl, or R 1 It is cyclopropyl; R 2 Hydrogen, halogen, CN, unsubstituted C 1-3 Alkyl groups or C atoms substituted with one or more halogens 1-3 alkyl; R 4 and R 5 Independently hydrogen or unsubstituted C 1-3 alkyl; R 7 For unreplaced C 1-3 Alkyl groups or C groups substituted with unsubstituted phenyl groups 1-3 alkyl; R 13 Cyclopropyl, pyridyl, unsubstituted phenyl, C-terminated with one or more halogens or unsubstituted C 1-3 Alkyl-substituted phenyl groups, unsubstituted 6-membered heterocyclic alkyl groups, 6-membered heterocyclic alkyl groups substituted with tert-butoxycarbonyl groups, and unsubstituted C66 groups. 1-4 Alkyl groups, C groups substituted with unsubstituted phenyl groups 1-4 C-aryl groups or phenyl groups substituted with one or more halogens 1-4 Alkyl; and R 14 It is hydrogen, halogen, cyclopropyl or unsubstituted C 1-3 alkyl.

5. The compound according to claim 1, having a structure according to formula (XIII). (XIII) Or its pharmaceutically acceptable salt, wherein: R 2 Hydrogen, halogen, CN, unsubstituted C 1-3 Alkyl groups or C atoms substituted with one or more halogens 1-3 alkyl; R 4 and R 5 Independently hydrogen or unsubstituted C 1-3 Alkyl; and R 13 It is an unsubstituted phenyl, pyridyl, or halogen-substituted phenyl.

6. The compound according to claim 1, having a structure according to formula (XIX). (XIX) Or its pharmaceutically acceptable salt, wherein: R 1 For unreplaced C 1-3 Alkyl or OR 7 , halogen or halogen-substituted phenyl C 1-3 Alkyl, or R 1 It is cyclopropyl; R 2 Hydrogen, halogen, CN, unsubstituted C 1-3 Alkyl groups or C atoms substituted with one or more halogens 1-3 alkyl; R 4 and R 5 Independently hydrogen or unsubstituted C 1-3 alkyl; R 7 For unreplaced C 1-3 Alkyl groups or C groups substituted with unsubstituted phenyl groups 1-3 Alkyl; and R 13 Cyclopropyl, unsubstituted phenyl, C-shaped with one or more halogens or unsubstituted C 1-3 Alkyl-substituted phenyl, pyridyl, unsubstituted 6-membered heterocyclic alkyl, 6-membered heterocyclic alkyl substituted with tert-butoxycarbonyl, unsubstituted C 1-4 Alkyl groups, C groups substituted with unsubstituted phenyl groups 1-4 C-aryl groups or phenyl groups substituted with one or more halogens 1-4 alkyl.

7. The compound according to claim 1, having a structure according to formula (XX). (XX) Or its pharmaceutically acceptable salt, wherein: R 1 For unreplaced C 1-3 Alkyl or OR 7 , halogen or halogen-substituted phenyl C 1-3 Alkyl, or R 1 It is cyclopropyl; R 2 Hydrogen, halogen, CN, unsubstituted C 1-3 Alkyl groups or C atoms substituted with one or more halogens 1-3 alkyl; R 4 and R 5 Independently hydrogen or unsubstituted C 1-3 alkyl; R 7 For unreplaced C 1-3 Alkyl groups or C groups substituted with unsubstituted phenyl groups 1-3 Alkyl; and R 13 Cyclopropyl, unsubstituted phenyl, C-shaped with one or more halogens or unsubstituted C 1-3 Alkyl-substituted phenyl, pyridyl, unsubstituted 6-membered heterocyclic alkyl, 6-membered heterocyclic alkyl substituted with tert-butoxycarbonyl, unsubstituted C 1-4 Alkyl groups, C groups substituted with unsubstituted phenyl groups 1-4 C-aryl groups or phenyl groups substituted with one or more halogens 1-4 alkyl.

8. The compound according to claim 1, having a structure according to formula (XXI). (XXI) Or its pharmaceutically acceptable salt, wherein: R 1 For unreplaced C 1-3 Alkyl or OR 7 , halogen or halogen-substituted phenyl C 1-3 Alkyl, or R 1 It is cyclopropyl; R 2 Hydrogen, halogen, CN, unsubstituted C 1-3 Alkyl groups or C atoms substituted with one or more halogens 1-3 alkyl; R 4 and R 5 Independently hydrogen or unsubstituted C 1-3 Alkyl; and R 7 For unreplaced C 1-3 Alkyl groups or C groups substituted with unsubstituted phenyl groups 1-3 alkyl.

9. The compound according to claim 1, wherein R 1 Cyclopropyl or OR 7 , halogen or halogen-substituted phenyl C 1-3 alkyl.

10. The compound according to claim 9, wherein R 1 It is cyclopropyl or difluoromethyl.

11. The compound according to claim 1, wherein R 1 For the unreplaced C 1-3 alkyl.

12. The compound according to claim 11, wherein R 1 It is CH2CH3.

13. The compound according to claim 11, wherein R 1 It is CH3.

14. The compound according to claim 1, wherein R 1 C substituted with phenyl 1-3 Alkyl group, wherein the phenyl group is substituted with a halogen.

15. The compound according to claim 1, wherein R 2 It is hydrogen.

16. The compound according to claim 1, wherein R 2 For the unreplaced C 1-3 alkyl.

17. The compound according to claim 16, wherein R 2 It is CH3.

18. The compound according to claim 1, wherein R 4 It is hydrogen and R 5 It is hydrogen.

19. The compound according to claim 1, wherein R 4 It is hydrogen and R 5 For unreplaced C 1-3 alkyl.

20. The compound according to claim 19, wherein R 5 It is CH3.

21. The compound according to claim 1, wherein R 4 For unreplaced C 1-3 Alkyl and R 5 For unreplaced C 1-3 alkyl.

22. The compound according to claim 21, wherein R 4 It is CH3 and R 5 It is CH3.

23. The compound according to claim 1, having any one of the following structures: Or its pharmaceutically acceptable salt.

24. The compound according to claim 1, having any one of the following structures: Or its pharmaceutically acceptable salt.

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein at least one hydrogen atom is replaced by a deuterium atom.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24 in the preparation of a medicament for treating diseases mediated by PHD activity.

28. The use according to claim 27, wherein the disease mediated by PHD activity is ischemia-reperfusion injury.

29. The use according to claim 28, wherein the ischemic reperfusion injury is selected from stroke, myocardial infarction, and acute kidney injury.

30. The use according to claim 27, wherein the disease mediated by PHD activity is inflammatory bowel disease.

31. The use according to claim 30, wherein the inflammatory bowel disease is ulcerative colitis.

32. The use according to claim 30, wherein the inflammatory bowel disease is Crohn's disease.

33. The use according to claim 27, wherein the disease mediated by PHD activity is cancer.

34. The use according to claim 33, wherein the cancer is colorectal cancer.

35. The use according to claim 27, wherein the disease mediated by PHD activity is liver disease.

36. The use according to claim 27, wherein the disease mediated by PHD activity is atherosclerosis.

37. The use according to claim 27, wherein the disease mediated by PHD activity is a cardiovascular disease.

38. The use according to claim 27, wherein the disease mediated by PHD activity is an eye disease or condition.

39. The use according to claim 38, wherein the eye disease or condition is selected from radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia.

40. The use according to claim 27, wherein the disease is anemia.

41. The use according to claim 40, wherein the anemia is anemia associated with chronic kidney disease.

42. The use according to claim 27, wherein the disease is chronic kidney disease.

43. The use according to claim 27, wherein the disease is associated with hyperoxia.

44. The use according to claim 43, wherein the disease is retinopathy of prematurity.

45. The use according to claim 43, wherein the disease is bronchopulmonary dysplasia (BPD).

46. ​​The use according to claim 27, 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 cirrhosis.

47. The use according to claim 27, wherein the disease is a respiratory disease or a lung disease.

48. The use according to claim 47, wherein the respiratory disease is a respiratory viral infection and the lung disease is a pulmonary viral infection.

49. The use according to claim 47, wherein the respiratory disease is selected from respiratory tract infection, acute respiratory distress syndrome, pulmonary inflammation, and acute lung injury.

50. The use according to claim 47, wherein the lung disease is acute lung injury (ALI), bronchitis, pneumonia, pulmonary fibrosis, asthma, or acute respiratory distress syndrome (ARDS).

51. The use according to claim 27, wherein the disease is damage and / or failure of one or more organs.

52. The use according to claim 51, wherein the disease is acute organ injury.

53. The use according to claim 51, wherein the disease is organ failure.

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