Pyrazole derivatives as PHD inhibitors

Abstract

A compound which is a substituted azine of formula (I), a substituted pyrimidine of formula (IV), or a pharmaceutically acceptable salt thereof. [Formula 1] JPEG2026503683000255.jpg48170 [C2] JPEG2026503683000256.jpg38170

Description

[Technical Field]

[0001] The present invention relates to a series of novel compounds and their use as hypoxia-inducible factor prolyl hydroxylase domain inhibitors (PHD inhibitors). [Background technology]

[0002] Hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are therapeutic targets for applications including the treatment of anemia and other ischemia-related diseases, including cancer and inflammation. PHDs are Fe(II)- and 2-oxoglutarate (2OG)-dependent oxygenases that catalyze the hydroxylation of specific prolyl residues within the oxygen degradation domain (ODD) of the HIF-α subunit. When oxygen levels decrease, HIF-α levels increase; HIF-α dimerizes with HIF-β, and the α,β-HIF complex promotes the transcription of HIF target genes. However, none of the current "clinical" PHD inhibitors are fully selective for PHD over other human 2OG oxygenases. This lack of selectivity can result in unpredictable off-target effects, meaning that treatment may be unsafe. Therefore, more selective small-molecule PHD inhibitors are needed.

[0003] Anemia is a reduction in the amount of red blood cells (erythrocytes) in the circulation and is a major cause of global mortality and morbidity in humans. Recent studies suggest that it may affect one-third of the world's population. Anemia can have a variety of causes, including infection, nutrition, chronic kidney disease, and iron deficiency.

[0004] Erythropoietin (EPO) deficiency is widely associated with anemia associated with multiple chronic diseases, particularly those associated with systemic inflammation. EPO production occurs primarily in the liver and kidney, but many other organs express the EPO gene. EPO production has been shown to be highly sensitive to changes in atmospheric oxygen concentration.

[0005] Recombinant human EPO (rhEPO) is currently used to treat anemia in patients, but EPO cannot be delivered orally. Numerous clinical studies have shown that higher doses of rhEPO correlate with increased cardiovascular events. This is associated with high rhEPO doses, not increased hemoglobin levels. High plasma concentrations of EPO are associated with vascular toxicity.

[0006] Therefore, there is a need to find alternative treatments for anemia that are easier to administer and that do not present the risks mentioned above.

[0007] Previous clinical studies using PHD inhibitors have shown that therapeutically useful levels of hemoglobin can be achieved, corresponding to normal physiological plasma concentrations of EPO. HIF target genes have been reported to be involved in iron metabolism, transport, and absorption, potentially increasing iron availability for red blood cell production. However, the effects of HIF beyond EPO regulation are difficult to predict due to its wide tissue distribution and the complexity of the HIF system.

[0008] Hypoxia occurs in ischemic environments. Poor blood flow (organ ischemia) is a major modern clinical problem, occurring in circulatory and cardiovascular diseases, and can also occur during surgery and in wound healing disorders. Poor blood flow commonly affects the kidneys, limbs, heart, and brain and can be chronic or acute. PHD inhibitors stabilize HIF and are thought to be protective and / or reparative and respond to ischemic disorders.

[0009] When designing PHD inhibitors, it is desirable to find candidates that are not only target selective but also highly potent and exhibit favorable properties suitable for pharmaceutical use.

[0010] Currently available PHD inhibitors, including roxadustat, daprostat, molidustat, decidustat, and vadadustat, exhibit only limited target selectivity for PHDs; for example, inhibition by one or more of them has been observed in collagen prolyl hydroxylase (CPH); 2-oxoglutarate and iron-dependent oxygenase domain-containing 1 (OFGOD1); and jumonji domain-containing 6 (JMJD6). It is well known that the lack of selectivity of enzyme inhibitors can result in unpredictable and unwanted off-target effects.

[0011] Thus, there is a need for more specific PHD inhibitors that have physical properties that make them suitable for use as drugs. Summary of the Invention [Means for solving the problem]

[0012] The present invention provides a series of novel compounds that have been shown to be highly potent and selective inhibitors of human hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) 2. Some compounds of the present invention exhibit IC 3 activity against PHD2. 50 It has been shown that the IC50 activity is less than 200 nM, which is a significant improvement compared to known clinically applied inhibitors (e.g., roxadustat has an IC50 activity of 2.7 μM in a liquid chromatography-based PHD2 hydroxylation assay). 50 (having).

[0013] In addition to their potency, compounds of the present invention were found to be highly selective for PHD, with over 100-fold selectivity over other tested 2OG oxygenases.

[0014] In addition to these desirable biochemical properties, the compounds of the present invention have been shown to possess desirable physiochemical properties, including good solubility and permeability in cells.

[0015] These physicochemical properties mean that the compounds of the present invention have been found to stabilize cellular HIF-α at concentrations in the nM potency range as measured by enzymatic assays. Furthermore, low doses of the compounds have been shown to induce erythropoiesis in animal models.

[0016] The compounds therefore have potential utility in treating conditions in which HIF-PHD is a therapeutic target, including, for example, anemia and other ischemia-related diseases, inflammation, and additional conditions described below.

[0017] Accordingly, the present invention provides compounds that are substituted azines of formula (I) or pharmaceutically acceptable salts thereof: [ka] (In the formula, X is CR 6 or N; R 0 is H or unsubstituted or substituted C 1~6 is alkyl; R 1 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v , -C(O)OR w or -C(O)N(R x )R 7 and; R 2 H, -OR q or unsubstituted or substituted C 1~6 alkyl; R 3 H, -OR 8 or unsubstituted or substituted C 1~6 alkyl; or R 2 is -N = R 3 is =C(R y )- and R 2 and R 3 together give the equation -N=C(R y )-form a group; R 4 is H, unsubstituted or substituted C 1~6 Alkyl, -OR 9 or -C(O)OR 10 and; R 5 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v , -C(O)OR w or -C(O)N(R x )R 7 and; R 6 is H or unsubstituted or substituted C 1~6 is alkyl; R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11 )-Cyc, -CH2C≡CCH3, -Cyc or -Ar, where Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 is alkyl; R 8 , R 9 and R 10 are each independently H and unsubstituted or substituted C 1~6 alkyl; R t , R u , R v , R w , R x , R y , and R z are each independently H, unsubstituted or substituted C 1~6 selected from alkyl, and unsubstituted or substituted phenyl; Rq is H, unsubstituted or substituted C 1~6 alkyl, or unsubstituted or substituted phenyl; However, R 1 and R 5 One of them is -C(O)N(R x )R 7 and R 1 and R 5 The other is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v or -C(O)OR w (It is).

[0018] Preferred embodiments of compounds that are substituted azines of formula (I) or pharmaceutically acceptable salts thereof are described below, and include substituted azines of formulas (Ia), (Ib), (Ic) and (Id) as defined below, and pharmaceutically acceptable salts thereof.

[0019] In another aspect, the present invention provides a compound that is a substituted pyrimidine of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R 0 is H or unsubstituted or substituted C 1~6 is alkyl; R 2 H, -OR q or unsubstituted or substituted C 1~6 is alkyl; R 4 -OR 9 and; R 5 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN or -C(O)OR w and; R 6is H or unsubstituted or substituted C 1~6 is alkyl; R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11 )-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 is alkyl; R 9 is H and unsubstituted or substituted C 1~6 alkyl; R w and R z are each independently H, unsubstituted or substituted C 1~4 selected from alkyl, and unsubstituted or substituted phenyl; R q is H, unsubstituted or substituted C 1~6 alkyl, or unsubstituted or substituted phenyl).

[0020] The present invention also provides a pharmaceutical composition comprising a compound of the invention as defined above and a pharmaceutically acceptable carrier or diluent, which may further comprise one or more additional active agents, for example as mentioned below.

[0021] In another aspect, the present invention provides a compound of the invention or a pharmaceutical composition of the invention as defined above for use in the treatment of the human or animal body by therapy.

[0022] The present invention also provides a compound of the invention, or a pharmaceutical composition of the invention, as defined above, for use as a modulator of hypoxia-inducible factor prolyl hydroxylase activity. Typically, the compound or composition is for use as an inhibitor of hypoxia-inducible factor prolyl hydroxylase activity.

[0023] The present invention further provides a compound of the present invention or a pharmaceutical composition of the present invention as defined above for use in treating a PHD-related disorder, i.e., a disorder that can be treated by modulating (e.g., inhibiting) hypoxia-inducible factor prolyl hydroxylase activity. As mentioned below, such conditions include, but are not limited to, anemia, ischemia-related diseases, inflammation, non-fatty liver disease, irritable bowel disease, cardiovascular disease, heart failure, chronic kidney disease, renal failure, Parkinson's disease, Alzheimer's disease, sickle cell anemia, and cancer. The disorder may be, for example, a HIF-related disorder, an EPO-related disorder, or a VHL-related disorder, such as von Hippel-Lindau syndrome.

[0024] The present invention also provides the compound of the present invention or the pharmaceutical composition of the present invention as defined above for use in treating anemia, ischemia, inflammation, Parkinson's disease, Alzheimer's disease, non-fatty liver disease, irritable bowel disease, cardiovascular disease, heart failure, chronic kidney disease, sickle cell anemia, cancer, or renal failure; or for use in repairing skeletal muscle damage, increasing red blood cell count (RBC), increasing hemoglobin (HGB) production, increasing hematocrit (HCT) production, increasing erythropoietin (EPO) production, wound healing, angiogenesis, revascularization, stem cell activation, or cardioprotection after myocardial infarction. The anemia may be renal anemia (e.g., anemia associated with chronic kidney disease, anemia in dialysis patients), anemia induced by chemotherapy, sickle cell anemia (including that caused by increased expression of fetal hemoglobin F), age-related anemia, or anemia resulting from cancer such as leukemia, multiple myeloma, and smoldering myeloma. The ischemia can be ischemia in circulatory or cardiovascular disease, myocardial infarction, ischemia during surgery, organ ischemia, ischemic disease or diabetic limb ischemia, or sickle cell anemia.

[0025] The present invention also provides a method for treating a subject suffering from or susceptible to a PHD-related disorder, comprising administering to said subject an effective amount of a compound of the invention or a pharmaceutical composition of the invention as defined above.

[0026] The present invention further provides a method for treating a subject suffering from or susceptible to anemia, ischemia, inflammation, Parkinson's disease, Alzheimer's disease, non-fatty liver disease, irritable bowel disease, cardiovascular disease, heart failure, chronic kidney disease, renal failure, or repair of skeletal muscle damage, which method comprises administering to said subject an effective amount of a compound of the invention as defined above, or a pharmaceutical composition of the invention.

[0027] The present invention further provides a method for increasing red blood cell count (RBC), increasing hemoglobin (HGB) production, increasing hematocrit (HCT) production, increasing erythropoietin (EPO) production, wound healing, angiogenesis, revascularization, stem cell activation, or cardioprotection after myocardial infarction in a subject, the method comprising administering to said subject an effective amount of a compound of the present invention as defined above, or a pharmaceutical composition of the present invention. [Brief explanation of the drawings]

[0028] [Figure 1] Immunoblots of Hep3B cells treated with PHD inhibitors 117, 119, 122, and 123 (Examples 93, 95, 98, and 99) at 100 μM (A) and 20 μM (B) for 3 hours. The blots show HIF1-α and β-actin protein levels 3 hours after treatment. [Figure 2]

[0023] Figure 1 shows an immunoblot of HEK293 T cells treated with Compound 68 (Example 46) at 0.5, 1, 5, 10, 20, 50, and 100 μM for 18 hours. The blot shows HIF1-α and GAPDH protein levels 18 hours after treatment. [Figure 3](A) Red blood cell counts (10 / μL) (y-axis) of groups of seven C57BL / 6 mice treated with vehicle (1% methylcellulose) or control (daprodustat) compared to Compound 68 (Example 46) of the present invention (x-axis); (B) mouse hemoglobin levels (g / dL) (y-axis) of mice treated with vehicle (1% methylcellulose) or control (daprodustat) compared to Compound 68 (Example 46) of the present invention (x-axis); and (C) percentage of mouse hemocrit (y-axis) of mice treated with vehicle (1% methylcellulose) or control (daprodustat) compared to Compound 68 (Example 46) of the present invention (x-axis). Values ​​are shown before treatment and after 4 and 8 days of treatment. [Figure 4] 1 shows the IC50 of compound 68 (Example 46) of the present invention when tested at off-target sites commonly inhibited by existing PHD inhibitors. DETAILED DESCRIPTION OF THE INVENTION

[0029] definition As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical. n~m "Alkyl" refers to an alkyl having n to m carbon atoms. Thus, an alkyl group is a C 1~20 Alkyl group, C 1~18 Alkyl group, C 1~14 Alkyl group, C 1~10 Alkyl group, C 1~6 Alkyl group or C 1~4 It can be an alkyl group. 1~10 Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl. 1~6 Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl or hexyl. 1~4Examples of alkyl groups are methyl, ethyl, i-propyl, n-propyl, t-butyl, s-butyl, or n-butyl. When the term "alkyl" is used anywhere in this specification without a prefix specifying the number of carbons, it has 1 to 6 carbons. For the avoidance of doubt, when two alkyl moieties are present in a group, the alkyl moieties may be the same or different.

[0030] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon radical. n~m "Cycloalkyl" refers to a cycloalkyl having n to m carbon atoms. Thus, a cycloalkyl group is a C 3~20 Cycloalkyl groups, C 3~10 Cycloalkyl groups, C 3~8 Cycloalkyl group or C 3~6 It can be a cycloalkyl group. 3~8 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexa-1,3-dienyl, cycloheptyl, and cyclooctyl. 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0031] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing one or more double bonds. n~m "Alkenyl" refers to an alkenyl having n to m carbon atoms. Thus, an alkenyl group is 2~18 Alkenyl group, C 2~14 Alkenyl group, C 2~10 Alkenyl group, C 2~6 Alkenyl group or C 2~4 It may be an alkenyl group. 2~10 Examples of alkenyl groups are ethenyl (vinyl), propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl. 2~6Examples of alkenyl groups are ethenyl, propenyl, butenyl, pentenyl, and hexenyl. 2~4 Examples of alkenyl groups are ethenyl, i-propenyl, n-propenyl, s-butenyl, or n-butenyl. Alkenyl groups typically contain one or two double bonds.

[0032] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing one or more triple bonds. n~m "Alkynyl" refers to an alkynyl having n to m carbon atoms. Thus, an alkynyl group is 2~18 Alkynyl group, C 2~14 Alkynyl group, C 2~10 Alkynyl group, C 2~6 Alkynyl group or C 2~4 It may be an alkynyl group. 2~10 Examples of alkynyl groups are ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl or decynyl. 1~6 Examples of alkynyl groups are ethynyl, propynyl, butynyl, pentynyl or hexynyl. Alkynyl groups typically contain one or two triple bonds.

[0033] C 3~20 A heterocyclyl group is a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has 3 to 20 ring atoms (unless otherwise specified), of which 1 to 10 are ring heteroatoms. n~m "Heterocyclyl" refers to a heterocyclyl having n to m ring atoms. Preferably, the ring has 3 to 7 ring atoms (i.e., C 3~7 heterocyclyl), of which 1 to 4 are ring heteroatoms.

[0034] Examples of 5- and 6-membered saturated heterocyclyl groups include piperazine, piperidine, morpholine, 1,3-oxazinane, pyrrolidine, imidazolidine, and oxazolidine, including their quaternized derivatives as defined herein. Examples of 5- and 6-membered partially saturated heterocyclyl groups include tetrahydropyrazine, tetrahydropyridine, dihydro-1,4-oxazine, tetrahydropyrimidine, dihydro-1,3-oxazine, dihydropyrrole, dihydroimidazole, and dihydrooxazole, including their quaternized derivatives as defined herein. Heterocyclyl groups thus include pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S,S-dioxo-thiomorpholinyl, morpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, 1,3-dioxolanyl, 1,4-dioxolyl and pyrazolinyl groups and moieties. Pyrazolidinyl, piperidyl, piperazinyl, pyrazolidinylmorpholinyl and imidazolidinyl groups and moieties are typical examples.

[0035] Examples of 9- and 10-membered fused heterobicyclic groups include 9-membered fused heterobicyclic groups such as indoline, 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b]thiophene, 2,3-dihydro-1H-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydrobenzo[d]thiazole, benzo[d][1,3]dioxole, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine and 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine (including quaternized derivatives thereof as defined herein); and 1,2,3,4-tetrahydroquinoline, 1,2,3 and 10-membered heterobicyclic groups such as 1,4-tetrahydroisoquinoline, chroman, isochroman, thiochroman, isothiochroman, 1,2,3,4-tetrahydroquinoxaline, 1,2,3,4-tetrahydroquinazoline, 1,4-dihydro-2H-benzo[d][1,3]oxazine, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 3,4-dihydro-2H-benzo[b][1,4]thiazine, 1,4-dihydro-2H-benzo[d][1,3]thiazine, 4H-benzo[d][1,3]dioxin, and 2,3-dihydrobenzo[b][1,4]dioxin (including quaternized derivatives thereof). Preferably, the fused heterobicyclic group contains 1, 2, or 3, preferably 1 or 2, nitrogen atoms.

[0036] For the avoidance of doubt, references to heterocyclyl groups also include fused polycyclic ring systems, including, for example, fused bicyclic systems in which a heterocyclic group is fused to an aryl group. When the heterocyclyl group is such a fused heterocyclyl group, preferred examples are fused ring systems in which a 5- to 6-membered heterocyclyl group is fused to a phenyl group. References to heterocyclic groups also include spirocyclic systems, for example, 7-membered heterocyclic groups, such as 2,6-diazaspiro[3.3]heptane.

[0037] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic aromatic ring containing up to 14 carbon atoms, typically 6 to 10 carbon atoms, in the ring portion. Examples include phenyl, naphthyl, indenyl, and indanyl groups. Phenyl is preferred.

[0038] As used herein, the term "heteroaryl" refers to a monocyclic or bicyclic heteroaromatic ring, typically containing 5 to 10, e.g., 6 to 10, atoms in the ring portion containing one or more heteroatoms. Heteroaryl groups are generally 5- or 6-membered rings and contain at least one heteroatom selected from O, S, N, P, Se, and Si, more typically selected from O, S, and N. It may contain, for example, 1, 2, or 3 heteroatoms. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridazolyl, quinolyl, and isoquinolyl. Furanyl, thienyl, pyridazolyl, pyrazolyl, pyrimidinyl, and thiazolyl groups are typical examples.

[0039] As used herein, the terms "alkylene," "cycloalkylene," "heterocyclylene," "alkenylene," "alkynylene," "arylene," and "heteroarylene" refer to a divalent group obtained by removing a hydrogen atom from an alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl group, respectively. Such bidentate groups may be substituted or unsubstituted. An alkylene group is a C 1~20 Alkylene group, C 1~18 Alkylene group, C 1~14 Alkylene group, C 1~10 Alkylene group, C 1~6 Alkylene group or C 1~4 It can be an alkylene group. 1~6Examples of alkylene groups are methylene, ethylene, propylene, butylene, pentylene and hexylene. Cycloalkylene groups include C 3~10 Cycloalkylene group, C 3~8 Cycloalkylene group or C 3~6 It may be a cycloalkylene group. 3~6 Examples of cycloalkylene groups include cyclopentylene and cyclohexylene. Alkenylene groups are C 2~18 Alkenylene group, C 2~14 Alkenylene group, C 2~10 Alkenylene group, C 2~6 Alkenylene group or C 2~4 It may be an alkenylene group. 2~4 Examples of alkenylene groups include ethenylene (vinylene), propenylene, and butenylene. 2~18 Alkynylene group, C 2~14 Alkynylene group, C 2~10 Alkynylene group, C 2~6 Alkynylene group or C 2~4 It may be an alkynylene group. 2-4 Examples of alkynylene groups include ethynylene and propynylene. Examples of arylene groups include phenylene, and examples of heteroarylene groups include, for example, diradicals derived from pyridine, diradicals derived from thiophene, diradicals derived from chroman, and diradicals derived from chromanol. For alkylene, cycloalkylene, alkenylene, alkynylene, arylene, and heteroarylene, these groups can be bonded to other groups at any two positions on the group (for heteroarylene and heterocyclylene, the positions are typically carbon atoms). Thus, propylene includes -CH2CH2CH2- and -CH2CH(CH3)-, and phenylene includes ortho-, meta-, and para-phenylene.

[0040] As used herein, the term "substituted" as used in the context of substituted organic compounds and substituents means C 1~10 Alkyl, C 3~10 Cycloalkyl, C 3-7Heterocyclyl, aryl, heteroaryl, cyano, amino, nitro, C 2~10 Alkenyl, C 2~10 Alkynyl, C 1~10 Alkylamino, di(C 1~10 ) alkylamino, arylamino, diarylamino, aryl(C 1~10 ) Alkylamino, Amido, Acyl Amido, Hydroxy, Oxo, Halo, Carboxy, Ester, Acyl, Acyloxy, C 1~10 Alkoxy, aryloxy, halo(C 1~10 ) Alkyl, sulfonic acid, thiol, C 1~10 Alkylthio, arylthio, sulfonyl, phosphoric acid, phosphate ester, phosphonic acid, phosphonate ester and SO3 -

[0023] The term "organic compound" refers to an organic compound or group (e.g., an alkyl group, an alkylene group, a cycloalkyl group, a heterocyclyl group, an aryl group, an arylene group, a heteroaryl group, or a heteroarylene group) having one or more substituents selected from the group consisting of cyano, amino, nitro, amido, acylamide, hydroxy, oxo, halo, carboxy, ester, acyl, acyloxy, sulfonic acid, thiol, sulfonyl, phosphoric acid, phosphate ester, phosphonic acid, phosphonate ester, and SO3. - When a compound or group is substituted, it typically has 1, 2, 3, or 4 substituents. For example, a substituted compound or group can have 1, 2, or 3 substituents, or for example, 1 or 2 substituents.

[0041] However, when a group is halo-substituted, for example fluoro-substituted, the group may have 1, 2, 3, or 4 halo substituents, or may have more than 4 halo substituents. In fact, the group may be perhalo-substituted, i.e., all hydrogen atoms of the group may be replaced by halogen atoms. The group may be, for example, perfluoro-substituted, i.e., perfluorinated, i.e., all hydrogen atoms of the group may be replaced by fluorine atoms. Thus, as used herein, the term "substituted" encompasses perhalo-substituents, particularly perfluoro-substituents, in the context of substituted organic groups, for example, substituted hydrocarbyl groups, substituted alkyl groups, substituted cycloalkyl groups, substituted alkenyl groups, substituted alkynyl groups, substituted aryl groups, substituted hydrocarbylene groups, substituted alkylene groups, substituted cycloalkylene groups, substituted alkenylene groups, substituted alkynylene groups, and substituted arylene (including substituted heteroarylene) groups. Thus, for example, the term "substituted C" as used herein includes perhalo-substituents, particularly perfluoro-substituents. n~m "Alkyl" is C n~m The term "substituted C" as used herein includes perfluoroalkyl. n~m Alkylene" is C n~m The term "substituted C" as used herein includes perfluoroalkylene. n~m Hydrocarbyl" is C n~m As used herein, the term "substituted C n~m Hydrocarbylene is C n~m The term "substituted C" as used herein includes perfluorohydrocarbylenes. n~m "Alkoxy" is C n~m perfluoroalkoxy, and the like.

[0042] As used herein, the term oxo represents a group of the formula: =O.

[0043] As used herein, the term acyl refers to a group of the formula: -C(=O)R, where R is an acyl substituent, such as a substituted or unsubstituted C 1~20 Alkyl group, substituted or unsubstituted C 3~20Examples of acyl groups include, but are not limited to, -C(=O)CH3 (acetyl), -C(=O)CH2CH3 (propionyl), -C(=O)C(CH3)3 (t-butyryl), and -C(=O)Ph (benzoyl, phenone).

[0044] As used herein, the term ester (or carboxylate, carboxylic acid ester, or oxycarbonyl) refers to a group of the formula: -C(=O)OR, where R is an ester substituent, e.g., a substituted or unsubstituted C 1~20 Alkyl group, substituted or unsubstituted C 3~20 represents a heterocyclyl group, or a substituted or unsubstituted aryl group (typically a phenyl group). Examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh.

[0045] As used herein, the term acyloxy (or reverse ester) refers to a group of the formula: -OC(=O)R, where R is an acyloxy substituent, such as a substituted or unsubstituted C 1~20 Alkyl group, substituted or unsubstituted C 3~20 a heterocyclyl group, or a substituted or unsubstituted aryl group, typically C 1~6 Examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, -OC(=O)Ph, and -OC(=O)CH2Ph.

[0046] As used herein, the term phosphonic acid refers to a group of the formula: -P(=O)(OH). As will be understood by one of ordinary skill in the art, the phosphonic acid group can exist in protonated and deprotonated forms (i.e., -P(=O)(OH), -P(=O)(O-), and -P(=O)(OH)(O-)), all of which are within the scope of the term "phosphonic acid."

[0047] As used herein, the term phosphonate refers to a group that is a salt of a phosphonic acid group. For example, a phosphonate can be a group of the formula -P(=O)(OH)(O - X + ) where X is a monovalent cation. + X may be an alkali metal cation. + For example, Na + or K + It could be.

[0048] As used herein, the term phosphonate ester refers to esters of the formula: -P(=O)(OR) and -P(=O)(OR)O - wherein each R independently represents a phosphonate ester substituent, e.g., —H, substituted or unsubstituted C 1~20 Alkyl, substituted or unsubstituted C 3~20 Heterocyclyl, further C 3~20 Heterocyclyl-substituted C 3~20 Heterocyclyl, substituted or unsubstituted C 1~20 Alkylene-C 3~20 Heterocyclyl, substituted or unsubstituted C 3~25 Cycloalkyl, substituted or unsubstituted C 1~20 Alkylene-C 3~25 Cycloalkyl, aryl, substituted or unsubstituted C 1~20 Examples of phosphonate ester groups include, but are not limited to, -P(=O)(OCH), -P(=O)(OCHCH), -P(=O)(Ot-Bu), and -P(=O)(OPh).

[0049] As used herein, the term phosphate represents a group of formula: —OP(═O)(OH) 2 .

[0050] As used herein, the term phosphate ester refers to esters of the formula: -OP(=O)(OR) and -OP(=O)(OR)O - wherein each R independently represents a phosphate ester substituent, e.g., —H, substituted or unsubstituted C 1~20 Alkyl, substituted or unsubstituted C3~20 Heterocyclyl, further C 3~20 Heterocyclyl-substituted C 3~20 Heterocyclyl, substituted or unsubstituted C 1~20 Alkylene-C 3~20 Heterocyclyl, substituted or unsubstituted C 3~25 Cycloalkyl, substituted or unsubstituted C 1~20 Alkylene-C 3~25 Cycloalkyl, aryl, substituted or unsubstituted C 1~20 Examples of phosphate ester groups include, but are not limited to, -OP(=O)(OCH3)2, -OP(=O)(OCH2CH3)2, -OP(=O)(Ot-Bu)2, and -OP(=O)(OPh)2.

[0051] As used herein, the term amino refers to a group of formula -NH2. 10 The term alkylamino denotes a group of formula -NHR', where R' is a C as defined above. 1~10 Alkyl groups, preferably C 1~6 It is an alkyl group. 1~10 The term alkylamino denotes a group of formula -NR'R'', where R' and R'' are the same or different and are C as defined above. 1~10 Alkyl groups, preferably C 1~6 The term arylamino denotes a group of formula -NHR', where R' is an aryl group as defined above, preferably a phenyl group. The term diarylamino denotes a group of formula -NR'R'', where R' and R'' are the same or different and represent an aryl group as defined above, preferably a phenyl group. The term arylalkylamino denotes a group of formula -NR'R'', where R' is C 1~10 Alkyl groups, preferably C 1~6 is an alkyl group, and R'' is an aryl group, preferably a phenyl group.

[0052] As used herein, the term amide refers to a group of the formula: —C(═O)NR′R″, where R′ and R″ are independently di(C1~10 ) an amino substituent as defined for alkylamino groups. Examples of amido groups include, but are not limited to, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -C(=O)NHCHCH, and -C(=O)N(CHCH), as well as amido groups where R' and R'', together with the nitrogen atom to which they are attached, form a heterocyclic structure such as, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.

[0053] As used herein, the term acylamido refers to a group of the formula: -NR 1 C(=O)R 2 (In the formula, R 1 is an amide substituent, e.g., hydrogen, C 1~20 Alkyl group, C 3~20 Heterocyclyl groups, aryl groups, preferably hydrogen or C 1~20 is an alkyl group, and R 2 is an acyl substituent, e.g., C 1~20 Alkyl group, C 3~20 Heterocyclyl or aryl groups, preferably hydrogen or C 1~20 Examples of acylamide groups include -NHC(=O)CH3, -NHC(=O)CH2CH3, -NHC(=O)Ph, -NHC(=O)C 15 H 31 and -NHC(=O)CH 19 These include, but are not limited to, the substitution C 1~20 The alkyl group is -NHC(=O)C 15 H 31 or -NHC(=O)CH 19 and the formula -NHC(=O)-C 1~20 R may contain acylamide substituents defined as alkyl. 1 and R 2 may together form a cyclic structure, for example, in succinimidyl, maleimidyl, phthalimidyl, etc.: [ka]

[0054] C 1~10 The alkylthio group is the C bonded to the thio group. 1~10 Alkyl groups, preferably C 1~6 An arylthio group is an aryl group, preferably a phenyl group, attached to a thio group.

[0055] C 1~20 The alkoxy group is a substituted or unsubstituted C 1~20 It is an alkyl group. 1~6 The alkoxy group is a substituted or unsubstituted C 1~6 It is an alkyl group. 1~4 An alkoxy group is a substituted or unsubstituted C bonded to an oxygen atom. 1~4 It is an alkyl group. 1~20 Alkoxy groups include C 1~20 Contains perfluoroalkoxy groups. 1~20 The perfluoroalkoxy group is a C bonded to an oxygen atom. 1~20 It is a perfluoroalkyl group. 1~20 An example of a perfluoroalkoxy group is the tert-nonafluorobutyloxy group, —OC(CF 3 ) 3 .

[0056] An aryloxy group is a substituted or unsubstituted aryl group, as defined herein, attached to an oxygen atom. It can be, for example, unsubstituted or substituted phenoxy. An example of an aryloxy group is -OPh (phenoxy).

[0057] The term "amino acid" as used herein in connection with any of the compounds described herein refers to an amino acid residue. An amino acid residue is typically bound to the atom in the compound described herein to which it is said to be bound via its C-terminus or its N-terminus. For example, as will be understood by those skilled in the art, when an amino acid is said to be bound to the carbon atom of a carbonyl group in a compound described herein, the N-terminal nitrogen atom of the amino acid is typically bound to that carbon atom. Similarly, when an amino acid is said to be bound to the nitrogen atom of an amine group in a compound described herein, the C-terminal carbon atom of the amino acid will generally be bound to that nitrogen atom. Alternatively, the C-terminal carbon atom of the amino acid can be bound to an oxygen atom in a compound described herein. An amino acid in any of the compounds described herein can be, for example, an amino acid residue selected from arginine (Arg), histidine (His), lysine (Lys), aspartic acid (Asp), glutamic acid (Glu), serine (Ser), threonine (Thr), asparagine (Asn), glutamine (Gln), cysteine ​​(Cys), selenocysteine ​​(Sec), glycine (Gly), proline (Pro), alanine (Ala), valine (Val), isoleucine (Ile), leucine (Leu), methionine (Met), phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp).

[0058] The term azine, as used herein, refers to a heterocyclic compound containing a six-membered aromatic ring in which one or more of the ring carbon atoms is replaced by a nitrogen atom. For example, pyridine is an azine, as is pyridazine.

[0059] Unless otherwise specified, known ionic, salt, solvate, and protected forms of these substituents are included above. For example, a reference to a carboxylic acid or carboxyl group (-COOH) also includes the anionic (carboxylate) form (-COO - ), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group also includes the protonated form (—N + HR1 R 2 ), salts or solvates of an amino group, for example, hydrochloride salts, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (—O - ), a salt or solvate thereof, and conventional protected forms thereof.

[0060] It is to be understood that the compounds of the present invention may exist in different tautomeric forms, and that the present invention encompasses all such tautomeric forms.

[0061] In some of the compounds of the present invention, depending on the nature of the substituents, chiral carbon atoms may be present and the compounds may therefore exist as stereoisomers. The present invention extends to all optical isomers, such as stereoisomeric forms of the compounds of the present invention, including enantiomers, diastereomers, and mixtures thereof, such as racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional stereoselective or stereospecific synthesis.

[0062] It should also be understood that any atom present in the compounds of the present invention may be present in any available natural isotopic form. For example, a carbon atom may be 12 C or 13 C. The hydrogen atom can be 1 H or 2 It can be H (deuterium).

[0063] As used herein, the terms "treat," "treating," and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow (alleviate) unwanted physiological changes or disorders, such as the onset or spread of disease. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in whom the condition or disorder is to be prevented.

[0064] The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or with the patient being treated therewith.

[0065] Compounds of the Invention The present invention relates to a series of novel compounds and their use as hypoxia-inducible factor prolyl hydroxylase domain inhibitors (PHD inhibitors). The compounds therefore have potential utility in treating conditions in which HIF-PHD is a therapeutic target, including, for example, anemia and other ischemia-related diseases, as well as additional conditions described below.

[0066] Accordingly, the present invention provides compounds that are substituted azines of formula (I) or pharmaceutically acceptable salts thereof: [ka]

[0067] In the above formula (I), X is C(R 6 ) or N. Preferably, X is C(R 6 ), i.e., preferably, X is R 6 (in which case the substituted azine is a substituted pyridine). However, more often X is N (in which case the substituted azine is a substituted pyridazine).

[0068] R 0 is H or unsubstituted or substituted C 1~6 Typically, R 0 is H or unsubstituted C 1~6 It is usually an alkyl group. 0 is selected from H, methyl and ethyl. Often, R 0 is H or methyl.

[0069] R 1 is H, unsubstituted or substituted C 1~6Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v , -C(O)OR w or -C(O)N(R x )R 7 is.

[0070] Typically, R 1 is -C(O)N(R x )R 7 This is R 5 -C(O)N(R x )R 7 This is particularly typical when the 1 -C(O)N(R x )R 7 That is, R 5 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v or -C(O)OR w This is particularly typical when

[0071] R 1 is also typically H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v , or -C(O)OR w This can be R 5 -C(O)N(R x )R 7 This is particularly typical when, for example, R 1 is H, unsubstituted or substituted C 1~6 Alkyl, -CN or -C(O)OR w and preferably H, —CN or —C(O)OR w This is R 5 -C(O)N(R x)R 7 This is often the case.

[0072] Therefore, R 1 is H, unsubstituted or substituted C 1~6 Alkyl, -CN, -C(O)OR w and -C(O)N(R x )R 7 R 1 is, for example, H, -CN, -C(O)OR w and -C(O)N(R x )R 7 R 1 is, for example, H, unsubstituted or substituted C 1~6 Alkyl, -CN and -C(O)OR w or, for example, H, —CN and —C(O)OR w may be selected from:

[0073] R 2 H, -OR q or unsubstituted or substituted C 1~6 alkyl; or R 2 is -N = , in this case R 3 is =C(R y )- and R 2 and R 3 are taken together to form the equation -N=C(R y )- group.

[0074] R 2 For example, H, -OR q or unsubstituted or substituted C 1~6 Typically, in that case, R 2 is H or unsubstituted or substituted C 1~6 alkyl. For example, R 2 is H or unsubstituted C 1~6 It may be alkyl, for example, R 2 can be H, ethyl or methyl. 2 can be, for example, H or methyl.

[0075] R 3 H, -OR8 or unsubstituted or substituted C 1~6 alkyl; or R 3 is =C(R y )-, in this case, R 2 where -N = R 2 and R 3 are taken together to form the equation -N=C(R y )- group.

[0076] R 3 For example, H, -OR 8 or unsubstituted or substituted C 1~6 Typically, in that case, R 3 is H or -OR 8 R 3 is also typically H or unsubstituted or substituted C 1~6 However, R 3 is often -OR 8 is.

[0077] In some embodiments, R 2 where -N = R 3 is =C(R y )- and R 2 and R 3 are taken together to form the equation -N=C(R y )- group.

[0078] R 4 is H, unsubstituted or substituted C 1~6 Alkyl, -OR 9 or -C(O)OR 10 R 4 is, for example, H, unsubstituted C 1~6 Alkyl, -OR 9 or -C(O)OR 10 However, in many cases, R 4 H, -OR 9 or -C(O)OR 10 Typically, R 4 HA-OR 9 and -C(O)OR 10 or R4 HA-OR 9 Or, R 4 is H or unsubstituted or substituted C 1~6 alkyl, for example, R 4 can be H. However, in many cases, R 4 is C(O)OH or OH. 4 is often, for example, OH.

[0079] R 5 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v , -C(O)OR w or -C(O)N(R x )R 7 is.

[0080] R 5 is typically H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v or -C(O)OR w This is R 1 -C(O)N(R x )R 7 This is particularly typical when, for example, R 5 is H, unsubstituted or substituted C 1~6 Alkyl, -CN or -C(O)OR w and preferably H, —CN or —C(O)OR w This is R 1 -C(O)N(R x )R 7 This is often the case.

[0081] R 5 is also typically represented by -C(O)N(R x )R 7 This can be R1 -C(O)N(R x )R 7 This is particularly typical when the 5 -C(O)N(R x )R 7 That is, R 1 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v or -C(O)OR w This is particularly typical when

[0082] Typically, R 5 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -C(O)OR w , or -C(O)N(R x )R 7 In many cases, R 5 is H, unsubstituted or substituted C 1~6 Alkyl, -CN, -C(O)OR w and -C(O)N(R x )R 7 Selected from: R 5 is, for example, H, -CN, -C(O)OR w and -C(O)N(R x )R 7 R 5 is, for example, H, unsubstituted or substituted C 1~6 Alkyl, -CN and -C(O)OR w or, for example, H, —CN and —C(O)OR w R 5 For example, -C(O)OR w In many cases, R 5 is —C(O)OH.

[0083] R 6 is H or unsubstituted or substituted C 1~6 It is usually an alkyl group.6 is H or unsubstituted C 1~6 Typically, R 6 is H.

[0084] R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11 )-Cyc, -CH2C≡CCH3, -Cyc or -Ar. R 7 For example, -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar or -CH(R 11 )-Cyc.

[0085] Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl. For example, Ar can be unsubstituted or substituted aryl or unsubstituted heteroaryl. For example, Ar can be unsubstituted or substituted phenyl or unsubstituted heteroaryl. Ar can be, for example, selected from unsubstituted phenyl, unsubstituted pyrimidyl, unsubstituted benzothiazole, and phenyl substituted with -C(O)OH, -C(O)OMe, -C(O)OEt, -C(O)NH, -C(O)N(H)Me, -OMe, or N-morpholino.

[0086] Ary is unsubstituted or substituted arylene, or unsubstituted or substituted heteroarylene. Ary can be, for example, unsubstituted arylene or unsubstituted heteroarylene. Typically, Ary is unsubstituted phenylene or unsubstituted pyridylene.

[0087] Cyc is unsubstituted or substituted C 3~10 Cyc is cycloalkyl. Typically, Cyc is unsubstituted or substituted cyclohexyl. For example, Cyc can be unsubstituted cyclohexyl or cyclohexyl substituted with -CF3 or -OCF3.

[0088] R 11 -H, -C(O)OR zor unsubstituted or substituted C 1~4 R is alkyl. 11 is, for example, H, -C(O)OR z or unsubstituted C 1~4 It can be alkyl. Usually, R 11 -H, -C(O)OR z Or methyl.

[0089] R 8 , R 9 and R 10 are each independently H and unsubstituted or substituted C 1~6 alkyl.

[0090] Therefore, R 8 is H or unsubstituted or substituted C 1~6 Typically, R 8 is H.

[0091] R 9 is also H or unsubstituted or substituted C 1~6 alkyl. Typically, R 9 is H.

[0092] R 10 is also H or unsubstituted or substituted C 1~6 alkyl. Typically, R 10 is H.

[0093] Usually, R 8 , R 9 and R 10 may be the same or different and each independently represent H, unsubstituted C 1~6 Alkyl, and phenyl or -OC(O)R 99 C replaced with 1~6 R is selected from alkyl. 99 is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid. a , Rb , R c and R d are each independently H, unsubstituted or substituted C 1~6 It is selected from alkyl and amino acids.

[0094] Therefore, in many cases, R 8 H, unsubstituted C 1~6 Alkyl, and phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above.

[0095] Typically, R 9 H, unsubstituted C 1~6 Alkyl, and phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above.

[0096] In many cases, R 10 H, unsubstituted C 1~6 Alkyl, and phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above.

[0097] R 8 , R 9 or R 10 Structures of formula (I) where R is other than H include prodrug compounds. 8 , R 9 or R 10 is unsubstituted or substituted C 1~6 Alkyl, especially substituted C 1~6 Substituted azines of formula (I) that are alkyl include prodrug compounds. For example, R 8 , R 9 or R 10 is phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, and R 99Substituted azines of formula (I), where R is defined above, include prodrug compounds. 8 , R 9 , or R 10 For example, the substitution C 1~6 alkyl, where C 1~6 The or one of the substituents on the alkyl is of the formula -OC(O)R 99 is a group of R 99 is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 Such compounds include prodrugs. Thus, in many cases, R 8 is -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above. Similarly, R 9 is -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above. R 10 is -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above.

[0098] Typically, R a , R b , R c and R d are each independently H or unsubstituted or substituted C 1~6 alkyl. Usually, R a , R b , R c and R d are each independently selected from H, methyl, or ethyl.

[0099] R t , R u , R v , R w , R x , R y , and R z are each independently H, unsubstituted or substituted C 1~6 It is selected from alkyl, and unsubstituted or substituted phenyl.

[0100] Usually, R t is unsubstituted or substituted C 1~4 alkyl, or H. Typically, R t is the unsubstituted C 1~4 alkyl or H. Usually, R t is H.

[0101] Usually, R u is unsubstituted or substituted C 1~4 alkyl, or H. Typically, R u is the unsubstituted C 1~4 alkyl or H. Usually, R u is H.

[0102] Usually, R v is unsubstituted or substituted C 1~4 alkyl, or H. Typically, R v is the unsubstituted C 1~4 alkyl or H. Usually, R v is H.

[0103] Therefore, in many cases, R t , R u and R v are all H.

[0104] Usually, R x is H.

[0105] Typically, R y is H or unsubstituted C 1~6 alkyl, e.g., R y can be H or methyl.

[0106] Typically, R z is H.

[0107] R w is H, unsubstituted or substituted C 1~6 alkyl, or unsubstituted or substituted phenyl. R w is H or unsubstituted or substituted C 1~6 Typically, for example, R w H, unsubstituted C 1~6 Alkyl, or phenyl or -OC(O)R ww C replaced with 1~6 alkyl, where R ww is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 It is selected from alkyl and amino acids.

[0108] R w Substituted azines of formula (I) where R is other than H include prodrug compounds. w is unsubstituted or substituted C 1~6 Compounds of formula (I) that are alkyl, or unsubstituted or substituted phenyl include prodrug compounds. For example, R w C substituted with phenyl 1~6 Alkyl or -OC(O)R ww and R ww Compounds of formula (I) where R is as defined above include prodrug compounds. w For example, the substitution C 1~6 alkyl, where C 1~6 The or one of the substituents on the alkyl is of the formula -OC(O)R ww is a group of R wwis phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 Such compounds include prodrugs. Thus, in many cases, R w is -OC(O)R ww C replaced with 1~6 alkyl, where R ww is as defined above. Typically, R a , R b , R c and R d are each independently H or unsubstituted or substituted C 1~6 alkyl. Usually, R a , R b , R c and R d are each independently selected from H, methyl, or ethyl. w H, unsubstituted C 1~6 Alkyl, or phenyl or -OC(O)R ww C replaced with 1~6 alkyl, where R ww is phenyl or unsubstituted C 1~6 It is alkyl.

[0109] R w can be H.

[0110] R q is H, unsubstituted or substituted C 1~6 alkyl, or unsubstituted or substituted phenyl. R q is typically H.

[0111] Typically, in formula (I), R 1 and R 5One of them is -C(O)N(R x )R 7 and R 1 and R 5 The other is -C(O)N(R x )R 7 Other than. R 1 and R 5 One of the groups is -C(O)N(R x )R 7 If other than R, it is 1 or R 5 It can be any of the other definitions for H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v , or -C(O)OR w It can be either of the following.

[0112] In many cases, in formula (I), R 1 and R 5 One of them is -C(O)N(R x )R 7 and R 1 and R 5 The other is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v or -C(O)OR w Typically, R 1 and R 5 One of them is -C(O)N(R x )R 7 and R 1 and R 5 The other is H, unsubstituted or substituted C 1~6 Alkyl, -CN or -C(O)OR w For example, R 1 and R 5 One of them is -C(O)N(R x )R 7 R 1 and R5 The other is H, -CN or -C(O)OR w It could be.

[0113] In some embodiments of the substituted azines of formula (I): R 0 is H or unsubstituted C 1~6 is alkyl; R 1 -H, -CN, -C(O)OR w or -C(O)N(R x )R 7 and; R 2 is H or unsubstituted C 1~6 alkyl; R 3 is H or -OR 8 or R 2 where -N = R 3 is =C(R y )- and R 2 and R 3 together give the equation -N=C(R y In such embodiments, R 4 H, -OR 9 or -C(O)OR 10 R 5 -H, -CN, -C(O)OR w , or -C(O)N(R x )R 7 R 6 is H. Furthermore, R 7 is typically -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar or -CH(R 11 )-Cyc, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted arylene or unsubstituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted C 1~4 It is alkyl.

[0114] Typically, in such embodiments, R 8 , R 9 and R 10 are each independently H and unsubstituted or substituted C 1~6 alkyl. Typically, R x is H and R z is H and R y is H or unsubstituted C 1~6 alkyl, and R w is H, unsubstituted C 1~6 Alkyl, or phenyl or -OC(O)R ww C replaced with 1~6 alkyl, and R ww is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 alkyl and amino acids. Typically, R a , R b , R c and R d are each independently H or unsubstituted or substituted C 1~6 alkyl. Usually, R a , R b , R c and R d are each independently selected from H, methyl, or ethyl.

[0115] Typically, R 1 and R 5 One of them is -C(O)N(R x )R 7 and R 1 and R 5 The other is H, -CN or -C(O)OR w A compound is provided wherein:

[0116] Therefore, typically, R 0is H or unsubstituted C 1~6 alkyl; R 1 -H, -CN, -C(O)OR w or -C(O)N(R x )R 7 and;R 2 is H or unsubstituted C 1~6 alkyl; R 3 is H or -OR 8 or R 2 where -N = R 3 is =C(R y )- and R 2 and R 3 together give the equation -N=C(R y )- group; R 4 H, -OR 9 or -C(O)OR 10 and;R 5 -H, -CN, -C(O)OR w or -C(O)N(R x )R 7 and;R 6 is H;R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar or -CH(R 11 )-Cyc, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted arylene or unsubstituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted C 1~4 alkyl; R 8 , R 9 and R 10 are each independently H and unsubstituted or substituted C 1~6 alkyl; R x is H and R z is H and R y is H or unsubstituted C 1~6 alkyl, and R w is H, unsubstituted C 1~6 Alkyl, or phenyl or -OC(O)Rww C replaced with 1~6 alkyl, and R ww is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 alkyl and amino acids; 1 and R 5 One of them is -C(O)N(R x )R 7 and R 1 and R 5 The other is H, -CN or -C(O)OR w is.

[0117] In some embodiments of the substituted azines of formula (I), R 0 is H or methyl; R 1 -H, -CN, -C(O)OR w or -C(O)N(R x )R 7 and;R 2 is H or methyl; R 3 is H or -OR 8 or R 2 where -N = R 3 is =C(R y )- and R 2 and R 3 together give the equation -N=C(R y )- group.

[0118] Typically, in such compounds, R 4 H, -OR 9 or -C(O)OR 10 and;R 5 -H, -CN, -C(O)OR w , or -C(O)N(R x )R 7 and;R 6is H;R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar or -CH(R 11 )-Cyc; where Ar is unsubstituted phenyl, unsubstituted pyrimidyl, unsubstituted benzothiazole, or phenyl substituted with —C(O)OH, —C(O)OMe, —C(O)OEt, —C(O)NH2, —C(O)N(H)Me, —OMe, or N-morpholino; Ary is unsubstituted phenylene or unsubstituted pyridylene; Cyc is unsubstituted cyclohexyl, or cyclohexyl substituted with —CF3 or —OCF3; R 11 -H, -C(O)OR z Or methyl.

[0119] Usually, R 8 , R 9 and R 10 are each independently H, unsubstituted C 1~6 Alkyl, and phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 alkyl and amino acids. Typically, R a , R b , R c and R d are each independently H and unsubstituted or substituted C 1~6 alkyl. Usually, R a , R b , R c and R d are each independently selected from H, methyl, or ethyl.

[0120] Usually, R x is H;R z is H;R w H, unsubstituted C 1~6 Alkyl, or phenyl or -OC(O)R ww C replaced with 1~6 alkyl, where R ww is phenyl or unsubstituted C 1~6 alkyl; R y is H or methyl.

[0121] For such compounds of the invention, R 1 and R 5 One of them is -C(O)N(R x )R 7 and R 1 and R 5 The other is H, -CN or -C(O)OR w is.

[0122] Therefore, typically, R 0 is H or methyl; R 1 -H, -CN, -C(O)OR w or -C(O)N(R x )R 7 and;R 2 is H or methyl; R 3 is H or -OR 8 or R 2 where -N = R 3 is =C(R y )- and R 2 and R 3 together give the equation -N=C(R y )- group; R 4 H, -OR 9 or -C(O)OR 10 and;R 5 -H, -CN, -C(O)OR w or -C(O)N(R x )R 7 and;R 6 is H;R 7 is -CH(R 11 )-Ar, -CH(R11 )-Ary-Ar, -Ary-Ar or -CH(R 11 )-Cyc; where Ar is unsubstituted phenyl, unsubstituted pyrimidyl, unsubstituted benzothiazole, or phenyl substituted with —C(O)OH, —C(O)OMe, —C(O)OEt, —C(O)NH2, —C(O)N(H)Me, —OMe, or N-morpholino; Ary is unsubstituted phenylene or unsubstituted pyridylene; Cyc is unsubstituted cyclohexyl, or cyclohexyl substituted with —CF3 or —OCF3; R 11 -H, -C(O)OR z or methyl; R 8 , R 9 and R 10 are each independently H, unsubstituted C 1~6 Alkyl, and phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 R is selected from alkyl and amino acids; x is H;R z is H;R w H, unsubstituted C 1~6 Alkyl, or phenyl or -OC(O)R ww C replaced with 1~6 alkyl, where R ww is phenyl or unsubstituted C 1~6 alkyl; R y is H or methyl; provided that R 1 and R 5 One of them is -C(O)N(R x )R 7 and R 1 and R 5The other is H, -CN or -C(O)OR w is.

[0123] In many cases, in the substituted azines of formula (I), (a) R 5 is -C(O)N(R x )R 7 and (b) R 3 HA-OR 8 or R 4 HA-OR 9 R x , R 7 , R 8 and R 9 In these embodiments, may be as defined anywhere herein for compounds of the invention.

[0124] In another exemplary case, in the substituted azine of formula (I), (a) R 1 is -C(O)N(R x )R 7 and (b) R 4 HA-OR 9 or -C(O)OR 10 or R 5 -C(O)OR w R x , R 7 , R 8 and R 9 In these embodiments, may be as defined anywhere herein for compounds of the invention.

[0125] Thus, typically in a substituted azine of formula (I): (1)(a)R 5 is -C(O)N(R x )R 7 and (b) R 3 HA-OR 8 or R 4 HA-OR 9 or (2)(a)R 1 is -C(O)N(R x )R 7 and (b) R 4 HA-OR9 or -C(O)OR 10 or R 5 -C(O)OR w is.

[0126] R x , R 7 , R 8 and R 9 may be as further defined herein. In some embodiments, for example, R x is H and R 8 is H and R 9 is H and R 7 is as defined elsewhere herein. For example, R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar or -CH(R 11 )-Cyc, where Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted arylene or unsubstituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted C 1~4 R is alkyl. z can be as defined anywhere herein, but is often H. R 7 For example, -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar or -CH(R 11 )-Cyc; where Ar is unsubstituted phenyl, unsubstituted pyrimidyl, unsubstituted benzothiazole, or phenyl substituted with —C(O)OH, —C(O)OMe, —C(O)OEt, —C(O)NH2, —C(O)N(H)Me, —OMe, or N-morpholino; Ary is unsubstituted phenylene or unsubstituted pyridylene; Cyc is unsubstituted cyclohexyl or cyclohexyl substituted with —CF3 or —OCF3; R 11 -H, -C(O)OR zor methyl. z can be as defined anywhere herein, but is often H.

[0127] In the compounds of the invention, the substituted azine may have the formula (Ia) shown below. Thus, in some embodiments, the invention relates to compounds that are substituted azines of formula (Ia) or pharmaceutically acceptable salts thereof: [ka]

[0128] R in formula (Ia) 0 , R 9 , X, R x and R 7 Each of R in Formula (Ia) can be as defined anywhere herein for Formula (I). 1 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v , or -C(O)OR w where R t , R u , R v and R w may be as defined anywhere herein for formula (I). R in formula (Ia) 2 H, -OR q or unsubstituted or substituted C 1~6 alkyl, where R q is H, unsubstituted or substituted C 1~6 R in formula (Ia) is alkyl or unsubstituted or substituted phenyl. 3 is H or unsubstituted or substituted C 1~6 It is alkyl.

[0129] Thus, when the substituted azine compounds of the invention have the formula (Ia), typically X is C(R 6 ) or N. Preferably, X is C(R6 ) Alternatively, however, X may be N.

[0130] Typically, R 0 is H or unsubstituted or substituted C 1~6 However, R in formula (Ia) is alkyl. 0 may be as further defined elsewhere herein for formula (I).

[0131] R 1 is usually H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN or -C(O)OR w However, R in formula (Ia) 1 may be as further defined elsewhere herein for formula (I).

[0132] R 2 H, -OR q or unsubstituted or substituted C 1~6 alkyl, and R 3 is H or unsubstituted or substituted C 1~6 However, R in formula (Ia) is alkyl. 2 and R 3 may be as further defined elsewhere herein for formula (I).

[0133] Typically, R 6 is H or unsubstituted or substituted C 1~6 However, R in formula (Ia) is alkyl. 6 may be as further defined elsewhere herein for formula (I).

[0134] R 7 is usually -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11)-Cyc, -CH2C≡CCH3, -Cyc or -Ar, where Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 is typically H, -C(O)OR z or unsubstituted or substituted C 1~4 However, R in formula (Ia) is alkyl. 7 and R 11 may be as further defined elsewhere herein for formula (I).

[0135] In embodiments where the substituted azine has formula (Ia), R 9 is typically H or unsubstituted or substituted C 1~6 R is alkyl. w , R x and R z are each independently H, unsubstituted or substituted C 1~4 R may be selected from alkyl, and unsubstituted or substituted phenyl. q is typically H, unsubstituted or substituted C 1~6 However, R in formula (Ia) is an alkyl, or an unsubstituted or substituted phenyl. 9 , R w , R x , R z and R q may be as further defined elsewhere herein for formula (I).

[0136] In some preferred embodiments, the substituted azine has the formula (Ia), R 9 is H.

[0137] The compound of the invention can be a substituted azine of formula (Ia) selected from any one of the following structures, or a pharmaceutically acceptable salt thereof: [ka] [ka] [ka] [ka]

[0138] The numbers in parentheses next to the above structures correspond to the compound numbers shown in the Examples section below.

[0139] In the compounds of the present invention, the substituted azine may have the formula (Ib) shown below: Thus, in some embodiments, the present invention relates to compounds that are substituted azines of formula (Ib) or pharmaceutically acceptable salts thereof: [ka]

[0140] R in formula (Ib) 0 , R 4 , R 6 , R 7 , R 8 and R x Each of R in formula (Ib) can be as defined anywhere herein for formula (I). 1 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v , or -C(O)OR w where R t , R u , R v and R w may be as defined anywhere herein for formula (I). 2 H, -OR q or unsubstituted or substituted C 1~6alkyl, where R q is H, unsubstituted or substituted C 1~6 It is alkyl or unsubstituted or substituted phenyl.

[0141] Thus, when the substituted azine of the compound of the invention has the formula (Ib), typically R 0 is H or unsubstituted or substituted C 1~6 However, R in formula (Ib) is alkyl. 0 may be as further defined elsewhere herein for formula (I).

[0142] R 1 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN or -C(O)OR w However, R in formula (Ib) can be 1 may be as further defined elsewhere herein for formula (I).

[0143] Usually, R 2 H, -OR q or unsubstituted or substituted C 1~6 However, R in formula (Ib) is alkyl. 2 may be as further defined elsewhere herein for formula (I).

[0144] Typically, R in formula (Ib) 4 is H or unsubstituted or substituted C 1~6 R is alkyl. 6 is H or unsubstituted or substituted C 1~6 For example, R 4 is H or unsubstituted C 1~6 It can be alkyl and is often H. R in formula (Ib) 4 may be as further defined elsewhere herein for formula (I).

[0145] Typically, R 6is H or unsubstituted or substituted C 1~6 alkyl. For example, R 6 is H or unsubstituted C 1~6 It can be alkyl and is often H. R in formula (Ib) 6 may be as further defined elsewhere herein for formula (I).

[0146] Typically, R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11 )-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 However, R in formula (Ib) is alkyl. 7 and R 11 may be as further defined elsewhere herein for formula (I).

[0147] Typically, for a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, R 8 is H or unsubstituted or substituted C 1~6 However, R in formula (Ib) is alkyl. 8 may be as further defined elsewhere herein for formula (I).

[0148] Usually, R w , R x and R z are each independently H, unsubstituted or substituted C 1~4 R is selected from alkyl, and unsubstituted or substituted phenyl. q is typically H, unsubstituted or substituted C 1~6alkyl, or unsubstituted or substituted phenyl. R q is often, for example, H. However, R in formula (Ib) w , R x , R z and R q may be as further defined elsewhere herein for formula (I).

[0149] In some preferred substituted azines of formula (Ib), R 8 is H.

[0150] The compound of the invention can be a substituted azine of formula (Ib) selected from any one of the following structures, or a pharmaceutically acceptable salt thereof: [ka]

[0151] The numbers in parentheses next to the above structures correspond to the compound numbers shown in the Examples section below.

[0152] In the compounds of the invention, the substituted azine may have the formula (Ic) shown below. Thus, in some embodiments, the invention relates to compounds that are substituted azines of formula (Ic) or pharmaceutically acceptable salts thereof: [ka]

[0153] R in formula (Ic) 0 , R 4 , R 6 , R x and R 7 Each of R in formula (Ic) can be as defined anywhere herein for formula (I). 5 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )Rv , or -C(O)OR w where R t , R u , R v and R w may be as defined anywhere herein for formula (I). 2 H, -OR q or unsubstituted or substituted C 1~6 alkyl, where R q is H, unsubstituted or substituted C 1~6 R in formula (Ic) is alkyl or unsubstituted or substituted phenyl. 3 H, -OR 8 or unsubstituted or substituted C 1~6 alkyl, and R 8 is H and unsubstituted or substituted C 1~6 alkyl.

[0154] Thus, when the substituted azine of the compound of the invention has the formula (Ic), typically R 0 is H or unsubstituted or substituted C 1~6 However, R in formula (Ic) is alkyl. 0 may be as further defined elsewhere herein for formula (I). Typically, R 2 H, -OR q or unsubstituted or substituted C 1~6 However, R in formula (Ic) is alkyl. 2 R may be as further defined elsewhere herein for formula (I). 3 H, -OR 8 or unsubstituted or substituted C 1~6 However, R in formula (Ic) may be alkyl. 3 is R 8 and may be as further defined elsewhere herein for formula (I). R in formula (Ic) 3 is often H or -OR 8 R 8 For example, unsubstituted C 1~6 It can be alkyl.

[0155] For substituted azines of formula (Ic), typically R 4 is H, unsubstituted or substituted C 1~6 Alkyl, -OR 9 or -C(O)OR 10 where R 9 and R 10 is as defined elsewhere herein for formula (I). However, R in formula (Ic) 4 R may be as further defined elsewhere herein for formula (I). 4 For example, H, -OR 9 or -C(O)OR 10 R 4 may be selected from, for example, H, —OH and —C(O)OH.

[0156] R in formula (Ic) 5 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN or -C(O)OR w However, R in formula (Ic) can be 5 is R w as well as as further defined elsewhere herein for formula (I).

[0157] Typically, R 6 is H or unsubstituted or substituted C 1~6 However, R in formula (Ic) is alkyl. 6 may be as further defined elsewhere herein for formula (I).

[0158] R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11)-Cyc, -Cyc, or -Ar, where Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 However, R in formula (Ic) is alkyl. 7 and R 11 may be as further defined elsewhere herein for formula (I).

[0159] In embodiments where the substituted azine has the formula (Ic), R 8 , R 9 and R 10 are each independently H and unsubstituted or substituted C 1~6 However, R in formula (Ic) is selected from alkyl. 8 , R 9 and R 10 may each be as further defined elsewhere herein for formula (I).

[0160] R w , R x and R z are typically each independently H, unsubstituted or substituted C 1~4 However, R in formula (Ic) is selected from alkyl, and unsubstituted or substituted phenyl. w , R x and R z may each be as further defined elsewhere herein for formula (I).

[0161] R q is H, unsubstituted or substituted C 1~6 However, R in formula (Ic) may be alkyl, or unsubstituted or substituted phenyl. q may be as further defined elsewhere herein for formula (I).

[0162] Often, in the substituted azine of formula (Ic), R 4 is OH or C(O)OH. For example, in the substituted azine of formula (Ic), R 4 is OH or C(O)OH, and R 5 is often H. For example, R 4 can be OH, R 5 can be H. Also typically, R 4 is C(O)OH and R 5 is H. Also, typically, R 4 is OH or C(O)OH, and R 5 is a CN. For example, R 4 can be OH, R 5 can be CN.

[0163] In the substituted azine of formula (Ic), R 5 is often C(O)OH. For example, in the substituted azine of formula (Ic), R 5 is C(O)OH and R 4 is often H. Also, typically, R 5 is C(O)OH and R 4 is OH.

[0164] Thus, in some preferred embodiments of the substituted azine of formula (Ic): (i) R 4 is OH or C(O)OH, and / or (ii) R 5 is C(O)OH.

[0165] Indeed, preferably, in the substituted azine of formula (Ic): (a) R 4 is OH; or (b) R 4 is C(O)OH; or (c) R 5 is C(O)OH; or (d) R 4 is OH and R 5 is C(O)OH.

[0166] The compound of the invention can be a substituted azine of formula (Ic) selected from any one of the following structures, or a pharmaceutically acceptable salt thereof: [ka] [ka] [ka]

[0167] The numbers in parentheses next to the above structures correspond to the compound numbers shown in the Examples section below.

[0168] In the compounds of the invention, the substituted azine may have the formula (Id) shown below. Thus, in some embodiments, the invention relates to compounds that are substituted azines of formula (Id) or pharmaceutically acceptable salts thereof: [ka]

[0169] R in formula (Id) 0 , R 1 , R 6 , R 9 , R y , R x and R 7 may be as defined anywhere herein for formula (I). However, R in formula (Id) 1 is usually H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v , or -C(O)OR w where R t , R u , R v and R wmay be as defined anywhere herein for formula (I).

[0170] Thus, when the substituted azine of the compound of the invention has the formula (Id), typically R 0 is H or unsubstituted or substituted C 1~6 However, R in formula (Id) is alkyl. 0 may be as further defined elsewhere herein for formula (I). R in formula (Id) 0 is often H or methyl. Typically, it is methyl.

[0171] R in formula (Id) 1 is typically H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN or -C(O)OR w However, R in formula (Id) 1 may be as further defined elsewhere herein for formula (I). R in formula (Id) 1 is preferably H.

[0172] R in formula (Id) w is H, unsubstituted or substituted C 1~4 However, R in formula (Id) is selected from alkyl, and unsubstituted or substituted phenyl. w may be as further defined elsewhere herein for formula (I).

[0173] R y is typically H, unsubstituted or substituted C 1~4 R in formula (Id) is selected from alkyl, and unsubstituted or substituted phenyl. y may be as further defined elsewhere herein for formula (I). However, in many cases, R in formula (Id) y is H or methyl.

[0174] In many cases, in formula (Id), Ry and R 0 are all methyl. y and R 0 can both be H.

[0175] Typically, R 6 is H or unsubstituted or substituted C 1~6 R in formula (Id) is alkyl. 6 may be as further defined elsewhere herein for formula (I). However, in many cases, R in formula (Id) 6 is H.

[0176] For compounds of formula (Id) or pharmaceutically acceptable salts thereof, R 7 is usually -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11 )-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 is typically H, -C(O)OR z or unsubstituted or substituted C 1~4 However, R in formula (Id) is alkyl. 7 and R 11 R may be as further defined elsewhere herein for formula (I). z is H, unsubstituted or substituted C 1~4 However, R in formula (Id) is selected from alkyl, and unsubstituted or substituted phenyl. z may also be as further defined elsewhere herein for formula (I).

[0177] R 9 is typically H or unsubstituted or substituted C 1~6 It is alkyl.

[0178] R in formula (Id) x is H, unsubstituted or substituted C 1~4 However, R in formula (Id) is selected from alkyl, and unsubstituted or substituted phenyl. x may be as further defined elsewhere herein for formula (I). Typically, R in formula (Id) x is H.

[0179] In some preferred embodiments, the substituted azine has the formula (Id), R 9 is H.

[0180] The compound of the invention can be a substituted azine of formula (Id) selected from any one of the following structures, or a pharmaceutically acceptable salt thereof: [ka] [ka] [ka]

[0181] The numbers in parentheses next to the above structures correspond to the compound numbers shown in the Examples section below.

[0182] In another embodiment, the substituted azine of formula (I) has any one of the following structures: Accordingly, the present invention provides substituted azine compounds having any of the following structures, or pharmaceutically acceptable salts thereof: [ka]

[0183] The numbers in parentheses next to the above structures correspond to the compound numbers shown in the Examples section below.

[0184] The present invention also provides compounds which are substituted azines of formula (Ia) as defined herein, or pharmaceutically acceptable salts thereof, wherein R in said formula (Ia) 9 is other than H (also, X, R 0 , R 1 , R 2 , R 3 , R 7 and R x is as defined herein for Formula Ia). Such compounds include prodrugs. Typically, R in this embodiment 9 is unsubstituted or substituted C 1~6 In one aspect of this embodiment, R 9 is a substitution C 1~6 R is alkyl. 9 is, for example, phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above. Therefore, R 99 is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, where R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 alkyl and amino acids. Typically, R a , R b , R c and R d are each independently H or unsubstituted or substituted C 1~6 alkyl. Usually, R a , R b , R c and R d are each independently selected from H, methyl, or ethyl. 9 For example, -OC(O)R 99 C replaced with 1~6 alkyl, where R 99is as defined above. In another aspect of this embodiment, R 9 is the unsubstituted C 1~6 R is alkyl. 9 may be, for example, methyl. The substituted azine of formula (Ia) may be, for example, selected from any one of the following structures: [ka] [ka] [ka] [ka]

[0185] The numbers in parentheses next to the above structures correspond to the compound numbers shown in the Examples section below.

[0186] The present invention also provides a compound which is a substituted azine of formula (Ib) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R in said formula (Ib) 8 is other than H (and R 0 , R 1 , R 2 , R 4 , R 6 , R 7 and R x is as defined herein for Formula Ib). Such compounds include prodrugs. Typically, R in this embodiment 8 is unsubstituted or substituted C 1~6 In one aspect of this embodiment, R 8 is a substitution C 1~6 R is alkyl. 8 is, for example, phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above. Therefore, R 99 is phenyl, unsubstituted C1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, where R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 alkyl and amino acids. Typically, R a , R b , R c and R d are each independently H or unsubstituted or substituted C 1~6 alkyl. Usually, R a , R b , R c and R d are each independently selected from H, methyl, or ethyl. 8 For example, -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above. In another aspect of this embodiment, R 8 is the unsubstituted C 1~6 R is alkyl. 8 may be, for example, methyl. The substituted azine of formula (Ib) may be, for example, selected from any one of the following structures: [ka]

[0187] The numbers in parentheses next to the above structures correspond to the compound numbers shown in the Examples section below.

[0188] The present invention also provides compounds which are substituted azines of formula (Ic) as defined herein, or pharmaceutically acceptable salts thereof, wherein R 4 -OR 9 or -C(O)OR 10 and / or R 5 is -C(O)OR w where R9 , R 10 and R w is other than H (and R 0 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R x is as defined herein for formula Ic). Such compounds include prodrugs. Typically, in the substituted azine of formula (Ic): (a) R 4 HA-OR 9 or (b) R 4 is C(O)OR 10 or (c) R 5 is C(O)OR w or (d) R 4 is OR 9 and R 5 is C(O)OR w R 9 , R 10 and R w are the same or different and are unsubstituted or substituted C 1~6 It is an alkyl group.

[0189] In one aspect of this embodiment, R 9 , R 10 and R w is a substitution C 1~6 is an alkyl group. 9 and R 10 is, for example, phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above. Therefore, R 99 is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, where R a , R b , R c and R dare each independently H, unsubstituted or substituted C 1~6 alkyl and amino acids. Typically, R a , R b , R c and R d are each independently H or unsubstituted or substituted C 1~6 alkyl. Usually, R a , R b , R c and R d are each independently selected from H, methyl, or ethyl. 9 and R 10 For example, -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above. Similarly, in this aspect of this embodiment, R w is a substitution C 1~6 R can be an alkyl group. w is, for example, phenyl or -OC(O)R ww C replaced with 1~6 alkyl, where R ww is as defined above. Therefore, R ww is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, where R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 alkyl and amino acids. Typically, R a , R b , R c and R d are each independently H or unsubstituted or substituted C 1~6 alkyl. Usually, R a , R b , R c and R dare each independently selected from H, methyl, or ethyl. w For example, -OC(O)R ww C replaced with 1~6 alkyl, where R ww is as defined above.

[0190] In another aspect of this embodiment, R 9 , R 10 and R w may be the same or different, and unsubstituted C 1~6 is an alkyl group. 9 , R 10 and R w may be selected from, for example, methyl and ethyl groups.

[0191] The substituted azine of formula (Ic) can be selected, for example, from any one of the following structures: [ka] [ka]

[0192] The numbers in parentheses next to the above structures correspond to the compound numbers shown in the Examples section below.

[0193] The present invention also provides compounds which are substituted azines of formula (Id) as defined herein, or pharmaceutically acceptable salts thereof, wherein R 9 is other than H (and R 0 , R 1 , R y , R 6 , R 7 and R x is as defined herein for formula Id). Such compounds include prodrugs. Typically, R in this embodiment 9 is unsubstituted or substituted C 1~6 In one aspect of this embodiment, R 9 is a substitution C 1~6R is alkyl. 9 is, for example, phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above. Therefore, R 99 is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, where R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 alkyl and amino acids. Typically, R a , R b , R c and R d are each independently H or unsubstituted or substituted C 1~6 alkyl. Usually, R a , R b , R c and R d are each independently selected from H, methyl, or ethyl. 9 For example, -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above. In another aspect of this embodiment, R 9 is the unsubstituted C 1~6 R is alkyl. 9 can be, for example, methyl. The substituted azine of formula (Id) can have, for example, the following structure: [ka]

[0194] The numbers in parentheses next to the above structures correspond to the compound numbers shown in the Examples section below.

[0195] R 8 , R9 , R 10 or R w is typically unsubstituted or substituted C 1~6 The alkyl compounds of formula (Ia), (Ib), (Ic) and (Id) above have surprising advantages as prodrug structures for the compounds of formula (Ia), (Ib), (Ic) or (Id) that are effective HIF-PHD inhibitors. In particular, compounds having the above structures have surprisingly been shown to improve the efficacy of inhibitors in cellular assays, even if they themselves do not have high potency as HIF-PHD inhibitors. The reduced potency but higher activity in cellular assays means that these compounds have the potential to provide targeted inhibition with reduced off-target effects.

[0196] The present invention also provides a compound which is a substituted pyrimidine of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R 0 is H or unsubstituted or substituted C 1~6 is alkyl; R 2 H, -OR q or unsubstituted or substituted C 1~6 is alkyl; R 4 -OR 9 where R 9 is H and unsubstituted or substituted C 1~6 alkyl; R 5 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN or -C(O)OR w and; R 6 is H or unsubstituted or substituted C 1~6 is alkyl; R 7 is -CH(R 11 )-Ar, -CH(R 11)-Ary-Ar, -Ary-Ar, -CH(R 11 )-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 is alkyl; R x is H, unsubstituted or substituted C 1~4 alkyl, or unsubstituted or substituted phenyl; R w and R z are each independently selected from H, unsubstituted or substituted C1-4 alkyl, and unsubstituted or substituted phenyl; R q is H, unsubstituted or substituted C 1~6 alkyl, or unsubstituted or substituted phenyl).

[0197] Typically, in formula (IV), R 0 is H or unsubstituted C 1~6 alkyl, e.g., H or methyl. Often, R 0 is H.

[0198] Typically, in formula (IV), R 2 is H or unsubstituted C 1~6 alkyl, e.g., H or methyl. Often, R 2 is H.

[0199] Typically, in formula (IV), R 0 is H and R 2 is H.

[0200] In many cases, in formula (IV), R 5 is -CN.

[0201] R in formula (IV)6 is often H or unsubstituted C 1~6 alkyl, for example, H or methyl. R in formula (IV) 6 is typically H.

[0202] R in formula (IV) 4 -OR 9 and R 9 is H and unsubstituted or substituted C 1~6 However, R in formula (IV) is selected from alkyl. 9 is R in formula (I) 9 may be as defined anywhere herein.

[0203] In many cases, in formula (IV), R 9 is H. R 9 is H (i.e., R 4 is OH), R 5 is typically -CN.

[0204] However, in some embodiments, R in formula (IV) 9 is unsubstituted or substituted C 1~6 Such embodiments encompass prodrugs. In one aspect of this embodiment, R in formula (IV) can be alkyl. 9 is a substitution C 1~6 R is alkyl. 9 is, for example, phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above. Therefore, R 99 is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, where R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6alkyl and amino acids. Typically, R a , R b , R c and R d are each independently H or unsubstituted or substituted C 1~6 alkyl. Usually, R a , R b , R c and R d are each independently selected from H, methyl, or ethyl. 9 For example, -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is as defined above. In another aspect of this embodiment, R in formula (IV) 9 is the unsubstituted C 1~6 R is alkyl. 9 can be, for example, methyl.

[0205] R in formula (IV) x is typically H or unsubstituted C 1~4 alkyl, e.g., H or methyl. In many cases, R in formula (IV) x is H.

[0206] R in formula (IV) w is H, unsubstituted or substituted C 1~6 alkyl, or unsubstituted or substituted phenyl. R w is H or unsubstituted or substituted C 1~6 Typically, for example, R w H, unsubstituted C 1~6 Alkyl, or phenyl or -OC(O)R ww C replaced with 1~6 alkyl, where R ww is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, R a , R b , Rc and R d are each independently H, unsubstituted or substituted C 1~6 In many cases, R in formula (IV) is selected from alkyl and amino acids. w is H.

[0207] Typically, R in formula (IV) z is H or unsubstituted C 1~4 alkyl, e.g., H or methyl. In many cases, R in formula (IV) z is H.

[0208] R in formula (IV) q is typically H or unsubstituted C 1~6 alkyl, or unsubstituted phenyl. This is often, for example, H or unsubstituted C 1~4 alkyl, e.g., H or methyl. Typically, R in formula (IV) q is H.

[0209] Typically, R in formula (IV) 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, or -CH(R 11 )-Cyc, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 R is alkyl. 11 is typically H or unsubstituted C 1~4 alkyl, e.g., H or methyl. Often, R 11 is H.

[0210] R in formula (IV) 7 For example, -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, or -CH(R11 )-Cyc; where Ar is unsubstituted phenyl, unsubstituted pyrimidyl, unsubstituted benzothiazole, or phenyl substituted with —C(O)OH, —C(O)OMe, —C(O)OEt, —C(O)NH2, —C(O)N(H)Me, —OMe, or N-morpholino; Ary is unsubstituted phenylene or unsubstituted pyridylene; Cyc is unsubstituted cyclohexyl, or cyclohexyl substituted with —CF3 or —OCF3; R 11 is as defined above and is typically H. In many cases, R in formula (IV) 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, or -CH(R 11 )-Cyc; where Ar is unsubstituted phenyl or phenyl substituted with —C(O)OH or —C(O)OMe; Ary is unsubstituted phenylene or unsubstituted pyridylene; Cyc is unsubstituted cyclohexyl or cyclohexyl substituted with —CF3; R 11 is as defined above and is typically H.

[0211] Compounds of formula (IV) may be represented by one of the following structures or a pharmaceutically acceptable salt thereof: [ka]

[0212] The numbers in parentheses next to the above structures correspond to the compound numbers shown in the Examples section below.

[0213] General synthesis method The compounds of the invention may be prepared by any suitable method. Detailed general synthetic routes for the compounds of the invention are described below and in the Examples.

[0214] Substituted azines of formula (I) and substituted pyrimidines of formula (IV) can be synthesized, for example, using the methods described in the Examples section below under the headings "General Procedure A," "General Procedure B," "General Procedure C," and "General Procedure D." The application of these general procedures to produce substituted azines of formula (I) is shown and described below with reference to Schemes 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and specific synthetic examples are described in the Examples section below. Similarly, the application of the general procedures to produce substituted pyrimidines of formula (IV) is shown and described below with reference to Scheme 11.

[0215] Substituted azines of formula (I) and substituted pyrimidines of formula (IV) can be synthesized using an amide coupling procedure (General Procedure A or B), which involves coupling an amide group (e.g., a group of formula -C(O)N(R x )R 7 A Pd-catalyzed coupling procedure (General Procedure C) can then be used to further modify the amide group introduced in the previous step to give the desired C(O)N(R x )R 7 An alkoxy-dealkylation step (General Procedure D) can then be used as the final step to impart an OH group to the final compound.

[0216] For example, Scheme 10 below shows how substituted azines of formula (Ia) can be produced using general procedures B, C, and D provided in the Examples section. The same general procedures B, C, and D can also be used to produce substituted azines of formula (Ib). Scheme 6 below shows how substituted azines of formula (Ic) can be produced using general procedures B and D described in the Examples section. Schemes 7, 8, and 12 below illustrate the synthesis of pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-amide structures of formula (Id) using general procedures A and D in the Examples. Additionally, Scheme 11 shows how substituted pyrimidines of formula (IV) can be produced using general procedure B. Schemes 1 and 2 are also provided below to illustrate general methods for the preparation of some of the Reference Examples described herein. As will be appreciated by those skilled in the art, alternative precursor compounds having different substituents than those shown in the schemes below may be used in the same manner to achieve variations within the scope of formulas (I), (Ia), (Ib), (Ic), (Id), and (Iv) herein.

[0217] Thus, the compounds described herein can be prepared according to the following reaction scheme:

[0218] [ka] Scheme 1 Step (i) of Scheme 1 can be carried out using treatment with any suitable peptide coupling reagent. Typically, step (i) involves treatment with an acid anhydride, e.g., propanephosphonic anhydride, in the presence of a base such as N,N-diisopropylethylamine (DIPEA). The reaction is typically carried out in a solvent. The solvent can be a polar solvent. Typically, the solvent can be a polar aprotic solvent. The polar aprotic solvent can be dimethylacetamide (DMAc). Typically, step (i) is carried out at standard temperature and atmospheric pressure (SATP), i.e., about 25°C and 1 atmosphere (about 100,000 Pa). This step can last from 1 to 24 hours, e.g., about 16 hours.

[0219] Step (ii) of Scheme 1 involves treatment in the presence of a catalyst. The catalyst can be a palladium catalyst. Typically, the catalyst is Pd t The base may be BuXPhos. This step may also be carried out in the presence of a base. The base may be a carbonate. Typically, the base is cesium carbonate (Cs2CO3). The reaction is typically carried out in a solvent. The solvent may be a mixture of solvents. Typically, the solvent may be a mixture of one or more polar solvents, often polar aprotic solvents. Typically, the reaction is carried out in a mixture of dimethylacetamide (DMAc) and tetrahydrofuran (THF). This mixture may be a 1:1 mixture (1:1). Step (ii) is typically carried out at a temperature above room temperature. For example, step (ii) is typically carried out at 60°C to 100°C. Typically, this step is carried out at around 80°C. This step may last for 1 to 24 hours, for example, about 16 hours.

[0220] Step (iii) of Scheme 1 is a deprotection step, which may involve treatment with any suitable reagent known to those skilled in the art. In some instances, a silyl halide compound is used. Typically, trimethylsilyl iodide (TMS-I) is used. This step is typically carried out in the presence of a solvent. The solvent is typically a polar solvent, more typically a polar aprotic solvent. The solvent may be dichloromethane (CHCl). Step (iii) is typically carried out at a temperature above room temperature. For example, step (iii) is typically carried out at 40°C to 80°C. Typically, this step is carried out at around 60°C. This step may last from 1 to 24 hours, for example, about 8 hours.

[0221] [ka] Scheme 2 Step (i) of Scheme 2 can involve treatment with any suitable amide coupling reagent. Typically, step (i) involves treatment with an acid anhydride, for example, propanephosphonic anhydride (T3P), in the presence of a base such as N,N-diisopropylethylamine (DIPEA). The reaction is typically carried out in a solvent. The solvent can be a polar solvent. Typically, the solvent can be a polar aprotic solvent. The polar aprotic solvent can be dimethylacetamide (DMAc). Typically, step (i) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0222] Step (ii) of Scheme 2 involves treatment in the presence of a catalyst. The catalyst can be a palladium catalyst. Typically, the catalyst is Pd tBuXPhos. This step can also be carried out in the presence of a base. The base can be a carbonate. Typically, the base is Cs2CO3. The reaction is typically carried out in a solvent. The solvent can be a mixture of solvents. Typically, the solvent can be a mixture of one or more polar solvents, often polar aprotic solvents. Typically, the reaction is carried out in a mixture of DMAc and tetrahydrofuran (THF). This mixture can be approximately a 1:1 mixture (1:1). Step (ii) is typically carried out at a temperature above room temperature. For example, step (ii) is typically carried out at 80°C to 120°C. Typically, this step is carried out at around 100°C. This step can last from 30 minutes to 6 hours, for example, about 1 hour.

[0223] [ka] Scheme 3 Scheme 3 above shows how certain substituted azines of formula (I) can be produced using the general synthetic procedures described in the Examples section below (see General Procedures A, B, C and D in the Examples).

[0224] Step (i) of Scheme 3 can involve treatment with any suitable peptide coupling reagent. Typically, step (i) involves treatment with an acid anhydride, e.g., propanephosphonic anhydride, in the presence of a base such as N,N-diisopropylethylamine (DIPEA). The reaction is typically carried out in a solvent. The solvent can be a polar solvent. Typically, the solvent can be a polar aprotic solvent. The polar aprotic solvent can be dimethylacetamide (DMAc). Typically, step (i) is carried out with SATP. This step can last from 1 to 24 hours, e.g., about 16 hours.

[0225] Step (ii) of Scheme 3 involves treatment in the presence of a catalyst. The catalyst can be a palladium catalyst. Typically, the catalyst is Pd tThe base may be BuXPhos. This step may also be carried out in the presence of a base. The base may be a carbonate. Typically, the base is Cs2CO3, Na2CO3, or K2CO3. Usually, the base is Cs2CO3. The reaction is typically carried out in a solvent. The solvent may be a mixture of solvents. Typically, the solvent may be a mixture of one or more polar solvents, often polar aprotic solvents. Usually, the reaction is carried out in a mixture of DMAc and tetrahydrofuran (THF). This mixture may be a 1:1 mixture (1:1). Step (ii) is typically carried out at a temperature above room temperature. For example, step (ii) is typically carried out at 80°C to 120°C. Usually, this step is carried out at around 100°C. This step may last from 30 minutes to 6 hours, for example, about 1 hour.

[0226] Step (iii) can be carried out using any suitable reagent for ester hydrolysis. Typically, the reaction can be carried out in the presence of a hydroxide base, usually lithium hydroxide. The reaction is usually carried out in the presence of a solvent. The solvent can be one or more solvents, typically a mixture of one or more polar solvents. The one or more polar solvents can be protic or aprotic. For example, the solvent can be a mixture of THF and HO. Typically, the mixture is approximately a 1:1 mixture. Typically, step (iv) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0227] [ka] Scheme 4 Scheme 4 above shows how the 4-hydroxypyridine / pyridinone structures of formula (Ia) can be produced using the general synthetic procedures described in the Examples section below (see General Procedures A and D in the Examples).

[0228] Step (i) of Scheme 4 typically involves treatment with R-NH2. Step (i) of Scheme 4 can involve treatment with any suitable amide coupling reagent. Typically, step (i) involves treatment with an acid anhydride, for example, propanephosphonic anhydride, in the presence of a base such as N,N-diisopropylethylamine (DIPEA). The reaction is typically carried out in a solvent, which can be a polar solvent. Typically, the solvent can be a polar aprotic solvent. The polar aprotic solvent can be dimethylacetamide (DMAc). Typically, step (i) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0229] Step (ii) of Scheme 4 can involve treatment with additional reagents such as pyrazoles and substituted pyrazoles. Step (ii) of Scheme 4 can involve treatment in the presence of a catalyst. The catalyst can be a palladium catalyst. Typically, the catalyst is Pd t The reaction may be carried out in the presence of a base. The base may be a carbonate. Typically, the base is cesium carbonate (Cs2CO3). The reaction is typically carried out in a solvent. The solvent may be a mixture of solvents. Typically, the solvent may be a mixture of one or more polar solvents, often polar aprotic solvents. Typically, the reaction is carried out in tert-butanol or 1,4-dioxane. Step (ii) is typically carried out at a temperature above room temperature. For example, step (ii) is typically carried out at 40°C to 80°C. Typically, this step is carried out at around 60°C. This step may last from 1 hour to 48 hours, for example, about 16 hours.

[0230] Step (iii) of Scheme 4 is a deprotection step, which may involve treatment with any suitable reagent known to those skilled in the art. In some instances, lithium chloride is used. This step is typically carried out in the presence of a solvent. The solvent is typically a polar solvent, more typically a polar aprotic solvent. The solvent may be DMAc. Step (v) is typically carried out at a temperature higher than room temperature. For example, step (v) is typically carried out at 80°C to 120°C. Usually, this step is carried out around 100°C. This step may last from 30 minutes to 6 hours, for example, about 2 hours.

[0231] Step (iv) of Scheme 4 can be carried out using any suitable reagent for ester hydrolysis, if necessary. Typically, the reaction can be carried out in the presence of a hydroxide compound, usually lithium hydroxide. The reaction is usually carried out in the presence of a solvent. The solvent can be one or more solvents, typically a mixture of one or more polar solvents. The one or more polar solvents can be protic or aprotic. For example, the solvent can be a mixture of THF and HO. Typically, the mixture is a 1:1 mixture. Typically, step (ii) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0232] [ka] Scheme 5 Scheme 5 above shows how the 4-hydroxypyridine / pyridinone structures of formula (Ic) can be produced using the general synthetic procedures described in the Examples section below (see General Procedures A and D in the Examples).

[0233] Step (i) of Scheme 5 can involve treatment with any suitable amide coupling reagent. Typically, step (i) involves treatment with an acid anhydride, for example, propanephosphonic anhydride, in the presence of a base such as N,N-diisopropylethylamine (DIPEA). The reaction is typically carried out in a solvent. The solvent can be a polar solvent. Typically, the solvent can be a polar aprotic solvent. The polar aprotic solvent can be dimethylacetamide (DMAc). Typically, step (i) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0234] Step (ii) of Scheme 5 involves treatment in the presence of a catalyst. The catalyst can be a palladium catalyst. Typically, the catalyst is Pd t The reaction may be carried out in the presence of a base. The base may be a carbonate. Typically, the base is cesium carbonate (Cs2CO3). The reaction is typically carried out in a solvent. The solvent may be a mixture of solvents. Typically, the solvent may be a mixture of one or more polar solvents, often polar aprotic solvents. Typically, the reaction is carried out in tert-butanol or 1,4-dioxane. Step (ii) is typically carried out at a temperature above room temperature. For example, step (ii) is typically carried out at 40°C to 80°C. Typically, this step is carried out at around 60°C. This step may last from 1 hour to 48 hours, for example, about 16 hours. Step (ii) may also include treatment with additional reagents such as pyrazole and substituted pyrazoles.

[0235] Step (iii) of Scheme 5 is a deprotection step, which may involve treatment with any suitable reagent known to those skilled in the art. In some instances, lithium chloride is used. This step is typically carried out in the presence of a solvent. The solvent is typically a polar solvent, more typically a polar aprotic solvent. The solvent may be DMAc. Step (v) is typically carried out at a temperature higher than room temperature. For example, step (v) is typically carried out at 80°C to 120°C. Usually, this step is carried out around 100°C. This step may last from 30 minutes to 6 hours, for example, about 2 hours.

[0236] [ka] Scheme 6 Scheme 6 above shows how substituted azines of formula (Ic) can be prepared using the general synthetic procedures described in the Examples section below (see General Procedures B and D in the Examples).

[0237] Step (i) of Scheme 6 involves treatment in the presence of a catalyst. The catalyst may be a palladium catalyst. Typically, the catalyst may be RockPhos Pd G3. This step may also be carried out in the presence of a base. The base may be a carbonate. Typically, the base is cesium carbonate (Cs2CO3). The reaction is typically carried out in a solvent. The solvent may be a non-polar solvent. Typically, the solvent is a non-polar protic solvent. Usually, the solvent is tert-butanol ( t BuOH). Step (i) is typically carried out at a temperature above room temperature. For example, step (i) is typically carried out at 60°C to 100°C. Usually, this step is carried out at around 80°C. This step can last from 1 hour to 24 hours, for example, about 16 hours.

[0238] Step (ii) can be carried out using any suitable reagent for ester hydrolysis. Typically, the reaction can be carried out in the presence of a hydroxide base, usually lithium hydroxide. The reaction is usually carried out in the presence of a solvent. The solvent can be one or more solvents, typically a mixture of one or more polar solvents. The one or more polar solvents can be protic or aprotic. For example, the solvent can be a mixture of THF and HO. Typically, the mixture is a 1:1 mixture. Typically, step (ii) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0239] In step (iii) of Scheme 6, the starting material is treated with the group R-NH2. Any suitable peptide coupling reagent can be used for step (iii). Typically, step (iii) of Scheme 6 involves treatment with an acid anhydride, for example, propanephosphonic anhydride, in the presence of a base such as N,N-diisopropylethylamine (DIPEA). The reaction is typically carried out in a solvent. The solvent can be a polar solvent. Typically, the solvent can be a polar aprotic solvent. The polar aprotic solvent can be dimethylacetamide (DMAc). Typically, step (iii) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0240] Step (iv) of Scheme 6 is a deprotection step, which may involve treatment with any suitable reagent known to those skilled in the art. In some instances, lithium chloride is used. This step is typically carried out in the presence of a solvent. The solvent is typically a polar solvent, more typically a polar aprotic solvent. The solvent may be DMAc. Step (iv) is typically carried out at a temperature higher than room temperature. For example, step (iv) is typically carried out at 80°C to 120°C. Usually, this step is carried out around 100°C. This step may last from 30 minutes to 6 hours, for example, about 2 hours.

[0241] [ka] Scheme 7 Scheme 7 above shows how pyrazolo[1,5-a]pyrido[3,2-e]-pyrimidine-7-amide structures of formula (Id) can be produced using the general synthetic procedures described.

[0242] Step (i) of Scheme 7 is a Michael addition reaction that can be treated with any suitable reagent known to those skilled in the art. In some instances, sodium ethoxide is used. This step is typically carried out in the presence of a solvent. The solvent is typically a polar solvent, more typically a polar aprotic solvent. The solvent can be EtOH. Step (i) is typically carried out at a temperature above room temperature, typically between 80°C and 120°C. Usually, this step is carried out at around 100°C. This step can last between 1 hour and 48 hours, for example, about 2 hours.

[0243] Step (ii) of Scheme 7 is an intramolecular cyclization that can be treated with any suitable reagent known to those skilled in the art. This step is typically carried out in the presence of a solvent. The solvent typically has a high boiling point. The solvent can be diphenyl ether. Step (ii) is typically carried out at a temperature higher than room temperature. Typically, the temperature is between 140°C and 250°C. Usually, this step is carried out around 250°C. This step can last from 10 minutes to 8 hours, for example, about 30 minutes.

[0244] Step (iii) of Scheme 7 is a direct amide coupling from an ethyl ester, which involves treatment in the presence of a catalyst. Typically, the catalyst can be DABCO-(AlMe3)2. The reaction is typically carried out in a solvent. The solvent can be a mixture of solvents. Usually, the reaction occurs in tetrahydrofuran. Step (iii) is typically carried out at a temperature above room temperature. For example, step (iii) is typically carried out at a temperature between 40°C and 150°C. Usually, this step is carried out around 130°C. This step can last from 10 minutes to 12 hours, for example, about 1 hour.

[0245] [ka] Scheme 8 Scheme 8 above shows how pyrazolo[1,5-a]pyrido[3,2-e]-pyrimidine-7-amide structures of formula (Id) can be prepared using the general synthetic procedures described in the Examples section below (see General Procedures A and D in the Examples).

[0246] In step (i) of Scheme 8, the starting material is treated with a group R—NH. Any suitable amide coupling reagent can be used for step (i). Typically, step (i) of Scheme 4 involves treatment with an acid anhydride, for example, propanephosphonic anhydride, in the presence of a base such as N,N-diisopropylethylamine (DIPEA). The reaction is typically carried out in a solvent. The solvent can be a polar solvent. Typically, the solvent is a polar aprotic solvent. The polar aprotic solvent can be dimethylacetamide (DMAc). Typically, step (i) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0247] Step (ii) of Scheme 8 involves treatment with ethyl orthoformate. The reaction is typically carried out without a solvent. Typically, step (ii) is carried out at a temperature above room temperature. For example, step (ii) can be carried out at 100°C to 140°C. Usually, this step is carried out at around 120°C. This step can last from 30 minutes to 6 hours, for example, about 2 hours.

[0248] Step (iii) of Scheme 8 involves heating the reagents above room temperature. Typically, the reagents are heated to above 200°C, typically around 240°C. This step may last from 10 minutes to 2 hours, for example around 30 minutes. This step may also be carried out in the presence of an additional reagent, such as diphenyl ether.

[0249] [ka] Scheme 9 Scheme 9 above shows how 3-hydroxypyridine structures of formula (Ib) can be produced using the general synthetic procedures described in the Examples section below (see General Procedures A and D in the Examples).

[0250] Step (i) of Scheme 9 typically involves treatment with R—NH2. Step (i) of Scheme 9 can involve treatment with any suitable amide coupling reagent. Typically, step (i) involves treatment with an acid anhydride, for example, propanephosphonic anhydride, in the presence of a base, such as N,N-diisopropylethylamine (DIPEA). The reaction is typically carried out in a solvent, which can be a polar solvent. Typically, the solvent can be a polar aprotic solvent. The polar aprotic solvent can be dimethylacetamide (DMAc). Typically, step (i) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0251] Step (ii) of Scheme 9 involves treatment with additional reagents such as pyrazoles and substituted pyrazoles. Step (ii) of Scheme 9 involves treatment in the presence of a catalyst. The catalyst can be a palladium catalyst. Typically, the catalyst is Pd tThe reaction may be carried out in the presence of a base. The base may be a carbonate. Typically, the base is cesium carbonate (Cs2CO3). The reaction is typically carried out in a solvent. The solvent may be a mixture of solvents. Typically, the solvent may be a mixture of one or more polar solvents, often polar aprotic solvents. Typically, the reaction is carried out in tert-butanol or 1,4-dioxane. Step (ii) is typically carried out at a temperature above room temperature. For example, step (ii) is typically carried out at 40°C to 80°C. Typically, this step is carried out at around 60°C. This step may last from 1 hour to 48 hours, for example, about 16 hours. Step (ii) may also include treatment with additional reagents such as pyrazole and substituted pyrazoles.

[0252] Step (iii) of Scheme 9 is a deprotection step, which may involve treatment with any suitable reagent known to those skilled in the art. In some instances, lithium chloride is used. This step is typically carried out in the presence of a solvent, typically a polar solvent, more typically a polar aprotic solvent. The solvent may be DMAc. Step (v) is typically carried out at a temperature above room temperature. For example, step (v) is typically carried out at 80°C to 120°C. Usually, this step is carried out around 100°C. This step may last from 30 minutes to 6 hours, for example, about 2 hours.

[0253] Step (iv) of Scheme 9 can be carried out using any suitable reagent for ester hydrolysis, if necessary. Typically, the reaction can be carried out in the presence of a hydroxide compound, usually lithium hydroxide. The reaction is usually carried out in the presence of a solvent. The solvent can be one or more solvents, typically a mixture of one or more polar solvents. The one or more polar solvents can be protic or aprotic. For example, the solvent can be a mixture of THF and HO. Typically, the mixture is a 1:1 mixture. Typically, step (ii) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0254] [ka] Scheme 10 Scheme 10 above shows how substituted azines of formula (Ia) can be prepared using the general synthetic procedures described in the Examples section below (see General Procedures B, C and D in the Examples).

[0255] Step (i) of Scheme 10 can be carried out using any suitable esterification reagent known to those skilled in the art. In some cases, N'-ethylcarboimide hydrochloride (EDC.HCl) is used. Typically, a catalyst is also present. The catalyst present is usually an organic catalyst. 4-dimethylaminopyridine (DMAP) is used as the catalyst. A base can also be present in step (i) of Scheme 10. The base can be N,N-diisopropylethylamine (DIPEA). Typically, step (i) of Scheme 10 is carried out in the presence of a solvent. The solvent can be a mixture of two solvents. Typically, the solvent is a mixture of two polar solvents. Typically, the solvent is a mixture of a polar protic solvent and a polar aprotic solvent. Thus, the solvent can be a mixture of dimethylformamide (DMF) and ethanol. Typically, step (i) is carried out with SATP. This step can last from 1 hour to 24 hours, for example, around 16 hours.

[0256] In step (ii) of Scheme 10, the product of step (i) is treated with a pyrazole. Step (ii) involves treatment in the presence of a catalyst. The catalyst can be a palladium catalyst. Typically, the catalyst is Pd t The base may be BuxPhos G3. This step may also be carried out in the presence of a base. The base may be a carbonate. Typically, the base is cesium carbonate (Cs2CO3). Step (ii) is typically carried out at a temperature higher than room temperature. For example, step (ii) is typically carried out at 40°C to 80°C. Typically, this step is carried out at around 60°C. This step may last from 1 hour to 24 hours, for example, about 16 hours.

[0257] Step (iii) can be carried out using any suitable reagent for ester hydrolysis. Typically, the reaction can be carried out in the presence of a hydroxide, usually lithium hydroxide. The reaction is usually carried out in the presence of a solvent. The solvent can be one or more solvents, typically a mixture of one or more polar solvents. The one or more polar solvents can be protic or aprotic. For example, the solvent can be a mixture of THF and HO. Typically, the mixture is approximately a 1:1 mixture. Typically, step (iii) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0258] In step (iv) of Scheme 10, the product of step (iii) is treated with the group R-NH2. Any suitable peptide coupling reagent can be used in step (iv). Typically, step (iv) of Scheme 10 involves treatment with HATU in the presence of a base such as DIPEA. The reaction is typically carried out in a solvent. The solvent can be a polar solvent. Typically, the solvent can be a polar aprotic solvent. The polar aprotic solvent can be N,N-dimethylacetamide (DMAc). Typically, step (iv) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0259] Step (v) of Scheme 10 is a deprotection step, which may involve treatment with any suitable reagent known to those skilled in the art. In some instances, lithium chloride is used. This step is typically carried out in the presence of a solvent. The solvent is typically a polar solvent, more typically a polar aprotic solvent. The solvent may be DMAc. Step (v) is typically carried out at a temperature higher than room temperature. For example, step (v) is typically carried out at 80°C to 120°C. Usually, this step is carried out around 100°C. This step may last from 30 minutes to 6 hours, for example, about 2 hours.

[0260] Step (vi) of Scheme 10 involves a reaction in the presence of a catalyst. The catalyst can be a palladium catalyst. Typically, the catalyst can be PdAmPhos. This step can also be carried out in the presence of a base. The base can be a carbonate. Typically, the base is cesium carbonate (Cs2CO3). In step (vi), the product of step (iv) is typically treated with an organoborane compound containing a group -R. Typically, this compound is a compound of the formula RB(OH)2 or RB-pinacol ester. Step (vi) is typically carried out at a temperature higher than room temperature. For example, step (vi) is typically carried out at 80°C to 120°C. Typically, this step is carried out at around 100°C. This step can last for 30 minutes to 6 hours, for example, about 2 hours. This step is typically carried out in the presence of a solvent. The solvent is typically a polar solvent, more typically a non-polar aprotic solvent. The solvent can be 1,4-dioxane.

[0261] [ka] Scheme 11 Scheme 11 above shows how substituted pyrimidines of formula (IV) can be produced using the general synthetic procedures described in the Examples section below (see General Procedure B in the Examples).

[0262] Step (i) of Scheme 11 typically involves treatment with an acid. Typically, the acid is a protic acid such as HCl. For example, 4 M HCl in 1,4-dioxane can be used. Step (i) is typically carried out at a temperature above room temperature. For example, step (i) is typically carried out at 80°C to 120°C. Typically, this step is carried out at around 100°C. This step can last from 1 hour to 24 hours, for example, about 16 hours.

[0263] Step (ii) of Scheme 11 typically involves treatment in the presence of a base. Any suitable base can be used. Typically, the base is a carbonate. K2CO3 can be used. Step (ii) is typically carried out in a solvent. The solvent can be a polar solvent, typically a polar protic solvent. Usually, the solvent is methanol. Typically, step (ii) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0264] Step (iii) can be carried out using any suitable reagent for ester hydrolysis. Typically, the reaction can be carried out in the presence of a hydroxide base, usually lithium hydroxide. The reaction is usually carried out in the presence of a solvent. The solvent can be one or more solvents, typically a mixture of one or more polar solvents. The one or more polar solvents can all be protic. For example, the solvent can be a mixture of methanol and HO. Typically, the mixture is a 1:1 mixture. Typically, step (iii) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0265] In step (iv) of Scheme 11, the product of step (iii) is treated with the group R-NH. Any suitable peptide coupling reagent can be used in step (iv). Typically, step (iv) of Scheme 11 involves treatment with T3P in the presence of a base, such as N,N-diisopropylethylamine (DIPEA). The reaction is typically carried out in a solvent. The solvent can be a polar solvent. Typically, the solvent can be a polar aprotic solvent. The polar aprotic solvent can be N,N-dimethylacetamide (DMAc). Typically, step (iv) is carried out with SATP. This step can last from 1 to 24 hours, for example, about 16 hours.

[0266] [ka] Scheme 12 Scheme 12 above shows how pyrazolo[1,5-a]pyrido[3,2-e]-pyrimidine-7-amide structures of formula (Id) can be prepared using the general synthetic procedures described in the Examples section below (see General Procedures A and D in the Examples).

[0267] In Scheme 12, step (i) generally involves heating the starting materials together. Typically, heating is performed at a temperature of 100°C to 200°C, more typically, heating is performed at a temperature of 140°C to 160°C. Heating can occur at about 150°C. This step can last from 30 minutes to 6 hours, for example, about 1 hour.

[0268] Step (ii) of Scheme 12 involves heating the product of step (i) with diethyl ethoxymethylene malonate. Step (ii) is typically carried out in a solvent. The solvent can be a polar solvent or a non-polar protic solvent. Usually, the solvent is toluene. Typically, heating is carried out at a temperature of 80°C to 160°C, more typically, heating is carried out at a temperature of 100°C to 140°C. Heating can occur at about 120°C. Step (ii) typically lasts from about 24 hours to about 72 hours. For example, step (ii) can last about 48 hours.

[0269] Step (iii) of Scheme 12 typically involves treatment with a reagent to promote ring formation. Any suitable reagent can be used. Typically, Eaton's reagent (10 wt % phosphorus pentoxide solution in methanesulfonic acid) is used. Step (iii) is typically carried out at a temperature higher than room temperature. For example, step (iii) is typically carried out at 50°C to 90°C. Usually, this step is carried out at around 70°C. This step can last for 16 to 30 hours, for example, about 24 hours.

[0270] Step (iv) of Scheme 12 typically involves treatment with a chlorinating agent. Any suitable chlorinating agent known to those skilled in the art can be used. Typically, phosphoryl chloride (POCl) is used. Step (iv) is typically carried out at a temperature above room temperature. For example, step (iv) is typically carried out at 50°C to 90°C. Typically, this step is carried out at around 70°C. This step can last from 1 hour to 6 hours, for example, about 3 hours.

[0271] Step (v) of Scheme 12 typically involves treatment with sodium methoxide (NaOMe). Step (v) is typically carried out in a solvent. The solvent can be a polar solvent, typically a polar protic solvent. Usually, the solvent is methanol. Typically, step (v) is carried out with SATP. This step can last from 1 to 10 hours, for example, about 4 hours.

[0272] Step (vi) of Scheme 12 typically involves treatment with R—NH in the presence of an agent to promote amide formation. The agent can be an organoaluminum reagent, typically bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (DABAL-AlMe). Typically, step (vi) is carried out in the presence of a solvent. The solvent is usually a polar solvent, often a non-polar aprotic solvent such as THF. Step (vi) is typically carried out at a temperature above room temperature. For example, step (vi) is typically carried out at 100° C. to 140° C. Typically, this step is carried out around 120° C. This step can last from 30 minutes to 6 hours, for example, about 3 hours.

[0273] Step (vii) of Scheme 12 can involve treatment with any agent suitable for converting an ether to a hydroxyl. Typically, lithium chloride can be used. The reaction is typically carried out in a solvent. The solvent can be a polar solvent. Typically, the solvent can be a polar aprotic solvent. The polar aprotic solvent can be N,N-dimethylacetamide (DMAc). Step (vii) is typically carried out at a temperature above room temperature. For example, step (vii) is typically carried out at 80°C to 120°C. Usually, this step is carried out around 100°C. This step can last from 30 minutes to 6 hours, for example, about 2 hours.

[0274] The compounds of the present invention that contain one or more chiral centers can be used in enantiomerically or diastereomerically pure form, or in the form of a mixture of isomers.For the avoidance of doubt, the compounds of the present invention can be used in the form of solvates, if necessary.Furthermore, for the avoidance of doubt, the compounds of the present invention can be used in any tautomeric form.

[0275] As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, or nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, malic acid, ascorbic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) hydroxides, as well as organic bases such as alkylamines, aralkylamines, and heterocyclic amines. A substituted azine of formula (I), (Ia), (Ib), (Ic), or (Id), or a substituted pyrimidine of formula (IV), can be converted into a pharmaceutically acceptable salt by conventional methods, and the salt can be converted into the free compound.

[0276] Pharmaceutical Composition The present invention also provides a pharmaceutical composition comprising a compound of the invention as defined anywhere herein and a pharmaceutically acceptable carrier or diluent.

[0277] Typically, the composition contains up to 85 wt% of the compound of the present invention. More typically, it contains up to 50 wt% of the compound of the present invention. Preferred pharmaceutical compositions are sterile and pyrogen-free. Furthermore, when the pharmaceutical composition provided by the present invention contains an optically active compound of the present invention, the compound of the present invention is typically a substantially pure optical isomer.

[0278] The compositions of the invention may be provided as a kit, including instructions to enable the kit to be used as described herein, or details as to which subjects the compositions may be used for.

[0279] The compositions of the present invention are typically formulated for administration with pharmaceutically acceptable carriers or diluents.For example, solid oral forms may contain, together with active compounds, diluents (e.g., lactose, dextrose, saccharose, cellulose, corn starch, or potato starch), lubricants (e.g., silica, talc, stearic acid, magnesium stearate, or calcium stearate, and / or polyethylene glycol), binders (e.g., starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone), dispersants (e.g., starch, alginic acid, alginates, or sodium starch glycolate), effervescent mixtures, dyes, sweeteners, wetting agents (e.g., lecithin, polysorbates, lauryl sulfate, etc.), and non-toxic and pharmacologically inactive substances generally used in pharmaceutical preparations.Such pharmaceutical preparations can be prepared by known methods, for example, by mixing, granulating, tableting, sugar-coating, or film-coating processes.

[0280] The compositions of the present invention may be formulated for inhalation (aerosolization) administration as a solution or suspension. The compounds or combinations of the present invention may be administered by a nebulizer, such as a metered-dose inhaler (MDI) or an electronic or jet nebulizer. Alternatively, the compounds or combinations of the present invention may be formulated for inhalation administration as a powder, and such formulations may be administered from a dry powder inhaler (DPI). When formulated for inhalation administration, the compounds or combinations of the present invention may be delivered in the form of particles having a mass median aerodynamic diameter (MMAD) of 1 to 100 μm, preferably 1 to 50 μm, more preferably 1 to 20 μm, e.g., 3 to 10 μm, e.g., 4 to 6 μm. When the compounds or combinations of the present invention are delivered as a nebulized aerosol, references to particle size refer to the MMAD of the aerosol droplets. MMAD can be measured by any suitable technique, such as laser diffraction.

[0281] Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain, for example, saccharose or saccharose with glycerine and / or mannitol and / or sorbitol as carriers.

[0282] Suspensions and emulsions may contain, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol as a carrier. Suspensions or solutions for intramuscular injection or inhalation may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols (e.g., propylene glycol), and, optionally, an appropriate amount of lidocaine hydrochloride.

[0283] Solutions for inhalation, injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions. Pharmaceutical compositions suitable for delivery by needle-free injection, for example transdermal, may also be used.

[0284] The compositions of the present invention may further comprise one or more additional active agents, which may be selected from ACE inhibitors, angiotensin II receptor agonists, beta-receptor blockers, calcium antagonists, PDE inhibitors, mineralocorticoid receptor antagonists, diuretics, aspirin, iron supplements, vitamin B12 and folic acid supplements, statins, digitalis (digoxin) derivatives, tumor chemotherapeutic agents, and antibiotics.

[0285] therapeutic use The compounds of the present invention have been shown to have high potency and specificity as hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) inhibitors. For example, some compounds of the present invention have IC 3 activity against PHD2. 50 have been shown to have an IC of less than 200 nM, which is a significant improvement compared to known inhibitors (e.g., roxadustat has an IC of 2.7 μM in the LCMS PHD2 hydroxylation assay used herein). 50 In addition to their potency, the compounds of the present invention were found to be highly selective for PHD, with over 100-fold selectivity over other tested 2OG oxygenases.

[0286] In addition to these desirable biochemical properties, the compounds of the present invention have been shown to have desirable physical properties, including good solubility and permeability in cells. These physical properties mean that the compounds of the present invention have been found to effectively stabilize cellular HIF-1α. Furthermore, in animal models, low in vivo doses of the compounds have been shown to induce erythropoiesis.

[0287] Thus, the compounds and pharmaceutical compositions of the present invention have potential utility in treating conditions in which PHD is a therapeutic target.

[0288] Accordingly, the present invention provides a compound of the invention as defined herein or a pharmaceutical composition of the invention as defined herein for use in the treatment of the human or animal body by therapy. As stated herein above, the terms "treatment", "treat" and "treating" refer to both therapeutic treatment and prophylactic or preventative measures.

[0289] The present invention also provides a compound of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein, for use as a modulator of hypoxia-inducible factor prolyl hydroxylase activity. Typically, the compound or pharmaceutical composition is for use as an inhibitor of hypoxia-inducible factor prolyl hydroxylase activity. Thus, the present invention also provides a compound of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein, for use as a PHD inhibitor.

[0290] The present invention also provides a compound of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein, for use in the treatment of a PHD-related disorder.

[0291] The term "PHD-related disorder" as used herein refers to a disorder that can be treated by regulating hypoxia-inducible factor prolyl hydroxylase activity. Typically, a PHD-related disorder is a disorder that can be treated by inhibiting hypoxia-inducible factor prolyl hydroxylase activity. Those skilled in the art can easily identify PHD-related disorders experimentally.

[0292] PHD-related disorders include, but are not limited to, anemia, ischemia, inflammation, Parkinson's disease, sickle cell anemia (including that due to increased expression of fetal hemoglobin F), Alzheimer's disease, non-fatty liver disease, irritable bowel disease, cardiovascular disease, heart failure, chronic kidney disease, cancer, and renal failure. Thus, the compounds or pharmaceutical compositions of the invention may be for use in treating any of the aforementioned conditions.

[0293] Similarly, the compounds or pharmaceutical compositions of the present invention may be for use in repairing skeletal muscle damage, increasing red blood cell count (RBC), increasing hemoglobin (HGB) production, increasing hematocrit (HCT) production, increasing erythropoietin (EPO) production, wound healing, angiogenesis, revascularization, stem cell activation, or cardioprotection after myocardial infarction.

[0294] Thus, the present invention provides a compound of the present invention as defined herein, or a pharmaceutical composition of the present invention as defined herein, for use in treating anemia, ischemia, inflammation, Parkinson's disease, Alzheimer's disease, non-fatty liver disease, irritable bowel disease, sickle cell anemia, cancer, cardiovascular disease, heart failure, chronic kidney disease, or renal failure; or for use in repairing skeletal muscle damage, increasing red blood cell count (RBC), increasing hemoglobin (HGB) production, increasing hematocrit (HCT) production, increasing erythropoietin (EPO) production, wound healing, angiogenesis, revascularization, stem cell activation, or cardioprotection after myocardial infarction. Sickle cell anemia can be sickle cell anemia mediated by increased expression of fetal hemoglobin F.

[0295] In most cases, the compound or pharmaceutical composition of the present invention is used for treating anemia.Anemia can be renal anemia (for example, anemia associated with chronic kidney disease, anemia in dialysis patients), anemia induced by chemotherapy, cancer-related anemia, age-related anemia, or anemia resulting from cancer, such as leukemia, multiple myeloma, and smoldering myeloma.Anemia can be sickle cell anemia, for example, sickle cell anemia caused by increased expression of fetal hemoglobin F.

[0296] In many cases, the compounds or pharmaceutical compositions of the invention are for use in increasing red blood cell count (RBC), increasing hemoglobin (HGB) production, increasing hematocrit (HCT) production, or increasing erythropoietin (EPO) production.

[0297] Also, typically, the compound or pharmaceutical composition of the present invention is for use in the treatment of ischemia.Therefore, the compound or pharmaceutical composition of the present invention can treat ischemia-related diseases.Therefore, the compound or pharmaceutical composition of the present invention can be for use in the treatment of ischemia in circulatory or cardiovascular diseases, myocardial infarction, ischemia during surgery, organ ischemia, ischemic disease or diabetic limb ischemia, or sickle cell anemia.The compound or pharmaceutical composition of the present invention can be for use in providing cardioprotection after myocardial infarction.

[0298] The present invention also provides a method for treating a subject suffering from or susceptible to a PHD-related disorder, comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutical composition of the present invention as defined herein. The PHD-related disorder can be, for example, anemia, ischemia, sickle cell anemia, cancer, inflammation, Parkinson's disease, Alzheimer's disease, non-fatty liver disease, irritable bowel disease, cardiovascular disease, heart failure, chronic kidney disease, or renal failure. The disorder can be, for example, an HIF-related disorder, an EPO-related disorder, or a VHL-related disorder, such as von Hippel-Lindau (VHL) syndrome.

[0299] The present invention also provides a method for repairing skeletal muscle damage, increasing red blood cell count (RBC), increasing hemoglobin (HGB) production, increasing hematocrit (HCT) production, increasing erythropoietin (EPO) production, wound healing, angiogenesis, revascularization, stem cell activation, or cardioprotection after myocardial infarction in a subject, the method comprising administering to said subject an effective amount of a compound of the invention as defined herein, or a pharmaceutical composition of the invention.

[0300] The subject is generally a mammal, typically a human. However, the subject may also be a non-human. Preferred non-human animals include, but are not limited to, primates such as marmosets or monkeys, commercially raised animals such as horses, cows, sheep or pigs, and pets such as dogs, cats, mice, rats, guinea pigs, ferrets, gerbils or hamsters.

[0301] Diseases such as anemia, ischemia, and inflammation, which may be associated with hypoxia, have been shown to be closely related to erythropoietin (EPO) deficiency. Previous studies have shown that activating the HIF pathway can improve the effects of EPO. As mentioned above, PHD is an oxygenase that catalyzes the hydroxylation of specific prolyl residues in the oxygen degradation domain of the hypoxia-inducible factor alpha (HIF-α) subunit. Therefore, the compounds and compositions of the present invention, which are effective PHD inhibitors, can be useful for treating HIF pathway-related diseases and EPO-related diseases such as anemia, ischemia, and inflammation.

[0302] Increased EPO production can also lead to increased red blood cell (RBC) count and increased hemoglobin (HGB) production. Increasing red blood cell count can promote wound healing, angiogenesis, revascularization, or stem cell activation.

[0303] Both Parkinson's disease and Alzheimer's disease are associated with neuronal hypoxia. In particular, it has been suggested that stabilizing HIF in Parkinson's disease patients increases dopamine synthesis and dopaminergic neutron growth. In Alzheimer's disease patients, hypoxia can stimulate the production of amyloid-β peptide, which disrupts the membrane localization of glucose transporters (GLUTs) and affects glucose levels in the brain. Stabilizing HIF can upregulate neuronal glucose transporters such as GLUT-1 and GLUT-3, thereby alleviating this effect.

[0304] Thus, the compounds or pharmaceutical compositions of the invention are typically for use in the treatment of anemia.

[0305] The anemia referred to herein may be any form of anemia, including, for example, iron deficiency anemia, vitamin deficiency anemia, anemia of inflammation, aplastic anemia (such as pure red cell aplasia and Fanconi anemia), anemia associated with bone marrow disease, hemolytic anemia, sickle cell anemia, thalassemia, renal anemia (such as anemia associated with chronic kidney disease and anemia in dialysis patients), anemia of endocrine disease, megaloblastic anemia (such as pernicious anemia and folate deficiency anemia), anemia of prematurity, anemia due to congenital hematopoietic deficiency, and anemia associated with blood cell production disorders such as myelophthisic anemia and myelodysplastic syndrome.

[0306] Anemia can also be anemia associated with increased destruction of red blood cells (hemolytic anemia), which can be caused by intrinsic abnormalities (such as hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia, enzyme deficiencies, and sickle cell anemia), extrinsic abnormalities (such as antibody-mediated anemia, including Rh incompatibility and transfusion reactions, or mechanical trauma to red blood cells, including cardiac surgery, hemodialysis, and infections), or parasites such as Trypanosoma congolense.

[0307] The anemia can also be anemia associated with blood loss, such as anemia of prematurity, trauma or surgery, gastrointestinal pathology, gynecological disorders, menstruation, iatrogenic anemia, and the like.

[0308] Further causes of anemia can include fluid overload and intestinal inflammation (caused, for example, by Helicobacter pylori infection, gluten-related disorders such as celiac disease, or inflammatory bowel disease).

[0309] Typically, the anemia is renal anemia (e.g., anemia associated with chronic kidney disease, anemia in dialysis patients), chemotherapy-induced anemia, sickle cell anemia, cancer-related anemia, age-related anemia, or anemia resulting from cancer such as leukemia, multiple myeloma, and smoldering myeloma.

[0310] Often the anemia will be renal anemia, such as anemia associated with chronic kidney disease or anemia in dialysis patients.

[0311] The compounds or compositions of the invention may also be for use in the treatment of ischemia.

[0312] As used herein, ischemia may refer to any type of ischemia, including cardiac or circulatory ischemia (ischemia in circulatory or cardiovascular disease, myocardial infarction, coronary artery ischemia, coronary artery disease, myocardial ischemia, ischemic heart disease, etc.).

[0313] Ischemia also includes organ ischemia such as intestinal ischemia (such as intestinal ischemia, including ischemic colitis, and mesenteric ischemia), cerebral ischemia (including acute ischemia such as ischemic stroke and transient ischemic attack, and chronic ischemia that can lead to vascular dementia), and renal ischemia.

[0314] The ischemia can also be limb ischemia (acute limb ischemia, chronic limb ischemia, diabetic limb ischemia, etc.).

[0315] Ischemia can also be associated with ischemic disease. Ischemia can be ischemia during surgery. Ischemia can also be cutaneous ischemia (such as cyanosis and gangrene).

[0316] Typically, the ischemia is in circulatory or cardiovascular disease, myocardial infarction, ischemia during surgery, organ ischemia, ischemic disease or diabetic limb ischemia.

[0317] A therapeutically effective amount of a compound of the present invention is administered to a subject. As used herein, the term "therapeutically effective amount" refers to a therapeutically effective amount or a prophylactically effective amount. Similarly, a composition containing a therapeutically effective amount of a compound of the present invention can be administered to a subject. The dosage can be determined depending on various parameters, particularly the compound used; the age, weight, and condition of the subject being treated; the route of administration; and the required regimen. Again, a physician can determine the route of administration and dosage required for any particular subject. A typical daily dosage is about 0.01 to 100 mg / kg body weight, preferably about 0.1 mg / kg to 50 mg / kg, e.g., about 1 to 10 mg / kg body weight, depending on the activity of the specific inhibitor, the age, weight, and condition of the subject being treated, the type and severity of the disease, and the frequency and route of administration. Preferably, the daily dosage level is 1 mg to 2 g.

[0318] The present invention is further illustrated in the following examples and reference examples. [Example]

[0319] Synthesis Example General Procedure All reactions involving moisture-sensitive reagents were carried out under a nitrogen atmosphere using standard vacuum line techniques. Glassware was oven-dried and cooled under nitrogen before use. Commercially available anhydrous and HPLC-grade solvents used in reactions were used for workup and chromatography. Aqueous solutions were made using deionized water and purified using an Elix UV-10 system. Thin-layer chromatography (TLC) was performed using Merck (Darmstadt, Germany) silica gel 60 F254 TLC plates. TLC visualization was performed under UV light and stained with one of three stains: ninhydrin, potassium permanganate, or anisaldehyde. Chromatography was performed using Biotage® (Uppsala, Sweden) Isolera One or Biotage® SP4 flash purification systems using Biotage® prepacked SNAP columns. Reactions were monitored using an Agilent (Cheshire, UK) 1200 Series, 6120 quadrupole LC-MS system using a Merck Chromolith® Performance RP-18 HPLC column. Deuterated solvents were from Sigma-Aldrich, and 1H NMR spectra were obtained using a Bruker Avance AVIII HD 400 nanobay (400 MHz) instrument or a Bruker AV500 (500 MHz) instrument equipped with a 13C cryoprobe. All signals are reported in δ ppm, and multiplets are designated as singlet, doublet, triplet, quartet, and multiplet using the abbreviations s, d, t, q, and m, respectively. Chemical shifts in the presented NMR spectra were referenced using residual solvent peaks with coupling constants J reported in hertz (Hz) to an accuracy of 0.5 Hz. High-resolution mass spectrometry (HR-MS) was performed using a Bruker MicroTOF instrument equipped with an ESI source and a time-of-flight (TOF) analyzer. MS data are expressed as mass-to-charge ratio (m / z) in Daltons. Fourier transform infrared spectra (FT-IR) were obtained using a Bruker Tensor 27 instrument.Optical rotations were obtained using spectroscopic grade solvents and a Perkin Elmer 241 polarimeter.

[0320] All chemicals, reagents, and solvents were obtained from Sigma-Aldrich (Dorset, UK) and used without further purification. HPLC-grade solvents were used for reactions, chromatography, and workup.

[0321] General Procedure A Ethyl ester amide coupling: The relevant ethyl ester (1 equiv.), relevant amine (1 equiv.), and DABACO-(AlMe3)2 (1.0 equiv.) were added; the microwave vial was flushed with N2, which was removed in vacuo (3 times), and then anhydrous THF was added. The reaction mixture was then heated at 130 °C for 8 min using biotage microwave irradiation (unless otherwise noted). The reaction mixture was diluted with a mixture of CHCl:IPA (3:1, 20 ml), followed by KNaCHO 4HO. aq (50 ml) was added. The resulting mixture was stirred for 1 hour. The phases were then separated, and the organic phase was washed with water, brine, and dried over Na2SO4. The solvent was removed in vacuo. The crude compounds were purified by flash column chromatography using 20 column volumes (conditions described for each reaction) to give the desired compounds.

[0322] General Procedure B: Amide coupling: Carboxylic acid (1 eq.) and DIPEA (2.5 eq.) were dissolved in DMF. T3P (1.5 eq., 50% in DMF) or HATU (2 eq.) was then added. The resulting reaction mixture was stirred at room temperature for 30 minutes, after which an amine (1.2 eq.) was added. The resulting mixture was stirred at room temperature overnight. EtOAc (20 ml) and HO (100 ml) were added to the reaction mixture. The organic and aqueous fractions were separated. The aqueous layer was extracted twice more with EtOAc (30 ml). The organic fractions were combined, washed with brine, and dried over anhydrous Na2SO4. The crude compound was then purified using flash column chromatography over 20 column volumes to give the desired compound.

[0323] General procedure C: Pd-catalyzed amination: An aryl halide (1 equiv.), an amine (1.2 equiv.), CsCO (2 equiv.), and a Pd-ligand conjugate (0.1 equiv.) were placed under an anhydrous N atmosphere, followed by the addition of tert-butanol. The resulting mixture was heated at 80 °C for 16 h. The reaction mixture was then allowed to cool to room temperature. EtOAc (20 mL) and H2O (100 mL) were added to the reaction mixture. The organic and aqueous fractions were separated. The aqueous layer was extracted twice more with EtOAc (30 mL). The organic fractions were combined, then washed with brine and dried using anhydrous Na2SO4. The crude compound was then purified using flash column chromatography using 20 column volumes (0–100% EtOAc in cyclohexane) to give the desired compound.

[0324] General Procedure D: C-4 methoxy demethylation: The methoxy starting material (1 equiv.) was dissolved in DMAc, followed by the addition of LiCl.HO (10 equiv.). The resulting mixture was heated at 120°C for 2 hours by microwave irradiation (unless otherwise noted). The resulting mixture was diluted with water (100 ml) and extracted with EtOAc (3 x 20 ml). The organic phases were combined, washed with water, brine, and dried over anhydrous NaSO. The volatiles were then evaporated in vacuo, and the desired compound was purified by flash column chromatography using 100% to 95% CHCl, 0% to 20% MeOH over 15 column volumes (unless otherwise noted) to give the desired compound.

[0325] Reference Example 1 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-4-chloro-2-methoxybenzamide (14) [ka] Following general procedure B, 14 (451 mg, 1.24 mmol, 95%) was obtained from 4-chloro-2-methoxybenzoic acid (250 mg, 1.34 mmol), 4-phenylbenzylamine (294 mg, 1.6 mmol), T3P (1.06 g, 3.36 mmol), and DIPEA (412 mg, 3.36 mmol). 1 H NMR(400MHz,chloroform-d)δ 8.21(d,J=8.5Hz,1H),8.12(t,J=6.0Hz,1H),7.60-7.56(m,4H),7.46-7.41(m,4H),7.37-7.30 (m,1H),7.08(dd,J=8.5,2.0Hz,1H),6.97(d,J=2.0Hz,1H),4.71(d,J=6.0Hz,2H),3.93(s,3H). C 21 H 19 O2N 35 Cl[M+H] + HRMS (ESI-TOF) calculated value: 352.1098, observed value: 352.1098.

[0326] Reference Example 2 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-2-methoxy-4-(1H-pyrazol-1-yl)benzamide (15) [ka] According to general procedure C, 14 (100 mg, 0.284 mmol), Pd t 15 (28 mg, 0.073 mmol, 26%) was obtained from BuXPhos G3 (20 mg, 0.028 mmol), Cs2CO3 (185 mg, 0.568 mmol), and pyrazole (23 mg, 0.34 mmol). 1 H NMR(400MHz,DMSO-d6)δ 8.77(t,J=6.0Hz,1H),8.66(d,J=2.5Hz,1H),7.80(d,J=1.5Hz,1H),7.69-7 .32(m,12H),6.60(dd,J=2.5,1.5Hz,1H),4.56(d,J=6.0Hz,2H),4.01(s,3H) C 24 H22 O2N3[M+H] + HRMS (ESI-TOF) calculated value: 384.1704, observed value: 384.1704.

[0327] Reference Example 3 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-2-hydroxy-4-(1H-pyrazol-1-yl)benzamide (16) [ka] TMS-I (39 mg, 0.195 mmol) was added to a solution of 15 (25 mg, 0.0652 mmol) and CHCl (2.5 mL). The resulting mixture was refluxed at 90 °C for 8 h, then cooled to room temperature and treated with HCl. aq (1.5 ml, 1 M) was added followed by extraction with CHCl (3 × 10 ml). The organic fractions were combined, dried over anhydrous NaSO, concentrated in vacuo, and the crude compound was then purified using flash column chromatography using (0–5% MeOH, CHCl, 1% NH) over 20 column volumes to give 16 (7.5 mg, 0.020 mmol, 31%). 1 H NMR(400MHz,DMSO-d6)δ 12.96(s,1H),9.43(t,J=6.0Hz,1H),8.61(dd,J=2.5,1.0Hz,1H),8.05(d,J=8.0Hz,1H),7. 79(d,J=1.5Hz,1H),7.70-7.31(m,11H),6.58(dd,J=2.5,1.5Hz,1H),4.57(d,J=6.0Hz,2H). C 23 H 20 O2N3[M+H] + HRMS (ESI-TOF) calculated value: 370.1548, observed value: 370.1548.

[0328] Reference Example 4 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-2-chloropyrimidine-5-carboxamide (17) [ka] Following general procedure B, 17 (285 mg, 0.88 mmol, 47%) was obtained from 2-chloro-5-carboxypyrimidine (300 mg, 1.89 mmol), 4-phenylbenzylamine (370 mg, 2.26 mmol), T3P (819 mg, 2.83 mmol) and DIPEA (365 mg, 2.83 mmol). 1 H NMR (400MHz, DMSO-d6) δ 9.46 (t, J = 6.0 Hz, 1H), 9.18 (s, 2H), 7.87-6.86 (m, 9H), 4.56 (d, J = 6.0Hz, 2H). C 18 H 15 35 ClNO[M+H] + HRMS (ESI-TOF) calculated value: 324.0898, observed value: 324.0899.

[0329] Reference Example 5 - Synthesis of 2-chloro-N-(4-phenoxybenzyl)pyrimidine-5-carboxamide (18) [ka] Following general procedure B, 18 (336 mg, 0.99 mmol, 52%) was obtained from 2-chloro-5-carboxypyrimidine (300 mg, 1.89 mmol), 4-phenoxybenzylamine (410 μl, 2.26 mmol) and T3P (1.5 g, 4.72 mmol). 1 H NMR (400MHz, DMSO-d6) δ 9.41 (t, J = 6.0 Hz, 1H), 9.16 (s, 2H), 7.53-7.27 (m, 4H), 7.19-6.78 (m, 5H), 4.50 (d, J = 6.0Hz, 2H). C 18 H 14 35 ClNO[M+H] + HRMS (ESI-TOF) calculated value: 340.0847, observed value: 340.1327.

[0330] Reference Example 6 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-6-chloronicotinamide (19) [ka] Following general procedure A, 19 (154 mg, 0.48 mmol, 91%) was obtained from 2-chloroethyl nicotinate (83 μl, 0.53 mmol), 4-phenylbenzylamine (97 mg, 0.53 mmol), and DABCO-(AlMe) (108 mg, 0.424 mmol). 1 H NMR(400MHz,DMSO-d6)δ 9.34(t,J=6.0Hz,1H),8.90(d,J=2.5Hz,1H),8.30(dd,J=8.5,2.5Hz,1H),7.87-7.19(m,10H),4.54(d,J=6.0Hz,2H). C 19 H 15 ClNO[M+H] + HRMS (ESI-TOF) calculated value: 322.0873, observed value: 322.0821.

[0331] Reference Example 7 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamide (20) [ka] According to general procedure C, 17 (57 mg, 0.176 mmol), Pd t 20 (10 mg, 0.0281 mmol, 16%) was obtained from BuXPhos G3 (15 mg, 0.0176 mmol), Cs2CO3 (201 mg, 0.619 mmol), and pyrazole (42 mg, 0.619 mmol). 1 H NMR(400MHz,DMSO-d6)δ 9.44(t,J=6.0Hz,1H),9.27(s,2H),8.73(d,J=3.0Hz,1H),7.93(d,J=1.5Hz,1H),7.74-7.60(m ,4H),7.51-7.40(m,4H),7.39-7.31(m,1H),6.65(dd,J=3.0,1.5Hz,1H),4.58(d,J=5.8Hz,2H). C21 H 18 ON5[M+H] + HRMS (ESI-TOF) calculated value: 356.1505, observed value: 356.1504.

[0332] Example 8 - Synthesis of N-(4-phenoxybenzyl)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamide (21) [ka] According to general procedure C, 18 (100 mg, 0.294 mmol), pyrazole (40 mg, 0.589 mmol), Pd t 21 (64 mg, 0.172 mmol, 58%) was obtained from BuXPhos G3 (23 mg, 0.0294 mmol) and Cs2CO3 (238 mg, 0.735 mmol). 1 H NMR(400MHz,DMSO-d6)δ 8.96(d,J=3.0Hz,1H),8.68(d,J=3.0Hz,1H),8.51-8.37(m,1H),8.03-7. 98(m,1H),7.48-6.90(m,10H),6.62-6.61(m,1H),4.51(d,J=6.0Hz,2H). C 21 H 17 N5O2[MH] - HRMS (ESI-TOF) calculated value: 370.1382, observed value: 370.1309.

[0333] Example 9 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-6-(1H-pyrazol-1-yl)nicotinamide (22) [ka] Following procedure C, 19 (100 mg, 0.31 mmol), pyrazole (40 mg, 0.589 mmol), and Pd t 22 (53 mg, 0.028 mmol, 48%) was obtained from BuXPhos G3 (25 mg, 0.031 mmol) and Cs2CO3 (238 mg, 0.735 mmol). 1 H NMR(400MHz,DMSO-d6)δ 9.32(t,J=6.0Hz,1H),8.97(d,J=2.0Hz,1H),8.69(d,J=2.5Hz,1H),8.47(dd,J=9.0,2.0Hz,1H),8.30(dd,J= 9.0,2.0Hz,1H),7.90(d,J=1.5Hz,1H),7.74-7.22(m,9H),6.63(dd,J=2.5,1.5Hz,1H),4.57(d,J=6.0Hz,2H). C 22 H 19 ON4[M+H] + HRMS (ESI-TOF) calculated value: 355.1553, observed value: 355.1551.

[0334] Reference Example 1 Synthesis of 0-N-benzyl-6-chloronicotinamide (28) [ka] Following general procedure A, 28 (220 mg, 0.897 mmol, 83%) was obtained from 2-chloro-ethyl nicotinate (200 mg, 1.081 mmol), benzylamine (116 mg, 1.08 mmol), and DABACO-AlMe (221 mg, 0.864 mmol). Solvent system used for purification: 0% to 100% EtOAc in cyclohexane. 1 H NMR(400MHz,DMSO-d6)δ 9.32(t,J=6.0Hz,1H),8.89(dd,J=2.5,1.0Hz,1H),8.29(dd,J=8.5,2.5Hz,1H),7.87-7.57(m,1H),7.50-6.86(m,5H),4.51(d,J=6.0Hz,2H). C 13 H 10 ON2 35 Cl[MH] - HRMS (ESI-TOF) calculated value: 245.0487, observed value: 245.0482.

[0335] Example 1 Synthesis of 1-ethyl 1-(5-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (29) [ka] Following general procedure C, 29 (97 mg, 0.227 mmol, 59%) was obtained from 19 (125 mg, 0.388 mmol), pyrazole-4-carboxylate ethyl ester (65 mg, 0.465 mmol), PdtBuxPhos G3 (31 mg, 0.0388 mmol), Cs2CO3 (252 mg, 0.776 mmol), and tBuOH (3 mL). 1 H NMR(400MHz,DMSO-d6)δ 9.38(t,J=6.0Hz,1H),9.04(s,1H),9.02(d,J=2.5Hz,1H),8.51(dd,J=8.5,2.5Hz,1H),8.27(s,1H),8.07 (d,J=8.5Hz,1H),7.69-7.30(m,9H),4.54(d,J=6.0Hz,2H),4.21(q,J=7.0Hz,2H),1.31(t,J=7.0Hz,3H). C 25 H 21 O3N4[MH] - HRMS (ESI-TOF) calculated value: 425.1619, observed value: 425.1622.

[0336] Example 1 Synthesis of 2-ethyl 1-(5-(benzylcarbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (30) [ka] According to general procedure C, 28 (80 mg, 0.325 mmol), Pd t BuXPhos G3 (25 mg, 0.0325 mmol), Cs2CO3 (317 mg, 0.97 mmol), pyrazole-4-carboxylate ethyl ester (67 mg, 0.48 mmol), and t BuOH (3 ml) gave 30 (41 mg, 0.117 mmol, 36%). 1 H NMR(400MHz,DMSO-d6)δ 9.33(t,J=6.0Hz,1H),9.04(d,J=1.0Hz,1H),8.99(dd,J=2.5,1.0Hz,1H),8.49(dd,J=8.5,2.5Hz,1H),8.27(d,J=1.0Hz, 1H,),8.06(dd,J=8.5,1.0Hz,1H),7.38-7.32(m,5H),4.53(d,J=6.0Hz,2H),4.28(q,J=7.0Hz,2H),1.31(t,J=7.0Hz,3H). C 19 H 17 O3N4[MH] - HRMS (ESI-TOF) calculated value: 349.1306, observed value: 349.1302.

[0337] Example 13 - Synthesis of 1-(5-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (31) [ka] 29 (63 mg, 0.147 mmol) was dissolved in a mixture of THF and water (10 mL (10:1)), followed by the addition of LiOH monohydrate (19 mg, 0.45 mmol). The resulting mixture was allowed to stir for 16 h and was found to be complete by TLC. HCl aq (10 ml, 1 M) was added to the reaction mixture, and the resulting mixture was extracted with EtOAc (3 × 20 ml). The organic fractions were combined, washed with brine, dried over NaSO, and purified by flash column chromatography using (CHCl, MeOH 0–5%, formic acid 1%) over 20 column volumes to give 31 (15 mg, 0.037 mmol, 26%). 1H NMR(400MHz,DMSO-d6)δ 9.37-9.34(m,1H),9.01(d,J=2.5Hz,1H),8.92(d,J=2.5Hz,1H),8.53-8.47(m,1H),8.09-8.0 1(m,1H),7.70-7.62(m,4H),7.46(t,J=7.8Hz,4H),7.39-7.30(m,2H),4.56(d,J=6.0Hz,2H). C 23 H 17 O3N4[MH] - HRMS (ESI-TOF) calculated value: 397.1306, observed value: 397.1310.

[0338] Example 14 - Synthesis of 1-(5-(benzylcarbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (32) [ka] 30 (20 mg, 0.043 mmol) was dissolved in THF (2 mL), and MeOH (2 mL) and water (0.5 mL) were added to the reaction mixture, followed by LiOH monohydrate (16 mg, 0.40 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was acidified to pH 3 with HCl (1 M) solution, extracted with EtOAc (3 × 25 mL), washed with brine, and dried over anhydrous NaSO. The crude compound was then purified using flash column chromatography using 20 column volumes (CHCl, 0–5% MeOH, 1% formic acid) to give 32 (13 mg, 0.040 mmol, 94%). 1 H NMR(400MHz,DMSO-d6)δ 9.34(t,J=6.0Hz,1H),8.99(dd,J=2.5,1.0Hz,1H),8.96(s,1H),8.48(dd,J=8.5,2. 5Hz,1H),8.19(s,1H),8.08-8.02(m,1H),7.48-7.21(m,5H),4.54(d,J=6.0Hz,2H). C 17 H 13 O3N4[MH] -HRMS (ESI-TOF) calculated value: 321.0993, observed value: 321.0994.

[0339] Example 15 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-6-chloro-4-methoxynicotinamide (33) [ka] Following general procedure B, 33 (432 mg, 1.22 mmol, 76%) was obtained from 6-chloro-4-methoxynicotinic acid (300 mg, 1.60 mmol), 4-phenylbenzylamine (439 mg, 2.4 mmol), T3P (1.27 g, 4 mmol) and DIPEA (825 μl, 4.8 mmol). 1 H NMR(400MHz,DMSO-d6)δ 8.82(t,J=6.0Hz,1H),8.51(s,1H),7.68-7.60(m,4H),7.57-7.27(m,6H),4.53(d,J=6.0Hz,2H),3.99(s,3H). C 20 H 18 O2N2 35 Cl[M+H] + HRMS (ESI-TOF) calculated value: 353.1051, observed value: 353.1048.

[0340] Reference Example 1 Synthesis of 6-N-([1,1'-biphenyl]-4-yl)-6-chloro-4-methoxynicotinamide (34) [ka] Following general procedure B, 34 (311 mg, 0.92 mmol, 34%) was obtained from 6-chloro-4-methoxynicotinic acid (500 mg, 2.67 mmol), 4-aminobiphenyl (540 mg, 3.2 mmol), T3P (2.12 g, 6.68 mmol) and DIPEA (846 μl, 6.68 mmol). 1H NMR(400MHz,DMSO-d6)δ 10.36(s,1H),8.46(s,1H),7.87-7.77(m,2H),7.71-7.62(m,4H),7.52-7.30(m,4H),3.99(s,3H). C 19 H 16 O2N2 35 Cl[M+H] + HRMS (ESI-TOF) calculated value: 339.0894, observed value: 339.0893.

[0341] Reference Example 17-Synthesis of 6-chloro-4-methoxy-N-(3-(trifluoromethyl)benzyl)nicotinamide (35) [ka] Following general procedure B, 35 (518 mg, 1.505 mmol, 56%) was obtained from 6-chloro-4-methoxynicotinic acid (500 mg, 2.67 mmol), 3-trifluoromethylbenzylamine (566 mg, 3.2 mmol), T3P (2.12 g, 6.68 mmol) and DIPEA (846 μl, 6.68 mmol). 1 H NMR (400MHz, DMSO-d6) δ 8.91 (t, J = 6.0 Hz, 1H), 8.48 (s, 1H), 7.75-7.53 (m, 4H), 7.35 (s, 1H), 4.57 (d, J = 6.0Hz, 2H), 3.98 (s, 3H). C 15 H 13 O2N2 35 ClF3[M+H] + HRMS (ESI-TOF) calculated value: 345.0612, observed value: 345.0613.

[0342] Reference Example 18-6-chloro-N-(cyclohexylmethyl)-4-methoxynicotinamide (36) [ka] Following general procedure B, 36 (438 mg, 1.55 mmol, 58%) was obtained from 6-chloro-4-methoxynicotinic acid (500 mg, 2.67 mmol), cyclohexanemethylamine (361 mg, 3.2 mmol), T3P (2.12 g, 6.68 mmol) and DIPEA (846 μl, 6.68 mmol). 1 H NMR(400MHz,DMSO-d6)δ 8.40(s,1H),8.17(t,J=6.0Hz,1H),7.30(s,1H),3.95(s,3H,),3.12-3.06(m,2H),1.87-0.75(m,11H). C 14 H 20 O2N2 35 Cl[M+H] + HRMS (ESI-TOF) calculated value: 283.1207, observed value: 283.1208.

[0343] Example 19 - N-([1,1'-biphenyl]-4-ylmethyl)-4-methoxy-6-(1H-pyrazol-1-yl)nicotinamide (37) [ka] According to general procedure C, 33 (50 mg, 0.142 mmol), Pd t 37 (30 mg, 0.078 mmol, 55%) was obtained from BuXPhos G3 (11.2 mg, 0.0142 mmol), Cs2CO3 (138 mg, 0.426 mmol), and pyrazole (24 mg, 0.355 mmol). 1 H NMR(400MHz,DMSO-d6)δ 8.79(t,J=6.0Hz,1H),8.68-8.65(m,2H),7.88(dd,J=1.5,1.0Hz,1H),7.67-7.46(m,9 H),7.39-7.33(m,1H),6.61(dd,J=2.5,1.5Hz,1H),4.55(d,J=6.0Hz,2H),4.08(s,3H). C 23 H 21 O2N4[M+H] +HRMS (ESI-TOF) calculated value: 385.1659, observed value: 385.1658.

[0344] Example 20 - Synthesis of N-([1,1'-biphenyl]-4-yl)-4-methoxy-6-(1H-pyrazol-1-yl)nicotinamide (38) [ka] According to general procedure C, 34 (150 mg, 0.43 mmol), Pd t 38 (67 mg, 0.181 mmol, 40%) was obtained from BuXPhos G3 (34 mg, 0.043 mmol), Cs2CO3 (354 mg, 1.09 mmol), and pyrazole (74 mg, 1.09 mmol). 1 H NMR(400MHz,DMSO-d6)δ 8.68(d,J=2.5Hz,1H),8.59(s,1H),7.90(d,J=1.5Hz,1H),7.70-7.63(m,6H),7.52-7.42(m,4H),6.63(dd,J=2.5,1.5Hz,1H),4.08(s,3H). C 22 H 19 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 371.1502, observed value: 371.1501.

[0345] Example 21 - Synthesis of 6-chloro-4-methoxy-N-(3-(trifluoromethyl)benzyl)nicotinamide (39) [ka] According to general procedure C, 35 (150 mg, 0.43 mmol), Pd t 39 (72 mg, 0.191 mmol, 44%) was obtained from BuXPhos G3 (34 mg, 0.043 mmol), Cs2CO3 (354 mg, 1.09 mmol), and pyrazole (74 mg, 1.09 mmol). 1H NMR(400MHz,DMSO-d6)δ 9.26(t,J=6.0Hz,1H),8.66(dd,J=2.5,1.0Hz,1H),8.62(s,1H),8.33(d,J=2.5Hz,1H),7.88(dd,J= 1.5,1.0Hz,1H),7.68-7.57(m,4H),6.61(dd,J=2.5,1.5Hz,1H),4.59(d,J=6.0Hz,2H),4.07(s,3H). C 18 H 16 O2N4F3[M+H] + HRMS (ESI-TOF) calculated value: 377.1219, observed value: 377.1220.

[0346] Example 2 Synthesis of 2-N-(cyclohexylmethyl)-4-methoxy-6-(1H-pyrazol-1-yl)nicotinamide (40) [ka] According to general procedure C, 36 (150 mg, 0.43 mmol), Pd t 40 (67 mg, 0.21 mmol, 40%) was obtained from BuXPhos G3 (34 mg, 0.043 mmol), Cs2CO3 (354 mg, 1.09 mmol), and pyrazole (74 mg, 1.09 mmol). 1 H NMR(400MHz,DMSO-d6)δ 8.68(dd,J=2.5,1.0Hz,1H),8.56(s,1H),7.90(dd,J=1.5,1.0Hz,1H),7.57(s,1H),6.64(dd,J=2.5, 1.5Hz, 1H), 3.95 (s, 3H), 3.06-3.03 (m, 2H), 1.79-1.58 (m, 5H), 1.28-1.09 (m, 4H), 1.00-0.83 (m, 2H). C 17 H 23 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 315.1815, observed value: 315.1816.

[0347] Example 23 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-4-hydroxy-6-(1H-pyrazol-1-yl)nicotinamide (41) [ka] TMS-I (17 mg, 0.0858 mmol) was added to a mixture of 37 (11 mg, 0.0286 mmol) and CHCl (1 mL). The resulting mixture was heated at 90 °C for 90 min, then cooled to room temperature and treated with HCl. aq (1.5 ml, 1 M) was added followed by extraction with CHCl (3 × 10 ml). The organic fractions were combined, dried over anhydrous NaSO, concentrated in vacuo, and the crude compound was then purified using flash column chromatography using (0–5% MeOH, CHCl, 1% NH) over 20 column volumes to give 41 (2 mg, 0.0054 mmol, 20%). 1 H NMR(400MHz,DMSO-d6)δ 8.76(s,1H),8.64(d,J=2.5Hz,1H),7.86(d,J=1.5Hz,1H),7.70-7.60(m,5 H),7.52-7.29(m,6H),6.60(dd,J=2.5,1.5Hz,1H),4.59(d,J=6.0Hz,2H). C 22 H 19 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 371.1502, observed value: 371.1502.

[0348] Example 24 Synthesis of N-([1,1'-biphenyl]-4-yl)-4-hydroxy-6-(1H-pyrazol-1-yl)nicotinamide (42) [ka] TMS-I (66 mg, 0.33 mmol) was added to a reaction mixture of 38 (41 mg, 0.11 mmol) and CHCl (2.5 mL). The resulting mixture was heated at 90 °C for 90 min, then cooled to room temperature and treated with HCl. aq(1.5 ml, 1 M) was added followed by extraction with CHCl (3 × 10 ml). The organic fractions were combined, dried over anhydrous NaSO, concentrated in vacuo, and the crude compound was then purified using flash column chromatography using (0–5% MeOH, CHCl, 1% NH) over 20 column volumes to give 42 (7 mg, 0.0196 mmol, 18%). 1 H NMR(400MHz,DMSO-d6)δ 8.70(d,J=2.0Hz,1H),8.64(s,1H),7.92(d,J=2.0Hz,1H),7.72-7.62(m,5H),7.55-7.27(m,6H),6.65(dd,J=2.0Hz,1H). C 21 H 17 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 357.1346, observed value: 357.1343.

[0349] Example 25 - Synthesis of 4-hydroxy-6-(1H-pyrazol-1-yl)-N-(3-(trifluoromethyl)benzyl)nicotinamide (43) [ka] TMS-I (59 mg, 0.295 mmol) was added to a reaction mixture of 39 (37 mg, 0.0986 mmol) and CHCl (2.5 mL). The resulting mixture was heated at 90 °C for 90 min, then cooled to room temperature and treated with HCl. aq (1.5 ml, 1 M) was added followed by extraction with CHCl (3 × 10 ml). The organic fractions were combined, dried over anhydrous NaSO, concentrated in vacuo, and the crude compound was then purified using flash column chromatography using (0–5% MeOH, CHCl, 1% NH) over 20 column volumes to give 43 (20 mg, 0.055 mmol, 57%). 1H NMR(400MHz,DMSO-d6)δ 8.66(s,1H),8.59(dd,J=2.5,1.0Hz,1H),7.82(dd,J=1.5,1.0Hz,1H),7.71- 7.49(m,4H),7.26(s,1H),6.55(dd,J=2.5,1.5Hz,1H),4.59(d,J=6.0Hz,2H). C 17 H 14 O2N4F3[M+H] + HRMS (ESI-TOF) calculated value: 363.1063, observed value: 363.1067.

[0350] Example 26 - Synthesis of N-(cyclohexylmethyl)-4-hydroxy-6-(1H-pyrazol-1-yl)nicotinamide (44) [ka] TMS-I (128 mg, 0.64 mmol) was added to a reaction mixture of 40 (67 mg, 0.214 mmol) and CHCl (2.5 mL). The resulting mixture was heated at 90 °C for 90 min, then cooled to room temperature and treated with HCl. aq (1.5 ml, 1 M) was added followed by extraction with CHCl (3 × 10 ml). The organic fractions were combined, dried over anhydrous NaSO, concentrated in vacuo, and the crude compound was then purified using flash column chromatography using (0–5% MeOH, CHCl, 1% NH) over 20 column volumes to give 44 (17 mg, 0.056 mmol, 26%). 1 H NMR(400MHz,DMSO-d6)δ 8.63(d,J=2.5Hz,1H),8.47(s,1H),8.29(d,J=2.5Hz,1H),8.21(s,1H),6.65-6.63(m ,1H),3.05(t,J=6.0Hz,2H),1.75-1.44(m,5H),1.27-1.10(m,3H),1.05-0.80(m,2H). C 16 H 21 O2N4[M+H] +HRMS (ESI-TOF) calculated value: 301.1659, observed value: 301.1656.

[0351] Reference Example 27-Synthesis of 6-chloro-4-methoxy-N-(4-(trifluoromethyl)benzyl)nicotinamide (45) [ka] Following general procedure B, 45 (437 mg, 1.27 mmol, 66%) was obtained from 6-chloro-5-methoxynicotinic acid (350 mg, 1.87 mmol), 4-trifluoromethylbenzylamine (448 mg, 2.56 mmol), T3P (1.48 g, 4.67 mmol) and DIPEA (803 μl, 4.67 mmol). 1 H NMR(400MHz,chloroform-d)δ 9.02(s,1H),7.81(t,J=6.0Hz,1H),7.58(d,J=8.0Hz,2H,),7.43(d,J=8.0Hz,2H),6.93(s,1H),4.69(d,J=6.0Hz,2H),4.01(s,3H). C 15 H 13 O2N2 35 ClF3[M+H] + HRMS (ESI-TOF) calculated value: 345.0612, observed value: 345.0608.

[0352] Reference Example 2 Synthesis of 8-N-([1,1'-biphenyl]-3-ylmethyl)-6-chloro-4-methoxynicotinamide (46) [ka] Following general procedure B, 46 (570 mg, 1.61 mmol, 76%) was obtained from 6-chloro-5-methoxynicotinic acid (400 mg, 2.13 mmol), 3-phenylbenzylamine (469 mg, 2.56 mmol), T3P (1.62 g, 5.12 mmol) and DIPEA (880 μl, 5.12 mmol). 1H NMR (400MHz, DMSO-d6) δ 8.85 (t, J = 6.0 Hz, 1H), 8.48 (s, 1H), 7.70-7.30 (m, 10H), 4.56 (d, J = 6.0Hz, 2H), 3.96 (s, 3H). C 20 H 18 O2N2 35 Cl[M+H] + HRMS (ESI-TOF) calculated value: 353.1051, observed value: 353.1053.

[0353] Reference Example 2: Synthesis of 9-N-([1,1'-biphenyl]-3-yl)-6-chloro-4-methoxynicotinamide (47) [ka] Following general procedure B, 47 (421 mg, 1.24 mmol, 66%) was obtained from 6-chloro-5-methoxynicotinic acid (350 mg, 1.87 mmol), 3-aminobiphenyl (411 mg, 2.43 mmol), T3P (1.48 g, 4.67 mmol) and DIPEA (803 μl, 4.67 mmol). 1 H NMR (400 MHz, chloroform-d) δ 9.24 (s, 1H), 9.05 (s, 1H), 7.90-7.87 (m, 1H), 7.66-7.30 (m, 8H), 6.91 (s, 1H), 4.06 (s, 3H). C 19 H 16 O2N2 35 Cl[M+H] + HRMS (ESI-TOF) calculated value: 339.0894, observed value: 339.0894.

[0354] Reference Example 30: Synthesis of 6-chloro-4-methoxy-N-(4-(trifluoromethoxy)benzyl)nicotinamide (48) [ka] Following general procedure B, 48 (434 mg, 1.20 mmol, 75%) was obtained from 6-chloro-5-methoxynicotinic acid (300 mg, 1.60 mmol), 4-trifluoromethoxybenzylamine (367 mg, 1.92 mmol), T3P (1.01 g, 3.2 mmol) and DIPEA (803 μl, 4.67 mmol). 1 H NMR (400 MHz, chloroform-d) δ 8.97 (s, 1H), 7.78 (t, J = 6.0 Hz, 1H), 7.37-7.29 (m, 2H), 7.17-7.11 (m, 2H), 6.90 (s, 1H), 4.61 (d, J = 6.0 Hz, 2H), 3.98 (s, 3H). C 15 H 13 O3N2 35 ClF3[M+H] + HRMS (ESI-TOF) calculated value: 361.0561, observed value: 361.0563.

[0355] Reference Example 3: Synthesis of 1-6-chloro-4-methoxy-N-((4-(trifluoromethyl)cyclohexyl)methyl)nicotinamide (49) [ka] Following general procedure B, 49 (402 mg, 1.14 mmol, 86%) was obtained from 6-chloro-5-methoxynicotinic acid (250 mg, 1.33 mmol), C-(4-trifluoromethylcyclohexylamine (255 mg, 1.59 mmol), T3P (827 mg, 2.6 mmol) and DIPEA (803 μl, 4.67 mmol). 1 H NMR(400MHz,CDCl3)δ 8.89(s,1H),7.31(s,1H),6.82(s,1H),3.94(s,3H),3.23(t,J=6.2Hz,2H),1.95-1.74 (m,5H),1.57-1.42(m,1H),1.21(qd,J=12.7,2.9Hz,2H),0.93(qd,J=12.8,3.1Hz,2H). C 15 H 19 O2N2 35ClF3[M+H] + HRMS (ESI-TOF) calculated value: 351.1081, observed value: 351.1078.

[0356] Reference Example 3 Synthesis of 2-tert-butyl((6-chloropyridin-3-yl)methyl)carbamate (50) [ka] 6-Chloropyridin-3-yl)methamine (4.0 g, 0.0281 mol) was dissolved in CHCl (50 mL), followed by the addition of DIPEA (36.9 mL, 0.049 mol). Di-tert-butyl dicarbonate (7.6 g, 0.035 mol) was slowly added to the reaction mixture, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then washed with water (3 × 50 mL), brine (50 mL), and dried over NaSO. The organic phase was reduced in vacuo and then purified by flash column chromatography using 20 column volumes (cyclohexane 100% to 50%, EtOAc 0% to 50%) to give 50 (6.08 g, 0.0251 mmol, 89%). 1 H NMR(400MHz,chloroform-d)δ 8.25(dd,J=2.5,1.0Hz,1H),7.58(dd,J=8.5,2.5Hz,1H,),7.24(d,J=1.0Hz,1H),5.08(s,1H),4.26(d,J=6.0Hz,2H),1.41(s,9H). C 11 H 16 O2N2 35 Cl[M+H] + HRMS (ESI-TOF) calculated value: 243.0894, observed value: 243.0895.

[0357] Reference Example 3 Synthesis of 3-tert-butyl((6-phenylpyridin-3-yl)methyl)carbamate (51) [ka] 50 (500 mg, 2.06 mmol), phenylboronic acid (249 mg, 2.06 mmol), Pd tetrakis (118 mg, 0.103 mmol), and CsCO (1.33 g, 4.12 mmol) were dissolved in anhydrous dioxane (5 mL). The resulting mixture was heated at 100 °C for 30 min under microwave irradiation. The reaction mixture was filtered through a Celite pad, and water (25 mL) was added to the reaction mixture, followed by extraction with CHCl (3 × 25 mL). The organic fractions were combined, washed with water (3 × 50 mL), brine (50 mL), and dried over NaSO. The organic phase was removed in vacuo and then purified by flash column chromatography using 20 column volumes (cyclohexane 100% to 50%, EtOAc 0% to 50%) to give 51 (520 mg, 1.83 mmol, 89%). 1 H NMR (400 MHz, chloroform-d) δ 8.58 (t, J = 1.5 Hz, 1H), 7.98-7.93 (m, 2H), 7.67 (d, J = 1.5 Hz, 2H), 7.48-7.38 (m, 3H), 5.08 (s, 1H), 4.34 (d, J = 6.0 Hz, 2H), 1.46 (s, 9H). C 17 H 21 O2N2[M+H] + HRMS (ESI-TOF) calculated value: 285.1597, observed value: 285.1594.

[0358] Reference Example 3 Synthesis of 4-(6-phenylpyridin-3-yl)methanamine (52) [ka] 51 (500 mg, 1.76 mmol) was dissolved in CHCl (5 mL), and HCl (2 M in ether (3 mL)) was added to the solution. The resulting mixture was placed under vacuum and flushed with N. This was repeated three times. The resulting mixture was stirred at room temperature for 16 h. The volatiles were evaporated in vacuo to give 52 (312 mg, 1.69 mmol, 96%). 1H NMR(400MHz,DMSO-d6)δ 8.85(s,2H),8.79(dd,J=2.5,1.0Hz,1H),8.15-8.07(m,3H,),8.02(dd,J=8.0,1.0Hz,1H),7.55-7.41(m,3H),4.08(s,2H). C 12 H 13 N2[M+H] + HRMS (ESI-TOF) calculated value: 185.1073, observed value: 185.1073.

[0359] Reference Example 3: Synthesis of 5-6-chloro-4-methoxy-N-((6-phenylpyridin-3-yl)methyl)nicotinamide (53) [ka] Following general procedure B, 52 (100 mg, 0.54 mmol), 6-chloro-4-methoxynicotinic acid (85 mg, 0.45 mmol) and T3P (358 mg, 1.125 mmol) gave 53 (144 mg, 0.41 mmol, 90%). 1 H NMR(400MHz,DMSO-d6)δ 8.91(t,J=6.0Hz,1H,),8.51(s,1H),8.13-7.79(m,4H),7.63-7.37(m,4H),7.32(s,1H),4.54(d,J=6.0Hz,2H),3.98(s,3H)C 19 H 17 O2N3 35 Cl[M+H] + HRMS (ESI-TOF) calculated value: 354.1003, observed value: 354.1002.

[0360] Example 36 - Synthesis of 4-methoxy-6-(1H-pyrazol-1-yl)-N-(4-(trifluoromethyl)benzyl)nicotinamide (56) [ka] According to general procedure C, 45 (200 mg, 0.58 mmol), Pd tBuXPhos G3 (46 mg, 0.058 mmol), Cs2CO3 (377 mg, 1.16 mmol), pyrazole (42 mg, 0.63 mmol) and t BuOH (2 ml) gave 56 (69 mg, 0.185 mmol, 32%). 1 H NMR(400MHz,DMSO-d6)δ 8.88(t,J=6.0Hz,1H),8.66(dd,J=2.5,1.0Hz,1H),8.64(s,1H),7.89(t,J=1.5,1.0Hz,1H),7.72(d,J=7.0H z,2H),7.60(s,1H),7.56(d,J=7.0Hz,2H),6.62(dd,J=2.5,1.5Hz,1H),4.59(d,J=6.0Hz,2H),4.08(s,3H). C 18 H 16 O2N4F3[M+H] + HRMS (ESI-TOF) calculated value: 377.1221, observed value: 377.1221.

[0361] Example 37 - Synthesis of N-([1,1'-biphenyl]-3-ylmethyl)-4-methoxy-6-(1H-pyrazol-1-yl)nicotinamide (57) [ka] According to general procedure C, 46 (150 mg, 0.42 mmol), Pd t BuXPhos G3 (33 mg, 0.0426 mmol), Cs2CO3 (341 mg, 1.05 mmol), pyrazole (42 mg, 0.63 mmol) and t BuOH (2 ml) gave 57 (78 mg, 0.203 mmol, 48%). 1H NMR(400MHz,chloroform-d)δ 9.03(d,J=2.0Hz,1H),8.53(d,J=2.5Hz,1H,),7.85-7.76(m,1H),7.70-7.63(m,1H),7.56-7. 20(m,9H),7.20-7.15(m,1H),6.40(dd,J=2.5,2.0Hz,1H),4.66(d,J=6.0Hz,2H),3.97(s,3H). C 23 H 21 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 385.1659, observed value: 385.1656.

[0362] Example 38 - Synthesis of N-([1,1'-biphenyl]-3-yl)-4-methoxy-6-(1H-pyrazol-1-yl)nicotinamide (58) [ka] According to general procedure C, 47 (100 mg, 0.295 mmol), Pd t BuXPhos G3 (20 mg, 0.028 mmol), Cs2CO3 (185 mg, 0.568 mmol), pyrazole (23 mg, 0.34 mmol) and t BuOH (2 ml) gave 58 (50 mg, 0.13 mmol, 46%). 1 H NMR (400 MHz, chloroform-d) δ 9.42 (s, 1H), 9.18 (s, 1H), 8.64 (dd, J = 2.5, 1.0 Hz, 1H), 7.91 (m, 1H), 7.78 (dd, J = 1.5, 1.0 Hz, 1H), 7.69-7.33 (m, 9H), 6.51 (dd, J = 2.5, 1.5 Hz, 1H), 4.23 (s, 3H). C 22 H 19 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 371.1502, observed value: 371.1497.

[0363] Example 39 - Synthesis of 4-methoxy-6-(1H-pyrazol-1-yl)-N-(4-(trifluoromethoxy)benzyl)nicotinamide (59) [ka] According to general procedure C, 48 (100 mg, 0.277 mmol), Pd t BuXPhos G3 (19 mg, 0.027 mmol), Cs2CO3 (180 mg, 0.554 mmol), pyrazole (23 mg, 0.33 mmol) and t BuOH (2 ml) gave 59 (79 mg, 0.201 mmol, 73%). 1 H NMR(400MHz,chloroform-d)δ 9.12(s,1H),8.63(dd,J=2.5,1.0Hz,1H),7.76(t,J=1.5,1.0Hz,1H),7.61(s,1H),7.40(d,J=7.5 Hz,2H),7.20(d,J=7.5Hz,2H),6.50(dd,J=2.5,1.5Hz,1H,),4.68(d,J=6.0Hz,2H),4.10(s,3H). C 18 H 16 O3N4F3[M+H] + HRMS (ESI-TOF) calculated value: 393.1169, observed value: 393.1163.

[0364] Example 40 - Synthesis of 4-methoxy-6-(1H-pyrazol-1-yl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)nicotinamide (60) [ka] According to general procedure C, 49 (100 mg, 0.277 mmol), Pd t BuXPhos G3 (19 mg, 0.027 mmol), Cs2CO3 (180 mg, 0.554 mmol), pyrazole (23 mg, 0.33 mmol) and t BuOH (2 ml) gave 60 (49 mg, 0.127 mmol, 46%). 1H NMR(400MHz,CDCl3)δ 9.07(s,1H),8.62(dd,J=2.6,0.7Hz,1H),7.75(d,J=1.6Hz,1H),7.60(s,1H),7.54(d,J=6.2Hz,1H),6.49(dd,J=2.7,1.7Hz,1 H),4.13(s,3H),3.35(t,J=6.4Hz,2H),2.06-1.90(m,5H),1.69-1.57(m,1H),1.43-1.20(m,2H),1.05(qd,J=12.8,2.6Hz,2H). C 18 H 22 O2N4F3[M+H] + HRMS (ESI-TOF) calculated value: 383.1689, observed value: 383.1689.

[0365] Example 41 - Synthesis of 4-methoxy-N-((6-phenylpyridin-3-yl)methyl)-6-(1H-pyrazol-1-yl)nicotinamide (61) [ka] According to general procedure C, 53 (80 mg, 0.226 mmol), Pd t BuXPhos G1 (14 mg, 0.0226 mmol), Cs2CO3 (145 mg, 0.452 mmol), pyrazole (15 mg, 0.226 mmol) and t BuOH (2 ml) gave 61 (16 mg, 0.043 mmol, 19%). 1 H NMR(400MHz,chloroform-d)δ 9.11(s,1H),8.69(dd,J=2.5,1.0Hz,1H),8.62(dd,J=2.5,1.0Hz,1H),8.01-7.68(m,7 H),7.52-7.38(m,3H),6.48(dd,J=2.5,1.5Hz,1H),4.73(d,J=6.0Hz,2H),4.10(s,3H). C 22 H 20 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 386.1611, observed value: 386.1604.

[0366] Example 42 - Synthesis of 4-hydroxy-6-(1H-pyrazol-1-yl)-N-(4-(trifluoromethyl)benzyl)nicotinamide (64) [ka] Following general procedure D, 56 (12 mg, 0.0319 mmol) and LiCl (19 mg, 0.319 mmol) in DMAc (2 ml) gave 64 (6 mg, 0.016 mmol, 52%). 1 H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.68(s,1H),8.64-8.58(m,1H),7.81(s,1H,),7.71(d,J=8.0Hz,2 H),7.56(d,J=8.0Hz,2H),7.20(m,1H),6.60-6.53(m,1H),4.61(d,J=6.0Hz,2H). C 17 H 12 O2N4F3[MH] - HRMS (ESI-TOF) calculated value: 361.0917, observed value: 361.0917.

[0367] Example 43 - Synthesis of N-([1,1'-biphenyl]-3-ylmethyl)-4-hydroxy-6-(1H-pyrazol-1-yl)nicotinamide (65) [ka] Following general procedure D, 57 (50 mg, 0.129 mmol) and LiCl (78 mg, 1.29 mmol) in DMAc (5 ml) gave 65 (30 mg, 0.081 mmol, 63%). 1H NMR(400MHz,DMSO-d6)δ 13.21(s,1H),9.26(t,J=6.0Hz,1H),8.69(dd,J=2.5,1.0Hz,1H),8.64(d,J=2.5Hz,1H),8.28(d,J=2.5Hz ,1H),7.91(dd,J=1.5,1.0Hz,1H),7.59-7.29(m,9H),6.64(dd,J=2.5,1.5Hz,1H),4.63(d,J=6.0Hz,2H,). C 22 H 19 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 371.1502, observed value: 371.1507

[0368] Example 44 Synthesis of N-([1,1'-biphenyl]-3-yl)-4-hydroxy-6-(1H-pyrazol-1-yl)nicotinamide (66) [ka] Following general procedure D, 58 (40 mg, 0.107 mmol) and LiCl (45 mg, 1.07 mmol) in DMAc (2 ml) gave 66 (19 mg, 0.053 mmol, 50%). 1 H NMR(400MHz,DMSO-d6)δ 8.74-8.64(m,2H),8.04(s,1H),7.93(s,1H),7.76-7.63(m,3H),7.56-7.29(m,7H),6.68-6.63(m,1H). C 21 H 17 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 357.1346, observed value: 357.1345.

[0369] Example 45 - Synthesis of 4-hydroxy-6-(1H-pyrazol-1-yl)-N-(4-(trifluoromethoxy)benzyl)nicotinamide (67) [ka] Following general procedure D, 59 (70 mg, 0.178 mmol) and LiCl (74 mg, 1.78 mmol) in DMAc (2 ml) gave 67 (43 mg, 0.114 mmol, 64%). 1 H NMR(400MHz,DMSO-d6)δ 13.16(s,1H),9.41(s,1H),8.76(s,1H),8.67-8.61(m,1H),7.89-7.84(m,1H), 7.51-7.45(m,2H),7.35-7.31(m,3H),6.61-6.58(m,1H),4.57(d,J=6.0Hz,2H). C 17 H 12 O3N4F3[MH] - HRMS (ESI-TOF) calculated value: 377.0867, observed value: 377.865.

[0370] Example 46 - Synthesis of 4-hydroxy-6-(1H-pyrazol-1-yl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)nicotinamide (68) [ka] Following general procedure D, 60 (30 mg, 0.078 mmol) and LiCl (33 mg, 0.78 mmol) in DMAc (2 ml) gave 68 (8.5 mg, 0.023 mmol, 30%). 1 H NMR(400MHz,DMSO)δ 13.33(s,1H),9.10(s,1H),8.72(s,1H),8.63(d,J=2.6Hz,1H),7.86(d,J=1.6Hz,1H),7.28(s,1H),6.60(dd,J=2. 7,1.7Hz,1H),3.20(t,J=6.3Hz,2H),2.29-2.13(m,1H),1.96-1.78(m,4H),1.65-1.47(m,1H),1.32-0.96(m,4H). C 17 H 20 O2N4F3[M+H] + HRMS (ESI-TOF) calculated value: 369.1532, observed value: 369.1533.

[0371] Example 47 - Synthesis of 4-hydroxy-N-((6-phenylpyridin-3-yl)methyl)-6-(1H-pyrazol-1-yl)nicotinamide (69) [ka] Following general procedure D, 61 (16 mg, 0.041 mmol) and LiCl (17 mg, 0.41 mmol) in DMAc (2 ml) gave 69 (6 mg, 0.0161 mmol, 40%). 1 H NMR(400MHz,DMSO-d6)δ 8.80-8.62(m,3H),8.15-7.86(m,6H),7.56-7.43(m,4H),6.62-6.59(m,1H),4.62(d,J=6.0Hz,2H). C 21 H 18 O2N5[M+H] + HRMS (ESI-TOF) calculated value: 372.1455, observed value: 372.1447.

[0372] Reference Example 4 Synthesis of 8-N-([1,1'-biphenyl]-4-ylmethyl)-6-chloro-5-methoxynicotinamide (72) [ka] Following general procedure B, 72 (502 mg, 1.42 mmol, 31%) was obtained from 6-chloro-5-methoxynicotinic acid (850 mg, 4.55 mmol), 4-phenylbenzylamine (1 g, 5.46 mmol), T3P (4.32 g, 13.6 mmol) and DIPEA (2.2 ml, 6.68 mmol). 1 H NMR(400MHz,DMSO-d6)δ 9.32(t,J=6.0Hz,1H),8.50(d,J=2.0Hz,1H),7.96(d,J=2.0Hz,1H),7.74-7.31(m,9H),4.56(d,J=6.0Hz,2H),3.96(s,3H)C 20 H 18 O2N2 35Cl[M+H] + HRMS (ESI-TOF) calculated value: 353.1051, observed value: 353.1049.

[0373] Example 49 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-5-methoxy-6-(1H-pyrazol-1-yl)nicotinamide (73) [ka] According to general procedure C, 72 (100 mg, 0.284 mmol), Pd t BuXPhos G3 (22 mg, 0.0284 mmol), Cs2CO3 (279 mg, 0.852 mmol), pyrazole (38 mg, 0.568 mmol) and t BuOH (2 ml) gave 73 (23 mg, 0.0598 mmol, 20%). 1 H NMR(400MHz,chloroform-d)δ 8.46(d,J=2.0Hz,1H),8.30(dd,J=2.5,1.0Hz,1H),7.97(d,J=2.0Hz,1H),7.76(dd,J=1.5,1. 0Hz, 1H), 7.64-7.32 (m, 9H), 6.46 (dd, J=2.5, 1.5Hz, 1H), 4.67 (d, J=6.0Hz, 2H), 3.93 (s, 3H). C 23 H 21 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 385.1659, observed value: 385.1661.

[0374] Example 50 - Synthesis of N-([1,1'-biphenyl]-3-ylmethyl)-5-methoxy-6-(1H-pyrazol-1-yl)nicotinamide (74) [ka] According to General Procedure B, [N-([1,1'-biphenyl]-3-ylmethyl)-6-chloro-5-methoxynicotinamide] was obtained from 6-chloro-5-methoxynicotinic acid (250 mg, 1.33 mmol), 3-phenylbenzylamine (285 mg, 1.56 mmol), T3P (1.08 g, 3.4 mmol), and DIPEA (574 μL, 3.34 mmol). The crude material was carried to the next step without purification, and according to General Procedure C, N-([1,1'-biphenyl]-3-ylmethyl)-6-chloro-5-methoxynicotinamide (100 mg, 0.284 mmol), Pd t 74 (54 mg, 0.14 mmol, 49%) was obtained from BuXPhos G3 (20 mg, 0.028 mmol), Cs2CO3 (185 mg, 0.568 mmol), and pyrazole (23 mg, 0.34 mmol). 1 H NMR(400MHz,DMSO-d6)δ 9.37(t,J=6.0Hz,1H),8.62(d,J=2.0Hz,1H),8.28(dd,J=2.5,1.0Hz,1H),8.10(d,J=2.0Hz,1H),7.77(t ,J=1.5,1.0Hz,1H),7.69-7.32(m,9H),6.53(dd,J=2.5,1.5Hz,1H),4.62(d,J=6.0Hz,2H),3.94(s,3H). C 23 H 21 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 385.1659, observed value: 385.1661.

[0375] Example 51 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-5-hydroxy-6-(1H-pyrazol-1-yl)nicotinamide (75) [ka] Following general procedure D, 73 (12 mg, 0.031 mmol) and LiCl (19 mg, 0.31 mmol) in DMAc (2 ml) gave 75 (4 mg, 0.01 mmol, 35%). 1H NMR(500MHz,DMSO-d6)δ 11.68(s,1H),9.28(t,J=6.0Hz,1H),8.76(d,J=2.5Hz,1H),8.52(d,J=2.0Hz,1H),7.96(d,J=2.0Hz,1 H),7.72-7.60(m,4H),7.48-7.41(m,4H),7.39-7.30(m,1H),6.74-6.72(m,1H),4.55(d,J=6.0Hz,2H). C 22 H 19 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 371.1502, observed value: 371.1503.

[0376] Example 52 Synthesis of N-([1,1'-biphenyl]-3-ylmethyl)-5-hydroxy-6-(1H-pyrazol-1-yl)nicotinamide (76) [ka] Following general procedure D, 74 (45 mg, 0.117 mmol) and LiCl (71 mg, 1.17 mmol) in DMAc (3.5 ml) gave 76 (14 mg, 0.037 mmol, 32%). 1 H NMR(400MHz,DMSO-d6)δ 11.68(s,1H),9.28(t,J=6.0Hz,1H),8.76(d,J=2.5Hz,1H),8.52(d,J=2.0Hz,1H),7 .97(d,J=2.0Hz,1H),7.71-7.32(m,10H),6.75-6.71(m,1H),4.59(d,J=6.0Hz,2H). C 22 H 19 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 371.1502, observed value: 371.1502.

[0377] Example 5 Synthesis of 3-ethyl 1-(5-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-4-methoxypyridin-2-yl)-1H-pyrazole-4-carboxylate (77) [ka] According to general procedure C, 33 (150 mg, 0.43 mmol), Pd t BuXPhos G3 (34 mg, 0.043 mmol), Cs2CO3 (354 mg, 1.09 mmol), pyrazole-4-carboxylate ethyl ester (89 mg, 0.649 mmol), and t BuOH (2 ml) gave 77 (93 mg, 0.20 mmol, 48%). 1 H NMR(400MHz,DMSO-d6)δ 9.37(s,1H),9.00(s,1H),8.85(s,1H),8.24(s,1H),7.69-7.62(m,4H),7.54-7.29(m, 6H), 4.59(d,J=6.0Hz,2H),4.28(q,J=7.0Hz,2H),4.09(s,3H),1.31(t,J=7.0Hz,3H). C 26 H 25 O4N4[M+H] + HRMS (ESI-TOF) calculated value: 457.1870, observed value: 457.1876.

[0378] Example 5 Synthesis of 4-N-([1,1'-biphenyl]-4-ylmethyl)-6-(4-cyano-1H-pyrazol-1-yl)-4-methoxynicotinamide (78) [ka] According to general procedure C, 33 (150 mg, 0.426 mmol), Pd t BuXPhos G3 (16 mg, 0.0213 mmol), Cs2CO3 (276 mg, 0.852 mmol), pyrazole-4-nitrile (47 mg, 0.511 mmol) and t BuOH (4 ml) gave 78 (9 mg, 0.022 mmol, 5%). 1H NMR(400MHz,DMSO-d6)δ 9.47(d,J =.0 1Hz,1H), 8.87(t,J=6.0Hz,1H),8.66(s,1H),8.48(d,J=1.0Hz,1H),7.70-7.31(m,10H),4.55(d,J=6.0Hz,2H),4.09(s,3H). C 24 H 18 O2N5[MH] - HRMS (ESI-TOF) calculated value: 408.1466, observed value: 408.1467.

[0379] Example 5 Synthesis of 5-ethyl 1-(5-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-3-methoxypyridin-2-yl)-1H-pyrazole-4-carboxylate (79) [ka] According to general procedure C, 72 (150 mg, 0.43 mmol), Pd t BuXPhos G3 (34 mg, 0.043 mmol), Cs2CO3 (354 mg, 1.09 mmol), pyrazole-4-carboxylate ethyl ester (89 mg, 0.649 mmol), and t BuOH (4 ml) gave 79 (44 mg, 0.096 mmol, 23%). 1 H NMR(400MHz,DMSO-d6)δ 9.41(d,J=6.0Hz,1H),8.78-8.75(m,1H),8.64(d,J=2.5Hz,1H),8.15(d,J=2.5Hz,1H),7.67-7.61(m,5H),7.53-7.4 2(m,4H),7.39-7.34(m,1H),4.59(d,J=6.0Hz,2H),4.27(q,J=7.0Hz,2H),4.00-3.94(s,3H),1.30(t,J=7.0Hz,3H). C 26 H 25 O4N4[M+H] + HRMS (ESI-TOF) calculated value: 457.1870, observed value: 457.1874.

[0380] Example 5 Synthesis of 6-ethyl 1-(4-methoxy-5-((4-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (80) [ka] According to general procedure C, 45 (100 mg, 0.29 mmol), RockPhos Pd G3 (20 mg, 0.029 mmol), Cs2CO3 (188 mg, 0.58 mmol), 4-ethyl ester pyrazole (24 mg, 0.63 mmol) and t BuOH (4 ml) gave 80 (86 mg, 0.192 mmol, 66%). 1 H NMR(400MHz,chloroform-d)δ 9.12(s,1H),9.07(d,J=1.0Hz,1H),8.11(d,J=1.0Hz,1H),7.89(t,J=6.0Hz,1H),7.63(s,1H),7.62-7.58( m,2H),7.50-7.45(m,2H),4.73(d,J=6.0Hz,2H),4.35(q,J=7.0Hz,2H),4.11(s,3H),1.37(t,J=7.0Hz,3H). C 21 H 18 O4N4F3[MH] - HRMS (ESI-TOF) calculated value: 447.1285, observed value: 447.1281.

[0381] Example 57 - Synthesis of 6-(4-cyano-1H-pyrazol-1-yl)-4-methoxy-N-(4-(trifluoromethyl)benzyl)nicotinamide (81) [ka] According to general procedure C, 45 (100 mg, 0.29 mmol), RockPhos Pd G3 (24 mg, 0.029 mmol), Cs2CO3 (180 mg, 0.554 mmol), pyrazole-4-nitrile (24 mg, 0.35 mmol) and tBuOH (4 ml) gave 81 (23 mg, 0.057 mmol, 20%). 1 H NMR(400MHz,chloroform-d)δ 9.13(s,1H),9.04(d,J=1.0Hz,1H),7.99(d,J=1.0Hz,1H),7.88(t,J=6.0Hz,1 H),7.67-7.56(m,3H),7.51-7.42(m,2H),4.74(d,J=6.0Hz,2H),4.03(s,3H). C 18 H 15 O4N4F3[M+H] + HRMS (ESI-TOF) calculated value: 402.1172, observed value: 402.1172.

[0382] Example 5 Synthesis of 8-ethyl 1-(4-methoxy-5-(((6-phenylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (82) [ka] According to general procedure C, 53 (80 mg, 0.226 mmol), RockPhosPd G3 (19 mg, 0.0226 mmol), Cs2CO3 (145 mg, 0.452 mmol), 4-ethyl ester pyrazole (31 mg, 0.226 mmol) and t BuOH (2.5 ml) gave 82 (11 mg, 0.024 mmol, 11%). 1 H NMR(400MHz,chloroform-d)δ 9.13(s,1H),9.08(s,1H),8.70-8.68(m,1H),8.12(s,1H),8.01-7.94(m,2H),7.90(t,J=6.0Hz,1H), 7.84-7.37(m,6H),4.73(d,J=6.0Hz,2H),4.32(q,J=7.0Hz,2H),4.11(s,3H),1.37(t,J=7.0Hz,3H). C 25 H 24 O4N5[M+H] +HRMS (ESI-TOF) calculated value: 458.1822, observed value: 458.1816.

[0383] Example 5 Synthesis of 9-ethyl 1-(5-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-4-hydroxypyridin-2-yl)-1H-pyrazole-4-carboxylate (83) [ka] Following general procedure D, 80 (82 mg, 0.179 mmol) and LiCl ( mg, 1.79 mmol) in DMAc (35 ml) gave 83 (70 mg, 0.158 mmol, 90%). 1 H NMR(400MHz,DMSO-d6)δ 9.42(s,1H),9.00(s,1H),8.85(s,1H),8.24(s,1H),7.72-7.58(m,4H),7.54-7.39(m,5H) ,7.38-7.29(m,1H),4.59(d,J=6.0Hz,2H,),4.27(q,J=7.0Hz,2H),1.30(t,J=7.0Hz,3H). C 25 H 23 O4N4[M+H] + HRMS (ESI-TOF) calculated value: 443.1713, observed value: 443.1713.

[0384] Example 60 - Synthesis of 1-(5-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-4-hydroxypyridin-2-yl)-1H-pyrazole-4-carboxylic acid (84) [ka] 83 (65 mg, 0.147 mmol) was dissolved in THF (5 ml), water (0.5 ml) was added to the reaction mixture, followed by LiOH monohydrate (16 mg, 0.40 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with HCl aqThe crude compound was then purified using flash column chromatography using (0-20% CHCl:MeOH:1% formic acid) over 20 column volumes to give 84 (52 mg, 0.125 mmol, 85%). 1 H NMR (400MHz, DMSO-d6) δ 13.34(s,1H),9.42(s,1H),9.00(s,1H),8.96(s,1H),8.19(s,1H),7.71-7.31(m,11H),4.59(d,J=6.0Hz,2H). C 23 H 19 O4N4[M+H] + HRMS (ESI-TOF) calculated value: 415.1400, observed value: 415.1401.

[0385] Example 61 Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-6-(4-cyano-1H-pyrazol-1-yl)-4-hydroxynicotinamide (85) [ka] 78 (6 mg, 0.0146 mmol) was dissolved in DMAc (1.5 mL) in a microwave vial, followed by the addition of CsCO (14.3 mg, 0.044 mmol). The resulting reaction mixture was heated at 130 °C under microwave irradiation for 1 h. HO (50 mL) was added, and the resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic fractions were washed with brine, dried over NaSO, and the solvent was removed in vacuo. The crude compound was then purified using flash column chromatography using (CHCl, MeOH 0–10%) over 20 column volumes to give 85 (2.5 mg, 0.006 mmol, 44%). 1 H NMR(400MHz,DMSO-d6)δ 9.45(s,1H),8.87(d,J=2.0Hz,1H),8.44(s,1H),7.73-7.42(m,11H),4.60(d,J=6.0Hz,2H). C 23 H 16 O2N5[MH] - HRMS (ESI-TOF) calculated value: 394.1309, observed value: 394.1309.

[0386] Example 62-Synthesis of 1-(5-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-3-hydroxypyridin-2-yl)-1H-pyrazole-4-carboxylic acid (86) [ka] 79 (20 mg, 0.043 mmol) was dissolved in THF (2 ml), and MeOH (2 ml) and water (0.5 ml) were added to the reaction mixture, followed by LiOH monohydrate (16 mg, 0.40 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with HCl aq The crude compound was then purified using flash column chromatography (CH2Cl2:MeOH 0-20%:formic acid 1%) over 20 column volumes to give 86 (8 mg, 0.019 mmol, 45%). 1 H NMR (400MHz, DMSO-d6) δ 9.09 (s, 1H), 8.90 (d, J = 6.0 Hz, 1 H), 7.92-7.09 (m, 12 H), 4.47 (d, J = 6.0 Hz, 2 H). C 23 H 17 O4N4[MH] - HRMS (ESI-TOF) calculated value: 413.1255, observed value: 413.1252.

[0387] Example 6 Synthesis of 3-ethyl 1-(4-hydroxy-5-((4-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (87) [ka] Following general procedure D, 80 (68 mg, 0.151 mmol) and LiCl (91 mg, 1.51 mmol) in DMAc (3.5 ml) gave 87 (48 mg, 0.110 mmol, 73%). 1 H NMR(400MHz,THF-d8)δ 13.46(s,1H),8.99(d,J=1.0Hz,1H),8.93-8.85(m,1H),8.74(s,1H),8.07(d,J=1.0Hz,1H),7.65(d,J=7.0Hz ,2H),7.58(d,J=7.0Hz,2H),7.48(s,1H),4.71(d,J=6.0Hz,2H),4.29(q,J=7.0Hz,2H),1.33(t,J=7.0Hz,3H). C 20 H 16 O4N4F3[MH] - HRMS (ESI-TOF) calculated value: 433.1129, observed value: 433.1125.

[0388] Example 6 Synthesis of 4-ethyl 1-(4-hydroxy-5-(((6-phenylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (88) [ka] Following general procedure D, 82 (7 mg, 0.015 mmol) and LiCl (9 mg, 0.15 mmol) in DMAc (2 ml) gave 88 (3.5 mg, 0.0079 mmol, 53%). 1 H NMR(400MHz,DMSO-d6)δ 9.00(s,1H),8.80(s,1H),8.67(d,J=2.0Hz,1H),8.24(s,1H),8.07(dd,J=8.0,2.0Hz,2H),7.95(d,J=8.0Hz,1H),7 .85(dd,J=8.0,2.0Hz,1H),7.54-7.39(m,5H),4.61(d,J=6.0Hz,2H),4.26(q,J=7.0Hz,2H),1.30(t,J=7.0Hz,3H). C 24 H 22O4N5[M+H] + HRMS (ESI-TOF) calculated value: 444.1666, observed value: 444.1659.

[0389] Example 65 - Synthesis of 6-(4-cyano-1H-pyrazol-1-yl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)nicotinamide (89) [ka] Following general procedure D, 81 (20 mg, 0.049 mmol) and LiCl (30 mg, 0.50 mmol) in DMAc (2 ml) gave 89 (5 mg, 0.012 mmol, 26%). 1 H NMR(400MHz,DMSO-d6)δ 9.43(d,J=1.0Hz,1H),8.81(s,1H),8.43(d,J=1.0Hz,1H),7.71(d,J=8.0Hz,2H),7.57(d,J=8.0Hz,2H),7.42(s,1H),4.63(d,J=6.0Hz,2H). C 18 H 11 O4N4F3[MH] - HRMS (ESI-TOF) calculated value: 386.0870, observed value: 386.0867.

[0390] Example 66 - Synthesis of 1-(4-hydroxy-5-((4-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (90) [ka] 87 (40 mg, 0.092 mmol) was dissolved in THF (2 ml), and MeOH (2 ml) and water (0.5 ml) were added to the reaction mixture, followed by LiOH monohydrate (19 mg, 0.46 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with HCl aqThe crude compound was then purified using flash column chromatography using (0-20% CHCl:MeOH:1% formic acid) over 20 column volumes to give 90 (17 mg, 0.042 mmol, 46%). 1 H NMR(400MHz,DMSO-d6)δ 9.56(s,1H),8.94(s,1H),8.78(s,1H),8.17(s,1H),7.70(d,J=8.0Hz,2H),7.56(d,J=8.0Hz,2H),7.38(s,1H),4.63(d,J=6.0Hz,2H). C 18 H 12 O4N4F3[MH] - HRMS (ESI-TOF) calculated value: 405.0816, observed value: 405.0815.

[0391] Example 67 - Synthesis of 1-(4-hydroxy-5-(((6-phenylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (91) [ka] 88 (3 mg, 0.0072 mmol) was dissolved in THF (0.8 ml), and MeOH (0.15 ml) and water (0.05 ml) were added to the reaction mixture, followed by LiOH monohydrate (1 mg, 0.023 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with HCl aq (1 M) to pH 3 and preparative HPLC was used to give 91 (1 mg, 0.0024 mmol, 33%). 1 H NMR(500MHz,DMSO-d6)δ 8.94(s,1H),8.68(s,1H),8.19(s,1H),8.13-8.05(m,2H),7.96(d,J=8.5 Hz,1H),7.87(d,J=8.5Hz,1H),7.55-7.39(m,6H),4.62(d,J=6.0Hz,2H). C 22 H18 O4N5[M+H] + HRMS (ESI-TOF) calculated value: 416.1353, observed value: 416.1352.

[0392] Reference Example 6 Synthesis of 8-N-([1,1'-biphenyl]-4-ylmethyl)-1H-pyrazole-4-carboxamide (92) [ka] Following general procedure B, 92 (462 mg, 1.66 mmol, 19%) was obtained from 1H-pyrazole-4-carboxylic acid (1 g, 8.9 mmol), 4-phenylbenzylamine (2.44 g, 13.35 mmol), T3P (7.05 g, 22.2 mmol) and DIPEA (4.6 g, 35.7 mmol). 1 H NMR(400MHz,DMSO-d6)δ 8.66(t,J=6.0Hz,1H),8.09(s,2H),7.70-7.58(m,4H),7.50-7.30(m,5H,),4.47(d,J=6.0Hz,2H). C 17 H 16 ON3[M+H] + HRMS (ESI-TOF) calculated value: 278.1287, observed value: 278.1290.

[0393] Example 69: Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-1-(5-cyano-4-methoxypyridin-2-yl)-1H-pyrazole-4-carboxamide (93) [ka] General Procedure C: 6-chloro-4-methoxynicotinonitrile (40 mg, 0.238 mmol), 92 (65 mg, 0.238 mmol), Pd t BuXPhos Pd G3 (19 mg, 0.023 mmol) and Cs2CO3 (232 mg, 0.714 mmol) gave 93 (14 mg, 0.034 mmol, 12%). 1H NMR(400MHz,DMSO-d6)δ 9.03(t,J=6.0Hz,1H),8.82(s,1H),8.30-8.29(m,1H),7.70-7.59(m,5H),7.50-7.31(m,6H),4.50(d,J=6.0Hz,2H),4.12(s,3H)C 24 H 20 O2N5[M+H] + HRMS (ESI-TOF) calculated value: 410.1622, observed value: 410.1611.

[0394] Example 7 Synthesis of 0-ethyl 6-(4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-1H-pyrazol-1-yl)-4-methoxynicotinate (94) [ka] According to general procedure C, ethyl 6-chloro-4-methoxynicotinate (39 mg, 0.18 mmol), 92 (50 mg, 0.18 mmol), Pd t BuXPhos Pd G3 (25 mg, 0.009 mmol) and dioxane (3 ml) gave 94 as a clear oil (23 mg, 0.05 mmol, 28%). 1 H NMR(400MHz,THF-d8)δ 9.08(d,J=1.0Hz,1H),8.68(s,1H),8.13(d,J=1.0Hz,1H),8.05(t,J=6.0Hz,1H),7.69(s,1H),7. 64-7.23(m,9H),4.59(d,J=6.0Hz,2H),4.30(q,J=7.0Hz,2H),4.03(s,3H),1.34(t,J=7.0Hz,3H). C 26 H 25 O4N4[M+H] + HRMS (ESI-TOF) calculated value: 457.1870, observed value: 457.1868.

[0395] Example 71 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-1-(5-cyano-4-hydroxypyridin-2-yl)-1H-pyrazole-4-carboxamide (95) [ka] Following general procedure D, 93 (6 mg, 0.014 mmol) and LiCl (8.5 mg, 0.14 mmol) in DMAc (1 ml) gave 95 (1.9 mg, 0.0048 mmol, 35%). 1 H NMR(400MHz,DMSO-d6)δ 9.14(s,1H),8.95(t,J=6.0Hz,1H),8.45(s,1H),8.16(s,1H),7.70-7.59(m,4H),7.53-7.29(m,5H),7.16(s,1H),4.48(d,J=6.0Hz,2H). C 23 H 18 O2N5[M+H] + HRMS (ESI-TOF) calculated value: 396.1466, observed value: 396.1456.

[0396] Example 72 - Synthesis of 6-(4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-1H-pyrazol-1-yl)-4-hydroxynicotinic acid (96) [ka] Following general procedure D, 94 (23 mg, 0.0504 mmol) and LiCl (30 mg, 0.504 mmol) in DMAc (3 ml) gave 96 (9 mg, 0.0216 mmol, 43%) as a yellow oil. 1 H NMR(600MHz,DMSO-d6)δ 9.21(s,1H),8.96(t,J=6.0Hz,1H),8.71(s,1H),8.22(s,1H),7.64(m,5H),7.51-7.32(m,5H),4.49(d,J=6.0Hz,2H). C 23 H 19 O4N4[M+H] +HRMS (ESI-TOF) calculated value: 415.1400, observed value: 415.1401.

[0397] Example 73 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-1-(5-cyanopyridin-2-yl)-1H-pyrazole-4-carboxamide (97) [ka] Following general procedure C, 97 (6 mg, 0.015 mmol, 16%) was obtained from 6-chloro-nicotinonitrile (30 mg, 0.216 mmol), 92 (30 mg, 0.108 mmol), PdtBuXPhos G3 (17 mg, 0.0216 mmol), and Cs2CO3 (175 mg, 0.432 mmol). 1 H NMR(400MHz,DMSO-d6)δ 9.27(d,J=1.0Hz,1H),9.10-8.96(m,2H),8.51(dd,J=8.5,2.0Hz,1H),8.29(d,J=1.0Hz,1H ),8.10(dd,J=8.5,1.0Hz,1H),7.67-7.59(m,4H),7.51-7.31(m,5H),4.50(d,J=6.0Hz,2H). C 23 H 16 ON5[MH] - HRMS (ESI-TOF) calculated value: 378.1360, observed value: 378.1354.

[0398] Example 74 Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-1-(4-methoxypyridin-2-yl)-1H-pyrazole-4-carboxamide (98) [ka] Following general procedure C, 98 (28 mg, 0.072 mmol, 63%) was obtained from 2-chloro-4-methoxypyridine (16 mg, 0.114 mmol), 92 (31 mg, 0.114 mmol), RockPhos Pd G3 (9.5 mg, 0.0114 mmol) and Cs2CO3 (92 mg, 0.285 mmol). 1 H NMR(400MHz,DMSO-d6)δ 9.18(d,J=1.0Hz,1H),8.95(t,J=6.0Hz,1H),8.32(d,J =6.0Hz,1H),8.19(d,J=1.0Hz,1H),7.69-7.31(m,10H),7.00(dd,J=6.0,2.5Hz,1H),4.49(d,J=6.0Hz,2H),3.93(s,3H). C 23 H 21 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 385.1690, observed value: 385.1659.

[0399] Example 75 - Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-1-(4-hydroxypyridin-2-yl)-1H-pyrazole-4-carboxamide (99) [ka] Following general procedure D, 92 (7 mg, 0.018 mmol) and LiCl (11 mg, 0.18 mmol) in DMAc (1 ml) gave 99 (3 mg, 0.008 mmol, 45%). 1 H NMR(400MHz,DMSO-d6)δ 9.14(d,J=1.0Hz,1H),8.89(t,J=6.0Hz,1H),8.73-8.66(m,1H),8.33-8.29(m,1H),7.91-7.89(m,1H),7.50-7.28(m,9H),6.77(dd,J =6.0,2.5Hz,1H),4.48(d,J=6.0Hz,2H). C 22 H 19 O2N4[M+H] +HRMS (ESI-TOF) calculated value: 371.1506, observed value: 371.1506.

[0400] Example 7 Synthesis of 6-ethyl 6-(4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-1H-pyrazol-1-yl)nicotinate (100) [ka] Following general procedure C, 100 (10 mg, 0.023 mmol, 21%) was obtained from ethyl 6-chloronicotinate (42 mg, 0.23 mmol), 92 (30 mg, 0.108 mmol), PdtBuXPhos G3 (18 mg, 0.023 mmol), and Cs2CO3 (149 mg, 0.46 mmol) in dioxane (5 ml). 1 H NMR(400MHz,THF-d8)δ 9.09(d,J=1.0Hz,1H),9.00(dd,J=2.0,1.0Hz,1H),8.70-8.60(m,1H),8.14-8.10(m,1H),7.96(t,J= 6.0Hz,1H),7.67-7.35(m,10H,),4.59(d,J=6.0Hz,2H),4.40(q,J=7.0Hz,2H),1.38(t,J=7.0Hz,3H). C 25 H 23 O3N4[M+H] + HRMS (ESI-TOF) calculated value: 427.1766, observed value: 427.1766.

[0401] Example 77 - Synthesis of 6-(4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-1H-pyrazol-1-yl)nicotinic acid (101) [ka] 100 (8 mg, 0.0187 mmol) was dissolved in a mixture of THF and water (3 mL (10:1). Lithium hydroxide monohydrate (1.5 mg, 0.0374 mmol) was added to the reaction mixture, and the resulting mixture was allowed to stir at room temperature for 16 hours. The reaction was confirmed to be complete by TLC, and the reaction mixture was diluted with HCl. aq (5 ml, 1 M) was added. The resulting mixture was extracted with EtOAc (3 × 10 ml), then washed with brine, then dried over anhydrous NaSO, and purified using flash column chromatography using (CHCl, MeOH 0–5%, 1% formic acid) to give 101 (2 mg, 0.005 mmol, 27%). 1 H NMR(400MHz,DMSO-d6)δ 9.26(d,J=1.0Hz,1H),8.97(t,J=6.0Hz,1H),8.87(s,1H),8.35(d,J=2.0Hz,1H),8.19(d,J=7 .0Hz,1H),7.89(d,J=7.0Hz,1H),7.68-7.55(m,4H),7.52-7.29(m,5H),4.49(d,J=6.0Hz,2H). C 23 H 17 O3N4[MH] - HRMS (ESI-TOF) calculated value: 397.1304, observed value: 397.1304.

[0402] Example 7 Synthesis of 8-methyl 2-(4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-1H-pyrazol-1-yl)isonicotinate (102) [ka] According to general procedure C, methyl 2-chloroisonictinate (37 mg, 0.216 mmol), 92 (30 mg, 0.108 mmol) in dioxane (3 ml), t BuXPhos Pd G3 (17 mg, 0.0216 mmol) and Cs2CO3 (175 mg, 0.54 mmol) gave 102 (6 mg, 0.014 mmol, 13%). 1 H NMR(400MHz,DMSO-d6)δ 9.24(d,J=1.0Hz,1H),8.99(t,J=6.0Hz,1H),8.73(dd,J=5.0,1.0Hz,1H),8.34(dd,J=1.5,1.0Hz,1H),8.26(d,J= 1.0Hz,1H), 7.85(dd,J=5.0,1.5Hz,1H),7.66-7.61(m,4H),7.51-7.29(m,5H),4.50(d,J=6.0Hz,2H),3.95(s,3H). C 24 H 21 O3N4[M+H] + HRMS (ESI-TOF) calculated value: 413.1608, observed value: 413.1608.

[0403] Example 79 - Synthesis of 2-(4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-1H-pyrazol-1-yl)isonicotinic acid (103) [ka] 102 (4 mg, 0.0097 mmol) was dissolved in a mixture of THF and water (3 mL (10:1). To the reaction mixture was added lithium hydroxide monohydrate (1 mg, 0.0194 mmol) and the resulting mixture was allowed to stir at room temperature for 16 hours. The reaction was complete as determined by LCMS and the reaction mixture was diluted with HCl. aq (5 ml, 1 M) was added. The resulting mixture was extracted with EtOAc (3 × 10 ml), then washed with brine, dried over anhydrous NaSO, and purified using flash column chromatography over 20 column volumes (CHCl, MeOH 0-5%, formic acid 1%) to give 103 (3 mg, 0.0075 mmol, 78%). 1H NMR(400MHz,DMSO-d6)δ 9.24(s,1H),8.98(t,J=6.0Hz,1H),8.68(d,J=5.0Hz,1H),8.33(t,J=1.5Hz,1H),8.24(s,1H) ),7.81(dd,J=5.0,1.5Hz,1H),7.69-7.61(m,4H),7.50-7.37(m,5H),4.50(d,J=6.0Hz,2H). C 23 H 17 O3N4[MH] - HRMS (ESI-TOF) calculated value: 397.1304, observed value: 397.1304.

[0404] Reference Example 8 Synthesis of 0-ethyl 1-(4-methoxypyridin-2-yl)-1H-pyrazole-4-carboxylate (104) [ka] According to general procedure C, 4-methoxy-2-chloropyridine (500 mg, 3.49 mmol), 4-ethyl ester pyrazole (725 mg, 5.2 mmol), RockPhos Pd G3 (244 mg, 0.349 mmol), Cs2CO3 (2.8 g, 8.7 mmol) and t BuOH (10 ml) gave 104 (190 mg, 0.769 mmol, 22%). 1 H NMR(400MHz,THF-d8)δ 8.23(d,J=5.5Hz,1H),8.13(d,J=5.5Hz,1H),7.57(d,J=2.0Hz,1H),6.94( d,J=2.0Hz,2H),4.29(q,J=7.0Hz,2H),3.94(s,3H),1.33(t,J=7.0Hz,3H). C 12 H 14 O3N3[M+H] + HRMS (ESI-TOF) calculated value: 248.1029, observed value: 248.1033.

[0405] Reference Example 8: Synthesis of 1-1-(4-methoxypyridin-2-yl)-1H-pyrazole-4-carboxylic acid (105) [ka] 104 (190 mg, 0.769 mmol) was dissolved in a mixture of THF and water (11 mL (10:1). Lithium hydroxide monohydrate (78 mg, 2.19 mmol) was added to the reaction mixture and the resulting mixture was allowed to stir at room temperature for 16 h. The reaction was confirmed to be complete by LCMS and HCl (1 M, 5 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (3 × 10 mL), then washed with brine and then dried over NaSO. The solvent was removed in vacuo to give 105 (73 mg, 0.33 mmol, 44%). 1 H NMR(400MHz,DMSO-d6)δ 8.90(s,1H),8.34(d,J=6.0Hz,1H),8.15(s,1H),7.45(d,J=2.5Hz,1H),7.03(dd,J=6.0,2.5Hz,1H),3.93(s,3H). C 10 H8O3N3[MH] - HRMS (ESI-TOF) calculated value: 218.0569, observed value: 218.0571.

[0406] Example 82 Synthesis of N-([1,1'-biphenyl]-4-yl)-1-(4-methoxypyridin-2-yl)-1H-pyrazole-4-carboxamide (106) [ka] Following general procedure B, 105 (30 mg, 0.136 mmol), 4-aminobiphenyl (35 mg, 0.204 mmol), T3P (108 mg, 0.34 mmol) and DIPEA (116 μl, 0.68 mmol) gave 106 (27 mg, 0.072 mmol, 54%). 1H NMR(400MHz,THF-d8)δ 9.29(s,1H),9.18(d,J=1.0Hz,1H),8.24(d,J=6.0Hz,1H),8.17(d,J=1.0Hz,1 H),7.91-7.84(m,2H),7.68-7.21(m,8H),6.87(d,J=6.0Hz,1H),3.95(s,3H). C 22 H 19 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 371.1502, observed value: 371.1396.

[0407] Example 83 Synthesis of N-([1,1'-biphenyl]-3-ylmethyl)-1-(4-methoxypyridin-2-yl)-1H-pyrazole-4-carboxamide (107) [ka] Following general procedure B, 105 (30 mg, 0.136 mmol), 3-aminomethylbiphenyl (36 mg, 0.204 mmol), T3P (108 mg, 0.34 mmol) and DIPEA (116 μl, 0.68 mmol) gave 107 (32 mg, 0.083 mmol, 61%). 1 H NMR(400MHz,chloroform-d)δ 8.97(d,J=1.0Hz,1H),8.15(d,J=6.0Hz,1H),8.07(d,J=1.0Hz,1H),7.58-7.28(m,10 H),6.73(d,J=6.0Hz,1H),6.59(t,J=6.0Hz,1H),4.64(d,J=6.0Hz,2H),3.90(s,3H). C 23 H 21 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 385.1659, observed value: 385.1656.

[0408] Example 84 Synthesis of N-([1,1'-biphenyl]-4-yl)-1-(4-hydroxypyridin-2-yl)-1H-pyrazole-4-carboxamide (108) [ka] Following general procedure D, 106 (27 mg, 0.073 mmol) and LiCl (29 mg, 0.73 mmol) in DMAc (2 ml) gave 108 (15 mg, 0.0421 mmol, 57%) over 8 h. 1 H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),9.39(s,1H),8.32-8.18(m,2H),7.91-7.82(m,2H),7.70-7.63(m,4H),7.50-7.31(m,4H),6.82(dd,J=5.5,2.5Hz,1H). C 21 H 17 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 357.1346, observed value: 357.1348.

[0409] Example 85 - Synthesis of N-([1,1'-biphenyl]-3-ylmethyl)-1-(4-hydroxypyridin-2-yl)-1H-pyrazole-4-carboxamide (109) [ka] Following general procedure D, 107 (32 mg, 0.083 mmol) and LiCl (35 mg, 0.83 mmol) in DMAc (2 ml) gave 109 (11 mg, 0.029 mmol, 36%). 1 H NMR(400MHz,DMSO-d6)δ 11.23(s,1H),9.14(d,J=1.0Hz,1H),8.93(t,J=6.0Hz,1H),8.19(d,J=5.5Hz,1H),8.15( d,J=1.0Hz,1H),7.70-7.27(m,10H),6.78(dd,J=5.5,2.5Hz,1H),4.52(d,J=6.0Hz,2H). C 22 H 19 O2N4[M+H] + HRMS (ESI-TOF) calculated value: 371.1502, observed value: 371.1497.

[0410] Reference Example 8 Synthesis of 6-ethyl 1-(5-cyano-4-methoxypyridin-2-yl)-1H-pyrazole-4-carboxylate (110) [ka] According to general procedure C, 6-chloro-4-methoxynicotinonitrile (400 mg, 2.38 mmol), pyrazole-4-carboxylate ethyl ester (500 mg, 3.57 mmol), in dioxane (10 ml), t BuxPhos Pd G3 (188 mg, 0.238 mmol) and Cs2CO3 (2.3 g, 7.14 mmol) gave 110 (110 mg, 0.40 mmol, 17%). 1 H NMR(400MHz,DMSO-d6)δ 9.02(s,1H),8.83(s,1H),8.32(s,1H),7.69(s,1H),4.28(q,J=7.0Hz,2H),4.13(s,3H),1.30(t,J=7.0Hz,3H). C 13 H 13 O3N4[M+H] + HRMS (ESI-TOF) calculated value: 273.0978, observed value: 273.0978.

[0411] Reference Example 87-Synthesis of 1-(5-cyano-4-methoxypyridin-2-yl)-1H-pyrazole-4-carboxylic acid (111) [ka] 110 (95 mg, 0.399 mmol) was dissolved in a mixture of THF and water (11 mL (10:1). Lithium hydroxide monohydrate (14 mg, 0.399 mmol) was added to the reaction mixture, and the resulting mixture was allowed to stir at room temperature for 16 h. The reaction was confirmed to be complete by TLC, and HCl (10 mL, 1 M) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (3 × 10 mL), washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give 111 (90 mg, 0.368 mmol, 93%). 1 H NMR (400MHz, DMSO-d6) δ 8.89 (d, J = 1.0 Hz, 1H), 8.76 (s, 1H), 8.20 (d, J = 1.0 Hz, 1H), 7.63 (s, 1H), 4.08 (s, 3H). C 11 H7O3N4[MH] - HRMS (ESI-TOF) calculated value: 243.0523, observed value: 243.0520.

[0412] Example 88 - Synthesis of 1-(5-cyano-4-methoxypyridin-2-yl)-N-((6-phenylpyridin-3-yl)methyl)-1H-pyrazole-4-carboxamide (112) [ka] Following general procedure B, 111 (40 mg, 0.164 mmol), 52 (56 mg, 0.306 mmol), T3P (130 mg, 0.409 mmol) and DIPEA (116 μl, 0.68 mmol) gave 112 (28 mg, 0.068 mmol, 35%). 1 H NMR(400MHz,THF-d8)δ 9.06(d,J=1.0Hz,1H),8.57(s,1H),8.34(dd,J=8.5,1.5Hz,1H),8.18(t,J=6.0Hz,1H),8.12-8.04 (m,2H),7.81(d,J=1.5Hz,2H),7.73(s,1H),7.44-7.31(m,4H),4.59(d,J=6.0Hz,2H),4.12(s,3H). C23 H 19 O2N6[M+H] + HRMS (ESI-TOF) calculated value: 411.1564, observed value: 411.1555.

[0413] Example 89 - Synthesis of 1-(5-cyano-4-methoxypyridin-2-yl)-N-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide 113 [ka] Following general procedure B, 111 (40 mg, 0.164 mmol), 4-trifluoromethylbenzylamine (54 mg, 0.306 mmol), T3P (130 mg, 0.409 mmol) and DIPEA (116 μl, 0.68 mmol) gave 113 (38 mg, 0.0947 mmol, 47%). 1 H NMR(400MHz,THF-d8)δ 8.82(s,1H),8.41(dd,J=4.5,1.5Hz,1H),8.11(dd,J=8.5,1.5Hz,1H),7.50(s,1 H),7.39-7.29(m,4H),7.23(t,J=6.0Hz,1H),4.39(d,J=6.0Hz,2H),3.89(s,3H). C 19 H 13 O2N5F3[MH] - HRMS (ESI-TOF) calculated value: 400.1026, observed value: 400.1022.

[0414] Example 90 - Synthesis of 1-(5-cyano-4-hydroxypyridin-2-yl)-N-((6-phenylpyridin-3-yl)methyl)-1H-pyrazole-4-carboxamide (114) [ka] Following general procedure D, 112 (20 mg, 0.0487 mmol) and LiCl (20.5 mg, 0.487 mmol) in DMAc (2 ml) gave 114 (8 mg, 0.020 mmol, 42%). 1 H NMR(400MHz,DMSO-d6)δ 9.11(d,J=1.0Hz,1H),9.10-9.04(m,1H),8.64-8.61(m,1H),8.37(s,1H),8.16(s,1H),8.09-8.03(m,2H),7. 93(dd,J=8.0,1.0Hz,1H),7.81(dd,J=8.0,2.5Hz,1H),7.53-7.38(m,3H),7.15(s,1H),4.49(d,J=6.0Hz,2H). C 22 H 17 O2N6[M+H] + HRMS (ESI-TOF) calculated value: 397.1407, observed value: 397.1407.

[0415] Example 91 - Synthesis of 1-(5-cyano-4-hydroxypyridin-2-yl)-N-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (115) [ka] Following general procedure D, 113 (25 mg, 0.062 mmol) and LiCl (26 mg, 0.62 mmol) in DMAc (2 ml) gave 115 (5 mg, 0.0129 mmol, 21%). 1 H NMR(400MHz,DMSO-d6)δ 9.06(s,1H),8.96(t,J=6.0Hz,1H),8.13(s,1H),8.08(s,1H),7.70(d,J=8.0Hz,2H),7.53(d,J=8.0Hz,2H),6.78(s,1H),4.51(d,J=6.0Hz,2H). C 18 H 11 O2N5F3[MH] - HRMS (ESI-TOF) calculated value: 386.0864, ​​observed value: 386.0867.

[0416] Reference Example 9: Synthesis of 2-ethyl 6-hydroxypyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylate (116) [ka] Pyrazolo[1,5-a]pyrimidin-7-amine (250 mg, 1.86 mmol) and diethyl ethoxymethylenemalonate (402 mg, 1.86 mmol) were added to a microwave vial and dissolved in absolute EtOH (5 mL), followed by the addition of NaOEt (189 mg, 2.79 mmol). The reaction mixture was heated at 100 °C under microwave irradiation for 2 h and then allowed to cool to room temperature. The reaction mixture was then filtered and dried, after which diphenyl ether (2 mL) was added. The resulting mixture was then heated to 240 °C for 30 min and then allowed to cool to room temperature. The reaction mixture was then filtered, washed with EtO (4 × 50 mL), and dried to give 116 (210 mg, 0.81 mmol, 43%). 1 H NMR(400MHz,DMSO-d6)δ 8.97(s,1H),8.62(s,1H),8.15(d,J=2.0Hz,1H),6.68(d,J=2.0Hz,1H),4.20(q,J=7.0Hz,2H),1.28(t,J=7.0Hz,3H). C 12 H 11 O3N4[M+H] + HRMS (ESI-TOF) calculated value: 259.0825, observed value: 259.0826.

[0417] Example 9 Synthesis of 3-N-([1,1'-biphenyl]-4-ylmethyl)-6-hydroxypyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (117) [ka] General Procedure A: 116 (100 mg, 0.38 mmol), 4-phenylbenzylamine (70 mg, 0.38 mmol), and DABCO-(AlMe) (100 mg, 0.38 mmol) gave 117 (4 mg, 0.01 mmol, 3%). Solvent system used for purification: 0%-5% MeOH in CH3Cl. 1H NMR(400MHz,DMSO-d6)δ 9.04(s,1H),8.72(s,1H),8.26(d,J=2.0Hz,1H),7.74-7.59(m,4H),7.54-7.25(m,5H),6.78(d,J=2.0Hz,1H),4.60(d,J=6.0Hz,2H). C 23 H 16 O2N5[MH] - HRMS (ESI-TOF) calculated value: 394.1309, observed value: 394.1303.

[0418] Reference Example 9: Synthesis of 4-methyl 3-([1,1'-biphenyl]-4-ylamino)-3-oxopropanoate (118) [ka] Following general procedure B, 118 (230 mg, 0.855 mmol, 24%) was obtained from methyl hydrogen malonate (585 mg, 4.97 mmol), 4-aminobiphenyl (600 mg, 3.55 mmol), T3P (3.16 g, 9.94 mmol), and DIPEA (1.8 g, 14.2 mmol). 1 H NMR (400 MHz, chloroform-d) δ 9.27 (s, 1H), 7.68-7.30 (m, 9H), 3.82 (s, 3H), 3.52 (s, 2H). C 16 H 16 O3N[M+H] + HRMS (ESI-TOF) calculated value: 270.1124, observed value: 270.1122.

[0419] Example 9 Synthesis of 5-N-([1,1'-biphenyl]-4-yl)-6-hydroxypyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (119) [ka] 118 (100 mg, 0.37 mmol) was placed in a microwave vial, flushed with N2, and removed in vacuo (three times), followed by the addition of anhydrous ethyl orthoformate (3 mL). The reaction mixture was heated at 120 °C for 3 h. Excess ethyl orthoformate was removed in vacuo, and the resulting mixture was dissolved in diphenyl ether (5 mL). Pyrazolo[1,5-a]pyrimidin-7-amine (75 mg, 0.55 mmol) was added, and the resulting mixture was heated at 240 °C for 30 min, allowed to cool to room temperature, and directly purified by flash column chromatography using 20 column volumes of (CHCl, 0-10% MeOH, 1% HCOOH) to give 119 (5.5 mg, 0.015 mmol, 4%). 1 H NMR(400MHz,DMSO-d6)δ 13.31(s,1H),9.11(s,1H),8.95(s,1H),8.11(d,J=2.0Hz,1H),7.85-7.27(m,9H),6.68(d,J=2.0Hz,1H). C 22 H 14 O2N5[MH] - HRMS (ESI-TOF) calculated value: 380.1153, observed value: 380.1150.

[0420] Reference Example 9: Synthesis of 6-methyl-3-(([1,1'-biphenyl]-4-ylmethyl)amino)-3-oxopropanoate (120) [ka] Following general procedure B, 120 (1.5 g, 5.3 mmol, 60.0%) was obtained from methyl hydrogen malonate (1.00 g, 8.9 mmol), 4-aminomethylbiphenyl (1.83 g, 10.0 mmol), T3P (6.7 g, 21.1 mmol), and DIPEA (2.7 g, 21.1 mmol). 1 H NMR (400MHz, THF-d8) δ 7.71 (s, 1H), 7.41-7.03 (m, 9H), 4.23 (d, J = 6.0Hz, 2H), 3.46 (s, 3H), 3.10 (s, 2H). C 17 H18 O3N[M+H] + HRMS (ESI-TOF) calculated value: 284.1281, observed value: 284.1281.

[0421] Reference Example 9: Synthesis of 7-methyl 3-oxo-3-((4-(trifluoromethyl)benzyl)amino)propanoate (121) [ka] Following general procedure B, 121 (736 mg, 2.67 mmol, 30%) was obtained from methyl hydrogen malonate (1.00 g, 8.9 mmol), 4-trifluorobenzylamine (1.75 g, 10.0 mmol), T3P (6.7 g, 21.1 mmol), and DIPEA (2.7 g, 21.1 mmol). 1 H NMR (400MHz, chloroform-d) δ 7.86(s,1H),7.52(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),4.46(d,J=6.0Hz,2H),3.68(s,3H),3.33(s,2H). C 12 H 13 O3NF3[M+H] + HRMS (ESI-TOF) calculated value: 276.0842, observed value: 276.0843.

[0422] Example 98 Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (122) [ka] 120 (200 mg, 0.70 mmol) was placed in a microwave vial, flushed with N2, and removed in vacuo (three times), followed by the addition of anhydrous ethyl orthoformate (5 mL). The reaction mixture was heated at 120 °C for 3 h under microwave irradiation. Excess ethyl orthoformate was removed in vacuo, and the resulting mixture was dissolved in diphenyl ether (5 mL). 2,5-Dimethylpyrazolo[1,5-a]pyrimidin-7-amine (114 mg, 0.70 mmol) was added, and the resulting mixture was heated at 240 °C for 30 min, cooled to room temperature, and directly purified by flash column chromatography using (CHCl:MeOH 0–10%, 1% formic acid) over 20 column volumes to give 122 (10 mg, 0.024 mmol, 3%). 1 H NMR(400MHz,DMSO-d6)δ 10.54(s,1H),8.59(s,1H),7.69-7.30(m,9H),6.44(s,1H),4.59(d,J=6.0Hz,2H),2.88(s,3H),2.45(s,3H). C 25 H 22 O2N5[M+H] + HRMS (ESI-TOF) calculated value: 424.1768, observed value: 424.1768.

[0423] Example 99: Synthesis of 6-hydroxy-2,5-dimethyl-N-(4-(trifluoromethyl)benzyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (123) [ka] 121 (200 mg, 0.70 mmol) was placed in a microwave vial, flushed with N2, and vacuumed three times before adding anhydrous ethyl orthoformate (5 mL). The reaction mixture was heated at 120 °C for 3 h under microwave irradiation. Excess ethyl orthoformate was removed in vacuo, and the resulting mixture was dissolved in diphenyl ether (5 mL). 2,5-Dimethylpyrazolo[1,5-α]pyrimidin-7-amine (114 mg, 0.70 mmol) was added, and the resulting mixture was heated at 240 °C for 30 min, cooled to room temperature, and directly purified by flash column chromatography using (CHCl:MeOH 0–10%, 1% formic acid) over 20 column volumes to give 123 (8 mg, 0.020 mmol, 3%). 1 H NMR(400MHz,DMSO-d6)δ 8.52(s,1H),7.71(d,J=8.1Hz,2H),7.55(d,J=8.0Hz,2H),6.50(s,1H),4.64(d,J=6.0Hz,2H),2.89(s,3H),2.47(s,3H). C 20 H 15 O2N5F3[MH] - HRMS (ESI-TOF) calculated value: 414.1183, observed value: 414.1182.

[0424] Example 100 Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-6-(4-cyano-1H-pyrazol-1-yl)-5-methoxynicotinamide (124) [ka] Following general procedure C, 72 (147 mg, 0.42 mmol) PdtBuXPhos G3 (33 mg, 0.04 mmol), cesium carbonate (273 mg, 0.84 mmol) and 1H-pyrazole-4-carbonitrile (70 mg, 0.5 mmol) gave the title compound (56 mg, 0.137 mmol, 33%). 1H NMR(400MHz,DMSO)δ 9.41(t,J=6.0Hz,1H),9.11(d,J=1.0Hz,1H),8.65(d,J=2.0Hz,1H),8.36(d,J=1.0Hz,1H),8.18(d,J=2 .0Hz,1H),7.67-7.62(m,4H),7.49-7.42(m,4H),7.40-7.32(m,1H),4.59(d,J=6.0Hz,2H),3.97(s,3H).

[0425] Example 10 Synthesis of 1-N-([1,1'-biphenyl]-4-ylmethyl)-6-(4-cyano-1H-pyrazol-1-yl)-5-hydroxynicotinamide (125) [ka] Following general procedure D, 125 (56 mg, 0.14 mmol) and lithium chloride (58 mg, 1.37 mmol) were combined, followed by the addition of N,N-dimethylacetamide (3 mL). The resulting mixture was microwaved at 150 °C for 8 h. The crude product was then purified using reverse-phase flash chromatography (HO, 0.1% formic acid (0-100% ACN, 0.1% formic acid)) to afford the title compound (3 mg, 0.007 mmol, 5%). 1 H NMR(400MHz,DMSO)δ 9.35(t,J=5.9Hz,1H),9.24(s,1H),8.53(d,J=1.9Hz,1H),8.42(s,1H),7.95(d,J=1.9Hz,1H ),7.67-7.62(m,4H),7.45(qd,J=7.1,1.9Hz,4H),7.38-7.32(m,1H),4.55(d,J=6.0Hz,2H).

[0426] Reference Example 10 Synthesis of 2-6-chloro-5-methoxy-N-((4-(trifluoromethyl)cyclohexyl)methyl)nicotinamide (126) [ka] Following general procedure B, 6-chloro-5-methoxynicotinic acid (1000 mg, 5.35 mmol), HATU (4064 mg, 10.70 mmol), C-4 trifluorocyclohexylamine (1209 μL, 8.02 mmol) and DIPEA (2759 μL, 16.04 mmol) gave the title compound (1625 mg, 4.64 mol, 86%). C 15 H 19 ClF3N2O2[M+H] + LRMS m / z measured value: 351.1, actual value: 351.1

[0427] Example 10 Synthesis of 3-ethyl 1-(3-methoxy-5-(((4-(trifluoromethyl)cyclohexyl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (127) [ka] Following general procedure C, the desired compound (92 mg, 0.20 mmol, 23%) was obtained from 127 (300 mg, 0.86 mmol), PdtBuXPhos G3 (68 mg, 0.09 mmol), ethyl 1H-pyrazole-4-carboxylate (180 mg, 1.29 mmol), and Cs2CO3 (835 mg, 2.57 mmol). 1 H NMR(400MHz,DMSO)δ 8.80(t,J=6.0Hz,1H),8.74(d,J=0.7Hz,1H),8.57(d,J=1.8Hz,1H),8.14(d,J=0.6Hz,1H),8.07(d,J=1.8Hz,1H),4.27(q,J=7.0Hz,2H) ,3.96(s,3H),3.19(t,J=6.0Hz,2H),2.35-2.16(m,1H),1.94-1.82(m,4H),1.63-1.50(m,1H),1.30(t,J=7.0Hz,3H),1.27-0.98(m,4H). C 21 H 26 F3N4O4[M+H] + LRMS m / z measurement: 455.19, actual measurement: 455.30

[0428] Example 10 Synthesis of 4-ethyl 1-(3-hydroxy-5-(((4-(trifluoromethyl)cyclohexyl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (128) [ka] Following general procedure D, 128 (92 mg, 0.20 mmol), LiCl (85 mg, 2.03 mmol) and DMSO (2 ml) gave the title compound (20 mg, 0.04 mmol, 20%). 1 H NMR(400MHz,DMSO)δ 8.95(s,1H),8.69(t,J=6.0Hz,1H),8.42(d,J=2.0Hz,1H),8.24(s,1H),7.87(d,J=2.0Hz,1H),4.28(q,J=7.0Hz,2H),3.15(t,J=6.3Hz, 2H),1.92-1.79(m,5H),1.55(dp,J=18.8,7.4,5.7Hz,1H),1.29(t,J=7.0Hz,3H),1.25-1.16(m,2H),1.02(qd,J=13.8,13.1,3.9Hz,2H).

[0429] Example 105-Synthesis of 1-(3-hydroxy-5-(((4-(trifluoromethyl)cyclohexyl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (129) [ka] 129 (20 mg, 0.04 mmol) was dissolved in THF (10 mL), followed by the addition of aqueous LiOH (500 μL, 2 M). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was neutralized with formic acid, followed by the addition of Celite. The solvent was then removed in vacuo, and the crude mixture was purified using reverse-phase flash column chromatography (0% to 100% ACN (0.1% formic acid) in HO (0.1% formic acid)) to afford the title compound (6 mg, 0.014 mmol, 36%). 1H NMR(400MHz,DMSO)δ 8.82(s,1H),8.65(t,J=6.0Hz,1H),8.40(d,J=2.0Hz,1H),8.09(s,1H),7.88(d,J=2.0Hz,1H),3.14(t,J=6.0H z,2H),2.28-2.15(m,1H),1.92-1.80(m,5H),1.21(qt,J=13.9,6.7Hz,3H),1.02(qd,J=13.7,12.9,4.0Hz,2H). C 18 H 18 F3N4O4[MH] - LRMS m / z measurement: 411.13, actual measurement: 411.0

[0430] Reference Example 10: Synthesis of 6-ethyl 6-chloro-4-methoxynicotinate (130) [ka] 6-Chloro-4-methoxynicotinic acid (5 g, 0.03 mol), EDC.HCl (6.22 g, 0.04 mol), and DMAP (0.05 g, 1.2 mmol) were dissolved in DMF (50 mL). DIPEA (4.60 mL, 0.03 mmol) and EtOH (5 mL) were then added to the reaction mixture. The resulting mixture was then stirred at room temperature for 16 hours. EtOAc (50 mL), 1 M HCl (50 mL), and H2O (100 mL) were added to the reaction mixture. The organic and aqueous layers were separated. This process was repeated two more times. The combined organic layers were washed with brine and then dried over anhydrous Na2SO4. The crude compound was then purified using flash column chromatography using 15 column volumes (cyclohexane 100% to 50%, EtOAc 0% to 50%) to give the desired compound (2.02 g, 9.39 mmol, 31%). C9H 11 ClNO3[M+H] + LRMS m / z measurement value: 216.0, actual value: 216.2

[0431] Reference Example 10: Synthesis of 7-ethyl 4-methoxy-6-(1H-pyrazol-1-yl)nicotinate (131) [ka] Following general procedure C, the title compound (1.9 g, 7.65 mmol, 87%) was obtained from 130 (1.90 g, 0.088 mol), PdtBuXPhos G3 (0.35 g, 0.00044 mol), cesium carbonate (4.30 g, 0.0132 mol), pyrazole (0.90 g, 0.0132 mol) and anhydrous 1,4-dioxane (50 ml). C 12 H 14 N3O3[M+H] + LRMS m / z measured value: 248.10, actual value: 248.10

[0432] Reference Example 108: Synthesis of 4-methoxy-6-(1H-pyrazol-1-yl)nicotinic acid (132) [ka] 131 (1.9 g, 7.65 mmol) was dissolved in a mixture of THF (65 mL), MeOH (35 mL), and HO (10 mL), followed by the addition of lithium hydroxide monohydrate (3.7 g, 90.5 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction was confirmed to be complete by TLC. The reaction mixture was acidified, cooled to 5 °C, and filtered to collect the precipitate. The precipitate was washed with diethyl ether to give the title compound (1.4 g, 6.39 mmol, 84%). C 10 H 10 N3O4[M+H] + LRMS m / z measurement value: 220.07, actual value: 220.2.

[0433] Example 109 Synthesis of N-(but-2-yn-1-yl)-4-methoxy-6-(1H-pyrazol-1-yl)nicotinamide (133) [ka] Following general procedure B, 132 (187 mg, 0.85 mmol), HATU (646 mg, 1.7 mmol), but-2-yn-1-amine hydrochloride (135 mg, 1.27 mmol) and DIPEA (438 μL, 2.55 mmol) gave the title compound (148 mg, 0.54 mmol, 63%). C 14 H 15 N4O2[M+H] + LRMS m / z measurement: 271.1, actual measurement: 271.2

[0434] Example 110 Synthesis of N-(but-2-yn-1-yl)-4-hydroxy-6-(1H-pyrazol-1-yl)nicotinamide (134) [ka] Following general procedure D, 133 (143 mg, 0.53 mmol) and lithium chloride (111 mg, 2.64 mmol) gave the title compound (44 mg, 0.171 mmol, 33%). 1 H NMR(400MHz,DMSO)δ 11.38(t,J=5.4Hz,1H),8.48-8.39(m,2H),7.73-7.62(m,1H),6.73(d,J=3.1Hz ,1H),6.42(q,J=2.1Hz,1H),4.01(dq,J=5.2,2.5Hz,2H),1.78(t,J=2.7Hz,3H). C 13 H 13 N4O2[M+H] + LRMS m / z measurement value: 257.10, actual value: 257.30

[0435] Example 111 Synthesis of 1-N-((6-chloropyridin-3-yl)methyl)-4-methoxy-6-(1H-pyrazol-1-yl)nicotinamide (135) [ka] Following general procedure B, 132 (900 mg, 4.11 mmol), HATU (3123 mg, 8.22 mmol), (6-chloropyridin-3-yl)methanamine (700 mg, 4.93 mmol) and DIPEA (2.1 mL, 12.33 mmol) gave the title compound (1.315 g, 3.83 mmol, 93%). C 16 H 15 ClNO2[M+H] + LRMS m / z measurement: 344.1, actual measurement: 344.2

[0436] Example 11 Synthesis of 2-ethyl 4-(5-((4-methoxy-6-(1H-pyrazol-1-yl)nicotinamido)methyl)pyridin-2-yl)benzoate (136) [ka] Following general procedure C, 135 (44 mg, 0.128 mmol), (4-ethoxycarbonyl)phenyl)boronic acid (42 mg, 0.22 mmol), Pd Amphos (5.16 mg, 0.01 mmol), and cesium carbonate (142.13 mg, 0.44 mmol) gave the title compound (50 mg, 0.109 mmol, 54%). C 25 H 24 N5O4[M+H] + The observed LRMS m / z was 458.18, the actual value was 458.3, and the [M+2H] / 2 was 229.7.

[0437] Example 11 Synthesis of 3-4-methoxy-6-(1H-pyrazol-1-yl)-N-((6-(pyrimidin-5-yl)pyridin-3-yl)methyl)-nicotinamide (137) [ka] Following general procedure C, 135 (27 mg, 0.078 mmol), pyrimidin-5-ylboronic acid (27 mg, 0.22 mmol), Pd Amphos (5.16 mg, 0.01 mmol), and cesium carbonate (142.13 mg, 0.44 mmol) gave the title compound (9 mg, 0.012 mmol, 15%). C 20 H 18 N7O2[M+H] + LRMS m / z measured: 388.15, actual value: 388.00. [M+2H] / 2 was observed to be 194.8.

[0438] Example 11 Synthesis of 4-4-methoxy-N-((6-(4-(methylcarbamoyl)phenyl)pyridin-3-yl)methyl)-6-(1H-pyrazol-1-yl)nicotinamide (138) [ka] Following general procedure C, 135 (50 mg, 0.15 mmol), (4-(methylcarbamoyl)phenyl)boronic acid (39 mg, 0.22 mmol), Pd Amphos (5.16 mg, 0.01 mmol), and cesium carbonate (142.13 mg, 0.44 mmol) gave the title compound (39 mg, 0.088 mmol, 59%). C 24 H 23 N6O3[M+H] + The observed LRMS m / z was 443.18, the actual value was 443.1, and the [M+2H] / 2 was 222.20.

[0439] Example 11 Synthesis of 5-N-((6-(4-carbamoylphenyl)pyridin-3-yl)methyl)-4-methoxy-6-(1H-pyrazol-1-yl)nicotinamide (139) [ka] Following general procedure C, 135 (50 mg, 0.15 mmol), (4-(carbamoyl)phenyl)boronic acid (36 mg, 0.22 mmol), Pd Amphos (5.16 mg, 0.01 mmol), and cesium carbonate (142.13 mg, 0.44 mmol) gave the title compound (22 mg, 0.051 mmol, 34%). C 23 H 21 N6O3[M+H] + LRMS m / z measurement: 429.17, actual measurement: 429.2

[0440] Example 11 Synthesis of 6-4-methoxy-N-((6-(4-morpholinophenyl)pyridin-3-yl)methyl)-6-(1H-pyrazol-1-yl)nicotinamide (140) [ka] Following general procedure C, 135 (50 mg, 0.15 mmol), (4-morpholinophenyl)boronic acid (59 mg, 0.22 mmol), Pd Amphos (5.16 mg, 0.01 mmol), and cesium carbonate (142.13 mg, 0.44 mmol) gave the title compound (50 mg, 0.106 mmol, 71%). C 26 H 27 N6O3[M+H] + The observed LRMS m / z was 471.21, the actual value was 471.20, and [M+2H] / 2 was 236.20.

[0441] Example 117 Synthesis of N-((6-(benzo[d]thiazol-5-yl)pyridin-3-yl)methyl)-4-methoxy-6-(1H-pyrazol-1-yl)nicotinamide (141) [ka] Following general procedure C, 135 (50 mg, 0.15 mmol), (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (57.07 mg, 0.22 mmol), Pd Amphos (5.16 mg, 0.01 mmol), and cesium carbonate (142.13 mg, 0.44 mmol) gave the title compound (22 mg, 0.0497 mmol, 33%). C 23 H 19 N6O2S[M+H] + LRMS m / z measured: 443.13, actual value [M+2H] 2+ / 2:222.0

[0442] Example 11 Synthesis of 8-ethyl 4-(5-((4-hydroxy-6-(1H-pyrazol-1-yl)nicotinamido)methyl)pyridin-2-yl)benzoate (142) [ka] Following general procedure D, 140 (50 mg, 0.11 mmol) and lithium chloride (46 mg, 1.09 mmol) gave the title compound (10 mg, 0.022 mmol, 22%), which was purified by reverse-phase flash chromatography (0 to 100% ACN (0.1% formic acid) in HO (0.1% formic acid)) to give the title compound (10 mg, 0.0225 mmol, 22%). C 24 H 22 N5O4[M+H] + LRMS m / z measured: 444.10, actual value: 444.2, [M+2H] 2+ / 2 was observed to be 222.7.

[0443] Example 119 - Synthesis of 4-(5-((4-hydroxy-6-(1H-pyrazol-1-yl)nicotinamido)methyl)pyridin-2-yl)benzoic acid (143) [ka] 143 (6 mg, 0.0135 mmol) was dissolved in a mixture of MeOH (5 mL) and HO (1 mL), followed by the addition of lithium hydroxide (2.84 mg, 0.07 mmol). The resulting mixture was stirred at room temperature for 16 h. 1 M HCl (1 mL) was added to the reaction mixture, and the resulting precipitate was filtered, washed with EtO, and dried to give the title compound (2 mg, 0.0048 mmol, 35%). 1 H NMR(400MHz,DMSO)δ 11.88(t,J=5.8Hz,1H),8.65(d,J=2.3Hz,1H),8.48(s,1H),8.44(s,1H),8.15(d,J=8.2Hz,2H),8.01(dd,J=8.3,6.3Hz, 3H),7.82(dd,J=8.0,2.5Hz,1H),7.65(d,J=1.5Hz,1H),6.68(s,1H),6.41(dd,J=2.1,2.1Hz,1H),4.55(d,J=5.8Hz,2H). C 22 H 18 N5O4[M+H] + LRMS m / z measured: 416.14, actual value: 416.20, [M+2H] + / 2 was observed to be 208.6.

[0444] Example 120 Synthesis of 4-hydroxy-6-(1H-pyrazol-1-yl)-N-((6-(pyrimidin-5-yl)pyridin-3-yl)methyl)nicotinamide (144) [ka] Following general procedure D, 137 (9 mg, 0.02 mmol) and lithium chloride (9.77 mg, 0.23 mmol) gave the title compound (6 mg, 0.0160 mmol, 81%). 1H NMR(400MHz,DMSO)δ 9.43(d,J=1.9Hz,2H),9.24(s,1H),8.75(d,J=2.2Hz,1H),8.64(d,J=2.7Hz,1H),8.15-8 .10(m,1H),7.97-7.85(m,2H),7.35(s,1H),6.61(q,J=2.1Hz,1H),4.63(d,J=5.9Hz,2H). C 19 H 16 N7O2[M+H] + LRMS m / z measured: 374.14, actual value: 374.00, [M+2H] + / 2=187.5

[0445] Example 12 Synthesis of 1-4-hydroxy-N-((6-(4-(methylcarbamoyl)phenyl)pyridin-3-yl)methyl)-6-(1H-pyrazol-1-yl)nicotinamide (145) [ka] Following general procedure D, 138 (35 mg, 0.09 mmol) and lithium chloride (37 mg, 0.88 mmol) gave the title compound (6 mg, 0.0160 mmol, 81%). 1 H NMR(400MHz,DMSO)δ 9.57(s,1H),8.74(s,1H),8.70(d,J=2.2Hz,1H),8.64(d,J=2.6Hz,1H),8.50(q,J=4.5Hz,1H),8.21-8.09(m,2H),8.02(d,J=8.2 Hz,1H),7.98-7.90(m,2H),7.90-7.79(m,2H),7.33(s,1H),6.60(t,J=2.7Hz,1H),4.62(d,J=5.9Hz,2H),2.81(d,J=4.5Hz,3H). C 23 H 21 N6O3[M+H] + LRMS m / z measured: 429.17, actual value: 429.10, [M+2H] 2+ / 2=215.1

[0446] Example 12 Synthesis of 2-N-((6-(4-carbamoylphenyl)pyridin-3-yl)methyl)-4-hydroxy-6-(1H-pyrazol-1-yl)nicotinamide (146) [ka] Following general procedure D, 139 (22 mg, 0.05 mmol) and lithium chloride (21.59 mg, 0.51 mmol) gave the title compound (8 mg, 0.019 mmol, 38%). 1 H NMR(400MHz,DMSO)δ 9.72(s,1H),8.75-8.66(m,2H),8.62(d,J=2.6Hz,1H),8.18-8.10(m,2H),8.06-7.94(m,4H),7 .92-7.78(m,2H),7.40(s,1H),7.30(s,1H),6.58(dd,J=2.7,1.7Hz,1H),4.61(d,J=5.9Hz,2H). C 22 H 19 N6O3[M+H] + LRMS m / z measured: 415.15, actual value: 415.20, [M+2H] 2+ / 2=208.40

[0447] Example 12 Synthesis of 3-4-hydroxy-N-((6-(4-morpholinophenyl)pyridin-3-yl)methyl)-6-(1H-pyrazol-1-yl)nicotinamide (147) [ka] Following general procedure D, 140 (35 mg, 0.11 mmol) and lithium chloride (44.68 mg, 1.06 mmol) gave the title compound (6 mg, 0.0160 mmol, 81%). 1H NMR(400MHz,DMSO)δ 9.65(s,1H),8.72(s,1H),8.63(dd,J=2.6,0.7Hz,1H),8.58(dd,J=2.3,0.9Hz,1H),8.00-7.92(m,2H),7.88-7.80(m,2H),7.77(dd,J=8.2,2. 3Hz,1H),7.29(s,1H),7.06-6.98(m,2H),6.59(dd,J=2.6,1.7Hz,1H),4.56(d,J=5.9Hz,2H),3.75(dd,J=5.8,3.9Hz,4H),3.22-3.15(m,4H). C 25 H 25 N6O3[M+H] + LRMS m / z measured: 457.20, actual value: 457.40, [M+2H] 2+ / 2=229.2

[0448] Example 123a—Synthesis of N-((6-(benzo[d]thiazol-5-yl)pyridin-3-yl)methyl)-4-hydroxy-6-(1H-pyrazol-1-yl)nicotinamide (148) [ka] Following general procedure D, 141 (22 mg, 0.05 mmol) and lithium chloride (21 mg, 0.5 mmol) gave the title compound (14 mg, 0.032 mmol, 65%). 1 H NMR(400MHz,DMSO)δ 9.45(s,1H),8.84-8.59(m,3H),8.35-8.19(m,2H),8.17-8.07(m,2H),7.95- 7.82(m,2H),7.34(s,1H),6.60(dd,J=3.8,3.0Hz,1H),4.62(d,J=6.2Hz,2H). C 22 H 17 N6O2S[M+H] + LRMS m / z measured: 429.11, actual value: 429.10, [M+2H] 2+ / 2=215.2

[0449] Reference Example 12 Synthesis of 4-methyl 6-chloro-4-methoxypyridazine-3-carboxylate (149) [ka] Methyl 4,6-dichloropyridazine-3-carboxylate (1000 mg, 4.93 mmol) was dissolved in THF (10 mL). The resulting mixture was cooled to 0 °C, and then sodium methoxide (319 mg, 5.91 mmol) was slowly added. The resulting mixture was allowed to warm to room temperature and stirred for 6 h. The solvent was then removed in vacuo, and the resulting residue was taken up in a mixture of EtOAc (50 mL) and HO (50 mL). The organic and aqueous layers were separated, and the aqueous layer was washed two more times with EtOAc (50 mL). The organic layers were combined, dried (NaSO), and purified using flash column chromatography (0% to 100% EtOAc, cyclohexane 100% to 0%) to afford the title compound (103 mg, 0.509 mmol, 10%). C7H8ClN2O3[M+H] + LRMS m / z measurement: 203.02, actual measurement: 203.1

[0450] Reference Example 12 Synthesis of 5-methyl 4-methoxy-6-(1H-pyrazol-1-yl)pyridazine-3-carboxylate (150) [ka] According to general procedure C, 149 (103 mg, 0.29 mmol), pyrazole (30 mg, 0.44 mmol), Pd t The title compound (37 mg, 0.16 mmol, 55%) was obtained from BuXPhos G3 (23 mg, 0.03 mmol) and cesium carbonate (284 mg, 0.88 mmol). C 10 H 11 N4O3[M+H] + LRMS m / z measurement: 235.08, actual measurement: 235.2

[0451] Reference Example 12 Synthesis of 6-4-methoxy-6-(1H-pyrazol-1-yl)pyridazine-3-carboxylic acid (151) [ka] 150 (37 mg, 0.16 mmol) was taken up in a mixture of methanol (5 mL) and HO (0.5 mL), and then lithium hydroxide (33.21 mg, 0.79 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. 1 M HCl (5 mL) was added to the reaction mixture. The precipitate was then collected and washed with EtO to give the title compound (22 mg, 0.099 mmol, 62%). C9H9N4O4[M+H] + LRMS m / z measurement: 221.07, actual measurement: 221.1

[0452] Example 127 Synthesis of 4-methoxy-6-(1H-pyrazol-1-yl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)pyridazine-3-carboxamide (152) [ka] Following general procedure B, 151 (22 mg, 0.10 mmol), HATU (76 mg, 0.20 mmol), (4-trifluoromethyl)cyclohexyl)methanamine (15 μL, 0.1 mmol) and DIPEA (51 μL, 0.3 mmol) gave the title compound (34 mg, 0.088 mmol, 89%). C 17 H 21 F3N5O2[M+H] + LRMS m / z measurement: 384.16, actual measurement: 384.2

[0453] Example 128 Synthesis of 4-hydroxy-6-(1H-pyrazol-1-yl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)pyridazine-3-carboxamide (153) [ka] Following general procedure D, 152 (34 mg, 0.08 mmol) and lithium chloride (78 mg, 1.86 mmol) gave the title compound (8 mg, 0.0216 mmol, 11%). 1 H NMR(400MHz,DMSO)δ 9.92(s,1H),8.79-8.74(m,1H),7.94(d,J=1.7Hz,1H),7.46(s,1H),6.68(dd,J=2.7,1.7Hz,1H),3.22(t,J =6.5Hz,2H),2.32-2.14(m,1H),1.93-1.79(m,4H),1.63(ddt,J=11.7,8.3,4.4Hz,1H),1.32-0.99(m,4H). C 16 H 19 NO2[M+H] + LRMS m / z measurement: 370.15, actual measurement: 370.2

[0454] Example 12 Synthesis of 9-methyl 1-(3-hydroxy-5-(((4-(trifluoromethyl)cyclohexyl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (154) [ka] 128 (10 mg, 0.02 mmol) was added to a 10 mL round-bottom flask and flushed with N2, followed by the addition of anhydrous MeOH (3 mL). A 10% sodium methoxide in methanol solution (500 μL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 16 h. Formic acid was added to neutralize the reaction mixture, followed by the addition of Celite. The solvent was removed in vacuo, and the crude mixture was purified using flash column chromatography (0–10% MeOH in CHCl2) to give the title compound (4.5 mg, 0.010 mmol, 52%). 1H NMR(400MHz,DMSO)δ 8.93(d,J=0.7Hz,1H),8.71(t,J=6.0Hz,1H),8.47(d,J=1.9Hz,1H),8.28(d,J=0.7Hz,1H),7. 90(d,J=1.9Hz,1H),3.82(s,3H),3.15(t,J=6.5Hz,2H),1.95-1.78(m,5H),1.30-0.96(m,5H). C 19 H 22 F3N4O4[M+H] + LRMS m / z measurement: 427.16, actual measurement: 427.2

[0455] Reference Example 13 Synthesis of 0-ethyl 1-carbamimidoyl-1H-pyrazole-4-carboxylate (155) [ka] To a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (6.66 g, 47.62 mmol), cyanamide (2 g, 47.62 mmol), and dioxane (30 mL) was added a solution of 4 M HCl in dioxane (20 mL). The reaction mixture was heated to 100 °C for 3 h. The reaction was cooled to room temperature, and EtO (30 mL) was added. The precipitate was collected to give the title compound (3 g, 16.4 mmol, 35%). C7H 11 N4O2[M+H] + LRMS m / z measurement: 183.09, actual measurement: 183.1

[0456] Reference Example 13 Synthesis of 1-methyl 1-(5-cyano-4-hydroxypyrimidin-2-yl)-1H-pyrazole-4-carboxylate (156) [ka] Ethyl (E)-2-cyano-3-ethoxyacrylate (3.0 g, 17.75 mmol) was added to a solution of 155 (3.23 g, 17.75 mmol), K2CO3 (4.9 g, 35.50 mmol), and methanol (100 mL). The resulting mixture was stirred at room temperature for 1 h. HO (50 mL) was added, and the white precipitate was filtered to give the title compound (3.52 g, 13.59 mmol, 76%). C 10 H8N5O3[M+H] + LRMS m / z measurement: 246.06, actual measurement: 246.1

[0457] Reference Example 13: Synthesis of 2-1-(5-cyano-4-hydroxypyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid (157) [ka] A solution of 156 (3.0 g, 13.1 mmol) in MeOH (15 mL) and HO (10 mL) was prepared, followed by the addition of lithium hydroxide monohydrate (904 mg, 39.3 mmol). The reaction mixture was stirred for 4 h. The reaction mixture was neutralized with 1 N HCl, and the MeOH was removed in vacuo. The precipitate was collected to give the title compound (2.49 g, 10.8 mmol, 83%). C9H4N5O3[MH] - LRMS m / z measurement: 230.03, actual measurement: 230.4

[0458] Example 13 Synthesis of 3-N-([1,1'-biphenyl]-4-ylmethyl)-1-(5-cyano-4-hydroxypyrimidin-2-yl)-1H-pyrazole-4-carboxamide (158) [ka] Following general procedure B, 157 (10 mg, 0.04 mmol), HATU (33 mg, 0.09 mmol), 4-phenylbenzylamine (11.88 mg, 0.06 mmol), and DIPEA (22 μL, 0.13 mmol) gave the title compound (8 mg, 0.020 mmol, 57%). 1 H NMR(400MHz,DMSO)δ 9.15(s,1H),8.99(t,J=6.0Hz,1H),8.59(s,1H),8.23(s,1H),7.64(dd,J=7.9,4.7Hz,4H),7.51-7.31(m,5H),4.48(d,J=6.0Hz,2H). C 22 H 17 N6O2[M+H] + LRMS m / z measurement: 397.14, actual measurement: 397.2

[0459] Example 134 Synthesis of 1-(5-cyano-4-hydroxypyrimidin-2-yl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)-1H-pyrazole-4-carboxamide (159) [ka] Following general procedure B, 157 (37 mg, 0.16 mmol), C-4 trifluoromethylcyclohexylmethamine (28 μL, 0.19 mmol), T3P (190 μL, 0.32 mmol), and DIPEA (83 μL, 0.48 mmol) gave the title compound (9 mg, 0.022 mmol, 14%). 1 H NMR(400MHz,DMSO)δ 9.05(s,1H),8.27(d,J=6.7Hz,2H),7.98(s,1H),3.07(t,J=6.0Hz,2H),2.29-2.12(m, 1H), 1.85 (t, J=16.4Hz, 4H), 1.64-1.42 (m, 1H), 1.27-1.13 (m, 2H), 1.05-0.91 (m, 2H). C 17 H 18 F3N6O2[M+H] + LRMS m / z measurement: 395.14, actual measurement: 395.2

[0460] Example 13 Synthesis of 5-1-(5-cyano-4-hydroxypyrimidin-2-yl)-N-((6-phenylpyridin-3-yl)methyl)-1H-pyrazole-4-carboxamide (160) [ka] Following general procedure B, 157 (100 mg, 0.43 mmol), (6-phenylpyridin-3-yl)methanamine (119 mg, 0.65 mmol), T3P (515 μL, 0.87 mmol), and DIPEA (223 μL, 0.130 mmol) gave the title compound (65 mg, 0.163 mmol, 38%). 1 H NMR(400MHz,DMSO)δ 9.28-8.99(m,2H),8.87-8.60(m,2H),8.43-8.19(m,1H),8.09-8.03(m,2H),7.95(d,J=8 .1Hz,1H),7.82(ddd,J=16.8,8.3,2.4Hz,1H),7.54-7.39(m,3H),4.46(d,J=5.5Hz,2H). C 21 H 16 N7O2[M+H] + LRMS m / z measurement: 398.14, actual measurement: 398.1

[0461] Example 13 Synthesis of 6-methyl 4-(5-((1-(5-cyano-4-hydroxypyrimidin-2-yl)-1H-pyrazole-4-carboxamido)-methyl)-pyridin-2-yl)-benzoate (161) [ka] Following general procedure B, 157 (100 mg, 0.43 mmol), methyl 4-(5-(aminomethyl)pyridin-2-yl)benzoate (157 mg, 0.65 mmol), T3P (515 μL, 0.87 mmol), and DIPEA (223 μL, 0.130 mmol) gave the title compound (11 mg, 0.0241 mmol, 6%). 1H NMR(400MHz,DMSO)δ 9.05(s,1H),8.27(d,J=6.7Hz,2H),7.98(s,1H),3.07(t,J=6.0Hz,2H),2.29-2.12(m, 1H), 1.85 (t, J=16.4Hz, 4H), 1.64-1.42 (m, 1H), 1.27-1.13 (m, 2H), 1.05-0.91 (m, 2H). C 23 H 18 N7O4[M+H] + LRMS m / z measurement value: 456.14, actual value: 456.2.

[0462] Example 137 - Synthesis of 4-(5-((1-(5-cyano-4-hydroxypyrimidin-2-yl)-1H-pyrazole-4-carboxamido)methyl)pyridin-2-yl)benzoic acid (162) [ka] Following general procedure D, 161 (5 mg, 0.01 mmol), LiCl (4.51 mg, 0.11 mmol) in DMF (1 mL) gave the title compound (2 mg, 0.0045 mmol, 45%). 1 H NMR(400MHz,DMSO)δ 9.13(s,1H),9.04(t,J=5.5Hz,1H),8.68(d,J=2.2Hz,1H),8.57(s,1H),8.23-8.16(m ,3H),8.04(dd,J=8.3,4.0Hz,3H),7.86(dd,J=8.3,2.3Hz,1H),4.52(d,J=5.5Hz,2H). C 22 H 14 N7O4[MH] - LRMS m / z measured: 440.11, actual value: 439.3, [M-2H] 2- / 2=220.0

[0463] Example 13 Synthesis of 8-ethyl 6-(4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-1H-pyrazol-1-yl)-5-methoxynicotinate (163a) [ka] Ethyl 6-chloro-5-methoxynicotinate (30 mg, 0.14 mmol), 92 (30 mg, 0.108 mmol), RockPhos G3 (10 mg, 0.014 mmol), and CsCO (77 mg, 0.238 mmol) in dioxane (5 ml) over 7 days gave 163a (5 mg, 0.01 mmol, 9%) as a clear oil. 1H NMR(400MHz,THF-d8)δ 8.71(s,1H,),8.65(d,J=1.0Hz,1H),8.07-8.05(m,1H),7.91(t,J=6.0Hz,1H),7.75(d,J=1.0Hz,1H) ,7.46-7.24(m,9H),4.58(d,J=6.0Hz,2H),4.40(q,J=7.0Hz,2H),3.98(s,3H),1.42(t,J=7.0Hz,3H). C 26 H 25 O4N4[M+H] + HRMS (ESI-TOF) calculated value: 457.1870, observed value: 457.1867.

[0464] Example 139 - Synthesis of 6-(4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-1H-pyrazol-1-yl)-5-methoxynicotinic acid (164a) [ka] 163a (5 mg, 0.0109 mmol) was dissolved in a mixture of THF and water (1.5 mL (10:1)). Lithium hydroxide monohydrate (1.0 mg, 0.021 mmol) was added to the reaction mixture, and the resulting mixture was allowed to stir at room temperature for 16 h. TLC confirmed the reaction was complete, and HCl (5 mL, 1 M) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (3 × 10 mL), washed with brine, dried over anhydrous NaSO, and purified using flash column chromatography using 20 column volumes (CHCl, 0–5% MeOH, 1% formic acid) to give 164a (3.5 mg, 0.0082 mmol, 76%) as a clear oil. 1H NMR(400MHz,DMSO-d6)δ 8.69(s,1H),8.47(s,1H),8.12(s,1H),7.99(s,1H),7.70-7.61(m,4H),7.50-7.32(m,5H),4.50(d,J=6.0Hz,2H),3.89(s,3H). C 24 H 21 O4N4[M+H] + HRMS (ESI-TOF) calculated value: 429.1557, observed value: 429.1557.

[0465] Reference Example 140: Synthesis of 2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amine (163) [ka] 3-Aminocrotononitrile (10 g, 0.12 mol) and 3-methyl-1H-pyrazol-5-amine (11.83 g, 0.12 mol) were combined and heated at 140° C. for 2 hours. The resulting mixture was allowed to cool. The crude mixture was then recrystallized from EtOH to give the title compound (6.68 g, 0.041 mol, 35%). C8H 11 N4[M+H] + LRMS m / z measurement: 163.1, actual measurement: 163.10

[0466] Reference Example 14 Synthesis of 1-diethyl 2-(((2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methylene)malonate (164) [ka] 163 (1.50 g, 0.01 mmol) was taken up in toluene (10 mL) and diethyl 2-(ethoxymethylene)malonate (2.24 mL, 0.01 mmol) was added. The resulting mixture was heated to 120 °C for 48 h. The reaction mixture was cooled to room temperature. Celite was added to the reaction mixture and the solvent was removed under vacuum. The crude compound was purified using flash chromatography (0–10% MeOH) to give the title compound (2.26 g, 0.0068 mmol, 74%). C 16 H 21 N4O4[M+H] + LRMS m / z measurement: 333.16, actual measurement: 333.2

[0467] Reference Example 14 Synthesis of 2-ethyl 6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylate (165) [ka] 164 (6.15 g, 18.52 mmol) was dissolved in Eaton's reagent (10 ml). The resulting mixture was heated to 70 °C for 4 h, and its progress was monitored by LCMS. Once the starting material was consumed, the reaction mixture was cooled to 0 °C and slowly poured into saturated NaHCO solution to quench the Eaton's reagent. The resulting mixture was then extracted with a mixture of CHCl and IPA (3 × 100 ml (3:1)). The organic fractions were combined, dried (NaSO), and the solvent was removed under vacuum. The crude compound was purified using flash column chromatography (CHCl:MeOH (0–20%)) to give the title compound (4.67 g, 16.32 mmol, 88%). C 14 H 15 N4O3[M+H] +LRMS m / z measured: 287.11, actual value: 287.20

[0468] Reference Example 14 Synthesis of 3-ethyl 6-chloro-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylate (166) [ka] 165 (4.67 g, 16.32 mmol) was dissolved in phosphorus oxychloride (25 mL) and refluxed at 100 °C for 3 h. The reaction mixture was cooled to 0 °C and slowly quenched with saturated NaHCO solution. The resulting mixture was extracted with a CHCl:IPA mixture (3:1 (3 × 100 ml)). The organic fractions were combined, dried (NaSO), and the solvent was removed in vacuo. The crude mixture was then subjected to the next step without further purification (4.54 g, 14.93 mmol, 91%). C 14 H 14 ClN4O4[M+H] + LRMS m / z measurement: 305.08, actual measurement: 305.2

[0469] Reference Example 14 Synthesis of 4-methyl 6-methoxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylate (167) [ka] 166 (156 mg, 0.51 mmol) was dissolved in MeOH (10 mL), followed by the addition of sodium methoxide solution (5 mL, 0.5 M). The resulting mixture was stirred at room temperature for 4 h. Celite was added to the reaction mixture, and the solvent was removed under vacuum. The crude mixture was then purified using flash column chromatography (MeOH (0–10%) in CHCl3) to afford the title compound (38 mg, 0.13 mmol, 26%). C 14 H 15 N4O3[M+H] + LRMS m / z measured: 287.11, actual value: 287.2

[0470] Example 14 Synthesis of 5-6-methoxy-2,5-dimethyl-N-((4-(trifluoromethyl)cyclohexyl)methyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (168) [ka] Following general procedure A, 167 (30 mg, 0.1 mmol), 4-trifluoromethylcyclohexylamine (19 μL, 0.16 mmol) and DABAL (26.85 mg, 0.1 mmol) gave the title compound (9 mg, 0.02 mmol, 20%). Solvent system used for purification: 0%-15% MeOH in CH3Cl. C 21 H 25 F3N5O2[M+H] + LRMS m / z measurement value: 436.20, actual value: 436.2.

[0471] Example 14 Synthesis of 6-N-([1,1'-biphenyl]-4-ylmethyl)-6-hydroxypyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (169) [ka] Following general procedure D, 168 (9 mg, 0.02 mmol), LiCl (8.6 mg, 0.21 mmol) in DMSO (1 ml) gave the title compound (1.5 mg, 0.0035 mmol, 18%). Solvent system used for purification: reversed phase (0% to 100% ACN (0.1% formic acid)) in HO (0.1% formic acid). 1H NMR(400MHz,DMSO)δ 8.91(s,1H),6.42(s,1H),3.23(d,J=5.1Hz,2H),2.66(s,3H),2.41(s,3H),2.07(s,1H),1.83-1 .75(m,2H),1.65(d,J=12.7Hz,2H),1.48(d,J=9.6Hz,1H),1.25-1.08(m,2H),0.95-0.81(m,2H). C 20 H 23 F3N5O2[M+H] + LRMS m / z measured: 422.18, actual value + :422.2

[0472] Example 14 Synthesis of 7-N-((6-chloropyridin-3-yl)methyl)-6-methoxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (170) [ka] Following general procedure A, 167 (900 mg, 3.15 mmol), (6-chloropyridin-3-yl)methanamine (532 mg, 3.78 mmol) and DABAL (805 mg, 3.15 mmol) gave the title compound (364 mg, 0.91 mmol, 29%). Solvent system used for purification: 0%-15% MeOH in CH3Cl. C 19 H 18 ClN6O2[M+H] + LRMS m / z measurement: 397.12, actual measurement: 397.10

[0473] Example 14 Synthesis of 8-N-((6-(4-carbamoylphenyl)pyridin-3-yl)methyl)-6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (171) [ka] Following general procedure C, 170 (15 mg, 0.04 mmol), (4-(carbamoyl)phenyl)boronic acid (9.75 mg, 0.06 mmol), Pd Amphos (2.77 mg, 0.0039 mmol), and cesium carbonate (38.19 mg, 0.12 mmol) gave the title compound (2 mg, 0.0042 mmol, 11%). 1 H NMR(400MHz,DMSO)δ 8.77(s,1H),8.69-8.66(m,1H),8.31(s,1H),8.14(t,J=4.2Hz,3H),7.99(dd,J=17.9,8.4Hz,3H),7. 86(dd,J=8.1,2.5Hz,1H),6.53(s,2H),6.20(s,1H),4.59(d,J=6.0Hz,2H),2.87(s,3H),2.36(s,3H). C 25 H 22 N7O3[M+H] + LRMS m / z measured: 468.18, actual value: 468.1, [M+2H] 2+ / 2=234.70

[0474] Example 14 Synthesis of 9-6-hydroxy-2,5-dimethyl-N-((6-(pyrimidin-5-yl)pyridin-3-yl)methyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (172) [ka] Following general procedure C, the title compound (2.5 mg, 0.0058 mmol, 15%) was obtained from 170 (15 mg, 0.04 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (12.1 mg, 0.06 mmol), Pd Amphos (1.39 mg, 0.0019 mmol), and cesium carbonate (38.19 mg, 0.12 mmol). 1H NMR(400MHz,DMSO)δ 10.69(s,1H),9.42(s,2H),9.24(s,1H),8.74(d,J=2.2Hz,1H),8.59(s,1H),8.14-8.09(m,1H),7.9 3(dd,J=8.2,2.3Hz,1H),6.52(s,1H),6.42(s,1H),4.63(d,J=6.0Hz,2H),2.89(s,3H),2.45(s,3H). C 22 H 19 N8O2[M+H] + LRMS m / z measured: 427.16, actual value: 427.1, [M+2H] 2+ / 2=214.20

[0475] Example 15 Synthesis of 0-6-hydroxy-2,5-dimethyl-N-((6-(4-morpholinophenyl)pyridin-3-yl)methyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (173) [ka] Following general procedure C, 170 (15 mg, 0.04 mmol), 4-morpholinephenylboronic acid (12.1 mg, 0.06 mmol), Pd Amphos (1.39 mg, 0.0019 mmol), and cesium carbonate (38.19 mg, 0.12 mmol) gave the title compound (5 mg, 0.009 mmol, 25%). 1 H NMR(400MHz,DMSO)δ 10.50(s,1H),8.59-8.48(m,2H),7.98-7.93(m,2H),7.83(dd,J=8.3,0.9Hz,1H),7.76(dd,J=8.2,2.3Hz,1H),7.05-6.99 (m,2H),6.53(s,1H),6.45(s,1H),4.57(d,J=5.9Hz,2H),3.77-3.71(m,4H),3.23-3.14(m,4H),2.88(s,3H),2.46(s,3H). C 28 H 28 N7O3[M+H] +LRMS m / z measured: 510.22, actual value [M+2H] 2+ / 2=255.70

[0476] Example 15 Synthesis of 1-6-hydroxy-2,5-dimethyl-N-((6-(4-(methylcarbamoyl)phenyl)pyridin-3-yl)methyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (174) [ka] Following general procedure C, 170 (15 mg, 0.04 mmol), 4-N-methylcarbonylphenylboronic acid (10.52 mg, 0.06 mmol), Pd Amphos (2.77 mg, 0.0039 mmol), and cesium carbonate (38.19 mg, 0.12 mmol) gave the title compound (1 mg, 0.0021 mmol, 5%). 1 H NMR(400MHz,DMSO)δ 8.67(d,J=6.2Hz,2H),8.51(d,J=5.0Hz,1H),8.18-8.10(m,2H),8.02(d,J=8.2Hz,1H),7.93(d,J=8.4Hz,2H),7.8 8-7.78(m,1H),6.52(s,1H),6.34(s,1H),4.61(d,J=5.8Hz,2H),2.88(s,3H),2.80(d,J=2.3Hz,3H),2.41(s,3H). C 26 H 24 N7O3[M+H] + LRMS m / z measured: 482.19, actual value: [M+2H] 2+ / 2=241.50

[0477] Example 15 Synthesis of 2-6-hydroxy-2,5-dimethyl-N-((6-phenylpyridin-3-yl)methyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (175) [ka] Following general procedure C, 170 (50 mg, 0.13 mmol), phenylboronic acid (46.21 mg, 0.38 mmol), Pd Amphos (8.94 mg, 0.01 mmol) and cesium carbonate (123 mg, 0.38 mmol) gave the title compound (9 mg, 0.0212 mmol, 22%). 1 H NMR(400MHz,DMSO)δ 9.42(s,1H),8.95(s,1H),8.49(s,1H),8.09-8.00(m,2H),7.89(d,J=8.2Hz,1H),7.69 -7.62(m,1H),7.51-7.36(m,3H),6.47(s,1H),4.64(s,2H),2.84(s,3H),2.43(s,3H). C 24 H 21 N6O2[M+H] + LRMS m / z measured: 425.17, actual value: 425.2, [M+2H] 2+ / 2=213.2

[0478] Example 15 Synthesis of 3-6-hydroxy-2,5-dimethyl-N-((6-(3-morpholinophenyl)pyridin-3-yl)methyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (176) [ka] Following general procedure C, 170 (40 mg, 0.10 mmol), 3-morpholino-phenylboronic acid (63 mg, 0.30 mmol), Pd Amphos (7.15 mg, 0.01 mmol) and cesium carbonate (99 mg, 0.30 mmol) gave the title compound (14 mg, 0.275 mmol, 28%). 1H NMR(400MHz,DMSO)δ 9.52(s,1H),8.95(s,1H),8.46(d,J=2.2Hz,1H),7.88(d,J=8.2Hz,1H),7.68-7.56(m,2H),7.46(d,J=7.6Hz,1H),7.31(t,J=7.9Hz,1H),7 .00(dd,J=8.3,2.5Hz,1H),6.46(s,1H),4.67-4.60(m,2H),3.75(t,J=4.7Hz,4H),3.16(dd,J=6.6,3.2Hz,4H),2.84(s,3H),2.43(s,3H). C 28 H 28 N7O3[M+H] + LRMS m / z measured: 510.22, actual value: 510.30, [M+2H] 2+ / 2=255.80

[0479] Example 15 Synthesis of 4-N-((6-(3-carbamoylphenyl)pyridin-3-yl)methyl)-6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (177) [ka] Following general procedure C, 170 (40 mg, 0.10 mmol), 3-amido-phenylboronic acid (50 mg, 0.30 mmol), Pd Amphos (7.15 mg, 0.01 mmol) and cesium carbonate (99 mg, 0.30 mmol) gave the title compound (11 mg, 0.0235 mmol, 24%). 1 H NMR(400MHz,DMSO)δ 9.41(s,1H),8.95(s,1H),8.56-8.49(m,2H),8.21-8.06(m,2H),7.97(d,J=8.2Hz,1H),7.91(d,J=7.7Hz,1H),7.71(dd ,J=8.3,2.3Hz,1H),7.55(t,J=7.7Hz,1H),7.43(s,1H),6.47(s,1H),4.66(d,J=4.1Hz,2H),2.85(s,3H),2.43(s,3H). C 25 H22 N7O3[M+H] + LRMS m / z measured: 468.18, actual value: 468.2, [M+2H] 2+ / 2=234.80

[0480] Example 15 Synthesis of 5-N-((6-(benzo[d]thiazol-5-yl)pyridin-3-yl)methyl)-6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (178) [ka] Following general procedure C, the title compound (5 mg, 0.0103 mmol, 8%) was obtained from 170 (50 mg, 0.13 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (98.86 mg, 0.38 mmol), Pd Amphos (8.94 mg, 0.01 mmol), and cesium carbonate (123 mg, 0.38 mmol). 1 H NMR(400MHz,DMSO)δ 9.44(s,1H),8.96(s,1H),8.73(d,J=1.6Hz,1H),8.54(d,J=2.3Hz,1H),8.27-8.19(m,2H),8.08(d,J= 8.2Hz,1H),7.71(dd,J=8.3,2.3Hz,1H),6.46(s,1H),4.65(d,J=4.6Hz,2H),2.85(s,3H),2.43(s,3H). C 25 H 20 N7O2S[M+H] + LRMS m / z measured: 482.14, actual value 482.20, [M+2H] 2+ / 2=241.70

[0481] Example 15 Synthesis of 6-6-hydroxy-2,5-dimethyl-N-((6-(3-(methylcarbamoyl)phenyl)pyridin-3-yl)methyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (179) [ka] Following general procedure C, 170 (29 mg, 0.07 mmol), 3-(methylcarbamoyl)phenyl)boronic acid (39.33 mg, 0.22 mmol), Pd Amphos (5.18 mg, 0.01 mmol), and cesium carbonate (71 mg, 0.22 mmol) gave the title compound (11 mg, 0.0228 mmol, 32%). 1 H NMR(400MHz,DMSO)δ 9.96(s,1H),8.96(s,1H),8.60-8.44(m,3H),8.16(d,J=7.9Hz,1H),7.95(d,J=8.2Hz,1H),7.86(d,J=7.7Hz,1H),7.70( dd,J=8.2,2.3Hz,1H),7.54(t,J=7.7Hz,1H),6.45(s,1H),4.64(s,2H),2.84(s,3H),2.80(d,J=4.4Hz,3H),2.42(s,3H). C 26 H 23 N7O3[M+H] + LRMS m / z calculated: 482.19, found: 482.2, [M+2H] 2+ / 2=241.60

[0482] Example 15 Synthesis of 7-(S)-6-hydroxy-N-(1-(4-methoxyphenyl)ethyl)-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxamide (180) [ka] Following general procedure A, 167 (50 mg, 0.17 mmol), (S)-1-(4-methoxyphenyl)ethan-1-amine (31 μL, 0.21 mmol) and DABAL-Me3 (44.76 mg, 0.17 mmol) gave the title compound (7 mg, 0.0179 mmol, 11%). Solvent system used for purification: 0%-15% MeOH in CH3Cl. 1H NMR(400MHz,DMSO)δ 10.40(d,J=7.9Hz,1H),8.51(s,1H),7.35-7.28(m,2H),6.91(dd,J=8.5,1.9Hz,2H),6.47 (s,1H),5.16-5.05(m,1H),3.74(s,3H),2.89(s,3H),2.46(s,3H),1.47(d,J=6.9Hz,3H). C 21 H 22 N5O3[M+H] + LRMS m / z measurement: 392.17, actual measurement: 392.20

[0483] Active Examples General Experimental Methods Preparation of tPHD2 (residues 181-426) Briefly, a cDNA encoding the catalytic domain of tPHD2 (residues 181–426) was cloned into the pET28a(+) / pET24a(+) vector (Novagen) to enable production of tPHD2 (residues 181–426) protein with or without an N-terminal His6 tag. The construct encoding tPHD2 (residues 181–426) was transformed into Escherichia coli BL21 DE3 cells; protein production was induced with 0.5 mM isopropyl-b-D-thiogalactosidase (3–5 h at 28°C). Cells were harvested and lysed by sonication in 20 mM Tris-HCl (pH 7.0) and 0.3 M NaCl; the soluble protein (approximately 5% of the total soluble extract) was purified by immobilized Ni ion affinity chromatography using pentadentate Tris-carboxymethylethylenediamine resin, followed by cleavage of the His6 tag with thrombin (or alternatively, cation exchange chromatography) and final purification by gel filtration chromatography. The protein was exchanged into 50 mM Tris-HCl buffer (pH 7.5) and concentrated to 40 mg / ml. The protein had a purity of >95% as determined by SDS-PAGE analysis and electrospray ionization mass spectrometry.

[0484] PHD2 hydroxylation assay The PHD2 RF-MS RapidFire chromatography-mass spectrometry (RF-MS) assay monitors the turnover of the C-terminal oxygenase-dependent domain (CODD) peptide substrate DLDLEMLAPYIPMDDDFQL-CONH2 and the appearance of the hydroxylated peptide product (Pro564) in an endpoint-type assay format (typical enzyme incubation time: 15 min). Tris(hydroxymethyl)aminomethane was obtained from Fisher. Ferrous ammonium sulfate (FAS), 2-oxoglutarate (2OG), and L-ascorbic acid were from Sigma-Aldrich; these solutions were prepared fresh daily. All inhibition assays were performed in 384-well polypropylene plates (Greiner Bio-One). PHD2 assays were performed in assay buffer (50 mM Tris.Cl pH 7.5, 50 mM NaCl). IC 50 Titration of compounds for measurement (3-fold and 11-point IC 50) was prepared using an ECHO 550 acoustic dispenser (Labcyte) and dry dispensed into 384-well polypropylene assay plates. The final assay concentration of DMSO was kept constant at 0.5%. PHD2 protein was prepared at a concentration of 300 nM in assay buffer, and 25 μL was dispensed into each 384-well assay plate. The PHD2 solution was allowed to equilibrate with the inhibitor for 15 min at room temperature, and then 25 μL of substrate (20 μM FAS, 200 μM L-ascorbic acid, 10 μM CODD peptide, and 20 μM 2OG in assay buffer) was dispensed to initiate the enzymatic reaction. The enzymatic reaction proceeded for 20 min at room temperature and was terminated by the addition of 10% formic acid (5 μL). The assay plate was then transferred to a RapidFire RF360 sampling robot (Agilent) connected to an Agilent 6530 accurate-mass quadrupole time-of-flight (Q-TOF) mass spectrometer. Assay samples were aspirated under vacuum and loaded onto a C4 solid-phase extraction (SPE) cartridge. After loading, the C4 SPE was washed with 0.1% formic acid in water to remove non-volatile buffer salts, and then peptides were eluted from the SPE into the mass spectrometer using 85% acetonitrile, 15% water containing 0.1% formic acid. Peptide charge states were monitored in positive mode. RapidFire Integrator software (Agilent) was used to extract ion chromatogram data for the +2 charge state and peak area data. The percent conversion of the CODD peptide substrate to the +16 hydroxylated peptide was calculated using the following formula: Conversion (%) = 100 × hydroxylation / (hydroxylated + non-hydroxylated peptide). IC 50 Values ​​were determined from nonlinear regression plots using GraphPad Prism.

[0485] Cell culture and immunoblotting using Hep3B cells These were performed as reported by TLYeh et al., Chem Sci, 2017, 8, 7651-7668.

[0486] Cell culture using HEK293T cells: HEK293T cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) (high glucose, pyruvate, glutamine-free, Gibco) supplemented with 10% FBS (Sigma Aldrich F7524-500ML) and 1% GlutaMAX (Gibco) in an incubator at 37°C with 5% CO. Cells were grown to 90% confluence.

[0487] Inhibitor addition and incubation: 1.2 x 10 cells in a T75 flask 6 Cells were plated at a density of 1000 x g / ml. Cells were exposed to inhibitors at a final concentration of 1% DMSO and incubated at 37°C for 3–18 h.

[0488] Protein extraction and analysis using HEK293T cells: Cells were washed twice with ice-cold PBS (Sigma, D8537). Protein extraction was performed using 1x RIPA buffer (Sigma, R0278) and protease inhibitors (Complete™ Mini, EDTA-free protease inhibitor cocktail, Roche). Adherent cells were scraped off using a scraper and transferred to an ice-cold microcentrifuge tube. The cell suspension was either frozen at -20°C or incubated on ice for 45 min and sonicated for three cycles of 10-second pulses with 5-second intervals. After centrifugation (16,000 g, 15 min, 4°C), the cell supernatant was collected into a new microcentrifuge tube. Protein concentration was measured using a BCA protein assay kit (Thermo Scientific™ Pierce™ BCA protein assay kit).

[0489] SDS-PAGE analysis using HEK293T cells For polyacrylamide gel electrophoresis, all samples were loaded onto precast NuPAGE 4-12% Bis-Tris Proteingels (Life Technologies). Gels were run at 180 V for 45 minutes in 1x Tris / glycine / SDS running buffer (20x NuPAGE MES SDS running buffer, Life Technologies) (Mini Gel Tank, Life Technologies). Five microliters of a protein ladder marker (Page Ruler Prestained Protein Ladder, Thermo Scientific) was used to compare protein sizes.

[0490] Western blot analysis using HEK293T cells The gel containing the separated proteins was then transferred to a nitrocellulose membrane (Amersham Protran Premium 0.2 NC 300 mm, GE Healthcare) using 1x transfer buffer (20x NuPAGE Transfer Buffer, Invitrogen). A Mini Protean Tetra Cell (Bio-Rad) was used for the transfer. The transfer was performed at 100 volts for 1 hour. The membrane was blocked with 5% milk powder in 1x PBS-T for 30 minutes and then incubated overnight at 4°C with primary antibody (1:1000 dilution) prepared in 1% milk powder in 1x PBS-T buffer. The membrane was washed three times for 10 minutes with 1x PBS-T, followed by a second incubation at room temperature for 1 hour in horseradish peroxidase (HRP)-conjugated secondary antibody (1:5000 dilution) prepared in 1% milk powder in 1x PBS-T. Blots were then washed three times for 10 minutes with 1x PBS-T and rinsed with GE Healthcare Amersham™ ECL™ Prime Western Blotting Detection Reagent (RPN2236). Protein levels were measured by densitometry using a Bio-Rad Universal Hood III. Values ​​were normalized to corresponding controls, such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 1% (v / v) dimethyl sulfoxide (DMSO), 20 μM roxadustat. The primary antibody used was purified mouse anti-human HIF-1α [Cat. No. 610959]. The secondary antibody used was rabbit anti-mouse IgG (D3V2A) mAb (HRP conjugated).

[0491] In vivo blood counts - reticulocytes and hemoglobin Groups of seven C57BL / 6 mice were administered vehicle (1% methylcellulose), Compound 68 (Example 46) at 15 mg / kg or 30 mg / kg, or daprodustat (2) at 30 mg / kg twice daily (IP). Blood samples were collected before treatment, on day 4, or on day 8 of treatment. Blood samples were analyzed using a Celltac Alpha MEK-6500K. Statistically significant increases in red blood cell count (RBC), hemoglobin (HGB), and hematocrit (HCT) were observed in compound-treated mice.

[0492] Example 158 - Structure-Activity Relationship (SAR) Studies on PHD Inhibition The compounds of the present invention were subjected to SAR testing for PHD2 inhibition. The compounds were screened against PHD2 using RF-MS hydroxylation assay. The results are shown in Table 1, which indicates that the compounds of the present invention have high potency as PHD2 inhibitors.

[0493] [Table 1]

[0494] Example 159-2OG Oxygenase Selectivity 68 (Example 46) The selectivity of 68 (Example 46) for the following purified human 2OG-dependent oxygenases was investigated using the reported assay procedure (TLYeh et al, Chem Sci, 2017, 8, 7651-7668): FIH (Factor Inhibiting HIF) (IC for 68) 50 =>100 μM), KDM4A: lysine-specific demethylase 4A (IC for 68 50 =>100 μm), KDM5B: lysine-specific demethylase 5B (IC for 68 50 =>100 μm), and KDM6B: lysine-specific demethylase 6B (IC for 68 50 =>100 μm). These results indicate that 68 is selective for PHD.

[0495] Example 160 - Immunoblot of Hep3B cells treated with compounds of the invention Hep3B cells were treated with the PHD inhibitors 117, 119, 122, and 123 of the present invention (Examples 93, 95, 98, and 99) at 100 μM (A) and 20 μM (B) for 3 hours. The blots show the protein levels of HIF1-α and β-actin at 3 hours. The cell culture and immunoblotting protocols were as described in TLYeh et al., Chem Sci, 2017, 8, 7651-7668. The results of this example, as shown in Figure 1, demonstrate that the compounds of the present invention stabilize HIF-1α.

[0496] Example 161 - Immunoblot of HEK293 cells treated with low concentrations of compounds of the invention HEK293 T cells were treated with compound 68 (Example 46) of the present invention. Cells were treated at 0.5, 1, 5, 10, 20, 50, and 100 μM for 18 hours. The blots show HIF1-α and GAPDH protein levels at specific times after treatment. Protocols for cell culture and immunoblotting were performed using established methods. The results of this example, as seen in Figure 2, demonstrate that compounds of the present invention stabilize cellular HIF-1α.

[0497] Example 162 - In vivo efficacy testing Groups of seven C57BL / 6 mice were administered vehicle (1% methylcellulose), compound 68 (Example 46) at 15 mg / kg or 30 mg / kg, or daprodustat (2) at 30 mg / kg twice daily (IP) (Figure 3). Samples were collected before treatment, on day 4, or on day 8 of treatment. Blood samples were analyzed using a Celltac Alpha MEK-6500K. A statistically significant increase in red blood cell count (RBC), hemoglobin (HGB), and hematocrit (HCT) was observed in compound-treated mice. 68 showed similar levels compared to 2. 15 mg / kg of 68 produced similar levels of RBC, HCT, and HGB compared to 30 mg / kg of 2. Indeed, the similarity between different doses of 68 suggests that the dose can be lowered. Mice showed no adverse effects to the administered compounds.

[0498] Example 163 - Selectivity for PHD The lack of selectivity of enzyme inhibitors can lead to unpredictable and unwanted off-target effects. Currently available PHD inhibitors, including roxadustat, daprostat, molidustat, decidustat, and vadadustat, exhibit limited target selectivity for PHDs; for example, inhibition by one or more of them has been observed in collagen prolyl hydroxylase (CPH); 2-oxoglutarate and iron-dependent oxygenase domain-containing 1 (OFGOD1); and jumonji domain-containing 6 (JMJD6).

[0499] Compound 68 (Example 46) was evaluated to observe inhibitory activity at sites commonly inhibited by existing PHD inhibitors.

[0500] Production, purification and SPE-MS IC of recombinant PHD2 50 measurement Recombinant PHD2 was produced and purified, as described by Yeh et al. 1 The IC50 was determined as reported in.

[0501] Production, purification and SPE-MS IC of recombinant FIH50 measurement Recombinant FIH was produced and purified as described by Yeh et al. 1 The IC50 was determined as reported in.

[0502] Production and purification of recombinant JMJD6 Recombinant JMJD6 was produced as a full-length protein in E. coli and analyzed by Cockman et al. and Islam et al. 2,3 Purification was carried out as reported.

[0503] JMJD6 IC 50 measurement All reagents were from Sigma-Aldrich and were of the highest grade available. Ferrous ammonium sulfate (FAS) was freshly prepared by dissolving it in 20 mM HCl to 400 mM and then diluting it to 1 mM in deionized water. 2-Oxoglutaric acid (2OG, 10 mM) and L-ascorbic acid (LAA, 50 mM) were freshly prepared by dissolving it in deionized water. The N-terminal peptide (RSKKRKKSKSRS) of RNA-binding motif protein 39 (RBM39 residues 31-42) was used to assess inhibition of the catalytic activity of recombinant human JMJD6 by monitoring the appearance of the hydroxylated peptide product in 50 mM Tris.Cl pH 7.5. IC 50 68 titrations (3-fold and 11-point IC 50 ) was performed using an ECHO 550 acoustic dispenser (Labcyte) and dry dispensed into 384-well polypropylene assay plates. The final assay concentration of DMSO was kept constant at 0.5% (v / v). Full-length JMJD6 was prepared at a concentration of 1.0 mM in 50 mM Tris.Cl pH 7.5, and 25 μl was dispensed across the 384-well plate. JMJD6 was pre-incubated with compound dilutions for 15 minutes. The reaction was performed with 25 μl of substrate (20 μM ferrous sulfate, 200 μM L-ascorbic acid, 10 μM RBM39) across each 384-well assay plate. 31-42The reaction was initiated by the addition of 20 μM 2-oxoglutaric acid (and 20 μM 2-oxoglutaric acid). The reaction was allowed to proceed for 30 min and then quenched by the addition of 5 μL of 10% formic acid. Peptide analysis was performed by liquid chromatography-mass spectrometry (LCMS) using an Agilent 1290 infinity II LC system equipped with an Agilent 1290 multisampler and an Agilent 1290 high-speed pump, connected to an Agilent 6550 accurate-mass iFunnel quadrupole time-of-flight (QTOF) mass spectrometer. 10 ml of the assay mixture was injected onto a ZORBAX RRHD Eclipse Plus C18 column (Agilent). Solvent A consisted of LCMS-grade water containing 0.1% (v / v) formic acid, and solvent B consisted of acetonitrile containing 0.1% (v / v) formic acid. Peptides were separated using a stepwise gradient (0 min - 95% solvent A, 1.0 min - 80% solvent A, 3.0 min - 45% solvent A, 4.0 min - 45% solvent A, 5.0 min - 0% solvent A, 6.0 min - 0% solvent A, 7.0 min - 95% solvent A). This was followed by a 1-min postrun at 95% (v / v) solvent A to re-equilibrate the column, with a total flow rate of 0.2 ml / min. The mass spectrometer was operated in positive ion mode with a drying gas temperature of 280 °C, a drying gas flow rate of 13 L / min, a nebulizer pressure of 40 psig, a sheath gas temperature of 350 °C, a sheath gas flow rate of 12 L / min, a capillary voltage of 4000 V, and a nozzle voltage of 1000 V. All acquired data were analyzed using Agilent MassHunter Qualitative Analysis (version B.07.00) software.

[0504] JMJD6 solid phase extraction mass spectrometry (SPE-MS) assay The JMJD6 inhibitory activity of daprodustat, roxadustat, and molidustat was evaluated in bromodomain-containing protein 4 (BRD4) 511-550 ) 2The enzyme activity was assessed by monitoring the hydroxylation of the peptide product in 50 mM Tris.HCl pH 7.5 buffer using a 40-mer peptide substrate. Compound titrations were prepared using an ECHO 550 acoustic dispenser (Labcyte). Eleven-point and three-fold dilutions of each compound were prepared and dry-dispensed into a 384-well polypropylene plate. A solution of full-length JMJD6 was prepared at a concentration of 1.0 mM, and 25 μL was dispensed across the plate using a multidrop dispenser equipped with a low-volume dispense cassette (Thermo). Compound dilutions were preincubated with JMJD6 for 15 minutes. The enzymatic reaction was performed in 50 mM Tris.HCl pH 7.5 (200 mM L-ascorbic acid, 20 mM ferrous ammonium sulfate, 20 mM 2-oxoglutarate, and 10 mM JMJD6 substrate BRD4). 511-550 2 The reaction was initiated by dispensing 25 μL of the substrate mixture in 10% (v / v) DMSO. The reaction proceeded for 15 min at room temperature and was stopped by dispensing 5 μL of 10% (v / v) formic acid. The final concentration of DMSO was 0.5% (v / v). The assay plate was transferred to a RapidFire RF365-type throughput sampling robot (Agilent) connected to an Agilent 6550 quadrupole time-of-flight (Q-TOF) mass spectrometer. Samples were aspirated under vacuum and loaded onto a C4 solid-phase extraction (SPE) cartridge. The C4 SPE cartridge was washed with 0.1% (v / v) aqueous formic acid at a flow rate of 1.5 ml / min for 5.5 s to remove non-volatile buffer salts. Peptides were then eluted from the SPE into the mass spectrometer with 80% (v / v) acetonitrile, 20% (v / v) water containing 0.1% (v / v) formic acid for 5.5 s at a flow rate of 1.6 ml / min. The mass spectrometer was operated in positive ion mode with a drying gas temperature of 280°C, a drying gas flow rate of 13 L / min, a nebulizer pressure of 40 psig, a sheath gas temperature of 350°C, a sheath gas flow rate of 12 L / min, a capillary voltage of 4000 V, and a nozzle voltage of 1000 V. Peak area data for the +8 charge state were integrated using RapidFire Integrator software (Agilent). 511-550The percent conversion of to hydroxylated products was calculated as follows: Conversion rate (%) = 100 × hydroxylation / (hydroxylated + non-hydroxylated peptide): IC 50 Data were determined from nonlinear regression plots using GraphPad Prism 6.0.

[0505] KDM4A, KDM5B, and KDM6B Liquid Chromatography Mass Spectrometry (LCMS) Assays The inhibitory activity of 68 was assessed for KDM4A, KDM5B, and KDM6B by monitoring the demethylation of their respective peptide substrates. The peptide substrate for KDM4A was determined as described by Hutchinson et al. 4 The peptide substrate for KDM5B was a 21-mer histone H3 peptide (ARTK(me3)QTARKSTGGKAPRKQLA) synthesized by Peptide Protein Research (Hampshire, UK). The peptide substrate for KDM6B was a 17-mer histone H3 peptide (LATKAARK(me3)SAPATGGVK) synthesized by GL Biochem (Shanghai) Ltd (Shanghai, China). Recombinant KDM4A, residues M1-L359, was produced in Escherichia coli (E. coli) and synthesized by Ng et al. 5 Recombinant KDM5B, residues M1-R822, was expressed in a baculovirus expression system and purified as described by Johansson et al. 6 KDM6B (residues D1141-E1590) was expressed in Escherichia coli (E. coli) and purified as previously described by Rose et al. 7 Purified as previously described by.

[0506] KDM4A reactions were performed under optimized buffer conditions (50 μM MES pH 7.0). KDM4A (0.15 mM) was preincubated for 15 min in the presence of 68 (100 mM), and the enzymatic reaction was initiated by the addition of substrates (100 mM L-ascorbic acid, 10 mM ferrous ammonium sulfate, 10 mM 2-oxoglutaric acid, and 10 mM peptide substrate). The enzymatic reaction was allowed to proceed for 50 min and stopped by adding formic acid to a final concentration of 1% (v / v). Control reactions in the presence of 0.5% (v / v) DMSO and a known inhibitor of KDM4A (50 mM 2,4-pyridinedicarboxylic acid, 8 Control reactions in the presence of ) were also set up.

[0507] KDM5B enzymatic reactions were performed under optimized buffer conditions (50 μM MES pH 7.0, 50 mM NaCl, 1 mM TCEP). KDM5A (0.15 mM) was preincubated in the presence of 68 (100 mM) for 15 min, and the enzymatic reaction was initiated by the addition of substrates (100 mM L-ascorbic acid, 10 mM ferrous ammonium sulfate, 10 mM 2-oxoglutaric acid, and 5 mM peptide). The enzymatic reaction proceeded for 30 min and was stopped by the addition of formic acid to a final concentration of 1% (v / v). Control reactions included a 0.5% DMSO control and a known KDM5B inhibitor (10 mM KDOAM25, 9 ) reactions were included.

[0508] KDM6B reactions were performed under optimized buffer conditions (50 μM MES pH 7.0). KDM6B (0.15 mM) was preincubated in the presence of 68 (100 mM) for 15 min, and the enzymatic reaction was initiated by the addition of substrates (100 mM L-ascorbic acid, 10 mM ferrous ammonium sulfate, 10 mM 2-oxoglutaric acid, and 5 mM peptide). The enzymatic reaction was allowed to proceed for 30 min and then stopped by the addition of formic acid to a final concentration of 1% (v / v). Control reactions included a 0.5% DMSO control and a known KDM6B inhibitor (10 mM GSKJ1, 10 ) reactions were included.

[0509] The enzyme reaction mixture was transferred to a 96-well polypropylene plate, and peptide analysis was performed by LCMS using an Agilent 1290 Infinity II LC system equipped with an Agilent 1290 Multisampler and an Agilent 1290 High-Speed ​​Pump, connected to an Agilent 6550 Accurate-Mass iFunnel Quadrupole Time-of-Flight (QTOF) Mass Spectrometer. A 4 ml enzyme reaction mixture was injected and loaded onto a ZORBAX RRHD Eclipse Plus C18 column (Agilent Technologies, CA, USA). Solvent A consisted of LCMS-grade water containing 0.1% (v / v) formic acid, and solvent B consisted of acetonitrile containing 0.1% (v / v) formic acid. Peptides were separated using a stepwise gradient (0 min - 95% solvent A, 1.0 min - 80% solvent A, 3.0 min - 45% solvent A, 4.0 min - 45% solvent A, 5.0 min - 0% solvent A, 6.0 min - 0% solvent A, 7.0 min - 95% solvent A). This was followed by a 3-min postrun at 95% solvent A to re-equilibrate the column, with a total flow rate of 0.2 ml / min. The mass spectrometer was operated in positive ion mode with a drying gas temperature of 280 °C, a drying gas flow rate of 13 L / min, a nebulizer pressure of 40 psig, a sheath gas temperature of 350 °C, a sheath gas flow rate of 12 L / min, a capillary voltage of 4000 V, and a nozzle voltage of 1000 V. All acquired data were analyzed using Agilent MassHunter Qualitative Analysis (version B.07.00) software.

[0510] OGFOD1 solid-phase extraction mass spectrometry (SPE-MS) assay The OGFOD1 gene was cloned into the pET-28a vector and expressed and purified as a full-length enzyme (Met1-Glu542) with an N-terminal 6-His tag in Escherichia coli (E. coli) strain BL21(DE3). The synthetic peptide substrate RPS23 (Ala47-Lys76 AKGIVLEKVGVEAKQPNSAIRKAVRVQLIK-NH2) was synthesized with a purity exceeding 95% by GL Biochem (Shanghai, China). Ferrous ammonium sulfate (FAS), 2-oxoglutarate (2-OG), and L-ascorbic acid (LAA) were obtained from Sigma-Aldrich. Ferrous ammonium sulfate was freshly prepared by dissolving 50–100 mg of FAS in 20 mM HCl to a concentration of 400 mM and further diluting with deionized water to 1 mM. Both 2-OG (10 mM) and L-AA (50 mM) were freshly prepared in deionized water.

[0511] I C 50 Measurements were performed in a 384-well plate format using polypropylene plates (Greiner Bio One, Cat. No. 781096). Compounds were prepared as 20 mM DMSO stock solutions, and all compound dispensing was performed using an ECHO 550 acoustic dispenser (Labcyte, Sunnyvale, CA). The positive control compound (2,4-PDCA, 100 mM) was dispensed into column 1 (250 nl), and DMSO was dispensed into column 13 (250 nl). All test compounds were serially diluted (11-point IC 50A 3-fold dilution series was performed over a 30-well plate (approximately 3-fold dilutions across 1000-10 ... The reaction was allowed to proceed for 20 min, followed by quenching with the addition of 10% (v / v) formic acid (5 ml), and the assay plate was transferred to a Rapidfire RF 365 connected to a 6550 Accurate-Mass quadrupole time-of-flight (QTOF) mass spectrometer (Agilent). The sample was aspirated under vacuum and loaded onto a C4 solid-phase extraction (SPE) cartridge. The SPE cartridge was washed with 0.1% (v / v) formic acid in LCMS-grade water at a flow rate of 1.5 ml / min for 5.5 s to remove nonvolatile buffer components. After the water wash, peptides were eluted from the C4 SPE cartridge with an organic elution step (80% (v / v) acetonitrile, 20% (v / v) LCMS-grade water containing 0.1% formic acid) at a flow rate of 1.6 ml / min for 5.5 s. The mass spectrometer was operated in positive ion mode with a drying gas temperature of 280°C, a drying gas flow rate of 13 L / min, a nebulizer pressure of 40 psig, a sheath gas temperature of 350°C, a sheath gas flow rate of 12 L / min, a capillary voltage of 4000 V, and a nozzle voltage of 1000 V. Ion data for the substrate and hydroxylated (+16) peptide product were extracted, and peak area data were integrated using RapidFire Integrator software version 4.3.017235 (Agilent).The percent conversion of peptide substrate to hydroxylated product was calculated in Excel, and IC50 curves were generated using graphpad prism version 7.0.

[0512] conclusion As shown in Figure 4 of the present application, compound 68 (Example 46) had very high IC for each of the off-target sites tested. 50 This indicates that the compound has excellent selectivity and inhibitory activity, particularly against PHD. Therefore, the compound of the present invention is expected to have reduced side effects compared to existing PHD inhibitors.

[0513] References 1 Yeh, TLet al.Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.Chem Sci 8,7651-7668(2017).https: / / doi.org / 10.1039 / c7sc02103h 2 Cockman,MEet al.Widespreadhydroxylation of unstructured lysine-rich protein domains by JMJD6.Proc Natl Acad Sci USA 119,e2201483119(2022).https: / / doi.org / 10.1073 / pnas.2201483119 3 Islam, MSet al.Biochemical and structural investigations clarify the substrate selectivity of the 2-oxoglutarate oxygenase JMJD6.J Biol Chem 294,11637-11652(2019).https: / / doi.org / 10.1074 / jbc.RA119.008693 4 Hutchinson,S.E.et al.Enabling Lead Discovery for Histone Lysine Demethylases by High-Throughput RapidFire Mass Spectrometry.Journal of Biomolecular Screening 17,39-48(2011).https: / / doi.org / 10.1177 / 1087057111416660 5 Ng,S.S.et al.Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity.Nature 448,87-91(2007).https: / / doi.org / 10.1038 / nature05971 6 Johansson,C.et al.Structural analysis of human KDM5B guides histone demethylase inhibitor development.Nature Chemical Biology 12,539-545(2016).https: / / doi.org / 10.1038 / nchembio.2087 7 Rose,N.R.et al.Plant Growth Regulator Daminozide Is a Selective Inhibitor of Human KDM2 / 7 Histone Demethylases.Journal of Medicinal Chemistry 55,6639-6643(2012).https: / / doi.org / 10.1021 / jm300677j 8 Rose,N.R.et al.Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases.J Med Chem 51,7053-7056(2008).https: / / doi.org / 10.1021 / jm800936s 9 Tumber,A.et al.Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells.Cell Chemical Biology 24,371-380(2017).https: / / doi.org / https: / / doi.org / 10.1016 / j.chembiol.2017.02.006 10 Kruidenier, L. et al.A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.Nature 488,404-408(2012).https: / / doi.org / 10.1038 / nature11262

[0514] Further aspects and embodiments of the present invention are defined in the following numbered paragraphs: 1. A compound which is a substituted azine of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X is CR 6 or N; R 0 is H or unsubstituted or substituted C 1~6 is alkyl; R 1 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v , -C(O)OR w or -C(O)N(R x )R 7 and; R 2 H, -ORq or unsubstituted or substituted C 1~6 alkyl; R 3 H, -OR 8 or unsubstituted or substituted C 1~6 alkyl; or R 2 is -N = R 3 is =C(R y )- and R 2 and R 3 together give the equation -N=C(R y )-form a group; R 4 is H, unsubstituted or substituted C 1~6 Alkyl, -OR 9 or -C(O)OR 10 and; R 5 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v , -C(O)OR w or -C(O)N(R x )R 7 and; R 6 is H or unsubstituted or substituted C 1~6 is alkyl; R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11 )-Cyc, -CH2C≡CCH3, -Cyc or -Ar, where Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 is alkyl; R 8 , R 9 and R 10are each independently H and unsubstituted or substituted C 1~6 alkyl; R t , R u , R v , R w , R x , R y , and R z are each independently H, unsubstituted or substituted C 1~6 selected from alkyl, and unsubstituted or substituted phenyl; R q is H, unsubstituted or substituted C 1~6 alkyl, or unsubstituted or substituted phenyl; However, R 1 and R 5 One of them is -C(O)N(R x )R 7 and R 1 and R 5 The other is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN, -N(R t )C(O)N(R u )R v or -C(O)OR w (It is). 2. The compound according to item 1, R 0 is H or unsubstituted C 1~6 is alkyl; R 1 -H, -CN, -C(O)OR w or -C(O)N(R x )R 7 and; R 2 is H or unsubstituted C 1~6 alkyl; R 3 is H or -OR 8 or R 2 where -N = R 3 is =C(R y )- and R 2 and R 3 together give the equation -N=C(R y )-form a group; R4 H, -OR 9 or -C(O)OR 10 and; R 5 -H, -CN, -C(O)OR w or -C(O)N(R x )R 7 and; R 6 is H; R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar or -CH(R 11 )-Cyc, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted arylene or unsubstituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted C 1~4 is alkyl; R 8 , R 9 and R 10 are each independently H and unsubstituted or substituted C 1~6 alkyl; R x is H and R z is H and R y is H or unsubstituted C 1~6 alkyl, and R w is H, unsubstituted C 1~6 Alkyl, or phenyl or -OC(O)R ww C replaced with 1~6 alkyl, and R ww is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6selected from alkyl and amino acids; However, R 1 and R 5 One of them is -C(O)N(R x )R 7 and R 1 and R 5 The other is H, -CN or -C(O)OR w A compound. 3. The compound according to item 1 or 2, R 0 is H or methyl; R 1 -H, -CN, -C(O)OR w or -C(O)N(R x )R 7 and; R 2 is H or methyl; R 3 is H or -OR 8 or R 2 where -N = R 3 is =C(R y )- and R 2 and R 3 together give the equation -N=C(R y )-form a group; R 4 H, -OR 9 or -C(O)OR 10 and; R 5 -H, -CN, -C(O)OR w or -C(O)N(R x )R 7 and; R 6 is H; R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar or -CH(R 11)-Cyc; where Ar is unsubstituted phenyl, unsubstituted pyrimidyl, unsubstituted benzothiazole, or phenyl substituted with —C(O)OH, —C(O)OMe, —C(O)Oet, —C(O)NH2, —C(O)N(H)Me, —Ome, or N-morpholino; Ary is unsubstituted phenylene or unsubstituted pyridylene; Cyc is unsubstituted cyclohexyl or cyclohexyl substituted with —CF3 or —OCF3; R 11 -H, -C(O)OR z or methyl; R 8 , R 9 and R 10 are each independently H, unsubstituted C 1~6 Alkyl, and phenyl or -OC(O)R 99 C replaced with 1~6 alkyl, where R 99 is phenyl, unsubstituted C 1~6 Alkyl, -N(R a )(R b ), -C(O)R c , -OR d or an amino acid, R a , R b , R c and R d are each independently H, unsubstituted or substituted C 1~6 selected from alkyl and amino acids; R x is H; R z is H; R w H, unsubstituted C 1~6 Alkyl, or phenyl or -OC(O)R ww C replaced with 1~6 alkyl, where R ww is phenyl or unsubstituted C 1~6 is alkyl; R y is H or methyl; However, R 1 and R 5 One of them is -C(O)N(R x )R 7 and R1 and R 5 The other is H, -CN or -C(O)OR w A compound. 4. The compound according to any one of items 1 to 3, (1)(a)R 5 is -C(O)N(R x )R 7 and (b) R 3 HA-OR 8 or R 4 HA-OR 9 or (2)(a)R 1 is -C(O)N(R x )R 7 and (b) R 4 HA-OR 9 or -C(O)OR 10 or R 5 -C(O)OR w A compound. 5. The compound according to any one of items 1 to 4, wherein the substituted azine has the formula (Ia): [ka] (In the formula, X is CR 6 or N; R 0 is H or unsubstituted or substituted C 1~6 is alkyl; R 1 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN or -C(O)OR w and; R 2 H, -OR q or unsubstituted or substituted C 1~6 is alkyl; R 3 is H or unsubstituted or substituted C 1~6 is alkyl; R 6 is H or unsubstituted or substituted C 1~6 is alkyl; R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11 )-Cyc, -CH2C≡CCH3, -Cyc or -Ar, where Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 is alkyl; R 9 is H or unsubstituted or substituted C 1~6 is alkyl; R w , R x and R z are each independently H, unsubstituted or substituted C 1~4 selected from alkyl, and unsubstituted or substituted phenyl; R q is H, unsubstituted or substituted C 1~6 alkyl, or unsubstituted or substituted phenyl). 6.R 9 Item 6. The compound according to item 5, wherein is H. 7. The compound according to any one of items 1 to 6, wherein the substituted azine has one of the following structures: [ka] [ka] [ka] [ka] 8. The compound according to any one of items 1 to 4, wherein the substituted azine has the formula (Ib): [ka] (In the formula, R 0 is H or unsubstituted or substituted C 1~6 is alkyl; R 1 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN or -C(O)OR w and; R 2 H, -OR q or unsubstituted or substituted C 1~6 is alkyl; R 4 is H or unsubstituted or substituted C 1~6 is alkyl; R 6 is H or unsubstituted or substituted C 1~6 is alkyl; R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11 )-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 is alkyl; R 8 is H or unsubstituted or substituted C 1~6 is alkyl; R w , R x and R z are each independently H, unsubstituted or substituted C 1~4 selected from alkyl, and unsubstituted or substituted phenyl; R q is H, unsubstituted or substituted C 1~6alkyl, or unsubstituted or substituted phenyl). 9.R 8 Item 9. The compound according to item 8, wherein is H. 10. The compound according to item 8 or 9, wherein the substituted azine has one of the following structures: [ka] 11. The compound according to any one of items 1 to 4, wherein the substituted azine has the formula (Ic): [ka] (In the formula, R 0 is H or unsubstituted or substituted C 1~6 is alkyl; R 2 H, -OR q or unsubstituted or substituted C 1~6 is alkyl; R 3 H, -OR 8 or unsubstituted or substituted C 1~6 is alkyl; R 4 is H, unsubstituted or substituted C 1~6 Alkyl, -OR 9 or -C(O)OR 10 and; R 5 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN or -C(O)OR w and; R 6 is H or unsubstituted or substituted C 1~6 is alkyl; R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11)-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 is alkyl; R 8 , R 9 and R 10 are each independently H and unsubstituted or substituted C 1~6 alkyl; R w , R x and R z are each independently H, unsubstituted or substituted C 1~4 selected from alkyl, and unsubstituted or substituted phenyl; R q is H, unsubstituted or substituted C 1~6 alkyl, or unsubstituted or substituted phenyl). 12.(i)R 4 is OH or C(O)OH, and / or (ii) R 5 Item 12. The compound according to item 11, wherein is C(O)OH. 13. The compound according to item 11 or 12, wherein the substituted azine has one of the following structures: [ka] [ka] [ka] 14. The compound according to any one of items 1 to 4, wherein the substituted azine has the formula (Id): [ka] (In the formula, R 0is H or unsubstituted or substituted C 1~6 is alkyl; R 1 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN or -C(O)OR w and; R 6 is H or unsubstituted or substituted C 1~6 is alkyl; R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11 )-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 is alkyl; R 9 is H or unsubstituted or substituted C 1~6 is alkyl; R w , R x , R y , and R z are each independently H, unsubstituted or substituted C 1~4 alkyl, and unsubstituted or substituted phenyl). 15.R 9 Item 15. The compound according to item 14, wherein is H. 16. The compound according to item 14 or 15, wherein the substituted azine has one of the following structures: [ka] [ka] [ka] 17. The compound according to any one of items 1 to 3, wherein the substituted azine has one of the following structures: [ka] 18. The compound according to item 5, wherein R 9 is unsubstituted or substituted C 1~6 alkyl, and optionally the substituted azine of formula (Ia) has any one of the following structures: [ka] [ka] [ka] 19. The compound according to item 8, wherein R 8 is unsubstituted or substituted C 1~6 alkyl, and optionally the substituted azine of formula (Ib) has any one of the following structures: [ka] 20. The compound according to item 11, wherein R 4 HA-OR 9 or -C(O)OR 10 and / or R 5 -C(O)OR w and R 9 , R 10 and R w are each independently unsubstituted or substituted C 1~6 is alkyl; optionally, the substituted azine of formula (Ic) is a compound having any one of the following structures: [ka] [ka] 21. The compound according to item 14, wherein R 9is unsubstituted or substituted C 1~6 alkyl; and optionally, the substituted azine of formula (Id) is a compound having the structure: [ka] 22. A compound which is a substituted pyrimidine of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R 0 is H or unsubstituted or substituted C 1~6 is alkyl; R 2 H, -OR q or unsubstituted or substituted C 1~6 is alkyl; R 4 -OR 9 where R 9 is H and unsubstituted or substituted C 1~6 alkyl; R 5 is H, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -CN or -C(O)OR w and; R 6 is H or unsubstituted or substituted C 1~6 is alkyl; R 7 is -CH(R 11 )-Ar, -CH(R 11 )-Ary-Ar, -Ary-Ar, -CH(R 11 )-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C 3~10 is cycloalkyl, and R 11 -H, -C(O)OR z or unsubstituted or substituted C 1~4 is alkyl; R x is H, unsubstituted or substituted C 1~4 alkyl, or unsubstituted or substituted phenyl; R w and R z are each independently H, unsubstituted or substituted C 1~4 selected from alkyl, and unsubstituted or substituted phenyl; R q is H, unsubstituted or substituted C 1~6 alkyl, or unsubstituted or substituted phenyl). 23.R 4 is OH, preferably R 4 is OH and R 5 Item 23. The compound according to item 22, wherein is CN. 24. The compound according to item 22 or 23, wherein the substituted pyrimidine has any one of the following structures: [ka] 25. A pharmaceutical composition comprising the compound according to any one of items 1 to 24 and a pharmaceutically acceptable carrier or diluent; Optionally, the pharmaceutical composition further comprises one or more additional active agents selected from ACE inhibitors, angiotensin II receptor agonists, beta-receptor blockers, calcium antagonists, PDE inhibitors, mineralocorticoid receptor antagonists, diuretics, aspirin, iron supplements, vitamin B12 and folic acid supplements, statins, digitalis (digoxin) derivatives, tumor chemotherapeutic agents, and antibiotics. 26. A compound according to any one of clauses 1 to 24 or a pharmaceutical composition according to clause 25 for use in the treatment of the human or animal body by therapy. 27. A compound as defined in any one of items 1 to 24, or a pharmaceutical composition as defined in item 25, for use in the treatment of anemia, ischemia, inflammation, Parkinson's disease, Alzheimer's disease, cancer, non-fatty liver disease, irritable bowel disease, cardiovascular disease, heart failure, chronic kidney disease, renal failure, or sickle cell anemia, or for use in repairing skeletal muscle damage, increasing red blood cell count (RBC), increasing hemoglobin (HGB) production, increasing hematocrit (HCT) production, increasing erythropoietin (EPO) production, wound healing, angiogenesis, revascularization, stem cell activation, or cardioprotection after myocardial infarction, Optionally, the anemia is renal anemia, e.g., anemia associated with chronic kidney disease, anemia in dialysis patients; chemotherapy-induced anemia; age-related anemia; or anemia resulting from cancer, such as leukemia, multiple myeloma, and smoldering myeloma; Optionally, the ischemia ischemia in circulatory or cardiovascular disease, myocardial infarction, ischemia during surgery, organ ischemia, ischemic disease, diabetic limb ischemia, or sickle cell anemia.

Claims

1. A compound which is a substituted azine of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, X is CR ６ or N; R ０ is H or unsubstituted or substituted C １～６ is alkyl; R １ is H, unsubstituted or substituted C １～６ alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, —CN, —N(R ｔ )C(O)N(R ｕ ) R ｖ , -C(O)OR ｗ or -C(O)N(R ｘ ) R ７ and R ２ is H, -OR ｑ or unsubstituted or substituted C １～６ alkyl; R ３ is H, -OR ８ or unsubstituted or substituted C １～６ alkyl; or R ２ is -N= and R ３ is = C(R ｙ )- and R ２ and R ３ are taken together to form the formula -N=C(R ｙ )- group; R ４ is H, unsubstituted or substituted C １～６ Alkyl, -OR ９ or -C(O)OR １０ and R ５ is H, unsubstituted or substituted C １～６ alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, —CN, —N(R ｔ )C(O)N(R ｕ ) R ｖ , -C(O)OR ｗ or -C(O)N(R ｘ ) R ７ and R ６ is H or unsubstituted or substituted C １～６ is alkyl; R ７ is -CH(R １１ )-Ar,-CH(R １１ )-Ary-Ar, -Ary-Ar, -CH(R １１ )-Cyc, -CH ２ C≡CCH ３ , -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C ３～１０ is cycloalkyl, and R １１ is H, -C(O)OR ｚ or unsubstituted or substituted C １～４ is alkyl; R ８ , R ９ and R １０ are each independently H and unsubstituted or substituted C １～６ alkyl; R ｔ , R ｕ , R ｖ , R ｗ , R ｘ , R ｙ , and R ｚ are each independently H, unsubstituted or substituted C １～６ selected from alkyl, and unsubstituted or substituted phenyl; R ｑ is H, unsubstituted or substituted C １～６ alkyl, or unsubstituted or substituted phenyl; However, R １ and R ５ One of them is -C(O)N(R ｘ ) R ７ and R １ and R ５ The other is H, unsubstituted or substituted C １～６ alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, —CN, —N(R ｔ )C(O)N(R ｕ ) R ｖ or -C(O)OR ｗ (It is).

2. 2. The compound of claim 1 , R ０ is H or unsubstituted C １～６ is alkyl; R １ is H, -CN, -C(O)OR ｗ or -C(O)N(R ｘ ) R ７ and R ２ is H or unsubstituted C １～６ alkyl; R ３ is H or -OR ８ or R ２ is -N= and R ３ is = C(R ｙ )- and R ２ and R ３ are taken together to form the formula -N=C(R ｙ )- group; R ４ is H, -OR ９ or -C(O)OR １０ and R ５ is H, -CN, -C(O)OR ｗ or -C(O)N(R ｘ ) R ７ and R ６ is H; R ７ is -CH(R １１ )-Ar,-CH(R １１ )-Ary-Ar, -Ary-Ar or -CH(R １１ )-Cyc, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted arylene or unsubstituted heteroarylene, and Cyc is unsubstituted or substituted C ３～１０ is cycloalkyl, and R １１ is H, -C(O)OR ｚ or unsubstituted C １～４ is alkyl; R ８ , R ９ and R １０ are each independently H and unsubstituted or substituted C １～６ alkyl; R ｘ is H and R ｚ is H and R ｙ is H or unsubstituted C １～６ alkyl, and R ｗ is H, unsubstituted C １～６ Alkyl, or phenyl or —OC(O)R ｗｗ C substituted with １～６ alkyl, and R ｗｗ is phenyl, unsubstituted C １～６ Alkyl, —N(R ａ ) (R ｂ ), -C(O)R ｃ , -OR ｄ or an amino acid, R ａ , R ｂ , R ｃ and R ｄ are each independently H, unsubstituted or substituted C １～６ selected from alkyl and amino acids; However, R １ and R ５ One of them is -C(O)N(R ｘ ) R ７ and R １ and R ５ the other is H, —CN or —C(O)OR ｗ A compound.

3. 3. A compound according to claim 1 or claim 2, R ０ is H or methyl; R １ is H, -CN, -C(O)OR ｗ or -C(O)N(R ｘ ) R ７ and R ２ is H or methyl; R ３ is H or -OR ８ or R ２ is -N= and R ３ is = C(R ｙ )- and R ２ and R ３ are taken together to form the formula -N=C(R ｙ )- group; R ４ is H, -OR ９ or -C(O)OR １０ and R ５ is H, -CN, -C(O)OR ｗ or -C(O)N(R ｘ ) R ７ and R ６ is H; R ７ is -CH(R １１ )-Ar,-CH(R １１ )-Ary-Ar, -Ary-Ar or -CH(R １１ )-Cyc; where Ar is unsubstituted phenyl, unsubstituted pyrimidyl, unsubstituted benzothiazole, or —C(O)OH, —C(O)Ome, —C(O)Oet, —C(O)NH ２ , —C(O)N(H)Me, —Ome, or N-morpholino-substituted phenyl; Ary is unsubstituted phenylene or unsubstituted pyridylene; Cyc is unsubstituted cyclohexyl, or —CF ３ Or -OCF ３ cyclohexyl substituted with R １１ is H, -C(O)OR ｚ or methyl; R ８ , R ９ and R １０ are each independently H, unsubstituted C １～６ Alkyl, and phenyl or —OC(O)R ９９ C substituted with １～６ alkyl, where R ９９ is phenyl, unsubstituted C １～６ Alkyl, —N(R ａ ) (R ｂ ), -C(O)R ｃ , -OR ｄ or an amino acid, R ａ , R ｂ , R ｃ and R ｄ are each independently H, unsubstituted or substituted C １～６ selected from alkyl and amino acids; R ｘ is H; R ｚ is H; R ｗ is H, unsubstituted C １～６ Alkyl, or phenyl or —OC(O)R ｗｗ C substituted with １～６ alkyl, where R ｗｗ is phenyl or unsubstituted C １～６ is alkyl; R ｙ is H or methyl; However, R １ and R ５ One of them is -C(O)N(R ｘ ) R ７ and R １ and R ５ the other is H, —CN or —C(O)OR ｗ A compound.

4. A compound according to any one of claims 1 to 3, (1)(a)R ５ is -C(O)N(R ｘ ) R ７ and (b) R ３ Ha-OR ８ or R ４ Ha-OR ９ or (2)(a)R １ is -C(O)N(R ｘ ) R ７ and (b) R ４ Ha-OR ９ Or -C(O)OR １０ or R ５ is -C(O)OR ｗ A compound.

5. 5. The compound of any one of claims 1 to 4, wherein the substituted azine has the formula (Ia): 【Chemistry 2】 (In the formula, X is CR ６ or N; R ０ is H or unsubstituted or substituted C １～６ is alkyl; R １ is H, unsubstituted or substituted C １～６ Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, —CN, or —C(O)OR ｗ and R ２ is H, -OR ｑ or unsubstituted or substituted C １～６ is alkyl; R ３ is H or unsubstituted or substituted C １～６ is alkyl; R ６ is H or unsubstituted or substituted C １～６ is alkyl; R ７ is -CH(R １１ )-Ar,-CH(R １１ )-Ary-Ar, -Ary-Ar, -CH(R １１ )-Cyc, -CH ２ C≡CCH ３ , -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C ３～１０ is cycloalkyl, and R １１ is H, -C(O)OR ｚ or unsubstituted or substituted C １～４ is alkyl; R ９ is H or unsubstituted or substituted C １～６ is alkyl; R ｗ , R ｘ and R ｚ are each independently H, unsubstituted or substituted C １～４ selected from alkyl, and unsubstituted or substituted phenyl; R ｑ is H, unsubstituted or substituted C １～６ alkyl, or unsubstituted or substituted phenyl).

6. R ９ The compound of claim 5 , wherein is H.

7. 7. The compound of any one of claims 1 to 6, wherein the substituted azine has any one of the following structures: 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】

8. 5. The compound of any one of claims 1 to 4, wherein the substituted azine has the formula (Ib): 【Transformation 7】 (In the formula, R ０ is H or unsubstituted or substituted C １～６ is alkyl; R １ is H, unsubstituted or substituted C １～６ Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, —CN, or —C(O)OR ｗ and R ２ is H, -OR ｑ or unsubstituted or substituted C １～６ is alkyl; R ４ is H or unsubstituted or substituted C １～６ is alkyl; R ６ is H or unsubstituted or substituted C １～６ is alkyl; R ７ is -CH(R １１ )-Ar,-CH(R １１ )-Ary-Ar, -Ary-Ar, -CH(R １１ )-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C ３～１０ is cycloalkyl, and R １１ is H, -C(O)OR ｚ or unsubstituted or substituted C １～４ is alkyl; R ８ is H or unsubstituted or substituted C １～６ is alkyl; R ｗ , R ｘ and R ｚ are each independently H, unsubstituted or substituted C １～４ selected from alkyl, and unsubstituted or substituted phenyl; R ｑ is H, unsubstituted or substituted C １～６ alkyl, or unsubstituted or substituted phenyl).

9. R ８ The compound of claim 8 , wherein is H.

10. 10. The compound of claim 8 or claim 9, wherein the substituted azine has any one of the following structures: 【Transformation 8】

11. 5. The compound of any one of claims 1 to 4, wherein the substituted azine has the formula (Ic): 【Chemistry 9】 (In the formula, R ０ is H or unsubstituted or substituted C １～６ is alkyl; R ２ is H, -OR ｑ or unsubstituted or substituted C １～６ is alkyl; R ３ is H, -OR ８ or unsubstituted or substituted C １～６ is alkyl; R ４ is H, unsubstituted or substituted C １～６ Alkyl, -OR ９ or -C(O)OR １０ and R ５ is H, unsubstituted or substituted C １～６ Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, —CN, or —C(O)OR ｗ and R ６ is H or unsubstituted or substituted C １～６ is alkyl; R ７ is -CH(R １１ )-Ar,-CH(R １１ )-Ary-Ar, -Ary-Ar, -CH(R １１ )-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C ３～１０ is cycloalkyl, and R １１ is H, -C(O)OR ｚ or unsubstituted or substituted C １～４ is alkyl; R ８ , R ９ and R １０ are each independently H and unsubstituted or substituted C １～６ alkyl; R ｗ , R ｘ and R ｚ are each independently H, unsubstituted or substituted C １～４ selected from alkyl, and unsubstituted or substituted phenyl; R ｑ is H, unsubstituted or substituted C １～６ alkyl, or unsubstituted or substituted phenyl).

12. 12. The compound of claim 11, wherein the substituted azine has any one of the following structures: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】

13. 5. The compound of any one of claims 1 to 4, wherein the substituted azine has the formula (Id): 【Chemistry 13】 (In the formula, R ０ is H or unsubstituted or substituted C １～６ is alkyl; R １ is H, unsubstituted or substituted C １～６ Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, —CN, or —C(O)OR ｗ and R ６ is H or unsubstituted or substituted C １～６ is alkyl; R ７ is -CH(R １１ )-Ar,-CH(R １１ )-Ary-Ar, -Ary-Ar, -CH(R １１ )-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C ３～１０ is cycloalkyl, and R １１ is H, -C(O)OR ｚ or unsubstituted or substituted C １～４ is alkyl; R ９ is H or unsubstituted or substituted C １～６ is alkyl; R ｗ , R ｘ , R ｙ , and R ｚ are each independently H, unsubstituted or substituted C １～４ alkyl, and unsubstituted or substituted phenyl).

14. 14. The compound of claim 13, wherein the substituted azine has any one of the following structures: 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】

15. 4. The compound of any one of claims 1 to 3, wherein the substituted azine has any one of the following structures: 【Chemistry 17】

16. 6. The compound of claim 5, wherein R ９ is unsubstituted or substituted C １～６ alkyl, and optionally the substituted azine of formula (Ia) has any one of the following structures: [Chemistry 18] 【Chemistry 19】 【Chemistry 20】

17. 9. The compound of claim 8, wherein R ８ is unsubstituted or substituted C １～６ alkyl, and optionally the substituted azine of formula (Ib) has any one of the following structures: 【Chemistry 21】

18. 12. The compound of claim 11, wherein R ４ Ha-OR ９ Or -C(O)OR １０ and / or R ５ is -C(O)OR ｗ and R ９ , R １０ and R ｗ are each independently unsubstituted or substituted C １～６ alkyl; optionally, the substituted azine of formula (Ic) is a compound having any one of the following structures: 【Chemistry 22】 【Chemistry 23】

19. 14. The compound of claim 13, wherein R ９ is unsubstituted or substituted C １～６ alkyl; and optionally, the substituted azine of formula (Id) is a compound having the structure: 【Chemistry 24】

20. A compound which is a substituted pyrimidine of formula (IV) or a pharmaceutically acceptable salt thereof: 【Chemistry 25】 (In the formula, R ０ is H or unsubstituted or substituted C １～６ is alkyl; R ２ is H, -OR ｑ or unsubstituted or substituted C １～６ is alkyl; R ４ is -OR ９ where R ９ is H and unsubstituted or substituted C １～６ alkyl; R ５ is H, unsubstituted or substituted C １～６ Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, —CN, or —C(O)OR ｗ and R ６ is H or unsubstituted or substituted C １～６ is alkyl; R ７ is -CH(R １１ )-Ar,-CH(R １１ )-Ary-Ar, -Ary-Ar, -CH(R １１ )-Cyc, -Cyc or -Ar, wherein Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, Ary is unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene, and Cyc is unsubstituted or substituted C ３～１０ is cycloalkyl, and R １１ is H, -C(O)OR ｚ or unsubstituted or substituted C １～４ is alkyl; R ｘ is H, unsubstituted or substituted C １～４ alkyl, or unsubstituted or substituted phenyl; R ｗ and R ｚ are each independently H, unsubstituted or substituted C １～４ selected from alkyl, and unsubstituted or substituted phenyl; R ｑ is H, unsubstituted or substituted C １～６ alkyl, or unsubstituted or substituted phenyl).

21. R ４ is OH, and preferably R ４ is OH and R ５ 21. The compound of claim 20, wherein is CN.

22. 22. The compound of claim 20 or claim 21, wherein the substituted pyrimidine has any one of the following structures: 【Chemistry 26】

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 and a pharmaceutically acceptable carrier or diluent; Optionally, the pharmaceutical composition further comprises one or more additional active agents selected from ACE inhibitors, angiotensin II receptor agonists, beta-receptor blockers, calcium antagonists, PDE inhibitors, mineralocorticoid receptor antagonists, diuretics, aspirin, iron supplements, vitamin B12 and folic acid supplements, statins, digitalis (digoxin) derivatives, tumor chemotherapeutic agents, and antibiotics.

24. A compound according to any one of claims 1 to 22 or a pharmaceutical composition according to claim 23 for use in the treatment of the human or animal body by therapy.

25. 24. A compound according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23, for use in the treatment of anemia, ischemia, inflammation, Parkinson's disease, Alzheimer's disease, non-fatty liver disease, irritable bowel disease, cardiovascular disease, heart failure, chronic kidney disease, renal failure, or sickle cell anemia, or for use in repairing skeletal muscle damage, increasing red blood cell count (RBC), increasing hemoglobin (HGB) production, increasing hematocrit (HCT) production, increasing erythropoietin (EPO) production, wound healing, angiogenesis, revascularization, stem cell activation, or cardioprotection after myocardial infarction, Optionally, the anemia is renal anemia, e.g., anemia associated with chronic kidney disease, anemia in dialysis patients; chemotherapy-induced anemia; age-related anemia; or anemia resulting from cancer, such as leukemia, multiple myeloma, and smoldering myeloma; Optionally, said ischemia ischemia in circulatory or cardiovascular disease, myocardial infarction, ischemia during surgery, organ ischemia, ischemic disease, diabetic limb ischemia, or sickle cell anemia.

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