Phd inhibitor compounds, compositions, and methods of use

Abstract

Part of this invention provides novel small molecule PHD inhibitors having structures according to formula (I) and its derivatives: or pharmaceutically acceptable salts thereof. The compounds provided herein may be used to treat the following diseases: including heart diseases (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung diseases (e.g., lung inflammation, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory diseases (e.g., respiratory infections, acute respiratory distress syndrome), liver diseases (e.g., acute liver failure, liver fibrosis, and cirrhosis), and kidney diseases (e.g., acute kidney injury and chronic kidney disease), inflammatory bowel disease (IBD), ischemic-reperfusion injury (e.g., stroke), and retinopathy of prematurity (ROP).

Description

Prior Technology

[0001] Hypoxia is a condition or state in which the oxygen supply is insufficient to maintain normal bodily functions, such as low arterial oxygen supply. Hypoxia can lead to functional and structural damage to cells. Activation of cellular defense mechanisms during hypoxia is mediated by HIF (hypoxia-inducible factor) proteins. In response to hypoxia, HIFα levels are increased in most cells due to decreased HIFα prolyl hydroxylation. HIFα prolyl hydroxylation is achieved by a family of proteins with different names, namely proteins containing prolyl hydroxylase domains (PHD1, 2, and 3) (also known as HIF prolyl hydroxylases (HPH-3, 2, and 1) or EGLN-2, 1, and 3). These PHD proteins act as oxygen sensors and regulate HIF stability in an oxygen-dependent manner. These three PHD isoforms act in different ways in regulating HIF and may also have other non-HIF-related regulatory roles.

[0002] In fact, many studies have shown that stabilizing HIF can reduce tissue inflammation and promote tissue repair. Therefore, compounds that can inhibit the activity of PHD proteins may be particularly beneficial therapies (Lee et al. (2019) Exp. Mol. Med. 51:68).

[0003] This article describes novel small-molecule PHD inhibitors effective in treating the following diseases, including (but not limited to) heart diseases (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung diseases (e.g., lung inflammation, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory diseases (e.g., respiratory infections, acute respiratory distress syndrome), liver diseases (e.g., acute liver failure, liver fibrosis, and cirrhosis), and kidney diseases (e.g., acute kidney injury and chronic kidney disease), inflammatory bowel disease (IBD), ischemic-reperfusion injury (e.g., stroke), and retinopathy of prematurity (ROP). Summary of the Invention

[0004] This invention particularly provides novel small molecule PHD inhibitors effective in treating diseases including (but not limited to) heart diseases (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung diseases (e.g., lung inflammation, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory diseases (e.g., respiratory infections, acute respiratory distress syndrome), liver diseases (e.g., acute liver failure, liver fibrosis, and cirrhosis), and kidney diseases (e.g., acute kidney injury and chronic kidney disease), inflammatory bowel disease (IBD), ischemic-reperfusion injury (e.g., stroke), and retinopathy of prematurity (ROP).

[0005] In one state, this paper provides compounds having a structure according to formula (I), (I) Or a medically acceptable salt thereof, wherein: R1 may be a substituted C1-3 alkyl, a substituted C3-6 cycloalkyl, or a substituted 3- to 6-membered heterocyclic alkyl, depending on the situation; R2 is hydrogen, a substituted C1-3 alkyl group, a halogen, CN, or a substituted cycloalkyl group, depending on the situation; R3 is hydrogen, aryl (substituted as appropriate), heteroaryl (substituted as appropriate), cycloalkyl (substituted as appropriate), heterocycloalkyl (substituted as appropriate), carbonyl, diethyl ether, thioether, arylsulfonyl (substituted as appropriate), heteroarylsulfonyl (substituted as appropriate), arylalkyl (substituted as appropriate), alkynyl (substituted as appropriate), or heteroalkynyl (substituted as appropriate); R4 and R5 are independently hydrogen, or, where appropriate, substituted C1-3 alkyl groups, or R4 and R5 together with their attached carbons form, where appropriate, substituted cycloalkyl or heterocycloalkyl groups; and R6 is OH or an ester (e.g., OR18 as described herein).

[0006] In the embodiments, the compound has a structure according to formula (I). (I) Or a medically acceptable salt thereof, wherein: R1 is a C1-3 alkyl group substituted with OR7, a halogen, or an aryl group, wherein the aryl group is substituted with a halogen group, and wherein R7 is a C1-3 alkyl group substituted with an aryl group, or R1 is a C3-6 cycloalkyl group or a 3- to 6-membered heterocycloalkyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; The R3 series is selected from the following groups: hydrogen; X is a covalent bond, O, S, SO2, C1-4 alkylene, C2-4 ynynylene, or C2-4 heteroynylene; each A is independently N or CR9, R8 and R9 are independently hydrogen, halogen, OR10, or, as appropriate, a C1-3 alkyl substituted with one or more halogens, while R10 is a C1-3 alkyl or aryl; Where B is N or CR11, D is N, NH or CR11, E is N, CR11 or CHR12, and R11 and R12 are independently hydrogen or C1-3 alkyl, and the dashed circles represent the presence or absence of a conjugated system; Each G is independently N, NH, NR13, or CR14; R13 is a C3-6 cycloalkyl, a 3- to 6-membered heterocycloalkyl, an aryl group substituted with one or more halogens, an aryl group substituted with one or more C1-3 alkyl groups, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group, a C1-4 alkyl group substituted with an aryl group and the aryl group is substituted with one or more halogens, and R14 is hydrogen, a halogen, a C3-6 cycloalkyl, a 3- to 6-membered heterocycloalkyl, or a C1-3 alkyl; Where I is O, S, or CH, J is N or CH, R15 is hydrogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or C1-3 alkyl, and R19 is hydrogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or aryl; OR16, where R16 is aryl; Where X1 is N or CH, and R20 is an aryl group that is substituted, as appropriate; and COR17, where R17 is aryl; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbon atoms they are attached to form, as appropriate, substituted cycloalkyl or heterocycloalkyl groups; and R6 is OH or OR18, where R18 is a C1-6 alkyl group.

[0007] In the embodiments, the compound of formula (I) has a structure according to formula (II). (II) Or a medically acceptable salt thereof, wherein: R1 is a C1-3 alkyl group substituted with OR7, a halogen, or an aryl group, wherein the aryl group is substituted with a halogen group, and wherein R7 is a C1-3 alkyl group substituted with an aryl group, or R1 is a C3-6 cycloalkyl group or a 3- to 6-membered heterocycloalkyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; The R3 series is selected from the following groups: hydrogen; X is a covalent bond, O, S, SO2, C1-4 alkylene, C2-4 ynynylene, or C2-4 heteroynylene; each A is independently N or CR9, R8 and R9 are independently hydrogen, halogen, OR10, or, as appropriate, a C1-3 alkyl substituted with one or more halogens, while R10 is a C1-3 alkyl or aryl; Where B is N or CR11, D is N, NH or CR11, E is N, CR11 or CHR12, and R11 and R12 are independently hydrogen or C1-3 alkyl, and the dashed circles represent the presence or absence of a conjugated system; Each G is independently N, NR13, CR14, R13 is a C3-6 cycloalkyl, a 3- to 6-membered heterocycloalkyl, an aryl group substituted with one or more halogens, an aryl group substituted with one or more C1-3 alkyl groups, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group, or a C1-4 alkyl group substituted with an aryl group and the aryl group is substituted with one or more halogens, while R14 is hydrogen, a halogen, a C3-6 cycloalkyl, a 3- to 6-membered heterocycloalkyl, or a C1-3 alkyl; Where I is O, S, or CH, J is N or CH, R15 is hydrogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or C1-3 alkyl, and R19 is hydrogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or aryl; OR16, where R16 is aryl; Where X1 is N or CH, and R20 is an aryl group that is substituted, as appropriate; and COR17, where R17 is aryl; and R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form cyclic or heterocyclic alkyl groups substituted as appropriate.

[0008] In the embodiments, R1 is a substituted C1-3 alkyl group, as appropriate; and / or R3 is hydrogen, an aryl group (substituted as appropriate), a heteroaryl group (substituted as appropriate), a cycloalkyl group (substituted as appropriate), a heterocycloalkyl group (substituted as appropriate), a carbonyl group, or an ether.

[0009] In the embodiments, R1 is a C1-3 alkyl group substituted with OR7 or an aryl group, and the aryl group is substituted with a halogen group, wherein R7 is a C1-3 alkyl group substituted with an aryl group, and / or The R3 group is selected from the following compositional groups: hydrogen, , , ,or .

[0010] In the embodiment, R3 is , , , , , , , ,or .

[0011] In the examples, R1 is an unsubstituted C1-3 alkyl group, R2 is hydrogen, R4 and R5 are each hydrogen, and R6 is OH.

[0012] In the examples, R1 and R2 are each unsubstituted C1-3 alkyl groups, R4 and R5 are each hydrogen, and R6 is OH.

[0013] In the examples, R2 is an unsubstituted C1-3 alkyl group, R3 is hydrogen, R4 and R5 are each hydrogen, and R6 is OH.

[0014] In the embodiments, the compound has a structure according to formula (III). (III) Or a medically acceptable salt, in which Each A is independently either N or CR9; R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; R8 and R9 are independently hydrogen, halogen, OR10, or, where appropriate, C1-3 alkyl groups substituted with one or more halogens; and R10 is a C1-3 alkyl or aryl group.

[0015] In the embodiments, the compound has a structure according to formula (IV). (IV) Or a medically acceptable salt, in which R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; R8 and R9 are independently hydrogen, halogen, OR10, or, where appropriate, C1-3 alkyl groups substituted with one or more halogens; and R10 is a C1-3 alkyl or aryl group.

[0016] In the embodiments, the compound has a structure according to formula (V). (V) Or a medically acceptable salt thereof, wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; R8 and each R9 are independently hydrogen, halogen, OR10, or, where appropriate, C1-3 alkyl groups substituted with one or more halogens; and R10 is a C1-3 alkyl or aryl group.

[0017] In the embodiments, the compound has a structure according to formula (VI). (VI) Or a medically acceptable salt, in which B is either N or CR11; D is N, NH, or CR11; E is N, CR11, or CHR12; R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; R11 and R12 are independently hydrogen or C1-3 alkyl; and The dashed circles represent the presence or absence of conjugate systems.

[0018] In the embodiments, the compound has a structure according to formula (VII). (VII) Or a medically acceptable salt.

[0019] In the embodiments, the compound has a structure according to formula (VIII). (VIII) Or a medically acceptable salt thereof, wherein: B is either N or CR11; R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; and R12 is hydrogen or a C1-3 alkyl group.

[0020] In the embodiments, the compound has a structure according to formula (IX). (IX) Or a medically acceptable salt thereof, wherein: Each G is independently N, NH, NR13, or CR14; R1 is a C1-3 alkyl group substituted with OR7, a halogen, or an aryl group, wherein the aryl group is substituted with a halogen, and wherein R7 is a C1-3 alkyl group substituted with an aryl group, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocyclic alkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate; and R14 is hydrogen, halogen, cyclopropyl, or C1-3 alkyl.

[0021] In the embodiments, the compound has a structure according to formula (X). (X) Or a medically acceptable salt thereof, wherein: Each G is independently N, NR13, or CR14; R1 is a C1-3 alkyl group substituted with OR7, a halogen, or an aryl group, wherein the aryl group is substituted with a halogen, and wherein R7 is a C1-3 alkyl group substituted with an aryl group, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocyclic alkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate; and R14 is hydrogen, halogen, cyclopropyl, or C1-3 alkyl.

[0022] In the embodiments, the compound has a structure according to formula (XI). (XI) Or a medically acceptable salt, in which Each G is independently either N or NR13; R1 is a C1-3 alkyl group substituted with OR7, a halogen, or an aryl group, wherein the aryl group is substituted with a halogen, and wherein R7 is a C1-3 alkyl group substituted with an aryl group, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R13 is cyclopropyl, heteroaryl, aryl substituted with one or more halogens as appropriate, aryl substituted with one or more C1-3 alkyl groups as appropriate, heterocyclic alkyl substituted with t-butoxycarbonyl as appropriate, or C1-4 alkyl substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate; and R14 is hydrogen, halogen, cyclopropyl, or C1-3 alkyl.

[0023] In the embodiments, the compound has a structure according to formula (XIIa) or formula (XIIb). (XIIa) (XIIb) Or a medically acceptable salt thereof, wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; R13 is cyclopropyl, heteroaryl, aryl substituted with one or more halogens as appropriate, aryl substituted with one or more C1-3 alkyl groups as appropriate, heterocyclic alkyl substituted with t-butoxycarbonyl as appropriate, or C1-4 alkyl substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate; and R14 is hydrogen, halogen, cyclopropyl, or C1-3 alkyl.

[0024] In the embodiments, the compound has a structure according to formula (XIII). (XIII) Or a medically acceptable salt thereof, wherein: R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbon atoms they are attached to form, as appropriate, substituted cycloalkyl or heterocycloalkyl groups; and R13 is an aryl or heteroaryl group.

[0025] In the embodiments, the compound has a structure according to formula (XIV). (XIV) Or a medically acceptable salt thereof, wherein: I represents O, S, or CH; J is either N or CH; R1 is a C1-3 alkyl group substituted with OR7, a halogen, or an aryl group, wherein the aryl group is substituted with a halogen, and wherein R7 is a C1-3 alkyl group substituted with an aryl group, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R15 is hydrogen or a C1-3 alkyl group; and R19 is hydrogen or aryl.

[0026] In the embodiments, the compound has a structure according to formula (XV). (XV) Or a medically acceptable salt thereof, wherein: I represents O, S, or CH; R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; and R15 is hydrogen or C1-3 alkyl. R19 is hydrogen or aryl.

[0027] In the embodiments, the compound has the structure according to formula (XVI). (XVI) Or a medically acceptable salt, in which X is O, S, or SO2; R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; R8 and R9 are independently hydrogen, halogen, OR10, or, where appropriate, C1-3 alkyl groups substituted with one or more halogens; and R10 is a C1-3 alkyl or aryl group.

[0028] In the embodiments, the compound has a structure according to formula (XVII). (XVII) Or a medically acceptable salt, in which R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; R8 and R9 are independently hydrogen, halogen, OR10, or, where appropriate, C1-3 alkyl groups substituted with one or more halogens; and R10 is a C1-3 alkyl or aryl group.

[0029] In the embodiments, the compound has a structure according to formula (XVIII). (XVIII) Or a medically acceptable salt, in which R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; R8 and R9 are independently hydrogen, halogen, OR10, or, where appropriate, C1-3 alkyl groups substituted with one or more halogens; and R10 is a C1-3 alkyl or aryl group.

[0030] In the embodiments, the compound has a structure according to formula (XIX). (XIX) Or a medically acceptable salt thereof, wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; and R13 is cyclopropyl, aryl group substituted with one or more halogens as appropriate, aryl group substituted with one or more C1-3 alkyl groups as appropriate, heteroaryl group, heterocyclic alkyl group substituted with t-butoxycarbonyl group as appropriate, or C1-4 alkyl group substituted with aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate.

[0031] In the embodiments, the compound has a structure according to formula (XX). (XX) Or a medically acceptable salt thereof, wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; and R13 is cyclopropyl, aryl group substituted with one or more halogens as appropriate, aryl group substituted with one or more C1-3 alkyl groups as appropriate, heteroaryl group, heterocyclic alkyl group substituted with t-butoxycarbonyl group as appropriate, or C1-4 alkyl group substituted with aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate.

[0032] In the embodiments, the compound has a structure according to formula (XXI). (XXI) Or a medically acceptable salt thereof, wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbon atoms they are attached to form, as appropriate, substituted cycloalkyl or heterocycloalkyl groups; and R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate.

[0033] In the embodiments, the compound has a structure according to formula (XXII). (XXII) Or a medically acceptable salt thereof, wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; and R20 is an aryl group that is substituted as appropriate.

[0034] In the embodiments, the compound has a structure according to formula (XXIII). (XXIII) Or a medically acceptable salt thereof, wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or aryl, where the aryl group is substituted with halogen, or R1 is a cyclopropyl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group that is substituted with an aryl group, as appropriate; and R20 is an aryl group that is substituted as appropriate.

[0035] In this embodiment, R3 is not hydrogen.

[0036] In the examples, R3 is an unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, or trifluorotolyl.

[0037] In the examples, R3 is OR16, SR16, SO2R16, CH2R16, CH2CH2R16, C≡CR16, or C≡CCH2OR16, wherein R16 is aryl. In the examples, R16 is phenyl.

[0038] In the examples, R3 is pyrrole, tetrazolyl, triazolyl or pyrazolyl, which may be substituted with aryl or cycloalkyl groups as appropriate.

[0039] In the examples, R3 is piperidinyl or piperazine, which may be arylated as appropriate.

[0040] In the examples, R3 is unsubstituted or cyclopropyl substituted, or is an unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl or trifluorotolyl.

[0041] In the examples, R3 is COR17, and R17 is aryl. In the examples, R17 is phenyl.

[0042] In the examples, R1 is cyclopropyl or a substituted C1-3 alkyl group.

[0043] In the examples, R1 is cyclopropyl or difluoromethyl.

[0044] In the examples, R1 is a C1-3 alkyl group. In the examples, R1 is CH2CH3. In the examples, R1 is CH3. In the examples, R1 is an aryl-substituted C1-3 alkyl group with the aryl group substituted by a halogen. In the examples, R1 is... In the examples, R1 is a C1-3 alkyl group substituted with OBn. In the examples, R1 is CH2CH2OBn.

[0045] In the examples, R2 is hydrogen. In the examples, R2 is a C1-3 alkyl group. In the examples, R2 is CH3.

[0046] In the examples, R4 is hydrogen and R5 is hydrogen. In the examples, R4 is hydrogen and R5 is a C1-3 alkyl group. In the examples, R5 is CH3. In the examples, R4 is a C1-3 alkyl group and R5 is a C1-3 alkyl group. In the examples, R4 is CH3 and R5 is CH3.

[0047] In embodiments, R4 and R5, together with the carbon atoms they are attached to, form a cycloalkyl or heterocycloalkyl group. In an embodiment, the cycloalkyl group is cyclopropyl. In an embodiment, the cycloalkyl group is cyclobutyl. In an embodiment, the heterocycloalkyl group is... .

[0048] In the embodiments, the compound is any one of compounds 1 to 50: Compound numbering structure Compound numbering structure 1 26 2 27 3 28 4 29 5 30 6 31 7 32 8 33 9 34 10 35 11 36 12 37 13 38 14 39 15 40 16 41 17 42 18 43 19 44 20 45 21 46 22 47 23 48 24 49 25 50 Or a medically acceptable salt.

[0049] In the embodiments, the compound is any one of compounds 51 to 70. Compound numbering structure Compound numbering structure 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 Or a medically acceptable salt.

[0050] In the embodiments, at least one hydrogen atom in the compounds of formula (I)–(XXIII) (such as any of compounds 1–70) is replaced by a deuterium atom.

[0051] In another embodiment, the invention is characterized as a pharmaceutical composition comprising any of the compounds described herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0052] In another embodiment, the invention is characterized by a method for treating diseases mediated by PHD activity, comprising administering to an individual any of the compounds described herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or a pharmaceutically acceptable salt thereof.

[0053] In the embodiments, the disease mediated by PHD activity is ischemia-reperfusion injury (e.g., stroke, myocardial infarction, or acute kidney injury).

[0054] In the embodiments, the disease mediated by PHD activity is an inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease).

[0055] In the embodiments, the disease mediated by PHD activity is cancer (e.g., colorectal cancer).

[0056] In this embodiment, the disease mediated by PHD activity is a liver disease.

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

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

[0059] In the embodiments, the diseases mediated by PHD activity are eye diseases or conditions (e.g., radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia).

[0060] In this embodiment, the disease mediated by PHD activity is anemia (e.g., anemia associated with chronic kidney disease).

[0061] In this embodiment, the disease mediated by PHD activity is chronic kidney disease.

[0062] In the embodiments, the disease mediated by PHD activity is related to hyperoxia.

[0063] In this embodiment, the disease mediated by PHD activity is retinopathy of prematurity.

[0064] In this embodiment, the disease mediated by PHD activity is bronchodystrophy (BPD).

[0065] In the embodiments, the diseases mediated by PHD activity are ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, and cirrhosis.

[0066] In the embodiments, the diseases mediated by PHD activity are respiratory diseases, lung diseases, respiratory viral infections, or lung viral infections.

[0067] In this embodiment, the respiratory disease is selected from respiratory infection, acute respiratory distress syndrome, lung inflammation, pneumonia, and acute lung injury.

[0068] In this embodiment, the lung disease is acute lung injury (ALI), bronchitis, pneumonia, pulmonary fibrosis, asthma, or acute respiratory distress syndrome (ARDS).

[0069] In the embodiments, the disease mediated by PHD activity is damage and / or failure of one or more organs (e.g., acute organ damage or organ failure). Simple Explanation of the Diagram

[0070] [picture] [1] An illustrative schematic diagram illustrating the principle of the TR-FRET assay for PHD enzymes (PHD1, PHD2, and PHD3). In the presence of 2-side-oxyglutarate and O2, the PHD enzyme hydroxylates the proline 564 of the biotin-labeled HIF-1α peptide, resulting in the generation of biotin-labeled HIF-1α-hydroxyproline, succinate, and CO2. The proximity of the donor luciferase complex monoclonal antibody against 6His-tib(Tb)-caecinoid Gold, which binds to the His-labeled VHL protein, EloB, and EloC complex (His-VBC), to the acceptor luciferase SA-D2 complex, which binds to HIF-1α-hydroxyproline, leads to the detection and quantification of the fluorescence resonance energy transfer signal. Implementation

[0071] [Cross-reference to related applications] This application claims priority to U.S. Provisional Application No. 63 / 065,642, filed on August 14, 2020, the entire contents of which are incorporated herein by reference. definition

[0072] To facilitate understanding of this invention, certain terms are defined below. Additional definitions of accompanying and other terms are provided throughout this specification. Publications and other references describing the background of the invention and providing additional details on its practice are incorporated herein by reference.

[0073] Animal: 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 stage of development. In some embodiments, "animal" refers to a non-human animal at any stage of development. In some embodiments, non-human animals are mammals (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cattle, primates, and / or pigs). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, animals may be genetically modified animals, genetically engineered animals, and / or purebreds.

[0074] Approximately or about: As used herein, the term “approximately” or “about” when applied to one or more values ​​of interest means a value similar to the stated reference value. In certain specific instances, unless otherwise stated or apparent from the context, the term “approximately” or “about” means a series of values ​​within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the stated reference value in any direction (except where such values ​​would exceed 100% of the probability value).

[0075] When used in the description and the appended claims, unless the context clearly requires otherwise, the singular forms "a," "an," and "this" include plural references. Thus, for example, a reference to "composition" includes a mixture of two or more such compositions.

[0076] In this specification and the following claims, several terms will be used, which shall be defined to have the following meanings: throughout the description of this specification and the claims, the term "comprising" and other forms of the term, such as "including" and "containing", are meant to include without limitation and not to exclude, for example, other additives, components, integers, or steps.

[0077] "Subject to circumstances" or "subject to circumstances" means that the event or situation described below may or may not occur, and the description includes examples of the event or situation occurring as well as examples of the event or situation not occurring.

[0078] Improvement, increase, or decrease: As used herein, the terms “improvement,” “increase,” or “decrease,” or their grammatical equivalents, refer to a value relative to a baseline measurement, such as a measurement in the same individual prior to the initiation of the treatment described herein, or a measurement in a control subject (or multiple control subjects) in the absence of the treatment described herein. A “control individual” is an individual with the same form of disease as the treated individual and approximately the same age as the treated individual.

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

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

[0081] Patient: As used herein, the terms "patient" or "individual" mean any organism that may be administered the provided components for, for example, experimental, diagnostic, preventative, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. Humans include both prenatal and postnatal forms.

[0082] Medically acceptable: As used in this article, "medically acceptable" means a substance that is suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions or other problems or complications, and is commensurate with a reasonable benefit / risk ratio.

[0083] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in this art (such as ion exchange). Other medically acceptable salts include adipic acid salts, alginate salts, ascorbate salts, aspartate salts, benzenesulfonate salts, benzoate salts, hydrogen sulfate salts, borate salts, butyrate salts, camphorate salts, camphor sulfonate salts, citrate salts, cyclopentanepropionate salts, digluconate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, transbutenedioic acid salts, gluconate salts, glycerol phosphate salts, gluconate salts, hemisulfate salts, heptaate salts, hexanoate salts, hydroiodate salts, 2-hydroxyethanesulfonate salts, and lactobionate salts. Lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, papoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, p-valerates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and their analogues. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N+(C1–4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and their analogues. Other pharmaceutically acceptable salts appropriately include non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates, and arylsulfonates. Further pharmaceutically acceptable salts include those formed from the quaternization of amines using suitable electrophilic agents (e.g., alkyl halides) to form quaternized alkylamine salts.

[0084] Individual: As used herein, the term "individual" means human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Human includes both prenatal and postnatal forms. In many embodiments, an individual is a human. An individual can be a patient, which refers to a human who goes to a healthcare provider for diagnosis or treatment of a disease. The term "individual" may be used interchangeably with "person" or "patient" herein. An individual may have or be susceptible to a disease or condition, but may or may not show symptoms of that disease or condition.

[0085] In essence: As used herein, the term "in essence" refers to a qualitative condition that exhibits the full or near full range or extent of the feature or property of interest. Those of ordinary skill in the field of biology will understand that biological and chemical phenomena rarely (if any) reach completion and / or proceed to full or achieve or avoid absolute results. Therefore, the term "in essence" is used herein to encompass the inherent potential lack of completeness in many biological and chemical phenomena.

[0086] Therapeutic effective dose: As used herein, the term "therapeutic effective dose" means, when administered to an individual who has or is susceptible to a disease, condition, and / or symptom, sufficient to treat, diagnose, prevent, and / or delay the onset of that disease, condition, and / or symptom. Those generally skilled in this art will recognize that therapeutic effective doses are typically administered via a dosing regimen comprising at least one unit dose.

[0087] Treatment: As used herein, the term "treatment" means any method used to partially or completely reduce, improve, alleviate, suppress, prevent, delay the onset, reduce the severity, and / or decrease the incidence of one or more symptoms or features of a particular disease, condition, and / or symptom. Treatment may be administered to subjects who do not exhibit signs of disease and / or only exhibit early signs of disease in order to reduce the risk of developing disease-related symptoms.

[0088] Aliphatic: As used herein, the term aliphatic refers to C1–C40 hydrocarbons and includes both saturated and unsaturated hydrocarbons. Aliphatic groups can be straight-chain, branched, or cyclic. For example, C1–C20 aliphatic groups can include C1–C20 alkyl groups (e.g., straight-chain or branched C1–C20 saturated alkyl groups), C2–C20 alkenyl groups (e.g., straight-chain or branched C4–C20 dienyl, straight-chain or branched C6–C20 trienyl, etc.), and C2–C20 alkynyl groups (e.g., straight-chain or branched C2–C20 alkynyl). C1–C20 aliphatic groups can include C3–C20 cyclic aliphatic groups (e.g., C3–C20 cycloalkyl, C4–C20 cycloalkenyl, or C8–C20 cycloalkynyl). In some embodiments, the aliphatic group may comprise one or more cyclic aliphatic groups and / or one or more heteroatoms (such as oxygen, nitrogen, or sulfur), and may be substituted with one or more substituents (such as alkyl, halogen, alkoxy, hydroxyl, amino, aryl, ether, ester, or amide). The aliphatic group is either unsubstituted or substituted with one or more substituents as described herein. For example, the aliphatic group may be substituted with one or more of halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R' (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents), wherein Each example of [R'] is independently a C1–C20 aliphatic group (e.g., C1–C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). In some embodiments, [R'] is independently an unsubstituted alkyl group (e.g., unsubstituted C1–C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). In some embodiments, [R'] is independently an unsubstituted C1–C3 alkyl group. In some embodiments, the aliphatic group is unsubstituted. In some embodiments, the aliphatic group does not contain any heteroatoms.

[0089] Alkyl: As used herein, the term "alkyl" refers to an acyclic, straight-chain or branched hydrocarbon group, for example, "C1–C20 alkyl" refers to an alkyl group having 1–20 carbon atoms. Alkyl groups can be straight-chain or branched. Examples of alkyl groups include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, etc. The term "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms, whether straight-chain or branched. Other alkyl groups will readily become apparent to those skilled in the art in view of the benefits of this invention. Alkyl groups can be unsubstituted or substituted with one or more substituents as described herein. For example, the alkyl group can be substituted with one or more of the following: halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R' (e.g., 1, 2, 3, 4, 5, or 6 independently chosen substituents), wherein... Each example of [R'] is independently a C1–C20 aliphatic group (e.g., C1–C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). In some embodiments, [R'] is independently an unsubstituted alkyl group (e.g., unsubstituted C1-C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). In some embodiments, [R'] is independently an unsubstituted C1–C3 alkyl group. In some embodiments, the alkyl group is substituted (e.g., substituted by 1, 2, 3, 4, 5, or 6 substituents as described herein). In some embodiments, the alkyl group is substituted with a –OH group and may also be referred to herein as a “hydroxyalkyl” group, wherein the prefix indicates a –OH group and “alkyl” is as described herein. In some embodiments, the alkyl group is substituted with a -OR' group and may also be referred to herein as an “alkoxy” group.

[0090] Adding the suffix "-ene" to a group indicates that the group is a divalent part. For example, arylene is the divalent part of aryl, while heteroarylene is the divalent part of heteroaryl.

[0091] Alkylene: As used herein, the term "alkylene" refers to a saturated divalent straight-chain or branched hydrocarbon group, exemplified by methylene, ethylene, isopropylene, etc. Similarly, as used herein, the term "alkenylene" refers to an unsaturated divalent straight-chain or branched hydrocarbon group having one or more unsaturated carbon-carbon double bonds, which may be present at any stable point along the chain, and the term "alkynylene" herein refers to an unsaturated divalent straight-chain or branched hydrocarbon group having one or more unsaturated carbon-carbon triple bonds, which may be present at any stable point along the chain. In some embodiments, alkylene, alkenylene, or alkynylene may comprise one or more cyclic aliphatic groups and / or one or more heteroatoms (such as oxygen, nitrogen, or sulfur), and may be substituted, as appropriate, with one or more substituents (such as alkyl, halogen, alkoxy, hydroxyl, amino, aryl, ether, ester, or amide). For example, the alkylene, alkenylene, or ynylene group may be substituted with one or more of the following (e.g., 1, 2, 3, 4, 5, or 6 independently chosen substituents): halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R'. Each example of [R'] is independently a C1–C20 aliphatic group (e.g., C1–C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). In some embodiments, [R'] is independently an unsubstituted alkyl group (e.g., unsubstituted C1–C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). In some embodiments, [R'] is independently an unsubstituted C1–C3 alkyl group. In some embodiments, the alkylene, alkenyl, or ynylene group is unsubstituted. In some embodiments, the alkylene, alkenyl, or ynylene group does not include any heteroatoms.

[0092] Alkenyl: As used herein, "alkenyl" refers to any straight-chain or branched hydrocarbon chain having one or more unsaturated carbon-carbon double bonds, which may be present at any stable point along the chain. For example, "C2-C20 alkenyl" refers to an alkenyl having 2-20 carbons. Examples of alkenyl include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like. In some embodiments, an alkenyl comprises 1, 2, or 3 carbon-carbon double bonds. In some embodiments, an alkenyl comprises a single carbon-carbon double bond. In some embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. Alkenyl may be unsubstituted or substituted with one or more substituents as described herein. For example, the alkenyl group can be substituted by one or more of the following: halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R' (e.g., 1, 2, 3, 4, 5, or 6 independently chosen substituents), wherein... Each example of [R'] is independently a C1–C20 aliphatic group (e.g., C1–C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). In some embodiments, [R'] is independently an unsubstituted alkyl group (e.g., unsubstituted C1–C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). In some embodiments, [R'] is independently an unsubstituted C1–C3 alkyl group. In some embodiments, the alkenyl group is unsubstituted. In some embodiments, the alkenyl group is substituted (e.g., substituted by 1, 2, 3, 4, 5, or 6 substituents as described herein). In some embodiments, the alkenyl group is substituted with a –OH group and may also be referred to herein as a “hydroxyalkenyl” group, wherein the prefix indicates a –OH group and “alkenyl” is as described herein.

[0093] Alkynyl: As used herein, "alkynyl" refers to any hydrocarbon chain, whether straight-chain or branched, having one or more carbon-carbon triple bonds at any stable point along the chain. For example, "C2-C20 alkynyl" refers to an alkynyl group having 2-20 carbons. Examples of alkynyl groups include prop-2-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-2-alkynyl, 3-methylpent-4-alkynyl, hex-2-alkynyl, hex-5-alkynyl, and so on. In some embodiments, the alkynyl group comprises a single carbon-carbon triple bond. The alkynyl group may be unsubstituted or substituted with one or more substituents as described herein. For example, the alkynyl group can be substituted by one or more of halogens, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R' (e.g., 1, 2, 3, 4, 5, or 6 independently chosen substituents), wherein Each example of [R'] is independently a C1–C20 aliphatic group (e.g., C1–C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). In some embodiments, [R'] is independently an unsubstituted alkyl group (e.g., unsubstituted C1–C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). In some embodiments, [R'] is independently an unsubstituted C1–C3 alkyl group. In some embodiments, the alkynyl group is unsubstituted. In some embodiments, the alkynyl group is substituted (e.g., substituted by 1, 2, 3, 4, 5 or 6 substituents as described herein).

[0094] Aryl: The term "aryl" when used alone or as part of a larger portion of "araneyl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein the ring system has a single connection point to the rest of the molecule, at least one ring in the ring system is aromatic, and each ring in the ring system contains four to seven ring members. In some embodiments, an aryl has six ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, an aryl has ten ring carbon atoms ("C10 aryl", e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl has fourteen ring carbon atoms ("C14 aryl", e.g., anthracene). "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the attachment group or attachment point is on the aryl ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Exemplary aromatic rings include phenyl, naphthyl, and anthracene.

[0095] arylene: As used herein, "aryl" refers to a divalent aryl group (i.e., one with two bonding sites with the molecule). Examples of arylene groups include phenylene (e.g., unsubstituted or substituted phenylene).

[0096] Halogen or halogen group: As used herein, the term "halogen" or "halogen group" refers to fluorine, chlorine, bromine or iodine.

[0097] Acetylamine: The term "acetylamine" or "acetylamine group" refers to a chemical moiety having the formula C(O)N(R')2, -C(O)N(R')-, -NR'C(O)R', -NR'C(O)N(R')2- or -NR'C(O)-, wherein each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (chain-carbon bonded), cycloalkyl, aryl, aralkyl, heteroaryl (cycle-carbon bonded), heteroarylalkyl or heterocycloalkyl (cycle-carbon bonded), unless otherwise specified in this specification, each moiety may be substituted as described herein, or the two R' may combine with a nitrogen atom to form a 3-, 4-, 5-, 6- or 7-membered ring.

[0098] Amine group: The term "amine" or "amine" refers to a -N(R')2 group, wherein each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (chain-carbon bonded), cycloalkyl, aryl, aralkyl, heteroaryl (cycle-carbon bonded), heteroarylalkyl, heterocycloalkyl (cycle-carbon bonded), sulfonylurea, amide, or carbonyl groups. Unless otherwise specified herein, each part may be substituted as described herein, or the two R's may combine with a nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. In the examples, the amine group is –NHR', wherein R' is aryl ("arylamino"), heteroaryl ("heteroarylamino"), amide, or alkyl ("alkylamino").

[0099] Ether: The term "ether" refers to an R'-O-R' group, wherein R' is independently selected from alkyl, heteroalkyl (chain-carbon bonded), aralkyl, heteroaralkyl, heterocycloalkyl (cycle-carbon bonded), cycloalkyl, aryl, heteroaryl (cycle-carbon bonded), and each part may be substituted as described herein, unless otherwise specified in this specification.

[0100] Ester: The term "ester" refers to an R'-C(=O)OR group, wherein R' is independently selected from alkyl, heteroalkyl (chain-carbon bonded), aralkyl, heteroaralkyl, heterocycloalkyl (cycle-carbon bonded), cycloalkyl, aryl, heteroaryl (cycle-carbon bonded), and each part may be substituted as described herein, unless otherwise specified in this specification.

[0101] Sulfoyl: The term "sulfoyl" refers to a -S(=O)2R' or -S(=O)2- group, wherein R' is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (chain-carbon bonded), amino, cycloalkyl, aryl, aralkyl, heteroaryl (cycle-carbon bonded), heteroarylalkyl, and heterocycloalkyl (cycle-carbon bonded). Unless otherwise specified in this specification, each part may be substituted as described herein. For example, in one embodiment, the sulfoyl group is -SO2R', wherein R' is an alkyl group substituted with a carbonyl group.

[0102] Sulphinyl: The term "sulphinyl" refers to a chemical moiety having the formula -S(=O)R', -S(=O)-, or -S(=O)(=NR')-, wherein R' is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (chain-carbon bonded), cycloalkyl, aryl, aralkyl, heteroaryl (cycle-carbon bonded), heteroarylalkyl, and heterocycloalkyl (cycle-carbon bonded). Unless otherwise specified in this specification, each moiety may be substituted as described herein.

[0103] Carbonyl: The term "carbonyl" refers to a -C(=O)R' or -C(=O)- group, wherein R' is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (chain-carbon bonded), cycloalkyl, aryl, aralkyl, heteroaryl (cycle-carbon bonded), heteroarylalkyl, and heterocycloalkyl (cycle-carbon bonded). Unless otherwise specified in this specification, each part may be substituted as described herein.

[0104] Phosphoryl group: The term "phosphoryl group" refers to -P(=O)(R')2 or -P(=O)(R')- group, wherein R' is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (linked by carbon atom or heteroatom), cycloalkyl, aryl, aralkyl, amino, hydroxyl, heteroaryl (linked by carbon atom), heteroarylalkyl or heterocycloalkyl (linked by carbon atom). Unless otherwise specified in this specification, each part may be substituted as described herein, or the two R' may combine with a nitrogen atom to form a 3-, 4-, 5-, 6- or 7-membered ring.

[0105] Heteroalkyl: The term "heteroalkyl" refers to a branched or straight-chain alkyl, alkenyl, or alkynyl group having 1-14 carbon atoms, and also having 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyl includes tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphate diesters, phosphonates, sulfonamides, and disulfides. Heteroalkyl may include monocyclic, bicyclic, or tricyclic rings, wherein each ring is preferably 3-6 members. Examples of heteroalkyl include polyethers, such as methoxymethyl and ethoxyethyl.

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

[0107] Heteroaryl: As used herein, "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein the ring system has a single connection point to the rest of the molecule, wherein at least one ring in the ring system is aromatic, wherein each ring in the ring system contains four to seven ring members, and wherein at least one ring atom is a heteroatom, such as (but not limited to) nitrogen and oxygen.

[0108] Heterocyclic alkyl: As used herein, "heterocyclic alkyl" refers to a non-aromatic ring in which at least one atom is a heteroatom, such as (but not limited to) nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. Heterocyclic alkyl can be substituted or unsubstituted.

[0109] Deuterium: The term "deuterium" ("D" or "2H") is also known as heavy hydrogen. Deuterium is an isotope of hydrogen, having an atomic nucleus consisting of one proton and one neutron, and its mass is twice that of a normal hydrogen nucleus (one proton).

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

[0111] The term "substituted" means that the specified group or part has one or more substituents. The term "unsubstituted" means that the specified group does not have substituents. The term "substituted as appropriate" means that the specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, substitution is intended to occur at any position on the system where the valence allows; for example, substitution results in a stable compound (e.g., a compound that does not spontaneously undergo transformations (such as by rearrangement, cyclization, elimination, or other reactions)). Where no specified substituent is explicitly indicated as substituted or replaced as appropriate for a specified part or group, it should be understood that such part or group is intended to be unsubstituted.

[0112] When a ring system (e.g., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) is substituted with substituents varying within a well-defined range, the total number of substituents naturally does not exceed the normally available valences under existing conditions. It should also be understood that hydrogen atoms are assumed to be present to fill the remaining valences of the ring system. Substituted groups only encompass combinations of substituents and variables that result in stable or chemically viable compounds. A stable or chemically viable compound is one that, among other things, possesses sufficient stability to allow its preparation and detection.

[0113] Many substituents are well known, and methods for their formation and the introduction of various parental groups are also well known. Representative substituents include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aralkyl, alkylaryl, aryl, arylalkoxy, arylamino, heteroarylamino, heteroaryl, heteroarylalkoxy, heterocycloalkyl, hydroxyalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxylalkyl, imidazolyl, indolealkyl, monohaloalkyl, dihaloalkyl and trihaloalkyl, monohaloalkoxy, dihaloalkoxy and trihaloalkoxy, amino, alkylamino, dialkylamino, amide, cyano, alkoxy, hydroxy, sulfonylmethylene, halogen (e.g., -Cl and -Br), nitro, hydroxyimino, -COOR50, -COR50, -SO0-2R50, -SO2NR50R51, NR52SO 2R50, ═C(R50R51), ═N—OR50, ═N—CN, ═C(halo)2, ═S, ═O, —CON(R50R51), —OCOR50, —OCON(R50R51), —N(R52)CO(R50), —N(R52)COOR50 and —N(R52)CON(R50(R51), wherein R50, R51 and R52 may be independently selected from the following: hydrogen atom and branched or straight chain, C1–6-alkyl, C3–6-cycloalkyl, C4–6-heterocycloalkyl, heteroaryl and aryl groups, and may or may not have substituents. Where permissible, R50 and R51 may be linked together to form a carbocyclic or heterocyclic ring system.

[0114] In a preferred embodiment, the substituent system is selected from halogens, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', and -SO2R', wherein Each example of [R'] is independently a C1–C20 aliphatic group (e.g., C1–C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). In some embodiments, [R'] is independently an unsubstituted alkyl group (e.g., unsubstituted C1–C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3 alkyl). Preferably, [R'] is independently an unsubstituted C1–C3 alkyl group.

[0115] Any formula given herein is intended to represent a compound having the structure described by the structural formula and a particular variant or form. Specifically, compounds of any formula given herein may have an asymmetric center and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the general formula and mixtures thereof are considered to fall within the scope of this formula. Therefore, any formula given herein is intended to represent racemic compounds, one or more enantiomeric forms, one or more diastereomeric forms, one or more lag isomeric forms, and mixtures thereof. Furthermore, certain structures may exist in geometric isomeric form (i.e., cis and trans isomers), tautomeric form, or lag isomeric form. Additionally, any formula given herein is intended to include hydrates, solvates, and allotropes of such compounds, and mixtures thereof. Compounds of the present invention

[0116] This article discloses potent inhibitors of PHD. In some embodiments, the half-maximal inhibitory concentration (IC50) of the compounds of the present invention against any of PHD1, PHD2, and PHD3 is less than 100 µM. In some embodiments, the IC50 of the compounds of the present invention against any of PHD1, PHD2, and PHD3 is less than 50 µM. In some embodiments, the IC50 of the compounds of the present invention against any of PHD1, PHD2, and PHD3 is less than 25 µM. In some embodiments, the IC50 of the compounds of the present invention against any of PHD1, PHD2, and PHD3 is less than 20 µM. In some embodiments, the IC50 of the compounds of the present invention against any of PHD1, PHD2, and PHD3 is less than 15 µM. In some embodiments, the IC50 of the compounds of the present invention against any of PHD1, PHD2, and PHD3 is less than 10 µM. In some embodiments, the IC50 of the compounds of the present invention against any of PHD1, PHD2, and PHD3 is less than 5 µM. In some embodiments, the IC50 value of the compounds of the present invention for any one of PHD1, PHD2, and PHD3 is less than 1 µM. In some embodiments, the IC50 value of the compounds of the present invention for any one of PHD1, PHD2, and PHD3 is about 3 nM to about 5 nM. In some embodiments, the IC50 value of the compounds of the present invention for any one of PHD1, PHD2, and PHD3 is about 5 nM to about 10 nM. In some embodiments, the IC50 value of the compounds of the present invention for any one of PHD1, PHD2, and PHD3 is about 10 nM to about 20 nM. In some embodiments, the IC50 value of the compounds of the present invention for any one of PHD1, PHD2, and PHD3 is about 20 nM to about 50 nM. In some embodiments, the IC50 value of the compounds of the present invention for any one of PHD1, PHD2, and PHD3 is about 50 nM to about 100 nM. In some embodiments, the IC50 value of the compounds of the present invention for any one of PHD1, PHD2, and PHD3 is about 100 nM to about 200 nM. In some embodiments, the IC50 values ​​of the compounds of the present invention for any one of PHD1, PHD2, and PHD3 are from about 200 nM to about 500 nM. In some embodiments, the IC50 values ​​of the compounds of the present invention for any one of PHD1, PHD2, and PHD3 are from about 500 nM to about 1000 nM.

[0117] Representative examples of this category demonstrate inhibitory activity against PHD1, PHD2, and PHD3 in vitro.

[0118] This article describes exemplary compounds. Compounds of formula (I)–(XXIII)

[0119] In particular, the PHD inhibitors described in this article are characterized by the 3-hydroxypyridine amino group. The applicant unexpectedly discovered that substituting the R1 position (where R1 is not hydrogen) with 3-hydroxypyridinamide significantly increases the potency of the inhibitor. Examples of such substitutions include (but are not limited to) substituted or unsubstituted alkyl groups.

[0120] In one state, this paper provides compounds having the structure according to formula (I): (I) Or a medically acceptable salt thereof, wherein: R1 may be a substituted C1-3 alkyl, a substituted C3-6 cycloalkyl, or a substituted 3- to 6-membered heterocyclic alkyl, depending on the situation; R2 is hydrogen, a substituted C1-3 alkyl group, a halogen, CN, or a substituted cycloalkyl group, depending on the situation; R3 is hydrogen, aryl (substituted as appropriate), heteroaryl (substituted as appropriate), cycloalkyl (substituted as appropriate), heterocycloalkyl (substituted as appropriate), carbonyl, diethyl ether, thioether, arylsulfonyl (substituted as appropriate), heteroarylsulfonyl (substituted as appropriate), arylalkyl (substituted as appropriate), alkynyl (substituted as appropriate), or heteroalkynyl (substituted as appropriate); R4 and R5 are independently hydrogen, or, where appropriate, substituted C1-3 alkyl groups, or R4 and R5 together with their attached carbons form, where appropriate, substituted cycloalkyl or heterocycloalkyl groups; and R6 is OH or an ester (e.g., OR18 as described herein).

[0121] In the examples, R1 is an unsubstituted C1-3 alkyl group. In the examples, R1 is a substituted C1-3 alkyl group (e.g., a C1-3 alkyl group containing 1, 2, or 3 substituents).

[0122] In the examples, R1 is an unsubstituted C3-6 cycloalkyl group (e.g., an unsubstituted cyclopropyl group). In the examples, R1 is a substituted C3-6 cycloalkyl group (e.g., a C3-6 cycloalkyl group containing 1, 2, or 3 substituents).

[0123] In the examples, R1 is an unsubstituted 3- to 6-membered heterocyclic alkyl group. In the examples, R1 is a substituted 3- to 6-membered heterocyclic alkyl group (e.g., a 3- to 6-membered heterocyclic alkyl group containing 1, 2, or 3 substituents).

[0124] In the examples, R2 is hydrogen. In the examples, R2 is a substituted C1-3 alkyl group, as appropriate. In the examples, R2 is an unsubstituted C1-3 alkyl group. In the examples, R2 is an unsubstituted C1-3 alkyl group (e.g., a C1-3 alkyl group containing 1, 2, or 3 substituents). In the examples, R2 is a halogen. In the examples, R2 is CN. In the examples, R2 is a substituted cycloalkyl group, as appropriate (e.g., a C3-6 cycloalkyl group). In the examples, R2 is an unsubstituted cycloalkyl group. In the examples, R2 is a substituted cycloalkyl group (e.g., a cycloalkyl group containing 1, 2, or 3 substituents).

[0125] In the examples, R3 is hydrogen. In the examples, R3 is an unsubstituted aryl group (e.g., phenyl, naphthalene). In the examples, R3 is a substituted aryl group (e.g., phenyl, naphthalene). In the examples, R3 is an unsubstituted heteroaryl group (e.g., quinolineone, isoquinolineone, pyridine, pyrazole, pyrrole, triazole, tetrazolium, oxazole, thiazole). In the examples, R3 is a substituted heteroaryl group (e.g., quinolineone, isoquinolineone, pyridine, pyrazole, pyrrole, triazole, tetrazolium, oxazole, thiazole). In the examples, R3 is an unsubstituted cycloalkyl group. In the examples, R3 is a substituted cycloalkyl group. In the examples, R3 is an unsubstituted heterocycloalkyl group (e.g., N-containing heterocycloalkyl group). In the examples, R3 is a substituted heterocycloalkyl group (e.g., N-containing heterocycloalkyl group). In the examples, R3 is a carbonyl group (e.g., COR17, where R17 is according to any of the examples described herein). In the embodiments, R3 is an ether (e.g., OR16, where R16 is according to any of the embodiments described herein). In the embodiments, R3 is a thioether (e.g., SR16, where R16 is according to any of the embodiments described herein). In the embodiments, R3 is an unsubstituted arylsulfonyl group (e.g., benzenesulfonyl). In the embodiments, R3 is a substituted arylsulfonyl group. In the embodiments, R3 is an unsubstituted heteroarylsulfonyl group. In the embodiments, R3 is a substituted heteroarylsulfonyl group. In the embodiments, R3 is an unsubstituted arylalkyl group (e.g., benzyl). In the embodiments, R3 is a substituted arylalkyl group (e.g., benzyl). In the embodiments, R3 is an unsubstituted alkynyl group. In the embodiments, R3 is a substituted alkynyl group (e.g., aryl-substituted alkynyl). In the embodiments, R3 is an unsubstituted heteroalkynyl group. In the embodiments, R3 is a substituted heteroalkynyl group (e.g., aryl-substituted heteroalkynyl). In the embodiments, R3 is OR16, SR16, SO2R16, CH2R16, CH2CH2R16, C≡CR16, or C≡CCH2OR16, and R16 is an aryl group.

[0126] In the embodiments, R4 and R5 are independently hydrogen or, as appropriate, substituted C1-3 alkyl groups. In the embodiments, R4 and R5 are independently hydrogen or unsubstituted C1-3 alkyl groups. In the embodiments, R4 and R5 are each hydrogen. In the embodiments, one of R4 and R5 is hydrogen and the other is an unsubstituted C1-3 alkyl group. In the embodiments, R4 and R5, together with their attached carbon, form, as appropriate, substituted cycloalkyl groups (e.g., C3-6 cycloalkyl groups). In the embodiments, R4 and R5, together with their attached carbon, form, as appropriate, unsubstituted cycloalkyl groups (e.g., unsubstituted C3-6 cycloalkyl groups). In the embodiments, R4 and R5, together with their attached carbon, form, as appropriate, substituted heterocyclic alkyl groups (e.g., 3- to 6-membered heterocyclic alkyl groups). In the embodiments, R4 and R5, together with their attached carbon, form, unsubstituted heterocyclic alkyl groups (e.g., unsubstituted 3- to 6-membered heterocyclic alkyl groups).

[0127] In the examples, R6 is hydrogen. In the examples, R6 is an ester (e.g., OR18 as described herein). In the examples, R6 is OR18, wherein R18 is a C1-6 alkyl group.

[0128] In the examples, R1 is a C1-3 alkyl group that has been substituted as appropriate; and / or R3 is hydrogen, an aryl group that has been substituted as appropriate, a heteroaryl group that has been substituted as appropriate, a cycloalkyl group that has been substituted as appropriate, a heterocycloalkyl group that has been substituted as appropriate, a carbonyl group, or an ether.

[0129] In the examples, R1 is an unsubstituted C1-3 alkyl group (e.g., CH3 or CH2CH3). In the examples, R1 is CH3. In the examples, R2 is hydrogen. In the examples, R4 and R5 are each hydrogen. In the examples, R6 is OH.

[0130] In the examples, R1 and R2 are each unsubstituted C1-3 alkyl groups. In the examples, R1 and R2 are each CH3. In the examples, R4 and R5 are each hydrogen. In the examples, R6 is OH.

[0131] In the examples, R2 is an unsubstituted C1-3 alkyl group (e.g., CH3 or CH2CH3). In the examples, R2 is CH3. In the examples, R3 is hydrogen. In the examples, R4 and R5 are each hydrogen. In the examples, R6 is OH.

[0132] In the embodiments, the compound has a structure according to formula (I), (I), Or a medically acceptable salt, in which R1 is a C1-3 alkyl group substituted with OR7, a halogen, or an aryl group, wherein the aryl group is substituted with a halogen, and wherein R7 is a C1-3 alkyl group substituted with an aryl group, or R1 is a C3-6 cycloalkyl group substituted with a substituted aryl group or a 3- to 6-membered heterocycloalkyl group substituted with a substituted aryl group; R2 is hydrogen, halogen, CN, or, where appropriate, a C1-3 alkyl group substituted with one or more halogens; The R3 series is selected from the following groups: hydrogen; X is a covalent bond, O, S, SO2, C1-4 alkylene, C2-4 ynynylene, or C2-4 heteroynylene; each A is independently N or CR9, R8 and R9 are independently hydrogen, halogen, OR10, or, as appropriate, a C1-3 alkyl substituted with one or more halogens, while R10 is a C1-3 alkyl or aryl; Where B is N or CR11, D is N, NH or CR11, E is N, CR11 or CHR12, and R11 and R12 are independently hydrogen or C1-3 alkyl, and the dashed circles represent the presence or absence of a conjugated system; Each G is independently N, NH, NR13, or CR14; R13 is a C3-6 cycloalkyl, a 3- to 6-membered heterocycloalkyl, an aryl group substituted with one or more halogens, an aryl group substituted with one or more C1-3 alkyl groups, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group, a C1-4 alkyl group substituted with an aryl group and the aryl group is substituted with one or more halogens, and R14 is hydrogen, a halogen, a C3-6 cycloalkyl, a 3- to 6-membered heterocycloalkyl, or a C1-3 alkyl; Where I is O, S, or CH, J is N or CH, R15 is hydrogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or C1-3 alkyl, and R19 is hydrogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or aryl; OR16, where R16 is aryl; Where X1 is N or CH, and R20 is an aryl group that is substituted, as appropriate; and COR17, where R17 is aryl; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbon atoms they are attached to form, as appropriate, substituted cycloalkyl or heterocycloalkyl groups; and R6 is OH or OR18, where R18 is a C1-6 alkyl group.

[0133] In the examples, R1 is an unsubstituted C1-3 alkyl group. In the examples, R1 is CH3 or CH2CH3.

[0134] In the examples, R1 is a substituted C1-3 alkyl group. In the examples, R1 is a C1-3 alkyl group substituted with OR7. In the examples, R7 is an unsubstituted C1-3 alkyl group. In the examples, R7 is a substituted C1-3 alkyl group. In the examples, R7 is an aryl-substituted C1-3 alkyl group. In the examples, the aryl group is phenyl. In the examples, R7 is a phenyl-substituted C1-3 alkyl group. In the examples, R1 is a C1-3 alkyl group substituted with OBn. In the examples, R1 is CH2CH2OBn.

[0135] In the examples, R1 is a C1-3 alkyl group substituted with one or more halogens (e.g., F, Cl, Br, or I). In the examples, R1 is a difluoromethyl group.

[0136] In the embodiments, R1 is, as appropriate, a C1-3 alkyl group substituted with an aryl group, and the aryl group is, as appropriate, substituted with a halogen. In the embodiments, the aryl group substituted with the aryl group is, as appropriate, a phenyl group substituted with the aryl group. In the embodiments, the aryl group or phenyl group is substituted with one or more halogens. In the embodiments, R1 is... .

[0137] In the examples, R1 is a C3-6 cycloalkyl group that is substituted as appropriate (e.g., a substituted cyclopropyl group that is substituted as appropriate). In the examples, R1 is a C3-6 cycloalkyl group (e.g., an unsubstituted cyclopropyl group). In the examples, R1 is a substituted C3-6 cycloalkyl group (e.g., a C3-6 cycloalkyl group containing 1, 2, or 3 substituents).

[0138] In the examples, R1 is a substituted 3- to 6-membered heterocyclic alkyl group, depending on the specific embodiment. In the examples, R1 is an unsubstituted 3- to 6-membered heterocyclic alkyl group. In the examples, R1 is a substituted 3- to 6-membered heterocyclic alkyl group (e.g., a 3- to 6-membered heterocyclic alkyl group containing 1, 2, or 3 substituents).

[0139] In the examples, R2 is hydrogen.

[0140] In this embodiment, R2 is CN.

[0141] In the embodiments, R2 is a halogen. In the embodiments, the halogen is F, Cl, Br, or I.

[0142] In the examples, R2 is an unsubstituted C1-3 alkyl group. In the examples, R2 is CH3.

[0143] In the embodiments, R2 is a C1-3 alkyl group substituted with one or more halogens.

[0144] In one embodiment, R3 is hydrogen. In another embodiment, R3 is not hydrogen.

[0145] In the embodiment, R3 is ,in X is a covalent bond, O, S, SO2, C1-4 alkylene, C2-4 ynynide, or C2-4 heteroynide; Each A is independently either N or CR9; R8 and R9 are independently hydrogen, halogen, OR10, or, where appropriate, C1-3 alkyl groups substituted with one or more halogens; and R10 is a C1-3 alkyl or aryl group.

[0146] In the examples, R3 is an unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, or trifluorotolyl.

[0147] In the embodiment, R3 is ,in B is either N or CR11; D is N, NH, or CR11; E is N, CR11, or CHR12; and R11 and R12 are independently hydrogen or C1-3 alkyl; and wherein The dashed circle represents the presence or absence of a conjugate system.

[0148] In the embodiment, R3 is ,in Each G is independently N, NH, NR13, or CR14; R13 is a C3-6 cycloalkyl, a 3- to 6-membered heterocycloalkyl, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate; and R14 is hydrogen, halogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or C1-3 alkyl.

[0149] In the examples, R3 is pyrrolo, tetrazolol, triazolol, or pyrazolol, which may be substituted with aryl or cycloalkyl groups as appropriate. In the examples, R3 (e.g., pyrrolo, tetrazolol, triazolol, or pyrazolol) is substituted with cyclopropyl or is an unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, or trifluorotolyl group.

[0150] In the embodiment, R3 is ,in I represents O, S, or CH; J is either N or CH; R15 is hydrogen, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, or C1-3 alkyl; and R19 is hydrogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or aryl.

[0151] In the examples, R3 is OR16, where R16 is an aryl group. In the examples, the aryl group is a phenyl group. In the examples, R3 is OPh.

[0152] In the embodiment, R3 is in X1 is either N or CH; and R20 is an aryl group that is substituted as appropriate.

[0153] In the examples, R3 is piperidinyl or piperazine, which may be substituted with cyclopropyl or aryl groups as appropriate. In the examples, R3 (e.g., piperidinyl or piperazine) is substituted with cyclopropyl or is an unsubstituted phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, or trifluorotolyl group.

[0154] In the examples, R3 is COR17, where R17 is an aryl group. In the examples, the aryl group is a phenyl group. In the examples, R3 is COPh.

[0155] In the embodiment, R3 is , , , , , , , ,or .

[0156] In the embodiments, both R4 and R5 are hydrogen.

[0157] In the examples, one of R4 and R5 is hydrogen, and the other is a C1-3 alkyl group. In the examples, the C1-3 alkyl group is unsubstituted. In the examples, the C1-3 alkyl group is substituted with one or more halogens. In the examples, the C1-3 alkyl group is CH3.

[0158] In the examples, R4 and R5 are both C1-3 alkyl groups. In the examples, the C1-3 alkyl group is unsubstituted. In the examples, the C1-3 alkyl group is substituted with one or more halogens. In the examples, the C1-3 alkyl group is CH3.

[0159] In the embodiments, R4 and R5, together with the carbon atoms they are attached to, form a cycloalkyl or heterocycloalkyl group. In the embodiments, the cycloalkyl or heterocycloalkyl group is unsubstituted. In the embodiments, the cycloalkyl or heterocycloalkyl group is unsubstituted (e.g., a cycloalkyl or heterocycloalkyl group containing 1, 2, or 3 substituents). In the embodiments, the cycloalkyl or heterocycloalkyl group is a 3-membered ring. In the embodiments, the cycloalkyl or heterocycloalkyl group is a 4-membered ring. In the embodiments, the heterocycloalkyl group is an oxygen-containing heterocycloalkyl group. In the embodiments, the cycloalkyl or heterocycloalkyl group is selected from cyclopropyl, cyclobutyl, and... The groups that are formed.

[0160] In the examples, R6 is OH.

[0161] In the examples, R6 is OR18, where R18 is a C1-6 alkyl group.

[0162] In the examples, R1 is an unsubstituted C1-3 alkyl group (e.g., CH3 or CH2CH3). In the examples, R1 is CH3. In the examples, R2 is hydrogen. In the examples, R4 and R5 are each hydrogen. In the examples, R6 is OH.

[0163] In the examples, R1 and R2 are each unsubstituted C1-3 alkyl groups. In the examples, R1 and R2 are each CH3. In the examples, R4 and R5 are each hydrogen. In the examples, R6 is OH.

[0164] In the examples, R2 is an unsubstituted C1-3 alkyl group (e.g., CH3 or CH2CH3). In the examples, R2 is CH3. In the examples, R3 is hydrogen. In the examples, R4 and R5 are each hydrogen. In the examples, R6 is OH.

[0165] In the embodiments, R1 is a C1-3 alkyl group substituted with OR7 or an aryl group, wherein the aryl group is substituted with a halogen group, and wherein R7 is a C1-3 alkyl group substituted with an aryl group, and / or R3 is selected from the group consisting of hydrogen, , , ,or .

[0166] In the embodiments, the compound of formula (I) has the following structure, (II), or a medically acceptable salt thereof, wherein R1, R2, R3, R4 and R5 are as defined anywhere in this document.

[0167] In the embodiments, the compound of formula (I) or formula (II) has the following structure, (III), or a medically acceptable salt thereof, wherein R1, R2, R4 and R5 are as defined anywhere in this document, and wherein Each A is independently either N or CR9; R8 and R9 are independently hydrogen, halogen, OR10, or, where appropriate, C1-3 alkyl groups substituted with one or more halogens; and R10 is a C1-3 alkyl or aryl group.

[0168] In this embodiment, A is N. In this embodiment, A is CR9. In this embodiment, all three A groups are CR9. In this embodiment, one A is CR9, while the other two A groups are N. In this embodiment, one A is N, while the other two A groups are CR9. In this embodiment, all three A groups are N.

[0169] In the embodiment, at least one of R8 and R9 is hydrogen.

[0170] In the embodiments, neither R8 nor R9 is hydrogen.

[0171] In the embodiments, R8 is hydrogen.

[0172] In this embodiment, R8 is a halogen. In this embodiment, the halogen is F, Cl, Br, or I. In this embodiment, R8 is Cl.

[0173] In the examples, R8 is OR10, where R10 is a C1-3 alkyl group. In the examples, R8 is OMe.

[0174] In the examples, R8 is OR10, where R10 is an aryl group. In the examples, the aryl group is a phenyl group. In the examples, R8 is OPh.

[0175] In the examples, R8 is an unsubstituted C1-3 alkyl group. In the examples, R8 is a C1-3 alkyl group substituted with one or more halogens.

[0176] In the examples, R9 is hydrogen.

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

[0178] In the examples, R9 is OR10, where R10 is a C1-3 alkyl group. In the examples, R9 is OMe.

[0179] In the examples, R9 is OR10, where R10 is an aryl group. In the examples, the aryl group is a phenyl group. In the examples, R9 is OPh.

[0180] In the examples, R9 is an unsubstituted C1-3 alkyl group. In the examples, R9 is a C1-3 alkyl group substituted with one or more halogens. In the examples, R9 is CH3. In the examples, R9 is CF3.

[0181] In the embodiments, the compounds of formula (I), formula (II), or formula (III) have the following structures, (IV), or its medically acceptable salts, wherein R1, R2, R4, R5, R8 and R9 are as defined anywhere in this document.

[0182] In the embodiments, the compounds of formula (I), formula (II), or formula (III) have the following structures, (V), or a medically acceptable salt thereof, wherein R1, R2, R4, R5, R8 and R9 are as defined anywhere in this document.

[0183] In the embodiment, for In the embodiments, R9 is a halogen, OR10, or a C1-3 alkyl group substituted with one or more halogens, as appropriate. In the embodiments, R9 is a halogen.

[0184] In the embodiment, for In the embodiments, R9 is a halogen, OR10, or a C1-3 alkyl group substituted with one or more halogens, as appropriate. In the embodiments, R9 is a halogen.

[0185] In the embodiment, for In the embodiments, R8 is a halogen, OR10, or a C1-3 alkyl group substituted with one or more halogens, as appropriate. In the embodiments, R8 is a halogen.

[0186] In the embodiments, the compound of formula (I) or formula (II) has the following structure, (VI), or a medically acceptable salt thereof, wherein R1, R2, R4 and R5 are as defined anywhere in this document, and wherein B is either N or CR11; D is N, NH, or CR11; E is N, CR11, or CHR12; and R11 and R12 are independently hydrogen or C1-3 alkyl; and The dashed circle represents the presence or absence of a conjugate system.

[0187] In the embodiment, the dashed circle system exists and R3 is... Where B is N or CR11, D is N or CR11, and E is N or CR12.

[0188] In the embodiment, D is CR11, E is CR12, and B is N.

[0189] In the embodiment, B is CR11, E is CR12, and D is N.

[0190] In the embodiment, B and D are both CR11, while E is N.

[0191] In the embodiment, B and D are both CR11, while E is CR12.

[0192] In the embodiment, the dashed circle does not exist and R3 is... Where B is N or CR11; D is NH; and E is CHR12.

[0193] In the embodiment, B is CR11, and E is CHR12.

[0194] In the examples, R11 is hydrogen.

[0195] In the examples, R11 is a C1-3 alkyl group. In the examples, R11 is CH3.

[0196] In the examples, R12 is hydrogen.

[0197] In the examples, R12 is a C1-3 alkyl group. In the examples, R12 is CH3.

[0198] In the embodiments, the compounds of formula (I), formula (II), or formula (VI) have the following structures, (VII), or a medically acceptable salt thereof, wherein B, D, E, R1, R2, R4 and R5 are as defined anywhere in this document.

[0199] In the embodiment, for .

[0200] In the embodiment, for .

[0201] In the embodiment, for In the examples, R12 is hydrogen or a C1-3 alkyl group. In the examples, R12 is hydrogen. In the examples, R12 is CH3.

[0202] In the embodiment, for .

[0203] In the embodiments, the compounds of formula (I), formula (II), or formula (VI) have the following structures, (VIII), or a medically acceptable salt thereof, wherein B, R1, R2, R4, R5 and R12 are as defined anywhere in this document.

[0204] In the embodiment, for In the examples, R12 is a C1-3 alkyl group. In the examples, R12 is CH3.

[0205] In the embodiments, the compound of formula (I) or formula (II) has the following structure, (IX), or a medically acceptable salt thereof, wherein R1, R2, R4 and R5 are as defined anywhere in this document, and wherein Each G is independently N, NH, NR13, or CR14; R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocyclic alkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate; and R14 is hydrogen, halogen, cyclopropyl, or C1-3 alkyl.

[0206] In this embodiment, G is N. In this embodiment, G is NH. In this embodiment, G is NR13. In this embodiment, G is CR14.

[0207] In the embodiments, R13 is cyclopropyl.

[0208] In the embodiments, R13 is an unsubstituted aryl group. In the embodiments, R13 is an aryl group substituted with one or more halogens. In the embodiments, R13 is an aryl group substituted with one or more C1-3 alkyl groups (e.g., C1-3 alkyl groups substituted with one or more halogens) as appropriate. In the embodiments, the aryl group is phenyl. In the embodiments, R13 is an unsubstituted phenyl group. In the embodiments, R13 is a phenyl group substituted with one or more halogens. In the embodiments, R13 is a phenyl group substituted with one or more C1-3 alkyl groups (e.g., C1-3 alkyl groups substituted with one or more halogens) as appropriate. In the embodiments, R13 is selected from the group consisting of: p-trifluoromethylphenyl, m-fluorophenyl, p-fluorophenyl, p-chlorophenyl, 2,4-dichlorophenyl, and 3,5-dichlorophenyl.

[0209] In the embodiments, R13 is a heteroaryl group. In the embodiments, the heteroaryl group is unsubstituted. In the embodiments, the heteroaryl group is substituted. In the embodiments, the heteroaryl group is pyridyl. In the embodiments, R13 is 2-pyridyl, 3-pyridyl, or 4-pyridyl.

[0210] In the examples, R13 is an unsubstituted heterocyclic alkyl group. In the examples, R13 is a heterocyclic alkyl group substituted with a t-butoxycarbonyl group. In the examples, the heterocyclic alkyl group is a 6-membered heterocyclic alkyl group. In the examples, the heterocyclic alkyl group is a nitrogen-containing heterocyclic alkyl group. In the examples, the heterocyclic alkyl group is an oxygen-containing heterocyclic alkyl group. In the examples, R13 is... ,or .

[0211] In the examples, R13 is an unsubstituted C1-4 alkyl group. In the examples, R13 is... or .

[0212] In the examples, R13 is an aryl-substituted C1-4 alkyl group. In the examples, the aryl group is unsubstituted. In the examples, the aryl group is substituted with one or more halogens. In the examples, the aryl group is phenyl. In the examples, the phenyl group is unsubstituted. In the examples, the phenyl group is substituted with one or more halogens. In the examples, R13 is... or .

[0213] In the examples, R14 is hydrogen.

[0214] In this embodiment, R14 is a halogen. In this embodiment, the halogen is F, Cl, Br, or I. In this embodiment, R14 is F.

[0215] In the embodiments, R14 is cyclopropyl.

[0216] In the examples, R14 is a C1-3 alkyl group. In the examples, R14 is CH3.

[0217] In the embodiment, for .

[0218] In the embodiment, for In the embodiments, R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is an unsubstituted aryl group. In the embodiments, R13 is Ph. In the embodiments, R13 is an aryl group substituted with one or more halogens. In the embodiments, R13 is... or In the embodiments, R13 is cyclopropyl.

[0219] In the embodiment, for In the embodiments, R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is an aryl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is a Ph group, , ,or .

[0220] In the embodiment, for In the embodiments, for , ,or In the embodiments, R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is an aryl group. In the embodiments, R13 is Ph. In the embodiments, R13 is Ph. , , , , , , 2-pyridyl , or .

[0221] In the examples, R14 is hydrogen, halogen, cyclopropyl, or C1-3 alkyl. In the examples, R14 is a C1-3 alkyl (e.g., methyl).

[0222] In the embodiment, for In the embodiments, R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is an aryl group. In the embodiments, R13 is Ph.

[0223] In the embodiments, the compounds of formula (I), formula (II), or formula (IX) have the following structures, (X), or a medically acceptable salt thereof, wherein G, R1, R2, R4 and R5 are as defined anywhere in this document.

[0224] In the embodiment, for In the embodiments, R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is an aryl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is a Ph group, , ,or .

[0225] In the embodiments, the compounds of formula (I), formula (II), formula (IX) or formula (X) have the following structures, (XI), or a medically acceptable salt thereof, wherein R1, R2, R4, R5 and R14 are as defined anywhere in this document.

[0226] In the embodiments, the compounds of formula (I), formula (II), formula (IX), formula (X), or formula (XI) have the following structures. (XIIa), or (XIIb), or a medically acceptable salt thereof, wherein R1, R2, R4, R5, R13 and R14 are as defined anywhere in this document.

[0227] In the examples, R14 is a halogen or a C1-3 alkyl group. In the examples, R14 is a methyl group. In the examples, R14 is F.

[0228] In the embodiments, R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is a Ph, 3-fluorophenyl, or 4-fluorophenyl.

[0229] In the embodiment, R14 is hydrogen and for In the embodiment, R14 is hydrogen and for In the embodiments, R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocyclic alkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is a C1-4 alkyl group. In the embodiments, R13 is a heteroaryl group. In the embodiments, R13 is a heterocyclic alkyl group. In the embodiments, R13 is an aryl group substituted with one or more halogens as appropriate. In the embodiments, R13 is an aryl group substituted with a C1-3 alkyl group as appropriate (e.g., a C1-3 alkyl group substituted with one or more halogens as appropriate). In the embodiments, R13 is a Ph group. , , , , , 2-pyridyl , or .

[0230] In the embodiments, the compounds of formula (I), formula (II), formula (IX), formula (X), formula (XI), or formula (XIIa) have the following structures. (XIII), or a medically acceptable salt thereof, wherein R2, R4, R5 and R13 are as defined anywhere in this document.

[0231] In the embodiments, R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocyclic alkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is a heterocyclic alkyl group substituted with a t-butoxycarbonyl group. In the embodiments, R13 is an aryl group. In the embodiments, R13 is an aryl group substituted with one or more halogens as appropriate. In the embodiments, R13 is an aryl group substituted with a C1-3 alkyl group as appropriate (e.g., a C1-3 alkyl group substituted with one or more halogens as appropriate). In the embodiments, R13 is Ph, , , , , 2-pyridyl , , ,or .

[0232] In the embodiments, the compounds of formula (I), formula (II), formula (IX), formula (X), or formula (XI) have the following structures. (XIX), or a medically acceptable salt thereof, wherein R1, R2, R4, R5 and R13 are as defined anywhere in this document.

[0233] In the embodiments, R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate and the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is an unsubstituted aryl group. In the embodiments, R13 is Ph.

[0234] In the embodiments, the compounds of formula (I), formula (II), or formula (IX) have the following structures, (XX), or a medically acceptable salt thereof, wherein R1, R2, R4, R5 and R13 are as defined anywhere in this document.

[0235] In the embodiments, R13 is a cyclopropyl group, an aryl group substituted with one or more halogens as appropriate, an aryl group substituted with one or more C1-3 alkyl groups as appropriate, a heteroaryl group, a heterocycloalkyl group substituted with a t-butoxycarbonyl group as appropriate, or a C1-4 alkyl group substituted with an aryl group as appropriate, wherein the aryl group is substituted with one or more halogens as appropriate. In the embodiments, R13 is an unsubstituted aryl group. In the embodiments, R13 is Ph. In the embodiments, R13 is an aryl group substituted with one or more halogens. In the embodiments, R13 is... or In the embodiments, R13 is cyclopropyl.

[0236] In the embodiments, the compounds of formula (I), formula (II), or formula (IX) have the following structures, (XXI), or a medically acceptable salt thereof, wherein R1, R2, R4 and R5 are as defined anywhere in this document.

[0237] In the embodiments, the compound of formula (I) or formula (II) has the following structure, (XIV), or its medically acceptable salts, wherein R1, R2, R4 and R5 are as defined anywhere in this document, and wherein I represents O, S, or CH; J is either N or CH; R15 is hydrogen or a C1-3 alkyl group; and R19 is hydrogen or aryl.

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

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

[0240] In the examples, R15 is hydrogen.

[0241] In the examples, R15 is a C1-3 alkyl group. In the examples, R15 is CH3.

[0242] In the examples, R19 is hydrogen.

[0243] In the examples, R19 is an aryl group. In the examples, R19 is a phenyl group.

[0244] In the embodiments, the compounds of formula (I), (II), or (XIV) have the following structures, (XV), or a medically acceptable salt thereof, wherein I, R1, R2, R4, R5, R15 and R19 are as defined anywhere in this document.

[0245] In the embodiment, for In the examples, R19 is aryl. In the examples, R19 is phenyl. In the examples, R15 is hydrogen or C1-3 alkyl. In the examples, R15 is hydrogen or CH3.

[0246] In the embodiment, for In the examples, R19 is an aryl group. In the examples, R19 is a phenyl group.

[0247] In the embodiments, the compound of formula (I) or formula (II) has the following structure, (XVI), or a medically acceptable salt thereof, wherein R1, R2, R4, R5, R8 and 9 are as defined anywhere in this document, and wherein X is O, S, or SO2.

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

[0249] In the embodiments, the compound of formula (I) or formula (II) has the following structure, (XVII), or a medically acceptable salt thereof, wherein R1, R2, R4, R5, R8 and R9 are as defined anywhere in this document.

[0250] In the embodiments, the compound of formula (I) or formula (II) has the following structure, (XVIII), or a medically acceptable salt thereof, wherein R1, R2, R4, R5, R8 and R9 are as defined anywhere in this document.

[0251] In the embodiments, the compound of formula (I) or formula (II) has the following structure, (XXII), wherein R1, R2, R4 and R5 are as defined anywhere in this document, and R20 is an aryl group that is substituted as appropriate.

[0252] In the examples, R20 is a substituted aryl group (e.g., containing 1, 2, or 3 substituents). In the examples, R20 is an unsubstituted aryl group. In the examples, the aryl group is phenyl. In the examples, R20 is Ph.

[0253] In the embodiments, the compound of formula (I) or formula (II) has the following structure, (XXIII), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4 and R5 are as defined anywhere in this document, and R20 is, where appropriate, a substituted aryl group.

[0254] In the examples, R20 is a substituted aryl group (e.g., containing 1, 2, or 3 substituents). In the examples, R20 is an unsubstituted aryl group. In the examples, the aryl group is phenyl. In the examples, R20 is Ph. Exemplary compounds

[0255] In some embodiments, the PHD inhibitor compound is any one of compounds 1-50 or a pharmaceutically acceptable salt thereof. Compound numbering structure Compound numbering structure 1 26 2 27 3 28 4 29 5 30 6 31 7 32 8 33 9 34 10 35 11 36 12 37 13 38 14 39 15 40 16 41 17 42 18 43 19 44 20 45 21 46 22 47 twenty three 48 twenty four 49 25 50

[0256] In some embodiments, the PHD inhibitor compound is any one of compounds 51-70 or a pharmaceutically acceptable salt thereof. Compound numbering structure Compound numbering structure 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 Isotope molecules

[0257] It should be understood that in the compounds described herein (e.g., any of the compounds of formulas (I)–(XXIII), such as any of compounds 1–70), atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a specific isotope, the isotope having the same number of atoms as the dominant naturally occurring element, but with a different atomic mass or mass number than the dominant naturally occurring element. This invention is intended to include all suitable isotopic variations of the compounds described herein (e.g., any of the compounds of formulas (I)–(XXIII), such as any of compounds 1–70). For example, different isotopic forms of hydrogen (H) include protium (¹H), deuterium (²H), and tritium (³H). Protium is the dominant hydrogen isotope found in nature. [ ]

[0258] In some embodiments, one or more hydrogen series in the compounds described herein (e.g., any of the compounds in formulas (I)–(XXIII), such as any of compounds 1–70) are replaced by deuterium. Concentration of deuterium can produce certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or providing compounds suitable for characterizing biological samples. In some embodiments, one or more hydrogen series in the compounds described herein (e.g., any of the compounds in formulas (I)–(XXIII), such as any of compounds 1–70) are replaced by tritium. Tritium is radioactive and therefore provides compounds that can be radiolabeled, which can be used as tracers in metabolic or kinetic studies. [ ]

[0259] The isotope-enriched compounds disclosed herein (e.g., any of the compounds in formulas (I)–(XXIII), such as any of compounds 1–70) can be produced without excessive experimentation using appropriate isotope-enriching reagents and / or intermediates, either by conventional techniques known to those skilled in the art or by methods similar to those described in the procedures and examples herein. [ ]

[0260] The term "isotope-like molecule" refers to a molecule that, except for isotopic substitution at one or more sites and / or isotopic enrichment, isotopic substituted at those sites. Beyond [degree], substances having the same chemical structure and formula as the specific compounds provided herein, such as hydrogen and deuterium. Therefore, as used herein, the term "compound" encompasses a collection of molecules having the same chemical structure, but also exhibiting isotopic variations among the constituent atoms of these molecules. Thus, it will be apparent to those skilled in the art that a compound containing a specified deuterium atom, represented by a specific chemical structure, also contains a smaller amount of isotopic molecules with hydrogen atoms at one or more specified deuterium positions in that structure. The relative amounts of these isotopic molecules in the provided compounds depend on a variety of factors, including (but not limited to) the isotopic purity of the deuterating reagent used to prepare the compound and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound.

[0261] When a position is specifically designated as "H" or "hydrogen", that position shall be considered to have hydrogen as its natural abundance isotope composition. When a position is specifically designated as "D" or "deuterium", that position shall be considered to have deuterium with an abundance at least 3340 times greater than the natural abundance of deuterium (which is 0.015%) (that is, the terms "D" or "deuterium" refer to the inclusion of at least 50.1% deuterium).

[0262] In the embodiments, the compounds provided herein are for each deuterium present at sites designated as potential sites for deuteration of the compound. The enrichment factor of the isotope is at least 3500 (incorporating 52.5% deuterium), at least 4000 (incorporating 60% deuterium), at least 4500 (incorporating 67.5% deuterium), at least 5000 (75% deuterium), at least 5500 (incorporating 82.5% deuterium), at least 6000 (incorporating 90% deuterium), at least 6333.3 (incorporating 95% deuterium), at least 6466.7 (incorporating 97% deuterium), at least 6600 (incorporating 99% deuterium), or at least 6633.3 (incorporating 99.5% deuterium). Synthesis of the compounds of this invention

[0263] The compounds described herein (e.g., any of the compounds in formulas (I)–(XXIII), such as any of compounds 1–70) may Preparation is carried out [according to] methods known in the art, including exemplary synthesis of examples provided herein.

[0264] The abbreviations and acronyms used in this article include the following: [the term] [Acronyms] 4-Dimethylaminopyridine DMAP Acetyl Ac Aqueous solution aq. Benzotriazine hexafluorophosphate-1-yl-oxytripyrrolidine PyBOP benzyl Bn 1,1'-Bis(diphenylphosphine)ferrocene dppf Tertiary butoxycarbonyl Boc Surface width single peak brs dichloromethane DCM dimethyl monoxide DMSO Twin Peaks d Electrospraying ionization method ESI equivalent eq Ethyl acetate EtOAc gram g hexane Hex High performance liquid chromatography HPLC Hour hr Isopropyl i-Pr Liquid Chromatography Mass Spectrometer LCMS megahertz MHz m-chloroperoxybenzyl acid m-CPBA methanol MeOH mg mg milliliters mL minute min molar concentration M multiplets m N,N-Diisopropylethylamine DIPEA N,N-Dimethylformamide DMF N,N-Dimethylformamide dimethyl acetal DMF-DMA Normal N Nuclear magnetic resonance NMR Palladium on carbon Pd / C Five Peaks p petroleum ether PE Phenyl Ph Preparative Prep Four Peaks q room temperature RT Single peak s Tetrahydrofuran THF Thin-layer chromatography TLC Triethylamine TEA Trifluoroacetic acid TFA Trimethylsilyl TMS Triple Peak t Composition and Method

[0265] This invention provides the use of any compound of formulas (I)–(XXIII) in the manufacture of a medicament for treating the various conditions or ailments described herein. In one embodiment, a pharmaceutical composition is provided comprising at least one compound of any one of formulas (I)–(XXIII) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In various embodiments, the medicament or pharmaceutical composition may further comprise, or be used in combination with, at least one additional therapeutic agent.

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

[0267] In one embodiment, the method of the present invention comprises administering to a patient in need a therapeutically effective amount of any compound of formula (I)–(XXIII) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds of formula (I)–(XXIII).

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

[0269] In other embodiments, the compounds disclosed herein (e.g., any of the compounds in formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts are used to treat or prevent anemia, including anemia associated with chronic kidney disease, polycystic kidney disease, aplastic anemia, autoimmune hemolytic anemia, bone marrow transplant anemia, Churg-Strauss syndrome, and congenital pure red cell aplastic anemia (Diamond Blackfan syndrome). Anemia, Fanconi's anemia, Felty's syndrome, graft-versus-host disease, hematopoietic stem cell transplantation, hemolytic uremic syndrome, myelodysplastic syndrome, nocturnal paroxysmal hemoglobinuria, myelofibrosis, pancytopenia, pure red cell aplasia, Schoenlein-Henoch purpura, refractory anemia with polyblastic blasts, rheumatoid arthritis, Shwachman syndrome, sickle cell disease, severe thalassemia. Anemia, mild thalassemia, thrombocytopenic purpura, anemia or non-anemia in patients undergoing surgery, trauma-related or secondary anemia, sideroblastic anemia, and other treatments for secondary anemia, including: reverse transcriptase inhibitors for HIV treatment, corticosteroids, cisplatin-containing or cisplatin-free chemotherapy drugs, vinca alkaloids, mitotic inhibitors, topoisomerase II inhibitors, anthracyclines, tranexamic acid, alkylating agents, especially anemia secondary to inflammation, aging, and / or chronic diseases. PHD suppression can also be used to treat symptoms of anemia, including chronic fatigue, pallor, and dizziness.

[0270] In other embodiments, the compounds disclosed herein (e.g., compounds of formula (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts are used to treat or prevent metabolic disorders, including but not limited to diabetes and obesity.

[0271] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts are used to treat or prevent vascular diseases. These diseases include, but are not limited to, diseases related to hypoxia or wound healing that require angiogenesis mediators for angiogenesis, vascularization, and arterial regeneration.

[0272] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts are used to treat or prevent local ischemia-reperfusion. These conditions include, but are not limited to, stroke, myocardial infarction, and acute kidney injury.

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

[0274] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts have been shown to be useful for treating cancers, such as colorectal cancer.

[0275] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts are used to treat atherosclerosis.

[0276] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts are used to treat cardiovascular diseases.

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

[0278] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts are used to treat diseases associated with hyperoxia.

[0279] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts are used to treat bronchodystrophy (BPD).

[0280] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I)–(XXIII), such as any one of compounds 1–70) or their pharmaceutically acceptable salts are used to treat heart conditions. These conditions include, but are not limited to, myocardial ischemia following pancreatic surgery, myocardial injury following percutaneous coronary intervention (PCI), myocardial injury following non-cardiac surgery, myocardial ischemia throughout the procedure for elective abdominal aortic aneurysm surgery, myocardial injury after PCI, myocardial injury in patients undergoing coronary artery bypass grafting (CABG), minimally invasive mitral valve (MIMV) repair or replacement, adult patients undergoing open-heart surgery, chronic heart failure, NYHA class II–IV.

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

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

[0283] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts are used to treat liver diseases. These conditions include, but are not limited to, non-alcoholic hepatitis (NASH).

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

[0285] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts are used to treat damage and / or failure of one or more organs (e.g., damage or failure of the lungs, heart, liver, or kidneys). Such conditions include (but are not limited to) acute organ injury or organ failure, and induced organ dysfunction.

[0286] In other embodiments, the compounds disclosed herein (e.g., compounds of formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts are used to treat respiratory viral (e.g., coronavirus) infections or pulmonary viral (e.g., coronavirus) infections.

[0287] Furthermore, the compounds disclosed herein (e.g., any of the compounds in formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts may be used in combination with additional active ingredients to treat the aforementioned conditions. These additional compounds may be co-administered separately from the compounds disclosed herein (e.g., any of the compounds in formulas (I)–(XXIII), such as any of compounds 1–70) or their pharmaceutically acceptable salts, or may be included together with the additional active ingredient in a pharmaceutical composition according to the invention. In one exemplary embodiment, the additional active ingredient is an active ingredient known or found to be effective in treating PHD enzyme-mediated conditions, symptoms, or diseases, or an active ingredient active against another target associated with that particular condition, symptom, or disease, such as an alternative PHD modulator. This combination may help improve efficacy (e.g., by including compounds in the composition that enhance the efficacy or effectiveness of the compounds of the invention), reduce one or more side effects, or reduce the required dosage of the compounds of the invention.

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

[0289] "Pharmaceutical-acceptable excipients" refer to substances that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject, such as inert substances, which are added to pharmaceutical compositions or otherwise used as carriers, diluents, or loads to facilitate drug administration and are compatible with the drug. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Suitable excipients may also include antioxidants. These antioxidants can be used in pharmaceutical compositions or in storage media to extend the shelf life of the pharmaceutical product. Pharmaceutical preparations and administration routes

[0290] As is known in the art, the compounds and compositions of the present invention can be delivered directly or as pharmaceutical compositions or drugs together with suitable carriers or excipients. Treatment methods of the present invention may include administering an effective amount of the compounds of the present invention to an individual in need. In a preferred embodiment, the individual is a mammalian individual; in a most preferred embodiment, the individual is a human individual.

[0291] The effective amount of the compound, composition, or drug can be readily determined by routine experiments, as can the most effective and convenient route of administration and the most suitable formulation. Various formulations and drug delivery systems exist in the art. See, for example, Gennaro, AR ed. (1995), Remington's Pharmaceutical Sciences, above.

[0292] For example, suitable routes of administration may include oral, rectal, local, nasal, pulmonary, ocular, intestinal, and non-enteric routes. Primary routes of administration for non-enteric administration include intravenous, intramuscular, and subcutaneous administration. Secondary routes of administration include intraperitoneal, intra-articular, intra-articular, intracardiac, intracisional, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intracardiac administration. The indication for treatment and the physical, chemical, and biological properties of the drug determine the type of formulation and the route of administration, as well as whether local or systemic administration will be preferred.

[0293] Pharmaceutical dosage forms of the compounds of this invention can be provided in the form of rapid-release, controlled-release, sustained-release, or targeted drug delivery systems. Common dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, sugar-coated pills, soft-shell or hard-shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized formulations. Depending on the route of administration used, special devices may be required to administer or deliver the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. Pharmaceutical dosage forms often consist of the drug, excipients, and a container / sealing system. One or more excipients (also known as inactive ingredients) may be added to the compounds of this invention to improve or facilitate the manufacture, stability, administration, and safety of the drug, and to provide a method for obtaining the desired drug release profile. Therefore, the type of excipient added to the drug can be determined by various factors, such as the physical and chemical properties of the drug, the route of administration, and the preparation steps. Pharmaceutical excipients exist in this field and include those listed in various pharmacopoeias. See, for example, the United States Pharmacopeia (USP), the Japanese Pharmacopoeia (JP), the European Pharmacopoeia (EP), and the British Pharmacopoeia (BP); the U.S. Food and Drug Administration.

[0294] Publications from the Centre for Drug Evaluation and Research (CEDR) of the Federal Registry (www.fda.gov), such as the Guide to Inactive Ingredients (1996); the Handbook of Drug Additives, edited by Ash and Ash (2002), Synapse Information Resources, Endicott NY, et al.

[0149] Pharmaceutical dosage forms of the compounds of the present invention may be manufactured by any method known in the art, such as by conventional mixing, sieving, dissolving, melting, granulation, manufacturing of sugar-coated pills, tableting, suspension, extrusion, spray drying, grinding, emulsification, (nano / micron) encapsulation, packaging, or lyophilization processes. As described above, the components of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate the processing of active molecules into formulations for pharmaceutical use.

[0295] The appropriate formulation depends on the desired route of administration. For example, for intravenous administration, the composition may be formulated in an aqueous solution, using physiologically compatible buffers, such as phosphates, histidines, or citrates to adjust the pH of the formulation, and permeabilizers, such as sodium chloride or dextran. For transmucosal or nasal administration, semi-solid, liquid, or patch formulations are preferred, and may contain permeation enhancers. These permeabilizers are generally known in the art. For oral administration, the compound may be formulated in liquid or solid dosage forms and as a rapid-release or controlled-release / sustained-release formulation. Suitable dosage forms for individual oral intake include tablets, pills, sugar-coated pills, hard-shell and soft-shell capsules, liquids, gels, syrups, ointments, suspensions, and emulsions. The compound may also be formulated in rectal components, such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

[0296] Solid oral dosage forms can be obtained using excipients, which include fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, flow aids, anti-adhesion agents, cationic exchange resins, humectants, antioxidants, preservatives, colorants, and flavoring agents. These excipients can be of synthetic or natural origin. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gums, magnesium carbonate, magnesium lauryl sulfate / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, hydrogenated vegetable oils, and waxes. Ethanol and water can be used as granulation aids. In some cases, it is necessary to coat the tablets with, for example, a taste-masking film, an acid-resistant film, or a delayed-release film. Natural and synthetic polymers are often combined with colorants, sugars, and organic solvents or water to coat tablets, resulting in sugar-coated pills. When capsules are preferred over tablets, drug powders, suspensions, or solutions can be delivered in compatible hard-shell or soft-shell capsule forms.

[0297] In one embodiment, the compounds of the present invention can be administered topically, for example via skin patches, semi-solid or liquid formulations such as gels, (micro)emulsions, ointments, solutions, (nano / micro) suspensions, or foams. Skin and subtissue penetration of the drug can be modulated, for example, by using penetration enhancers; by using appropriate selections and combinations of lipophilic, hydrophilic, and bipolar excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, and emulsifiers; by adjusting the pH value; and by using chelating agents. Other techniques, such as iontophoresis, can also be used to modulate the skin penetration of the compounds of the present invention. For example, transdermal or local administration is preferred in cases where local administration with minimal systemic exposure is required.

[0298] For inhalation or nasal administration, the compounds used according to the invention are conveniently administered from a pressurized pack or nebulizer in the form of a solution, suspension, emulsion, or semi-solid aerosol, typically by means of a propellant, such as carbon halogenates derived from methane and ethane, carbon dioxide, or any other suitable gas. For localized aerosols, hydrocarbons such as butane, isobutene, and pentane are suitable. In the case of pressurized aerosols, appropriate dosage units can be determined by providing a valve to deliver the metering amount. Capsules and cartridges containing, for example, gelatin can be formulated for use in inhalers or blowpipes. These typically contain a powder mixture of the compound with a suitable powder matrix (such as lactose or starch).

[0299] Compounds and compositions formulated for non-enteral administration by injection are typically sterile and available in unit dosage forms, such as ampoules, syringes, injection pens, or multi-dose containers, which typically contain preservatives. Compositions may be in the form of suspensions, solutions, or emulsions in oily or aqueous media and may contain formulation agents such as buffers, penetrants, viscosity enhancers, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives. Depending on the injection site, the media may contain water, synthetic or vegetable oils, and / or organic co-solvents. In some cases, such as for lyophilized products or concentrates, the non-enteral formulation may be reconstituted or diluted prior to administration. Reservoir formulations providing controlled or sustained release of the compounds of the present invention may comprise injectable suspensions of nano / micron-sized particles or nano / micron-sized or non-micronized crystals. Polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof may be used as controlled / sustaining release matrices, or other well-known matrices in this art may be used. Other reservoir-type drug delivery systems can be provided in the form of implants that require incisions and pumps.

[0300] Suitable carriers for intravenous injection of the compounds of the present invention are well known in the art and include aqueous solutions containing a base (such as sodium hydroxide) for forming ionic compounds, sucrose or sodium chloride as a permeabilizing agent, and buffers containing phosphates or histidine. Cosolvents such as polyethylene glycol may be added. These aqueous systems effectively dissolve the compounds of the present invention and produce low toxicity after systemic administration. The proportions of the components in the solution system can be significantly altered without compromising solubility and toxicity characteristics. Furthermore, the nature of the components can be modified. For example, low-toxicity surfactants such as polysorbates or poloxamer may be used, as may polyethylene glycol or other cosolvents, biocompatible polymers such as polyvinylpyrrolidone may be added, and other sugars and polyols may be used to replace dextrose.

[0301] The effective therapeutic dose can first be estimated using various techniques well known in the art. The initial dose for animal studies can be determined based on the effective concentration established in cell culture assays. The appropriate dose range for human individuals can be determined, for example, using data obtained from animal studies and cell culture assays. In some embodiments, the compounds of the present invention are formulated for oral administration. In pharmaceutical formulations for oral administration, an exemplary dose of the compounds of the present invention is about 0.5 to about 10 mg / kg body weight. In some embodiments, the pharmaceutical formulation comprises about 0.7 to about 5.0 mg / kg body weight, or about 1.0 to about 2.5 mg / kg body weight. A typical dosing regimen for oral administration would be to administer the oral pharmaceutical formulation three times a week, twice a week, once a week, or daily.

[0302] The effective amount or therapeutically effective amount or dose of a pharmaceutical agent (such as the compounds of the present invention) refers to the amount of the agent or compound that causes improvement in individual symptoms or prolongs survival. The toxicity and therapeutic efficacy of the molecule can be determined in cell cultures or laboratory animals using standard pharmaceutical procedures, for example, by determining the LD50 (the dose that causes 50% lethality in a population) and ED50 (the dose that is 50% therapeutically effective in a population). The dose ratio of toxicity to therapeutic effect is the therapeutic index, which can be expressed as the LD50 / ED50 ratio. Agents exhibiting a high therapeutic index are preferred.

[0303] An effective or therapeutically effective dose is the amount of a compound or pharmaceutical ingredient that will elicit a biological or medical response in a tissue, system, animal, or human that is being sought by researchers, veterinarians, physicians, or other clinicians. The dose is preferably within a cyclic concentration range including the ED50, which has minimal or no toxicity. The dose may vary within this range depending on the dosage form and / or route of administration. The precise formulation, route of administration, dose, and dosing interval should be selected according to methods known in this art, taking into account the specificities of individual circumstances.

[0304] Dosage and intervals can be individually adjusted to provide a sufficient plasma concentration of the active component to achieve the desired effect; i.e., the minimum effective concentration (MEC). The MEC will vary from compound to compound but can be estimated, for example, from in vitro data and animal studies. The dose necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective absorption, the effective local concentration of the drug may be independent of plasma concentration.

[0305] The amount of medication or composition administered may vary depending on various factors, including the individual's sex, age and weight, the severity of the illness, the method of administration, and the prescribing physician's judgment.

[0306] When needed, the compounds and compositions of the present invention can be provided using packaging or dispensing devices containing one or more unit dosage forms (containing the active ingredient). For example, the packaging or device may comprise metal or plastic foil (such as foam packaging) or glass and rubber stoppers, as in vials. The packaging or dispensing device may be accompanied by instructions for use. Compositions of the compounds of the present invention, formulated in a compatible pharmaceutical carrier, can also be prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0307] In view of the disclosure herein, these and other embodiments of the present invention will readily be apparent to those skilled in the art and are expressly covered by the present invention. [ ] Example Overall Approach

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

[0309] ¹H NMR or ¹⁹F NMR spectra were recorded on a Bruker AVⅢ 400 or Bruker AVⅢ 500.

[0310] The LCMS assay was run on an Agilent 1200 HPLC / 6100 SQ system under the following conditions:

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

[0312] [method] [B]: Mobile phase: A: Water (10 mM NH4HCO3) B: Acetonitrile; Gradient phase: Increased from 5% B to 95% B over 1.5 minutes, maintained at 95% B for 1.5 minutes (total run time: 3 minutes); Flow rate: 2.0 mL / min; Column: XBridge C18, 4.6*50 mm, 3.5 μm; Column temperature: 40 ºC. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API). Overall process for synthesizing compound (I)

[0313] Compound (I) is based on [process] [A] Prepared using commercially available materials. Halogenated pyridine (compound) [a]) reacts with the oxidant to produce a compound ( [b]) N-oxide pyridine compounds. Compound ( [b]) cyanidation provides the compound ( [c]). Compound ( [c]) cross-coupling with boric acid produced a compound ( [e]). Using benzyl alcohol to replace compounds ( [e]) halogens provide compounds ( [f]). Compounds ( [f]) nitrile hydrolysis followed by amide formation via amide ester yields amide (compound ( [i])). The removal of the protecting group from the benzyl group provides the compound of formula (I), and the subsequent saponification of the ester provides the compound ( [j]). Process A: Synthesis of compound (I) Example of Synthesis of an Indicative Compound 1: Preparation of Compound 1

[0314] 3,5-Dichloro-4-methylpyridine 1-oxide [ ]

[0315] 3-Chloroperoxybenzoic acid (8.12 g, 40.11 mmol, 85%) was added to a solution of 3,5-dichloro-4-methylpyridine (5.0 g, 30.8 mmol) in dichloromethane (70.0 mL) at 0 °C. The mixture was stirred at room temperature for 18.0 h and potassium carbonate (4.42 g, 32.0 mmol) was added. The mixture was stirred for another 1 h and the insoluble solids were filtered off. The filtrate was concentrated to give 3,5-dichloro-4-methylpyridine 1-oxide (4.7 g, 26.4 mmol, yield 85.1%) as a white solid. LC-MS: m / z = 178.1 [M+H]+, residence time 1.47 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0316] 3,5-Dichloro-4-methylcyanopyridine

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

[0318] 3-Chloro-5-(3-fluorophenyl)-4-methylcyanopyridine

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

[0320] 3-(Benzoxy)-5-(3-Fluorophenyl)-4-methylcyanopyridine

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

[0322] 3-(benzoxy)-5-(3-fluorophenyl)-4-methylpyridinecarboxylic acid

[0323] Add 5.0 mL of 30% sodium hydroxide aqueous solution to a solution of 3-(benzoxy)-5-(3-fluorophenyl)-4-methylcyanopyridine (378 mg, 1.19 mmol) in ethanol (10.0 mL). Stir the mixture at 100 °C for 5.0 h, cool, and concentrate to remove ethanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. Filter and dry the precipitate to give 3-(benzoxy)-5-(3-fluorophenyl)-4-methylpyridinecarboxylic acid (340 mg, 1.01 mmol, 85% yield) as a white solid. LC-MS: m / z = 338.1 [M+H]+, residence time 2.00 min (Method A). The product was of sufficient purity and used directly in the next step.

[0324] Ethyl (3-(benzooxy)-5-(3-fluorophenyl)-4-methylpyridinyl)glycine

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

[0326] Ethyl (5-(3-fluorophenyl)-3-hydroxy-4-methylpyridinyl)glycine

[0327] A mixture of ethyl (3-(benzoxy)-5-(3-fluorophenyl)-4-methylpyridinyl)glycine (200 mg, 0.47 mmol) and 10% palladium on carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under hydrogen atmosphere for 18.0 h. The insoluble solids were filtered off and the filtrate was concentrated to give ethyl (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinyl)glycine (150 mg, 0.45 mmol, 95% yield) as a yellow solid. LC-MS: m / z = 333.1 [M+H]+, residence time 2.19 min (Method A). The product was of sufficient purity and was used directly in the next step.

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

[0329] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinyl)glycine (150 mg, 0.45 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give a white solid of (5-(3-fluorophenyl)-3-hydroxy-4-methylpyridinyl)glycine (24.0 mg, 0.06 mmol, yield 13%). LC-MS: m / z = 305.1 [M+H]+, residence time 4.37 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 9.38 (t, J = 5.9 Hz, 1H), 8.06 (s, 1H), 7.57 (dd, J = 14.1, 7.8 Hz, 1H), 7.42 – 7.16 (m, 3H), 4.01 (d, J = 6.1 Hz, 2H), 2.16 (s, 3H). Example 2: Preparation of Compound 2

[0330] 3-Chloro-5-(3-methoxyphenyl)-4-methylcyanopyridine

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

[0332] 3-(Benzoxy)-5-(3-Methoxyphenyl)-4-methylcyanopyridine

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

[0334] 3-(benzoxy)-5-(3-methoxyphenyl)-4-methylpyridinecarboxylic acid

[0335] Add 5.0 mL of 30% sodium hydroxide aqueous solution to a solution of 3-(benzoxy)-5-(3-methoxyphenyl)-4-methylcyanopyridine (350 mg, 1.06 mmol) in ethanol (10.0 mL). Stir the mixture at 100 °C for 3.0 h, cool, and concentrate to remove ethanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. Filter and dry the precipitate to give 3-(benzoxy)-5-(3-methoxyphenyl)-4-methylpyridinecarboxylic acid (350 mg, 1.0 mmol, yield 94.61%) as a white solid. LC-MS: m / z = 350.0 [M+H]+, residence time 1.38 min (Method B). The product was of sufficient purity and used directly in the next step.

[0336] (3-(benzooxy)-5-(3-methoxyphenyl)-4-methylpyridinyl)glycine ethyl ester

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

[0338] Ethyl (3-hydroxy-5-(3-methoxyphenyl)-4-methylpyridinyl)glycine

[0339] A mixture of ethyl (3-(benzoxy)-5-(3-methoxyphenyl)-4-methylpyridinyl)glycine (180 mg, 0.42 mmol) and 10% palladium on carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred overnight under hydrogen atmosphere. The insoluble solids were filtered off, and the filtrate was concentrated to give ethyl (3-hydroxy-5-(3-methoxyphenyl)-4-methylpyridinyl)glycine (180 mg, crude) as a yellow solid. LC-MS: m / z = 345.0 [M+H]+, residence time 1.88 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0340] (3-hydroxy-5-(3-methoxyphenyl)-4-methylpyridinyl)glycine

[0341] Sodium hydroxide (160 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-5-(3-methoxyphenyl)-4-methylpyridinyl)glycine (160 mg, 0.47 mmol) in tetrahydrofuran / water (10.0 mL / 4.0 mL). The mixture was stirred at 40 °C for 12.0 h and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give a white solid of (3-hydroxy-5-(3-methoxyphenyl)-4-methylpyridinyl)glycine (62 mg, 0.20 mmol, yield 42%). LC-MS: m / z = 317.0 [M+H]+, residence time 4.40 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 9.37 (t, J = 6.0 Hz, 1H), 8.05 (s, 1H), 7.44 (dd, J = 10.1, 6.1 Hz, 1H), 7.03 (dt, J = 7.4, 3.8 Hz, 1H), 6.99 (dd, J = 3.7, 1.9 Hz, 2H), 4.02 (t, J = 7.9 Hz, 2H), 3.82 (s, 3H), 2.17 (s, 3H). Example 3: Preparation of Compound 3

[0342] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoquinoline

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

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

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

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

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

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

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

[0350] Ethyl (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpyridinyl)glycine

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

[0352] (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpyridinyl)glycine

[0353] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpyridinyl)glycine (140 mg, 0.38 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to give a white solid of (3-hydroxy-5-(isoquinoline-6-yl)-4-methylpyridinyl)glycine (72.6 mg, 0.22 mmol, 56% yield). LC-MS: m / z = 338.1 [M+H]+, residence time 2.28 min (Method A). 1HNMR (500 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.71 (s, 1H), 9.45 (t, J = 6.0 Hz, 1H), 8.68 (d, J = 6.1 Hz, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.27 (s, 1H), 8.24 (d, J = 6.1 Hz, 1H), 8.19 (s, 1H), 7.95 (dd, J = 8.5, 1.4 Hz, 1H), 4.04 (d, J = 6.1 Hz, 2H), 2.20 (s, 3H). Example 4: Preparation of Compound 4

[0354] 3-Chloro-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)cyanopyridine

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

[0356] 3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)cyanopyridine

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

[0358] 3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinecarboxylic acid

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

[0360] (3-(benzooxy)-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinyl)glycine ethyl ester

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

[0362] Ethyl (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)pyridinyl)glycine

[0363] A mixture of ethyl (3-(benzoxy)-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)pyridinemethyl)glycine (200 mg, 0.42 mmol) and 10% palladium on carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under hydrogen atmosphere for 18 hours. The insoluble solids were filtered off, and the filtrate was concentrated to give ethyl (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazole-4-yl)pyridinemethyl)glycine (150 mg, 0.39 mmol, 94% yield) as a white solid. LC-MS: m / z = 381.0 [M+H]+, residence time 2.16 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0364] (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinyl)glycine

[0365] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinecarboxylic)glycine (150 mg, 0.39 mmol) in tetrahydrofuran / water (6.0 mL / 3.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give a white solid of (3-hydroxy-4-methyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinecarboxylic)glycine (121.6 mg, 0.35 mmol, yield 88.5%). LC-MS: m / z = 353.1 [M+H]+, residence time 4.534 min (Method A). 1HNMR (500 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.32 (t, J = 6.1 Hz, 1H), 8.94 (s, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 7.94 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 4.01 (d, J = 6.1 Hz, 2H), 2.38 (s, 3H). Example 5: Preparation of Compound 5

[0366] 2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)quinoline

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

[0368] 3-Chloro-4-methyl-5-(2-methylquinolin-6-yl)cyanopyridine

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

[0370] 3-((4-methoxybenzyl)oxy)-4-methyl-5-(2-methylquinolin-6-yl)cyanopyridine

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

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

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

[0374] (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)pyridinyl)glycine ethyl ester

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

[0376] (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)pyridinyl)glycine

[0377] Lithium hydroxide monohydrate (140 mg, 3.3 mmol) was added to a solution of ethyl (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)pyridinyl)glycine (120 mg, 0.33 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to give a white solid of (3-hydroxy-4-methyl-5-(2-methylquinoline-6-yl)pyridinyl)glycine (5.9 mg, 0.017 mmol, 5.09%). LC-MS: m / z = 352.1 [M+H]+, residence time 2.05 min (Method B). 1HNMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 3.72 (d, J = 4.3 Hz, 2H), 2.70 (s, 3H), 2.20 (s, 3H). Example 6: Preparation of Compound 6

[0378] 4-(4-(5-chloro-6-cyano-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0379] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (110 mg, 0.15 mmol) was added to a solution of 3,5-dichloro-4-methylpyridin-2-carboxylonitrile (561 mg, 3.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (1.13 mmol, 3.0 mmol), and potassium carbonate (497 mg, 3.6 mmol). The mixture was stirred at 50 °C under nitrogen for 16.0 h and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with concentrated brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid, 4-(4-(5-chloro-6-cyano-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (400 mg, 1.0 mmol, yield 33%). LC-MS: m / z = 346.2 [M-56]+, residence time 2.078 min (Method A).

[0380] 4-(4-(5-(benzyloxy)-6-cyano-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0381] Sodium hydride (72 mg, 1.79 mmol, in 60% w / w suspension in mineral oil) was added to a solution of 4-(4-(5-chloro-6-cyano-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (600 mg, 1.49 mmol) in N,N-dimethylformamide (10.0 mL). The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (194 mg, 1.79 mmol). The solution was stirred at 0 °C for 1.0 h and diluted with ethyl acetate and water. The organic layer was washed with concentrated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a yellow solid, tert-butyl 4-(4-(5-(benzoxy)-6-cyano-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid (330 mg, 0.70 mmol, yield 46%). LC-MS: m / z = 474.0 [M+H]+, retention time 2.21 min (Method A).

[0382] 3-(benzyloxy)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-methylpyridinecarboxylic acid

[0383] A 30% aqueous sodium hydroxide solution (5.0 mL) was added to a solution of terbutyl 4-(4-(5-(benzoxy)-6-cyano-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid (330 mg, 0.70 mmol) in ethanol (15.0 mL). The mixture was stirred at 100 °C for 1.0 h, cooled, and concentrated to remove ethanol. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-5-(1-(1-(terbutoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-methylpyridinic acid (330 mg, 0.33 mmol, 96% yield) as a white solid. LC-MS: m / z = 493.2 [M+H]+, residence time 1.97 min (Method A). The product purity is sufficient and can be used directly in the next step.

[0384] 4-(4-(5-(benzyloxy)-6-((2-ethoxy-2-yloxyethyl)aminomethoxy)-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0385] A mixture of 3-(benzoxy)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-methylpyridinecarboxylic acid (165 mg, 0.33 mmol), glycine ethyl hydrochloride (47 mg, 0.33 mmol), benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (192 mg, 0.37 mmol), and triethylamine (167 mg, 1.67 mmol) in dichloromethane (10.0 mL) was stirred overnight at room temperature. The reaction was terminated with water and extracted with dichloromethane. The organic layer was separated, washed with concentrated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl 4-(4-(5-(benzoxy)-6-((2-ethoxy-2-thoxyethyl)aminomethoxy)-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid (165 mg, 0.29 mmol, yield 85%) as a white solid. LC-MS: m / z = 578.0 [M+H]+, retention time 2.14 min (Method A).

[0386] 4-(4-(6-((2-ethoxy-2-sideoxyethyl)aminomethoxy)-5-hydroxy-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0387] A mixture of 4-(4-(5-(benzoxy)-6-((2-ethoxy-2-sideoxyethyl)aminomethoxy)-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tributyl ester (165 mg, 0.29 mmol) and 10% palladium on carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under hydrogen atmosphere for 18.0 hours. The insoluble solids were filtered off and the filtrate was concentrated to give 4-(4-(6-((2-ethoxy-2-sideoxyethyl)aminomethoxy)-5-hydroxy-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tributyl ester (135 mg, 0.27 mmol, yield 97%) as a yellow solid. LC-MS: m / z = 460.1 [M+H]+, residence time 2.19 min (Method A). The product purity was sufficient and it could be used directly in the next step.

[0388] (5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpyridinyl)glycine

[0389] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of 4-(4-(6-((2-ethoxy-2-t-oxyethyl)aminomethyl)-5-hydroxy-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid (135 mg, 0.27 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give a white solid of (5-(1-(1-(terbutoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpyridinyl)glycine.

[0390] (85.5 mg, 0.18 mmol, yield 67%). LC-MS: m / z = 502.1 [M+H]+, residence time 5.33 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.62 – 9.10 (m, 1H), 8.28 (s, 1H), 8.23 ​​(s, 1H), 7.88 (s, 1H), 4.56 – 4.30 (m, 1H), 4.15 – 4.03 (m, 2H), 4.00 (d, J = 6.1 Hz, 2H), 2.93 (br s, 2H), 2.29 (d, J = 8.5 Hz, 3H), 2.14 – 2.00 (m, 2H), 1.92 – 1.77 (m, 2H), 1.43 (s, 9H). Example 7: Preparation of Compound 7

[0391] 2-Phenylacetyl-5-(tributyltinyl)thiazole

[0392] N-Butyllithium (30.98 mL, 77.54 mmol, 2.5 M in hexane) was added to a solution of 2-phenylthiazole (10.0 g, 62.03 mmol) in anhydrous tetrahydrofuran (200.0 mL) at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 30 min, followed by the addition of tributyltin chloride (20.8 mL, 71.34 mmol). The mixture was heated to 0°C and stirred for another 1 h. The reaction was terminated with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with concentrated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 2-phenyl-5-(tributyltinalkyl)thiazole (27.7 g, 61.6 mmol, 99% yield) as a yellow solid. LC-MS: m / z = 451.2 [M+H]+, residence time 2.30 minutes (Method A).

[0393] 3-Chloro-4-methyl-5-(2-phenylthiazo-5-yl)cyanopyridine

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

[0395] 3-Hydroxy-4-methyl-5-(2-phenylthiazolyl-5-yl)cyanopyridine

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

[0397] 3-Hydroxy-4-methyl-5-(2-phenylthiazolyl-5-yl)pyridinecarboxylic acid

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

[0399] (3-hydroxy-4-methyl-5-(2-phenylthiazolyl-5-yl)pyridinyl)glycine ethyl ester

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

[0401] (3-hydroxy-4-methyl-5-(2-phenylthiazolyl-5-yl)pyridinyl)glycine

[0402] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-4-methyl-5-(2-phenylthiazol-5-yl)pyridinyl)glycine (140 mg, 0.35 mmol) in tetrahydrofuran / water (8.0 mL / 4.0 mL). The mixture was stirred overnight at 40 °C and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give a white solid of (3-hydroxy-4-methyl-5-(2-phenylthiazol-5-yl)pyridinyl)glycine (106.6 mg, 82% yield). LC-MS: m / z = 370.0 [M+H]+, residence time 4.92 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 9.41 (t, J = 6.1 Hz, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 8.12 – 7.87 (m, 2H), 7.78 – 7.38 (m, 3H), 4.02 (d, J = 6.1 Hz, 2H), 2.38 (s, 3H). Example 8: Preparation of Compound 8

[0403] 4,4,5,5-Tetramethyl-2-(3-phenoxyphenyl)-1,3,2-dioxane

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

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

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

[0407] 3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)cyanopyridine

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

[0409] 3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)pyridinecarboxylic acid

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

[0411] (3-(benzooxy)-4-methyl-5-(3-phenoxyphenyl)pyridinyl)glycine ethyl ester

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

[0413] Ethyl (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)pyridinemethyl)glycine

[0414] A mixture of ethyl (3-(benzoxy)-4-methyl-5-(3-phenoxyphenyl)pyridinemethyl)glycine (210 mg, 0.42 mmol) and 10% palladium on carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred at 40 °C under hydrogen atmosphere for 5.0 h. The insoluble solids were filtered off and the filtrate was concentrated to give ethyl (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)pyridinemethyl)glycine (140 mg, 0.34 mmol, yield 81%) as a yellow solid. LC-MS: m / z = 407.0 (M+H)+, residence time 2.32 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0415] (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)pyridinyl)glycine

[0416] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)pyridinyl)glycine (140 mg, 0.34 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to give a white solid of (3-hydroxy-4-methyl-5-(3-phenoxyphenyl)pyridinyl)glycine (38.7 mg, 0.10 mmol, 30% yield). LC-MS: m / z = 379.0 [M+H]+, residence time 5.76 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 9.46 – 9.14 (m, 1H), 8.05 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.47 – 7.38 (m, 2H), 7.25 – 7.14 (m, 2H), 7.13 – 7.04 (m, 4H), 3.96 (d, J = 6.0 Hz, 2H), 2.16 (s, 3H). Example 9: Preparation of Compound 9

[0417] 5-Chloro-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxynitrile

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

[0419] 5-(benzoxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carboxynitrile

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

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

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

[0423] Ethyl (5-(benzooxy)-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine

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

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

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

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

[0428] Lithium hydroxide monohydrate (219 mg, 5.22 mmol) was added to a solution of ethyl (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine (200.00 mg, 0.52 mmol) in methanol / water (10.0 mL / 2.0 mL). The mixture was stirred overnight at 40 °C and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to give a yellow solid of (5-hydroxy-4-methyl-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-carbonyl)glycine (formate) (48.2 mg, 0.14 mmol, 26% yield). LC-MS: m / z = 356 [M+H]+, residence time = 4.420 min (Method A). 1H NMR (500 MHz, DMSO-d6) δ 12.88 (br, 2H), 9.43 (t, J = 6.0 Hz, 1H), 8.90 (d, J = 1.5 Hz, 1H), 8.24 (dd, J = 8.5 Hz, J = 2.0 Hz, 1H), 8.16 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 4.01 (d, J = 6.0 Hz, 2H), 2.18 (s, 3H). Example 10: Preparation of Compound 10

[0429] 5-Chloro-4-methyl-[3,3'-bipyridine]-6-carboxynitrile

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

[0431] 5-(benzoxy)-4-methyl-[3,3'-bipyridine]-6-carboxynitrile

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

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

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

[0435] Ethyl (5-(benzooxy)-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine

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

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

[0438] A mixture of ethyl (5-(benzoxy)-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine (240 mg, 0.59 mmol) and 10% palladium on carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred at room temperature under hydrogen atmosphere for 18.0 h. The insoluble solids were filtered off and the filtrate was concentrated to give ethyl (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine (185 mg, 0.59 mmol, 99% yield) as a white solid. LC-MS: m / z = 316.1 [M+H]+, residence time 2.19 min (Method A). The product was of sufficient purity and was used directly in the next step.

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

[0440] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine (185 mg, 0.59 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to give a white solid of (5-hydroxy-4-methyl-[3,3'-bipyridine]-6-carbonyl)glycine (formate) (34.0 mg, 0.118 mmol, 20% yield). LC-MS: m / z = 288.1 [M+H]+, residence time 2.20 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 2H), 9.41 (t, J = 6.1 Hz, 1H), 8.84 – 8.50 (m, 2H), 8.13 (s, 1H), 8.10 (s, 1H), 8.04 – 7.81 (m, 1H), 7.73 – 7.41 (m, 1H), 4.01 (d, J = 6.1 Hz, 2H), 2.17 (s, 3H). Example 11: Preparation of Compound 11

[0441] 5-Chloro-4-methyl-[3,4'-bipyridine]-6-carboxynitrile

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

[0443] 5-(benzoxy)-4-methyl-[3,4'-bipyridine]-6-carboxynitrile

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

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

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

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

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

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

[0450] Lithium hydroxide monohydrate (22.79 mg, 0.95 mmol) was added to a solution of ethyl (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycine (30.00 mg, 0.10 mmol) in methanol / water (4.0 mL / 1.0 mL). The mixture was stirred at 40 °C for 16.0 h and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give (5-hydroxy-4-methyl-[3,4'-bipyridine]-6-carbonyl)glycine (13.2 mg, 46% yield) as a white solid. LC-MS: m / z = 288 [M+H]+, residence time = 2.159 min (Method A). 1H NMR (500 MHz, DMSO-d6) δ 12.85 (br, 2H), 9.42 (s, 1H), 8.72 (dd, J = 4.5 Hz, J = 1.5 Hz, 2H), 8.08 (s, 1H), 7.51 (dd, J = 4.0 Hz, J = 1.5 Hz, 2H), 4.01 (d, J = 6.0 Hz, 2H), 2.17 (s, 3H). Example 12: Preparation of Compound 12

[0451] 5'-Chloro-4'-methyl-[2,3'-bipyridine]-6'-carboxynitrile [ ]

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

[0453] 5'-(benzoxy)-4'-methyl-[2,3'-bipyridine]-6'-carboxynitrile

[0454] Sodium hydride (33 mg, 0.84 mmol, 60% w / w suspension in mineral oil) was added to a solution of 5'-chloro-4'-methyl-[2,3'-bipyridine]-6'-carboxynitrile (160.0 mg, 0.70 mmol) in N,N-dimethylformamide (5.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (90 mg, 0.84 mmol). The solution was stirred at 0 °C for 1.0 h and diluted with ethyl acetate and water. The organic layer was washed with concentrated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 1 / 2) to give 5'-(benzoxy)-4'-methyl-[2,3'-bipyridine]-6'-carboxynitrile (120 mg, 0.40 mmol, 57% yield) as a yellow solid. LC-MS: m / z = 302.1 [M+H]+, residence time 2.21 minutes (Method A).

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

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

[0457] (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)ethyl glycine

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

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

[0460] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycine (50 mg, 0.16 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to give (5'-hydroxy-4'-methyl-[2,3'-bipyridine]-6'-carbonyl)glycine (9.6 mg, 21% yield) as a white solid. LC-MS: m / z = 288.0 [M+H]+, residence time 2.54 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.82 (s, 2H), 9.42 (t, J = 6.0 Hz, 1H), 8.76 (d, J = 4.3 Hz, 1H), 8.21 (s, 1H), 7.99 (td, J = 7.8, 1.7 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.50 (dd, J = 6.8, 4.9 Hz, 1H), 4.02 (d, J = 6.2 Hz, 2H), 2.24 (s, 3H). Example 13: Preparation of Compound 13

[0461] 3-Chloro-5-(3-Chlorophenyl)-4-methylcyanopyridine

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

[0463] 3-(Benzoxy)-5-(3-Chlorophenyl)-4-methylcyanopyridine

[0464] Sodium hydride (584 mg, 14.60 mmol, 60% w / w suspension in mineral oil) was added to a solution of 3-chloro-5-(3-chlorophenyl)-4-methylcyanopyridine (3.2 g, 12.16 mmol) in N,N-dimethylmethoxymethylamine (40.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min, followed by the addition of benzyl alcohol (1.58 g, 14.60 mmol). The solution was stirred at 0 °C for 1.0 h and diluted with ethyl acetate and water. The organic layer was washed with concentrated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-(benzoxy)-5-(3-chlorophenyl)-4-methylcyanopyridine (3.2 g, 9.56 mmol, 80% yield) as a yellow solid. LC-MS: m / z = 335.1 [M+H]+, residence time 2.21 minutes (Method A).

[0465] 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpyridinecarboxylic acid

[0466] A 30% sodium hydroxide aqueous solution (20.0 mL) was added to a solution of 3-(benzoxy)-5-(3-chlorophenyl)-4-methylcyanopyridine (3.2 g, 9.56 mmol) in ethanol (60.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpyridinecarboxylic acid (2.1 g, 5.96 mmol, yield 64%) as a white solid. LC-MS: m / z = 354.1 [M+H]+, residence time 2.00 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0467] 2-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpyridininamido)-2-methylpropionate methyl ester

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

[0469] Methyl 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridininamido)-2-methylpropionate

[0470] A mixture of methyl 2-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpyridinamide)-2-methylpropionate (500 mg, 1.10 mmol) and 10% palladium on carbon (50.0 mg) in tetrahydrofuran (10.0 mL) was stirred under hydrogen atmosphere for 18.0 h. The insoluble solids were filtered off and the filtrate was concentrated to give methyl 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinamide)-2-methylpropionate (240 mg, 0.66 mmol, 60% yield) as a white solid. LC-MS: m / z = 363.1 [M+H]+, residence time 2.19 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0471] 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridininamido)-2-methylpropionic acid

[0472] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of methyl 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinamide)-2-methylpropionic acid (240 mg, 0.66 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give 2-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinamide)-2-methylpropionic acid (176.3 mg, 0.51 mmol, 77% yield) as a white solid. LC-MS: m / z = 349.0 [M+H]+, residence time 5.36 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.93 (br s, 1H), 12.70 (s, 1H), 9.07 (s, 1H), 8.04 (s, 1H), 7.67 – 7.45 (m, 3H), 7.47 – 7.18 (m, 1H), 2.14 (s, 3H), 1.59 (s, 6H). Example 14: Preparation of Compound 14

[0473] 1-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpyridinylamino)cyclopropane-1-carboxylic acid ethyl ester

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

[0475] ethyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinylamino)cyclopropane-1-carboxylate

[0476] A mixture of ethyl 1-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpyridinamide)cyclopropane-1-carboxylate (500 mg, 1.08 mmol) and 10% palladium on carbon (50.0 mg) in tetrahydrofuran (10.0 mL) was stirred under hydrogen atmosphere for 18.0 h. The insoluble solids were filtered off and the filtrate was concentrated to give ethyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinamide)cyclopropane-1-carboxylate (250 mg, 0.67 mmol, yield 62%) as a white solid. LC-MS: m / z = 375.1 [M+H]+, residence time 2.19 min (Method A). The product was of sufficient purity and was used directly in the next step.

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

[0478] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinylamino)cyclopropane-1-carboxylic acid (250 mg, 0.67 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinylamino)cyclopropane-1-carboxylic acid (133.0 mg, 0.38 mmol, 58% yield) as a white solid. LC-MS: m / z = 347.0 [M+H]+, residence time 4.93 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 12.57 (s, 1H), 9.71 (s, 1H), 8.02 (s, 1H), 7.67 – 7.46 (m, 3H), 7.45 – 7.36 (m, 1H), 2.14 (s, 3H), 1.44 (dd, J = 7.8, 4.6 Hz, 2H), 1.25 (dd, J = 7.9, 4.6 Hz, 2H). Example 15: Preparation of Compound 15

[0479] methyl 1-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpyridinylamino)cyclobutane-1-carboxylate

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

[0481] methyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinylamino)cyclobutane-1-carboxylate

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

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

[0484] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of methyl 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinylamino)cyclobutane-1-carboxylic acid (250 mg, 0.67 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give 1-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinylamino)cyclobutane-1-carboxylic acid (93.0 mg, 0.26 mmol, 39% yield) as a white solid. LC-MS: m / z = 361.0 [M+H]+, residence time 5.37 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ δ 12.80 (s, 1H), 12.69 (br s, 1H), 9.63 (s, 1H), 8.05 (s, 1H), 7.75 – 7.44 (m, 3H), 7.49 – 7.26 (m, 1H), 2.76 – 2.38 (m, 6H), 2.14 (s, 3H), 2.03 – 1.85 (m, 2H). Example 16: Preparation of Compound 16

[0485] methyl 3-(3-(benzoxy)-5-(3-chlorophenyl)-4-methylpyridinylamino)oxetane-3-carboxylate

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

[0487] methyl 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinylamino)oxetane-3-carboxylate

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

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

[0490] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of methyl 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinylamino)oxetane-3-carboxylic acid (300 mg, 0.80 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give 3-(5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinylamino)oxetane-3-carboxylic acid (71.4 mg, 0.20 mmol, 25% yield) as a white solid. LC-MS: m / z = 363.0 [M+H]+, residence time 4.85 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.18 (s, 1H), 8.08 (s, 1H), 7.58 – 7.53 (m, 3H), 7.45 – 7.37 (m, 1H), 4.94 – 4.80 (m, 4H), 2.14 (s, 3H). Example 17: Preparation of Compound 17

[0491] 3-(benzoxy)-4-methyl-5-(2-methylquinolin-6-yl)cyanopyridine [ ]

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

[0493] 3-(benzoxy)-4-methyl-5-(2-methylquinoline-6-yl)pyridinecarboxylic acid

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

[0495] (3-(benzooxy)-4-methyl-5-(2-methylquinoline-6-yl)pyridinyl)glycine ethyl ester

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

[0497] Ethyl (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)pyridinyl)glycine

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

[0499] (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)pyridinyl)glycine

[0500] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)pyridinyl)glycine (100 mg, 0.26 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to give a white solid of (3-hydroxy-4-methyl-5-(2-methyl-1,2,3,4-tetrahydroquinoline-6-yl)pyridinyl)glycine (formate) (17.9 mg, 0.05 mmol, 19.39%). LC-MS: m / z = 356.1 [M+H]+, residence time 3.91 minutes (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 9.17 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 6.94 (d, J = 6.3 Hz, 2H), 6.56 (d, J = 8.7 Hz, 1H), 5.93 (br s, 1H), 3.95 (d, J = 5.5 Hz, 2H), 2.82 – 2.60 (m, 3H), 2.58 – 2.53 (m, 1H), 2.18 (s, 3H), 1.93 – 1.81 (m, 1H), 1.56 – 1.37 (m, 1H), 1.17 (d, J = 6.1 Hz, 3H). Example 18: Preparation of Compound 18

[0501] 2-(4-bromo-1H-pyrazol-1-yl)pyridine

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

[0503] 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazol-1-yl)pyridine

[0504] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (391.88 mg, 0.54 mmol) was added to a solution of 2-(4-bromo-1H-pyrazol-1-yl)pyridine (1.2 g, 5.36 mmol), bis(pinacolyl)diboron (6.8 g, 26.78 mmol), and potassium acetate (2.63 g, 26.78 mmol) in 1,4-dioxane (15.0 mL). The mixture was stirred at 90 °C under nitrogen for 16.0 h and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with concentrated brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-pyrazol-1-yl)pyridine (1.38 g, 5.09 mmol, 95% yield). LC-MS: m / z = 272 [M+H]+, retention time 2,000 min (Method B).

[0505] 3-Chloro-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)cyanopyridine

[0506] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (134.9 mg, 0.18 mmol) was added to a solution of 3,5-dichloro-4-methylcyanopyridine (862.2 mg, 4.61 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazol-1-yl)pyridine (1.25 g, 4.61 mmol), and potassium carbonate (764.6 mg, 5.53 mmol). The mixture was stirred at 45 °C under nitrogen for 16.0 h and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with concentrated brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by rapid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 3-chloro-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)cyanopyridine (342 mg, 1.16 mmol, yield 25%). LC-MS: m / z = 296 [M+H]+, retention time 2.090 min (Method A).

[0507] 3-(benzoxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)cyanopyridine

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

[0509] 3-(benzoxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridinecarboxylic acid

[0510] A 30% aqueous sodium hydroxide solution (1.0 mL) was added to a solution of 3-(benzoxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)cyanopyridine (70.0 mg, 0.19 mmol) in ethanol (3.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove ethanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridinecarboxylic acid (72 mg, crude) as a white solid. LC-MS: m / z = 387 [M+H]+, residence time 1.290 min (Method B). The product was of sufficient purity and was used directly in the next step.

[0511] (3-(benzooxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridinyl)ethyl glycine

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

[0513] (3-hydroxy-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridinyl)ethyl glycine

[0514] A mixture of ethyl (3-(benzoxy)-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridinyl)glycine (60.0 mg, 0.13 mmol) and 10% palladium on carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under hydrogen atmosphere for 5.0 h. The insoluble solids were filtered off and the filtrate was concentrated to give ethyl (3-hydroxy-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridinyl)glycine (50 mg, crude) as a white solid. LC-MS: m / z = 382 [M+H]+, residence time 2.127 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0515] (3-hydroxy-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridinyl)glycine [ ]

[0516] Lithium hydroxide monohydrate (55.0 mg, 1.31 mmol) was added to a solution of ethyl (3-hydroxy-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridinyl)glycine (50.0 mg, 0.13 mmol) in tetrahydrofuran / water (10.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to give a white solid of (3-hydroxy-4-methyl-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridinyl)glycine (formate) (28.5 mg, 0.08 mmol, 62% yield). LC-MS: m / z = 354 [M+H]+, residence time = 4.255 minutes (Method A). 1H NMR (500 MHz, DMSO-d6) δ 12.84 (br, 1H), 9.27 (br, 1H), 9.01 (s, 1H), 8.53 (d, J = 4.0 Hz, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 8.08–8.00 (m, 2H), 7.44–7.41 (m, 1H), 3.97 (d, J = 6.0 Hz, 2H), 2.37 (s, 3H). Example 19: Preparation of Compound 19

[0517] 4-Bromo-1-(4-Fluorophenyl)-1H-pyrazole

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

[0519] 1-(4-Fluorophenyl)-4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole

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

[0521] 3-Chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylcyanopyridine

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

[0523] 3-(benzyloxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylcyanopyridine

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

[0525] 3-(benzoxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpyridinecarboxylic acid

[0526] A 30% aqueous sodium hydroxide solution (1.0 mL) was added to a solution of 3-(benzoxy)-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylcyanopyridine (35 mg, 0.09 mmol) in ethanol (3.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)-4-methylpyridinecarboxylic acid (32 mg, crude) as a white solid. LC-MS: m / z = 404.1 [M+H]+, residence time 2.014 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0527] Ethyl (3-(benzooxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpyridinyl)glycine

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

[0529] (5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpyridinyl)ethyl glycine

[0530] A mixture of ethyl (3-(benzoxy)-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpyridinyl)glycine (40 mg, 0.08 mmol) and 10% palladium on carbon (10.0 mg) in tetrahydrofuran (5.0 mL) was stirred overnight under hydrogen atmosphere. The insoluble solids were filtered off, and the filtrate was concentrated to give ethyl (5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpyridinyl)glycine (30 mg, 0.08 mmol, 100% yield) as a yellow solid. LC-MS: m / z = 399.0 [M+H]+, residence time 2.15 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0531] (5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpyridinyl)glycine [ ]

[0532] Lithium hydroxide monohydrate (42 mg, 1.0 mmol) was added to a solution of ethyl (5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpyridinyl)glycine (30 mg, 0.08 mmol) in tetrahydrofuran / water (5.0 mL / 1.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give a white solid of (5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-hydroxy-4-methylpyridinyl)glycine (20.1 mg, 0.05 mmol, yield 67.9%). LC-MS: m / z = 371.0 [M+H]+, residence time 4.641 min (Method A). 1H NMR (500 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.21 (s, 1H), 8.91 (s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.07 – 7.84 (m, 2H), 7.53 – 7.28 (m, 2H), 3.92 (d, J = 5.7 Hz, 2H), 2.37 (s, 3H). Example 20: Preparation of Compound 20

[0533] 4-Bromo-1-isopropyl-1H-pyrazole

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

[0535] 1-Isopropyl-4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole

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

[0537] 3-Chloro-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylcyanopyridine

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

[0539] 3-(benzyloxy)-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylcyanopyridine

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

[0541] 3-(benzoxy)-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpyridinecarboxylic acid

[0542] A 30% aqueous sodium hydroxide solution (1.0 mL) was added to a solution of 3-(benzoxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylcyanopyridine (180 mg, 0.54 mmol) in ethanol (5.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove the ethanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpyridinecarboxylic acid (100 mg, 0.28 mmol, yield 53%) as a white solid. LC-MS: m / z = 352.1 [M+H]+, residence time 2.00 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0543] (3-(benzooxy)-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpyridinyl)ethyl glycine

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

[0545] Ethyl (3-hydroxy-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpyridinyl)glycine

[0546] A mixture of ethyl (3-(benzoxy)-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpyridinyl)glycine (100 mg, 0.18 mmol) and 10% palladium on carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under hydrogen atmosphere for 18 hours. The insoluble solids were filtered off, and the filtrate was concentrated to give ethyl (3-hydroxy-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpyridinyl)glycine (80 mg, crude) as a yellow solid. LC-MS: m / z = 347.1 [M+H]+, residence time 2.19 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0547] (3-hydroxy-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpyridinyl)glycine

[0548] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpyridinyl)glycine (80 mg, crude) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give a white solid of (3-hydroxy-5-(1-isopropyl-1H-pyrazole-4-yl)-4-methylpyridinyl)glycine (45.7 mg, 62% yield). LC-MS: m / z = 319.1 [M+H]+, residence time 3.81 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ δ 12.75 (s, 1H), 9.24 (t, J = 6.0 Hz, 1H), 8.23 ​​(s, 2H), 7.86 (s, 1H), 4.58 (dt, J = 13.3, 6.6 Hz, 1H), 3.99 (d, J = 6.1 Hz, 2H), 2.31 (s, 3H), 1.48 (d, J = 6.7 Hz, 6H). Example 21: Preparation of Compound 21

[0549] 4-Bromo-1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazole

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

[0551] 1-(tetrahydro-2H-piperan-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole

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

[0553] 3-Chloro-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)cyanopyridine

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

[0555] 3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)cyanopyridine

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

[0557] 3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)pyridinecarboxylic acid

[0558] A 30% aqueous sodium hydroxide solution (1.5 mL) was added to a solution of 3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)cyanopyridine (100 mg, 0.27 mmol) in ethanol (5.0 mL). The mixture was stirred at 100 °C for 5.0 h, cooled, and concentrated to remove ethanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered and dried to give 3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)pyridinecarboxylic acid (90 mg, 0.23 mmol, yield 86%) as a white solid. LC-MS: m / z = 394.1 [M+H]+, residence time 2.00 min (Method A). The product has sufficient purity and can be used directly in the next step.

[0559] (3-(benzooxy)-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)pyridinyl)ethyl glycine

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

[0561] (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)pyridinyl)ethyl glycine

[0562] A mixture of (3-(benzoxy)-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazole-4-yl)pyridinecarboxylic acid ethyl ester (90 mg, 0.19 mmol) and 10% palladium on carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under hydrogen atmosphere for 18 hours. The insoluble solids were filtered off, and the filtrate was concentrated to give a yellow solid of (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazole-4-yl)pyridinecarboxylic acid ethyl ester (70 mg, 0.18 mmol, yield 96%). LC-MS: m / z = 389.1 [M+H]+, residence time 2.19 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0563] (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)pyridinyl)glycine

[0564] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazole-4-yl)pyridinecarboxylic acid (70 mg, 0.18 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and purified by reverse-phase preparative HPLC to give a white solid of (3-hydroxy-4-methyl-5-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazole-4-yl)pyridinecarboxylic acid (10.8 mg, 0.03 mmol, 17% yield). LC-MS: m / z = 361.1 [M+H]+, residence time 3.45 min (Method A). ¹H NMR (500 MHz, DMSO-d6) δ 12.76 (s, 2H), 9.25 (t, J = 6.0 Hz, 1H), 8.28 (s, 1H), 8.23 ​​(s, 1H), 7.89 (s, 1H), 4.69 – 4.32 (m, 1H), 3.98 (d, J = 6.2 Hz, 4H), 3.58 – 3.43 (m, 3H), 2.31 (s, 3H), 2.07 – 1.93 (m, 4H). Example 22: Preparation of Compound 22

[0565] 4-Bromo-1-isobutyl-1H-pyrazole

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

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

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

[0569] 3-Chloro-5-(1-isobutyl-1H-pyrazol-4-yl)-4-methylcyanopyridine

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

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

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

[0573] 3-(benzyloxy)-5-(1-isobutyl-1H-pyrazol-4-yl)-4-methylpyridinecarboxylic acid

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

[0575] (3-(benzooxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpyridinyl)glycine ethyl ester

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

[0577] Ethyl (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpyridinyl)glycine

[0578] A mixture of ethyl (3-(benzoxy)-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpyridinyl)glycine (25.0 mg, 0.06 mmol) and 10% palladium on carbon (20.0 mg) in tetrahydrofuran (10.0 mL) was stirred under hydrogen atmosphere for 18.0 h. The insoluble solids were filtered off and the filtrate was concentrated to give ethyl (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpyridinyl)glycine (30.0 mg, crude) as a yellow solid. LC-MS: m / z = 361 [M+H]+, residence time 1.966 min (Method B). The product was of sufficient purity and was used directly in the next step.

[0579] (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpyridinyl)glycine [ ]

[0580] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpyridinyl)glycine (25.00 mg, 0.07 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was purified by reverse-phase preparative HPLC to give a yellow solid of (3-hydroxy-5-(1-isobutyl-1H-pyrazole-4-yl)-4-methylpyridinyl)glycine (formate) (6.4 mg, 0.02 mmol, 27% yield). LC-MS: m / z = 333 [M+H]+, residence time = 4.188 minutes (Method A). 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.27–9.25 (m, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.87 (s, 1H), 4.00 (s, 2H), 3.98 (d, J = 2.4 Hz, 2H), 2.30 (s, 3H), 2.19–2.15 (m, 1H), 0.88 (d, J = 6.8 Hz, 6H). Example 23: Preparation of Compound 23

[0581] methyl 3-heptyl-6-enoate

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

[0583] 4-(2-(benzooxy)ethyl)-3-hepta-6-enoic acid methyl ester

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

[0585] 2,2-Diazido-4-(2-(benzooxy)ethyl)-3-hepta-6-enoic acid methyl ester

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

[0587] 4-(2-(benzooxy)ethyl)-3-hydroxy-6-methylpyridinecarboxylate

[0588] A mixture of methyl 2,2-diazido-4-(2-(benzoxy)ethyl)-3-t-oxyhept-6-enoate (300.0 mg, 0.81 mmol) in toluene (5.0 mL) was stirred at 110 °C for 16.0 h. The solution was cooled and concentrated to dryness. The residue was purified by rapid chromatography (petroleum ether / ethyl acetate = 3 / 1) to give methyl 4-(2-(benzoxy)ethyl)-3-hydroxy-6-methylpyridinecarboxylate (65 mg, 0.22 mmol, yield 27%). LC-MS: m / z = 302 [M+H]+, residence time 1.991 min (Method A).

[0589] 4-(2-(benzooxy)ethyl)-3-hydroxy-6-methylpyridinecarboxylic acid

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

[0591] (4-(2-(benzooxy)ethyl)-3-hydroxy-6-methylpyridinyl)glycine ethyl ester

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

[0593] (4-(2-(benzooxy)ethyl)-3-hydroxy-6-methylpyridinyl)glycine [ ]

[0594] Lithium hydroxide monohydrate (54.2 mg, 1.29 mmol) was added to a solution of ethyl (4-(2-(benzoxy)ethyl)-3-hydroxy-6-methylpyridinyl)glycine (48.0 mg, 0.13 mmol) in methanol / water (4.0 mL / 1.0 mL). The mixture was stirred overnight and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was purified by reverse-phase preparative HPLC to give (4-(2-(benzoxy)ethyl)-3-hydroxy-6-methylpyridinyl)glycine (formate) as a red solid (29.7 mg, 0.09 mmol, 66% yield). LC-MS: m / z = 345 [M+H]+, residence time = 4.596 min (Method A). 1H NMR (500 MHz, DMSO-d6) δ 12.75 (br, 1H), 12.40 (s, 1H), 9.11 (t, J = 6.0 Hz, 1H), 7.34-7.31 (m, 3H), 7.28-7.25 (m, 3H), 4.48 (s, 2H), 3.99 (d, J = 6.0 Hz, 2H), 3.69 (t, J = 6.5 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H), 2.42 (s, 3H). Example 24: Preparation of Compound 24

[0595] 4-(4-fluorobenzyl)-3-sideoxyhept-6-enoic acid methyl ester [ ]

[0596] Freshly prepared lithium diisopropylamine (7.04 mmol, 3.52 mL, 2.0 M in n-hexane) was added to a solution of methyl 3-heptyl-3-yl-2-(t-oxy-6-enoate) (the intermediate used in Example 22) (500.0 mg, 3.20 mmol) in anhydrous tetrahydrofuran (20.0 mL). The mixture was stirred at 0 °C for 30 min and 1-(bromomethyl)-4-fluorobenzene (726.2 mg, 3.84 mmol) was added. The mixture was heated to 20 °C and stirred for 3.0 h. The reaction was terminated with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with concentrated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 4-(4-fluorobenzyl)-3-t-oxyhept-6-enoate as a yellow oil (650 mg, 2.46 mmol, yield 77%). LC-MS: m / z = 265 [M+H]+, retention time 1.934 min (Method B).

[0597] 2,2-Diazido-4-(4-fluorobenzyl)-3-sideoxyhept-6-enoic acid methyl ester

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

[0599] Methyl 4-(4-fluorobenzyl)-3-hydroxy-6-methylpyridinecarboxylate

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

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

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

[0603] Ethyl (4-(4-fluorobenzyl)-3-hydroxy-6-methylpyridinyl)glycine

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

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

[0606] Lithium hydroxide monohydrate (31.53 mg, 0.75 mmol) was added to a solution of ethyl (4-(4-fluorobenzyl)-3-hydroxy-6-methylpyridinyl)glycine (26.00 mg, 0.08 mmol) in methanol / water (4.0 mL / 1.0 mL). The mixture was stirred overnight and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was purified by reverse-phase preparative HPLC to give a white solid of (4-(4-fluorobenzyl)-3-hydroxy-6-methylpyridinyl)glycine (formate) (11.2 mg, 0.04 mmol, 47% yield). LC-MS: m / z = 319 [M+H]+, residence time = 4.616 min (Method A). 1H NMR (400 MHz, DMSO-d6) δ 12.85 (br, 1H), 12.47 (s, 1H), 9.15-9.11 (m, 1H), 7.32-7.25 (m, 3H), 7.11 (t, J = 8.8 Hz, 2H), 3.98 (d, J = 6.4 Hz, 2H), 3.93 (s, 2H), 2.41 (s, 3H). Example 25: Preparation of Compound 25

[0607] 3,5-Dibromo-2,4-dimethylpyridine 1-oxide [ ]

[0608] 3-Chloroperoxybenzoic acid (400 mg, 1.96 mmol, 85%) was added to a solution of 3,5-dibromo-2,4-dimethylpyridine (400 mg, 1.51 mmol) in dichloromethane (10.0 mL) at 0 °C. The mixture was stirred at room temperature for 18.0 h and potassium carbonate (400 mg, 3.20 mmol) was added. The mixture was stirred for another 1 h and the insoluble solids were filtered off. The filtrate was concentrated to give 3,5-dibromo-2,4-dimethylpyridine 1-oxide (400 mg, 1.43 mmol, 94% yield) as a white solid. LC-MS: m / z = 281.1 [M+H]+, residence time 1.47 min (Method A). The product was of sufficient purity and was used directly in the next step.

[0609] 3,5-Dibromo-4,6-dimethylcyanopyridine

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

[0611] 3-Bromo-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)cyanopyridine

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

[0613] 3-Hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)cyanopyridine

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

[0615] 3-Hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinecarboxylic acid

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

[0617] Ethyl (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinyl)glycine

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

[0619] (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinyl)glycine

[0620] Lithium hydroxide monohydrate (164 mg, 4.0 mmol) was added to a solution of ethyl (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinyl)glycine (20 mg, 0.05 mmol) in methanol / water (6.0 mL / 3.0 mL). The mixture was stirred overnight and concentrated to remove methanol. The resulting aqueous solution was acidified to pH 3–4 with 10% hydrochloric acid. The precipitate was filtered, washed with water, and dried to give a white solid of (3-hydroxy-4,6-dimethyl-5-(1-phenyl-1H-pyrazol-4-yl)pyridinyl)glycine (6.4 mg, 0.017 mmol, yield 36%). LC-MS: m / z = 367.0 [M+H]+, residence time 4.81 min (Method A). 1HNMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.18 (t, J = 6.0 Hz, 1H), 8.73 (s, 1H), 8.01 – 7.81 (m, 3H), 7.54 (t, J = 7.9 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 4.02 (d, J = 6.1 Hz, 2H), 2.39 (s, 3H), 2.12 (s, 3H). Example 26: Preparation of Compound 26

[0621] 3,5-Dichloro-4-methylpyridine 1-oxide [ ]

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

[0623] 3,5-Dichloro-4-methylcyanopyridine [ ]

[0624] TMS-CN (9 g, 89.88 mmol) and TEA (9.4 mL) were added to a solution of 3,5-dichloro-4-methylpyridine 1-oxide (8 g, 44.94 mmol) in MeCN (150 mL) at room temperature. The reaction mixture was refluxed overnight. After TLC analysis indicated that the reaction was complete, the reaction was terminated with brine (150 mL) and extracted with EA (150 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 (60 g), filtered, and concentrated under vacuum. The residue was purified by silicone column chromatography (PE:EtOAc = 10:1) to give 6.8 g of the title compound. ¹H-NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 2.57 (s, 3H)).

[0625] 3-Chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)cyanopyridine

[0626] Under nitrogen protection, a mixture of 3,5-dichloro-4-methylcyanopyridine (3.72 g, 20 mmol), B2Pin2 (7.62 g, 30 mmol), Pd(dppf)Cl2 (1.4 g, 2 mmol), and KOAc (5.88 g, 60 mmol) in dioxane (100 mL) was stirred overnight at 100°C. After TLC indicated that the reaction was complete, the resulting suspension was filtered. The filter cake was washed with EtOAc (200 mL), and the combined filtrates were concentrated to dryness. The resulting residue was dissolved in NaOH aqueous solution (60 mL, 1N) and stirred for half an hour. The aqueous solution was washed with EtOAc (100 mL). After separation, the organic phase was treated again with NaOH aqueous solution (30 mL, 1N). After separation, the combined aqueous phases were acidified to pH 4-5 with dilute HCl solution (2N), and a large amount of solid precipitated. The suspension was filtered to give 407 mg of the title compound. ¹H-NMR (300 MHz, CDCl₃) δ 8.68 (s, 1H), 2.61 (s, 3H), 1.34 (s, 12H).

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

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

[0629] 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)cyanopyridine

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

[0631] 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)pyridinecarboxylic acid

[0632] A 1.6 mL (30 wt%) aqueous solution of NaOH was added to a solution of 167 mg (0.45 mmol) of 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)cyanopyridine in EtOH (15 mL) at room temperature. The reaction mixture was stirred overnight at reflux. After LC-MS analysis indicated that the reaction was complete, the mixture was cooled to room temperature and acidified to pH 4–5 with dilute hydrochloric acid. A large amount of solid precipitated. The suspension was filtered to give 158 mg of the title compound. LC-MS (ESI+): m / z 387 (M+H)+.

[0633] (3-(benzooxy)-4-methyl-5-(2-phenyloxazol-5-yl)pyridinyl)glycine methyl ester [ ]

[0634] Glycine methyl hydrochloride (62 mg, 0.49 mmol), DIEA (212 mg, 1.64 mmol), and HATU (234 mg, 0.45 mmol) were added to a solution of 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)pyridinecarboxylic acid (158 mg, 0.41 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. After TLC analysis indicated that the reaction was complete, the reaction was terminated with H2O (20 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 (5 g), filtered, and concentrated under vacuum. The residue was purified by silicone column chromatography (PE / DCM = 1 / 1) to give 115 mg of the title compound. LC-MS (ESI+): m / z 458 (M+H)+; 1H-NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 8.37 (brs, 1H), 8.14-8.11 (m, 2H), 7.55-7.49 (m, 6H), 7.42-7.35 (m, 3H), 5.13 (s, 2H), 4.29 (d, J = 6 Hz, 2H), 3.81 (s, 3H), 2.44 (s, 3H).

[0635] (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)pyridinyl)glycine methyl ester [ ]

[0636] Pd / C (10 wt%, 34 mg) was added to a solution of methyl 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)pyridinylmethylglycine (167 mg, 0.45 mmol) in MeOH (6 mL) and DCM (3 mL) at room temperature. The reaction mixture was stirred for 45 min under atmospheric hydrogen pressure from a balloon. After TLC analysis indicated that the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under vacuum to give 80 mg of the title compound. 1H-NMR (300 MHz, CDCl3) δ 12.27 (s, 1H), 8.47 (s, 2H), 8.14-8.11 (m, 2H), 7.51 (d, J = 3.6 Hz, 4H), 4.27 (d, J = 6 Hz, 2H), 3.83 (s, 3H), 2.50 (s, 3H). [ ]

[0637] (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)pyridinyl)glycine [ ]

[0638] LiOH·H2O (92 mg, 2.2 mmol) was added to a solution of methyl (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)pyridinyl)glycine (80 mg, 0.22 mmol) in THF (5 mL) and H2O (2 mL) at room temperature. The reaction mixture was stirred at 50°C for 2 hours. After TLC analysis indicated that the reaction was complete, the mixture was acidified to pH 4–5 with dilute hydrochloric acid solution (1N). A large amount of solid precipitated. The suspension was filtered to give 45 mg of the title compound. HPLC purity was 99.1%; LC-MS (ESI+): m / z 354 (M+H)+; 1H-NMR (300 MHz, DMSO-d6) δ 12.95 (s, 1H), 12.85 (brs, 1H), 9.38 (t, J = 6.0 Hz, 1H), 8.61 (s, 1H), 8.15–8.12 (m, 2H), 7.95 (s, 1H), 7.64–7.58 (m, 3H), 4.03 (d, J = 6.0 Hz, 2H), 2.67 (s, 3H). Example 27: Preparation of Compound 27

[0639] 5-Chloro-4,6'-dimethyl-[3,3'-bipyridine]-6-carboxynitrile [ ]

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

[0641] 5-(benzoxy)-4,6'-dimethyl-[3,3'-bipyridine]-6-carboxynitrile

[0642] This compound was synthesized according to the preparation procedure of 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)cyanopyridine. LC-MS (ESI+): m / z 316 (M+H)+; 1H-NMR (300 MHz, CDCl3) δ 8.45 (d, J = 1.8 Hz, 1H), 8.30 (s, 1H), 7.55–7.48 (m, 3H), 7.55–7.42 (m, 3H), 7.37–7.28 (m, 1H), 5.28 (s, 2H), 2.65 (s, 3H), 2.17 (s, 3H). [ ]

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

[0644] This compound was synthesized according to the preparation procedure of 3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)pyridinecarboxylic acid. LC-MS (ESI+): m / z 335 (M+H)+; 1H-NMR (300 MHz, DMSO-d6) δ 13.45 (brs, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.28 (s, 1H), 7.81 (dd, J = 7.8, 2.1 Hz, 1H), 5.03 (s, 2H), 2.55 (s, 3H), 2.15 (s, 3H). [ ]

[0645] Methyl glycine (5-(benzooxy)-4,6'-dimethyl-[3,3'-bipyridine]-6-carbonyl) [ ]

[0646] This compound was synthesized according to the preparation procedure of methyl (3-(benzoxy)-4-methyl-5-(2-phenyloxazol-5-yl)pyridinemethyl)glycine. LC-MS (ESI+): m / z 406 (M+H)+. [ ]

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

[0648] This compound was synthesized according to the preparation procedure of methyl (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)pyridinemethyl)glycine. LC-MS (ESI+): m / z 316 (M+H)+; 1H-NMR (300 MHz, CDCl3) δ 12.16 (s, 1H), 8.49 (d, J = 1.8 Hz, 2H), 7.96 (s, 1H), 7.56 (dd, J = 8.1 Hz, 2.1 Hz, 1H), 7.29 (s, 1H), 4.26 (d, J = 5.7 Hz, 2H), 3.82 (s, 3H), 2.64 (s, 3H), 2.23 (s, 3H). [ ]

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

[0650] This compound was synthesized according to the preparation procedure of (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)pyridinecarboxylic acid). LC-MS (ESI+): m / z 302 (M+H)+; 1H-NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.38 (t, J = 6 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 7.82–7.79 (m, 1H), 7.42 (d, J = 8.1 Hz, 1H), 4.01 (d, J = 6.6 Hz, 2H), 2.55 (s, 3H), 2.16 (s, 3H). [ ] Example 28: Preparation of Compound 28

[0651] The compound was synthesized according to the preparation procedure of (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)pyridinemethyl)glycine. LC-MS (ESI+): m / z 338 (M+H)+; 1H-NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H), 12.80 (brs, 1H), 9.45 (t, J = 6.Hz, 1H), 9.00 (d, J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.23 ​​(s, 1H), 8.10 (t, J = 8.1 Hz, 2H), 7.88-7.73 (m, 1H), 7.71-7.68 (m, 1H), 4.03 (d, J = 6 Hz, 2H), 2.50 (s, 3H). Example 29: Preparation of Compound 29 [ ]

[0652] The compound was synthesized according to the preparation procedure of (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)pyridinemethyl)glycine. LC-MS (ESI+): m / z 302 (M+H)+; 1H-NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.39 (t, J = 6.5 Hz, 1H), 8.55 (dd, J = 4.9, 1.8 Hz, 1H), 7.99 (s, 1H), 7.62 (dd, J = 7.6, 1.8 Hz, 1H), 7.36 (dd, J = 7.7, 4.9 Hz, 1H), 4.00 (d, J = 6.0 Hz, 2H), 2.25 (s, 3H), 1.96 (s, 3H). [ ] Example 30: Preparation of Compound 30 [ ]

[0653] The compound was synthesized according to the preparation procedure of (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)pyridinemethyl)glycine. LC-MS (ESI+): m / z 367 (M+H)+; 1H-NMR (300 MHz, DMSO-d6) δ 12.88 (brs, 1H), 12.78 (s, 1H), 9.17 (d, J = 7.7 Hz, 1H), 8.92 (s, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 4.51 (t, J = 7.2 Hz, 1H), 2.37 (s, 3H), 1.47 (d, J = 7.2 Hz, 3H). [ ] Example 31: Preparation of Compound 31 [ ]

[0654] The compound was synthesized according to the preparation procedure of (3-hydroxy-4-methyl-5-(2-phenyloxazol-5-yl)pyridinemethyl)glycine. LC-MS (ESI+): m / z 367 (M+H)+; 1H-NMR (300 MHz, DMSO-d6) δ 12.90 (brs, 1H), 12.77 (s, 1H), 9.17 (d, J = 7.6 Hz, 1H), 8.93 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 4.51 (t, J = 7.4 Hz, 1H), 2.37 (s, 3H), 1.47 (d, J = 7.2 Hz, 3H). Example 32: Preparation of Compound 32

[0655] 3,5-Dichloro-4-methylpyridine 1-oxide [ ]

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

[0657] 3,5-Dichloro-4-methylcyanopyridine [ ]

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

[0659] 3-Chloro-5-(3-Chlorophenyl)-4-methylcyanopyridine

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

[0661] 3-(Benzoxy)-5-(3-Chlorophenyl)-4-methylcyanopyridine

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

[0663] 3-(benzoxy)-5-(3-chlorophenyl)-4-methylpyridinecarboxylic acid

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

[0665] Ethyl (3-(benzooxy)-5-(3-chlorophenyl)-4-methylpyridinyl)glycine

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

[0667] Ethyl (5-(3-chlorophenyl)-3-hydroxy-4-methylpyridinyl)glycine [ ]

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

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

[0670] A 1N NaOH aqueous solution (0.5 mL) was added to a stirred solution of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxy-4-methylpyridine-2-carbonyl]amino]acetate (132 mg, 0.378 mmol) in THF (1.5 mL) and methanol (1.5 mL). The reaction mixture was stirred at 40 °C for 1.5 h. The reaction mixture was directly concentrated to remove THF and methanol. The residue was acidified with 1N HCl aqueous solution (0.6 mL). The precipitate was filtered, washed with water, and dried in air. The crude product was purified by preparative HPLC (in water with 30-80% MeCN for 25 min). LC-MS (ESI+): m / z 321.0 (M+H)+; 1H NMR (400 MHz, DMSO) δ 12.79 (s, 2H), 9.38 (t, J = 6.1 Hz, 1H), 8.04 (d, J = 4.7 Hz, 1H), 7.60 – 7.46 (m, 3H), 7.46 – 7.35 (m, 1H), 4.00 (d, J = 6.2 Hz, 2H), 2.14 (s, 3H). Example 33: Preparation of Compound 33

[0671] 3-Chloro-4-methyl-5-(naphth-2-yl)cyanopyridine [ ]

[0672] Pd(dppf)Cl2 (0.032 g, 0.0248 mmol) was added to 3,5-dichloro-4-methylpyridin-2-carboxynitrile (0.4 g, 2.14 mmol), 2-naphthylboronic acid (368 mg, 2.14 mmol), and K2CO3 (354 mg, 2.57 mmol) in DMF (8 mL) and water (0.8 mL) and stirred. The resulting mixture was heated at 45 °C under nitrogen for 17 hours. TLC (in 30% ethyl acetate in hexane) indicated that the starting material had been completely consumed. The reactants were diluted with ethyl acetate (20 mL) and water (15 mL). The layers were separated. The organic layer was washed with concentrated brine (10 mL), dried over Na2SO4, and concentrated. The crude product was obtained by column chromatography (24 μL). Purification was performed using a g column in hexane (0-50% ethyl acetate) to give two positional isomers (520 mg, 87%) as a white solid. This mixture was then used for the next reaction. LC-MS (ESI+): m / z 279.0 (M+H)+.

[0673] 3-(benzoxy)-4-methyl-5-(naphth-2-yl)cyanopyridine

[0674] 3-Chloro-4-methyl-5-(2-naphthyl)pyridine-2-carboxynitrile (520 mg, 1.87 mmol) was dissolved in DMF (10 mL) and cooled to 0 °C. NaH (60% suspension in mineral oil, 90 mg, 2.24 mmol) was added at 0 °C and the mixture was stirred for 3 minutes. Benzyl alcohol (0.23 mL, 2.24 mmol) was added at 0 °C. The reaction mixture was heated to room temperature and stirred for 30 minutes. The reaction was terminated with an aqueous solution of NH4Cl (50 mL), and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with concentrated brine (20 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (20 g, 0-50% ethyl acetate in hexane) to give a product as a white solid (344 mg, 52%). LC-MS (ESI+): m / z 351.0 (M+H)+.

[0675] 3-(benzoxy)-4-methyl-5-(naphth-2-yl)pyridinecarboxylic acid

[0676] A mixture of 3-benzyloxy-4-methyl-5-(2-naphthyl)pyridine-2-carboxynitrile (...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, (I), wherein: R1 is a C1-3 alkyl group or a C3-6 cycloalkyl group, substituted as appropriate; R2 is hydrogen, a C1-3 alkyl group, halogen, CN, or a cycloalkyl group, substituted as appropriate; R3 is hydrogen, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, a C(O)-phenyl group, OR16, SR16, an arylsulfonyl group, a heteroarylsulfonyl group, or an aryl alkyl group, substituted as appropriate; R4 and R5 are independently hydrogen, a C1-3 alkyl group, substituted as appropriate, or R4 and R5 together with the carbon atom to which they are attached form a cycloalkyl group or a heterocycloalkyl group, substituted as appropriate; R6 is OH or OR18; R16 is an aryl group; and R18 is a C1-6 alkyl group.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (I): (I), wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or halogen-substituted aryl group as appropriate, wherein R7 is a C1-3 alkyl group substituted with aryl group as appropriate, or R1 is a C3-6 cycloalkyl group; R2 is hydrogen, halogen, CN, or C1-3 alkyl group substituted with one or more halogens as appropriate; R3 is selected from the group consisting of: hydrogen; , wherein X is covalent, O, S, SO2, or C1-4 alkylene, each A is independently N or CR9, R8 and R9 are independently hydrogen, halogen, OR10, or C1-3 alkyl group substituted with one or more halogens as appropriate, and R10 is a C1-3 alkyl group or aryl group; , wherein B is N or CR11, D is N, NH or CR11, E is N, CR11 or CHR12, and R11 and R12 are independently hydrogen or C1-3 alkyl, and the dashed circle represents the presence or absence of a conjugated system; , wherein each G is independently N, NH, NR13 or CR14; R13 is C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, aryl group substituted with one or more halogens as appropriate, aryl group substituted with one or more C1-3 alkyl groups as appropriate, heteroaryl group, heterocycloalkyl group substituted with t-butoxycarbonyl group as appropriate, C1-4 alkyl group substituted with aryl group as appropriate and the aryl group is substituted with one or more halogens as appropriate, and R14 is hydrogen, halogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or C1-3 alkyl; R15 is hydrogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or C1-3 alkyl, and R19 is hydrogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or aryl; OR16, wherein R16 is aryl; X1 is N or CH, and R20 is an aryl group if substituted; and COR17, wherein R17 is aryl; R4 and R5 are independently hydrogen, C1-3 alkyl groups if substituted with one or more halogens, or R4 and R5 together with the carbons attached thereto form a cycloalkyl or heterocycloalkyl group if substituted; and R6 is OH or OR18, wherein R18 is a C1-6 alkyl.

3. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula II: (II), wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or halogen-substituted aryl group as appropriate, wherein R7 is a C1-3 alkyl group substituted with aryl group as appropriate, or R1 is a C3-6 cycloalkyl group; R2 is hydrogen, halogen, CN, or C1-3 alkyl group substituted with one or more halogens as appropriate; R3 is selected from the group consisting of: hydrogen; , wherein X is covalent, O, S, SO2, or C1-4 alkylene, each A is independently N or CR9, R8 and R9 are independently hydrogen, halogen, OR10, or C1-3 alkyl group substituted with one or more halogens as appropriate, and R10 is a C1-3 alkyl group or aryl group; , where B is N or CR11, D is N, NH or CR11, E is N, CR11 or CHR12, and R11 and R12 are independently hydrogen or C1-3 alkyl, and the dashed circles represent the presence or absence of a conjugated system; , where each G is independently N, NR13, CR14, R13 is C3-6 cycloalkyl or 3 to 6-membered heterocycloalkyl, aryl group substituted with one or more halogens as appropriate, aryl group substituted with one or more C1-3 alkyl groups as appropriate, heteroaryl group, heterocycloalkyl group substituted with t-butoxycarbonyl group as appropriate, C1-4 alkyl group substituted with aryl group as appropriate and the aryl group is substituted with one or more halogens as appropriate, and R14 is hydrogen, halogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or C1-3 alkyl; R15 is hydrogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or C1-3 alkyl, and R19 is hydrogen, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, or aryl; OR16, wherein R16 is aryl; X1 is N or CH, and R20 is an aryl group if substituted; and COR17, wherein R17 is aryl; and R4 and R5 are independently hydrogen, C1-3 alkyl groups if substituted with one or more halogens, or R4 and R5 together with the carbons attached to them form an alkyl or heterocycloalkyl group if substituted.

4. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, or hydrate, wherein: R1 is a substituted C1-3 alkyl group, and / or R3 is hydrogen, a substituted aryl group, a substituted heteroaryl group, a substituted cycloalkyl group, -C(O)-phenyl, or -OR16.

5. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (III): (III), wherein each A is independently N or CR9; R1 is a C1-3 alkyl group substituted with OR7, halogen, or an aryl group substituted with halogen, or R1 is cyclopropyl; R2 is hydrogen, halogen, CN, or a C1-3 alkyl group substituted with one or more halogens, as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens, or R4 and R5 together with the carbons attached thereto form a substituted cycloalkyl or heterocycloalkyl group, as appropriate; R7 is a C1-3 alkyl group substituted with aryl, as appropriate; R8 and R9 are independently hydrogen, halogen, OR10, or a C1-3 alkyl group substituted with one or more halogens, as appropriate; and R10 is a C1-3 alkyl group or an aryl group.

6. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (IV): (IV), wherein R1 is a C1-3 alkyl group substituted with OR7, a halogen, or an aryl group substituted with a halogen, or R1 is cyclopropyl; R2 is hydrogen, a halogen, CN, or a C1-3 alkyl group substituted with one or more halogens, as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens, or R4 and R5 together with the carbons attached thereto form a substituted cycloalkyl or heterocycloalkyl group, as appropriate; R7 is a C1-3 alkyl group substituted with an aryl group, as appropriate; R8 and R9 are independently hydrogen, a halogen, OR10, or a C1-3 alkyl group substituted with one or more halogens, as appropriate; and R10 is a C1-3 alkyl group or an aryl group.

7. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (V): (V), wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or an aryl group substituted with halogen, or R1 is cyclopropyl; R2 is a C1-3 alkyl group substituted with hydrogen, halogen, CN, or one or more halogens, as appropriate; R4 and R5 are independently C1-3 alkyl groups substituted with hydrogen, or one or more halogens, as appropriate, or R4 and R5 together with the carbons attached to them form a substituted cycloalkyl or heterocycloalkyl group, as appropriate; R7 is a C1-3 alkyl group substituted with aryl, as appropriate; R8 and each R9 are independently C1-3 alkyl groups substituted with hydrogen, halogen, OR10, or one or more halogens, as appropriate; and R10 is a C1-3 alkyl group or an aryl group.

8. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (VI): (VI), wherein: B is N or CR11; D is N, NH, or CR11; E is N, CR11, or CHR12; R1 is a C1-3 alkyl group substituted with OR7, halogen, or halogen-substituted aryl group as appropriate, or R1 is cyclopropyl; R2 is hydrogen, halogen, CN, or C1-3 alkyl group substituted with one or more halogens as appropriate; R4 and R5 are independently hydrogen, C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group substituted with aryl group as appropriate; R11 and R12 are independently hydrogen or C1-3 alkyl groups; and the dashed circles represent the presence or absence of a conjugated system.

9. The compound of claim 8 or a pharmaceutically acceptable salt, stereoisomer or hydrate thereof, wherein the compound has a structure according to formula (VII): (VII).

10. A compound of claim 8 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (VIII): (VIII), wherein: B is N or CR11; R1 is a C1-3 alkyl group substituted with OR7, halogen, or halogen-substituted aryl group as appropriate, or R1 is cyclopropyl; R2 is hydrogen, halogen, CN, or C1-3 alkyl group substituted with one or more halogens as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons they are attached to form substituted cycloalkyl or heterocycloalkyl groups as appropriate; R7 is a C1-3 alkyl group substituted with aryl group as appropriate; and R12 is hydrogen or C1-3 alkyl group.

11. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (IX): (IX), wherein: Each G is independently N, NH, NR13, or CR14; R1 is a C1-3 alkyl group substituted with OR7, halogen, or halogen-substituted aryl group as appropriate, wherein R7 is a C1-3 alkyl group substituted with aryl group as appropriate, or R1 is cyclopropyl; R2 is hydrogen, halogen, CN, or C1-3 alkyl group substituted with one or more halogens as appropriate; R4 and R5 are independently hydrogen, C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbon attached thereto form a substituted cycloalkyl or heterocycloalkyl group as appropriate; R13 is cyclopropyl, aryl group substituted with one or more halogens as appropriate, aryl group substituted with one or more C1-3 alkyl groups as appropriate, heteroaryl group, heterocycloalkyl group substituted with t-butoxycarbonyl group as appropriate, C1-4 alkyl group substituted with aryl group as appropriate and the aryl group is substituted with one or more halogens as appropriate; and R14 is hydrogen, halogen, cyclopropyl, or C1-3 alkyl.

12. A compound of claim 11 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (X): (X), wherein: Each G is independently N, NR13, or CR14; R1 is a C1-3 alkyl group substituted with OR7, halogen, or halogen-substituted aryl group as appropriate, wherein R7 is a C1-3 alkyl group substituted with aryl group as appropriate, or R1 is cyclopropyl; R2 is hydrogen, halogen, CN, or C1-3 alkyl group substituted with one or more halogens as appropriate; R4 and R5 are independently hydrogen, C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbon attached thereto form a substituted cycloalkyl or heterocycloalkyl group as appropriate; R13 is cyclopropyl, aryl group substituted with one or more halogens as appropriate, aryl group substituted with one or more C1-3 alkyl groups as appropriate, heteroaryl group, heterocycloalkyl group substituted with t-butoxycarbonyl group as appropriate, C1-4 alkyl group substituted with aryl group as appropriate and the aryl group is substituted with one or more halogens as appropriate; and R14 is hydrogen, halogen, cyclopropyl, or C1-3 alkyl.

13. A compound of claim 11 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (XI): (XI), wherein each G is independently N or NR13; R1 is a C1-3 alkyl group substituted with OR7, halogen, or halogen-substituted aryl group as appropriate, and wherein R7 is a C1-3 alkyl group substituted with aryl group as appropriate, or R1 is cyclopropyl; R2 is hydrogen, halogen, CN, or C1-3 alkyl group substituted with one or more halogens as appropriate; R4 and R5 are independently hydrogen, C1-3 alkyl groups substituted with one or more halogens as appropriate, or R4 and R5 together with the carbons attached thereto form a substituted cycloalkyl or heterocycloalkyl group as appropriate; R13 is cyclopropyl, heteroaryl, aryl substituted with one or more halogens as appropriate, aryl substituted with one or more C1-3 alkyl substituted as appropriate, heterocycloalkyl substituted with t-butoxycarbonyl as appropriate, C1-4 alkyl substituted with aryl and the aryl group is substituted with one or more halogens as appropriate; and R14 is hydrogen, halogen, cyclopropyl, or C1-3 alkyl.

14. A compound of claim 11 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (XIIa) or formula (XIIb): (XIIa) (XIIb), wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or an aryl group substituted with halogen, or R1 is cyclopropyl; R2 is hydrogen, halogen, CN, or a C1-3 alkyl group substituted with one or more halogens, as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens, or R4 and R5 together with the carbon atom to which they are attached form a substituted cycloalkyl or heterocycloalkyl group, as appropriate; R7 is a C1-3 alkyl group substituted with aryl, as appropriate; R13 is cyclopropyl, heteroaryl, aryl group substituted with one or more halogens, aryl group substituted with one or more substituted C1-3 alkyl groups, heterocycloalkyl group substituted with t-butoxycarbonyl, or C1-4 alkyl group substituted with aryl and the aryl group is substituted with one or more halogens, as appropriate; and R14 is hydrogen, halogen, cyclopropyl, or C1-3 alkyl.

15. A compound of claim 11 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (XIII): (XIII), wherein: R2 is hydrogen, halogen, CN, or a C1-3 alkyl group substituted with one or more halogens, as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens, as appropriate, or R4 and R5 together with the carbons they are attached to form a substituted cycloalkyl or heterocycloalkyl group, as appropriate; and R13 is aryl or heteroaryl.

16. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (XIV): (XIV), wherein: I is O, S, or CH; J is N or CH; R1 is a C1-3 alkyl group substituted with OR7, halogen, or halogen-substituted aryl group as appropriate, wherein R7 is a C1-3 alkyl group substituted with aryl group as appropriate, or R1 is cyclopropyl; R2 is hydrogen, halogen, CN, or C1-3 alkyl group substituted with one or more halogens as appropriate; R4 and R5 are independently hydrogen, C1-3 alkyl group substituted with one or more halogens as appropriate, or R4 and R5 together with the carbon attached thereto form a substituted cycloalkyl or heterocycloalkyl group as appropriate; R15 is hydrogen or C1-3 alkyl; and R19 is hydrogen or aryl.

17. A compound of claim 16 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (XV): (XV), wherein: I is O, S, or CH; R1 is a C1-3 alkyl group substituted with OR7, halogen, or an aryl group substituted with halogen, or R1 is cyclopropyl; R2 is hydrogen, halogen, CN, or a C1-3 alkyl group substituted with one or more halogens, as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens, or R4 and R5 together with their attached carbons form a substituted cycloalkyl or heterocycloalkyl group, as appropriate; R7 is a C1-3 alkyl group substituted with aryl, as appropriate; and R15 is hydrogen or a C1-3 alkyl group. R19 is hydrogen or aryl.

18. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (XVI): (XVI), wherein X is O, S, or SO2; R1 is a C1-3 alkyl group substituted with OR7, a halogen, or an aryl group substituted with a halogen, or R1 is cyclopropyl; R2 is hydrogen, a halogen, CN, or a C1-3 alkyl group substituted with one or more halogens, as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens, or R4 and R5 together with the carbons attached thereto form a substituted cycloalkyl or heterocycloalkyl group, as appropriate; R7 is a C1-3 alkyl group substituted with an aryl group, as appropriate; R8 and R9 are independently hydrogen, a halogen, OR10, or a C1-3 alkyl group substituted with one or more halogens, as appropriate; and R10 is a C1-3 alkyl group or an aryl group.

19. A compound of claim 11 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (XIX): (XIX), wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or an aryl group substituted with halogen, or R1 is cyclopropyl; R2 is hydrogen, halogen, CN, or a C1-3 alkyl group substituted with one or more halogens, as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens, or R4 and R5 together with the carbon atom to which they are attached form a cyclic or heterocyclic alkyl group substituted with halogens, as appropriate; R7 is a C1-3 alkyl group substituted with aryl, as appropriate; and R13 is cyclopropyl, an aryl group substituted with one or more halogens, an aryl group substituted with one or more substituted C1-3 alkyl groups, a heterocyclic alkyl group substituted with t-butoxycarbonyl, or a C1-4 alkyl group substituted with aryl and the aryl group is substituted with one or more halogens, as appropriate.

20. A compound of claim 11 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (XX): (XX), wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or an aryl group substituted with halogen, or R1 is cyclopropyl; R2 is hydrogen, halogen, CN, or a C1-3 alkyl group substituted with one or more halogens, as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens, or R4 and R5 together with the carbon atom to which they are attached form a cyclic or heterocyclic alkyl group substituted with halogens, as appropriate; R7 is a C1-3 alkyl group substituted with aryl, as appropriate; and R13 is cyclopropyl, an aryl group substituted with one or more halogens, an aryl group substituted with one or more substituted C1-3 alkyl groups, a heterocyclic alkyl group substituted with t-butoxycarbonyl, or a C1-4 alkyl group substituted with aryl and the aryl group is substituted with one or more halogens, as appropriate.

21. A compound of claim 11 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (XXI): (XXI), wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or an aryl group substituted with halogen, or R1 is cyclopropyl; R2 is a C1-3 alkyl group substituted with hydrogen, halogen, CN, or one or more halogens, as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens, as appropriate, or R4 and R5 together with the carbons attached to them form a substituted cycloalkyl or heterocycloalkyl group, as appropriate; and R7 is a C1-3 alkyl group substituted with aryl, as appropriate.

22. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (XXII): (XXII), wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or an aryl group substituted with halogen, or R1 is cyclopropyl; R2 is a C1-3 alkyl group substituted with hydrogen, halogen, CN, or one or more halogens, as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens, as appropriate, or R4 and R5 together with the carbons attached to them form a substituted cycloalkyl or heterocycloalkyl group, as appropriate; R7 is a C1-3 alkyl group substituted with aryl, as appropriate; and R20 is an aryl group substituted, as appropriate.

23. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to formula (XXIII): (XXIII), wherein: R1 is a C1-3 alkyl group substituted with OR7, halogen, or an aryl group substituted with halogen, or R1 is cyclopropyl; R2 is a C1-3 alkyl group substituted with hydrogen, halogen, CN, or one or more halogens, as appropriate; R4 and R5 are independently hydrogen, or C1-3 alkyl groups substituted with one or more halogens, as appropriate, or R4 and R5 together with the carbons attached to them form a substituted cycloalkyl or heterocycloalkyl group, as appropriate; R7 is a C1-3 alkyl group substituted with aryl, as appropriate; and R20 is an aryl group substituted, as appropriate.

24. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has a structure according to any one of compounds 1 to 50: Compound Number Structure 1 26 2 27 3 28 4 29 5 30 6 31 7 32 8 33 9 34 10 35 11 36 12 37 13 38 14 39 15 40 16 41 17 42 18 43 19 44 20 45 21 46 22 47 23 48 24 49 25 50.

25. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein the compound has the structure of any one of compounds 51, 52, 54 to 61 and 63 to 70: Compound Number Structure 51 52 54 55 56 57 58 59 60 61 63 64 65 66 67 68 69 70.

26. A pharmaceutical composition comprising a compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, and a pharmaceutically acceptable excipient.

27. Use of a compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, for the preparation of a medicament for the treatment of diseases mediated by prolyl hydroxylase domain (PHD) enzyme activity.

28. As claimed in claim 27, wherein the disease mediated by the PHD enzyme activity is ischemia-reperfusion injury, inflammatory bowel disease, cancer, liver disease, atherosclerosis, cardiovascular disease, eye disease or condition, anemia, chronic kidney disease, disease associated with hyperoxia, respiratory disease, lung disease, respiratory viral infection, pulmonary viral infection, or damage and / or failure of one or more organs.

29. As claimed in claim 28, wherein the ischemic-reperfusion injury is selected from stroke, myocardial infarction, and acute kidney injury; the inflammatory bowel disease is ulcerative colitis or Crohn's disease; the cancer is colorectal cancer; the eye disease or condition is selected from radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia; the anemia is anemia associated with chronic kidney disease; the disease associated with hyperoxia is retinopathy of prematurity or bronchodystrophy (BPD); the respiratory disease is selected from respiratory infection, acute respiratory distress syndrome, lung inflammation, pneumonia, and acute lung injury; the lung disease is acute lung injury (ALI), bronchitis, pneumonia, pulmonary fibrosis, asthma, or acute respiratory distress syndrome (ARDS); or the injury and / or failure of one or more organs is acute organ injury or organ failure.

30. As claimed in claim 27, wherein the disease is selected from ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, and cirrhosis.

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