PHD inhibitor compounds, compositions, and their uses

Abstract

The present invention provides, in part, novel small molecule inhibitors of PHD having a structure according to Formula (A) and subformulas thereof: or pharmaceutically acceptable salts thereof. The compounds provided herein may be useful in the treatment of diseases, including diseases of the heart (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver (e.g., acute liver failure, liver fibrosis, and cirrhosis), and kidney (e.g., acute kidney injury and chronic kidney disease). [Formula 1] TIFF2023518543000231.tif22170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 992,616, filed on 20 March 2020, which is incorporated herein by reference in its entirety. [Background technology]

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

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

[0004] Novel small molecule PHD inhibitors useful in treating diseases including those of the heart (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), the lungs (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), the liver (e.g., acute liver failure, hepatic fibrosis, and cirrhosis), and the kidneys (e.g., acute kidney injury and chronic kidney disease) are described herein. [Overview of the Initiative]

[0005] The present invention provides, in particular, novel small molecule inhibitors of PHD that are useful in treating diseases including, but not limited to, diseases of the heart (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lungs (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver (e.g., acute liver failure, hepatic fibrosis, and cirrhosis), and kidneys (e.g., acute kidney injury and chronic kidney disease).

[0006] In one embodiment, the structure follows formula (A), [ka] A compound having a pharmaceutically acceptable salt thereof is provided herein, in the formula, Ar 1 C is optionally substituted with a halogen, CN, OH, CN, or one or more halogens. 1-3 Alkyl and C 1-3 An aryl or heteroaryl compound optionally substituted with one or more groups selected from alkoxys, Ar 2 is a halogen; amino; amide; OH; sulfonyl group; sulfinyl group; carbonyl group; phosphoryl group; C 3-6 Cycloalkyl; sulfonyl group or optionally substituted with =O C 3-6 Heterocycloalkyl; carbonyl or optionally substituted with one or more halogens C 1-3 Alkyl and C 1-3 It is a pyrido-2-yl optionally substituted with one or more groups selected from heteroaryls optionally substituted with alkyl or phenyl.

[0007] In an embodiment, Ar 1 is [Chemical formula] wherein X is N or CR 1a and Y and Z are independently CH or N, R 1a is H, CN, halogen, C 1-3 alkoxy, OH, or C 1-3 alkyl optionally substituted with CN, R 1 is independently each time hydrogen, halogen, CN, OH, C 1-3 alkyl optionally substituted with one or more halogens, and C 1-3 alkoxy, and m is 1, 2, 3, or 4.

[0008] In an embodiment, Ar 1 is as follows [Chemical formula] .

[0009] In an embodiment, Ar 1 is [Chemical formula] wherein R<00oo019>is H, CN, halogen, C 1-3 alkoxy, OH, or C 1-3 alkyl optionally substituted with CN.

[0010] In an embodiment, R 1a is H, CN, halogen, C 1-3 alkoxy, OH, or C 1-3 alkyl optionally substituted with CN.

[0011] In an embodiment, R 1Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys.

[0012] In this embodiment, Ar 2 teeth, [ka] And in the formula, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 3 SO2R 6 SOR 7 R 8 SOR 9 COR 10 , (CH2) p COOH, NHR 11 , POR 12 R 13 , halogen, cycloalkyl, SO2R 14 Alternatively, a heterocycloalkyl group arbitrarily substituted with =O, C 1-3 A heteroaryl group optionally substituted with alkyl or phenyl, or a C group optionally substituted with one or more halogens. 1-3 It is alkyl, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R 17 , or phenyl, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And, R 8 It is NH or NCH3, R 10 C 1-3 Alkyl or NHSO2R20 and R 11 is COR 21 or SO2R 22 and R 9 R 12 R 13 R 14 R 15 and R 20 are each independently C 1-3 alkyl R 21 is heterocycloalkyl, cycloalkyl, or C 1-3 alkyl R 22 is NR 23 R 24 or C 1-3 alkyl optionally substituted with carboxyl R 4 R 5 R 16 R 17 R 18 R 19 R 23 and R 24 are each independently H or C 1-3 alkyl p is 1, 2, or 3 n is 0, 1, 2, or 3. <00022​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​is heterocycloalkyl, cycloalkyl, or C 1-3 alkyl, and R 22 is NR 23 R 24 , or C 1-3 alkyl optionally substituted with carboxyl, and R 23 and R 24 are independently H or C 1-3 alkyl.

[0015] In an embodiment, Ar 2 is

Chemical formula

[0016] In an embodiment, Ar 2 is

Chemical formula

[0017] In an embodiment, cycloalkyl or optionally substituted heterocycloalkyl is

Chemical formula

[0018] In an embodiment, optionally substituted heteroaryl is

Chemical formula

[0019] In an embodiment, R 2Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, where R 4 and R 5 Each is independently H or C 1-3 It is alkyl.

[0020] In this embodiment, R 3 SO2R 6 SOR 7 R 8 SOR 9 COR 10 , (CH2) p COOH, NHR 11 , POR 12 R 13 , halogen, cycloalkyl, SO2R 14 Alternatively, a heterocycloalkyl group arbitrarily substituted with =O, C 1-3 A heteroaryl group optionally substituted with alkyl or phenyl, or a C group optionally substituted with one or more halogens. 1-3 It is an alkyl, and in the formula, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R 17 , or phenyl, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And R 8 is NH or NCH3, and R 10 C 1-3 Alkyl or NHSO2R 20 And R 11 COR 21 Or SO2R 22 And R 9 , R 12 , R 13 R 14 , R 15 , and R 20 Each is independent of C 1-3 It is alkyl, R 21is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is alkyl, R 4 , R 5 , R 16 , R 17 , R 18 , R 19 , R 23 , and R 24 Each is independently H or C 1-3 It is an alkyl group, and p is 1, 2, or 3.

[0021] In this embodiment, the compound of formula (A) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0022] In the embodiment of formula (I), X is N or CR 1a Y and Z are independently CH or N, and R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl, R 3 SO2R 6 SOR 7 R 8 SOR 9 COR 10 , (CH2) p COOH, NHR 11 , POR 12R 13 , halogen, cycloalkyl, SO2R 14 Alternatively, a heterocycloalkyl group arbitrarily substituted with =O, C 1-3 A heteroaryl group optionally substituted with alkyl or phenyl, or a C group optionally substituted with one or more halogens. 1-3 It is alkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R 17 , or phenyl, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And R 8 is NH or NCH3, and R 9 C 1-3 It is alkyl, R 10 C 1-3 Alkyl or NHSO2R 20 And R 11 COR 21 Or SO2R 22 And R 12 and R 13 Each is independent of C 1-3 It is alkyl, R 14 C 1-3 It is alkyl, R 15 C 1-3 It is alkyl, R 16 and R 17 Each is independently H or C 1-3 It is alkyl, R 18 and R 19 Each is independently H or C 1-3 It is alkyl, R 20 C 1-3 It is alkyl, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24, or C optionally substituted with carboxyl 1-3 It is alkyl, R 23 and R 24 Each is independently H or C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, n is 0, 1, 2, or 3, and p is 1, 2, or 3.

[0023] In the embodiment, the compound of formula (A) or formula (I) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0024] In this embodiment, X is N or CR 1a And Z is CH or N, and R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl, R 3 SO2R 6 SOR 7 R 8 SOR 9 COR 10 , (CH2) p COOH, NHR 11 , POR 12 R 13 , halogen, cycloalkyl, SO2R 14 Alternatively, a heterocycloalkyl group arbitrarily substituted with =O, C 1-3 A heteroaryl group optionally substituted with alkyl or phenyl, or a C group optionally substituted with one or more halogens. 1-3It is alkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R 17 , or phenyl, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And R 8 is NH or NCH3, and R 9 C 1-3 It is alkyl, R 10 C 1-3 Alkyl or NHSO2R 20 And R 11 COR 21 Or SO2R 22 And R 12 and R 13 Each is independent of C 1-3 It is alkyl, R 14 C 1-3 It is alkyl, R 15 C 1-3 It is alkyl, R 16 and R 17 H or C 1-3 It is alkyl, R 18 and R 19 H or C 1-3 It is alkyl, R 20 C 1-3 It is alkyl, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is alkyl, R 23 and R 24 H or C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, n is 0, 1, 2, or 3, and p is 1, 2, or 3.

[0025] In the embodiment, the compound of formula (A), formula (I), or formula (II) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0026] In the embodiment of formula (III), R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl, R 3 SO2R 6 SOR 7 R 8 SOR 9 COR 10 , (CH2) p COOH, NHR 11 , POR 12 R 13 , halogen, cycloalkyl, SO2R 14 Alternatively, a heterocycloalkyl group arbitrarily substituted with =O, C 1-3 A heteroaryl group optionally substituted with alkyl or phenyl, or a C group optionally substituted with one or more halogens. 1-3 It is alkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R 17 , or phenyl, R 7 C1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And R 8 is NH or NCH3, and R 9 C 1-3 It is alkyl, R 10 C 1-3 Alkyl or NHSO2R 20 And R 11 COR 21 Or SO2R 22 And R 12 and R 13 Each is independent of C 1-3 It is alkyl, R 14 C 1-3 It is alkyl, R 15 C 1-3 It is alkyl, R 16 and R 17 H or C 1-3 It is alkyl, R 18 and R 19 H or C 1-3 It is alkyl, R 20 C 1-3 It is alkyl, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is alkyl, R 23 and R 24 H or C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, n is 0, 1, 2, or 3, and p is 1, 2, or 3.

[0027] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0028] In the embodiment of formula (IV), R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 It is an alkoxy, R 1a C is optionally substituted with H, CN, halogen, C1-3 alkoxy, OH, or CN. 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And R 8 is NH or NCH3, and R 18 and R 19 Each is independently H or C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, and n is 0, 1, 2, or 3.

[0029] In this embodiment, R 1 C 1-3 It is alkyl. In this embodiment, R 1 This is CH3.

[0030] In the embodiment, the compound of formula (A), formula (I), formula (II), formula (III), or formula (IV) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0031] In this embodiment, R 1a is CN or halogen, and R 2 is hydrogen or C 1-3Selected from the group consisting of alkyl, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And R 8 is NH or NCH3, and R 18 and R 19 Each is independently H or C 1-3 It is alkyl.

[0032] In this embodiment, R 1a This is CN.

[0033] In this embodiment, R 1a is a halogen. In this embodiment, R 1a It is Cl.

[0034] In this embodiment, R 2 C 1-3 It is alkyl.

[0035] In this embodiment, R 2 This is CH3.

[0036] In this embodiment, R 7 C 1-3 It is alkyl. In this embodiment, R 7 This is CH3. In this embodiment, R 7 is CH2CH3. In the embodiment, R 7 This is CH(CH3)2. In the embodiment, R 7 C 3-5 It is a cycloalkyl group. In this embodiment, R 7 is cyclopropyl. In the embodiment, R 7 is cyclopentyl. In the embodiment, R 7 R is phenyl. In this embodiment, R 7 , NR 18 R 19 And in the formula, R 18 and R 19 Each is independently H or C 1-3 It is alkyl.

[0037] In this embodiment, R 18 and R 19 Independently, is H. In this embodiment, R 18 H is R 19 C 1-3 It is alkyl. In this embodiment, R 19 This is CH3. In this embodiment, R 18 and R 19 It is independently CH3.

[0038] In this embodiment, R 8 is NH. In the embodiment, R 8 This is NCH3.

[0039] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0040] In this embodiment, X is N or CR 1a And Z is N or CH, and R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 It is an alkoxy, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R 17, or phenyl, R 15 C 1-3 It is alkyl, R 16 and R 17 Each is independently H or C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, and n is 0, 1, 2, or 3.

[0041] In the embodiment, X is N. In the embodiment, X is CR. 1a That is the case.

[0042] In this embodiment, R 1a is CN. In this embodiment, R 1a is a halogen. In this embodiment, R 1a is Cl. In this embodiment, R 1a F is F. In this embodiment, R 1a is Br. In this embodiment, R 1a C 1-3 It is an alkoxy.

[0043] In this embodiment, R 1a is methoxy. In this embodiment, R 1a H is H. In this embodiment, R 1a is a C arbitrarily replaced by CN. 1-3 It is alkyl. In this embodiment, R 1a This is CH2CN. In the embodiment, R 1a It is OH.

[0044] In the embodiment, Z is CH. In the embodiment, Z is N.

[0045] In this embodiment, R 1 H is H. In this embodiment, R 1 C 1-3 It is alkyl. In this embodiment, R 1 This is CH3. In this embodiment, R 1 C 1-3 It is an alkoxy. In this embodiment, R 1 is methoxy. In this embodiment, R 1 This is CN.

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

[0047] In this embodiment, R 6 C 1-3 It is alkyl. In this embodiment, R 6 This is CH3. In this embodiment, R 6 NHCOR 15 And in the formula, R 15 C 1-3 It is alkyl. In this embodiment, R 15 This is CH3. In this embodiment, R 6 , NR 16 R 17 And in the formula, R 16 and R 17 Each is independently H or C 1-3 It is alkyl. In this embodiment, R 6 is NH2. In the embodiment, R 6 It is phenyl.

[0048] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 3 is cycloalkyl, or SO2R 14 Alternatively, it is a heterocycloalkyl group arbitrarily substituted with =O.

[0049] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 It is an alkoxy, R 1a H, CN, halogen, C 1-3C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 14 C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, and n is 0, 1, 2, or 3.

[0050] In the embodiment, the compound of formula (A), formula (I), formula (II), formula (III), or formula (VI) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 3 is cycloalkyl, or SO2R 14 Alternatively, it is a heterocycloalkyl group arbitrarily substituted with =O.

[0051] In this embodiment, R 2 is hydrogen or C 1-3 It is alkyl, R 14 C 1-3 It is alkyl.

[0052] In this embodiment, R 2 H is H. In this embodiment, R 2 C 1-3 It is alkyl. In this embodiment, R 2 This is CH3.

[0053] In this embodiment, R 3 It is a cycloalkyl compound.

[0054] In this embodiment, R 3 It is cyclopropyl.

[0055] In this embodiment, R 3 SO2R 14 Alternatively, it is a heterocycloalkyl group arbitrarily substituted with =O, where R 14 C 1-3 It is alkyl.

[0056] In this embodiment, R 3 teeth, [ka] That is the case.

[0057] In this embodiment, R 3 teeth, [ka] That is the case.

[0058] In this embodiment, R 3 teeth, [ka] That is the case.

[0059] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0060] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 It is an alkoxy, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 11 COR 21 Or SO2R 22 And R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is alkyl, R 23 and R 24 H or C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, and n is 0, 1, 2, or 3.

[0061] In the embodiment, the compound of formula (A), formula (I), formula (II), formula (III), or formula (VII) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0062] In this embodiment, R 2 is hydrogen or C 3-6 It is cycloalkyl, R 11 COR 21 Or SO2R 22 And R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is an alkyl, and in the formula, R 23 and R 24 H or C 1-3 It is alkyl.

[0063] In this embodiment, R 2 H is H. In this embodiment, R 2C 1-3 It is alkyl. In this embodiment, R 2 This is CH3.

[0064] In this embodiment, R 11 COR 21 And in the formula, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl.

[0065] In this embodiment, R 21 is a heterocycloalkyl. In this embodiment, R 21 teeth, [ka] In this embodiment, R 21 teeth, [ka] In this embodiment, R 21 is a cycloalkyl. In this embodiment, R 21 is cyclopropyl. In the embodiment, R 21 C 1-3 It is alkyl. In this embodiment, R 21 It is CH2CH3.

[0066] In this embodiment, R 11 SO2R 22 And in the formula, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is an alkyl, and in the formula, R 23 and R 24 H or C 1-3 It is alkyl.

[0067] In this embodiment, R 22 is a C which is optionally substituted with a carboxyl. 1-3 It is alkyl. In this embodiment, R 22 This is CH3. In this embodiment, R 22is CH2CH3. In the embodiment, R 22 is CH2COOH. In the embodiment, R 22 , NR 23 R 24 And in the formula, R 23 and R 24 H or C 1-3 It is alkyl. In this embodiment, R 22 This is NHCH3. In this embodiment, R 22 This is N(CH3)2.

[0068] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 3 C 1-3 It is a heteroaryl compound optionally substituted with alkyl or phenyl.

[0069] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 It is an alkoxy, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independently H or C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, and n is 0, 1, 2, or 3.

[0070] In the embodiment, the compound of formula (A), formula (I), formula (II), formula (III), or formula (VIII) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 3 C 1-3 It is a heteroaryl compound optionally substituted with alkyl or phenyl.

[0071] In this embodiment, R 2 H is H.

[0072] In this embodiment, R 3 is a heteroaryl. In this embodiment, R 3 teeth, [ka] In this embodiment, R 3 teeth, [ka] In this embodiment, R 3 teeth, [ka] In this embodiment, R 3 teeth, [ka] In this embodiment, R 3 teeth, [ka] In this embodiment, R 3 teeth, [ka] In this embodiment, R 3 C 1-3 It is a heteroaryl compound optionally substituted with alkyl or phenyl. In the embodiment, R 3 teeth, [ka] In this embodiment, R 3 teeth, [ka] In this embodiment, R 3 teeth, [ka] That is the case.

[0073] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0074] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 It is an alkoxy, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independently H or C 1-3 Alkyl, R 10 C 1-3 Alkyl or NHSO2R 20 And R 20 C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, and n is 0, 1, 2, or 3.

[0075] In the embodiment, the compound of formula (A), formula (I), formula (II), formula (III), or formula (IX) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0076] In this embodiment, R 1a is CN or halogen, and R 10 C 1-3 Alkyl or NHSO2R 20 And R 20 C 1-3 It is alkyl.

[0077] In this embodiment, R 1a is CN. In this embodiment, R 1a is a halogen. In this embodiment, R 1a It is Cl.

[0078] In this embodiment, R 10 C 1-3 It is alkyl. In this embodiment, R 10 This is CH3. In this embodiment, R 10 This is CH(CH3)2. In the embodiment, R 10 is CH2CH3. In the embodiment, R 10 NHSO2R 20 And in the formula, R 20 C 1-3 It is alkyl. In this embodiment, R 20 This is CH3.

[0079] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0080] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 It is an alkoxy, R1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 9 C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, and n is 0, 1, 2, or 3.

[0081] In this embodiment, R 1a This is CN.

[0082] In this embodiment, R 1 H is H.

[0083] In this embodiment, R 2 H is H.

[0084] In this embodiment, R 9 C 1-3 It is alkyl. In this embodiment, R 9 This is CH3.

[0085] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0086] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 It is an alkoxy, R 1a H, CN, halogen, C 1-3C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independently H or C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, n is 0, 1, 2, or 3, and p is 1, 2, or 3.

[0087] In this embodiment, R 1a This is CN.

[0088] In this embodiment, R 1 H is H.

[0089] In this embodiment, R 2 H is H.

[0090] In this embodiment, p is 1.

[0091] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 3 It is a halogen.

[0092] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 It is an alkoxy, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independently H or C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, and n is 0, 1, 2, or 3.

[0093] In this embodiment, R 1a This is CN.

[0094] In this embodiment, R 1 H is H.

[0095] In this embodiment, R 2 H is H.

[0096] In this embodiment, R 3 is Cl. In this embodiment, R 3 is Br. In this embodiment, R 3 It is F.

[0097] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0098] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 It is an alkoxy, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 12 C 1-3 It is alkyl, R 13 C 1-3 It is an alkyl group, and m is 1, 2, 3, or 4.

[0099] In this embodiment, R 1a This is CN.

[0100] In this embodiment, R 1 H is H.

[0101] In this embodiment, R 2 C 1-3 It is alkyl. In this embodiment, R 2 This is CH3.

[0102] In this embodiment, R 12 C 1-3 It is alkyl. In this embodiment, R 12 This is CH3.

[0103] In this embodiment, R 13 C 1-3 It is alkyl. In this embodiment, R 13 This is CH3.

[0104] In some embodiments, the compound is one of compounds 1 to 33. [Table 1] TIFF0007856575000045.tif228170TIFF0007856575000046.tif171170

[0105] In the embodiment, at least one hydrogen atom in one of the compounds of formula (A) and (I) to (XIII), such as any one of compounds 1 to 33, is replaced by a deuterium atom.

[0106] In another embodiment, the present invention is characterized by a pharmaceutical composition comprising any compound described herein (for example, any one of compounds of formula (A) and (I) to (XIII), such as any one of compounds 1 to 33), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0107] In another embodiment, the present invention features a method for treating a disease mediated by PHD activity, the method comprising administering any of the compounds described herein (e.g., any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)) or a pharmaceutically acceptable salt thereof to a target.

[0108] In this embodiment, the disease mediated by PHD activity is ischemia-reperfusion injury (e.g., stroke, myocardial infarction, or acute kidney injury).

[0109] In this embodiment, the disease mediated by PHD activity is inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease).

[0110] In this embodiment, the disease mediated by PHD activity is cancer (e.g., colorectal cancer).

[0111] In this embodiment, the disease mediated by PHD activity is a liver disease.

[0112] In this embodiment, the disease mediated by PHD activity is atherosclerosis.

[0113] In this embodiment, the disease mediated by PHD activity is a cardiovascular disease.

[0114] In the embodiments, the diseases mediated by PHD activity are eye diseases or conditions (e.g., radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia).

[0115] In this embodiment, the disease mediated by PHD activity is anemia (e.g., anemia associated with chronic kidney disease).

[0116] In this embodiment, the disease mediated by PHD activity is associated with hyperoxia.

[0117] In this embodiment, the disease mediated by PHD activity is retinopathy of prematurity.

[0118] In this embodiment, the disease mediated by PHD activity is bronchopulmonary dysplasia (BPD).

[0119] In this embodiment, the diseases mediated by PHD activity include ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, or cirrhosis. [Brief explanation of the drawing]

[0120] [Figure 1] This is an exemplary schematic diagram illustrating the principle of the TR-FRET assay for PHD enzymes (PHD1, PHD2, and PHD3). In the presence of 2-oxoglutarate and O2, the PHD enzymes hydroxylate proline 564 of the biotin-tagged HIF-1α peptide, resulting in the production of biotin-tagged HIF-1α-hydroxyproline, succinate, and CO2. The His-tagged VHL protein, EloB, EloC complex (His-VBC), donor fluorophore complex, monoclonal antibody, anti-6His-terbium (Tb)-cryptate gold, and acceptor fluorophore, SA-D2 complex, bound to HIF-1α-hydroxyproline, yield fluorescence resonance energy transfer signals that can be detected and quantified. [Modes for carrying out the invention]

[0121] definition To make the present invention more easily understood, certain terms are first defined below. Further definitions of the following terms and other terms are provided throughout this specification. Publications and other reference materials referenced herein to provide background to the present invention and to offer further details relating to its implementation are incorporated herein by reference.

[0122] Animals: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to a human at any developmental stage. In some embodiments, “animal” refers to a non-human animal at any developmental stage. In certain embodiments, a non-human animal is a mammal (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cattle, primates, and / or pigs). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or parasites. In some embodiments, animals may be transgenic animals, genetically modified animals, and / or clones.

[0123] Approximately or about: As used herein, the terms “approximately” or “about” applied to one or more values ​​of interest refer to values ​​similar to the specified reference values. In certain embodiments, unless otherwise indicated or evident from the context (except where such number exceeds 100% of the possible values), the terms “approximately” or “about” refer to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than any of the specified reference values ​​(greater than or less than).

[0124] As used in this description and in the accompanying claims, the singular forms “a,” “an,” and “the” refer to multiple subjects unless otherwise clearly indicated by the context. For example, the term “composition” includes mixtures of two or more such compositions.

[0125] Throughout this specification and the claims, the word “comprise,” as well as other forms of the word such as “comprising” and “comprises,” means “comprises,” but is not intended to exclude, for example, other additives, components, integers, or processes.

[0126] "Optional" or "optional" means whether or not the event or situation described thereafter may occur, and the description includes both cases where the event or situation occurs and cases where it does not.

[0127] To improve, increase, or decrease: As used herein, “improve,” “increase,” or “decrease,” or grammatical synonyms, refer to a value compared to a baseline measurement, e.g., a measurement in the same individual before the initiation of the treatment described herein, or a measurement in a control subject (or control subjects) in the absence of the treatment described herein. A “control subject” is a subject suffering from the same disease form as the subject being treated and being approximately the same age as the subject being treated.

[0128] In vitro: As used herein, the term “in vitro” refers to events that occur in an artificial environment, such as in a test tube, reaction vessel, or cell culture medium, rather than in a multicellular organism.

[0129] In vivo: As used herein, the term “in vivo” refers to events occurring within multicellular organisms such as humans and non-human animals. In the context of cell-based systems, the term may be used to refer to events occurring within living cells (as opposed to, for example, in vitro systems).

[0130] Patient: As used herein, the terms “patient” or “subject” mean any living organism to which the provided composition may be administered, for example, for experimental, diagnostic, preventive, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. Humans include prenatal and postnatal forms.

[0131] Pharmacologically acceptable: As used herein, the term "pharmaceutically acceptable" means a substance that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, and that is commensurate with a reasonable benefit-to-risk ratio.

[0132] pharmaceutically acceptable salts: pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids, as well as inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or using organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. Examples include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N+(C1-4 alkyl) 4 salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.Further pharmaceutically acceptable salts include non-toxic ammonium cations, quaternary ammonium cations, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfons, and arylsulfons, where appropriate. Further pharmaceutically acceptable salts include salts formed from the quaternization of amines using a suitable electrophile, for example, an alkyl halide to form a quaternary alkylated amino salt.

[0133] Subject: As used herein, the term “Subject” means a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, pig, sheep, horse, or primate). Human includes prenatal and postnatal forms. In many embodiments, the subject is a human. The subject may be a patient and refers to a human being who visits a healthcare provider for the diagnosis or treatment of a disease. The term “Subject” is used herein interchangeably with “individual” or “patient.” The subject may be susceptible to or prone to a disease or disorder, and may or may not exhibit symptoms of the disease or disorder.

[0134] Substantially: As used herein, the term “substantially” refers to a qualitative state that exhibits all or nearly all range or degree of the desired characteristics or properties. Those skilled in the biological art will understand that biological and chemical phenomena rarely, if ever, complete and / or reach completion, or achieve or avoid absolute results. Therefore, the term “substantially” is used herein to capture the inherent lack of completion in many biological and chemical phenomena.

[0135] Therapeutic dose: As used herein, the term “therapeutic dose” of a therapeutic agent means an amount sufficient to treat, diagnose, prevent, and / or delay the onset of symptoms of a disease, disorder, and / or condition when administered to a subject suffering from or susceptible to such disease, disorder, and / or condition. Those skilled in the art will understand that a therapeutic dose is typically administered in a dosing regimen comprising at least one unit dose.

[0136] Treatment: As used herein, the terms “treatment,” “therapy,” or “to treat” mean any method used to partially or completely alleviate, improve, reduce, suppress, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. Treatment may be administered to subjects who are not showing signs of the disease and / or who are showing only early signs of the disease, for the purpose of reducing the risk of developing a condition associated with that disease.

[0137] Aliphatic: As used herein, the term aliphatic refers to C1-C 40 This term refers to hydrocarbons, including both saturated and unsaturated hydrocarbons. Aliphatic hydrocarbons can be linear, branched, or cyclic. For example, C1-C 20 Aliphatic species include C1-C 20 Alkyl (e.g., linear or branched C1-C) 20 Saturated alkyl), C2-C 20 Alkenyls (e.g., linear or branched C4-C) 20 Dienyl, linear or branched C6-C 20 Trienyl, etc., and C2-C 20 Alkynyl (e.g., linear or branched C2-C) 20 (Alkinyl) may be included. C1-C 20 In aliphatic organisms, C3-C 20 Cyclic aliphatic (e.g., C3-C) 20 Cycloalkyl, C4-C 20 Cycloalkenyl, or C8-C 20A cycloalkynyl may be included. In certain embodiments, the aliphatic group may comprise one or more cyclic aliphatic and / or one or more heteroatoms, e.g., oxygen, nitrogen, or sulfur, and may optionally be substituted with one or more substituents such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester, or amide. The aliphatic group is either unsubstituted or substituted with one or more substituents as described herein. For example, the aliphatic group may be substituted with one or more of halogens, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R' (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents), where each example of R' is independently C1-C 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 The element is alkyl, or C1-C3 alkyl. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the aliphatic element is unsubstituted. In some embodiments, the aliphatic element does not contain any heteroatoms.

[0138] Alkyl: As used herein, the term "alkyl" means acyclic linear and branched hydrocarbon groups, for example, "C1-C 20"Alkyl" refers to an alkyl group having 1 to 20 carbon atoms. Alkyl groups can be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentylhexyl, and isohexyl. The term "lower alkyl" means a linear or branched alkyl group having 1 to 6 carbon atoms. Other alkyl groups will be readily apparent to those skilled in the art in consideration of the interests of this disclosure. Alkyl groups may be unsubstituted or substituted with one or more substituents described herein. For example, the alkyl group may be substituted with one or more of the following (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents): halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', where each example of R' is independently C1-C 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 The alkyl group is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl group. In some embodiments, the alkyl group is substituted (for example, with one, two, three, four, five, or six substituents as described herein). In some embodiments, the alkyl group is substituted with an -OH group, which may also be referred to herein as a "hydroxyalkyl" group, where the prefix indicates an -OH group and "alkyl" is as described herein. In some embodiments, the alkyl group is substituted with an -OR' group, which may also be referred to herein as an "alkoxy" group.

[0139] The suffix "-ene" is added to a base to indicate that the base is a divalent part. For example, arylene is the divalent part of aryl, and heteroarylene is the divalent part of heteroaryl.

[0140] Alkylene: As used herein, the term “alkylene” refers to a saturated divalent linear or branched hydrocarbon group, exemplified by methylene, ethylene, isopropylene, and the like. Similarly, as used herein, the term “alkenylene” refers to an unsaturated divalent linear or branched hydrocarbon group having one or more unsaturated carbon-carbon double bonds that may occur at any stable point along the chain, and as used herein, the term “alkynylene” refers to an unsaturated divalent linear or branched hydrocarbon group having one or more unsaturated carbon-carbon triple bonds that may occur at any stable point along the chain. In certain embodiments, the alkylene group, alkenylene group, or alkynylene group may contain one or more cyclic aliphatic and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur, and may be optionally substituted with one or more substituents such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester, or amide. For example, alkylene, alkenylene, or alkynylene may be substituted with one or more of the following (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents): halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', where each example of R' is independently C1-C 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10It is an alkyl group (or a C1-C3 alkyl group). In some embodiments, R' is independently an unsubstituted C1-C3 alkyl group. In certain embodiments, the alkylene, alkenylene, or alkynylene is unsubstituted. In certain embodiments, the alkylene, alkenylene, or alkynylene does not contain any heteroatoms.

[0141] Alkenyl: As used herein, “alkenyl” means any linear or branched hydrocarbon chain having one or more unsaturated carbon-carbon double bonds that can occur at any stable point along the chain, for example, “C2-C 20 An "alkenyl" refers to an alkenyl group having 2 to 20 carbon atoms. For example, alkenyl groups include prop-2-enyl, buta-2-enyl, buta-3-enyl, 2-methylprop-2-enyl, hexa-2-enyl, hexa-5-enyl, and 2,3-dimethylbuta-2-enyl. In some embodiments, the alkenyl contains one, two, or three carbon-carbon double bonds. In some embodiments, the alkenyl contains a single carbon-carbon double bond. In some embodiments, multiple double bonds (e.g., two or three) are conjugated. The alkenyl group may be unsubstituted or may be substituted with one or more substituents described herein. For example, the alkenyl group may be substituted with one or more of the following (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents): halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', where each example of R' is independently C1-C 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10The group is alkyl, or C1-C3 alkyl. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the alkenyl is unsubstituted. In some embodiments, the alkenyl is substituted (for example, with one, two, three, four, five, or six substituents as described herein). In some embodiments, the alkenyl group is substituted with an -OH group, which may also be referred to herein as a "hydroxyalkenyl" group, where the prefix indicates an -OH group and "alkenyl" is as described herein.

[0142] Alkynyl: As used herein, “alkynyl” means any hydrocarbon chain having one or more carbon-carbon triple bonds occurring at any stable point along the chain, either in a linear or branched configuration, for example, “C2-C 20 "Alkynyl" refers to an alkynyl group having 2 to 20 carbon atoms. Examples of alkynyl groups include prop-2-inyl, buta-2-inyl, buta-3-inyl, penta-2-inyl, 3-methylpenta-4-inyl, hexa-2-inyl, hexa-5-inyl, and the like. In some embodiments, the alkynyl contains one carbon-carbon triple bond. The alkynyl group may be unsubstituted or substituted with one or more substituents as described herein. For example, the alkynyl group may be substituted with one or more of the following (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents): halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', where each example of R' is independently C1-C 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group, or a C1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C3 alkyl group). 20 Alkyl, C1-C 15 Alkyl, C1-C 10The alkyl (or C1-C3 alkyl) is used. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the alkynyl is unsubstituted. In some embodiments, the alkynyl is substituted (for example, with one, two, three, four, five, or six substituents as described herein).

[0143] Aryl: As with "aralkyl," the term "aryl," used alone or as part of a larger term, refers to a monocyclic, bicyclic, or tricyclic carbocyclic structure having a total of 6 to 14 ring members, wherein the aforementioned ring structure has a single bond with the rest of the molecule, at least one ring in the system is aromatic, and each ring in the system contains 4 to 7 ring members. In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl," e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl (such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl"; for example, anthracyl. "Aryl" also includes ring systems, in which the aryl ring is condensed with one or more carbocyclic or heterocyclyl groups as defined above, and in this case the bonding radical or bond site is on the aryl ring, and in such examples the number of carbon atoms then specifies the number of carbon atoms in the aryl ring system. Examples of aryls include phenyl, naphthyl, and anthracene.

[0144] Arylene: As used herein, the term "arylene" refers to a divalent aryl group (i.e., having two bonding sites with respect to the molecule). Examples of arylenes include phenylene (e.g., unsubstituted phenylene or substituted phenylene).

[0145] Halogen or halo: As used herein, the terms "halogen" or "halo" mean fluorine, chlorine, bromine, or iodine.

[0146] Amide: The term "amide" or "amido" is derived from the formula -C(O)N(R ’ )2, -C(O)N(R ’ )-, -NR ’ C(O)R ’ , -NR ’ C(O)N(R ’ )2-, or -NR ’ This refers to the chemical part containing C(O)-, and in the formula, each R ’ Unless otherwise specified herein, each of these is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded via chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded via ring carbon), each of which may be optionally substituted as described herein, or two R' atoms may be combined with a nitrogen atom to form a 3, 4, 5, 6, or 7-membered ring.

[0147] Amino: The term "amino" or "amine" refers to the -N(R')2 group, where each R is ’ R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (linked via chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (linked via ring carbon), heteroarylalkyl, heterocycloalkyl (linked via ring carbon), sulfonyl, amide, or carbonyl groups, each of which may be optionally substituted as described herein, or two R' may be combined with a nitrogen atom to form a 3, 4, 5, 6, or 7-membered ring. In embodiments, the amino group is -NHR', where R' is aryl ("arylamino"), heteroaryl ("heteroarylamino"), amide, or alkyl ("alkylamino").

[0148] Sulfonyl: The term "sulfonyl" refers to the -S(=O)2R' or -S(=O)2- group, where R is in the formula.’ Unless otherwise specified herein, the group is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded via chain carbon), amino, cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via ring carbon), heteroarylalkyl, and heterocycloalkyl (bonded via ring carbon), each of which may be optionally substituted as described herein. For example, in one embodiment, the sulfonyl group is -SO2R', where R' is an alkyl group substituted with a carbonyl group.

[0149] Sulfinyl: The term "sulfinyl" refers to a chemical part having the formula -S(=O)R', -S(=O)-, or -S(=O)(=NR')-, where R ’ Unless otherwise specified herein, these are selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded via chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via ring carbon), heteroarylalkyl, and heterocycloalkyl (bonded via ring carbon), each of which may be optionally substituted as described herein.

[0150] Carbonyl: The term "carbonyl" refers to a -C(=O)R' or -C(=O)- group, where R is in the formula. ’ Unless otherwise specified herein, these are selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (linked via chain carbon), cycloalkyl, aryl, arylalkyl, amino, hydroxyl, heteroaryl (linked via ring carbon), heteroarylalkyl, and heterocycloalkyl (linked via ring carbon), each of which may be optionally substituted as described herein.

[0151] Phosphoryl: The term "phosphoryl" refers to the -P(=O)(R')2 or -P(=O)(R')- group, where R ’Unless otherwise specified herein, these groups are selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded via chain carbons or heteroatoms), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded via ring carbons), heteroarylalkyl, or heterocycloalkyl (bonded via ring carbons) groups, each of which may be optionally substituted as described herein, or two R' groups may be combined with a nitrogen atom to form a 3, 4, 5, 6, or 7-membered ring.

[0152] Heteroalkyl: The term "heteroalkyl" refers to a branched or unbranched alkyl, alkenyl, or alkynyl group having 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P, in addition to 1 to 14 carbon atoms. Heteroalkyls include tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. Heteroalkyls may optionally include monocyclic, bicyclic, or tricyclic rings, each ring preferably having 3 to 6 members. Examples of heteroalkyls include polyethers such as methoxymethyl and ethoxyethyl.

[0153] Heteroalkylene: As used herein, the term "heteroalkylene" refers to the divalent form of the heteroalkyl group described herein.

[0154] Heteroaryl: The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system having a total of 6 to 14 ring members, wherein the aforementioned ring system has a single attachment site to the rest of the molecule, at least one ring in the system is aromatic, each ring in the system contains 4 to 7 ring members, and at least one ring atom is a heteroatom, such as but not limited to nitrogen and oxygen.

[0155] Heterocycloalkyl: As used herein, the term “heterocycloalkyl” means a non-aromatic ring in which at least one atom is a heteroatom, such as but not limited to nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. Heterocycloalkyl groups may be substituted or unsubstituted.

[0156] Deuterium: "Deuterium" ("D" or " 2 The term "H" is also called heavy hydrogen. Deuterium is an isotope of hydrogen that has a nucleus consisting of one proton and one neutron, which is twice the mass of the nucleus of ordinary hydrogen (one proton).

[0157] Isotopes: The term "isotope" refers to variants of a particular chemical element that differ in the number of neutrons and, consequently, the number of nucleons. All isotopes of a given element have the same number of protons but different numbers of neutrons in each atom.

[0158] The term "substituted" means that the specified group or part has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is either unsubstituted or substituted by one or more substituents. When the term "substituted" is used to describe a structural system, substitution means that it occurs at any valence-allowed position on the system, for example, resulting in a stable compound (e.g., a compound that does not spontaneously undergo transformation by recombination, cyclization, removal, or other reactions). Unless it is explicitly stated that the specified part or group is optionally substituted or substituted by any specified substituent, it is understood that such part or group is intended to be unsubstituted.

[0159] When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl) is substituted with a different number of substituents within an explicitly defined range, it is understood that the total number of substituents does not exceed the normal available valencies under existing conditions. It is also understood that hydrogen atoms are assumed to be present to satisfy the remaining valencies of the ring system. Substituents include only combinations of substituents and variables that result in a stable or chemically feasible compound. A stable or chemically feasible compound is, among other factors, a compound that is stable enough to allow its preparation and detection.

[0160] A wide range of substituents are known, and methods for their formation and introduction into various parent groups are also well known. Typical substituents include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, arylalkoxy, arylamino, heteroarylamino, heteroaryl, heteroarylalkoxy, heterocycloalkyl, hydroxyalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono, di, and trihaloalkyl, mono, di, and trihaloalkoxy, amino, alkylamino, dialkylamino, amide, cyano, alkoxy, hydroxy, sulfonamide, halo (e.g., -Cl and -Br), nitro, oxyimino, -COOR 50 , -COR 50 , -SO 0-2 R 50 -SO2NR 50 R 51 , NR 52 SO2R 50 , =C(R 50 R 51 ), = N-OR 50 ,=N-CN,=C(HALO)2,=S,=O,-CON(R 50 R 51 ), -OCOR 50 ,-OCON(R 50 R 51 ), -N(R 52 )CO(R 50), -N(R 52 )COOR 50 , and -N(R 52 )CON(R 50 (R 51 ) are some examples, but are not limited to these, and in the formula, R 50 , R 51 , and R 52 The following can be independently selected: hydrogen atoms, and branched or straight-chain carbon atoms. 1-6 -alkyl, C 3-6 -Cycloalkyl, C 4-6 - Heterocycloalkyl, heteroaryl, and aryl groups (with or without substituents). If permitted, R 50 and R 51 These elements can be bonded together to form a carbocyclic or heterocyclic ring system.

[0161] In preferred embodiments, substituents are selected from halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', and -SO2R', where each example of R' is independently C1-C 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is an alkyl group (or a C1-C3 alkyl group). In certain 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 It is an alkyl group (or a C1-C3 alkyl group). Preferably, R' is independently an unsubstituted C1-C3 alkyl group.

[0162] Any formula provided herein is intended to represent compounds having the structures shown by the structural formulas, as well as certain modifications or forms. In particular, compounds of any formula provided herein may have chiral centers and thus exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds of the general formula, as well as mixtures thereof, are considered to be within the scope of the formula. Accordingly, any formula provided herein is intended to represent racemates, one or more enantiomers, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Further, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Further, any formula provided herein is intended to encompass hydrates, solvates, and polymorphs of such compounds, as well as mixtures thereof. <(

[0163] The compounds of the present invention Compounds that are potent inhibitors of PHD are disclosed herein. In some embodiments, the compounds of the present invention have an enzymatic half-maximal inhibitory concentration (IC 50 ) value of less than 100 μM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC 50 , value of less than 50 μM against any one of PHD1, PHD2, and PHD). In some embodiments, the compounds of the present invention have an IC 50 value of less than 25 μM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC 50 value of less than 20 μM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC 50 value of less than 15 μM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC 50have a value. In some embodiments, the compounds of the invention have an IC of less than 5 μM against any one of PHD1, PHD2, and PHD3 50 have a value. In some embodiments, the compounds of the invention have an IC of less than 1 μM against any one of PHD1, PHD2, and PHD3 50 have a value. In some embodiments, the compounds of the invention have an IC of from about 3 nM to about 5 nM against any one of PHD1, PHD2, and PHD3 50 have a value. In some embodiments, the compounds of the invention have an IC of from about 5 nM to about 10 nM against any one of PHD1, PHD2, and PHD3 50 have a value. In some embodiments, the compounds of the invention have an IC of from about 10 nM to about 20 nM against any one of PHD1, PHD2, and PHD3 50 have a value. In some embodiments, the compounds of the invention have an IC of from about 20 nM to about 50 nM against any one of PHD1, PHD2, and PHD3 50 have a value. In some embodiments, the compounds of the invention have an IC of from about 50 nM to about 100 nM against any one of PHD1, PHD2, and PHD3 50 have a value. In some embodiments, the compounds of the invention have an IC of from about 100 nM to about 200 nM against any one of PHD1, PHD2, and PHD3 50 have a value. In some embodiments, the compounds of the invention have an IC of from about 200 nM to about 500 nM against any one of PHD1, PHD2, and PHD3 50 have a value. In some embodiments, the compounds of the invention have an IC of from about 500 nM to about 1000 nM against any one of PHD1, PHD2, and PHD3 50 have a value.

[0164] Representative examples from this class show inhibitory activity against PHD1, PHD2, and PHD3 in vitro.

[0165] Exemplary compounds are described herein. In particular, these selective inhibitors can be characterized by a pyrazole moiety (e.g., a 5-hydroxysubstituted pyrazole) linking two aromatic moieties.

[0166] Compounds of formulas (A) and (I) to (XIII) In one embodiment, a compound having a structure according to formula (A): [ka] or a pharmaceutically acceptable salt thereof, in the formula, Ar 1 C is optionally substituted with a halogen, CN, OH, CN, or one or more halogens. 1-3 Alkyl and C 1-3 An aryl or heteroaryl compound optionally substituted with one or more groups selected from alkoxys, Ar 2 is a halogen; amino; amide; OH; sulfonyl group; sulfinyl group; carbonyl group; phosphoryl group; C 3-6 Cycloalkyl; sulfonyl group or optionally substituted with =O C 3-6 Heterocycloalkyl; carbonyl or optionally substituted with one or more halogens C 1-3 Alkyl and C 1-3 A compound or a pharmaceutically acceptable salt thereof that is pyrido-2-yl optionally substituted with one or more groups selected from heteroaryls optionally substituted with alkyl or phenyl.

[0167] In this embodiment, Ar 1 is an unsubstituted aryl. In this embodiment, Ar 1 is a substitution aryl. In this embodiment, Ar 1 It is a substituted phenyl compound.

[0168] In another embodiment, Ar 1 In another embodiment, Ar 1 This is a substituted six-membered heteroaryl compound.

[0169] In this embodiment, Ar 1 C is optionally substituted with a halogen, CN, OH, CN, or one or more halogens. 1-3 Alkyl and C 1-3 It is substituted with one or more groups selected from alkoxy groups. In some embodiments, Ar 1 It is substituted with one substituent. In some embodiments, Ar 1 It is substituted with two substituents. In some embodiments, Ar 1 It is substituted with three substituents. In some embodiments, Ar 1 It is substituted with four substituents.

[0170] In this embodiment, Ar 1 is one or more R 1 It includes a group, and in the formula, each R 1 Independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from alkoxys. In this embodiment, Ar 1 R is represented by m 1 The amount of the base is included, and m is 1, 2, 3, or 4. 1 If R exists, 1 This can replace hydrogen atoms in the parent molecular structure. In the embodiment, R 1 If R exists and is a non-hydrogen portion, 1 represents a substituent. In this embodiment, R 1 C is a halogen, CN, OH, or C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 It is selected independently of alkoxy.

[0171] Therefore, for any value of m described herein, hydrogen is Ar such that the molecule is a stable compound (for example, a compound that does not spontaneously undergo transformation by reconstitution, cyclization, removal, or other reactions). 1 It is also understood that Ar may be present as needed to satisfy the valence requirements among the constituent atoms. 1 , R 1Exemplary embodiments of , and m are described herein.

[0172] In this embodiment, Ar 1 teeth, [ka] And in the formula, X is N or CR 1a And, Y and Z are independently CH or N. m is 1, 2, 3, or 4.

[0173] In this embodiment, R 1 It is not hydrogen. In the embodiment, R 1 If R exists and is a non-hydrogen portion, 1 represents a substituent.

[0174] In the embodiments, the value of m is based on the number of nitrogen atoms present in the ring. In the embodiments, if one and only one of Y and Z are N, then m is 1, 2, or 3. In the embodiments, if each of Y and Z is N, then m is 1 or 2.

[0175] In the embodiment, X is N. In the embodiment, X is CR. 1a That is the case.

[0176] In this embodiment, Y is CH. In this embodiment, Z is N.

[0177] In this embodiment, m is 1. In this embodiment, m is 2. In this embodiment, m is 3. In this embodiment, m is 4.

[0178] In the embodiment, both Y and Z are N, and m is 1 or 2. In the embodiment, m is 1, and any remaining unsubstituted carbo-ring atoms are assumed to be bonded to hydrogen to satisfy their valence. In the embodiment, m is 2.

[0179] In the embodiment, both Y and Z are CH, and m is 1, 2, 3, or 4. In the embodiment, m is 1, and any remaining unsubstituted carbolo ring atoms are assumed to be bonded to hydrogen to satisfy their valence. In the embodiment, m is 2, and any remaining unsubstituted carbolo ring atoms are assumed to be bonded to hydrogen to satisfy their valence. In the embodiment, m is 3, and any remaining unsubstituted carbolo ring atoms are assumed to be bonded to hydrogen to satisfy their valence. In the embodiment, m is 4.

[0180] In the embodiment, one of Y and Z is CH and the other is N, and m is 1, 2, or 3. In the embodiment, m is 1 and any remaining unsubstituted carbolo ring atoms are assumed to be bonded to hydrogen to satisfy the valence. In the embodiment, m is 2 and any remaining unsubstituted carbolo ring atoms are assumed to be bonded to hydrogen to satisfy the valence. In the embodiment, m is 3.

[0181] In this embodiment, Ar 1 teeth, [ka] And in the formula, X is N or CR 1a And, Z is either CH or N, m is 1, 2, 3, or 4.

[0182] In the embodiment, Z is N and m is 1, 2, or 3. In the embodiment, m is 1 and any remaining unsubstituted carboelectric ring atoms are assumed to be bonded to hydrogen to satisfy their valence. In the embodiment, m is 2 and any remaining unsubstituted carboelectric ring atoms are assumed to be bonded to hydrogen to satisfy their valence. In the embodiment, m is 3.

[0183] In the embodiment, Z is CH and m is 1, 2, 3, or 4. In the embodiment, m is 1 and any remaining unsubstituted carboelectric atoms are assumed to be bonded to hydrogen to satisfy their valence. In the embodiment, m is 2 and any remaining unsubstituted carboelectric atoms are assumed to be bonded to hydrogen to satisfy their valence. In the embodiment, m is 3 and any remaining unsubstituted carboelectric atoms are assumed to be bonded to hydrogen to satisfy their valence. In the embodiment, m is 4.

[0184] In the embodiment, X is N. In the embodiment, X is CR. 1a That is the case.

[0185] In this embodiment, Ar 1 teeth, [ka] And in the formula, m is 1, 2, 3, or 4.

[0186] In this embodiment, m is 1, and any remaining unsubstituted carboelectric atoms are assumed to be bonded to hydrogen to satisfy their valence. In this embodiment, m is 2, and any remaining unsubstituted carboelectric atoms are assumed to be bonded to hydrogen to satisfy their valence. In this embodiment, m is 3, and any remaining unsubstituted carboelectric atoms are assumed to be bonded to hydrogen to satisfy their valence. In this embodiment, m is 4.

[0187] In this embodiment, R 1a H is H.

[0188] In this embodiment, R 1a This is CN.

[0189] In this embodiment, R 1a It is OH.

[0190] In this embodiment, R 1a is a halogen. In this embodiment, R 1ais F. In an embodiment, R 1a is Cl. In an embodiment, R 1a is Br. In an embodiment, R 1a is I.

[0191] In an embodiment, R 1a is C 1-3 alkoxy. In an embodiment, R 1a is methoxy. In an embodiment, R 1a is ethoxy. In an embodiment, R 1a is propoxy.

[0192] In an embodiment, R 1a is C 1-3 alkyl.

[0193] In an embodiment, R 1a is unsubstituted C 1-3 alkyl. In an embodiment, R 1a is CH3.

[0194] In an embodiment, R 1a is substituted C 1-3 alkyl. In an embodiment, R 1a is C 1-3 alkyl substituted with a CN group. In an embodiment, R 1a is CH2CN.

[0195] In an embodiment, R 1 is hydrogen each time.

[0196] In an embodiment, R 1 is CN each time.

[0197] In an embodiment, R 1 is OH each time.

[0198] In an embodiment, R 1 is halogen each time. In an embodiment, the halogen is Cl. In an embodiment, the halogen is Br. In an embodiment, the halogen is I.

[0199] In this embodiment, R 1 Every time, C 1-3 It is alkyl.

[0200] In this embodiment, R 1 Each time, non-substituted C 1-3 It is alkyl. In this embodiment, R 1 It is always CH3.

[0201] In this embodiment, R 1 Each time, substitution C 1-3 It is alkyl. In this embodiment, R 1 Each time, C is replaced with one or more halogens. 1-3 It is alkyl. In the embodiment, the halogen is F. In the embodiment, the halogen is Cl. In the embodiment, the halogen is Br. In the embodiment, the halogen is I.

[0202] In this embodiment, R 1 It is CF3 every time.

[0203] In this embodiment, R 1 Every time, C 1-3 It is an alkoxy. In this embodiment, R 1 It is OMe every time.

[0204] In this embodiment, Ar 2 This includes halogens; aminos; amides; OH; sulfonyl groups (e.g., SO2R) 6 ); sulfinyl group (for example, SOR 7 R 8 or SOR 9 ); carbonyl group (for example, COR 10 ); phosphoryl group (e.g., POR 12 R 13 );C 3-6 Cycloalkyl; sulfonyl group or optionally substituted with =O C 3-6 Heterocycloalkyl; carbonyl or optionally substituted with one or more halogens C 1-3 Alkyl and C 1-3It is a pyrido-2-yl optionally substituted with one or more groups selected from heteroaryls optionally substituted with alkyl or phenyl. In embodiments, Ar 2 is unsubstituted pyrido-2-yl. In the embodiment, Ar 2 is a substituted pyrido-2-yl. In one embodiment, Ar 2 is pyrido-2-yl substituted with one or two substituents as described herein. In embodiments, Ar 2 This is pyrido-2-yl substituted with the three substituents described herein.

[0205] In this embodiment, Ar 2 teeth, [ka] And in the formula, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 3 SO2R 6 SOR 7 R 8 SOR 9 COR 10 , (CH2) p COOH, NHR 11 , POR 12 R 13 , halogen, cycloalkyl, SO2R 14 Alternatively, a heterocycloalkyl group arbitrarily substituted with =O, C 1-3 A heteroaryl group optionally substituted with alkyl or phenyl, or a C group optionally substituted with one or more halogens. 1-3 It is alkyl, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R 17 , or phenyl, R 7 C1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And, R 8 It is NH or NCH3, R 10 C 1-3 Alkyl or NHSO2R 20 And, R 11 COR 21 Or SO2R 22 And, R 9 , R 12 , R 13 , R 14 , R 15 , and R 20 Each is independent of C 1-3 It is alkyl, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is alkyl, R 4 , R 5 , R 16 , R 17 , R 18 , R 19 , R 23 , and R 24 Each is independently H or C 1-3 It is alkyl, p is 1, 2, or 3. n is 0, 1, 2, or 3.

[0206] In the embodiment, n is 0. In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0207] In this embodiment, n is 0, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to satisfy their valence.

[0208] In this embodiment, n is 1, and any remaining unsubstituted carboelectric ring atoms are assumed to be bonded to hydrogen to satisfy their valence. In this embodiment, n is 2, and any remaining unsubstituted carboelectric ring atoms are assumed to be bonded to hydrogen to satisfy their valence. In this embodiment, n is 3.

[0209] In this embodiment, R 2 It is hydrogen each time.

[0210] In this embodiment, R 2 It is OH every time.

[0211] In this embodiment, R 2 Each time, the halogen is a halogen. In the embodiment, the halogen is Cl. In the embodiment, the halogen is Br. In the embodiment, the halogen is I.

[0212] In this embodiment, R 2 Every time, NR 4 R 5 And in the formula, R 4 and R 5 Each is independently H or C 1-3 It is alkyl.

[0213] In this embodiment, R 4 and R 5 Both are H.

[0214] In this embodiment, R 4 and R 5 One of them is H, and the other is C 1-3 It is alkyl. In this embodiment, C 1-3 Alkyl groups are CH3.

[0215] In this embodiment, R 2 Every time, C 1-3 It is alkyl.

[0216] In this embodiment, R 2 Every time, C 3-6 It is a cycloalkyl group.

[0217] In this embodiment, R 3 SO2R 6 And in the formula, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R 17 , or phenyl.

[0218] In this embodiment, R 3 SOR 7 R 8 And in the formula, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And in the formula, R 8 It is either NH or NCH3.

[0219] In this embodiment, R 3 SOR 9 And in the formula, R 9 C 1-3 It is alkyl.

[0220] In this embodiment, R 3 COR 10 And in the formula, R 10 C 1-3 Alkyl or NHSO2R 20 And in the formula, R 20 C 1-3 It is alkyl.

[0221] In this embodiment, R 3 (CH2) p It is COOH.

[0222] In the embodiment, p is 1, 2, or 3. In the embodiment, p is 1. In the embodiment, p is 2. In the embodiment, p is 3. In this embodiment, R 3 NHR 11 And in the formula, R 11 COR 21Or SO2R 22 And in the formula, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is an alkyl, and in the formula, R 23 and R 24 Each is independently H or C 1-3 It is alkyl.

[0223] In this embodiment, R 3 POR 12 R 13 And in the formula, R 12 and R 13 C 1-3 It is alkyl.

[0224] In this embodiment, R 3 It is a halogen.

[0225] In this embodiment, R 3 is a cycloalkyl or heterocycloalkyl group. In the embodiment, the cycloalkyl or heterocycloalkyl group is unsubstituted. In the embodiment, the cycloalkyl or heterocycloalkyl group is substituted.

[0226] In this embodiment, R 3 is a heteroaryl compound. In the embodiment, the heteroaryl compound is unsubstituted. In the embodiment, the heteroaryl compound is substituted.

[0227] In this embodiment, R 3 C 1-3 It is alkyl. In this embodiment, C 1-3 The alkyl group is unsubstituted. In this embodiment, C 1-3 The alkyl group is substituted with one or more halogens.

[0228] In this embodiment, the compound of formula (A) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R 1 , R 2 , and R 3 This is defined as any other part thereof.

[0229] In the embodiment, the compound of formula (A) or formula (I) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, wherein X, Z, R 1 , R 2 , and R 3 This is defined as any other part thereof.

[0230] In the embodiment, the compound of formula (A), formula (I), or formula (II) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , R 2 , and R 3 This is defined as any other part thereof.

[0231] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is defined as any other part thereof.

[0232] In the embodiment, the compound of formula (A), formula (I), formula (II), formula (III), or formula (IV) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula A, R 1a and R 2 This is defined as any other part thereof.

[0233] In this embodiment, R 7 C 1-3 It is alkyl.

[0234] In this embodiment, R 7 C 3-5 It is a cycloalkyl group.

[0235] In this embodiment, R 7 It is phenyl.

[0236] In this embodiment, R 7 , NR 18 R 19 And in the formula, R 18 and R 19 Each is independently H or C 1-3 It is alkyl.

[0237] In this embodiment, R 18 and R 19 Both are H.

[0238] In this embodiment, R 18 and R 19 Both are C 1-3 It is alkyl. In this embodiment, R 18 and R 19 Both are CH3.

[0239] In this embodiment, R 18 H is R 19 C 1-3 It is alkyl. In this embodiment, R 19 This is CH3.

[0240] In this embodiment, R 8 It is NH.

[0241] In this embodiment, R 8 This is NCH3.

[0242] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, wherein X, Z, R 1 , and R 2 This is defined as any other part thereof.

[0243] In this embodiment, R 6 is a C1-3 alkyl group. In this embodiment, R 6 This is CH3.

[0244] In this embodiment, R 6 NHCOR 15 And in the formula, R 15 is a C1-3 alkyl group. In this embodiment, R 6 It is NHCOCH3.

[0245] In this embodiment, R 6 , NR 16 R 17 And in the formula, R 16 and R 17 Each is independently H or C 1-3 It is alkyl.

[0246] In this embodiment, R 16 and R 17 Both are H.

[0247] In this embodiment, R 16 and R 17 Both are C 1-3 It is alkyl. In this embodiment, R 16 and R 17 Both are CH3.

[0248] In this embodiment, R 16 H is R 17 C 1-3 It is alkyl. In this embodiment, R17 This is CH3.

[0249] In this embodiment, R 6 It is phenyl.

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

[0251] In the embodiment, the compound of formula (A), formula (I), formula (II), formula (III), or formula (VI) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 2 This is defined as any other part thereof.

[0252] In this embodiment, R 3 It is a cycloalkyl compound.

[0253] In this embodiment, R 3 is an unsubstituted cycloalkyl. In the embodiment, R 3 teeth, [ka] That is the case.

[0254] In this embodiment, R 3 is a substituted cycloalkyl. In this embodiment, R 3 SO2R 14 Alternatively, it is a cycloalkyl group substituted with =O, where R 14 C 1-3 It is alkyl.

[0255] In this embodiment, R 3 It is a heterocycloalkyl group.

[0256] In this embodiment, R 3 is an unsubstituted heterocycloalkyl. In the embodiment, R 3 teeth, [ka] That is the case.

[0257] In this embodiment, R 3 is a substituted heterocycloalkyl. In this embodiment, R 3 SO2R 14 Alternatively, it is a heterocycloalkyl substituted with =O, where R 14 C 1-3 It is alkyl. In this embodiment, R 3 teeth, [ka] That is the case.

[0258] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is defined as any other part thereof.

[0259] In the embodiment, the compound of formula (A), formula (I), formula (II), formula (III), or formula (VII) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 2 This is defined as any other part thereof.

[0260] In this embodiment, R 11 COR 21 And in the formula, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl.

[0261] In this embodiment, R 21 is a cycloalkyl. In this embodiment, R 21 teeth, [ka] That is the case.

[0262] In this embodiment, R 21 is a heterocycloalkyl. In this embodiment, R 21 teeth, [ka] That is the case.

[0263] In this embodiment, R 21 C 1-3 It is alkyl. In this embodiment, R 21 It is CH2CH3.

[0264] In this embodiment, R 11 SO2R 22 And in the formula, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is an alkyl, and in the formula, R 23 and R 24 Each is independently H or C 1-3 It is alkyl.

[0265] In this embodiment, R 22 C 1-3 It is alkyl. In this embodiment, R 22 is unsubstituted C 1-3 It is alkyl. In this embodiment, R 22 is a C substituted with a carboxyl group. 1-3 It is alkyl. In this embodiment, R22 It is CH2COOH.

[0266] In this embodiment, R 22 , NR 23 R 24 And in the formula, R 23 and R 24 H or C 1-3 It is alkyl.

[0267] In this embodiment, R 23 and R 24 Both are H.

[0268] In this embodiment, R 23 and R 24 Both are C 1-3 It is alkyl. In this embodiment, R 23 and R 24 Both are CH3.

[0269] In this embodiment, R 23 H is R 24 C 1-3 It is alkyl. In this embodiment, R 24 This is CH3.

[0270] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is defined as any other part thereof.

[0271] In the embodiment, the compound of formula (A), formula (I), formula (II), formula (III), or formula (VIII) has the following structure [ka] or a pharmaceutically acceptable salt thereof.

[0272] In this embodiment, R 3 This is a heteroaryl. In the embodiment, the heteroaryl is a thiazole, oxazole, pyridine, triazole, tetrazole, or pyrazole.

[0273] In this embodiment, R 3 is an unsubstituted heteroaryl. In this embodiment, R 3 teeth, [ka] That is the case.

[0274] In this embodiment, R 3 C 1-3 It is a heteroaryl substituted with alkyl or phenyl. In the embodiment, R 3 teeth, [ka] That is the case.

[0275] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is defined as any other part thereof.

[0276] In the embodiment, the compound of formula (A), formula (I), formula (II), formula (III), or formula (IX) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a This is defined as any other part thereof.

[0277] In this embodiment, R 10 C1-3 It is alkyl.

[0278] In this embodiment, R 10 NHSO2R 20 And in the formula, R 20 C 1-3 It is alkyl. In this embodiment, R 10 This is NHSO2CH3.

[0279] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is defined as any other part thereof.

[0280] In this embodiment, R 9 C 1-3 It is alkyl.

[0281] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is defined as any other part thereof.

[0282] In this embodiment, p is 1. In this embodiment, p is 2. In this embodiment, p is 3.

[0283] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R1a , R 1 , and R 2 This is defined as any other part thereof.

[0284] In this embodiment, R 3 is a halogen. In this embodiment, R 3 F is F. In this embodiment, R 3 is Cl. In this embodiment, R 3 is Br. In this embodiment, R 3 It is I.

[0285] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is defined as any other part thereof.

[0286] In this embodiment, R 12 and R 13 Both are C 1-3 It is alkyl. In this embodiment, R 12 and R 13 Both are CH3.

[0287] Exemplary Compounds In some embodiments, the PHD inhibitor compound is one of compounds 1 to 33, or a pharmaceutically acceptable salt thereof. [Table 2] TIFF0007856575000078.tif232170TIFF0007856575000079.tif216170

[0288] Isotope substitution In the compounds described herein (for example, any one of compounds (A) and any one of (I) to (XIII), such as any one of compounds 1 to 33), it should be understood that atoms may exhibit their natural isotopic abundance, or that one or more atoms may have the same atomic number but specific isotopes having different atomic masses or mass numbers than those primarily found in nature, which can be artificially enriched. The present invention is intended to include all suitable isotopic variations of the compounds described herein (for example, any one of compounds (A) and any one of (I) to (XIII), such as any one of compounds 1 to 33). For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H), and tritium ( 3 It contains H). Protium is the major hydrogen isotope found in nature.

[0289] In some embodiments, one or more hydrogen atoms in the compounds described herein (e.g., any one of compounds of formula (A) and any one of compounds (I) to (XIII), such as any one of compounds 1 to 33) are replaced with deuterium. Deuterium enrichment may result in specific therapeutic benefits, such as an extension of the in vivo half-life or a reduction in dosage requirements, or may provide compounds useful as standards for characterizing biological samples. In some embodiments, one or more hydrogen atoms in the compounds described herein (e.g., any one of compounds of formula (A) and any one of compounds (I) to (XIII), such as any one of compounds 1 to 33) are replaced with tritium. Because tritium is radioactive, it may provide radiolabeled compounds useful as tracers in metabolic or kinetic studies.

[0290] The isotopic enrichment of the compounds disclosed herein (for example, any one of compounds of formula (A) and any one of compounds of formula (I) to (XIII), such as any one of compounds 1 to 33) can be achieved without excessive experimentation by conventional techniques well known to those skilled in the art, or by processes similar to those described herein in schemes and examples using appropriate isotopically enriched reagents and / or intermediates.

[0291] The term "isotope substitution" refers to a species having the same chemical structure and formula as a particular compound provided herein, except for the position of isotopic substitution and / or the level of isotopic enrichment at one or more positions, e.g., hydrogen versus deuterium. Therefore, as used herein, the term "compound" encompasses a collection of molecules that have the same chemical structure but also exhibit isotopic variation between the constituent atoms of the molecule. Thus, it will be apparent to those skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom will also contain, in its structure, a smaller amount of isotopic substitution having a hydrogen atom at one or more of the specified deuterium positions. The relative amount of such isotopic substitutions in the provided compounds depends on many factors, including, but not limited to, the isotopic purity of the deuterating reagent used to prepare the compound and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound.

[0292] When a position is designated as "H" or "hydrogen," that position is understood to contain hydrogen in its isotopic composition at its natural abundance. When a position is designated as "D" or "deuterium," that position is understood to contain deuterium at an abundance at least 3340 times its natural abundance, which is 0.015% (i.e., the terms "D" or "deuterium" indicate an inclusion of at least 50.1% deuterium).

[0293] In embodiments, the compounds provided herein may have isotopic enrichment factors for each deuter present at sites designated as potential sites for deuteration on the compound, such as at least 3500 (52.5% deuterium incorporated), at least 4000 (60% deuterium incorporated), at least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated), at least 6466.7 (97% deuterium incorporated), at least 6600 (99% deuterium incorporated), or at least 6633.3 (99.5% deuterium incorporated).

[0294] Synthesis of the Compound of the Present Invention The compounds described herein (for example, any one of compounds of formula (A) and any one of compounds of formula (I) to (XIII), such as any one of compounds 1 to 33) can be prepared according to methods known in the art, including the exemplary synthesis of the examples provided herein. Abbreviations and acronyms used herein include the following: [Table 3]

[0295] Compositions and methods The present invention provides the use of any one compound of formulas (A) and (I) to (XIII), or a pharmaceutically acceptable salt thereof, for the manufacture of a drug for use in the treatment of various conditions or disorders described herein. A pharmaceutical composition is provided comprising at least one compound of formulas (A) and (I) to (XIII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In various embodiments, the drug or pharmaceutical composition may further comprise or be used in combination with at least one additional therapeutic agent.

[0296] The compound of the present invention, or a drug or composition containing the compound, can be used to inhibit the activity of PHD. Inhibition of PHD may be particularly useful in the treatment of diseases including those of the heart (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), the lungs (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), the liver (e.g., acute liver failure, hepatic fibrosis, and cirrhosis), and the kidneys (e.g., acute kidney injury and chronic kidney disease).

[0297] In one embodiment, the method of the present invention involves administering to a patient in need a pharmaceutical composition containing a therapeutically effective amount of any one compound from formulas (A) and (I) to (XIII), or a pharmaceutically acceptable salt thereof, or one or more compounds from formulas (A) and (I) to (XIII).

[0298] The present invention also relates to a method for inhibiting the activity of PHD. In one embodiment, the method comprises contacting PHD with an effective amount of one or more compounds selected from the group comprising any one of the compounds of formula (A) and (I) to (XIII), or a pharmaceutically acceptable salt thereof.

[0299] In further embodiments, the compounds disclosed herein (e.g., any one of compounds of formula (A) and any one of (I) to (XIII), such as any one of compounds 1 to 33), or pharmaceutically acceptable salts thereof, are used to treat anemia associated with chronic kidney disease, polycystic kidney disease, aplastic anemia, autoimmune hemolytic anemia, bone marrow transplant anemia, Churg-Strauss syndrome, Diamond-Blackfan anemia, Fanconi anemia, Felty syndrome, graft-versus-host disease, hematopoietic stem cell transplantation, hemolytic uremic syndrome, myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, myelofibrosis, pancytopenia, pure red cell aplasia, Schönlein-Henoch purpura, and bud PHD1 inhibitors are useful in treating or preventing anemia, particularly refractory anemia with cytosis, rheumatoid arthritis, Schwakman syndrome, sickle cell disease, severe Mediterranean anemia, mild Mediterranean anemia, thrombocytopenic purpura, anemic or non-anemic patients undergoing surgery, anemia associated with or secondary to trauma, sideroblastic anemia, and anemia secondary to other treatments, including: reverse transcriptase inhibitors for treating HIV, corticosteroid hormones, cyclic cisplatin or non-cisplatin-containing chemotherapeutic agents, vinca alkaloids, mitotic inhibitors, topoisomerase II inhibitors, anthracyclines, alkylating agents, and especially anemia secondary to inflammatory, age-related, and / or chronic diseases. PHD1 inhibitors may also be used to treat symptoms of anemia, including chronic fatigue, pallor, and dizziness.

[0300] In other embodiments, the compounds disclosed herein (for example, any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful for the treatment or prevention of metabolic disorders, including but not limited to diabetes and obesity.

[0301] In further embodiments, the compounds disclosed herein (e.g., any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful for the treatment or prevention of vascular disorders. These include, but are not limited to, hypoxic or wound-healing-related diseases requiring angiogenic mediators for vasoconstriction, angiogenesis, and arteriogenesis.

[0302] In further embodiments, the compounds disclosed herein (e.g., any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful for the treatment or prevention of ischemia-reperfusion injury. These include, but are not limited to, stroke, myocardial infarction, and acute kidney injury.

[0303] In other embodiments, the compounds disclosed herein (e.g., any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of inflammatory bowel diseases. These include, but are not limited to, ulcerative colitis and Crohn's disease.

[0304] In other embodiments, the compounds disclosed herein (for example, any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of cancers such as colorectal cancer.

[0305] In other embodiments, the compounds disclosed herein (for example, any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of atherosclerosis.

[0306] In other embodiments, the compounds disclosed herein (for example, any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of cardiovascular disease.

[0307] In other embodiments, the compounds disclosed herein (e.g., any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of eye diseases or conditions. These include, but are not limited to, radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia.

[0308] In other embodiments, the compounds disclosed herein (for example, any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of diseases associated with hyperoxia.

[0309] In other embodiments, the compounds disclosed herein (for example, any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of bronchopulmonary dysplasia (BPD).

[0310] In further embodiments, the compounds disclosed herein (e.g., any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of heart disease. Conditions include, but are not limited to, postoperative myocardial ischemia in pancreatic surgery, myocardial injury after percutaneous coronary intervention (PCI), myocardial injury after non-cardiac surgery, perioperative myocardial ischemia in selective surgery for abdominal aortic aneurysms, myocardial injury after PCI, myocardial injury in patients undergoing coronary artery bypass grafting (CABG), minimally invasive mitral valve (MIMV) repair or replacement, adult patients undergoing open-heart surgery, chronic heart failure, and NYHA classes II to IV.

[0311] In other embodiments, the compounds disclosed herein (e.g., any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of lung diseases. These conditions include, but are not limited to, lung injury during selective lobectomy, lung injury during CABG, and lung transplantation.

[0312] In other embodiments, the compounds disclosed herein (e.g., any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of liver disease. Conditions include, but are not limited to, non-alcoholic steatohepatitis (NASH).

[0313] In other embodiments, the compounds disclosed herein (e.g., any one of compounds 1 to 33, or compounds of formulas (A) and (I) to (XIII)), or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of kidney disease. 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, chronic kidney disease patients who have started dialysis, and non-dialysis-dependent chronic kidney disease.

[0314] In addition, compounds disclosed herein (e.g., any one of compounds of formula (A) and any one of (I) to (XIII), such as any one of compounds 1 to 33), or pharmaceutically acceptable salts thereof, may be used in combination with additional active ingredients in the treatment of the above-mentioned conditions. The additional compounds may be administered separately and concurrently with the compounds disclosed herein (e.g., any one of compounds of formula (A) and any one of (I) to (XIII), such as any one of compounds 1 to 33), or pharmaceutically acceptable salts thereof, or may be included in a pharmaceutical composition according to the present invention together with the additional active ingredient. In exemplary embodiments, the additional active ingredient is an active ingredient known or discovered to be effective in the treatment of a PHD enzyme-mediated condition, disorder, or disease, or is active against another target associated with a particular condition, disorder, or disease, such as an alternative PHD modulator. The combination may help to enhance efficacy (e.g., by including in the combination a compound that enhances the potency or effectiveness of the compound according to the present invention), reduce one or more side effects, or reduce the required dose of the compound according to the present invention.

[0315] The compounds of the present invention are used alone or in combination with one or more other active ingredients to formulate the pharmaceutical compositions of the present invention. The pharmaceutical compositions of the present invention comprise (a) an effective amount of the compounds disclosed herein (for example, one of any of the compounds of formula (A) and any of the compounds of formula (I) to (XIII), such as any one of compounds 1 to 33), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite; and (b) a pharmaceutically acceptable excipient.

[0316] "Pharmacologically acceptable excipients" refer to inert substances, such as those added to a pharmacological composition or used as a compatible vehicle, carrier, or diluent to facilitate the administration of a drug, that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a target. Examples of excipients include calcium carbonate, calcium phosphate, various types of sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Suitable excipients may also include antioxidants. Such antioxidants can be used in pharmaceutical compositions or storage media to extend the shelf life of pharmaceuticals.

[0317] Pharmaceutical preparations and routes of administration The compounds and compositions of the present invention can be delivered directly or in combination with suitable carriers or excipients in pharmaceutical compositions or drugs, as is well known in the art. A therapeutic method of the present invention may include administering an effective amount of the compound of the present invention to a subject in need. In preferred embodiments, the subject is a mammalian subject, and in most preferred embodiments, the subject is a human subject.

[0318] The effective dose of such compounds, compositions, or drugs can be readily determined by routine experiments, as can the most effective and convenient route of administration and the most appropriate formulation. Various formulations and drug delivery systems are available in the art. See, for example, Gennaro, AR, ed. (1995) Remington's Pharmaceutical Sciences (see above).

[0319] Preferred routes of administration may include, for example, oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration. Primary routes of parenteral administration include intravenous, intramuscular, and subcutaneous administration. Secondary routes of administration include intraperitoneal, intra-arterial, intra-articular, intracardiac, intrasacral, intradermal, intrafocal, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration. The indications to be treated, along with the physical, chemical, and biological properties of the drug, determine the type of formulation used, the route of administration, and whether topical or systemic delivery is preferred.

[0320] The pharmaceutical dosage forms of the compounds of the present invention may be provided as 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 tablets, soft or hard-shell capsules, suppositories, vaginal suppositories, implants, amorphous or crystalline powders, aerosols, and lyophilized formulations. Depending on the route of administration used, special devices may be required for the application or administration of the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. Pharmaceutical dosage forms often consist of the drug, excipients, and a container / closure system. One or more excipients, also referred to as inactive components, can be added to the compounds of the present invention to improve or enhance the manufacture, stability, administration, and safety of the drug and provide a means to achieve a desired drug release profile. Therefore, the type of excipient added to the drug may depend on various factors, such as the physical and chemical properties of the drug, the route of administration, and the manufacturing procedure. Pharmaceutically acceptable excipients include those available in the art and listed in various pharmacopoeias, such as the United States Pharmacopeia (USP), the Japanese Pharmacopoeia (JP), the European Pharmacopoeia (EP), and the United Kingdom Pharmacopoeia (BP); the US Food and Drug.

[0321] See publications from the Administration (www.fda.gov) Center for Drug Evaluation and Research (CEDR), e.g., Inactive Ingredient Guide (1996), Ash and Ash, Eds. (2002) Handbook of Pharmaceutical Additives, Synapse Information Resources, Inc., Endicott NY.

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

[0322] The appropriate formulation depends on the desired route of administration. For intravenous injection, for example, the composition may be formulated in aqueous solution with, if necessary, physiologically compatible buffering agents, such as phosphates, histidine, or citrates to adjust the formulation's pH, and isotonic agents such as sodium chloride or dextrose. For transmucosal or transnasal administration, semi-solid, liquid formulations, or patches may be preferred, and may optionally contain penetration enhancers. Such penetration enhancers are generally known in the art. For oral administration, the compound may be formulated in liquid or solid dosage forms and as immediate or controlled / sustained-release formulations. Suitable dosage forms for oral ingestion by subjects include tablets, pills, sugar-coated tablets, hard and soft-shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions. The compound may also be formulated into rectal compositions such as suppositories or retained enemas, containing conventional suppository bases such as cocoa butter or other glycerides.

[0323] Solid oral dosage forms may be obtained using excipients, which may include fillers, disintegrants, binders (drying and wetting), dissolution retarders, lubricants, flow enhancers, anti-adhesion agents, cationic exchange resins, wetting agents, antioxidants, preservatives, colorants, and flavoring agents. These excipients may be of synthetic or natural origin. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silicate, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, hydrogenated vegetable oils, and waxes. Ethanol and water may act as granulation aids. In certain cases, for example, coating tablets with taste-masking films, gastric acid-resistant films, or release-delay films is desirable. Natural and synthetic polymers combined with colorants, sugars, and organic solvents or water are often used to coat tablets, resulting in sugar-coated tablets. When capsules are preferred over tablets, the drug powder, suspension, or solution can be delivered in a suitable hard or soft shell capsule.

[0324] In one embodiment, the compounds of the present invention may be administered topically, for example, via skin patches, semi-solid or liquid formulations, such as gels, (micro)emulsions, ointments, solutions, (nano / micro)suspensions, or foams. The penetration of the drug into the skin and underlying tissues can be modulated, for example, by the use of penetration enhancers, appropriate selection and combination of lipophilic, hydrophilic, and amphiphilic excipients including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, and emulsifiers, pH adjustment, and the use of complexing agents. Other techniques, such as iontophoresis, may be used to modulate the skin penetration of the compounds of the present invention. Transdermal or topical administration may be preferred, for example, in situations where topical delivery with minimal systemic exposure is desirable.

[0325] For administration by inhalation or nasal administration, the compounds for use according to the present invention are conveniently delivered in the form of solutions, suspensions, emulsions, or semi-solid aerosols from a pressurized pack or nebulizer, usually with the use of a propellant such as, for example, a halogenated carbon derived from methane and ethane, carbon dioxide, or any other suitable gas. For topical aerosols, hydrocarbons such as butane, isobutene, and pentane are useful. In the case of pressurized aerosols, the appropriate dose unit can be determined by providing a valve for delivering the measured amount. For example, gelatin capsules and cartridges for use in inhalers or blowers can be formulated. These typically contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0326] Compounds and compositions formulated for parenteral administration by injection are typically sterile and may be presented in unit dosage forms, e.g., ampoules, syringes, injection pens, or multi-dose containers, the latter typically containing preservatives. Compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulation agents such as buffers, isotonic agents, viscosity enhancers, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives. Depending on the injection site, the vehicle may contain water, synthetic oil or vegetable oil, and / or organic cosolvents. In certain cases, such as having lyophilized products or concentrates, parenteral formulations will be reconstituted or diluted before administration. Depot formulations providing controlled or sustained release of the compounds of the present invention may comprise injectable suspensions of nano / microparticles or nano / micro or non-micronized crystals. Polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, in addition to others well known in the art, can act as controlled / sustained-release matrices. Other depot delivery systems may be presented in the form of implants and pumps requiring incision.

[0327] Suitable carriers for intravenous injection of the compounds of the present invention are well known in the art and include, for example, an aqueous solution containing a base such as sodium hydroxide for forming the ionized compound, sucrose or sodium chloride as an isotonic agent, and a buffer, such as a buffer containing phosphate or histidine. A cosolvent such as polyethylene glycol may be added. These aqueous systems are effective in dissolving the compounds of the present invention and result in low toxicity upon systemic administration. The proportions of the components of the solution system can be changed considerably without destroying the solubility and toxicity properties. Furthermore, the identity of the components can be changed. For example, a low-toxicity surfactant such as polysorbate or poloxamer may be used so that polyethylene glycol or other cosolvents, biocompatible polymers such as polyvinylpyrrolidone, etc. may be added, and other sugars and polyols may be used instead of dextrose.

[0328] The therapeutically effective dose may be initially estimated using various techniques known in the art. The initial dose used in animal studies may be based on the effective concentration established in cell culture assays. An appropriate dose range for human subjects may be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the Disclosure are formulated for oral administration. Exemplary doses of the compounds of the Disclosure in pharmaceutical formulations for oral administration are about 0.5 to about 10 mg / kg body weight. In some embodiments, the pharmaceutical formulations constitute about 0.7 to about 5.0 mg / kg body weight, or alternatively, about 1.0 to about 2.5 mg / kg body weight. Typical administration regimens for oral administration would be administration of the pharmaceutical formulation for oral administration three times a week, twice a week, once a week, or daily.

[0329] The effective amount or therapeutically effective amount or dose of a drug, for example, the compound of the present invention, refers to the amount of drug or compound that results in improvement of symptoms or extension of survival in a subject. The toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (lethal dose for 50% of the population) and ED50 (therapeutably effective dose for 50% of the population). The dose-to-toxicity ratio is the therapeutic index, which can be expressed as the LD50 / ED50 ratio. Drugs exhibiting a high therapeutic index are preferred.

[0330] The effective dose or therapeutically effective dose is the amount of compound or pharmaceutical composition that elicits a biological or medical response in a tissue, system, animal, or human, as determined by researchers, veterinarians, physicians, or other clinicians. The dose is particularly within the range of circulating concentrations containing little to no toxicity (ED50). The dose may vary within this range depending on the dosage form used and / or the route of administration utilized. The exact formulation, route of administration, dose, and dosing interval must be selected according to methods known in the art, taking into account the specifics of the condition of the subject.

[0331] Dosage and intervals may be individually adjusted to provide the plasma level of the active portion sufficient to achieve the desired effect, i.e., the minimum effective concentration (MEC). The MEC varies for each compound but can be estimated, for example, from in vitro data and animal studies. The dose required to achieve the MEC will depend on the individual characteristics and route of administration. In the case of topical administration or selective uptake, the effective topical concentration of the drug may not be related to the plasma concentration.

[0332] The amount of compound or composition administered may depend on various factors, including the sex, age, and weight of the person being treated, the severity of their suffering, the method of administration, and the judgment of the prescribing physician.

[0333] The compound and composition may, if necessary, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such pack or device may include, for example, metal or plastic foil such as a blister pack, or glass and rubber stoppers such as those found in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions containing the compound of the present invention, formulated on a suitable pharmaceutical carrier, may also be prepared, placed in a suitable container, and labeled for the treatment of the indicated condition.

[0334] These and other embodiments of the present invention will be readily conceivable to those skilled in the art in consideration of the disclosure herein and are specifically intended. [Examples]

[0335] Purity measurement by HPLC The purity of the compounds and their synthetic intermediates was determined by reversed-phase HPLC using one of the methods described below:

[0336] Method A: Mobile phase: A: Water (0.01% TFA) B: Acetonitrile (0.01% TFA); Gradient phase: Increase from 5%B to 95%B within 1.4 minutes, 95%B in 1.6 minutes (total run time: 3 minutes); Flow rate: 2.3 mL / min. Column: SunFire C18, 4.6*50 mm, 3.5 μm; Column temperature: 50°C. Detector: ADC ELSD, DAD (214 nm and 254 nm), ES-API.

[0337] Method B: Mobile phase: A: Water (10 mM NH4HCO3) B: Acetonitrile; 5% to 95% B within 1.5 min, 95% B in 1.5 min (total run time: 3 min); Flow rate: 2.0 mL / min; Column: XBridge C18, 4.6*50 mm, 3.5 μm; Column temperature: 40 °C. Detector: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).

[0338] Exemplary compound synthesis Example 1: Preparation of Compound 1 tert-butyl 6-chloronicotinate [ka]

[0339] Di-tert-butyl dicarbonate (10.41 g, 47.77 mmol) was added to a solution of 6-chloronicotinic acid (5.0 g, 6.37 mmol) and 4-dimethylaminopyridine (0.39 g, 0.64 mmol) in tetrahydrofuran (50.0 mL). The reaction mixture was refluxed for 4 hours and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain tert-butyl 6-chloronicotinate (5.5 g, 5.17 mmol, yield 81.12%) as a yellow solid. LCMS: m / z = 214.0 (M + H) + , retention time 1.83 min (Method A).

[0340] tert-butyl 6-hydrazine ylnicotinate [ka]

[0341] To a solution of tert-butyl 6-chloronicotinate (5.5 g, 25.82 mmol) in ethanol (25.0 mL), hydrazine hydrate (6.46 g, 129.11 mmol, 85% in water) was added. The mixture was stirred at 100°C for 2 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was pulverized with petroleum ether and filtered to obtain tert-butyl 6-hydrazinylnicotinate (5.0 g, 23.9 mmol, yield 92.76%) as a yellow solid. LCMS: m / z = 210.0 (M + H) + , retention time 1.19 min (Method A).

[0342] tert-butyl 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinate [ka]

[0343] To a solution of ethyl (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate (2.5 g, 10.86 mmol) and tert-butyl 6-hydrazinyl nicotinate (2.27 g, 10.86 mmol) in ethanol (25.0 mL), p-toluenesulfonic acid monohydrate (410 mg, 2.17 mmol) was added. The mixture was stirred at 80°C for 12 hours, concentrated, and dried. The residue was purified by flash chromatography (methanol / dichloromethane = 1 / 8) to obtain tert-butyl 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinate (3.0 g, 8.35 mmol, yield 76.92%) as a yellow solid. LCMS: m / z = 363.1 (M + H) + , retention time 1.98 min (Method A).

[0344] 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinic acid [ka]

[0345] A solution of tert-butyl 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinate (1.00 g, 2.76 mmol) in dichloromethane (10.0 mL) was mixed with trifluoroacetic acid (5.0 mL). The mixture was stirred at 40°C for 2 hours and then concentrated. The residue was ground with ethyl acetate and filtered to obtain 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinic acid (900 mg, crude) as a yellow solid. LCMS: m / z = 307.0 (M + H) + , retention time 1.77 min (Method A).

[0346] 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinoyl chloride [ka]

[0347] A solution of 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinic acid (900 mg, 2.94 mmol) in dichloromethane (10.0 mL) was mixed with thionyl chloride (10.0 mL). The mixture was stirred at 40°C for 3 hours, concentrated, and dried. A crude product (900 mg) was obtained and used in the next step. LCMS: m / z = 325.1 (M + H) + , retention time 1.96 minutes (Method A).

[0348] 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)-N-(methoxy-N-methylnicotinamide) [ka]

[0349] To a solution of N,O-dimethylhydroxylamine hydrochloride (407.43 mg, 4.16 mmol) and N,N-diisopropylethylamine (1.07 g, 8.31 mmol) in dichloromethane (5.0 mL), 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinoyl chloride (900 mg, 2.77 mmol) was added at 0°C. The mixture was stirred at 0°C for 3 hours, concentrated, and dried. The residue was purified by flash chromatography (dichloromethane / methanol = 10 / 1) to obtain 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)-N-methoxy-N-methylnicotinamide (900 mg, 2.58 mmol, yield 93.17%) as a yellow solid. LCMS: m / z = 350.1 [M + H] + , retention time 1.63 min (Method A).

[0350] 4-(1-(5-acetylpyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile [ka]

[0351] To a solution of methylmagnesium bromide (0.76 mL, 2.29 mmol, 3 M in ether) in anhydrous tetrahydrofuran (5.0 mL), 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)-N-methoxy-N-methylnicotinamide (200 mg, 0.57 mmol) was added at -20°C. The mixture was heated to 0°C and stirred for 1 hour. The reaction product was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 4-(1-(5-acetylpyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile (35 mg, 0.11 mmol, yield 20.23%) as a white solid. LCMS: m / z = 305.0 (M + H) + , retention time 4.504 minutes (Method A). 1 H NMR (400MHz, DMSO-d6) δ 9.00(s,1H), 8.58-8.43(m,3H), 8.18-8.09(m,3H), 7.73-7.69(m,2H), 2.63(s,3H).

[0352] Example 2: Preparation of Compound 2 4-(5-hydroxy-1-(5-propionylpyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile [ka]

[0353] To a solution of ethylmagnesium bromide (0.76 mL, 2.29 mmol, 3 M in ether) in anhydrous tetrahydrofuran (5.0 mL), 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)-N-methoxy-N-methylnicotinamide (intermediate from Example 1) (200 mg, 0.57 mmol) was added at -20°C. The mixture was heated to 0°C and stirred for a further 1 hour. The reaction product was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 4-(5-hydroxy-1-(5-propionylpyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (25 mg, 0.08 mmol, yield 13.81%) as a white solid. LCMS: m / z = 319.0(M+H) + , retention time 5.01 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ 13.56(s,1H), 9.02(s,1H), 8.67(s,1H), 8.49(d,J=8.2Hz,2H), 8.15-8. 10(m,2H), 7.79(d,J=4.2Hz,2H), 3.14-3.02(m,2H), 1.18-1.09(m,3H).

[0354] Example 3: Preparation of Compound 3 4-(5-hydroxy-1-(5-isobutylpyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile [ka]

[0355] To a solution of ethylmagnesium bromide isopropylmagnesium chloride (2.29 mL, 2.29 mmol, 1 M in tetrahydropyran) in anhydrous tetrahydrofuran (5.0 mL), 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)-N-methoxy-N-methylnicotinamide (intermediate from Example 1) (200 mg, 0.57 mmol) was added at -20°C. The mixture was heated to 0°C and stirred for a further 1 hour. The reaction product was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by back-preparative HPLC to obtain 4-(5-hydroxy-1-(5-isobutylpyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (16.5 mg, 0.05 mmol, yield 9.5%) as a white solid. LCMS: m / z = 333.1(M+H) + , retention time 5.10 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ 9.01(s,1H), 8.54(s,1H), 8.40(d,J=7.8Hz,1H), 8.27(s,1H), 8.14(s,1H), 8. 05(d,J=8.5Hz,2H), 7.63(d,J=8.5Hz,2H), 3.63(s,1H), 1.12(d,J=6.7Hz,6H).

[0356] Example 4: Preparation of Compound 4 2-(4-cyanophenyl)methyl acetate [ka]

[0357] To a mixture of 2-(4-cyanophenyl)acetic acid (5.0 g, 31.0 mmol) in methanol (10.0 mL), hydrochloric acid in methanol (20.0 mL, 3.0 N) was added at 0°C. The mixture was stirred at 70°C for 3 hours and then cooled to precipitate the solid. The solid was filtered, washed with methanol, and dried to obtain methyl 2-(4-cyanophenyl)acetate (5.0 g, 28.4 mmol, yield 92%) as a yellow solid. LCMS: m / z = 176.0 [M + H] +, retention time 1.54 min (Method A).

[0358] (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl acrylate [ka]

[0359] To a solution of methyl 2-(4-cyanophenyl)acetate (5.0 g, 28.5 mmol) in N,N-dimethylformamide (25.0 mL), N,N-dimethylformamide diethyl acetal (14.0 g, 114.16 mmol) was added. The mixture was stirred at 100°C for 16 hours and then cooled. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried on sodium sulfate, and concentrated to obtain (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (5.20 g, 25.4 mmol, yield 89%) as a yellow solid. LCMS: m / z = 231.0 [M + H] + The holding time was 1.70 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0360] 2-Bromo-5-(methylsulfonyl)pyridine [ka]

[0361] To a solution of 3,6-dibromopyridine (2.5 g, 12.7 mmol) in anhydrous tetrahydrofuran (10.0 mL), isopropyl magnesium chloride (8.25 mL, 16.5 mmol, 2.0 N in hexane) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 45 minutes, and then a solution of methanesulfonyl chloride (1.89 g, 16.5 mmol) in anhydrous tetrahydrofuran (5.0 mL) was added. The mixture was warmed to room temperature and stirred for a further 1 hour. The reaction product was quenched with water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 2-bromo-5-(methylsulfonyl)pyridine (1.4 g, 5.98 mmol, yield 47.1%) as a yellow solid. LCMS: m / z = 236.0(M+H) + , retention time 1.54 min (Method A).

[0362] 2-Hydrazineyl-5-(methylsulfonyl)pyridine [ka]

[0363] To a solution of 2-bromo-5-(methanesulfonyl)-pyridine (1.0 g, 4.25 mmol) in ethanol (10.0 mL), hydrazine hydrate (1.0 g, 17.0 mmol, 85% in water) was added. The mixture was stirred at 80°C for 4 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was ground with petroleum ether and filtered to obtain 2-hydrazinyl-5-(methylsulfonyl)pyridine (1.2 g, 6.4 mmol, 75% yield) as a white solid. LCMS: m / z = 188.0 (M + H)+, retention time 0.43 min (Method A).

[0364] 4-(5-hydroxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile [ka]

[0365] To a solution of (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (230 mg, 1.0 mmol) and 2-hydrazineyl-5-(methylsulfonyl)pyridine (187 mg, 1.0 mmol) in ethanol (3.0 mL), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(5-hydroxy-1-(5-methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (58 mg, 0.17 mmol, yield 17.0%) as a white solid. LCMS: m / z = 341.0 (M + H) + , retention time 3.93 minutes (Method A). 1 H NMR(400MHz,DMSO-d6)δ 13.68(s,1H), 8.93(s,1H), 8.68-8.76(m,2H), 8.49-8.51(m,2H), 8.15-8.17(d,J=6.5Hz,2H), 7.78-7.80(d,J=6.9Hz,2H), 3.35(s,3H).

[0366] Example 5: Preparation of Compound 5 2-(3-cyanophenyl)ethyl acetate [ka]

[0367] A mixture of ethyl 2-(3-bromophenyl) (2.5 g, 10.3 mmol) and zinc cyanide (1.20 g, 10.3 mmol) in N,N-dimethylformamide (30.0 mL) was mixed with tetrakis(triphenylphosphine)palladium (1.16 g, 1.0 mmol). The mixture was stirred under nitrogen at 90 °C for 18.0 hours and then cooled to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain ethyl 2-(3-cyanophenyl) (1.72 g, 9.1 mmol, yield 88.3%) as a yellow oil. LC-MS: m / z = 190.0 (M + H) + , retention time 1.65 min (Method A).

[0368] (E)-2-(3-cyanophenyl)-3-(dimethylamino)acrylate ethyl [ka]

[0369] To a solution of ethyl 2-(3-cyanophenyl)(1.2 g, 6.35 mmol) in 8.0 mL of N,N-dimethylformamide, N,N-dimethylformamide diethyl acetal (4.7 g, 31.74 mmol) was added. The mixture was stirred at 100°C for 16.0 hours and then cooled. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried on sodium sulfate, and concentrated to obtain (E)-2-(3-cyanophenyl)-3-(dimethylamino)acrylate ethyl (1.34 g, 5.49 mmol, yield 86.5%) as a yellow solid. LC-MS: m / z = 245.0 [M + H] + , retention time 1.50 min (Method A).

[0370] 3-(5-hydroxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile [ka]

[0371] To a solution of (E)-2-(3-cyanophenyl)-3-(dimethylamino)acrylate ethyl (200 mg, 0.82 mmol) and 2-hydrazineyl-5-(methylsulfonyl)pyridine (intermediate from Example 4) (153 mg, 0.82 mmol) in ethanol (3.0 mL), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) was added. The mixture was stirred in a sealed tube at 90°C for 12.0 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 3-(5-hydroxy-1-(5-methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (60 mg, 0.17 mmol, yield 21.5%) as a white solid. LC-MS: m / z = 341.1 (M + H) + , retention time 1.57 min (Method A). 1 HNMR(400MHz,DMSO-d6)δ 13.43(s,1H), 8.94(s,1H), 8.66-8.73(m,2H), 8.49-8.52(d,J=10.8Hz,2H) , 8.41(s,1H), 8.30-8.31(d,J=6.5Hz,1H), 7.55-7.62(m,2H), 3.36(s,3H).

[0372] Example 6: Preparation of Compound 6 2-(4-cyano-2-methylphenyl)ethyl acetate [ka]

[0373] A mixture of 4-bromo-3-methylbenzonitrile (5.0 g, 25.6 mmol), diethyl malonate (27 g, 168 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.24 g, 0.26 mmol), tri-tert-butylphosphine tetrafluoroborate (0.08 g, 0.26 mmol), potassium carbonate (5.3 g, 38.4 mmol), and potassium bicarbonate (3.84 g, 38.4 mmol) was stirred at 160°C for 12.0 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 2-(4-cyano-2-methylphenyl)ethyl acetate (2.0 g, 8.11 mmol, yield 31.7%) as a yellow oil. LC-MS: m / z = 204.1(M+H) + , retention time 1.87 min (Method A).

[0374] (E)-2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylate ethyl: [ka]

[0375] To a solution of ethyl 2-(4-cyano-2-methylphenyl)(1.0 g, 5.0 mmol) in N,N-dimethylformamide (10.0 mL), N,N-dimethylformamide diethyl acetal (2.9 g, 25.0 mmol) was added. The mixture was stirred overnight at 100 °C 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 on sodium sulfate, and concentrated. The residue was purified by flash chromatography (dichloromethane / methanol = 98 / 2) to obtain (E)-2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylate ethyl (600 mg, 2.36 mmol, yield 47.2%) as a yellow oil. LC-MS: m / z = 259.0 [M + H] + , retention time 1.68 min (Method B).

[0376] 4-(5-hydroxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)-3-methylbenzonitrile: [ka]

[0377] To a solution of (E)-2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylate ethyl (391 mg, 1.60 mmol) and 2-hydrazineyl-5-(methylsulfonyl)pyridine (intermediate from Example 4) (300 mg, 1.60 mmol) in ethanol (10.0 mL), 4-methylbenzenesulfonic acid (34.4 mg, 0.2 mmol) was added. The mixture was stirred at 90°C for 12.0 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(5-hydroxy-1-(5-methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)-3-methylbenzonitrile (77 mg, 0.21 mmol, yield 13.6%) as a white solid. LC-MS: m / z = 355.1.0 (M + H) + , retention time 1.79 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ 13.19(s,1H), 8.95(s,1H), 8.64-8.68(m,1H), 8.48-8.51(d,J=8.1Hz,1H), 8.28(s,1H), 7.60-7.80(m,3H), 3.35(s,3H), 2.36(s,3H).

[0378] Example 7: Preparation of Compound 7 5-Hydroxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-carboxylate ethyl [ka]

[0379] A mixture of 2-hydrazineyl-5-(methylsulfonyl)pyridine (intermediate from Example 4) (0.4 g, 2.1 mmol), 2-(ethoxymethylene)malonate diethyl (1.15 g, 5.3 mmol), and potassium carbonate (0.73 g, 5.3 mmol) in water / ethanol (30.0 mL / 10.0 mL) was stirred overnight at 60°C. Aqueous hydrochloric acid (10.0 mL, 3N) was added to the solution to precipitate the solid. The solid was filtered, washed with water, and dried to obtain 5-hydroxy-1-(5-methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-carboxylate ethyl (0.4 g, 1.3 mmol, yield 61.5%) as a yellow solid. LCMS: m / z = 312.0 (M + H) + , retention time 1.63 min (Method A).

[0380] 5-Methoxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-carboxylate ethyl [ka]

[0381] To a solution of 5-hydroxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-carboxylate ethyl (373 mg, 1.2 mmol) in dichloromethane / methanol (10.0 mL / 1.0 mL), (diazomethyl)trimethylsilane (1.61 mL, 3.23 mmol, 2N in hexane) was added. The mixture was stirred overnight at 25°C, concentrated, and dried. The residue was purified by flash chromatography (dichloromethane / methanol = 100 / 2) to obtain 5-methoxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-carboxylate ethyl (0.3 g, 0.92 mmol, yield 76.9%) as a yellow solid. LCMS: m / z = 326.0 [M + H] + , retention time 1.75 min (Method A).

[0382] 5-Methoxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-carboxylic acid [ka]

[0383] To a solution of ethyl 5-methoxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-carboxylic acid (0.3 g, 0.92 mmol) in 1,4-dioxane (10.0 mL), aqueous lithium hydroxide (3.0 mL, 3.0 mmol, 1.0 N) was added at 0°C. The mixture was warmed to room temperature and stirred for 18 hours. The solution was acidified with 1 N hydrochloric acid and extracted with dichloromethane. The organic layer was separated, washed with brine, dried on sodium sulfate, and concentrated under reduced pressure to obtain 5-methoxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-carboxylic acid (0.2 g, 0.61 mmol, yield 66.8%) as a yellow solid. LCMS: m / z = 326.0 (M + H) + , retention time 1.25 min (Method A).

[0384] 2-(4-bromo-5-methoxy-1H-pyrazole-1-yl)-5-(methylsulfonyl)pyridine [ka]

[0385] A mixture of 5-methoxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-carboxylic acid (0.2 g, 0.61 mmol), N-bromosuccinimide (0.18 g, 1.0 mmol), and sodium bicarbonate (0.17 g, 2.0 mmol) in N,N-dimethylformamide (10.0 mL) was stirred at 25°C for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 2-(4-bromo-5-methoxy-1H-pyrazole-1-yl)-5-(methylsulfonyl)pyridine (0.16 g, 0.47 mmol, yield 78%) as a yellow solid. LCMS: m / z = 332.0 (M + H)+ , retention time 1.55 min (Method A).

[0386] 2-(4-(5-methoxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)phenyl)acetonitrile [ka]

[0387] A mixture of 2-(4-bromo-5-methoxy-1H-pyrazole-1-yl)-5-(methylsulfonyl)pyridine (0.1 g, 0.3 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (0.15 g, 0.6 mmol), sodium carbonate (64 mg, 0.60 mmol), and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) in 10.0 mL / 1.0 mL of 1,4-dioxane / water was stirred overnight at 110°C. The mixture was cooled, concentrated, and dried. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 2-(4-(5-methoxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl))phenyl)acetonitrile (0.1 g, 0.27 mmol, 90% yield) as a yellow solid. LCMS: m / z = 369.0 [M + H] + , retention time 1.55 min (Method B).

[0388] 2-(4-(5-hydroxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)phenyl)acetonitrile [ka]

[0389] A mixture of 2-(4-(5-methoxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)phenyl)acetonitrile (0.1 g, 0.3 mmol) and lithium chloride (0.04 g, 0.90 mmol) in N,N-dimethylformamide (5.0 mL) was stirred overnight at 60°C. The solution was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to dry. The residue was purified by reverse preparative HPLC to obtain 2-(4-(5-hydroxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)phenyl)acetonitrile (55 mg, 0.15 mmol, yield 51.8%) as a white solid. LCMS: m / z = 355.0 (M + H) + , retention time 3.42 minutes (Method B). 1 H NMR(400MHz,DMSO-d6)δ 13.18(s,1H), 8.94(s,1H), 8.47-8.55(m,3H), 7.95-7.97(d,J=6.5Hz,2H), 7.32-7.34(d,J=6.5Hz,2H), 4.01(s,2H), 3.29(s,3H).

[0390] Example 8: Preparation of Compound 8 2-(2-methoxypyridine-4-yl)ethyl acetate [ka]

[0391] To a solution of 2-methoxy-4-methylpyridine (2.0 g, 16.2 mmol) in anhydrous tetrahydrofuran (50.0 mL), lithium diisopropylamide (16.0 mL, 32.0 mmol, 2.0 N in n-heptane) was added under nitrogen at -78°C. The mixture was stirred at -78°C for 10 minutes, and diethyl carbonate (3.78 g, 32.0 mmol) was added. The mixture was warmed to room temperature and stirred for 2 hours. The reaction product was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain ethyl 2-(4-cyano-2-methylphenyl)-3-oxobutanoate (2.0 g, 10.2 mmol, yield 63.4%) as a yellow oil. LCMS: m / z = 196.1(M+H) + , retention time 1.97 min (Method A).

[0392] (E)-3-(dimethylamino)-2-(2-methoxypyridine-4-yl)ethyl acrylate [ka]

[0393] To a solution of ethyl 2-(2-methoxypyridine-4-yl)(1.95 g, 10 mmol) in N,N-dimethylformamide (3.0 mL), N,N-dimethylformamide diethyl acetal (5.95 g, 50 mmol) was added. The mixture was stirred at 100°C for 12 hours and then cooled. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried on sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (dichloromethane / methanol = 98 / 2) to obtain ethyl (E)-3-(dimethylamino)-2-(2-methoxypyridine-4-yl)acrylate (1.1 g, 4.4 mmol, yield 44%) as a colorless oil. LCMS: m / z = 251.0 [M + H] + , retention time 1.68 min (Method B).

[0394] 4-(2-methoxypyridine-4-yl)-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol [ka]

[0395] To a solution of (E)-3-(dimethylamino)-2-(2-methoxypyridine-4-yl)ethyl acrylate (0.25 g, 1.0 mmol) and 2-hydrazineyl-5-(methylsulfonyl)pyridine (intermediate from Example 4) (0.2 g, 1.0 mmol) in ethanol (3.0 mL), p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(2-methoxypyridine-4-yl)-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol (90 mg, 0.26 mmol, yield 26%) as a white solid. LCMS: m / z = 347.0 (M + H) + , retention time 2.28 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ 8.94-8.97(d,J=8.5Hz,2H), 8.67-8.70(d,J=8.5Hz,1H), 8.49-8.52(d,J=7.5Hz ,1H), 8.18-8.19(d,J=7.6Hz,1H), 7.77-7.83(m,2H), 4.03(s,3H), 3.36(s,3H).

[0396] Example 9: Preparation of Compound 9 (E)-2-(4-bromophenyl)-3-(dimethylamino)acrylate ethyl [ka]

[0397] To a solution of ethyl 2-(4-bromophenyl) (1.5 g, 6.2 mmol) in N,N-dimethylformamide (3.0 mL), N,N-dimethylformamide diethyl acetal (3.7 g, 31 mmol) was added. The mixture was stirred at 100°C for 12 hours and then cooled. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried on sodium sulfate, and concentrated to obtain (E)-2-(4-bromophenyl)-3-(dimethylamino)acrylate (1.1 g, 3.7 mmol, yield 59.5%) as a yellow oil. LCMS: m / z = 298.0 [M + H] + The retention time was 2.08 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0398] 4-(4-bromophenyl)-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol [ka]

[0399] To a solution of (E)-2-(4-bromophenyl)-3-(dimethylamino)acrylate ethyl (0.5 g, 1.7 mmol) and 2-hydrazineyl-5-(methylsulfonyl)pyridine (intermediate from Example 4) (0.31 g, 1.7 mmol) in ethanol (10.0 mL), p-toluenesulfonic acid monohydrate (64 mg, 0.34 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(4-bromophenyl)-1-(5-methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol (0.3 g, 0.76 mmol, yield 44.9%) as a white solid. LCMS: m / z = 394.0 (M + H) + , retention time 1.88 min (Method A). 1H NMR(400MHz,DMSO-d6)δ 13.28(s,1H), 8.93(s,1H), 8.50-8.53(m,3H), 7.91-7.93(d,J=8.5Hz,2H), 7.53-7.55(d,J=8.9Hz,2H), 3.35(s,3H).

[0400] Example 10: Preparation of Compound 10 2-Bromo-5-(1H-pyrazole-1-yl)pyridine [ka]

[0401] A mixture of 2-bromo-5-iodopyridine (1.00 g, 3.52 mmol), 1H-pyrazole (239.8 mg, 3.52 mmol), cuprous iodide (67.09 mg, 0.35 mmol), potassium phosphate (1.87 g, 8.81 mmol), and (1R,2R)-cyclohexane-1,2-diamine (45.6 mg, 0.4 mmol) in 1,4-dioxane (10.0 mL) was stirred at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain 2-bromo-5-(1H-pyrazole-1-yl)pyridine (220 mg, 2.85 mmol, yield 81.12%) as a yellow oil. LCMS: m / z = 224.1(M+H) + , retention time 1.55 min (Method A).

[0402] 2-Hydrazineyl-5-(1H-pyrazole-1-yl)pyridine [ka]

[0403] To a solution of 2-bromo-5-(1H-pyrazole-1-yl)pyridine (200 mg, 0.89 mmol) in ethanol (2.0 mL), hydrazine hydrate (223.2 mg, 4.46 mmol, 85% in water) was added. The mixture was stirred in a sealed tube at 100°C for 2 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was pulverized with petroleum ether and filtered to obtain 2-hydrazineyl-5-(1H-pyrazole-1-yl)pyridine (140 mg, 0.80 mmol, yield 90.32%) as a yellow solid. LCMS: m / z = 176.1 (M + H) + , retention time 1.01 min (Method B).

[0404] 4-(1-(5-(1H-pyrazole-1-yl)pyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile [ka]

[0405] To a solution of (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (210.29 mg, 0.91 mmol) and 2-hydrazineyl-5-(1H-pyrazole-1-yl)pyridine (160.00 mg, 0.91 mmol) in ethanol (5.0 mL), p-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(1-(5-(1H-pyrazole-1-yl)pyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile (74 mg, 0.22 mmol, yield 24.8%) as a white solid. LCMS: m / z = 329.1 (M + H) + , retention time 4.50 min (Method A). 1H NMR(400MHz,DMSO-d6)δ 13.44(s,1H), 8.99(t,J=1.2Hz,1H), 8.62(d,J=6.6Hz,2H), 8.50-8.48(m,2H), 8.16(d,J=4.0Hz,2H), 7.85-7.79(m,3H), 6.64(t,J=2.0Hz,1H).

[0406] Example 11: Preparation of Compound 11 2-(6-chloropyridine-3-yl)oxazole [ka]

[0407] To a solution of 2-chloro-5-iodopyridine (1.5 g, 6.26 mmol) in anhydrous tetrahydropyran (5.0 mL), n-butyllithium (4.26 mL, 10.65 mmol, 2.5 N in hexane) was added under nitrogen at -78°C. The mixture was stirred at -78°C for 30 minutes, and then zinc chloride (18.79 mg, 18.79 mmol, 1.0 N in dichloromethane) was added. The mixture was warmed to room temperature, and a solution of tetrakis(triphenylphosphine)palladium (361.78 mg, 0.31 mmol) and oxazole (605.65 mg, 8.77 mmol) in anhydrous tetrahydrofuran (10.0 mL) was added. The mixture was stirred at 60°C for 4 hours and concentrated. The residue was separated 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 flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 2-(6-chloropyridine-3-yl)oxazole (900 mg, 4.94 mmol, yield 79.93%) as a white solid. LCMS: m / z = 181.1 (M + H) + , retention time 1.51 min (Method A).

[0408] 2-(6-hydrazineylpyridine-3-yl)oxazole [ka]

[0409] A solution of 2-(6-chloropyridine-3-yl)oxazole (700 mg, 3.13 mmol) in ethanol (5.0 mL) was mixed with hydrazine hydrate (781.25 mg, 15.63 mmol, 85% in water). The mixture was stirred in a sealed tube at 100°C for 2 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was ground with petroleum ether and filtered to obtain 2-(6-hydrazinylpyridine-3-yl)oxazole (400 mg, 2.25 mmol, yield 72.72%) as a yellow solid. LCMS: m / z = 176.1 (M + H) + , retention time 0.99 min (Method B).

[0410] 4-(5-hydroxy-1-(5-(oxazol-2-yl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile [ka]

[0411] To a solution of (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (328.57 mg, 1.43 mmol) and 2-(6-hydrazinylpyridine-3-yl)oxazole (250.00 mg, 1.43 mmol) in ethanol (5.0 mL), p-toluenesulfonic acid monohydrate (55 mg, 0.29 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(5-hydroxy-1-(5-(oxazole-2-yl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (150 mg, 0.46 mmol, yield 31.91%) as a white solid. LCMS: m / z = 330.0 (M + H) + , retention time 1.74 min (Method B). 1H NMR(400MHz,DMSO-d6)δ 13.54(s,1H), 9.04(s,1H), 8.64(s,1H), 8.61-8.46(m,2H), 8.32(d,J=0.7H z,1H), 8.14(d,J=8.4Hz,2H), 7.78(d,J=8.6Hz,2H), 7.46(d,J=0.7Hz,1H). Example 12: Preparation of Compound 12

[0412] 2-(6-chloropyridine-3-yl)thiazole [ka]

[0413] To a solution of 5-bromo-2-chloropyridine (500.0 mg, 2.60 mmol) and 2-(tributylstannyl)thiazole (1458.2 mg, 3.90 mmol) in N,N-dimethylformamide (10.0 mL), bis(triphenylphosphine)palladium(II) dichloride (182.37 mg, 0.26 mmol) was added. The reaction mixture was stirred in a sealed tube at 100°C for 3 hours. The mixture was cooled to room temperature, concentrated, and dried. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 2-(6-chloropyridine-3-yl)thiazole (350 mg, 1.77 mmol, yield 68%). LCMS: m / z = 197.0 [M + H] + , retention time 1.719 min (Method A).

[0414] 2-(6-hydrazineylpyridine-3-yl)thiazole [ka]

[0415] A mixture of 2-(6-chloropyridine-3-yl)thiazole (300.0 mg, 1.53 mmol) and hydrazine hydrate (3.0 mL, 85% in water) in ethanol (3.0 mL) was stirred in a sealed tube at 110°C for 3 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was ground over petroleum ether and filtered to obtain 2-(6-hydrazinylpyridine-3-yl)thiazole (185 mg, 0.96 mmol, 63% yield). LCMS: m / z = 193.0 [M + H] + The retention time was 1.120 minutes (Method B). The product was sufficiently pure and used directly in the next step.

[0416] 4-(5-hydroxy-1-(5-(thiazole-2-yl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile [ka]

[0417] To a solution of (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (200.0 mg, 0.87 mmol) and 2-(6-hydrazinylpyridine-3-yl)oxazole (166.97 mg, 0.87 mmol) in ethanol (8 mL), p-toluenesulfonic acid monohydrate (17 mg, 0.09 mmol) was added. The reaction mixture was stirred at 90°C for 16 hours, and the mixture was cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(5-hydroxy-1-(5-(thiazole-2-yl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (80 mg, 0.23 mmol, yield 27%) as a yellow solid. LCMS: m / z = 346.0 [M + H] + , retention time 1.893 minutes (Method B). 1H NMR(400MHz,DMSO-d6)δ 13.51(br,1H), 9.05(s,1H), 8.65(s,1H), 8.53(s,2H), 8.14(d,J=7.5Hz,2H), 8.01(d,J=2.5Hz,1H), 7.90(d,J=3.0Hz,1H), 7.79(d,J=8.0Hz,2H).

[0418] Example 13: Preparation of Compound 13 6'-Chloro-2,3'-bipyridine [ka]

[0419] A mixture of 2-bromopyridine (390 mg, 2.5 mmol), (6-chloropyridine-3-yl)boronic acid (470 mg, 3.0 mmol), potassium carbonate (828 mg, 6.0 mmol), and palladium(II) acetate (56 mg, 0.6 mmol) in 1,2-dimethoxyethane / water (10.0 mL / 2.0 mL) was stirred overnight at 90°C. The mixture was cooled, concentrated, and dried. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 6'-chloro-2,3'-bipyridine (380 mg, 2.0 mmol, yield 80%) as a yellow solid. LCMS: m / z = 191.0 [M + H] + , retention time 2.20 min (method A).

[0420] 6'-Hydrazineyl-2,3'-bipyridine [ka]

[0421] A solution of 6'-chloro-2,3'-bipyridine (380 mg, 2.0 mmol) in ethanol (10.0 mL) was mixed with hydrazine hydrate (5.0 mL, 85% in water). The mixture was stirred overnight in a sealed tube at 120°C. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain 6'-hydrazinyl-2,3'-bipyridine (200 mg, 1.07 mmol, 54% yield) as a yellow oil. LCMS: m / z = 187.1 [M + H] + The retention time was 0.54 minutes (Method A). The product was used directly in the next step.

[0422] 4-(1-([2,3'-bipyridine]-6'-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile [ka]

[0423] To a solution of (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (240 mg, 1.07 mmol) and 6'-hydrazineyl-2,3'-bipyridine (200 mg, 1.07 mmol) in ethanol (4.0 mL), p-toluenesulfonic acid monohydrate (38.2 mg, 0.20 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(1-([2,3'-bipyridine]-6'-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile (35 mg, 0.10 mmol, yield 9.64%) as a white solid. LCMS: m / z = 340.2 (M + H) + , retention time 4.71 min (Method A). 1 H NMR(500MHz,DMSO-d6)δ 9.19(s,1H), 8.81-8.66(m,2H), 8.60(s,1H), 8.49(s,1H), 8.12(dd,J=17.7, 7.9Hz,3H), 7.96(t,J=7.6Hz,1H), 7.79(d,J=8.3Hz,2H), 7.49-7.38(m,1H).

[0424] Example 14: Preparation of Compound 14 4-(5-hydroxy-1-(5-(trifluoromethyl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile [ka]

[0425] To a solution of (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (130 mg, 0.56 mmol) and 2-hydrazineyl-5-(trifluoromethyl)pyridine (100 mg, 0.56 mmol) in ethanol (4.0 mL), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(5-hydroxy-1-(5-(trifluoromethyl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (70.8 mg, 0.21 mmol, yield 38%) as a white solid. LCMS: m / z = 331.0 (M + H) + , retention time 5.08 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ 13.54(s,1H), 8.86(s,1H), 8.73(s,1H), 8.65(d,J=8.6Hz,1H), 8.41(dd,J=8.9,2.1Hz,1H), 8.15(d,J=8.3Hz,2H), 7.78(d,J=8.4Hz,2H).

[0426] Example 15: Preparation of Compound 15 1-(6-bromopyridine-3-yl)pyrrolidine-2-one [ka]

[0427] A mixture of 2-bromo-5-iodopyridine (2.0 g, 7.04 mmol), potassium phosphate (4.5 g, 21.13 mmol), cuprous iodide (134 mg, 0.70 mmol), pyrrolidine-2-one (1.2 g, 14.09 mmol), and ethylene glycol (44 mg, 0.70 mmol) in isopropyl alcohol (20.0 mL) was stirred in a sealed tube at 110°C for 12 hours. The mixture was cooled to room temperature, concentrated, and dried. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 1-(6-bromopyridine-3-yl)pyrrolidine-2-one (0.8 g, 9.93 mmol, yield 47%) as a white solid. LCMS: m / z = 241.1 [M + H] + , retention time 1.67 min (Method A).

[0428] 1-(6-hydrazineylpyridine-3-yl)pyrrolidine-2-one [ka]

[0429] A solution of 1-(6-bromopyridine-3-yl)pyrrolidine-2-one (400 mg, 1.66 mmol) in ethanol (4.0 mL) was mixed with hydrazine hydrate (2.0 mL, 85% in water). The mixture was stirred in a sealed tube at 130°C for 18 hours. The mixture was cooled, concentrated, and dried. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 1-(6-hydrazinylpyridine-3-yl)pyrrolidine-2-one (160 mg, 0.83 mmol, 50% yield) as a yellow oil. LCMS: m / z = 193.2 [M + H] + , retention time 0.69 min (Method B).

[0430] 4-(5-hydroxy-1-(5-(2-oxopyrrolidine-1-yl)pyridine-2-yl)-1H-pyrazole-4-yl)benzo-nitrile [ka]

[0431] To a solution of (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (120 mg, 0.52 mmol) and 1-(6-hydrazinylpyridine-3-yl)pyrrolidine-2-one (100 mg, 0.52 mmol) in ethanol (4.0 mL), p-toluenesulfonic acid monohydrate (19 mg, 0.10 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was purified by reverse-phase preparative HPLC to obtain 4-(5-hydroxy-1-(5-(2-oxopyrrolidine-1-yl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (9.0 mg, 0.03 mmol, yield 5.0%) as a white solid. LCMS: m / z = 346.4 (M + H) + , retention time 4.08 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ 13.38(s,1H), 8.99-8.70(m,1H), 8.70-8.41(m,1H), 8.31(d,2H), 8.11(d,J=7.2Hz,2H ), 7.79(d,J=8.5Hz,2H), 3.90(t,J=7.0Hz,2H), 2.56-2.51(m,2H), 2.20-2.03(m,2H).

[0432] Example 16: Preparation of Compound 16 5-Cyclopropyl-2-Fluoropyridine [ka]

[0433] A mixture of 5-bromo-2-fluoropyridine (435 mg, 2.5 mmol), cyclopropylboronic acid (260 mg, 3.0 mmol), potassium phosphate (1.27 g, 6.0 mmol), palladium(II) acetate (56 mg, 0.6 mmol), and tricyclohexylphosphine (340 mg, 1.2 mmol) in 1,2-dimethoxyethane / water (10.0 mL / 2.0 mL) was stirred overnight at 80°C. The mixture was cooled, concentrated, and dried. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 5-(cyclopropyl-2-fluoropyridine (246 mg, 1.8 mmol, yield 72%) as a yellow solid. LCMS: m / z = 138.1 (M + H) + , retention time 2.25 minutes (Method A).

[0434] 5-Cyclopropyl-2-Hydrazineylpyridine [ka]

[0435] A solution of 5-cyclopropyl-2-fluoropyridine (246 mg, 1.8 mmol) in ethanol (10.0 mL) was mixed with hydrazine hydrate (5.0 mL, 85% in water). The mixture was stirred overnight in a sealed tube at 120°C. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain 5-cyclopropyl-2-hydrazinylpyridine (150 mg, 1.00 mmol, 55% yield) as a yellow oil. LCMS: m / z = 150.1 [M + H] + The retention time was 0.50 minutes (Method A). The product was used directly in the next step.

[0436] 4-(1-(5-(cyclopropylpyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile [ka]

[0437] To a solution of methyl (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate (230 mg, 1.00 mmol) and 5-cyclopropyl-2-hydrazinylpyridine (150 mg, 1.00 mmol) in ethanol (4.0 mL), p-toluenesulfonic acid monohydrate (38.0 mg, 0.20 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(1-(5-cyclopropylpyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile (36 mg, 0.12 mmol, yield 12%) as a white solid. LCMS: m / z = 303.3 (M + H) + , retention time 5.189 minutes (Method A). 1 H NMR(400MHz,DMSO-d6)δ 8.30(s,1H), 8.15(s,1H), 8.14-8.07(m,1H), 8.02(d,J=7.5Hz,2H), 7.67-7 .53(m,3H), 1.96-1.82(m,1H), 0.95(d,J=7.0Hz,2H), 0.67(d,J=7.0Hz,2H).

[0438] Example 17: Preparation of Compound 17 5-Fluoro-2-hydrazineylpyridine [ka]

[0439] A solution of 2,5-difluoropyridine (500 mg, 4.34 mmol) in ethanol (2.0 mL) was mixed with hydrazine hydrate (434 mg, 8.69 mmol, 85% in water). The mixture was stirred overnight in a sealed tube at 120°C. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was ground with petroleum ether and filtered to obtain 5-fluoro-2-hydrazinylpyridine (270 mg, 2.13 mmol, 49% yield) as a white solid. LCMS: m / z = 128.1 (M + H) +, retention time 0.33 min (Method A).

[0440] 4-(1-(5-fluoropyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile [ka]

[0441] To a solution of methyl (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate (181 mg, 0.79 mmol) and 5-fluoro-2-hydrazinylpyridine (100 mg, 0.79 mmol) in ethanol (4.0 mL), p-toluenesulfonic acid monohydrate (30.4 mg, 0.16 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(1-(5-fluoropyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile (94.6 mg, 0.34 mmol, yield 43%) as a white solid. LCMS: m / z = 281.3 (M + H) + , retention time 4.38 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ 13.30(s,1H), 8.61(s,1H), 8.52(d,J=2.7Hz,1H), 8.46(m,1H), 8.14(d,J=8.1Hz,2H), 8.00(td,J=8.8,2.9Hz,1H), 7.78(d,J=8.4Hz,2H).

[0442] Example 18: Preparation of Compound 18 4-(1-(5-chloropyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile [ka]

[0443] To a solution of methyl (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate (150.0 mg, 0.65 mmol) in ethanol (3.0 mL), 5-chloro-2-hydrazinylpyridine (93.52 mg, 0.65 mmol) and p-toluenesulfonic acid monohydrate (13.3 mg, 0.07 mmol) were added. The reaction mixture was stirred in a sealed tube at 90°C for 16 hours. The reaction mixture was cooled, concentrated, and dried. The residue was purified by flash chromatography (dichloromethane / ethyl acetate = 100 / 1) to obtain 4-(1-(5-chloropyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile (77 mg, 0.26 mmol, yield 40%) as a yellow solid. LCMS: m / z = 297.0 [M + H] + , retention time 5.095 minutes (Method A). 1 H NMR(500MHz,DMSO-d6)δ 13.35(s,1H), 8.65(s,1H), 8.55(d,J=2.5Hz,1H), 8.46(s,1H), 8.16-8.12(m,3H), 7.78(d,J=6.8Hz,2H).

[0444] Example 19: Preparation of Compound 19 4-(4-chlorophenyl)-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol [ka]

[0445] To a solution of ethyl (E)-3-(dimethylamino)-2-(4-chlorophenyl)acrylate (200 mg, 0.79 mmol) and 2-hydrazineyl-5-(methylsulfonyl)pyridine (intermediate from Example 4) (147.83 mg, 0.79 mmol) in ethanol (5.0 mL), p-toluenesulfonic acid monohydrate (30.4 mg, 0.16 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(4-chlorophenyl)-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol (95.00 mg, 0.27 mmol, yield 34.54%) as a white solid. LCMS: m / z = 350.1 (M + H) + , retention time 1.93 minutes (Method A). 1 H NMR(400MHz,DMSO-d6)δ 8.94(d,J=2.8Hz,1H), 8.81-8.56(m,2H), 8.49(dd,J=8.9,2.4Hz,1H), 7.98(d,J=8.1Hz,2H), 7.42(d,J=8.6Hz,2H), 3.38(s,3H).

[0446] Example 20: Preparation of Compound 20 4-(4-fluorophenyl)-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol [ka]

[0447] To a solution of (E)-3-(dimethylamino)-2-(4-fluorophenyl) ethyl acrylate (127 mg, 0.53 mmol) and 2-hydrazineyl-5-(methylsulfonyl)pyridine (intermediate from Example 4) (100 mg, 0.53 mmol) in ethanol (5.0 mL), p-toluenesulfonic acid monohydrate (20.9 mg, 0.11 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(4-fluorophenyl)-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol (93.8 mg, yield 52%) as a white solid. LCMS: m / z = 334.3 (M + H) + , retention time 4.02 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ 13.01(s,1H), 8.93(d,J=2.1Hz,1H), 8.67(m,1H), 8.58-8.37(m,2H), 7.98(dd,J=8.3,5.7Hz,2H), 7.20(t,J=8.9Hz,2H), 3.35(s,3H)

[0448] Example 21: Preparation of Compound 21 4-(1-(5-bromopyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile [ka]

[0449] To a solution of methyl (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate (612 mg, 2.66 mmol) and 5-bromo-2-hydrazinylpyridine (500 mg, 2.66 mmol) in ethanol (10.0 mL), p-toluenesulfonic acid monohydrate (51 mg, 0.27 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(1-(5-bromopyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile (680 mg, 1.99 mmol, yield 75%) as a white solid. LCMS: m / z = 340.9 (M + H) + , retention time 4.99 minutes (Method A). 1 H NMR(500MHz,DMSO-d6)δ 13.35(s,1H), 8.69-8.58(m,2H), 8.41(s,1H), 8.25(dd,J=8.9,2.3Hz,1H), 8.14(d,J=8.2Hz,2H), 7.78(d,J=8.4Hz,2H).

[0450] Example 22: Preparation of Compound 22 N-(6-fluoropyridine-3-yl)cyclopropanecarboxamide [ka]

[0451] To a solution of 6-fluoropyridine-3-amine (500.0 mg, 4.46 mmol) in dichloromethane (20.0 mL), cyclopropane carbonyl chloride (559.4 mg, 5.35 mmol, 0.48 mL) and triethylamine (902.6 mg, 8.92 mmol, 1.24 mL) were added at 0°C. The mixture was warmed to room temperature and stirred for 2 hours. The reaction product was diluted with water and extracted twice with dichloromethane. The organic layer was washed with brine, dried on sodium sulfate, and concentrated to obtain N-(6-fluoropyridine-3-yl)cyclopropanecarboxamide (850 mg crude). LCMS: m / z = 181.0 [M + H] +The retention time was 1.577 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0452] N-(6-Hydrazineylpyridine-3-yl)cyclopropanecarboxamide [ka]

[0453] A mixture of N-(6-fluoropyridine-3-yl)cyclopropanecarboxamide (850.0 mg, 4.72 mmol) and hydrazine hydrate (5.0 mL, 85% in water) in ethanol (5.0 mL) was stirred in a sealed tube at 110°C for 3 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was pulverized with petroleum ether and filtered to obtain N-(6-hydrazinylpyridine-3-yl)cyclopropanecarboxamide (312 mg crude). LCMS: m / z = 193.0 [M + H] + The retention time was 0.867 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0454] N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)cyclopropanecarboxamide [ka]

[0455] To a solution of (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (200.0 mg, 0.87 mmol) and N-(6-hydrazinylpyridine-3-yl)cyclopropanecarboxamide (166.9 mg, 0.87 mmol) in ethanol (4.0 mL), p-toluenesulfonic acid monohydrate (17.1 mg, 0.09 mmol) was added. The mixture was stirred at 90°C for 3 hours, cooled to room temperature, and evaporated to dry. The residue was purified by flash chromatography (dichloromethane / methanol = 20 / 1) to obtain N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)-cyclopropanecarboxamide (78 mg, 0.22 mmol, yield 26%) as a yellow solid. LCMS: m / z = 346.0 [M + H] + , retention time 4.330 min (method A). 1 H NMR(400MHz,DMSO-d6)δ 10.56(s,1H), 8.77(d,J=2.4Hz,1H), 8.51-8.44(m,1H), 8.27-8.24(m,1H), 8.17-8.13(m,1 H), 8.09(d,J=8.0Hz,2H), 7.78(d,J=8.4Hz,2H), 1.82-1.78(m,1H), 0.85(d,J=6.0Hz,4H).

[0456] Example 23: Preparation of Compound 23 N-(6-fluoropyridine-3-yl)propionamide [ka]

[0457] To a solution of 6-fluoropyridine-3-amine (500.0 mg, 4.46 mmol) in dichloromethane (20 mL), propionyl chloride (495.16 mg, 5.35 mmol, 0.47 mL) and triethylamine (902.60 mg, 8.92 mmol, 1.24 mL) were added at 0°C. The mixture was warmed to room temperature and stirred for 2 hours. The reaction product was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried on sodium sulfate, and concentrated to obtain N-(6-fluoropyridine-3-yl)propionamide (808 mg crude). LCMS: m / z = 169.0 [M + H] + The retention time was 1.498 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0458] N-(6-Hydrazineylpyridine-3-yl)propionamide [ka]

[0459] A mixture of N-(6-fluoropyridine-3-yl)propionamide (800.00 mg, 4.76 mmol) and hydrazine hydrate (5.0 mL, 85% in water) in ethanol (5 mL) was stirred in a sealed tube at 110°C for 3 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was pulverized with petroleum ether and filtered to obtain N-(6-hydrazinylpyridine-3-yl)propionamide (294 mg crude). LCMS: m / z = 181.0 [M + H] + The retention time was 0.317 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0460] N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)propionamide [ka]

[0461] To a solution of methyl (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate (200.0 mg, 0.87 mmol) and N-(6-hydrazinylpyridine-3-yl)propionamide (156.5 mg, 0.87 mmol) in ethanol (4.0 mL), p-toluenesulfonic acid monohydrate (14.9 mg, 0.09 mmol) was added. The mixture was stirred at 90°C for 3 hours, cooled to room temperature, and evaporated to dry. The residue was purified by flash chromatography (dichloromethane / methanol = 20 / 1) to obtain N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)propionamide (23 mg, 0.07 mmol, yield 8.0%) as a yellow solid. LCMS: m / z = 334.0 [M + H] + , retention time 4.322 minutes (Method A). 1 H NMR(400MHz,DMSO-d6)δ 10.23(s,1H), 8.78(s,1H), 8.51-8.44(m,1H), 8.26-8.21(m,1H), 8.18-8.15(m,1H), 8. 09(d,J=8.0Hz,2H), 7.78(d,J=8.4Hz,2H), 2.37(q,J=7.6Hz,2H), 1.58(t,J=7.6Hz,3H).

[0462] Example 24: Preparation of Compound 24 N-(6-fluoropyridine-3-yl)methanesulfonamide [ka]

[0463] To a solution of 6-fluoropyridine-3-amine (500 mg, 4.46 mmol) in pyridine (2.5 mL), methanesulfonyl chloride (0.5 mL) was added at 0°C. The mixture was warmed to room temperature and stirred for a further 1 hour. The reaction product was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain N-(6-fluoropyridine-3-yl)methanesulfonamide (600 mg, 3.12 mmol, 70% yield) as a yellow oil. LCMS: m / z = 190.9 [M + H] + , retention time 1.38 min (Method A).

[0464] N-(6-Hydrazineylpyridine-3-yl)methanesulfonamide [ka]

[0465] A solution of N-(6-fluoropyridine-3-yl)methanesulfonamide (600 mg, 3.15 mmol) in ethanol (4.0 mL) was mixed with hydrazine hydrate (2.0 mL, 85% in water). The mixture was stirred overnight in a sealed tube at 110°C. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain N-(6-hydrazineyl-3-yl)methanesulfonamide (300 mg, 1.48 mmol, 47% yield) as a yellow oil. LCMS: m / z = 203.2 [M + H] + The retention time was 0.34 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0466] N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)methanesulfonamide [ka]

[0467] To a solution of (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (341 mg, 1.48 mmol) and N-(6-hydrazinylpyridine-3-yl)methanesulfonamide (300 mg, 1.48 mmol) in ethanol (4.0 mL), p-toluenesulfonic acid monohydrate (28.5 mg, 0.15 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)methanesulfonamide (250 mg, 0.72 mmol, yield 49%) as a white solid. LCMS: m / z = 356.4 (M + H) + , retention time 3.74 minutes (Method A). 1 H NMR(500MHz,DMSO-d6)δ 10.03(s,1H), 8.51(s,1H), 8.32(d,J=13.4Hz,2H), 8.11(d,J=7.8Hz,2H), 7.86(d,J=8.1Hz,1H), 7.77(d,J=7.9Hz,2H), 3.08(s,3H).

[0468] Example 25: Preparation of Compound 25 N-(6-fluoropyridine-3-yl)ethanesulfonamide [ka]

[0469] To a solution of 6-fluoropyridine-3-amine (500 mg, 4.46 mmol) in pyridine (5.0 mL), ethanesulfonyl chloride (689.71 mg, 5.36 mmol) was added at 0°C. The mixture was warmed to room temperature and stirred for a further 1 hour. The reaction product was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried on sodium sulfate, and concentrated to obtain N-(6-fluoropyridine-3-yl)ethanesulfonamide (900 mg, 4.38 mmol, yield 98.26%) as a white solid. LCMS: m / z = 205.1 [M + H] + , retention time 1.32 min (Method A).

[0470] N-(6-Hydrazineylpyridine-3-yl)ethanesulfonamide [ka]

[0471] A solution of N-(6-fluoropyridine-3-yl)ethanesulfonamide (910 mg, 4.46 mmol) in ethanol (5.0 mL) was mixed with hydrazine hydrate (1.05 g, 17.84 mmol, 85% in water). The mixture was stirred in a sealed tube at 100°C for 4 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was ground with petroleum ether and filtered to obtain N-(6-hydrazinylpyridine-3-yl)ethanesulfonamide (810.0 mg, 3.75 mmol, 84.11%) as a white solid. LCMS: m / z = 217.0 (M + H) + , retention time 0.36 min (Method A).

[0472] N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)ethanesulfonamide [ka]

[0473] To a solution of methyl (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate (212.96 mg, 0.93 mmol) and N-(6-hydrazinylpyridine-3-yl)ethanesulfonamide (200.00 mg, 0.93 mmol) in ethanol (5.0 mL), p-toluenesulfonic acid monohydrate (36.1 mg, 0.19 mmol) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)ethanesulfonamide (75 mg, 0.20 mmol, 21.86%) as a white solid. LCMS: m / z = 370.0 (M + H) + , retention time 4.01 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H), 8.55(s,1H), 8.34(s,1H), 8.32-8.18(m,1H), 8.11(d,J=7.5Hz,2H), 7.86(dd,J =9.0,2.5Hz,1H), 7.79(d,J=8.4Hz,2H), 3.18(dd,J=14.6,7.3Hz,2H), 1.24(t,J=7.3Hz,3H).

[0474] Example 26: Preparation of Compound 26 2-Chloro-5-(methylthio)pyridine

[0475] [ka] To a solution of 5-bromo-2-chloropyridine (1.92 g, 10.0 mmol) and N,N,N',N'-tetramethylethylenediamine (1.51 g, 13.0 mmol) in anhydrous tetrahydrofuran (15.0 mL), n-butyllithium (7.5 mL, 12.0 mmol, 1.6 M in hexane) was added under nitrogen at -78°C. The mixture was stirred at -78°C for 50 minutes, and dimethyl disulfide (1.13 g, 12.0 mmol) was added. The mixture was warmed to 20°C and stirred for a further 1 hour. The reaction product was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 50 / 1) to obtain 2-chloro-5-(methylthio)pyridine (1.0 g, 6.29 mmol, yield 62.9%) as a yellow oil. LC-MS: m / z = 160 (M + H) + , retention time 0.85 min (Method A).

[0476] 2-Chloro-5-(methylsulfinyl)pyridine [ka]

[0477] To a solution of 2-chloro-5-(methylthio)pyridine (900 mg, 5.66 mmol) in dichloromethane (10.0 mL), 3-chloroperoxybenzoic acid (1.26 g, 6.22 mmol, 85%) was added at 0°C. The mixture was stirred at this temperature for 1 hour. The reaction product was basicized with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 2-chloro-5-(methylsulfinyl)pyridine (700 mg, 4.0 mmol, yield 70.6%) as a white solid. LC-MS: m / z = 176.1 (M + H) + , retention time 0.55 min (Method A).

[0478] 2-Hydrazineyl-5-(methylsulfinyl)pyridine [ka]

[0479] To a solution of 2-chloro-5-(methylsulfinyl)pyridine (700 mg, 4.0 mmol) in ethanol (10.0 mL), hydrazine hydrate (1.23 g, 20.0 mmol, 85% in water) was added. The mixture was stirred at 80°C for 4.0 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was pulverized with petroleum ether and filtered to obtain 2-hydrazinyl-5-(methylsulfinyl)pyridine (400 mg, 2.34 mmol, yield 58.5%) as a yellow solid. LC-MS: m / z = 172.0 (M + H)+, retention time 0.38 min (Method A).

[0480] (6-chloropyridine-3-yl)(imino)(methyl)-λ 6 -Sulfanone [ka]

[0481] A mixture of 2-chloro-5-(methylsulfinyl)pyridine (200 mg, 1.14 mmol) (intermediate from Example 12) and sodium azide (223 mg, 3.43 mmol) in chloroform (5.0 mL) was mixed with concentrated sulfuric acid (1.0 mL) at 0°C. The mixture was stirred at 55°C for 16.0 hours and then cooled. The reaction product was diluted with ice water, and the organic layer was removed. The aqueous phase was made basic by the addition of ammonium hydroxide solution, and the oil was immediately separated and extracted with dichloromethane. The organic layer was separated, washed with brine, dried on sodium sulfate, and concentrated to obtain (6-chloropyridine-3-yl)(imino)(methyl)-λ 6 -Sulfanone (120 mg, 0.63 mmol, yield 55.4%) was obtained as a yellow solid. LC-MS: m / z = 191.0 (M + H)+ , retention time 1.3 min (Method A).

[0482] (6-Hydrazineylpyridine-3-yl)(imino)(methyl)-λ 6 -Sulfanone [ka]

[0483] (6-chloropyridine-3-yl)(imino)(methyl)-λ in ethanol (10.0 mL) 6 To a solution of sulfanone (120 mg, 0.63 mmol), hydrazine hydrate (200 mg, 3.15 mmol, 85% in water) was added. The mixture was stirred at 80°C for 4.0 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was ground with petroleum ether, filtered, and (6-hydrazinylpyridine-3-yl)(imino)(methyl)-λ 6 -Sulfanone (100 mg, 0.54 mmol, yield 85.3%) was obtained as a yellow solid. LC-MS: m / z = 187.0 (M + H)+, retention time 0.36 min (Method A).

[0484] 4-(5-hydroxy-1-(5-(S-methylsulfonimidoyl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile [ka]

[0485] (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (150 mg, 0.65 mmol) and (6-hydrazinylpyridine-3-yl)(imino)(methyl)-λ in ethanol (6.0 mL) 6To a solution of sulfanone (121 mg, 0.65 mmol), p-toluenesulfonic acid monohydrate (24.7 mg, 0.13 mmol) was added. The mixture was stirred overnight in a sealed tube at 90°C and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 4-(5-hydroxy-1-(5-(S-methylsulfonimidoyl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (14 mg, 0.04 mmol, yield 5.5%) as a white solid. LC-MS: m / z = 340.0 (M + H) + , retention time 3.50 min (Method A). 1 HNMR(400MHz,DMSO-d6)δ 8.90(s,1H), 8.61-8.63(m,1H), 8.30-8.33(m,2H), 8.14(s,1H), 8.03-8.05(d,J=7.4Hz,2H), 7.61-7.63(d,J=8.9Hz,2H), 3.13(s,3H).

[0486] Example 27: Preparation of Compound 27 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)-N-(methylsulfonyl)nicotinamide [ka]

[0487] To a solution of methanesulfonamide (35.3 mg, 0.37 mmol) and triethylamine (74.9 mg, 0.74 mmol) in dichloromethane (5.0 mL), 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinoyl chloride (intermediate from Example 1) (100 mg, 0.31 mmol) was added at 0°C. The mixture was stirred overnight at room temperature, concentrated, and dried. The residue was purified by reverse preparative HPLC to obtain 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)-N-(methylsulfonyl)nicotinamide (17.6 mg, 0.05 mmol, yield 6.2%) as a white solid. LC-MS: m / z = 384.1 (M + H) + , retention time 4.24 min (Method A).1 HNMR (400MHz, DMSO-d6) δ 8.28-8.20 (m, 3H), 8.01-7.99 (m, 4H), 7.55-7.50 (m, 2H), 2.89 (s, 3H).

[0488] Example 28: Preparation of Compound 28 tert-butyl 6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)nicotinate [ka]

[0489] To a solution of tert-butyl 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinate (intermediate from Example 1) (1.0 g, 2.76 mmol) in dichloromethane / methanol (29.0 mL / 5.0 mL), (diazomethyl)trimethylsilane (2.07 mL, 4.14 mmol, 2 M in hexane) was added. The mixture was stirred overnight at 25°C, concentrated, and dried. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain tert-butyl 6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)nicotinate (200 mg, 0.53 mmol, yield 19.2%) as a yellow solid. LC-MS: m / z = 377.0 [M + H] + , retention time 2.40 min (Method A).

[0490] 6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)nicotinic acid [ka]

[0491] A solution of tert-butyl 6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)nicotinate (200 mg, 0.53 mmol) in dichloromethane (10.0 mL) was mixed with trifluoroacetic acid (5.0 mL). The mixture was stirred at 40°C for 2.0 hours and concentrated. The residue was ground with ethyl acetate and filtered to obtain 6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)nicotinic acid (150 mg, 0.47 mmol, yield 88.4%) as a yellow solid. LC-MS: m / z = 321.0 (M + H) + , retention time 1.98 min (Method A).

[0492] 4-(1-(5-isocyanatopyridine-2-yl)-5-methoxy-1H-pyrazole-4-yl)benzonitrile [ka]

[0493] A mixture of 6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)nicotinic acid (150 mg, 0.47 mmol), diphenylphosphonic acid azide (194 mg, 0.71 mmol), and triethylamine (95 mg, 0.94 mmol) in toluene (5.0 mL) was stirred at 110°C for 3 hours. The reaction product was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Crude 4-(1-(5-isocyanatopyridine-2-yl)-5-methoxy-1H-pyrazole-4-yl)benzonitrile (150 mg, crude) was obtained as a yellow syrup. LC-MS: m / z = 345.9 (M + H) + The holding time was 2.01 minutes (Method A). The crude product was used in the next step.

[0494] N-(6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)pyridine-3-yl)morpholine-4-carboxamide [ka]

[0495] A mixture of 4-(1-(5-isocyanatopyridine-2-yl)-5-methoxy-1H-pyrazole-4-yl)benzonitrile (150 mg, crude) and morpholine (174 mg, 2.0 mmol) in dichloromethane (5.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, concentrated, and dried. The residue was purified by flash chromatography (methanol / dichloromethane = 1 / 10) to obtain N-(6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)pyridine-3-yl)morpholine-4-carboxamide (50 mg, 0.12 mmol, yield 26.3%) as a yellow solid. LC-MS: m / z = 405.1 [M + H] + The holding time was 1.96 minutes (Method A). The product was used in the next step.

[0496] N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)morpholine-4-carboxamide [ka]

[0497] To a solution of N-(6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)pyridine-3-yl)morpholine-4-carboxamide (50 mg, 0.12 mmol) in N,N-dimethylformamide (6.0 mL), lithium chloride (50.4 mg, 1.2 mmol) was added. The mixture was stirred overnight at 60°C. The solution was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was purified by back-preparative HPLC to obtain N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)morpholine-4-carboxamide (formate) (9.7 mg, 0.02 mmol, yield 18.6%) as a white solid. LC-MS: m / z = 391.0 (M + H)+ , retention time 4.27 min (Method A). 1 HNMR(400MHz,DMSO-d6)δ 8.87(s,1H), 8.64(s,1H), 8.37(s,1H), 8.17(s,1H), 8.08-8.03(m,3H), 7.74-7.72(m,2H), 3.63-3.62(m,4H), 3.47-3.45(m,4H).

[0498] Example 29: Preparation of Compound 29 6-Hydrazineylpyridine-3-sulfonamide [ka]

[0499] A solution of 6-chloropyridine-3-sulfonamide (1.63 g, 8.5 mmol) in ethanol (5.0 mL) was mixed with hydrazine hydrate (5.0 mL, 85% in water). The mixture was stirred in a sealed tube at 100°C for 4 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was ground with petroleum ether and filtered to obtain 6-hydrazinylpyridine-3-sulfonamide (600 mg, 3.20 mmol, yield 37.7%) as a yellow solid. LCMS: m / z = 189.0 (M + H) + , retention time 0.32 min (Method A).

[0500] 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-sulfonamide [ka]

[0501] To a solution of methyl (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate (452 ​​mg, 1.97 mmol) and 6-hydrazinylpyridine-3-sulfonamide (370 mg, 1.97 mmol) in ethanol (8.0 mL), p-toluenesulfonic acid monohydrate (76.4 mg, 0.4 mmol) was added. The mixture was stirred at 90°C for 16.0 hours and cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried to obtain 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-sulfonamide (340 mg, 1.0 mmol, yield 50.8%) as a white solid. LC-MS: m / z = 342.0 (M + H) + , retention time 1.76 min (Method A).

[0502] 6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)pyridine-3-sulfonamide and 6-(4-(4-cyanophenyl)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazole-1-yl)pyridine-3-sulfonamide [ka]

[0503] To a solution of 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-sulfonamide (340 mg, 1.0 mmol) in dichloromethane / methanol (15.0 mL / 3.0 mL), (diazomethyl)trimethylsilane (0.75 mL, 1.5 mmol, 2 M in hexane) was added. The mixture was stirred overnight at 25°C, concentrated, and dried. The residue was purified by flash chromatography (dichloromethane / methanol = 100 / 2) to obtain two isomers as yellow solids: 6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)pyridine-3-sulfonamide and 6-(4-(4-cyanophenyl)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazole-1-yl)pyridine-3-sulfonamide (245 mg, 0.69 mmol, yield 69%). LC-MS: m / z = 356.0 [M+H] + The retention time was 1.66 minutes (Method A). The two isomers were used in the next step without separation.

[0504] N-((6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)pyridine-3-yl)sulfonyl)acetamide and N-((6-(4-(4-cyanophenyl)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazole-1-yl)pyridine-3-yl)sulfonyl)acetamide [ka]

[0505] To a solution of 6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)pyridine-3-sulfonamide and 6-(4-(4-cyanophenyl)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazole-1-yl)pyridine-3-sulfonamide (245 mg, 0.69 mmol) in anhydrous tetrahydrofuran (10.0 mL), triethylamine (140 mg, 1.38 mmol) and acetyl chloride (69 mg, 0.90 mmol) were added at 0°C. The mixture was stirred overnight at room temperature, concentrated, and dried. The residue was purified by flash chromatography (dichloromethane / methanol = 20 / 1) to obtain two isomers as yellow solids: N-((6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)pyridine-3-yl)sulfonyl)acetamide and N-((6-(4-(4-cyanophenyl)-2-methyl-5-oxo-2.5-dihydro-1H-pyrazole-1-yl)pyridine-3-yl)sulfonyl)acetamide (200 mg, 0.40 mmol, yield 58.3%). LC-MS: m / z = 398.0 [M+H] + The retention time was 1.73 minutes (Method A). The two isomers were used in the next step without separation.

[0506] N-((6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)sulfonyl)acetamide [ka]

[0507] Lithium chloride (168 mg, 4.0 mmol) was added to a solution of N-((6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)pyridine-3-yl)sulfonyl)acetamide and N-((6-(4-(4-cyanophenyl)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazole-1-yl)pyridine-3-yl)sulfonyl)acetamide (200 mg, 0.40 mmol) in N,N-dimethylformamide (10.0 mL). The mixture was stirred overnight at 60°C. The solution was diluted with ethyl acetate and water. The organic layer was washed with brine, dried on sodium sulfate, and evaporated to dryness. The residue was purified by reverse preparative HPLC to obtain N-((6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)sulfonyl)acetamide (formate) (15.3 mg, 0.04 mmol, yield 8.92%) as a white solid. LC-MS: m / z = 384.0 (M + H) + , retention time 3.42 minutes (Method A). 1 HNMR(500MHz,DMSO-d6)δ 12.77(br,1H), 8.89(s,1H), 8.66(d,J=8.0Hz,1H), 8.48(s,1H), 8.34(dd,J=8 .5Hz,J=2.0Hz,1H), 8.09(d,J=8.0Hz,2H), 7.69(d,J=8.5Hz,2H), 1.93(s,3H).

[0508] Example 30: Preparation of Compound 30 (6-bromopyridine-3-yl)dimethylphosphine oxide [ka]

[0509] A mixture of 2-bromo-5-iodopyridine (500 mg, 1.76 mmol), dimethylphosphine oxide (275 mg, 3.53 mmol), potassium phosphate (1.12 g, 5.28 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (203 mg, 0.35 mmol), and palladium acetate (156 mg, 0.7 mmol) in 1,4-dioxane (15.0 mL) was stirred overnight at 100°C under nitrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain (6-bromopyridine-3-yl)dimethylphosphine oxide (50 mg, 0.21 mmol, yield 12.1%) as a yellow oil. LC-MS: m / z = 234 [M + H] + , retention time = 1.36 min (method A).

[0510] (6-Hydrazineylpyridine-3-yl)dimethylphosphine oxide [ka]

[0511] To a solution of (6-bromopyridine-3-yl)dimethylphosphine oxide (120 mg, 0.51 mmol) in ethanol (5.0 mL), hydrazine hydrate (160 mg, 2.55 mmol, 85% in water) was added. The mixture was stirred at 80°C for 4.0 hours. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was pulverized with petroleum ether and filtered to obtain (6-hydrazinylpyridine-3-yl)dimethylphosphine oxide (80 mg, 0.43 mmol, 80% yield) as a yellow solid. LC-MS: m / z = 186.0 (M + H)+, retention time 0.36 min (Method A).

[0512] 4-(1-(5-(dimethylphosphoryl)pyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile [ka]

[0513] To a solution of (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate methyl (100 mg, 0.43 mmol) and (6-hydrazinylpyridine-3-yl)dimethylphosphine oxide (80.4 mg, 0.43 mmol) in ethanol (5.0 mL), p-toluenesulfonic acid monohydrate (19 mg, 0.1 mmol) was added. The mixture was stirred overnight in a sealed tube at 100 °C and cooled to precipitate the solid. The solid was purified by reverse preparative HPLC to obtain 4-(1-(5-(dimethylphosphoryl)pyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile (formate) (15.0 mg, 0.04 mmol, yield 9.3%) as a white solid. LC-MS: m / z = 339.0 (M + H) + , retention time 3.48 min (Method A). 1 HNMR(400MHz,DMSO-d6)δ 8.79-8.77(m,1H), 8.51-8.45(m,2H), 8.31-8.26(m,1H), 8.10-8.08(m,2H), 7.72-7.70(m,2H), 1.74-1.70(m,6H).

[0514] Example 31: Preparation of Compound 31 4-(5-chloropyridine)-2-yl)-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol [ka]

[0515] The compound was synthesized using 5-chloropyridine-2-acetic acid according to the preparation procedure for 4-(5-hydroxy-1-(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (Example 4). LCMS(ESI+): m / z 365(M+H) + ; 1H NMR(300MHz,DMSO-d6)δ 8.91(s,1H), 8.70(d,J=5.7Hz,1H), 8.55(d,J=1.5Hz,1H), 8.46(d,J=8.7Hz,1H), 8.27(d,J=8.7Hz,1H), 7.51(dd,J=8.7Hz,J=2.4Hz,1H), 3.34(s,3H), 2.73(s,3H).

[0516] Example 32: Preparation of Compound 32 3-methyl-4-vinylbenzonitrile [ka]

[0517] Under a nitrogen atmosphere, a mixture of 4-bromo-3-methylbenzonitrile (6.14 g, 31.34 mmol), Cs2CO3 (40.87 g, 125.38 mmol), potassium trifluoro(vinyl)borate (8.40 g, 62.69 mmol), and Pd(dppf)Cl2 (2.29 g, 3.13 mmol) in THF (300 mL) and water (30 mL) was stirred at 75°C for 6 hours. After the reaction was complete as shown by TLC analysis, the resulting mixture was diluted with brine (80 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layer was dried over Na2SO4 (30 g), filtered, and concentrated. The residue was purified by silica gel column chromatography (RINKAN:Hex=1:50) to obtain 6.74 g of the desired product as oil. GC-MS: m / z 143(M) + .

[0518] 2-(4-cyano-2-methylphenyl)acetic acid [ka]

[0519] A mixture of 3-methyl-4-vinylbenzonitrile (6.74 g, 47.13 mmol) and I2 (1.20 g, 4.71 mmol) in DME (400 mL) and water (96 mL) was stirred at room temperature for 5 minutes. Oxon (57.97 g, 94.26 mmol) was added all at once. The reaction mixture was stirred at room temperature overnight. After the reaction was complete as shown by TLC analysis, the resulting mixture was diluted with aqueous Na2S2O3 (100 mL) and extracted with ethyl acetate (50 mL x 5). The combined organic layer was dried over Na2SO4 (30 g), filtered, and concentrated. The residue was purified by slurry to obtain 3.4 g of crude product as a solid, which was used directly in the next step without further purification.

[0520] 2-(4-cyano-2-methylphenyl)methyl acetate [ka]

[0521] To a mixture of 2-(4-cyano-2-methylphenyl)acetic acid (3.40 g, 21.66 mmol) in MeOH (60 mL), SOCl2 (7 mL) was added dropwise over 5 minutes. The mixture was stirred at room temperature for 40 minutes. After the reaction was complete, as shown by TLC analysis, the resulting mixture was concentrated directly. The residue was purified by silica gel column chromatography (siRNA:n-Hex=1:50~1:10) to obtain 1.66 g of the desired product as oil. 1 H-NMR (300MHz, CDCl3) δ 7.46(m,2H), 7.30(d,J=8.1Hz,1H), 3.71(s,3H), 3.69(s,2H), 2.34(s,3H).

[0522] (Z)-2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylate methyl [ka]

[0523] A mixture of methyl 2-(4-cyano-2-methylphenyl)acetate (1.66 g, 8.78 mmol) in DMF-DMA (6 mL) was stirred at 100°C for 5 hours. After the reaction was complete, as shown by TLC analysis, the resulting mixture was directly concentrated. The residue was purified by silica gel column chromatography (Â:n-Hex=1:50~1:5) to obtain 2.0 g of the desired product as oil. LCMS(ESI+): m / z 245(M+H) + ; 1 H-NMR (300MHz, CDCl3) δ 7.61(s,1H), 7.46(s,1H), 7.42(d,J=8.1Hz,1H), 7.22(d,J=8.1Hz,1H), 3.61(s,3H), 2.66(s,6H), 2.22(s,3H).

[0524] 4-(5-hydroxy-1H-pyrazole-4-yl)-3-methylbenzonitrile [ka]

[0525] To a solution of methyl (Z)-2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylate (0.34 g, 1.39 mmol) in EtOH (10 mL), N2H4.H2O (0.64 g, 10.20 mmol) was added. The reaction mixture was stirred overnight at 70°C. After the reaction was complete as shown by TLC, the resulting mixture was concentrated directly. The residue was purified by silica gel column chromatography (siRNA:n-Hex=1:50~1:10) to obtain 287 mg of the desired product as oil. 1 H-NMR (300MHz, DMSO-d6) δ 11.96(brs,1H), 10.21(brs,1H), 7.74(s,1H), 7.67(s,1H), 7.62(d,J=8.1Hz,2H), 2.36(s,3H).

[0526] 2,3-Dichloro-5-(methylthio)pyridine [ka]

[0527] A mixture of 5,6-dichloropyridine-3-amine (0.50 g, 3.07 mmol) in concentrated HCl (2.5 mL) at 0°C was mixed dropwise with aqueous NaNO2 solution (0.32 g, 4.60 mmol, 1 mL water) over 5 minutes. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was filtered to remove inorganic salts. The solution was added dropwise to a suspension of MeSNa (1.29 g, 3.68 mmol, 20%) and NaBF4 (3.4 mg, 0.031 mmol) in acetonitrile (2.5 mL) over 10 minutes at 0°C. The resulting orange suspension was stirred at room temperature for 2 hours. After the reaction was complete as shown by TLC, the reaction mixture was quenched with aqueous NaOH solution (1 N, 5 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was dried over Na2SO4 (20 g), filtered, and concentrated to obtain 456 mg of the desired product as a black solid. 1 H-NMR (300MHz, CDCl3) δ 8.15 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 2.50 (d, J = 6.0 Hz, 3H).

[0528] 2,3-Dichloro-5-(methylsulfonyl)pyridine [ka]

[0529] To a solution of 2,3-dichloro-5-(methylthio)pyridine (0.46 g, 2.35 mmol) in DCM (30 mL), m-CPBA (0.85 g, 4.94 mmol) was added in one step. The reaction mixture was then stirred at room temperature for 3.5 hours. After the reaction was complete as shown by TLC, the mixture was concentrated directly. The residue in Depositphotos (50 mL) was washed with an aqueous solution of Na₂S₂O₃ (10 mL). The aqueous phase was extracted with Depositphotos (2 × 50 mL). The combined organic layer was dried over Na₂SO₄ (30 g), filtered, and concentrated. The residue was purified by silica gel column chromatography ( Depositphotos:n-Hex=1:50~1:20) to obtain 460 mg of the desired product as a solid. 1 H-NMR (300MHz, CDCl3) δ 8.82 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 3.15 (s, 3H).

[0530] 4-(1-(3-chloro-5-(methylsulfonyl)pyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl)-3-methylbenzonitrile [ka]

[0531] A mixture of 4-(5-hydroxy-1H-pyrazole-4-yl)-3-methylbenzonitrile (0.15 g, 0.75 mmol) in DMF (3 mL) was gradually mixed with NaH (60 mg, 1.50 mmol) over 5 minutes. The reaction mixture was stirred at room temperature for 40 minutes. 2,3-dichloro-5-(methylsulfonyl)pyridine (0.25 g, 1.13 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete as shown by TLC analysis, the resulting mixture was directly concentrated and dried. The residue was purified by preparative HPLC to obtain 11 mg of the desired product as a solid. LCMS(ESI+): m / z 389(M+H) + ; 1H-NMR(300MHz,CDCl3)δ 10.23(brs,1H), 8.44(d,J=2.1Hz,1H), 8.18(d,J=2.1Hz,1H), 7.69(s,1H), 7.50(s,1H), 7.38-7.45(m,2H), 3.06(s,3H), 2.41(s,3H).

[0532] Example 33: Preparation of Compound 33 N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)piperazine-1-carboxamide [ka]

[0533] The compound was synthesized using tert-butylpiperazine-1-carboxylate according to the preparation procedure for N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)morpholine-4-carboxamide (Example 28).

[0534] In vitro assays demonstrate PHD inhibition. Enzymatic semi-maximal inhibitory concentration (IC) 50 The values ​​were determined on the selected compounds of the present invention.

[0535] Time-resolved fluorescence resonance energy transfer (TR-FRET) assays were used to determine the enzymatic semi-maximal inhibitory concentration (IC) of PHD inhibitors against the full-length human prolyl-4-hydroxylase domain (PHD) enzymes, PHD1, PHD2, and PHD3. 50The value was determined. The TR-FRET assay was developed based on the specific binding of a hydroxylated HIF-1α peptide, which generates a fluorescent signal, to a complex formed by VHL, EloB, and EloC (VBC). The terbium (Tb) donor (anti-monoclonal antibody, anti-6His-Tb-cryptate gold) and D2 acceptor (streptavidin [SA]-D2) of TR-FRET are linked to the VBC complex and the HIF-1α peptide, respectively. The VBC complex specifically binds to the HIF-1α peptide when hydroxylated, enabling energy transfer from the TR-FRET donor to the acceptor (Figure 1).

[0536] Materials and methods Unless otherwise noted, all chemicals and materials are standard laboratory grade and purchased from Sigma-Aldrich (St. Louis, MO, USA).

[0537] reagent TR-FRET reagent I purchased the monoclonal antibody, anti-6His-Tb-cryptate gold (catalog number 61HI2TLA), and streptavidin (SA)-D2 (catalog number 610SADLA) from CisBio International (Bedford, MA, USA).

[0538] We purchased an N-terminal biotinylated HIF-1α C35 synthetic peptide representing amino acids 547-581 and containing the proline 564 PHD2 hydroxylation site from California Peptide Research (Salt Lake City, UT, USA).

[0539] Recombinant protein VBC complex His-tagged recombinant VHL protein, EloB, and EloC complex (His-VBC) was supplied by Axxam (Milan, Italy). Recombinant human VHL (National Center for Biotechnology Information [NCBI] accession number NP_00542.1) contains a His tag at the C-terminus between amino acids 55 and 213 and is referred to as VHL-His. VHL-His was co-expressed with full-length human EloB (NCBI accession number Q15370.1) and full-length human EloC (NCBI accession number Q15369.1) in E. coli, and the His-VBC complex was purified by affinity chromatography on a nickel-nitrilotriacetic acid (Ni-NTA) column. Purity (approximately 80%) was evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).

[0540] PHD1 Recombinant human PHD1 protein (catalog number 81064, lot number 24717001) was purchased from Active Motif (Carlsbad, CA, USA). PHD1 was expressed as a full-length protein (NCBI accession number NP_542770.2) with an N-terminal FLAG tag (molecular weight 44.9 kDa) in a baculovirus expression system. Purity (over 90%) was evaluated by SDS-PAGE.

[0541] PHD2 Full-length human PHD2 enzyme was produced using a baculovirus-infected insect cell (BIIC) expression system developed by Beryllium (Bedford, MA, USA). The PHD2 construct contained amino acids 1-426 of PHD2 (UniProt Knowledgebase [UniProtKB] / Swiss-Prot accession number Q9GZT9.1), as well as a His tag and a tobacco etch virus (TEV) protease cleavage site at the N-terminus. The construct was expressed in Sf9 insect cells, purified by Ni-NTA column, and digested with TEV protease to remove the His tag. The purity of the final cleaved protein was evaluated by SDS-PAGE and found to be over 94% pure.

[0542] PHD3 Recombinant human PHD3 protein (molecular weight 31.1 kDa) was purchased from Active Motif (Carlsbad, CA, USA). This was expressed as a full-length protein (NCBI accession number NP_071356.1) in E. coli, along with an N-terminal 6-His tag (catalog number 81033, lot number 24417001). Purity was evaluated by SDS-PAGE and found to be over 75% pure.

[0543] PHD inhibitor. Small molecule PHD inhibitors were synthesized, and their identity was confirmed as described herein.

[0544] TR-FRET assay procedure PHD inhibitor compounds were pre-incubated with PHD enzymes in a white 384-well Optiplate microplate (catalog no. 6007290, Perkin Elmer, Waltham, MA, USA) at a reaction volume of 10 μL. For this purpose, 5 μL of the PHD inhibitor compound was serially diluted with dilution buffer (50 mM HEPES [4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid] pH 7.5, 50 mM sodium chloride [NaCl], 0.01% Tween-20, 0.01% purified bovine serum albumin [BSA]), and 5 μL of the PHD enzyme mix (60 nM PHD1, 20 nM PHD2, 140 nM PHD3), prepared as a 4-fold concentrate in the dilution buffer containing the PHD enzymes, was mixed with 40 μM ferrous ammonium sulfate (FAS) and 4 mM sodium ascorbate (Na). The plates were incubated at room temperature for 30 minutes without rotation.

[0545] Next, 5 microliters of a VBC / anti-6His-Tb-cryptate gold mix, prepared as a 4-fold concentrate in a dilution buffer containing 20 nM His-VBC, 1.32 nM monoclonal antibody, and anti-6His-Tb-cryptate gold, were added. Immediately after this step, 5 μL of a HIF-1α C35 substrate mix, prepared as a 4-fold concentrate in a dilution buffer containing 120 nM biotin-labeled HIF-1α C35, 132 nM SA-D2, and 4 μM 2-oxoglutarate (2-OG), was added to reach a final reaction volume of 20 μL.

[0546] The final assay reaction product contained 50 mM HEPES, pH 7.5, 50 mM NaCl, 1 μM 2-OG, 10 μM FAS, 1 mM sodium ascorbate, 0.01% Tween-20, 0.01% purified BSA, 30 nM biotin-labeled HIF-1α C35, 5 nM His-VBC, 0.33 nM monoclonal antibody, anti-6His-Tb-cryptate gold, 33 nM SA-D2, and PHD enzyme (15 nM PHD1, 5 nM PHD2, or 35 nM PHD3) along with the diluted compound.

[0547] PHD inhibitor compound IC 50 For the measurement, the reactants were incubated at room temperature for 10 minutes, and then read on a Perkin Elmer EnVision (Waltham, MA, USA) at an excitation wavelength of 340 nm and emission wavelengths of 615 nm and 665 nm. The data represents the signal intensity quotients at 665 nm and 615 nm, automatically calculated by the Envision Manager software (Perkin Elmer, Waltham, MA, USA). 50 The values ​​(mean, standard deviation, standard error of the mean, geometric mean, and 95% confidence interval) were determined using 4-parameter curve fitting with GraphPad Prism 7.0 (GraphPad, La Jolla, CA, USA) and represent the compound concentrations plotted against the calculated ratios at 665 nm and 615 nm. The TR-FRET assay was performed three times for each compound concentration, and the assay was repeated three times independently.

[0548] Let Ki be defined as IC based on the following Chen-Prusov equation. 50 It was calculated from that. Ki = IC50 / (1 + [2 - OG] / km)

[0549] The final concentration of 2-OG in both the PHD1 and PHD2 assays was 1 μM. The Km of 2-OG in PHD1 was determined to be 12.7 nM, while the Km of 2-OG in PHD2 was determined to be 22.6 nM. Exemplary Compounds [Table 4] TIFF0007856575000180.tif227170TIFF0007856575000181.tif236170TIFF0007856575000182.tif228170TIFF0007856575000183.tif80170

[0550] From the current description, those skilled in the art can easily identify the essential characteristics of the present invention and make various changes and modifications to the invention to suit various uses and conditions without departing from its spirit and scope.

[0551] All U.S. or foreign references, patents, or applications cited herein are incorporated herein by reference in their entirety as if they were described herein. In the event of any conflict, the material literally disclosed herein shall prevail. This application provides the invention in the following embodiments. (Aspect 1) Compound of formula A, (chemical 1) TIFF0007856575000184.tif22170 or a pharmaceutically acceptable salt thereof, in the formula, Ar 1 C is optionally substituted with a halogen, CN, OH, CN, or one or more halogens. 1-3 Alkyl and C 1-3 An aryl or heteroaryl compound optionally substituted with one or more groups selected from alkoxys, Ar 2 is a halogen; amino; amide; OH; sulfonyl group; sulfinyl group; carboxyl group; phosphoryl group; C 3-6 Cycloalkyl; sulfonyl group or optionally substituted with =O C 3-6 Heterocycloalkyl; carbonyl or optionally substituted with one or more halogens C 1-3 Alkyl and C 1-3 A compound or a pharmaceutically acceptable salt thereof that is pyrido-2-yl optionally substituted with one or more groups selected from heteroaryls optionally substituted with alkyl or phenyl. (Aspect 2) Ar 1 but, (Case 2) TIFF0007856575000185.tif22170 And in the formula, X is N or CR 1a And, Y and Z are independently CH or N. R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, The compound according to embodiment 1, wherein m is 1, 2, 3, or 4. (Aspect 3) Ar 1 but, (C3) TIFF0007856575000186.tif18170 The compound described in embodiment 2. (Aspect 4) Ar 1 but, (C4) TIFF0007856575000187.tif25170 And in the formula, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 The compound according to embodiment 2 or 3, which is alkyl. (Appendix 5) Ar 2 but, (C5) TIFF0007856575000188.tif25170 And in the formula, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 3 SO 2 R 6 SOR 7 R8 SOR 9 COR 10 , (CH 2 ) p COOH, NHR 11 , POR 12 R 13 , halogens, cycloalkyls, SO 2 R 14 Alternatively, a heterocycloalkyl group arbitrarily substituted with =O, C 1-3 A heteroaryl group optionally substituted with alkyl or phenyl, or a C group optionally substituted with one or more halogens. 1-3 It is alkyl, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R 17 , or phenyl, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And, R 8 NH or NCH 3 And, R 10 C 1-3 Alkyl or NHSO 2 R 20 And, R 11 COR 21 or SO 2 R 22 And, R 9 、R 12 、R 13、R 14 、R 15 , and R 20 Each is independent of C 1-3 It is alkyl, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is alkyl, R 4 、R 5 、R 16 、R 17 、R 18 、R 19 、R 23 , and R 24 Each is independently H or C 1-3 It is alkyl, p is 1, 2, or 3. The compound according to any one of embodiments 1 to 4, wherein n is 0, 1, 2, or 3. (Aspect 6) Ar 2 but, (a) (6) TIFF0007856575000189.tif20170 And in the formula, R 3 It is selected from the group consisting of F, Cl, Br, and I, or (b) (7) TIFF0007856575000190.tif19170 And in the formula, R 11 COR 21 Or SO 2 R 22 And, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 or C optionally substituted with carboxyl 1-3 It is alkyl, R 23 and R 24 H or C 1-3 The compound according to embodiment 5, which is alkyl. (Aspect 7) R 22 However, CH 3 CH 2 CH 3 CH 2 COOH, NHCH 3 , or N(CH 3 ) 2 Is it, or R 21 but, (C8) TIFF0007856575000191.tif19170 Or CH 2 CH 3 The compound described in embodiment 6. (Pattern 8) Ar 2 but, (9) TIFF0007856575000192.tif20170 And in the formula, (a)R 3 is cycloalkyl, or SO 2 R14 Alternatively, it is a heterocycloalkyl group arbitrarily substituted with =O. R 14 C 1-3 Is it alkyl? or (b)R 3 C 1-3 The compound according to embodiment 5, which is a heteroaryl optionally substituted with alkyl or phenyl. (Aspect 9) The aforementioned cycloalkyl or optionally substituted heterocycloalkyl is (C10) TIFF0007856575000193.tif22170 Selected from the group consisting of, The arbitrarily substituted heteroaryl is (Chem.11) TIFF0007856575000194.tif46170 A compound according to embodiment 8, selected from the group consisting of the following. (Aspect 10) Formula I: (C12) TIFF0007856575000195.tif32170 It has a structure that follows the formula, X is N or CR 1a And, Y and Z are independently CH or N. R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C3-6 Selected from the group consisting of cycloalkyl groups, R 3 SO 2 R 6 SOR 7 R 8 SOR 9 COR 10 , (CH 2 ) p COOH, NHR 11 , POR 12 R 13 , halogens, cycloalkyls, SO 2 R 14 Alternatively, a heterocycloalkyl group arbitrarily substituted with =O, C 1-3 A heteroaryl group optionally substituted with alkyl or phenyl, or a C group optionally substituted with one or more halogens. 1-3 It is alkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R 17 , or phenyl, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And, R 8 NH or NCH 3 And, R 9 C 1-3 It is alkyl, R 10 C 1-3 Alkyl or NHSO 2 R 20 And, R 11 COR 21 or SO 2 R 22 And, R 12 and R 13 Each is independent of C 1-3 It is alkyl, R 14 C 1-3 It is alkyl, R 15 C 1-3 It is alkyl, R 16 and R 17 Each is independently H or C 1-3 It is alkyl, R 18 and R 19 Each is independently H or C 1-3 It is alkyl, R 20 C 1-3 It is alkyl, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is alkyl, R23 and R 24 Each is independently H or C 1-3 It is alkyl, m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3. (Aspect 11) Formula II: (C13) TIFF0007856575000196.tif31170 It has a structure that follows the formula, X is N or CR 1a And, Z is either CH or N, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 3 SO 2 R 6 SOR 7 R 8 SOR 9 COR 10 , (CH 2 ) p COOH, NHR 11 , POR12 R 13 , halogens, cycloalkyls, SO 2 R 14 Alternatively, a heterocycloalkyl group arbitrarily substituted with =O, C 1-3 A heteroaryl group optionally substituted with alkyl or phenyl, or a C group optionally substituted with one or more halogens. 1-3 It is alkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R 17 , or phenyl, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And, R 8 NH or NCH 3 And, R 9 C 1-3 It is alkyl, R 10 C 1-3 Alkyl or NHSO 2 R 20 And, R 11 COR 21 or SO 2 R 22 And, R 12 and R 13 Each is independent of C 1-3 It is alkyl, R 14 C 1-3 It is alkyl, R 15 C 1-3 It is alkyl, R 16 and R 17 H or C 1-3 It is alkyl, R 18 and R 19 H or C 1-3 It is alkyl, R 20 C 1-3 It is alkyl, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is alkyl, R 23 and R 24 H or C 1-3 It is alkyl, m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3. (Aspect 12) Formula III: (C14) TIFF0007856575000197.tif39170 It has a structure that follows the formula, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 3 SO 2 R 6 SOR 7 R 8 SOR 9 COR 10 , (CH 2 ) p COOH, NHR 11 , POR 12 R 13 , halogens, cycloalkyls, SO 2 R 14 Alternatively, a heterocycloalkyl group arbitrarily substituted with =O, C 1-3 A heteroaryl group optionally substituted with alkyl or phenyl, or a C group optionally substituted with one or more halogens. 1-3 It is alkyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16R 17 , or phenyl, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And, R 8 NH or NCH 3 And, R 9 C 1-3 It is alkyl, R 10 C 1-3 Alkyl or NHSO 2 R 20 And, R 11 COR 21 or SO 2 R 22 And, R 12 and R 13 Each is independent of C 1-3 It is alkyl, R 14 C 1-3 It is alkyl, R 15 C 1-3 It is alkyl, R 16 and R 17 H or C 1-3 It is alkyl, R 18 and R19 H or C 1-3 It is alkyl, R 20 C 1-3 It is alkyl, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is alkyl, R 23 and R 24 H or C 1-3 It is alkyl, m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3. (Aspect 13) Formula IV: (C15) TIFF0007856575000198.tif38170 It has a structure that follows the formula, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And, R 8 NH or NCH 3 And, R 18 and R 19 Each is independently H or C 1-3 It is alkyl, m is 1, 2, 3, or 4. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. (Aspect 14) R 1 However, C 1-3 The compound according to embodiment 13, which is alkyl. (Aspect 15) R 1 However, CH 3 The compound described in embodiment 14. (Aspect 16) Formula IVa: (C16) TIFF0007856575000199.tif36170 It has the structure, and in the formula, R 1a It is CN or halogen, R 2 is hydrogen or C 1-3 Selected from the group consisting of alkyl groups, R 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl, or NR 18 R 19 And, R 8 NH or NCH 3 And, R 18 and R 19 Each is independently H or C 1-3 A compound according to embodiment 13, which is alkyl, or a pharmaceutically acceptable salt thereof. (Aspect 17) R 1a However, the compound is CN as described in any one of embodiments 13 to 16. (Aspect 18) R 1a However, the compound is a halogen, as described in any one of embodiments 13 to 16. (Aspect 19) R 1a However, the compound is Cl as described in embodiment 18. (Aspect 20) R 2 However, C 1-3 A compound according to any one of embodiments 13 to 19, wherein the compound is alkyl. (Aspect 21) R 2 However, CH 3 The compound described in embodiment 20. (Aspect 22) R 7 However, C 1-3 A compound according to any one of embodiments 13 to 21, wherein the compound is alkyl. (Aspect 23) R 7 However, CH 3 The compound described in embodiment 22. (Aspect 24) R 7 However, CH(CH 3 ) 2 The compound described in embodiment 22. (Aspect 25) R 7 However, CH 2 CH 3 The compound described in embodiment 22. (Aspect 26) R 7 However, C 3-5 A compound according to any one of embodiments 13 to 21, which is a cycloalkyl compound. (Aspect 27) R 7 The compound according to embodiment 26, wherein the compound is cyclopropyl. (Aspect 28) R 7 However, the compound is cyclopentyl, as described in embodiment 26. (Aspect 29) R 7 The compound is phenyl, as described in any one of embodiments 13 to 21. (Aspect 30) R 7 However, NR 18 R 19 And in the formula, R 18 and R 19 Each is independently H or C 1-3 A compound according to any one of embodiments 13 to 21, wherein the compound is alkyl. (Aspect 31) R 18 and R 19 The compound according to embodiment 30, wherein is independently H. (Aspect 32) R 18 However, H is R 19 However, C 1-3 The compound according to embodiment 30, which is alkyl. (Aspect 33) R 19 However, CH 3 The compound according to embodiment 32. (Aspect 34) R 18 and R 19 CH became independent,3 The compound according to embodiment 30. (Aspect 35) R 8 The compound according to any one of embodiments 13 to 34, wherein the compound is NH. (Aspect 36) R 8 However, NCH 3 The compound according to any one of embodiments 13 to 34. (Aspect 37) Formula V: (C17) TIFF0007856575000200.tif34170 It has a structure that follows the formula, X is N or CR 1a And, Z is either N or CH. R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 6 C 1-3 Alkyl, NHCOR 15 , NR 16 R17 , or phenyl, R 15 C 1-3 It is alkyl, R 16 and R 17 Each is independently H or C 1-3 It is alkyl, m is 1, 2, 3, or 4. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. (Aspect 38) The compound according to embodiment 37, wherein X is N. (Aspect 39) X, CR 1a The compound according to embodiment 37. (Approach 40) R 1a However, the compound according to embodiment 39 is CN. (Aspect 41) R 1a However, the compound according to embodiment 39 is a halogen. (Aspect 42) R 1a However, the compound is Cl as described in embodiment 41. (Aspect 43) R 1a However, the compound described in embodiment 41 is F. (Aspect 44) R 1a However, the compound is Br as described in embodiment 41. (Aspect 45) R 1a However, C 1-3 The compound according to embodiment 39, which is an alkoxy. (Aspect 46) R 1a The compound according to embodiment 45, wherein the compound is methoxy. (Aspect 47) R 1a The compound according to embodiment 39, wherein H is present. (Aspect 48) R 1a However, C is arbitrarily replaced with CN. 1-3 The compound according to embodiment 39, which is alkyl. (Aspect 49) R 1a However, CH 2 The compound according to embodiment 48, wherein CN. (Appearance 50) R 1a The compound according to embodiment 39, wherein it is an OH group. (Aspect 51) A compound according to any one of embodiments 37 to 50, wherein Z is CH. (Appearance 52) A compound according to any one of embodiments 37 to 50, wherein Z is N. (Aspect 53) R 1 A compound according to any one of embodiments 37 to 52, wherein H is present. (Aspect 54) R 1 However, C 1-3 A compound according to any one of embodiments 37 to 52, wherein the compound is alkyl. (Aspect 55) R 1 However, CH 3 The compound described in embodiment 54. (Aspect 56) R 1 However, C 1-3 A compound according to any one of embodiments 37 to 52, which is an alkoxy compound. (Aspect 57) R 1 The compound according to embodiment 56, wherein the compound is methoxy. (Pattern 58) R 1 However, the compound is CN as described in any one of embodiments 37 to 52. (Aspect 59) R2 A compound according to any one of embodiments 37 to 58, wherein H is present. (Appendix 60) R 2 However, C 1-3 A compound according to any one of embodiments 37 to 58, wherein the compound is alkyl. (Aspect 61) R 2 However, CH 3 The compound according to embodiment 60. (Aspect 62) R 6 However, C 1-3 A compound according to any one of embodiments 37 to 61, wherein the compound is alkyl. (Aspect 63) R 6 However, CH 3 The compound described in embodiment 62. (Personal aspect 64) R 6 However, NR 16 R 17 And in the formula, R 16 and R 17 Each is independently H or C 1-3 A compound according to any one of embodiments 37 to 61, wherein the compound is alkyl. (Patent 65) R 6 However, NH 2 The compound described in embodiment 64. (Aspect 66) R 6 However, NHCOR 15 And in the formula, R 15 C 1-3 A compound according to any one of embodiments 37 to 61, wherein the compound is alkyl. (Personal aspect 67) R 6 The compound is phenyl, as described in any one of embodiments 37 to 61. (Pattern 68) Equation VI: (C18) TIFF0007856575000201.tif37170 It has a structure that follows the formula, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 3 is cycloalkyl, or SO 2 R 14 Alternatively, it is a heterocycloalkyl group arbitrarily substituted with =O. R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 14 C 1-3 It is alkyl, m is 1, 2, 3, or 4. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. (Patent 69) Formula VIa: (C19) TIFF0007856575000202.tif36170 It has the structure, and in the formula, R 2 is hydrogen or C 1-3 It is alkyl, R 3 is cycloalkyl, or SO 2 R 14 Alternatively, it is a heterocycloalkyl group arbitrarily substituted with =O. R 14 C 1-3 A compound according to embodiment 68, which is alkyl, or a pharmaceutically acceptable salt thereof. (Aspect 70) R 2 The compound according to embodiment 68 or 69, wherein H is present. (Aspect 71) R 2 However, C 1-3 The compound according to embodiment 68 or 69, which is alkyl. (Aspect 72) R 2 However, CH 3 The compound described in embodiment 71. (Aspect 73) R 3 The compound according to any one of embodiments 68 to 72, wherein it is a cycloalkyl compound. (Aspect 74) R 3 The compound according to embodiment 73, wherein the compound is cyclopropyl. (Aspect 75) R 3 However, SO 2 R 14 Or a heterocycloalkyl which is optionally substituted with =O, where R 14 C 1-3 A compound according to any one of embodiments 68 to 72, wherein the compound is alkyl. (Aspect 76) R 3 but, (20) TIFF0007856575000203.tif22170 The compound described in embodiment 75. (Aspect 77) R 3 but, (21) TIFF0007856575000204.tif35170 The compound described in embodiment 75. (Pattern 78) R 3 but, (22) TIFF0007856575000205.tif27170 The compound described in embodiment 75. (Aspect 79) Formula VII: (23) TIFF0007856575000206.tif36170 It has a structure that follows the formula, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 11 COR 21 or SO 2 R 22 And, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is alkyl, R 23 and R 24 H or C 1-3 It is alkyl, m is 1, 2, 3, or 4. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. (Appendix 80) Formula VIIa: (24) TIFF0007856575000207.tif38170 It has the structure, and in the formula, R 2 is hydrogen or C 3-6 It is a cycloalkyl, R 11 COR 21 or SO 2 R 22 And, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is alkyl, R 23 and R 24 H or C 1-3 A compound according to embodiment 79, which is alkyl, or a pharmaceutically acceptable salt thereof. (Aspect 81) R 2 The compound according to embodiment 79 or 80, wherein H is present. (Aspect 82) R 2 However, C 1-3 The compound according to embodiment 79 or 80, which is alkyl. (Aspect 83) R 2 However, CH 3 The compound described in embodiment 82. (Pattern 84) R 11 However, COR 21 And in the formula, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 A compound according to any one of embodiments 79 to 83, wherein the compound is alkyl. (Pattern 85) R 21 The compound according to embodiment 84, wherein the compound is a heterocycloalkyl. (Pattern 86) R 21 but, (25) TIFF0007856575000208.tif26170 The compound described in embodiment 85. (Aspect 87) R 21 but, (26) TIFF0007856575000209.tif21170 The compound described in embodiment 85. (Pattern 88) R 21 However, the compound according to embodiment 84 is a cycloalkyl compound. (Pattern 89) R 21 The compound according to embodiment 88, wherein the compound is cyclopropyl. (Aspect 90) R21 However, C 1-3 The compound according to embodiment 84, which is alkyl. (Aspect 91) R 21 However, CH 2 CH 3 The compound described in embodiment 90. (Pattern 92) R 11 However, SO 2 R 22 And in the formula, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 It is an alkyl, and in the formula, R 23 and R 24 H or C 1-3 A compound according to any one of embodiments 79 to 83, wherein the compound is alkyl. (Aspect 93) R 22 However, C is arbitrarily substituted with carboxyl. 1-3 The compound according to embodiment 92, which is alkyl. (Aspect 94) R 22 However, CH 3 The compound described in embodiment 93. (Aspect 95) R 22 However, CH 2 CH 3 The compound described in embodiment 93. (Personal aspect 96) R 22 However, CH 2 The compound according to embodiment 93, which is COOH. (Patent 97) R 22 However, NR 23 R 24 And in the formula, R 23 and R 24 H or C 1-3 The compound according to embodiment 93, which is alkyl. (Pattern 98) R 22 However, NHCH 3 The compound described in embodiment 97. (Pattern 99) R 22 However, N(CH 3 ) 2 The compound described in embodiment 97. (Aspect 100) Formula VIII: (27) TIFF0007856575000210.tif38170 It has a structure that follows the formula, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 3 C 1-3 A heteroaryl compound optionally substituted with alkyl or phenyl, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, m is 1, 2, 3, or 4. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. (Aspect 101) Formula VIIIa: (28) TIFF0007856575000211.tif35170 It has the structure, and in the formula, R 3 C 1-3 A compound according to embodiment 100, which is a heteroaryl optionally substituted with alkyl or phenyl, or a pharmaceutically acceptable salt thereof. (Aspect 102) R 3 The compound according to embodiment 100 or 101, wherein the compound is a heteroaryl compound. (Aspect 103) R 3 but, (C29) TIFF0007856575000212.tif26170 The compound described in embodiment 102. (Aspect 104) R 3 but, (30) TIFF0007856575000213.tif27170 The compound described in embodiment 102. (Aspect 105) R 3 but, (31) TIFF0007856575000214.tif26170 The compound described in embodiment 102. (Aspect 106) R 3 but, (32) TIFF0007856575000215.tif27170 The compound described in embodiment 102. (Aspect 107) R 3 but, (33) TIFF0007856575000216.tif26170 The compound described in embodiment 102. (Aspect 108) R 3 but, (34) TIFF0007856575000217.tif27170 The compound described in embodiment 102. (Aspect 109) R 3 However, C 1-3 The compound according to embodiment 100 or 101, which is a heteroaryl optionally substituted with alkyl or phenyl. (Aspect 110) R 3 but, (35) TIFF0007856575000218.tif26170 The compound described in embodiment 109. (Aspect 111) R 3 but, (36) TIFF0007856575000219.tif34170 The compound described in embodiment 109. (Aspect 112) R 3 but, (37) TIFF0007856575000220.tif27170 The compound described in embodiment 109. (Aspect 113) Formula IX: (38) TIFF0007856575000221.tif38170 It has a structure that follows the formula, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 10 C 1-3 Alkyl or NHSO 2 R 20 And, R 20 C 1-3 It is alkyl, m is 1, 2, 3, or 4. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. (Aspect 114) Formula IXa: (39) TIFF0007856575000222.tif45170 It has the structure, and in the formula, R 1a It is CN or halogen, R 10 C 1-3 Alkyl or NHSO 2 R 20 And, R 20 C 1-3 A compound according to embodiment 113, which is alkyl, or a pharmaceutically acceptable salt thereof. (Aspect 115) R 1a The compound according to embodiment 113 or 114, wherein CN is present. (Aspect 116) R 1a The compound according to embodiment 113 or 114, wherein the compound is a halogen. (Aspect 117) R 1a However, the compound is Cl as described in embodiment 116. (Aspect 118) R 10 However, C 1-3 A compound according to any one of embodiments 113 to 117, wherein the compound is alkyl. (Aspect 119) R 10 However, CH 3 The compound described in embodiment 118. (Aspect 120) R 10 However, CH(CH 3 ) 2 The compound described in embodiment 118. (Aspect 121) R 10 However, CH 2 CH 3 The compound described in embodiment 118. (Aspect 122) R 10 However, NHSO 2 R 20 And in the formula, R 20 C 1-3 A compound according to any one of embodiments 113 to 117, wherein the compound is alkyl. (Aspect 123) R 20 However, CH 3 The compound described in embodiment 122. (Aspect 124) Formula X: (40) TIFF0007856575000223.tif38170 It has a structure that follows the formula, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 9 C 1-3 It is alkyl, m is 1, 2, 3, or 4. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. (Aspect 125) R 1a However, the compound described in embodiment 124 is CN. (Aspect 126) R 1 The compound according to embodiment 124 or 125, wherein H is present. (Aspect 127) R 2 A compound according to any one of embodiments 124 to 126, wherein H is present. (Aspect 128) R 9 However, C 1-3 A compound that is alkyl, as described in any one of embodiments 124 to 127. (Aspect 129) R 9 However, CH 3 The compound described in embodiment 128. (Aspect 130) Formula XI: (C41) TIFF0007856575000224.tif38170 It has a structure that follows the formula, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3. (Aspect 131) R 1a However, the compound described in embodiment 130 is CN. (Aspect 132) R 1 The compound according to embodiment 130 or 131, wherein H is present. (Aspect 133) R 2 A compound according to any one of embodiments 130 to 132, wherein H is present. (Aspect 134) A compound according to any one of embodiments 130 to 133, wherein p is 1. (Aspect 135) Formula XII: (C42) TIFF0007856575000225.tif38170 It has a structure that follows the formula, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 3 However, it is a halogen, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, m is 1, 2, 3, or 4. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. (Aspect 136) R 1a However, the compound described in embodiment 135 is CN. (Aspect 137) R 1 The compound according to embodiment 135 or 6, wherein H is present. (Aspect 138) R 2 A compound according to any one of embodiments 135 to 137, wherein H is present. (Aspect 139) R 3 However, the compound is Cl, as described in any one of embodiments 135 to 138. (Aspect 140) R 3 However, the compound is Br, as described in any one of embodiments 135 to 138. (Aspect 141) R 3 However, the compound is F, as described in any one of embodiments 135 to 138. (Aspect 142) Formula XIII: (C43) TIFF0007856575000226.tif38170 It has a structure that follows the formula, R 1 Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens. 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 12 C 1-3 It is alkyl, R 13 C 1-3 It is alkyl, The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or 4. (Aspect 143) R 1a However, the compound described in embodiment 142 is CN. (Aspect 144) R 1 The compound according to embodiment 142 or 143, wherein H is present. (Aspect 145) R 2 However, C 1-3 A compound according to any one of embodiments 142 to 144, wherein the compound is alkyl. (Aspect 146) R 2 However, CH 3 The compound described in embodiment 145. (Aspect 147) R 12 However, C 1-3 A compound according to any one of embodiments 142 to 146, wherein the compound is alkyl. (Aspect 148) R 12 However, CH 3 The compound described in embodiment 147. (Aspect 149) R 13 However, C 1-3 A compound according to any one of embodiments 142 to 148, wherein the compound is alkyl. (Aspect 150) R 13 However, CH 3 The compound described in embodiment 149. (Aspect 151) The aforementioned compound, (Table 1) TIFF0007856575000227.tif39170TIFF0007856575000228.tif235170TIFF0007856575000229.tif203170 The compound according to embodiment 1, selected from the group consisting of, or a pharmaceutically acceptable salt thereof. (Aspect 152) A compound according to any one of embodiments 1 to 151, or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen atom is replaced by a deuterium atom. (Aspect 153) A pharmaceutical composition comprising a compound described in any one of embodiments 1 to 152, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Aspect 154) A method for treating a disease mediated by PHD activity, comprising administering a compound described in any one of embodiments 1 to 152, or a pharmaceutically acceptable salt thereof, to a target. (Aspect 155) The method according to embodiment 154, wherein the disease mediated by PHD activity is ischemia-reperfusion injury. (Aspect 156) The method according to embodiment 155, wherein the ischemia-reperfusion injury is selected from stroke, myocardial infarction, and acute kidney injury. (Aspect 157) The method according to embodiment 154, wherein the disease mediated by PHD activity is inflammatory bowel disease. (Aspect 158) The method according to embodiment 157, wherein the inflammatory bowel disease is ulcerative colitis. (Aspect 159) The method according to embodiment 157, wherein the inflammatory bowel disease is Crohn's disease. (Aspect 160) The method according to embodiment 154, wherein the disease mediated by PHD activity is cancer. (Aspect 161) The method according to embodiment 160, wherein the cancer is colorectal cancer. (Aspect 162) The method according to embodiment 154, wherein the disease mediated by PHD activity is a liver disease. (Aspect 163) The method according to embodiment 154, wherein the disease mediated by PHD activity is atherosclerosis. (Aspect 164) The method according to embodiment 154, wherein the disease mediated by PHD activity is a cardiovascular disease. (Aspect 165) The method according to embodiment 154, wherein the disease mediated by PHD activity is a disease or condition of the eye. (Aspect 166) The method according to embodiment 165, wherein the disease or condition of the eye is selected from radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia. (Aspect 167) The method according to embodiment 155, wherein the disease is anemia. (Aspect 168) The method according to embodiment 167, wherein the anemia is anemia associated with chronic kidney disease. (Aspect 169) The method according to embodiment 154, wherein the disease is a chronic kidney disease. (Aspect 170) The method according to embodiment 154, wherein the disease is related to hyperoxia. (Aspect 171) The method according to embodiment 170, wherein the disease is retinopathy of prematurity. (Aspect 172) The method according to embodiment 170, wherein the disease is bronchopulmonary dysplasia (BPD). (Aspect 173) The method according to embodiment 154, wherein the disease is selected from ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, and liver cirrhosis.

Claims

1. Compound of formula A, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, Ar １ This includes halogens, CN, OH, and C optionally substituted with CN or one or more halogens. １－３ A phenyl compound substituted with one or more groups selected from alkyl groups, Ar ２ are NR 4 R 5 , NHR 11; OH; SO 2 R 6 ; SOR 7 R 8 ; SOR 9 ; (CH 2 ) p COOH; POR 12 R 13; C ３－６ Cycloalkyl; C optionally substituted with a sulfonyl group or =O ３－６ Heterocycloalkyl; C optionally substituted with one or more halogens １－３ Alkyl and C １－３ Pyrido-2-yl substituted with one or more groups selected from heteroaryls optionally substituted with alkyl or phenyl, R4 and R5 are each independently H or C1-3 alkyl. R 6 is C1-3 alkyl, NHCOR 15, NR 16, R 17, or phenyl. R7 is C1-3 alkyl, C3-5 cycloalkyl, phenyl, or NR18 R19. R 8 is NH or NCH 3, R9 is a C1-3 alkyl group, R 11 is SO 2 R 22, R12 and R13 are each independently C1-3 alkyl groups. R14 and R15 are each independently C1-3 alkyl groups. R16 and R17 are each independently C1-3 alkyl groups. R18 and R19 are each independently C1-3 alkyl groups. R22 is NR23, R24, or a C1-3 alkyl optionally substituted with carboxyl. R23 and R24 are each independently H or C1-3 alkyl. p is a compound or a pharmaceutically acceptable salt thereof, where p is 1, 2, or 3.

2. Ar １ but, 【Chemistry 2】 And in the formula, R １ａ is C １－３ alkyl optionally substituted with CN, halogen, OH, or CN, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Selected from the group consisting of alkyl groups, Ar ２ but, 【Transformation 3】 And in the formula, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ３ SO ２ R ６ , SOR ７ R ８ , SOR ９ , (CH ２ ) ｐ COOH, NHR １１ , POR １２ R １３ is or, R ３ teeth, 【Chemistry 4】 A cycloalkyl or SO selected from the group consisting of the following ２ R １４ Alternatively, it may be a heterocycloalkyl group arbitrarily substituted with =O, or R ３ is a cycloalkyl group, or an optionally substituted heterocycloalkyl group. 【Transformation 5】 Selected from the group consisting of, R ３ teeth, 【Transformation 6】 Selected from the group consisting of C １－３ A heteroaryl group optionally substituted with alkyl or phenyl, or a C group optionally substituted with one or more halogens. １－３ It is alkyl, R ６ C １－３ Alkyl, NHCOR １５ , NR １６ R １７ , or phenyl, R ７ C １－３ Alkyl, C ３－５ Cycloalkyl, phenyl, or NR １８ R １９ And, R ８ is NH or NCH ３ And, R １１ SO ２ R ２２ And, R ９ , R １２ , R １３ , R １４ , and R １５ Each is independent of C １－３ It is alkyl, R ２２ NR ２３ R ２４ , or C optionally substituted with carboxyl １－３ It is alkyl, R ４ , R ５ , R １６ , R １７ , R １８ , R １９ , R ２３ , and R ２４ Each is independently H or C １－３ It is alkyl, m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. The compound according to claim 1, wherein p is 1, 2, or 3.

3. Formula III: 【Transformation 7】 It has a structure that follows the formula, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Selected from the group consisting of alkyl groups, R １ａ C is CN, halogen, OH, or C optionally substituted with CN. １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ３ is SO ２ R ６ , SOR ７ R ８ , SOR ９ , (CH ２ ) ｐ COOH, NHR １１ , POR １２ R １３ , cycloalkyl, SO ２ R １４ or heterocycloalkyl optionally substituted with =O, C １－３ alkyl or heteroaryl optionally substituted with phenyl, or C １－３ alkyl optionally substituted with one or more halogens, and R ４ and R ５ each independently is H or C １－３ alkyl, R ６ C １－３ Alkyl, NHCOR １５ , NR １６ R １７ , or phenyl, R ７ C １－３ Alkyl, C ３－５ Cycloalkyl, phenyl, or NR １８ R １９ And, R ８ is NH or NCH ３ And, R ９ C １－３ It is alkyl, R １１ SO ２ R ２２ And, R １２ and R １３ Each is independent of C １－３ It is alkyl, R １４ C １－３ It is alkyl, R １５ C １－３ It is alkyl, R １６ and R １７ H or C １－３ It is alkyl, R １８ and R １９ H or C １－３ It is alkyl, R ２２ NR ２３ R ２４ , or C optionally substituted with carboxyl １－３ It is alkyl, R ２３ and R ２４ H or C １－３ It is alkyl, m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3.

4. Formula IV: 【Transformation 8】 It has a structure that follows the formula, R １ Each time, it is independently selected from the group consisting of hydrogen, halogen, CN, and OH, or R １ C is optionally substituted with one or more halogens. １－３ It is alkyl, R １ａ C is CN, halogen, OH, or C optionally substituted with CN. １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, R ７ C １－３ Alkyl, C ３－５ Cycloalkyl, phenyl, or NR １８ R １９ And, R ８ is NH or NCH ３ And, R １８ and R １９ Each is independently H or C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

5. Formula IVa: 【Chemistry 9】 It has the structure, and in the formula, R １ａ It is CN or halogen, R ２ is hydrogen or C １－３ Selected from the group consisting of alkyl groups, R ７ C １－３ Alkyl, C ３－５ Cycloalkyl, phenyl, or NR １８ R １９ And, R ８ is NH or NCH ３ And, R １８ and R １９ Each is independently H or C １－３ The compound according to claim 3, which is alkyl, or a pharmaceutically acceptable salt thereof.

6. R １ａ Cl is, R ２ CH ３ And, R ７ However, CH ３ , CH (CH ３ ) ２ ,CH ２ CH ３ , cyclopropyl, or cyclopentyl, and / or R １８ and R １９ Each of them independently CH ３ The compound according to claim 5.

7. Formula VI: 【Chemistry 10】 It has a structure that follows the formula, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Selected from the group consisting of alkyl groups, R １ａ C is CN, halogen, OH, or C optionally substituted with CN. １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ３ is a cycloalkyl or SO ２ R １４ Alternatively, it is a heterocycloalkyl group arbitrarily substituted with =O, R ４ and R ５ Each is independently H or C １－３ It is alkyl, R １４ C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

8. Formula VIa: 【Chemistry 11】 It has the structure, and in the formula, R ２ is hydrogen or C １－３ It is alkyl, R ３ is either cycloalkyl or R ３ SO ２ R １４ Or = O (where R １４ is C １－３ The compound according to claim 5, or a pharmaceutically acceptable salt thereof, which is a heterocycloalkyl optionally substituted with an alkyl group.

9. R ３ but, 【Chemistry 12】 A compound according to claim 8, selected from the group consisting of the following.

10. R ２ CH ３ and / or R ３ The compound according to claim 8, wherein is cyclopropyl.

11. Formula VII: 【Chemistry 13】 It has a structure that follows the formula, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Selected from the group consisting of alkyl groups, R １ａ C is CN, halogen, OH, or C optionally substituted with CN. １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, R １１ SO ２ R ２２ And, R ２２ NR ２３ R ２４ , or C optionally substituted with carboxyl １－３ It is alkyl, R ２３ and R ２４ H or C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

12. R ２ CH ３ and / or R ２２ However, NHCH ３ , N (CH ３ ) ２ ,CH ３ ,CH ２ CH ３ , or CH ２ The compound according to claim 11, wherein it is a COOH group.

13. Formula VIIa: 【Chemistry 14】 It has the structure, and in the formula, R ２ is hydrogen or C ３－６ It is a cycloalkyl, R １１ SO ２ R ２２ And, R ２２ NR ２３ R ２４ , or C optionally substituted with carboxyl １－３ It is alkyl, R ２３ and R ２４ H or C １－３ The compound according to claim 11, which is alkyl, or a pharmaceutically acceptable salt thereof.

14. Formula VIII: 【Chemistry 15】 It has a structure that follows the formula, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Selected from the group consisting of alkyl groups, R １ａ C is CN, halogen, OH, or C optionally substituted with CN. １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ３ C １－３ A heteroaryl compound optionally substituted with alkyl or phenyl, R ４ and R ５ Each is independently H or C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

15. Formula VIIIa: 【Chemistry 16】 It has the structure, and in the formula, R ３ teeth, 【Chemistry 17】 Selected from the group consisting of C １－３ The compound according to claim 14, or a pharmaceutically acceptable salt thereof, which is a heteroaryl optionally substituted with alkyl or phenyl.

16. Formula X: [Chemistry 18] It has a structure that follows the formula, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Selected from the group consisting of alkyl groups, R １ａ C is CN, halogen, OH, or C optionally substituted with CN. １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, R ９ C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

17. R ９ CH ３ The compound according to claim 16.

18. Formula XI: 【Chemistry 19】 It has a structure that follows the formula, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Selected from the group consisting of alkyl groups, R １ａ C is CN, halogen, OH, or C optionally substituted with CN. １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3.

19. Equation XII: 【Chemistry 20】 It has a structure that follows the formula, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Selected from the group consisting of alkyl groups, R １ａ C is CN, halogen, OH, or C optionally substituted with CN. １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

20. Equation XIII: 【Chemistry 21】 It has a structure that follows the formula, R １ Each time, independently, hydrogen, halogen, CN, OH, and C optionally substituted with one or more halogens are used. １－３ Selected from the group consisting of alkyl groups, R １ａ C is CN, halogen, OH, or C optionally substituted with CN. １－３ It is alkyl, R ２ Each time, independently, hydrogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ４ and R ５ Each is independently H or C １－３ It is alkyl, R １２ C １－３ It is alkyl, R １３ C １－３ It is alkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or 4.

21. R ２ , R １２ , and R １３ Each of them independently CH ３ The compound according to claim 20.

22. The aforementioned compound, Table 1 The compound according to claim 1, selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

23. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen atom is replaced by a deuterium atom.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition for treating a disease mediated by PHD activity, comprising a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein the disease mediated by PHD activity is selected from the group consisting of ischemia-reperfusion injury, inflammatory bowel disease, cancer, liver disease, atherosclerosis, cardiovascular disease, eye disease or condition, anemia, chronic kidney disease, and hyperoxia-related diseases.

26. The pharmaceutical composition according to claim 25, wherein the ischemia-reperfusion injury is selected from stroke, myocardial infarction, and acute kidney injury.

27. The pharmaceutical composition according to claim 25, wherein the inflammatory bowel disease is ulcerative colitis.

28. The pharmaceutical composition according to claim 25, wherein the inflammatory bowel disease is Crohn's disease.

29. The pharmaceutical composition according to claim 25, wherein the cancer is colorectal cancer.

30. The pharmaceutical composition according to claim 25, wherein the disease or condition of the eye is selected from radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia.

31. The pharmaceutical composition according to claim 25, wherein the anemia is anemia related to chronic kidney disease.

32. The pharmaceutical composition according to claim 25, wherein the disease is retinopathy of prematurity.

33. The pharmaceutical composition according to claim 25, wherein the disease is bronchopulmonary dysplasia (BPD).

34. A pharmaceutical composition for treating a disease mediated by PHD activity, comprising a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein the disease mediated by PHD activity is selected from the group consisting of ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, hepatic fibrosis, and cirrhosis.

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