BENZALDEED REPLACED, ITS USES, AND PHARMACEUTICAL COMPOSITION

专利摘要:
Patent Application: "Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation". The present invention relates to substituted benzaldehydes and derivatives thereof are provided, which act as allosteric hemoglobin modulators, methods and intermediates for their preparation, pharmaceutical compositions comprising the modulators, and methods for their use in the treatment of hemoglobin mediated disorders. and disorders that would benefit from increased tissue oxygenation.
公开号:BR112014016165B1
申请号:R112014016165-8
申请日:2012-12-28
公开日:2019-06-11
发明作者:Brian Metcalf；Chihyuan Chuang；Jeffrey Warrington；Kumar Paulvannan；Matthew P. Jacobson；Lan Hua；Bradley Morgan
申请人:Global Blood Therapeutics, Inc.；The Regents Of The University Of California；
IPC主号:

专利说明:

Invention Patent Descriptive Report for SUBSTITUTED BENZALDEHYDE, ITS USES, AND PHARMACEUTICAL COMPOSITION.
REFERENCES TO RELATED REQUESTS [001] This application claims priority to US Provisional Application No. 61 / 581,053, filed on December 28, 2011, and US Provisional Application No. 61 / 661,320, filed on June 18, 2012, to all of which are incorporated herein by reference. FIELD OF THE INVENTION [002] The present invention generally relates to substituted benzaldehydes and derivatives thereof that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions comprising the modulators, and methods for their use in treating mediated disorders by hemoglobin and disorders that would benefit from increased tissue oxygenation.
BACKGROUND OF THE INVENTION [003] Hemoglobin (Hb) is a tetrameric protein in red blood cells that transport up to four oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen by conformational changes, and is in the tense state (T) when it is linked to oxygen and in the relaxed state (R) when it is linked to oxygen. The balance between the two conformational states is under allosteric regulation. Natural compounds such as 2,3-bisphosphoglycerate (2,3-BPG), protons, and carbon dioxide stabilize hemoglobin in its deoxygenated T state, while oxygen stabilizes hemoglobin in its oxygenated R state. Other relaxed R states were similarly found, however their role in allosteric regulation has not been fully elucidated.
2/108 [004] Sickle cell disease is particularly prevalent among those of African and Mediterranean descent. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is substituted with valine, allowing the T state to become susceptible to polymerization to produce HbS containing red blood cells in their characteristic sickle cell form. Sickle cells are just as rigid as normal red blood cells, and their lack of flexibility can lead to blocked blood vessels. Certain synthetic aldehydes have been found to shift the balance from the polymer-forming T state to the non-polymer-forming R state (Nnamani et al. Chemistry & Biodiversity Vol. 5, 2008 pp. 1762-1769) acting as allosteric modulators for stabilize the R state by forming a Schiff base with an amino group in hemoglobin.
[005] US 7,160,910 describes 2-furfuraldehydes and related compounds that are likewise allosteric modulators of hemoglobin. A particular 5-hydroxymethyl-2-furfuraldehyde compound (5HMF) has been found to be a potent hemoglobin modulator both in vitro and in vivo. Transgenic mice producing human HbS that were treated with 5HMF were found to have significantly improved survival times when exposed to extreme hypoxia (5% oxygen). Under these hypoxic conditions, 5HMF-treated mice were similarly found to have reduced amounts of hypoxia-induced red sickle cell blood compared to untreated mice. [006] A need exists for therapies that can shift the balance between the deoxygenated and oxygenated states of Hb to treat disorders that are mediated by Hb or by abnormal Hb such as HbS. There is also a need for therapies to treat disorders that would benefit from having Hb in
3/108 state R with an increased affinity for oxygen. Such therapies would have applications ranging, for example, from sensitizing hypoxic tumor cells that are resistant to standard radiation or chemotherapy due to low levels of oxygen in the cell, to treat pulmonary and hypertensive disorders, and to promote wound healing.
BRIEF SUMMARY OF THE INVENTION [007] The present invention provides, in one aspect, allosteric modulators of hemoglobin. In another aspect, pharmaceutical compositions are provided comprising the allosteric modulators described herein. In other respects, methods are provided for treating hemoglobin-mediated disorders and methods for increasing tissue oxygenation to treat disorders that would benefit from increased oxygenation, such methods comprising administering the allosteric modulators described herein to an individual in need thereof. In still other aspects, methods are provided for preparing the allosteric modulators described herein. These and other embodiments of the invention are more fully described in the description that follows.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions [008] When used herein, the terms below have the following meanings unless otherwise stated.
[009] The abbreviations used here are conventional, unless otherwise defined: aq = aqueous; Boc = t-butylcarboxy, (Boc) ₂ O = di-tert-butyl dicarbonate, ° C = degrees celcius, mCPBA = m-chloroperoxybenzoic acid, DCM = dichloromethane (CH ₂ Cl ₂ ), DIBAL = diisobutylaluminum hydride, DMF = dimethyl formamide, EtOAc = ethyl acetate, g = gram, H2 = hydrogen; H2O = water; HBr = hydrogen bromide; HCl = hydrogen chloride, HPLC = liquid chromatography
High pressure 4/108, h = hour, LAH = lithium aluminum hydride (LiAlH4); MeCN = acetonitrile; MS = Mass Spectrum, m / z = mass-to-charge ratio, MHz = Mega Hertz, MeOH = methanol, μΜ = micromolar, pL = microliter, mg = milligram, mM = millimolar, mmol = millimol, mL = milliliter, min = minute, M = molar, Na2CO3 = sodium carbonate, ng = nanogram, N = Normal, NMR = nuclear magnetic resonance, Pd / C = palladium on carbon, rp = reverse phase, sat = saturated, rt = room temperature, TEA = triethylamine, THF = tetrahydrofuran, TFA = trifluoroacetic acid, TLC = thin layer chromatography, and TMS = trimethylsilyl.
[0010] It is noted here that as used in this specification, and in the appended claims, the singular forms one, one and o / a include plural references unless the context clearly dictates otherwise.
[0011] Aloxy refers to -O (alkyl) where alkyl is as defined herein. Representative examples of alkoxy groups include methoxy, ethoxy, tbutoxy, and the like.
[0012] Alkyl, either alone or as part of another substituent, means, unless stated otherwise, a straight or branched chain, fully saturated aliphatic hydrocarbon radical having the number of designated carbon atoms. For example, C _1-8 alkyl refers to a straight or branched chain hydrocarbon radical, containing 1 to 8 carbon atoms, which is derived by the removal of a hydrogen atom from a single carbon atom of an alkane of origin. Alkyl includes branched chain isomers of straight chain alkyl groups such as isopropyl, tbutyl, isobutyl, sec-butyl, and the like. Representative alkyl groups include straight and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Additional representative alkyl groups include straight and branched chain alkyl groups
5/108 having 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms ,.
[0013] Alkenyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond, but not more than three double bonds. For example, C _2-8 alkenyl is intended to include, ethylene, propenyl, 1,3-butadienyl, and the like.
[0014] Alquinyl means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix. The term alkynyl is likewise intended to include those alkyl groups that have a triple bond and a double bond. For example, C2-8alkynyl is intended to include ethynyl, propynyl, and the like.
[0015] The term allosteric modulators refers to compounds that bind to hemoglobin to modulate its affinity for oxygen. In a group of modalities, allosteric modulators act to stabilize or destabilize a particular hemoglobin conformation. In a group of modalities, modulators stabilize the relaxed R state. In other modalities, modulators destabilize the tense T state. In a group of modalities, allosteric modulators can destabilize one conformation while stabilizing the other. In some such modalities, modulators stabilize a relaxed R state and destabilize the tense T state. Modulators, in addition to modulating hemoglobin affinity for oxygen, can likewise impart additional properties to hemoglobin such as increasing its solubility. The present description is not intended to be limited to the mechanism by which allosteric modulators interact with and regulate hemoglobin. In a group of modalities, allosteric modulators inhibit polymerization of
6/108
HbS, and the pumping of red blood cells. In a group of modalities, the binding of allosteric modulators provided here for hemoglobin can happen through covalent or non-covalent interactions. In one embodiment, allosteric modulators react by their aldehyde substituent with an amine group on a hemoglobin amino acid side chain to form a Schiff base.
[0016] Amino refers to a monovalent radical -NH ₂ .
[0017] Aryl alone or as part of another substituent refers to a polyunsaturated, aromatic hydrocarbon group containing 6 to 14 carbon atoms that can be a single ring or multiple rings (up to three rings) that are fused together or covalently linked. Thus, the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthyl by way of example. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl and 4-biphenyl.
[0018] Linking when used as an element in a Markush group means that the corresponding group does not exist, and the groups on both sides are directly linked.
[0019] Cycloalkyl refers to a saturated or partially saturated cyclic group of 3 to 14 carbon atoms and no ring heteroatom and having a single ring or multiple rings including fused, bridged and spiro ring systems. The term cycloalkyl includes cycloalkenyl groups, a partially saturated cycloalkyl ring having at least one ring setting site> C = C <. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl. C _u ' _-v Oicloalkyl refers to cycloalkyl groups having u' av 'carbon atoms as ring members. OC _u ' _-v Oicloalkyl refers to cycloalkenyl groups having u' av 'carbon atoms as ring members.
7/108 [0020] The term hemoglobin, as used herein, refers to any hemoglobin protein, including normal hemoglobin (Hb) and sickle hemoglobin (HbS).
[0021] Heteroaryl refers to a cyclic or polycyclic radical having at least one aromatic ring and one to five ring hetero atom (s) selected from N, O, and S, and optionally one or more oxo (= O) substituents attached to one or more carbon ring atoms, and in which the nitrogen and sulfur ring atoms are optionally oxidized. A heteroaryl group can be attached to the rest of the molecule by a heteroatom or a carbon atom and can contain 5 to 10 carbon atoms. Heteroaryl groups include aromatic polycyclic ring (s) fused to non-aromatic cycloalkyl or heterocycloalkyl groups, and where the point of attachment to the rest of the molecule can be through any suitable ring atom of any ring. In a polycyclic heteroaryl group, the ring heteroatom (s) can be in an aromatic or non-aromatic ring or both. The term aromatic ring includes any ring having at least one planar resonance structure where 2n + 2 pi electrons are relocated around the ring. Examples of heteroaryl groups include, but are not limited to, imidazopyridinyl groups, pyrrolopyridinyl groups, pyrazolopyridinyl groups, triazolopyridinyl groups, pyrazolopyrazinyl groups, pyridinyl groups, pyrazinyl groups, oxazolyl groups, pyridine groups, pyridine groups , isoquinolinyl groups, indazolyl groups, benzooxazolyl groups, naphthyridinyl groups, and quinoxalinyl groups. Other non-limiting examples of heteroaryl groups include xanthine, hypoxanthine, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, azaindol, 1isoquinolyl, 5-isoquinolyl, 2 quinoxalinyl, 5-quinoxalinyl, 6-quinolyl, 3-quinolyl -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,
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3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4pyridyl, 2- pyrimidyl and 4-pyrimidyl. Bicyclic heteroaryl refers to a heteroaryl radical that contains two rings.
[0022] The term heterocycloalkyl refers to a cycloalkyl group containing at least one ring heteroatom and optionally one or more oxo substituents. As used here, the term heteroatom is intended to include oxygen (O), nitrogen (N), and sulfur (S), where the hetero atoms are optionally oxidized, and the nitrogen atom (s) is (are) optionally quaternized (s). Each heterocycle can be attached to any available ring or heteroatom carbon. Each heterocycle can have one or more rings. When multiple rings are present, they can be fused together. Each heterocycle typically contains 1, 2, 3, 4 or 5, independently selected heteroatoms. Preferably, these groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, 0, 1, 2, 3, 4 or 5 nitrogen atoms, 0, 1 or 2 atoms sulfur and 0, 1 or 2 oxygen atoms. More preferably, these groups contain 1, 2 or 3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Non-limiting examples of heterocycle groups include morpholin-3-one, piperazine-2one, piperazine-1-oxide, piperidine, morpholine, piperazine, isoxazoline, pyrazoline, imidazoline, pyrrolidine, and the like.
[0023] Halo or halogen by themselves or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. In addition, terms such as haloalkyl are intended to include alkyl in which one or more hydrogen is replaced with halogen atoms that can be the same or different, in a number ranging from one to the maximum number of halogen allowed, for example, for alkyl, (2m '+ 1), where m' is the total number of carbon atoms in the group al
9/108 kilo. For example, the term haloC1-8alkyl is intended to include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3bromopropyl, and the like. The term haloalkenyl, and haloalkynyl refers to alkenyl and alkynyl radicals having one or more halogen atoms. Additionally, the term haloalkoxy refers to an alkoxy radical substituted with one or more halogen atoms. In a group of modalities, the haloalkyl, haloalkenyl, haloalkynyl, and haloalkoxy groups have one to five or one to three halo atoms. Examples of haloalkoxy groups include difluoromethoxy and trifluoromethoxy. In a group of modalities, the halo atoms of the haloalkenyl and haloalkynyl groups are attached to the aliphatic portions of these groups.
[0024] The terms optionally or optionally as used throughout the specification mean that the subsequently described event or circumstance may, however, not necessarily occur, and that the description includes examples where the event or circumstance occurs and examples where it does not. For example, heteroaryl group optionally substituted with an alkyl group means that alkyl may, however, not necessarily be present, and the description includes situations where the heteroaryl group is replaced with an alkyl group and situations where the heteroaryl group is not substituted with the alkyl group.
[0025] Oxo refers to the divalent atom = O.
[0026] In each of the previous modalities that designate several atoms, for example, "C _1-8 " it is intended to include all possible modalities that have some atom. Non-limiting examples include C1-4, C1-5, C1-6, C1-7, C2-8, C2-7, C3-8, C3-7, and the like.
[0027] The term pharmaceutically acceptable salts are intended to include salts of the active compounds that are prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the
10/108 stations of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either liquid or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N, N'dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, Netylpiperidine, glycamine, glycosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, trimethine, trineamine, purine tripropylamine, tromethamine, and the like. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either liquid or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogen carbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogen sulfuric, hydrophilic, and the like, and phosphorous, and phosphorous and similar, and phosphorous, and phosphoric and similar, and phosphorous, and phosphorous, and phosphoric and similar, and phosphorous, and phosphorous, and phosphoric, and phosphoric, and phosphorous, and phosphoric, and phosphoric and phosphoric acids. of relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, subterranean, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Likewise included are the amino acid salts as
11/108 as arginate, and the like, and salts of organic acids like glucuronic or galacturonic acids, and the like (see, for example, Berge,
S.M. et al., “Pharmaceutical Salts, Journal of Pharmaceutical Science, 66: 11-1977). Certain specific compounds of the present invention also contain basic and acidic functionalities that allow the compounds to be converted into base or acid addition salts.
[0028] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The form of origin of the compound differs from the various forms of salt in certain physical properties, such as solubility in polar solvents, however, otherwise the salts are equivalent to the form of origin of the compound for the purpose of the present invention.
[0029] The term pharmaceutically acceptable vehicle or excipient means the vehicle or excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a vehicle or excipient that is acceptable for use veterinary as well as human pharmaceutical use. A pharmaceutically acceptable vehicle or excipient as used in the specification and claims also includes one or more than one such vehicle or excipient.
[0030] The terms pharmaceutically effective amount, therapeutically effective amount or therapeutically effective dose refer to the amount of the object compound that will elicit the biological or medical response of a tissue, system, animal or human being sought by the researcher, veterinarian, doctor doctor or other clinician. The term therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The amount
12/108 of therapeutically effective will vary, depending on the compound, the disorder or condition and its severity, and the age, weight etc., of the mammal to be treated.
[0031] Protective group refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed when desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 ^to Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (TES), trityl and substituted trityl groups , allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), and the like. Representative hydroxy protecting groups include, but are not limited to, those where the hydroxy group is acylated or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.
[0032] The term aldehyde protecting group refers to any protecting group known to mask aldehyde functionality. Aldehyde protecting groups include acetals and hemiacetals. Acetals and hemiacetals can be prepared from C1-8 alcohols or C2-8 diols. In a group of modalities, the aldehyde protecting group is a cyclic acetal of five or six members formed from the condensation of the aldehyde with ethylene or propylene glycol. In another group of modalities, the protecting group is an imine or hydroxyimine. The aldehyde protecting group of the present description likewise includes
13/108 prodrug groups that convert the aldehyde to a prodrug where the aldehyde is formed in vivo as the active agent under physiological conditions in administration of the prodrug. The prodrug group can likewise serve to increase the bioavailability of the aldehyde. In a group of modalities, the prodrug group is hydrolyzed in vivo to the aldehyde. In a group of modalities, the aldehyde protecting group is a thiazolidine or nacetiltiazolidine prodrug group. In a group of modalities, the aldehyde protecting group is a thiazolidine prodrug group described in US 6,355,661. In a group of embodiments, the modulators provided here are condensed with L-cysteine or a derivative of L-cysteine to form the corresponding thiazolidine protected aldehyde prodrug. In a group of modalities, thiazolidine has the formula in which R ¹¹ is selected from the group consisting of OH, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, N (R ¹³ ) 2 where R ¹³ is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R ¹² is H or -LR ¹⁴ where L is carbonyl or sulfonyl; R ¹⁴ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; the wavy line means the point of attachment to the phenyl ring of the allosteric modulators described here; and the term substituted refers to the substitution by one or more substituents selected from the group consisting of COOH, CHO, oxyacyl, acyloxy, cycloacyloxy, phenol, phenoxy, pyridinyl, pyrrolidinyl, amino, starch, hydroxy, alkoxy, cycloalkoxy, F , Cl, Br, NO2, cyano, sulfuryl, and the like. In a group of modalities,
14/108 modulators having a thiazolidine protecting group where R ¹¹ is alkoxy and R ¹² is H, or where R ¹¹ is OH and R ¹² is -C (O) alkyl, or where R ¹¹ is NH (heteroaryl) and R ¹² is - C (O) alkyl.
[0033] The term sickle cell disease refers to diseases mediated by sickle hemoglobin (HbS) resulting from a single point mutation in hemoglobin (Hb). Sickle cell diseases include sickle cell anemia, sickle cell hemoglobin C (HbSC), sickle cell beta-plustalassemia (HbS / 3 ⁺ ) and sickle cell beta-zero-thalassemia (HbS / β ⁰ ).
[0034] The individual is defined here to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like . In preferred embodiments, the individual is a human.
[0035] Tautomer refers to alternating forms of a molecule that differs in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups that contain an atom arrangement of ring -N = C (H) -NH-, such as pyrazoles, imidazoles, benzimidazoles, triazpois and tetrazoles. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible.
[0036] The terms treat, treating, treatment and grammatical variations thereof as used herein, include partially or completely delaying, relieving, mitigating or reducing the intensity, progress, or worsening of one or more auxiliary symptoms of a disorder or condition and / or relieve, mitigate or prevent one or more causes of a disorder or condition. Treatments according to the invention can be applied preventively, prophylactically, palliative or remedially.
[0037] The> symbol when used with respect to a substituent
15/108 means that the substituent is a divalent substituent attached to two different atoms by a single atom in the substituent.
[0038] The term wavy line means the point of attachment of the substituent to the rest of the molecule. When the wavy line is not described as being specifically joined to a specific ring atom, the point of attachment can be at any suitable atom of the substituent. For example, the wavy line in the following structure:
it is intended to include, as the attachment point, any of the six replaceable carbon atoms.
[0039] Compounds that have the same molecular formula, however, differ in the nature or binding sequence of their atoms or the arrangement of their atoms in space are called isomers. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers and stereoisomers refer to compounds that exist in different stereoisomeric forms if they have one or more asymmetric centers or a double bond with asymmetric substitution and therefore can be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not reflected images that do not overlap with each other are called diastereomers and those that are reflected images that cannot overlap with each other are called enantiomers. When a compound has an asymmetric center, for example, it is linked to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by Cahn and Prelog's R and S sequencing rules, or by the way in which the molecule rotates the polarized light plane and designated as dextrogiratory or levogiratory (that is, how isome
16/108 ros (+) or (-) respectively). A chiral compound can exist as an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a racemic mixture. Unless otherwise indicated, the description is intended to include the individual stereoisomers as well as mixtures. Methods for determination of stereochemistry and the separation of stereoisomers are known in the art (see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th edition J. March, John Wiley and Sons, New York, 1992) and differ in chirality of one or more stereocenters.
[0040] The compounds of the present invention may likewise contain unnatural proportions of atomic isotopes in one or more of the atoms that constitute such compounds. For example, compounds can be radio-labeled with isotopes, such as, for example, deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon 14 ( ¹⁴ C). All variations of the isotopic compounds of the compounds of the present invention, whether radioactive or not, are intended to be within the scope of the present invention.
[0041] Unless otherwise indicated, the nomenclature of substituents that are not explicitly defined here is obtained by naming the terminal portion of the functionality followed by the functionality adjacent to the point of attachment. For example, the alkoxyalkyl substituent refers to an alkyl group that is substituted with alkoxy and hydroxyalkyl refers to an alkyl group that is substituted with hydroxy. For both of these substituents, the point of attachment is on the alkyl group.
[0042] It is understood that the definitions and formulas provided here are not intended to include impermissible substitution patterns (for example, methyl substituted with 5 fluorine groups). Such impermissible substitution patterns are well known to the skilled technician.
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II. Hemoglobin modulators [0043] In a group of modalities, a compound of
Formula (I):
(I) or a tautomer or pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each of which optionally substituted with one to three R ^a ;
Y is O or CR ^1a R ^1b , where R ^1a is H or halo and R ^1b is selected from the group consisting of H, halo, and OH;
X is selected from the group consisting of O,> CH (CH ₂ ) _n R ⁸ , and C (R ⁹ ) ₂ where n is 0 or 1, R ⁸ is OH, and R ⁹ is independently H or halo; or YX used together is -NHC (O) - or C (O) NH-;
R ² , R ³ , R ⁴ , and R ⁵ are independently selected from the group consisting of hydrogen, halo, R ^b , OR ^d , O (CH2) zOR ^d , O (CH2) zNR ^d R ^d , OC (O ) R ^e , SR ^d , CN, NO2, CO2R ^d , CONR ^d R ^d , C (O) R ^d , OC (O) NR ^d R ^d , NR ^d R ^d , NR ^d C (O) R ^e , NR ^d C (O) 2R ^e , NR ^d C (O) NR ^d R ^d , S (O) R ^e , S (O) 2R ^e , NR ^d S (O) 2R ^e , S (OhNR ^d R ^d , e N3, where z is 0, 1, 2, 3, 4, 5, or 6; or R ⁵ is - (CH2) _p R ^5a where p is 0 or 1 and R ^5a is OH;
R ⁶ and R ⁷ together form oxo or an aldehyde protecting group, or R ⁶ together with R ^1b , R ⁸ , or R ⁵ forms a cyclic ether where one of R ^1b , R ⁸ , or R ^5a is O, R ⁶ is a bond, and R ⁷ is selected from the group consisting of OH, C _1-8 alkoxy, and haloC _1-8 alkoxy;
each R ^a is independently selected from the group consisting of halo, R ^b , OR ^d , O (CH2) uOR ^d , O (CH2) uNR ^d R ^d , O (CH2) uNR ^d C (O) R ^e , O (CH2) uNR ^d C (O) 2R ^e , O (CH2) uNR ^d S (O) 2R ^e , NH2, (CH2) kOC (O) R ^e , - (CH2) kSR ^d , CN, NO2, - ( CH2) kCO2 (C1-8alkyl) OH, 18/108 (CH ₂ ) _k CO ₂ (C1-8alkyl) (heteroaryl) C (O) (C ₁ -8alkyl), - (CH2) _k CO2R ^d , (CH2) kCONR ^d R ^d , - (CH2) kNR ^d C (O) R ^e , - (CH2) kNR ^d C (O) 2R ^e , (CH2) kC (O) R ^d , - (CH2) kOC (O) NR ^d R ^d , -NR ^d (CH2) uOR ^d , NR ^d (CH2) _u NR ^d R ^d , -NR ^d (CH2) uNR ^d C (O) R ^e , -NR ^d (CH2) _u NR ^d C ( O) 2R ^e , NR ^d (CH2) uNR ^d S (O) 2R ^e , - (CH2) kNR ^d C (O) R ^e , - (CH2) kNR ^d C (O) 2R ^d , (CH2) kNR ^d C (O) NR ^d R ^d , - (CH2) kS (O) R ^e , - (CH2) kS (O) 2R ^e , (CH2) _k NR ^d S (O) 2R ^e , - (CH2) _k S (O) ₂ NR ^d R ^d , N3, - (CH2) karila optionally substituted with one to three R ^c , -NR ^d (CH2) _k aryl optionally substituted with one to three R ^c , - (CH2) kheteroarila optionally substituted with one to three R ^c , -NR ^d (CH2) _k heteroaryl optionally substituted with one to three R ^c , - (CH2) kheterocycloalkyl optionally substituted with one to three R ^c , and -NR ^d (CH2) _k heterocycloalkyl optionally substituted with one to three R ^c where k is 0, 1,2, 3, 4, 5, or 6 eu is 1,2, 3, 4, 5, or 6;
each R ^b is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, and C _2-8 alkynyl, each optionally independently substituted with one to three halo, OR ^d , or NR ^d R ^d ;
each R ^c is independently selected from the group consisting of halo, C _1-8 alkyl, haloC _1-8 alkyl, C _2-8 alkenyl, haloC _2-8 alkenyl, C _2-8 alkynyl, haloC _2-8 alkynyl, (CH ₂ ) _m OR ^f , OC (O) R ^g , SR ^f , CN, NO2, CO2R ^f , CONR ^f R ^f , C (O) R ^f , OC (O) NR ^f R ^f , (CH2) mNR ^f R ^f , NR ^f C (O) R ^g , NR ^f C (O) 2R ^g , NR ^f C (O) NR ^f R ^f , S (O) R ^g , S (O) 2R ^g , NR ^f S (O) 2R ^g , S (O) 2NR ^f R ^f , N3, heteroaryl optionally substituted with one to three R ^h , and heterocycloalkyl optionally substituted with one to three R ^h where m is selected from the group consisting of 0, 1 , 2, 3, 4, 5, and 6;
each R ^h is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, OR ^j , OC (O) R, SR ^j , NO2, CO ₂ R ^j , CONR ^j R ^j , C (O) R ^j , OC (O) NR ^j R ^j , NR ^j R ^j , NR ^j C (O) R ^l , NR ^j C (O) 2R ^t , NR ^j C (O) NR ^j R ^j , S (O) R ^t , S (O) 2R ^t , NR ^j S (O) 2R ^t , and S (O) 2NR ^j R ^j ;
10/198
R ^d , R ^f , and R ^j are each independently selected from the group consisting of hydrogen, C _1-8 alkyl, haloC ₁₈ alkyl, C _2-8 alkenyl, haloC _2-8 alkenyl, C _2-8 alkynyl, and haloC _{2 8} alkynyl; and
R ^e , R ^g , and R ^t are each independently selected from the group consisting of C _1-8 alkyl, haloC _1-8 alkyl, C _2-8 alkenyl, haloC _2-8 alkenyl, C _2-8 alkynyl, and haloC _2-8 alkynyl.
[0044] In a group of modalities, X and Y are not both O.
[0045] In a group of modalities, when X is O, R ^1b is not
OH.
[0046] In a group of modalities, when Y is O, and n is 0, R ⁸ is not OH.
[0047] In a group of modalities, when R ⁶ and R ⁷ together are oxo, Y is CH2, X is O or CH2, and R ⁵ is H, halo, OH, CHO, or OCH3, then Q is V or W.
[0048] In a group of modalities, V is selected from the group consisting of
10/20

and naphthalene containing three to four nitrogen atoms in the ring; where V is optionally substituted with one to three R ^a ; and
W is selected from the group consisting of pyridin-2-
X ~ N NN N ~ N x W ^N X xxx
JJJ ila, pyridin-3-yl, and pyridine-4-yl, n ~ _n
Ny, and ^N 'Y, where W is optionally substituted with one to three R ^a or is substituted with one to three R ^a when W is pyridin-2-yl, pyridin3-yl, or pyridine-4-yl, and that the wavy line means the point of attachment to Y, provided that when V is
optionally substituted with an R ^a , then at least one of R ² , R ³ , R ⁴ , and R ⁵ is OR ^d ; and as long as when V is «/ wv


then V is replaced with one to three R ^a .
[0049] In one group of modalities, z is 0. In another group of modalities
21/108 modalities, z is 1. In yet another modalities group, z is 2. In yet another modalities group, z is 3. In another modalities group, z is 4. In yet another modalities group, z is 5. In yet another group of modalities, z is 6.
[0050] In a group of modalities, a compound of Formula (Ia) is provided:
(Ia) or a tautomer or pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each of which optionally substituted with one to three R ^a ;
Y is O or CR ^1a R ^1b , where R ^1a is H or halo and R ^1b is selected from the group consisting of H, halo, and OH;
X is selected from the group consisting of O,> CH (CH ₂ ) _n R ⁸ , and C (R ⁹ ) ₂ where n is 0 or 1, R ⁸ is OH, and R ⁹ is independently H or halo;
R ² , R ³ , R ⁴ , and R ⁵ are independently selected from the group consisting of hydrogen, halo, R ^b , OR ^d , OC (O) R ^e , SR ^d , CN, NO2, CO2R ^d , CONR ^d R ^d , C (O) R ^d , OC (O) NR ^d R ^d , NR ^d R ^d , NR ^d C (O) R ^e , NR ^d C (O) 2R ^e , NR ^d C (O) NR ^d R ^d , S (O) R ^e , S (O) 2R ^e , NR ^d S (O) 2R ^e , S (O) 2NR ^d R ^d , and N3; or R ⁵ is - (CH ₂ ) _p R ^5a where p is 0 or 1 and R ^5a is OH;
R ⁶ and R ⁷ together form oxo or an aldehyde protecting group, or R ⁶ together with R ^1b , R ⁸ , or R ⁵ forms a cyclic ether where one of R ^1b , R ⁸ , or R ^5a is -O-, R ⁶ is a bond, and R ⁷ is selected from the group consisting of OH, C _1-8 alkoxy, and haloC _1-8 alkoxy;
each R ^a is independently selected from the group consisting of halo, R ^b , OR ^d , OC (O) R ^e , SR ^d , CN, NO ₂ , CO ₂ R ^d ,
10/22
CONR ^d R ^d , C (O) R ^d , OC (O) NR ^d R ^d , NR ^d C (O) R ^e , NR ^d C (O) 2R ^d , NR ^d C (O) NR ^d R ^d , S (O) R ^e , S (O) 2R ^e , NR ^d S (O) 2R ^e , S (O) 2NR ^d R ^d , N ₃ , aryl optionally substituted with one to three R ^c , heteroaryl optionally substituted with a to three R ^c , and heterocycloalkyl optionally substituted with one to three R ^c ;
each R ^b is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, and C _2-8 alkynyl, each optionally independently substituted with one to three halo, OR ^d , or NR ^d R ^d ;
each R ^c is independently selected from the group consisting of halo, C1-8alkyl, halo C1-8alkyl, C2-8alkenyl, haloC2-8 alkenyl, C2-8alquinyl, haloC2-8alquinyl, (CH2) mOR ^f , OC (O) R ^g , SR ^f , CN, NO2, CO2R ^f , CONR ^f R ^f , C (O) R ^f , OC (O) NR ^f R ^f , (CH2) mNR ^f R ^f , NR ^f C (O) R ^g , NR ^f C (O) 2R ^g , NR ^f C (O) NR ^f R ^f , S (O) R ^g , S (O) 2R ^g , NR ^f S (O) 2R ^g , S (O) 2NR ^f R ^f , and N3 where m is selected from the group consisting of 0, 1,2, 3, 4, 5, and 6;
each R ^d and R ^f is independently selected from the group consisting of hydrogen, C _1-8 alkyl, haloC _1-8 alkyl, C _2-8 alkenyl, haloC _2-8 alkenyl, C _2-8 alkynyl, and haloC _{2 -8} alkynyl; and each R ^e and R ^g is independently selected from the group consisting of C _1-8 alkyl, haloC _1-8 alkyl, C _2-8 alkenyl, haloC ₂₈ alkenyl, C _2-8 alkynyl, and haloC _2-8 alkynyl ;
as long as X and Y are not both O;
provided that when X is O, R ^1b is not OH;
provided that when Y is O, en is 0, R ⁸ is not OH; and provided that when R ⁶ and R ⁷ together are oxo, Y is CH2, X is O or CH2, and R ⁵ is H, halo, OH, CHO, or OCH3, then Q is V or W;
V is selected from the group consisting of
10/23


and naphthalene containing three to four nitrogen atoms in the ring; where V is optionally substituted with one to three R ^a ; and
W is selected from the group consisting of pyridin-2yl, pyridin-3-yl, and pyridine-4-yl

where W is optionally substituted with one to three R ^a or is replaced with one to three R ^a when W is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, and where the wavy line means the connection point for Y, as long as when V is
optionally substituted with an R ^a , then at least one of R ² , R ³ , R ⁴ , and R ⁵ is OR ^d .
24/108 [0051] In a group of modalities when R ⁶ and R ⁷ together are oxo, Y is CH2, X is O or CH2, and R ⁵ is H, halo, OH, CHO, or OCH3,
Q is not
J
J
J
J
J
J
J [0052]
In a group and
_R 6 of modalities,, J - -
R ⁷ together form oxo.
In [0053] a thiazolidine.
a group of modalities, _R 6
R ⁷ together form
0. In another group of [0054] In one group of modalities, z modalities, z is 1. In yet another group of modalities, z is 2. In yet another group of modalities, z is 3. In another group of modali
25/108, z is 4. In yet another group of modalities, z is 5. In yet another group of modalities, z is 6.
[0055] In a group of modalities, provided is a compound having the Formula (Ic), (Id), or (Ie):
same, where R ¹⁰ is selected from the group consisting of H, C _1-8 alkyl, and haloC _1-8 alkyl.
[0056] In a group of modalities, Q is a heteroaryl or heterocycloalkyl group optionally substituted with one to three R ^a .
[0057] In a group of modalities, Q is a bicyclic heteroaryl or heterocycloalkyl group optionally substituted with one to three R ^a .
[0058] In a group of modalities, Q is a bicyclic heteroaryl group optionally substituted with one to three R ^a . In a group of embodiments, Q is isoquinolin-4-yl optionally substituted with one to three R ^a in which at least one R ^a is heteroaryl optionally substituted with one to three R ^c . In a group of modalities, at least
26/108 an R ^a is heteroaryl bonded to said Q at the ring atom adjacent to the ring atom carrying Y. In a group of embodiments, at least one R ^a is heteroaryl substituted with at least one C1-8alkyl. In a group of modalities, at least one R ^the heteroaryl is replaced with at least one methyl. In a group of modalities, at least one R ^a is pyrazolyl substituted with at least one C1-8 alkyl. In a group of modalities, at least one R ^a is pyrazazo substituted with at least one methyl. In a group of modalities, R ^a is pyrazol-5-yl. In a group of embodiments, R ^a is 4-methyl-pyrazol-5-yl. [0059] In a group of modalities, Q is a bicyclic heteroaryl group substituted with one to three R ^a .
[0060] In a group of modalities, Q is V.
[0061] In a group of modalities, V is selected from the group consisting of


and
where V is optionally substituted with one to three R ^a .
[0062] In a group of modalities, Q is substituted with CONR ^d R ^d , NR ^d R ^d , or heteroaryl optionally substituted with one to three R ^c . In a group of modalities, Q is substituted with heteroaryl having one to two nitrogen ring atoms.
[0063] In a group of modalities, Q is W.
[0064] In a group of modalities, Q is selected from the group consisting of
10/278
jvw σννν j j
/ =
N
JWV
N = N /
UWV [0065] In a group of modalities, at least one R ^a is hetero aryl optionally substituted with one to three R ^c .
[0066] In a group of modalities, at least one R ^a is hetero aryl linked to Q at the ring atom adjacent to the ring atom carrying Y.
[0067] In a group of modalities, at least one R ^a is heteroaryl substituted with at least one C _1-8 alkyl. In a group of modalities, at least one R ^the heteroaryl is replaced with at least one methyl.
[0068] In a group of modalities, at least one R ^a is pyrazolyl replaced with at least one C1-8alkyl. In a group of modalities, at least one R ^a is pyrazoleyl substituted with at least one C1-8alkyl. In a group of embodiments, at least one R ^a is pyrazol-5-yl. In a group of embodiments, at least one R ^a is 4 methyl-pyrazol-5-yl.
[0069] In a group of modalities, Q is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, said Q is optionally substituted with one to three R ^a in which at least one R ^a is heteroaryl optionally substituted with one to three R ^c . In a group of modalities, at least one R ^a is heteroaryl bonded to said Q at the ring atom adjacent to the ring atom carrying Y. In a group of modalities, at least one R ^a is heteroaryl substituted with at least one C1-8alkyl . In a group of modalities, at least one R ^the heteroaryl is replaced with at least one methyl. In a group of modalities, at least one R ^a is pyrazolyl substituted with at least one C1-8 alkyl. In a group of modalities, at least one R ^a is pyrazazo substituted with at least one methyl. In a group of modalities, R ^a is pyrazol-5-yl. In a group of embodiments, R ^a is 4-methyl-pyrazol-5-yl.
28/108 [0070] In a group of modalities, Q is replaced with at least one R ^a selected from the group consisting of - (CH ₂ ) _k OH, - (CH2W2, - (CH2) _k NH (C1.8alkyl ), - (CH2) kN (C1_8alkyl) (C1_8alkyl), (CH2) kNHC (O) (C1-8alkyl), - (CH2) kN (C1-8alkyl) C (O) (C1-8alkyl), (CH2) kNHC (O) 2 (C1-8alkyl), - (CH2) kN (C1-8alkyl) C (O) 2 (C1-8alkyl), (CH2) kNHS (O) 2 (C1-8alkyl), - (CH2) kN (C1-8alkyl) S (O) 2 (C1-8alkyl), and (CH2) kheterocycloalkyl optionally substituted with one to three R ^c . In some embodiments, the heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, -C ( O) C1-8alkyl, C (O) 2C1-8alkyl, or -S (O) 2C1-8alkyl.
[0071] In a group of modalities, Q is replaced with at least one R ^a selected from the group consisting of NR ^d (CH2) uOH, -NR ^d (CH2) uNH2, -NR ^d (CH2) uNH (C1- 8alkyl), NR ^d (CH2) uN (C1-8alkyl) (C1-8alkyl), -NR ^d (CH2) uNHC (O) (C1-8alkyl), NR ^d (CH2) uN (C1-8alkyl) C (O ) (C1-8alkyl), -NR ^d (CH2) uNHC (O) 2 (C1-8alkyl), -NR ^d (CH2) uN (C1-8alkyl) C (O) 2 (C1-8alkyl), -NR ^d (CH2) uNHS (O) 2 (C18alkyl), -NR ^d (CH2) uN (C1-8alkyl) S (O) 2 (C1-8alkyl), and NR ^d (CH2) kheterocycloalkyl optionally substituted with one to three R ^c where u is 1, 2, 3, 4, 5, or 6 and k is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, R ^d is H or C1-8alkyl. In some embodiments, the heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, -C (O) C1-8alkyl, -C (O) 2C1-8alkyl, or -S (O) 2C1-8alkyl.
[0072] In a group of modalities, Q is replaced with at least one R ^a selected from the group consisting of
O (CH2) uOH, O (CH2) uNH2, O (CH2) uNH (C1-8alkyl), O (CH2) uN (C18alkyl) (C1-8alkyl), O (CH2) uNHC (O) (C1-8alkyl) , O (CH2) uN (C18alkyl) C (O) (C1-8alkyl), O (CH2) uNHC (O) 2 (C1-8alkyl), O (CH2) uN (C18alkyl) C (O) 2 (C1- 8alkyl), O (CH2) uNHS (O) 2 (C1-8alkyl), O (CH2) uN (C18alkyl) S (O) 2 (C1-8alkyl), and O (CH2) uheterocycloalkyl optionally substituted with one to three R ^c where u is 1, 2, 3, 4, 5, or 6. In some
29/108 modalities, the heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, -C (O) C _1-8 alkyl, -C (O) ₂ C ₁₈ alkyl, or -S (O) ₂ C _1-8 alkyl .
[0073] In a group of modalities, W is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, said W substituted with CN or CONR ^d R ^d .
[0074] In a group of modalities, R ² is H.
[0075] In a group of modalities, R ³ is H.
[0076] In a group of modalities, R ⁵ is H.
[0077] In a group of modalities, R ⁴ is C _1-8 alkoxy.
[0078] In a group of modalities, R ² , R ³ , R ⁵ are H and R ⁴ is C ₁₈ alkoxy.
[0079] In a group of modalities, R ⁴ is methoxy.
[0080] In a group of modalities, R ⁴ is haloalkoxy. In a group of modalities, R ⁴ is OCHF ₂ . In a group of modalities, R ⁴ is OCF3.
[0081] In a group of modalities, R ² , R ³ , R ⁴ , and R ⁵ are H.
[0082] In a group of modalities, one of R ² , R ³ , R ⁴ , and R ⁵ is selected from the group consisting of -O (CH ₂ ) _z OH, O (CH2) zO (C1-8alkyl) , -O (CH2) zNH2, -O (CH2) zNH (C1-8alkyl), and O (CH ₂ ) _z N (C _1-8 alkyl) (C _1-8 alkyl) where z is 0, 1,2 , 3, 4, 5, or 6.
[0083] [0001] In a group of modalities, X is O.
[0084] [0002] In a group of modalities, X is CH ₂ .
[0085] [0003] In a group of modalities, X is C (R ⁹ ) ₂ and at least one of R ⁹ is F.
[0086] [0004] In a group of modalities, Y is CH ₂ .
[0087] [0005] In a group of modalities, Y is CR ^1a R ^1b and at least one of R ^1a or R ^1b is F.
[0088] [0006] In one group of modalities, z is 0. In another group of modalities, z is 1. In yet another group of modalities, z is
2. In yet another group of modalities, z is 3. In another group of modalities
10/308 modalities, z is 4. In yet another group of modalities, z is 5. In yet another group of modalities, z is 6.
[0089] [0007] In other embodiments, the invention provides a compound according to Formula (Ib):
or a tautomer or pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each optionally substituted with one to three R ^a ;
Y is O or CH _2;
X is O or CH _2;
R ² and R ³ are independently selected from the group consisting of hydrogen, halo, R ^b , OR ^d , -O (CH2) zOR ^d , O (CH2) zNR ^d R ^d , OC (O) R ^e , SR ^d , CN, NO2, CO2R ^d , CONR ^d R ^d , C (O) R ^d , OC (O) NR ^d R ^d , NR ^d R ^d , NR ^d C (O) R ^e , NR ^d C (O) 2R ^e , NR ^d C (O) NR ^d R ^d , S (O) R ^e , S (O) 2R ^e , NR ^d S (O) 2R ^e , S (OhNR ^d R ^d , e N3, where z is 0 , 1, 2, 3, 4, 5, or 6, or R ⁵ is - (CH ₂ ) _p R ^5a where p is 0 or 1 and R ^5a is OH;
R ⁴ is selected from the group consisting of hydrogen and OR ^d ;
R ⁵ is selected from the group consisting of hydrogen, halo, and OR ^d ;
R ⁶ and R ⁷ together form oxo or an aldehyde protecting group;
each R ^a is independently selected from the group consisting of halo, R ^b , OR ^d , O (CH2) uOR ^d , O (CH2) uNR ^d R ^d , O (CH2) uNR ^d C (O) R ^e , O (CH2) uNR ^d C (O) 2R ^e , O (CH2) uNR ^d S (O) 2R ^e , NH2, (CH2) kOC (O) R ^e , - (CH2) kSR ^d , CN, NO2, - ( CH2) kCO2 (C1-8alkyl) OH, 31/108 (CH ₂ ) _k CO ₂ (C1-8alkyl) (heteroaryl) C (O) (C ₁ -8alkyl), - (CH2) _k CO2R ^d , (CH2) kCONR ^d R ^d , - (CH2) kNR ^d C (O) R ^e , - (CH2) kNR ^d C (O) 2R ^e , (CH2) kC (O) R ^d , - (CH2) kOC (O) NR ^d R ^d , -NR ^d (CH2) uOR ^d , NR ^d (CH2) _u NR ^d R ^d , -NR ^d (CH2) uNR ^d C (O) R ^e , -NR ^d (CH2) _u NR ^d C ( O) 2R ^e , NR ^d (CH2) uNR ^d S (O) 2R ^e , - (CH2) kNR ^d C (O) R ^e , - (CH2) kNR ^d C (O) 2R ^d , (CH2) kNR ^d C (O) NR ^d R ^d , - (CH2) kS (O) R ^e , - (CH2) kS (O) 2R ^e , (CH2) kNR ^d S (O) 2R ^e , -C (O) (CH2 ) kNR ^d S (O) 2R ^e , - (CH2) kC (O) NR ^d S (O) 2R ^e , (CH2) _k S (O) ₂ NR ^d R ^d , N3, - (CH2) optionally substituted karila with one to three R ^c , -NR ^d (CH2) _k aryl optionally substituted with one to three R ^c , - (CH2) kheteroaryl optionally substituted with one to three R ^c , NR ^d (CH2) _k het eroaryl optionally substituted with one to three R ^c , (CH2) kheterocycloalkyl optionally substituted with one to three R ^c , and -NR ^d (CH2) _k heterocycloalkyl optionally substituted with one to three R ^c where k is 0, 1,2, 3 , 4, 5, or 6 eu is 1,2, 3, 4, 5, or 6;
each R ^b is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, and C _2-8 alkynyl, each optionally independently substituted with one to three halo, OR ^d , or NR ^d R ^d ;
each R ^c is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, haloC28alkenyl, C2-8alquinyl, haloC2-8alquinyl, (CH2) mOR ^f , OC (O) R ^g , SR ^f , CN, NO2, (CH2) mCO2R ^f , CONR ^f R ^f , C (O) R ^f , OC (O) NR ^f R ^f , (CH2) mNR ^f R ^f , NR ^f C (O) R ^g , NR ^f C (O) 2R ^g , NR ^f C (O) NR ^f R ^f , S (O) R ^g , S (O) 2R ^g , NR ^f S (O) 2R ^g , S (O) 2NR ^f R ^f , N3, (R ^f ) _m SiC _1-8 alkyl, heteroaryl optionally substituted with one to three R ^h , cycloalkyl optionally substituted with one to three R ^h , and heterocycloalkyl optionally substituted with one to three R ^h where m is selected a from the group consisting of 0, 1, 2, 3, 4, 5, and 6;
each R ^h is independently selected from the group consisting of halo, C _1-8 alkyl, haloC _1-8 alkyl, OR ^j , OC (O) R, SR ^j ,
10/328
NO ₂ , CO ₂ R ^j , CONR ^j R ^j , C (O) R ^j , OC (O) NR ^j R ^j , NR ^j R ^j , NR ^j C (O) R ^l , NROíORR ', NR ^j C ( O) NR ^j R ^j , S (O) R ', SíORR', NR ^ O ^ R ¹ , and S (OhNR ^j R ^j ;
R ^d , R ^f , and R ^j are each independently selected from the group consisting of hydrogen, C _1-8 alkyl, haloC ₁₈ alkyl, C2-8 alkenyl, haloC2-8 alkenyl, C2-8 alkynyl, and haloC28alquinyl; and
R ^e , R ^g , and R ^t are each independently selected from the group consisting of C _1-8 alkyl, haloC _1-8 alkyl, C _2-8 alkenyl, haloC _2-8 alkenyl, C _2-8 alkynyl, and haloC _2-8 alkynyl;
as long as X and Y are not both O;
as long as at least one of R ⁴ and R ⁵ is H;
provided that if R ⁴ is OR ^d , then Q is not phenyl, pyridinyl, or imidazo [1,2-a] pyridin-2-yl, R ^{a is} not oxo, oxide, or halo, and X is O, provided that if R ⁵ is OR ^d , then R ^{a is} not oxo, oxide, or halo; and as long as if R ² -R ⁵ is H, then Q is not phenyl.
[0090] In a group of embodiments, the invention provides a compound of formula Ib, or a tautomer or pharmaceutically acceptable salt thereof, wherein R ⁶ and R ⁷ together form oxo.
[0091] In a group of embodiments, the invention provides a compound of formula Ib, or a tautomer or pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from the group consisting of hydrogen and OR ^d .
[0092] In a group of embodiments, the invention provides a compound of formula Ib, or a tautomer or pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from the group consisting of hydroxy and fluorine.
[0093] In a group of modalities, the invention provides a
33/108 compound of formula Ib, in which R ² and R ³ are independently selected from the group consisting of hydrogen, R ^b , OR ^d , O (CH2) zOR ^d , O (CH2) zNR ^d R ^d , OC ( O) R ^e , CO2R ^d , CONR ^d R ^d , and C (O) R ^d , where z is 1, 2, or 3.
[0094] In a group of modalities, the invention provides a compound of formula Ib, where R ² and R ³ are H.
[0095] In a group of modalities, the invention provides a compound of formula Ib, where Q is selected from the group consisting of:

and
J
34/108 and where Q is optionally substituted with one to three R ^a .
[0096] In a group of modalities, the invention provides a compound of formula Ib, where Q is selected from the group consisting of an imidazopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinyl group, a triazolopyridinyl group, a pyrazolopyrazinyl group, a pyridinyl group, a pyrazinyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, a pyrazolyl group, a quinolinyl group, an isoquinolinyl group, and an indazolyl group, a benzooxazolyl group, a naftiridinyl group, a quinoxalin group ; and where Q is optionally substituted with one to three R ^a .
[0097] In one group of modalities, the invention provides a compound of formula Ib, where z is 0. In another group of modalities, z is 1. In yet another group of modalities, z is 2. In yet another group of modalities, z is 3. In another group of modalities, z is
4. In yet another group of modalities, z is 5. In yet another group of modalities, z is 6.
[0098] In other embodiments, the invention provides a compound according to Formula Ic:
Q
I (Ic) or a tautomer or pharmaceutically acceptable salt thereof, where:
Y is O or CH _2;
X is O or CH _2;
Q is selected from the group consisting of:
i) imidazopyridinyl, methylimidazopyridinyl, indazolyl pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl, pyrazolopyrazinyl, and
35/108 quinolinyl, each of which is optionally substituted with one to three R ^a ; on what
R ² , R ³ , R ⁴ , and R ⁵ , are independently selected from the group consisting of hydrogen, halo, R ^b , OR ^d , O (CH2) zOR ^d , O (CH2) zNR ^d R ^d , OC ( O) R ^e , SR ^d , CN, NO2, CO2R ^d , CONR ^d R ^d , C (O) R ^d , OC (O) NR ^d R ^d , NR ^d R ^d , NR ^d C (O) R ^e , NR ^d C (O) 2R ^e , NR ^d C (O) NR ^d R ^d , S (O) R ^e , S (O) 2R ^e , NR ^d S (O) 2R ^e , S (O) 2NR ^d R ^d , and N3 where z is 1,2, or 3; and ii) pyridinyl and piperidinyl, each of which is optionally substituted with one to three R ^a ; on what
R ² , R ³ , and R ⁴ are independently selected from the group consisting of hydrogen, halo, R ^b , OR ^d , O (CH2) zOR ^d , O (CH2) zNR ^d R ^d , OC (O) R ^e , SR ^d , CN, NO2, CO2R ^d , CONR ^d R ^d , C (O) R ^d , OC (O) NR ^d R ^d , NR ^d R ^d , NR ^d C (O) R ^e , NR ^d C ( O) 2R ^e , NR ^d C (O) NR ^d R ^d , S (O) R ^e , S (O) 2R ^e , NR ^d S (O) 2R ^e , S (O) 2NR ^d R ^d , and N3 where z is 1,2, or 3; and
R ⁵ is selected from the group consisting of halo and OR ^d ;
R ⁶ and R ⁷ together form oxo or an aldehyde protecting group;
each R ^a is independently selected from the group consisting of halo, oxo, R ^b , OR ^d , O (CH2) uOR ^d , O (CH2) _u NR ^d R ^d , O (CH2) uNR ^d C (O) R ^e , O (CH2) uNR ^d C (O) 2R ^e , O (CH2) uNR ^d S (O) 2R ^e , NH2, (CH2) kOC (O) R ^e , - (CH2) kSR ^d , CN, NO2 , - (CH2) kCO2 (C1-8alkyl) OH, (CH2) kCO2 (C1-8alkyl) (heteroaryl) C (O) (C1-8alkyl), - (CH2) kCO2R ^d , (CH2) kCONR ^d R ^d , - (CH2) kNR ^d C (O) R ^e , - (CH2) kNR ^d C (O) 2R ^e , (CH2) kC (O) R ^d , - (CH2) kOC (O) NR ^d R ^d , - NR ^d (CH2) uOR ^d , NR ^d (CH2) uNR ^d R ^d , -NR ^d (CH2) uNR ^d C (O) R ^e , -NR ^d (CH2) uNR ^d C (O) 2R ^e , NR ^d (CH2) uNR ^d S (O) 2R ^e , - (CH2) kNR ^d C (O) R ^e , - (CH2) kNR ^d C (O) 2R ^d , (CH2) kNR ^d C (O) NR ^d R ^d , - (CH2) kS (O) R ^e , - (CH2) kS (O) 2R ^e , (CH2) kNR ^d S (O) 2R ^e , -C (O) (CH2) kNR ^d S (O) 2R ^e , - (CH2) kC (O) NR ^d S (O) 2R ^e , (CH2) kS (O) 2NR ^d R ^d , N3, - (CH ₂ ) _k aryl optionally substituted with a
36/108 to three R ^c , -NR ^d (CH ₂ ) _k aryl optionally substituted with one to three R ^c , - (CH2) kheteroaryl optionally substituted with one to three R ^c , NR ^d (CH2) _k heteroaryl optionally substituted with one to three R ^c , (CH2) kheterocycloalkyl optionally substituted with one to three R ^c , and -NR ^d (CH2) _k heterocycloalkyl optionally substituted with one to three R ^c where k is 0, 1,2, 3, 4, 5 , or 6 eu is 1,2, 3, 4, 5, or 6;
each R ^b is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, and C _2-8 alkynyl, each optionally independently substituted with one to three halo, OR ^d , or NR ^d R ^d ;
each R ^c is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, haloC28alkenyl, C2-8alquinyl, haloC2-8alquinyl, (CH2) mOR ^f , OC (O) R ^g , SR ^f , CN, NO2, (CH2) mCO2R ^f , CONR ^f R ^f , C (O) R ^f , OC (O) NR ^f R ^f , (CH2) mNR ^f R ^f , NR ^f C (O) R ^g , NR ^f C (O) 2R ^g , NR ^f C (O) NR ^f R ^f , S (O) R ^g , S (O) 2R ^g , NR ^f S (O) 2R ^g , S (O) 2NR ^f R ^f , N3, (R ^f ) _m SiC _1-8 alkyl, heteroaryl optionally substituted with one to three R ^h , cycloalkyl optionally substituted with one to three R ^h , and heterocycloalkyl optionally substituted with one to three R ^h where m is selected a from the group consisting of 0, 1, 2, 3, 4, 5, and 6;
each R ^h is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, OR ^j , OC (O) R, SR ^j , NO2, CO ₂ R ^j , CONR ^j R ^j , C (O) R ^j , OC (O) NR ^j R ^j , NR ^j R ^j , NR ^j C (O) R ^l , NR ^j C (O) 2R ^l , NR ^j C (O) NR ^j R ^j , S (O) R ¹ , SCOfeR *, NR ^j S (O) 2R ^l , and S (O) 2NR ^j R ^j ;
R ^d , R ^f , and R ^j are each independently selected from the group consisting of hydrogen, C _1-8 alkyl, haloC ₁₈ alkyl, C2-8 alkenyl, haloC2-8 alkenyl, C2-8 alkynyl, and haloC28alquinyl; and
R ^e , R ^g , and R ^t are each independently selected from the group consisting of C _1-8 alkyl, haloC _1-8 alkyl, C _2-8 alkyl
37/108 nila, haloC _2-8 alkenyl, C _2-8 alkynyl, and haloC _2-8 alkynyl.
[0099] In a group of modalities, the invention provides a compound of formula Ic, where Q is selected from the group consisting of imidazo [1,5-a] pyridin-8-yl, imidazo [1,5-a ] pyridin-6-yl, imidazo [1,5-a] pyridin-5-yl, imidazo [1,2-a] pyridin-8-yl, imidazo [1,2-
a] pyridin-7-yl, imidazo [1,2-a] pyridin-6-yl, imidazo [1,2-a] pyridin-5-yl, imidazo [1,2-a] pyridin-3-yl, 8-methylimidazo [1,2-a] pyridin-2-yl, indazol-4-yl, pyrrolo [2,3-b] pyridin-4-yl, pyrrole [1,2-a] pyrazin-6-yl, pyrrole [1,2-a] pyrazin-
4-yl, pyrazolo [3,4-b] pyridin-4-yl, pyrazolo [1,5-a] pyrazin-3-yl, and quinolin-
5-a, each of which is optionally substituted with one to three R ^a .
[00100] [0008] In one group of modalities, the invention provides a compound of formula Ic, where z is 1. In another group of modalities, z is 2. In yet another group of modalities, z is 3.
[00101] [0009] In a group of embodiments, the invention provides a compound in which: Y is CH _{2; and} X is CH ₂ .
[00102] [0010] In a group of modalities, the invention provides a compound of formula Ic, wherein R ² is selected from the group consisting of H and OR ^d ;
R ³ is selected from the group consisting of H, CN, halo, and OR ^d ;
R ⁴ is selected from the group consisting of H, CN, and OR ^d : and
R ⁵ is H.
[00103] [0011] In a group of embodiments, the invention provides a compound of formula Ic, where R ⁴ is methoxy.
[00104] [0012] In a group of embodiments, the invention provides a compound of formula Ic, wherein Q is selected from the group consisting of pyridine-3-yl and piperidin-1-yl.
[00105] [0013] In a group of modalities, the invention provides a compound of formula Ic, in which R ⁵ is selected from the group
38/108 consisting of hydroxy and fluorine.
[00106] In a group of embodiments, the invention provides a compound of formula Ic, in which R ⁶ and R ⁷ together form oxo.
[00107] In a group of modalities, a compound is selected from Table 1 below or a tautomer or pharmaceutically acceptable salt thereof.
Table 1
Compound Structure Name 1 Ό The 2- (imidazo [1,2-a] pyridin-8-ylmethoxy) -5methoxybenzaldehyde 2 Ό 0[ Κ 4-formyl-3- (imidazo [1,2-a] pyridin-8ylmethoxy) benzonitrile 3 Ό Ο, ζζ 2- (imidazo [1,2-a] pyridin-8-ylmethoxy) -4methoxybenzaldehyde 4 Ò Ό Ο ^Ο χ 2- (imidazo [1,2-a] pyridin-6-ylmethoxy) -5methoxybenzaldehyde
10/39
10/40
10 Ό Ο 5-methoxy-2- (quinolin-5ylmethoxy) benzaldehyde 11 COΌ 0<Λ ·Br 5-bromo-2- (imidazo [1,2-a] pyridin-8ylmethoxy) benzaldehyde 12 Ό Ο 4-chloro-2- (imidazo [1,2-a] pyridin-8-ilmetoxy) benzaldehyde 13 Ό Ο 0 ^a 2- (imidazo [1,2-a] pyridin-8ylmethoxy) benzaldehyde 14 ÇOΌ 0, ΖΛ 4-fluoro-2- (imidazo [1,2-a] pyridin-8ylmethoxy) benzaldehyde 15 Ό 0 2- (imidazo [1,2-a] pyridin-8-ylmethoxy) -3methoxybenzaldehyde
41/108
16 Ό Ο y 2- (imidazo [1,2-a] pyridin-8-ylmethoxy) -5methylbenzaldehyde 17 CO Ό Ο <Λ ^Ο ^ 5-methoxy-2- (pyrrolo [1,2-a] pyrazin-4ylmethoxy) benzaldehyde 18 Ν-ηX 2- (imidazo [1,5-a] pyridin-6-ylmethoxy) -4methoxybenzaldehyde 19 Ό Ο Φ ^Λ “ 2- (imidazo [1,5-a] pyridin-5-ylmethoxy) -5methoxybenzaldehyde 20 Ό 0 χCN 3-formyl-4- (imidazo [1,5-a] pyridin-5ylmethoxy) benzonitrile 21 toΌ Ο y 2 - ((1 H-pyrrolo [2,3-b] pyridin-4-il) methoxy) -5-methoxybenzaldehyde
42/108
22 Ό Ο 5-ethyl-2- (imidazo [1,2-a] pyridin-8ylmethoxy) benzaldehyde 23 ^Ν ^ ίί ^ <ο Ό Ο 5-methoxy-2 - ((1-methyl-1 H-indazol-4-il) methoxy) benzaldehyde 24 Ό Ο 5-methoxy-2 - ((8-methylimidazo [1,2-a] pyridin-2-yl) methoxy) benzaldehyde 25 Η ^N OJ Ό Ο 0 ^a 2 - ((1 H-indazol-4-yl) methoxy) -5methoxybenzaldehyde 26 Η ΜΝ ^ χΐ%COCT çn —ο 2 - ((1 H-pyrrolo [2,3-b] pyridin-4-il) methoxy) -5-methoxybenzaldehyde
43/108
27 ΓΠ nX-XΌ ΟCN 3-formyl-4- (imidazo [1,2-a] pyridin-8ylmethoxy) benzonitrile 28 Ό Ο ¢ / - 5-methoxy-2- (pyrrolo [1,2-a] pyrazin-6ylmethoxy) benzaldehyde 29 Ν ^ ΧΌ Ο¢ / - 6 - (((2-formyl-4methoxyphenoxy) methyl) pyrrole [1,2a] pyrazine-7-carbonitrile 30 Ν = Χ ^ ^ ⁿ C ^ meet ₂ Ό Ο ¢ / - 6 - (((2-formyl-4methoxyphenoxy) methyl) pyrrole [1,2a] pyrazine-7-carboxamide 31 Η Μ - ^Ν Ίί X <υ cr Si / —Ο 2 - ((1H-pyrazolo [3,4-b] pyridin-4-il) methoxy) -5-methoxybenzaldehyde
44/108
32 Ν-Ν Ό Ο ^Ο χ 5-methoxy-2- (pyrazolo [1,5-a] pyrazin-3ylmethoxy) benzaldehyde 33 C> Ο ί / · 5-methoxy-2- (pyrrolo [1,2-a] pyrazin-6ylmethoxy) benzaldehyde 34 / Τ ^Ν ί 2- (imidazo [1,5-a] pyridin-6-ylmethoxy) -5methoxybenzaldehyde 35 νχχο> οCN 3-formyl-4- (imidazo [1,2-a] pyridin-8ylmethoxy) benzonitrile 36 ΟΗ OC ° ο ^Ν 3- (imidazo [1,2-a] pyridin-8-ylmethyl) -1,3dihydroisobenzofuran-1 -ol
45/108
37 c> Ο γ 2- (imidazo [1,2-a] pyridin-5-ylmethoxy) -5methoxybenzaldehyde 38 ζΓ'Ν ^ ί _n aj Ο ΗΝ ^ Χ) γ N- (2-formyl-4-methoxyphenyl) imidazo [1,2a] pyridine-8-carboxamide 39 / Γ-Ν ^ Ι ^Νΐί ^ ι Ο ΗΝ'Χ) -Υ N- (2-formylphenyl) imidazo [1,2-a] pyridine-8-carboxamide 40 Οκ, ΝΗ γ Ο fj] ^Η 2-formyl-N- (imidazo [1,2-a] pyridin-8yl) benzamide 41 οΌ Ο γΟ 5-methoxy-2- (pyridin-3ylmethoxy) benzaldehyde 42 ΟγΟΗ ιΓί γγΌ Ο Υ: acid 4 - ((2-formyl-3-hydroxyphenoxy) methyl) benzoyl
46/108
43 ^N ' ^N y-- ο ^r òÇ 2-hydroxy-6 - ((2- (1-isopropyl-1 Hpyazol-5-yl) pyridin-3yl) methoxy) benzaldehyde 44 ν = ν λ ^ΝΗ 0 ^a ”'Ό Ο 2 - ((3- (2H-tetrazol-5-yl) benzyl) oxy) -6hydroxybenzaldehyde 45 Ν-ΝΗ ι> 'Ν, ΝιΓίΌ Ο 2 - ((4- (2H-tetrazol-5-yl) benzyl) oxy) -6hydroxybenzaldehyde 46 1 ° γ ° ιΓί Ό Ο 0 ^a methyl 4 - ((2-formylphenoxy) methyl) benzoate 47 ΟγΟΗ ιΓί Ό Ο 0 ^a acid 4 - ((2-formylphenoxy) methyl) benzoyl
47/108
48 Ο çA Ό ο 0 ^a methyl 3 - ((2-formylphenoxy) methyl) benzoate 49 N ^ yXo / zL.Br OÇ ^h o 2-bromo-3 - ((2- (1-isopropyl-1 Hpyazol-5-yl) pyridin-3yl) methoxy) benzaldehyde 50 X _n ⁿ 3j cr or- OH 2-hydroxy-6 - ((2- (1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl) pyridin-3-il) methoxy) benzaldehyde 51 F z Ύ VU ⁿ uj cr cb ° OH 2- hydroxy-6 - ((2- (1- (3,3,3-trifluoropropyl) -1H-pyrazol-5-yl) pyridin-3- il) methoxy) benzaldehyde 52 N ^ j ^N ' ^N Ί3 O ^{, Λ} ' 0 / 2-fluoro-6 - ((2- (1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl) pyridin-3-il) methoxy) benzaldehyde 53 N ^ jn l _o 2- fluoro-6 - ((2- (1- (3,3,3-trifluoropropyl) -1H-pyrazol-5-yl) pyridin-3- il) methoxy) benzaldehyde
48/108
54 N ^ j to ^r / 2-fluoro-6 - ((2- (1-isopropyl-1 H-pyrazole-5-yl) pyridin-3-yl) methoxy) benzaldehyde 55 ΟγΟΗ ò 1 ° ^H 1- (2-formyl-3- acidhydroxyphenethyl) piperidine-4-carboxylic [00108] In a fashion group ages, the compound is selected from
from:
2- (imidazo [1,2-a] pyridin-8-ylmethoxy) -5-methoxybenzaldehyde,
2- (imidazo [1,2-a] pyridin-2-ylmethoxy) -5-methoxybenzaldehyde,
2- (imidazo [1,5-a] pyridin-8-ylmethoxy) -5-methoxybenzaldehyde,
5-methoxy-2- (quinolin-5-ylmethoxy) benzaldehyde,
5-methoxy-2 - (((1-methyl-1 H-indazol-4-yl) methoxy) benzaldehyde,
5-methoxy-2 - (((8-methylimidazo [1,2-a] pyridin-2-yl) methoxy) benzaldehyde,
2 - ((1H-indazol-4-yl) methoxy) -5-methoxybenzaldehyde,
5-methoxy-2- (pyridin-3-ylmethoxy) benzaldehyde,
2 - ((2- (1-isopropyl-1 H-pyrazol-5-yl) pyridin-3-yl) methoxy) -5methoxybenzaldehyde,
2-hydroxy-6 - ((2- (1-isopropyl-1 H-pyrazol-5-yl) pyridin-3yl) methoxy) benzaldehyde,
2 - ((3- (2H-tetrazol-5-yl) benzyl) oxy) -6-hydroxybenzaldehyde,
2 - ((4- (2H-tetrazol-5-yl) benzyl) oxy) -6-hydroxybenzaldehyde, methyl 4 - (((2-formylphenoxy) methyl) benzoate, 4 - (((2-formylphenoxy) methyl) benzoic acid, methyl 3 - ((2-formylphenoxy) methyl) benzoate,
49/108
2-bromo-3 - ((2- (1-isopropyl-1 H-pyrazol-5-yl) pyridin-3yl) methoxy) benzaldehyde,
2-hydroxy-6 - ((2- (1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl) pyridin-3yl) methoxy) benzaldehyde,
2-hydroxy-6 - ((2- (1- (3,3,3-trifluoropropyl) -1H-pyrazol-5-yl) pyridin-3yl) methoxy) benzaldehyde,
2-fluoro-6 - ((2- (1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl) pyridin-3yl) methoxy) benzaldehyde,
2-fluoro-6 - ((2- (1- (3,3,3-trifluoropropyl) -1H-pyrazol-5-yl) pyridin-3yl) methoxy) benzaldehyde,
2-fluoro-6 - ((2- (1-isopropyl-1H-pyrazol-5-yl) pyridin-3yl) methoxy) benzaldehyde, and 1- (2-formyl-3-hydroxyphenethyl) piperidine-4-carboxylic acid, or a tautomer or pharmaceutically acceptable salt thereof.
[00109] In a group of modalities, a compound is provided in any of the Examples or Tables. In another group of modalities, any combinations of submodalities are provided as described here including any combination of elements described here including a selection of any isolated elements.
[00110] In a group of embodiments, a pharmaceutical composition is provided comprising a compound of any of the above embodiments or a tautomer or pharmaceutically acceptable salt thereof.
[00111] In a group of modalities, a pharmaceutical composition is provided comprising a compound that is
or a pharmaceutically acceptable salt thereof.
[00112] The compounds of the present invention can be prepared
50/108 by known organic synthesis techniques, including the methods described in more detail in the Examples.
[00113] In a group of embodiments, an intermediate compound used in the preparation of the compounds described here is provided.
[00114] In a group of embodiments, methods are provided for preparing the compounds described here.
[00115] For example, Scheme I shows a synthetic routine for the synthesis of compounds of Formula (I) where X is O and Y is CH ₂ . Phenol
1.1 is contacted with intermediate 1.2 in the presence of base under ether formation conditions to produce ether 1.3, where Lg represents an leaving group such as a halogen leaving group. Conversely, when X is O and Y is CH ₂ , the compounds of Formula (I) can be prepared using the appropriate starting materials where the OH portion of intermediate 1.1 is replaced with a leaving group and the Lg group of intermediate 1.2 is replaced with an OH group.
Scheme I
1.1
1.2
1.3 [00116]
Scheme II shows an example of a synthetic routine for the synthesis of compounds of Formula (I) where X and Y are CH2. Alken 2.1 is contacted with alkene 2.2 under conditions of metathesis in the presence of an appropriate transition metal catalyst. Suitable catalysts include ruthenium catalysts such as a Grubbs catalyst. Product 2.3 is then hydrogenated to produce compound 2.4.
Scheme II
51/108
2.1
2.2
[00117]
Scheme III shows an example of a synthetic routine for the synthesis of compounds of Formula (I) where R ⁶ together with
R ^1b form a cyclic ether. Compound 3.1, is reacted with diethylphosphite and a base such as sodium methoxide to produce the intermediate
3.2, which is then condensed with aldehyde 3.3 to produce alkene 3.4. Treatment of the alkene with H ₂ under hydrogenation conditions produces lactone 3.4, which is then reduced with a suitable reducing agent such as LiBHEt ₃ to produce the cyclic hemiacetal 3.5.
Scheme III
[00118] Scheme IV shows an example of the synthesis of compounds of Formula (I) wherein Q is pyridine-3-R ^to ila and heteroaryl. Acid 4.1 is reduced to alcohol 4.2 using known methods such as forming the anhydride (for example, treatment with triethylamine and /-butyl chloroformate) followed by reduction with NaBH ₄ . Alcohol 4.2 is con
52/108 poured into chloride 4.3 as by treatment with thionyl chloride. Coupling the halide with alcohol 4.4 under ether-forming conditions produces precursor 4.5 which can be functionalized with a variety for heteroaryl groups R ^a . For example, 4.5 can be coupled with pyrazole 4.6 under known organometallic coupling conditions (eg Pd (PPh ₃ ) ₄ ) to produce 4.7, where PG is a nitrogen protecting group such as a silyl protecting group that can be removed to produce the product 4.8.
Scheme IV



[00119] Someone skilled in the art will recognize that in certain modalities it may be advantageous to use a protective group strategy. The protecting group can be removed using methods known to those skilled in the art.
[00120] In a group of embodiments, certain compounds described here can generally be used as the free base. Alternatively, certain compounds can be used in the form of acid addition salts.
[00121] It is understood that in another group of modalities, any
53/108 of the above embodiments can likewise be combined with other embodiments listed here, to form other embodiments of the invention. Similarly, it is understood that in other modalities, the listing of groups includes modalities in which one or more of the elements of those groups is not / are included.
III. Compositions and Methods of Administration [00122] Depending on the intended mode of administration, pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, preferably in unit dosage form suitable for single administration of a precise dosage. In addition to an effective amount of the active compound (s), the compositions may contain suitable pharmaceutically acceptable excipients, including adjuvants that facilitate the processing of the active compounds in preparations that can be used pharmaceutically. “Pharmaceutically acceptable excipient” refers to an excipient or mixture of excipients that does not interfere with the effectiveness of the biological activity of the active compound (s) and is non-toxic or otherwise undesirable to the individual to whom it is administered .
[00123] For solid compositions, conventional excipients include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmacologically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in water or an aqueous excipient, such as, for example, water, saline, dextrose aqueous, and the like, to form a solution or suspension. If desired, the pharmaceutical composition to be administered may likewise contain minor amounts of non-toxic auxiliary excipients such as
54/108 wetting or emulsifying agents, pH buffering agents, and the like, for example, sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate, etc.
[00124] For oral administration, the composition will generally take the form of a tablet or capsule, or it may be an aqueous or non-aqueous solution, suspension or syrup. Tablets and capsules are preferred oral forms of administration. Tablets and capsules for oral use will generally include one or more commonly used excipients such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are likewise typically added, such as. When liquid suspensions are used, the active agent can be combined with emulsifying and suspending excipients. If desired, flavoring, coloring and / or sweetening agents can be added as well. Other optional excipients for incorporation into an oral formulation include preservatives, suspending agents, thickening agents and the like.
[00125] Injectable formulations can be prepared in conventional forms, as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid before injection, or as emulsions or liposomal formulations. The sterile injectable formulation can likewise be a sterile injectable solution or a suspension in a non-toxic parenterally acceptable solvent or diluent. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
[00126] The pharmaceutical compositions of this invention can likewise be formulated in lyophilized form for administration
Parenteral 55/108. Lyophilized formulations can be reconstituted by adding water or another aqueous medium, and then also diluted with a suitable diluent before use. The liquid formulation is usually a buffered, isotonic, aqueous solution. Examples of suitable diluents are isotonic saline, 5% dextrose in water, and buffered sodium or ammonium acetate solution. Pharmaceutically acceptable solid or liquid excipients can be added to enhance or stabilize the composition, or facilitate preparation of the composition.
[00127] Typically, a pharmaceutical composition of the present invention is packaged in a container with a label, or instructions, or both, indicating use of the pharmaceutical composition in the treatment of the indicated disease.
[00128] The pharmaceutical composition may contain one or more other pharmacologically active agents in addition to a compound of this invention.
[00129] Dosage forms containing effective amounts of the modulators are within the boundaries of routine experimentation and within the scope of the invention. A therapeutically effective dose can vary depending on the routine of administration and dosage form. The representative compound or compounds of the invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose relationship between toxic and therapeutic effects that can be expressed as the relationship between LD50 and ED50. LD50 is the lethal dose for 50% of the population, and ED50 is the therapeutically effective dose in 50% of the population. LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals. It should be understood that a specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound.
56/108 co-employee, the age, body weight, general health, sex and diet of the patient, and the time of administration, excretion rate, drug combination, judgment of the treating physician and severity of the particular disease to be treated. The amount of active ingredient (s) will also depend on the particular compound and other therapeutic agent, if present, in the composition.
IV. Methods [00130] In a group of embodiments, a method for oxygenating increasing tissue is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the foregoing embodiments or a pharmaceutically acceptable tautomer or salt the same.
[00131] In a group of modalities, a method is provided to treat a condition associated with oxygen deficiency, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the foregoing modalities or a tautomer or pharmaceutically acceptable salt thereof.
[00132] In a group of modalities, a method is provided to treat sickle cell disease, cancer, a lung disorder, stroke, high altitude disease, an ulcer, a decubitus ulcer, Alzheimer's disease, airway disease syndrome acute respiratory, and an injury, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the foregoing embodiments or a pharmaceutically acceptable salt or tautomer.
[00133] In a group of modalities, a method is provided for oxygenating growing tissue or for treating a condition associated with oxygen deficiency, said method comprising
57/108 administering to an individual in need of him a therapeutically effective amount of a compound of Formula (II):
or a tautomer or pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each optionally substituted with one to three R ^a ;
Y is O or CR ^1a R ^1b , where R ^1a is H or halo and R ^1b is selected from the group consisting of H, halo, and OH;
X is selected from the group consisting of O,> CH (CH ₂ ) _n R ⁸ , and C (R ⁹ ) ₂ where n is 0 or 1, R ⁸ is OH, and R ⁹ is independently H or halo; or YX used together is -NHC (O) - or C (O) NH-;
R ² , R ³ , R ⁴ , and R ⁵ are independently selected from the group consisting of hydrogen, halo, R ^b , OR ^d , -O (CH2) zOR ^d , -O (CH2) zNR ^d R ^d , OC (O) R ^e , SR ^d , CN, NO2, CO2R ^d , CONR ^d R ^d , C (O) R ^d , OC (O) NR ^d R ^d , NR ^d R ^d , NR ^d C (O) R ^e , NR ^d C (O) 2R ^e , NR ^d C (O) NR ^d R ^d , S (O) R ^e , S (O) 2R ^e , NR ^d S (O) 2R ^e , S (O) 2NR ^d R ^d , and N3, where z is 0, 1, 2, 3, 4, 5, or 6; or R ⁵ is - (CH2) _p R ^5a where p is 0 or 1 and R ^5a is OH;
R ⁶ and R ⁷ together form oxo or an aldehyde protecting group, or R ⁶ together with R ^1b , R ⁸ , or R ⁵ forms a cyclic ether where one of R ^1b , R ⁸ , or R ^5a is O, R ⁶ is a bond, and R ⁷ is selected from the group consisting of OH, C _1-8 alkoxy, and haloC _1-8 alkoxy;
each R ^a is independently selected from the group consisting of halo, R ^b , OR ^d , O (CH2) uOR ^d , O (CH2) uNR ^d R ^d , O (CH2) uNR ^d C (O) R ^e , O (CH2) uNR ^d C (O) 2R ^e , O (CH2) uNR ^d S (O) 2R ^e , NH2, (CH2) kOC (O) R ^e , - (CH2) kSR ^d , CN, NO2, - ( CH2) kCO2 (C1-8alkyl) OH, 58/108 (CH ₂ ) _k CO ₂ (C1-8alkyl) (heteroaryl) C (O) (C ₁ -8alkyl), - (CH2) _k CO2R ^d , (CH2) kCONR ^d R ^d , - (CH2) kNR ^d C (O) R ^e , - (CH2) kNR ^d C (O) 2R ^e , (CH2) kC (O) R ^d , - (CH2) kOC (O) NR ^d R ^d , -NR ^d (CH2) uOR ^d , NR ^d (CH2) _u NR ^d R ^d , -NR ^d (CH2) uNR ^d C (O) R ^e , -NR ^d (CH2) _u NR ^d C ( O) 2R ^e , NR ^d (CH2) uNR ^d S (O) 2R ^e , - (CH2) kNR ^d C (O) R ^e , - (CH2) kNR ^d C (O) 2R ^d , (CH2) kNR ^d C (O) NR ^d R ^d , - (CH2) kS (O) R ^e , - (CH2) kS (O) 2R ^e , (CH2) _k NR ^d S (O) 2R ^e , - (CH2) _k S (O) ₂ NR ^d R ^d , N3, - (CH2) karila optionally substituted with one to three R ^c , -NR ^d (CH2) _k aryl optionally substituted with one to three R ^c , - (CH2) kheteroarila optionally substituted with one to three R ^c , -NR ^d (CH2) _k heteroaryl optionally substituted with one to three R ^c , - (CH2) kheterocycloalkyl optionally substituted with one to three R ^c , and -NR ^d (CH2) _k heterocycloalkyl optionally substituted with one to three R ^c where k is 0, 1,2, 3, 4, 5, or 6 eu is 1,2, 3, 4, 5, or 6;
each R ^b is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, and C _2-8 alkynyl, each optionally independently substituted with one to three halo, OR ^d , or NR ^d R ^d ;
each R ^c is independently selected from the group consisting of halo, C _1-8 alkyl, haloC _1-8 alkyl, C _2-8 alkenyl, haloC _2-8 alkenyl, C _2-8 alkynyl, haloC _2-8 alkynyl, (CH ₂ ) _m OR ^f , OC (O) R ^g , SR ^f , CN, NO2, CO2R ^f , CONR ^f R ^f , C (O) R ^f , OC (O) NR ^f R ^f , (CH2) mNR ^f R ^f , NR ^f C (O) R ^g , NR ^f C (O) 2R ^g , NR ^f C (O) NR ^f R ^f , S (O) R ^g , S (O) 2R ^g , NR ^f S (O) 2R ^g , S (O) 2NR ^f R ^f , N3, heteroaryl optionally substituted with one to three R ^h , and heterocycloalkyl optionally substituted with one to three R ^h where m is selected from the group consisting of 0, 1 , 2, 3, 4, 5, and 6;
R ^d , R ^f , and R ^j are each independently selected from the group consisting of hydrogen, C _1-8 alkyl, haloC ₁₈ alkyl, C2-8 alkenyl, haloC2-8 alkenyl, C2-8 alkynyl, and haloC28alquinyl; and
59/108
R ^e , R ^g , and R * are each independently selected from the group consisting of C _1-8 alkyl, haloC _1-8 alkyl, C _2-8 alkenyl, haloC _2-8 alkenyl, C _2-8 alkynyl, and haloC _2-8 alkynyl;
as long as X and Y are not both O;
provided that when X is O, R ^1b is not OH;
provided that when Y is O, en is 0, R ⁸ is not OH; and provided that when R ⁶ and R ⁷ together are oxo, one R ² , R ³ , R ⁴ , and R ⁵ is methoxy or ethoxy, and the other for R ² , R ³ , R ⁴ , and R ⁵ is H, then Q is not unsubstituted pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.
[00134] In one group of modalities, a method is provided where z is 0. In another group of modalities, z is 1. In yet another group of modalities, z is 2. In yet another group of modalities, z is
3. In another group of modalities, z is 4. In yet another group of modalities, z is 5. In yet another group of modalities, z is 6.
V. Examples [00135] The following examples are offered to illustrate, but not to limit, the claimed invention.
PREPARATIVE EXAMPLES [00136] The starting materials and reagents used in the preparation of these compounds are generally available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following the procedures mentioned in the references such as Fieser and FieserS Reagents for Organic Synthesis; Wiley & Sons: New York, 1967-2004, Volumes 1-22; Rodd’s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 2005, Volumes 1-65.
[00137] The starting materials and intermediates of the synthetic reaction schemes can be isolated and purified if desired u
60/108 using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
[00138] Unless otherwise specified, the reactions described herein are preferably conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range from about 78 ° C to about 150 ° C, more preferably at from about 0 ° C to about 125 ° C, and preferably and conveniently at about local (or ambient) temperature, for example, about 20 ° C to about 75 ° C.
[00139] Referring to the examples that follow, the present compounds of the invention were synthesized using the methods described herein, or other methods known in the art.
Example 1. Preparation of 2- (imidazo [1,5-a] pyridin-8-ylmethoxy) -5methoxybenzaldehyde
Step 1:
[00140] In a cold solution of 3-ethoxycarbonylpyridine (25 g, 165.4 mmol, 1 eq) in DCM mCPBA was added slowly (70% by weight, 198.5 mmol), and the reaction mixture was stirred at rt for in the evening. The reaction was cooled and diluted with DCM, and then neutralized with slow addition of sat. The aqueous layer was washed with
61/108
DCM (3X), and the combined organic layer was dried and evaporated to produce a residue, which was purified by column chromatography (EtOAc / MeOH) to produce 3-ethoxycarbonylpyridine N-oxide (13.6 g). MS: exact mass calculated for C ₈ H ₉ NO ₃ , 167.06; m / z found, 168 [M + H] ⁺ .
Step 2:
I
0 ’
Compound A, Main Compound B, Secondary [00141] In a solution of 3-ethoxycarbonylpyridine N-oxide in 330 mL of DCM, trimethylsilyl cyanide (TMSCN) (11.0 g, 65.9 mmol, 1.0 eq) was added ) and dimethylcarbamoyl chloride (7.1 g, 65.9 mmol, 1.0 eq), and the reaction mixture was stirred at rt for 2 days. Then, 10% K ₂ CO ₃ was added slowly to produce the basic reaction mixture. The organic layer was separated, dried and evaporated to provide the crude, which was purified by column chromatography to provide compounds A (5.7 g) and B (3.5 g).
Steps 3 and 4:
CO ₂ Et [00142] In a solution of ethyl 2-cyano-3-pyridinecarboxylate (2.5 g) and HCI conc. (5 ml) in 150 ml of ethanol 10% Pd / C (humidity, 250 mg) was added, and the reaction mixture was hydrogenated using a hydrogen balloon and stirred for 12 h. The reaction was filtered through celite and ethanol was evaporated to produce ethyl 2- (aminomethyl) -3pyridinecarboxylate HCI as a white solid, which was used in the next step without further purification.
[00143] A mixture of 44.8 ml of acetic anhydride and 19.2 ml of
62/108 formic acid was heated in an oil bath temperature at 50-60 ° C for 3 h, and then cooled in rt to produce formic acetic anhydride, which was then slowly added to ethyl 2- (HCl) aminomethyl) -3-pyridinecarboxylate solid, and then stirred at rt for 8 h. The excess reagent was evaporated to produce a residue, which was neutralized by very slow addition of sat. NaHCO3 solution. The solution was extracted with DCM, dried and evaporated to provide ethyl imidazo [1,5-a] pyridine-8- carboxylate as a yellow solid (raw weight 2.7 g). MS: exact mass calculated for C ₁₀ H ₁₀ N ₂ O ₂ , 190.07; m / z found, 191 [M + H] ⁺ .
Steps 5 and 6:

[00144] In a cold solution of lithium aluminum hydride (1.62 g, 42.4 mmol, 4.0 eq) in THF (50 mL), ethyl imidazo [1,5-
a] crude pyridine-8-carboxylate (2.7 g, 14.2 mmol, 1.0 eq), and the reaction mixture was heated to reflux for 2 h. The reaction was cooled and water (1.7 ml), 15% NaOH (1.7 ml) and water (5.1 ml) were added slowly. The solution was diluted with excess EtOAc and stirred at rt for 30 min . The solution was filtered, and the solid was washed with ethyl acetate. The organic layers were combined, dried, and the solvent was removed to produce crude imidazo [1,5-a] pyridine-8-methanol, which was purified by column chromatography (EtOAc / Hexane). MS: exact mass calculated for C8H8N2O, 148.06; m / z found, 149 [M + H] ⁺ .
[00145] In a solution of imidazo [1,5-a] pyridine-8-methanol (800 mg) in chloroform (50 ml), thionyl chloride (10 ml) was added slowly, and the reaction mixture was stirred at rt for 8 h. Chloroform was removed, and the residue was then taken up in toluene, and
63/108 toluene was evaporated (3x) to produce a solid, which was used in the next step without further purification. MS: exact mass calculated for C ₈ H ₇ ClN ₂ , 166.03; m / z found, 167 [M + H] ⁺ .
Step 7:
OH


[00146] In a solution of chloride (1.25 mmol, 1.0 eq) and phenol (1.25 mmol, 1.0 eq) in DMF (10 mL) was added K ₂ CO ₃ (3.0 eq) , and the reaction mixture was heated to 80-90 ° C for 5 h. The solvent was removed, and the residue was purified by column chromatography (EtOAc / MeOH). NMR (400 MHz, CDCl ₃ ): δ 3.82 (s, 3H), 5.45 (s, 2H), 6.58 (m, 1H), 6.81 (m, 1H), 7.03 ( s, 1H), 7.12 (m, 1H), 7.35 (m, 1H), 7.50 (s, 1H), 7.95 (m, 1H), 8.18 (s, 1H), 10.58 (s, 1H); MS: exact mass calculated for C ₁₆ H ₁₄ N ₂ O ₃ , 282.10; m / z found, 283 [M + H] ⁺ .
Example 2. Preparation of 2- (imidazo [1,5-a] pyridin-8-ylmethoxy) -4methoxybenzaldehyde
[00147] The title compound was prepared using 2-hydroxy-4-methoxybenzaldehyde in a similar manner as in Example 1. NMR (400 MHz, CDCl3): δ 3.85 (s, 3H), 5.50 (s, 2H), 6.50-6.60 (m, 3H), 6.88 (s, 1H), 7.48 (s, 1H), 7.88 (m, 2H), 8.18 (s, 1H), 10 , 58 (s, 1H); MS: exact mass calculated for C ₁₆ H ₁₄ N ₂ O ₃ , 282.10; m / z found, 283 [M + H] ⁺ .
64/108
Example 3.
Preparation of
2- (imidazo [1,5-a] pyridin-6-ylmethoxy) -5methoxybenzaldehyde
Steps 1 and 2:

CO ₂ Et [00148] In a solution of ethyl 6-cyano-3-pyridinecarboxylate (3.75
g) and conc. (7.5 mL) in 225 mL of ethanol was added Pd / C to
10% (humidity, 375 mg), and the reaction mixture was hydrogenated using a hydrogen balloon and stirred for 12 h. The solution was filtered through celite, and ethanol was evaporated to produce HCl of ethyl 6- (aminomethyl) -
3-pyridinecarboxylate as a white solid, which was used in the next step without further purification.
[00149] A mixture of 67.2 ml of acetic anhydride and 28.8 ml of formic acid was heated to an oil bath temperature at 50-60 ° C for 3 h, and then cooled in rt to produce formic anhydride. -acetic, which was then slowly added to the solid ethyl 2 (aminomethyl) -3-pyridinecarboxylate HCl, and then stirred at rt for 8 h. Excess reagent was evaporated to produce a residue, which was neutralized by very slow addition of sat. NaHCO ₃ solution. The solution was extracted with DCM, dried and evaporated to provide imidazo [1,5-a] pyridine as a yellow solid. . MS: exact mass calculated for C ₁₀ H ₁₀ N ₂ O ₂ , 190.07; m / z found, 191 [M + H] ⁺ .
65/108
Steps 3 and 4:
[00150] In a cold solution of lithium aluminum hydride (1.0 g,
26.3 mmol, 2.0 eq) in THF (40 mL) crude ethyl imidazopyridine nacarboxylate (2.5 g, 13.2 mmol, 1.0 eq) was added, and the reaction mixture was stirred at rt for 2 H. The reaction was cooled, and water (1.7 ml), 15% NaOH (1.7 ml) and water (5.1 ml) were added slowly. The solution was then diluted with excess EtOAc and stirred at rt for 30 min. The solution was filtered, and the solid was washed with ethyl acetate. The organic layers were combined, dried, and the solvent was removed to produce crude imidazo [1,5-a] pyridine-8-methanol, which was purified by column chromatography (EtOAc / Hexane). MS: exact mass calculated for C ₈ H ₈ N ₂ O, 148.06; m / z found, 149 [M + H] ⁺ .
[00151] In a solution of imidazopyridine methanol (700 mg, 4.7 mmol, 1.0 eq) in chloroform (20 mL), thionyl chloride (1.7 mL) was added slowly, and the reaction mixture was stirred at rt for 8 h. Chloroform was removed, and the residue was then taken up in toluene. Toluene was evaporated (3x) to produce a solid (550 mg), which was used in the next step without further purification.
Step 5:
OH

K ₂ CO ₃
DMF
66/108 [00152] In a solution of chloride (1.25 mmol, 1.0 eq) and phenol (1.25 mmol, 1.0 eq) in DMF (10 mL) was added K ₂ CO ₃ (3, 0 eq), and the reaction mixture was heated to 80-90 ° C for 5 h. The solvent was removed, and the residue was purified by column chromatography (EtOAc / MeOH). MS: exact mass calculated for C ₁₆ H ₁₄ N ₂ O ₃ , 282.10; m / z found, 283 [M + H] ⁺ .
Example 4. Preparation of methoxybenzaldehyde
2- (imidazo [1,5-a] pyridin-6-ylmethoxy) -4-
[00153] The title compound was prepared using 2-hydroxy-4 methoxybenzaldehyde in a similar manner as in Example 3.
Example 5. Preparation of methyl imidazo [1,2-a] pyridine-8-carboxylate
co ₂ ch ₃ [00154] In a solution of methyl 2-amino-pyridine-3-carboxylate (5 g, 35 mmol, 1.0 eq) in ethanol (250 ml) was added NaHCO ₃ (5.08 g) and chloroacetaldehyde in water (35 mL of 45% in water, 148 mmol,
4.5 eq). The reaction mixture was heated to reflux for 18h. The solvent was removed, and the residue was basified with Na2CO3, and then extracted with DCM. The organic layers were combined and evaporated to produce a residue, which was purified by column to produce the title compound.
Example 6. Preparation of imidazo [1,2-a] pyridin-8-ylmethanol
67/108 [00155]
In a cold solution of methyl imidazo [1,2-a] pyridine-8carboxylate and (5.55 g, 31.53 mmol eq) in THF (100 mL) LAH in ether (1 M solution in ether, 4 equiv.), and then stirred at rt for 6 h. The reaction mixture was cooled to 0 ° C and quenched with water / 15% NaOH / water. The reaction mixture was diluted with ethyl acetate and stirred at room temperature for 15 min, and then filtered. The solid was washed with ethanol, and the organic layers were combined, dried and evaporated to produce the alcohol, which was purified by column chromatography to produce the desired product in 40% yield.
Example 7. Preparation of 8- (chloromethyl) imidazo [1,2-a] pyridine
00 [00156] A mixture of imidazo [1,2-a] pyridin-8-ylmethanol (800 mg) and excess thionyl chloride was stirred at 70-80 ° C for 8 h. Excess thionyl chloride was removed in vacuo. The residue was then diluted with toluene and evaporated. This procedure was repeated 3 times.
Example 8. Preparation of 2- (imidazo [1,2-a] pyridin-8-ylmethoxy) -5methoxybenzaldehyde
[00157] In a solution of raw 8- (chloromethyl) imidazo [1,2-a] pyridine (6.8 mmol, 1 eq) and 2-hydroxy-5-methoxybenzaldehyde (1.3 g, 8.1 mmol, 1.2
68/108 eq) in DMF (20 ml) potassium carbonate (2.8 g, 20.4 mmol, 3 eq) was added, and the reaction mixture was heated to 85-90 ° C for 5 h. DMF was removed in vacuo, and the residue was taken up in ethyl acetate and filtered. The solid was washed with additional ethyl acetate, and then dried and evaporated to produce the crude, which was purified by column chromatography (EtOAc / Hexane) to produce the desired compound in 45% yield. NMR (400 MHz, CDCl ₃ ): δ 3.80 (s, 3H), 5.60 (s, 2H), 6.85 (d, 1H), 7.12 (d, 2H), 7.36 ( m, 2H), 7.66 (m, 2H), 8.14 (m, 1H), 10.58 (s, 1H); MS: exact mass calculated for C ₁₆ H ₁₄ N ₂ O ₃ , 282.10; m / z found, 283 [M + H] ⁺ .
Example 9. Preparation of 2- (imidazo [1,2-a] pyridin-8-ylmethoxy) -4methoxybenzaldehyde
[00158] The title compound was prepared using 2-hydroxy-4-methoxybenzaldehyde in a similar manner as in Example 3. NMR (400 MHz, CDCl ₃ ): δ 3.88 (s, 3H), 5.65 (s, 2H) , 6.58 (m, 1H), 6.68 (s,
1H), 6.88 (m, 1H), 7.42 (m, 1H), 7.66 (m, 2H), 7.83 (m, 1H), 8.14 (m,
1H), 10.45 (s, 1H); MS: exact mass calculated for C ₁₆ H ₁₄ N ₂ O ₃ , 282.10; m / z found, 283 [M + H] ⁺ .
Example 10. Preparation of 5-methoxy-2 - ((1-methyl-1H-indazol-4 yl) methoxy) benzaldehyde (Compound 115)

69/108
Step 1:
N i
NaBH ₄
THF
HO '[00159] In a mixture of 1-methyl-1H-indazole-4-carbaldehyde (180 mg, 1.12 mol) in THF (10 ml) NaBH ₄ (85 mg, 2.24 mmol) was added in rt . The reaction mixture was stirred at rt for 1 h, acidified to pH 3 and extracted with EtOAc. The combined organic layer was washed with saturated sodium bicarbonate solution and brine, dried over Na ₂ SO ₄ , filtered and concentrated to produce a crude solid (191 mg), which was used for the next step without further purification.
Step 2:
DCM
HO '
Cl [00160] In (1-methyl-1H-indazol-4-yl) methanol (191 mg) in DCM (5 ml) SOCl2 (2 ml) was added in rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to produce an off-white solid (210 mg), which was used for the next step without further purification.
Step 3:
OH [00161] A mixture of 2-hydroxy-5-methoxybenzaldehyde (170 mg,
1.12 mmol), 4- (chloromethyl) -1-methyl-1H-indazole (1.12 mmol) and K ₂ CO ₃
70/108 (618 mg, 4.48 mmol) was refluxed in CH ₃ CN (20 mL) for 2 h. The mixture was filtered, and the solid was washed with DCM. The filtrate was concentrated and purified on silica gel using a mixture of EtOAc and MeOH as eluent to produce 5-methoxy-2 - ((1-methyl-1H-indazol-4yl) methoxy) benzaldehyde (215 mg, 81% for three steps) as a white solid. ¹ H NMR (400 MHz; DMSO) δ = 10.39 (s, 1 H), 8.20 (d, 1 H), 7.63 (d, 1 H) 7.36-7.64 (m, 2 H), 7.23-7.29 (m, 2 H), 7.18 (d, 1 H), 5.58 (s, 2 H), 4.06 (s, 3 H), 3, 34 (s, 3 H). LRMS (M + H ⁺ ) m / z 297.1.
[00162] Example 11. Preparation of 2 - ((1H-indazol-4-yl) methoxy) -5methoxybenzaldehyde
Step 1:

NaBH
THF
Boc
[00163] In a mixture of 4- (chloromethyl) -1H-indazole (1.0 g, 6.0 mol) in DCM (20 mL) was added (Boc) 2O (1.96 g, 9.0 mmol) and
DMAP (dimethylamino pyridine 67.2 mg, 0.6 mmol) in rt. The reaction mixture was stirred at rt for 1 h, concentrated and purified on silica gel to produce tert-butyl 4- (chloromethyl) -1H-indazol-1-carboxylate (1.4 g, 88%) as a colorless oil.
Step 2:
71/108
[00164] A mixture of 2-hydroxy-5-methoxybenzaldehyde (46 mg, 0.3 mmol), tert-butyl 4- (chloromethyl) -1H-indazol-1-carboxylate (80 mg, 0.3 mmol) and K ₂ CO ₃ (166 mg, 1.2 mmol) in DMF (1.0 ml) was heated to 80 ° C for 2 h. The mixture was filtered, and the solid was washed with DCM. The filtrate was concentrated and purified on silica gel using a mixture of EtOAc and hexanes as the eluent to produce tert-butyl 4 - ((2formyl-4-methoxyphenoxy) methyl) -1H-indazol-1-carboxylate (88 mg, 77%) like a colorless oil.
Step 3:
[00165] In tert-butyl 4 - ((2-formyl-4-methoxyphenoxy) methyl) -1H-indazol1-carboxylate (88 mg, 0.23 mmol) in DCM (5.0 mL) was added TFA (2, 0 mL). The mixture was stirred at rt for 2 h and concentrated. The crude was purified on silica gel using a mixture of EtOAc and hexanes as the eluent to produce 2 - ((1H-indazol-4-yl) methoxy) -5methoxybenzaldehyde (50 mg, 77%) as a white solid. ¹ H NMR (400 MHz; CDCl ₃ ) δ = 10.53 (s, 1 H), 8.23 (s, 1 H), 7.54 (d, 1 H) 7.43 (t, 1 H) , 7.38 (d, 1 H), 7.25 (d, 1 H), 7.08-7.15 (m, 2 H), 5.51 (s, 2 H), 3.82 (s , 3 H). LRMS (M + H +) m / z 283.1.
Example 12. Preparation of 3- (imidazo [1,2-a] pyridin-8-ylmethyl) -1,3-di72 / 108 hydroisobenzofuran-1 -ol

To a solution of methyl imidazo [1,2-a] pyridine-8 [00166] carboxylate (1.76 g, 10 mmol) in toluene was added DIBAL (1M / THF, 20 ml) at -78 ° C dropwise . The mixture was stirred at -78 ° C for 1 h, quenched with MeOH (2 ml) and saturated NH4Cl solution (50 ml) and heated to rt. The mixture continued to stir at rt for 1 h and diluted with DCM (60 ml). The aqueous layer was extracted with DCM (60 ml) twice. The combined organic layer was dried over MgSO4 and concentrated. The residue was purified on silica gel with 10% MeOH / DCM to produce imidazo [1,2-a] pyridine-8carbaldehyde (0.8g, 55%). LRMS (M + H +) m / z 147.1.
Step 2:
MeOH (20 mL) was added diethyl phosphite (3.31 g, 24 mmol) at 0 ° C, followed by the addition of 2-formylbenzoic acid (3.0 g, 20 mmol) in portions over a period of 20 min. The resulting mixture was heated to rt and continued to stir for 2 h. Methanesulfonic acid (2.69 g, 28 mmol, 1.4 equiv.) Was added to the previous mixture over a period of 30 min. The reaction mixture was stirred for 30 min and
73/108 concentrated to remove most of the MeOH. The residue was divided between DCM (100 ml) and water (50 ml). The aqueous layer was extracted twice with DCM. The combined organic layer was dried over Na ₂ SO ₄ and concentrated to produce dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (4.6 g, 90%). LRMS (M + H +) m / z 257.1.
Step 3:
[00168] In a solution of dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (610 mg, 2.4 mmol), imidazo [1,2-
a] pyridine-8-carbaldehyde (350 mg, 2.4 mmol, 1 equiv.) in THF (5 ml) Et ₃ N (0.33 ml 2.4 mmol) was added. The mixture was stirred at rt for 48 h. The precipitation was filtered and washed with EtOAc. The filtrate was concentrated to produce 3- (imidazo [1,2-a] pyridin-8-methylene) isobenzofuran-1 (3H) -one (400 mg, 64%) as a yellow solid. The small crude sample (~ 20 mg) was purified on RPHPLC with CH3CN and water as an eluent to separate the E / Z isomers (10 mg, 7 mg). ¹ H NMR (400 MHz, CD ₃ OD) form Z: δ = 8.52 (d, 1 H), 7.95-7.91 (m, 2 H), 7.62-7.54 (m, 4 H), 7.52-7.48 (m, 1 H), 7.09 (s, 1 H), 7.04 (t, 1 H) Form E: δ = 8.38 (d, 1 H ), 8.15 (d, H), 8.05 (d, 1 H),
7.95 (d, 1 H), 7.90-7.84 (m, 2 H), 7.67 (t, 1 H), 7.64 (s, 1 H), 7.33 (s, 1 H). 7.05 (t, 1 H). LRMS (M + H ⁺ ) m / z 263.1

74/108 [00169] In a solution of 3- (imidazo [1,2-a] pyridin-8ylmethylene) isobenzofuran-1 (3H) -one (180 mg, 0.69 mmol) in EtOAc (12 mL) was added 10% Pd / C (110 mg). The mixture was stirred overnight under a hydrogen balloon. The catalyst was filtered, and the filtrate was concentrated and purified on silica gel with 10% MeOH / DCM as eluent to produce 3- (imidazo [1,2-a] pyridin-8ylmethyl) isobenzofuran-1 (3H) -one ( 140 mg, 78%). ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.37 (d, 1H). 7.88 (s, 1 H), 7.83 (d, 1 H), 7.74-7.63 (m, 2 H), 7.60-7.53 (m, 2 H). 7.22 (d, 1 H), 6.86 (t, 1 H), 6.04 (dd, 1 H), 3.76
(dd, 1 H), 3.24 (dd , 1 H). ). LRMS (M + H ⁺ ) m / z 265.1 Step 5: OOH LiBHEt ₃ IFV O DCM 'w [00170] On a solution in 3- (imidazo [1,2-a] pyridin-8-
ilmethyl) isobenzofuran-1 (3H) -one (80 mg, 0.3 mmol) in DCM (6 ml) at 78 ° C, lithium triethyl borohydride (1M / THF, 0.3 ml) was added dropwise drop. The reaction mixture was stirred at -78 ° C for 30 min, diluted with DCM (;; 10 ml) and quenched with MeOH (1 ml) and 5% HCl (2 ml). The mixture was heated to rt and stirred for 1 h. The solvents were removed, and the residue was purified on RP-HPLC using CH3CN and water as the eluent to produce 3- (imidazo [1,2-a] pyridin-8ylmethyl) -1,3-dihydroisobenzofuran-1-ol ( 20 mg, 25%). ¹ H NMR (400 MHz, CD3OD) δ = 8.56 (t, 1 H), 8.97 (d, 1 H), 7.74 (s, 1 H), 7.45-7.32 (m , 5 H), 7.07-7.00 (m, 1H), 6.38-6.30 (m, 1 H), 5.84-5.80 (m, 0.5 H), 5, 56 (dd, 0.5 H), 3.69 (t, 0.5 H), 3.65 (t, 0.5 H), 3.26 (dd, 0.5 H), 3.13 ( dd, 0.5 H). LRMS (M + H ⁺ ) m / z 267.1.
Example 13. Preparation of 5- (imidazo [1,2-a] pyridin-8-ylmethoxy) -2methoxybenzaldehyde.
75/108
Step 1:
OH

K ₂ with ₃ DMF
0.2 mol) and bromomethyl O period [00171] In a mixture of 6-methoxyphen-3-ol (25 g, K2CO3 (82.8 g, 0.6 mol) in DMF (250 ml) ether (30 g, 0.24 mmol) slowly at rt over a period of
1h. The reaction mixture is filtered, and the filtrate is concentrated. The residue is purified on silica gel with 25% EtOAc / hexanes as the eluant to produce 2-methoxy-5- (methoxymethoxy) benzene.
Step 2:

[00172] In a solution of 2-methoxy-5- (methoxymethoxy) benzene (20 g, 0.12 mol) in THF is added diisopropylamine (0.24 g, 2.4 mmol). The solution is cooled to -40 ° C, followed by the addition of MeLi (3M / THF, 72mL, 0.216 mol) slowly. The resulting mixture is heated to 0 ° C, stirred at 0 ° C for 3 h, cooled or repeatedly to -40 ° C and added N-formylpiperidine (24 ml, 0.216 mol). After stirring at 40 ° C for 2 h, the mixture is quenched with a mixed solution of HCl (37%, 120 ml) and THF (250 ml). The temperature is then raised to rt and diluted with water (200 ml) and EtOAc (200 ml). The pH of
76/108 mixture is adjusted to 8-9 with solid K ₂ CO ₃ and extracted with EtOAc (300 mL) twice. The organic layer is combined, dried over Na ₂ SO ₄ and concentrated. The residue is purified on silica gel with 25% EtOAc / hexanes as the eluent to produce 2-methoxy-5 (methoxymethoxy) benzaldehyde.
Step 3:
[00173] In a solution of 2-methoxy-5- (methoxymethoxy) benzaldehyde (10 g, 0.05 mol) in THF (100 ml) was added 3N HCl (150 ml). The reaction was stirred at 50 ° C for 30 min, cooled to rt and diluted with water (100 ml). The mixture was neutralized at pH 7-8 and extracted with EtOAc (200 ml) three times. The organic layer was dried over Na2SO4 and concentrated to produce 5-hydroxy-2-methoxybenzaldehyde. Step 4:
[00174] A mixture of 5-hydroxy-2-methoxybenzaldehyde (723.6 mg, 4.7 mmol), 8- (chloromethyl) -imidazole [1,2-one] pyridine (785 mg, 4.7 mmol) and K ₂ CO ₃ (1.9 g, 14.1 mmol) in DMF (20 mL) was heated in a microwave reactor at 125 ° C for 15 min. The mixture was filtered and concentrated. The residue was purified on silica gel (50-100% EtOAc in hexanes) to yield 5- (imidazo [1,2-a] pyridin-8-ylmethoxy) -2methoxybenzaldehyde.
[00175] The compounds in Examples 14-16 were prepared according to
77/108 according to the procedures described in Example 13.
Example 14. Preparation of 2- (imidazo [1,2-a] pyridin-2-ylmethoxy) -5methoxybenzaldehyde (Compound 5.) [00176] ¹ H NMR (400 MHz, DMSO) δ 10.39 (s, 1H) , 8.53 (d, J = 6.8 Hz, 1H), 8.06 (s, 1H), 7.54 (d, J = 9.1 Hz, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.29-7.22 (m, 2H), 7.17 (d, J = 3.3 Hz, 1H), 6.90 (t, J = 6.8 Hz, 1H), 5.35 (s, 2H), 3.76 (s, 3H).
Example 15. Preparation of 5-methoxy-2- (quinolin-5ylmethoxy) benzaldehyde (Compound 10).
[00177] ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.09 (s, 1H), 7.73 (dd, J = 4.0, 1.3 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.48 (t, J = 8.4 Hz, 1H), 6.40 (d, J = 6 , 9 Hz, 1H), 6.24 (dd, J = 8.5, 4.2 Hz, 1H), 6.10 (d, J = 2.6 Hz, 1H), 5.95 - 5.85 (m, 2H), 4.32 (s, 2H), 2.56 (s, 3H).
Example 16. Preparation of 5-methoxy-2 - ((8-methylimidazo [1,2-a] pyridin-2yl) methoxy) benzaldehyde (Compound 24).
[00178] ¹ H NMR (400 MHz, CD ₃ CN) δ 10.32 (s, 1H), 8.01 (d, J = 6.8 Hz, 1H), 7.68 (s, 1H), 7 , 19 (d, J = 9.0 Hz, 1H), 7.13 (d, J = 3.2 Hz, 1H), 7.08 (dd, J = 9.0, 3.3 Hz, 1H) , 6.90 (td, J = 6.8, 1.2 H 1H), 6.62 (t, J =
6.s Hz, 1H), 5.21 (s, 2H), 3.67 (s, 3H), 2.39 (s, 3H).
Example 17. Preparation of 2-hydroxy-6 - ((2- (1-isopropyl-1H-pyrazol-5yl) pyridin-3-yl) methoxy) benzaldehyde (Compound 43).

[00179] A mixture of 2,6-dihydroxybenzaldehyde (1.96 g, 14.2 mmol, 2 eq.) And Cs ₂ CO ₃ (7.5 g, 21.3 mmol, 3 eq.) In DMF (180 ml) was stirred at rt for 30 min. To this mixture was added hydrochloride
78/108 of 3- (chloromethyl) -2- (1-isopropyl-1H-pyrazol-5-yl) pyridine (1.93 g, 7.1 mmol, 1 eq.) In rt. The mixture continued to stir in rt, O / N, was filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to produce 2-hydroxy-6 - ((2- (1isopropyl-1H-pyrazol-5- il) pyridin-3-yl) methoxy) benzaldehyde (920 mg, 37%) as a pale yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J = 4.8, 1.5 Hz, 1H), 8 .00 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.49 - 7.34 (m, 2H), 6.59 (d, J = 8.5 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 6.29 (d, J = 8.2 Hz, 1H), 5.10 (s, 2H) , 4.67 (sep, J = 6.7 Hz, 1H), 1.50 (d, J = 6.6 Hz, 6H). LRMS (M + H ⁺ ) m / z
338.1
Example 18. Preparation of 2-hydroxy-6 - ((2- (1-isopropyl-1H-pyrazol-5yl) pyridin-3-yl) methoxy) benzaldehyde (Compound 43).

[00180] A mixture of 2,6-dihydroxybenzaldehyde (1.58 g, 11.47 mmol, 2 eq.) And K ₂ CO ₃ (2.4 g, 17.22 mmol, 3 eq.) In DMF (150 ml) was stirred at rt for 10 min. To this mixture was added 3- (chloromethyl) -2- (1-isopropyl-1H-pyrazol-5-yl) pyridine (1.56 g, 5.74 mmol, 1 eq.) In rt. The mixture was heated to 50 ° C for 2 h, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as the eluent to produce 2-hydroxy-6 - ((2- (1-isopropyl-1Hpyrazol-5- il) pyridin-3-yl) methoxy) benzaldehyde (1.71 g, 88%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J = 4.8, 1.5 Hz, 1H), 8 .00 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.49 - 7.34 (m, 2H), 6.59 (d, J = 8.5 Hz, 1H), 6.37 (d, J
79/108 = 1.8 Hz, 1H), 6.29 (d, J = 8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J = 6.7
Hz, 1H), 1.50 (d, J = 6.6 Hz, 6H). LRMS (M + H ⁺ ) m / z 338.1
Example 19. Preparation of 5 - ((2- (2H-tetrazol-5-yl) pyridin-3-yl) methoxy) -2 methoxybenzaldehyde.
Step 1:
Pd (PPh ₃ ) ₄
Zn (CN) ₂ DMF
mixture of 5 - ((2-bromopyridin-3-yl) methoxy) -2 [00181] In a methoxybenzaldehyde (100 mg, 0.31 mmol, 1 equiv), Zn (CN) 2 (71 mg,
0.62 mmol, 2.0 equiv), Pd (PPh ₃ ) ₄ (72 mg, 0.06 mmol, 0.2 equiv) in a 5 ml microwave tube DMF (2 ml) is added. The mixture is heated 15 min at 125 ° C in a microwave reactor. The solid is filtered, and the filtrate is concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as the eluent to produce 3 - ((4-formyl-6-methoxyphen-3-yloxy) methyl) picolinonitrile.
Step 2:

[00182] In TEA hydrochloride salt (123 mg, 0.89 mmol, 4 equiv.) And 3 - ((4-formyl-6-methoxyphen-3-yloxy) methyl) picolinonitrile (70 mg, 0.26 mmol , 1 equiv.) In chlorobenzene (5.0 ml) NaN3 (48 mg, 0.89 mmol, 4 equiv.) Is added in rt. The mixture is heated to 110 ° C for 2 h, cooled to rt, and water (5.0 ml) is added. The precipitate is filtered and
80/108 washed with EtOAc and water and dried under high vacuum to produce 5 - ((2 (2H-tetrazol-5-yl) phen-3-yl) methoxy) -2-methoxyisonicotinaldehyde.
[00183] The compounds in Examples 20 and 21 were prepared according to the procedures described in Example 19.
Example 20. Preparation of 2 - ((3- (2H-tetrazol-5-yl) benzyl) oxy) -6hydroxybenzaldehyde (Compound 44).
[00184] ¹ H NMR (400 MHz, CD ₃ CN) δ 11.95 (s, 1H), 10.45 (s, 1H),
8.17 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7 , 7 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 6.6 2 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 8, 5 Hz, 1H), 5.30 (s, 2H).
Example 21. Preparation of 2 - ((4- (2H-tetrazol-5-yl) benzyl) oxy) -6hydroxybenzaldehyde (Compound 45).
[00185] ¹ H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 10.40 (s, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 8.4 Hz, 1H), 6.7 3 (d, J = 8.4 Hz, 1H), 6.56 ( d, J = 8.5 Hz, 1H), 5.33 (s, 2H).
[00186] Example 22. Preparation of 5 - ((4-formyl-6-methoxyphenyl) acid
3-yloxy) methyl) nicotinic.
Step 1:

[00187] A mixture of 5-hydroxy-2-methoxybenzaldehyde (352 mg,
2.29 mmol, 1 eq.), Methyl 5- (chloromethyl) nicotinate hydrochloride (506 mg,
2.29 mmol, 1 eq.) And K ₂ CO ₃ (1.26 g, 9.16 mmol, 4 eq.) In DMF (8.0 ml) is heated to 60 ° C for 3 h. The mixture is cooled and added in water (50 ml) dropwise. The precipitate is filtered, washed with water and dried to produce methyl 5 - ((4-formyl-6-methoxyphen-3
81/108 (oxy) methyl) nicotinate.
Step 2:

[00188] In 5 - ((4-formyl-6-methoxyphen-3-yloxy) methyl) nicotinate (96 mg, 0.32 mmol, 1 eq.) In a MeOH / THF mixture (1/3, 8, 0 mL) NaOH (3 N, 1.7 mL, 5.1 mmol, 16 eq.) Is added. The mixture is stirred at rt for 2 h, acidified to pH 3, extracted with EtOAc (3 x 20 ml). The combined organic layers are dried over Na2SO4 and concentrated to produce 5 - (((4-formyl-6-methoxypyridin-3yloxy) methyl) nicotinic acid.
[00189] The compounds in Examples 23-25 were prepared according to the procedures described in Example 22.
Example 23. Preparation of methyl 4 - ((2-formylphenoxy) methyl) benzoate (Compound 46).
[00190] ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.51 (s, 1H), 8.01 (d, J = 8.3
Hz, 2H), 7.81 (dd, J = 7.7, 1.8 Hz, 1H), 7.51 - 7.40 (m, 3H), 7.00 (t, J =
7.5 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 5.19 (s, 2H), 3.86 (s, 3H).
Example 24. Preparation of 4 - ((2-formylphenoxy) methyl) benzoic acid (Compound 47).
[00191] ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.52 (s, 1H), 8.09 (d, J = 8.2
Hz, 2H), 7.81 (dd, J = 7.7, 1.6 Hz, 1H), 7.53 - 7.43 (m, 3H), 7.0 1 (t, J =
7.5 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 5.21 (s, 2H).
Example 25. Preparation of methyl 3 - ((2-formylphenoxy) methyl) benzoate (Compound 48).
82/108 [00192] ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.58 (s, 1H), 8.14 (s, 1H),
8.06 (d, J = 7.8 Hz, 1H), 7.90 (dd, J = 7.7, 1.8 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H ), 7.60 - 7.48 (m, 2H), 7.08 (dd, J = 14.4, 7.9 Hz, 2H), 5.26 (s, 2H), 3.96 (s, 3H).
Example 26. Preparation of 5-hydroxy-2-methoxybenzaldehyde.
Step 1:
[00193] In a solution of 6-methoxyphen-3-ol (20 g, 0.16 mol, 1 eq.) In DMF (200 mL) was added NaH (60% in mineral oil; 9.6 g, 0, 24 mol, 1.5 eq.) At 0-5 ° C in portions. Upon completion of the addition, the mixture continued to stir at 0-5 ° C for 15 min, chloromethyl methyl ether (15.5 g, 0.19 mol, 1.2 eq.) Was added, stirred at 0-5 ° C for another 20 min and quenched with NH4Cl solution (sat.). The aqueous layer was extracted with EtOAc (3 x 100 mL), and the combined organic layers were washed with water and brine, dried over Na2SO4, concentrated and purified on silica gel using 25% EtOAc / hexanes as the eluent to produce 2-methoxy -5 (methoxymethoxy) benzene (24.1 g, 89.3%) as a colorless oil.
Step 2:
[00194]

In a mixture of 2-methoxy-5- (methoxymethoxy) benzene (30 g, 0.178 mol, 1 eq.) And diisopropylamine (507 µL, 3.6 mmol, 0.02 eq.) In THF (500 mL) Methylithium (1.6 M / THF, 200 mL, 0.32 mol, 1.8 eq.) was added at -40 ° C. Upon completion of the addition, the mixture was heated to 0 ° C, continued to stir at 0 ° C for 3 h, cooled again to 83/108 ° C and DMF (24.7 mL, 0.32 mol, 1, 8 eq.) Slowly. The mixture was then stirred at -40 ° C for 1 h, quenched with a mixture of HCl (12 N, 120 ml) and THF (280 ml), heated in rt, and water (200 ml) added. The pH of the mixture was adjusted to pH 8-9 with solid K2CO3. The aqueous layer was extracted with EtOAc (300 ml) twice. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to produce 2-methoxy-5 (methoxymethoxy) benzaldehyde (33.5 g, 95.7%) as a brown solid, which was used for the next step without further purification. ¹ H NMR (400 MHz; CD ₃ OD) 7.90 (s, 1 H), 6.92 (s, 1 H), 5.64 (s, 1 H), 5.20 (s, 2 H) , 3.84 (s, 3 H), 3.48 (s, 3 H). LRMS (M + H ⁺ ) m / z 198.1
Step 3:
[00195] In a solution of 2-methoxy-5- (methoxymethoxy) benzaldehyde (33.5 g, 0.17 mol, 1 eq.) In THF (150 ml) was added HCl (3 N, 250 ml, 4, 4 eq.). The reaction was stirred at 50 ° C for 1 h, cooled to rt and diluted with water (500 ml). The mixture was neutralized at pH 7-8 with solid K ₂ CO ₃ . The pale yellow solid was collected, washed with water and dried to produce 5-hydroxy-2-methoxybenzaldehyde (17.9 g, 74.6%) as a pale yellow solid. ¹ H NMR (400 MHz; DMSO) δ = 10.31 (s, 1 H), 8.03 (s, 1 H), 6.89 (s, 1 H), 3.80 (s, 3 H) . LRMS (M + H ⁺ ) m / z 154.0.
Example 27. Preparation of 5 - ((2- (1-isopropyl-1H-pyrazol-5-yl) pyridin-3yl) methoxy) -2-methoxybenzaldehyde (Compound 150).
Step 1:
84/108
ο
[00196] In a solution of 2-bromonicotinic acid (4.0 g, 20 mmol) and triethylamine (3.34 mL, 24 mmol, 1.2 eq.) In THF (100 mL) / -butyl chloroformate was added (3.12 mL, 24 mmol, 1.2 eq.) AOO. The mixture was stirred at 0 Ό for 10 min and filtered. To this filtrate was added a suspension of NaBH ₄ (1.52 g, 40 mmol, 2 eq.) In water (1.0 mL) at 0 Ό. The mixture was stirred for 30 min, water added (3 ml), continued to stir for 2 h and concentrated to dryness. The crude was purified on silica gel using a mixture of acetate
ethyl and hexanes how eluent for to produce (2-bromopyridin-3- il) methanol (3.4 g, 90%) like a solid White. LRMS (M + H ⁺ ) m / z 188.0.Step 2 NIIimidazole NII TBSCI Br · ^ ΌΗ OTBS
[00197] In a mixture of (2-bromopyridin-3-yl) methanol (20.0 g, 106.4 mmol, 1 eq.) And imidazole (14.5 g, 212.8 mmol, 2 eq.) In DMF (50.0 mL) was added TBSCI (19.2 g, 150.7 mmol, 1.2 eq.) In rt. The mixture was stirred at rt for 1 h and diluted with a mixture of water (100 ml) and EtOAc (300 ml). The organic layer was washed with NH ₄ CI solution (sat.) And brine, dried over Na ₂ SO ₄ , concentrated and purified on silica gel using 10% EtOAc / hexanes as the eluent to produce 2-bromo-3 - (( tert-butyldimethylsilyloxy) methyl) pyridine (30.1 g, 94%) as a colorless oil. LRMS (M + H ⁺ ) m / z 302.0.
85/108

Step 3 [00198] A mixture of 2-bromo-3 - ((tert-butyldimethylsilyloxy) methyl) pyridine (30.1 g, 100.0 mmol, 1 eq.) And Zn (CN) ₂ (23.5 g, 200, 0 mmol, 2.0 eq.) In DMF (100.0 ml) was purged with N ₂ for 5 min and Pd (PPh ₃ ) ₄ (5.78 g, 5.0 mmol, 0.05 eq.) Added . The mixture was heated at 120 ° C for 2 h under N 2, cooled, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to produce 3 - ((tert-butyldimethylsilyloxy) methyl) picolinonitrile (20.4 g , 82%) as a colorless oil. LRMS (M + H ⁺ ) m / z 249.1.
Step 4:
MeMgBr
THF
[00199] Methylmagnesium bromide (3M / ether, 41.0 mL, 123.4 mmol) was added to a stirred solution of 3 - ((tert-butyldimethylsilyloxy) methyl) picolinonitrile (20.4 g, 82.25 mmol) in THF (100.0 ml) at -78 ° C. The reaction mixture was heated in rt, quenched with aqueous citric acid solution and extracted with EtOAc (50 ml) twice. The combined organic layers were washed with NaHCO3 (sat) solution and brine, dried over Na2SO4, concentrated and purified on silica gel using a mixture of EtOAc / hexanes as eluent to produce 1- (3 - ((tert-butyldimethylsilyloxy) methyl) pyridin-2yl) ethanone (12.9 g, 59%) as a colorless oil. LRMS (M + H ⁺ ) m / z
266.2.
86/108

OTBS
Step 5:
N DMF.DMA
OTBS [00200] 1 - (3 - ((tert-butyldimethylsilyloxy) methyl) pyridin-2-yl) ethanone (10.8 g, 40.75 mmol) in N-dimethoxy, N-dimethylmethanamine (15.0 mL) was heated to reflux for 3 days. The mixture was concentrated and used for the next step without further purification. LRMS (M + H ⁺ ) m / z 321.1.
Step 6:
ΌΗ [00201] In (E) -1- (3 - ((tert-butyldimethylsilyloxy) methyl) pyridin-2-yl) -3 (dimethylamino) prop-2-en-1-one (1.03 g raw, 3 , 22 mmol, 1 eq.) In EtOH (10 ml) isopropylhydrazine hydrochloride (430 mg, 3.86 mmol, 1.2 eq.) Was added. The mixture was heated to 80 ° C for 2 h, cooled, added HCl (6 N, 0.5 ml) and stirred O / N. The mixture was concentrated and diluted with EtOAc (80 ml) and NaHCO3 solution (sat) (10 ml). The layers were separated, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated and purified on silica gel using EtOAc as the eluent to produce (2- (1-isopropyl-1H-pyrazol-5-yl) pyridin-3-yl) methanol (500 mg, 71% ) and (2- (1-isopropyl-1H-pyrazol-3-yl) pyridin-5-yl) methanol (55 mg, 25%) as pale yellow oils. Data for 2- (1-isopropyl-1Hpyrazol-5-yl) pyridin-3-yl) methanol: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.67 (dd, J = 4.7, 1.5 Hz , 1H), 8.0 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 7.8, 4, 8 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 4.67 (s, 2H),
87/108
4.55 (sep, J = 6.6 Hz 1H), 1.98-2.05 (br, 1H), 1.47 (d, J = 6.6 Hz, 6H). LRMS (M + H ⁺ ) m / z 218.1 Data for (2- (1-isopropyl-1H-pyrazol-3yl) pyridin-5-yl) methanol: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8, 62 (dd, J = 4.8,
1.6 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 7.6, 4.8 Hz, 1H), 6.99 (dd, J = 8.0, 6.5 Hz, 1H), 6.07 (t, J = 7.6 Hz, 1H), 4.67 (d, J = 7.6 Hz, 2H), 4.58 (sep, J = 6.7 Hz, 1H), 1.60 (d, J =
6.7 Hz, 1H). LRMS (M + H ⁺ ) m / z 218.1.
Step 7:

HCl [00202] In (2- (1-iospropyl-1H-pyrazol-5-yl) pyridin-3-yl) methanol (560 mg, 2.58 mmol) in DCM (10 mL) SOCl ₂ (3, 0 mL) in rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried in vacuo to produce 3- (chloromethyl) -2- (1-isopropyl-1H-pyrazol-5-yl) pyridine hydrochloride (700 mg) as an off-white solid, which was used to next step without further purification.
Step 8:
[00203] A mixture of 5-hydroxy-2-methoxybenzaldehyde (395 mg, 2.58 mmol, 1 eq.), 3- (chloromethyl) -2- (1-isopropyl-1H-pyrazol5-yl) pyridine hydrochloride ( 700 mg, 2.58 mmol, 1 eq.) And K ₂ CO ₃ (1.4 g, 10.32 mmol, 4 eq.) In DMF (10.0 ml) was heated to 70 ° C for 2 h. The mixture was
88/108 cooled, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to produce 5 - ((2- (1isopropyl-1H-pyrazol-5-yl) pyridin-3-yl) methoxy) - 2-methoxybenzaldehyde (590 mg, 65%) as an off-white solid.
HCI

[00204] 5 - ((2- (1-isopropyl-1 H-pyrazol-5-yl) pyridin-3-yl) methoxy) -2 methoxybenzaldehyde (980 mg, 2.78 mmol, 1 eq.) In solution HCl (6 N, 9.2 mL, 20 eq.) Was frozen at -78 ° C. The mixture was lyophilized O / N to produce 5 - ((2- (1-isopropyl-1 H-pyrazol-5-yl) pyridin-3-yl) methoxy) -2 methoxybenzaldehyde as a yellow solid.
Example 28. Preparation of 2-bromo-3 - ((2- (1-isopropyl-1H-pyrazol-5yl) pyridin-3-yl) methoxy) benzaldehyde (Compound 49).
[00205] The title compound was prepared according to the procedures described in Example 27.
[00206] ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.46 (s, 2H), 8.77 (d, J = 4.6
Hz, 2H), 8.22 (d, J = 7.9 Hz, 2H), 7.64 (s, 2H), 7.59 (d, J = 7.8 Hz, 2H), 7.47 ( dd, J = 8.0, 4.8 Hz, 2H), 7.37 (t, J = 7.9 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 6, 43 (d, J = 1.0 Hz, 2H), 5.11 (s, 4H), 4.67 (sep, J = 6.6 Hz, 3H), 1.50 (d, J = 6.6 Hz, 11H).
Example 29. Preparation of 2-hydroxy-6 - ((2- (1- (2,2,2-trifluoroethyl) -1Hpyrazol-5-yl) pyridin-3-yl) methoxy) benzaldehyde (Compound 50).
Step 1:
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70% by weight in water
HCl (12 N)
[00207] In (3,3,3-trifluoroethyl) hydrazine (25 g, 50% by weight in water, 153.5 mmol, 1 eq.) In a bottle of RB (250 mL) was added HCl (12 N, 25.6 mL, 307.0 mmol, 2 eq.). The mixture was concentrated to produce (3,3,3-trifluoroethyl) hydrazine dihydrochloride (1.07 g) as a yellow solid. LRMS (M + H) m / z 129.1.
Step 2:

[00208] In (E) -1 - (3 - ((tert-buti Id i meti Isi I i loxy) meti I) pi rid i η-2-yl) -3 (dimethylamino) prop-2-en-1 -one (above crude, 5.91 g, 18.44 mmol, 1 eq.) in EtOH (20 mL) was added (3,3,3trifluoroethyl) hydrazine dihydrochloride (4.13 g, above crude, 22.13 mmol, 1.2 eq.) in rt. The mixture was heated to 80 Ό for 1 h, concentrated and diluted with EtOAc (50 ml) and NaHCO ₃ solution _(sa t) (10 ml). The layers were separated, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na ₂ SO ₄ , concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to produce 3 - ((tert-butyldimethylsilyloxy) methyl) -2- (1 (3,3,3 -trifluoroethyl) -1H-pyrazol-5-yl) pyridine (5.90 g; 86% for 2 steps). LRMS (M + H ⁺ ) m / z 372.2.
Step 3:
90/108

HCl
MeOH [00209] In 3 - ((tert-butyldimethylsilyloxy) methyl) -2- (1- (3,3,3-trifluoroethyl) 1H-pyrazol-5-yl) pyridine (5.91 g, 15.93 mmol) in MeOH (20 ml) HCl (4 N, 8.0 ml) was added. The mixture was stirred at rt for 1 h, concentrated and diluted with EtOAc (50 ml) and NaHCO3 solution (sat) (10 ml). The layers were separated, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to produce (2- (1- (3,3,3trifluoroethyl) -1H-pyrazol-5-yl) pyridin-3-yl) methanol (4.1 g, quantitative yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.54 (dd, J =
4.7, 1.5 Hz, 1H), 7.92 (dd, J = 7.9, 1.2 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7, 30 (dd, J = 7.8, 4.8 Hz, 1H), 6.50 (d, J = 1.9 Hz, 1H), 5.09 (q, J =
8.6 Hz, 2H), 4.63 (s, 2H), 1.76 (s, 1H). LRMS (M + H ⁺ ) m / z 272.1
Step 4:

HCl [00210] In (2- (1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl) pyridin-3yl) methanol (408 mg, 1.59 mmol) in DCM (5 mL) was SOCl ₂ (1.5 ml) is added in rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to produce 3- (chloromethyl) -2- (1- (2,2,2-trifluoroethyl) hydrochloride)
91/108
1H-pyrazol-5-yl) pyridine (498 mg) as an off-white solid, which was used for the next step without further purification. Step 5:
OH [00211] A mixture of 2,6-dihydroxybenzaldehyde (438 mg, 11.47 mmol, 2 eq.) And K ₂ CO ₃ (2.4 g, 17.22 mmol, 3 eq.) In DMF ( 150 ml) was stirred at rt for 10 min. To this mixture was added 3- (chloromethyl) -2- (1- (2,2,2-trifluoroethyl) -1 H-pyrazol-5-yl) pyridine (498 mg, 1.59 mmol, 1 eq. ) in rt. The mixture was heated to 50 ° C for 2 h, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as the eluent to produce 2-hydroxy-6 - ((2- (1 (2,2,2- trifluoroethyl) -1H-pyrazol-5-yl) pyridin-3-yl) methoxy) benzaldehyde (338.4 mg, 56%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.99 (s, 1H), 10.41 (s, 1H), 8.76 (dd, J = 4.7, 1.6 Hz, 1H), 8 , 01 (dd, J = 7.9, 1.4 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.49 - 7.39 (m, 2H), 6, 61 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 1.9 Hz, 1H), 6.32 (d, J = 8.3 Hz, 1H),
5.30 (q, J = 8.6 Hz, 2H), 5.17 (s, 2H). LRMS (M + H ⁺ ) m / z 378.1 Example 30. Preparation of 2-hydroxy-6 - ((2- (1- (3 _! 3,3-trifluoropropyl) -1Hpyrazol-5-yl) pyridin-3 -yl) methoxy) benzaldehyde (Compound 51).
Step 1:
[00212] In a mixture of benzylhydrazinecarboxylate (5.0 g, 30.3 mmol, 1 eq.) And DIEA (15.0 mL, 90.9 mmol, 3 eq.) In DMF (20 mL)
92/108 3,3,3-trifluoropropyl bromide (10.7 g 60.6 mmol, 2 eq.) Is added in rt. The mixture was heated to 80 ° C for 20 h, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to produce benzyl 2- (3,3,3-trifluoropropyl) hydrazinecarboxylate (4.2 g; 53% ) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 - 7.17 (m, 5H), 6.11 (s, 1H), 5.01 (s, 2H), 4.00 (s, 1H) , 3.00 (dd, J =
12.2, 7.1 Hz, 2H), 2.17 (qt, J = 10.8, 7.3 Hz, 2H). LRMS (M + H ⁺ ) m / z
263.1
Step 2:
Pd / C
EtOH, HCl (12 N)
HCl HCl [00213] In benzyl 2- (3,3,3-trifluoropropyl) hydrazinecarboxylate (1.7 g, 6.49 mmol, 1 eq.) In a mixture of EtOH (30 mL) Pd / C (1 , 0 g) and HCl (12 N, 2.0 ml). The mixture was charged with H ₂ (4.22 kg / cm ² ), stirred at rt for 1 h, filtered and concentrated to produce (3,3,3-trifluoropropyl) hydrazine dihydrochloride (1.07 g) as a solid yellow. LRMS (M + H) m / z 129.1.
Step 3:

[00214] In (E) -1- (3 - ((tert-butyldimethylsilyloxy) methyl) pyridin-2-yl) -3 (dimethylamino) prop-2-en-1-one (raw above, 1.73 g, 5.41 mmol, 1 eq.)
93/108 in EtOH (10 mL) (3,3,3trifluoropropyl) hydrazine dihydrochloride (1.30 g, crude above, 6.49 mmol, 1.2 eq.) Was added in rt. The mixture was heated to 80 ° C for 1 h, concentrated and diluted with EtOAc (50 ml) and NaHCO ₃ solution _(sat) (10 ml). The layers were separated, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to produce 3 - ((tert-butyldimethylsilyloxy) methyl) -2- (1 (3,3,3-trifluoropropyl) -1H-pyrazol-5-yl) pyridine (1.58 g; 76% for 2 steps). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.53 (dd, J = 4.7, 1.6 Hz, 1H), 7.96 7.88 (m, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 7.9, 4.7 Hz, 1H), 6.34 (d, J = 1.9 Hz, 1H), 4.62 (s , 2H), 4.45 - 4.33 (m, 2H), 2.82 - 2.61 (m, 2H), 0.85 (s, 8H), -0.00 (s, 5H). LRMS (M + H ⁺ ) m / z 386.2.
Step 4:
HCl
MeOH
[00215] In 3 - ((tert-butyldimethylsilyloxy) methyl) -2- (1- (3,3,3trifluoropropyl) -1H-pyrazol-5-yl) pyridine (1.58 g, 4.1 mmol) in MeOH (20 ml) HCl (4 N, 4.0 ml) was added. The mixture was stirred at rt for 1 h, concentrated and diluted with EtOAc (50 ml) and NaHCO3 solution (sat) (10 ml). The layers were separated, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4 and concentrated to produce (2- (1 (3,3,3-trifluoropropyl) -1H-pyrazol-5-yl) pyridin-3-yl) methanol (1.1 g, 99% ) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.64 (dd, J = 4.7, 1.7 Hz, 1H), 8.00 (dd, J = 7.9, 1.7 Hz, 1H) , 7.57 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 7.9, 4.8 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 4.69 (s, 2H), 4.51 94/108
4.43 (m, 2H), 2.85 - 2.72 (m, 2H), 2.70 (s, 1H). LRMS (M + H ⁺ ) m / z
272.1.
Step 5:
HCl [00216] In (2- (1- (2,2,2-trifluoropropyl) -1H-pyrazol-5-yl) pyridin-3yl) methanol (140 mg, 0.52 mmol) in DCM (5 mL) was SOCl ₂ (2.0 mL) is added in rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried in vacuo to yield 3- (chloromethyl) -2- (1- (2,2,2trifluoropropyl) -1H-pyrazol-5-yl) pyridine hydrochloride (498 mg) as an almost solid white, which was used for the next step without further purification.
Step 6:
OH
OH [00217] A mixture of 2,6-dihydroxybenzaldehyde (144 mg, 1.04 mmol, 2 eq.) And K ₂ CO ₃ (214 mg, 1.56 mmol, 3 eq.) In DMF (20 mL ) was stirred at rt for 10 min. To this mixture was added 3- (chloromethyl) -2- (1- (2,2,2-trifluoropropyl) -1 H-pyrazol-5-yl) pyridine (168 mg, 0.52 mmol, 1 eq. ) in rt. The mixture was heated at 50 ° C for 2 h, filtered and concentrated on RP-HPLC (Gemini 21.2 x 150 mm) using a mixture of CH3CN and water as the eluent to produce 2-hydroxy-6 - ((2- (1- (3,3,3-trifluoropropyl) -1H-pyrazol-5-yl) pyridin-3yl) methoxy) benzaldehyde (53.5 mg, 26%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.98 (s, 1H), 10.38 (s, 1H), 8.77 (dd, J = 4.7, 1.6 Hz, 1H), 8 , 01 (dd, J = 7.9, 1.6 Hz, 1H), 7.61 (d, J = 1.9 Hz,
95/108
1H), 7.49 - 7.39 (m, 2H), 6.61 (d, J = 8.5 Hz, 1H), 6.44 (d, J = 1.9 Hz, 1H), 6, 34 (d, J = 8.2 Hz, 1H), 5.15 (s, 2H), 4.56 (dd, J = 8.3, 6.7 Hz, 2H), 3.02 - 2.72 (m, 2H). LRMS (M + H ⁺ ) m / z 392.1.
Example 31. Preparation of Benzaldehyde Derivatives.
[00218] Compounds 52-55 were prepared according to the methods described above.
[00219] 2-Fluoro-6 - ((2- (1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl) pyridin-3yl) methoxy) benzaldehyde (Compound 52). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.51 (s, 1H), 8.74 (dd, J = 4.7, 1.6 Hz, 1H), 8.21 (dd, J = 7, 9, 1.6 Hz, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.54 - 7.41 (m, 2H), 6.82 (dd, J = 10.0 ,
8.6 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 1.9 Hz, 1H), 5.28 (q, J = 8.6 Hz , 2H), 5.20 (s, 2H).
[00220] 2-Fluoro-6 - ((2- (1- (3,3,3-trifluoropropyl) -1H-pyrazol-5-yl) pyridin-
3-yl) methoxy) benzaldehyde (Compound 53). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.50 (s, 1H), 8.75 (dd, J = 4.7, 1.6 Hz, 1H), 8.22 (dd, J = 7, 9, 1.6 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.54 - 7.42 (m, 2H), 6.83 (dd, J = 10.0 ,
8.7 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.46 (d, J = 1.9 Hz, 1H), 5.19 (s, 2H), 4.59 - 4.51 (m, 2H), 2.96 - 2.76 (m, 2H).
[00221] 2-Fluoro-6 - ((2- (1-isopropyl-1H-pyrazol-5-yl) pyridin-3yl) methoxy) benzaldehyde (Compound 54). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.41 (s, 1H), 8.66 (dd, J = 4.7, 1.6 Hz, 1H), 8.13 (dd, J = 7, 9, 1.4 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.46 - 7.29 (m, 2H), 6.72 (dd, J = 10.0 ,
8.7 Hz, 1H), 6.59 (d, J = 8.5 Hz, 1H), 6.29 (d, J = 1.8 Hz, 1H), 5.03 (s, 2H), 4 , 56 (sep, J = 6.7 Hz, 1H), 1.40 (d, J = 6.6 Hz, 6H).
Example 32 Preparation of 1- (2-formyl-3-hydroxyphenethyl) piperidine-
4- carboxylic (Compound 55).
96/108

[00222] In a solution of 2-bromo-6-hydroxybenzaldehyde (3.8 g, 18.91 mmol, 1 eq.) In a mixture of THF and MeOH (4/1, 25 mL) was added NaBH ₄ (1 , 4 g, 37.81 mmol, 1.5 eq.) In rt in portions. Upon completion of the addition, the mixture continued to stir at rt for 30 min. The mixture was quenched with HCI (4 N) and extracted with EtOAC twice. The combined organic layer was dried over Na ₂ SO ₄ , concentrated and purified on silica gel using 25% EtOAc / hexanes as the eluant to produce 3-bromo-2- (hydroxymethyl) phenol (2.3 g, 60%) as a colorless oil.

[00223] In 3-bromo-2- (hydroxymethyl) phenol (2.3 g, 11.3 mmol, 1 eq.) In acetone (20.0 ml) 2,2-dimethoxypropane (6.0 ml) was added , PTSA (215 mg, 1.13 mmol, 0.1 eq.) And Na ₂ SO ₄ (5.0 g). The mixture was heated to 40 Ό O / N, cooled to rt and diluted with EtOAc.
[00224] The organic layer was washed with NaHCO ₃ solution _(sa t) and brine, dried over Na ₂ SO ₄ , concentrated and purified on silica gel using a mixture of EtOAc and hexanes to produce 5-bromo-2,2-dimethyl- 4H-benzo [d] [1,3] dioxin (2.1 g, 76%) as a colorless oil. ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.13 (dd, J = 8.0, 1.2 Hz, 1H), 7.07 (t, J = 8.0
97/108
Hz, 1H), 6.81 (dd, J = 8.0, 1.2 Hz, 1H), 4.77 (s, 2H), 1.56 (s, 6H).
Pd ₂ (dba) ₃ / Q-Phos
ZnCI (CH ₂ CO ₂ tBu) (0.5M / _ether )
[00225] In a mixture of 5-bromo-2,2-dimethyl-4Hbenzo [d] [1,3] dioxin (2.1 g, 8.64 mmol, 1 eq.), Pd ₂ (dba) ₃ ( 400 mg, 0.43 mmol, 0.05 eq.), Q-Phos (460 mg, 0.65 mmol, 0.075 mmol) in THF (100 mL) purged with N ₂ for 10 min ZnCI (CH ₂ CO ₂ ^f Bu) (0.5 M / ether, 35 ml, 17.38 mmol, 2 eq.). The mixture was heated to 50 Ό for 16 h, cooled in rt, NH ₄ CI solution _(sa t) was added and diluted with EtOAc. The organic layer was separated, dried over Na ₂ SO ₄ , concentrated and purified on silica gel using a mixture of EtOAc and hexanes to produce tert-butyl 2- (2,2-dimethyl-4Hbenzo [d] [1,3] dioxin -5-yl) acetate (2.6 g, 80% pure, 87%) as a brown oil. ¹ H NMR (400 MHz, CDCI3) 8 7.06 (t, J = 7.9 Hz, 1H), 6.73 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 4.78 (s, 2H), 1.47 (s, 6H), 1.36 (s, 9H).

[00226] In a solution of tert-butyl 2- (2,2-dimethyl-4Hbenzo [d] [1,3] dioxin-5-yl) acetate (2.6 g, 80% pure 9.34 mmol, 1 eq.) in THF (20 ml) LiBH ₄ (7.0 ml, 14.01 mmol, 1.5 eq.) and MeOH (1.0 ml) were added in rt. The mixture was stirred at rt for 30 min, added MeOH (20 ml), concentrated to dryness, added MeOH (20 ml) and silica gel and concentrated to dryness again. The mixture was directly loaded onto silica gel for purification using a
98/108 mixture of EtOAc and hexanes as eluent to produce 2- (2,2dimethyl-4H-benzo [d] [1,3] dioxin-5-yl) ethanol (1.1 g, 71%) as a brown oil pale. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.28 (t, J = 7.9 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 5.02 (s, 2H), 3.99 (q, J = 6.4 Hz, 2H), 2.86 (t, J = 6.6 Hz, 2H), 1.68 (s, 6H), 1.57 (t, J = 5.5 Hz, 1H).

MsCl, TEA
THF
[00227] In a solution of 2- (2,2-dimethyl-4H-benzo [d] [1,3] dioxin-5yl) ethanol (400 mg, 1.92 mmol, 1 eq.) In THF (20 mL ) MsCl (438 mg, 3.84 mmol, 2.0 eq.) and TEA (0.8 mL, 5.76 mmol, 3.0 eq.) were added in rt. The mixture was stirred at rt for 1 h and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and concentrated to produce 2- (2,2-dimethyl-4Hbenzo [d] [1,3] dioxin-5-yl) ethyl methanesulfonate (400 mg, raw) as a pale brown oil, which was used for the next step without purification.

[00228] In 2- (2,2-dimethyl-4H-benzo [d] [1,3] dioxin-5-yl) ethyl methanesulfonate (176 mg, 0.59 mmol, crude above, 1 eq.) In DMF (1.0 ml) ethyl piperidine-4-carboxylate (186 mg, 1.18 mmol, 2.0 eq.) Was added in rt. The mixture was stirred at 60 ° C for 2 h, cooled in rt and purified on RP-HPLC (Gemini 21.2 mm x 150 mm) using a mixture of CH ₃ CN and water (0.1% HCOOH) as eluant to produce 199/108 ethyl (2- (2,2-dimethyl-4H-benzo [d] [1,3] dioxin-5-yl) ethyl) piperidine-4-carboxylate (100 mg, 49% for two steps) . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 7.13 (t, J = 7.9 Hz, 1H), 6.73 (d, J = 7.9 Hz, 2H ), 4.86 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.22 (s, 2H), 3.09 - 2.95 (m, 1H), 2 , 95 - 2.79 (m, 4H), 2.76 (s, 1H), 2.66 - 2.48 (m, 1H), 2.23 - 1.99 (m, 4H), 1.55 (s, 6H), 1.29 (t, J = 7.1 Hz, 3H). LRMS (M + H ⁺ ) m / z 348.1.
Ethyl HCl / THF
[00229] On
1- (2- (2,2-dimethyl-4H-benzo [d] [1,3] dioxin-5yl) ethyl) piperidine-4-carboxylate (100 mg, 0.49 mmol, 1 eq.) In THF ( 10 ml) HCl (6 N, 10 drops) and water (1.0 ml) were added in rt. The mixture was stirred at 60 ° C for 2 h, cooled and basified with NaHCO3 solution (sat.). The mixture was filtered and concentrated. The residue was taken up in THF (10 ml) and filtered. The filtrate was concentrated to produce ethyl 1- (3-hydroxy-2- (hydroxymethyl) phenethyl) piperidine-4carboxylate (85 mg, crude) as a pale brown oil, which was used for the next step without purification. LRMS (M + H ⁺ ) m / z 308.1.
MnO ₂
THF
[00230] In ethyl 1- (3-hydroxy-2- (hydroxymethyl) phenethyl) piperidine-4 carboxylate (85 mg, crude above) in THF (20.0 mL) MnO2 (500 mg, 5.75 mmol) was added in rt. The mixture was stirred at rt for 1 h, fil100 / 108 filtered and concentrated to produce ethyl 1- (2-formyl-3hydroxyphenethyl) piperidine-4-carboxylate (80 mg, raw) as a pale brown solid, which was used for next step with purification. LRMS (M + H ⁺ ) m / z 306.1.
NaOH (3N)
THF
[00231] In ethyl 1- (2-formyl-3-hydroxyphenethyl) piperidine-4-carboxylate (80 mg, crude above) in THF (5.0 ml) NaOH (3 N, 1.0 ml) was added. The mixture was stirred at rt for 2 h and acidified to pH 3-4 using HCl (2 N). The mixture was concentrated and purified on RP-HPLC (Gemini 21.2 mm x 150 mm) using a mixture of CH ₃ CN and water (0.1% HCOOH) as eluent to produce 1- (2-formyl-3hydroxyphenethyl acid) ) piperidine-4-carboxylic (40 mg, 29% for three steps) as a yellow solid. ¹ H NMR (400 MHz, DMSO) δ 10.26 (s, 1H), 8.65 (s, 2H), 6.91 (dd, J = 8.7, 6.9 Hz, 1H), 6, 16 (d, J = 7.9 Hz, 1H), 5.76 (d, J = 6.7 Hz, 1H), 3.01 - 2.89 (m, 4H), 2.50 - 2.36 (m, 2H), 2.03 (t, J = 10.3 Hz, 2H), 1.92 - 1.76 (m, 3H), 1.69 - 1.49 (m, 2H). LRMS (M + H ⁺ ) m / z 278.4. ¹ H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.55 (s, 2H), 6.75 (dd, J = Hz, 1H), 6.05 (d, J = Hz, 1H), 5.6 (d, J = Hz, 1H),
2.7 (m, 4H), 2.3 (m, 2H), 1.85 (m, 2H), 1.7 (m, 3H), 1.5 (m, 2H).
IN VITRO TEST
Example 33. Hemoglobin Oxygen Affinity Modulation for Substituted Benzaldehyde Compounds - Assay Procedure.
[00232] The oxygen balance (OEC) curves in purified hemoglobin S (HbS) were measured by the change in p50, the partial pressure of oxygen at which the heme binding sites in the HbS sample are 50% saturated with oxygen. HbS was purified by a pro
101/108 modified disposal (Antonini and Brunori, 1971; Heomoglobin and Myoglobin in their Reactions with Ligands; North Holland Publishing Company; Amsterdam, London) of blood obtained from patients with homozygous sickle cell by the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI ) with approval from the Institutional Review Board. Oxygen balance curves were performed with a HEMOX analyzer, (TCS Scientific, New Hope, PA). Five hundred pL of 250 μΜ of purified HbS was diluted in
4.5 mL of HEMOX buffer (30 mM TES, 130 mM NaCl, 5 mM KCl, pH = 7.4) resulting in a hemoglobin concentration of 25 μM. The compounds were added to the final desired concentrations. The mixture was incubated for 45 min at 37 ° C, and then transferred to the Hemox sample chamber. The samples were saturated with oxygen and stimulated with compressed air for 10 minutes. The samples were then stimulated with pure nitrogen and the absorbance of deoxy-Hb was recorded as a function of the pO ₂ solution. The oxygen balance data were then adjusted to the Hill Model to obtain values for p50. Deoxygenation curves equally for HbS alone (control) and HbS in the presence of the compound were collected with the TCS software. The p50 for purified Hbs was typically 13.8 + 1.6. Delta p50 values were obtained from the p50 value for control minus the p50 value for HbS treated with compound divided by the p50 value for control. A positive delta p50 value corresponds to a shifted curve on the left and a lower p50 value compared to the control, indicating that the compounds act to modulate HbS to increase its affinity for oxygen.
Example 34. Hemoglobin Oxygen Affinity Modulation for Substituted Benzaldehyde Compounds - Test Results. [00233] The compounds in Table 1 that were tested in the assay
102/108 above were all found to have positive p50 delta values. The% delta p50 is calculated from [[50 (HbS) - p50 (compound-treated HbS)] / p50 (HbS)] X 100. Table 2 below lists the% of the delta p50 values where + indicates a delta p50% between 0 and 29 and ++ indicates a delta p50% of 30 or greater. Unless otherwise noted, the compounds in Table 2 were tested at 30 μΜ.
Table 2. Delta p50
Compound Delta p50 1 ++ 2 + 3 + (100 μΜ) 4 + 5 ++ 6 + (100 μΜ) 7 ++ 8 + 9 + 10 ++ 11 + 12 + (100 μΜ) 13 + 14 + 15 + (100 μΜ) 16 + 21 + (100 μΜ) 23 ++ 24 ++ 25 ++ 33 + (100 μΜ) 34 + 35 + 37 + 38 ++ (100 μΜ) 39 + (100 μΜ) 40 + 4142434445
103/108
Example 35. Polymerization test.
[00234] Polymerization tests are performed in vitro using purified HBS exchanged in 1.8 M of potassium phosphate buffer at pH 7.4. Using a slightly modified protocol (Antonini and Brunori, 1971), HbS is purified by CRO VIRUSYS, from blood obtained from patients with homozygous sickle cell by the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with approval from the Institutional Review Board. The compounds are prepared in 100% DMSO and a desired amount is added to 50 μΜ of purified HBS in a final DMSO concentration of 0.3%. The final potassium phosphate concentration is adjusted to 1.8 M using a combination of 2.5 M of potassium phosphate raw material solution and water at pH 7.4. The reaction mixture is incubated for one hour at 37 ° C, and then transferred to a 24 well plate for deoxygenation in a glove box containing 99.5% nitrogen and 0.5% oxygen. The 24-well plate is not covered and incubated at 4 ° C in a plate cooler inside the glove box for an hour and a half. Fifty μΐ of the reaction mixture is transferred in a 96-well plate, and the absorbance at 700 nm is measured every minute for one hour at 37 ° C in a plate reader located inside the glove box. A plot of absorbance in relation to time is adjusted using a sigmoidal Boltzman adjustment, and the delay time (from zero to time in almost Vmax) is measured. To compare and classify compounds, delay times are expressed as the percentage of delay (% DT) which is defined as the difference in delay times by HBS / compound and HBS alone multiplied by 100 and divided by the delay time for HBS alone.
[00235] The compounds listed below were tested in the polymerization test. Activity ranges are defined by the number of
104/108 cross symbols (t) indicated. t denotes activity> 40% but <80%; tt denotes activity> 80% but <120%; ttt denotes activity> 120% but <140%; fttt denotes activity> 160%.
Compound Delta% Delay 42 tt 43 tt 44 t 45 tt 46 t 47 tt 48 t 49 t
Example 36. R / T assay [00236] A relaxed-to-tension transition assay (R / T assay) was used to determine the ability of the substituted benzaldehyde compounds to maintain the relaxed (R) high affinity state of hemoglobin oxygen under deoxygenated conditions. This ability can be expressed as a delta R value (that is, the change in the time period of the R state after hemoglobin is treated with a compound, compared to the period without treatment with the comound). Delta R is the% R to remain after treatment of the compounds compared to the untreated (for example, if R% without treatment is 8% while with treatment with a target compound it is 48% R at 30 μΜ, then% R is 40% for that compound.
[00237] A mixture of HbS / A was purified from blood obtained from patients with homozygous sickle cell by the Hemoglobinopaty Center at Childreris Hospital Oakland Research Institute (CHORI) with approval from the Institutional Review Board. HbS / A (at a final concentration of 3 μΜ) was incubated for 1 hr at 37 ° C in the presence or absence of compounds in 50 μΜ of phosphate buffer of
105/108 potassium, pH = 7.4 and 30 μΜ of 2.3 diphosphoglycerate (DPG) in 96-well plates in a final volume of 160 μΚ The compounds were added in different concentrations (final concentrations from 3 μΜ to 100 μΜ ). The plates were coated with a Mylar film. After the incubation was completed, the Mylar cover was removed, and the plates were placed in a Spectrostar Nano plate reader previously heated to 37 ° C. Five minutes later, N ₂ (flow rate = 20 L / min) was circulated by the spectrophotometer. Spectroscopic measurements (300 nm to 700 nm) were taken every 5 min for 2 hours. Data analysis was performed using linear regression from the recovered data for all wavelengths.
[00238] Table 4 below lists delta R values where + indicates a delta R between 0 and 30, ++ indicates a delta R between 30 and 50, and +++ indicates a delta R of 50 or greater. Unless otherwise noted, the compounds in Table 2 were tested at 9 μΜ.
Table 3. delta R
Compound delta R(%) 5 ++ 10 ++ 24 + 25 ++ 41 + 42 +++(30 μπ) 43 +++(30 μm) 44 +++ 45 +++
106/108
Example 37. Whole Blood Assay [00239] Oxygen Equilibrium (OEC) curves of whole blood before and after treatment with different concentrations of substituted benzaldehyde compounds were performed as follows using a HEMOX analyzer (TCS Scientific, New Hope, PA ). Blood samples from patients with homozygous sickle cell were obtained by the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with approval from the Institutional Review Board. The hematocrit was adjusted to 20% using autologous plasma and blood samples were incubated for 1 hour at 37 ° C in the absence or presence of compounds. 100 pl of these samples were added in 5 mL of Hemox buffer (30 mM TES, 130 mM NaCl, 5 mM KCl, pH = 7.4) at 37 ° C, and then transferred to a Hemox sample chamber . The samples were saturated with oxygen and stimulated with compressed air for 10 minutes. The samples were then stimulated with pure nitrogen, and the respective absorbances of oxi- and deoxy-Hb are recorded as a function of pO2 solution. The oxygen balance data were then adjusted to the Hill Model to obtain values for p50. Deoxygenation curves equally for whole blood only (control) and whole blood in the presence of the compound were collected using the TCS software.
[00240] Table 5 below lists the delta p50% values where + indicates a delta p50% between 0 and 29, ++ indicates a delta p50% between 30 and 50, and +++ indicates a delta p50% of 50 or bigger. The compounds in Table 2 were tested at 1000 pM. A positive delta p50 value corresponds to a shifted curve on the left and a lower p50 value compared to the control, indicating that the compound acts to modulate HbS to increase its affinity for oxygen.
Table 4. Delta values p50% for Whole Blood Assay
107/108
Compound delta p50% 42 + 43 +++ 44 + 45 +
Example 38. Pharmacokinetic Study of Compound 43 (HCl salt)
IV STUDY [00241] Sprague Dawley rats were treated with 7.8 mg / kg of Compound 43 dissolved in 10% DMA: 50% PEG: 16% approx. of vitron. At specified time points, 10 μL of whole blood / plasma were removed from rats and treated with 490 μl of pH 3 buffer + 500 μL of ACN / IS, then stirred for 1 hour, centrifuged for 10 minutes at 57 rpm at 4 ^o C. The supernatant was transferred to a filter plate and centrifuged at 2000 rpm for 1 minute at 4 ^o C. The samples were then analyzed by LC-MS / MS monitoring the source aldehyde. Blood and plasma concentrations are shown in Table 5. Fundamental P / K parameters are shown in Table 6.
Table 5
Compound 43 7.8mpk IV in ratconc. of blood (uM) Conc. plasma (uM) time (min) THE B Ç THE B Ç 0 BLLOQ BLLOQ BLLOQ BLLOQ BLLOQ BLLOQ 5 259 246 281 7.56 8.68 7.44 15 287 341 285 8.38 8.42 7.16 30 283 333 292 no sample 8.66 7.1 60 256 203 285 6.12 7.52 7.22 120 263 274 280 3.92 6.02 5.22 240 248 225 259 3.72 5.24 5.88 480 118 136 22.9 2.06 2.66 3.15 1440 81.1 85 70.8 1.07 1.38 1.51
108/108
Table 6
Compound 43 7.8mpk IV in rat Blood Plasma t1 / 2 beta min 749.0 619.1 CL ml / min / kg 0.08 4.45 Vss L / kg 0.09 4.11 AUClast min * umol / L 215846.3 4114.8
ORAL STUDY [00242] SD rats were treated by gavage with 44 mg / kg and 100 mg / kg dissolved in 10% DMA: 90% PEG. At specified time points, blood was drawn and prepared as described above in Study IV. Fundamental parameters are shown in Table 7.
Table 7
Compound 43: 2 PO in rats Blood Plasma relationship relationship dose mg / kg 44 100 2.27 44 100 2.27 Tmax min 320.00 720.00200.00 680.00Cmax umol / L 381.33 1096.67 2.88 14.79 44.53 3.01 AUClast min * umol / L 395638.27 1384,101.11 3.50 12517.54 52836.17 4.22
[00243] All patents, patent applications, publications and presentations referred to herein are incorporated by reference in their entirety. Any conflict between any reference cited here, and the teaching of this specification must be resolved in favor of the latter. Similarly, any conflict between a definition recognized in the technique of a word or phrase and a definition of the word or phrase as provided in this specification must be resolved in favor of the latter.

权利要求:
Claims (7)
[1]
1. Compound, characterized by the fact that it presents the formula:
or a pharmaceutically acceptable salt thereof.
[2]
2. Compound according to claim 1, characterized by the fact that it is:
[3]
3. Pharmaceutical composition, characterized in that it comprises a compound, as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
[4]
4. Pharmaceutical composition according to the claim
3, characterized by the fact that the compound is
[5]
5. Use of a compound, as defined in claim 1 or 2, characterized by the fact that it is for the preparation of a drug for the treatment of sickle cell disease.
[6]
6. Compound according to claim 1 or 2, characterized by the fact that it is for use in the treatment of sickle cell disease.
Petition 870180157459, of 11/30/2018, p. 5/10
2/2
[7]
7. Pharmaceutical composition according to the claim
3 or 4, characterized by the fact that it is for the treatment of sickle cell disease.

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法律状态:
2017-07-18| B25G| Requested change of headquarter approved|Owner name: GLOBAL BLOOD THERAPEUTICS, INC. (US) , CYTOKINETIC |

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2017-08-01| B25A| Requested transfer of rights approved|Owner name: GLOBAL BLOOD THERAPEUTICS, INC. (US) , THE REGENTS |

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2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-08-28| B25G| Requested change of headquarter approved|Owner name: GLOBAL BLOOD THERAPEUTICS, INC. (US) ; THE REGENTS OF THE UNIVERSITY OF CALIFORNIA (US) Owner name: GLOBAL BLOOD THERAPEUTICS, INC. (US) ; THE REGENTS |

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2018-12-11| B65X| Notification of requirement for priority examination of patent application|

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2019-01-15| B65Y| Grant of priority examination of the patent application (request complies with dec. 132/06 of 20061117)|

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2019-03-19| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-05-14| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2019-06-11| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 28/12/2012, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 28/12/2012, OBSERVADAS AS CONDICOES LEGAIS |

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2020-11-03| B25G| Requested change of headquarter approved|Owner name: GLOBAL BLOOD THERAPEUTICS, INC. (US) ; THE REGENTS OF THE UNIVERSITY OF CALIFORNIA (US) |

优先权:

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申请号 | 申请日 | 专利标题

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US201161581053P| true| 2011-12-28|2011-12-28|

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US61/581,053|2011-12-28|

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US201261661320P| true| 2012-06-18|2012-06-18|

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US61/661,320|2012-06-18|

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PCT/US2012/072177|WO2013102142A1|2011-12-28|2012-12-28|Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation|

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