Derivatives of ([1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate as PHD inhibitor compounds, compositions, and methods of use

Abstract

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

Description

PHD INHIBITOR COMPOUNDS, COMPOSITIONS, AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS [1] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 612,140, filed December 19, 2023, the content of which is hereby incorporated by reference in its entirety. BACKGROUND [2] Hypoxia is a condition or state in which the supply of oxygen is insufficient for normal life function, for example, where there is low arterial oxygen supply. Hypoxia can lead to functional impairment of cells and structural tissue damage. The activation of cellular defense mechanisms during hypoxia is mediated by HIF (Hypoxia-inducible factor) protein. In response to hypoxic conditions, levels of HIFα are elevated in most cells because of a decrease in HIFα prolyl hydroxylation. Prolyl hydroxylation of HIFα is accomplished by a family of proteins variously termed the prolyl hydroxylase domain-containing proteins (PHD1, 2, and 3), also known as HIF prolyl hydroxylases (HPH-3, 2, and 1) or EGLN-2, 1, and 3. The PHD proteins are oxygen sensors and regulate the stability of HIF in an oxygen dependent manner. The three PHD isoforms function differently in their regulation of HIF and may have other non-HIF related regulatory roles. [3] In fact, many studies demonstrate that stabilization of HIF can dampen tissue inflammation and promote tissue repair. Accordingly, compounds that can inhibit the activity of PHD proteins may be particularly beneficial new therapies (Lee et al. (2019) Exp. Mol. Med.51:68) [4] Described herein are novel small molecule PHD inhibitors that have utility for the treatment or prevention of disease including heart (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung (e.g., lung inflammation, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory (e.g., respiratory infection, acute respiratory distress syndrome), liver (e.g. acute liver failure and liver fibrosis and cirrhosis), and kidney (e.g. acute kidney injury and chronic kidney disease) disease, inflammatory bowel disease (IBD), ischemic reperfusion injury (e.g., stroke), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), or white matter injury (WMI). SUMMARY [5] The present invention provides, among other things, novel small molecule inhibitors of PHD and have utility for the treatment or prevention of diseases, including but not limited to heart (e.g. ischemic heart disease, congestive heart failure, and valvular heart disease), lung (e.g., lunginflammation, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory (e.g., respiratory infection, acute respiratory distress syndrome), liver (e.g. acute liver failure and liver fibrosis and cirrhosis), and kidney (e.g. acute kidney injury and chronic kidney disease) disease, inflammatory bowel disease (IBD), ischemic reperfusion injury (e.g., stroke), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and white matter injury (WMI). [6] In one aspect, the invention features a compound of Formula (I), R Ror a pharmaceutically acceptable salt thereof, wherein: X1, X2, X3, and X5are each independently N, C, or CH; X4is independently N or C; R1is H, C1-3alkyl, or C1-3alkylhalo; R2is H, C1-3alkyl, or C1-3alkylhalo; R3and R4together with the atoms to which they are attached combine to form C5-6aryl or heteroaryl, optionally substituted with one or more groups selected from halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, and indole, wherein alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, and indole are each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxine or dioxoline; and R5is H, C1-3alkyl, C1-3alkylhalo, C1-3alkoxy or aryl, or R5is absent with X4is N. [7] In embodiments, R1is -H.[8] In embodiments, R2is -H. [9] In embodiments, a compound of Formula (I) has a structure according for Formula (II), mor a pharmaceutically acceptable salt thereof, wherein: X1, X2, X3, and X5are each independently N, C, or CH; X4is independently N or C; Y1, Y2, and Y3are each independently N, C, or CH; R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, C1-3alkoxy, or aryl, or R5is absent with X4is N; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane; and m is 0, 1, 2, or 3.

[0010] In embodiments, R1is H.

[0011] In embodiments, R2is H.

[0012] In embodiments, m is 0.

[0013] In embodiments, m is 1.

[0014] In embodiments, m is 2.

[0015] In embodiments, m is 3.

[0016] In embodiments, a compound of Formula (I) has a structure according to Formula (III), nor a pharmaceutically acceptable salt thereof, wherein: X1, X2, X3, and X5are each independently N, C, or CH; X4is independently N or C; Y1, Y2, and Y3are each independently N, C, or CH; Z1, Z2, and Z3are each independently N, C, CH, S, or O; R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, C1-3alkoxy or aryl, or R5is absent with X4is N; R7is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; and n is 0, 1, 2, or 3.

[0017] In embodiments, R1is -H.

[0018] In embodiments, R2is -H.

[0019] In embodiments, n is 0.

[0020] In embodiments, n is 1.

[0021] In embodiments, n is 2.

[0022] In embodiments, n is 3.

[0023] In embodiments, a compound of Formula (I) has a structure according to Formula (IIa), mor a pharmaceutically acceptable salt thereof, wherein: R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, C1-3alkoxy, or aryl; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane; and m is 0, 1, 2, or 3.

[0024] In embodiments, R1is -H.

[0025] In embodiments, R2is -H.

[0026] In embodiments, R5is -H.

[0027] In embodiments, R6is -H.

[0028] In embodiments, R5is alkoxy. In embodiments, the alkoxy is methoxy. In embodiments, the alkoxy is ethoxy.

[0029] In embodiments, R5is alkylhalo. In embodiments, the alkylhalo is -CF3.

[0030] In embodiments, R5is alkyl. In embodiments, the alkyl is -CH3. 55

[0031] In embodiments, R is aryl. In embodiments, R is .

[0032] In embodiments, R6is halo. In embodiments, halo is -Cl. In embodiments, halo is -Br. In embodiments, halo is -F.

[0033] In embodiments, R6is alkyl, optionally substituted with halo or phenyl. In embodiments, alkyl is methyl. In embodiments, R6is -CF3. In embodiments,

[0034] In embodiments, R6is aryl, optionally substituted with halo, cyano, alkyl, or alkylhalo.

[0035] In embodiments,

[0036] In embodiments,e, ,

[0037] In embodiments, R6is aryloxy, optionally substituted with alkyl, halo, or alkoxy. In.

[0038] In embodiments, R6is cycloalkyl. In embodiments, R6is cyclopropane. In embodiments, R6is cyclohexane.

[0039] In embodiments, R6is heterocycloalkyl.

[0040] In embodiments, Ris .

[0041] In embodiments,

[0042] In embodiments, R6is heteroaryl, optionally substituted with aryl, cycloalkyl, alkyl, or a [ [.

[0045] In embodiments, R. , .

[0046] In embodiments, Rs .

[0047] In embodiments, R6is heterocycloalkyl, optionally substituted with aryl. In embodiments, R

[0048] In embodiments, R6is alkoxy. In embodiments,

[0049] In embodiments, R

[0050] In embodiments, R.

[0051] In embodiments, m is 0.

[0052] In embodiments, m is 1.

[0053] In embodiments, m is 2.

[0054] In embodiments, m is 3.

[0055] In embodiments, a compound of Formula (I) has a structure according to Formula (IIb), mor a pharmaceutically acceptable salt thereof, wherein: Y1is N, C, or CH; R1is H or C1-3alkyl;R2is H or C1-3alkyl; R5is H, C1-3 alkyl, C1-3 alkylhalo, C1-3 alkoxy, or aryl; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; and m is 0, 1, 2, or 3.

[0056] In embodiments, Y1is N.

[0057] In embodiments, R1is H.

[0058] In embodiments, R2is H.

[0059] In embodiments, m is 0.

[0060] In embodiments, m is 1.

[0061] In embodiments, m is 2.

[0062] In embodiments, m is 3.

[0063] In embodiments, R5is H.

[0064] In embodiments, R6is aryl optionally substituted with halo. In embodiments, R6is e, .

[0065] In embodiments, a compound of Formula (I) has a structure according to Formula (IIc), mc or a pharmaceutically acceptable salt thereof, wherein:Y2is N, C, or CH; R1is H or C1-3 alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; and m is 0, 1, 2, or 3.

[0066] In embodiments, Y2is N.

[0067] In embodiments, R1is H.

[0068] In embodiments, R2is H.

[0069] In embodiments, R5is H.

[0070] In embodiments, R6is aryl optionally substituted with halo. In embodiments, R6is e, .

[0071] In embodiments, m is 0.

[0072] In embodiments, m is 1.

[0073] In embodiments, m is 2.

[0074] In embodiments, m is 3.

[0075] In embodiments, a compound of Formula (I) has a structure according to Formula (IId), mR(IId) or a pharmaceutically acceptable salt thereof, wherein: Y3is N, C, or CH; R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; and m is 0, 1, 2, or 3.

[0076] In embodiments, Y3is N.

[0077] In embodiments, R1is H.

[0078] In embodiments, R2is H.

[0079] In embodiments, R5is H.

[0080] In embodiments, R6is aryl optionally substituted with halo.

[0081] In embodiments, R6is. In embodiments, R6is. In embodiments, R6is. In embodiments, Rs .

[0082] In embodiments, m is 0.

[0083] In embodiments, m is 1.

[0084] In embodiments, m is 2.

[0085] In embodiments, m is 3.

[0086] In embodiments, a compound of Formula (I) has a structure according to Formula (IIe),mor a pharmaceutically acceptable salt thereof, wherein: R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; and m is 0, 1, 2, or 3.

[0087] In embodiments, R1is H.

[0088] In embodiments, R2is H.

[0089] In embodiments, R5is H.

[0090] In embodiments, R6is H.

[0091] In embodiments, R6is halo. In embodiments, R6is Cl.

[0092] In embodiments, a compound of Formula (I) has a structure according to Formula (IIf), mor a pharmaceutically acceptable salt thereof, wherein:R1is H or C1-3alkyl; R2is H or C1-3 alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; and m is 0, 1, 2, or 3.

[0093] In embodiments, R1is H.

[0094] In embodiments, R2is H.

[0095] In embodiments, R5is H.

[0096] In embodiments, R6is H.

[0097] In embodiments, R6is halo. In embodiments, R6is Cl.

[0098] In embodiments, m is 0.

[0099] In embodiments, m is 1.

[0100] In embodiments, m is 2.

[0101] In embodiments, m is 3.

[0102] In embodiments, a compound of Formula (I) has a structure according to Formula (IIIa), nor a pharmaceutically acceptable salt thereof, wherein: Z1is N, C, CH, S, or O; R1is H or C1-3 alkyl; R2is H or C1-3alkyl;R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R7is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; and n is 0, 1, 2, or 3.

[0103] In embodiments, Z1is N.

[0104] In embodiments, Z1is O.

[0105] In embodiments, Z1is S.

[0106] In embodiments, R1is H.

[0107] In embodiments, R2is H.

[0108] In embodiments, n is 0.

[0109] In embodiments, n is 1.

[0110] In embodiments, n is 2.

[0111] In embodiments, n is 3.

[0112] In embodiments, R5is H.

[0113] In embodiments, R7is H.

[0114] In embodiments, a compound of Formula (I) has a structure according to Formula (IIIb), nor a pharmaceutically acceptable salt thereof, wherein: Z3is N, C, CH, S, or O; R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy;R7is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; and n is 0, 1, 2, or 3.

[0115] In embodiments, Z3is N.

[0116] In embodiments, Z3is S.

[0117] In embodiments, Z3is O.

[0118] In embodiments, R1is H.

[0119] In embodiments, R2is H.

[0120] In embodiments, R5is H.

[0121] In embodiments, R7is H.

[0122] In embodiments, R7is aryl.

[0123] In embodiments, R7is arylhalo. In embodiments, R7is.

[0124] In embodiments, n is 0.

[0125] In embodiments, n is 1.

[0126] In embodiments, n is 2.

[0127] In embodiments, n is 3.

[0128] In embodiments, a compound of Formula (I) has a structure according to Formula (IIIc), nor a pharmaceutically acceptable salt thereof, wherein: Z2and Z3are each independently N, C, CH, S, or O; R1is H or C1-3alkyl; R2is H or C1-3alkyl;R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R7is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; and n is 0, 1, 2, or 3.

[0129] In embodiments, Z3is N.

[0130] In embodiments, Z3is S.

[0131] In embodiments, Z3is O.

[0132] In embodiments, R1is H.

[0133] In embodiments, R2is H.

[0134] In embodiments, R5is H.

[0135] In embodiments, R7is H.

[0136] In embodiments, R7is aryl.

[0137] In embodiments, R7is arylhalo.

[0138] In embodiments, R.

[0139] In embodiments, n is 0.

[0140] In embodiments, n is 1.

[0141] In embodiments, n is 2.

[0142] In embodiments, n is 3.

[0143] In embodiments, a compound of Formula (I) has a structure according to Formula (IIId), nor a pharmaceutically acceptable salt thereof, wherein: Z1and Z2are each independently N, C, CH, S, or O;R1is H or C1-3alkyl; R2is H or C1-3 alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R7is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; and n is 0, 1, 2, or 3.

[0144] In embodiments, Z1is N.

[0145] In embodiments, Z1is S.

[0146] In embodiments, Z1is O.

[0147] In embodiments, R1is H.

[0148] In embodiments, R2is H.

[0149] In embodiments, R5is H.

[0150] In embodiments, R7is H.

[0151] In embodiments, R7is aryl.

[0152] In embodiments, R7is arylhalo. In embodiments, R7is.

[0153] In embodiments, n is 0.

[0154] In embodiments, n is 1.

[0155] In embodiments, n is 2.

[0156] In embodiments, n is 3.

[0157] In embodiments, a compound of Formula (I) is selected from the group consisting of Compounds (1)-(118):or a pharmaceutically acceptable salt thereof.

[0158] In embodiments, any compound described herein comprises at least one hydrogen atom that is replaced with a deuterium atom.

[0159] In another aspect, the invention features a pharmaceutical composition comprising any compound described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)– (118)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0160] In another aspect, the invention features a method for treating a disease mediated by PHD activity comprising administering to a subject any compound described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)), or a pharmaceutically acceptable salt thereof. In some embodiments, the method for treating a disease mediated by PHD activity comprises administering to a subject a pharmaceutical composition described herein.

[0161] In embodiments, a disease mediated by PHD activity is an ischemic reperfusion injury. In some embodiments, the ischemic reperfusion injury is stroke. In some embodiments, the ischemic reperfusion injury is myocardial infarction. In some embodiments, the ischemic reperfusion injury is acute kidney injury.

[0162] In embodiments, a disease mediated by PHD activity is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the inflammatory bowel disease is Crohn’s disease.

[0163] In embodiments, a disease mediated by PHD activity is cancer. In some embodiments, the cancer is colorectal cancer. In embodiments, the cancer is a blood cancer (e.g., leukemia or myeloma such as acute myeloid leukemia, chronic myeloid leukemia, or multiple myeloma). In someembodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is chronic myeloid leukemia. In some embodiments, the cancer is multiple myeloma.

[0164] In embodiments, a disease mediated by PHD activity is liver disease.

[0165] In embodiments, a disease mediated by PHD activity is atherosclerosis.

[0166] In embodiments, a disease mediated by PHD activity is cardiovascular disease.

[0167] In embodiments, a disease mediated by PHD activity is a disease or condition of the eye. In some embodiments, the disease or condition of the eye is radiation retinopathy. In some embodiments, the disease or condition of the eye is retinopathy of prematurity. In some embodiments, the disease or condition of the eye is diabetic retinopathy. In some embodiments, the disease or condition of the eye is age-related macular degeneration. In some embodiments, the disease or condition of the eye is ocular ischemia.

[0168] In embodiments, a disease mediated by PHD activity is anemia. In some embodiments, the anemia is associated with chronic kidney disease.

[0169] In embodiments, a disease mediated by PHD activity is chronic kidney disease.

[0170] In embodiments, a disease mediated by PHD activity is associated with hyperoxia.

[0171] In embodiments, a disease mediated by PHD activity is retinopathy of prematurity.

[0172] In embodiments, a disease mediated by PHD activity is bronchopulmonary dysplasia (BPD).

[0173] In embodiments, a disease mediated by PHD activity is periventricular leukomalacia (PVL).

[0174] In embodiments, a disease mediated by PHD activity is ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, or cirrhosis. In some embodiments, a disease mediated by PHD activity is ischemic heart disease. In some embodiments, a disease mediated by PHD activity is valvular heart disease. In some embodiments, a disease mediated by PHD activity is congestive heart failure. In some embodiments, a disease mediated by PHD activity is acute lung injury. In some embodiments, a disease mediated by PHD activity is pulmonary fibrosis. In some embodiments, a disease mediated by PHD activity is pulmonary hypertension. In some embodiments, a disease mediated by PHD activity is chronic obstructive pulmonary disease (COPD). In some embodiments, a disease mediated by PHD activity is acute liver failure. In some embodiments, a disease mediated by PHD activity is liver fibrosis. In some embodiments, a disease mediated by PHD activity is cirrhosis.

[0175] In some embodiments, a disease mediated by PHD activity is hemorrhagic shock.

[0176] In some embodiments, a disease mediated by PHD activity is intraventricular hemorrhage.

[0177] In embodiments, a disease mediated by PHD activity is a respiratory disease, a lung disease, a respiratory viral or bacterial infection, or a pulmonary viral or bacterial infection. In some embodiments, a disease mediated by PHD activity is a respiratory disease. In some embodiments, a disease mediated by PHD activity is a lung disease. In some embodiments, a disease mediated by PHD activity is a respiratory viral or bacterial infection. In some embodiments, a disease mediated by PHD activity is a pulmonary viral infection.

[0178] In embodiments, the respiratory disease is selected from respiratory infection, acute respiratory distress syndrome, lung inflammation, pneumonia, and acute lung injury. In some embodiments, the respiratory disease is respiratory infection. In some embodiments, the respiratory disease is acute respiratory distress syndrome. In some embodiments, the respiratory disease is lung inflammation. In some embodiments, the respiratory disease is pneumonia. In some embodiments, the respiratory disease is acute lung injury.

[0179] In embodiments, the lung disease is acute lung injury (ALI), bronchitis, pneumonia, pulmonary fibrosis, asthma, or acute respiratory distress syndrome (ARDS). In some embodiments, the lung disease is acute lung injury (ALI). In some embodiments, the lung disease is bronchitis. In some embodiments, the lung disease is pneumonia. In some embodiments, the lung disease is pulmonary fibrosis. In some embodiments, the lung disease is asthma. In some embodiments, the lung disease is acute respiratory distress syndrome (ARDS).

[0180] In embodiments, a disease mediated by PHD activity is injury to and / or failure of one or more organs. In some embodiments, a disease mediated by PHD activity is acute organ injury. In some embodiments, a disease mediated by PHD activity is organ failure.

[0181] In one aspect, the invention features a method for treating retinopathy of prematurity comprising administering to a subject any compound described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)), or a pharmaceutically acceptable salt thereof. In some embodiments, the method for treating retinopathy of prematurity comprises administering to a subject a pharmaceutical composition described herein.

[0182] In another aspect, the invention features a method for preventing retinopathy of prematurity comprising administering to a subject any compound described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)), or a pharmaceutically acceptable salt thereof. In some embodiments, the method for preventing retinopathy of prematurity comprises administering to a subject a pharmaceutical composition described herein.

[0183] In one aspect, the invention features a method for treating bronchopulmonary dysplasia comprising administering to a subject any compound described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)), or a pharmaceutically acceptable salt thereof. Insome embodiments, the method for treating bronchopulmonary dysplasia comprises administering to a subject a pharmaceutical composition described herein.

[0184] In another aspect, the invention features a method for preventing bronchopulmonary dysplasia comprising administering to a subject any compound described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)), or a pharmaceutically acceptable salt thereof. In some embodiments, the method for preventing bronchopulmonary dysplasia comprises administering to a subject a pharmaceutical composition described herein.

[0185] In one aspect, the invention features a method for treating white matter injury (WMI) comprising administering to a subject any compound described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)), or a pharmaceutically acceptable salt thereof. In some embodiments, the method for treating white matter injury (WMI) comprises administering to a subject a pharmaceutical composition described herein.

[0186] In another aspect, the invention features a method for preventing white matter injury (WMI) comprising administering to a subject any compound described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118(), or a pharmaceutically acceptable salt thereof. In some embodiments, the method for preventing white matter injury (WMI) comprises administering to a subject a pharmaceutical composition described herein. BRIEF DESCRIPTION OF DRAWINGS

[0187] FIG.1 is an exemplary schematic illustration demonstrating the principle of the TR-FRET Assay for PHD enzymes (PHD1, PHD2, and PHD3). In the presence of 2-oxoglutarate and O2, PHD enzyme hydroxylates proline 564 of biotin-tagged HIF-1α peptide resulting in generation of biotin- tagged HIF-1α-hydroxyproline, succinate and CO2. The resulting proximity of the donor fluorophore complex, monoclonal antibody anti-6His-Terbium (Tb)-cryptate Gold, bound to the His-tagged VHL protein, EloB, EloC complex (His-VBC) and the acceptor fluorophore, SA-D2 complex, bound to HIF- 1α-hydroxyproline results in a fluorescence resonance energy transfer signal that can be detected and quantified

[0188] FIG.2 illustrates the phases of development for retinopathy of prematurity (ROP). Exposure to high oxygen levels induce HIF1a degradation and prevent normal vascular development in the retina (vaso-obliteration). Upon return to room air, the retina becomes ischemic, degradation of HIF1a slows, and there is a rapid increase in VEGF, EPO, and IGF-1 that results in chaotic formation of abnormal vasculature (neovascularization).

[0189] FIG.3 shows exemplary methodology to test the effect of an exemplary Compound compared to a vehicle control in an oxygen-induced retinopathy mouse model.

[0190] FIG.4 displays representative images of retinas from OIR model mice after treatment with a vehicle control or exemplary compound.

[0191] FIG.5 shows exemplary methodology to test the effect of an exemplary Compound compared to a vehicle control in an oxygen-induced retinopathy rat model.

[0192] FIG.6 displays representative images of retinas from OIR model rats after treatment with a vehicle control or exemplary compound. DETAILED DESCRIPTION OF THE DISCLOSURE Definitions

[0193] In order for the present invention to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications and other reference materials referenced herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference.

[0194] Animal: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development. In certain embodiments, the non- human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, a bovine, a primate, and / or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, an animal may be a transgenic animal, genetically-engineered animal, and / or a clone.

[0195] Approximately or about: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0196] As used in the description and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions.

[0197] Throughout the description and claims of this specification the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.

[0198] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0199] Improve, increase, or reduce: As used herein, the terms “improve,” “increase,” or “reduce,” or grammatical equivalents, indicate values that are relative to a baseline measurement, such as a measurement in the same individual prior to initiation of the treatment described herein, or a measurement in a control subject (or multiple control subject) in the absence of the treatment described herein. A “control subject” is a subject afflicted with the same form of disease as the subject being treated, who is about the same age as the subject being treated.

[0200] In Vitro: As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.

[0201] In Vivo: As used herein, the term “in vivo” refers to events that occur within a multi-cellular organism, such as a human and a non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur within a living cell (as opposed to, for example, in vitro systems).

[0202] Patient: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition may be administered, e.g., for experimental, diagnostic, prophylactic, 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, a patient is a human. A human includes pre- and post-natal forms.

[0203] Pharmaceutically acceptable: The term “pharmaceutically acceptable,” as used herein, refers to substances that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0204] Pharmaceutically acceptable salt: Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, andperchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium. quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate, and aryl sulfonate. Further pharmaceutically acceptable salts include salts formed from the quaternization of an amine using an appropriate electrophile, e.g., an alkyl halide, to form a quaternized alkylated amino salt.

[0205] Subject: As used herein, the term “subject” refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse, or primate). A human includes pre- and post-natal forms. In many embodiments, a subject is a human being. A subject can be a patient, which refers to a human presenting to a medical provider for diagnosis or treatment of a disease. The term “subject” is used herein interchangeably with “individual” or “patient.” A subject can be afflicted with or is susceptible to a disease or disorder but may or may not display symptoms of the disease or disorder.

[0206] Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0207] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” of a therapeutic agent means an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the symptom(s) of the disease, disorder, and / or condition. It will be appreciated bythose of ordinary skill in the art that a therapeutically effective amount is typically administered via a dosing regimen comprising at least one unit dose.

[0208] Treating: As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and / or reduce incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease and / or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.

[0209] Aliphatic: As used herein, the term aliphatic refers to C1–C40hydrocarbons and includes both saturated and unsaturated hydrocarbons. An aliphatic may be linear, branched, or cyclic. For example, C1–C20aliphatics can include C1–C20alkyls (e.g., linear or branched C1–C20saturated alkyls), C2–C20alkenyls (e.g., linear or branched C4–C20dienyls, linear, or branched C6–C20trienyls, and the like), and C2–C20alkynyls (e.g., linear or branched C2–C20alkynyls). C1–C20aliphatics can include C3– C20cyclic aliphatics (e.g., C3–C20cycloalkyls, C4–C20cycloalkenyls, or C8–C20cycloalkynyls). In certain embodiments, the aliphatic may comprise one or more cyclic aliphatic and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur and may optionally be substituted with one or more substituents such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester or amide. An aliphatic group is unsubstituted or substituted with one or more substituent groups as described herein. For example, an aliphatic may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, -OCOR’, -OCO2R’, -NH2, -NHR’, - N(R’)2, -SR’ or-SO2R’, wherein each instance of R’ independently is C1–C20aliphatic (e.g., C1–C20alkyl, C1–C15alkyl, C1–C10alkyl, or C1–C3alkyl). In some embodiments, R’ independently is an unsubstituted alkyl (e.g., unsubstituted C1–C20alkyl, C1–C15alkyl, C1–C10alkyl, or C1–C3alkyl). In some embodiments, R’ independently is unsubstituted C1–C3alkyl. In some embodiments, the aliphatic is unsubstituted. In some embodiments, the aliphatic does not include any heteroatoms.

[0210] Alkyl: As used herein, the term “alkyl” means acyclic linear and branched hydrocarbon groups, e.g. “C1–C20alkyl” refers to alkyl groups having 1–20 carbons. An alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl tert-pentylhexyl, isohexyl, etc. The term “lower alkyl" means an alkyl group straight chain or branched alkyl having 1 to 6 carbon atoms. Other alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. An alkyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, - OCOR’, -OCO2R’, -NH2, -NHR’, -N(R’)2, -SR’ or-SO2R’, wherein each instance of R’ independently isC1–C20aliphatic (e.g., C1–C20alkyl, C1–C15alkyl, C1–C10alkyl, or C1–C3alkyl). In some embodiments, R’ independently is an unsubstituted alkyl (e.g., unsubstituted C1-C20 alkyl, C1–C15 alkyl, C1–C10 alkyl, or C1–C3alkyl). In some embodiments, R’ independently is unsubstituted C1–C3alkyl. In some embodiments, the alkyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). In embodiments, an alkyl (e.g., a C1-3alkyl) comprises at least one substituent group that is a halogen (e.g., F, Cl, or Br) and may be referred to as an “alkylhalo” group. In some embodiments, an alkyl group is substituted with a–OH group and may also be referred to herein as a “hydroxyalkyl” group, where the prefix denotes the –OH group and “alkyl” is as described herein. In some embodiments, an alkyl connected to another group via an oxygen atom (e.g., having the structure -O- alkyl, where ‘alkyl’ includes exemplary embodiments as described herein) and may also be referred to herein as “alkoxy” group.

[0211] Alkaryl: The term “alkaryl,” as used herein, represents a C1–C6alkyl group having a C6–C10aryl or a 5- to 10-membered heteroaryl located at any position of the carbon chain. In embodiments, an alkaryl group comprises a C6–C10aryl. In embodiments, an alkaryl group comprises a 5- to 10- membered heteroaryl. The C1–C6alkyl group may be linear or branched. An alkaryl group may be unsubstituted or substituted with, for example, 1, 2, 3, 4, or 5 substituents on the alkyl group and / or on the aryl or heteroaryl moiety. Exemplary alkaryl groups include benzyl, phenethyl, and -CH2C6H4tBu.

[0212] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0213] Alkylene: The term “alkylene,” as used herein, represents a saturated divalent straight or branched chain hydrocarbon group and is exemplified by methylene, ethylene, isopropylene and the like. Likewise, the term “alkenylene” as used herein represents an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon double bonds that may occur in any stable point along the chain, and the term “alkynylene” herein represents an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon triple bonds that may occur in any stable point along the chain. In certain embodiments, an alkylene, alkenylene, or alkynylene group may comprise one or more cyclic aliphatic and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur and may optionally be substituted with one or more substituents such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester or amide. For example, an alkylene, alkenylene, or alkynylene may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, -OCOR’, - OCO2R’, -NH2, -NHR’, -N(R’)2, -SR’ or -SO2R’, wherein each instance of R’ independently is C1–C20aliphatic (e.g., C1–C20alkyl, C1–C15alkyl, C1–C10alkyl, or C1–C3alkyl). In some embodiments, R’ independently is an unsubstituted alkyl (e.g., unsubstituted C1–C20alkyl, C1–C15alkyl, C1–C10alkyl, or C1–C3alkyl). In some embodiments, R’ independently is unsubstituted C1–C3alkyl. In certainembodiments, an alkylene, alkenylene, or alkynylene is unsubstituted. In certain embodiments, an alkylene, alkenylene, or alkynylene does not include any heteroatoms.

[0214] Alkenyl: As used herein, “alkenyl” means any linear or branched hydrocarbon chains having one or more unsaturated carbon-carbon double bonds that may occur in any stable point along the chain, e.g. “C2-C20alkenyl” refers to an alkenyl group having 2-20 carbons. For example, an alkenyl group includes 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, the alkenyl comprises 1, 2, or 3 carbon-carbon double bond. In some embodiments, the alkenyl comprises a single carbon-carbon double bond. In some embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. An alkenyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkenyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, -OCOR’, -OCO2R’, -NH2, -NHR’, - N(R’)2, -SR’ or-SO2R’, wherein each instance of R’ independently is C1–C20aliphatic (e.g., C1–C20alkyl, C1–C15alkyl, C1–C10alkyl, or C1–C3alkyl). In some embodiments, R’ independently is an unsubstituted alkyl (e.g., unsubstituted C1–C20alkyl, C1–C15alkyl, C1–C10alkyl, or C1–C3alkyl). In some embodiments, R’ independently is unsubstituted C1-C3alkyl. In some embodiments, the alkenyl is unsubstituted. In some embodiments, the alkenyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). In some embodiments, an alkenyl group is substituted with a– OH group and may also be referred to herein as a “hydroxyalkenyl” group, where the prefix denotes the –OH group and “alkenyl” is as described herein.

[0215] Alkynyl: As used herein, “alkynyl” means any hydrocarbon chain of either linear or branched configuration, having one or more carbon-carbon triple bonds occurring in any stable point along the chain, e.g. “C2-C20alkynyl” refers to an alkynyl group having 2-20 carbons. Examples of an alkynyl group include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2- ynyl, hex-5-ynyl, etc. In some embodiments, an alkynyl comprises one carbon-carbon triple bond. An alkynyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkynyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, -OCOR’, - OCO2R’, -NH2, -NHR’, -N(R’)2, -SR’ or-SO2R’, wherein each instance of R’ independently is C1–C20aliphatic (e.g., C1–C20alkyl, C1–C15alkyl, C1–C10alkyl, or C1–C3alkyl). In some embodiments, R’ independently is an unsubstituted alkyl (e.g., unsubstituted C1-C20alkyl, C1–C15alkyl, C1–C10alkyl, or C1–C3alkyl). In some embodiments, R’ independently is unsubstituted C1–C3alkyl. In some embodiments, the alkynyl is unsubstituted. In some embodiments, the alkynyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein).

[0216] Aryl: The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein said ring system has a single point of attachment to the rest of the molecule, at least one ring in the system is aromatic and wherein each ring in the system contains 4 to 7 ring members. In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl,” e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl,” e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl,” e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. In embodiments, an aryl (e.g., a C6-10aryl) comprises at least one substituent group that is a halogen (e.g., F, Cl, or Br) and may be referred to as an “arylhalo” group. In some embodiments, the aryl is attached to another group via an oxygen atom (e.g., having the structure -O- aryl, where aryl includes embodiments as described herein) and may also be referred to herein as “aryloxy” group. Exemplary aryls include phenyl, naphthyl, and anthracene.

[0217] Arylene: The term “arylene” as used herein refers to an aryl group that is divalent (that is, having two points of attachment to the molecule). Exemplary arylenes include phenylene (e.g., unsubstituted phenylene or substituted phenylene).

[0218] Halogen or Halo: As used herein, the term “halogen” or “halo” means fluorine, chlorine, bromine, or iodine.

[0219] Amide: The term “amide” or “amido” refers to a chemical moiety with formula -C(O)N(R’)2, -C(O)N(R’)-, -NR’C(O)R’, -NR’C(O)N(R’)2-, or -NR’C(O)-, where each R’is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein, or two R’ can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring.

[0220] Amino: The term “amino” or “amine” refers to a -N(R’)2group, where each R’is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), sulfonyl, amide or carbonyl group, unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein, or two R’ can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. In embodiments, an amino group is –NHR’, where R’ is aryl (“arylamino”), heteroaryl (“heteroarylamino”), amide or alkyl (“alkylamino”).

[0221] Carboxamide: The term “carboxamide” refers to a -C(=O)NH2, - C(=O)NHR’, -C(=O)N(R’)2, R’C(=O)NH-, or R’C(=O)NR’- group, where each R’ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), amino, cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein. For example, in one embodiment, a carboxamide group is -C(=O)NHR’, where R’ is a cycloalkyl group.

[0222] Ether: The term “ether” refers to a R’-O-R’ group, where each R’ is independently selected from alkyl, heteroalkyl (bonded through a chain carbon), arylalkyl, heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein.

[0223] Ester: The term “ester” refers to a R’-C(=O)O-R group, where each R’ is independently selected from alkyl, heteroalkyl (bonded through a chain carbon), arylalkyl, heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein.

[0224] Indole: The term “indole” refers to a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. The indole group can be substituted or unsubstituted.

[0225] Sulfanyl: The term “sulfanyl” refers to a -SH or -SR’ group, where R’ is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), amino, cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein. For example, in one embodiment, the sulfanyl group is -SR’, where R’ is a phenyl group.

[0226] Sulfonamide: The term “sulfonamide” refers to a -S(=O)2NH2, -S(=O)2NHR’, or -S(=O)2N(R’)2, where each R’ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), amino, cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein. For example, in one embodiment, the sulfonamide group is -S(=O)2NHR’, where R’ is a phenyl group.

[0227] Sulfonyl: The term “sulfonyl” refers to a -S(=O)2R’, or -S(=O)2- group, where R’is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), amino, cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon) and where ‘group’ may refer to any other molecular moiety (including as described herein). Unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein. For example, in one embodiment, the sulfonyl group is - SO2R’, where R’ is a phenyl group.

[0228] Sulfinyl: The term “sulfinyl” refers to a chemical moiety with formula -S(=O)R’, -S(=O)-, or -S(=O)(=NR’)-, where R’is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein.

[0229] Carbonyl: The term “carbonyl” refers to a -C(=O)R’, or -C(=O)- group, where R’is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, amino, hydroxyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein.

[0230] Phosphoryl: The term “phosphoryl” refers to a -P(=O)(R’)2, or -P(=O)(R’)- group, where R’is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon or through the heteroatom), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon) group, unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein, or two R’ can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring.

[0231] Heteroalkyl: The term “heteroalkyl” is meant a branched or unbranched alkyl, alkenyl, or alkynyl group having from 1 to 14 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls include tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl group may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. Examples of heteroalkyls include polyethers, such as methoxymethyl and ethoxyethyl.

[0232] Heteroalkylene: The term “heteroalkylene,” as used herein, represents a divalent form of a heteroalkyl group as described herein.

[0233] Heteroaryl: The term “heteroaryl,” as used herein, refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein said ringsystem has a single point of attachment to the rest of the molecule, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 4 to 7 ring members, and wherein at least one ring atom is a heteroatom such as, but not limited to, nitrogen and oxygen. A heteroaryl may be substituted or unsubstituted. Non-limiting examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

[0234] Heterocycloalkyl: The term “heterocycloalkyl” or “heterocyclyl” as used herein, is a non- aromatic ring wherein at least one atom is a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon, and with the proviso that the ring of said group does not contain two adjacent O or two adjacent S atoms. The heterocycloalkyl group can be substituted or unsubstituted. Exemplary heterocycloalkyl groups include diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, and tetrahydropyranyl.

[0235] Deuterium: The term “deuterium” (“D” or “2H”) is also called heavy hydrogen. Deuterium is isotope of hydrogen with a nucleus consisting of one proton and one neutron, which is double the mass of the nucleus of ordinary hydrogen (one proton).

[0236] Isotope: The term “isotope” refers to a variant of a particular chemical element which differs in neutron number, and consequently in nucleon number. All isotopes of a given element have the same number of protons but different numbers of neutrons in each atom.

[0237] The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system, e.g., the substitution results in a stable compound (e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction). In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.

[0238] When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl) is substituted with a number of substituents varying within an expressly defined range, it is understood that the total number of substituents does not exceed the normal available valencies under the existing conditions. It is alsounderstood that hydrogen atoms are presumed present to fill the remaining valence of a ring system. The substituted group encompasses only those combinations of substituents and variables that result in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one that, among other factors, has stability sufficient to permit its preparation and detection.

[0239] A wide variety of substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known. Representative substituents include but are not limited to alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, arylalkoxy, arylamino, heteroarylamino, heteroaryl, heteroarylalkoxy, heterocycloalkyl, hydroxyalkyl, aminoalkyl, alkylhalo, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino, dialkylamino, amide, cyano, alkoxy, hydroxy, sulfonamide, halo (e.g., —Cl and —Br), nitro, oximino, —COOR50, —COR50, —SO0-2R50, — S C(halo)2, ═S, ═O, —CON(R50R51), — Oand —N(R52)CON(R50(R51), wherein R50, R51and R52may be independently selected from the following: a hydrogen atom and a branched or straight-chain, C1–6-alkyl, C3–6-cycloalkyl, C4–6-heterocycloalkyl, heteroaryl and aryl group, with or without substituents. When permissible, R50and R51can be joined together to form a carbocyclic or heterocyclic ring system.

[0240] In preferred embodiments, the substituent is selected from halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, -OCOR’, -OCO2R’, -NH2, -NHR’, -N(R’)2, -SR’, and -SO2R’, wherein each instance of R’ independently is C1–C20aliphatic (e.g., C1–C20alkyl, C1–C15alkyl, C1–C10alkyl, or C1–C3alkyl). In certain embodiments thereof, R’ independently is an unsubstituted alkyl (e.g., unsubstituted C1–C20alkyl, C1–C15alkyl, C1–C10alkyl, or C1–C3alkyl). Preferably, R’ independently is unsubstituted C1–C3alkyl.

[0241] Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to embrace hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.Compounds of the Invention

[0242] Disclosed herein are compounds that are potent inhibitors of PHD. In some embodiments, the compounds of the present invention have enzymatic half maximal inhibitory concentration (IC50) values of less than 100 µM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of less than 50 µM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of less than 25 µM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of less than 20 µM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of less than 15 µM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of less than 10 µM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of less than 5 µM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of less than 1µM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of about 3 nM to about 5 nM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of about 5 nM to about 10 nM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of about 10 nM to about 20 nM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of about 20 nM to about 50 nM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of about 50 nM to about 100 nM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of about 100 nM to about 200 nM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of about 200 nM to about 500 nM against any one of PHD1, PHD2, and PHD3. In some embodiments, the compounds of the present invention have an IC50value of about 500 nM to about 1000 nM against any one of PHD1, PHD2, and PHD3.

[0243] In embodiments, the compounds of the present invention have an IC50value of less than about 10 nM against any one of PHD1, PHD2, and PHD3. In embodiments, the compounds of the present invention have an IC50value of less than about 100 nM against any one of PHD1, PHD2, and PHD3. In embodiments, the compounds of the present invention have an IC50value of less than about 1,000 nM against any one of PHD1, PHD2, and PHD3. In embodiments, the compounds of the present invention have an IC50value of less than about 10,000 nM against any one of PHD1, PHD2, and PHD3.

[0244] In embodiments, the compounds of the present invention have an IC50value of about 10 nM to about 100 nM any one of PHD1, PHD2, and PHD3. In embodiments, the compounds of the presentinvention have an IC50value of about 100 nM to about 1,000 nM any one of PHD1, PHD2, and PHD3. In embodiments, the compounds of the present invention have an IC50 value of about 1,000 nM to about 10,000 nM any one of PHD1, PHD2, and PHD3. In embodiments, the compounds of the present invention have an IC50value of greater than about 10,000 nM.

[0245] Representative examples from this class show inhibitory activity for PHD1, PHD2 and PHD3 in vitro.

[0246] Exemplary formulas and compounds are described herein. Compounds of Formulas (I)–(III)

[0247] Exemplary formulas and compounds are described herein. Also provided herein are exemplary embodiments of structural features which may be present in any formula or compound described herein. Any exemplary embodiment of a structural feature may occur in combination with any other exemplary structural feature(s) described herein. Formula (I)

[0248] In one aspect, the invention features a compound of Formula (I), R Ror a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, R1, R2, R3, R4, and R5is independently according to any embodiment and combinations thereof as described herein.

[0249] In embodiments of Formula (I), X1, X2, X3, and X5are each independently N, C, or CH; X4is independently N or C; R1is H, C1-3alkyl, or C1-3alkylhalo; R2is H, C1-3alkyl, or C1-3alkylhalo; R3and R4together with the atoms to which they are attached combine to form C5-6aryl or heteroaryl, optionally substituted with one or more groups selected from halo, alkyl, aryl,heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, and indole, optionally wherein an alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, and indole are each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxine or 44ioxolane and R5is H, C1-3alkyl, C1-3alkylhalo, C1-3alkoxy or aryl, or R5is absent with X4is N.

[0250] In embodiments, R1is -H. In embodiments, R1is C1-3alkyl (e.g., CH3, CH2CH3, (CH2)2CH3, or CH(CH3)2). In embodiments, R1is C1-3alkylhalo (e.g., C1-3alkyl comprising 1-5 halo groups or a perhalo C1-3alkyl, such as CH2F, CHF2, CF3, CH2CF3, or CF2CF3).

[0251] In embodiments, R2is -H. In embodiments, R2is C1-3alkyl (e.g., CH3, CH2CH3, (CH2)2CH3, or CH(CH3)2). In embodiments, R2is C1-3alkylhalo (e.g., C1-3alkyl comprising 1-5 halo groups or a perhalo C1-3alkyl, such as CH2F, CHF2, CF3, CH2CF3, or CF2CF3).

[0252] In embodiments, R1is H and / or R2is H. In embodiments, R1is H and R2is H.

[0253] In embodiments, one or more of X1, X2, X3, X4, and X5is independently N. In embodiments, one of X1, X2, X3, X4, and X5is independently N. In embodiments, two of X1, X2, X3, X4, and X5are each independently N. In embodiments, three of X1, X2, X3, X4, and X5are each independently N. In embodiments, one of X1and X2is independently N. In embodiments, one of X1and X2is independently N, and each of X3and X5is independently N. In embodiments, X4is C.

[0254] In embodiments, R3and R4together with the atoms to which they are attached combine to form C5-6aryl, optionally substituted with one or more groups selected from halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, and indole, optionally wherein an alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, and indole are each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxine or dioxolane.

[0255] In embodiments, R3and R4together with the atoms to which they are attached combine to form unsubstituted C5-6aryl. In embodiments, R3and R4together with the atoms to which they are attached combine to form unsubstituted C5aryl. In embodiments, R3and R4together with the atoms to which they are attached combine to form unsubstituted C6aryl.

[0256] In embodiments, R3and R4together with the atoms to which they are attached combine to form substituted C5-6 aryl. In embodiments, R3and R4together with the atoms to which they are attached combine to form substituted C5-6aryl comprising one or more substituents (e.g., C5-6aryl having 1-3 substituents, C5-6aryl having 1 substituent, C5-6aryl having 2 substituents, or C5-6aryl having 3 substituents). In embodiments, a substituent is selected from halo (e.g., F, Cl, or Br),

[0257] In embodiments, R3and R4together with the atoms to which they are attached combine to form heteroaryl (e.g., 5- to 6-membered heteroaryl), optionally substituted with one or more groups selected from halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, and indole, optionally wherein an alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, and indole are each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxine or dioxolane.

[0258] In embodiments, R3and R4together with the atoms to which they are attached combine to form unsubstituted heteroaryl (e.g., 5- to 6-membered heteroaryl). In embodiments, R3and R4together with the atoms to which they are attached combine to form unsubstituted 5-membered heteroaryl. In embodiments, R3and R4together with the atoms to which they are attached combine to form unsubstituted 6-membered heteroaryl.

[0259] In embodiments, R3and R4together with the atoms to which they are attached combine to form substituted heteroaryl (e.g., 5- to 6-membered heteroaryl). In embodiments, R3and R4together with the atoms to which they are attached combine to form substituted C5-6aryl comprising one or more substituents (e.g., heteroaryl (e.g., 5- to 6-membered heteroaryl) having 1-3 substituents, heteroaryl (e.g., 5- to 6-membered heteroaryl) having 1 substituent, heteroaryl (e.g., 5- to 6-membered heteroaryl) having 2 substituents, or heteroaryl (e.g., 5- to 6-membered heteroaryl) having 3 substituents).

[0260] In embodiments where R3and R4combine to form a substituted C5-6aryl or heteroaryl, the one or more optional substituents (e.g., 1, 2, 3, 4, or 5 substituent groups) may be selected from: - halo (e.g., F, Cl, or Br), - unsubstituted alkyl (e.g., C1-3alkyl) or substituted alkyl (e.g., C1-3alkyl) as described herein, - unsubstituted aryl (e.g., C6-10aryl) or substituted aryl (e.g., C6-10aryl) as described herein, - unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl such as 5- to 6-membered heteroaryl) or substituted heteroaryl (e.g., 5- to 10-membered heteroaryl such as 5- to 6- membered heteroaryl) as described herein,- unsubstituted alkoxy (e.g., C1-3alkoxy) or substituted alkoxy (e.g., C1-3alkoxy) as described herein, - unsubstituted aryloxy (e.g., C5-6aryloxy) or substituted aryloxy (e.g., C5-6aryloxy) as described herein, - unsubstituted cycloalkyl (e.g., C3-6 alkyl) or substituted cycloalkyl (e.g., C3-6 alkyl) as described herein, - unsubstituted heterocycloalkyl (e.g., 3- to 7-membered heterocycloalkyl) or substituted heterocycloalkyl (e.g., 3- to 7-membered heterocycloalkyl), - unsubstituted sulfanyl or substituted sulfanyl as described herein, - unsubstituted sulfonyl or substituted sulfonyl as described herein, - unsubstituted sulfonamide or substituted sulfonamide as described herein, - unsubstituted carboxamide or substituted carboxamide as described herein, and - unsubstituted indole or substituted indole as described herein.

[0261] In embodiments, R5is -H. In embodiments, R5is C1-3alkyl (e.g., CH3, CH2CH3, (CH2)2CH3, or CH(CH3)2). In embodiments, R5is C1-3alkylhalo (e.g., C1-3alkyl comprising 1-5 halo groups or a perhalo C1-3alkyl, such as CH2F, CHF2, CF3, CH2CF3, or CF2CF3). In embodiments, R5is C1-3alkoxy (e.g., OCH3, OCH2CH3, O(CH2)2CH3, or OCH(CH3)2). In embodiments, R5is aryl (e.g. C6-10 aryl which is substituted or unsubstituted). Formula (II)

[0262] In embodiments, a compound of Formula (I) has a structure according for Formula (II), m, pharmaceutically acceptable saltthereof, wherein each of X1, X2, X3, X4, X5, Y1, Y2, Y3, R1, R2, R5, R6, and m is independently according to any embodiment and combinations thereof as described herein.

[0263] In embodiments of Formula (II), X1, X2, X3, and X5are each independently N, C, or CH; X4is independently N or C;Y1, Y2, and Y3are each independently N, C, or CH; R1is H or C1-3 alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, C1-3alkoxy, or aryl, or R5is absent with X4is N; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane; and m is 0, 1, 2, or 3.

[0264] In embodiments, m is 0.

[0265] In embodiments, m is 1, 2, or 3.

[0266] In embodiments, m is 1.

[0267] In embodiments, m is 2.

[0268] In embodiments, m is 3.

[0269] In embodiments, R1is H.

[0270] In embodiments, R2is H.

[0271] In embodiments, R1is H and / or R2is H. In embodiments, R1is H and R2is H.

[0272] In embodiments, R1is H, R2is H, and / or R5is H. In embodiments, R1is H, R2is H, and R5is H.

[0273] In embodiments, one or more of X1, X2, X3, X4, and X5is independently N. In embodiments, one of X1, X2, X3, X4, and X5is independently N. In embodiments, two of X1, X2, X3, X4, and X5are each independently N. In embodiments, three of X1, X2, X3, X4, and X5are each independently N. In embodiments, one of X1and X2is independently N. In embodiments, one of X1and X2is independently N, and each of X3and X5is independently N. In embodiments, X4is C.

[0274] In embodiments, a compound of Formula (I) has a structure according to Formula (IIa), mor a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R6, and m is independently according to any embodiment and combinations thereof as described herein.

[0275] In embodiments of Formula (IIa), R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, C1-3alkoxy, or aryl; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxine or dioxoline; and m is 0, 1, 2, or 3.

[0276] In embodiments, m is 0.

[0277] In embodiments, m is 1, 2, or 3.

[0278] In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3.

[0279] In embodiments, a compound of Formula (IIa) has a structure according to Formula (IIa-1),a- or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, and R6is independently according to any embodiment and combinations thereof as described herein.

[0280] In embodiments, a compound of Formula (IIa) has a structure according to Formula (IIa-2), Ror a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, and R6is independently according to any embodiment and combinations thereof as described herein.

[0281] In embodiments, R1is -H.

[0282] In embodiments, R2is -H.

[0283] In embodiments, R5is -H.

[0284] In embodiments, R6is -H.

[0285] In embodiments, one or more (e.g., 1, 2, 3, or 4) of R1, R2, R5, and R6is -H. In embodiments, R1is H and R2is H. In embodiments, R1is H, R2is H, and R5is H. In embodiments, R1is H, R2is H, and R6is H. In embodiments, each of R1, R2, R5, and R6is -H.

[0286] In embodiments, R5is alkoxy (e.g., C1-3alkoxy such as OCH3, OCH2CH3, O(CH2)2CH3, or OCH(CH3)2). In embodiments, the alkoxy is methoxy. In embodiments, the alkoxy is ethoxy.

[0287] In embodiments, R5is alkylhalo (e.g., C1-3alkyl comprising 1-5 halo groups or a perhalo C1-3alkyl, such as CH2F, CHF2, CF3, CH2CF3, or CF2CF3). In embodiments, the alkylhalo is -CF3.

[0288] In embodiments, R5is alkyl (e.g., C1-3alkyl such as CH3, CH2CH3, (CH2)2CH3, or CH(CH3)2). In embodiments, the alkyl is -CH3.

[0289] In embodiments, R5is aryl (e.g., C6-10aryl such as phenyl or naphthyl). In embodiments, R5is.

[0290] In embodiments, R6is halo. In embodiments, halo is -Cl. In embodiments, halo is -Br. In embodiments, halo is -F.

[0291] In embodiments, R6is alkyl (e.g., C1-3alkyl), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0292] In embodiments, R6is alkyl (e.g., C1-3alkyl), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0293] In embodiments, R6is alkyl (e.g., C1-3alkyl), optionally substituted with halo or phenyl. In embodiments, R6is unsubstituted. In embodiments, R6is substituted by 1-5 substituent groups (e.g., 1, 2, or 3 substituent groups) as valency permits.

[0294] In embodiments, R6is CH3, CH2CH3, (CH2)2CH3, or CH(CH3)2). In embodiments, R6is methyl. In embodiments, R6is alkyl (e.g., C1-3alkyl) substituted with 1-5 halogens (e.g., F). In embodiments, R6is -CF3. In embodiments, R6is alkyl (e.g., C1-3alkyl) substituted by phenyl. In embodiments, R.

[0295] In embodiments, R6is aryl (e.g., C6-10aryl such as phenyl or naphthyl), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0296] In embodiments, R6is aryl (e.g., C6-10aryl such as phenyl or naphthyl), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0297] In embodiments, R6is aryl (e.g., C6-10aryl such as phenyl or naphthyl), optionally substituted with halo (e.g., F, Cl, or Br), cyano, alkyl (e.g., C1-3alkyl such as CH3, CH2CH3, (CH2)2CH3, or CH(CH3)2), or alkylhalo (e.g., C1-3alkyl comprising 1-5 halo groups or a perhalo C1-3alkyl, such as CH2F, CHF2, CF3, CH2CF3, or CF2CF3). In embodiments, R6is unsubstituted. In embodiments, R6is substituted by 1-5 substituent groups (e.g., 1, 2, or 3 substituent groups) as valency permits. In embodiments, R6(e.g., C6-10aryl such as phenyl or naphthyl) is substituted by 1 or 2 substituent groups. In embodiments, a substituent group is selected from CN, CF3, F, Cl, or CH3.

[0298] In embodiments, R6is a 2-substituted phenyl group (i.e., an ortho-substituted phenyl group). In embodiments, a substituent group is selected from CN, CF3, F, Cl, or CH3.

[0299] In embodiments, R6is a 3-substituted phenyl group (i.e., a meta-substituted phenyl group). In embodiments, a substituent group is selected from CN, CF3, F, Cl, or CH3.

[0300] In embodiments, R6is a 4-substituted phenyl group (i.e., a para-substituted phenyl group). In embodiments, a substituent group is selected from CN, CF3, F, Cl, or CH3.

[0301] In embodiments, R6is a 3,5-disubstituted phenyl group. In embodiments, a substituent group is selected from CN, CF3, F, Cl, or CH3. [ [, . , . [ e, . , . ,. e o e s, s . e o e s, s .

[0305] In embodiments, R6is aryloxy (e.g., C6-10aryloxy such as phenol or naphthol), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl,arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0306] In embodiments, R6is aryloxy (e.g., C6-10aryloxy such as phenol or naphthol), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0307] In embodiments, R6is aryloxy (e.g., C6-10aryloxy such as phenol or naphthol), optionally substituted with alkyl (e.g., C1-3alkyl such as CH3, CH2CH3, (CH2)2CH3, or CH(CH3)2)), halo (e.g., F, Cl, or Br), or alkoxy (e.g., C1-3alkoxy such as OCH3, OCH2CH3, O(CH2)2CH3, or OCH(CH3)2). In embodiments, R6is unsubstituted. In embodiments, R6is substituted by 1-5 substituent groups (e.g., 1, 2, or 3 substituent groups) as valency permits. In embodiments, R6(e.g., C6-10aryloxy such as phenol or naphthol) is substituted by 1 or 2 substituent groups. In embodiments, a substituent group is selected from F, Cl, CH3, or OCH3. Rs .

[0310] In embodiments, R6is cycloalkyl (e.g., C3-6cycloalkyl such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0311] In embodiments, R6is cycloalkyl (e.g., C3-6cycloalkyl such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0312] In embodiments, R6is cycloalkyl (e.g., C3-6cycloalkyl such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane). In embodiments, R6is cyclopropane. In embodiments, R6is cyclohexane.

[0313] In embodiments, R6is a sulfonyl group, optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0314] In embodiments, R6is a sulfonyl group. In embodiments,.

[0315] In embodiments, R6is a sulfanyl group, optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0316] In embodiments, R6is a sulfanyl group that is.

[0317] In embodiments, R6is sulfonamide, optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane. In embodiments, R6is selected from the group consisting of,. e o e s, s .

[0318] In embodiments, R6is sulfonamide, optionally substituted with one or more groups selected from aryl (e.g., C6-10 aryl such as phenyl or naphthyl) and cycloalkyl (e.g., C3-6 cycloalkyl such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane).

[0319] In embodiments, R6is carboxamide, optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0320] In embodiments, R6is carboxamide, optionally substituted with one or more groups selected from alkyl (e.g., a C1-4alkyl such as CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, or C(CH3)3), alkaryl (e.g., benzyl), and cycloalkyl (e.g., C3-6cycloalkyl such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane). In embodiments, R6is selected from the group consisting oe.

[0321] In embodiments, R6is heteroaryl (e.g., 5- to 10-membered heteroaryl), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0322] In embodiments, R6is heteroaryl (e.g., 5- to 10-membered heteroaryl), optionally substituted with aryl (e.g., a C6-10aryl such as phenyl or naphthyl), cycloalkyl (e.g., C3-6cycloalkyl such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane), alkyl alkyl (e.g., C1-3 alkyl such as CH3, CH2CH3, (CH2)2CH3, or CH(CH3)2), or arylhalo (e.g., C6-10aryl such as phenyl or naphthyl comprising 1-5 halo groups or a perhalo C6-10aryl such as perhalo-phenyl or perhalo-naphthyl). In embodiments, R6is unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl). In embodiments, R6is substituted heteroaryl (e.g., 5- to 10-membered heteroaryl).

[0323] In embodiments, R6is a 5- to 10-membered heteroaryl (e.g., a 5- to 6-membered heteroaryl) comprising at least one nitrogen. In embodiments, R6is a C-linked heteroaryl. In embodiments, R6is an N-linked heteroaryl. In embodiments, R6is 5- to 10-membered heteroaryl (e.g., a 5- to 6-membered heteroaryl) comprising 1-3 nitrogens. In embodiments, R6is pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, cinnoline, indole, benzimidazole, indazole, or benzotriazole. In embodiments, R6is unsubstituted. In embodiments, R6is substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane. In embodiments, R6is substituted (e.g., substituted with halo (e.g., F, Cl, or Br), cyano, alkyl (e.g., C1-3alkyl such as CH3, CH2CH3, (CH2)2CH3, or CH(CH3)2), or alkylhalo (e.g., C1-3alkyl comprising 1-5 halo groups or a perhalo C1-3alkyl, such as CH2F, CHF2, CF3, CH2CF3, or CF2CF3). In embodiments, R6is substituted with CH3.

[0324] In embodiments, R6is an optionally substituted 5- to 6-membered heteroaryl comprising 1 or 2 nitrogen atoms (e.g., pyridyl or pyrazole). In embodiments, R6is unsubstituted. [.[ [ [ [ [ [3] n emo ments, s .

[0332] Inemo mens, s.

[0333] In embodiments,

[0334] In embodiments, R6is heterocycloalkyl (e.g., 3- to 9-membered heterocycloalkyl), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0335] In embodiments, R6is heterocycloalkyl (e.g., 3- to 9-membered heterocycloalkyl). In embodiments, R6is heterocycloalkyl (e.g., 3- to 9-membered heterocycloalkyl) comprising 1 or 2 heteroatoms. In embodiments, R6is heterocycloalkyl (e.g., 3- to 9-membered heterocycloalkyl) comprising at least one nitrogen or oxygen atom. In embodiments, R6is heterocycloalkyl (e.g., 3- to 9- membered heterocycloalkyl) comprising at least one sulfur atom.

[0336] In embodiments, R6is heterocycloalkyl, optionally substituted with aryl (e.g., C6-10aryl such as phenyl or naphthyl).

[0337] In embodiments, R6is selected from the group consisting of:, [, . embodiments, Rs . n embodiments, Rs .

[0339] In embodiments, R6is alkoxy. In embodiments, Rs .

[0340] In embodiments, a compound of Formula (I) has a structure according to Formula (IIb), m(IIb), or a pharmaceutically acceptable saltthereof, wherein each of R1, R2, R5, R6, Y1, and m is independently according to any embodiment and combinations thereof as described herein.

[0341] In embodiments of Formula (IIb), Y1is N, C, or CH; R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, C1-3alkoxy, or aryl; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; and m is 0, 1, 2, or 3.

[0342] In embodiments, m is 0.

[0343] In embodiments, m is 1, 2, or 3.

[0344] In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3.

[0345] In embodiments, a compound of Formula (IIb) has a structure according to Formula (IIb-1),- , o a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R6, and Y1is independently according to any embodiment and combinations thereof as described herein.

[0346] In embodiments, a compound of Formula (IIb) has a structure according to Formula (IIb-2), Rpharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R6, and Y1is independently according to any embodiment and combinations thereof as described herein.

[0347] In embodiments, Y1is N or CH.

[0348] In embodiments, Y1is N.

[0349] In embodiments, R1is H.

[0350] In embodiments, R2is H.

[0351] In embodiments, R5is H.

[0352] In embodiments, one or more of R1, R2, and R5is -H. In embodiments, R1is H and R2is H. In embodiments, R1is H, R2is H, and R5is H.

[0353] In embodiments, R6is aryl (e.g., C6-10 aryl such as phenyl or naphthyl), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0354] In embodiments, R6is aryl (e.g., C6-10aryl such as phenyl or naphthyl) optionally substituted with halo (e.g., F, Cl, or Br).

[0355] In embodiments, R6is a 2-substituted phenyl group (i.e., an ortho-substituted phenyl group). In embodiments, a substituent group is selected from F, Cl, or Br.

[0356] In embodiments, R6is a 3-substituted phenyl group (i.e., a meta-substituted phenyl group). In embodiments, a substituent group is selected from F, Cl, or Br.

[0357] In embodiments, R6is a 4-substituted phenyl group (i.e., a para-substituted phenyl group). In embodiments, a substituent group is selected from F, Cl, or Br.

[0358] In embodiments, R6 is selected from the group consisting of:,[ e

[0360] In embodiments, a compound of Formula (I) has a structure according to Formula (IIc), m,thereof, wherein each of R1, R2, R5, R6, Y2, and m is independently according to any embodiment and combinations thereof as described herein.

[0361] In embodiments of Formula (IIc), Y2is N, C, or CH; R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; and m is 0, 1, 2, or 3.

[0362] In embodiments, m is 0.

[0363] In embodiments, m is 1, 2, or 3.

[0364] In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3.

[0365] In embodiments, a compound of Formula (II-c) has a structure according to Formula (IIc-1), Y(IIc-1), or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R6, and Y2is independently according to any embodiment and combinations thereof as described herein.

[0366] In embodiments, a compound of Formula (II-c) has a structure according to Formula (IIc-2), R(IIc-2), or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R6, and Y2is independently according to any embodiment and combinations thereof as described herein.

[0367] In embodiments, Y2is N.

[0368] In embodiments, R1is H.

[0369] In embodiments, R2is H.

[0370] In embodiments, R5is H.

[0371] In embodiments, one or more of R1, R2, and R5is -H. In embodiments, R1is H and R2is H. In embodiments, R1is H, R2is H, and R5is H.

[0372] In embodiments, R6is aryl (e.g., C6-10aryl such as phenyl or naphthyl), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0373] In embodiments, R6is aryl (e.g., C6-10aryl such as phenyl or naphthyl) optionally substituted with halo (e.g., F, Cl, or Br).

[0374] In embodiments, R6is a 2-substituted phenyl group (i.e., an ortho-substituted phenyl group). In embodiments, a substituent group is selected from F, Cl, or Br.

[0375] In embodiments, R6is a 3-substituted phenyl group (i.e., a meta-substituted phenyl group). In embodiments, a substituent group is selected from F, Cl, or Br.

[0376] In embodiments, R6is a 4-substituted phenyl group (i.e., a para-substituted phenyl group). In embodiments, a substituent group is selected from F, Cl, or Br.

[0377] In embodiments, R6 is selected from the group consisting of:,[ e, . , .

[0379] In embodiments, a compound of Formula (I) has a structure according to Formula (IId), mor a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R6, Y3, and m is independently according to any embodiment and combinations thereof as described herein.

[0380] In embodiments of Formula (IId), Y3is N, C, or CH; R1is H or C1-3alkyl;R2is H or C1-3alkyl; R5is H, C1-3 alkyl, C1-3 alkylhalo, or C1-3 alkoxy; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; and m is 0, 1, 2, or 3.

[0381] In embodiments, m is 0.

[0382] In embodiments, m is 1, 2, or 3.

[0383] In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3.

[0384] In embodiments, a compound of Formula (IId) has a structure according to Formula (IId-1), Ror a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R6, and Y3is independently according to any embodiment and combinations thereof as described herein.

[0385] In embodiments, Y3is N.

[0386] In embodiments, R1is H.

[0387] In embodiments, R2is H.

[0388] In embodiments, R5is H.

[0389] In embodiments, one or more of R1, R2, and R5is -H. In embodiments, R1is H and R2is H. In embodiments, R1is H, R2is H, and R5is H.

[0390] In embodiments, R6is aryl (e.g., C6-10aryl such as phenyl or naphthyl), optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane.

[0391] In embodiments, R6is aryl (e.g., C6-10aryl such as phenyl or naphthyl) optionally substituted with halo (e.g., F, Cl, or Br).

[0392] In embodiments, R6is a 2-substituted phenyl group (i.e., an ortho-substituted phenyl group). In embodiments, a substituent group is selected from F, Cl, or Br.

[0393] In embodiments, R6is a 3-substituted phenyl group (i.e., a meta-substituted phenyl group). In embodiments, a substituent group is selected from F, Cl, or Br.

[0394] In embodiments, R6is a 4-substituted phenyl group (i.e., a para-substituted phenyl group). In embodiments, a substituent group is selected from F, Cl, or Br.

[0395] In embodiments, R6is selected from the group consisting of,

[0396] In embodiments, R6is. In embodiments, R6is. embodiments, R6is. In embodiments, R.

[0397] In embodiments, a compound of Formula (I) has a structure according to Formula (IIe), m(IIe), or a pharmaceutically acceptable saltthereof, wherein each of R1, R2, R5, R6, and m is independently according to any embodiment and combinations thereof as described herein.

[0398] In embodiments of Formula (IIe), R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or moregroups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; and m is 0, 1, 2, or 3.

[0399] In embodiments, m is 0.

[0400] In embodiments, m is 1, 2, or 3.

[0401] In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3.

[0402] In embodiments, a compound of Formula (IIe) has a structure according to Formula (IIe-1),(IIe-1), or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, and R6is independently according to any embodiment and combinations thereof as described herein.

[0403] In embodiments, a compound of Formula (IIe) has a structure according to Formula (IIe-2), R, pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, and R6is independently according to any embodiment and combinations thereof as described herein.

[0404] In embodiments, R1is H.

[0405] In embodiments, R2is H.

[0406] In embodiments, R5is H.

[0407] In embodiments, R6is H.

[0408] In embodiments, one or more (e.g., 1, 2, 3, or 4) of R1, R2, R5, and R6is -H. In embodiments, R1is H and R2is H. In embodiments, R1is H, R2is H, and R5is H. In embodiments, R1is H, R2is H, and R6is H. In embodiments, each of R1, R2, R5, and R6is -H.

[0409] In embodiments, R6is halo (e.g., F, Cl, or Br). In embodiments, R6is Cl. In embodiments, R1is H, R2is H, and R5is H.

[0410] In embodiments, a compound of Formula (I) has a structure according to Formula (IIf), mpharmaceutically acceptable saltthereof, wherein each of R1, R2, R5, R6, and m is independently according to any embodiment and combinations thereof as described herein.

[0411] In embodiments of Formula (IIf), R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R6is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; and m is 0, 1, 2, or 3.

[0412] In embodiments, m is 0.

[0413] In embodiments, m is 1, 2, or 3.

[0414] In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3.

[0415] In embodiments, a compound of Formula (IIf) has a structure according to Formula (IIf-1),pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, and R6is independently according to any embodiment and combinations thereof as described herein.

[0416] In embodiments, a compound of Formula (IIf) has a structure according to Formula (IIf-2), Rpharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, and R6is independently according to any embodiment and combinations thereof as described herein.

[0417] In embodiments, R1is H.

[0418] In embodiments, R2is H.

[0419] In embodiments, R5is H.

[0420] In embodiments, R6is H.

[0421] In embodiments, one or more (e.g., 1, 2, 3, or 4) of R1, R2, R5, and R6is -H. In embodiments, R1is H and R2is H. In embodiments, R1is H, R2is H, and R5is H. In embodiments, R1is H, R2is H, and R6is H. In embodiments, each of R1, R2, R5, and R6is -H.

[0422] In embodiments, R6is halo (e.g., F, Cl, or Br). In embodiments, R6is Cl. In embodiments, R1is H, R2is H, and R5is H.Formula (III)

[0423] In embodiments, a compound of Formula (I) has a structure according to Formula (III), nor a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, Z1, Z2, Z3, R1, R2, R5, R7, and n is independently according to any embodiment and combinations thereof as described herein.

[0424] In embodiments of Formula (III), X1, X2, X3, and X5are each independently N, C, or CH; X4is independently N or C; Y1, Y2, and Y3are each independently N, C, or CH; Z1, Z2, and Z3are each independently N, C, CH, S, or O; R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, C1-3alkoxy or aryl, or R5is absent with X4is N; R7is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; and n is 0, 1, 2, or 3.

[0425] In embodiments, n is 0.

[0426] In embodiments n is 1, 2, or 3.

[0427] In embodiments, n is 1.

[0428] In embodiments, n is 2.

[0429] In embodiments, n is 3.

[0430] In embodiments, R1is -H.

[0431] In embodiments, R2is -H.

[0432] In embodiments, R1is H and / or R2is H. In embodiments, R1is H and R2is H.

[0433] In embodiments, one or more of X1, X2, X3, X4, and X5is independently N. In embodiments, one of X1, X2, X3, X4, and X5is independently N. In embodiments, two of X1, X2, X3, X4, and X5are each independently N. In embodiments, three of X1, X2, X3, X4, and X5are each independently N. In embodiments, one of X1and X2is independently N. In embodiments, one of X1and X2is independently N, and each of X3and X5is independently N. In embodiments, X4is C.

[0434] In embodiments, a compound of Formula (I) has a structure according to Formula (IIIa), n(IIIa) or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R7, Z1, and n is independently according to any embodiment and combinations thereof as described herein.

[0435] In embodiments of Formula (IIIa), Z1is N, C, CH, S, or O; R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R7is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; and n is 0, 1, 2, or 3.

[0436] In embodiments, n is 0.

[0437] In embodiments, n is 1, 2, or 3.

[0438] In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.

[0439] In embodiments, Z1is N.

[0440] In embodiments, Z1is O.

[0441] In embodiments, Z1is S.

[0442] In embodiments, R1is H.

[0443] In embodiments, R2is H.

[0444] In embodiments, R5is H.

[0445] In embodiments, R7is H.

[0446] In embodiments, one or more (e.g., 1, 2, 3, or 4) of R1, R2, R5, and R7is -H. In embodiments, R1is H and R2is H. In embodiments, R1is H, R2is H, and R5is H. In embodiments, R1is H, R2is H, and R7is H. In embodiments, each of R1, R2, R5, and R7is -H.

[0447] In embodiments, a compound of Formula (I) has a structure according to Formula (IIIb), n(IIIb) or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R7, Z3, and n is independently according to any embodiment and combinations thereof as described herein.

[0448] In embodiments of Formula (IIIb), Z3is N, C, CH, S, or O; R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R7is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; and n is 0, 1, 2, or 3.

[0449] In embodiments, n is 0.

[0450] In embodiments, n is 1, 2, or 3.

[0451] In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.

[0452] In embodiments, Z3is N.

[0453] In embodiments, Z3is S.

[0454] In embodiments, Z3is O.

[0455] In embodiments, R1is H.

[0456] In embodiments, R2is H.

[0457] In embodiments, R5is H.

[0458] In embodiments, R7is H.

[0459] In embodiments, one or more (e.g., 1, 2, 3, or 4) of R1, R2, R5, and R7is -H. In embodiments, R1is H and R2is H. In embodiments, R1is H, R2is H, and R5is H. In embodiments, R1is H, R2is H, and R7is H. In embodiments, each of R1, R2, R5, and R7is -H.

[0460] In embodiments, R7is aryl (e.g., C6-10aryl such as phenyl or naphthyl). In embodiments, R1is H, R2is H, and R5is H.

[0461] In embodiments, R7is arylhalo (e.g., C6-10aryl such as phenyl or naphthyl comprising 1-5 halo groups or a perhalo C6-10aryl). In embodiments, R7is phenyl comprising one or more Cl groups. embodiments, R7is phenyl substituted by Cl. In embodiments, R7is.

[0462] In embodiments, a compound of Formula (I) has a structure according to Formula (IIIc), n, pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R7, Z2, Z3, and n is independently according to any embodiment and combinations thereof as described herein.

[0463] In embodiments of Formula (IIIc), Z2and Z3are each independently N, C, CH, S, or O; R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R7is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; andn is 0, 1, 2, or 3.

[0464] In embodiments, n is 0.

[0465] In embodiments, n is 1, 2, or 3.

[0466] In embodiments, n is 1.

[0467] In embodiments, n is 2.

[0468] In embodiments, n is 3.

[0469] In embodiments, a compound of Formula (IIIc) has a structure according to Formula (IIIc- 1), Zpharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R7, Z2, and Z3is independently according to any embodiment and combinations thereof as described herein.

[0470] In embodiments, Z2 is N.

[0471] In embodiments, Z2is S.

[0472] In embodiments, Z2is O.

[0473] In embodiments, Z3is N.

[0474] In embodiments, Z3is S.

[0475] In embodiments, Z3is O.

[0476] In embodiments, each of Z2and Z3is N.

[0477] In embodiments, R1is H.

[0478] In embodiments, R2is H.

[0479] In embodiments, R5is H.

[0480] In embodiments, R7is H.

[0481] In embodiments, one or more (e.g., 1, 2, 3, or 4) of R1, R2, R5, and R7is -H. In embodiments, R1is H and R2is H. In embodiments, R1is H, R2is H, and R5is H. In embodiments, R1is H, R2is H, and R7is H. In embodiments, each of R1, R2, R5, and R7is -H.

[0482] In embodiments, R7is aryl (e.g., C6-10aryl such as phenyl or naphthyl). In embodiments, R1is H, R2is H, and R5is H.

[0483] In embodiments, R7is arylhalo.

[0484] In embodiments, R7is arylhalo (e.g., C6-10aryl such as phenyl or naphthyl comprising 1-5 halo groups or a perhalo C6-10aryl). In embodiments, R7is phenyl comprising one or more Cl groups. embodiments, R7is phenyl substituted by Cl. In embodiments, R7is.

[0485] In embodiments, a compound of Formula (I) has a structure according to Formula (IIId), n(IIId) or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R7, Z1, Z2, and n is independently according to any embodiment and combinations thereof as described herein.

[0486] In embodiments of Formula (IIId), Z1and Z2are each independently N, C, CH, S, or O; R1is H or C1-3alkyl; R2is H or C1-3alkyl; R5is H, C1-3alkyl, C1-3alkylhalo, or C1-3alkoxy; R7is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; and n is 0, 1, 2, or 3.

[0487] In embodiments, n is 0.

[0488] In embodiments, n is 1, 2, or 3.

[0489] In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.

[0490] In embodiments, Z1is N.

[0491] In embodiments, Z1is S.

[0492] In embodiments, Z1 is O.

[0493] In embodiments, Z2is N.

[0494] In embodiments, each of Z1 and Z2 is N.

[0495] In embodiments, a compound of Formula (IIId) has a structure according to Formula (IIId- 1), Zpharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R7, Z1, and Z2is independently according to any embodiment and combinations thereof as described herein.

[0496] In embodiments, Z1is N.

[0497] In embodiments, each of Z1and Z2is N.

[0498] In embodiments, R1is H.

[0499] In embodiments, R2is H.

[0500] In embodiments, R5is H.

[0501] In embodiments, R7is H.

[0502] In embodiments, one or more (e.g., 1, 2, 3, or 4) of R1, R2, R5, and R7is -H. In embodiments, R1is H and R2is H. In embodiments, R1is H, R2is H, and R5is H. In embodiments, R1is H, R2is H, and R7is H. In embodiments, each of R1, R2, R5, and R7is -H.

[0503] In embodiments, R7is aryl (e.g., C6-10aryl such as phenyl or naphthyl). In embodiments, R1is H, R2is H, and R5is H.

[0504] In embodiments, R7is arylhalo (e.g., C6-10aryl such as phenyl or naphthyl comprising 1-5 halo groups or a perhalo C6-10aryl). In embodiments, R7is phenyl comprising one or more Cl groups. 77embodiments, R is phenyl substituted by Cl. In embodiments, R is .Exemplary Compounds

[0505] In some embodiments, the PHD inhibitor compounds is any one of Compounds (1)-(118) of Table A or a pharmaceutically acceptable salt thereof. Table A. Exemplary Compounds

[0506] In embodiments, a compound is Compound (1), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (2), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (3), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (4), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (5), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (6), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (7), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (8), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (9), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (10), or a pharmaceutically acceptable salt thereof.

[0507] In embodiments, a compound is Compound (11), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (12), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (13), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (14), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (15), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (16), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (17), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (18), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (19), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (20), or a pharmaceutically acceptable salt thereof.

[0508] In embodiments, a compound is Compound (21), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (22), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (23), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (24), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (25), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (26), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (27), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (28), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (29), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (30), or a pharmaceutically acceptable salt thereof.

[0509] In embodiments, a compound is Compound (31), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (32), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (33), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (34), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (35), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (36), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (37), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (38), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (39), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (40), or a pharmaceutically acceptable salt thereof.

[0510] In embodiments, a compound is Compound (41), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (42), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (43), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (44), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (45), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (46), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (47), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (48), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (49), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (50), or a pharmaceutically acceptable salt thereof.

[0511] In embodiments, a compound is Compound (51), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (52), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (53), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (54), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (55), or a pharmaceutically acceptable salt thereof. Inembodiments, a compound is Compound (56), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (57), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (58), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (59), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (60), or a pharmaceutically acceptable salt thereof.

[0512] In embodiments, a compound is Compound (61), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (62), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (63), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (64), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (65), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (66), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (67), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (68), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (69), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (70), or a pharmaceutically acceptable salt thereof.

[0513] In embodiments, a compound is Compound (71), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (72), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (73), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (74), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (75), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (76), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (77), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (78), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (79), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (80), or a pharmaceutically acceptable salt thereof.

[0514] In embodiments, a compound is Compound (81), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (82), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (83), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (84), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (85), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (86), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (87), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (88), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (89), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (90), or a pharmaceutically acceptable salt thereof.

[0515] In embodiments, a compound is Compound (91), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (92), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (93), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (94), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (95), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (96), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (97), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (98), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (99), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (100), or a pharmaceutically acceptable salt thereof.

[0516] In embodiments, a compound is Compound (101), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (102), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (103), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (104), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (105), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (106), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (107), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (108), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (109), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (110), or a pharmaceutically acceptable salt thereof.

[0517] In embodiments, a compound is Compound (111), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (112), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (113), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (114), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (115), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (116), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (117), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound (118), or a pharmaceutically acceptable salt thereof. Isotopologues

[0518] It should be understood that in the compounds described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass ormass number predominately found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the compounds described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)). For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H). Protium is the predominant hydrogen isotope found in nature.

[0519] In some embodiments, one or more of the hydrogens of the compounds described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)) is replaced by a deuterium. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. In some embodiments, one or more of the hydrogens of the compounds described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)) is replaced by tritium. Tritium is radioactive and may therefore provide for a radiolabeled compound, useful as a tracer in metabolic or kinetic studies.

[0520] Isotopic-enrichment of compounds disclosed herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)), may be achieved without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0521] The term “isotopologue” refers to a species that has the same chemical structure and formula as a specific compound provided herein, with the exception of the positions of isotopic substitution and / or level of isotopic enrichment at one or more positions, e.g., hydrogen vs. deuterium. Thus, the term “compound,” as used herein, encompasses a collection of molecules having identical chemical structure, but also having isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound provided depends upon a number of factors including, but not limited to, the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.

[0522] When a position is designated as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. When a position is designated as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term “D” or “deuterium” indicates at least 50.1% incorporation of deuterium).

[0523] In embodiments, a compound provided herein may have an isotopic enrichment factor for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Synthesis of Compounds of the Inventions

[0524] The compounds described herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)) can be prepared according to methods known in the art, including the exemplary syntheses of the Examples provided herein.

[0525] Abbreviations and acronyms used herein including the following:Compositions and Methods

[0526] The invention provides for use of a compound of any one of Formulas (I)–(III), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treating various conditions or disorders as described herein. In one embodiment, a pharmaceutical composition is provided comprising at least one compound of any one of Formulas (I)–(III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In various embodiments, the medicament or pharmaceutical composition can further comprise or be used in combination with at least one additional therapeutic agent.

[0527] The compounds of the present invention, or medicaments or compositions comprising the compounds, can be used to inhibit the activity of PHD. Inhibition of PHD may be of particular benefit in treating diseases including heart (e.g. ischemic heart disease, congestive heart failure, and valvular heart disease), lung (e.g., lung inflammation, pneumonia, acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), respiratory (e.g., respiratory infection, acute respiratory distress syndrome), liver (e.g. acute liver failure and liver fibrosis and cirrhosis), and kidney (e.g. acute kidney injury and chronic kidney disease) disease, inflammatory bowel disease (IBD), ischemic reperfusion injury (e.g., stroke), retinopathy of prematurity (ROP), and cancer (e.g., colorectal cancer or a blood cancer (e.g., leukemia or myeloma such as acute myeloid leukemia, chronic myeloid leukemia, or multiple myeloma). In embodiments, a disease is heart, lung, respiratory, liver, or kidney disease. In embodiments, a disease is inflammatory bowel disease (IBD). In embodiments, a disease is ischemic reperfusion injury (e.g., stroke). In embodiments, a disease is retinopathy of prematurity (ROP). In embodiments, a disease is cancer. In embodiments, a cancer is colorectal cancer. In embodiments, a cancer is a blood cancer (e.g., leukemia or myeloma such as acute myeloid leukemia, chronic myeloid leukemia, or multiple myeloma).

[0528] In one embodiment, the method of the invention comprises administering to a patient in need a therapeutically effective amount of a compound of any one of Formulas (I)–(III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds of any one of Formulas (I)–(III).

[0529] The invention is also directed to a method of inhibiting the activity of PHD. In one embodiment, the method comprises contacting PHD with an effective amount of one or morecompounds selected from the group comprising compounds of any one of Formulas (I)–(III), or a pharmaceutically acceptable salt thereof.

[0530] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful for the treatment or prevention of diseases mediated by PHD activity, including but not limited to ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, acute respiratory distress syndrome (ARDS), pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, and cirrhosis.

[0531] In still other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)), or a pharmaceutically acceptable salt thereof, are useful for the treatment or prevention of anemia comprising treatment or prevention of anemic conditions associated with chronic kidney disease, polycystic kidney disease, aplastic anemia, autoimmune hemolytic anemia, bone marrow transplantation anemia, Churg-Strauss syndrome, Diamond Blackfan anemia, Fanconi's anemia, Felty syndrome, graft versus host disease, hematopoietic stem cell transplantation, hemolytic uremic syndrome, myelodysplastic syndrome, nocturnal paroxysmal hemoglobinuria, osteomyelofibrosis, pancytopenia, pure red-cell aplasia, purpura Schoenlein-Henoch, refractory anemia with excess of blasts, rheumatoid arthritis, Shwachman syndrome, sickle cell disease, thalassemia major, thalassemia minor, thrombocytopenic purpura, anemic or non-anemic patients undergoing surgery, anemia associated with or secondary to trauma, sideroblastic anemia, anemic secondary to other treatment including: reverse transcriptase inhibitors to treat HIV, corticosteroid hormones, cyclic cisplatin or non-cisplatin-containing chemotherapeutics, vinca alkaloids, mitotic inhibitors, topoisomerase II inhibitors, anthracyclines, alkylating agents, particularly anemia secondary to inflammatory, aging and / or chronic diseases. PHD inhibition may also be used to treat symptoms of anemia including chronic fatigue, pallor, and dizziness.

[0532] In still other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)–(III) such as any one of Compounds (1)–(118)), or a pharmaceutically acceptable salt thereof, are useful for the treatment or prevention of retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), or white matter injury (WMI). Retinopathy of Prematurity

[0533] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of retinopathy of prematurity (ROP).

[0534] In humans, development of the retinal vasculature occurs in relative hypoxia in utero and is complete at the time of birth. Premature birth interrupts this process and places the premature child atrisk for multiorgan damage due to a simple paradox of oxygen—oxygen is necessary to keep premature infants alive, but is toxic to premature developing tissues, including the pre-term retina.

[0535] Retinopathy of prematurity (ROP) is a retinovascular disease of premature infants characterized by neovascularization at the intersection of developed, vascularized retina and undeveloped avascular retina. ROP is the most common cause of childhood blindness, and has two phases, based on the oxygen-regulated expression of vascular endothelial growth factor (VEGF). Phase I begins at birth when the infant is placed into hyperoxia, which results in a reduction in the secretion of VEGF that is associated with oxygen-induced vascular obliteration. Phase II is a hypoxic state created by weaning of oxygen supplementation and increased retinal metabolic demand exacerbated by vessel loss from phase I. Phase II is characterized by an overexpression of growth factors, such as VEGF, in the ischemic retina, resulting in pathologic neovascularization.

[0536] For example, thirteen million infants are born prematurely worldwide each year, of which 75,000 will become legally blind from ROP. ROP is a developmental, vascular disorder that occurs in the retina of preterm infants with incomplete retinal vascularization. To treat underdeveloped lungs, prematurely-born babies can receive supplemental oxygen therapy; however, persistent exposure to high levels of oxygen can cause injury to organs such as the eyes, which can result in ROP. Thus, while oxygen is critical to the health of pre-term babies, its use also can result in adverse effects to retinal development.

[0537] ROP is typically treated by surgery. ROP surgery stops the growth of abnormal blood vessels. The goal of ROP surgery is to stop the progression of the disease and prevent blindness. Yet, up to 25% of babies who have ROP surgery face loss of some or all of their vision. Other methods for treating ROP include laser therapy, anti-angiogenesis drugs (e.g., bevacizumab and ranibizumab), hypoxic preconditioning, cryotherapy, and IGF-1 / IGFBP3 (insulin growth factor 1 / IGF binding protein- 3) therapy. However, there is still an unmet need for non-invasive, preventative, and safe drug therapy. Bronchopulmonary Dysplasia

[0538] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of bronchopulmonary dysplasia (BPD).

[0539] Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that affects newborns. Infants are not born with BPD, but BPD is a complication of prematurity. Around 10,000 to 15,000 newborns annually develop BPD in the United States.

[0540] When a newborn’s lungs are underdeveloped at birth, mechanical ventilation or oxygen therapy is required. BPD is often a result of damage to the lungs caused by this therapy. The high amounts of oxygen and pressure can cause inflammation and damage to the inside lining of the airways,the alveoli, and the blood vessels around them. BPD causes further damage to the alveoli and blood vessels, which decreases the number of working alveoli. As the number of working alveoli decreases, more time is needed on a ventilator, which can cause even more damage to the lungs.

[0541] BPD can eventually lead to pulmonary hypertension and even heart failure in severe cases. Infants with BPD may also have trouble feeding and face delayed development. Lung problems can persist into adulthood as people who had BPD as infants can develop reactive airway disease, asthma, and / or exercise intolerance. People who had BPD are also more susceptible to viral infections, such as the flu or cold.

[0542] BPD is currently treated with diuretics, bronchodilators, corticosteroids, and cardiac medications, optionally with oxygen therapy and ventilation. These medications treat the symptoms of BPD, and there is still a need for safe and preventative drug therapy. White Matter Injury

[0543] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of white matter injury (WMI).

[0544] White matter injury (WMI) is one of the most common consequences of premature birth, occurring to some degree in up to 50% of very low birth weight infants.

[0545] Underdeveloped lungs in infants and the resulting insufficient oxygen supply can lead to hypoxia. Hypoxia prevents oligodendrocyte progenitor cells (OPCs) from maturing properly into oligodendrocytes, the myelin-producing cells in white matter, and causes the cells to die. Without the myelin produced by these cells, the brain cannot effectively process nerve impulses which can lead to significant developments delays in sensorimotor skills and cognition.

[0546] Currently, no treatment exists to improve function in infants with WMI after the injury has occurred. There remains an unmet need for safe and preventative drug therapy.

[0547] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful for the treatment or prevention of diseases of metabolic disorders, including but not limited to diabetes and obesity.

[0548] In yet other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)–(III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful for the treatment or prevention of vascular disorders. These include but are not limited to hypoxic or wound healing related diseases requiring pro-angiogenic mediators for vasculogenesis, angiogenesis, and arteriogenesis.

[0549] In still other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)–(III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful for the treatment or prevention of ischemia reperfusion injury. These include but are not limited to stroke, myocardial infarction, and acute kidney injury.

[0550] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of inflammatory bowel disease. These include but are not limited to ulcerative colitis, and Crohn’s disease.

[0551] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of cancers, such as colorectal cancer or a blood cancer (e.g., leukemia or myeloma such as acute myeloid leukemia, chronic myeloid leukemia, or multiple myeloma). In embodiments, a cancer is colorectal cancer. In embodiments, a cancer is a blood cancer (e.g., leukemia or myeloma such as acute myeloid leukemia, chronic myeloid leukemia, or multiple myeloma).

[0552] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of atherosclerosis.

[0553] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of cardiovascular disease.

[0554] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of a disease or condition of the eye. These include but are not limited to radiation retinopathy, retinopathy of prematurity (ROP), diabetic retinopathy, age-related macular degeneration, and ocular ischemia.

[0555] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of a disease that is associated with hyperoxia.

[0556] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of periventricular leukomalacia (PVL).

[0557] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of hemorrhagic shock.

[0558] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of intraventricular hemorrhage.

[0559] In yet other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)–(III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of heart diseases. The conditions include but are not limited to postoperative myocardial ischemia in pancreatic surgery, myocardial injury after percutaneous coronary intervention (PCI), myocardial injury after non-cardiac surgery, perioperative myocardial ischemia in elective operation of abdominal aortic aneurysm, myocardial injury after PCI, myocardial damage in patients undergoing coronary artery bypass graft (CABG) surgery, Minimally invasive mitral valve (MIMV) repair or replacement, adult patient undergoing open heart surgery, chronic heart failure, NYHA class II–IV.

[0560] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of lung diseases, such as lung inflammation, pneumonia, bronchitis, acute lung injury (ALI), pulmonary hypertension, pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), or chronic obstructive pulmonary disease. The conditions include but are not limited to lung injury during elective lung lobectomy, lung injury during coronary artery bypass graft surgery (CABG surgery), and lung transplantation.

[0561] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of respiratory diseases. The conditions include but are not limited to respiratory infection, acute respiratory distress syndrome (ARDS), lung inflammation, pneumonia, and acute lung injury.

[0562] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of liver disease. The conditions include but are not limited to non- alcoholic steatohepatitis (NASH).

[0563] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of kidney disease. The conditions include but are not limited to contrast- induced acute kidney injury, stage III–IV chronic kidney disease undergoing planned coronary angiography, acute kidney injury in patients undergoing valvular heart surgery, non-dialysis dependent chronic kidney disease, chronic kidney disease patients initiating dialysis, non-dialysis dependent chronic kidney disease. In some embodiments, the kidney disease is chronic kidney disease.

[0564] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of injury to and / or failure of one or more organs (e.g., injury to and / or failure of lung, heart, liver, or kidney). The conditions include but are not limited to acute organ injury or organ failure, and induced organ dysfunction.

[0565] In other embodiments, the compounds disclosed herein (e.g., a compound of Formulas (I)– (III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, are useful in the treatment or prevention of respiratory viral (e.g., coronavirus) infection or pulmonary viral (e.g., coronavirus) infection.

[0566] In addition, the compounds disclosed herein (e.g., a compound of Formulas (I)–(III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, may be used in combination with additional active ingredients in the treatment or prevention of the above conditions. The additional compounds may be co-administered separately with the compounds disclosed herein (e.g., a compound of Formulas (I)–(III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt thereof, or included with an additional active ingredient in a pharmaceutical composition according to the invention. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment or prevention of conditions, disorders, or diseases mediated by PHD enzyme or that are active against another targets associated with the particular condition, disorder, or disease, such as an alternate PHD modulator. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of a compound according to the invention), decrease one or more side effects, or decrease the required dose of the compound according to the invention.

[0567] The compounds of the invention are used, alone or in combination with one or more other active ingredients, to formulate pharmaceutical compositions of the invention. A pharmaceutical composition of the invention comprises: (a) an effective amount of the compounds disclosed herein (e.g., a compound of Formulas (I)–(III) such as any one of compounds (1)-(118)), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and (b) a pharmaceutically acceptable excipient.

[0568] A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. Suitable excipients may also include antioxidants.Such antioxidants may be used in a pharmaceutical composition or in a storage medium to prolong the shelf-life of the drug product. Pharmaceutical Formulations and Routes of Administration

[0569] The compounds and compositions of the present invention can be delivered directly or in pharmaceutical compositions or medicaments along with suitable carriers or excipients, as is well known in the art. Present methods of treatment can comprise administration of an effective amount of a compound of the invention to a subject in need. In a preferred embodiment, the subject is a mammalian subject, and in a most preferred embodiment, the subject is a human subject.

[0570] An effective amount of such compound, composition, or medicament can readily be determined by routine experimentation, as can the most effective and convenient route of administration, and the most appropriate formulation. Various formulations and drug delivery systems are available in the art. See, e.g., Gennaro, A.R., ed. (1995) Remington's Pharmaceutical Sciences, supra.

[0571] Suitable routes of administration may, for example, include oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration. Primary routes for parenteral administration include intravenous, intramuscular, and subcutaneous administration. Secondary routes of administration include intraperitoneal, intra-arterial, intra-articular, intracardiac, intracisternal, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration. The indication to be treated, along with the physical, chemical, and biological properties of the drug, dictate the type of formulation and the route of administration to be used, as well as whether local or systemic delivery would be preferred.

[0572] Pharmaceutical dosage forms of a compound of the invention may be provided in an instant release, controlled release, sustained release, or target drug-delivery system. Commonly used dosage forms include, for example, solutions and suspensions, (micro-) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized formulations. Depending on route of administration used, special devices may be required for application or administration of the drug, such as, for example, syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. Pharmaceutical dosage forms are often composed of the drug, an excipient(s), and a container / closure system. One or multiple excipients, also referred to as inactive ingredients, can be added to a compound of the invention to improve or facilitate manufacturing, stability, administration, and safety of the drug, and can provide a means to achieve a desired drug release profile. Therefore, the type of excipient(s) to be added to the drug can depend on various factors, such as, for example, the physical and chemical properties of the drug, the route of administration, and the manufacturing procedure.Pharmaceutically acceptable excipients are available in the art and include those listed in various pharmacopoeias. See, e.g., the U.S. Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British pharmacopeia (BP); the U.S. Food and Drug.

[0573] Administration (www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications, e.g., Inactive Ingredient Guide (1996); Ash and Ash, Eds. (2002) Handbook of Pharmaceutical Additives, Synapse Information Resources, Inc., Endicott NY; etc.)

[0149] Pharmaceutical dosage forms of a compound of the present invention may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray-drying, levigating, emulsifying, (nano / micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of the present invention can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.

[0574] Proper formulation is dependent upon the desired route of administration. For intravenous injection, for example, the composition may be formulated in aqueous solution, if necessary using physiologically compatible buffers, including, for example, phosphate, histidine, or citrate for adjustment of the formulation pH, and a tonicity agent, such as, for example, sodium chloride or dextrose. For transmucosal or nasal administration, semisolid, liquid formulations, or patches may be preferred, possibly containing penetration enhancers. Such penetrants are generally known in the art. For oral administration, the compounds can be formulated in liquid or solid dosage forms, and as instant or controlled / sustained release formulations. Suitable dosage forms for oral ingestion by a subject include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions. The compounds may also be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0575] Solid oral dosage forms can be obtained using excipients, which may include fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adherents, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring, and flavoring agents. These excipients can be of synthetic or natural source. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatine, magnesium carbonate, magnesium / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starches, stearic acid or a salt thereof, sugars (e.g., dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated), and waxes. Ethanol and water may serve as granulation aides. In certain instances, coating of tablets with, for example, a taste- masking film, a stomach acid resistant film, or a release-retarding film is desirable. Natural and synthetic polymers, in combination with colorants, sugars, and organic solvents or water, are often used to coat tablets,resulting in dragees. When a capsule is preferred over a tablet, the drug powder, suspension, or solution thereof can be delivered in a compatible hard or soft shell capsule.

[0576] In one embodiment, the compounds of the present invention can be administered topically, such as through a skin patch, a semi-solid, or a liquid formulation, for example a gel, a (micro-) emulsion, an ointment, a solution, a (nano / micro)-suspension, or a foam. The penetration of the drug into the skin and underlying tissues can be regulated, for example, using penetration enhancers; the appropriate choice and combination of lipophilic, hydrophilic, and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers; by pH adjustment; and use of complexing agents. Other techniques, such as iontophoresis, may be used to regulate skin penetration of a compound of the invention. Transdermal or topical administration would be preferred, for example, in situations in which local delivery with minimal systemic exposure is desired.

[0577] For administration by inhalation, or administration to the nose, the compounds for use according to the present invention are conveniently delivered in the form of a solution, suspension, emulsion, or semisolid aerosol from pressurized packs, or a nebulizer, usually with the use of a propellant, e.g., halogenated carbons derived from methane and ethane, carbon dioxide, or any other suitable gas. For topical aerosols, hydrocarbons like butane, isobutene, and pentane are useful. In the case of a pressurized aerosol, the appropriate dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin, for use in an inhaler or insufflator, may be formulated. These typically contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0578] Compounds and compositions formulated for parenteral administration by injection are usually sterile and can be presented in unit dosage forms, e.g., in ampoules, syringes, injection pens, or in multi-dose containers, the latter usually containing a preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as buffers, tonicity agents, viscosity enhancing agents, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives. Depending on the injection site, the vehicle may contain water, a synthetic or vegetable oil, and / or organic co-solvents. In certain instances, such as with a lyophilized product or a concentrate, the parenteral formulation would be reconstituted or diluted prior to administration. Depot formulations, providing controlled or sustained release of a compound of the invention, may include injectable suspensions of nano / micro particles or nano / micro or non-micronized crystals. Polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, can serve as controlled / sustained release matrices, in addition to others well known in the art. Other depot delivery systems may be presented in form of implants and pumps requiring incision.

[0579] Suitable carriers for intravenous injection for the compounds of the invention are well- known in the art and include water-based solutions containing a base, such as, for example, sodium hydroxide, to form an ionized compound; sucrose or sodium chloride as a tonicity agent; and a buffer, for example, a buffer that contains phosphate or histidine. Co-solvents, such as, for example, polyethylene glycols, may be added. These water-based systems are effective at dissolving compounds of the invention and produce low toxicity upon systemic administration. The proportions of the components of a solution system may be varied considerably, without destroying solubility and toxicity characteristics. Furthermore, the identity of the components may be varied. For example, low-toxicity surfactants, such as polysorbates or poloxamers, may be used, as can polyethylene glycol or other co- solvents, biocompatible polymers such as polyvinyl pyrrolidone may be added, and other sugars and polyols may substitute for dextrose.

[0580] A therapeutically effective dose can be estimated initially using a variety of techniques well- known in the art. Initial doses used in animal studies may be based on effective concentrations established in cell culture assays. Dosage ranges appropriate for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays. In certain some embodiments, a compound of the disclosure is formulated for oral administration. An exemplary dose of a compound of the disclosure in a pharmaceutical formulation for oral administration is from about 0.5 to about 10 mg / kg body weight of subject. In some embodiments, a pharmaceutical formulation comprises from about 0.7 to about 5.0 mg / kg body weight of subject, or alternatively, from about 1.0 to about 2.5 mg / kg body weight of subject. A typical dosing regimen for oral administration would be administration of the pharmaceutical formulation for oral administration three times per week, two times per week, once per week or daily.

[0581] An effective amount or a therapeutically effective amount or dose of an agent, e.g., a compound of the invention, refers to that amount of the agent or compound that results in amelioration of symptoms or a prolongation of survival in a subject. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Agents that exhibit high therapeutic indices are preferred.

[0582] The effective amount or therapeutically effective amount is the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Dosages particularly fall within a range of circulating concentrations that includes the ED50 with little or no toxicity. Dosages may vary within this range depending upon the dosage form employed and / orthe route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject's condition.

[0583] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety that are sufficient to achieve the desired effects; i.e., the minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from, for example, in vitro data and animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0584] The amount of compound or composition administered may be dependent on a variety of factors, including the sex, age, and weight of the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0585] The present compounds and compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack; or glass and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment or prevention of an indicated condition.

[0586] These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein and are specifically contemplated. EXEMPLIFICATION General Method

[0587] Unless otherwise noted, all reagents were used without further purification. Most of chemicals were purchased from Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other vendors.

[0588] 1H NMR or19F NMR spectra were recorded on Bruker AVⅢ 400 or Bruker AVⅢ 500 or Bruker 300 MHz instrument.

[0589] LCMS measurement was run on Agilent 1200 HPLC / 6100 SQ System using the conditions in Table 1. Table 1. Column conditions for analysis and purification.General Scheme for Synthesis of a Compound of the Present Invention

[0590] Compounds of Formula (I) are prepared according to Scheme A using commercially available materials. The reaction with benzyl bromides of Compound (a) with N-[(4- Methylphenyl)sulfonyl]glycine methyl ester in presence of base and followed by cyclization furnishes isoquinoline compounds of Compound (b). Benzylation of hydroxy affords Compound (c). Oxidation of Compound (c) furnishes compounds of Compound (d). Amination of Compound (d) gives compounds of Compound (e). The reaction of amine of Compound (e) and ethoxycarbonylisothiocyanate yields thiourea compounds of Compound (f). The cyclization of Compound (f) affords amino-triazolo compounds of Compound (g). The deamination of amino-triazolo compounds of Compound (g) provides triazolo compounds of Compound (h). Ester hydrolysis of Compound (h) produces carboxylic acids Compound (i). The amide formation with amino esters of Compound (j) yields amides of Compound (k). The cross-coupling of Compound (k) and boronic acids yields Compound (l). Deprotection of the benzyl group to Compound (m) followed by saponification of the ester furnishes Compound (n).Scheme A: Synthesis of a Compound of the Present InventionSynthesis for Exemplary Compounds Example 1: Preparation of Compound (1) Scheme 1: Synthesis of Compound (1)Compound 1

[0591] Step 1: 4-(Benzyloxy)-2-chloroquinoline:

[0592] To the solution of 2,4-dichloroquinoline (2000.00 mg, 10.10 mmol) in anhydrous tetrahydrofuran (40 mL) was added sodium hydride (242.36 mg, 9.59 mmol, 60 percent in oil) at 0 °C. After stirring for 30 min, 18-crown-6 (2669.22 mg, 10.10 mmol) and benzyl alcohol (1037.45 mg, 10.10 mmol) were added to the mixture and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage, 40 g normal phase silica gel, UV 254, petroleum ether / ethyl acetate = 10 / 1) to give 4-(benzyloxy)-2-chloroquinoline (1914 mg, 7.11 mmol, 70% yield) as yellow solid. LC-MS: m / z= 270 (M+H)+, retention time 2.220 min (Method A).

[0593] Step 2: 4-(Benzyloxy)-2-hydrazineylquinoline:

[0594] A mixture of 4-(benzyloxy)-2-chloroquinoline (1750.00 mg, 6.49 mmol) and hydrazine hydrate (3247.88 mg, 64.88 mmol) in 1,4-dioxane (10.0 mL) was stirred at 90 °C for 16 h in a sealed tube. The mixture was cooled and concentrated to give dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to afford 4-(benzyloxy)-2- hydrazineylquinoline (1.51 g, crude) as yellow solid. LC-MS: m / z = 266 (M+H)+, retention time 1.492 min (Method A).

[0595] Step 3: 5-(Benzyloxy)-[1,2,4]triazolo[4,3-a]quinoline:

[0596] To a solution of 4-(benzyloxy)-2-hydrazineylquinoline (1510.00 mg, 5.69 mmol) in trimethyl orthoformate (10 mL) was added p-toluenesulfonic acid (541.29 mg, 2.85 mmol). The reaction was stirred at 60°C for 1.0 h. The mixture was cooled and concentrated to give dryness. The residue was purified by flash chromatography (Biotage, 40 g normal phase silica gel, UV 254, dichloromethane / methanol = 100 / 3) to give the 5-(benzyloxy)-[1,2,4]triazolo[4,3-a]quinoline (861 mg, 3.13 mmol, 55% yield) as yellow solid. LC-MS: m / z= 276 (M+H)+, retention time 1.747 min (Method A).

[0597] Step 4: Ethyl 5-(benzyloxy)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylate:

[0598] To a solution of 5-(benzyloxy)-[1,2,4]triazolo[4,3-a]quinoline (800.00 mg, 2.91 mmol) in anhydrous tetrahydrofuran (50.0 mL) was added n-butyllithium (2.3 mL, 5.81 mmol, 2.5M in hexane) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 30 min and ethyl carbonocyanidate (431.91 mg, 4.36 mmol) was added. The mixture was allowed to warm up to room temperature and left stirring for 16.0 h. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried oversodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 100 / 15) to obtain ethyl 5-(benzyloxy)- [1,2,4]triazolo[4,3-a]quinoline-4-carboxylate (350 mg, 1.01 mmol, 35% yield) as yellow solid. LC-MS: m / z= 348 (M+H)+, retention time 2.031 min (Method A).

[0599] Step 5: Ethyl 5-hydroxy-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylate:

[0600] A mixture ethyl 5-(benzyloxy)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylate (150.00 mg, 0.43 mmol) and 10% palladium on carbon (30.00 mg) in tetrahydrofuran (10.0 mL) was stirred at room temperature for 3.0 h under hydrogen. The reaction mixture was filtered with celite, and the filtrate was concentrated under reduced pressure. The residue was triturated with petroleum ether and filtered to afford ethyl 5-hydroxy-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylate (125 mg, crude) as yellow solid. LC-MS: m / z = 258 (M+H)+, retention time 1.611 min (Method A).

[0601] Step 6: (5-Hydroxy-[1,2,4]triazolo[4,3-a]quinoline-4-carbonyl)glycine

[0602] A mixture of ethyl 5-hydroxy-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylate (110.00 mg, 0.43 mmol) and glycine (96.30 mg, 1.28 mmol) in dimethyl sulfoxide (5 mL) was stirred at 110°C for 2.0 h in a sealed tube. The reaction was diluted in ice-water and acidified to pH < 7 with hydrochloric acid. The crude solid was filtered and purified by prep-HPLC (water (formic acid) / acetonitrile) to afford (5-hydroxy-[1,2,4]triazolo[4,3-a]quinoline-4-carbonyl)glycine (17.5 mg, 0.06 mmol, 14% yield) as grey solid. LC-MS: m / z= 287 (M+H)+, retention time 2.829 min (Method A).1HNMR (400 MHz, DMSO-d6) δ 12.64 (br, 1H), 9.95 (br, 1H), 8.07-8.01 (m, 2H), 7.75-7.66 (m, 2H), 7.38 (t, J = 6.8 Hz, 1H), 3.96 (d, J = 5.6 Hz, 2H).Example 2: Preparation of Compound (2) Scheme 2: Synthesis of Compound (2)Compound 2

[0603] Step 1: 2-Amino-4-hydroxyquinoline-3-carbonitrile:

[0604] To a solution of malononitrile (2.43 g, 36.81 mmol) in N,N-dimethylformamide (50.0 mL) was added sodium hydride (1.47 g, 36.81 mmol, 60 percent in oil) at 0 °C. The mixture was stirred at 0 °C for 30 min and 1H-benzo[d][1,3]oxazine-2,4-dione (5.0 g, 30.67 mmol) was added. The mixture was stirred at 60 °C for 30 min. The reaction was quenched with ice-water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The target compound (300 mg, 1.47 mmol, 85.1% yield) was obtained as white solid. LC-MS: m / z= 186.1 (M+H)+, retention time 1.13 min (Method B).

[0605] Step 2: 2-Amino-4-chloroquinoline-3-carbonitrile:

[0606] A solution of 2-amino-4-hydroxyquinoline-3-carbonitrile (10 g, 54.05 mmol) in phosphorus oxychloride (60.0 mL) was stirred at 110 °C for 5.0 h. The reaction was basified with saturated sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The desired product was obtained (6.5 g, 59.24% yield) as white solid. LC-MS: m / z= 203.9 (M+H)+, retention time 1.75 min (Method A).

[0607] Step 3: 2-Amino-4-methoxyquinoline-3-carbonitrile:

[0608] To a solution of 2-amino-4-chloroquinoline-3-carbonitrile (6.5 g, 32.02 mmol) in methanol (50.0 mL) was added sodium methanolate (3.71 g, 64.04 mmol) at 0 °C. The mixture was stirred at 80 °C for 3.0 h. The mixture was cooled and concentrated to give dryness. The residue was purified by flash chromatography (dichloromethane / methanol = 20 / 1) to give 2-amino-4-methoxyquinoline-3- carbonitrile (5.9 g, 92.59% yield) as white solid. LC-MS: m / z= 200.1 (M+H)+, retention time 1.31 min (Method A).

[0609] Step 4: 5-Hydroxyimidazo[1,2-a]quinoline-4-carbonitrile:

[0610] A mixture of 2-amino-4-methoxyquinoline-3-carbonitrile (3.00 g, 15.08 mmol) and 2- chloroacetaldehyde (4.41 g, 22.61 mmol) in ethanol (50.0 mL) was stirred at 80 °C for 12.0 h. The mixture was cooled and concentrated to give dryness. The residue was triturated with petroleum ether and filtered to afford 5-hydroxyimidazo[1,2-a]quinoline-4-carbonitrile (2.5 g, 79.32% yield) as yellow solid. LC-MS: m / z= 210.1 (M+H)+, retention time 1.20 min (Method B).

[0611] Step 5: 5-Hydroxyimidazo[1,2-a]quinoline-4-carboxylic acid:

[0612] A mixture of 5-hydroxyimidazo[1,2-a]quinoline-4-carbonitrile (800 mg, 3.83 mmol) in 50% sulfuric acid (8.0 mL) was stirred at room temperature for 1.0 d. The solution was diluted with ice- water. The resulting solid was filtered, washed with water and dried to obtain 5-hydroxyimidazo[1,2- a]quinoline-4-carboxylic acid (100 mg, 11.45% yield) as grey solid. LC-MS: m / z= 229.1 (M+H)+, retention time 1.52 min (Method A).

[0613] Step 6: 5-Chloroimidazo[1,2-a]quinoline-4-carbonyl chloride:

[0614] To a solution of 5-hydroxyimidazo[1,2-a]quinoline-4-carboxylic acid (180 mg, 0.93 mmol) in dichloromethane (5.0 mL) was added oxalyl chloride (235.67 mg, 1.86 mmol) and N,N- dimethylformamide (one drop) at 0 °C. The reaction mixture was stirred at room temperature for 2.0 h and concentrated to dryness. The crude product (180 mg, 73.04% yield) was obtained and used to the next step. LC-MS: m / z=261.0 (M+H)+, retention time =1.55 min (Method A).

[0615] Step 7: tert-butyl (5-chloroimidazo[1,2-a]quinoline-4-carbonyl)glycinate:

[0616] To a mixture of tert-butyl glycinate hydrochloride (231.23 mg, 1.38 mmol) and triethylamine (209.77 mg, 2.08 mmol) in dichloromethane (5.0 mL) was added 5-chloroimidazo[1,2- a]quinoline-4-carbonyl chloride (180 mg, 0.69 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2.0 h and concentrated to dryness. The resulting residue was purified by reverse Prep- HPLC to obtain tert-butyl (5-chloroimidazo[1,2-a]quinoline-4-carbonyl)glycinate (180 mg, 72.66% yield) as yellow solid. LC-MS: m / z=360.0 (M+H)+, retention time =1.61 min (Method A).

[0617] Step 8: (5-Hydroxyimidazo[1,2-a]quinoline-4-carbonyl)glycine

[0618] To a solution of tert-butyl (5-chloroimidazo[1,2-a]quinoline-4-carbonyl)glycinate (160.00 mg, 0.77 mmol) in dimethyl sulfoxide (2.0 mL) was added sodium hydroxide (153.1mg, 3.83 mmol). The mixture was stirred at 120 °C for 12.0 h and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The resulting residue was purified by reverse Prep-HPLC to obtain (5-hydroxyimidazo[1,2-a]quinoline-4-carbonyl)glycine (64.3 mg, 0.23 mmol, 29.30% yield). LC-MS: m / z=286.0 (M+H)+, retention time =2.72 min (Method A).1HNMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.75 (s, 1H), 8.37 (d, J = 6.9 Hz, 2H), 8.26 (d, J = 8.3 Hz, 1H), 7.81 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 4.06 (d, J = 5.4 Hz, 2H). Example 3: Preparation of Compound (3) Scheme 3: Synthesis of Compound (3)Compound 3

[0619] Step 1: 2-amino-7-chloro-4-hydroxyquinoline-3-carbonitrile C2

[0620] 7-chloro-1H-3,1-benzoxazine-2,4-dione (2.4 g, 12.15 mmol) in DMF (10 mL) was added to a stirred solution of propanedinitrile (802 mg, 12.15 mmol) and triethylamine (1.69 mL, 12.15 mmol) in DMF (10 mL) at rt. The resulting reaction mixture was stirred at 60 °C for 1.5 h. The reaction was cooled to rt, poured into 200 mL ice cold water and acidified with aqueous 5 N HCl (precipitation occurred). The solid was separated by filtration, washed with water. The half white solid was dried inair over weekend. The crude was suspended in DMF (40 mL) and refluxed for 15 min (155 °C) and cooled to rt, diluted with water (50 mL), precipitate was filtered, and tan solid was washed with water (20 mL) and dried to afford white solid. LC-MS: m / z=220.0 (M+H)+.

[0621] Step 2: 8-chloro-5-hydroxyimidazo[1,2-a]quinoline-4-carbonitrile C

[0622] A volume of 0.3 mL conc. H2SO4was added to a mixture of 2-bromo-1,1-dimethoxyethane (5 mL) in 12 mL water. The reaction was heated to 90 °C for 2 h. The reaction was cooled to rt, extracted with ether (50 mL). The crude aldehyde was used in the reaction.

[0623] A mixture of 2-amino-7-chloro-4-hydroxy-quinoline-3-carbonitrile (250 mg, 1.14 mmol), crude bromo aldehyde in ethanol (10 mL) and 2 g of NaHCO3were refluxed for 2 h. LCMS indicated complete conversion to desired mass (MS / 244). The reaction was cooled to rt, filtered, filtrate was concentrated to afford 8-chloro-5-hydroxyimidazo[1,2-a]quinoline-4-carbonitrile (150 mg, 54%) as yellow solid. The crude was subjected to the next reaction without further purification. LC-MS: m / z=291.0 (M+H)+.

[0624] Step 3: ethyl 8-chloro-5-hydroxyimidazo[1,2-a]quinoline-4-carboxylate C

[0625] A mixture of 8-chloro-5-hydroxy-imidazo[1,2-a]quinoline-4-carbonitrile (150 mg, 0.620 mmol), ethanol (20 mL, 0.620 mmol) and Sulfuric acid (0.2 mL, 3.75 mmol) was heated to 130 °C for 1 h in a microwave reactor. LCMS indicated complete conversion. The reaction was quenched with solid NaHCO3, filtered, and rinsed with methanol. The filtrate was concentrated to afford ethyl 8-chloro-5- hydroxyimidazo[1,2-a]quinoline-4-carboxylate (90 mg, 50%). The crude was subjected to the next reaction.

[0626] Step 4: (8-chloro-5-hydroxyimidazo[1,2-a]quinoline-4-carbonyl)glycine C

[0627] A mixture of ethyl 8-chloro-5-hydroxy-imidazo[1,2-a]quinoline-4-carboxylate (90 mg, 0.310 mmol), 2-aminoacetic acid (116 mg, 1.55 mmol) and 0.5 M NaOMe in methanol (3 mL, 1.5 mmol) was heated to 120 °C for 20 min in a microwave reactor. LCMS indicated 50% conversion (MS / 320). The reaction again heated to 120 °C for 30 min. The reaction cooled to rt, diluted with aqueous 0.5 N HCl (10 mL), solid was separated by filtration to afford (8-chloro-5- hydroxyimidazo[1,2-a]quinoline-4-carbonyl)glycine (18 mg, 17%). LC-MS: m / z=320.0 (M+H)+.1H NMR (400 MHz, DMSO) δ 12.59 (s, 1H), 12.42 (s, 1H), 10.65 (t, J = 5.5 Hz, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.41 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 7.60 (dd, J = 8.5, 1.6 Hz, 1H), 7.45 (s, 1H), 4.06 (d, J = 5.6 Hz, 2H). Example 4: Preparation of Compound (4) Scheme 4: Synthesis of Compound (4)

[0628] Step 1: 4-Iodoisoquinolin-1-amine:I

[0629] To a solution of isoquinolin-1-amine (3000.0 mg, 20.81 mmol) in acetonitrile (150.0 mL) was added N-iodosuccinimide (5617.48 mg, 24.97 mmol). The mixture was stirred at room temperature for 16.0 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (Biotage, 40 g normal phase silica gel, UV 254, petroleum ether / ethyl acetate = 1 / 1) to give the 4-iodoisoquinolin-1-amine (5.8 g, 20.55 mmol, 99% yield) as grey solid. LC-MS: m / z= 271 (M+H)+, retention time 1.339 min (Method A).

[0630] Step 2: N'-(4-iodoisoquinolin-1-yl)-N,N-dimethylformimidamide: I

[0631] To a solution of 4-iodoisoquinolin-1-amine (5500.00 mg, 20.37 mmol) in N,N- dimethylformamide (30.0 mL) was added N,N-dimethylformamide dimethyl acetal (6.0 mL), thereaction was stirred at 80 oC for 2.0 h in a sealed tube. The reaction mixture was quenched with waterand extracted with ethyl acetate. The organic phase was washed with saturated brine solution, dried (sodium sulfate) and concentrated to afford 6.2 g of crude solid, which was used to next step withoutany purification. LC-MS: m / z = 326 (M+H)+, retention time 1.490 min (Method A).

[0632] Step 3: 6-Iodo-[1,2,4]triazolo[5,1-a]isoquinoline:

[0633] To a solution of N'-(4-iodoisoquinolin-1-yl)-N,N-dimethylformimidamide (6000.00 mg, 18.45 mmol) and (aminooxy)sulfonic acid (2712.91 mg, 23.99 mmol) in methanol (100.0 mL) was added pyridine (3357.16 mg, 42.44 mmol), the reaction was stirred at 65 °C for 16.0 h in a sealed tube. The mixture was diluted with ice-water to precipitate a solid. The solid was purified by flash chromatography (Biotage, 40 g normal phase silica gel, UV 254, petroleum ether / ethyl acetate = 10 / 3) to afford the 6-iodo-[1,2,4]triazolo[5,1-a]isoquinoline (1.77 g, 6.00 mmol, 32% yield) as brown solid. LC-MS: m / z= 296 (M+H)+, retention time 1.918 min (Method A).

[0634] Step 4: 6-(Benzyloxy)-[1,2,4]triazolo[5,1-a]isoquinoline:

[0635] To a solution of 6-iodo-[1,2,4]triazolo[5,1-a]isoquinoline (1500.00 mg, 5.08 mmol) in benzyl alcohol (2.63 mL, 25.42 mmol) was added 1,10-phenanthroline (183.21 mg, 1.02 mmol), cuprous iodide (96.81 mg, 0.51 mmol) and caesium carbonate (3312.53 mg, 10.17 mmol). The reaction was stirred at 110 °C for 16.0 h in a sealed tube. After that reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage, 40 g normal phase silica gel, UV 254, petroleum ether / ethyl acetate = 6 / 1) to give 6-(benzyloxy)-[1,2,4]triazolo[5,1- a]isoquinoline (265 mg, 0.96 mmol, 19% yield) as yellow solid. LC-MS: m / z= 276 (M+H)+, retention time 1.994 min (Method A).

[0636] Step 5: 6-(Benzyloxy)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylic acid:

[0637] To a solution of 6-(benzyloxy)-[1,2,4]triazolo[5,1-a]isoquinoline (230.00 mg, 0.84 mmol) in anhydrous tetrahydrofuran (10.0 mL) was added n-butyllithium (0.37 mL, 0.92 mmol, 2.5M in hexane) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 30 min and dry ice (2.0 g) was added in portions. The mixture was allowed to warm up to -40 °C and left stirring for another one hour. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Biotage, 12 g normal phase silica gel, UV 254, dichloromethane / methanol = 10 / 1) to give the 6-(benzyloxy)- [1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylic acid (83 mg, 0.26 mmol, 31% yield) as white solid. LC- MS: m / z = 320 (M+H)+, retention time 1.894 min (Method A).

[0638] Step 6: Tert-Butyl (6-(benzyloxy)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate:

[0639] To a solution of 6-(benzyloxy)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylic acid (60.00 mg, 0.19 mmol) and tert-butyl glycinate hydrochloride (29.58 mg, 0.23 mmol) in dichloromethane (5.0 mL) was added benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (107.56 mg, 0.21 mmol) and triethylamine (95.07 mg, 0.94 mmol). The mixture was stirred overnight and concentrated. The residue was purified by flash chromatography (Biotage, 12 g normal phase silica gel, UV 254, dichloromethane / ethyl acetate = 5 / 1) to give the tert-butyl (6-(benzyloxy)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycinate (71 mg, 0.16 mmol, 86% yield) as yellow solid. LC-MS: m / z= 433 (M+H)+, retention time 2.047 min (Method A).

[0640] Step 7: tert-Butyl (6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate:

[0641] A mixture of tert-butyl (6-(benzyloxy)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate (60.0 mg, 0.14 mmol) and 10% palladium on carbon (10.0 mg) in tetrahydrofuran (10.0 mL) was stirred at room temperature for 1.0 h under hydrogen. The mixture was filtered with celite, and the filtrate was concentrated under reduced pressure. The desired product (60 mg, crude) wasobtained as yellow solid. LC-MS: m / z = 343 (M+H)+, retention time 2.172 min (Method A).

[0642] Step 8: (6-Hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine:

[0643] A mixture of tert-butyl (6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (60.0 mg, 0.18 mmol) and trifluoroacetic acid (0.5 mL) in dichloromethane (5.0 mL) was stirred at room temperature overnight. The mixture was concentrated to give dryness. The residue was purified by prep-HPLC (water (formic acid) / acetonitrile) to obtain (6-hydroxy-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycine (9.7 mg, 0.03 mmol, 19% yield) as white solid. LC-MS: m / z= 287 (M+H)+, retention time 3.796 min (Method A).1HNMR (400 MHz, DMSO-d6) δ 14.63 (br, 1H), 12.91 (br, 1H), 10.54-10.51 (m, 1H), 8.69 (s, 1H), 8.57 (dd, J = 8.0 Hz, J = 0.8 Hz, 1H), 8.37 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H), 8.04-7.95 (m, 2H), 4.27 (d, J = 5.6 Hz, 2H).Example 5: Preparation of Compound (5) Scheme 5: Synthesis of Compound (5)Compound 5

[0644] Step 1: 3-Bromoisoquinolin-4-ol:NBr

[0645] To a solution of isoquinolin-4-ol (3.5 g, 24.1 mmol) in N,N-dimethylformamide (20.0 mL) was added N-bromosuccinimide (4.29 g, 24.1 mmol). The mixture was stirred for 2.0 h at room temperature. The reaction was diluted with water and extracted twice with ethyl acetate. The organiclayer was separated, washed with brine, dried over sodium sulfate and concentrated. The crude 3- bromoisoquinolin-4-ol (1.5 g, 6.72 mmol, 27.9% yield) was obtained as yellow solid. LC-MS: m / z= 224.0 (M+H)+, retention time 1.744 min (Method A).

[0646] Step 2: 4-(Benzyloxy)-3-bromoisoquinoline:

[0647] To a solution of 3-bromoisoquinolin-4-ol (1.5 g, 6.7 mmol) in N,N-dimethylformamide (20.0 mL) was added benzyl bromide (1.56 g, 6.7 mmol) and potassium carbonate (1.85g, 6.7mmol). The mixture was stirred at room temperature for 2.0 h. The solution was quenched with ice water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (dichloromethane / methanol =10 / 1) to afford 4-(benzyloxy)-3-bromoisoquinoline (1.2 g, 57.2% yield) as yellow solid. LC-MS: m / z= 314.0 (M+H)+, retention time 2.2 min (Method A).

[0648] Step 3: 2-Amino-4-(benzyloxy)-3-bromoisoquinolin-2-ium 2,4,6-trimethylbenzenesulfonate:

[0649] To a solution of 4-(benzyloxy)-3-bromoisoquinoline (1.00 g, 3.2 mmol) in dichloromethane (5.0 mL) was added dropwise a solution of O-(mesitylsulfonyl)hydroxylamineglycine (0.82 g, 3.8 mmol) in dichloromethane (20.0 mL) under ice-cooling. After stirring at room temperature for 1 h, diethyl ether (50.0 mL) was added. The solid was collected by filtration to give the target compound (0.86 g, 81.4% yield) as white solid. LC-MS: m / z= 330.0 (M+H)+, retention time 1.43 min (Method A).

[0650] Step 4: Methyl 6-(benzyloxy)-5-bromopyrazolo[5,1-a]isoquinoline-1-carboxylate: MeOOC

[0651] To a solution of 2-amino-4-(benzyloxy)-3-bromoisoquinolin-2-ium 2,4,6- trimethylbenzenesulfonate (0.86 g, 2.6 mmol) in acetonitrile (20.0 mL) was added potassium carbonate (0.75 g, 5.4 mmol) under ice-cooling. After stirring under ice-cooling for 10 min, methyl propiolate(0.28 g, 3.3 mmol) was added to the mixture. The mixture was gradually warmed to room temperature and stirred at room temperature overnight, then water (50.0 mL) and ethyl acetate (50.0 mL) were poured into the reaction mixture under ice-cooling. The aqueous layer was extracted twice with ethyl acetate, the organic layers were combined and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain methyl 6-(benzyloxy)-5- bromopyrazolo[5,1-a]isoquinoline-1-carboxylate (0.8 g, 75.1% yiled) as yellow solid. LC-MS: m / z= 411.0 (M+H)+, retention time 2.09 min (Method A).

[0652] Step 5: 6-(Benzyloxy)-5-bromopyrazolo[5,1-a]isoquinoline-1-carboxylic acid:

[0653] To a solution of crude methyl 6-(benzyloxy)-5-bromopyrazolo[5,1-a]isoquinoline-1- carboxylate (800 mg, 2.0 mmol) in tetrahydrofuran / water = 1 / 1 (10.0 mL / 10.0 mL) was added 4N sodium hydroxide solution (5.0 mL) under ice-cooling. The mixture was warmed to room temperature and stirred overnight. The resulting aqueous solution was acidified with 3N / L hydrochloric acid to pH=3~4.The resulting solid was filtered and dried to afford 6-(benzyloxy)-5-bromopyrazolo[5,1- a]isoquinoline-1-carboxylic acid (500 mg, 63.1% yield) as white solid. LC-MS: m / z= 397.0 (M+H)+, retention time 2.09 min (Method A).

[0654] Step 6: 6-(Benzyloxy)pyrazolo[5,1-a]isoquinoline:

[0655] 6-(Benzyloxy)-5-bromopyrazolo[5,1-a]isoquinoline-1-carboxylic acid (500 mg, 1.2 mmol), copper(I) oxide (180 mg, 1.3 mmol) and quinoline (3.0 mL) were mixed in a sealed tube. The mixture was warmed to 200 °C and then stirred for 1.0 h. After cooling to room temperature, ethyl acetate (20 mL) and 1N hydrochloric acid solution (20.0 mL) were added. Insoluble material was filtered off, and the filtrate was separated. The organic layer was washed successively with 1N hydrochloric acid solution and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford 6-(benzyloxy)pyrazolo[5,1-a]isoquinoline (300 mg, 91.4% yield). LC-MS: m / z= 275.00(M+H)+, retention time 2.15 min (Method A).

[0656] Step 7: Ethyl 6-(benzyloxy)pyrazolo[5,1-a]isoquinoline-5-carboxylate:

[0657] To a solution of 6-(benzyloxy)pyrazolo[5,1-a]isoquinoline (0.3 g, 1.10 mmol) in anhydrous tetrahydrofuran (20.0 mL) was added n-butyllithium (0.88 mL, 2.2 mmol, 2.5M in hexane) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 50 min and ethyl cyanoformate (0.13 g, 1.3 mmol) was added. The mixture was allowed to warm up to room temperature and left stirring for 12 h. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ethyl 6-(benzyloxy)pyrazolo[5,1-a]isoquinoline-5-carboxylate (0.3 g, 79.3%) as yellow solid. LC-MS: m / z= 347.0 (M+H)+, retention time 2.13 min (Method A).

[0658] Step 8: 6-(Benzyloxy)pyrazolo[5,1-a]isoquinoline-5-carboxylic acid:

[0659] To a solution of ethyl 6-(benzyloxy)pyrazolo[5,1-a]isoquinoline-5-carboxylate (300 mg, 0.86 mmol) in tetrahydrofuran / water (10.0 mL / 5.0 mL) was added lithium hydroxide monohydrate (164 mg, 4.0 mmol). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified with 10% hydrochloric acid solution to pH=3~4. The precipitate was filtered, washed with water and dried to obtain 6-(Benzyloxy)pyrazolo[5,1- a]isoquinoline-5-carboxylic acid (200 mg, 73.2% yield) as yellow solid. LC-MS: m / z= 319.0 (M+H)+, retention time 2.09 min (Method A).

[0660] Step 9: Ethyl (6-(benzyloxy)pyrazolo[5,1-a]isoquinoline-5-carbonyl)glycinate:

[0661] A mixture of 2-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)acetic acid (200 mg, 0.62 mmol), ethyl glycinate hydrochloride (105 mg, 0.75 mmol), benzotriazole-1-yl- oxytripyrrolidinophosphonium hexafluoro phosphate (0.39 g, 0.75 mmol) and triethylamine (300 mg,3.0 mmol) in dichloromethane (8.0 mL) was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane = 1 / 20) to obtain ethyl (6- (benzyloxy)pyrazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (150 mg, 59.2% yield) as yellow solid. LC-MS: m / z= 404.0 (M+H)+, retention time 2.02 min (Method A).

[0662] Step 10: Ethyl (6-hydroxypyrazolo[5,1-a]isoquinoline-5-carbonyl)glycinate:

[0663] A mixture of ethyl (6-(benzyloxy)pyrazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (0.15 g, 0.37 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 solid was filtered and the filtrate was concentrated to give ehyl (6-hydroxypyrazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (100 mg, 86.2% yield) as yellow solid. LC-MS: m / z= 314.0 (M+H)+, retention time 1.57 min (Method A).

[0664] Step 11: (6-Hydroxypyrazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0665]

[0666] To a solution of ethyl (6-hydroxypyrazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (100 mg, 0.32 mmol) in tetrahydrofuran / water (8.0 mL / 2.0 mL) was added lithium hydroxide monohydrate (128 mg, 3.2 mmol). The mixture was stirred overnight and concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified with 10% hydrochloric acid solution to pH=3~4. The precipitate was filtered, washed with water and dried to obtain (6-hydroxypyrazolo[5,1-a]isoquinoline- 5-carbonyl)glycin (10.8 mg, 11.8% yield) as white solid. LC-MS: m / z= 286.0 (M+H)+, retention time 4.55 min (Method A).1HNMR (400 MHz, DMSO-d6) δ 14.75 (br, 1H), 12.99 (br, 1H), 11.19 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.86-7.90 (m, 1H), 7.75-7.77 (m, 1H), 7.44 (s, 1H), 4.29 (s, 2H).Example 6: Preparation of Compound (6) Scheme 6: Synthesis of Compound (6)Compound 6

[0667] Step 1: Methyl 2-(chlorocarbonyl)benzoate:

[0668] A mixture of 2-(methoxycarbonyl)benzoic acid (5.0 g, 27.7 mmol) in thionyl chloride (80.0 mL) was stirred at 80 °C for 4.0 h and concentrated to give dryness. Methyl 2-(chlorocarbonyl)benzoate (5.0 g, 25.1 mmol, 91% yield) was obtained as yellow oil. LC-MS: m / z= 199.1 (M+H)+, retention time 1.819 min (Method B).

[0669] Step 2: Methyl 2-(isothiocyanatocarbonyl)benzoate:O

[0670] A mixture of methyl 2-(chlorocarbonyl) benzoate (5.0 g, 25.0 mmol) and potassiumthiocyanate (2.5 g, 25 mmol) in acetonitrile (30.0 mL) was stirred at 80 oC for 3.0 h. The mixture wascooled and concentrated to give dryness. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Methyl 2-(isothiocyanatocarbonyl)benzoate (5.0 g, 22.5 mmol, 91% yield) was obtained as yellow solid. LC-MS: m / z= 222.0 (M+H)+, retention time 1.764 min (Method B).

[0671] Step 3: Methyl 2-((ethoxycarbonothioyl)carbamoyl)benzoate:

[0672] A mixture of methyl 2-(isothiocyanatocarbonyl)benzoate (5.0 g, 22.5 mmol) in ethanol (100.0 mL) was stirred at 80 °C for 8.0 h . The mixture was cooled and concentrated to give dryness. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Methyl 2- ((ethoxycarbonothioyl)carbamoyl)benzoate (4.0 g, 14.9 mmol, 66% yield) was obtained as yellow solid. LC-MS: m / z= 268.1 (M+H)+, retention time 1.862 min (Method B).

[0673] Step 4: Methyl 2-(3-ethoxy-1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-5-yl)benzoate :

[0674] A mixture of methyl 2-((ethoxycarbonothioyl)carbamoyl)benzoate (1.0 g, 3.75 mmol), ethyl hydrazinoacetate hydrochloride (694.80 mg, 4.49 mmol) and sodium acetate (368.30 mg, 4.49 mmol) in ethanol (15.0 mL) was stirred at 80 °C for 4.0 h. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Methyl 2-(3-ethoxy-1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-5- yl)benzoate (550 mg, 1.65 mmol, 44% yield) was obtained as yellow solid. LC-MS: m / z= 334.0 (M+H)+, retention time 1.854 min (Method B).

[0675] Step 5: Ethyl 2-ethoxy-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate :

[0676] To a solution of methyl 2-(3-ethoxy-1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-5-yl)benzoate (550 mg, 1.65 mmol) in ethanol (15.0 mL) was added sodium ethoxide (225 mg, 3.3 mmol). The mixture was stirred at 90 °C for 2.0 h. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford ethyl 2-ethoxy-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (150 mg, 0.50 mmol, 30.2% yield) as yellow solid. LC-MS: m / z= 302.1 (M+H)+, retention time 2.07 min (Method A).

[0677] Step 6: (2-Ethoxy-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0678] To a solution of methyl 2-(3-ethoxy-1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-5-yl)benzoate (90.00 mg, 0.30 mmol) in dimethyl sulfoxide (2.0 mL) was added glycine (67.30 mg, 0.90 mmol) and potassium carbonate (124.00 mg, 0.90 mmol). The mixture was stirred at 110°C for about 2.0 h. The mixture was cooled diluted with ice-water. The resulting aqueous solution was acidified with 3N / L hydrochloric acid to pH=3~4. The resulting solid was filtered and dried to afford (2-ethoxy-6-hydroxy- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (44 mg, 0.3 mmol, 44.6% yield) as white solid. LC-MS: m / z=331.0 (M+H)+, retention time 4.59 min (Method A).1HNMR (400 MHz, DMSO-d6) δ 14.28 (s, 1H), 10.34 (s, 1H), 8.34-7.89 (m, 4H), 4.51-4.25 (m, 4H), 1.44-1.42 (m, 3H).Example 7: Preparation of Compound (7) Scheme 7: Synthesis of Compound (7)Co pou d 7

[0679] Step 1: 3-(Trifluoromethyl)-1H-1,2,4-triazol-5-amine:

[0680] A mixture of aminoguanidine bicarbonate (5.0 g, 5.30 mmol) and trifluoroacetic acid (10.0 mL) was stirred at room temperature for 2.0 h. Toluene (20 mL) was added, and the reaction mixture was stirred at 110 °C for 24 h with a Dean-Stark apparatus. The mixture was cooled and a solid was precipitated. The solid was filtered, washed with water and dried to obtain 3-(trifluoromethyl)-1H- 1,2,4-triazol-5-amine (800 mg, 2.06 mmol, 38.9% yield) as yellow solid. LC-MS: m / z= 153.1 (M+H)+,retention time 1.293 min (Method A).

[0681] Step 2: 3-(Trifluoromethyl)-1H-1, 2, 4-triazol-5-amine: B3

[0682] To a mixture of cupric bromide (7.3 g, 32.9 mmol) and 3-(trifluoromethyl)-1H-1,2,4-triazol- 5-amine (5.0 g, 32.9 mmol) in acetonitrile (60.0 mL) was added tert-butyl nitrite (3.4 g, 32.9 mmol) dropwise. The reaction was stirred at 60 °C for 30 min. After completion, the reaction was quenched with ice-water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain 3-(trifluoromethyl)-1H-1,2,4- triazol-5-amine (3.0 g, 32.9 mmol, 42.9% yield) as yellow solid. LC-MS: m / z= 215.9 (M+H)+, retention time 1.71 min (Method A).

[0683] Step 3: Ethyl 2-(5-bromo-3-(trifluoromethyl)-1H-1, 2, 4-triazol-1-yl) acetate: B

[0684] A mixture of 3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine (1.0 g, 4.65 mmol), sodium ethoxide (640.0 mg, 9.30 mmol) and ethyl 2-bromoacetate (1.5 g, 9.30 mmol) in ethanol (15.0 mL) was stirred at 55 °C for about 3.0 h. The mixture was evaporated to give dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford ethyl 2-(5-bromo-3- (trifluoromethyl)-1H-1,2,4-triazol-1-yl)acetate (400 mg, 4.65 mmol, 28.80 % yield) as white solid. LC- MS: m / z= 302.10 (M+H)+, retention time 1.960 min (Method A).

[0685] Step 4: Ethyl 6-hydroxy-2-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate:3

[0686] A mixture of ethyl 2-(5-bromo-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)acetate (250.0 mg, 0.83 mmol), (2-(methoxycarbonyl)phenyl)boronic acid (193.60 mg, 1.08mmol), potassium phosphate tribasic (350.4 mg, 1.66 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (38.10 mg, 0.08 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (31.50 mg, 0.04 mmol) in 1,4-dioxane / water (10.0 mL / 2.5 mL) was stirred at 100 °C for about 3.0 h under nitrogen. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate =5 / 1) to afford ethyl 6-hydroxy-2-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (43.0 mg, 0.83 mmol, 14.90% yield)as white solid. LC-MS: m / z= 326.0 (M+H)+, retention time 2.22 min (Method A).

[0687] Step 5: (6-Hydroxy-2-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine

[0688] To a solution of ethyl 6-hydroxy-2-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (43.00 mg, 0.13 mmol) in dimethyl sulfoxide (4.0 mL) was added glycine (30.0 mg, 0.40 mmol) and potassium carbonate (55.2 mg, 0.40 mmol). The mixture was stirred at 110°C for about 2.0 h. The mixture was cooled diluted with ice-water. The resulting aqueous solution was acidified with 3N / L hydrochloric acid to pH=3~4. The resulting solid was filtered and dried to afford (6-hydroxy-2- (trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (25.0 mg, 0.13 mmol, 53% yield) as white solid. LC-MS: m / z= 354.8 (M+H)+, retention time 4.82 min (Method A).1HNMR (400 MHz, DMSO-d6) δ 14.20 (s, 1H), 10.02-9.99 (m, 1H), 8.63-8.60 (m, 1H), 8.44-8.41 (m, 1H), 8.08- 8.402 (m, 1H), 4.30 (d, J = 5.6Hz, 2H).Example 8: Preparation of Compound (8) Scheme 8: Synthesis of Compound (8)Compound 8

[0689] Step 1: Benzyl 2,6-dibromobenzoate:r

[0690] To a solution of 2,6-dibromobenzoic acid (8.4 g,30 mmol) in N,N-dimethylformamide (200.0 mL) was added benzyl bromide (7.5 g, 45 mmol) and potassium carbonate (8.1 g,60 mmol). The mixture was stirred at 60°C for 2.0 h. The solution was quenched with ice water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with ethyl acetate and filtered to benzyl 2,6-dibromobenzoate (9.2 g, 83.6% yield) as yellow solid. LC-MS: m / z= 369.0 (M+H)+, retention time 2.86 min (Method A).

[0691] Step 2: Benzyl 3-bromo-[1,1'-biphenyl]-2-carboxylate:

[0692] A mixture of benzyl 2,6-dibromobenzoate (9.2 g, 25 mmol), phenylboronic acid (3.05 g, 25 mmol), tetrakis(triphenylphosphine) palladium (1.44 g, 1.25 mmol) and sodium carbonate (2.65 g, 25 mmol) in toluene / water (100.0 mL / 10.0 mL) was stirred at 90 °C for 12.0 h. The reaction was partitioned between ethyl acetate and water. The residue was triturated with ethyl acetate and filtered to afford benzyl 3-bromo-[1,1'-biphenyl]-2-carboxylate (7.0 g, 76.5%) as white solid. LC-MS: m / z= 367.1 (M+H)+, retention time 3.08 min (Method A).

[0693] Step 3: 2-Benzyl 3-methyl [1,1'-biphenyl]-2,3-dicarboxylate:

[0694] A mixture of benzyl 3-bromo-[1,1'-biphenyl]-2-carboxylate (5.0 g, 13.6 mmol), 1,1'- bis(diphenylphosphino)ferrocene (1.51 g, 2.72 mmol), palladium (II) acetate (2.9 g, 13.6 mol), triethylamine (4.12g, 40.8 mmol), dimethyl sulfoxide (50.0 mL) and methanol (50.0 mL) was stirred at 90° C. for 12.0 h under carbon monoxide atmosphere. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford 2-benzyl 3-methyl [1,1'-biphenyl]-2,3-dicarboxylate (3.0 g, 63.8% yield). LC- MS: m / z= 347.0 (M+H)+, retention time 2.17 min (Method A).

[0695] Step 4: 3-(Methoxycarbonyl)-[1,1'-biphenyl]-2-carboxylic acid:

[0696] A mixture of 2-benzyl 3-methyl [1,1'-biphenyl]-2,3-dicarboxylate (3 g, 8.6 mmol) and 10% palladium on carbon (100.0 mg) in tetrahydrofuran (20.0 mL) was stirred under hydrogen atmospherefor 2.0 h. The insoluble solid was filtered and the filtrate was concentrated to give 3- (methoxycarbonyl)-[1,1'-biphenyl]-2-carboxylic acid (1.6 g, 66.7% yield) as white solid. LC-MS: m / z= 279.1 (M+H)+, retention time 1.84 min (Method A).

[0697] Step 5: Methyl 2-(chlorocarbonyl)-[1,1'-biphenyl]-3-carboxylate:

[0698] To a solution of 3-(methoxycarbonyl)-[1,1'-biphenyl]-2-carboxylic acid (0.5 g, 2.0 mmol) in dichloromethane (15.0 mL) was added oxalyl dichloride (0.5 g, 4.0 mmol) at 0° C. The mixture was stirred at this temperature for 2.0 h and concentrated. The crude product (0.54 g, 92.5% yield) was obtained as yellow solid, which was used to the next step. LC-MS: m / z= 271.0 (M+H)+, retention time 2.00 min (Method A).

[0699] Step 6: Methyl 2-(isothiocyanatocarbonyl)-[1,1'-biphenyl]-3-carboxylate:

[0700] A mixture of methyl 2-(chlorocarbonyl)-[1,1'-biphenyl]-3-carboxylate (0.54 g ,2.0 mmol) and potassium thiocyanate (0.36 g, 4.0 mmol) in acetonitrile (30.0 mL) was stirred at room temperature for 4.0 h. The mixture was cooled and concentrated to give dryness. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Methyl 2-(isothiocyanatocarbonyl)-[1,1'-biphenyl]-3- carboxylate (0.5 g, 83.8% yield) was obtained as white solid. LC-MS: m / z= 298.0 (M+H)+, retention time 1.92 min (Method A).

[0701] Step 7: Methyl 2-((ethoxycarbonothioyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylate:

[0702] A mixture of methyl 2-(isothiocyanatocarbonyl)-[1,1'-biphenyl]-3-carboxylate (0.5 g, 1.8 mmol) in ethanol (20.0 mL) was stirred at room temperature for 12.0 h. The mixture was cooled and concentrated to give dryness. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Methyl 2-((ethoxycarbonothioyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylate (0.33 g, 50.3% yield) was obtained as yellow solid. LC-MS: m / z= 366.1 (M+H)+, retention time 1.98 min (Method B).

[0703] Step 8: Methyl 2-(3-ethoxy-1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-5-yl)-[1,1'-biphenyl]- 3-carboxylate:

[0704] A mixture of methyl 2-((ethoxycarbonothioyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylate (0.34 g ,1.0 mmol), ethyl aminoglycinate (0.3 g, 2.0 mmol) and sodium acetate (0.16 g, 2.0 mmol) in acetic acid (5.0 mL) was stirred at 110 °C for 2.0 h. The mixture was cooled and concentrated to give dryness. The residue was purified by flash chromatography (dichloromethane / methanol = 20 / 1) to afford methyl 2-(3-ethoxy-1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-5-yl)-[1,1'-biphenyl]-3-carboxylate (0.13 g, 31.7% yield) as white solid. LC-MS: m / z= 410.0 (M+H)+, retention time 1.98 min (Method A).

[0705] Step 9: Ethyl 2-ethoxy-6-hydroxy-10-phenyl-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate:

[0706] To a solution of methyl 2-(3-ethoxy-1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-5-yl)-[1,1'- biphenyl]-3-carboxylate (0.1 g, 0.24 mmol) in ethanol (5.0 mL) was added sodium ethoxide (30 mg, 0.48 mmol). The mixture was stirred at 70 °C for 12.0 h. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodiumsulfateand concentrated under reduced pressure. The residue was purified by flash chromatography(petroleum ether / ethyl acetate = 1 / 1) to afford ethyl 2-ethoxy-6-hydroxy-10-phenyl-[1,2,4]triazolo[5,1- a]isoquinoline-5-carboxylate (50 mg, 54.3% yield) as yellow solid. LC-MS: m / z= 378.11 (M+H)+, retention time 2.357 min (Method A).

[0707] Step 10: (2-Ethoxy-6-hydroxy-10-phenyl-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine

[0708] To a solution of ethyl 2-ethoxy-6-hydroxy-10-phenyl-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (0.05 g ,0.13 mmol) in dimethyl sulfoxide (2.0 mL) was added glycine (30 mg, 0.39 mmol) and potassium carbonate (50 mg, 0.39 mmol)). The mixture was stirred at 100°C for about 2.0 h. The mixture was cooled diluted with ice-water. The resulting aqueous solution was acidified with 3N / L hydrochloric acid to pH=3~4. The resulting solid was filtered and dried to afford (2-ethoxy-6-hydroxy- 10-phenyl-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (11.5 mg, 21.3%) as white solid. LC- MS: m / z=407.1 (M+H)+, retention time 3.44 min (Method A).1HNMR (400 MHz, DMSO-d6) δ 14.43 (s, 1H), 10.49 (s, 1H), 8.40 (d, J = 8.1Hz, 1H), 7.95-7.91(m, 1H), 7.74 (d, J =6.5Hz, 1H), 7.42 (s, 5H), 4.27-4.17 (m, 4H), 1.24 (t, J = 7.0 Hz, 3H).Example 9: Preparation of Compound (9) Scheme 9: Synthesis of Compound (9)Compound 9

[0709] Step 1: methyl 3-bromo-2-(bromomethyl)benzoate

[0710] A mixture of methyl 3-bromo-2-methyl-benzoate (25 g, 109.14 mmol), 1-bromopyrrolidine- 2,5-dione (19.42 g, 109.14 mmol) and BPO (100 mg) in Chloroform (363.79 mL) was heated to 75oCovernight. TLC (5% ethyl acetate in hexanes): complete conversion to less polar spot. The reaction was cooled to rt, diluted with water (10 mL) and hexanes (200 mL), white solid was crashed out. The mixture was filtered through a pad of celite. The filtrate was concentrated to afford methyl 3-bromo-2- (bromomethyl)benzoate (33.7 g, 109.1 mmol, 100%) as brown liquid. The crude was subjected to the next reaction without further purification. LC-MS: m / z=309 (M+H)+.

[0711] Step 2: methyl 8-bromo-4-hydroxyisoquinoline-3-carboxylate

[0712] K2CO3(22.58 g, 163.65 mmol) and NaI (100 mg) were added to a stirred mixture of methyl 3-bromo-2-(bromomethyl)benzoate (33.6 g, 109.1 mmol) and methyl 2-(p-tolylsulfonylamino)acetate (26.54 g, 109.1 mmol) in DMF (200 mL) at rt. The resulting reaction mixture was heated to 60 °C for 4 h. TLC and LCMS indicated complete consumption of starting materials occurred. The reaction was cooled to 0 °C, 25% sodium methoxide in methanol (62.37 mL, 272.75 mmol)) was added and warmed to rt. After 1.5 h, LCMS indicated formation of product (MS / 283). The reaction was acidified with acetic acid (25 mL). The reaction mixture was slowly added to ice-water mixture (600 mL) with vigorous stirring. The precipitate was filtered, solid was dried in air. The solid was suspended in acetone (200 mL), filtered to afford methyl 8-bromo-4-hydroxyisoquinoline-3-carboxylate (20 g, 70.9 mmol, 65% yield) as pale-brown solid. LC-MS: m / z= 283 [M+H]+. The product was pure enough and used directly to the next step.

[0713] Step 3: methyl 4-(benzyloxy)-8-bromoisoquinoline-3-carboxylate

[0714] Bromo methylbenzene (9.33 mL, 77.99 mmol) was added to a stirred mixture of methyl 8- bromo-4-hydroxy-isoquinoline-3-carboxylate (22.g, 77.99 mmol), K2CO3 (21.52 g, 155.98 mmol) and NaI (100 mg) in DMF (220 mL) at rt. The resulting reaction mixture was stirred at 80 °C for 1 h and stirred at rt overnight. LCMS indicated complete consumption of starting material occurred. The reaction mixture was poured slowly to ice-cold water (600 mL). The solid was separated by filtration. The solid was dissolved in ethyl acetate and DCM mixture (9:1, 200 mL), washed with water (60 mL),brine (60 mL) and dried over Na2SOd and concentrated to afford methyl 4-(benzyloxy)-8- bromoisoquinoline-3-carboxylate (23.6 g, 63.4 mmol, 81% yield) as brown solid. LC-MS: m / z= 373 [M+H]+. The product was pure enough and used directly to the next step without further purification.

[0715] Step 4: 4-(benzyloxy)-8-bromo-3-(methoxycarbonyl)isoquinoline 2-oxide

[0716] 3-chlorobenzenecarboperoxoic acid (16.69g, 96.72mmol) was added lot wise to a stirred solution of methyl 4-benzyloxy-8-bromo-isoquinoline-3-carboxylate (18 g, 48.36 mmol) in DCM (200 mL) and acetone (10 mL) at 0 °C and warmed to rt. The resulting reaction mixture was stirred for 20 h at rt. The reaction was quenched slowly with aq. NaHCO3 solution (250 mL), stirred for 10 min and the layers were separated. The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (0-100% ethyl acetate in DCM) afford 4-(benzyloxy)-8-bromo-3-(methoxycarbonyl)isoquinoline 2-oxide (16.2 g, 41.7 mmol, 86 % yield) as yellow solid. LC-MS: m / z= 389 [M+H]+.

[0717] Step 5: methyl 1-amino-4-(benzyloxy)-8-bromoisoquinoline-3-carboxylate

[0718] 4-methylbenzenesulfonyl chloride (15.91 g, 83.46 mmol) was added in 3 lots to a stirred solution of methyl 4-benzyloxy-8-bromo-2-oxo-isoquinoline-3-carboxylate (16.2 g, 41.73 mmol) in pyridine (162 mL) at 0 °C over 10 min. The resulting reaction mixture was stirred at 0 °C for 20 min, TLC (50% ethyl acetate in hexanes) indicated complete conversion to a less polar spot occurred. The reaction was cooled to at 0 °C and 2-aminoethanol (42 mL) was added dropwise to reaction mixture. The resulting red reaction mixture was stirred at 0 °C for 15 min and ice-water bath removed. The reaction was stirred at rt for 1 h at rt. The reaction was quenched with water and added 5N HCl (30 mL), yellow solid was crashed out, filtered. The aqueous layer was extracted with ethyl acetate. The organic layer was concentrated. Both crude solid (10 g) and extracted crude was purified by column separately (0-60% ethyl acetate in DCM) afford methyl 1-amino-4-(benzyloxy)-8-bromoisoquinoline-3- carboxylate (9.1 g, 23.5 mmol, 56% yield) as pale-yellow solid. LC-MS: m / z= 388 [M+H]+.

[0719] Step 6: methyl 4-(benzyloxy)-8-bromo-1-(3-(ethoxycarbonyl)thioureido)isoquinoline-3- carboxylate

[0720] Ethoxycarbonyl isothiocyanate (4.11mL, 34.86 mmol) was added to a stirred solution of methyl 1-amino-4-benzyloxy-8-bromo-isoquinoline-3-carboxylate (9 g, 23.24 mmol) in 1,4-Dioxane (105.88 mL) at rt. The resulting reaction mixture was stirred at rt for 48 h. TLC (50% ethyl acetate in hexanes) indicated complete consumption of starting material occurred. The reaction was concentrated directly to afford methyl 4-(benzyloxy)-8-bromo-1-(3-(ethoxycarbonyl)thioureido)isoquinoline-3- carboxylate (12 g, 23.1 mmol, 99% yield) as pale yellow solid. The crude was subjected to the next reaction without further purification. LC-MS: m / z= 519 [M+H]+.

[0721] Step 7: Methyl 2-amino-6-(benzyloxy)-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate

[0722] Hydroxylamine;hydrochloride (8.04 g, 115.75 mmol) and N,N-Diisopropylethylamine (20.45 mL, 115.75 mmol) were added to a suspension of methyl 4-benzyloxy-8-bromo-1- (ethoxycarbonylcarbamothioylamino)isoquinoline-3-carboxylate (12 g, 23.15 mmol) in isopropyl alcohol (350 mL) at rt. The resulting reaction mixture was stirred at 50 °C for 4 h and let it stir overnight at 40 °C. The reaction was concentrated. The residue was suspended in water (200 mL) and solid was separated by filtration. The solid was dried in air to afford methyl 2-amino-6-(benzyloxy)-10- bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (9.9 g) as brown solid. The crude was subjected to the next reaction without further purification. LC-MS: m / z= 428 [M+H]+.

[0723] Step 8: methyl 6-(benzyloxy)-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate

[0724] tert-butyl nitrite (6 mL, 50.45mmol) was added to a stirred suspension of methyl 2-amino-6- benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (9.9 g, 23.17 mmol) in THF (150mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 24 h. LCMS indicated complete consumption of starting material occurred. The reaction was concentrated directly, and crude was purified by column (0-90% ethyl acetate in DCM) afford methyl 6-(benzyloxy)- 10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (7.2 g, 17.5 mmol, 75% over 3 steps) as brown solid. LC-MS: m / z= 413 [M+H]+.

[0725] Step 9: 6-(benzyloxy)-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylic acid

[0726] Aqueous 1 N NaOH (36 mL, 36 mmol) was added to a stirred suspension of methyl 6- benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (5.6 g, 13.58 mmol) in THF (67.9 mL) at rt. The resulting reaction mixture was stirred at 50 °C for 2 h. LCMS indicated complete conversion occurred. The reaction was concentrated directly to remove THF. The aqueous solution was cooled to 0 °C, acidified with aqueous 1 N HCl (36 mL), the precipitate was filtered and solid was dried in air to afford 6-(benzyloxy)-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylic acid (5.3 g, 13.3 mmol, 98%) as off-white solid. LC-MS: m / z= 399 [M+H]+.

[0727] Step 10: ethyl (6-(benzyloxy)-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0728] PyBOP (7.61 g, 14.64 mmol) was added to a stirred mixture of 6-benzyloxy-10-bromo- [1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylic acid (5.3 g, 13.31 mmol) in DCM (66.548mL) at room temperature. After 3 min, ethyl 2-aminoacetate;hydrochloride (2.78 g, 19.96 mmol) and triethylamine (9.24 mL, 66.55 mmol) were added and the resulting reaction mixture was stirred at room temperature overnight. LC-Ms indicated complete consumption of starting material occurred. The reaction was diluted with water (50 mL), stirred for 5 min at rt. The organic layer was separated. The aqueous layer was extracted with DCM (50 mL). The combined organic layer was dried over Na2SO4and concentrated. The crude was purified by column (24 g, 0-100% ethyl acetate in hexanes) afford ethyl (6-(benzyloxy)-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (4.6 g, 9.5 mmol, 71.5%) as off-white solid. LC-MS: m / z= 484 [M+H]+.

[0729] Step 11: (10-bromo-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0730] A mixture of ethyl 2-[(6-benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (95 mg, 0.2000 mmol) and TFA (1 mL) was heated to 70 °C for 1 h. LC-Ms indicated complete conversion. The reaction was concentrated directly. The crude was suspended in THF (2 mL) and 1 mL 1 N NaOH solution. The reaction was heated to 40 °C for 1 h. LCMS indicated complete conversion. The reaction was dilute with water (5 mL), extracted with ethyl acetate (5 mL). The aqueous layer was cooled to 0 °C, acidified with 1 N HCl (1 mL), the white precipitate was filtered, solid was washes with water, dried in air afford (10-bromo-6-hydroxy-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycine (26 mg, 0.1 mmol, 35.6%) as white solid. LC-MS: m / z= 366.1 [M+H]+.1H NMR (500 MHz, DMSO) δ 14.69 (s, 1H), 13.03 (s, 1H), 10.60 (t, J = 5.2 Hz, 1H), 8.74 (s, 1H), 8.42 (d, J = 8.1 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 4.28 (d, J = 5.5 Hz, 2H). Example 10: Preparation of Compound (10) Scheme 10: Synthesis of Compound (10)

[0731] Step 1: ethyl (6-(benzyloxy)-10-phenyl-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0732] A mixture of ethyl 2-[(6-benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (1.0 g, 2.07 mmol), phenylboronic acid (378.42 mg, 3.1 mmol), K2CO3(1.5 g, 10.87 mmol), Pd(dppf)Cl2.DCM (84.42mg, 0.1000mmol) in 1,4-Dioxane (30 mL) and Water (0.5000 mL) was heated to 90 °C overnight. The reaction was cooled to rt, diluted with 1 N HCl, filtered, rinsed with DCM (100 mL). The organic layer was separated and concentrated. The crude was purified by column chromatography ( 0-100% ethyl acetate in hexanes) afford ethyl (6-(benzyloxy)-10-phenyl- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (780 mg, 1.6 mmol, 78%) as brown solid. LC- MS: m / z= 481.5 (M+H)+.

[0733] Step 2: ethyl (6-hydroxy-10-phenyl-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate

[0734] A mixture of ethyl 2-[(6-benzyloxy-10-phenyl-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (780 mg, 1.62 mmol) and 10% Pd on Carbon (50 mg) in THF (10 mL) and Ethyl acetate (20 mL) was degassed with Hydrogen and stirred under Hydrogen pressure for 12 h. LC- MS indicated complete conversion. The reaction was filtered through a pad of Celite, rinsed with DCM. The filtrate was concentrated, and crude was purified by column chromatography (0-50% ethyl acetate in DCM) afford ethyl (6-hydroxy-10-phenyl-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (465 mg, 1.2 mmol, 73%) as white solid. LC-MS: m / z= 391.4 (M+H)+.

[0735] Step 3: (6-hydroxy-10-phenyl-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0736] Aqueous 1 N NaOH (6 mL, 150 mmol) was added to a stirred solution of ethyl 2-[(6- hydroxy-10-phenyl-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)amino]acetate (510 mg, 1.31 mmol) on THF (24 mL) at rt. The reaction mixture was stirred at 50 °C for 2 h. LC-MS indicated complete consumption of starting material occurred. The reaction was concentrated directly to evaporate THF. The residue was cooled to 0 °C and acidified with 1 N HCl (6 mL), white precipitate occurred. The solid was separated by filtration, washed with water (20 mL) and ethanol (10 mL) to afford (6-hydroxy- 10-phenyl-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (421 mg, 1.2 mmol, 88%) as white solid. LC-MS: m / z= 363 (M+H)+.1H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 13.02 (s, 1H), 10.58 (t, J = 5.4 Hz, 1H), 8.44 (dd, J = 8.2, 1.2 Hz, 1H), 8.38 (s, 1H), 7.95 (dd, J = 8.1, 7.5 Hz, 1H), 7.75 (dd, J = 7.4, 1.2 Hz, 1H), 7.48 – 7.36 (m, 5H), 4.28 (d, J = 5.5 Hz, 2H). Example 11: Preparation of Compound (11) Scheme 11: Synthesis of Compound (11)

[0737] Step 1: ethyl (6-(benzyloxy)-10-(3-chlorophenyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0738] A mixture of ethyl 2-[(6-benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (1.5 g, 3.1 mmol), (3-chlorophenyl)boronic acid (0.97 g, 6.21 mmol), K2CO3 (1.28 g, 9.31 mmol), water (0.56 mL, 31.04 mmol) and Pd(dppf)Cl2.DCM (253.25 mg, 0.31 mmol) washeated to 110 °C under Nitrogen overnight. LC-MS indicated complete consumption of starting material occurred. The reaction was diluted with water (100 mL) and the mixture was filtered, filtrated was extracted with ethyl acetate (100 mL X 3). The combined organic layer was concentrated, crude was purified by column (0-100% ethyl acetate in hexanes) afford ethyl (6-(benzyloxy)-10-(3-chlorophenyl)- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (1.43 g, 2.79 mmol, 90%).

[0739] Step 2: ethyl (10-(3-chlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate C

[0740] A mixture of ethyl 2-[[6-benzyloxy-10-(3-chlorophenyl)-[1,2,4]triazolo[5,1-a]isoquinoline- 5-carbonyl]amino]acetate (1.46 g, 2.84 mmol), 10% Pd on Carbon (0.2 mg) in Ethyl acetate (50 mL) and THF (50 mL) was degassed with Hydrogen for 3 min and stirred at rt for 2 h under Hydrogen pressure. TLC indicated complete conversion occurred. The reaction was filtered through a pad of celite, rinsed with DCM-ethyl acetate mixture. The filtrate was concentrated. The crude was purified by column (12 g, 0-100% ethyl acetate in DCM) afford ethyl (10-(3-chlorophenyl)-6-hydroxy- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (1.2 g, 2.8 mmol, 99%) as off-white solid. LC- MS: m / z= 430 (M+H)+.

[0741] Step 3: (10-(3-chlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine Cl

[0742] Aqueous 1 N NaOH (10.76 mL, 10.76 mmol) was added to a solution of ethyl 2-[[10-(3- chlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl]amino]acetate (1.3 g, 3.06 mmol) in THF (50 mL) at rt. The reaction mixture was heated to 60 °C for 1 h. LC-MS indicated complete consumption of starting material occurred. The reaction was concentrated directly to evaporate THF. The aqueous layer was cooled to 0 °C, acidified by 1 N HCl (12 ml), precipitate was filtered, white solid was washed with water (50 m L), methanol (10 mL), dried in air. The solid wassuspended in ethyl acetate and sonicated for 5 min, filtered and white solid was dried under high vacuum to afford (10-(3-chlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine. LC-MS: m / z= 398 (M+H)+.1H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 13.00 (s, 1H), 10.57 (t, J = 5.4 Hz, 1H), 8.46 (dd, J = 8.2, 1.2 Hz, 1H), 8.43 (s, 1H), 8.00 – 7.93 (m, 1H), 7.78 (dd, J = 7.4, 1.2 Hz, 1H), 7.52 – 7.44 (m, 3H), 7.39 (dt, J = 6.6, 1.8 Hz, 1H), 4.28 (d, J = 5.5 Hz, 3H). Example 12: Preparation of Compound (12) Scheme 12: Synthesis of Compound (12)C

[0743] Step 1: ethyl (10-(2-chlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate C

[0744] A mixture of ethyl 2-[(6-benzyloxy-9-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (250 mg, 0.52 mmol), (2-chlorophenyl)boronic acid (161.77 mg, 1.03 mmol), Pd(dppf)Cl2.DCM (42.24 mg, 0.050 mmol), K2CO3(356.91mg, 2.59mmol) and water (0.09 mL, 5.17 mmol) in 1,4-Dioxane (5 mL) was heated to 100 °C for 24 h in a shield tube. The reaction was cooled to rt, diluted with ethyl acetate (30 mL) and aqueous HCl. The organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layer was concentrated, crude was purified by column (0-100% ethyl acetate in DCM) afford ethyl (10-(2-chlorophenyl)-6-hydroxy- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (108 mg, 0.3 mmol, 49%) as white solid. LC- MS: m / z= 430 (M+H)+.

[0745] Step 2: (10-(2-chlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine C

[0746] Aqueous1 N NaOH (4.08 mL, 102 mmol) was added to a stirred solution of ethyl 2-[[10-(2- chlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl]amino]acetate (102 mg, 0.240 mmol) in THF (10 mL) at rt. The resulting reaction mixture was heated to 45 °C for 2 h. LCMS indicated complete consumption of starting material occurred. The reaction was concentrated directly. The crude was acidified with aq.1 H HCl (4 ml), precipitate was filtered. The solid was washed with water, dried in air. The crude was suspended in ethanol (10 mL), stirred for 30 min at rt and filtered to afforded (10-(2-chlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (71 mg,0.2 mmol, 71%) as off-white solid. LC-MS: m / z= 398 (M+H)+.1H NMR (400 MHz, DMSO) δ 14.62 (s,1H), 10.55 (t, J = 5.2 Hz, 1H), 8.48 (dd, J = 8.2, 1.2 Hz, 1H), 8.40 (s, 1H), 8.00 (dd, J = 8.2, 7.4 Hz, 1H), 7.73 (dd, J = 7.4, 1.2 Hz, 1H), 7.57 – 7.52 (m, 1H), 7.44 (dqd, J = 7.5, 7.0, 2.1 Hz, 3H), 4.16 (d, J = 5.0 Hz, 2H). Example 13: Preparation of Compound (13) Scheme 13: Synthesis of Compound (13)Cl Cl

[0747] Step 1: ethyl (10-(4-chlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0748] A mixture of ethyl 2-[(6-benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (200 mg, 0.410 mmol), (4-chlorophenyl)boronic acid (129.42 mg, 0.830 mmol), K2CO3(171.32mg, 1.24mmol), Pd(dppf)Cl2.DCM (33.77 mg, 0.040 mmol) and water (0.04 mL, 2.07 mmol) in 1,4-Dioxane (5 mL) was heated to 100 °C for 20 h. LC-MS indicated complete consumption of starting material occurred. The reaction was diluted with water and ethyl acetate, filtered through a pad of Celite, organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4and concentrated. The crude was purified by column (0-100% ethyl acetate in hexanes) afford ethyl (10-(4-chlorophenyl)-6-hydroxy- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (121 mg, 0.2 mmol, 69%) as white solid. LC- MS: m / z= 426 (M+H)+.

[0749] Step 2: (10-(4-chlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine

[0750] Aqueous 1 N NaOH (75 mL, 75 mmol) was added to a stirred solution of ethyl 2-[[10-(4- chlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl]amino]acetate (121 mg, 0.280 mmol) in THF (10 mL) at rt. The resulting reaction mixture was heated to 50 °C for 2 h. The reaction mixture was concentrated directly to remove THF. The crude was acidified with aq.1 N HCl (4 ml), precipitate was filtered. The solid was washed with water, dried in air. The crude was suspended in ethanol (6 mL), stirred for 30 min at rt and filtered to afforded white solid. LC-MS: m / z= 398 (M+H)+.1H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 13.02 (s, 1H), 10.57 (t, J = 5.4 Hz, 1H), 8.44 (dd, J = 8.2, 1.2 Hz, 1H), 8.42 (s, 1H), 7.96 (dd, J = 8.1, 7.5 Hz, 1H), 7.76 (dd, J = 7.4, 1.2 Hz, 1H), 7.52 – 7.42 (m, 4H), 4.27 (d, J = 5.5 Hz, 2H).Example 14: Preparation of Compound (14) Scheme 14: Synthesis of Compound (14) P

[0751] Step 1: ethyl (6-(benzyloxy)-10-(phenylethynyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0752] Triethylamine (0.36 mL, 2.59 mmol) was added to a stirred mixture of ethyl 2-[(6- benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)amino]acetate (250 mg, 0.520 mmol), ethynylbenzene (105.66 mg, 1.03 mmol), Pd(PPh3)2Cl2(36.31 mg, 0.050 mmol) and CuI (19.7 mg, 0.100 mmol) in THF (6 mL) at rt. The reaction mixture was heated to 60 °C for 5 h. LC-MS indicated complete consumption of starting material occurred. The reaction was quenched with aqueous NH4OH and stirred for 30 min at rt. The reaction was filtered through a pad of Celite, filtrate was washed with brine (5 mL) and concentrated. The crude was purified by column chromatography (0- 100% ethyl acetate in hexanes) afford ethyl (6-(benzyloxy)-10-(phenylethynyl)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycinate (170 mg, 0.3 mmol, 65%) as brown solid. LC-MS: m / z= 505 (M+H)+.

[0753] Step 2: ethyl (6-hydroxy-10-phenethyl-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0754] A mixture of ethyl 2-[[6-benzyloxy-10-(2-phenylethynyl)-[1,2,4]triazolo[5,1-a]isoquinoline- 5-carbonyl]amino]acetate (170 mg, 0.340 mmol) and 10% Pd on Carbon (20 mg) in THF (10 mL) and Ethyl acetate (6 mL) was degassed with Hydrogen for 2 min and stirred at rt under Hydrogen pressure over weekend. LCMS indicated complete consumption of starting material occurred. The reaction was filtered, filtrate was concentrated and crude was purified by column (0-100% ethyl acetate in DCM) afford ethyl (6-hydroxy-10-phenethyl-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (120 mg, 0.3 mmol, 85%) as white solid. LC-MS: m / z= 419 (M+H)+.

[0755] Step 3: (6-hydroxy-10-phenethyl-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0756] Aqueous 1 N NaOH (3 mL, 75 mmol) was added to a stirred solution of ethyl 2-[[6- hydroxy-10-(2-phenylethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl]amino]acetate (120 mg, 0.290 mmol) in THF (10 mL) at rt. The resulting reaction mixture was heated to 50 °C for 2 h. The reaction was concentrated directly to remove THF. The crude was neutralized with aqueous 1 N HCl (4 ml), precipitate was filtered. The solid was washed with water, dried in air. The crude was suspended in ethanol (10 mL), stirred for 30 min at rt and filtered to afford (6-hydroxy-10-phenethyl- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (37 mg, 0.1 mmol, 31%)as white solid. LC-MS: m / z= 391 (M+H)+.1H NMR (400 MHz, DMSO) δ 14.62 (s, 1H), 13.04 (s, 1H), 10.60 (t, J = 5.4 Hz, 1H), 8.76 (s, 1H), 8.24 (dd, J = 7.8, 1.6 Hz, 1H), 7.87 – 7.69 (m, 2H), 7.40 – 7.33 (m, 2H), 7.30 (dd, J = 10.3, 4.8 Hz, 2H), 7.24 – 7.16 (m, 1H), 4.29 (d, J = 5.5 Hz, 2H), 3.92 – 3.79 (m, 2H), 3.01 – 2.89 (m, 2H).Example 15: Preparation of Compound (15) Scheme 15: Synthesis of Compound (15)

[0757] Step 1: ethyl (6-hydroxy-10-(pyridin-3-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0758] A mixture of ethyl 2-[(6-benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (200 mg, 0.410 mmol), 3-pyridylboronic acid (101.73 mg, 0.830 mmol), K2CO3(171.32mg, 1.24mmol), Pd(dppf)Cl2.DCM (33.77mg, 0.0400mmol) and water (0.07 mL, 4.14 mmol) in 1,4-Dioxane (4.5 mL) was heated to 100 °C for 20 h. The reaction mixture was cooled to rt, diluted with water and ethyl acetate and filtered. The organic layer was separated, concentrated. The crude was purified by column (0-100% ethyl acetate in DCM) afford ethyl (6-hydroxy-10-(pyridin-3-yl)- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (20 mg, 0.1 mmol, 12%). LC-MS: m / z= 392 (M+H)+.

[0759] Step 2: (6-hydroxy-10-(pyridin-3-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycineN

[0760] Aqueous 1 N NaOH (0.3 mL, 0.300 mmol) was added to a stirred mixture of ethyl 2-[[6- hydroxy-10-(3-pyridyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl]amino]acetate (20 mg, 0.050 mmol) in THF (1.5 mL). The reaction was heated to 50 °C for 3 h. The reaction was concentrated directly, crude was acidified with 1 N HCl (0.5 mL) at 0 °C. The precipitate was filtered. The solid was washed with water, dried in air to afford (6-hydroxy-10-(pyridin-3-yl)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycine (8 mg, 40%) as brown solid. LC-MS: m / z= 364 (M+H)+.1H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 13.03 (s, 1H), 10.56 (t, J = 5.4 Hz, 1H), 8.69 – 8.61 (m, 2H), 8.48 (d, J = 7.3 Hz, 1H), 8.41 (s, 1H), 8.05 – 7.96 (m, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.83 (dd, J = 7.4, 1.0 Hz, 1H), 7.52 (dd, J = 7.8, 4.9 Hz, 1H), 4.28 (d, J = 5.5 Hz, 2H). Example 16: Preparation of Compound (16) Scheme 16: Synthesis of Compound (16)p

[0761] Step 1: ethyl (6-hydroxy-10-(pyridin-4-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinateN

[0762] A mixture of ethyl 2-[(6-benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (200 mg, 0.410 mmol), 4-pyridylboronic acid (101.73 mg, 0.830 mmol), K2CO3(228.42 mg, 1.66 mmol), Pd(dppf)Cl2.DCM (33.77 mg, 0.040 mmol) and water (0.07 mL, 4.14 mmol) in 1,4-Dioxane (4.5 mL) was heated to 100 °C for 20 h. The reaction was cooled to rt, diluted with aq. HCl and DCM and filtered. The organic layer was separated, concentrated. The crude was purified by column (0-100% methanol in DCM) afford ethyl (6-hydroxy-10-(pyridin-4-yl)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycinate (60 mg, 0.2 mmol, 37%) as white solid. LC-MS: m / z= 392 (M+H)+.

[0763] Step 2: (6-hydroxy-10-(pyridin-4-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0764] Aqueous 1 N NaOH (01 mL, 0.30 mmol) was added to a stirred mixture of ethyl 2-[[6- hydroxy-10-(4-pyridyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl]amino]acetate (60 mg, 0.150 mmol) in THF (6 mL). The reaction was heated to 50 °C for 3 h. The reaction mixture was concentrated directly, crude was acidified with 1 N HCl (1 mL) at 0 °C. The precipitate was filtered. The solid was washed with water, dried in air to afford brown solid. The solid was dissolved in water, purified by prep-HPLC afford (6-hydroxy-10-(pyridin-4-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (10 mg, 17%) as brown solid. LC-MS: m / z= 364 (M+H)+.1H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.57 (d, J = 5.9 Hz, 2H), 7.82 (s, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 5.9 Hz, 2H), 3.68 (d, J = 4.2 Hz, 2H).Example 17: Preparation of Compound (17) Scheme 17: Synthesis of Compound (17)

[0765] Step 1: ethyl (10-(4-fluorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0766] A mixture of ethyl 2-[(6-benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (200 mg, 0.410 mmol), (4-fluorophenyl)boronic acid (115 mg, 0.830 mmol), Pd(dppf)Cl2.DCM (33.77 mg, 0.040 mmol), K2CO3(285 mg, 2.07 mmol) in 1,4-Dioxane (4.5 mL) and Water (0.20 mL) was heated to 95 °C for 20 h. The reaction was cooled to rt, diluted with dil. HCl and ethyl acetate, filtered. The organic layer was separated from filtrate and concentrated. The crude was purified by column (0-70% ethyl acetate in DCM) afford ethyl (10-(4-fluorophenyl)-6-hydroxy- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate (125 mg, 0.3 mmol, 74%) as white solid. LC- MS: m / z= 409 (M+H)+.

[0767] Step 2: (10-(4-fluorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine

[0768] Aqueous 1 N NaOH (3 mL, 3 mmol) was added to a stirred solution of ethyl 2-[[10-(4- fluorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl]amino]acetate (125 mg, 0.310 mmol) in THF (20 mL) at rt. The resulting reaction mixture was heated to 50 °C for 1 h. LCMS indicated complete conversion. The reaction was concentrated directly. The crude was acidified with 1 N HCl (3 mL) at 0 °C. The precipitate was filtered, solid was washed with water, dried in air afford white solid. LC-MS: m / z= 381 (M+H)+.1H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 13.03 (s, 1H), 10.57 (t, J = 5.4 Hz, 1H), 8.44 (dd, J = 8.2, 1.2 Hz, 1H), 8.41 (s, 1H), 7.95 (dd, J = 8.2, 7.5 Hz, 1H), 7.76 (dd, J = 7.4, 1.2 Hz, 1H), 7.50 – 7.41 (m, 2H), 7.29 – 7.18 (m, 2H), 4.27 (d, J = 5.5 Hz, 2H). Example 18: Preparation of Compound (18) Scheme 18: Synthesis of Compound (18)3 3

[0769] Step 1: ethyl (6-hydroxy-10-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[5,1-a]isoquinoline- 5-carbonyl)glycinate

[0770] A mixture of ethyl 2-[(6-benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (200 mg, 0.410 mmol), [4-(trifluoromethyl)phenyl]boronic acid (157.19 mg, 0.830 mmol), K2CO3(285.53 mg, 2.07 mmol) and Pd(dppf)Cl2.DCM (33.77 mg, 0.040 mmol) in 1,4- Dioxane (4.5 mL) and Water (0.20 mL) was heated to 95 °C for 20 h. The reaction was cooled to rt, diluted with dil. HCl (10 mL) and ethyl acetate (20 mL), filtered. The organic layer was separated from filtrate and concentrated. The crude was purified by column (0-60% ethyl acetate in DCM) afford (120 mg, 0.3 mmol, 63%) as off-white solid. LC-MS: m / z= 459 (M+H)+.

[0771] Step 2: (6-hydroxy-10-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine3

[0772] Aqueous 1 N NaOH (7.5 mL, 7.50 mmol) was added to a stirred solution of ethyl 2-[[6- hydroxy-10-[4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl]amino]acetate (120 mg, 0.26 mmol) in THF (20 mL) at rt. The resulting reaction mixture was heated to 50 °C for 1 h. LCMS indicated complete conversion. The reaction was concentrated directly. The crude was acidified with 1 N HCl (7.5 mL) at 0 °C. The precipitate was filtered, solid was washed with water, dried in air to afford brown solid. LC-MS: m / z= 431 (M+H)+.1H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 13.02 (s, 1H), 10.56 (t, J = 5.4 Hz, 1H), 8.48 (dd, J = 8.2, 1.2 Hz, 1H), 8.42 (s, 1H), 8.08 – 7.92 (m, 1H), 7.80 (dd, J = 4.8, 3.7 Hz, 3H), 7.67 (d, J = 7.9 Hz, 2H), 4.28 (d, J = 5.5 Hz, 2H).Example 19: Preparation of Compound (19) Scheme 19: Synthesis of Compound (19)

[0773] Step 1: ethyl (6-hydroxy-10-(1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[5,1-a]isoquinoline- 5-carbonyl)glycinate

[0774] A mixture of ethyl 2-[(6-benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (100 mg, 0.205 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole (75 mg, 0.280 mmol), K3PO4(131.59 mg, 0.69 mmol) and Pd(dppf)Cl2.DCM (16.88 mg, 0.020 mmol) in 1,4-Dioxane (5 mL) and Water (0.10 mL) was heated to 110 °C for 3 h in a microwave reactor. The reaction was diluted with dil. HCl and filtered, rinsed with DCM. The organic layer was separated, concentrated and crude was purified by column (4 g, 0-100% ethyl acetate in DCM) afford ethyl (6-hydroxy-10-(1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate (16 mg, 0.1 mmol, 17%) as brown solid. LC-MS: m / z= 457 (M+H)+.

[0775] Step 2: (6-hydroxy-10-(1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine

[0776] Aqueous 1 N NaOH (0.5 mL, 0.500 mmol) was added to a stirred solution of ethyl 2-[[6- hydroxy-10-(1-phenylpyrazol-4-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl]amino]acetate (16 mg, 0.040 mmol) in THF (3 mL) at rt. The reaction mixture was stirred at 50 °C for 1 h. The reaction was concentrated directly, crude was acidified with 1 N HCl (0.5 mL), solid was separated by filtration. The solid was washed with water and dried in air to afford (6-hydroxy-10-(1-phenyl-1H-pyrazol-4-yl)- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine as brown solid. LC-MS: m / z= 429 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.62 (t, J = 4.9 Hz, 1H), 8.84 (s, 1H), 8.51 (s, 1H), 8.40 (p, J = 3.5 Hz, 1H), 8.04 – 7.99 (m, 1H), 7.93 (ddd, J = 10.3, 9.7, 4.3 Hz, 4H), 7.53 (dd, J = 8.4, 7.6 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 4.11 (d, J = 4.5 Hz, 2H). Example 20: Preparation of Compound (20) Scheme 20: Synthesis of Compound (20)

[0777] Step 1: ethyl (10-(1-cyclopropyl-1H-pyrazol-3-yl)-6-hydroxy-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycinate

[0778] A mixture of ethyl 2-[(6-benzyloxy-9-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (100 mg, 0.210 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (96.87 mg, 0.410 mmol), K3PO4(300 mg, 1.42 mmol) and Pd(dppf)Cl2.DCM (16.88 mg, 0.020 mmol) in 1,4-Dioxane (5 mL) and Water (0.100 mL) was heated to 95 °C for 24 h. The reaction was cooled to rt, diluted with dil HCl, filtered, rinsed with DCM. The organic layer was separated from filtrate and concentrated. The crude was purified by column (0-80% ethyl acetate in DCM) afford a mixture of ethyl (6-(benzyloxy)-10-cyclopropyl-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycinate and ethyl (10-cyclopropyl-6-hydroxy-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycinate (100 mg, 95%) as white solid. The product mixture was suspended in TFA (1 mL) and heated to 60 °C for 1 h and concentrated. The crude was portioned between aqueous NaHCO3solution (2 mL) and DCM (10 mL), organic layer was separated and concentrated to afford ethyl (10-(1-cyclopropyl-1H-pyrazol-3-yl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate (60 mg, 0.1 mmol, 69%). LC-MS: m / z= 421 (M+H)+.

[0779] Step 2: (10-(1-cyclopropyl-1H-pyrazol-3-yl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline- 5-carbonyl)glycine

[0780] Aqueous 1 N NaOH (0.5 mL, 0.50 mmol) was added to a stirred solution of ethyl 2-[[10-(1- cyclopropylpyrazol-4-yl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl]amino]acetate (89 mg, 0.210 mmol) in THF (3 mL) at rt. The resulting reaction mixture was stirred at 50 °C for 2 h. The reaction was concentrated directly, crude was acidified with 1 N HCl (0.5 mL) at 0 °C. The precipitate was filtered and solid was washed with water, dried in air. The white solid was suspended in ethanol (5mL), stirred at 45 °C for 1 h, cooled to rt, filtered to afford (10-(1-cyclopropyl-1H-pyrazol-3-yl)-6- hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (35 mg, 0.1 mmol, 42%) as white solid. LC-MS: m / z= 393 (M+H)+.1H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 13.04 (s, 1H), 10.60 (t, J = 5.4 Hz, 1H), 8.53 (s, 1H), 8.33 (dd, J = 8.0, 1.4 Hz, 1H), 8.12 (s, 1H), 7.89 (dd, J = 9.6, 5.9 Hz, 1H), 7.83 (dd, J = 7.5, 1.4 Hz, 1H), 7.70 (d, J = 0.6 Hz, 1H), 4.28 (d, J = 5.5 Hz, 2H), 3.80 (tt, J = 7.4, 3.9 Hz, 1H), 1.16 – 1.06 (m, 2H), 1.07 – 0.94 (m, 2H). Example 21: Preparation of Compound (21) Scheme 21: Synthesis of Compound (21)

[0781] Step 1: ethyl (6-hydroxy-10-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[5,1-a]isoquinoline- 5-carbonyl)glycinate

[0782] A mixture of ethyl 2-[(6-benzyloxy-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (150 mg, 0.310 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (129.15 mg, 0.620mmol), K3PO4 (197.64 mg, 0.930 mmol) and Pd(dppf)Cl2.DCM (25.33mg, 0.030 mmol) in 1,4-Dioxane (4.5 mL) and Water (0.20 mL) was heated to 120 °C in a microwave reactor for 1 h. LCMS indicated complete consumption of starting material occurred. The reaction was cooled to rt, filtered, rinsed with a mixture of methanol (5 mL) and DCM (10 mL). The filtrate was concentrated. The crude is mixture of products (product with Bn protection and product without Bnprotection). The crude was suspended in TFA (2 mL) and heated to 65 °C for 2 h, LCMS indicated complete conversion. The reaction was concentrated. The crude was purified by column (0-100% ethyl acetate in DCM) afford ethyl (6-hydroxy-10-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycinate (110 mg, 0.3 mmol, 85%) as white solid. LC-MS: m / z= 395 (M+H)+.

[0783] Step 2: (6-hydroxy-10-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine

[0784] Aqueous 1 N NaOH (1.5 mL, 1.5 mmol) was added to a stirred mixture of ethyl 2-[[6- hydroxy-10-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl]amino]acetate (110 mg, 0.280 mmol) and THF (5 mL). The resulting reaction mixture was heated to 50 °C for 1.5 h. LCMS indicated complete consumption of starting material occurred. The reaction was concentrated directly. The aqueous layer was acidified with 1 N HCl (1.5 mL) and solid was separated by filtration and dried in air. The solid was slurry purified from ethanol to afford (6-hydroxy-10-(1-methyl-1H-pyrazol-3-yl)- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (80 mg, 0.2 mmol, 75%) as white solid. LC-MS: m / z= 367 (M+H)+.1H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 13.04 (s, 1H), 10.60 (t, J = 5.4 Hz, 1H), 8.52 (s, 1H), 8.33 (dd, J = 8.1, 1.3 Hz, 1H), 8.02 (s, 1H), 7.92 – 7.85 (m, 1H), 7.81 (dd, J = 7.5, 1.3 Hz, 1H), 7.68 (d, J = 0.7 Hz, 1H), 4.28 (d, J = 5.5 Hz, 2H), 3.92 (s, 3H).Example 22: Preparation of Compound (22) Scheme 22: Synthesis of Compound (22)Compound 22

[0785] Step 1: methyl (6-(benzyloxy)-10-(3,5-dichlorophenyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate C

[0786] Under nitrogen protection, a suspension of ethyl (6-(benzyloxy)-10-bromo- [1,2,4]triazolo[5,1-a] isoquinoline-5-carbonyl)glycinate (200 mg, 0.43 mmol), (3,5- dichlorophenyl)boronic acid (121 mg, 0.64 mmol), Cs2CO3(280 mg, 0.86 mmol) and Pd(dppf)Cl2(32 mg, 0.043 mmol) in 1,4-dioxane (5 mL) was stirred at 80oC for 4 hour. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (15 mL) and extracted with EtOAc (25 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica-gel column chromatography (EA: PE = 1:10) to give 92 mg of the title compound. LC-MS (ESI+): m / z 535, 537, 539 (M+H)+.

[0787] Step 2: methyl (10-(3,5-dichlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate (27)C

[0788] A suspension of ethyl (6-(benzyloxy)-10-(3,5-dichlorophenyl)-[1,2,4]triazolo[5,1- a]isoquinoline-5- carbonyl)glycinate (92 mg, 0.17 mmol) and Pd / C (10 mg, 10%) in MeOH (3 mL) was stirred under hydrogen atmosphere at rt for about 2 hrs. After the reaction was completed as indicated by TLC analysis, the suspension was filtered through a package of Celite. The filtrate was purified by silica-gel column chromatography (EA : PE = 1:10) to give 62 mg of the title compound.1H-NMR (300 MHz, CDCl3) δ 14.26 (s, 1 H), 10.83 (s, 1 H), 8.56 (d, J = 8.1 Hz, 1 H), 8.16 (s, 1 H), 7.83 (m, 1 H), 7.70-7.66 (d, J = 8.1 Hz, 1 H), 7.47 (s, 1 H), 7.30 (s, 2H), 4.38 (d, J = 5.1 Hz, 2 H), 3.83 (s, 3 H).

[0789] Step 3: (10-(3,5-dichlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine C

[0790] To a solution of ethyl (10-(3,5-dichlorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1- a]isoquinoline-5- carbonyl)glycinate (62 mg, 0.14 mmol) in THF (3 mL) was water (3 mL) was added LiOH (30 mg, 0.68 mmol). The reaction was stirred at rt for 3.5hr. After the reaction was completed by TLC analysis, the reaction was acidified pH to 3 with a diluted HCl solution (1N). A large amount of solid was precipitated. The solid was collected by filtration. After drying, 60 g of the title compound was obtained. LC-MS (ESI+): m / z 431 (M+H)+; 1H-NMR (300 MHz, DMSO-d6) δ 14.59 (brs, 1 H), 13.03 (brs, 1 H), 10.57 (s, 1 H), 8.47 (m, 2 H), 7.98 (m, 1 H), 7.83 (m, 1 H), 7.68 (s, 1 H), 7.61-7.52 (s, 2 H), 4.28 (d, J = 5.1 Hz, 2 H).Example 23: Preparation of Compound (23) Scheme 23: Synthesis of Compound (23)Compound 23

[0791] Step 1: methyl (10-(3,5-difluorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0792] Under nitrogen protection, a suspension of ethyl (6-(benzyloxy)-10-bromo- [1,2,4]triazolo[5,1-a] isoquinoline-5-carbonyl)glycinate (200 mg, 0.43 mmol), (3,5- difluorophenyl)boronic acid (102 mg, 0.64 mmol), Cs2CO3(280 mg, 0.86 mmol) and Pd(dppf)Cl2(32 mg, 0.043 mmol) in 1,4-dioxane (5 mL) was stirred at 80°C for 4 hour. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (15 mL) and extracted with EtOAc (25 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica-gel column chromatography (EtOAc: PE = 1:10) to give 92 mg of the title compound. LC-MS (ESI+): m / z 413(M+H)+.

[0793] Step 2: (10-(3,5-difluorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycineF

[0794] To a solution of ethyl (10-(3,5-difluorophenyl)-6-hydroxy-[1,2,4]triazolo[5,1- a]isoquinoline-5 -carbonyl)glycinate (62 mg, 0.14 mmol) in THF (3 mL) and water (3 mL) was added LiOH (32 mg, 0.68 mmol). The reaction was stirred at rt for 3.5hr. After the reaction was completed by TLC analysis, the reaction was acidified pH to 3 with a diluted HCl solution (1N). A large amount of solid was precipitated. The solid was collected by filtration. After drying, 60 mg of the title compoundwas obtained. LC-MS (ESI+): m / z 399(M+H)+;1H-NMR (300 MHz, DMSO-d6) δ 14.72 (s, 1 H), 13.07(s, 1H), 10.57 (t, J = 5.4 Hz, 1H), 8.47 (m, 2H), 7.98 (m, 1H), 7.83(d, J = 7.5 Hz, 1H), 7.30 (m, 1H), 7.19 (d, J = 6.3Hz, 2H), 4.29 (d, J = 5.4 Hz, 2H). Example 24: Preparation of Compound (24) Scheme 24: Synthesis of Compound (24)Compound 24

[0795] Step 1: methyl (6-(benzyloxy)-10-methyl-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinateN

[0796] Under nitrogen protection, a suspension of ethyl (6-(benzyloxy)-10-bromo- [1,2,4]triazolo[5,1-a] isoquinoline-5-carbonyl)glycinate (200 mg, 0.43 mmol), methylboronic acid (52mg, 0.85 mmol), Cs2CO3(280 mg, 0.86 mmol) and Pd(dppf)Cl2(32 mg, 0.043 mmol) in 1,4-dioxane (5 mL) was stirred at 80 °C for 4 hour. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (15 mL) and extracted with EtOAc (25 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica-gel column chromatography (EtOAc: PE = 1:10) to give 68 mg of the title compound. LC-MS (ESI+): m / z 405+H)+.

[0797] Step 2: ethyl (6-hydroxy-10-methyl-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycinate

[0798] A suspension of ethyl (6-(benzyloxy)-10-methyl-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl) glycinate (68 mg, 0.17 mmol) and Pd / C (10 mg, 10%) in MeOH (3 mL) was stirred under hydrogen atmosphere at rt for about 2 hrs. After the reaction was completed as indicated by TLC analysis, the suspension was filtered through a package of Celite. The filtrate was purified by silica-gel column chromatography (EtOAc : PE = 1:1) to give 61 mg of the title compound. LC-MS (ESI+): m / z 315 (M+H)+.

[0799] Step 3: (6-hydroxy-10-methyl-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0800] To a solution of ethyl (6-hydroxy-10-methyl-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate (61 mg, 0.19 mmol) in THF (3 mL) and water (3 mL) was added LiOH (40 mg, 0.97 mmol). The reaction was stirred at rt for 3.5hr. After the reaction was completed by TLC analysis, the reaction was acidified pH to 3 with a diluted HCl solution (1N). A large amount of solid was precipitated. The solid was collected by filtration. After drying, 32 mg of the title compound was obtained. LC-MS (ESI+): m / z 301(M+H)+;1H-NMR (300 MHz, DMSO-d6) δ 14.63(brs, 1H), 13.06 (brs, 1H), 10.62 (d, J = 5.7 Hz, 1H), 8.71(s, 1H), 8.25 (m, 1H), 7.83 (d, J = 9.3 Hz, 2H), 4.28(d, J = 5.7Hz, 2H), 3.07(s, 3H).Example 25: Preparation of Compound (25) Scheme 25: Synthesis of Compound (25)Compound 25

[0801] Step 1: methyl (6-(benzyloxy)-10-cyclopropyl-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0802] Under nitrogen protection, a suspension of ethyl (6-(benzyloxy)-10-bromo- [1,2,4]triazolo[5,1-a] isoquinoline-5-carbonyl)glycinate (100 mg, 0.22 mmol), cyclopropylboronic acid (38 mg, 0.42 mmol), Cs2CO3(140 mg, 0.43 mmol) and Pd(dppf)Cl2(17 mg, 0.022 mmol) in 1,4-dioxane (4 mL) was stirred at 80°C for 4 hour. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (15 mL) and extracted with EtOAc (25 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica-gel column chromatography (EtOAc: PE = 1:10) to give 68 mg of the title compound. LC-MS (ESI+): m / z 431(M+H)+.

[0803] Step 2: methyl (10-cyclopropyl-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0804] A suspension of ethyl (6-(benzyloxy)-10-cyclopropyl-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl) glycinate (68 mg, 0.16 mmol) and Pd / C (10 mg, 10%) in MeOH (3 mL) was stirred under hydrogen atmosphere at rt for about 2 hrs. After the reaction was completed as indicated by TLC analysis, the suspension was filtered through a package of Celite. The filtrate was purified by silica-gel column chromatography (EtOAc : PE = 1:1) to give 50 mg of the title compound. LC-MS (ESI+): m / z 341H)+.

[0805] Step 3: (10-cyclopropyl-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0806] To a solution of ethyl (10-cyclopropyl-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate (50 mg, 0.15 mmol) in THF (3 mL) and water (3 mL) was added LiOH (31 mg, 0.73 mmol). The reaction was stirred at rt for 3.5hr. After the reaction was completed by TLC analysis, the reaction was acidified pH to 3 with a diluted HCl solution (1N). A large amount of solid was precipitated. The solid was collected by filtration. After drying, 18 mg of the title compound was obtained. LC-MS (ESI+): m / z 327(M+H)+;1H-NMR (300 MHz, DMSO-d6) δ 14.69 (s, 1H), 13.08 (m, 1H), 10.70 (t, J = 5.4 Hz, 1H), 8.71 (s, 1H), 8.22 (d, J = 8.1Hz, 1H), 7.84-7.79 (m, 1H), 7.52 (d, J = 7.5 Hz, 1H), 4.92 (d, J = 5.4Hz, 2H), 4.04 (m, 1H), 1.24-1.18 (m, 2H), 0.94-0.89 (m, 2H).Example 26: Preparation of Compound (26) Scheme 26: Synthesis of Compound (26)

[0807] Step 1: ethyl (6-(benzyloxy)-10-(cyclohex-1-en-1-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0808] Under nitrogen protection, a suspension of ethyl (6-(benzyloxy)-10-bromo- [1,2,4]triazolo[5,1-a] isoquinoline-5-carbonyl)glycinate (250 mg, 0.53 mmol), cyclohex-1-en-1- ylboronic acid (101 mg, 0.80 mmol), Cs2CO3(346 mg, 1.06 mmol) and Pd(dppf)Cl2(39 mg, 0.053 mmol) in 1,4-dioxane (4 mL) was stirred at 80°C for 4 hour. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (15 mL) and extracted with EtOAc (25 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica-gel column chromatography (EtOAc: PE = 1:10) to give 140 mg of the title compound. LC-MS (ESI+): m / z 471(M+H)+.

[0809] Step 2: methyl (10-cyclohexyl-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0810] A suspension of ethyl (6-(benzyloxy)-10-(cyclohex-1-en-1-yl)-[1,2,4]triazolo[5,1- a]isoquinoline -5-carbonyl)glycinate (121 mg, 0.25 mmol) and Pd / C (10 mg, 10%) in MeOH (3 mL) was stirred under hydrogen atmosphere at rt for about 2 hrs. After the reaction was completed as indicated by TLC analysis, the suspension was filtered through a package of Celite. The filtrate was purified by silica-gel column chromatography (EtOAc : PE = 1:1) to give 81 mg of the title compound. LC-MS (ESI+): m / z 383(M+H)+.

[0811] Step 3: (10-cyclohexyl-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0812] To a solution of ethyl (10-cyclohexyl-6-hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl) glycinate (81 mg, 0.21 mmol) in THF (3 mL) and water (3 mL) was added LiOH (45 mg, 1.06 mmol). The reaction was stirred at rt for 3.5hr. After the reaction was completed by TLC analysis, the reaction was acidified pH to 3 with a diluted HCl solution (1N). A large amount of solid was precipitated. The solid was collected by filtration. After drying, 51 mg of the title compound was obtained. LC-MS (ESI+): m / z 369(M+H)+;1H-NMR (300 MHz, DMSO-d6) δ 14.61 (s, 1H), 13.07 (s, 1H), 10.66-10.62 (t, J = 5.4Hz, 1H), 8.74(s, 1H), 8.27(d, J = 7.8Hz, 1H), 7.96-7.86 (m, 2H), 4.79-4.76 (m, 1H), 4.29(d, J = 5.4Hz, 2H), 1.95-1.79 (m, 6H), 1.64-1.47 (m, 4H), 1.35(m, 1H).Example 27: Preparation of Compound (27) Scheme 27: Synthesis of Compound (27)Compound 27

[0813] Step 1: methyl (6-(benzyloxy)-10-(pyridin-2-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate N

[0814] Under nitrogen protection, a solution of methyl (6-(benzyloxy)-10-bromo- [1,2,4]triazolo[5,1-a] isoquinoline-5- carbonyl)glycinate (200 mg, 0.43 mmol), tributyl(phenyl)stannane (315 mg, 0.64 mmol) and Pd(PPh3)4(50 mg, 0.043 mmol) in toluene (5 mL) was stirred at 100°C for 20 hour. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (15 mL) and extracted with EtOAc (25 mL x 5). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica-gel column chromatography (DCM : MeOH = 100:1) to give 80 mg of the title compound. LC-MS (ESI+): m / z 468 (M+H)+.

[0815] Step 2: methyl (6-hydroxy-10-(pyridin-2-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinateN

[0816] A suspension of methyl (6-(benzyloxy)-10-(pyridin-2-yl)-[1,2,4]triazolo[5,1-a]isoquinoline- 5-carbonyl) glycinate (80 mg, 0.17 mmol) and Pd / C (10 mg, 10%) in MeOH (3 mL) was stirred under hydrogen atmosphere at rt for about 2 hrs. After the reaction was completed as indicated by TLC analysis, the suspension was filtered through a package of Celite. The filtrate was purified by silica-gel column chromatography (DCM : MeOH = 10:1) to give 56 mg of the title compound. LC-MS (ESI+): m / z 378 (M+H)+.

[0817] Step 3: (6-hydroxy-10-(pyridin-2-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0818] To a solution of methyl (6-hydroxy-10-(pyridin-2-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl) glycinate (56 mg, 0.15 mmol) in THF (3 mL) and water (3 mL) was added LiOH (32 mg, 0.74 mmol). The reaction was stirred at rt for 3.5hr. After the reaction was completed by TLC analysis, the reaction was acidified pH to 3 with a diluted HCl solution (1N). A large amount of solid was precipitated. The solid was collected by filtration. After drying, 60 mg of the title compound was obtained. LC-MS (ESI+): m / z 364 (M+H)+;1H-NMR (300 MHz, DMSO-d6) δ 14.72 (s, 1 H), 13.05 (s, 1 H), 10.58-10.56 (s, 1 H), 8.66 (d, J = 4.5 Hz, 1 H), 8.49 (d, J = 8.1 Hz, 1 H), 8.39 (s, 1 H), 8.02 (m, 1 H), 7.89-7.84 (m, 2 H), 7.57 (d, J = 7.8 Hz, 2 H), 7.46 (m, 1 H), 4.29 (d, J = 5.4 Hz, 2 H).Example 28: Preparation of Compound (28) Scheme 28: Synthesis of Compound (28)

[0819] Step 1: methyl 4-(benzyloxy)-8-phenoxyisoquinoline-3-carboxylate

[0820] A mixture of methyl 4-benzyloxy-8-bromo-isoquinoline-3-carboxylate (3 g, 8.06 mmol), phenol (986 mg, 10.48 mmol), Copper(I) bromide (1.156 g, 8.06 mmol), Acetylacetone (806 mg, 8.06 mmol) and K2CO3(2.224 g, 16.12 mmol) in DMF (50 mL) was heated to 95 °C overnight. The reaction was cooled to rt, diluted with aqueous 0.5 N HCl (60 mL), extracted with ethyl acetate (50 mL X 3). The combined organic layer was washed with aq. NH4OH, dried over Na2SO4and concentrated. The crude was purified by column (0-100% ethyl acetate in hexanes) afford methyl 4-(benzyloxy)-8- phenoxyisoquinoline-3-carboxylate (2.82 g, 87%) as brown solid. LC-MS: m / z= 386 (M+H)+.

[0821] Step 2: 4-(benzyloxy)-3-(methoxycarbonyl)-8-phenoxyisoquinoline 2-oxide

[0822] 3-chlorobenzenecarboperoxoic acid (2.70 g, 15.56 mmol) was added to a stirred solution of methyl 4-benzyloxy-8-phenoxy-isoquinoline-3-carboxylate (3 g, 7.78 mmol) in DCM (50 mL) at rt. The reaction was stirred for 3 h at rt. LCMS indicated complete conversion of starting material occurred. The reaction was concentrated directly, crude was purified by column (0-100% ethyl acetate in hexanes) afford 4-(benzyloxy)-3-(methoxycarbonyl)-8-phenoxyisoquinoline 2-oxide (1.8 g, 4.5 mmol, 57%) as white solid. LC-MS: m / z= 402 (M+H)+.

[0823] Step 3: methyl 1-amino-4-(benzyloxy)-8-phenoxyisoquinoline-3-carboxylate

[0824] 4-methylbenzenesulfonyl chloride (1.18 g, 8.97 mmol) was added to a stirred solution of methyl 4-benzyloxy-2-oxo-8-phenoxy-isoquinoline-3-carboxylate (1.8 g, 4.48 mmol) in Pyridine (11.21mL) at 0 oC. The reaction was stirred for 30 min at room temperature. 2-aminoethanol (2738.95mg,44.84mmol) was added at 0 °C and stirred for 1 h at room temperature. The reaction was diluted with water (50 mL). The solid was separated by filtration. The crude was purified by column (0-100% ethyl acetate in DCM) afford methyl 1-amino-4-(benzyloxy)-8-phenoxyisoquinoline-3-carboxylate (900 mg, 2.2 mmol, 50%) as off-white solid. LC-MS: m / z= 401 (M+H)+.

[0825] Step 4: methyl 4-(benzyloxy)-1-(3-(ethoxycarbonyl)thioureido)-8-phenoxyisoquinoline-3- carboxylate

[0826] Ethoxycarbonyl isothiocyanate (0.53 mL, 4.5 mmol) was added to a stirred solution of methyl 1-amino-4-benzyloxy-8-phenoxy-isoquinoline-3-carboxylate (900 mg, 2.25 mmol) in 1,4- Dioxane (25 mL) at rt. The resulting reaction mixture was stirred overnight at rt. LCMS indicated complete consumption of starting material occurred. The reaction was concentrated directly to afford methyl 4-(benzyloxy)-1-(3-(ethoxycarbonyl)thioureido)-8-phenoxyisoquinoline-3-carboxylate (1.2 g, 100%) as orange solid. The crude was subjected to the next reaction without further purification. LC- MS: m / z= 532 (M+H)+.

[0827] Step 5: methyl 2-amino-6-(benzyloxy)-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate

[0828] A mixture of methyl 4-benzyloxy-1-(ethoxycarbonylcarbamothioylamino)-8-phenoxy- isoquinoline-3-carboxylate (1.1 g, 2.07 mmol), hydroxylamine; hydrochloride (431 mg, 6.21 mmol) and DIPEA (1.83 mL, 10.35 mmol) in isopropyl alcohol (50 mL) was heated to 66 °C for 5 h. LC-MS indicated complete consumption of starting material occurred. The reaction was concentrated directly. The crude was suspended in water (100 mL), solid was separated by filtration, washed with water and dries in air to afford methyl 2-amino-6-(benzyloxy)-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (960 mg, 100%). The crude solid was subjected to the next reaction without further purification. LC-MS: m / z= 441 (M+H)+.

[0829] Step 6: methyl 6-(benzyloxy)-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate

[0830] tert-butyl nitrite (426 mg, 4.14 mmol) was added to a stirred suspension of methyl 2-amino- 6-benzyloxy-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (911 mg, 2.07 mmol) in THF (20 mL) at rt. The reaction was stirred overnight at rt. LC-MS indicated complete consumption of starting material occurred. The reaction was concentrated directly, and crude was purified by column (0-100% ethyl acetate in hexanes) afford methyl 6-(benzyloxy)-10-phenoxy-[1,2,4]triazolo[5,1- a]isoquinoline-5-carboxylate (800 mg, 1.9 mmol, 90%) as white solid. LC-MS: m / z= 426 (M+H)+.

[0831] Step 7: 6-(benzyloxy)-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylic acid

[0832] Aqueous 1 N NaOH (5.64 mL, 5.64 mmol) was added to a stirred suspension of methyl 6- benzyloxy-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (800 mg, 1.88 mmol) in THF (25 mL) at rt. The resulting reaction mixture was heated to 45 °C for 2 h. LC-MS indicated complete consumption of starting material occurred. The reaction was concentrated directly to remove THF. The aqueous layer was cooled to 0 °C, acidified by aqueous 1 N HCl (6 mL). The precipitate was filtered, washed with water and the solid was dried in air afford 6-(benzyloxy)-10-phenoxy-[1,2,4]triazolo[5,1- a]isoquinoline-5-carboxylic acid (780 mg, 1.9 mmol, 100%) as brown solid. The crude was subjected to the next reaction without further purification. LC-MS: m / z= 412 (M+H)+.

[0833] Step 8: ethyl (6-(benzyloxy)-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0834] Triethylamine (1.32 mL, 9.48 mmol) was added to a stirred mixture of 6-benzyloxy-10- phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylic acid (780 mg, 1.9 mmol), ethyl 2- aminoacetate;hydrochloride (529 mg, 3.79 mmol) and PyBOP (1.085 g, 2.09 mmol) in DCM (9.5 mL) at rt. The resulting reaction mixture was stirred for 16 h at rt. LC-MS indicated complete consumption of starting material occurred. The reaction was concentrated directly, crude was purified by column (0- 100% ethyl acetate in hexanes) afford ethyl (6-(benzyloxy)-10-phenoxy-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycinate (801 mg, 1.6 mmol, 85%) as white solid. LC-MS: m / z= 497 (M+H)+.

[0835] Step 9: ethyl (6-hydroxy-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0836] A mixture of ethyl 2-[(6-benzyloxy-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)amino]acetate (801 mg, 1.61 mmol) and 10% Pd on Carbon (80 mg) in Ethyl acetate (20 mL) and THF (10 mL) was degassed with Hydrogen and stirred under Hydrogen over weekend at rt. TLC indicated complete consumption of starting material occurred. The reaction was filtered through a pad of Celite, washed with DCM. The filtrate was concentrated, and crude was purified by column (0-50% ethyl acetate in DCM) afford ethyl (6-hydroxy-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate (550 mg, 1.4 mmol, 83%) as white solid. LC-MS: m / z= 407 (M+H)+.

[0837] Step 10: (6-hydroxy-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0838] Aqueous 1 N NaOH (10 mL, 10 mmol) was added to a stirred mixture of ethyl 2-[(6- hydroxy-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)amino]acetate (550 mg, 1.35 mmol) in THF (20 mL) at rt. The resulting reaction mixture was stirred for 1 h at 60 °C. The reaction was concentrated directly to remover THF, aqueous layer was acidified with aqueous 1 N HCl (10 mL), the precipitate was filtered. The solid was suspended in methanol (10 mL), filtered. The solid was dried under vacuum to afford (6-hydroxy-10-phenoxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine(450 mg, 1.1 mmol, 84%) as white solid. LC-MS: m / z= 379 (M+H)+.1H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 13.04 (s, 1H), 10.60 (t, J = 5.4 Hz, 1H), 8.60 (s, 1H), 8.17 (dd, J = 8.2, 1.0 Hz, 1H), 7.89 (dd, J = 10.4, 5.8 Hz, 1H), 7.46 (dd, J = 8.0, 1.0 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.18 – 7.10 (m, 1H), 7.07 – 7.00 (m, 2H), 4.28 (d, J = 5.5 Hz, 2H). Example 29: Preparation of Compound (29) Scheme 29: Synthesis of Compound (29)MeCompound 29

[0839] Step 1: methyl 6-(benzyloxy)-10-(4-methoxyphenoxy)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate

[0840] Under nitrogen protection, a solution of methyl 6-(benzyloxy)-10-bromo-[1,2,4]triazolo[5,1- a] isoquinoline-5-carboxylate (300 mg, 0.73 mmol), 4-methoxyphenol (181 mg, 1.46 mmol), Pd(OAc)2(16.4 mg, 0.073 mmol), Trixiephos (87 mg, 0.22 mmol) and Cs2CO3(476 mg, 1.46 mmol) in toluene (10 mL) was stirred at 100°C for 20 hour. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (25 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica-gel column chromatography (PE : EtOAc = 10:1 to 1:1) to give 150 mg of the title compound. LC-MS (ESI+): m / z 456 (M+H)+.

[0841] Step 2: 6-(benzyloxy)-10-(4-methoxyphenoxy)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylic acid

[0842] To a solution of methyl 6-(benzyloxy)-10-(4-methoxyphenoxy)-[1,2,4]triazolo[5,1- a]isoquinoline-5- carboxylate (152 mg, 0.33 mmol) in THF (2 mL) and water (2 mL) was added LiOH.H2O (28 mg, 0.67 mmol). The reaction was stirred at rt for 1 hr. After the reaction was completed by TLC analysis, the reaction was acidified pH to 3 with a diluted HCl solution (1N). The reaction was extracted with EtOAc (2 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give 91 mg of the title compound. LC-MS (ESI+): m / z 442 (M+H)+.

[0843] Step 3: methyl (6-(benzyloxy)-10-(4-methoxyphenoxy)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0844] To a suspension of 6-(benzyloxy)-10-(4-methoxyphenoxy)-[1,2,4]triazolo[5,1- a]isoquinoline-5- carboxylic acid (91 mg, 0.21 mmol) in DCM (2 mL) at rt was added methyl-2- aminoacetate HCl salt (34 mg, 0.27 mmol), HATU (102 g, 0.27 mmol) and TEA (52 mg, 0.52 mmol). The reaction was stirred at rt for 6 hrs. After the reaction was completed as indicated by LCMS analysis, the reaction was quenched with water (4mL) and extracted with DCM (2 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. Theresidue was purified by silica-gel column chromatography (DCM : MeOH = 50:1) to give 34 mg of thetitle compound. LC-MS (ESI+): m / z 513 (M+H)+.

[0845] Step 4: methyl (6-hydroxy-10-(4-methoxyphenoxy)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0846] A suspension of methyl 2-(6-(benzyloxy)-10-(4-methoxyphenoxy)-[1,2,4]triazolo[5,1- a]isoquinoline-5- carboxamido)acetate (34 mg, 0.07 mmol) and Pd / C (3 mg, 10%) in MeOH (2 mL) was stirred under hydrogen atmosphere at rt for about 2 hrs. After the reaction was completed as indicated by LCMS analysis, the suspension was filtered filtered and concentrated in vacuo to give 32mg of the title compound. LC-MS (ESI+): m / z 423 (M+H)+.

[0847] Step 5: (6-hydroxy-10-(4-methoxyphenoxy)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycineMe

[0848] To a solution of methyl 2-(6-hydroxy-10-(4-methoxyphenoxy)-[1,2,4]triazolo[5,1- a]isoquinoline-5- carboxamido)acetate (30 mg, 0.07 mmol) in THF (1 mL) and water (1 mL) was added LiOH (6 mg, 0.15 mmol). The reaction was stirred at rt for 1hr. After the reaction was completed by TLC analysis, The reaction was diluted with water (2 mL) and extracted with EtOAc (2 mL x 3). The aqueous phase was acidified pH to 3 with a diluted HCl solution (1N). A large amount of solid was precipitated. The solid was collected by filtration. After drying, 15 mg of the title compound was obtained. LC-MS (ESI+): m / z 409 (M+H)+;1H NMR (300 MHz, DMSO-d6) δ 14.68 (s, 1H), 13.03 (brs, 1H), 10.65 (t, J = 5.4 Hz, 1H), 8.65 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 4.30 (d, J = 5.4 Hz, 2H), 3.77 (s, 3H).Example 30: Preparation of Compound (30) Scheme 30: Synthesis of Compound (30)Compound 30

[0849] Step 1: methyl 6-(benzyloxy)-10-morpholino-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate

[0850] Under nitrogen protection, a solution of methyl 6-(benzyloxy)-10-bromo-[1,2,4]triazolo[5,1- a] isoquinoline-5-carboxylate (300 mg, 0.73 mmol), morpholine (190 mg, 2.18 mmol) , Pd2(dba)3(67 mg, 0.07 mmol), BINAP (136 mg, 0.22 mmol) and Cs2CO3(476 mg, 1.46 mmol) in toluene (10 mL) was stirred at 90 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction was quenched by water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (DCM : MeOH = 100:1 to 50:1) to give 190 mg of the desired product. LC-MS (ESI+): m / z 419 (M+H)+.

[0851] Step 2: 6-(benzyloxy)-10-morpholino-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylic acid

[0852] To a solution of methyl 6-(benzyloxy)-10-morpholino-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (180 mg, 0.43 mmol) in THF (3 mL) and H2O (3 mL) was added LiOH (36 mg, 0.86 mmol). The reaction was stirred at RT for about 1 hr. After the reaction was completed as indicated by TLC analysis, the reaction was concentrated in vacuo to remove THF and the residue was adjusted pH to 2 using a diluted HCl solution (2 N). A large amount of solid was precipitated. The resulting suspension was filtered to afford 210 mg of the title compound. LC-MS (ESI+): m / z 405 (M+H)+.

[0853] Step 3: methyl (6-(benzyloxy)-10-morpholino-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0854] To a solution of 6-(benzyloxy)-10-morpholino-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylic acid (190 mg, 0.47 mmol) in DCM (8 mL) was added methyl glycinate (88 mg, 0.71 mmol), HOBt (127 mg, 0.94 mmol) , EDCl (180 mg, 0.94 mmol) and DIEA (121 mg, 0.94 mmol). After the reaction was stirred at rt for 2 hrs. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic phases were dried with anhydrous Na2SO4(10 g), filtered and concentrated in vacuo. The residue was purified by silica column chromatography (MeOH: DCM= 1: 100~1:50) to give the desired product (185 mg) as solid. LC-MS (ESI+): m / z 476 (M+H)+.

[0855] Step 4: methyl (6-hydroxy-10-morpholino-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinateO

[0856] A suspension of methyl (6-(benzyloxy)-10-morpholino-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl) glycinate (165 mg, 0.35 mmol) and Pd / C (17 mg, 10 wt%) in methanol (5 mL) was degassed with hydrogen for 3 min and stirred under atmospheric hydrogen pressure for 2 hrs. After the reaction was completed as indicated by LCMS analysis, the suspension was filtered through a package of Celite. The filtrate was concentrated and the residue was purified by silica column chromatography (MeOH: DCM= 1: 200~1:80) to give the desired product (105 mg) as solid. LC-MS (ESI+): m / z 386(M+H)+.

[0857] Step 5: (6-hydroxy-10-morpholino-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0858] To a solution of methyl (6-hydroxy-10-morpholino-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl) glycinate (100 mg, 0.26 mmol) in THF (3 mL) and H2O (3 mL) was added LiOH (33 mg, 0.78 mmol). The reaction was stirred at RT for about 4 hrs. After the reaction was completed as indicated by TLC analysis, the reaction was concentrated in vacuo to remove THF and the residue was adjusted pH to 2 using a diluted HCl solution (2 N). A large amount of solid was precipitated. Theresulting suspension was filtered to afford 72 mg of the title compound. 1H-NMR (300 MHz, DMSO-d6) δ 14.60 (s, 1 H), 13.25-12.82 (m, 1H), 10.71-10.66 (m, 1H), 8.70 (s, 1 H), 8.04 (d, J = 7.5 Hz, 1H), 7.91-7.82 (m, 1H), 7.57 (d, J = 7.5 Hz, 1 H), 4.29 (d, J = 5.7 Hz, 2 H), 4.09-3.85 (m, 4H), 3.30-2.92 (m, 4H).Example 31: Preparation of Compound (31) Scheme 31: Synthesis of Compound (31)Compound 31

[0859] Step 1: methyl 6-(benzyloxy)-10-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carboxylate

[0860] Under nitrogen protection, a suspension of methyl 6-(benzyloxy)-10-bromo- [1,2,4]triazolo[5,1-a] isoquinoline-5-carboxylate (400 mg, 0.97 mmol), 1-phenylpiperazine (469 mg, 2.91 mmol), BINAP(181 mg, 0.29 mmol), Cs2CO3(633 mg, 1.94 mmol) and Pd2(dba)3(89 mg, 0.097 mmol) in toluene (10 mL) was stirred at 100°C overnight. After the reaction was completed by TLC analysis, the reaction was quenched with water (15 mL) and extracted with EtOAc (25 mL x 3). The combined organic phase was washed with water (5 mL) and saturated brine (5 mL), dried withanhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica-gel column chromatography (EtOAc: PE = 1:10 to 1:5) to give 270 mg of the title compound. LC-MS (ESI+): m / z 493 (M+H)+.

[0861] Step 2: 6-(benzyloxy)-10-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylic acid

[0862] A suspension of methyl 6-(benzyloxy)-10-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[5,1- a]isoquinoline -5-carboxylate (270 mg, 0.55 mmol) and LiOH·H2O (115 mg, 2.744 mmol) in THF (5 mL ) and H2O (5 mL) was stirred at rt for 2 h. After the reaction was completed by TLC analysis, the reaction was quenched with water (15 mL), adjusted PH to 3 with a diluted HCl solution. The resulting mixture was extracted with EtOAc (25 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give 270 mg of crude title compound. LC-MS (ESI+): m / z 479 (M+H)+.

[0863] Step 3: methyl (6-(benzyloxy)-10-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycinate

[0864] A suspension of 6-(benzyloxy)-10-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[5,1- a]isoquinoline -5-carboxylic acid (270 mg, 0.56 mmol), methyl glycinate (78 mg, 0.90 mmol), EDCl (239 mg, 1.24 mmol), HOBt (84 mg, 0.62 mmol) and TEA(171 mg, 1.70 mmol) in THF (10 mL) was stirred at rt for 2 h. After the reaction was completed by LCMS analysis, the reaction was quenched with water (15 mL) and extracted with EtOAc (25 mL x 3). The combined organic phase was washed with water and saturated brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica-gel column chromatography (EtOAc: PE = 1:3 to 1:1) to give 200 mg of the title compound. LC-MS (ESI+): m / z 550 (M+H)+.

[0865] Step 4: methyl (6-hydroxy-10-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0866] A suspension of methyl (6-(benzyloxy)-10-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[5,1-a] isoquinoline-5-carbonyl)glycinate (200 mg) and Pd / C (20 mg) in MeOH (10 mL) and 2N HCl (2 d) was stirred at rt under hydrogen protection for 1 h. After the reaction was completed by LCMS analysis, the suspension was filtered through a package of Celite. The filtrate was concentrated and purified by silica-gel column chromatography (EtOAc: PE = 1:1) to give 40 mg of the title compound. LC-MS (ESI+): m / z 460 (M+H)+.

[0867] Step 5: (6-hydroxy-10-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine

[0868] A suspension of methyl (6-hydroxy-10-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[5,1- a]isoquinoline -5-carbonyl)glycinate (40 mg, 0.098 mmol) and LiOH.H2O (20 mg, 0.488 mmol) in THF and H2O (1 mL, 1 mL) was stirred at rt for 1 h. After the reaction was completed by LCMS analysis, the reaction was quenched with water (15 mL), adjusted PH to 4. The resulting mixture was extracted with EtOAc (25 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was slurried in hexane and EtOH (1:1, 4 mL) for about 2 hrs. After filtration and drying, 18.8 mg of product was obtained. LC-MS (ESI+): m / z (M+H)+:446;1H- NMR (300 MHz, DMSO-d6) δ 14.65 (s, 1H), 10.67 (s, 1H), 8.73 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.88- 7.83 (m, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.37-7.36 (m, 4H), 7.25-7.22 (m, 1H), 4.25 (d, J = 5.1 Hz, 2H), 3.57 (m, 2H), 2.92-2.73 (m, 3H), 2.35-2.21 (m, 2H), 1.99-1.83 (m, 2H).Example 32: Preparation of Compound (32) Scheme 32: Synthesis of Compound (32)Compound 32

[0869] Step 1: methyl 6-(benzyloxy)-10-(piperidin-1-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate

[0870] Under nitrogen protection, a suspension of methyl 6-(benzyloxy)-10-bromo- [1,2,4]triazolo[5,1-a] isoquinoline-5-carboxylate (500 mg, 1.21 mmol), piperidine (309 mg, 3.64 mmol), BINAP(227 mg, 0.36 mmol), Cs2CO3(789 mg, 2.42 mmol) and Pd2(dba)3(111 mg, 0.12 mmol) in toluene (25 mL) was stirred at 100°C overnight. After the reaction was completed by TLC analysis, the reaction was quenched with water (15 mL) and extracted with EtOAc (25 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica-gel column chromatography (neat DCM) to give 199 mg of the title compound. LC- MS (ESI+): m / z 417 (M+H)+.

[0871] Step 2: 6-(benzyloxy)-10-(piperidin-1-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylic acid

[0872] A suspension of methyl 6-(benzyloxy)-10-(piperidin-1-yl)-[1,2,4]triazolo[5,1- a]isoquinoline- 5-carboxylate (170 mg, 0.37 mmol) and LiOH·H2O (47 mg, 1.11 mmol) in THF (5mL) and H2O (1 mL) was stirred at rt overnight. After the reaction was completed by TLC analysis, the reaction was quenched with water (15 mL), adjusted PH to 3. The resulting mixture was extracted with EtOAc (25 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give 170 mg of crude title compound. LC-MS (ESI+): m / z 403 (M+H)+.

[0873] Step 3: methyl (6-(benzyloxy)-10-(piperidin-1-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0874] A suspension of 6-(benzyloxy)-10-(piperidin-1-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylic acid (170 mg, 0.37 mmol), methyl glycinate (58 mg, 0.46 mmol), EDCl (177 mg, 0.92 mmol), HOBt (62 mg, 0.46 mmol) and TEA(136 mg, 1.34 mmol) in THF (3 mL) was stirred at rt for 2 h. After the reaction was completed by LCMS analysis, the reaction was quenched with water (15 mL) and extracted with EtOAc (25 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica-gel column chromatography (DCM: MeOH = 400:1 to 100:1) to give 71 mg of the title compound. LC-MS (ESI+): m / z 474 (M+H)+.

[0875] Step 4: methyl (6-hydroxy-10-(piperidin-1-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycinate

[0876] A suspension of methyl (6-(benzyloxy)-10-(piperidin-1-yl)-[1,2,4]triazolo[5,1- a]isoquinoline -5-carbonyl)glycinate (66 mg) and Pd / C (7 mg) in MeOH (5 mL) was stirred at rt under hydrogen atmosphere for 4 h. After the reaction was completed by TLC analysis, the suspension was filtered through a package of Celite. The filtrate was concentrated and purified by silica-gel column chromatography (DCM) to give 44 mg of the title compound. LC-MS (ESI+): m / z 384 (M+H)+.

[0877] Step 5: (6-hydroxy-10-(piperidin-1-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0878] A suspension of methyl (6-hydroxy-10-(piperidin-1-yl)-[1,2,4]triazolo[5,1-a]isoquinoline - 5-carbonyl)glycinate (44 mg, 0.11 mmol) and LiOH.H2O (14 mg, 0.34 mmol) in THF (1 mL) and H2O (0.25 mL) was stirred at rt for 1 h. After the reaction was completed by LCMS analysis, the reaction was quenched with water (10 mL), adjusted pH to 3. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was slurried in hexane (2 mL) for 2 hrs. After filtration and drying, 17.9 mg of the title compound was obtained. LC-MS (ESI+): m / z (M+H)+:446;1H-NMR (300 MHz, DMSO-d6) δ 14.65 (s, 1H), 10.67 (s, 1H), 8.73 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.88-7.83 (m, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.37-7.36 (m, 4H), 7.25- 7.22 (m, 1H), 4.25 (d, J = 5.1 Hz, 2H), 3.57 (m, 2H), 2.92-2.73 (m, 3H), 2.35-2.21 (m, 2H), 1.99-1.83 (m, 2H).Example 33: Preparation of Compound (33)

[0879] Step 1: Methyl 2-(bromomethyl)-3-(trifluoromethyl)benzoate:

[0880] To a solution of methyl 2-methyl-3-(trifluoromethyl)benzoate (2000.00 mg, 9.17 mmol) in carbon tetrachloride (50.0 ml) was added N-bromosuccinimide (1957.80 mg, 11.00 mmol) and dibenzoyl peroxide (222.05 mg, 0.92 mmol). The mixture was stirred at 85°C for 16.0 h. After that reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (Biotage, 40 g normal phase silica gel, UV 254, petroleum ether / ethyl acetate = 20 / 1) to give methyl 2-(bromomethyl)-3-(trifluoromethyl)benzoate (2.9 g, 9.17 mmol, 100% yield). LC-MS: m / z= 297 (M+H)+, retention time 2.210 min (Method A).

[0881] Step 2: Methyl 4-hydroxy-8-(trifluoromethyl)isoquinoline-3-carboxylate:

[0882] To a solution of methyl 2-(bromomethyl)-3-(trifluoromethyl)benzoate (2700.00 mg, 9.09 mmol) and methyl tosylglycinate (2874.45 mg, 11.82 mmol) in acetonitrile (75.0 mL) was added potassium carbonate (2512.32 mg, 18.18 mmol) and sodium iodide (136.23 mg, 0.91 mmol), the reaction was stirred at 85°C for 48 h. The reaction was concentrated under reduced pressure and the residue was dissolved in water (50.0 mL). Then it was acidified to pH < 7 with hydrochloric acid and some solid was precipitated. The mixture was filtered and the solid was collected as crude product (3.9 g), which was used to next step without any purification. LC-MS: m / z = 272 (M+H)+, retention time 2.115 min (Method A).

[0883] Step 3: Methyl 4-(benzyloxy)-8-(trifluoromethyl)isoquinoline-3-carboxylate:

[0884] To a solution of methyl 4-hydroxy-8-(trifluoromethyl)isoquinoline-3-carboxylate (3500.0 mg, 12.91 mmol) in N,N-dimethylformamide (30 ml) was added benzyl bromide (4414.49 mg, 25.81 mmol) and potassium carbonate (3567.37 mg, 25.81 mmol). The mixture was stirred at 50°C for 3.0 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine solution (50 mL), dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage, 40 g normal phase silica gel, UV 254, petroleum ether / ethyl acetate = 20 / 1) to give methyl 4-(benzyloxy)-8-(trifluoromethyl)isoquinoline-3-carboxylate (2.2 g, 6.09 mmol, 47% yield). LC-MS: m / z= 362 (M+H)+, retention time 2.236 min (Method A).

[0885] Step 4: 4-(Benzyloxy)-3-(methoxycarbonyl)-8-(trifluoromethyl)isoquinoline 2-oxide:

[0886] To a solution of methyl 4-(benzyloxy)-8-(trifluoromethyl)isoquinoline-3-carboxylate (2100.00 mg, 5.81 mmol) and urea - hydrogen peroxide (1640.21 mg, 17.44 mmol) in dichloromethane (60 ml) was added trifluoroacetic anhydride (3662.27 mg, 17.44 mmol). The mixture was stirred at room temperature for 3.0 h. The reaction mixture was quenched with sodium sulfite solution and extracted with dichloromethane (100 mL×3). The organic phase was washed with saturated brine solution (100 mL), dried (sodium sulfate) and concentrated. The residue was purified by flash chromatography (Biotage, 40 g normal phase silica gel, UV 254, dichloromethane / methanol = 20 / 1) to give 4-(benzyloxy)-3-(methoxycarbonyl)-8-(trifluoromethyl)isoquinoline 2-oxide (1.35 g, 3.58 mmol, 62% yield). LC-MS: m / z= 378 (M+H)+, retention time 2.030 min (Method A).

[0887] Step 5: Methyl 1-amino-4-(benzyloxy)-8-(trifluoromethyl)isoquinoline-3-carboxylate:

[0888] To a solution of 4-(benzyloxy)-3-(methoxycarbonyl)-8-(trifluoromethyl)isoquinoline 2- oxide (1250.00 mg, 3.31 mmol) in pyridine (18.0 ml) was added tosyl chloride (1263.19 mg, 6.63 mmol). The mixture was stirred at 0°C for 20 min. The ethanolamine (3642.27 mg, 59.63 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH < 7 with hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated brine solution , dried (sodium sulfate) and concentrated. The residue was purified by flash chromatography (Biotage, 40 g normal phase silica gel, UV 254, petroleum ether / ethyl acetate = 4 / 1) to give methyl 1-amino-4-(benzyloxy)-8-(trifluoromethyl) isoquinoline-3-carboxylate (250 mg, 0.66 mmol, 20% yield). LC-MS: m / z = 377 (M+H)+, retention time 2.069 min (Method A).

[0889] Step 6: Methyl 4-(benzyloxy)-1-(3-(ethoxycarbonyl)thioureido)-8-(trifluoromethyl) isoquinoline-3-carboxylate:

[0890] To a solution of methyl 1-amino-4-(benzyloxy)-8-(trifluoromethyl)isoquinoline-3- carboxylate (220.00 mg, 0.58 mmol) in dichloromethane (20 ml) was added ethyl 2-isothiocyanato-2- oxoacetate (230.00 mg, 1.75 mmol). The mixture was stirred at 40°C for 48 h. After that reaction mixture was concentrated under reduced pressure and the residue was purified by slurrying in (petroleum ether / ethyl acetate = 3 / 1) to give the methyl 4-(benzyloxy)-1-(3- (ethoxycarbonyl)thioureido)-8-(trifluoromethyl) isoquinoline-3-carboxylate (260 mg, 0.51 mmol, 88% yield). LC-MS: m / z= 508 (M+H)+, retention time 2.185 min (Method A).

[0891] Step 7: Methyl 2-amino-6-(benzyloxy)-10-(trifluoromethyl)-[1,2,4]triazolo[5,1-a] isoquinoline-5-carboxylate:

[0892] To a solution of methyl 4-(benzyloxy)-1-(3-(ethoxycarbonyl)thioureido)-8-(trifluoromethyl) isoquinoline-3-carboxylate (250.00 mg, 0.49 mmol) in 2-propanol (25 ml) was added hydroxylamine hydrochloride (171.16 mg, 2.46 mmol) and N,N-diisopropylethylamine (318.34 mg, 2.46 mmol). The mixture was stirred at 50°C for 16 h. The mixture was quenched with water and precipitates a solid. Then it was filtered to collect the solid as crude product (180 mg), which was used to next step without any purification. LC-MS: m / z = 417 (M+H)+, retention time 2.130 min (Method A).

[0893] Step 8: Methyl 6-(benzyloxy)-10-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate:

[0894] To a solution of methyl 2-amino-6-(benzyloxy)-10-(trifluoromethyl)-[1,2,4]triazolo[5,1-a] isoquinoline-5-carboxylate (160.00 mg, 0.38 mmol) in tetrahydrofuran (5 ml) was added tert-butyl nitrite (79.25 mg, 0.77 mmol). The mixture was stirred at room temperature for 16 h. After that reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (Biotage, 12 g normal phase silica gel, UV 254, petroleum ether / ethyl acetate = 5 / 1) to give the methyl 6-(benzyloxy)-10-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (145 mg, 0.36 mmol, 95% yield). LC-MS: m / z = 402 (M+H)+, retention time 2.222 min (Method A).

[0895] Step 9: Methyl 6-hydroxy-10-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate:

[0896] A mixture of methyl 6-(benzyloxy)-10-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline- 5-carboxylate (130.0 mg, 0.32 mmol) in trifluoroacetic acid (5.0 ml) was stirred at 45°C for 16 h in a sealed tube. After that reaction mixture was concentrated under reduced pressure and the residue was purified by slurrying in (petroleum ether / ethyl acetate = 10 / 1) to give methyl 6-hydroxy-10- (trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (105 mg, 0.27 mmol, 83% yield). LC-MS: m / z = 312 (M+H)+, retention time 2.01 min (Method A).

[0897] Step 10: (6-Hydroxy-10-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl) glycine

[0898] To a solution of methyl 6-hydroxy-10-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (100.0 mg, 0.32 mmol) and glycine (72.36 mg, 0.96 mmol) in dimethyl sulfoxide (5.0 mL) was added potassium carbonate (133.23 mg, 0.96 mmol), the reaction was stirred at 110°C for 2.0 h in a sealed tube. The reaction was dissolved in water and acidified to pH < 7 with hydrochloric acid. The precipitate was filtered, washed with water and dried to obtain (6-hydroxy-10-(trifluoromethyl)- [1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl) glycine (99.0 mg, 0.28 mmol, 87 % yield) as grey solid. LC-MS: m / z= 355 (M+H)+, retention time 3.995 min (Method A).1HNMR (500 MHz, DMSO-d6) δ 14.71 (s, 1H), 13.07 (br, 1H), 10.59 (t, J = 5.5 Hz, 1H), 8.78 (s, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.08 (t, J = 8.0 Hz, 1H), 4.30 (d, J = 5.5 Hz, 2H).Example 34: Preparation of Compound (34) Scheme 34: Synthesis of Compound (34)

[0899] Step 1: Methyl 6-(benzyloxy)-10-(phenylthio)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate:

[0900] A mixture of methyl 6-(benzyloxy)-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (150.0 mg, 0.36 mmol), benzenethiol (80.0 mg, 0.73 mmol), 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene (42.0 mg, 0.07 mmol), N,N-diisopropylethylamine (139.0 mg, 1.08 mmol) and tris(dibenzylideneacetone)dipalladium (33.0 mg ,0.04 mmol) in 1,4-dioxane (3.0 mL) was stirred at 110 °C for 1.0 h in a sealed tube. The reaction mixture was filtered and the filtrate was evaporated to give dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford methyl 6-(benzyloxy)-10-(phenylthio)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (126.0 mg, 0.36 mmol, 78.30% yield) as white solid. LC-MS: m / z= 442.0 (M+H)+, retention time 2.37 min (Method A).

[0901] Step 2: Methyl 6-hydroxy-10-(phenylthio)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate:

[0902] A solution of methyl 6-hydroxy-10-(phenylthio)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (50.0 mg, 0.11 mmol) in trifluoroacetic acid (4.0 mL) was stirred at 40 °C overnight. The mixture was evaporated to afford dryness. The residue was triturated with petroleum ether / ethyl acetate =3 / 1 to afford methyl 6-hydroxy-10-(phenylthio)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (25.0 mg, 0.10 mmol, 62.8% yield) as white solid. LC-MS: m / z= 352.0 (M+H)+, retention time 2.23 min (Method A).

[0903] Step 3: (6-Hydroxy-10-(phenylthio)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine

[0904] To a solution of methyl 6-hydroxy-10-(phenylthio)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (25.00 mg, 0.07 mmol) and glycine (16.0 mg, 0.21 mmol) in dimethyl sulfoxide (3.0 mL) were added potassium carbonate (29.0 mg, 0.21 mmol). The mixture was stirred at 110 °C for about 1.0 h. The mixture was diluted with ice-water. The resulting aqueous solution was acidified with 3N / L hydrochloric acid solution to pH=3~4. The resulting solid was filtered and dried to afford (6-hydroxy- 10-(phenylthio)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (12.0 mg, 0.08 mmol, 35.7% yield) as white solid. LC-MS: m / z= 395.0 (M+H)+, retention time 4.72 min (Method A).1HNMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 10.58 (s, 1H), 8.80 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.72-7.67 (m, 4H), 7.61-7.59 (m, 3H), 7.07 (d, J =8.4 Hz, 1H), 4.29 (d, J = 5.4 Hz, 2H).Example 35: Preparation of Compound (35) Scheme 35: Synthesis of Compound (35)Compound 35

[0905] Step 1: Methyl 6-(benzyloxy)-10-(phenylsulfonyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate:

[0906] To a solution of methyl 6-(benzyloxy)-10-(phenylthio)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (77.0 mg, 0.17 mmol) in dichloromethane (5.0 mL) was added 3-chloroperoxybenzoic acid (353.0 mg, 1.10 mmol, 85% percent) at 0 °C. The mixture was stirred at this temperature overnight. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain methyl 6-(benzyloxy)-10-(phenylsulfonyl)- [1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (63.0 mg, 0.13 mmol, 78.30% yield) as white solid. LC-MS: m / z= 474.0 (M+H)+, retention time 2.15 min (Method A).

[0907] Step 2: Methyl 6-hydroxy-10-(phenylsulfonyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate:

[0908] A solution of methyl 6-(benzyloxy)-10-(phenylsulfonyl)-[1,2,4]triazolo[5,1-a]isoquinoline- 5-carboxylate (70.0 mg, 0.15 mmol) in trifluoroacetic acid (4.0 mL) was stirred at 40 °C overnight. The mixture was evaporated to afford dryness. The residue was triturated with petroleum ether / ethyl acetate =3 / 1 to afford methyl 6-hydroxy-10-(phenylsulfonyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (32.0 mg, 0.15 mmol, 56.5% yield) as white solid. LC-MS: m / z= 384.1 (M+H)+, retention time 1.94 min (Method A).

[0909] Step 3: (6-Hydroxy-10-(phenylsulfonyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carbonyl)glycine

[0910] To a solution of methyl 6-hydroxy-10-(phenylsulfonyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (30.0 mg, 0.08 mmol) and glycine (19.0 mg, 0.26 mmo) in dimethyl sulfoxide (3.0 mL) were added potassium carbonate (37.0 mg, 0.27 mmol). The mixture was stirred at 110 °C for about 1.0 h. The mixture was diluted with ice-water. The resulting aqueous solution was acidified with 3N / L hydrochloric acid solution to pH=3~4. The resulting solid was filtered and dried to afford (6-hydroxy- 10-(phenylsulfonyl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (20.0 mg, 0.08 mmol, 56.20% yield) as white solid. LC-MS: m / z= 427.0 (M+H)+, retention time 3.81 min (Method A).1HNMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 10.46 (s, 1H), 8.99 (s, 1H), 8.81 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 4.26 (d, J = 5.4 Hz, 2H).Example 36: Preparation of Compound (36)

[0911] Step 1: (6-(Benzyloxy)-5-(methoxycarbonyl)-[1,2,4]triazolo[5,1-a]isoquinolin-10- yl)boronic acid: H

[0912] To a solution of methyl 6-(benzyloxy)-10-bromo-[1,2,4]triazolo[5,1-a]isoquinoline-5- carboxylate (200.0 mg, 0.49 mmol), bis(pinacolato)diboron (185 mg, 0.73 mmol) and potassium acetate (143 mg, 1.46 mmol) in 1,4-dioxane (5.0 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.5 mg, 0.05 mmol). The mixture was stirred at 90 °C under nitrogen overnight and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography (dichloromethane / methanol = 10 / 1) to afford methyl (6-(benzyloxy)-5-(methoxycarbonyl)- [1,2,4]triazolo[5,1-a]isoquinolin-10-yl)boronic acid (100 mg, 54.6% yield) as a white solid. LC-MS: m / z= 378.3 (M+H)+, retention time 2.07 min (Method A).

[0913] Step 2: Methyl 6-(benzyloxy)-10-(1-phenyl-1H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carboxylate:

[0914] To a solution of 4-bromo-1-phenyl-1H-1,2,3-triazole (59 mg, 0.27 mmol), (6-(benzyloxy)-5- (methoxycarbonyl)-[1,2,4]triazolo[5,1-a]isoquinolin-10-yl)boronic acid (100 mg, 0.27 mmol) and sodium carbonate (56 mg, 0.53 mmol) in 1,4-dioxane / water (2.0 mL / 0.3 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29.0 mg, 0.03 mmol). The mixture was stirred at 90 °C for 16.0 h under nitrogen and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 7 / 3) to afford methyl 6-(benzyloxy)-10-(1-phenyl-1H-1,2,3-triazol-4- yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (30 mg, 24% yield) as white solid. LC-MS: m / z= 477.3 (M+H)+, retention time 2.23 min (Method A).

[0915] Step 3: Methyl 6-hydroxy-10-(1-phenyl-1H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carboxylate:

[0916] A solution of methyl 6-(benzyloxy)-10-(1-phenyl-1H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carboxylate (30.0 mg, 0.06 mmol) in trifluoroacetic acid (2.0 mL) was stirred at 45 °C overnight. The mixture was evaporated to afford dryness. The residue was triturated with petroleum ether / ethyl acetate =3:1 to afford methyl 6-hydroxy-10-(1-phenyl-1H-1,2,3-triazol-4-yl)- [1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (22 mg, 90.5% yield) as a white solid. LC-MS: m / z= 387.3 (M+H)+, retention time 2.04 min (Method A).

[0917] Step 4: (6-Hydroxy-10-(1-phenyl-1H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[5,1-a]isoquinoline- 5-carbonyl)glycine

[0918] To a solution of methyl 6-hydroxy-10-(1-phenyl-1H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carboxylate (22 mg, 0.06 mmol) in dimethyl sulfoxide (3.0 mL) was added glycine (6.0 mg, 0.09 mmol) and potassium carbonate (16.0 mg, 0.11 mmol). The mixture was stirred at 110 °C for about 1.0 h. The mixture was cooled diluted with ice-water. The resulting aqueous solution was acidified with 3N / L hydrochloric acid to pH=3~4. The resulting solid was filtered and dried to afford (6-hydroxy-10-(1-phenyl-1H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carbonyl)glycine (9.8 mg, 40.2% yield) as white solid. LC-MS: m / z= 430.3 (M+H)+, retention time 4.11 min (Method A).1HNMR (400 MHz, DMSO-d6) δ 14.72 (s, 1H), 10.58 (t, J = 5.3 Hz, 1H), 9.21 (s, 1H), 8.57 – 8.48 (m, 2H), 8.17 (d, J = 7.3 Hz, 1H), 8.09 – 7.96 (m, 3H), 7.66 (t, J = 7.9 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 4.30 (d, J = 5.4 Hz, 2H). Example 37: Preparation of Compound (37) Scheme 37: Synthesis of Compound (37)

[0919] Step 1: Methyl 6-(benzyloxy)-10-(1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)- [1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate:

[0920] To a solution of 4-bromo-1-(3-chlorophenyl)-1H-1,2,3-triazole (80 mg, 0.32 mmol), (6- (benzyloxy)-5-(methoxycarbonyl)-[1,2,4]triazolo[5,1-a]isoquinolin-10-yl)boronic acid (0.12 g, 0.32 mmol) and sodium carbonate (36 mg, 0.64 mmol) in 1,4-dioxane / water (5.0 mL / 1.0 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23.0 mg, 0.03 mmol). The mixture was stirred at 90 °C for 16.0 h under nitrogen and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford methyl 6-(benzyloxy)-10-(1-(3-chlorophenyl)-1H-1,2,3- triazol-4-yl)-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (50 mg, 30.8% yield) as white solid. LC- MS: m / z= 510.0 (M+H)+, retention time 2.23 min (Method A).

[0921] Step 2: Methyl 10-(1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)-6-hydroxy-[1,2,4]triazolo[5,1- a]isoquinoline-5-carboxylate:

[0922] A solution of methyl 6-(benzyloxy)-10-(1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)- [1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (200 mg, 0.4 mmol) in trifluoroacetic acid (5.0 mL)was stirred at 45 oC overnight. The mixture was evaporated to afford dryness. The residue was trituratedwith petroleum ether / ethyl acetate to afford methyl 10-(1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)-6- hydroxy-[1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (50 mg, 29.7% yield) as yellow solid. LC- MS: m / z= 420.0 (M+H)+, retention time 2.06 min (Method A).

[0923] Step 3: (10-(1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)-6-hydroxy-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycine

[0924] To a solution of methyl 10-(1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)-6-hydroxy- [1,2,4]triazolo[5,1-a]isoquinoline-5-carboxylate (30 mg, 0.07 mmol) in dimethyl sulfoxide (3.0 mL) was added glycine (15 mg, 0.21 mmol) and potassium carbonate (19 mg, 0.14 mmol). The mixture was stirred at 110 °C for about 1.0 h. The mixture was cooled diluted with ice-water. The resulting aqueous solution was acidified with 3N / L hydrochloric acid to pH=3~4. The resulting solid was filtered and dried to afford (10-(1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)-6-hydroxy-[1,2,4]triazolo[5,1- a]isoquinoline-5-carbonyl)glycine (11.3 mg, 35.5% yield) as white solid. LC-MS: m / z= 463.1 (M+H)+, retention time 4.45 min (Method A).1HNMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.29 (s, 1H), 8.53 (s, 2H), 8.05-8.14 (m, 4H), 7.65-7.70 (m, 2H), 4.22 (d, J = 5.4 Hz, 2H). Example 38: Preparation of Compound (38) Scheme 38: Synthesis of Compound (38)

[0925] Step 1: Methyl 6-(benzyloxy)-10-(1-methyl-1H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[5,1- a]isoquinoline-5-carboxylate:

[0926] To a solution of 4-bromo-1-methyl-1H-1,2,3-triazole (58 mg, 0.36 mmol), (6-(benzyloxy)-5- (methoxycarbonyl)-[1,2,4]triazolo[5,1-a]isoquinolin-10-yl)boronic acid (92 mg, 0.20 mmol) and potassium phosphate tribasic (127 mg, 0.60 mmol) in 1,4-dioxane / water (5.0 mL / 1.0 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biph enyl)]palladium(II) (24 mg, 0.03 mmol). The mixture was stirred at 85 °C for 3.0 h under nitrogen and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash...

Claims

1. A compound of Formula (I), (I)or a pharmaceutically acceptable salt thereof, wherein:X1, X2, X3, X5 are each independently N, C, or CH;X4 is independently N or C;R1 is H, C1-3 alkyl, or C1-3 alkylhalo;R2 is H, C1-3 alkyl, or C1-3 alkylhalo;R3 and R4 together with the atoms to which they are attached combine to form C5-6 aryl or heteroaryl, optionally substituted with one or more groups selected from halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, and indole, wherein alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, and indole are each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxine or dioxoline; and R5 is H, C1-3 alkyl, C1-3 alkylhalo, C1-3 alkoxy or aryl, or R5 is absent with X4 is N.

2. The compound of claim 1, wherein R1 is -H.

3. The compound of claim 1 or 2, wherein R2 is -H.

4. The compound of claim 1, having a structure according for Formula (II), (II)or a pharmaceutically acceptable salt thereof, wherein:X1, X2, X3, X5 are each independently N, C, or CH;X4 is independently N or C;Y1, Y2, and Y3 are each independently N, C, or CH;R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, C1-3 alkoxy, or aryl, or R5 is absent with X4 is N;R6 is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxane or dioxolane; andm is 0, 1, 2, or 3.

5. The compound of claim 4, wherein R1 is H.

6. The compound of claim 4 or 5, wherein R2 is H.

7. The compound of any one of claims 4-6, wherein m is 0.

8. The compound of any one of claims 4-6, wherein m is 1.

9. The compound of any one of claims 4-6, wherein m is 2.

10. The compound of any one of claims 4-6, wherein m is 3.

11. The compound of claim 1, having a structure according to Formula (III), (III)or a pharmaceutically acceptable salt thereof, wherein:X1, X2, X3, X5 are each independently N, C, or CH;X4 is independently N or C;Y1, Y2, and Y3 are each independently N, C, or CH;Z1, Z2, and Z3 are each independently N, C, CH, S, or O;R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, C1-3 alkoxy or aryl, or R5 is absent with X4 is N;R7 is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; andn is 0, 1, 2, or 3.

12. The compound of claim 11, wherein R1 is -H.

13. The compound of claim 11 or 12, wherein R2 is -H. 14. The compound of any one of claims 11-13, wherein n is 0.

15. The compound of any one of claims 11-13, wherein n is 1.

16. The compound of any one of claims 11-13, wherein n is 2.

17. The compound of any one of claims 11-13, wherein n is 3.

18. The compound of claim 1, having a structure according to Formula (IIa), (IIa)or a pharmaceutically acceptable salt thereof, wherein:R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, C1-3 alkoxy, or aryl;R6 is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl, or wherein 2 alkoxys together with the atoms to which they are attached combine to form a dioxine or dioxoline; andm is 0, 1, 2, or 3.

19. The compound of claim 18, wherein R1 is -H. 20. The compound of claim 18 or 19, wherein R2 is -H.

21. The compound of any one of claims 18-20, wherein m is 0.

22. The compound of any one of claims 18-20, wherein m is 1.

23. The compound of any one of claims 18-20, wherein m is 2.

24. The compound of any one of claims 18-20, wherein m is 3.

25. The compound of any one of claims 18-25, wherein R5 is -H.

26. The compound of any one of claims 18-26, wherein R6 is -H.

27. The compound of any one of claims 18-24, wherein R5 is alkoxy.

28. The compound of claim 27, wherein the alkoxy is methoxy.

29. The compound of claim 27, wherein the alkoxy is ethoxy. 30. The compound of any one of claims 18-24, wherein R5 is alkylhalo.

31. The compound of claim 30, wherein the alkylhalo is -CF3.

32. The compound of any one of claims 18-24, wherein R5 is alkyl.

33. The compound of claim 32, wherein the alkyl is -CH3.

34. The compound of any one of claims 18-24, wherein R5 is aryl.

35. The compound of claim 34, wherein R5 is .

36. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is halo.

37. The compound of claim 36, wherein halo is -Cl.

38. The compound of claim 36, wherein halo is -Br.

39. The compound of claim 36, wherein halo is -F. 40. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is alkyl, optionally substituted with halo or phenyl.  41. The compound of claim 40, wherein alkyl is methyl.  42. The compound of claim 40, wherein R6 is -CF3.  43. The compound of claim 40, wherein R6 is .  44. The compound of any one of claims 18-25, 27, 30, and 32, where in R6 is aryl, optionally substituted with halo, cyano, alkyl, or alkylhalo.  45. The compound of claim 44, wherein R6 is .  46. The compound of claim 44, wherein R6 is .  47. The compound of claim 44, wherein R6 is .  48. The compound of claim 44, wherein R6 is .  49. The compound of claim 44, wherein R6 is .  50. The compound of claim 44, wherein R6 is .  51. The compound of claim 44, wherein R6 is .  52. The compound of claim 44, wherein R6 is .  53. The compound of claim 44, wherein R6 is .  54. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is aryloxy, optionally substituted with alkyl, halo, or alkoxy.  55. The compound of claim 54, wherein R6 is .  56. The compound of claim 54, wherein R6 is .  57. The compound of claim 54, wherein R6 is   58. The compound of claim 54, wherein R6 is .  59. The compound of claim 54, wherein R6 is .  60. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is cycloalkyl.  61. The compound of claim 60, wherein R6 is cyclopropane.  62. The compound of claim 60, wherein R6 is cyclohexane.  63. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is heterocycloalkyl.   64. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is .  65. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is .   66. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is heteroaryl, optionally substituted with aryl, cycloalkyl, alkyl, or arylhalo.  67. The compound of claim 66, wherein R6 is , , or .  68. The compound of claim 66, wherein R6 is .  69. The compound of claim 66, wherein R6 is .  70. The compound of claim 66, wherein R6 is .  71. The compound of claim 66, wherein R6 is .  72. The compound of claim 66, wherein R6 is .  73. The compound of claim 66, wherein R6 is .  74. The compound of claim 66, wherein R6 is .  75. The compound of claim 66, wherein R6 is .  76. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is heterocycloalkyl, optionally substituted with aryl.  77. The compound of claim 76, wherein R6 is .  78. The compound of claim 76, wherein R6 is .  79. The compound of claim 76, wherein R6 is .  80. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is alkoxy.  81. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is .  82. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is .  83. The compound of any one of claims 18-25, 27, 30, and 32, wherein R6 is .  84. The compound of claim 1, having a structure according to Formula (IIb), (IIb)or a pharmaceutically acceptable salt thereof, wherein:Y1 is N, C, or CH;R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, C1-3 alkoxy, or aryl;R6 is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; andm is 0, 1, 2, or 3.

85. The compound of claim 84, wherein Y1 is N.  86. The compound of claim 84 or 85, wherein R1 is H.  87. The compound of any one of claims 84-86, wherein R2 is H.   88. The compound of any one of claims 84-87, wherein m is 0.   89. The compound of any one of claims 84-87, wherein m is 1.   90. The compound of any one of claims 84-87, wherein m is 2.   91. The compoudn of any one of claims 84-87, wherein m is 3.   92. The compound of any one of claims 84-91, wherein R5 is H. 93. The compound of any one of claims 84-92, wherein R6 is aryl optionally substituted with halo.  94. The compound of claim 93, wherein R6 is .  95. The compound of claim 93, wherein R6 is . 96. The compound of claim 93, wherein R6 is .  97. The compound of claim 93, wherein R6 is .  98. The compound of claim 1, having a structure according to Formula (IIc), (IIc)or a pharmaceutically acceptable salt thereof, wherein:Y2 is N, C, or CH;R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, or C1-3 alkoxy;R6 is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; andm is 0, 1, 2, or 3.   99. The compound of claim 83, wherein Y2 is N.  100. The compound of claim 83 or 84, wherein R1 is H.  101. The compound of any one of claims 83-85, wherein R2 is H.  102. The compound of any one of claims 98-100, wherein m is 0.   103. The compound of any one of claims 98-100, wherein m is 1.   104. The compound of any one of claims 98-100, wherein m is 2.   105. The compound of any one of claims 98-100, wherein m is 3.   106. The compound of any one of claims 98-105, wherein R5 is H.  107. The compound of any one of claims 98-106, wherein R6 is aryl optionally substituted with halo.  108. The compound of claim 107, wherein R6 is .  109. The compound of claim 107, wherein R6 is .  110. The compound of claim 107, wherein R6 is .  111. The compound of claim 107, wherein R6 is .  112. The compound of claim 1, having a structure according to Formula (IId), (IId)or a pharmaceutically acceptable salt thereof, wherein:Y3 is N, C, or CH;R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, or C1-3 alkoxy;R6 is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; andm is 0, 1, 2, or 3.  113. The compound of claim 112, wherein Y3 is N.  114. The compound of claim 112 or 113, wherein R1 is H.  115. The compound of any one of claims 112-114, wherein R2 is H.  116. The compound of any one of claims 112-115, wherein m is 0.   117. The compound of any one of claims 112-115, wherein m is 1.   118. The compound of any one of claims 112-115, wherein m is 2.   119. The compound of any one of claims 112-115, wherein m is 3.   120. The compound of any one of claims 112-119, wherein R5 is H.  121. The compound of any one of claims 112-120, wherein R6 is aryl optionally substituted with halo.  122. The compound of claim 121, wherein R6 is .  123. The compound of claim 121, wherein R6 is .  124. The compound of claim 121, wherein R6 is .  125. The compound of claim 121, wherein R6 is .  126. The compound of claim 1, having a structure according to Formula (IIe), (IIe)or a pharmaceutically acceptable salt thereof, wherein:R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, or C1-3 alkoxy;R6 is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; andm is 0, 1, 2, or 3.   127. The compound of claim 103, wherein R1 is H.  128. The compound of claim 103 or 104, wherein R2 is H.  129. The compound of any one of claims 126-128, wherein m is 0.   130. The compound of any one of claims 126-128, wherein m is 1.

131. The compound of any one of claims 126-128, wherein m is 2.   132. The compound of any one of claims 126-128, wherein m is 3.   133. The compound of any one of claims 126-132, wherein R5 is H.  134. The compound of any one of claims 126-133, wherein R6 is H.  135. The compound of any one of claims 126-133, wherein R6 is halo.

136. The compound of claim 135, wherein R6 is Cl.  137. The compound of claim 1, having a structure according to Formula (IIf), (IIf)or a pharmaceutically acceptable salt thereof, wherein:R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, or C1-3 alkoxy;R6 is H, halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, hetercycloalkyl, sulfanyl, sulfonyl, sulfonamide, carboxamide, or indole, each optionally substituted with one or more groups selected from halo, alkyl, alkaryl, alkylhalo, cyano, alkoxy, aryl, heteroaryl, arylhalo, cycloalkyl, and heterocycloalkyl; andm is 0, 1, 2, or 3.

138. The compound of claim 137, wherein R1 is H.  139. The compound of claim 137 or 138, wherein R2 is H.  140. The compound of any one of claims 137-139, wherein m is 0.   141. The compound of any one of claims 137-139, wherein m is 1.   142. The compound of any one of claims 137-139, wherein m is 2.   143. The compound of any one of claims 137-139, wherein m is 3.   144. The compound of any one of claims 137-143, wherein R5 is H.  145. The compound of any one of claims 137-144, wherein R6 is H.  146. The compound of any one of claims 137-144, wherein R6 is halo.  147. The compound of claim 146, wherein R6 is Cl.  148. The compound of claim 1, having a structure according to Formula (IIIa), (IIIa)or a pharmaceutically acceptable salt thereof, wherein:Z1 is N, C, CH, S, or O;R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, or C1-3 alkoxy;R7 is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; andn is 0, 1, 2, or 3.  149. The compound of claim 148, wherein Z1 is N.  150. The compound of claim 148, wherein Z1 is O.  151. The compound of claim 148, wherein Z1 is S.  152. The compound of any one of claims 148-151, wherein R1 is H.

153. The compound of any one of claims 148-152, wherein R2 is H.  154. The compound of any one of claims 148-153, wherein n is 0.   155. The compound of any one of claims 148-153, wherein n is 1.  156. The compound of any one of claims 148-153, wherein n is 2.

157. The compound of any one of claims 148-153, wherein n is 3.

158. The compound of any one of claims 148-157, wherein R5 is H.

159. The compound of any one of claims 148-158, wherein R7 is H.  160. The compound of claim 1, having a structure according to Formula (IIIb), (IIIb)or a pharmaceutically acceptable salt thereof, wherein:Z3 is N, C, CH, S, or O;R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, or C1-3 alkoxy;R7 is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; andn is 0, 1, 2, or 3. 161. The compound of claim 160, wherein Z3 is N. 162. The compound of claim 160, wherein Z3 is S.

163. The compound of claim 160, wherein Z3 is O.

164. The compound of any one of claims 160-163, wherein R1 is H.

165. The compound of any one of claims 160-164, wherein R2 is H.

166. The compound of any one of claims 160-165, wherein n is 0.

167. The compound of any one of claims 160-165, wherein n is 1.

168. The compound of any one of claims 160-165, wherein n is 2.

169. The compound of any one of claims 160-165, wherein n is 3.

170. The compound of any one of claims 160-169, wherein R5 is H.

171. The compound of any one of claims 160-170, wherein R7 is H.  172. The compound of any one of claims 160-170, wherein R7 is aryl.  173. The compound of any one of claims 160-170, wherein R7 is arylhalo.  174. The compound of claim 173, wherein R7 is . 175. The compound of claim 1, having a structure according to Formula (IIIc), (IIIc)or a pharmaceutically acceptable salt thereof, wherein:Z2 and Z3 are each independently N, C, CH, S, or O;R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, or C1-3 alkoxy;R7 is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; andn is 0, 1, 2, or 3.

176. The compound of claim 175, wherein Z3 is N.

177. The compound of claim 175, wherein Z3 is S.

178. The compound of claim 175, wherein Z3 is O.  179. The compound of any one of claims 175-178, wherein R1 is H.

180. The compound of any one of claims 175-179, wherein R2 is H.

181. The compound of any one of claims 175-180, wherein n is 0.

182. The compound of any one of claims 175-180, wherein n is 1.

183. The compound of any one of claims 175-180, wherein n is 2.

184. The compound of any one of claims 175-180, wherein n is 3.   185. The compound of any one of claims 175-184, wherein R5 is H.  186. The compound of any one of claims 175-185, wherein R7 is H.  187. The compound of any one of claims 175-185, wherein R7 is aryl.  188. The compound of any one of claims 175-185, wherein R7 is arylhalo.  189. The compound of claim 188, wherein R7 is .  190. The compound of claim 1, having a structure according to Formula (IIId), (IIId)or a pharmaceutically acceptable salt thereof, wherein:Z1 and Z2 are each independently N, C, CH, S, or O;R1 is H or C1-3 alkyl;R2 is H or C1-3 alkyl;R5 is H, C1-3 alkyl, C1-3 alkylhalo, or C1-3 alkoxy;R7 is H, halo, alkyl, alkylhalo, cyano, alkoxy, aryl, arylhalo, cycloalkyl, or heterocycloalkyl; andn is 0, 1, 2, or 3.  191. The compound of claim 190, wherein Z1 is N.  192. The compound of claim 190, wherein Z1 is S.  193. The compound of claim 190, wherein Z1 is O.  194. The compound of any one of claims 190-193, wherein R1 is H.  195. The compound of any one of claims 190-194, wherein R2 is H.  196. The compound of any one of claims 190-195, wherein n is 0.   197. The compound of any one of claims 190-195, wherein n is 1.   198. The compound of any one of claims 190-195, wherein n is 2.  199. The compound of any one of claims 190-195, wherein n is 3.

200. The compound of any one of claims 190-199, wherein R5 is H. 201. The compound of any one of claims 190-200, wherein R7 is H.  202. The compound of any one of claims 190-200, wherein R7 is aryl.  203. The compound of any one of claims 190-200, wherein R7 is arylhalo.  204. The compound of claim 203, wherein R7 is .  205. The compound of claim 1, wherein the compound is selected from the group consisting of Compounds (1)-(118):Compound Compound (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117)(118)or a pharmaceutically acceptable salt thereof.   206. The compound of any one of claims 1-205, or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen atom is replaced with a deuterium atom.   207. A pharmaceutical composition comprising the compound of any one of claims 1-205, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

208. A method for treating a disease mediated by PHD activity comprising administering to a subject the compound of any one of claims 1-205, a pharmaceutically acceptable salt thereof.

209. A method for treating a disease mediated by PHD activity comprising administering to a subject the pharmaceutical composition of claim 207.  210. The method of claim 208 or 209, wherein the disease mediated by PHD activity is an ischemic reperfusion injury.   211. The method of claim 210, wherein the ischemic reperfusion injury is selected from stroke, myocardial infarction, and acute kidney injury.   212. The method of claim 208 or 209, wherein the disease mediated by PHD activity is inflammatory bowel disease.  213. The method of claim 212, wherein the inflammatory bowel disease is ulcerative colitis.   214. The method of claim 212, wherein the inflammatory bowel disease is Crohn’s disease.   215. The method of claim 208 or 209, wherein the disease mediated by PHD activity is cancer.   216. The method of claim 215, wherein the cancer is colorectal cancer.   217. The method of claim 215, wherein the cancer is acute myeloid leukemia.   218. The method of claim 215, wherein the cancer is chronic myeloid leukemia.  219. The method of claim 215, wherein the cancer is multiple myeloma.  220. The method of claim 208 or 209, wherein the disease mediated by PHD activity is liver disease.  221. The method of claim 208 or 209, wherein the disease mediated by PHD activity is atherosclerosis.  222. The method of claim 208 or 209, wherein the disease mediated by PHD activity is cardiovascular disease.  223. The method of claim 208 or 209, wherein the disease mediated by PHD activity is a disease or condition of the eye.   224. The method of claim 223, wherein the disease or condition of the eye is selected from radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia.   225. The method of claim 208 or 209, wherein the disease is anemia.   226. The method of claim 225, wherein the anemia is anemia associated with chronic kidney disease.   227. The method of claim 208 or 209, wherein the disease is chronic kidney disease.  228. The method of claim 208 or 209, wherein the disease is associated with hyperoxia.   229. The method of claim 208 or 209, wherein the disease is bronchopulmonary dysplasia (BPD).   230. The method of claim 208 or 209, wherein the disease is periventricular leukomalacia (PVL).  231. The method of claim 208 or 209, wherein the disease is selected from ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, acute respiratory distress syndrome (ARDS), pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, and cirrhosis.   232. The method of claim 208 or 209, wherein the disease is hemorrhagic shock.  233. The method of claim 208 or 209, wherein the disease is intraventricular hemorrhage.   234. The method of claim 208 or 209, wherein the disease is a respiratory disease, a lung disease, a respiratory viral infection, or a pulmonary viral infection.  235. The method of claim 234, wherein the respiratory disease is selected from respiratory infection, acute respiratory distress syndrome, lung inflammation, pneumonia, and acute lung injury.  236. The method of claim 234, wherein the lung disease is acute lung injury (ALI), bronchitis, pneumonia, pulmonary fibrosis, asthma, or acute respiratory distress syndrome (ARDS).  237. The method of claim 208 or 209, wherein the disease is injury to and / or failure of one or more organs. 238. The method of claim 237, wherein the disease is acute organ injury.

239. The method of claim 237, wherein the disease is organ failure.

240. A method for preventing retinopathy of prematurity comprising administering to a subject the compound of any one of claims 1-205, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 207.

241. A method for treating retinopathy of prematurity comprising administering to a subject the compound of any one of claims 1-205, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 207.

242. A method for treating bronchopulmonary dysplasia comprising administering to a subject the compound of any one of claims 1-205, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 207.

243. A method for preventing bronchopulmonary dysplasia comprising administering to a subject the compound of any one of claims 1-205, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 207.

244. A method for treating white matter injury (WMI) comprising administering to a subject the compound of any one of claims 1-205, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 207.

245. A method for preventing white matter injury comprising administering to a subject the compound of any one of claims 1-205, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 207. 

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