OA17478A - Compounds and uses thereof for the modulation of hemoglobin. - Google Patents

Abstract

Provide herein are compounds and pharmaceutical compositions suitable as modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.

Description

COMPOUNDS AND USES THEREOF FOR THE MODULATION OF HEMOGLOBIN

FIELD OFTHE INVENTION

[0001] This invention provides compounds and pharmaceutical compositions suitable as allosteric modulators of hemoglobin, methods and intermediates for their préparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygénation.

STATE OF THE ART

[0002] Sickle cell disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent. The basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prévalent peptide sequence of hemoglobin (Hb).

[0003] Hemoglobin (Hb) transports oxygen molécules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through conformational changes. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing HbS to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. US 7,160,910 discloses compounds that are allosteric modulators of hemoglobin. However, a need exists for additional therapeutics that can treat disorders that are mediated by Hb or by abnormal Hb such as HbS.

SUMMARY OF THE INVENTION

[0004] This invention relates generally to compounds and pharmaceutical compositions suitable as allosteric modulators of hemoglobin. In some aspects, this invention relates to 25 methods for treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygénation.

[0005] In certain aspects ofthe invention, a compound of Formula (A) is provided:

(A) or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein ring A is an optionally substituted 5-10 membered heteroaryl containing up to 3 ring N, O, and/or S atoms, and oxidized forms of N and/or S atoms;

wherein ring A is a or β substituted relative to the Y substituent;

ring B is an optionally substituted C₆-Ci₀ aryl or 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;

each Y and Z is independently CR^1OR^1X, O, S, SO, SO2, or NR¹²; each R¹⁰ and R¹¹ independently is hydrogen or Ci-C3 alkyl, optionally substituted with halo, OH, or alkoxy, or CR^XOR^XX is C=O; R¹² is hydrogen or Ci-C₆ alkyl; provided that if one of Y and Z is O, S, SO, SO₂, then the other is not CO, and provided that Y and Z are both not heteroatoms or oxidized forms thereof;

ring C is C₆-C₁₀ aryl, optionally subtituted;

V¹ and V² independently are Ci-C₆ alkoxy; or V¹ and V² together with the carbon atom they are attached to form a ring of formula:

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³ and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is or 2; each V⁵ is independently Ci-C₆ alkyl or CO₂R⁶⁰, where each R⁶⁰ independently is C_rC6 alkyl or hydrogen; t is 0,1, 2, or 4; or CV¹)/² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁸⁰ is optionally substituted Ci-C₆ alkyl;

R⁸¹ and R⁸² independently are selected from the group consisting of hydrogen, optionally substituted Ci-C₆ alkyl, COR⁸³, or CO2R⁸⁴;

R⁸³ is hydrogen or optionally substituted Ci-C₆ alkyl; and

R⁸⁴ is optionally substituted Ci-C₆ alkyl.

[0006] In one embodiment, thecompound provided is of formula (I):

-J-..

/ \^xCV¹V²H (r⁶)_p-----· c :

( OR⁵ (D wherein

R⁵ is hydrogen, Ci-C₆ alkyl or a prodrug moiety R, wherein the Ci-Ce alkyl is optionally substituted with 1-5 halo;

R⁶ is a substituent that is halo, Ci-C₆ alkyl, Ci-C₆ alkoxy, Ci-C₆ alkylthio, Ci-C₆ S(O)-, C_r C₆ S(O)₂-, wherein the C_rC₆ alkyl is optionally substituted with 1-5 halo; or

R⁶ is 4-10 membered cycloalkyl or heterocycle substituted with an R'R'N- moiety wherein each R' is independently C_rC6 alkyl or hydrogen;

k is 0 or 1; and p is 0,1, 2, or 3.

and the remaining variables are defined as above.

[0007] In further aspects ofthe invention, a composition is provided comprising any ofthe compounds described herein, and at least a pharmaceutically acceptable excipient.

[0008] In still further aspects ofthe invention, a method is provided for increasing oxygen affinity of hemoglobin S in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

[0009] In further aspects ofthe invention, a method is provided for treating oxygen deficiency associated with sickle cell anémia, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

DETAILED DESCRIPTION OF THE INVENTION

Définitions

[0010] It must be noted that as used herein and in the appended claims, the singular forms a, an, and the include plural referents unless the context clearly dictâtes otherwise. Thus, for example, reference to a solvent includes a plurality of such solvents. [0011] As used herein, the term comprising or comprises is intended to mean that the compositions and methods include the recited éléments, but not excluding others. Consisting essentially of when used to define compositions and methods, shall mean excluding other éléments of any essential significance to the combination for the stated purpose. Thus, a composition or process consisting essentially ofthe éléments as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) ofthe claimed invention. Consisting of shall mean excluding more than trace éléments of other ingrédients and substantial method steps. Embodiments defined by each of these transition terrns are within the scope of this invention.

[0012] Unless otherwise indicated, ail numbers expressing quantifies of ingrédients, reaction conditions, and so forth used in the spécification and claims are to be understood as being modified in ail instances by the term about. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following spécification and attached

claims are approximations. Each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. The term about when used before a numerical désignation, e.g., température, time, amount, and concentration, including range, indicates approximations which may vary by ( + ) or ( - ) 10 %, 5 % or 1 %.

[0013] As used herein, C_m-C_n, such as C1-C12, Ci-C₈, or Ci-Cô when used before a group refers to that group containing m to n carbon atoms.

[0014] The term alkoxy refers to -O-alkyl. The term alkylthio refers to -S-alkyl.

[0015] The term alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 30 carbon atoms (i.e., Ci-C₃₀ alkyl) or 1 to 22 carbon atoms (i .e., Ci-C₂₂ alkyl), 1 to 8 carbon atoms (i.e., Ci-C₈ alkyl), or 1 to 4 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH₃-), ethyl (CH3CH2-), n-propyl (CH₃CH₂CH₂-), isopropyl ((CH₃)₂CH-), n-butyl (CH₃CH₂CH₂CH₂-), isobutyl ((CH₃)₂CHCH₂-), sec-butyl ((CH₃)(CH₃CH₂)CH-), t-butyl ((CH₃)₃C-), n-pentyl (CH₃CH₂CH₂CH2CH₂), and neopentyl ((CH₃)₃CCH₂-).

[0016] The term aryl refers to a monovalent, aromatic mono- or bicyclic ring having 6-10 ring carbon atoms. Examples of aryl include phenyl and naphthyl. The condensed ring may or may not be aromatic provided that the point of attachment is at an aromatic carbon atom. For example, and without limitation, the following is an aryl group:

[0017] The term -CO₂H ester refers to an ester formed between the -CO₂H group and an alcohol, preferably an aliphatic alcohol. A preferred example included -CO2R^E, wherein R^E is alkyl or aryl group optionally substituted with an amino group.

[0018] The term chiral moiety refers to a moiety that is chiral. Such a moiety can possess one or more asymmetric centers. Preferably, the chiral moiety is enantiomerically enriched, and more preferably a single enantiomer. Non limiting examples of chiral moieties include chiral carboxylic acids, chiral amines, chiral amino acids, such as the naturally occurring amino acids, chiral alcohols including chiral steroids, and the likes.

[0019] The term cycloalkyl refers to a monovalent, preferably saturated, hydrocarbyl mono-, bi-, or tricyclic ring having 3-12 ring carbon atoms. While cycloalkyl, refers preferably to saturated hydrocarbyl rings, as used herein, it also includes rings contaîning 12 carbon-carbon double bonds. Nonlimiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamentyl, and the like. The condensed rings may or may not be non-aromatic hydrocarbyl rings provided that the point of attachment is at a cycloalkyl carbon atom. For example, and without limitation, the following is a cycloalkyl group:

[0020] The term halo refers to F, Cl, Br, and/or I.

[0021] The term heteroaryl refers to a monovalent, aromatic mono-, bi-, or tricyclic ring having 2-16 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 5 ring atoms. Nonlimiting examples of heteroaryl include furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the like. The condensed rings may or may not be a heteroatom contaîning aromatic ring provided that the point of attachment is a heteroaryl atom. For example, and without limitation, the following is a heteroaryl group:

[0022] The term heterocyclyl or heterocycle refers to a non-aromatic, mono-, bi-, or tricyclic ring contaîning 2-12 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 3 ring atoms. While heterocyclyl preferably refers to saturated ring Systems, it also includes ring Systems contaîning 1-3 double bonds, provided that the ring is non-aromatic. Nonlimiting examples of heterocyclyl include, azalactones, oxazoline, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl. The condensed rings may or may not contain a non-aromatic heteroatom contaîning ring

provided that the point of attachment is a heterocyclyl group. For example, and without limitation, the following is a heterocyclyl group:

[0023] The term hydrolyzing refers to breaking an R^H-O-CO-, R^H-O-CS-, or an R^H-O-SO₂5 moiety to an R^h-OH, preferably by adding water across the broken bond. A hydrolyzing is performed using various methods well known to the skilled artisan, non limiting examples of which include acidic and basic hydrolysis.

[0024] The term oxo refers to a C=O group, and to a substitution of 2 geminal hydrogen atoms with a C=O group.

[0025] The term optionally substituted refers to a substituted or unsubstituted group.

The group may be substituted with one or more substituents, such as e.g., 1, 2, 3, 4 or 5 substituents. Preferably, the substituents are selected from the group consisting of oxo, halo, -CN, NO₂, -N₂+, -CO₂R¹⁰⁰, -OR¹⁰⁰, -SR¹⁰⁰, -SOR¹⁰⁰, -SO2R¹⁰⁰, -NR¹⁰¹R¹⁰², -CONR¹⁰¹R¹⁰², SO2NR¹⁰¹R¹⁰², Ci-C6 alkyl, Cx-C6 alkoxy, -CR¹⁰⁰=C(R¹⁰⁰)2, -CCR¹⁰⁰, C₃-Ci₀ cycloalkyl, C₃-Ci₀ heterocyclyl, C₆-Ci₂aryl and C₂-Ci₂ heteroaryl, wherein each R¹⁰⁰ independently is hydrogen or Ci-Cg alkyl; C₃-Ci₂ cycloalkyl; C₃-Ci₀ heterocyclyl; C₆-Ci₂aryl; or C₂-C_i2 heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 halo, 1-3 Ci-C₆ alkyl, 1-3 C_rC6 haloalkyl or 1-3 Ci-C₆ alkoxy groups. Preferably, the substituents are selected from the group consisting of chloro, fluoro, -OCH₃, methyl, ethyl, /so-propyl, cyclopropyl, vinyl, ethynyl, -CO₂H, -CO₂CH₃, -OCF₃, -CF₃ and -OCHF₂.

[0026] R¹⁰¹ and R¹⁰² independently is hydrogen; Ci-C8 alkyl, optionally substituted with CO2H or an ester thereof, Ci-C6 alkoxy, oxo, -CR¹⁰³=C(R¹⁰³)2, -CCR, C₃-Ci₀ cycloalkyl, C₃-C_xo heterocyclyl, C6-C_i2 aryl, or C₂-Ci₂ heteroaryl, wherein each R¹⁰³ independently is hydrogen or Ci-C₈ alkyl; C₃-C_X2 cycloalkyl; C₃-Ci₀ heterocyclyl; C₆-Ci₂aryl; or C₂-C_i2 heteroaryl; wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halo groups, or R¹⁰¹ and R¹⁰² together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.

• [0027]

The term pharmaceutically acceptable refers to safe and non-toxic for in vivo, preferably, human administration.

[0028] The term pharmaceutically acceptable sait refers to a sait that is pharmaceutically acceptable.

[0029] The term sait refers to an ionic compound formed between an acid and a base.

When the compound provided herein contains an acidic functionality, such salts include, without limitation, alkali métal, alkaline earth métal, and ammonium salts. As used herein, ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases. Exemplary, and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NH₄, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds utilized herein contain basic functionality, such salts include, without limitation, salts of organic acids, such as carboxylic acids and sulfonic acids, and minerai acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes. Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisalfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.

[0030] The terms treat, treating or treatment, as used herein, include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting or suppressing the development of the disease or condition, relieving the disease or condition, causing régression of the disease or condition, relieving a condition caused by the disease or condition, or suppressing the symptoms of the disease or condition, and are intended to include prophylaxis. The terms also include relieving the disease or conditions, e.g., causing the régression of clinical symptoms. The terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant éradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the éradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual is still be afflicted with the underlying

disorder. For prophylactic benefit, the compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0031] The terms preventing or prévention refer to a réduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet expérience or display symptoms of the disease). The terms further include causing the clinical symptoms not to develop, for example in a subject at risk of suffering from such a disease or disorder, thereby substantially averting onset of the disease or disorder.

[0032] The term effective amount refers to an amount that is effective for the treatment of a condition or disorder by an intranasal administration of a compound or composition described herein. In some embodiments, an effective amount of any of the compositions or dosage forms described herein is the amount used to treat a disorder mediated by hemoglobin or a disorder that would benefit from tissue and/or cellular oxygénation of any of the compositions or dosage forms described herein to a subject in need thereof.

[0033] The term carrier as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells, e.g., red blood cells, ortissues.

[0034] As used herein, a prodrug is a compound that, after administration, is metabolized or otherwise converted to an active or more active form with respect to at least one property. To produce a prodrug, a pharmaceutically active compound can be modîfied chemically to render it less active or inactive, but the chemical modification is such that an active form of the compound is generated by metabolic or other biological processes. A prodrug may hâve, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity. For example, see the reference Nogrady, 1985, Médicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392. Prodrugs can also be prepared using compounds that are not drugs.

[0035] In certain aspects of the invention, a compound of Formula (I) is provided:

Compounds

/CV¹V²H

(l) or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein ring A is an optionally substituted 5-10 membered heteroaryl containing up to 3 ring N, O, and/or S atoms, and oxidized forms of N and/or S atoms;

wherein ring A is a or β substituted relative to the Y substituent;

ring B is an optionally substituted C₆-C₁₀ aryl or 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;

each Y and Z is independently CR¹⁰R¹¹, O, S, SO, SO2, or NR¹²; each R¹⁰ and R¹¹ independently is hydrogen or Ci-C3 alkyl, optionally substituted with halo, OH, or alkoxy, or CR¹⁰Rⁿ is C=O; R¹² is hydrogen or C_rC₆ alkyl; provided that if one of Y and Z is O, S, SO, SO₂, then the other is not CO, and provided that Y and Z are both not heteroatoms or oxidized forms thereof;

ring C is C₆-C₁₀ aryl;

V¹ and V² independently are Ci-C₆ alkoxy; or V¹ and V² together with the carbon atom they are attached to form a ring of formula:

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³ and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently C_rC₆ alkyi or CO₂R⁶⁰, where each R⁶⁰ independently is C_rC6 alkyi or hydrogen; t is 0,1, 2, or 4; or CVY is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁵ is hydrogen, Ci-C_s alkyi or a prodrug moiety R , wherein the Ci-C₅ alkyi is optionally substituted with 1-5 halo;

R⁶ is a substituent that is halo, C_rC6 alkyi, Ci-C₆ alkoxy, C_rC6 alkylthio, C_rC₆ S(O)-, Ci10 C₆ S(O)₂-, wherein the Ci-C₆ alkyi is optionally substituted with 1-5 halo; or

R⁶ is 4-10 membered cycloalkyl or heterocycle substituted with an R'R'N- moiety wherein each R' is independently Ci-C₆ alkyi or hydrogen;

R⁸⁰ is optionally substituted Ci-C₆ alkyi;

R⁸¹ and R⁸² independently are selected from the group consisting of hydrogen, optionally substituted Ci-C₆ alkyi, COR⁸³, or CO₂R⁸⁴;

R⁸³ is hydrogen or optionally substituted C1-C6 alkyi;

R⁸⁴ is optionally substituted C_rC₆ alkyi;

k is 0 or 1; and p is 0,1, 2, or 3.

[0036] In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3.

[0037] As used herein, R⁶⁰ can be hydrogen, provided that the CO₂R⁶⁰ is not joined to a nitrogen atom.

[0038] In certain embodiments, Y and Z are both not a heteroatom or a heteroatom containing moiety. In some preferred embodiments, one of Y and Z is a methylene or substituted methylene and the other is a heteroatom or a heteroatom containing moiety.

More preferably, Y is an alkylene, and Z is a heteroatom or a heteroatom containing moiety, which, yet more preferably is oxygen.

[0039] In certain embodiments, V¹ and V² together with the carbon atom they are attached to form a ring of formula:

[0040] In certain embodiments, V¹ and V² independently are C_rC6 alkoxy; or V¹ and V² together with the carbon atom they are attached to form a ring of formula:

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one or V³ and V⁴ 10 is S the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-C₆ alkyl or CO₂R⁶⁰, where each R⁶⁰ independently is C_rC₆ alkyl or hydrogen; t is 0,1, 2, or 4; or CVY² is C=V, wherein V is O, and wherein the remaining variables are defined herein.

[0041] In certain embodiments, ring B contains a double bond. In some other embodiments, ring B contains no double bonds.

[0042] In certain embodiments, the compound is of Formula (I¹):

wherein the remaining variables are defined herein.

or

IC wherein

is an optionally substituted 4-10 membered heterocycle as defined herein, and the remaining variables are defined herein.

[0044] In certain embodiments, ring A is substituted with 1-3: halo, OH, Ci-C₆ alkyl, and/or

Ci-C₆ alkoxy, wherein the C_rC6 alkyl is optionally substituted with 1-5 halo.

[0045] In certain embodiments, ring B is substituted with 1-3: halo, OH, Ci-C₆ alkyl, COR¹⁵, and/or COOR¹⁵; and

R¹⁵ is Ci-C₆ alkyl, C₆-C₁₀aryl, 5-10 membered heteroaryl or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted.

[0046] In certain embodiments, Y-Z is -CH₂O-, -CH₂CH₂-, -CONH- or -NHCO-, wherein the right hand side of the substituent is joined with the substituted aryl or substituted phenyl ring.

[0047] In certain embodiments, the compound is selected from the group consisting of

or an N oxide thereof wherein

Y and Z are as defined herein;

x is 0,1, or 2;

R¹⁴ is C1-C6 alkyl or C₃-C₈ cycloalkyl, COR¹⁵, or COOR¹⁵;

and R¹⁵ is optionally substituted Ci-C₆ alkyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.

[0048] In certain embodiments, the compound is selected from the group consisting of

or an N oxide thereof wherein x is 0,1, or 2;

R¹⁴ is Ci-C₆ alkyl and C₃-C₈ cycloalkyl, COR¹⁵, CNR¹⁵'R¹⁵or COOR¹⁵;

and R¹⁵ is optionally substituted C_rC_e alkyl, optionally substituted C₆-Ci_Oaryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.

[0049] In certain aspects ofthe invention, a compound is provided, wherein the compound is selected from the group consisting of:

ο

OH ;

R14

or an N oxide thereof, or a pharmaceutically acceptable sait of each thereof.

[0050] In certain aspects ofthe invention, a compound is provided, wherein the compound is selected from the group consisting of:

or a prodrug thereof, or a pharmaceuticlaly acceptable sait of each thereof.

[0051] Other compounds provided herein are included in the Examples section.

Prodrug Moiety

[0052] In one aspect, R is hydrogen, a phosphate or a diphosphate containing moiety, or another promoiety or prodrug moiety. Preferably the prodrug moiety imparts at least a 2 fold, more preferably a 4 fold, enhanced solubility and/or bîoavailability to the active moiety (where R is hydrogen), and more preferably is hydrolyzed in vivo. The promoieties are structurally and functionally defined herein.

[0053] In one embodiments, R is -COR⁹⁰, CO₂R⁹¹, or CONR⁹²R⁹³ wherein

R⁹⁰ and R⁹¹ independently are C_rC6 alkyl, C₃-C₈ cycloalkyl, 4-9 membered heterocycle, or a

5-10 membered heteroaryl, each containing at least 1 basic nitrogen moiety; and

R⁹² and R⁹³ independently are CrC6 alkyl; C3-C8 cycloalkyl, 4-9 membered heterocycle, or a 510 membered heteroaryl, each containing at least 1 basic nitrogen moiety; or R⁹² and R⁹³ together with the nitrogen atom they are bonded to for a 4-9 member heterocycle substituted with at least 1 amino, C1-C6 alkyl amino, or di Ci-C6 alkylamino group.

[0054] In certain embodiments, R is -C(O)R³¹, C(O)OR³¹, or CON(R¹³)2, each R³¹ is independently a C_rC6 alkyl; C₃-C₈ cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, containing at least 1 basic nitrogen moiety; and each R¹³ independently are CrC6 alkyl; C3-C8 cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, containing at least 1 basic nitrogen moiety; or 2 R¹³ moieties together with the nitrogen atom they are bonded to for a 4-9 member heterocycle substituted with at least 1 amino, Ci-C6 alkyl amino, or di Ci-C₆ alkylamino group.

[0055] In one aspect, R is C(O)OR³¹, C(S)OR³¹, C(O)SR³¹ or COR³¹, wherein R³¹ is as defined herein.

[0056] In one embodiment, R³¹ is a group ofthe formula (CR³²R³³)eNR³⁴R³⁵, wherein each R³² and R³³ is independently H, a CrC₈ alkyl, C₃-C₉ heterocyclyl, C₃-C₈ cycloalkyl, C₆-Cio aryl, C₃-C₉ heteroaryl or R³² and R³³ together with the carbon atom they are bond to form a C3-C8 cycloalkyl, C6-Ci0 aryl, C3-C9 heterocyclyl or C3-C9 heteroaryl ring System, or 2 adjacent R³² moieties or 2 adjacent R³³ moieties together with the carbon atom they are bond to form a C3-C₈ cycloalkyl, C₆-Ci₀ aryl, C₃-C₉ heterocyclyl or C₃-C₉ heteroaryl ring system;

each R³⁴ and R³⁵ is a Ci-C8 alkyl, C3-C9 heterocyclyl, C3-C8 cycloalkyl, or R³⁴ and R³⁵ together with the nitrogen atom they are bond to form a C3-C₈ cycloalkyl or C₃-C₉ heterocyclyl ring system;

each heterocyclic and heteroaryl ring System is optionally substituted with Ci-C₃ alkyl, -OH, amino and carboxyl groups; and e is an integer of from 1 to 4.

[0057] In some less preferred embodiments R³⁴ and R³⁵ can be hydrogen.

[0058] In one embodiment, the subscript e is preferably 2 and each R³² and R³³ is preferably independently selected from the group, H, CH₃, and a member in which R³² and R³³ are joined together to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or l,l-dioxo-hexahydro-IA⁶-thiopyran-4-yl or tetrahydropyran-4-yl group.

[0059] With regard to the prodrug group, preferred embodiments are compounds wherein Nr34r3s j_{s mor}pholi_no.

[0060] In one embodiment, R is:

r32 R³³ wherein each R³² and R³³ is independently H, Ci-C₈ alkyl, or optionally, if both présent on the same substituent, may be joined together to form a C₃-C₈ cycloalkyl, C₆-Ci₀ aryl, C₃-C₉ heterocyclyl or C3-C9 heteroaryl ring system.

[0061] Within this embodiment, each R³² and R³³ is independently, H, CH₃, or are joined together to form a cyclopropyl, cyclopbutyl, cyclopentyl, cyclohexyl, 1,1-dioxo- hexahydroIÀ⁶-thiopyran-4-yl ortetrahydropyran-4-yl group.

[0062] In a preferred embodiment, linkage ofthe prodrug moiety to the rest ofthe active molécule is stable enough so that the sérum half life ofthe prodrug is from about 8 to about 24 hours.

[0063] In an embodiment ofthe invention, the prodrug moiety comprises a tertiary amine having a pKa near the physiological pH of 7.5. Any amines having a pKa within 1 unit of 7.5 are suitable alternatives amines for this purpose. The amine may be provided by the amine of a morpholino group. This pKa range of 6.5 to 8.5 allows for significant concentrations of the basic neutral amine to be présent in the mildly alkaline small intestine. The basic,

neutral form of the amine prodrug is lipophilie and is absorbed through the wall of the small intestine into the blood. Following absorption into the bloodstream, the prodrug moiety is cleaved by esterases which are naturally présent in the sérum to release an active compound.

[0064] Examples of R include, without limitation:

[0001] In another embodiment, R is as tabulated below:

R	m	R34	R35	nr34r35
C(O)(CH2)mNR34R35	1	Me	Me
C(O)(CH2)mNR34R35	2	Me	Me
C(O)(CH2)mNR34R35	3	Me	Me
C(O)(CH2)mNR34R35	4	Me	Me
C(O)(CH2)mNR34R35	1			-çj-r/ /Q
C(O)(CH2)mNR34R35	2			s “5’N\___ o
C(O)(CH2)mNR34R35	3			J
C(O)(CH2)mNR34R35	4			S -γ
C(O)O(CH2)mNR34R35	2	Me	Me
C(O)O(CH2)mNR34R35	3	Me	Me
C(O)O(CH2)mNR34R35	4	Me	Me

C(O)O(CH2)mNR34R35	2			-$-N\___/0
C(O)O(CH2)mNR34R35	3			I ver ô
C(O)O(CH2)rnNR34R35	4			s -£-n___/0
P(O)(OH)2
an N oxide thereof, or a pharmaceutically acceptab	e sait of each thereof.

[0065] In another aspect, R is,

wherein

R³⁶ is lower alkyl {e.g. Ci-C₆ alkyl).

wherein X¹, Y¹ and X² are as defined herein.

[0067] In one embodiment, X¹ is selected from the group consisting of O, S and NR³⁷ wherein R³⁷ is hydrogen or C1-C6 alkyl;

Y¹ is -C(R³⁸)2 or a sugar moiety, wherein each R³⁸ is independently hydrogen or Ci-C6 alkyl, C₃-C₈ cycloalkyl, C3-C9 heterocyclyl, C6-C10 aryl, or C3-C9 heteroaryl;

X² is selected from the group consisting of halogen, Ci-C6 alkoxy, diacylglycérol, amino, Ci-C₆ alkylamino, Ci-C₆ dialkylamino, C_rC₆ alkylthio, a PEG moiety, a bile acid moiety, a sugar moiety, an amino acid moiety, a di-or tri-peptide, a PEG carboxylic acid, and -U-V wherein

U is O or S; and

V is selected from the group consisting of C_rC₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-Ci₀ aryl, C3-C9 heteroaryl, C(W²)X³, PO(X³)₂, and SO₂X³;

wherein W² is O or NR³⁹ wherein R³⁹ is hydrogen or Ci-C₆ alkyl, C₃-C₈ cycloalkyl, C3-C9 hetrocyclyl, C₆-Ci₀ aryl, or C3-C9 heteroaryl; and each X³ is independently amino, hydroxyl, mercapto, Ci-C₆ alkyl, heteroalkyl, cycloalkyl, hetrocyclyl, aryl, or heteroaryl, Ci-C₆ alkoxy, Ci-C₆ alkylamino, Ci-C₆ dialkylamino, Ci-C₆ alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and -O-CH₂-CH(OR⁴⁰)CH₂X⁴R⁴⁰, wherein:

X⁴ is selected from the group consisting of O, S, S=O, and SO₂; and each R⁴⁰ is independently Ci₀-C₂₂ alkyl, C3-C8 cycloalkyl, C3-C9 heterocyclyl, C₆-Cio aryl, or C3-C9 heteroaryl, Ci-C₈ alkylene, or C_rC₈ heteroalkylene.

[0068] Each heterocyclic and heteroaryl ring system is optionally substituted with C1-C3 alkyl, -OH, amino and carboxyl groups.

[0069] In one embodiment, the présent invention utilizes the following Y¹ groups: CH₂,

CHMe, CH(isopropyl), CH(tertiarybutyl), C(Me)₂, C(Et)₂, C(isopropyl)₂, and C(propyl)₂.

[0070] In another embodiment, the présent invention utilizes the following X² groups:

-OMe, -OEt, -O-isopropyl, O-isobutyl, O-tertiarybutyl, -O-COMe, -O-C(=O)(isopropyl), -O-C(=O)(isobutyl), -O-C(=O)(tertiarybutyl), -O-C(=O)-NMe₂, -O-C(=O)-NHMe, -O-C(=O)-NH₂, -O-C(=O)-N(H)-CH(R⁴¹)-CO2Et wherein R⁴¹ is a side chain Ci-C6 alkyl, or C3-C9 heterocyclyl group selected from the side chain groups présent in essential amino acids; -O-P(=O)(OMe)₂,

-O-P(=O)(O-isopropyl)₂, and -O-P(=O)(O-isobutyl)₂. Each heterocyclic is optionally substituted with one or more, preferably, 1-3, C_rC₃ alkyl, -OH, amino and/or carboxyl groups.

[0071] In another embodiment, In one embodiment, R is:

wherein

X³ is independently Ci-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃C₉ heteroaryl; and

R⁴² is independently hydrogen or Ci-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl,

C₆-Cio aryl or C₃-C₉ heteroaryl.

[0072] Each heterocyclic is optionally substituted with one or more, preferably, 1-3, C1-C3 alkyl, -OH, amino and/or carboxyl groups.

[0073] In one embodiment, R is:

wherein each X³ is independently amino, hydroxyl, mercapto, Ci-C6 alkyl, C3-C8 cycloalkyl, C3C9 heterocyclyl, C6-C10 aryl, or C3-C9 heteroaryl, CrC6 alkoxy, Ci-C6 alkylamino, C1-C6 dialkylamino, Ci-C6 alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and -O-CH2-CH(OR⁴⁰)CH2X⁴R⁴⁰, wherein:

X⁴ is selected from the group consisting of O, S, S=O, and SO₂; and each R⁴⁰ is independently Ci₀-C₂₂ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-Ci₀ aryl,

C₃-C₉ heteroaryl, C_rC₈ alkylene, or Ci-C₈ heteroalkylene; and

R⁴² is independently hydrogen or Ci-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-Ci₀ aryl, or C₃-C₉ heteroaryl.

[0074] In some embodiments, R⁴² is independently hydrogen or Ci-C6 alkyl, C3-C8 cycloalkyl, C3-C9 heterocyclyl, C6-C10 aryl, or C3-C9 heteroaryl; and each X³ independently is Ci-C6 alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-Cio aryl, or C₃-C₉ heteroaryl, C_rC6 alkoxy, Ci-C₆ alkylamino, C_rC₆ dialkylamino, or C_rC6 alkylthio.

[0075] In some embodiments, R is represented by the following structures:

CO_zEt wherein, in the above examples, R⁴³ is Cio-C22 alkyl or alkylene, R⁴⁴ is H or CrC₆ alkyl and R⁴⁵ represents side chain alkyl groups présent in naturally occurring alpha amino acids;

wherein R⁴⁶ is (CH2)n, f=2-4, and CO-R⁴⁷-NH2 represents an aminoacyl group; or

wherein R⁴⁶ is (CH2)n, n=2-4, R⁴⁷ is (CH2)_n, n=l-3 and R⁴⁹ is O or NMe.

[0076] In one embodiment, R is:

[0077] In one aspect, R is -C(R²⁰⁰R²⁰¹)O(R²⁰²R²⁰³)P(O)OR²⁰⁴NR²⁰⁵R²⁰⁶, wherein each R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, R²⁰⁴ R²⁰⁵ and R²⁰⁶ is independently H, a C_rC₈ alkyl, C₃-C₉ heterocyclyl, C₃-C₈ cycloalkyl, C₆-Ci₀ aryl, C₃-C₉ heteroaryl, wherein each alkyl, heterocyclyl, cycloalkyl, aryl, and heteroaryl is optionally substituted.

[0078] In some embodiments, R is -CH(R²⁰¹)OCH2P(O)OR²⁰⁴NHR²⁰⁶, wherein R²⁰¹ is CrC₈ alkyl, R²⁰⁴ is phenyl, optionally substituted. In one embodiment, R²⁰⁶ is -CHR²⁰⁷C(O)OR²⁰⁸ wherein R²⁰⁷ is selected from the group consisting ofthe naturally occurring amino acid side chains and CO2H esters thereof and R²⁰⁸ is Cx-C₈ alkyl. In one embodiment, R²⁰⁶ is Ci-C₆ alkyl, optionally susbtitued with 1-3, CO₂H, SH, NH₂, C₆-Ci₀ aryl, and C₂-Ci₀ heteroaryl.

[0079] In some embodiments, R is:

[0080] In one embodiment, R is:

¥%A<^peg V^ko^/PEG r = 0 to 12 _; or wherein Y¹ is -C(R³⁸)2, wherein each R³⁸ is independently hydrogen or Ci-C6 alkyl, C₃C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-Ci₀ aryl, or C₃-C₉ heteroaryl.

[0081] Various polyethylene glycol (PEG) moieties and synthetic methods related to them 5 that can be used or adapted to make compounds of the invention are described in U.S.

Patent Nos. 6,608,076; 6,395,266; 6,194,580; 6,153,655; 6,127,355; 6,111,107; 5,965,566;

5,880,131; 5,840,900; 6,011,042 and 5,681,567.

wherein

R⁵⁰ is -OH or hydrogen;

R⁵¹ is -OH, or hydrogen;

W is- CHiCHsJW¹;

wherein W¹ is a substituted Ci-C₈ alkyl group containing a moiety which is optionally negatively charged at physiological pH, said moiety is selected from the group consisting of CO₂H, SO₃H, SO₂H,

-P(O)(OR⁵²)(OH), -OP(O)(OR⁵²)(OH), and OSO₃H, wherein R⁵² is Cx-Ce alkyl, C₃-C₈ cycloalkyl, C₃-Cg heterocyclyl, C₆-Cio aryl, or C₃-C₉ heteroaryl.

[0083] Each heterocyclic and heteroaryl ring system is optionally substituted with one or more, preferably 1-3, Ci-C₃ alkyl, -OH, amino and/or carboxyl groups.

[0084] ln one embodiment, R is:

wherein R⁵³ is H or Ci-C₆ alkyl.

[0085] In another aspect, R is SO3H.

[0086] In another aspect, R comprises a cleavable linker, wherein the term cleavable linker refers to a linker which has a short half life in vivo. The breakdown ofthe linker Z in a compound releases or generates the active compound. In one embodiment, the cleavable linker has a half life of less than ten hours. In one embodiment, the cleavable linker has a half life of less than an hour. In one embodiment, the half life of the cleavable linker is between one and fifteen minutes. In one embodiment, the cleavable linker has at least one connection with the structure: C*- C(=X*)X*-C* wherein C* is a substituted or unsubstituted methylene group, and X* is S or O. In one embodiment, the cleavable linker has at least one

C*-C(=O)O-C* connection. In one embodiment, the cleavable linker has at least one C*C(=O)S-C* connection. In one embodiment, the cleavable linker has at least one -C(=O)N*C*-SO₂-N*-connection, wherein N* is -NH- or C_rC6 alkylamino. In one embodiment, the cleavable linker is hydrolyzed by an esterase enzyme.

[0087] In one embodiment, the linker is a self-immolating linker, such as that disclosed in 15 U.S. patent publication 2002/0147138, to Firestone; PCT Appl. No. US05/08161 and PCT

Pub. No. 2004/087075. In another embodiment, the linker is a substrate for enzymes. See generally Rooseboom et al., 2004, Pharmacol. Rev. 56:53-102.

Pharmaceutical Compositions

[0088] In further aspects ofthe invention, a composition is provided comprising any ofthe 20 compounds described herein, and at least a pharmaceutically acceptable excipient.

[0089] In another aspect, this invention provides a composition comprising any of the compounds described herein, and a pharmaceutically acceptable excipient.

[0090] Such compositions can be formulated for different routes of administration. Although compositions suitable for oral delivery will probably be used most frequently, other routes that may be used include transdermal, intravenous, intraarterial, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous, intracranial, and subcutaneous routes. Suitable dosage forms for administering any ofthe compounds described herein include tablets, capsules, pills, powders, aérosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and émulsions. Sustained

release dosage forms may also be used, for example, in a transdermal patch form. Ail dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16^th ed., A. Oslo editor, Easton Pa. 1980).

[0091] Pharmaceutically acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this invention. Such excipients may be any solid, liquid, semi-solid or, in the case of an aérosol composition, gaseous excipient that is generally available to one of skill in the art. Pharmaceutical compositions in accordance with the invention are prepared by conventional means using methods known in the art.

[0092] The compositions disclosed herein may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical préparations, e.g., talc, gum arabic, lactose, starch, magnésium stéarate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin dérivatives, glycols, etc. Coloring and flavoring agents may also be added to préparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as éthanol, 1,2propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycérides, partial esters of glycerin and the like.

[0093] Solid pharmaceutical excipients include starch, cellulose, hydroxypropyl cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnésium stéarate, 20 sodium stéarate, glycerol monostearate, sodium chloride, dried skim milk and the like.

Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, éthanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, minerai oil, sesame oil, etc. In certain embodiments, the compositions provided herein comprises one or more of α-tocopherol, gum arabic, and/or hydroxypropyl cellulose.

[0094] In one embodiment, this invention provides sustained release formulations such as drug depots or patches comprising an effective amount of a compound provided herein. In another embodiment, the patch further comprises gum Arabic or hydroxypropyl cellulose separately or in combination, in the presence of alpha-tocopherol. Preferably, the

hydroxypropyl cellulose has an average MW of from 10,000 to 100,000. In a more preferred embodiment, the hydroxypropyl cellulose has an average MW of from 5,000 to 50,000.

[0095] Compounds and pharmaceutical compositions of this invention maybe used alone or in combination with other compounds. When administered with another agent, the co5 administration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time. Thus, co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time. However, co-administration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such administration most advantageously proceeds by delivering both active ingrédients simultaneously in a novel pharmaceutical composition in accordance with the présent invention.

Methods of Treatment

[0096] In aspects of the invention, a method is provided for increasing tissue and/or cellular oxygénation, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

[0097] In aspects of the invention, a method is provided for increasing oxygen affinity of hemoglobin S in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

[0098] In aspects of the invention, a method is provided fortreating a condition associated with oxygen deficiency, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

[0099] In further aspects of the invention, a method is provided for treating oxygen deficiency associated with sickle cell anémia, the method comprising administering to a

subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

[0100] In further aspects of the invention, a method is provided for treating sickle cell disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the compounds or compositions described herein. In still further aspects of the invention, a method is provided for treating cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer's disease, acute respiratory disease syndrome, and a wound, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the compounds or compositions described herein.

Synthetic Methods

[0101] Certain methods for making the compounds described herein are also provided. The reactions are preferably carried out in a suitable inert solvent that will be apparent to the skilled artisan upon readingthis disclosure, for a sufficient period of time to ensure substantial completion of the reaction as observed by thin layer chromatography, ^XH-NMR, etc. If needed to speed up the reaction, the reaction mixture can be heated, as is well known to the skilled artisan. The final and the intermediate compounds are purified, if necessary, by various art known methods such as crystallization, précipitation, column chromatography, and the likes, as will be apparent to the skilled artisan upon reading this disclosure.

[0102] An illustrative and non-limiting method for synthesizing a compound of formula (I), is schematically shown below.

' A / In the following Schemes,

refer to rings A, B and C as described herein.

A⁵ and B⁵ are independently NR⁷⁰, O, S, S(O)x, NBoC, CH2, CHR⁷⁰, C(R⁷⁰)2 provided that when only one of A⁵ or B⁵ is présent, then A⁵ or B⁵ is not CH2, CHR⁷⁰, C(R⁷⁰)2; and when both A⁵ and B⁵ are présent in a ring, both are not CH2, CHR⁷⁰, C(R⁷⁰)2;

wherein R⁷⁰ is C_rC₆ alkyl or defined as R¹⁴ as defined herein;

X, and X⁵ represent a leaving group and are independently selected from Cl, F, Br, and I.

R⁷¹ is C_x-C6 alkyl;

R⁷² is Ci-C₆ alkyl;

n is 0,1, or 2; and

Where variables already used in the structures hereinabove are used in the shcemes, the context makes it unambiguous as to what the variable refers to.

General Synthetic Schemes

Scheme 1 ^xYa

Step

Step 2 (

31a (R=H) 31b(R=alkyl)

32c (R=Ar/HeteroAr)

[0103] Compounds of structure 34 can be synthesîzed via general synthetic scheme 1. Réduction of carboxylic acid dérivative 31 gives hydrxoymethyl analog 32, which can be Nderivativtized at via copper-mediated N-arylation reaction (Cul, Ar-I, base such as N,Ndimethylethylenediamine and potassium phosphate, heat) to give key hydroxymethyl intermediate 32. Coupling of 32 with phénol aldéhyde 33 produces the desired aldéhyde analog 34 via typical Mistunobu conditions using either triphenylphosphine or polymer supported triphenylphosphine.

[0104] General method step 1 - réduction of carboxylic acid dérivative 1 to methyl alcohol 2: To a suspension of carboxylic acid l(l-10mmol) in MeOH or EtOH (2-10 mL) at 0 °C was added SOCI₂ (1.5eq). After stirred at room température for l-12h, it was concentrated to remove ail solvents, dried under high vacuum to give correspondîng methyl or ethyl ester. The ester was dissolved in MeOH or EtOH (5-30 mL), to this solution, was added NaBH₄ (l-4eq) at 0 °C, the mixture was warmed up to room température and stirred for additional 1-24 h. The mixture was quenched with Sat. NH₄CI, filtered off the insolubles

and the filtrate was concentrated to give crude product, which was purified by flash silica gel chromatography to give the corresponding hydroxymethylene compound 32.

[0105] General method step 2 - N-alkylation (la to lb): The carboxylate 31a (Ri=H) can be first alkylated and then reduced to give N-alkyl hydroxymethylene analog 31b (Ri=alkyl).

In a typical procedure, the carboxylate 31a (l-10mmol) is first dissolved in DMF (2-20 mL); to this was then added a base such as NaH or CS2CO3 (1-1.2eq), followed by the addition of alkyl halide (eg, BnBr) (0.9-1.5eq). The reaction allowed to proceed at room température of heat at 40 to 115 °C for 0.5 to 24 h. In workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to préparative HPLC or flash silica gel chromatography purification. In workup B (for products that did not precipitate), diluted HCl or aqueous NH₄CI was added at 0 °C to adjusted the pH to ~7, the reaction mixture was partitioned between ethyl acetate or dichloromethane and aqueous sodium chloride and the organic layer separated, dried, and solvent removed under vacuum to afford crude product which was purified by automated silica gel column chromatography, reaction appropriate solvents mixture (e.g., ethyl acetate/hexanes).

[0106] General method step 3 - Copper-mediated N-arylation from 32a to 32c: For cyclic amines (X=H, H), to a solution of hydroxymethylene compound 32a (1-10 mmol) and aryl/hetero iodide (1-1.5eq) in iPrOH (0.5-10 mL) was added ethylene diol (1.3eq) and Cul (6.7mol%), followed by K3PO4 (1.3eq), then it was degassed and heated at 88 °C for 6-24 h.

Altematively, for lactams (X=O), to a solution of hydroxymethylene compound 32a (1lOmmol) and aryl/hetero iodide (1-1.5eq) in Dioxane (2-20 mL) was added Cul (0.17eq), Ν,Ν-dimethylethylenediamine (0.17eq), K3PO4 (1.7eq), then it was degassed and heated at 100 °C for 6-48 h.

[0107] Workup for both procedures: the reaction mixture was cooled to room température the mixture was diluted with EtOAc and water, organic layer was separated and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by flash silica gel chromatography to give N-aryl/heteroaryl compound 32c.

[0108] General method C -Mitsunobu conditions A hydroxyl (hetero)arylaldehyde dérivatives (34) (0.1-2 mmol) mixture with substituted methylene alcohol (33) (0.8 to 1.2eq) and (polymer-supported) PPh₃ (1-1.5eq) in anhydrous THF (1-lOmL) was stirred under

nitrogen until complété dissolution. The solution was cooled to 0 °C on ice bath and DIAD or

DEAD (1.1 eq) in THF or toluene was added dropwise over a 1-20 min period. The ice cooling bath was allowed to expire over 90 min and the mixture was stirred at RT for 2-48 hours.

The mixture was filtered through a pad of silica. The silica was washed with ethyl acetate 220mL. The combined filtrâtes were evaporated and the residue was dried on highvac. The residue was purified by préparative HPLC or flash silica gel chromatography.

4a

[0109] General method A for preparing aryloxy ether analogs (4a) from substituted methylene alcohol (1) and hydroxyl aryl aldéhyde dérivatives (3a). A hydroxyl (hetero)arylaldehyde dérivatives (3a) (0.1-2 mmol) mixture with substituted methylene alcohol (1) (0.8 to 1.2eq) and PPh₃ (l-1.5eq) in anhydrous THF (1-lOmL) was stirred under nitrogen until complété dissolution. The solution was cooled to 0 °C on ice bath and DIAD or DEAD (1.1 eq) in THF or toluene was added dropwise over a 1-20 min period. The ice cooling 15 bath was allowed to expire over 90 min and the mixture was stirred at RT for 2-48 hours.

The mixture was stirred for 10 min, then filtered through a pad of silica. The silica was washed with ethyl acetate 2-20mL. The combined filtrâtes were evaporated and the residue was dried on highvac. The residue was purified by préparative HPLC or flash silica gel chromatography.

[0110] General method B for preparing aryloxyether analogs (4a) from substituted methylene halide (2) and hydroxyl aryl aldéhyde dérivatives (3a). A mixture of hydroxyl (hetero)arylaldehyde dérivatives (3a) (0.1-2 mmol, 1-4 eq.), substituted methylene chloride or bromide (2) (leq), and K₂CO₃ (2-5 eq.) (catalytic amount of Nal or Bu₄NI may also be added) in DMF or acetonitrile (1 to 10 mL) was stirred at RT or heating up to 120 °C for 0.5-8 h under nitrogen atmosphère. In workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to préparative HPLC or flash silica gel chromatography purification. In workup B (for products that did not precipitate), diluted HCl or aqueous NH₄CI was added at 0 °C to adjusted the pH to ~7, the reaction mixture was partitioned between ethyl acetate or dichloromethane and aqueous sodium chloride and the organic layer separated, dried, and solvent removed under vacuum to afford crude product which was purified by automated silica gel column chromatography using appropriate solvents mixture (e.g., ethyl acetate/hexanes).

[0111] General method C for preparing substituted methylene chloride (2a). To a solution of substituted methylene alcohol (1) (0.1 to 2 mmol) in DCM (1-10 mL) was added SOCI₂ dropwise (2eq to 5eq ) at 0 °C or RT. The reaction mixture was stirred at RT for 10min to 6 h, or until reaction is judged complété (LC/MS). The reaction mixture is concentrated to dryness over a rotavap. The crude chloride residue was suspended in toluene, sonicated and concentrated to dryness. The process was repeated three times and dried under vacuum to give the substituted methylene chloride (2), usually as an off-white solid, which was used for next step without further purification. Altematively, a solution of aqueous IN Na₂CO₃ is then added to produce a solution of pH~ 8. the mixture was extracted with DCM (3 xl0-50mL), dried over sodium sulfate, and concentrated to the crude substituted methylene chloride (2a), which is then purified by column chromatography on silica gel (0100% ethyl acetate-hexanes).

[0112] General method D for preparing substituted methylene bromide (2b). To a solution of substituted methylene alcohol (1) (0.1 to 2 mmol) in DCM (1-10 mL) was added Ph₃P Br₂ dropwise (2eq to 5eq ) at 0 °C or RT. The reaction mixture was stirred at RT for 10 min to 2 h, or until reaction is judged complété (LC/MS). The reaction mixture is concentrated to dryness over a rotavap. The residue purified by column chromatography on silica gel (0-100% ethyl acetate-hexanes) to afford the pure bromide 2b.

_o Stepl II

CI'CDR⁷¹

Step3

Step2

Step4

LAH or DI BAL

Step5

10-X

12-OH-trans

Step 9

13-X-cis

[0113] General method E for preparing heterocyclic methylene dérivatives 9,10,12 and

13. Condensation of heterocyclic ketone analog 5 with chlorformate or dialkyl carbonate gives (hetero)cyclic beta-ketone ester 6 (Step 1). The ketone ester 6 is converted to the triflate intermediate 7 by treating with a triflating agent (e.g, triflic anhydride) in the presence of an organic base such as Hunig's base (Step 2). Suzuki coupling of the triflate 7 with a boronic acid or ester affords heterocyclohexene carboxylate 8 (Step 3). Subséquent réduction ofthe ester group by LAH or DIBAL gives the corresponding alcohol 9-OH (Step 4). Further reaction ofthe alcohol 9-OH with thionyl chloride, Ph₃PBr₂ (or CBr₄-Ph₃P or PBr₃), or 10 alkyl/aryl sufonyl chloride produces the corresponding 10-X chloride, bromide or sulfonate (Step 5).

[0114] Alternatively, the double bond of heterocyclohexene carboxylate 8 is reduced to give the c/s-heterocyclohexane 11-cis carboxylate under palladium catalyzed hydrogénation conditions (Step 6). Réduction of the ester group of 11-cis by LAH or DIBAL yields cis-alcohol

12-OH-cis (Step 8). Conversion of the alcohol 12-OH-cis to its chloride, bromide or sulfonate (such as mesylate, tosylate) 13-X-cis can be achieved by reacting with thionyl chloride, or

Ph₃PBr₂, or sufonyl chloride (such as mesyl chloride or tosyl chloride) (Step 9). The ciscyclohexane carboxylate 11-cis can also be isomerized to the thermodynamically more stable trans-isomer 11-trans by the treatment with an alcoholic alkoxide (e.g., ethoxide) solution. Analogously, transformation of 11-trans ester to 12-trans alcohol and 13-X-trans halide is accomplished by applying conditions of Step 8 and Step9 similar to these for the corresponding cis-isomers.

9-OH

12-OH-cis

12-OH-trans

Method A

3a or 3b

Method B

3a or 3b

10-x

13-X-cis

13-X-trans

[0115] Coupling of the (hetero)cyclic methylene dérivatives 9,10,12 and 13 with hydroxyl (hetero)arylaldehyde dérivatives (3a/3b) by general method A or B affords the corresponding aryloxy/heteroarylether analogs (4c and 4d).

Tf_PO

Stepl

TfO

COOEt θ^υΖυ“ ^aep2

Step5

[H]

* « »

18/20

III

3a or 3b

Method A

4e or 4f

b ;

L ₁ OH

Scheme 1

Method B

[0116] General method F Scheme 2 for preparing heterocyclic methylene dérivatives 18, 19, 20 and 21. The ketone ester 14 is converted to the triflate intermediate 15 by treating with a triflating agent (e.g, triflic anhydride) in the presence of an organic base such as Hunig's base (Step 1). Suzuki coupîing of the triflate 15 with a boronic acid or ester affords heterocyclo carboxylate 16 (Step 2). Subséquent réduction of the ester group by LAH or DIBAL gives the corresponding alcohol 18 (Step 3). Further reaction of the alcohol 18 with thionyl chloride, Ph₃PBr₂ (or CBr₄-Ph₃P or PBr₃), or alkyl/aryl sufonyl chloride produces the corresponding 19 chloride, bromide or sulfonate (Step 4).

[0117] Altematively, the double bond of 16 is reduced to give the saturated heterolic analog 17 under palladium catalyzed hydrogénation conditions (Step 5). Réduction of the ester group of 17 by LAH or DIBAL yields alcohol 20 (Step 7). Conversion of the alcohol 20 to its chloride, bromide or sulfonate (such as mesylate, tosylate) 21 can be achieved by reacting with thionyl chloride, or Ph₃PBr₂, or sufonyl chloride (such as mesyl chloride or tosyl chloride) (Step 8).

[0118] Coupling of the (hetero)cyclic methylene dérivatives 18,19, 20 and 21 with hydroxyl (hetero)arylaldehyde dérivatives (3a/3b) by general method A or B affords the corresponding aryloxy/heteroaryloxyether analogs (4e and 4f).

[0119] Chiral pyrrolidine methylene dérivatives 25 and 26 can be prepared according to reaction sequence depicted herein. The pyrrolidine ester 24 is produced via a 1,3-dipolar cycloaddition of alkene 22 with azomethine-ylide generated in situ from formaldéhyde and amino acid 23 alkene (Stepl). Subséquent réduction of the ester to alcohol 24 and further conversion 25 are accomplished by analogous methods described herein. If a chiral auxiliary group such as chiral oxazolidinone dérivative 22a is used, optically active pyrrolidine dérivatives 25 and 26 can also be obtained. Coupling of 25 and 26 with hydroxyl (hetero)arylaldehyde dérivatives (3a/3b) by general method A or B affords the corresponding aryloxy/heteroaryloxyether analogs (4).

[0120] Separate from the general synthesis of tetrahydrothiophenes (i.e., 20 and 21, A⁵=S) described herein, also described is a different synthetic approach to this class of analogs.

ch₂o

COOMe

dnrfi Method A	J	f	O)x	J	S(O)x
5 or 7 Method B
			''—OH		X
	8 or 9	' A,'	6		7

[0121] Other heterocyclic analogs (compound 5) with C-N linkage are synthesized by applying Buchwald/Hartwig amination conditions. Many ofthe cyclic amines (1) are available commercially (e.g., la, lb, le, ld, and le).

i ^0H

1a

c

[0122] Protected amides of formula -CONHR⁹⁵ and -CONHOR⁹⁵ can be converted e.g., hydrolyzed to the corresponding amides according to methods known to the skilled artisan.

Prodrug Synthesis

[0123] Synthèses of the ester prodrugs start with the free carboxylic acid bearing the tertiary amine. The free acid is activated for ester formation in an aprotic solvent and then reacted with a free alcohol group in the presence of an inert base, such as triethyl amine, to provide the ester prodrug. Activating conditions for the carboxylic acid include forming the acid chloride using oxalyl chloride or thionyl chloride in an aprotic solvent, optionally with a catalytic amount of dimethyl formamide, followed by évaporation. Examples of aprotic solvents, include, but are not limited to methylene chloride, tetrahydrofuran, and the like. Altematively, activations can be performed in situ by using reagents such as BOP

(benzotriazol-l-yloxytris(dimethylamino) phosphonium hexafluorolphosphate, and the like (see Nagy et al., 1993, Proc. Natl. Acad. Sci. USA 90:6373-6376) followed by reaction with the free alcohol. Isolation of the ester products can be affected by extraction with an organic solvent, such as ethyl acetate or methylene chloride, against a mildly acidic aqueous solution; followed by base treatment of the acidic aqueous phase so as to render it basic; followed by extraction with an organic solvent, for example ethyl acetate or methylene chroride; évaporation of the organic solvent layer; and recrystalization from a solvent, such as éthanol. Optionally, the solvent can be acidified with an acid, such as HCl or acetic acid to provide a pharmaceutically acceptable sait thereof. Alternatively the crude reaction can be passed over an ion exchange column bearing sulfonic acid groups in the protonated form, washed with deionized water, and eluted with aqueous ammonia; followed by évaporation.

[0124] Suitable free acids bearing the tertiary amine are commercially available, such as 2(N-morpholino)-propionic acid, N,N- dimethyl-beta-alanine, and the like. Non- commercial acids can be synthesized in straightforward manner via standard literature procedures.

[0125] Carbonate and carbamate prodrugs can be prepared in an analogous way. For example, amino alcohols and diamines can be activated using activating agents such as phosgene or carbonyl diimidazole, to provide an activated carbonates, which in turn can react with the alcohol and/or the phenolic hydroxy group on the compounds utilized herein to provide carbonate and carbamate prodrugs.

[0126] Various protecting groups and synthetic methods related to them that can be used or adapted to make compounds of the invention can be adapted from the references Testa et al., Hydrolysis in Drug and Prodrug Metabolism, June 2003, Wiley- VCH, Zurich, 419-534 and Beaumont et al., Curr. Drug Metab. 2003, 4:461-85.

[0127] Provided herein is a method of synthesizing an acyloxymethyl version of a prodrug by adapting a method from the reference Sobolev et al., 2002, J. Org. Chem. 67:401-410.

R⁵¹

[0128] Provided herein is a method for synthesizing a phosphonooxymethyl version of a prodrug by adapting a method from Mantyla et al., 2004, J. Med. Chem. 47:188-195.

R⁵¹ is C_rCg alkyl.

NaH, DMF

tetrabutylammonium bromide

NaH, THF

|^O Et

OEt

[0129] Provided herein is a method of synthesizing an alkyloxymethyl version of a prodrug

R⁵² is Ci-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C6-Ci₀ aryl, or C₃-Cg heteroaryl.

Examples

[0130] The following examples are given for the purpose of illustrâting various embodiments of the invention and are not meant to limit the présent invention in any fashion. The présent examples, along with the methods described herein are presently représentative of preferred embodiments, are exemplary, and are not întended as limitations on the scope ofthe invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will 15 occur to those skilled in the art.

[0131] In the examples below as well as throughout the application, the following abbreviations hâve the following meanings. If not defined, the terms hâve their generally accepted meanings.

°c	= degrees Celsius
RT	= Room température
min	= minute(s)
h	= hour(s)
RL	= Microliter

mL	Milliliter
mmol	=	Millimole
eq	=	Equivalent
mg	=	Milligram
PPm	=	Parts per million
atm	=	Atmospheric pressure
MS	=	Mass spectrometry
LC-MS	=	Liquid chromatography-mass spectrometry
HPLC	=	High performance liquid chromatography
NMR	=	Nuclear magnetic résonance
Sat.		Saturated
MeOH	=	Methanol
EtOH	=	Ethanol
EtOAc	=	Ethyl acetate
Et3N	=	Triethylamine
ACN	=	Acetonitrile
Ac2O	=	Acetic anhydride
Na(OAc)3BH	=	Sodium triacetoxy borohydride
PBr3	=	phosphorus tribromide
Ph3P	=	Triphenylphosphine
Ph3PBr2	=	Triphenylphosphine dibromide
CBr4		Tetrabromomethane
DMF	=	N, N-Dimethylformamide
DCM	=	Dichloromethane
LAH/ L1AIH4	=	Lithium aluminum hydride
THF	=	Tetrahydrofuran
DIBAL	=	Diisobutylaluminium hydride
DIAD	=	Diisopropyl azodicarboxylate
DEAD	=	Diethyl azodicarboxylate
DIPEA	=	Ν,Ν-Diisopropylethylamine
Tf2O	=	Trifluoromethanesulfonic (triflic) anhydride

Pd(dppf)Cl₂ = [l,l'-Bis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex

[0132] Préparation of 2-hydroxy-6-((5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydro-2H-pyran4-yl)methoxy)benzaldehyde

[0133] Step 1: To a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (1.0 g, 5.81 mmol)in DCM (30 mL) was added DIPEA (1.22 mL, 6.97 mmol) and Tf₂O (1.08 mL, 6.39 mmol) at -78 °C, then it was warmed up to room température and stirred at room temeperature for 2 h, the solution was diluted with DCM, washed with Sat. NaHCO₃, brine, dried and concentrated to give ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2Hpyran-4-carboxylate as crude product (2 g).

OTf O

PddppfCI2

Na₂CO₃

[0134] Step 2: To a solution of ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2Hpyran-4-carboxylate (crude from step 1) and l-isopropyl-5-(4,4,5,5-tetramethyl-l,3,215 dioxaborolan-2-yl)-lH-pyrazole (1.37 g, 5.82 mmol) in dioxane (20 ml) was added

Pd(dppf)CI₂ (430 mg, 0.58 mmol) and Na₂CO₃ (1.85 g, 17.46 mmol) in water (6 mL), the mixture was degased with N2 for 5 min, and was heated at 100 °C for 15 h, after cooling to

room température the mixture was diluted with EtOAc and washed with Sat. NaHCO₃ and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=3:l) to give ethyl 5-(l-isopropyllH-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-carboxylate (850 mg).

LiAIH₄

[0135] Step 3: To a solution of ethyl 5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydro-2H-pyran4-carboxylate (600 mg, 2.27 mmol) in THF (10 mL) was added LiAlH₄ (IM in THF, 2.72 mL, 2.72 mmol) at -20 °C, the reaction was stirred at -20 °C for 30 min, and was quenched with Sat. NH₄CI, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc= 100:0 to 20:80) to give (5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydro-2Hpyran-4-yl)methanol (500 mg).

PPh₃Br₂

[0136] Step 4: To a solution of (5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4yl)methanol (300 mg, 1.35 mmol) in DCM (5 mL) was added dibromotriphenylphosphorane (630 mg, 1.35 mmol) at room température, after stirring for 30 min, it was diluted with DCM, organic layer was washed with Sat. NaHCO₃, brine, dried and concentrated to give crude product, which was purified by column(Hexanes/EtOAc= 4:1) to give 5-(4(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-l-isopropyl-lH-pyrazole (360 mg).

69%

[0137] Step 5: To a solution of 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-lisopropyl-lH-pyrazole (110 mg, 0.38 mmol) and 2,6-dihydroxybenzaldehyde (100 mg, 0.76 mmol) in DMF (6 mL) was added K₂CO₃ (110 mg, 0.76 mmol). After stirred at room température for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc. Organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=l:l) to give 2-hydroxy-6-((5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydro-2Hpyran-4-yl)methoxy)benzaldehyde (90 mg). 1H NMR (400 MHz, CDCI₃) δ (ppm) 11.89 (s, 1H), 10.33 (s, 1H), 7.53 (d, J=1.6 Hz, 1H), 7.33(t, J=8.8 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 6.16 (d, J=8.0 Hz, 1H), 6.08 (d, J=2.0 Hz, 1H), 4.40 (dd, J = 12.8, 6.4 Hz, 1H), 4.35 (s, 2H), 4.18 (s, 2H), 3.97 (t, J=5.2 Hz, 2H), 2.44 (s, 2H), 1.40 (d, J=6.4 Hz, 6H); MS (ESI) m/z 343.3 [M+H]⁺.

[0138] Préparation of 2-[[l-acetyl-5-(2-propan-2-ylpyrazol-3-yl)-3,6-dihydro-2H-pyridin-4-

[0139] Step 1: To a solution of (5-(l-isopropyl-lH-pyrazol-5-yl)-l,2,3,6-tetrahydropyridin4-yl)methanol hydrochloride (110 mg, 0.41 mmol) in DCM (2 mL) at 0 °C was added Et₃N (0.12 mL, 0.82 mmol) and a solution of Ac₂O (0.04 mL, 0.41 mmol) in DCM (0.4 mL), after stirred for 15 min, it was diluted with Sat. NH₄CI and EtOAc, organic layer was separated and the aqueous layer was further extracted with EtOAc, organic layers were combined, washed with Sat. NaHCO₃, brine, dried over Na₂SO₄, and was concentrated to give l-(4-

(hydroxymethyl)-5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydropyridin-l(2H)-yl)ethan-l-one as crude product.

SOCI₂

[0140] Step 2: To a solution of l-(4-(hydroxymethyl)-3-phenyl-5,6-dihydropyridin-l(2H)yljethanone (88 mg, 0.41 mmol) in DCM (2 mL) was added SOCI₂ (0.58 mL, 8.25 mmol). After stirred at RT for 15 min, the mixture was concentrated and dried under high vacuum to give l-(4-(chloromethyl)-5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydropyridin-l(2H)-yl)ethan-l-one as crude product (80 mg).

[0141] Step 3: To a suspension of K₂CO₃ (80 mg, 0.56 mmol) and 2,6dihydroxybenzaldehyde (80 mg, 0.56 mmol) in DMF (2 ml) was added a solution of l-(4(chloromethyl)-5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydropyridin-l(2H)-yl)ethan-l-one (80 mg, 0.28 mmol) in DMF (2 mL), the mixture was heated at 50 °C for 3 h, cooled to room température, and was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO₃, brine, dried over Na₂SO₄, and was concentrated to give crude oil, which was purified by préparative HPLC (eluted with ACN/H₂O) to give 2-((l-acetyl-5-(l-isopropyl-lH-pyrazol-5-yl)- l,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-hydroxybenzaldehyde (9 mg). 1H NMR (400 MHz, CDCI₃, NMR shows rotamer exist, only one set of signal was reported) δ (ppm) 11.87 (s, 1H), 10.34 (s, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.15 (d, J

= 8.4 Hz, IH), 6.11(d, J = 1.6 Hz, IH), 4.36 (s, 2H), 4.34 (m, IH), 4.21 (s, 2H), 3.71 (t, J = 6.0

Hz, 2H), 2.51 (m, 2H), 2.19 (s, 3H), 1.42 (d, J = 6.8 Hz, 6H); MS (ESI) m/z 384.3 [M+H]⁺

[0142] Préparation of 2-hydroxy-6-[[l-methyl-5-(2-propan-2-ylpyrazol-3-yl)-3,6-dihydro2H-pyridin-4-yl]methoxy]benzaldehyde

[0143] Step 1: To a solid of tert-butyl 4-(hydroxymethyl)-5-(l-isopropyl-lH-pyrazol-5-yl)-

3,6-dihydropyridine-l(2H)-carboxylate (150 mg, 0.47 mmol) in round bottom flask was added 4N HCl in dioxane (3 mL) at room temeprature, and was stirred for 1 h, then the mixture was concentrated and dried under high vacuum to give (5-(l-isopropyl-lH-pyrazol5-yl)-l,2,3,6-tetrahydropyridin-4-yl)methanol as HCl sait (120 mg).

NaB(OAc)₃H

HCHO

AcCN

[0144] Step 2: To a solution of (5-(l-isopropyl-lH-pyrazol-5-yl)-l,2,3,6-tetrahydropyridin4-yl)methanol hydrochloride in ACN (3 mL) was added Et₃N followed by formalin. After stirred at room température for 10 min, it was added Na(OAc)₃BH and after another 30 min, the mixture was concentrated and pass through a short silica gel column, the column was washed with 10% MeOH in CHCI₃, and then the filtrated was collected and concentrated to give crude product, which was further diluted with EtOAc, filtered to get rid of triethylamine

HCl sait, the filtrate was concentrated again to give (5-(l-isopropyl-lH-pyrazol-5-yl)-lmethyl-l,2,3,6-tetrahydropyridin-4-yl)methanol (100 mg).

[0145] Step 3 : To a solution of (5-(l-isopropyl-lH-pyrazol-5-yl)-l-methyl-l,2,3,6tetrahydropyridin-4-yl)methanol (100 mg, 0.42 mmol) in DCM (2.5 mL) was added SOCI₂ (0.76 mL, 10.5 mmol) at room température and then was stirred at room température for 30 min, the mixture was concentrated and diluted with toluene and concentrated, dried under high vacuum to give 4-(chloromethyl)-5-(l-isopropyl-lH-pyrazol-5-yl)-l-methyl-

1,2,3,6-tetrahydropyridine as crude product.

[0146] Step 4: To a suspension of K₂CO₃ (230 mg, 1.68 mmol) and 2,6dihydroxybenzaldehyde (120 mg, 0.84 mmol) in DMF (2 ml) was added a solution of 4(chloromethyl)-5-(l-isopropyl-lH-pyrazol-5-yl)-l-methyl-l,2,3,6-tetrahydropyridine (110 mg, 0.42 mmol) in DMF (3 mL), the mixture was heated at 50 °C for 4 h, cooled to room température, and was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layer was combined, washed with Sat. NaHCO₃, brine, dried over Na₂SO₄, and was concentrated to give crude oil, which was purified by column (Hexane/EtOAc= 65:35 followed by DCM/MeOH= 95:5) to give 2-hydroxy-6-((5-(l-isopropyllH-pyrazol-5-yl)-l-methyl-l,2,3,6-tetrahydropyridin-4-yl)methoxy)benzaldehyde (44 mg). 1H NMR (400 MHz, CDCI₃) δ (ppm) 11.89 (s, 1H), 10.34 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.31 (dd, J = 8.4,7.2 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.16 (d, J = 7.2 Hz, 1H), 6.07 (d, J =1.6 Hz, 1H), 4.36 (m, 1H), 4.34 (s, 2H), 3.07 (s, 2H), 2.71 (s, 2H), 2.52 (s, 2H), 2.43 (s, 3H), 1.41 (d, J = 6.4 Hz, 6H); MS (ESI) m/z 356.3 [M+H]⁺.

[0147] The following exemplary A-ring and B-ring intermediates may also be incorporated into the compounds of the invention.

[0148] Préparation of:

[0149] Step 1: To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-l,4-dicarboxylate (2.0g, 7.37 mmol) in DCM (45 mL) was added DIPEA (1.54 ml, 8.84 mmol) and Tf₂O (1.36 mL, 8.11 mmol) at -78 °C, then the température was warmed up to room température and the solution was stirred at RT for 1.5 h, the mixture was diluted with DCM (100 mL), organic layer was washed with Sat. NaHCO₃, brine, dried and concentrated to give l-(tert-butyl) 4ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-l,4(2H)-dicarboxylate, which was used for next step without purification.

OTf O

PddppfCI₂

Na₂CO₃

[0150] Step 2: To a solution of 1-tert-butyl 4-ethyl 3-(((trifluoromethyl)sulfonyl)oxy)-5,6dihydropyridine-l,4(2H)-dicarboxylate (1.49 g, 3.7 mmol) and (l-isopropyl-lH-pyrazol-5yl)boronic acid (0.57 g, 3.7 mmol) in dioxane (10 mL) was added Pd(dppf)CI₂ (0.27 g, 0.37 mmol) and a solution of sodium carbonate (1.18 g, 11.10) in water (3 ml), the mixture was degased with N₂ for 5 min, and was heated at 100 °C for 15 h, after cooling to room

température the mixture was diluted with EtOAc and washed with Sat. NaHCO₃ and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=3:l) to give desired product 830 mg (62%).

[0151] Step 3: To a solution of l-(tert-butyl) 4-ethyl 5-(l-isopropyl-lH-pyrazol-5-yl)-3,6dihydropyridine-l,4(2H)-dicarboxylate (450 mg, 1.24 mmol) in THF (6 mL) was added LiAlH₄ (IM in THF, 1.49 mL, 1.49 mmol) at -20 °C, the reaction was stirred at -20 °C for 30 min, and was quenched with Sat. NH₄CI, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc= 100:0 to 40:60) to give tert-butyl 4-(hydroxymethyl)-5(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (370 mg, 91%).

[0152] Step 4: To a solution of give tert-butyl 4-(hydroxymethyl)-5-(l-isopropyl-lHpyrazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (25 mg, 0.08 mmol) in DCM (1 mL) was added triphenylphosphine bromine adduct (40 mg, 0.09 mmol) at room température, after stirring for 30 min, it was diluted with DCM, washed with Sat. NaHCO3, brine, dried and concentrated to give crude product, which was purified by column to give tert-butyl 4(bromomethyl)-5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (18 mg).

[0153] Préparation of 2-hydroxy-6-[[cis-3-(2-propan-2-ylpyrazol-3-yl)oxan-4yl]methoxy]benzaldehyde

[0154] Step 1: To a solution of ethyl 5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydro-2H-pyran4-carboxylate (100 mg, 0.38 mmol) in EtOH (2 mL) was added Pd/C (50 mg), then it was charged with H₂ (latm) and stirred at room température for 3 days, Mass spec shows about 50% conversion. The mixture was then added a solution of NH₄CO₂H (200 mg) in water (2 ml) and additional Pd/C, and the mixture was further heated at 75 °C for 1.5 h, after cooled 10 to room température, the reaction was diluted with EtOH, pd/C was filtered off, and the filtrate was concentrated to give crude oil, which was diluted with CHCI3, organic layer was washed with Sat. NaHCO₃, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=65:35) to give (±) ethyl (3S,4R)-3-(l-isopropyl-lH-pyrazol-5yl)tetrahydro-2H-pyran-4-carboxylate (70 mg).

[0155] Step 2: To a solution of (±) (3S,4R)-ethyl 3-(l-isopropyl-lH-pyrazol-5-yl)tetrahydro2H-pyran-4-carboxylate (70 mg, 0.26 mmol) in THF (1.5 mL) at -15 °C was added IM LiAH₄ solution in THF (0.34 mL, 0.34 mmol) slowly. After stirred for 30 min, it was quenched with Sat. NH₄CI; the mixture was extracted with EtOAc. Organic layers were combined, dried and

concentrated to give (±) (3S,4R)-3-(l-isopropyl-lH-pyrazol-5-yl)tetrahydro-2H-pyran-4yl)methanol as crude product (60 mg).

OH O

PPh3

DIAD

[0156] Step 3: To a solution of (±) ((3S, 4R)-3-(l-isopropyl-lH-pyrazol-5-yl)tetrahydro-2Hpyran-4-yl)methanol (50 mg, 0.22 mmol) and 2,6-dihydroxybenzaldehyde (60 mg, 0.44 mmol)in THF (1 mL) was added PPh₃ (120 mg, 0.44 mmol) and DIAD (0.09 mL, 0.44 mmol) at 0 °C. After stirred for 30 min, the solution was concentrated and the residue was purified by column (Hexanes/EtOAc=60:40) to give impure product, which was further purified by prep HPLC (eluted with ACN/H₂O) to give (±) 2-hydroxy-6-(((3S,4R)-3-(l-isopropyl-lH-pyrazol-5yl)tetrahydro-2H-pyran-4-yl)methoxy)benzaldehyde (6 mg). 1H NMR (400 MHz, CDCI₃) Ô (ppm) 11.90 (s, 1H), 10.36 (s, 1H), 7.79 (s, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.32 (t, J = 8.8 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 1.6 Hz, 1H), 6.16 (d, J = 8.0 Hz, 1H), 4.46 (m, 1H), 4.13 (dt, J = 11.2, 4.0 Hz, 1H), 3.95 (dd, J= 11.2, 3.2 Hz, 1H), 3.81 (dd, J = 11.6, 3.2 Hz, 1H), 3.73 (dd, J = 9.2, 5.6 Hz, 1H), 3.65 (dt, J = 11.6, 3.2 Hz, 1H), 3.57 (t, J = 8.8 Hz, 1H), 3.28 (d, J = 4.0 Hz, 1H), 2.56 (m, 1H), 1.87 (m, 1H), 1.58 (m, 1H), 1.31 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 7.6 Hz, 3H); MS (ESI) m/z 334.3 [M+H]⁺.

[0157] Step 5: To a solution of tert-butyl 4-(bromomethyl)-5-(l-isopropyl-lH-pyrazol-5-yl)r .'c'

3,6-dihydropyridine-l(2H)-carboxylate (18 mg, 0.05 mmol) and '-''10 mg, 0.06 mmol) in

DMF (1 mL) is added K₂CO₃ (14 mg, 0.1 mmol). After stirring at room température for 1 h, it is diluted with water and EtOAc, organic layer is separated, and the aqueous layer is extracted with EtOAc, organic layer is combined, washed with brine, dried and concetrated to give crude product, which is purified by column (Hexanes/EtOAc=2:l.

GBT902

2-hydroxy-6-(((3 S,4S)-3-(1 -isopropyl-1 H-pyrazol-5-yl)tetrahydro-2 H-pyran-4-yl)methoxy)benzaldehyde

[0158] GBT902- (±) 2-hydroxy-6-(((3S, 4S)-3-(l-isopropyl-lH-pyrazol-5-yl)tetrahydro-2Hpyran-4-yl)methoxy)benzaldehyde. The compound was synthesized in three steps starting from (±) (3S,4R)-ethyl S-fl-isopropyl-lH-pyrazol-S-ylftetrahydro-ZH-pyran-A-carboxylatei

[0159] Step 1: To EtOH (2 mL) in round bottom flask was added NaH (65% dispersion in minerai oil, 60 mg, 1.36 mmol), after stirring for 5 min, the mixture was added a solution of (±) (3S,4R)-ethyl 3-(l-isopropyl-lH-pyrazol-5-yl)tetrahydro-2H-pyran-4-carboxylate (297 mg, 1.13 mmol) in EtOH. The mixture was heated at 80 °C for 3 h, cooled and diluted with EtOAc and Sat. NH4CI, organic layer was separated and the aqueous layer was extracted with EtOAc, organic layer was combined, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=2:l) to give ethyl (3S,4S)-3-(l-isopropyl-lH-pyrazol5-yl)tetrahydro-2H-pyran-4-carboxylate 190 mg.

[0160] Step 2: To a solution of (35,4S)-ethyl 3-(l-isopropyl-lH-pyrazol-5-yl)tetrahydro-2H15 pyran-4-carboxylate (190 mg, 0.71 mmol) in THF (3 mL) at -20 °C was added LiAlH₄ (IM in THF, 0.89 mL, 0.89 mmol). After stirring at -20 °C for 15 min, the reaction was quenched with Sat. NH₄CI, extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give ((35,4S)-3-(l-isopropyl-lH-pyrazol-5-yl)tetrahydro-2H-pyran4-yl)methanol as crude product (160 mg).

[0161] Step 3: To a solution of ((35,4S)-3-(l-isopropyl-lH-pyrazol-5-yl)tetrahydro-2Hpyran-4-yl)methanol (160 mg, 0.71 mmol) in THF (2 mL) was added 2,6dihydroxybenbzaldehyde (0.15 g, 1.06 mmol) at room température, then it was cooled to 0 °C and added DIAD (0.20 mL, 1.06 mmol). After stirring for 1 h, the mixture was concentrated and subjected to column chromatography to (±) 2-hydroxy-6-(((3S, 4S)-3-(l

isopropyl-lH-pyrazol-5-yl)tetrahydro-2H-pyran-4-yl)methoxY)benzaldehyde 104 mg (Hexanes/EtOAc=100:0 to 65:35 to 55:45) to give ¹H NMR (400 MHz, Chloroform-d) δ 11.90 (d, J = 0.4 Hz, IH), 10.35 (d, J = 0.6 Hz, IH), 7.51 (dt, J = 2.0, 0.6 Hz, IH), 7.30 (t, J = 8.5 Hz, IH), 6.51 (dt, J = 8.5, 0.7 Hz, IH), 6.16 (dd, J = 8.3, 0.8 Hz, IH), 6.06 (dd, J = 1.9, 0.4 Hz, IH), 4.47 (p, J = 6.6 Hz, IH), 4.21 - 4.07 (m, IH), 3.99 - 3.84 (m, 2H), 3.80 (dd, J = 9.2, 5.2 Hz, IH), 3.65 - 3.53 (m, IH), 3.36 (t, J = 11.3 Hz, IH), 3.09 (td, J = 11.0, 4.4 Hz, IH), 2.29 - 2.21 (m, IH), 1.95 - 1.85 (m, 2H), 1.44 (d, J = 6.6 Hz, 3H), 1.33 - 1.21 (m, 3H). MS (M+H)+ found for C19H24N2O4: 345.3.

GBT906

(S)-2-hydroxy-6-((1-(1-isopropyl-1 H-pyrazol-5-yl)pyrrolidin-2yl)methoxy)benzaldehyde

[0162] GBT906 - Préparation of (S)-2-hydroxy-6-((l-(l-isopropyl-lH-pyrazol-5yl)pyrrolidin-2-yl)methoxy)benzaldehyde. The compound was prepared from (S)-pyrrolidin2-ylmethanol and 5-iodo-l-isopropyl-lH-pyrazole according to scheme 1, reaction steps 3 and 4. ^XH NMR (400 MHz, Chloroform-d) δ 11.92 (s, IH), 10.07 (d, J = 0.6 Hz, IH), 7.45 (dd, J = 2.0, 0.5 Hz, IH), 7.34 (t, J = 8.4 Hz, IH), 6.49 (dt, J = 8.5, 0.7 Hz, IH), 6.24 (dd, J = 8.3, 0.8 Hz, IH), 5.91 - 5.81 (m, IH), 4.70 - 4.55 (m, IH), 3.97 (dd, J = 9.3, 4.8 Hz, IH), 3.88 (dd, J = 9.3, 5.6 Hz, IH), 3.75 (dddd, J = 7.6, 6.6, 5.5, 4.8 Hz, IH), 3.48 - 3.37 (m, IH), 2.94 (dt, J = 9.2, 7.2 Hz, IH), 2.31 - 2.15 (m, IH), 2.09 - 1.81 (m, 3H), 1.45 (d, J = 6.7 Hz, 3H), 1.29 (d, J = 6.6 Hz, 3H). MS (M+H)+ found for C₁₈H₂3N₃O3: 330.3.

GBT918

(S)-2-hydroxy-6-((1-(1-isopropyl-1 /7-pyrazol-5-yl)piperidin-2yl)methoxy)benzaldehyde

[0163] GBT918 - Préparation of (S)-2-hydroxy-6-((l-(l-isopropyl-lH-pyrazol-5yl)piperidin-2-yl)methoxy)benzaldehyde. The compound was prepared from (S)-piperidin2-ylmethanol hydrochloride and 5-iodo-l-isopropyl-lH-pyrazole according to scheme 1, reaction steps 3 and 4. ^XH NMR (400 MHz, Chloroform-d) δ 11.88 (d, J = 0.4 Hz, 1H), 10.31 (d, J = 0.6 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.36 - 7.28 (m, 1H), 6.49 (dt, J = 8.5, 0.7 Hz, 1H), 6.09 (dd, J = 8.3, 0.8 Hz, 1H), 6.06 (d, J = 2.1 Hz, 1H), 4.84 (hept, J = 6.7 Hz, 1H), 3.87 - 3.75 (m, 2H), 3.17 (dq, J = 8.4, 3.8 Hz, 1H), 3.02 (dt, J = 11.8, 3.8 Hz, 1H), 2.75 (td, J = 11.2, 3.4 Hz, 1H), 2.03 - 1.86 (m, 2H), 1.71 (dddd, J = 16.8, 15.4,11.8, 7.2 Hz, 3H), 1.59 - 1.45 (m, 1H), 1.42 (d,

J = 6.7 Hz, 3H), 1.32 (d, J = 6.7 Hz, 3H). MS (M+H)+ found for Ci₉H25N₃O₃: 344.4.

GBT919

[0164] GBT919- 2-hydroxy-6-((4-(2-methoxypyridin-3-yl)-2,5-dihydrofuran-3yl)methoxy)benzaldehyde. The compound was synthesized according to scheme 2 in five steps starting from ethyl 4-oxotetrahydrofuran-3-carboxylate using reaction steps 1, 2, 3, 4 and method B.

Step4

[0165] Step 1: To a solution of ethyl 4-oxotetrahydrofuran-3-carboxylate (1.13 g, 7.15 mmol) in DCM (20 ml) was added DIPEA (1.38 mL, 7.87 mmol) and Tf₂O (1.20 mL, 7.15 mmol) at -78 °C, then it was warmed up to room température and was further stirred for 15 h, the mixture was diluted with DCM, washed with Sat. NaHCO₃, brine, dried and concentrated to give ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate as crude product, which was used for next step without purification (2.3 g).

[0166] Step 2: To a solution of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3carboxylate (2.3 g) and (2-methoxypyridin-3-yl)boronic acid (1.09 g, 7.15 mmol) in Dioxane (20 mL) was added Pd(dppf)CI₂ (530 mg, 0.72 mmol) and a solution of Na₂CO₃ (2.27 g, 21.45 mmol) in water (10 mL), the mixture was degassed and heated at 100 °C for 15 h, the solution was diluted with EtOAc, organic layer was washed with water, brine, dried over MgSO₄ and was concentrated to give crude product, which was purified by column chromatography to give ethyl 4-(2-methoxypyridin-3-yl)-2,5-dihydrofuran-3-carboxylate (1.1

g).

[0167] Step 3: To a solution of ethyl 4-(2-methoxypyridin-3-yl)-2,5-dihydrofuran-3carboxylate (146 mg, 0.60 mmol) in THF (2 ml) at -20 °C was added IM LiAlH₄ in THF (0.72 mL, 0.72 mmol). After stirred for 20 min, it was quenched with Sat. NH₄CI, the mixture was extracted with EtOAc (3X), organic layers were combined, dried over MgSO₄ and was concentrated to give (4-(2-methoxypyridin-3-yl)-2,5-dihydrofuran-3-yl)methanol as crude product (120 mg), which was used without purification in next step.

[0168] Step 4: To a solution of (4-(2-methoxypyridin-3-yl)-2,5-dihydrofuran-3-yl)methanol (120 mg, 0.58 mmol) in DCM (2 mL) was added PPh₃Br₂ (300 mg, 0.72 mmol). After stirred at room température for 30 min, it was diluted with DCM and washed with Sat. NaHCO₃, brine, dried over MgSO₄ and concentrated to give crude product, which was purified by column chromatography to give 3-(4-(bromomethyl)-2,5-dihydrofuran-3-yl)-2-methoxypyridine (62 mg).

[0169] Method B: To a solution of 3-(4-(bromomethyl)-2,5-dihydrofuran-3-yl)-2methoxypyridine (62 mg, 0.22 mmol) and 2,6-dihydroxybenzaldehyde (60 mg, 0.44 mmol) in DMF (1 mL) was added K₂CO₃ (90 mg, 0.66 mmol). After stirred at room température for 30 min, the mixture was added water, extracted with EtOAc (3X), organic layers were combined, washed with brine, dried and concentrated to give crude product, which was purified by column chromatography to give 2-hydroxy-6-((4-(2-methoxypyridin-3-yl)-2,5dihydrofuran-3-yl)methoxy)benzaldehyde (47 mg). ¹H NMR (400 MHz, Chloroform-d) δ 11.93 (s, 1H), 10.20 (d, J = 0.6 Hz, 1H), 8.16 (dd, J = 5.0,1.9 Hz, 1H), 7.42 (dd, J = 7.3, 1.9 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 6.96 - 6.87 (m, 1H), 6.52 (dt, J = 8.5, 0.7 Hz, 1H), 6.24 (dd, J = 8.3, 0.8 Hz, 1H), 5.00 (ddq, J = 4.9, 2.2,1.2 Hz, 2H), 4.97 - 4.90 (m, 2H), 4.73 - 4.67 (m, 2H), 3.94 (s, 3H). MS(M-H) found for C18H17NO5: 326.2.

GBT928

[0170] GBT928- 2-hydroxy-6-(((3S,4S)-4-(2-methoxypyridin-3-yl)tetrahydrofuran-3 yl)methoxy)benzaldehyde. The compound was synthesized in three steps according to scheme 2 starting from ethyl 4-(2-methoxypyridin-3-yl)-2,5-dihydrofuran-3-carboxylate using reaction steps 5, 6 and method A.

[0171] Step 5: To a solution of ethyl 4-(2-methoxypyridin-3-yl)-2,5-dihydrofuran-3carboxylate (500 mg, 1 mmol) in EtOH (3 mL) was added Pd/C (50 mg), charged with H₂ (1 atm). After stirred for 24 h, Pd/C was filtered off and the filtrate was concentrated to give crude product, which was purified by column chromatography to give (±) ethyl (3S,4S)-4-(2methoxypyridin-3-yl)tetrahydrofuran-3-carboxylate (140 mg) and (±) ethyl (3/?,4S)-4-(2methoxypyridin-3-yl)tetrahydrofuran-3-carboxylate (100 mg).

[0172] Step 6: To a solution of (3S,4S)-ethyl 4-(2-methoxypyridin-3-yl)tetrahydrofuran-3carboxylate (140 mg) in THF (2 mL) was added LiAlH₄ in THF at -20 °C, then after 30 min, it was quenched with Sat. NH₄CI, extracted with EtOAc, organic layers were combined, washed with brine, dried and concentrated to give ((3/?,4S)-4-(2-methoxypyridin-3yl)tetrahydrofuran-3-yl)methanol as crude oil 120 mg.

[0173] Method A: To a solution of ((3/?,4S)-4-(2-methoxypyridin-3-yl)tetrahydrofuran-3yljmethanol (120 mg, 0.57 mmol) and 2,6-dihydroxybenzaldehyde (0.10 g, 0.71 mmol) in

THF (lmL) was added PPh₃ (0.22 g, 0.85 mmol) and DIAD (0.17 mL, 0.85 mmol) at room température, after stirred for 1 h, it was concentrated to give drude oil, which was purified by column chromatography followed by préparative HPLC to give 2-hydroxy-6-(((3S,4S)-4-(2methoxypyridin-3-yl)tetrahydrofuran-3-yl)methoxy)benzaldehyde 6 mg. *H NMR (400 MHz, Chloroform-d) δ 11.90 (s, IH), 10.12 (t, J = 0.5 Hz, IH), 8.04 (dd, J = 5.0, 1.9 Hz, IH), 7.52 (ddd, J = 7.3,1.8, 0.6 Hz, IH), 7.29 (t, J = 8.4 Hz, IH), 6.85 (ddd, J = 7.4, 5.0, 0.5 Hz, IH), 6.46 (dq, J = 8.5, 0.6 Hz, IH), 6.06 (dd, J = 8.3, 0.8 Hz, IH), 4.23 - 4.12 (m, 3H), 3.92 (d, J = 0.4 Hz,

3H), 3.90 - 3.77 (m, 3H), 3.65 (dd, J = 9.3, 7.7 Hz, 1H), 3.20 (qt, J = 7.6, 6.2 Hz, 1H). MS found for C18H19NO5: 330.3.

GBT929

2-hydroxy-6-((4-(1-isopropyl-1 /7-pyrazol-5-yl)-2,5-dihydrofuran-3-yl)methoxy)benzaldehyde

[0174] GBT929- 2-hydroxy-6-((4-(l-isopropyl-lH-pyrazol-5-yl)-2,5-dihydrofuran-3yl)methoxy)benzaldehyde. The compound was synthesized according to scheme 2 in four steps starting from ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate using reaction steps 2, 3, 4 and method B

[0175] Step 2: To a solution of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3carboxylate (2.76 g, 9.5 mmol) and l-isopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)-lH-pyrazole (2.24 g, 9.50 mmol) in Dioxane (20 mL) was added Pd(dppf)Cl₂ (700 mg, 0.95 mmol) and a solution of Na₂CO₃ (3.02 g, 28.50 mmol) in water (10 mL), the mixture was degassed and heated at 100 °C for 15 h, the solution was diluted with EtOAc, organic layer was washed with water, brine, dried over MgSO4 and was concentrated to give crude product, which was purified by column chromatography (hexanes/EtOAc=3:l) to give ethyl 4-(2-methoxypyridin-3-yl)-2,5-dihydrofuran-3-carboxylate (900 mg).

[0176] Step 3: To a solution of ethyl 4-(l-isopropyl-lH-pyrazol-5-yl)-2,5-dihydrofuran-3carboxylate (250 mg, 1 mmol) in THF (3 mL) at -20 °C was added LiAlH₄ (IM in THF, 1.2 mL, 1.2 mmol). After stirred for 20 min, it was quenched with Sat. NH₄CI and was extracted with EtOAc, organic layers were combined, washed with brine, dried over MgSO₄ and was

concentrated to give (4-(l-isopropyl-lH-pyrazol-5-yl)-2,5-dihydrofuran-3-yl)methanol as crude product (210 mg).

[0177] Step 4: To a solution of (4-(l-isopropyl-lH-pyrazol-5-yl)-2,5-dihydrofuran-3yl)methanol (210 mg, 1 mmol) in DCM (3 mL) was added PPh₃Br₂ (420 mg, Immol) at room température, after stirred for 20 min, it was diluted with DCM, organic layer was washed with Sat. NaHCO₃, brine, dried over MgSO₄ and was concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=3:l) to give 5-(4(bromomethyl)-2,5-dihydrofuran-3-yl)-l-isopropyl-lH-pyrazole (110 mg).

[0178] Method B: To a solution of 5-(4-(bromomethyl)-2,5-dihydrofuran-3-yl)-l-isopropyllH-pyrazole (110 mg, 0.41 mmol) in DMF (2 mL) was added K₂CO₃ (170 mg, 1.23 mmol) and

2,6-dihydroxybenzaldehyde (0.11 g, 0.82 mmol) at room température, after stirred for 30 min, it was diluted with water and EtOAc, EtOAc layer was separated and the aqueous layer was extracted with EtOAc, organic layers were combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=2:l) to give 2-hydroxy-6-((4-(l-isopropyl-lH-pyrazol-5-yl)-2,5-dihydrofuran-3yl)methoxy)benzaldehyde (101 mg). *H NMR (400 MHz, Chloroform-d) δ 11.93 (d, J = 0.4 Hz, 1H), 10.23 (d, J = 0.6 Hz, 1H), 7.57 (dd, J = 1.8, 0.6 Hz, 1H), 7.35 (t, J = 8.5, 1H), 6.55 (dt, J = 8.5, 0.7 Hz, 1H), 6.23 (dd, J = 8.3, 0.8 Hz, 1H), 6.14 (d, J = 1.8 Hz, 1H), 4.97 (dt, J = 4.9, 3.3 Hz, 2H), 4.93 - 4.86 (m, 2H), 4.70 - 4.65 (m, 2H), 4.44 - 4.32 (m, 1H), 1.67 - 1.41 (m, 6H). MS found for Ci₈H₂₀N₂O₄: 329.3.

GBT932

[0179] GBT932- 2-hydroxy-6-(((3S,4ff)-4-(2-methoxypyridin-3-yl)tetrahydrofiiran-3 yl)methoxy)benzaldehyde. The compound was synthesized in two steps starting from (3S,4S)-ethyl 4-(2-methoxypyridin-3-yl)tetrahydrofuran-3-carboxylate using reaction steps 6 and method A.

[0180] Step 6: To a solution of (3S,4S)-ethyl 4-(2-methoxypyridin-3-yl)tetrahydrofuran-3carboxylate (100 mg, 0.40 mmol) in THF (2 mL) was added LÎAIH4 (IM in THF, 0.48 mL, 0.48 mmol) at -20 °C, after stirred for 30 min, it was quenched with Sat. NH₄CI, extracted with EtOAc, organic layers were combined, washed with brine, dried over MgSO₄, and was concentrated to give ((3S,4S)-4-(2-methoxypyridin-3-yl)tetrahydrofuran-3-yl)methanol as crude oil 80 mg.

[0181] Method A: To a solution of ((3R,4S)-4-(2-methoxypyridin-3-yl)tetrahydrofuran-3yl)methanol (80 mg, 0.40 mmol) and 2,6-dihydroxybenzaldehyde (0.07 g, 0.52 mmol) in THF (lmL) was added PPh₃ (0.16 g, 0.60 mmol) and DIAD (0.12 mL, 0.60 mmol) at room température, after stirred for 1 h, it was concentrated to give crude oil, which was purified by column chromatography to give 2-hydroxy-6-(((3S,4/î)-4-(2-methoxypyridin-3yl)tetrahydrofuran-3-yl)methoxy)benzaldehyde 20 mg. ^XH NMR (400 MHz, Chloroform-d) δ 11.93 (d, J = 0.3 Hz, 1H), 10.13 (d, J = 0.6 Hz, 1H), 8.08 (dd, J = 5.0,1.8 Hz, 1H), 7.53 (ddd, J = 7.3,1.8, 0.5 Hz, 1H), 7.43 - 7.32 (m, 1H), 6.93 - 6.83 (m, 1H), 6.52 (dt, J = 8.5, 0.7 Hz, 1H), 6.33 (dd, J = 8.3, 0.8 Hz, 1H), 4.20 (ddd, J = 8.7, 7.6, 5.2 Hz, 2H), 4.14 - 4.03 (m, 2H), 3.94 (s, 3H), 3.92 - 3.80 (m, 2H), 3.52 (q, J = 7.1 Hz, 1H), 2.93 (dq, J = 7.4, 6.6 Hz, 1H). MS found for Ci₈H₁₉NO₅: 330.3.

GBT947

2-hydroxy-6-(((3S,4S)-4-(1-isopropyl-1H-pyrazol-5-yl)tetrahydrofuran-3-yl)methoxy)benzaldehyde

[0182] GBT947- 2-hydroxy-6-(((3S,4S)-4-(l-isopropyl-lH-pyrazol-5-yl)tetrahydrofuran-3yl)methoxy)benzaldehyde. The compound was synthesized according scheme 2 in three steps starting from ethyl 4-(l-isopropyl-lH-pyrazol-5-yl)-2,5-dihydrofuran-3-carboxylate using reaction steps 5, 6 and method A.

[0183] Step 5: To a solution of ethyl 4-(l-isopropyl-lH-pyrazol-5-yl)-2,5-dihydrofuran-3carboxylate (325 mg, 1.32 mmol) in EtOH (4 mL) was added Pd/C (150 mg), then it was charged with H₂ (latm) and then stirred at room température for 3 h, H₂ balloon was removed and the mixture was added NH₄CO₂H in water (1 mL) and was heated at 75 °C for 3 h, the mixture was cooled and diluted with EtOAc and water, aqueous layer was separated and extracted with EtOAc, organic layers were combined, washed with brine, dried over MgSO₄ and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc=60:40) to give ethyl (3S,4S)-4-(l-isopropyl-lH-pyrazol-510 yl)tetrahydrofuran-3-carboxylate (216 mg).

[0184] Step 6: To a solution of (4-(l-isopropyl-lH-pyrazol-5-yl)-2,5-dihydrofuran-3yl)methanol (216 mg, 0.87 mmol) in THF (4 mL) at -20 °C was added LiAlH₄ (IM in THF, 1.04 mL, 1.04 mmol). After stirred for 20 min, it was quenched with Sat. NH₄CI, aqueous layer was extracted with EtOAc, organic layers were combined, washed with brine, dried and concentrated to give ((3/?,4S)-4-(l-isopropyl-lH-pyrazol-5-yl)tetrahydrofuran-3-yl)methanol as crude oil (180 mg).

[0185] Method A; To a solution of ((3R,4S)-4-(l-isopropyl-lH-pyrazol-5-yl)tetrahydrofuran3-yl)methanol (180 mg, 0.86 mmol) and 2,6-dihydroxybenzaldehyde (150 mg, 1.12 mmol) in THF (1.6 mL) was added PPh₃ (340 mg, 1.29 mmol) and DIAD (0.25 mL, 1.29 mmol) at 0 °C, then it was stirred at room température for 1 h, and was concentrated and purified by column (Hexanes/EtOAc = 60:40) to give 2-hydroxy-6-(((3S,4S)-4-(l-isopropyl-lH-pyrazol-5yl)tetrahydrofuran-3-yl)methoxy)benzaldehyde 82 mg. ^XH NMR (400 MHz, Chloroform-d) δ 11.88 (d, J = 0.4 Hz, IH), 10.27 (t, J = 0.5 Hz, IH), 7.50 (dd, J = 1.8, 0.6 Hz, IH), 7.35 (t, J = 8.5, IH), 6.51 (dq, J = 8.5, 0.6 Hz, IH), 6.10 (ddt, J = 5.4, 3.5, 0.6 Hz, IH), 4.53 (h, J = 6.5 Hz, IH),

4.29 - 4.22 (m, IH), 4.19 (dd, J = 8.9, 7.1 Hz, IH), 4.04 (dd, J = 8.6, 6.5 Hz, IH), 3.94 (dd, J =

8.9, 5.9 Hz, IH), 3.79 - 3.69 (m, 2H), 3.60 (dd, J = 9.3, 6.2 Hz, IH), 3.02 (dtd, J = 13.6, 7.7, 6.1 Hz, 2H), 1.46 (dd, J = 14.1, 6.6 Hz, 6H). MS found for Ci₈H₂₂N₂O₄: 331.3.

GBT966

[0186] GBT966- 2-hydroxy-6-((4-(l-isopropyl-lH-pyrazol-5-yl)-5,6-dihydro-2H-pyran-3 yl)methoxy)benzaldehyde. The compound was synthesized in five steps starting from oxan4-one.

Step 1

NCCOOEt

LDA, THF

[0187] Step 1: Into a 250-mL round-bottom flask, was placed a solution of oxan-4-one (5.0 g, 49.94 mmol, 1.00 equiv) in tetrahydrofuran (60 mL). This was followed by the addition of LDA (newly prepared from diisopropylamine and BuLi) (1.20 equiv) dropwise with stirring at -78 °C. The mixture was stirred for 1 h at 0 °C. HMPA (9.8 g, 54.69 mmol, 1.10 equiv) was then added to the reaction dropwise at -78 °C. The mixture was stirred for another 15 min at the same température. 2-Ethoxy-2-oxoacetonitrile (5 g, 50.46 mmol, 1.01 equiv) was then added to the reaction dropwise at -78 °C. The resulting solution was stirred for 2 h at 0 °C, and then it was quenched with 50 mL of water. The resulting mixture was concentrated under vacuum, and then it was extracted with EA (50 mL x 3). The combined organic layers were washed with 2x80 mL of water and 1x80 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30) as eluent to yield 1.82 g (21%) of ethyl 4oxooxane-3-carboxylate as a colorless oil.

[0188] Step 2: Into a 50-mL round-bottom flask, was placed a solution of ethyl 4-hydroxy-

5,6-dihydro-2H-pyran-3-carboxylate (570 mg, 3.31 mmol, 1.00 equiv) and DIEA (2.5 mL, 5.00

equiv) in dichloromethane (20 mL). Tf₂O (1.0 mL, 2.00 equiv) was added to the reaction dropwise at 0 °C. The resulting solution was stirred for 1 h at 0 C and for another 2 h at room température. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2x40 mL of ethyl acetate, and the combined organic layers were washed with 3x20 mL of water and 1x20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:25) as eluent to yield 0.67 g (67%) of ethyl 4[(trifluoromethane)sulfonyloxy]-5,6-dihydro-2H-pyran-3-carboxylate as a light yellow oil. [0189] Step 3: Into a 50-mL round-bottom flask, was placed a solution of ethyl 4[(trifluoromethane)sulfonyloxy]-5,6-dihydro-2H-pyran-3-carboxylate (540 mg, 1.77 mmol, 1.00 equiv), l-(propan-2-yl)-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (543 mg, 2.30 mmol, 1.30 equiv) in a solvent mixture of toluene (15.0 mL), aqueous solution of sodium carbonate (2M) (5.0 mL) and éthanol (5.0 mL). This was followed by the addition of Pd(dppf)CI₂CH₂CI₂ (115 mg, 0.08 equiv). The resulting solution was stirred for 4 h at 100 °C under N₂. The reaction was then quenched with 15 mL of water. The resulting solution was extracted with 3x30 mL of ethyl acetate. The combined organic layers were washed with 2x50 mL of water and 1x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15-1:6) as eluent to yield 372 mg (79%) of ethyl 4-[l(propan-2-yl)-lH-pyrazol-5-yl]-5,6-dihydro-2H-pyran-3-carboxylate as a light yellow oil.

[0190] Step 4: Into a 50-mL round-bottom flask, was placed a solution of ethyl 4-[l(propan-2-yl)-lH-pyrazol-5-yl]-5,6-dihydro-2H-pyran-3-carboxylate (234 mg, 0.89 mmol, 1.00 equiv) in tetrahydrofuran (15 mL). This was followed by the addition of LAH (51 mg, 1.34 mmol, 1.52 equiv) at 0 °C. The resulting solution was stirred for 1 h at 0 °C. The reaction was then quenched by the addition of 10 mL of 2.5 M sodium hydroxide aq. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x20 mL of water and 1x20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) as eluent to furnish 124 mg (63%) of [4-[l-(propan-2-yl)-lH-pyrazol-5-yl]-5,6-dihydro-2H-pyran-3yljmethanol as a colorless oil.

[0191] Step 5: Into a 25-mL round-bottom flask, was placed a solution of [4-[l-(propan-2yl)-lH-pyrazol-5-yl]-5,6-dihydro-2H-pyran-3-yl]methanol (124 mg, 0.56 mmol, 1.00 equiv),

2,6-dihydroxybenzaldehyde (116 mg, 0.84 mmol, 1.50 equiv), and PPh₃ (220 mg, 0.84 mmol, 1.50 equiv), in tetrahydrofuran (10 mL). This was followed by the addition of DIAD (170 mg, 0.84 mmol, 1.50 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 30 min at 0 °C and for an additîonal 1 h at room température. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x25 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x60 mL of water and 1x40 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:7) as eluent. The crude product was further purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column,5um, 19*150mm,; mobile phase, water with 0.05%TFAand MeCN (42.0% MeCN up to 55.0% in 8 min, up to 95.0% in 2 min,down to 42.0% in 2 min); Detector, Waters2545 UvDector 254&220nm. This provided 68 mg (36%) of 2-hydroxy-6-([4-[l(propan-2-yl)-lH-pyrazol-5-yl]-5,6-dihydro-2H-pyran-3-yl]methoxy)benzaldehyde as a light yellow solid. ¹HNMR (400MHz, CDCI₃, ppm): 11.90 (s, IH), 10.32 (s, IH), 7.56 (s, IH), 7.33 (t, J = 8.4 Hz, IH), 6.53 (d, J = 8.4 Hz, IH), 6.16 (d, J = 8.4 Hz, IH), 6.07 (s, IH), 4.44-4.40 (m, 5H), 3.96 (t, J = 5.6 Hz, 2H), 2.19 (s, 2H), 1.43 (d, J = 6.4 Hz, 6H); MS (ES, m/z:) 343.2 [M+l]⁺

GBT999 (S)-2-hydroxy-6-((1-(2-methoxypyridin-3-yl)-5-oxopyrrolidin-2-yl)methoxy)benzaldehyde

[0192] GBT999- Préparation of (S)-2-hydroxy-6-((l-(2-methoxypyridin-3-yl)-5oxopyrrolidin-2-yl)methoxy)benzaldehyde

[0193] The compound was prepared from (S)-5-(hydroxymethyl)pyrrolidin-2-one and 3iodo-2-methoxypyridine according to scheme 1, reaction steps 3 and 4. *H NMR (400 MHz,

Chloroform-d) δ 11.91 (d, J = 0.4 Hz, IH), 9.85 (d, J = 0.6 Hz, IH), 8.16 - 8.09 (m, IH), 7.56 7.49 (m, IH), 7.35 (ddd, J = 8.8, 8.1, 0.4 Hz, IH), 6.99 - 6.90 (m, IH), 6.53 (dt, J = 8.5, 0.7 Hz, IH), 6.21 (dd, J = 8.3, 0.8 Hz, IH), 4.67 (dtd, J = 8.5, 4.9, 3.7 Hz, IH), 4.07 - 3.95 (m, 2H), 3.93 (d, J = 0.5 Hz, 3H), 2.76 - 2.56 (m, 2H), 2.50 (dddd, J = 13.0, 9.5, 8.4, 7.4 Hz, IH), 2.20 - 2.04 (m, IH). MS found for Ci₈Hi₈N₂O₅: 343.3.

GBT1000

(S)-2-hydroxy-6-((1-(1-isopropyl-1 /7-pyrazol-5-yl)-5-oxopyrrolidin-2-yl)methoxy)benzaldehyde

[0194] GBT1000 - Préparation of (S)-2-hydroxy-6-((l-(l-isopropyl-lH-pyrazol-5-yl)-5oxopyrrolidin-2-yl)methoxy)benzaldehyde. The compound was prepared from (S)-5(hydroxymethyl)pyrrolidin-2-one and 5-iodo-l-isopropyl-lH-pyrazole according to scheme 1, reaction steps 3 and 4. ^XH NMR (400 MHz, Chloroform-d) δ 11.92 (s, IH), 10.13 (d, J = 0.6

Hz, IH), 7.56 (dd, J = 1.9, 0.6 Hz, IH), 7.38 (t, J = 8.4 Hz, IH), 6.57 (dt, J = 8.5, 0.7 Hz, IH), 6.25 (dd, J = 8.3, 0.8 Hz, IH), 6.02 (d, J = 1.9 Hz, IH), 4.34 - 4.19 (m, 2H), 4.08 (dd, J = 10.0,

3.4 Hz, IH), 4.02 (dd, J = 10.0, 3.6 Hz, IH), 2.79 - 2.60 (m, 2H), 2.52 (dddd, J = 13.3, 9.7, 8.4, 7.0 Hz, IH), 2.28 (dddd, J = 13.3, 9.9, 6.8, 5.4 Hz, IH), 1.48 (d, J = 6.6 Hz, 3H), 1.24 (d, J = 6.6 Hz, 3H). MS found for Ci₈H₂₁N₃O₄: 344.3.

GBT1042

(S)-2-hydroxy-6-((4-(1-isopropyl-1 /-/-pyrazol-5-yl)morpholin-3yl)methoxy)benzaldehyde

[0195] GBT1042 - Préparation of (S)-2-hydroxy-6-((4-(l-isopropyl-lH-pyrazol-5yl)morpholin-3-yl)methoxy)benzaldehyde. The compound was prepared from (R)-tert-butyl

3-(hydroxymethyl)morpholine-4-carboxylate and 3-iodo-2-methoxypyridine according to scheme 1, reaction stepsl, 3 and 4.¹H NMR (400 MHz, Chloroform-d) δ 11.88 (s, 1H), 10.26 (d, J = 0.6 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.40 - 7.28 (m, 1H), 6.51 (dt, J = 8.5, 0.7 Hz, 1H), 6.11 (dd, J = 8.4, 0.8 Hz, 1H), 6.07 (d, J = 2.0 Hz, 1H), 4.79 (hept, J = 6.6 Hz, 1H), 4.10 (ddd, J = 11.4, 3.4, 0.7 Hz, 1H), 3.98 - 3.86 (m, 3H), 3.86 - 3.73 (m, 2H), 3.42 - 3.32 (m, 1H), 3.04 10 2.91 (m, 2H), 1.52 - 1.37 (m, 3H), 1.33 (d, J = 6.7 Hz, 3H). MS found for C18H23N3O4: 346.3.

GBT1059

(S)-2-hydroxy-6-((5-oxo-1-(pyridin-3-yl)pyrrolidin-2-yl)methoxy)benzaldehyde

[0196] GBT1059- Préparation of (5)-2-hydroxy-6-((5-oxo-l-(pyridin-3-yl)pyrrolidin-215 yl)methoxy)benzaldehyde. The compound was prepared from (S)-5(hydroxymethyl)pyrrolidin-2-one and 3-iodopyridine according to scheme 1, reaction steps 3 and 4. 'H NMR (400 MHz, Chloroform-d) δ 11.88 (s, 1H), 10.05 (s, 1H), 8.64 (dd, J = 2.7, 0.7 Hz, 1H), 8.48 (dd,7 = 4.8, 1.5 Hz, 1H), 7.90 (ddd, J= 8.3, 2.6, 1.5 Hz, 1H), 7.39-7.28 (m, 2H), 6.55 (dd, J = 8.5, 0.8 Hz, 1H), 6.22 (dt, J = 8.3,1.0 Hz, 1H), 4.72 (dq, J = 8.3, 4.1

Hz, 1H), 4.19 - 4.05 (m, 2H), 2.84 - 2.61 (m, 2H), 2.54 (ddt, J = 13.2, 10.0, 8.3 Hz, 1H), 2.22 (dddd, J= 13.5, 9.9, 4.9, 3.7 Hz, 1H). MS found for C17H16N2O4: 313.3.

GBT1060

2-hydroxy-6-((4-(1-isopropyl-1 /7-pyrazol-5-yl)-1-methyl-2,5-dihydro-1 /7-pyrrol-3-yl)methoxy)benzaldehyde [0197] GBT1060- 2-hydroxy-6-((4-(l-isopropyl-lH-pyrazol-5-yl)-l-methyl-2,5-dihydro-lHpyrrol-3-yl)methoxy)benzaldehyde. The compound was synthesized in 7 steps according to a modified scheme 2 starting from 1-tert-butyl 3-ethyl 4-oxopyrrolidine-l,3-dicarboxylate_i

[0198] Steps 1&2: To a solution of 1-tert-butyl 3-ethyl 4-oxopyrrolidine-l,3-dicarboxylate (1.49 g, 5.81 mmol) in DCM (15 mL) at -78 °C was added DIPEA (1.22 mL) and Tf₂O (1.08 mL), then it was warmed to room température and was further stirred for 2 h, mixture was diluted with more DCM, DCM layer was washed with Sat. NaHCO₃, brine, dried over MgSO₄ and concentrated to give crude triflate. To a solution of this crude triflate in Dioxane (15 mL) was added l-isopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.37 g, 5.81 mmol) and Pd(dppf)CI₂ (0.42 g, 0.58 mmol) and a solution of Na₂CO₃ (1.23 g, 11.62 mmol) in water (5 mL). After heated at 100 °C for 15 h the solution was diluted with EtOAc, organic layer was washed with water, brine, dried over MgSO₄ and was concentrated to give crude product, which was purified by column chromatography to give ethyl 1-tert-butyl 3ethyl 4-(l-isopropyl-lH-pyrazol-5-yl)-lH-pyrrole-l,3(2H,5H)-dicarboxylate (0.59 g).

[0199] Step 3: To a solution of 1-tert-butyl 3-ethyl 4-(l-isopropyl-lH-pyrazol-5-yl)-lHpyrrole-l,3(2H,5H)-dicarboxylate (590 mg, 1.69 mmol) in THF (6 ml) at -20 °C was added IM LiAIH₄ in THF (2.03 mL, 2.03 mmol). After stirred for 20 min, it was quenched with Sat. NH₄CI, the mixture was extracted with EtOAc (3X), organic layers were combined, dried over MgSO₄ and was concentrated to give tert-butyl 3-(hydroxymethyl)-4-(l-isopropyl-lH-

pyrazol-5-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate as crude product, which was used without purification in next step.

[0200] Steps 4a&4: To a suspension of (4-(l-isopropyl-lH-pyrazol-5-yl)-2,5-dihydro-lHpyrrol-3-yl)methanol (200 mg, 0.96 mmol) in AcCN (2 mL) was added TEA (0.14 mL, 0.96 mmol) and HCHO aqueous solution (0.24 g). After stirred for 30 min, it was added NaB(OAc)₃H (0.41 g, 1.92 mmol). Another 15 min later, it was filtered and the filtrate was concentrated to give crude product, which was purified by column (DCM/MeOH=100:0to 80:20) to give (4-(l-isopropyl-lH-pyrazol-5-yl)-l-methyl-2,5-dihydro-lH-pyrrol-3yl)methanol (170 mg). To a solution of 4-(l-isopropyl-lH-pyrazol-5-yl)-l-methyl-2,5-dihydrolH-pyrrol-3-yl)methanol in DCM (3mL) was added S0CI2 (0.2 mL) at 0 °C, after stirred for 30 min, it was then concentrated to give 5-(4-(chloromethyl)-l-methyl-2,5-dihydro-lH-pyrrol-3yl)-l-isopropyl-lH-pyrazole as crude HCl sait (140 mg).

[0201] Method B: To a solution of 5-(4-(chloromethyl)-l-methyl-2,5-dihydro-lH-pyrrol-3yl)-l-isopropyl-lH-pyrazole (140 mg, 0.60 mmol) and 2,6-dihydroxybenzaldehyde (170 mg, 1.20 mmol) in DMF (3 mL) was added K₂CO₃ (330 mg, 2.4 mmol). After stirred at 50 °C for 30 min, the mixture was added water, extracted with EtOAc (3X), organic layers were combined, washed with brine, dried and concentrated to give crude product, which was purified by préparative HPLCto give 2-hydroxy-6-((4-(l-isopropyl-lH-pyrazol-5-yl)-l-methyl2,5-dihydro-lH-pyrrol-3-yl)methoxy)benzaldehyde (6 mg). ^XH NMR (400 MHz, Chloroform-d) δ 10.26 (d, J = 0.6 Hz, 1H), 8.26 (s, 1H), 7.55 (dd, J = 1.8, 0.6 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 6.54 (dt, J = 8.5, 0.7 Hz, 1H), 6.21 (dd, J = 8.3, 0.8 Hz, 1H), 6.11 (d, J = 1.8 Hz, 1H), 4.62 (d, J = 1.4 Hz, 2H), 4.47 - 4.33 (m, 1H), 3.98 - 3.88 (m, 4H), 2.67 (s, 3H), 1.44 (d, J = 6.7 Hz, 6H). MS (M+H) found for Ci₉H₂₃N₃O₃: 342.2.

[0202] From the foregoing it will be appreciated that, although spécifie embodiments of the invention hâve been described herein for purposes of illustration, various modifications may be made without deviatingfrom the spirit and scope ofthe invention.

[0203] Throughout the description of this invention, reference is made to various patent applications and publications, each of which are herein incorporated by reference in their entirety.

Claims (10)

1. (A)
2. 2. The compound of claim 1, wherein V¹ and V² independently are C_rC₆ alkoxy; or V¹ and V together with the carbon atom they are attached to form a ring of formula:

   wherein each V³ and V⁴ are independently O, S, or NH, provided that when one or V³ and V⁴ is S the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-Cê alkyl or CO2R⁶⁰, where each R⁶⁰ independently is Ci-C6 alkyl or hydrogen; t is 0,1, 2, or 4; or CvA is C=V, wherein V is O, and wherein the remaining

   20 variables are defined as in claim 1.
3. 3.

   The compound of claim 2, of formula (!'):

   wherein

   R⁵ is hydrogen, Ci-C₆ alkyl or a prodrug moiety R , wherein the C_rC₆ alkyl is
4. 4. The compound of claim 2 or 3, wherein the compound is of Formula IA, IB or IC:

   IA IB is an optionally substituted 4-10 membered heterocycle as defîned in claim 2,
5. 5 and R¹⁵ is optionally substituted Ci-C₆ alkyl, optionally substituted Cô-Cio aryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.

   *17478 \ n or an N oxide thereof, or a pharmaceutically acceptable sait of each thereof.

   11. A composition comprising a compound of any one of claims 2-10 and at least one pharmaceutically acceptable excipient.

   12. Use of a compound of any one of claims 2-10 in the manufacture of a composition for increasing oxygen affinity of hemoglobin S in a subject.

   5 and R¹⁵ is optionally substituted Ci-C₆ alkyl, optionally substituted C₆-Ci₀aryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N and/or S and/or oxidized forms of N and S.

   5. The compound of claim 2 or 3, wherein ring A is substituted with 1-3: halo, C_rC6 alkyl, and/or Ci-C₆ alkoxy, wherein the Ci-C₆ alkyl is optionally substituted with 1-5

   15 halo.

   5 R⁵ is hydrogen, Ci-C₆ alkyl or a prodrug moiety R, wherein the Ci-C₆ alkyl is optionally substituted with 1-5 halo;

   R⁶ is a substituent that is halo, Ci-C₆ alkyl, Ci-C₆ alkoxy, Ci-C₆ alkylthio, Cx-C₆ S(O)-, CiC₆ S(O)₂-, wherein the Ci-C₆ alkyl is optionally substituted with 1-5 halo; or

   R⁶ is 4-10 membered cycloalkyl or heterocycle substituted with an R'R'N- moiety

   10 wherein each R' is independently Ci-C₆ alkyl or hydrogen;and p is 0,1, 2, or 3; and the remaining variables are defîned as in claim 2.

   5 optionally substituted with 1-5 halo;

   R⁶ is a substituent that is halo, Ci-C₆ alkyl, Ci-C₆ alkoxy, Ci-C₆ alkylthio, Ci-C₆ S(O)-, CiC₆ S(O)₂-, wherein the C_rC6 alkyl is optionally substituted with 1-5 halo; or

   R⁶ is 4-10 membered cycloalkyl or heterocycle substituted with an R'R'N- moiety wherein each R' is independently Ci-C₆ alkyl or hydrogen;and

   10 p is 0,1, 2, or 3.

   and the remaining variables are defined as in claim 2.

   5 independently is Ci-C₆ alkyl or hydrogen; t is 0,1, 2, or 4; or CvY² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

   R⁸⁰ is optionally substituted C_rC6 alkyl;

   R⁸¹ and R⁸² independently are selected from the group consisting of hydrogen, optionally substituted CrC6 alkyl, COR⁸³, or CO2R⁸⁴;

   10 R⁸³ is hydrogen or optionally substituted Ci-C₆ alkyl; and

   R⁸⁴ is optionally substituted Cx-Ce alkyl.

   5 or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein ring A is an optionally substituted 5-10 membered heteroaryl contaîning up to 3 ring N, O, and/or S atoms, and oxidized forms of N and/or S atoms;

   wherein ring A is a or β substituted relative to the Y substituent;

   10 ring B is an optionally substituted C₆-Cio aryl or 4-10 membered heterocycle contaîning up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;

   each Y and Z is independently CR¹⁰R¹¹, O, S, SO, SO2, or NR¹²; each R¹⁰ and R¹¹ independently is hydrogen or CrC₃ alkyl, optionally substituted with halo,

   15 OH, or alkoxy, or CR¹⁰Rⁿ is C=O; R¹² is hydrogen or Ci-C₆ alkyl; provided that if one of Y and Z is O, S, SO, SO₂, then the other is not CO, and provided that Y and Z are both not heteroatoms or oxidized forms thereof;

   ring C is C6-C10 aryl, optionally substituted;

   V¹ and V² independently are C_rC₆ alkoxy; or V¹ and V² together with the carbon atom they are attachèd to form a ring of formula:

   wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³ and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently C_rC₆ alkyl or CO₂R⁶⁰, where each R⁶⁰
6. 6. The compound of claim 2 or 3, wherein ring B is substituted with 1-3: halo, C_rC₆ alkyl, COR¹⁵, and/or COOR¹⁵; and

   R¹⁵ is Ci-Q alkyl, C₆-Ci_Oaryl, 5-10 membered heteroaryl or a 4-10 membered heterocycle containîng up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted.

   5
7. 7. The compound of any one of claim 1-4, wherein Y-Z is -CH₂O-, -CH₂CH₂-, -CONH- or

   -NHCO-, wherein the right hand side ofthe substituent is joined with the substituted aryl or substituted phenyl ring.
8. 8. The compound of claim 2, wherein the compound is selected from the group consisting of (O)x (O)x or an N oxide thereof wherein

   Y and Z are defined as in claim 2;

   x is 0,1, or 2;

   R¹⁴ is Ci-C₆ alkyl, COR¹⁵, or COOR¹⁵;
9. 9. The compound of claim 2, wherein the compound is selected from the group

   10 consisting of or an N oxide thereof wherein x is 0, 1, or 2;

   R¹⁴ is Ci-C₆ alkyl, COR¹⁵, or COOR¹⁵;
10. 10 13. Use of a compound of any one of claims 2-10 in the manufacture of a composition for treating oxygen deficiency associated with sickle cell anémia.