PHD inhibitor compounds, compositions, and their uses

Abstract

Provided is a novel small molecule inhibitor of PHD, or a pharmaceutically acceptable salt thereof. 【Solution means】Compound of formula I: TIFF2026136124000230.tif32170 (Where: X is N or CR 1a ; Y and Z are independently CH or N; R 1 is independently each time hydrogen, CN, C 1-3 alkyl, and C 1-3 alkoxy selected from the group consisting of; R 1a is H, CN, or halogen; R 2 is independently each time selected from the group consisting of hydrogen and halogen; R 3 is SO2R 6 , COR 10 , NHR 11 , halogen, or heterocycloalkyl substituted with =O; R 6 is C 1-3 alkyl; R 10 is C 1-3 alkyl or NHSO2R 20 ; R 11 is COR 21 ; R 20 is C 1-3 alkyl; R 21 is heterocycloalkyl, cycloalkyl, or C 1-3 alkyl; m is 1, 2, 3, or 4; n is 0, 1, 2, or 3) or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is based on U.S. Provisional Patent Application No. 62 / 992,616, filed on March 20, 2020. This asserts priority over the title, which is incorporated herein by reference in its entirety. It gets included. [Background technology]

[0002] Hypoxia is a condition in which the supply of oxygen is insufficient for normal daily living functions, for example, when the supply of arterial blood oxygen is insufficient. A situation or condition of insufficient oxygen supply. Hypoxia can lead to cellular dysfunction and damage to structural tissues. There is a possibility that... Activation of cellular defense mechanisms during hypoxia is due to HIF (hypoxia-inducible factor) It is mediated by protein. In response to hypoxia, a decrease in HIFα-prolyl hydroxylase occurs. As a result, HIFα levels increase in most cells. Prolyl hydroxylation of HIFα is , various proteins containing the prolyl hydroxylase domain (PHD1, 2, and 3) It is called HIF prolyl hydroxylase (HPH-3, 2, and 1) or EGLN-2 This is achieved by a family of proteins also known as 1, and 3. PHD protein The chlorine is an oxygen sensor that regulates HIF stability in an oxygen-dependent manner. Three PHDs Isoforms function differently in their regulation of HIF and other non-HIF-related regulation. It may sometimes function as a clause.

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

[0004] 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, liver This includes diseases of the kidneys (e.g., fibrosis and cirrhosis), as well as diseases of the kidneys (e.g., acute kidney injury and chronic kidney disease). Novel small molecule PHD inhibitors that are useful in treating the disease are described herein. [Overview of the project]

[0005] In particular, the present invention provides novel small molecule inhibitors of PHD, which are used in the heart (e.g., ischemic heart disease). Diseases (congestive heart failure and heart valve 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 This includes, but is not limited to, diseases of the kidneys (e.g., acute kidney injury and chronic kidney disease). It is useful in treating diseases.

[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 C1 is optionally substituted with a halogen, CN, OH, CN, or one or more halogens. -3 Alkyl and C 1-3 Optionally substituted with one or more groups selected from alkoxys It is an aryl or heteroaryl, Ar 2 is halogen; amino; amide; OH; sulfonyl group; sulfinyl group; carbony C group; phosphoryl group; C 3-6Cycloalkyl; optionally substituted with a sulfonyl group or =O substituted C 3-6 Heterocycloalkyl; optionally substituted with a carbonyl or one or more halogens substituted C 1-3 Alkyl, and C 1-3 Heteroaryl optionally substituted with alkyl or phenyl is pyrid-2-yl optionally substituted with one or more groups selected from the above.

[0007] In an embodiment, Ar 1 is

Chemical formula

[0008] In an embodiment, Ar 1 is

Chemical formula

[0009] In an embodiment, Ar 1 is

Chemical formula

[0010] In this embodiment, R 1a H, CN, halogen, C 1-3 Alkoxy, OH, or CN C arbitrarily replaced by 1-3 It is alkyl.

[0011] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, one or more halogens C arbitrarily replaced with n 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys It can be done.

[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 C3 -6 Selected from the group consisting of cycloalkyl groups, R 3 SO2R 6 SOR 7 R 8 SOR 9 COR 10 , (CH2) p COOH, N HR 11 , POR 12 R 13 , halogen, cycloalkyl, SO2R 14 Or = O Optionally substituted heterocycloalkyl, C 1-3 Alkyl or phenyl can be arbitrarily used. A substituted heteroaryl or C optionally substituted with one or more halogens. 1-3 Alkyl And, 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 in can be, 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 Alkyl 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 Alkyl the law of nature, R 4 , R 5 , R 16 , R 17 , R 18 , R 19 , R 23 , and R 24 Each is independent of H or C 1-3 It is alkyl, p is 1, 2, or 3, and n is 0, 1, 2, or 3.

[0013] In an embodiment, Ar 2 is [Chemical formula] wherein R 3 is selected from the group consisting of F, Cl, Br, and I.

[0014] In an embodiment, Ar 2 is [Chemical formula] wherein R 11 is COR 21 or SO2R 22 where R 21 is heterocycloalkyl, cycloalkyl, or C alkyl, and R 1-3 is NR 22 R 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] wherein R 3 is cycloalkyl, or heterocycloalkyl optionally substituted with SO2R 14 or =O, and R is C 14 alkyl. 1-3

[0016] In an embodiment, Ar 2 is [ka] And in the formula, R 3 C 1-3 Heterozygous which are optionally substituted with alkyl or phenyl It is.

[0017] In the embodiment, a cycloalkyl or optionally substituted heterocycloalkyl is, [ka] It is selected from the group consisting of the following.

[0018] In this embodiment, the optionally substituted heteroaryl is [ka] It is selected from the group consisting of the following.

[0019] In this embodiment, R 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 a Lucuryl, and C 3-6 Selected from the group consisting of cycloalkyl groups, in the formula, R 4 and R 5 Each Each is independent of 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 1 4 Alternatively, a heterocycloalkyl group arbitrarily substituted with =O, C1-3 Alkyl or fu Heteroaryls optionally substituted with a halogen, or optionally substituted with one or more halogens C 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, f Enyl, or NR 18 R 19 And R 8 is NH or NCH3, and R 10 C1 -3 Alkyl or NHSO2R 20 And R 11 COR 21 Or SO2R 22 dea R 9 , R 12 , R 13 R 14 , R 15 , and R 20 Each is independent of C 1-3 Alki It is R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 Alkyl Yes, R 22 , NR 23 R 24 , or C optionally substituted with carboxyl 1-3 Alki It is R 4 , R 5 , R 16 , R 17 , R 18 , R 19 , R 23 , and R 24 Each is independent Standing, 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 And Y and Z are independent of CH or is N, and R 1 Each time, independently, hydrogen, halogen, CN, OH, and one or more halogens Arbitrarily substituted C 1-3 Alkyl and C 1-3 Selected from the group consisting of alkoxys, R 1a H, CN, halogen, C 1-3 Optionally substituted with alkoxy, OH, or CN Ta C 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 SO 2R 6 SOR 7 R 8 SOR 9 COR 10 , (CH2) p COOH, NHR 11 , P Ure 12 R 13 , halogen, cycloalkyl, SO2R 14 Alternatively, you can substitute it with =O as you like. A heterocycloalkyl, C 1-3 Heterozygous substituted with alkyl or phenyl C optionally substituted with loaryl or one or more halogens 1-3 It is alkyl, R 4 and R5 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, R 9 C 1-3 It is alkyl, R 10 C 1-3 Alkyl or NHSO 2R 20 And R 11 COR 21 Or SO2R 22 And R 12 and R 13 Each Each is independent, C 1-3 It is alkyl, R 14 C 1-3 It is alkyl, R 15 teeth, C 1-3 It is alkyl, R 16 and R 17 Each is independently H or C 1-3 Alkyl Yes, 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- It is 3 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 Alkyl ri, 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 Every time In addition, 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, Haro Gen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 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 S Ure 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 Heteroaryls optionally substituted with alkyl or phenyl, or one or more of these. C arbitrarily substituted with halogen 1-3 It is alkyl, R 4 and R 5 Each is independent of the others. 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, f Enyl, or NR 18 R 19 And R 8 is NH or NCH3, and R 9 C 1- It is 3 alkyl, R 10 C 1-3 Alkyl or NHSO2R 20 And R 11 teeth COR 21 Or SO2R 22 And R 12 and R 13 Each is independent of C 1-3 Al It's a kill, 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 is independent H or C 1-3 It is alkyl, R 20 C 1-3 It is alkyl, R 21 teeth, Heterocycloalkyl, cycloalkyl, or C1-3 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, and 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, 1 C optionally substituted with one or more halogens 1-3 Alkyl and C 1-3 From alkoxy Selected from the group, R 1a H, CN, halogen, C 1-3 Alkoxy, OH, or C C arbitrarily substituted with N 1-3 It is alkyl, R 2 Each time, independently, hydrogen, halogen, NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Select from the group consisting of cycloalkyl groups. And, R 3 SO2R 6 SOR 7 R 8 SOR 9 COR 10 , (CH2) p COO H, N HR 11 , POR12 R 13 , halogen, cycloalkyl, SO2R 14 or Heterocycloalkyl groups arbitrarily substituted with =O, C 1-3 Alkyl or phenyl A heteroaryl compound optionally substituted with one or more halogens, or C 1-3 a It is Rukiru, 4 and R 5 Each is independently H or C 1-3 It is alkyl, R 6 teeth, 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 a Lukil 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 Alkyl And R 15 C 1-3 It is alkyl, R 16 and R 17 H or C1 -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 These are heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 or optionally with carboxyl Replaced C 1-3 It is alkyl, R 23 and R 24 H or C 1-3 Alki It is ru, m is 1, 2, 3, or 4, n is 0, 1, 2, or 3, and p is, It is 1, 2, or 3.

[0027] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) is as follows: Structure [ka] or a pharmaceutically acceptable salt thereof.

[0028] In the embodiment of formula (IV), R 1 Each time, independently, hydrogen, halogen, CN, OH, one C arbitrarily substituted with the above halogens 1-3 Alkyl and C 1-3 It is an alkoxy, R 1a It is optionally substituted with H, CN, halogen, C1-3 alkoxy, OH, or CN. Ta C 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 1-3It 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 R 18 and R 19 Each is independently H or C 1-3 It is alkyl, and m is 1, 2, The value is 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 It is CH3 ru.

[0030] In the embodiment, the chemical formulas (A), (I), (II), (III), or (IV) The compound 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 1-3 Alki Selected from the group consisting of R, 7 C 1-3 Alkyl, C 3-5 Cycloalkyl, fer Nil, 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 It is CH3 In this embodiment, R 7 is CH2CH3. In the embodiment, R 7 CH(CH3 )2. In this embodiment, R 7 C 3-5 It is a cycloalkyl group. In this embodiment, R 7 is cyclopropyl. In the embodiment, R 7 This is cyclopentyl. Embodiment So, 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 And R 19 C 1-3 It is alkyl. In this embodiment, R 19 This is CH3. In this embodiment, R 18 and R19 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) is as follows: 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 Every time In addition, 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 a C optionally substituted with lucoxy, OH, or CN 1-3 It is alkyl, R 2 Each time is independent Then, hydrogen, halogen, NR 4 R 5 OH, C 1-3 Alkyl and C 3-6 Cycloal Selected from a group consisting of kills, R 4 and R 5 Each is independently H or C 1-3 Alkyl Yes, 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 17Each of them independently corresponds to H or C1 -3 It is an alkyl group, where m is 1, 2, 3, or 4, and n is 0, 1, 2, or 3. ru.

[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 It is a halogen. In terms of application form, R 1a is Cl. In this embodiment, R 1a This 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 It is H. In terms of form, R 1a is a C arbitrarily replaced by CN. 1-3 It is alkyl. In the 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 Alkoxy In this embodiment, R 1 is methoxy. In this embodiment, R1 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 It is CH3 In this embodiment, R 6 NHCOR 15 And in the formula, R 15 C 1-3 Alkyl In this embodiment, R 15 This is CH3. In this embodiment, R 6 , NR 16 R 1 7 And in the formula, R 16 and R 17 Each is independently H or C 1-3 It is alkyl. In terms of application form, 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) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 3 is cycloalkyl, or SO2R 1 4 Alternatively, it is a heterocycloalkyl group arbitrarily substituted with =O.

[0049] In this embodiment, R 1Each time, independently, hydrogen, halogen, CN, OH, one or more halogens C arbitrarily replaced with n 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 a It is Rukiru, 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Al Kill, and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independent H or C 1-3 It is alkyl, R 14 C 1-3 It is alkyl, and m is 1, 2 n is 0, 1, 2, or 3.

[0050] In the embodiment, the chemical formulas (A), (I), (II), (III), or (VI) The compound has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 3 is cycloalkyl, or SO2R 1 4 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 Alki It is.

[0052] In this embodiment, R 2 H is H. In this embodiment, R2 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, a heterocyclorama arbitrarily substituted with =O It is Lukil, and in the formula, 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) is as follows: Structure [ka] or a pharmaceutically acceptable salt thereof.

[0060] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, one or more halogens C arbitrarily replaced with n 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 a It is Rukiru, 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Al Kill, and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independent 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, and m is 1, 2, 3, or 4 And n is 0, 1, 2, or 3.

[0061] In the embodiment, formula (A), formula (I), formula (II), formula (III), or formula (VII) The compound 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 2 1 Or SO2R 22 And R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 It is alkyl, R 22 , NR 23 R 24 or optionally substituted with carboxyl Ta C 1-3 It is an alkyl, and in the formula, R 23 and R 24 H or C 1-3 Alki It is.

[0063] 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.

[0064] In this embodiment, R 11 COR 21 And in the formula, R 21 is 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 21is a cycloalkyl. In this embodiment, R 21 is, It is chloropropyl. 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 ,also C is optionally substituted with a carboxyl. 1-3 It is an alkyl, and in the formula, R 23 and R 24 teeth Independently, 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 22 It is CH2CH3. In this 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 terms of application form, R 22 This is NHCH3. In this embodiment, R 22 is N(CH3)2 be.

[0068] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 3 C 1-3 Alkyl or phenyl These are heteroaryl compounds with arbitrary substitutions.

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

[0070] In the embodiment, formula (A), formula (I), formula (II), formula (III), or formula (VIII) The compound has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 3 C 1-3 Alkyl or phenyl These are heteroaryl compounds with arbitrary substitutions.

[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 Heterozygous substituted with alkyl or phenyl It is a roaryl. In this 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) is as follows: Structure [ka] or a pharmaceutically acceptable salt thereof.

[0074] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, one or more halogens C arbitrarily replaced with n 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 a It is Rukiru, 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Al Kill, and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independent 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 It is 2, or 3.

[0075] In the embodiment, the chemical formulas (A), (I), (II), (III), or (IX) are used. The compound 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 It is a halogen. In terms of application form, R 1a It is Cl.

[0078] In this embodiment, R 10 C 1-3 It is alkyl. In this embodiment, R 10 CH3 In this embodiment, R 10 This is CH(CH3)2. In the embodiment, R 10 teeth, It 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) is as follows: Structure [ka] or a pharmaceutically acceptable salt thereof.

[0080] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, one or more halogens C arbitrarily replaced with n 1-3 Alkyl and C 1-3 It is an alkoxy, R 1aH CN, halogen, C 1-3 C optionally substituted with alkoxy, OH, or CN 1-3 a It is Rukiru, 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Al Kill, and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independent H or C 1-3 It is alkyl, R 9 C 1-3 It is alkyl, and m is 1, 2, The value is 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 It is CH3 ru.

[0085] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) is as follows: Structure [ka] or a pharmaceutically acceptable salt thereof.

[0086] In this embodiment, R 1 Each time, independently, hydrogen, halogen, CN, OH, one or more halogens C arbitrarily replaced with n 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 a It is Rukiru, 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Al Kill, and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independent H or C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, and n is 0, 1, The value is 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) is as follows: 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, one or more halogens C arbitrarily replaced with n 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 a It is Rukiru, 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Al Kill, and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independent H or C 1-3 It is an alkyl group, where m is 1, 2, 3, or 4, and n is 0, 1, It is either 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 the embodiment, R 3 It is F.

[0097] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) is as follows: Structure [ka] or a pharmaceutically acceptable salt thereof.

[0098] In this embodiment, R 1Each time, independently, hydrogen, halogen, CN, OH, one or more halogens C arbitrarily replaced with n 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 a It is Rukiru, 2 Each time, independently, hydrogen, halogen, and NR 4 R 5 OH, C 1-3 Al Kill, and C 3-6 Selected from the group consisting of cycloalkyl, R 4 and R 5 Each is independent 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 It is CH3 ru.

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

[0103] In this embodiment, R 13 C 1-3 It is alkyl. In this embodiment, R13 CH3 That is the case.

[0104] In some embodiments, the compound is one of compounds 1 to 33. [Table 1] TIFF2026136124000045.tif228170TIFF2026136124000046.tif171170

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

[0106] In another embodiment, the present invention applies to any of the compounds described herein (e.g., compounds 1 to 3) One of the compounds of formulas (A) and (I) to (XIII), or any one of the three, or A pharmaceutical composition comprising a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient. .

[0107] In another aspect, the present invention relates to a method for treating a disease mediated by PHD activity. A key feature of this method is that it can be used with any compound described herein (for example, compounds 1 to 33). One of the compounds of formulas (A) and (I) to (XIII), or their pharmaceutically appropriate This includes administering to a target of an acceptable salt.

[0108] In this embodiment, the disease mediated by PHD activity is ischemia-reperfusion injury (e.g., stroke). (This could be due to a moderate heart attack, myocardial infarction, or acute kidney injury.)

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

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

[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 embodiment, the disease mediated by PHD activity is an eye disease or condition (e.g., a disease of the eye). These include ray 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 (for example, related to chronic kidney disease). (This is related to anemia.)

[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). be.

[0119] In the embodiment, the diseases mediated by PHD activity include ischemic heart disease, valvular heart disease, and Congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute The condition is 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 facilitate understanding of this invention, certain terms are first defined below. The following terms and any additional definitions of other terms are provided throughout this specification. Background to the present invention and to provide further details regarding its implementation, the publications and Other reference materials 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 being at any developmental stage. Morphologically, "animal" refers to a non-human animal at any developmental stage. In a particular embodiment, Non-human animals are mammals (e.g., rodents, mice, rats, rabbits, monkeys, dogs, etc.) These are cows, sheep, cattle, primates, and / or pigs. In some embodiments, the animals are This includes mammals, birds, reptiles, amphibians, fish, insects, and / or parasites, but these It is not limited to these. In some embodiments, the animal is a transgenic animal, genetically engineered. They may be artificially created animals and / or clones.

[0123] Approximately or about: When used herein, "approximately" applies to one or more values ​​of the subject. The terms "approximately" or "about" refer to a value similar to the specified reference value. In this context, the terms "approximately" or "about" are used unless otherwise specified or are clear from the context. Unless otherwise (except when the number of such cases exceeds 100% of the possible values), the presented reference 25%, 20%, 19%, and 18% in either direction of the value (greater than or less than) , 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7 This refers to a range of values ​​that fall within %, 6%, 5%, 4%, 3%, 2%, 1%, or less than or equal to these percentages.

[0124] As used in this description and the accompanying claims, the singular form "one (a)" is used. Unless otherwise clearly defined by the context, "an" and "the" are plural. It includes a number of referents. Therefore, for example, the term "composition" refers to two or more such objects. It contains a mixture of the composition.

[0125] Throughout this specification and the claims, the term "comprise" does not mean "to include." The words, as well as "comprising" and "comprises". Other forms of the word, such as, mean that they include but are not limited to these, for example, other This is not intended to exclude any additives, components, integers, or processes.

[0126] "Optional" or "optionally" implies that the event or situation described there is a possibility that it may occur. Whether or not, and the explanation, includes cases where the event or situation occurs and cases where it does not. It means that.

[0127] To improve, increase, or decrease: When used herein, "improve," "increase" "Add" or "Reduce," or grammatical synonyms, are baseline measurements, for example. , measurements taken in the same individual before the commencement of the treatment described herein, or as described herein The values ​​compared to the measured values ​​in a control group (or multiple control groups) in the absence of the treatment. To show: The "control subjects" are those who have the same disease form as the subjects being treated, and have been treated. The subject is approximately the same age as the subject present.

[0128] In vitro: As used herein, the term “in vitro” refers to in a multicellular organism. However, events that occur in artificial environments such as inside a test tube, reaction vessel, or cell culture medium are not necessarily events that occur in artificial environments. To point.

[0129] In Vivo: As used herein, the term "in vivo" refers to human and non-human animals. This refers to events that occur within multicellular organisms such as objects. In the context of cell-based systems, this term means It can be used to refer to events that occur within living cells (for example, in contrast to in vitro systems). ru.

[0130] Patient: When used herein, the terms “patient” or “subject” refer to the set provided. The substance may be administered for purposes such as experimentation, diagnosis, prevention, cosmetic, and / or therapeutic purposes. It means an organism of intent. Typical patients are animals (e.g., mice, rats, rabbits, non-animals). This includes human primates and / or mammals such as humans. In some embodiments, the affected A person is a human being. A human being includes both the prenatal and postnatal forms.

[0131] Pharmaceutically acceptable: The term "pharmaceutically acceptable" as used herein refers to the context in which it is used. In addition, within the bounds of sound medical judgment, if excessive toxicity, irritation, allergic reaction, or other problems occur, It is suitable for use in contact with human and animal tissues without causing complications. This refers to substances that offer a reasonable benefit-to-risk ratio.

[0132] Pharmacologically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. published a study on pharmaceutically acceptable salts in J. Pharmaceuticals. This is described in detail in Cal Sciences (1977) 66:1-19. pharmaceutically acceptable salts of compounds include suitable inorganic acids and organic acids, as well as inorganic bases and organic salts. This includes those derived from the base. Examples of pharmaceutically acceptable, non-toxic acid addition salts include hydrochloric acid and bromide. Using inorganic acids such as hydrogen acids, phosphoric acid, sulfuric acid, and perchloric acid, or acetic acid, oxalic acid, maleic acid Using organic acids such as ic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or A formed by using other methods used in the art, such as on-exchange. It is a salt of the mino group. Other pharmaceutically acceptable salts include adipines and alginates. Ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, Borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentamp Ropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate Salts, glucoheptones, glycerophosphates, glucons, hemisulfates, heptanoic acid Salt, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobio Salts, lactates, laurates, lauryl sulfates, malates, maleates, malonic acid Salt, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleic acid Phenylate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenyl Lupropionate, phosphate, picrate, pivalate, propionate, stearin Salts, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, Examples include ndecanate and valerate. Suitable salts derived from a base include alkalis. Examples include metal salts, alkaline earth metal salts, ammonium salts, and N+(C1-4 alkyl) tetrasalts. Typical alkali metal salts or alkaline earth metal salts include sodium and lithium. Examples include um, potassium, calcium, and magnesium. Further pharmaceutically acceptable As for salts, when appropriate, halides, hydroxides, carboxylates, sulfates, phosphates, Formed using counterions such as nitrates, sulfonates, and aryl sulfonates. Examples include non-toxic ammonium cations, quaternary ammonium cations, and amine cations. Further pharmaceutically acceptable salts are those containing suitable electrophiles, such as quaternary alkylated amino acids. Salts formed from the quaternization of amines using alkyl halides to form the no salt. Includes.

[0133] Subject: As used herein, the term "subject" means human or any non-human animal. (For example, mice, rats, rabbits, dogs, cats, cows, pigs, sheep, horses, or primates) This refers to the same category. Humans include prenatal and postnatal forms. In many embodiments, the subject is The subject is a human being. The subject may be a patient who visits a healthcare provider for the diagnosis or treatment of a disease. Refers to a human being. The term "subject" is used interchangeably with "individual" or "patient" in this specification. The subjects are those who can contract a disease or disability, or are susceptible to contracting one, but who do not have symptoms of the disease or disability. They may or may not present a symptom.

[0134] Substantially: As used herein, the term “substantially” means the intended characteristics or This refers to a qualitative state exhibiting all or nearly all ranges or degrees of a characteristic. If a biological and chemical phenomenon is completed and / or reaches completion, or is absolutely Understand that achieving or avoiding the desired outcome is extremely rare, if at all possible. There will be. Therefore, the term "substantially" in this specification means many biological and It is used to capture the potential lack of completion inherent in chemical phenomena.

[0135] Therapeutic dose: As used herein, the term “therapeutic dose” of a therapeutic agent refers to the effective dose of a drug for a disease. When administered to subjects who have or are susceptible to a disorder and / or condition. , to treat, diagnose, prevent, and / or treat the symptoms of the disease, disorder, and / or condition. This means a sufficient amount to delay the onset of the disease. Those skilled in the art will know that a typical therapeutic dose is... It is understood that it is administered by a dosing regimen containing at least one unit dose. It is likely.

[0136] To treat: When used herein, “to treat,” “to cure,” or “to treat” The term "thing" refers to one or more symptoms or conditions of a particular disease, disorder, and / or condition. To partially or completely mitigate, improve, reduce, suppress, prevent, or alleviate a characteristic. Used to delay the onset of the disease, reduce its severity, and / or reduce its incidence. This refers to any method of treatment. Treatment is for subjects who are not showing signs of the disease and / or in the early stages of the disease. To reduce the risk of developing disease-related conditions in subjects who are only showing symptoms. It may be administered for a specific purpose.

[0137] Aliphatic: As used herein, the term aliphatic refers to C1-C 40 Hydrocarbons It includes both saturated and unsaturated hydrocarbons. Aliphatic hydrocarbons can be linear, branched, or ring-shaped. It can be in this state. For example, C1-C 20 Aliphatic species include C1-C 20 Alkyl (for example, linear Or branched C1-C 20 Saturated alkyl), C2-C 20 Alkenyls (for example, linear or segmented) 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. 1-C 20 Aliphatic species include C3-C 20 Cyclic aliphatic (e.g., C3-C) 20 Cycloalkyl, C4-C 20 Cycloalkenyl, or C8-C 20 It may contain cycloalkynyl. In certain embodiments, the aliphatic is one or more cyclic aliphatic and / or one or more heteroatoms For example, it may contain oxygen, nitrogen, or sulfur, and optionally alkyl, halo, alkoxyl, hydroxyl With one or more substituents such as droxy, amino, aryl, ether, ester, or amide It may be substituted. The aliphatic group is either unsubstituted or substituted with one or more as described herein. Substituting with a group. For example, aliphatic groups include halogens, -COR', -CO2H, and -CO2 R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR One or more of ', -N(R')2, -SR', or -SO2R' (for example, 1, 2, It may be substituted with 3, 4, 5, or 6 independently selected substituents, where each example of R' is Independent, C1-C 20 Aliphatic (e.g., C1-C) 20 Alkyl, C1-C 15 Alkyl, C1-C 10 It is alkyl, or C1-C3 alkyl. In some embodiments, R' These are independently unsubstituted alkyl groups (e.g., unsubstituted C1-C 20 Alkyl, C1-C 15 Alki Ru, C1-C 10 It is alkyl, or C1-C3 alkyl. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl group. In some embodiments, an aliphatic group is , unsubstituted. In some embodiments, the aliphatic group does not contain any heteroatoms.

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

[0139] When the suffix "-ene" is added to a base, it indicates that the base is a divalent part, for example. For example, arylene is the divalent part of aryl, and heteroarylene is the heteroaryl part. This is the divalent part.

[0140] Alkylene: As used herein, the term "alkylene" refers to saturated divalent linear or fractional alkylene. This represents a branched hydrocarbon group, exemplified by methylene, ethylene, and isopropylene. Similarly, the term "alkenylene" as used herein refers to any stable along the chain. An unsaturated divalent straight or branched chain having one or more unsaturated carbon-carbon double bonds may occur at this point. Representing a hydrocarbon group, the term "alkynylene" herein refers to any group along the chain. An unsaturated divalent linear chain having one or more unsaturated carbon-carbon triple bonds that can occur at a stable point or Represents a branched-chain hydrocarbon group. In certain embodiments, this may include an alkylene group, an alkenylene group, or The alkynylene group is one or more cyclic aliphatic and / or oxygen, nitrogen, or sulfur, etc. It may contain one or more heteroatoms, including alkyl, halo, alkoxyl, hydroxy, amino, It may be optionally substituted with one or more substituents such as aryl, ether, ester, or amide. For example, alkylene, alkenylene, or alkynylene are halogens, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R' -NH2, -NHR', -N(R')2, -SR', or -SO2R' It can be substituted with the above (for example, 1, 2, 3, 4, 5, or 6 independently selected substituents). In the formula, each example of R' is independent of C1-C 20 Aliphatic (e.g., C1-C) 20 Alkyl, C 1-C 15 Alkyl, C1-C 10 It is alkyl (or C1-C3 alkyl). In this embodiment, R' is independently an unsubstituted alkyl (e.g., unsubstituted C1-C 20 Alki Ru, C1-C 15 Alkyl, C1-C 10 It is alkyl, or C1-C3 alkyl. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl group. In the embodiment, alkylene, alkenylene, or alkynylene is unsubstituted. In a specific configuration, alkylene, alkenylene, or alkynylene is a heterogene. Children are not included.

[0141] Alkenyl: As used herein, “alkenyl” means any stable along a chain Any linear or branched structure having one or more unsaturated carbon-carbon double bonds can be formed at the point where it occurs. It means a hydrocarbon chain, for example, "C2-C 20 "Alkenyl" refers to a group containing 2 to 20 carbon atoms. This refers to the alkenyl group. For example, alkenyl groups include prop-2-enyl and buta-2- Enyl, buta-3-enyl, 2-methylprop-2-enyl, hexa-2-enyl, hex This includes sa-5-enyl, 2,3-dimethylbuta-2-enyl, etc. Several implementation forms In this state, an alkenyl contains one, two, or three carbon-carbon double bonds. Several implementations In terms of form, an alkenyl contains a single carbon-carbon double bond. In some embodiments, Multiple double bonds (e.g., two or three) are conjugated. The alkenyl group is unsubstituted. It may be or may be substituted with one or more substituents described herein. For example, Alke The nyl group is a halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR ', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR' , or one or more of -SO2R' (for example, 1, 2, 3, 4, 5, or 6 independent It may be substituted with a substituent selected by the formula, where each example of R' is independently C1-C 20 aliphatic (For example, C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl, or C It is a 1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted alkyl group. (For example, unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl, (or C1-C3 alkyl). In some embodiments, R' is independently an unsubstituted C It is a 1-C3 alkyl group. In some embodiments, the alkenyl group is unsubstituted. In several embodiments, the alkenil is (for example, 1, 2, 3, 4 described herein) It is substituted with 5 or 6 substituents. 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 the -OH group, and "alkenyl" is as described herein.

[0142] Alkinyl: As used herein, "alkinyl" means any stable along the chain At the point where it occurs, a linear or branched arrangement having one or more carbon-carbon triple bonds is formed. It means any of the hydrocarbon chains, for example, "C2-C 20 "Alkinyl" is 2 to 20 This refers to an alkynyl group having a carbon atom. An example of an alkynyl group is prop-2-inyl. Buta-2-inyl, Buta-3-inyl, Penta-2-inyl, 3-methylpenta-4-inyl Examples include yl, hexa-2-inyl, hexa-5-inyl, etc. In some embodiments... Alkynyl groups contain one carbon-carbon triple bond. Alkynyl groups can be unsubstituted. or may be substituted with one or more substituents described herein. For example, alkynyl The bases are halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or is one or more of -SO2R' (for example, 1, 2, 3, 4, 5, or 6 independently selected) It may be substituted with a selected substituent, where each example of R' is independently C1-C 20 Aliphatic (example) For example, C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl, or C1-C 3) alkyl). In some embodiments, R' is independently an unsubstituted alkyl (e.g. If, non-substituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl, or C It is a 1-C3 alkyl group. In some embodiments, R' is independently an unsubstituted C1-C3 alkyl group. It is alkyl. In some embodiments, the alkynyl is unsubstituted. In the application form, alkynyl is (for example, as described in 1, 2, 3, 4, 5 or ) It is substituted with six substituents.

[0143] Aryl: Similar to "aralkill," used alone or as part of a larger part. The term "aryl" as used refers to mono-ring and bi-ring structures with a total of 6 to 14 ring members. , or tricyclic carbocyclic structure, where the aforementioned ring structure is a single ring structure with the rest of the molecule. It has a bonding point, and at least one ring in the system is aromatic, and herein, Each ring in the stem contains 4 to 7 ring members. In some embodiments, the aryl group is , having six ring carbon atoms ("C6 aryl", e.g., phenyl). Several implementations Morphologically, the aryl group has 10 ring carbon atoms ("C 10 "Aryl"; for example, Naphthyl groups such as 1-naphthyl and 2-naphthyl. In some embodiments, aryl groups It has 14 ring carbon atoms ("C 14 "Aryl"; for example, anthracine (ant hracyl). "Aryl" also includes ring systems, and in this case as defined above. In this case, the aryl ring is condensed with one or more carbocyclic groups or heterocyclyl groups. The bond radical or bond point is on an aryl ring, and in such cases, the number of carbon atoms follows. Specify the number of carbon atoms in the Lille ring system. Examples of aryls include phenyl, naphthyl, and ammonium. Trasen is one example.

[0144] Arirene: As used herein, the term "arirene" means divalent This refers to an aryl group (i.e., having two bonding points in the molecule). Examples include arylenes. Examples include phenylene (for example, unsubstituted phenylene or substituted phenylene).

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

[0146] Amid: 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 ’ teeth Independently, unless otherwise stated herein, hydrogen, alkyl, alkenyl, alkynyl Heteroalkyl (bonded via chain carbons), cycloalkyl, aryl, arylalkyl , heteroaryl (bonded via ring carbon), heteroarylalkyl, or heteroalkyl Selected from rHalkyl (bonded via ring carbon), each of them is used herein. They can be arbitrarily substituted as described, or two R's can be combined with a nitrogen atom It can form a 3, 4, 5, 6, or 7-membered ring.

[0147] Amino: The term "amino" or "amine" refers to the -N(R')2 group, and in the formula, each R ’ These are independently hydrogen, alkyl, alkenyl, and aldehyde, unless otherwise stated herein. Quinyl, heteroalkyl (bonded via chain carbons), cycloalkyl, aryl, aryl Alkyl, heteroaryl (bonded via ring carbon), heteroarylalkyl, heteroalkyl Select from chloroalkyl (bonded via ring carbon), sulfonyl, amide, or carbonyl groups. Each of them may be substituted as described herein, or Two R' atoms combine with a nitrogen atom to form a 3, 4, 5, 6, or 7-membered ring. This can be done. In the embodiment, the amino group is -NHR', where R' is aryl( "Arylamino"), heteroaryl ("heteroarylamino"), amide, or A It is called "alkylamino".

[0148] Sulfonyl: The term "sulfonyl" is -S(=O)2R', or -S(=O)2 - Refers to the base, in the formula, R ’ Unless otherwise stated herein, hydrogen, alkyl, alke Nyl, alkynyl, heteroalkyl (linked via chain carbons), amino, cycloalkyl, Aryl, arylalkyl, heteroaryl (bonded via ring carbon), heteroaryl Selected from alkyl and heterocycloalkyl (bonded via ring carbon), each of them is It itself can be optionally replaced as described herein. For example, in one embodiment, The sulfonyl group is -SO2R', where R' is an alkyl group substituted with a carbonyl group. It is.

[0149] Sulfinyl: The term "sulfinyl" is derived from the formulas -S(=O)R', -S(=O)- , or refers to a chemical part having -S(=O)(=NR')-, where R ’ This specification Unless otherwise specified, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (chain) (bonded via carbon), cycloalkyl, aryl, arylalkyl, heteroaryl ( (bonded via ring carbon), heteroarylalkyl, heterocycloalkyl (bonded via ring carbon) Selected from (and combined), each of them can be placed as described herein. It can be exchanged.

[0150] Carbonyl: The term "carbonyl" refers to -C(=O)R' or -C(=O)- group It refers to, and in the formula, R ’ Unless otherwise stated herein, hydrogen, alkyl, alkenyl alkynyl, heteroalkyl (bonded via chain carbon), cycloalkyl, aryl, alpha Alkyl alkyl, amino, hydroxyl, heteroaryl (bonded via ring carbon), hetero Selected from loarylalkyl and heterocycloalkyl (bonded via ring carbon), Each of these may be optionally substituted as described herein.

[0151] Phosphoryl: The term "phosphoryl" refers to -P(=O)(R')2, or -P(=O )(R')- refers to the base, and in the formula, R ’ Unless otherwise stated herein, hydrogen, alkyl Alkenyl, alkynyl, heteroalkyl (via chain carbon or heteroatom) (bonded via), cycloalkyl, aryl, arylalkyl, heteroaryl (ring carbon) (bonded via ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded via ring carbon) A group is selected from the bonding groups, each of which can be arbitrarily placed as described herein. They can be replaced, or two R' atoms can be combined with a nitrogen atom to form 3, 4, 5, 6, or 7 It can form a member ring.

[0152] Heteroalkyl: The term "heteroalkyl" refers to a group consisting of N, O, S, and P. In addition to 1, 2, 3, or 4 heteroatoms independently selected, it has 1 to 14 carbon atoms. This refers to branched or unbranched alkyl, alkenyl, or alkynyl groups. Telolalkyls include tertiary amines, secondary amines, ethers, thioethers, amides, and thioamines. do, carbamate, thiocarbamate, hydrazone, imine, phosphodiester, phospho It contains amidates, sulfonamides, and disulfides. Heteroalkyl groups are optional. They may include monoring, biring, or triring rings, each preferably having 3 to 6 members. Examples of heteroalkyls include polyethers such as methoxymethyl and ethoxyethyl. Born.

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

[0154] Heteroaryl: The term "heteroaryl" refers to a compound with a total of 6 to 14 ring members. This refers to monocyclic, bicyclic, or tricyclic carbocyclic systems, where the aforementioned ring systems are molecules The rest have a single attachment point, and at least one ring in the system is aromatic, and in the system Each ring contains 4 to 7 ring members, and at least one ring atom is nitrogen and oxygen. These are heteroatoms, but are not limited to these.

[0155] Heterocycloalkyl: As used herein, “heterocycloalkyl” The term refers to a substance in which at least one atom is nitrogen, oxygen, sulfur, or phosphorus, but is not limited to these. It is a heteroatom, and the remaining atom is carbon, forming a non-aromatic ring. The L-alkyl group may be substituted or unsubstituted.

[0156] Deuterium: "Deuterium" ("D" or " 2 The term "H" is heavy Also called heavy hydrogen. Deuterium is composed of one proton and one It is an isotope of hydrogen that has a nucleus consisting of 1 neutron, and this has the same nucleus mass as ordinary hydrogen (1 It is twice the number of protons.

[0157] Isotopes: The term "isotopes" refers to specific isotopes that differ in the number of neutrons and, consequently, the number of nucleons. This refers to variants of an element. All isotopes of a given element have the same number of proto-isotopes in each atom. It has neutrons, but with different numbers of neutrons.

[0158] The term "substituted" means that the specified group or part has one or more substituents. This means that the term "unsubstituted" means that the specified group does not have substituents. The term "arbitrarily substituted" means that the specified group is either unsubstituted or has one or more substitutions. This means that it is substituted by a substituent. The term "substituted" describes the structural system. When used to clarify, substitution means that it occurs at any valence-allowed position in the system. For example, substitution is a stable compound (e.g., reconstitution, cyclization, removal, or other reaction). This results in a compound that does not spontaneously undergo transformation. The specified part or group, It is not explicitly stated that it will be substituted arbitrarily or substituted with any specified substituent. In such cases, it is understood that such part or base is intended to be non-substitutable.

[0159] Ring systems (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl) If substitution is performed with a different number of substituents within an explicitly defined range, the total number of substituents is already It is understood that the valence does not exceed the normal available valence under the conditions of existence. Also, the hydrogen atom It is also understood that substituents are presumed to exist to satisfy the remaining valences of the ring system. combinations of substituents and variables that result in stable compounds or chemically feasible compounds. It includes only those compounds that are stable or chemically feasible, among other factors. It is a compound that is stable enough to enable 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, and cycloalkyl. Kenyl, Alkinyl, Arylalkyl, Alkylaryl, Aryl, Arylalco xy, arylamino, heteroarylamino, heteroaryl, heteroarylalco Xy, heterocycloalkyl, hydroxyalkyl, aminoalkyl, haloalkyl, thi Oalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, ing Drillalkyl, mono, di, and trihaloalkyl, mono, di, and trihaloalkoxy compounds , amino, alkylamino, dialkylamino, amide, cyano, alkoxy, Hydroxy C, sulfonamides, halos (e.g., -Cl and -Br), nitros, oxyiminos, -C OOR 50 , -COR 50 , -SO 0-2 R 50 -SO2NR 50 R 51 , NR 52 SO 2R 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 5 1 ) are included, but not limited thereto, wherein R 50 , R 51 , and R 52 are independent and can be selected from the following: a hydrogen atom, and a branched or straight-chain C 1-6 -alkyl, C 3-6 -cycloalkyl, C 4-6 -heterocycloalkyl, heteroaryl, and aryl groups (with or without substituents). When permitted, R 50 and R 51 can be bonded together to form a carbocyclic or heterocyclic ring system.

[0161] In a preferred embodiment, the substituent is selected from halogen, -COR’, -CO2H, -CO2R’ , -CN, -OH, -OR’, -OCOR’, -OCO2R’, -NH2, -NHR’ , -N(R’)2, -SR’, and -SO2R’, wherein each example of R’ is independent and is C1-C 20 aliphatic (e.g., C1-C 20 alkyl, C1-C 15 alkyl, C1-C 10 alkyl, or C1-C3 alkyl). In a certain specific embodiment, R’ is independently unsubstituted alkyl (e.g., unsubstituted C1-C 20 alkyl, C1-C 15 alkyl , C1-C 10 alkyl, or C1-C3 alkyl). Preferably, R’ is independently unsubstituted C1-C3 alkyl.

[0162] Any formula provided herein is a compound having the structure shown by the structural formula, and It is intended to represent a particular variation or form of the above. In particular, any of the variations provided herein The compound in the formula may have a chiral center and therefore exists in different enantiomer forms. All optical isomers and stereoisomers of compounds of a general formula, as well as mixtures thereof, are within the scope of the formula. It is considered to be within the bounds. Therefore, any formula provided herein is a racemate, one or more The enantiomers of, one or more diastereomer forms, one or more atropisomer forms, and It is intended to represent mixtures of those. Furthermore, certain structures have geometric isomers ( That is, as cis and trans isomers, as tautomers, or as atrop isomers It may exist. Furthermore, any formula provided herein is a hydrate, solvated form of such compound. It is intended to encompass substances, polymorphisms, and mixtures thereof.

[0163] The compound of the present invention Compounds that are potent inhibitors of PHD are disclosed herein. In some embodiments The compound of the present invention is used in relation to any one of PHD1, PHD2, and PHD3. Enzymatic semi-maximal inhibitory concentration (IC) less than 100 μM 50 ) has a value. In some embodiments The compound of the present invention is one of PHD1, PHD2, and PHD3. ICs with a minimum particle size of 50 μM 50 It has a value. In some embodiments, the compounds of the present invention are P For any one of HD1, PHD2, and PHD3, the IC is less than 25 μm. 50 It has a value. In some embodiments, the compounds of the present invention are PHD1, PHD2, and P An IC value less than 20 μM for any one of HD3. In some embodiments, the compound of the present invention has an IC value less than 15 μM for any one of PHD1, PHD2, and PHD3. In some embodiments, the compound of the present invention has an IC value less than 10 μM for any one of PHD1, PHD2, and PHD3. In some embodiments, the compound of the present invention has an IC value less than 5 μM for any one of PHD1, PHD2, and PHD3. In some embodiments, the compound of the present invention has an IC value less than 1 μM for any one of PHD1, PHD2, and PHD3. In some embodiments, the compound of the present invention has an IC value of about 3 nM to about 5 nM for any one of PHD1, PHD2, and PHD3. In some embodiments, the compound of the present invention has an IC50 value of about 5 nM to about 10 nM for any one of PHD1, PHD2, and PHD3. In some embodiments, the compound of the present invention has an IC value of about 10 nM to about 20 nM for any one of PHD1, PHD2, and PHD3. In some embodiments, the compound of the present invention has an IC value of about 20 nM to about 50 nM for any one of PHD1, PHD2, and PHD3. In some embodiments, the compound of the present invention has an IC value of about 50 nM to about 100 nM for any one of PHD1, PHD2, and PHD3. 50 It has a value. In some embodiments, the compound of the present invention is for any one of PHD1, PHD2, and PHD3 less than 15 μM of IC 50 value. In some embodiments, the compound of the present invention is less than 10 μM for any one of PHD1, PHD2, and PHD3 IC 50 value. In some embodiments, the compound of the present invention is for any one of PHD1, PHD2 and PHD3 less than 5 μM of IC 50 value. In some embodiments, the compound of the present invention is for any one of PHD1, PHD2, and PHD3 less than 1 μM of IC 50 value. In some embodiments, the compound of the present invention is for any one of PHD1, PHD2, and PHD3 from about 3 nM to about 5 nM of IC 50 value. In some embodiments, the compound of the present invention is for any one of PHD1 PHD2, and PHD3 from about 5 nM to about 10 nM of IC5 0 value. In some embodiments, the compound of the present invention is for PHD1, PHD2, and PHD3 from about 10 nM to about 20 nM of IC 50 value. In some embodiments, the compound of the present invention is for any one of PHD1, PHD2, and PHD3 from about 20 nM to about 50 nM of IC 50 value. In some embodiments, the compound of the present invention is for any one of PHD1, PHD2, and PHD3 from about 50 nM to about 100 nM of IC 50 value. In some embodiments, the present The compound of the invention contains about 1 of any one of PHD1, PHD2, and PHD3. ICs with a capacitance of 00nM to approximately 200nM 50 It has a value. In some embodiments, the present invention The substance has approximately 200 nM~ for any one of PHD1, PHD2, and PHD3. IC with approximately 500 nM 50 It has a value. In some embodiments, the compounds of the present invention have a pH Approximately 500nM to approximately 1000 for any one of D1, PHD2, and PHD3 nM IC 50 It has a value.

[0164] A typical example from this class is PHD1, PHD2, and PHD3 in vitro. It exhibits inhibitory activity.

[0165] Exemplary compounds are described herein. In particular, these selective inhibitors are two aromatic compounds. Characterizing the pyrazole moiety (e.g., 5-hydroxysubstituted pyrazole) that links the group moieties. It is possible.

[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 C1 is optionally substituted with a halogen, CN, OH, CN, or one or more halogens. -3 Alkyl and C 1-3 Optionally substituted with one or more groups selected from alkoxys It is an aryl or heteroaryl, Ar 2 is halogen; amino; amide; OH; sulfonyl group; sulfinyl group; carbony C group; phosphoryl group; C 3-6 Cycloalkyl; sulfonyl group or optionally substituted with =O Ta C 3-6 Heterocycloalkyl; optionally substituted with carbonyl or one or more halogens. Ta C 1-3 Alkyl and C 1-3 Heteroalkyl or phenyl-substituted heteroalkyl groups A compound that is pyrido-2-yl optionally substituted with one or more groups selected from yl, or a pharmaceutically acceptable salt thereof.

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

[0168] In another embodiment, Ar 1 This is an unsubstituted 6-membered heteroaryl. In another embodiment, Ar 1 This is a substituted six-membered heteroaryl compound.

[0169] In this embodiment, Ar 1 This can be any halogen, CN, OH, CN, or one or more halogens. C replaced 1-3 Alkyl and C 1-3 One or more groups selected from alkoxy It is replaced. In some embodiments, Ar 1 It is substituted with one substituent. In some embodiments, Ar 1 It is substituted with two substituents. Several implementations In terms of attitude, Ar 1 It is substituted with three substituents. In some embodiments, Ar 1 teeth 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 Hydrogen, Halogen, CN, OH, 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 1 The parent-child structure It can replace the hydrogen in the production process. In this embodiment, R 1 There exists a non-hydrogen portion. In that case, R 1 represents a substituent. In this embodiment, R 1 This includes halogen, CN, OH, and one or more of the following: C arbitrarily substituted with halogen 1-3 Alkyl and C 1-3 Independent of alkoxy Selected.

[0171] Therefore, for any value of m described herein, hydrogen is used to stabilize the molecule. It is a compound (for example, molecules spontaneously undergoing rearrangement, cyclization, removal, or other reactions). (A compound that does not undergo transformation) 1 In order to satisfy the valence requirement with the constituent atoms It is also understood that it may exist as needed. 1 , R 1 , and exemplary embodiments of m This is described herein.

[0172] In this embodiment, Ar 1 teeth, [ka] And in the formula, X is N or CR1a 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 There exists a non-hydrogen portion. In that case, R 1 represents a substituent.

[0174] In the embodiment, the value of m is based on the number of nitrogen atoms present in the ring. If one of Y and Z and only one of them is N, then m is 1, 2, or 3. In the application configuration, if Y and Z are both N, then m is either 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 the embodiment, m is 4.

[0178] In this embodiment, both Y and Z are N, and m is 1 or 2. m is 1, and any remaining unsubstituted carbon ring atoms bond to hydrogen to satisfy their valence. It is considered that it is doing so. In this embodiment, m is 2.

[0179] In this embodiment, both Y and Z are CH, and m is 1, 2, 3, or 4. In this embodiment, m is 1, and any remaining unsubstituted carbon ring atoms satisfy the valence. It is considered to be bonded to hydrogen. In the embodiment, m is 2, and any remaining non-position The substituted carbon ring atom is considered to be bonded to hydrogen in order to satisfy its valence. In this embodiment, m is 3, and any remaining unsubstituted carbon ring atoms bond to hydrogen to satisfy their valence. It is considered to be doing so. In this embodiment, m is 4.

[0180] In this embodiment, one of Y and Z is CH, the other is N, and m is 1. 2 or 3. In the embodiment, m is 1, and any remaining unsubstituted carbon ring atoms are It is assumed that it is bonded to hydrogen in order to satisfy its valence. In the embodiment, m is 2. Any remaining unsubstituted carbon ring atoms are considered to be bonded to hydrogen in order to satisfy their valence. In this 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 The valency is 1, and any remaining unsubstituted carbo-ring atoms are bonded to hydrogen to satisfy the valency. It is considered that in this embodiment, m is 2, and any remaining unsubstituted carbon ring atoms are atoms It is assumed to be bonded to hydrogen in order to satisfy the value. In this embodiment, m is 3.

[0183] In the embodiment, Z is CH and m is 1, 2, 3, or 4. m is 1, and any remaining unsubstituted carbon ring atoms bond to hydrogen to satisfy their valence. It is considered that m is 2, and any remaining unsubstituted carbon ring atoms are It is considered to be bonded to hydrogen in order to satisfy the valence. In this embodiment, m is 3. Any remaining unsubstituted carbon ring atoms are considered to be bonded to hydrogen in order to satisfy their valence. In this 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 carbon ring atoms satisfy the valence. Therefore, it is considered to be bonded to hydrogen. In the embodiment, m is 2, and any remaining non Substitutive carbocyclic atoms are considered to be bonded to hydrogen in order to satisfy their valence. In embodiments In this case, m is 3, and any remaining unsubstituted carbon ring atoms bond to hydrogen to satisfy the valence. They are considered to be in combination. 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 an embodiment, R 1a is a halogen. In an embodiment, R 1a is 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 meth oxy. In an embodiment, R 1a is ethoxy. In an embodiment, R 1a is pro poxy.

[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 alkyl substituted with a C 1-3 N 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 1It is OH every time.

[0198] In this embodiment, R 1 The halogen is always a halogen. In the embodiment, the halogen is Cl. In the embodiment, the halogen is Br. In the 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 every Next, it's CH3.

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

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

[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 C3 -6 Selected from the group consisting of cycloalkyl groups, R 3 SO2R 6 SOR 7 R 8 SOR 9 COR 10 , (CH2)p COOH, N HR 11 , POR 12 R 13 , halogen, cycloalkyl, SO2R 14 Or = O Optionally substituted heterocycloalkyl, C 1-3 Alkyl or phenyl can be arbitrarily used. A substituted heteroaryl or C optionally substituted with one or more halogens. 1-3 Alkyl And, 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 in can be, 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 Alkyl 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 Alkyl the law of nature, R 4 , R 5 , R 16 , R 17 , R 18 , R 19 , R 23 , and R 24 Each is independent of 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 satisfy the valence. It is considered to be bonded to hydrogen.

[0208] In this embodiment, n is 1, and any remaining unsubstituted carbon ring atoms satisfy the valence. Therefore, it is considered to be bonded to hydrogen. In the embodiment, n is 2, and any remaining non Substitutive carbocyclic atoms are considered to be bonded to hydrogen in order to satisfy their valence. In embodiments In this case, 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 The halogen is always 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 2Every time, NR 4 R 5 And in the formula, R 4 and R 5 Each is independent of the others. 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 Alkyl Yes. In one 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, NHC Ure 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, C3 -5 Cycloalkyl, phenyl, or NR 18 R 19 And in the formula, R 8 is NH or N It is CH3.

[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 N HSO2R 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. Implementation In the given state, p is 2. In the embodiment, p is 3. In this embodiment, R 3 NHR 11 And in the formula, R 11 COR 21 Or SO2R 2 2 And in the formula, R 21 is a heterocycloalkyl, cycloalkyl, or C 1-3 Al It's a kill, 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 Alkyl ru.

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

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

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

[0226] In this embodiment, R 3 is a heteroaryl. In the embodiment, the heteroaryl is non This is a substitution. In this embodiment, the heteroaryl is substituted.

[0227] In this embodiment, R 3 C 1-3 It is alkyl. In this embodiment, C 1-3 Alkyl is , non-substitutable. In the embodiment, C 1-3 Alkyl is substituted with one or more halogens. Yes, they are.

[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 As defined anywhere in the specification.

[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 the details As defined elsewhere in the book.

[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 the details As defined elsewhere in the book.

[0231] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is at the discretion of this specification. It is defined as the place of meaning.

[0232] In the embodiment, the chemical formulas (A), (I), (II), (III), or (IV) The compound has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula A, R 1a and R 2 Any of the foregoing in this specification It is defined as the location.

[0233] In this embodiment, R 7 C 1-3It 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 independent 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 the 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) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, wherein X, Z, R 1 , and R 2 This is at the discretion of this specification. It is defined as the place of meaning.

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

[0244] In this embodiment, R 6 NHCOR 15 And in the formula, R 15 It is C1-3 alkyl Yes. In the 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 independent 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 the embodiment R 17 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) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is at the discretion of this specification. It is defined as the place of meaning.

[0251] In the embodiment, the chemical formulas (A), (I), (II), (III), or (VI) The compound has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 2 This is defined anywhere in this specification. That is correct.

[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 C1-3 Alki It is.

[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 is, S O2R 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) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is at the discretion of this specification. It is defined as the place of meaning.

[0259] In the embodiment, formula (A), formula (I), formula (II), formula (III), or formula (VII) The compound has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 2 This is defined anywhere in this specification. That is correct.

[0260] In this embodiment, R 11 COR 21 And in the formula, R 21 is 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 CH2 It is CH3.

[0264] In this embodiment, R 11 SO2R 22 And in the formula, R 22 , NR 23 R 24 ,also C is optionally substituted with a carboxyl. 1-3 It is an alkyl, and in the formula, R 23 and R 24 teeth Each 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 non-substituted C 1-3 It is alkyl. In this embodiment, R 22 is a C substituted with a carboxyl group. 1- It is 3 alkyl. In this embodiment, R 22 It is CH2COOH.

[0266] In this embodiment, R 22 , NR 23 R 24 And in the formula, R 23 and R 24 Independent , 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 the embodiment R 24 This is CH3.

[0270] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R1a , R 1 , and R 2 This is at the discretion of this specification. It is defined as the place of meaning.

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

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

[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 heteroaryls substituted with alkyl or phenyl Yes. 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) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R1a , R 1 , and R 2 This is at the discretion of this specification. It is defined as the place of meaning.

[0276] In the embodiment, the chemical formulas (A), (I), (II), (III), or (IX) are used. The compound has the following structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a This is defined anywhere in this specification. That is correct.

[0277] In this embodiment, R 10 C 1-3 It is alkyl.

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

[0279] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is at the discretion of this specification. It is defined as the place of meaning.

[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) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is at the discretion of this specification. It is defined as the place of meaning.

[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) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1 , and R 2 This is at the discretion of this specification. It is defined as the place of meaning.

[0284] In this embodiment, R 3 is a halogen. In this embodiment, R 3 This is F. Embodiment So, R 3 is Cl. In this embodiment, R 3 is Br. In this embodiment, R 3 teeth , is I.

[0285] In the embodiment, the compound of formula (A), formula (I), formula (II), or formula (III) is as follows: Structure [ka] or having a pharmaceutically acceptable salt thereof, in the formula, R 1a , R1 , and R 2 This is at the discretion of this specification. It is defined as the place of meaning.

[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 any one of compounds 1 to 33. It is either a salt or a pharmaceutically acceptable salt thereof. [Table 2] TIFF2026136124000078.tif232170TIFF2026136124000079.tif216170

[0288] Isotope substitution Compounds described herein (for example, any one of compounds 1 to 33, etc.) In (A) and any one of (I) to (XIII) compounds, the atom is It may indicate the natural isotopic abundance of the atoms, or one or more atoms may have the same atomic number. However, it has an atomic mass or mass number that is different from the atomic mass or mass number mainly found in nature. It should be understood that specific isotopes can be artificially enriched. This invention is described herein. The compounds listed (for example, any one of compounds 1 to 33, etc.) All suitable isotopic transformations of A) and any one of the compounds from (I) to (XIII) It is intended to include dynamic forms. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium (2 H), and tritium ( 3 It contains H). Protium is found in nature. It is the primary hydrogen isotope.

[0289] In some embodiments, the compounds described herein (for example, compounds 1 to 33) One of the following compounds: formula (A) and one of the following compounds (I) to (XIII) One or more of the hydrogen atoms in a substance are replaced by deuterium. The concentration of deuterium is in It may provide specific therapeutic benefits such as an extension of the vivo half-life or a reduction in dosage requirements, or This can provide compounds that are useful as standards for characterizing biological samples. In the application method, any one of the compounds described herein (for example, any one of compounds 1 to 33) The hydrogen atoms of one of the compounds (A) and (I) to (XIII) of the formulas (A and (I) to (XIII)) One or more of the atoms are replaced by tritium. Tritium is radioactive. This may provide radiolabeled compounds that are useful as tracers in metabolic or kinetic studies.

[0290] Compounds disclosed herein (for example, any one of compounds 1 to 33, etc.) The isotopic enrichment of (A) and any one of the compounds from (I) to (XIII) is carried out by the Company. By conventional techniques well known to the user, or by appropriate isotope-enriched reagents and / or intermediates By a process similar to that described herein in the schemes and examples, using This can be achieved without excessive experimentation.

[0291] The term "isotope substitution" refers to the position of isotope substitution and / or the isotopic substitution at one or more positions. The level of bioaccumulation, for example, with respect to hydrogen versus deuterium, and the specific compounds provided herein. This refers to species having the same chemical structure and formula. Therefore, as used herein, "combination" refers to species having the same chemical structure and formula. The term "substance" refers to a substance that has the same chemical structure but also exhibits isotopic variations between the constituent atoms of the molecule. It encompasses a collection of molecules. Therefore, it is a specific chemical structure containing a deuterium atom. Compounds represented as such have one or more hydrogen atoms in their structure at one of the specified deuterium positions. It will be obvious to those skilled in the art that it will also contain smaller amounts of isotopic substitutions that have offspring. It will be. The relative amounts of such isotopic substitutions in the provided compound will make up the compound. The isotopic purity of the deuterated reagent used, and the manner in which it is used to prepare the compound. This includes, but is not limited to, the efficiency of deuterium incorporation in various synthesis processes, and many other requirements. It depends on the cause.

[0292] When a position is specified as "H" or "hydrogen", that position is the isotopic set of its natural abundance. It is understood that it contains hydrogen. When the position is specified as "D" or "deuterium", that position This is understood to mean that it contains deuterium at an abundance at least 3340 times the natural abundance of deuterium. Therefore, this is 0.015% (i.e., the term "D" or "deuterium" is less (At least 50.1% deuterium is incorporated).

[0293] In embodiments, the compounds provided herein contain at least 3500 (52.5% by weight) (Hydrogen incorporated), at least 4000 (60% deuterium incorporated), at least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated) (mi), at least 6333.3 (95% deuterium incorporated), at least 6466.7 (9 (7% deuterium incorporated), at least 6600 (99% deuterium incorporated), or less Potential for deuteration on compounds with a concentration of 6633.3 (99.5% deuterium incorporated) It may have isotopic enrichment factors for each deuterium present in the designated site.

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

[0295] Compositions and methods The present invention relates to the manufacture of a drug for use in the treatment of various conditions or disorders described herein. For the construction of, one of the compounds of formula (A) and (I) to (XIII), or Provides the use of pharmaceutically acceptable salts of formula (A) and (I) to (XIII). At least one of any one compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable A pharmaceutical composition is provided comprising an excipient or carrier to be included. In various embodiments, the drug Alternatively, the pharmaceutical composition may further include at least one additional therapeutic agent, or be combined with it. They can be used together.

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

[0297] In one embodiment, the method of the present invention involves the therapeutically effective amount of formulas (A) and (I) to (XIII) Any one of the compounds, or a pharmaceutically acceptable salt thereof, or formula (A) and ( A pharmaceutical composition containing one or more compounds from I) to (XIII), This includes administering it to patients who require it.

[0298] The present invention also relates to a method for inhibiting the activity of PHD. In one embodiment, the method is: PHD is obtained by using an effective amount of one of the compounds from formulas (A) and (I) to (XIII). Contact with one or more compounds selected from the group, or a pharmaceutically acceptable salt thereof. This includes.

[0299] In further embodiments, compounds disclosed herein (for example, compounds 1 to 33) One of the following compounds: formula (A) and one of the compounds (I) to (XIII) ), or its pharmaceutically acceptable salts, are used in anemia associated with chronic kidney disease and polycystic kidney disease. Aplastic anemia, autoimmune hemolytic anemia, bone marrow transplant anemia, Churg-Strauss syndrome Diamond-Blackfan anemia, Fanconi anemia, Felty syndrome, graft pair Host disease, hematopoietic stem cell transplantation, hemolytic uremic syndrome, myelodysplastic syndrome, paroxysmal nocturnal hemoglobin Vilenuria, myelofibrosis, pancytopenia, pure red cell aplasia, Schönlein-Henoch purpura, bud Refractory anemia with cytosis, rheumatoid arthritis, Schwakman syndrome, sickle cell disease, severe illness Anemia of the Central Sea, mild Mediterranean anemia, thrombocytopenic purpura, anemia or non-anemia patients undergoing surgery. Anemia associated with or following trauma, sideroblastic anemia, and anemia secondary to other treatments, including: Reverse transcriptase inhibitors, corticosteroid hormones, and cyclic cisplatin are used to treat HIV. Chlorogenic agents containing tin or non-cisplatin, vinca alkaloids, mitotic inhibitors, topoi Somerase II inhibitors, anthracyclines, alkylating agents, especially those associated with inflammation and aging. It is useful for the treatment or prevention of anemia, including the treatment of anemia secondary to chronic diseases. PHD1 inhibitors are also used to treat symptoms of anemia, including chronic fatigue, pallor, and dizziness. It is possible.

[0300] In other embodiments, compounds disclosed herein (for example, among compounds 1 to 33) Compounds of formulas (A) and (I) to (XIII), or their pharmaceutically acceptable The salt used is for the treatment of metabolic disorders, including but not limited to diabetes and obesity. It is useful for prevention.

[0301] In further embodiments, compounds disclosed herein (for example, compounds 1 to 33) One of the compounds of formulas (A) and (I) to (XIII), or the pharmaceutically appropriate Tolerable salts are useful in the treatment or prevention of vascular disorders. These include vasoconstriction and neovascularization. Hypoxia or wound healing requiring angiogenesis-promoting mediators for growth and arterial formation. This includes, but is not limited to, related diseases.

[0302] In further embodiments, compounds disclosed herein (for example, compounds 1 to 33) One of the compounds of formulas (A) and (I) to (XIII), or the pharmaceutically appropriate Tolerable salts are useful in the treatment or prevention of ischemia-reperfusion injury. These include stroke, heart This includes, but is not limited to, myocardial infarction and acute kidney injury.

[0303] In other embodiments, compounds disclosed herein (for example, among compounds 1 to 33) Compounds of formulas (A) and (I) to (XIII), or their pharmaceutically acceptable Salts used in this context are useful in the treatment or prevention of inflammatory bowel disease. These include ulcerative colitis and This includes, but is not limited to, Crohn's disease.

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

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

[0306] In other embodiments, compounds disclosed herein (for example, among compounds 1 to 33) Compounds of formulas (A) and (I) to (XIII), or their pharmaceutically acceptable Salts used in this way are useful in the treatment or prevention of cardiovascular disease.

[0307] In other embodiments, compounds disclosed herein (for example, among compounds 1 to 33) Compounds of formulas (A) and (I) to (XIII), or their pharmaceutically acceptable Salts used in this context are useful in the treatment or prevention of eye diseases or conditions. These include radiation retinopathy. This includes, but is not limited to, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia. It is not determined.

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

[0309] In other embodiments, compounds disclosed herein (for example, among compounds 1 to 33) Compounds of formulas (A) and (I) to (XIII), or their pharmaceutically acceptable The salt used is useful in the treatment or prevention of bronchopulmonary dysplasia (BPD).

[0310] In further embodiments, compounds disclosed herein (for example, compounds 1 to 33) One of the compounds of formulas (A) and (I) to (XIII), or the pharmaceutically appropriate Tolerable salts are useful in the treatment or prevention of heart disease. In terms of conditions, such as in pancreatic surgery... Postoperative myocardial ischemia, myocardial injury after percutaneous coronary intervention (PCI), post-cardiac surgery Myocardial injury, perioperative myocardial ischemia in selective surgery for abdominal aortic aneurysm, myocardial injury after PCI, Myocardial injury in patients undergoing coronary artery bypass grafting (CABG), minimally invasive mitral valve ( Adult patients undergoing MIMV repair or replacement, open-heart surgery, chronic heart failure, NYHA class Last II-IV are examples, but the series is not limited to these.

[0311] In other embodiments, compounds disclosed herein (for example, among compounds 1 to 33) Compounds of formulas (A) and (I) to (XIII), or their pharmaceutically acceptable The salt used is useful in the treatment or prevention of lung diseases. It is particularly useful during selective lobectomy. Examples include, but are not limited to, lung injury, lung injury during CABG surgery, and lung transplantation.

[0312] In other embodiments, compounds disclosed herein (for example, among compounds 1 to 33) Compounds of formulas (A) and (I) to (XIII), or their pharmaceutically acceptable The salt used is useful in the treatment or prevention of liver disease. The condition is non-alcoholic fatty liver disease. Hepatitis (NASH) is one example, but it is not limited to this.

[0313] In other embodiments, compounds disclosed herein (for example, among compounds 1 to 33) Compounds of formulas (A) and (I) to (XIII), or their pharmaceutically acceptable The salt used is useful in the treatment or prevention of kidney disease. The condition is contrast-induced acute kidney injury. Injuries, stage III-IV chronic kidney disease undergoing planned coronary angiography, heart valve hand Acute kidney injury in patients undergoing surgery, non-dialysis-dependent chronic kidney disease, and patients starting dialysis This includes, but is not limited to, patients with chronic kidney disease and those with non-dialysis-dependent chronic kidney disease.

[0314] In addition, any one of the compounds disclosed herein (for example, any one of compounds 1 to 33) (A compound of any one of the formulas (A) and (I) to (XIII), or the drug Scientifically acceptable salts are used in combination with additional active ingredients in the treatment of the above conditions. It is possible. Additional compounds may be compounds disclosed herein (e.g., compounds 1 to 33). One of the following compounds: formula (A) and one of the following compounds (I) to (XIII) The substance, or a pharmaceutically acceptable salt thereof, can be administered separately and simultaneously, or according to the present invention. It may be included in the pharmaceutical composition along with additional active ingredients. In exemplary embodiments, additional active ingredients The minutes indicate that it is effective in treating conditions, disorders, or diseases mediated by the PHD enzyme. Whether it is known or discovered, or whether it is a specific alternative PHD modulator, etc. The active ingredient is active against another target related to the condition, disorder, or disease. Combining them enhances effectiveness (for example, increasing the potency or efficacy of the compound according to the present invention). By including a compound that enhances the effect in the combination, one or more side effects can be reduced, or This may help reduce the required dose of compounds according to the present invention.

[0315] The compounds of the present invention can be used alone or in combination with other compounds to formulate the pharmaceutical composition of the present invention. It is used in combination with other active ingredients. The pharmaceutical composition of the present invention is (a) an effective amount of the present specification The compounds disclosed in this document (for example, any one of compounds 1 to 33, such as formula (A) and (Any one of the compounds from (I) to (XIII)), or a pharmaceutically acceptable salt thereof. (b) a pharmaceutically acceptable prodrug or a pharmaceutically active metabolite, and (b) a pharmaceutically acceptable prodrug It includes an excipient that is permissible for use in the following context.

[0316] "Pharmacologically acceptable excipients" are those added to a pharmacological composition or used in the administration of a drug. To promote and to be used as a compatible vehicle, carrier, or diluent, Inert substances, etc., that are non-toxic, biologically tolerable, and otherwise biologically... This refers to a substance that is suitable for [the purpose]. Examples of excipients include calcium carbonate, calcium phosphate, and various other substances. Various types of sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene. Glycols are one example. Suitable excipients may also include antioxidants. The chemical substance can be used in a pharmaceutical composition or storage medium to extend the shelf life of the pharmaceutical product. .

[0317] Pharmaceutical preparations and routes of administration The compounds and compositions of the present invention, as well as are well known in the art, can be used directly or with a suitable carrier. Alternatively, it may be delivered in a pharmaceutical composition or drug together with an excipient. The therapeutic method of the present invention is This may include administering an effective amount of the compound of the present invention to a subject in need. In a preferred embodiment, the subject is a mammalian subject, and in the most preferred embodiment, the subject This is for human subjects.

[0318] The effective amount of such compound, composition, or drug is determined by the most effective and convenient route of administration, and most The appropriate formulation can be easily determined by routine experiments. Various formulations and drug delivery The system is available in the relevant technical field. For example, Gennaro, AR, ed (1995)Remington's Pharmaceutical Sciences Please refer to es (see above).

[0319] Suitable routes of administration include, for example, oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration. Possible routes of administration include intravenous, intramuscular, and subcutaneous administration. These include: secondary routes of administration such as intraperitoneal, intraarterial, intra-articular, intracardiac, intracapsular, and intradermal. These include intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration. The response depends on the type of formulation used, as well as the physical, chemical, and biological properties of the drug. The route of administration and whether local or systemic delivery is preferable will be determined.

[0320] The pharmaceutical dosage forms of the compounds of the present invention include immediate release, controlled release, sustained release, or targeted drug delivery systems. It can be supplied in a system. Commonly used dosage forms include, for example, solutions and suspensions, ( Micro-emulsions, ointments, gels and patches, liposomes, tablets, sugar-coated tablets, soft or hard tablets. Shell capsules, suppositories, vaginal suppositories, implants, amorphous or crystalline powders, aerosols Examples include lyophilized preparations. Depending on the route of administration used, for example, syringe and Special devices such as needles, inhalers, pumps, injection pens, applicators, or special flasks A substance may be required for the application or administration of a drug. Pharmaceutical dosage forms often consist of the drug, excipients, and It consists of a container / closed system. One or more excipients, also called inert components, are present in this product. It is added to the compound to improve or promote the manufacture, stability, administration, and safety of the drug. This enables the provision of means to achieve a desired drug release profile. Therefore, the type of excipient added to a drug depends, for example, on the physical and chemical properties of the drug. This can depend on various factors such as the route of administration and the manufacturing procedure. Pharmacologically acceptable excipients This includes those available in the relevant technical field and listed in various pharmacopoeias. For example, The Japanese Pharmacopoeia (USP), the Japanese Pharmacopoeia (JP), the European Pharmacopoeia (EP), and the British Pharmacopoeia (BP). ); the US Food and Drug.

[0321] Administration(www.fda.gov)Center for D Publications of rug Evaluation and Research (CEDR), for example Inactive Ingredient Guide (1996), Ash and d Ash, Eds. (2002) Handbook of Pharmaceuti cal Additives,Synapse Information Resour See ces, Inc., Endicott NY, etc.

[0149] The present invention The pharmaceutical dosage forms of the compounds include, for example, conventional mixing, sieving, dissolution, melting, granulation, and sugar-coated tablet preparation. Tabletization, suspension, extrusion, spray drying, atomization, emulsification, (nano / micro) capsules Manufactured by any of the methods well known in the art, such as chemicalization, encapsulation, or freeze-drying processes. It can be manufactured. As described above, the compositions of the present invention allow for the processing of active molecules into preparations for pharmaceutical use. It may contain one or more physiologically acceptable inert components to facilitate the process.

[0322] The appropriate formulation depends on the desired route of administration. For intravenous injection, for example, the composition If necessary, for example, phosphates, histidine, or citrate to adjust the pH of the formulation. A physiologically compatible buffering agent containing salts, and for example, sodium chloride or dextrochloride. It can be formulated in aqueous solution using isotonic agents such as sulfate. For transmucosal or transnasal administration. In this case, a semi-solid, liquid formulation, or patch may be preferred, and may optionally contain a penetration enhancer. It possesses. Such penetrating agents 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 administration by the target population include tablets, pills, sugar-coated tablets, and hard and soft tablets. Examples include capsules, liquids, gels, syrups, slurries, suspensions, and emulsions. The compound also contains conventional suppository bases, such as cocoa butter or other glycerides. It can be formulated into rectal compositions such as suppositories or retained enemas.

[0323] Solid oral dosage forms can be obtained using excipients, which include fillers, disintegrants, and binding agents. Compounds (dry and wet), dissolution retarders, lubricants, flow promoters, anti-adhesion agents, cationic exchange resins These excipients may include fats, humectants, antioxidants, preservatives, colorants, and flavorings. These may be synthetic or natural sources. Examples of such excipients include cellulose derivatives, kueh. Calcium sulfate, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / Sodium, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicate Silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or The salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, Examples include lagacant mucus, hydrogenated vegetable oil, and wax. Ethanol and water are also used. It can act as a granulation aid. In certain cases, for example, in taste masking films, Tablet coating with a gastric acid-resistant film or a release-delay film is desirable. Natural and synthetic polymers combined with agents, sugars, and organic solvents or water are often used in tablets. Used to coat the drug, resulting in sugar-coated tablets. Capsules are preferred over tablets. If not available, the drug powder, suspension, or solution should be placed in a suitable hard or soft shell capsule. It can be delivered inside.

[0324] In one embodiment, the compound of the present invention is used in skin patches, semi-solid or liquid formulations, for example, A (micro) emulsion, ointment, solution, (nano / micro) suspension, or foam It can be administered locally, for example, by means of a drug. The penetration of the drug into the skin and underlying tissues is, for example, penetration Use of accelerators, water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers Appropriate selection and combination of lipophilic, hydrophilic, and amphiphilic excipients, pH adjustment, Furthermore, it can be adjusted by the use of complexing agents. Other techniques such as iontophoresis can be used. This allows for the regulation of skin penetration of the compounds of the present invention. Transdermal or topical administration can be performed, for example, with minimal total Local delivery involving personal exposure would be preferable in situations where such delivery is desirable.

[0325] For administration by inhalation or nasal administration, the compounds for use according to the present invention are: Typically, for example, halogenated carbons derived from methane and ethane, carbon dioxide, or any other Solutions and suspensions from a pressurized pack or nebulizer, accompanied by the use of appropriate propellants such as gases. It is conveniently delivered in the form of a liquid, emulsion, or semi-solid aerosol. Therefore, hydrocarbons such as butane, isobutene, and pentane are useful. Pressurized aero In the case of a sol, the appropriate dose unit is provided by a valve for delivering the measured amount. It can be determined that, for example, gelatin capsules for use in inhalers or blowers and Cartridges can be formulated. These typically consist of a powder mix of compounds and a lac. It contains a suitable powder base such as toxin or starch.

[0326] Compounds and compositions formulated for parenteral administration by injection are usually sterile. The product is presented in a single dosage form, such as an ampoule, syringe, injection pen, or multi-dose container. The latter typically contains preservatives. The composition is a suspension or solution in an oily or aqueous vehicle. , or may take the form of an emulsion, and may function as a buffer, isotonic agent, viscosity enhancer, surfactant, Suspensions and dispersants, antioxidants, biocompatible polymers, chelating agents, and preservatives, etc. It may contain a formulation agent. Depending on the injection site, the vehicle may be water, synthetic oil, or vegetable oil. , and / or may contain an organic cosolvent. It may have a freeze-dried product or concentrate, etc. In certain cases, parenteral formulations will be reconstituted or diluted before administration. The compound of the present invention Depot formulations that provide controlled or sustained release of nano / microparticles, or nano / micro Alternatively, it may contain an injection suspension of non-micronized crystals. Poly(lactic acid), poly(glycol) Acids, or polymers such as copolymers thereof, in addition to other materials well known in the art. It can then act as a control / sustained-release matrix. Other depot delivery systems require incision. The required implant and pump configurations can be presented.

[0327] Suitable carriers for intravenous injection of the compounds of the present invention are well known in the art, for example For example, an aqueous solution containing a base such as sodium hydroxide to form an ionized compound, Sucrose or sodium chloride as an isotonic agent, and a buffering agent, such as phosphate or histamine. It contains a buffering agent containing thidine. For example, a cosolvent such as polyethylene glycol is added. These aqueous systems are effective in dissolving the compounds of the present invention and are suitable for systemic administration. It results in low toxicity. The proportion of the components in the solution system does not destroy the solubility and toxic properties. Furthermore, it can change considerably. Moreover, the identity of the constituent components can change. For example, polysorbate Low-toxicity surfactants such as tetraphosphate or poloxamer, polyethylene glycol or other cosolvents It can be used so that biocompatible polymers such as polyvinylpyrrolidone may be added, and others The sugars and polyols may be used as substitutes for dextrose.

[0328] The therapeutically effective dose can be initially estimated using various techniques known in the art. The initial dose used in the physical test may be based on the effective concentration established in the cell culture assay. The appropriate dosage range for human subjects is obtained, for example, from animal studies and cell culture assays. The data may be used to determine the combination of the compounds in this disclosure. The substance is formulated for oral administration. The compounds of this disclosure in pharmaceutical formulations for oral administration An exemplary dose of the substance is approximately 0.5 to approximately 10 mg / kg of body weight. Several embodiments So, the pharmaceutical preparation contains approximately 0.7 to approximately 5.0 mg / kg of body weight, or alternatively, approximately 1.0 to approximately The dosage is 2.5 mg / kg of body weight. A typical dosing regimen for oral administration is 3 times per week. This would involve administering a pharmaceutical preparation for oral use once a week, twice a week, once a week, or daily.

[0329] The effective amount or therapeutically effective amount or dose of the drug, for example, the compound of the present invention, is in the subject. This refers to the amount of a drug or compound that results in improvement of symptoms or prolonged survival. The toxicity of such molecules and Treatment effectiveness is measured, for example, by the LD50 (lethal dose for 50% of the population) and ED50 ( By determining the therapeutically effective dose in 50% of the population, the cell culture or actual This can be determined by standard pharmaceutical procedures in test animals. The dose-to-toxicity ratio is: This is a treatment index, which can be expressed as the ratio of LD50 / ED50. A high treatment index indicates The indicated drug is preferred.

[0330] The effective dose or therapeutically effective dose is determined by researchers, veterinarians, physicians, or other clinicians. Compounds or pharmaceutical compositions that induce a biological or medical response in a tissue, system, animal, or human. This is the amount. The dosage is particularly within the range of circulating concentrations including ED50, which is little to no toxicity. It is within this range. The dosage is within this range depending on the dosage form used and / or the route of administration used. It may vary within the body. The exact formulation, route of administration, dosage, and dosing interval should be determined based on the details of the patient's condition. Considering this, the selection must be made in accordance with methods known in the relevant art.

[0331] The dosage and interval are determined by ensuring that the plasma level of the active portion is sufficient to achieve the desired effect. In other words, it can be individually adjusted to provide the minimum effective concentration (MEC). MEC is individually adjusted It varies with respect to the compound, but can be estimated from, for example, in vitro data and animal experiments. The dosage required to achieve EC will depend on the individual characteristics and route of administration. In the case of local administration or selective uptake, the effective local concentration of the drug is not related to the plasma concentration. There are cases where this is not the case.

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

[0333] The compound and composition may optionally contain one or more unit dosage forms containing the active ingredient. It may be presented in a pack or dispenser device. Examples include metal or plastic foil such as blister packs, or vials. This may include glass and rubber stoppers as shown in the pack or dispenser device. This may be accompanied by instructions for administration. The present invention is formulated in a suitable pharmaceutical carrier. Compositions containing the compound have also been prepared, placed in appropriate containers, and used for the treatment of the indicated condition. It may be labeled as such.

[0334] These and other embodiments of the present invention are easily conceivable to those skilled in the art in consideration of the disclosure herein. And it is specifically intended. [Examples]

[0335] Purity measurement by HPLC The purity of the compound and its synthetic intermediates shall be determined by one of the methods described below. Determined by reverse-phase HPLC using:

[0336] Method A: Mobile phase: A: Water (0.01% TFA) B: Acetonitrile (0.01% TFA) ); Gradient phase: Increase from 5%B to 95%B in 1.4 minutes, 95%B in 1.6 minutes (total execution) 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(214n (m and 254nm), ES-API.

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

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

[0339] 6-chloronicotinic acid (5.0g, 6.37) in tetrahydrofuran (50.0mL) In a solution of mmol) and 4-dimethylaminopyridine (0.39 g, 0.64 mmol) Di-tert-butyl dicarbonate (10.41 g, 47.77 mmol) was added. The reaction mixture was refluxed for 4 hours and concentrated. The residue was then flash-chromatographed. Purified with petroleum ether / ethyl acetate (10 / 1), then tert-butyl 6-chloro Nicotinate (5.5 g, 5.17 mmol, yield 81.12%) was obtained 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] 5.5g of tert-butyl 6-chloronicotinate in ethanol (25.0mL) In a solution of 25.82 mmol, add hydrazine hydrate (6.46 g, 129.11 mmol) 1 liter (85% in water) was added. The mixture was stirred at 100°C for 2 hours. The mixture was cooled and concentrated. The mixture was shrunk and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine. The residue was dried on sodium sulfate and concentrated. The residue was ground with petroleum ether and filtered. ert-butyl 6-hydrazineyl nicotinate (5.0 g, 23.9 mmol, yield 9 2.76% was obtained as a yellow solid. LCMS: m / z = 210.0 (M + H) + , hold Time 1.19 minutes (Method A).

[0342] tert-butyl6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazo (Il-1-Il) Nicotinate [ka]

[0343] (E)-2-(4-cyanophenyl)-3-(dimethicone) in ethanol (25.0 mL) Ethyl aminoacrylate (2.5g, 10.86mmol) and tert-butyl 6 - In a solution of hydrazine yl nicotinate (2.27 g, 10.86 mmol), p-Tol Ensulfonic acid monohydrate (410 mg, 2.17 mmol) was added. The mixture was heated at 80°C. The mixture was stirred for 12 hours, concentrated, and dried. The residue was then flash-chromatographed (meth Purified with tert-butyl 6-(4-(4)) (1 / 8) -Cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinate (3 0.0 g, 8.35 mmol, yield 76.92% was obtained 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] tert-butyl 6-(4-(4-cyanophenic acid in dichloromethane (10.0 mL) (L)-5-hydroxy-1H-pyrazole-1-yl)nicotinate (1.00g, 2. Trifluoroacetic acid (5.0 mL) was added to a 76 mmol solution. The mixture was heated at 40°C. The mixture was stirred for 2 hours and concentrated. The residue was ground with ethyl acetate and filtered to obtain 6-(4-(4-C). Anophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinic acid (900ml) g (crude) was obtained as a yellow solid. LC-MS: m / z = 307.0 (M + H) + , retention time 1.77 minutes (Method A).

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

[0347] 6-(4-(4-cyanophenyl)-5-hydro in dichloromethane (10.0 mL) Dissolved in xy-1H-pyrazole-1-yl)nicotinic acid (900 mg, 2.94 mmol) Thionyl chloride (10.0 mL) was added to the solution. The mixture was stirred at 40°C for 3 hours and then concentrated. It was then dried. 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] N,O-dimethylhydroxylamine hydrochloride (40) in dichloromethane (5.0 mL) 7.43 mg, 4.16 mmol) and N,N-diisopropylethylamine (1.07 In a solution of (g, 8.31 mmol), 6-(4-(4-cyanophenyl)-5-hydroxy Nicotinoyl chloride (900 mg, 2.77 mmol) The mixture was added at 0°C. The mixture was stirred at 0°C for 3 hours, concentrated, and dried. The residue was then removed. Purified by sch chromatography (dichloromethane / methanol = 10 / 1) , 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl) -N-methoxy-N-methylnicotinamide (900 mg, 2.58 mmol, yield 93%) 0.17% was obtained as a yellow solid. LCMS: m / z = 350.1[M+H] + , when held for 1.63 minutes (method A).

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

[0351] Methylmagnesium bromide (0.76 mL) in anhydrous tetrahydrofuran (5.0 mL) 2.29 mmol, in a 3M solution of ether, 6-(4-(4-cyanophenyl)-5 -Hydroxy-1H-pyrazole-1-yl)-N-methoxy-N-methylnicotinamide D (200 mg, 0.57 mmol) was added at -20°C. The mixture was warmed to 0°C and further... The mixture was stirred for 1 hour. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layer was then bled. The product was washed in line, dried on sodium sulfate, and concentrated under reduced pressure. The crude product was then flattened. Purified by sulfonometry (petroleum ether / ethyl acetate = 1 / 1), 4- (1-(5-acetylpyridine-2-yl)-5-hydroxy-1H-pyrazole-4- Benzonitrile (35 mg, 0.11 mmol, yield 20.23%) is a white solid. The result obtained was: LCMS: m / z = 305.0 (M + H) + , retention time 4.504 min (method A ). 1 H NMR(400MHz,DMSO-d6)δ 9.00(s,1H), 8.5 8-8.43(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-pyrazo (Il-4-yl)benzonitrile [ka]

[0353] Ethylmagnesium bromide (0.76 mL) in anhydrous tetrahydrofuran (5.0 mL) 2.29 mmol, in a 3M solution of ether, 6-(4-(4-cyanophenyl)-5 -Hydroxy-1H-pyrazole-1-yl)-N-methoxy-N-methylnicotinamide D (intermediate from Example 1) (200 mg, 0.57 mmol) was added at -20°C. The mixture was heated to 0°C and stirred for another hour. The reaction mixture was quenched with water and ethyl acetate was added. The mixture was extracted twice. The organic layer was washed with brine, dried on sodium sulfate, and concentrated under reduced pressure. The crude product was then subjected to flash chromatography (petroleum ether / ethyl acetate = 1 / 1). Purified by ) and 4-(5-hydroxy-1-(5-propionylpyridine-2- (L)-1H-pyrazole-4-yl)benzonitrile (25 mg, 0.08 mmol, benzonitrile) A white solid was obtained with a concentration of 13.81%. LCMS: m / z = 319.0(M+H) + , Retention time 5.01 minutes (Method A). 1 1H NMR (400MHz, DMSO-d6) δ 1 3.56(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=4.2 Hz,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 (Lu-4-yl)benzonitrile [ka]

[0355] Ethylmagnesium bromide isopropyl magnesium in anhydrous tetrahydrofuran (5.0 mL) Dissolve nesium chloride (2.29 mL, 2.29 mmol, 1 M in tetrahydropyran) In the liquid, add 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1- (Lu)-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 another hour. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine. The product was dried on sodium sulfate and concentrated under reduced pressure. The crude product was then subjected to back-preparation HPLC. Purified, 4-(5-hydroxy-1-(5-isobutylpyridine-2-yl)-1H- Pyrazole-4-yl)benzonitrile (16.5 mg, 0.05 mmol, yield 9.5) The %) was obtained as a white solid. LCMS: m / z = 333.1(M+H) + , retention time 5. 10 minutes (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] 2-(4-cyanophenyl)acetic acid (5.0 g, 31.5 g) in methanol (10.0 mL). Add hydrochloric acid in methanol (20.0 mL, 3.0 N) at 0°C to a mixture of 0 mmol. The mixture was stirred at 70°C for 3 hours, then cooled to allow the solid to precipitate. The solid was filtered, and meta Wash with methyl 2-(4-cyanophenyl)acetate (5.0g, 28 0.4 mmol, yield 92%, was obtained 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] 2-(4-cyanophenyl)acetic acid in N,N-dimethylformamide (25.0 mL) In a solution of methyl (5.0 g, 28.5 mmol), N,N-dimethylformamide ethyl Luacetal (14.0 g, 114.16 mmol) was added. The mixture was heated at 100°C. The mixture was stirred for 6 hours and then cooled. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was divided into two parts. Wash in line, dry on sodium sulfate, concentrate, and (E)-2-(4-cyanophthol Methyl methyl(dimethylamino)acrylate (5.20g, 25.4mmol) 89% of the product was obtained as a yellow solid. LC-MS: m / z = 231.0 [M + H] + , hold Time: 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] 3,6-dibromopyridine (2.5 g) in anhydrous tetrahydrofuran (10.0 mL) In a 12.7 mmol solution, add isopropyl magnesium chloride (8.25 mL, 16 0.5 mmol (2.0 N in hexane) was added under nitrogen at 0°C. The mixture was then heated at 0°C. Stir for 45 minutes, then add methanesulfonyl in anhydrous tetrahydrofuran (5.0 mL). A solution of chloride (1.89 g, 16.5 mmol) was added. The mixture was warmed to room temperature. The mixture was stirred for another hour. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layer was then removed. The product was separated, washed with brine, dried on sodium sulfate, and concentrated under reduced pressure. Crude product Purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1). Then, 2-bromo-5-(methylsulfonyl)pyridine (1.4g, 5.98mmol, A 47.1% yield was obtained as a yellow solid. LC-MS: m / z = 236.0 (M + H) + , Retention time 1.54 minutes (Method A).

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

[0363] 2-bromo-5-(methanesulfonyl)-pyridine in ethanol (10.0 mL) In a solution of 1.0 g, 4.25 mmol, add hydrazine hydrate (1.0 g, 17.0 mmol) 1 liter (85% in water) was added. The mixture was stirred at 80°C for 4 hours. The mixture was cooled and concentrated. It was then dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine. The residue was dried over sodium sulfate and concentrated. The residue was ground with petroleum ether and filtered to obtain 2- Hydrazineyl-5-(methylsulfonyl)pyridine (1.2g, 6.4 mmol, yield) 75% was obtained as a white solid. LCMS: m / z = 188.0(M+H)+, retention time 0.43 minutes (method A).

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

[0365] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (3.0 mL) Methyl aminoacrylate (230 mg, 1.0 mmol) and 2-hydrazine yl-5 -(methylsulfonyl)pyridine (187 mg, 1.0 mmol) solution with p-True Sulfonic acid monohydrate (38 mg, 0.2 mmol) was added. The mixture was refluxed for 12 hours. Stirring was continued and the mixture was cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried. , 4-(5-hydroxy-1-(5-methylsulfonyl)pyridine-2-yl)-1H- Pyrazole-4-yl)benzonitrile (58 mg, 0.17 mmol, yield 17.0%) The substance was obtained as a white solid. LCMS: m / z = 341.0(M+H) + , retention time 3.9 3 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] 2-(3-bromophenyl)acetic acid in N,N-dimethylformamide (30.0 mL) Ethyl (2.5g, 10.3mmol) and zinc cyanide (1.20g, 10.3mmol) l) Mixture containing tetrakis(triphenylphosphine)palladium (1.16g, 1. (0 mmol) was added. The mixture was stirred under nitrogen at 90°C for 18.0 hours and then allowed to cool to room temperature. It was cooled. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and sulfur The product was dried on sodium acid and concentrated under reduced pressure. The crude product was then flash-chromatographed. Refined by (petroleum ether / ethyl acetate = 9 / 1), 2-(3-cyanophenic acid Ethyl acetate (1.72 g, 9.1 mmol, yield 88.3%) was obtained 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] 2-(3-cyanophenyl)acetic acid in N,N-dimethylformamide (8.0 mL) In a solution of Chill (1.2g, 6.35 mmol), add N,N-dimethylformamide diethyl Acetal (4.7g, 31.74 mmol) was added. The mixture was heated to 16.0°C at 100°C. The mixture was stirred for a certain amount of time and then cooled. Ethyl acetate and water were added to the solution and the layers were separated. The layer was bran. Wash with water, dry on sodium sulfate, concentrate, (E)-2-(3-cyanophenate Ethyl 3-(dimethylamino)acrylate (1.34g, 5.49mmol, saturates) 86.5% was obtained as a yellow solid. LC-MS: m / z = 245.0 [M + H] + , Retention time 1.50 minutes (Method A).

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

[0371] (E)-2-(3-cyanophenyl)-3-(dimethyl) in ethanol (3.0 mL) Ethyl aminoacrylate (200 mg, 0.82 mmol) and 2-hydrazine yl- 5-(methylsulfonyl)pyridine (intermediate from Example 4) (153 mg, 0.82 mg) To the solution of (mol), add p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol). The mixture was added. The mixture was stirred in a sealed tube at 90°C for 12.0 hours, then cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried, and 3-(5-hydroxy-1- (5-methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)benzo Nitrile (60 mg, 0.17 mmol, yield 21.5%) was obtained 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), 7.5 5-7.62 (m, 2H), 3.36 (s, 3H).

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

[0373] 4-Bromo-3-methylbenzonitrile (5.0g, 25.6mmol), di malonate Ethyl (27g, 168mmol), Tris(dibenzylideneacetone) dipalladium ( 0) (0.24g, 0.26mmol), tri-tert-butylphosphine tetraful Oroborate (0.08g, 0.26mmol), potassium carbonate (5.3g, 38.4mg) A mixture of (mol) and potassium bicarbonate (3.84 g, 38.4 mmol) is prepared at 160 The mixture was stirred at °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 on sodium sulfate, and concentrated. The residue was then flattened. Purified by sch chromatography (petroleum ether / ethyl acetate = 1 / 1), 2 -(4-cyano-2-methylphenyl)ethyl acetate (2.0 g, 8.11 mmol, yield) 31.7% was obtained as yellow oil. LC-MS: m / z = 204.1(M+H) + , hold Time 1.87 minutes (Method A).

[0374] (E)-2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylic Ethyl acid: [ka]

[0375] 2-(4-cyano-2-methyl phosphate in N,N-dimethylformamide (10.0 mL) In a solution of ethyl acetate (1.0 g, 5.0 mmol), N,N-dimethylform Midodiethyl acetal (2.9 g, 25.0 mmol) was added. The mixture was heated at 100°C. The mixture was stirred overnight and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. Organic The layers were washed with brine, dried on sodium sulfate, and concentrated. The residue was flushed. Purified by chromatography (dichloromethane / methanol = 98 / 2), (E) -2-(4-cyano-2-methylphenyl)-3-(dimethylamino)acrylate ethyl (600 mg, 2.36 mmol, yield 47.2%) was obtained as 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] (E)-2-(4-cyano-2-methylphenyl)- in ethanol (10.0 mL) 3-(dimethylamino)ethyl acrylate (391 mg, 1.60 mmol) and 2-H Drazinyl-5-(methylsulfonyl)pyridine (intermediate from Example 4) (300ml) In a solution of (g, 1.60 mmol), 4-methylbenzenesulfonic acid (34.4 mg, 0. 2 mmol) was added. The mixture was stirred at 90°C for 12.0 hours, then cooled to allow the solid to precipitate. The solid was filtered, washed with ethanol, and dried, and 4-(5-hydroxy-1-( 5-methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)-3 Tylbenzonitrile (77 mg, 0.21 mmol, yield 13.6%) as a white solid Obtained. LC-MS: m / z = 355.1.0(M+H) +, retention time 1.79 min (method A ). 1 HNMR(400MHz,DMSO-d6)δ 13.19(s,1H), 8.9 5(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-pyra ethyl zole-4-carboxylate [ka]

[0379] Water / Ethanol (30.0 mL / 10.0 mL) contains 2-hydrazine yl-5-(methicillin). (Sulfonyl)pyridine (intermediate from Example 4) (0.4g, 2.1mmol), 2- Diethyl ethoxymethylene malonate (1.15 g, 5.3 mmol), and potassium carbonate. A mixture of um (0.73 g, 5.3 mmol) was stirred overnight at 60°C. Aqueous hydrochloric acid (1 0.0 mL of 3N solution was added to the solution and the solid precipitated. The solid was filtered, washed with water, and dried. Dry and 5-hydroxy-1-(5-methylsulfonyl)pyridine-2-yl)-1H -Pyrazole-4-carboxylate ethyl (0.4g, 1.3 mmol, yield 61.5%) It was obtained as a yellow solid. LCMS: m / z = 312.0 (M + H) + , retention time 1.63 minutes (Method A).

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

[0381] 5-hydroxy-1- (5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-carboxylic acid (diazomethyl)trimethylsilane (373 mg, 1.2 mmol) is dissolved in a solution of ethyl ethyl (373 mg, 1.2 mmol). 1.61 mL of 3.23 mmol (in hexane, 2N) was added. The mixture was left overnight at 25°C. The mixture was stirred, concentrated, and dried. The residue was then flash-chromatographed (dichloromethane). Purified by methanol (100 / 2), 5-methoxy-1-(5-(methylsulfur Honyl)pyridine-2-yl)-1H-pyrazole-4-carboxylate ethyl (0.3g, 0.92 mmol, yielding 76.9%, was obtained as a yellow solid. LC-MS: m / z = 326 .0[M+H] + , retention time 1.75 min (Method A).

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

[0383] 5-methoxy-1-(5-(methylsulfonyl (Lu)pyridine-2-yl)-1H-pyrazole-4-carboxylate ethyl (0.3g, 0. (92 mmol) solution, aqueous lithium hydroxide (3.0 mL, 3.0 mmol, 1.0 N) The solution was added at 0°C. The mixture was heated to room temperature and stirred for 18 hours. The solution was acidified with 1N hydrochloric acid. The mixture was cured and extracted with dichloromethane. The organic layer was separated, washed with brine, and sodium sulfate was used. Dry on a surface and concentrate under reduced pressure to obtain 5-methoxy-1-(5-(methylsulfonyl) Lysine-2-yl)-1H-pyrazole-4-carboxylic acid (0.2g, 0.61 mmol) The product was obtained as a yellow solid with a yield of 66.8%. LC-MS: m / z = 326.0 (M + H) + , retention time 1.25 min (Method A).

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

[0385] 5-methoxy-1-(5-(methyl dimethylformamide) in N,N-dimethylformamide (10.0 mL) (Sulfonyl)pyridine-2-yl)-1H-pyrazole-4-carboxylic acid (0.2g, 0.61 mmol), N-bromosuccinimide (0.18 g, 1.0 mmol), and Mixture of sodium bicarbonate (0.17g, 2.0 mmol) is 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 and sodium sulfate. The product was dried on a sieve and concentrated under reduced pressure. The crude product was then flash-chromatographed. Refined with petroleum ether / ethyl acetate (10 / 1), 2-(4-bromo-5-meth Xy-1H-pyrazole-1-yl)-5-(methylsulfonyl)pyridine (0.16g) 0.47 mmol (78% yield) was obtained as a yellow solid. LC-MS: 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] 1,4-Dioxane / Water (10.0 mL / 1.0 mL) contains 2-(4-bromo-5-methyl Toxy-1H-pyrazole-1-yl)-5-(methylsulfonyl)pyridine (0.1g) , 0.3 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxymethyl) Saborolan-2-yl(phenyl)acetonitrile (0.15g, 0.6mmol), carbon Sodium phosphate (64 mg, 0.60 mmol), tetrakis(triphenylphosphine) A mixture of palladium (35 mg, 0.03 mmol) was stirred overnight at 110°C. The material was cooled, concentrated, and dried. The residue was then subjected to flash chromatography (petroleum ether). Purified by ethyl acetate (1 / 1), 2-(4-(5-methoxy-1-(5-( Methylsulfonyl pyridine-2-yl-1H-pyrazole-4-yl-phenyl Acetonitrile (0.1 g, 0.27 mmol, 90% yield) was obtained as a yellow solid. CMS: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] 2-(4-(5-methoxy-1-( 5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)phen (L) Acetonitrile (0.1g, 0.3 mmol) and lithium chloride (0.04g, 0. The mixture (90 mmol) 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 then evaporated to dry. The residue was purified by reverse preparative HPLC and obtained 2-(4-(5-hydroxy-1-(5-(methyl (Sulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)phenyl)aceto Nitrile (55 mg, 0.15 mmol, yield 51.8%) was obtained as a white solid. LC MS: m / z = 355.0 (M + H) + , retention time 3.42 minutes (Method B). 1 1H 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] 2-methoxy-4-methylpyridine (2) in anhydrous tetrahydrofuran (50.0 mL) In a solution of 0.0 g, 16.2 mmol, add lithium diisopropylamide (16.0 mL, 32.0 mmol (2.0 N in n-heptane) was added under nitrogen at -78°C. Stir the mixture at -78°C for 10 minutes, then add diethyl carbonate (3.78 g, 32.0 mmol). It was added. The mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with water and ethyl acetate was added. The organic layer was extracted twice using a saturates. The organic layer was washed with brine, dried on sodium sulfate, and then subjected to reduced pressure. The product was concentrated. The crude product was subjected to flash chromatography (petroleum ether / ethyl acetate = 1 Purified by (0 / 1), 2-(4-cyano-2-methylphenyl)-3-oxobuta Ethyl phosphate (2.0 g, 10.2 mmol, yield 63.4%) was obtained as a yellow oil. LC MS: m / z = 196.1 (M + H) + , retention time 1.97 min (Method A).

[0392] (E)-3-(dimethylamino)-2-(2-methoxypyridine-4-yl)acrylic Ethyl acid [ka]

[0393] 2-(2-methoxypyridine-4-) in N,N-dimethylformamide (3.0 mL) N,N-dimethylformamine is added to a solution of ethyl acetate (1.95 g, 10 mmol). Diethyl acetal (5.95 g, 50 mmol) was added. The mixture was heated at 100°C. The mixture was stirred for 2 hours and then cooled. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was divided into two parts. The product was washed in line, dried on sodium sulfate, and concentrated under reduced pressure. The crude product was then flattened. Purified by sulfonometry (dichloromethane / methanol = 98 / 2), (E)-3-(dimethylamino)-2-(2-methoxypyridine-4-yl)acrylic acid Ethyl (1.1 g, 4.4 mmol, 44% yield) was obtained 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] (E)-3-(dimethylamino)-2-(2-methoxy) in ethanol (3.0 mL) Ethyl pyridine-4-yl acrylate (0.25 g, 1.0 mmol) and 2-hydra Zinyl-5-(methylsulfonyl)pyridine (intermediate from Example 4) (0.2g, 1 In a solution of 0.0 mmol, add p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) l) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered. Wash with ethanol, dry, and 4-(2-methoxypyridine-4-yl)-1 -(5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol( 90 mg, 0.26 mmol, yield 26% was obtained as a white solid. LCMS: m / z = 347.0 (M+H) + , retention time 2.28 min (Method A). 1 1H 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,1 H), 8.18-8.19(d,J=7.6Hz,1H), 7.77-7.83(m,2 H), 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] 2-(4-bromophenyl)acetic acid in N,N-dimethylformamide (3.0 mL) In a solution of Chil (1.5g, 6.2 mmol), add N,N-dimethylformamide diethyl Cetal (3.7g, 31 mmol) was added. The mixture was stirred at 100°C for 12 hours. The solution was cooled. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine. Then, it is dried on sodium sulfate and concentrated to obtain (E)-2-(4-bromophenyl)-3 -(dimethylamino)acrylate (1.1g, 3.7 mmol, yield 59.5%) was yellow Obtained as a colored oil. LCMS: m / z = 298.0 [M + H] + , retention time 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] (E)-2-(4-bromophenyl)-3-(dimethicone) in ethanol (10.0 mL) Ethyl aminoacrylate (0.5g, 1.7mmol) and 2-hydrazine yl-5 -(methylsulfonyl)pyridine (intermediate from Example 4) (0.31g, 1.7mmo To the solution of (l), add p-toluenesulfonic acid monohydrate (64 mg, 0.34 mmol). The mixture was stirred under reflux for 12 hours and cooled to allow the solid to precipitate. The solid was filtered and ethanol was removed. Wash with 4-(4-bromophenyl)-1-(5-methylsulfony (L)pyridine-2-yl)-1H-pyrazole-5-ol (0.3g, 0.76mmo) 1, yield 44.9%, was obtained as a white solid. LCMS: m / z = 394.0(M+H) + , retention time 1.88 min (Method A). 1 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] 1,4-Dioxane (10.0 mL) contains 2-bromo-5-iodopyridine (1.00 g, 3.52 mmol), 1H-pyrazole (239.8 mg, 3.52 mmol), yo Cuprous phosphate (67.09 mg, 0.35 mmol), potassium phosphate (1.87 g, 8. 81 mmol), and (1R,2R)-cyclohexane-1,2-diamine (45.6 ml) The mixture of g, 0.4 mmol was stirred at room temperature for 12 hours. The reaction solution was then mixed with ethyl acetate and Diluted with water. The organic layer was washed with brine, dried on sodium sulfate, and concentrated. Residue The residue is purified by flash chromatography (petroleum ether / ethyl acetate = 6 / 1). Prepared as 2-bromo-5-(1H-pyrazole-1-yl)pyridine (220 mg, 2. 85 mmol, yield 81.12%, was obtained as 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] 2-bromo-5-(1H-pyrazole-1-yl)pyrazole in ethanol (2.0 mL) A solution of din (200 mg, 0.89 mmol) is mixed with hydrazine hydrate (223.2 mg, 4.46 mmol (85% in water) was added. The mixture was heated in a sealed tube at 100°C for 2 hours. The mixture was stirred for several hours. The mixture was cooled, concentrated, and dried. The residue was divided between ethyl acetate and water. Separated. The organic layer was separated, washed with brine, dried on anhydrous sodium sulfate, and concentrated. The residue was crushed with petroleum ether and filtered to obtain 2-hydrazineyl-5-(1H-pyrazo (1-yl)pyridine (140 mg, 0.80 mmol, yield 90.32%) was yellow It was obtained as a solid. LCMS: m / z = 176.1(M+H) + , retention time 1.01 min ( Law B).

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

[0405] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (5.0 mL) Methyl aminoacrylate (210.29 mg, 0.91 mmol) and 2-hydrazine Il-5-(1H-pyrazole-1-yl)pyridine (160.00 mg, 0.91 mm) To the solution of (ol), add p-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol). The mixture was stirred under reflux for 12 hours and cooled to allow the solid to precipitate. The solid was filtered and fermented. Wash with tanol and dry, then 4-(1-(5-(1H-pyrazole-1-yl)pyrazole (Zin-2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile (7 4 mg, 0.22 mmol, yield 24.8% was obtained as a white solid. LC-MS: m / z =329.1(M+H) + , retention time 4.50 min (Method A). 1 1H NMR (400 MHz) z,DMSO-d6)δ 13.44(s,1H), 8.99(t,J=1.2Hz,1 H), 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 = 2.0 Hz, 1 H).

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

[0407] 2-chloro-5-iodopyridine (1.5) in anhydrous tetrahydropyran (5.0 mL) In a solution of (g, 6.26 mmol), add n-butyllithium (4.26 mL, 10.65 ml) A solution (2.5 N in hexane) was added under nitrogen at -78°C. The mixture was then cooled at -78°C. Stir for 30 minutes, then add zinc chloride (18.79 mg, 18.79 mmol, dichloro Anhydrous tetrahydrofuran (10) was added to methane. The mixture was heated to room temperature and anhydrous tetrahydrofuran (10 Tetrakis(triphenylphosphine)palladium (361.78 mg) in 0.0 mL Solutions of 0.31 mmol) and oxazole (605.65 mg, 8.77 mmol) It was added. The mixture was stirred at 60°C for 4 hours and concentrated. The residue was divided between ethyl acetate and water. The layers were separated. The organic layer was washed with brine, dried on sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to flash chromatography (petroleum ether / ethyl acetate = 5 / 1). Then it is purified to make 2-(6-chloropyridine-3-yl)oxazole (900 mg, 4. 94 mmol (79.93% yield) was obtained as a white solid. LC-MS: m / z = 181. 1(M+H) + , retention time 1.51 min (Method A).

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

[0409] 2-(6-chloropyridine-3-yl)oxazole in ethanol (5.0 mL) A solution of 700 mg, 3.13 mmol of hydrazine hydrate (781.25 mg, 15 0.63 mmol (85% in water) was added. The mixture was incubated in a sealed tube at 100°C for 2 hours. The mixture was stirred. The mixture was cooled, concentrated, and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine, dried on sodium sulfate, and concentrated. The residue was petroleum. Grind with ether, filter, and obtain 2-(6-hydrazineylpyridine-3-yl)oxazo A solution (400 mg, 2.25 mmol, yield 72.72%) was obtained as a yellow solid. LC MS: 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] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (5.0 mL) Methyl aminoacrylate (328.57 mg, 1.43 mmol) and 2-(6-Hydroacrylate Radinylpyridine-3-yl)oxazole (250.00 mg, 1.43 mmol) p-toluenesulfonic acid monohydrate (55 mg, 0.29 mmol) was added to the solution. The mixture was stirred under reflux for 12 hours and cooled to allow the solid to precipitate. The solid was filtered and ethanol was extracted. Wash with water, dry, and 4-(5-hydroxy-1-(5-(oxazole-2-yl )pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (150 mg, 0.46 mmol (31.91% yield) was obtained as a white solid. LC-MS: m / z = 33 0.0(M+H) + , retention time 1.74 min (Method B). 1 1H NMR (400MHz, D MSO-d6)δ 13.54(s,1H), 9.04(s,1H), 8.64(s,1 H), 8.61-8.46(m,2H), 8.32(d,J=0.7Hz,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] 5-bromo-2-chloropyridine in N,N-dimethylformamide (10.0 mL) (500.0 mg, 2.60 mmol) and 2-(tributylstannyl)thiazole ( In a solution of 1458.2 mg, 3.90 mmol, add bis(triphenylphosphine) para Dium(II) dichloride (182.37 mg, 0.26 mmol) was added. Reaction product The 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 subjected to flash chromatography (petroleum ether / ethyl acetate = 20 / 1). Purified by ) and 2-(6-chloropyridine-3-yl)thiazole (350 mg, 1.77 mmol was obtained, with a yield of 68%. LC-MS: m / z = 197.0 [M + H] + , Retention time 1.719 minutes (Method A).

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

[0415] 2-(6-chloropyridine-3-yl)thiazole (3) in ethanol (3.0 mL) (0.0 mg, 1.53 mmol), and hydrazine hydrate (3.0 mL, 85% in water) The mixture was stirred in a sealed tube at 110°C for 3 hours. The mixture was cooled and concentrated to dry. It was dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine and sodium sulfate. The residue was dried on thorium and concentrated. The residue was ground with petroleum ether and filtered to obtain 2-(6- Hydrazineylpyridine-3-yl)thiazole (185 mg, 0.96 mmol, yield) A result of 63% was obtained. LCMS: m / z = 193.0 [M+H] + , retention time 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] (E)-2-(4-cyanophenyl)-3-(dimethylamine) in ethanol (8 mL) (n) Methyl acrylate (200.0 mg, 0.87 mmol) and 2-(6-hydrazine) Solution of ylpyridine-3-yl)oxazole (166.97 mg, 0.87 mmol) p-toluenesulfonic acid monohydrate (17 mg, 0.09 mmol) was added. Reaction The mixture was stirred at 90°C for 16 hours, then cooled to allow the solid to precipitate. The solid was filtered and then dissolved in ethanol. Wash and dry, then 4-(5-hydroxy-1-(5-(thiazole-2-yl)pyri (Zin-2-yl)-1H-pyrazole-4-yl)benzonitrile (80 mg, 0.23 mmol was obtained as a yellow solid (27% yield). LCMS: m / z = 346.0[M+H ] + , retention time 1.893 minutes (Method B). 11H 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=2.5 Hz,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] 2-bromopyridine in 1,2-dimethoxyethane / water (10.0 mL / 2.0 mL) (390 mg, 2.5 mmol), (6-chloropyridine-3-yl)boronic acid (470 (mg, 3.0 mmol), potassium carbonate (828 mg, 6.0 mmol), paradiacetate A mixture of Mu(II) (56 mg, 0.6 mmol) was stirred overnight at 90°C. The residue was cooled, concentrated, and dried. The residue was then flash-chromatographed (petroleum ether / Purified with ethyl acetate (3 / 1), 6'-chloro-2,3'-bipyridine (380 mg, 2.0 mmol, 80% yield was obtained as a yellow solid. LC-MS: m / z = 191 .0[M+H] + , retention time 2.20 min (Method A).

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

[0421] 6'-chloro-2,3'-bipyridine (380 mg) in ethanol (10.0 mL) Hydrazine hydrate (5.0 mL, 85% in water) was added to a 2.0 mmol solution. 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 and sodium sulfate. Dry on a humidifier and concentrate to obtain 6'-hydrazineyl-2,3'-bipyridine (200ml). g, 1.07 mmol, yield 54%) was obtained as yellow oil. LC-MS: 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-pyra Zole-4-yl)benzonitrile [ka]

[0423] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (4.0 mL) Methyl aminoacrylate (240 mg, 1.07 mmol) and 6'-hydrazine yl hydrate p-toluenesulfur dioxide in a solution of -2,3'-bipyridine (200 mg, 1.07 mmol) 38.2 mg, 0.20 mmol of folic acid monohydrate was added. The mixture was refluxed for 12 hours. Stirring was continued and the mixture was cooled to precipitate the solid. The solid was filtered, washed with ethanol, and dried. ,4-(1-([2,3'-bipyridine]-6'-yl)-5-hydroxy-1H-pyr Zole-4-yl)benzonitrile (35 mg, 0.10 mmol, yield 9.64%) It was obtained as a white solid. LC-MS: m / z = 340.2(M+H) + , retention time 4.71 minutes (Method A). 1H 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,1 H), 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)-1 H-pyrazole-4-yl)benzonitrile [ka]

[0425] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (4.0 mL) Methyl aminoacrylate (130 mg, 0.56 mmol) and 2-hydrazine yl- In a solution of 5-(trifluoromethyl)pyridine (100 mg, 0.56 mmol), p- Toluene sulfonic acid monohydrate (21 mg, 0.11 mmol) was added. The mixture was refluxed. The mixture was stirred for 12 hours and then cooled to allow the solid to precipitate. The solid was filtered, washed with ethanol, and dried. Dry the mixture, then add 4-(5-hydroxy-1-(5-(trifluoromethyl)pyridine-2-I (Lu)-1H-pyrazole-4-yl)benzonitrile (70.8 mg, 0.21 mmol) The product was obtained as a white solid with a yield of 38%. LCMS: m / z = 331.0 (M + H) + , protection Duration 5.08 minutes (Method A). 1 1H 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] 2-bromo-5-iodopyridine (2. (0g, 7.04 mmol), potassium phosphate (4.5g, 21.13 mmol), iodide Copper(134mg, 0.70mmol), Pyrrolidine-2-one(1.2g, 14.0) A mixture of 9 mmol of ethylene glycol (44 mg, 0.70 mmol) and ethylene glycol (44 mg, 0.70 mmol) is prepared in a densely packed state. The mixture 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 then subjected to flash chromatography (petroleum ether / ethyl acetate = 1 / 1). Then it is purified to produce 1-(6-bromopyridine-3-yl)pyrrolidine-2-one (0.8g) 9.93 mmol (47% yield) was obtained as a white solid. LC-MS: m / z = 241. 1[M+H] + , retention time 1.67 min (Method A).

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

[0429] 1-(6-bromopyridine-3-yl)pyrrolidine-2 in ethanol (4.0 mL) - In a solution of ONE (400 mg, 1.66 mmol), add hydrazine hydrate (2.0 mL, water 85% was added. The mixture was stirred in a sealed tube at 130°C for 18 hours. The material was cooled, concentrated, and dried. The residue was then subjected to flash chromatography (petroleum ether). Purified by (1 / 1) ethyl acetate, 1-(6-hydrazineylpyridine-3- Iyl)pyrrolidine-2-one (160 mg, 0.83 mmol, 50% yield) with yellow oil The result obtained was: 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] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (4.0 mL) Methyl aminoacrylate (120 mg, 0.52 mmol) and 1-(6-hydrazine) Dissolved in ylpyridine-3-yl)pyrrolidine-2-one (100 mg, 0.52 mmol) p-toluenesulfonic acid monohydrate (19 mg, 0.10 mmol) was added to the solution. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was then subjected to reverse-phase preparative HPLC. Then purify it to 4-(5-hydroxy-1-(5-(2-oxopyrrolidine-1-yl) Pyridine-2-yl)-1H-pyrazole-4-yl)benzonitrile (9.0 mg, 0 0.03 mmol (5.0% yield) was obtained as a white solid. LC-MS: m / z = 346.4 (M+H) +, retention time 4.08 min (Method A). 1 1H 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), 2.5 6-2.51(m,2H), 2.20-2.03(m,2H).

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

[0433] 5-bromo-2-fu in 1,2-dimethoxyethane / water (10.0 mL / 2.0 mL) Luoropyridine (435 mg, 2.5 mmol), Cyclopropylboronic acid (260 mg) (3.0 mmol), potassium phosphate (1.27 g, 6.0 mmol), palladium acetate (II) (56 mg, 0.6 mmol), and tricyclohexylphosphine (340 mg) The mixture (g, 1.2 mmol) was stirred overnight at 80°C. The mixture was cooled and concentrated to dry. The residue was dried. The residue was flash-chromatographed (petroleum ether / ethyl acetate = 3 / 1). ) is purified by 5-(cyclopropyl-2-fluoropyridine (246 mg, 1. 8 mmol, yield 72%, was obtained 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] 5-cyclopropyl-2-fluoropyridine (246) in ethanol (10.0 mL) Add hydrazine hydrate (5.0 mL, 85% in water) to a solution of (mg, 1.8 mmol). The mixture was stirred overnight in a sealed tube at 120°C. The mixture was cooled and concentrated. It was dried. The residue was separated between ethyl acetate and water. The organic layer was washed with brine and sulfuric acid. Dry on sodium and concentrate to obtain 5-cyclopropyl-2-hydrazineylpyridine (150 mg, 1.00 mmol, 55% yield) was obtained as yellow oil. LCMS: m / z =150.1[M+H] + The product was used directly in the next step. I used it.

[0436] 4-(1-(5-(Cyclopropylpyridine-2-yl)-5-hydroxy-1H-py Razole-4-yl)benzonitrile [ka]

[0437] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (4.0 mL) Methyl aminoacrylate (230 mg, 1.00 mmol) and 5-cyclopropyl- p-toluene in a solution of 2-hydrazineylpyridine (150 mg, 1.00 mmol) Sulfonic acid monohydrate (38.0 mg, 0.20 mmol) was added. The mixture was refluxed. The mixture was stirred for 2 hours and then cooled to allow the solid to precipitate. The solid was filtered, washed with ethanol, and dried. Furthermore, 4-(1-(5-cyclopropylpyridine-2-yl)-5-hydroxy-1H- Pyrazole-4-yl)benzonitrile (36 mg, 0.12 mmol, yield 12%) It was obtained as a white solid. LC-MS: 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] 2,5-difluoropyridine (500 mg, 4.34 mg) in ethanol (2.0 mL) Add hydrazine hydrate (434 mg, 8.69 mmol, 85% in water) to a mol solution. The mixture was added. The mixture was stirred overnight in a sealed tube at 120°C. The mixture was cooled and concentrated. It was then dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine. The residue was dried over sodium sulfate and concentrated. The residue was ground with petroleum ether and filtered to obtain 5- Fluoro-2-hydrazineylpyridine (270 mg, 2.13 mmol, 49% yield) It was obtained as a white solid. LCMS: m / z = 128.1(M+H) + , retention time 0.33 minutes (method A).

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

[0441] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (4.0 mL) Methyl aminoacrylate (181 mg, 0.79 mmol) and 5-fluoro-2-H In a solution of drazinylpyridine (100 mg, 0.79 mmol), p-toluene sulf 30.4 mg, 0.16 mmol of sodium acid monohydrate was added. The mixture was incubated under reflux for 12 hours. The mixture was stirred and cooled to allow the solid to precipitate. The solid was filtered, washed with ethanol, and dried. 4-(1-(5-fluoropyridine-2-yl)-5-hydroxy-1H-pyrazole- 4-yl)benzonitrile (94.6 mg, 0.34 mmol, yield 43%) is a white solid. The result was obtained as follows: 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-Il)benzonitrile [ka]

[0443] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (3.0 mL) In a solution of methyl aminoacrylate (150.0 mg, 0.65 mmol), 5-chloroacrylate was added. -2-Hydrazineylpyridine (93.52 mg, 0.65 mmol) and p-toluene Sulfonic acid monohydrate (13.3 mg, 0.07 mmol) was added. The reaction mixture was then placed in a sealed tube. The mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled, concentrated, and dried. The residue was then removed. Purification by flash chromatography (dichloromethane / ethyl acetate = 100 / 1) Prepared as 4-(1-(5-chloropyridine-2-yl)-5-hydroxy-1H-pyrazole (4-yl)benzonitrile (77 mg, 0.26 mmol, 40% yield) was solidified into a yellow solution. The sample was obtained as a whole. LCMS: m / z = 297.0 [M + H] + , retention time 5.095 minutes ( Law 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] (E)-3-(dimethylamino)-2-(4-chlorophate in ethanol (5.0 mL) Ethyl acrylate (200 mg, 0.79 mmol) and 2-hydrazine yl- 5-(methylsulfonyl)pyridine (intermediate from Example 4) (147.83 mg, 0. In a 79 mmol solution, add p-toluenesulfonic acid monohydrate (30.4 mg, 0.16 mg) A mole was added. The mixture was stirred under reflux for 12 hours, then cooled to precipitate the solid. Filter, wash with ethanol, dry, and 4-(4-chlorophenyl)-1-(5- (Methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol (95.0 0 mg, 0.27 mmol, yield 34.54%) were obtained as a white solid. LCMS: m / z = 350.1(M + H) + , retention time 1.93 minutes (Method A). 1 1H NMR (400M) Hz,DMSO-d6)δ 8.94(d,J=2.8Hz,1H), 8.81-8.5 6(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] (E)-3-(dimethylamino)-2-(4-fluoro in ethanol (5.0 mL) Ethyl phenylacrylate (127 mg, 0.53 mmol) and 2-hydrazine yl hydrate -5-(methylsulfonyl)pyridine (intermediate from Example 4) (100 mg, 0.53 In a solution of mmol, p-toluenesulfonic acid monohydrate (20.9 mg, 0.11 mmol) l) was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered. Wash with ethanol and dry, then 4-(4-fluorophenyl)-1-(5-( Methylsulfonyl)pyridine-2-yl)-1H-pyrazole-5-ol (93.8m g, yield 52%) was obtained as a white solid. LCMS: m / z = 334.3(M+H) + , Retention time 4.02 minutes (Method A). 1 1H NMR (400MHz, DMSO-d6) δ 1 3.01(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-Il)benzonitrile [ka]

[0449] (E)-2-(4-cyanophenyl)-3-(dimethicone) in ethanol (10.0 mL) Methyl aminoacrylate (612 mg, 2.66 mmol) and 5-bromo-2-hyaluronic acid p-toluenesulfone in a solution of drazinylpyridine (500 mg, 2.66 mmol) 51 mg, 0.27 mmol of sodium acid monohydrate was added. The mixture was stirred under reflux for 12 hours. Then, it was cooled to precipitate the solid. The solid was filtered, washed with ethanol, dried, and 4- (1-(5-bromopyridine-2-yl)-5-hydroxy-1H-pyrazole-4-yl Benzonitrile (680 mg, 1.99 mmol, yield 75%) is obtained 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,2 H).

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

[0451] 6-fluoropyridine-3-amine (500.0) in dichloromethane (20.0 mL) A solution of cyclopropane carbonyl chloride (559.4 mg, 4.46 mmol) is prepared. (g, 5.35 mmol, 0.48 mL) and triethylamine (902.6 mg, 8.9 2 mmol (1.24 mL) was added at 0°C. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted twice with dichloromethane. The organic layer was washed with brine. Dry on sodium sulfate and concentrate to obtain N-(6-fluoropyridine-3-yl) cyclamate. Lopropancarboxamide (850 mg crude) was obtained. LCMS: m / z = 181.0 [M +H] + The holding time was 1.577 minutes (Method A). The product was sufficiently pure and could be used in the next step. I used it directly.

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

[0453] N-(6-fluoropyridine-3-yl)cyclopropane in ethanol (5.0 mL) Carboxamide (850.0 mg, 4.72 mmol) and hydrazine hydrate (5.0 A mixture of mL (85% in water) 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 bleached. The residue was washed, dried on sodium sulfate, and concentrated. The residue was ground with petroleum ether and filtered. Over time, N-(6-hydrazineylpyridine-3-yl)cyclopropanecarboxamide (312 mg crude) was obtained. LCMS: m / z = 193.0 [M + H] + , retention time 0.8 67 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- Il)pyridine-3-yl)cyclopropanecarboxamide [ka]

[0455] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (4.0 mL) Methyl aminoacrylate (200.0 mg, 0.87 mmol) and N-(6-hydra Dinylpyridine-3-yl)cyclopropanecarboxamide (166.9 mg, 0.8 In a 7 mmol solution, add p-toluenesulfonic acid monohydrate (17.1 mg, 0.09 mg) (ol) was added. The mixture was stirred at 90°C for 3 hours, cooled to room temperature, evaporated, and dried. The residue was subjected to flash chromatography (dichloromethane / methanol = 20 / 1). Purified by N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H- Pyrazole-1-yl)pyridine-3-yl)cyclopropanecarboxamide (78mg) g, 0.22 mmol, yield 26%) was obtained as a yellow solid. LCMS: m / z = 346 .0[M+H] + , retention time 4.330 min (method A). 1 1H NMR (400MHz, D MSO-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), 8.17-8.1 3(m,1H), 8.09(d,J=8.0Hz,2H), 7.78(d,J=8.4H z,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] 6-fluoropyridine-3-amine (500.0 mg) in dichloromethane (20 mL) In a solution of 4.46 mmol, add propionyl chloride (495.16 mg, 5.35 mg) (mol, 0.47 mL) and triethylamine (902.60 mg, 8.92 mmol, 1.24 mL was added at 0°C. The mixture was warmed to room temperature and stirred for 2 hours. The reaction product was dissolved in water. The organic layer was diluted and extracted with dichloromethane. The organic layer was washed with brine and then on sodium sulfate. Dry and concentrate N-(6-fluoropyridine-3-yl)propionamide (80 An 8 mg crude sample was obtained. LC-MS: m / z = 169.0 [M + H] + , retention time 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] N-(6-fluoropyridine-3-yl)propionamide in ethanol (5 mL) (800.00 mg, 4.76 mmol) and hydrazine hydrate (5.0 mL, 85 mL in water) The mixture was stirred in a sealed tube at 110°C for 3 hours. The mixture was cooled and concentrated. It was dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine and sulfur The residue was dried on sodium phosphate and concentrated. The residue was ground with petroleum ether and filtered to obtain N-( 6-Hydrazineylpyridine-3-yl)propionamide (crude) (294 mg) was obtained. CMS:m / z=181.0[M+H] + The retention time was 0.317 minutes (Method A). The product was It was sufficiently pure and used directly in the next step.

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

[0461] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (4.0 mL) Methyl aminoacrylate (200.0 mg, 0.87 mmol) and N-(6-hydra Dinylpyridine-3-yl)propionamide (156.5 mg, 0.87 mmol) p-toluenesulfonic acid monohydrate (14.9 mg, 0.09 mmol) was added to the solution. The mixture was stirred at 90°C for 3 hours, cooled to room temperature, and evaporated to dry. The residue was then removed. Purification by flash chromatography (dichloromethane / methanol = 20 / 1) Then, N-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole- 1-yl)pyridine-3-yl)propionamide (23 mg, 0.07 mmol, yield) 8.0% was obtained as a yellow solid. LCMS: m / z = 334.0 [M + H] + , when held for 4.322 minutes (method A). 1 1H 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=8.0 Hz,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] 6-fluoropyridine-3-amine (500 mg, 4.4 mg) in pyridine (2.5 mL) 0.5 mL of methanesulfonyl chloride was added to a 6 mmol solution at 0°C. The mixture was warmed to room temperature and stirred for another hour. The reaction mixture 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)methanesulfonamide (600 mg, 3.12 mmol, A yield of 70% was obtained as yellow oil. LC-MS: m / z = 190.9 [M + H] + , when held for 1.38 minutes (method A).

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

[0465] N-(6-fluoropyridine-3-yl)methanesulfone in ethanol (4.0 mL) A solution of naamide (600 mg, 3.15 mmol) is mixed with hydrazine hydrate (2.0 mL, 85% of the mixture was added to the 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 bran. Wash with water, dry on sodium sulfate, concentrate, and N-(6-hydrazine yl-3) -yl)methanesulfonamide (300 mg, 1.48 mmol, yield 47%) in yellow oil The result was obtained as follows: LCMS: m / z = 203.2[M+H] + , retention time 0.34 min (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- Iyl(pyridine-3-yl)methanesulfonamide [ka]

[0467] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (4.0 mL) Methyl aminoacrylate (341 mg, 1.48 mmol) and N-(6-hydrazine) Dissolved in ylpyridine-3-yl)methanesulfonamide (300 mg, 1.48 mmol) p-toluenesulfonic acid monohydrate (28.5 mg, 0.15 mmol) was added to the solution. The mixture was stirred under reflux for 12 hours and cooled to allow the solid to precipitate. The solid was filtered and ethanol was extracted. Wash with a lint roller and dry, then N-(6-(4-(4-cyanophenyl)-5-hydroxy- 1H-Pyrazole-1-yl)pyridine-3-yl)methanesulfonamide (250mg) 0.72 mmol (49% yield) was obtained as a white solid. LC-MS: m / z = 356. 4(M+H) + , retention time 3.74 minutes (Method A). 1 1H NMR (500MHz, DMS) O-d6)δ 10.03(s,1H), 8.51(s,1H), 8.32(d,J=1 3.4Hz,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] 6-fluoropyridine-3-amine (500 mg, 4.4 mg) in pyridine (5.0 mL) In a 6 mmol solution, add ethanesulfonyl chloride (689.71 mg, 5.36 mmol) l) was added at 0°C. The mixture was heated to room temperature and stirred for another hour. The reaction mixture was diluted with water. The mixture was saturated and extracted twice with ethyl acetate. The organic layer was washed with brine and dried on sodium sulfate. Then concentrate it, N-(6-fluoropyridine-3-yl)ethanesulfonamide (90 0 mg, 4.38 mmol, yield 98.26% was obtained 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] N-(6-fluoropyridine-3-yl)ethanesulfone in ethanol (5.0 mL) A solution of naamide (910 mg, 4.46 mmol) is mixed with hydrazine hydrate (1.05 g, 17.84 mmol (85% in water) was added. The mixture was heated in a sealed tube at 100°C. The mixture was stirred for 4 hours. The mixture was cooled, concentrated, and dried. The residue was then mixed between ethyl acetate and water. Separation was performed. The organic phase was washed with brine, dried on sodium sulfate, and concentrated. Residue Grind with petroleum ether, filter, and obtain N-(6-hydrazineylpyridine-3-yl) ether Sulfonamide (810.0 mg, 3.75 mmol, 84.11%) is used as a white solid. The result obtained was: 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- Iyl)pyridine-3-yl)ethanesulfonamide [ka]

[0473] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (5.0 mL) Methyl aminoacrylate (212.96 mg, 0.93 mmol) and N-(6-Hydroacrylate) Rajinylpyridine-3-yl)ethanesulfonamide (200.00 mg, 0.93 mm) In a solution of (0.19 mmol), p-toluenesulfonic acid monohydrate (36.1 mg, 0.19 mmol) The mixture was added. The mixture was stirred under reflux for 12 hours and cooled to precipitate the solid. The solid was filtered. Wash with ethanol and dry, then N-(6-(4-(4-cyanophenyl)-5-H Droxy-1H-pyrazole-1-yl)pyridine-3-yl)ethanesulfonamide ( 75 mg, 0.20 mmol, 21.86%) was obtained as a white solid. LC-MS: m / z =370.0(M+H) + , retention time 4.01 min (Method A). 1 1H NMR (400 MHz) z,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] 5-bromo-2-chloropyridine (1.5%) in anhydrous tetrahydrofuran (15.0 mL) 92g, 10.0 mmol) and N,N,N',N'-tetramethylethylenediamine ( In a solution of 1.51 g, 13.0 mmol, add n-butyllithium (7.5 mL, 12.0 mmol (in hexane, 1.6 M) was added under nitrogen at -78°C. The mixture was then mixed at -7 Stir at 8°C for 50 minutes, then add dimethyl disulfide (1.13 g, 12.0 mmol). The mixture was heated to 20°C and stirred for another hour. The reaction product was saturated ammonium chloride. Quenched with solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, and sulfurized. The product was dried on sodium acid and concentrated under reduced pressure. The crude product was then flash-chromatographed. Refined by (petroleum ether / ethyl acetate = 50 / 1), 2-chloro-5-(me (Tilthiopyridine) (1.0 g, 6.29 mmol, yield 62.9%) was obtained as yellow oil. . LC-MS: m / z = 160(M+H) + , retention time 0.85 min (Method A).

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

[0477] 2-chloro-5-(methylthio)pyridine (90) in dichloromethane (10.0 mL) 3-chloroperoxybenzoic acid (1.26 g, 6 mg, 5.66 mmol) in a solution of 0 mg, 5.66 mmol. 0.22 mmol, 85%) was added at 0°C. The mixture was stirred at this temperature for 1 hour. The substance was basicized with a 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was then separated. The product was separated, washed with brine, dried on sodium sulfate, and concentrated under reduced pressure. Crude product The substance is purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1). Prepared as 2-chloro-5-(methylsulfinyl)pyridine (700 mg, 4.0 mmol) l was obtained as a white solid (yield 70.6%). LC-MS: m / z = 176.1(M+H ) + , retention time 0.55 min (Method A).

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

[0479] 2-chloro-5-(methylsulfinyl)pyridine in ethanol (10.0 mL) A solution of 700 mg (4.0 mmol) is mixed with hydrazine hydrate (1.23 g, 20.0 ml) ol (85% in water) was added. The mixture was stirred at 80°C for 4.0 hours. The mixture was cooled. The mixture was concentrated and dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine. The residue was purified, dried on sodium sulfate, and concentrated. The residue was ground with petroleum ether and filtered. , 2-Hydrazineyl-5-(methylsulfinyl)pyridine (400mg, 2.34mg) A mol (58.5% yield) was obtained 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] 2-chloro-5-(methylsulfinyl)pyridine in chloroform (5.0 mL) 200 mg, 1.14 mmol) (intermediate of Example 12) and sodium azide (223 A mixture of mg (3.43 mmol) 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 mixture was diluted with ice water, and the organic layer was removed. As soon as the aqueous phase is made basic by adding ammonium hydroxide solution, the oil is separated. This was extracted with dichloromethane. The organic layer was separated, washed with brine, and then sodium sulfate was used. Dry on top and concentrate (6-chloropyridine-3-yl)(imino)(methyl)-λ 6 -Sulfanone (120 mg, 0.63 mmol, yield 55.4%) as a yellow solid. Obtained. LC-MS: m / z = 191.0 (M + H) + , retention time 1.3 min (Method A).

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

[0483] (6-chloropyridine-3-yl)(imino)(methicone) in ethanol (10.0 mL) (Lu)-λ 6 -Hydrazine hydrate in a solution of sulfanone (120 mg, 0.63 mmol) A substance (200 mg, 3.15 mmol, 85% in water) was added. The mixture was heated at 80°C for 4.0°C. The mixture was stirred for several hours. The mixture was cooled, concentrated, and dried. The residue was divided between ethyl acetate and water. The organic phase was separated. The organic phase was washed with brine, dried on sodium sulfate, and concentrated. The residue was then removed. Grind with oil ether, filter, and obtain (6-hydrazineylpyridine-3-yl)(imino) (methyl)-λ 6 -Sulfanone (100 mg, 0.54 mmol, yield 85.3%) It was obtained as a yellow solid. LC-MS: m / z = 187.0(M+H)+, retention time 0.36 minutes (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-(dimethyl) in ethanol (6.0 mL) Methyl aminoacrylate (150 mg, 0.65 mmol) and (6-hydrazine yl hydrate) Pyridine-3-yl)(imino)(methyl)-λ 6 -Sulfanone (121 mg, 0.6 In a 5 mmol solution, add p-toluenesulfonic acid monohydrate (24.7 mg, 0.13 mg) (ol) was added. The mixture was stirred overnight in a sealed tube at 90°C, and then cooled to allow the solid to settle. 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%) is a white solid. The result obtained was: 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=8.9 Hz, 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] Methanesulfonamide (35.3 mg, 0.37 mg) in dichloromethane (5.0 mL) In a solution of (mol) and triethylamine (74.9 mg, 0.74 mmol), 6-(4 -(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotinoid Luchloride (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 back-preparative HPLC. 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl )-N-(methylsulfonyl)nicotinamide (17.6 mg, 0.05 mmol, yield 6.2% was obtained as a white solid. LC-MS: m / z = 384.1(M+H) + , hold Time 4.24 minutes (Method A). 1 HNMR (400 MHz, 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-butyl6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazole (Lu-1-il) Nicotinate [ka]

[0489] tert-butyl6- in dichloromethane / methanol (29.0 mL / 5.0 mL) (4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)nicotine (diazomethyl) is added to a solution of nate (intermediate from Example 1) (1.0 g, 2.76 mmol). 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 then flash-chromatographed. Refined by (petroleum ether / ethyl acetate = 3 / 1), tert-butyl 6-( 4-(4-cyanophenyl)-5-methoxy-1H-pyrazole-1-yl)nicotine 200 mg, 0.53 mmol, yield 19.2% was obtained as a yellow solid. LC-M S: m / z = 377.0 [M + H] + , retention time 2.40 min (Method A).

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

[0491] tert-butyl 6-(4-(4-cyanophenic acid in dichloromethane (10.0 mL) Nicotinate (200mg, 0.5) 5.0 mL of trifluoroacetic acid was added to a 3 mmol solution. The mixture was heated at 40°C. The mixture was stirred 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 (150ml) g, 0.47 mmol, yield 88.4%) was obtained 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 (Lu-4-yl)benzonitrile [ka]

[0493] 6-(4-(4-cyanophenyl)-5-methoxy-1H in toluene (5.0 mL) -Pyrazole-1-yl)nicotinic acid (150 mg, 0.47 mmol), diphenylmethyl phosphate Suphonate azide (194 mg, 0.71 mmol), and triethylamine (95 mg, The mixture (0.94 mmol) was stirred at 110°C for 3 hours. The reaction mixture was diluted with water and acetic acid was added. Extracted with ethyl acetate. The organic layer was separated, washed with brine, and dried on sodium sulfate. Concentrated under reduced pressure. Crude 4-(1-(5-isocyanatopyridine-2-yl)-5-methoxy C-1H-pyrazole-4-yl)benzonitrile (150 mg, crude) in yellow syrup The result obtained was: LC-MS: m / z = 345.9 (M + H) + , retention time 2.01 min (method A The crude product was used in the next step.

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

[0495] 4-(1-(5-isocyanatopyridine-2-yl) in dichloromethane (5.0 mL) )-5-methoxy-1H-pyrazole-4-yl)benzonitrile (150 mg, crude) and A mixture of morpholine (174 mg, 2.0 mmol) was stirred overnight at room temperature. Reaction product The solution was diluted with water and extracted with dichloromethane. The organic layer was separated, washed with brine, and then subjected to anhydrous sulfurization. The residue was dried on sodium acid, concentrated, and dried again. The residue was then subjected to flash chromatography. - Purified by (methanol / dichloromethane = 1 / 10), 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%) It was obtained as a yellow solid. LC-MS: m / z = 405.1 [M + H] + , retention time 1.96 Minutes (Method A). The product was used in the next step.

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

[0497] N-(6-(4-(4-cyanophenate in N,N-dimethylformamide (6.0 mL)) (Nyl)-5-methoxy-1H-pyrazole-1-yl)pyridine-3-yl)morpholine A solution of -4-carboxamide (50 mg, 0.12 mmol) is mixed with lithium chloride (50 mg). 4 mg (1.2 mmol) was added. The mixture was stirred overnight at 60°C. The solution was then treated with ethyl acetate. Diluted with water. The organic layer was washed with brine, dried on sodium sulfate, and evaporated. It was dried. The residue was purified by reverse preparative HPLC and N-(6-(4-(4-shea Nophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl)mo Ruforin-4-carboxamide (formate) (9.7 mg, 0.02 mmol, yield 18. 6% was obtained as a white solid. LC-MS: m / z = 391.0(M+H) + , retention time 4.27 minutes (Method A). 1 HNMR (400 MHz, 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] 6-chloropyridine-3-sulfonamide (1.63g) in ethanol (5.0mL) To a solution of 8.5 mmol of hydrazine, 5.0 mL of hydrazine hydrate (85% in water) was added. The mixture was stirred in a sealed tube at 100°C for 4 hours. The mixture was cooled and concentrated to dry. It was dried. The residue was separated between ethyl acetate and water. The organic phase was washed with brine and sodium sulfate. The residue was dried on thorium and concentrated. The residue was ground with petroleum ether and filtered to obtain 6-hydra. Dinylpyridine-3-sulfonamide (600 mg, 3.20 mmol, yield 37.7%) The %) was obtained as a yellow solid. LCMS: m / z = 189.0 (M + H) + , retention time 0. 32 minutes (Method A).

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

[0501] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (8.0 mL) Methyl aminoacrylate (452 ​​mg, 1.97 mmol) and 6-hydrazine ylpiol p-toluene in a solution of lysine-3-sulfonamide (370 mg, 1.97 mmol) Sulfonic acid monohydrate (76.4 mg, 0.4 mmol) was added. The mixture was heated at 90°C for 1 Stirred for 6.0 hours, then cooled to allow the solid to precipitate. The solid was filtered, washed with ethanol, and dried. Dry and prepare 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1 -yl)pyridine-3-sulfonamide (340 mg, 1.0 mmol, yield 50.8%) The substance was obtained as a white solid. LC-MS: m / z = 342.0(M+H) + , retention time 1. 76 minutes (Method A).

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

[0503] 6-(4-(4-shea in dichloromethane / methanol (15.0 mL / 3.0 mL) Nophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-sulfone (diazomethyl)trimethylsilane ( ) 0.75 mL (1.5 mmol in hexane, 2 M) was added. The mixture was stirred overnight at 25°C. Mixed, concentrated, and dried. The residue was flash-chromatographed (dichloromethane / Purified with methanol (100 / 2), 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 (Lu-1-yl)pyridine-3-sulfonamide (245 mg, 0.69 mmol, yield 6) Two isomers of 9% were obtained as yellow solids. LC-MS: m / z = 356.0[M+ H] + Retention time 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- Iyl)pyridine-3-yl)sulfonyl)acetamide and N-((6-(4-(4-cy Anophenyl)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazole-1- Iyl(pyridine-3-yl(sulfonyl)acetamide) [ka]

[0505] 6-(4-(4-cyanophenyl)-5 in anhydrous tetrahydrofuran (10.0 mL) -Methoxy-1H-pyrazole-1-yl)pyridine-3-sulfonamide and 6-(4 -(4-cyanophenyl)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazole Dissolved in (1-yl)pyridine-3-sulfonamide (245 mg, 0.69 mmol) The solution contains triethylamine (140 mg, 1.38 mmol) and acetyl chloride (69 mg) (0.90 mmol) was added at 0°C. The mixture was stirred overnight at room temperature, concentrated, and dried. The residue was subjected to flash chromatography (dichloromethane / methanol = 20 / 1). Purified by 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, Two isomers were obtained as yellow solids in quantities of 0.40 mmol each (58.3% yield). LC-M S:m / z=398.0[M+H] + Retention time 1.73 minutes (Method A). Two isomers It was used in the next process without separation.

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

[0507] N,N-dimethylformamide (10.0 mL) contains N-((6-(4-(4-cyano Phenyl)-5-methoxy-1H-pyrazole-1-yl)pyridine-3-yl)sulfon Nyl)acetamide and N-((6-(4-(4-cyanophenyl)-2-methyl-5- Oxo-2,5-dihydro-1H-pyrazole-1-yl)pyridine-3-yl)sulfon A solution of (200 mg, 0.40 mmol) of (nyl)acetamide is mixed with lithium chloride (168%). (mg, 4.0 mmol) was added. The mixture was stirred overnight at 60°C. The solution was then ethyl acetate. The mixture was then diluted with water. The organic layer was washed with brine, dried on sodium sulfate, and evaporated. It was dried. The residue was purified by reverse preparative HPLC and N-((6-(4-(4-shea Nophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyridine-3-yl) Rufonyl acetamide (formate) (15.3 mg, 0.04 mmol, yield 8.92%) The substance was obtained 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,3 H).

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

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

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

[0511] (6-bromopyridine-3-yl)dimethylphosphine in ethanol (5.0 mL) In a solution of oxide (120 mg, 0.51 mmol), add 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 The residue was washed with brine, dried on sodium sulfate, and concentrated. The residue was ground with petroleum ether. Then, filter it and (6-hydrazineylpyridine-3-yl)dimethylphosphine oxide (80 mg, 0.43 mmol, yield 80%) was obtained 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-1 H-pyrazole-4-yl)benzonitrile [ka]

[0513] (E)-2-(4-cyanophenyl)-3-(dimethyl) in ethanol (5.0 mL) Methyl aminoacrylate (100 mg, 0.43 mmol) and (6-hydrazine yl hydrate) Pyridine-3-yl)dimethylphosphine oxide (80.4 mg, 0.43 mmol) p-toluenesulfonic acid monohydrate (19 mg, 0.1 mmol) was added to the solution. The mixture was stirred overnight in a sealed tube at 100°C, then cooled to allow the solid to precipitate. Purified by reverse preparative HPLC, 4-(1-(5-(dimethylphosphoryl)pyridine- 2-yl)-5-hydroxy-1H-pyrazole-4-yl)benzonitrile (formate) (15.0 mg, 0.04 mmol, yield 9.3%) was obtained as a white solid. LC-MS :m / z=339.0(M+H) + , retention time 3.48 min (Method A). 1 HNMR (40 0MHz,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 is prepared using 5-chloropyridine-2-acetic acid, and 4-(5-hydroxy-1-( 5-(methylsulfonyl)pyridine-2-yl)-1H-pyrazole-4-yl)benzo It was synthesized according to the preparation procedure for nitrile (Example 4). LCMS(ESI+): m / z 3 65(M+H) + ; 1 H 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, 4-bromo-3-methyl phosphate in THF (300 mL) and water (30 mL) Rubenzonitrile (6.14g, 31.34mmol), Cs2CO3 (40.87g, 125.38 mmol), potassium trifluoro(vinyl)borate (8.40 g, 62. A mixture of 69 mmol) and Pd(dppf)Cl2 (2.29 g, 3.13 mmol). The mixture 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 layers were dried over Na2SO4 (30g), filtered, and concentrated. The residue was analyzed by silica gel column chromatography (Â:Hex=1:50). After purification, 6.74 g of the desired product was obtained as oil. GC-MS: m / z 143 (M) + .

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

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

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

[0521] 2-(4-cyano-2-methylphenyl)acetic acid (3.40g) in MeOH (60mL) SOCl2 (7 mL) was added dropwise to a mixture of 21.66 mmol of , over a period of 5 minutes. The mixture was stirred at room temperature for 40 minutes. The reaction was complete as shown by TLC analysis. The resulting mixture was then concentrated directly. The residue was subjected to silica gel column chromatography (E Purified by tOAc:n-Hex (1:50~1:10), yielding 1.66 g of the desired raw material. The finished product was obtained as oil. 1 H-NMR(300MHz,CDCl3)δ 7.46(m,2 H), 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)acrylic Methyl acid [ka]

[0523] Methyl 2-(4-cyano-2-methylphenyl)acetate in DMF-DMA (6 mL) A mixture of 1.66 g and 8.78 mmol was stirred at 100°C for 5 hours. TLC analysis was performed. As shown, after the reaction was complete, the resulting mixture was directly concentrated. The residue, sil Kagel column chromatography (Â:n-Hex=1:50~1:5) The mixture was purified 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,1 H), 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] (Z)-2-(4-cyano-2-methylphenyl)-3-( in EtOH (10 mL) In a solution of methyl dimethylaminoacrylate (0.34 g, 1.39 mmol), add N2H 4. Add H2O (0.64 g, 10.20 mmol). Stir the reaction mixture overnight at 70°C. The reaction was completed as shown by TLC, and the resulting mixture was directly concentrated. The residue was subjected to silica gel column chromatography (ÂTED:n-Hex=1:50~). The mixture was purified by a 1:10 ratio to obtain 287 mg of the desired product as oil. 1 H-NMR (300MHz,DMSO-d6)δ 11.96(brs,1H), 10.21(br s,1H), 7.74(s,1H), 7.67(s,1H), 7.62(d,J=8.1 Hz, 2H), 2.36(s, 3H).

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

[0527] 5,6-dichloropyridine-3-amine (0.5) in concentrated HCl (2.5 mL) at 0°C A mixture of 0g, 3.07 mmol, and an aqueous solution of NaNO2 (0.32g, 4.60 mmol) 1 ml of water was added dropwise over 5 minutes. The reaction mixture was stirred at 0°C for 1 hour. The solution was filtered to remove inorganic salts. The solution was then mixed with MeSNa in acetonitrile (2.5 ml). (1.29g, 3.68 mmol, 20%) and NaBF4 (3.4mg, 0.031mg) The substance was added dropwise to a (mol) suspension at 0°C over 10 minutes. The resulting orange suspension was then added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, as shown by TLC, the reactants were mixed with N2. The sample was quenched with an aqueous aOH solution (1N, 5 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was dried over Na2SO4 (20g), filtered, and concentrated to 45 6 mg of the desired product was obtained as a black solid. 1 H-NMR (300 MHz, CDCl3) )δ 8.15(d,J=2.1Hz,1H), 7.62(d,J=2.4Hz,1H) , 2.50 (d, J=6.0Hz, 3H).

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

[0529] 2,3-Dichloro-5-(methylthio)pyridine (0.46g) in DCM (30mL) Add m-CPBA (0.85g, 4.94 mmol) once to a solution of 2.35 mmol. It was added to the mixture. The reaction mixture was then stirred at room temperature for 3.5 hours. As shown by TLC After the reaction was complete, the mixture was directly concentrated. The residue in ethyl acetate (50 mL), Na Washed with 2S2O3 aqueous solution (10 mL). The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over Na2SO4 (30g), filtered, and concentrated. The residue was subjected to silica gel column chromatography ( Depositphotos:n-Hex=1:50~1: Purification by method 20) yielded 460 mg of the desired product as a solid. 1 H-NMR ( 300MHz, CDCl3)δ 8.82(d,J=2.1Hz,1H), 8.29(d ,J=2.4Hz,1H), 3.15(s,3H).

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

[0531] 4-(5-hydroxy-1H-pyrazole-4-yl)-3-methyl in DMF (3 mL) A mixture of thylbenzonitrile (0.15g, 0.75mmol) and NaH (60mg, The solution (1.50 mmol) was added in small amounts over 5 minutes. The reaction mixture was stirred at room temperature for 40 minutes. 2,3-Dichloro-5-(methylsulfonyl)pyridine (0.25g, 1.13mg) The reaction was carried out by adding (mol) and stirring the mixture overnight at room temperature. The reaction was shown by TLC analysis. After the reaction was complete, the resulting mixture was directly concentrated and dried. The residue was then separated by preparative HPLC. The sample was purified to obtain 11 mg of the desired product as a solid. LCMS(ESI+): m / z 389(M+H) + ; 1 H-NMR (300 MHz, CDCl3) δ 10.23(b rs,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,2 H), 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- Il)pyridine-3-yl)piperazine-1-carboxamide [ka]

[0533] The compound was prepared using tert-butylpiperazine-1-carboxylate, N-(6 -(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazole-1-yl)pyri Prepare din-3-yl)morpholine-4-carboxamide (Example 28) according to the preparation procedure. I did it.

[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] Using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay, full-length human Prolyl-4-hydroxylase domain (PHD) enzymes, PHD1, PHD2, and P Enzymatic semi-maximal inhibitory concentration (IC) of PHD inhibitors against HD3 50 The value was determined. TR- The FRET assay uses a hydroxylated HIF-1α peptide that generates a fluorescent signal. and specific binding of complexes formed by VHL, EloB, and EloC (VBC) Developed based on the TR-FRET terbium (Tb) donor (anti-monoclorose). (Nal antibody, anti-6His-Tb-cryptate gold) and D2-acceptor (Stra Putavidin [SA]-D2) is linked to the VBC complex and HIF-1α peptide, respectively. The VBC complex specifically binds to the HIF-1α peptide when hydroxylated. This enables energy transfer from the TR-FRET donor to the acceptor (Figure 1).

[0536] Materials and methods Unless otherwise specified, all chemicals and materials are of standard laboratory grade. I purchased it from igma-Aldrich (St. Louis, MO, USA).

[0537] reagent TR-FRET reagent Monoclonal antibody, anti-6His-Tb-cryptate gold (catalog number 61H) I2TLA) and streptavidin (SA)-D2 (catalog number 610SADLA) From CisBio International (Bedford, MA, USA) I bought it.

[0538] Represents amino acids 547-581, including proline 564 and the PHD2 hydroxylation site. N-terminal biotinylated HIF-1α C35 synthetic peptide, California Pep Purchased from Tide Research (Salt Lake City, UT, USA). did.

[0539] Recombinant protein VBC complex His-tagged recombinant VHL protein, EloB, EloC complex (His-VBC) ) was supplied by Axxam (Milan, Italy). Recombinant human VHL ( National Center for Biotechnology Inform ation [NCBI] Accession number NP_00542.1) is amino acid 55~ The 213 molecule contains a His tag at its C-terminus and is called VHL-His. VHL-His is Full-length human EloB (NCBI accession number Q15370.1) and full-length human E loC (NCBI accession number Q15369.1) and co-expressed in E. coli Therefore, as a His-VBC complex, on a nickel-nitrilotriacetic acid (Ni-NTA) column It was purified by affinity chromatography. The purified (approximately 80%) sodium dodecyl sulfate Evaluation was performed by polyacrylamide gel electrophoresis (SDS-PAGE).

[0540] PHD1 Recombinant human PHD1 protein (Catalog number 81064, Lot number 2471700) 1) I purchased it from Active Motif (Carlsbad, CA, USA). PHD1, along with its N-terminal FLAG tag (molecular weight 44.9 kDa), is a full-length protein. (NCBI accession number NP_542770.2) Baculovirus expression system The gene was expressed using [specific method / technology]. Purity (over 90%) was evaluated by SDS-PAGE.

[0541] PHD2 Full-length human PHD2 enzyme was introduced into Beryllium (Bedford, MA, USA). It was produced using a baculovirus-infected insect cell (BIIC) expression system. PHD2 construction The substance is PHD2 amino acids 1-426 (UniProt Knowledgebase[ UniProtKB] / Swiss-Prot accession number Q9GZT9.1), Furthermore, the N-terminus contains a His tag and a tobacco etch virus (TEV) protease cleavage site. The construct was expressed in Sf9 insect cells and purified by Ni-NTA column. The His tag was removed by digestion with TEV protease. The purity of the final cleaved protein was determined as follows: Evaluation by SDS-PAGE revealed that it was over 94% pure.

[0542] PHD3 Recombinant human PHD3 protein (molecular weight 31.1 kDa) is used in Active Moti Purchased from f (Carlsbad, CA, USA). This was tagged with an N-terminal 6-His tag ( Catalog number 81033, lot number 24417001) along with full-length protein ( It is expressed in E. coli under the NCBI accession number NP_071356.1. The 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 are placed in a white 384-well Optiplate microplate (Catalog). Log number 6007290, Perkin Elmer, Waltham, MA, USA) In addition, the PHD enzyme was pre-incubated in a reaction volume of 10 μL. For this purpose, 5 μL Dilute the PHD inhibitor compound with buffer (50 mM HEPES[4-(2-hydroxyethyl )-1-piperazineethanesulfonic acid] pH 7.5, 50 mM sodium chloride [NaC l], 0.01% Tween-20, 0.01% purified bovine serum albumin [BSA] 5 μL of a 4-fold concentrate prepared by serial dilution with ) in a dilution buffer containing PHD enzyme. PHD enzyme mix (60nM PHD1, 20nM PHD2, 140nM PHD 3) 40 μM ferrous ammonium sulfate (FAS), 4 mM sodium ascorbate Mixed with Na. The plate was incubated at room temperature for 30 minutes without rotation. Ta.

[0545] Next, 20 nM His-VBC, 1.32 nM monoclonal antibody, anti-6His Prepared as a 4-fold concentrate in a dilution buffer containing -Tb-cryptate gold, 5 Add microliters of VBC / anti-6His-Tb-cryptate gold mix. Immediately after this process, 120 nM biotin-labeled HIF-1α C35, 132 nM SA-D2 in a dilution buffer containing 4 μM 2-oxoglutarate (2-OG) Add 5 μL of HIF-1α C35 substrate mix, which was prepared as a 4-fold concentrate, and 2 The final reaction volume reached 0 μL.

[0546] The final assay reaction mixture is 50 mM HEPES, pH 7.5, 50 mM NaCl, 1 μM 2-OG, 10 μM FAS, 1 mM sodium ascorbate, 0.01% Twe en-20, 0.01% purified BSA, 30 nM biotin-labeled HIF-1α C35, 5nM His-VBC, 0.33nM monoclonal antibody, anti-6His-Tb-cri Ptate Gold, 33nM SA-D2, and PHD enzyme (15nM PHD1, 5n It contained M PHD2 or 35 nM PHD3 together with the diluted compound.

[0547] PHD inhibitor compound IC 50For measurement, incubate the reaction mixture at room temperature for 10 minutes. Then, with an excitation wavelength of 340 nm, and emission wavelengths of 615 nm and 665 nm... , on Perkin Elmer EnVision (Waltham, MA, USA) Read. The data is from the Envision Manager software (Perkin Automatically calculated by Elmer (Waltham, MA, USA), 665n This represents the quotient of signal strength at m and 615nm. 50 Values ​​(mean, standard deviation, standard error of mean) The difference, geometric mean, and 95% confidence interval are calculated using GraphPad Prism 7.0 (Gra Using phPad (La Jolla, CA, USA), we used 4-parameter curve fitting. The compound concentrations were determined using the calculated ratios for 665 nm and 615 nm and plotted against each other. The TR-FRET assay was performed three times at each concentration of the compound, and the assay was performed three times independently. He repeated it.

[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. Therefore, the Km of 2-OG of PHD1 was determined to be 12.7 nM, while PHD The Km of 2-OG was determined to be 22.6 nM. Exemplary Compounds [Table 4] TIFF2026136124000180.tif227170TIFF2026136124000181.tif236170TIFF2026136124000182.tif228170TIFF2026136124000183.tif80170

[0550] From the current description, a person skilled in the art can easily confirm the essential characteristics of the present invention, and the intent thereof. And without departing from the scope, various modifications of the present invention to suit various uses and conditions Updates and modifications can be made.

[0551] All U.S. or foreign references, patents, or applications cited herein are as specified herein. As if they were included, all of them are incorporated herein by reference. In the event of any inconsistency, the materials disclosed literally in this specification shall prevail.

Claims

1. Compound of formula A, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, Ar １ C is optionally substituted with halogen, CN, OH, CN, or one or more halogens. １－３ Alkyl and C １－３ Optionally substituted with one or more groups selected from alkoxys It is an aryl or heteroaryl, Ar ２ is halogen; amino; amide; OH; sulfonyl group; sulfinyl group; carbo xyl group; phosphoryl group; C ３－６ Cycloalkyl; optionally substituted with a sulfonyl group or =O. C ３－６ Heterocycloalkyl; optionally substituted with carbonyl or one or more halogens C １－３ Alkyl and C １－３ Heterozygous substituted with alkyl or phenyl A pyrido-2-yl compound optionally substituted with one or more groups selected from aryl groups. A substance, or a pharmaceutically acceptable salt thereof.

2. Ar １ is 【Chemistry 2】 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 Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, The compound according to claim 1, wherein m is 1, 2, 3, or 4.

3. Ar １ but, 【Transformation 3】 The compound according to claim 2.

4. Ar １ but, 【Chemistry 4】 And in the formula, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ The compound according to claim 2 or 3, wherein it is alkyl.

5. Ar ２ but, 【Transformation 5】 And in the formula, R ２ Each time, independently, hydrogen, halogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ３ は、SO ２ R ６ SOR ７ R ８ SOR ９ COLOR １０ 、(CH ２ ) ｐ COOH NHR １１ , POR １２ R １３ , halogens, cycloalkyl, SO ２ R １４ Or = O A heterocycloalkyl group optionally substituted with C １－３ Alkyl or phenyl (optional) A substituted heteroaryl or C optionally substituted with one or more halogens. １－３ Alki It is 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 Alki It is 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 Alkyl can be, R ４ , R ５ , R １６ , R １７ , R １８ , R １９ , R ２３ , and R ２４ Each is independent of the others. H or C １－３ It is alkyl, p is 1, 2, or 3. The compound according to any one of claims 1 to 4, wherein n is 0, 1, 2, or 3.

6. Ar ２ but, (a) 【Transformation 6】 And in the formula, R ３ is selected from the group consisting of F, Cl, Br, and I, or (b) 【Transformation 7】 And in the formula, R １１ is COR ２１ or SO ２ R ２２ and R ２１ is a heterocycloalkyl, cycloalkyl, or C １－３ Alkyl 、 R ２２ is NR ２３ R ２４ or C optionally substituted with carboxyl １－３ alkyl It is R ２３ and R ２４ H or C １－３ The alkyl group as described in claim 5. compound.

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, 【Transformation 8】 Or CH ２ CH ３ The compound according to claim 6.

8. Ar ２ but, 【Chemistry 9】 And in the formula, (a) R ３ is a cycloalkyl or SO ２ R １４ Alternatively, the value of the letter O can be arbitrarily substituted. It is a telocycloalkyl, R １４ C １－３ Is it alkyl? or (b) R ３ C １－３ A heteroaryl compound optionally substituted with alkyl or phenyl. The compound according to claim 5.

9. The aforementioned cycloalkyl or optionally substituted heterocycloalkyl is 【Chemistry 10】 Selected from the group consisting of, The arbitrarily substituted heteroaryl is 【Chemistry 11】 A compound according to claim 8, selected from the group consisting of the following.

10. Formula I: 【Chemistry 12】 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, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ３ は、SO ２ R ６ SOR ７ R ８ SOR ９ COLOR １０ 、(CH ２ ) ｐ COOH NHR １１ , POR １２ R １３ , halogens, cycloalkyl, SO ２ R １４ Or = O A heterocycloalkyl group optionally substituted with C １－３ Alkyl or phenyl (optional) A substituted heteroaryl or C optionally substituted with one or more halogens. １－３ Alki It is 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 Alkyl can be, 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, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3.

11. Formula II: 【Chemistry 13】 It has a structure that follows the formula, X is N or CR １ａ And, Z is CH or N, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ３ は、SO ２ R ６ SOR ７ R ８ SOR ９ COLOR １０ 、(CH ２ ) ｐ COOH NHR １１ , POR １２ R １３ , halogens, cycloalkyl, SO ２ R １４ Or = O A heterocycloalkyl group optionally substituted with C １－３ Alkyl or phenyl (optional) A substituted heteroaryl or C optionally substituted with one or more halogens. １－３ Alki It is 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 Alkyl can be, 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.

12. Formula III: 【Chemistry 14】 It has a structure that follows the formula, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, NR ４ R ５ OH, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R ３ は、SO ２ R ６ SOR ７ R ８ SOR ９ COLOR １０ 、(CH ２ ) ｐ COOH NHR １１ , POR １２ R １３ , halogens, cycloalkyl, SO ２ R １４ Or = O A heterocycloalkyl group optionally substituted with C １－３ Alkyl or phenyl (optional) A substituted heteroaryl or C optionally substituted with one or more halogens. １－３ Alki It is 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 Alkyl can be, 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.

13. Formula IV: 【Chemistry 15】 It has a structure that follows the formula, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, 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 claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

14. R １ However, C １－３ The compound according to claim 13, wherein it is alkyl.

15. R １ However, CH ３ The compound according to claim 14.

16. Formula IVa: 【Chemistry 16】 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 It is alkyl, as described in claim 13. Compounds thereof, or pharmaceutically acceptable salts thereof.

17. R １ａ The compound according to any one of claims 13 to 16, wherein the compound is CN.

18. R １ａ The compound according to any one of claims 13 to 16, wherein the compound is a halogen.

19. R １ａ The compound according to claim 18, wherein the compound is Cl.

20. R ２ However, C １－３ The compound according to any one of claims 13 to 19, wherein it is alkyl.

21. R ２ However, CH ３ The compound according to claim 20.

22. R ７ However, C １－３ The compound according to any one of claims 13 to 21, wherein it is alkyl.

23. R ７ However, CH ３ The compound according to claim 22.

24. R ７ However, CH(CH ３ ) ２ The compound according to claim 22.

25. R ７ However, CH ２ CH ３ The compound according to claim 22.

26. R ７ However, C ３－５ The chemical compound according to any one of claims 13 to 21, which is a cycloalkyl compound. Compound.

27. R ７ The compound according to claim 26, wherein the compound is cyclopropyl.

28. R ７ The compound according to claim 26, wherein the compound is cyclopentyl.

29. R ７ The compound according to any one of claims 13 to 21, wherein the compound is phenyl.

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 The compound according to any one of claims 13 to 21, wherein it is alkyl.

31. R １８ and R １９ The compound according to claim 30, wherein is independently H.

32. R １８ However, H is R １９ However, C １－３ The compound according to claim 30, which is alkyl. 。

33. R １９ However, CH ３ The compound according to claim 32.

34. R １８ and R １９ CH became independent, ３ The compound according to claim 30.

35. R ８ The compound according to any one of claims 13 to 34, wherein the compound is NH.

36. R ８ However, NCH ３ The compound according to any one of claims 13 to 34.

37. Formula V: 【Chemistry 17】 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, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, 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 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 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.

38. The compound according to claim 37, wherein X is N.

39. X is CR １ａ The compound according to claim 37.

40. R １ａ The compound according to claim 39, wherein the compound is CN.

41. R １ａ The compound according to claim 39, wherein the compound is a halogen.

42. R １ａ The compound according to claim 41, wherein the compound is Cl.

43. R １ａ However, the compound according to claim 41 is F.

44. R １ａ The compound according to claim 41, wherein the compound is Br.

45. R １ａ However, C １－３ The compound according to claim 39, which is an alkoxy.

46. R １ａ The compound according to claim 45, wherein the compound is methoxy.

47. R １ａ The compound according to claim 39, wherein H is present.

48. R １ａ However, C is arbitrarily replaced by CN. １－３ The compound according to claim 39 is alkyl thing.

49. R １ａ However, CH ２ The compound according to claim 48, wherein it is CN.

50. R １ａ The compound according to claim 39, wherein the OH group is present.

51. The compound according to any one of claims 37 to 50, wherein Z is CH.

52. The compound according to any one of claims 37 to 50, wherein Z is N.

53. R １ The compound according to any one of claims 37 to 52, wherein H is present.

54. R １ However, C １－３ A compound according to any one of claims 37 to 52, wherein it is alkyl.

55. R １ However, CH ３ The compound according to claim 54.

56. R １ However, C １－３ The compound according to any one of claims 37 to 52, which is an alkoxy compound. 。

57. R １ The compound according to claim 56, wherein the compound is methoxy.

58. R １ The compound according to any one of claims 37 to 52, wherein the compound is CN.

59. R ２ The compound according to any one of claims 37 to 58, wherein H is present.

60. R ２ However, C １－３ A compound according to any one of claims 37 to 58, wherein it is alkyl.

61. R ２ However, CH ３ The compound according to claim 60.

62. R ６ However, C １－３ The compound according to any one of claims 37 to 61, wherein it is alkyl.

63. R ６ However, CH ３ The compound according to claim 62.

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 The compound according to any one of claims 37 to 61, wherein it is alkyl.

65. R ６ However, NH ２ The compound according to claim 64.

66. R ６ However, NHCOR １５ And in the formula, R １５ C １－３ Claim 3, which is alkyl A compound described in any one of items 7 to 61.

67. R ６ The compound according to any one of claims 37 to 61, wherein the compound is phenyl.

68. Formula VI: [Chemistry 18] It has a structure that follows the formula, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, 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, a heterozygous being arbitrarily substituted with =O It is a chloroalkyl, 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.

69. Formula VIa: 【Chemistry 19】 It has the structure, and in the formula, R ２ is hydrogen or C １－３ It is alkyl, R ３ is a cycloalkyl or SO ２ R １４ Alternatively, a heterozygous being arbitrarily substituted with =O It is a chloroalkyl, R １４ C １－３ The compound according to claim 68, which is alkyl, or a pharmaceutically acceptable salt thereof.

70. R ２ The compound according to claim 68 or 69, wherein H is present.

71. R ２ However, C １－３ The compound according to claim 68 or 69, wherein it is alkyl.

72. R ２ However, CH ３ The compound according to claim 71.

73. R ３ The compound according to any one of claims 68 to 72, wherein it is a cycloalkyl compound.

74. R ３ The compound according to claim 73, wherein the compound is cyclopropyl.

75. R ３ However, SO ２ R １４ Or a heterocycloalkyl which is optionally substituted with =O, in the formula , R １４ C １－３ The compound according to any one of claims 68 to 72, which is alkyl. 。

76. R ３ but, 【Chemistry 20】 The compound according to claim 75.

77. R ３ but, 【Chemistry 21】 The compound according to claim 75.

78. R ３ but, 【Chemistry 22】 The compound according to claim 75.

79. Formula VII: 【Chemistry 23】 It has a structure that follows the formula, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, 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 Alkyl can be, 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.

80. Formula VIIa: 【Chemistry 24】 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 Alkyl can be, R ２３ and R ２４ H or C １－３ The chemical compound according to claim 79, which is alkyl. Compounds, or pharmaceutically acceptable salts thereof.

81. R ２ The compound according to claim 79 or 80, wherein H is present.

82. R ２ However, C １－３ The compound according to claim 79 or 80, wherein it is alkyl.

83. R ２ However, CH ３ The compound according to claim 82.

84. R １１ However, COR ２１ And in the formula, R ２１ These are heterocycloalkyl and cycloalkyl Ru, or C １－３ The compound according to any one of claims 79 to 83, wherein it is alkyl.

85. R ２１ The compound according to claim 84, wherein it is a heterocycloalkyl compound.

86. R ２１ but, 【Chemistry 25】 The compound according to claim 85.

87. R ２１ but, 【Chemistry 26】 The compound according to claim 85.

88. R ２１ The compound according to claim 84, wherein it is a cycloalkyl compound.

89. R ２１ The compound according to claim 88, wherein the compound is cyclopropyl.

90. R ２１ However, C １－３ The compound according to claim 84, wherein it is alkyl.

91. R ２１ However, CH ２ CH ３ The compound according to claim 90.

92. R １１ However, SO ２ R ２２ And in the formula, R ２２ NR ２３ R ２４ , or carboxyl C arbitrarily replaced by １－３ It is an alkyl group, and in the formula, R ２３ and R ２４ H is independent, is C １－３ The compound according to any one of claims 79 to 83, wherein it is alkyl.

93. R ２２ However, C is arbitrarily substituted with carboxyl. １－３ It is alkyl, as described in claim 92 The compound listed.

94. R ２２ However, CH ３ The compound according to claim 93.

95. R ２２ However, CH ２ CH ３ The compound according to claim 93.

96. R ２２ However, CH ２ The compound according to claim 93, which is COOH.

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 claim 93, wherein it is alkyl.

98. R ２２ However, NHCH ３ The compound according to claim 97.

99. R ２２ However, N(CH ３ ) ２ The compound according to claim 97.

100. Formula VIII: 【Chemistry 27】 It has a structure that follows the formula, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, 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.

101. Formula VIIIa: 【Chemistry 28】 It has the structure, and in the formula, R ３ C １－３ It is a heteroaryl compound optionally substituted with alkyl or phenyl. The compound described in item 100, or a pharmaceutically acceptable salt thereof.

102. R ３ The compound according to claim 100 or 101, wherein it is a heteroaryl compound.

103. R ３ but, 【Chemistry 29】 The compound according to claim 102.

104. R ３ but, 【Transformation 30】 The compound according to claim 102.

105. R ３ but, 【Chemistry 31】 The compound according to claim 102.

106. R ３ but, 【Chemistry 32】 The compound according to claim 102.

107. R ３ but, 【Transformation 33】 The compound according to claim 102.

108. R ３ but, 【Transformation 34】 The compound according to claim 102.

109. R ３ However, C １－３ It is a heteroaryl compound optionally substituted with alkyl or phenyl. The compound described in item 100 or 101.

110. R ３ but, 【Chemistry 35】 The compound according to claim 109.

111. R ３ but, 【Transformation 36】 The compound according to claim 109.

112. R ３ but, 【Chemistry 37】 The compound according to claim 109.

113. Formula IX: 【Chemistry 38】 It has a structure that follows the formula, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, 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 claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

114. Formula IXa: 【Chemistry 39】 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 The compound according to claim 113, which is alkyl, or a pharmaceutically acceptable salt thereof.

115. R １ａ The compound according to claim 113 or 114, wherein the compound is CN.

116. R １ａ The compound according to claim 113 or 114, wherein the compound is a halogen.

117. R １ａ The compound according to claim 116, wherein the compound is Cl.

118. R １０ However, C １－３ The chemical compound according to any one of claims 113 to 117, which is alkyl. Compound.

119. R １０ However, CH ３ The compound according to claim 118.

120. R １０ However, CH(CH ３ ) ２ The compound according to claim 118.

121. R １０ However, CH ２ CH ３ The compound according to claim 118.

122. R １０ However, NHSO ２ R ２０ And in the formula, R ２０ C １－３ It is alkyl, claim A compound described in any one of items 113 to 117.

123. R ２０ However, CH ３ The compound according to claim 122.

124. Formula X: 【Chemistry 40】 It has a structure that follows the formula, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, 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.

125. R １ａ The compound according to claim 124, wherein the compound is CN.

126. R １ The compound according to claim 124 or 125, wherein H is present.

127. R ２ The compound according to any one of claims 124 to 126, wherein H is present.

128. R ９ However, C １－３ The compound according to any one of claims 124 to 127, which is alkyl thing.

129. R ９ However, CH ３ The compound according to claim 128.

130. Formula XI: 【Chemistry 41】 It has a structure that follows the formula, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, 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.

131. R １ａ The compound according to claim 130, wherein the compound is CN.

132. R １ The compound according to claim 130 or 131, wherein H is present.

133. R ２ The compound according to any one of claims 130 to 132, wherein H is present.

134. The compound according to any one of claims 130 to 133, wherein p is 1.

135. Equation XII: 【Chemistry 42】 It has a structure that follows the formula, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, 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 claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

136. R １ａ The compound according to claim 135, wherein the compound is CN.

137. R １ The compound according to claim 135 or 6, wherein H is present.

138. R ２ The compound according to any one of claims 135 to 137, wherein H is present.

139. R ３ The compound according to any one of claims 135 to 138, wherein the compound is Cl.

140. R ３ The compound according to any one of claims 135 to 138, wherein the compound is Br.

141. R ３ The compound according to any one of claims 135 to 138, wherein F.

142. Equation XIII: 【Chemistry 43】 It has a structure that follows the formula, R １ Each time, it is independently substituted with hydrogen, halogen, CN, OH, or one or more halogens as desired. C １－３ Alkyl and C １－３ Selected from the group consisting of alkoxys, R １ａ H, CN, halogen, C １－３ Optionally substituted with alkoxy, OH, or CN C １－３ It is alkyl, R ２ Each time, independently, hydrogen, halogen, 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.

143. R １ａ The compound according to claim 142, wherein the compound is CN.

144. R １ The compound according to claim 142 or 143, wherein H is present.

145. R ２ However, C １－３ The compound according to any one of claims 142 to 144, which is alkyl thing.

146. R ２ However, CH ３ The compound according to claim 145.

147. R １２ However, C １－３ The chemical compound according to any one of claims 142 to 146, which is alkyl. Compound.

148. R １２ However, CH ３ The compound according to claim 147.

149. R １３ However, C １－３ The chemical compound according to any one of claims 142 to 148, which is alkyl. Compound.

150. R １３ However, CH ３ The compound according to claim 149.

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

152. Claims 1 to 151, wherein at least one hydrogen atom is replaced by a deuterium atom Any compound listed in one of the items, or a pharmaceutically acceptable salt thereof.

153. A compound according to any one of claims 1 to 152, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising a pharmaceutically acceptable excipient.

154. A method for treating a disease mediated by PHD activity, as described in claims 1 to 152. The administration of any compound listed in any one of the items, or a pharmaceutically acceptable salt thereof, Includes, method.

155. Claim 154 states that the disease mediated by PHD activity is ischemia-reperfusion injury. Method of loading.

156. Claim 1, wherein the ischemia-reperfusion injury is selected from stroke, myocardial infarction, and acute kidney injury. Method 55.

157. Claim 154 states that the disease mediated by PHD activity is inflammatory bowel disease. The method.

158. The method according to claim 157, wherein the inflammatory bowel disease is ulcerative colitis.

159. The method according to claim 157, wherein the inflammatory bowel disease is Crohn's disease.

160. The method according to claim 154, wherein the disease mediated by PHD activity is cancer.

161. The method according to claim 160, wherein the cancer is colorectal cancer.

162. The method according to claim 154, wherein the disease mediated by PHD activity is a liver disease. 。

163. Claim 1, the disease mediated by PHD activity is atherosclerosis. The method described in 54.

164. The disease mediated by PHD activity is a cardiovascular disease, according to claim 154. method.

165. Claim 154, wherein the disease mediated by PHD activity is a disease or condition of the eye. Method of description.

166. The aforementioned disease or condition of the eye is radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related jaundice. The method according to claim 165, selected from varicose degeneration and ocular ischemia.

167. The method according to claim 155, wherein the disease is anemia.

168. The method according to claim 167, wherein the anemia is anemia related to chronic kidney disease.

169. The method according to claim 154, wherein the disease is chronic kidney disease.

170. The method according to claim 154, wherein the disease is related to hyperoxia.

171. The method according to claim 170, wherein the disease is retinopathy of prematurity.

172. The method according to claim 170, wherein the disease is bronchopulmonary dysplasia (BPD).

173. The aforementioned diseases include ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, and lung disease. A selection from hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, hepatic fibrosis, and cirrhosis. The method according to claim 154.

Images