COMPOUNDS AND USES THEREOF FOR THE fvlGDULATiOISi OF HEMOGLOBIN

FiELD OF THE INVENTION

[OOOlj This invention provides compounds and pharmaceutical compositions suitable as allosteric 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.

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 prevalent peptide sequence of hemoglobin (Hb),

[0003] Hemoglobin (Hb) transports oxygen molecules 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 ceils their characteristic sickle shape. The slckled ceils are also more rigid than normal r ed 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 uch 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 methods for treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation. 05] in certain aspects of the invention, a compound of Formula (A) is provided:

H

'

(A)

or a tatitomer thereof, or pharmaceutically acceptable sait of each of thereof or a rmaceutically acceptable sait thereof, wherein

L ¹ is a bond or is NR ⁷⁰ , O, S, or (CR ⁷¹ R ⁷² ) _d ; wherein each R ⁷⁰ , and R ⁷²

independently are hydrogen or C _:l -C ₆ alkyl;

d is 1, 2, or 3;

L ² is C=0 or S0 ₂ ;

each Y and Z is ndependently CR ⁱ⁰ R ^u , O, 5, SO, S0 ₂ , or NR ¹⁰ ; each R ¹⁰ and ^u

independently is hydrogen or CY-C ₃ alkyl optionally substituted with 1-3 halo OH, or C C ₆ alkoxy, or CR ¹⁰ R ⁿ is C=0, provided that if one of Y and Z is O, S, SO, SO;-, then the other is not CO., and Y and Z are both not heteroatorrss or oxidized forms thereof;

wherein Y is a or β substituted relative to the -tW;

wherein Z and -CV"V ² H are joined to adjacent atoms on ring C;

V ¹ and V ² independently are C C ₆ alkoxy; or V ¹ and V ^"' together with the carbon atom they are attached to form a rin of formula:

wherein each V ³ and V ⁴ are independently 0, S, or NH, provided that when one of V ³ and V ⁴ is S, the other is NH, and provided that V ³ and V' ⁴ are both not NH; q is 1 or 2; each V is independently Ci-C _& alkyl or CO ₂ R ^b0 , where each ⁶⁰ independently is C C ₆ alkyl or hydrogen; t is 0, 1, 2, or 4; or CVV is C ~V, wherein V is 0, NOR ⁸⁰ , or NN R ³¹ R ^s ;

R°° is optionally su bstituted C C ₆ aikyl;

R ^cl and ^Q ' ^: independently are selected from the group consisting of hydrogen; optionally su bstituted C _r C ₆ aikyl, COR ⁸³ and C0 ₂ R ⁸⁴ ;

R ^OJ is hydrogen or optionally substituted Ci-Cg aikyl; 3nd

R* ^a is optionally substituted C _r -C ₆ aikyl.

and W, B, and C are defined as follows.

[0006] In one instance..

R ^J is C _r C ₆ alkyl, C _r C _g cycloaiky!, C C ₅ alkoxy, C ₃ -C ₃ cycloalkoxy, or ~N R ¹ R ² ;

each R ¹ and R ² independently is hydrogen, Cr-Ce aikyl, C3-C ₈ cycloalkyl, Ce-Cio aryl, 4- 10 rnernbered heterocycle or 5-10 membered heteroaryl, each containing up to 5 ring heteroatoms, wherein th e heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N a nd 5, wherein each alkyl, cycloalkyl, heterocycle, aryl or h eteroaryl is optiona lly substituted, or R ' and R ² together with the nitrogen atom they are attached to form an optionally substituted 4-7 membered heterocycle;

ring B is a optionally substituted C _& -Ci ₀ aryl, optionally substituted 5- 10 membered heteroaryl having 1-3 nitrogen atoms or oxidized forms of M, or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the grou p consisting of O, N, S, and oxidized forms of N and S; and

ring C is a optionally su bstituted Cg-Cjo aryl or optionally su bstituted 5-1.0 membered heteroaryl containing 1-3 n itrogen atoms, or an oxidized form of N, wherein certain preferred substituents include OH, halo, C Cg alkoxy, C ₃ -C ₃ cycloal koxy or O-R, where R is a prodrug moiety, wherein the C C& alkoxy is optionally substituted with 1-5 halo;.

[0007] In another instance,

R ³ is Ce-Cio aryl, or a 5-10 membered heteroaryl, wherein the heteroatom is selected from the group consisting of O, N, S, an d oxidized forms of N a nd 5, wh erein each of the a ryl, or heteroaryl is optionally su bstituted with 1- 4 Cr _> aikyl;

.5 ring B is a optionally substituted 4-10 membered heterocyde containing up to 5 ring, heteroatorns, wherein the heteroatorn is selected from the group consisting of O, is), S, and oxidized forms of N and S;

ring C is Ce-C _l0 aryl or a 5-10 membered heteroaryl containing up to 5 ring

heteroatorns, wherein the heteroatorn is selected from the group consisting of 0, H, S, and oxidized forms of and S, each of which is optionally substituted with 1-4: halo, oxo, -OR ^{! y} , C C ₆ aiky!, and/or C _r C ₆ alkoxy, wherein the C C _e , alky! is optionally substituted with 1-5 halo, C C ₆ alkoxy and/or a 4-10 membered heterocyde containing up to 5 ring heteroatorns, wherein the heteroatorn is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein certain preferred substituerrts include OH, halo, CrCg alkoxy, Cj-Cg cycloalkoxy or O-R, where R is a prodrug moiety, wherein the C C ₆ alkoxy is optionally substituted with 1-5 halo;; and

R ¹⁹ is hydrogen or a prodrug moiety R.

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

or a tautomer thereof, or pharmaceutically acceptable salt of each of thereof, wherein

R* is Ci-Ce alkyl, C ₃ -C ₈ cycloalkyl, C _r C ₆ alkoxy, C ₃ -C ₈ cycloalkoxy, or -NRV;

each R ~ ^' and R ^_ independently is hydrogen, C C _b alkyl, C ₃ -Cg cycloalkyl, Q-C ₁₀ aryl, 4- 10 membered heterocyde or 5-10 membered heteroaryl, each containing up to 5 ring heteroatorns, wherein the heteroatorn is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each alkyl, cyeloaikyl, heterocycle, aryl or heteroaryl is optionally substituted, or R ¹ and

R* together with the nitrogen atom they are attached to form an optionally substituted 4-7 membered heterocycle;

L is a bond or is NR ⁷⁰ , O, S, or (CR ⁿ R ⁷⁷ ) _d ; wherein each R ^;o , R ⁷ⁱ , and R ⁷² independently are hydrogen or C C _a aikyi;

d is 1,, 2, or 3;

ring B is a optionally substituted Ce-Oo aryl, optionally substituted 5-10 membered heteroaryl having 1-3 nitrogen atoms or oxidized forms of N, or optionall 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;

each Y and Z is independently CR ¹⁰ R ⁿ O, S, SO, S0 ₂ , or NR ¹⁰ .: each R ¹⁰ and R ¹¹

independently is hydrogen or C C ₃ aikyi optionally substituted with 1-3 halo, OH, or Ci-C ₆ alkoxy, or CR ¹⁰ R ^U is OO, provided that if one of Y and Z is O, S, SO, 50 ₂ , then the other is not CO, and Y and Z are both not heteroatoms or oxidized forms thereof;

wherein Y is a or β substituted relative to the -LCOR ³ ;

ring C is a optionally substituted CrCio aryl or optionally substituted 5-10 membered heteroaryl containing 1-3 nitrogen atoms, or an oxidized form of N;

wherein 2 and -CV'V'H are joined to adjacent atoms on ring C;

V ¹ and V ^z independently are Cj-Cg alkoxy; or V ¹ and V ^'2 together with the carbon

atom they are attached to form a rin of formula:

wherein each V ³ and V ⁴ are independently O, S, or NH, provided that when one of V ³ and V is S, the other is NH, and provided that V ^? and V ⁴ are both not NH; q Is 1 or 2; each V ⁵ is independently C Cg aikyi or CO _? R ' ^J , where each R ^(,,J independently is Cy alkyl or hydrogen : t is 0, 1, 2, or 4: or CV is C=V, wherein V is O, NOR ⁸⁰ , or NNR ^8l R ⁸² ; R. ⁴ is OH, halo, C Ce aikoxy, C ₃ -Cg cycloalkoxy or O-R, where R is a prodrug moiety, wherein the d-Q aikoxy is optionally substituted with 1-5 halo;

R ⁸⁰ is optionally substituted C _x - a!kyl;

R ⁸ ' and R" ² Independently are selected from the group consisting of hydrogen; optionally substituted C _r C ₆ aikyl, COR ⁸³ and C0 ₂ n^;

R ⁸ⁱ is hydrogen or optionally substituted C alkyl; and

R* ⁴ is optionally substituted C _r Q, alkyl. In certain aspects of the invention, a compound of formula (IV) is provided:

(IV)

wherein

3 is Ce-Cio aryl, or a 5-10 membered heteroaryl, wherein the heteroatom Is selected from the group consisting of O, N, S, and oxidized forms of and S, wherein each of the aryl, or heteroaryl is optionally substituted with 1-4: C _r t ₆ alkyl;

L ¹ is a bond or is R ⁷⁰ , O, S, or (CR R ² ) _d ; wherein each R ⁷⁰ , R ⁷¹ , and R ' ²

independently are hydrogen or Ci -C ₆ alkyl;

d is 1, 2, or 3;

1/ is OO or S0 ₂ ;

ring B is a optionally substituted 4-10 membered heterocycie containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, , S, and oxidized forms of N and S;

each Y and Z is independently (CR ¹⁰ R ⁿ ) _(: , O, S, SO, S0 ₂ , or R ¹⁰ ; e is 1 to 4, preferably 1; each R ¹⁰ and R ⁿ independently is hydrogen or QrC _? aikyl optionally substituted with 1-3 halo, OH, or C i -Q aikoxy, or CR ⁱ⁰ R" Is C=0, provided that if one of Y and 2 is 0, S, SO, S0 ₂₎ then the other is not CO, and Y and Z are both not heteroatoms or oxidized forms thereof;

wherein Y is a or B substituted relative to the ~iA ² R ³ ;

ring C is C _fc ~Cic« ary! or a 5-10 membered heteroaryl containing up to 5 ring

heteroatoms, wherein the heteroatom is selected from the group consisting of 0, N, S, and oxidized forms of N and S, each of which Is optionally substituted with 1-4: halo, oxo, OR ² , Ci- alkyi, and/or C C ₆ aikoxy, wherein the Ci-Ce alkyi is optionally substituted with 1-5 halo, Cj -Q, aikoxy and/or a 4- 10 membered heterocyde 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;

R ² is hydrogen or a prodrug moiety R; and

wherein 2 and -CV ^A V ² H are attached to adjacent atoms on ring C;

V ¹ and V ^" independently are C C ₆ aikoxy; or V ¹ and V ² together with the carbon atom they are attached to form a rin of formula:

wherein each V* and V ⁴ are independently 0, S, or NH provided that when one of V ³ and V ⁴ is S, the other is NH, and provided that V ³ and V ^"1 are both not NH; q is 1 or 2; each V is independently C _r C ₆ alkyi or CC½R ^G0 , where each R ⁶⁰ independently is C _r C _e alkyi or hydrogen; t is 0, 1, 2, or 4; or CVV is C=V, wherein V is O, OR ⁸⁰ , or NNR ⁸¹ R ⁸² ;

R ⁸⁰ is optionally substituted d-Q alkyi;

R ^8: and R ^b2 independently are selected from the group consisting of hydrogen;

optionally substituted C C ₆ alky!, COR ⁸³ and C0 ₂ R ⁸⁴ ;

R ⁸ * is hydrogen or optionally substituted C C ₆ alkyi; and

R ⁸ is optionally substituted C C ₆ alkyi.

[0010] In one embodiment, ring b is joined to L ¹ or L ² via a nitrogen atom. In another embodiment, R ³ is joined to L ² via a nitrogen atom. [0011] In further aspects of the invention, a composition is provided comprising any of the compounds described herein, and at least a pharmaceuticaiiy acceptable excipient.

[0012] In stili further 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.

[0013j In further aspects of the invention, a method is provided for treating oxygen deficiency associated with sickle cell anemia, 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

Definitions

[0014] it must he noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include piura! referents unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" includes a plurality of such solvents.

[0015] As used herein, the term "comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others.

"Consisting essentially of" when used to define compositions and methods, shall mean excluding other eiements of any essential significance to the combination for the stated purpose. Thus, a composition or process consisting essentiall of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of" shall mean excluding more than trace eiements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

[0016] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification 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 designation, e.g., temperature, time, amount, and concentration, including range, indicates approximations which may vary by ( + J or ( - } 10 %, 5 % or 1 %.

[0017] As used herein, C _m -C _n , such as C C ₈ , or C C ₆ when used before a group refers to that group containing m to n carbon atoms.

[0018] The term "alkoxy" refers to -O-aSkyl. Cyc!oalkoxy refers to -O-cycloaikyl.

[0019] The term "alkyl" refers to morioyalent saturated aliphatic hydrocarbv! groups having from 1 to 30 carbon atoms (i.e., CrC ₅₀ alkyl) or 1 to 22 carbon atoms (i.e., C ₁ -C ₂₂ aikyl), 1 to 8 carbon atoms (i.e., C Cg alkyl), or 1 to 4 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH ), ethyl (CH3CH2- ), n-propyi (CH ₃ CH ₂ CH ₂ -}, isopropyl {{CH ₃ ) ₂ CH-), n-buty! {CH3CH2CH2CH2-), isobutyl ((CH ₃ ) ₂ CHCH ₂ -), sec-butyl {(CH ₃ )(CH ₃ CH ₂ )CH-), f-butyl ((CH ₃ ) ₃ C-), n-pentyl (CH ₃ CH ₂ CH ₂ CH ₂ CH ₂ - ), and neopentyi ((CH ₃ ) ₃ CCH ₂ -}.

[0020] The term "aryl" refers to a monovalent, aromatic mono- or bicyclic ring having 6-10 ring carbon atoms. Examples of aryl include phenyl and naphthyi. 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 :

[0021] The term "-C0 ₂ H ester" refers to an ester formed between the -C0 ₂ H group and an alcohol, preferably an aliphatic alcohol. A preferred example included -CO;,R ^l: , wherein R ^l: is alkyl or aryl group optionally substituted with an amino group.

[0022] The term "chirai moiety" refers to a moiety that is chira!. Such a moiety can possess one or more asymmetric centers. Preferably, the chirai moiety is enantiomerically enriched, and more preferably a single enantlomer. Won limiting examples of chirai moieties include chira! carboxylic acids, chirai amines, chirai amino acids, such as the naturally occurring amino acids, chirai alcohols including chirai steroids, and the likes.

10023] The term "cycloalkyl" refers to a monovalent, preferably saturated, hydrocarbyl mono-, bl~, or tricyclic ring having 3-12 ring carbon atoms. While cycloalkyl, refers preferably to saturated hydrocarbyi rings, as used herein, it also includes rings contain ing 1 - 2 carbon-carbon double bonds. Noniimiting examples of cycloalkyl include cyclopropyi, cyc!obuty!, cyciopentyl, cyc!ohexyl, cycloheptyl, adamentyl, and the like. The condensed rings may or may not be non-aromaiic hydrocarbyi rings provided that the point of attachment is at a cycloalkyl carbon atom. For example, and without limitation, the following is a cycloalkyl group:

[0024] The term "halo" refers to F, Ci, Br, and/or !.

[0025] The term "heteroaryi" 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. Noniimiting examples of heteroaryi include furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the like. The condensed rings may or may not be a heteroatom containing aromatic ring provided that the point of attachment is a heteroaryi atom. For example, and without limitation, the following is a heteroaryi group:

[0026] The term "heterocyclyi" or heterocycle refers to a non-aromatic, mono-, bi-, or tricyclic ring containing 2-12 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, $., and P, provided that the ring contains at least 3 ring atoms. While heterocyclyi preferabl refers to saturated ring systems, it also includes ring systems containing 1-3 double bonds, provided that the ring is non -aromatic. Noniimiting examples of heterocyclyi include, aza!actones, oxazolme, piperidinyl, piperazinyl, pyrrolidinyl, fetrahydrofuranyl, and tetrahydropyranyl. The condensed rings may or may not contain a non- aromatic heteroatom containing ring provided that the point of attachment is a heterocyclyi group. For example, and without limitation, the following is a heterocyclyi group:

[0027] The term "hydroiyzing" refers to breaking an R ^H -0-CO, R ^H -0-CS-, or an R ^H -0-SO _z - moiety to an R ^h -OH, preferably by adding water across the broken bond, A hydroiyzing is performed using various methods well known to the skilled artisan, non limiting examples of which include acidic and basic hydrolysis.

[00283 The term "oxo" refers to a OO group, and to a substitution of 2 geminal hydrogen atoms with a C=0 group.

[0029] 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, N0 ₂ , -N ₂ +, -CC¾R ¹⁰⁰ , -OR ¹⁰⁰ , ~5R ¹⁰⁰ , -SOFT ⁰⁰ , -SG _? R ¹⁰⁰ , -NR ¹⁰ V ⁰² , -CONR ^:ot R ^10? , ·· SO ₂ NR ¹⁰¹ R ¹⁰² , C C ₆ alky!, C _r C ₆ alkoxy, -CR ^10c -C(R ⁱ⁰⁰ ) ₂ , -CCR ¹⁰⁰ , C ₃ -C _l0 cycloaikyl, C ₃ -C _I0 heterocyclyl, C _e -C ₁₂ aryl and C ₂ -C _l2 heteroaryi, wherein each R ^10u independently is hydrogen or CV-Cg aikyi; Cj-Ci i cycloaikyl; io heterocyclyl; C ₆ -C _a2 aryl: or CYC. ;, heteroaryi; wherein each aikyi, cycloaikyl, heterocyclyl, aryl, or heteroaryi is optionally substituted with 1- 3 halo _. , 1-3 Ct-Cg aikyi, 1-3 C _; -C _¾ naloalkyi or 1-3 Ci-Q alkoxy groups. Preferably, the substituents are selected from the group consisting of chloro, fluoro, -OCH ₃ , methyl, ethyl, /so propyi, cyciopropyl, vinyl, et.hyn.yi, -CO _? H, -C0 ₂ CH ₃ , -OCF ₃ , -CF ₃ and -OCHF ₂ .

[0030] R ^1G1 and R ^1C "' independently is hydrogen ; C C ₈ aikyi, optionally substituted with - CO,H or an ester thereof, C C _& alkoxy, oxo, -CR ¹⁰ⁱ =C(R ^l0J } _2> -CCR, C C _i0 cycloaikyl, CYG ₀ heterocyclyl, C ₆ -C _n aryl, or C C _i2 heteroaryi, wherein each R' ^w3 independently is hydrogen or CrCg aikyi; C3-C12 cycloaikyl; C _:! -C _l0 heterocyclyl; Cg-C^ aryl; or C C _;2 heteroaryi; wherein each cycloaikyl, heterocyclyl, aryl, or heteroaryi is optionally substituted with 1-3 alkyl groups or 1-3 halo groups, or R ¹⁰¹ and R ^iJi together with the nitrogen atom they are attached to form a 5-7 membered heterocycie.

[0031] The term "pharmaceutically acceptable" refers to safe and non-toxic for in vivo, preferably, human administration. [0032] The term "pharmaceutically acceptable salt." refers to a salt that is pharmaceutically acceptable.

[0033] The term "salt" refers to art sonic compound formed between an acid and a base. When the compound provided herein contains an acidic functionality, such salts include, without limitation, alkali metal, alkaline earth metal, 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 IMa, K, Rb, Cs, NH Ca, Ba, imidazollum, and ammonium cations based on naturally occurring amino acids. When the compounds utilized herein contain basic functionality, such salts include, without limitation, salts of organi acids, such as carboxy!lc acids and sulfonic acids, and mineral acids, such as hydrogen haiides, sulfuric acid, phosphoric acid, and the likes. Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, rnaieate, acetate,, propionate, succinate,, tartrate, chloride, sulfate, bisalfate, mono-, di-, and tribasic phosphate, mesylate, tosyiate, and the likes.

[0034] 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, inh ibiting the disease or condition, e.g., arresting or suppressing the

development of the disease or condition, relieving the disease or condition, causing regression 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 regression of clinical symptoms. The terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication 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.

[0035] The terms "preventing" or ' ^' prevention'' ^' refer to a reduction 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 3 subject that may be exposed to or predisposed to the disease but does not yet experience 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.

[0036J 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 oxygenation of any of the compositions or dosage forms described herein to a subject in need thereof.

[0037] 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 ceils, or tissues.

[0038] 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 modified 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 have, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity. For example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach , Oxford University Press, New York, pages 388-392. Prodrugs can also be prepared using compounds that are not drugs. Compounds

[0039] In certain aspects of the invention, a compound of Formula (I) is provided:

or a tautomer thereof, or pharmaceutically acceptable salt of each of thereof or a rmaceutically acceptable salt thereof, wherein

L ¹ is a bond or is NR ⁷⁰ , 0, S.. or (CR ⁷¹ R ⁷² ) _d ; wherein each R ⁷⁰ , R ⁷ⁱ . and R ⁷²

independently are hydrogen or C _:r Cg aikyi;

d is 1, 2, or 3;

L ² is OO or S0 ₂ ;

each Y and Z is independently CR ¹⁰ R . O, S, SO., S0 ₂ , or N ¹⁰ ; each R ⁱ⁰ and R ⁿ

independentiy is hydrogen or C _r C ₃ aikyi optionally substituted with 1-3 halo, OH, or Ci-Ce alkoxy, or CR ¹⁰ R ^ia is C=0.. provided that if one of Y and Z Is 0, S, SO, SO.;, then the other is not CO, and Y and Z are both not heteroatorns or oxidized forms thereof;

wherein Y is a or β substituted relative to the -L ¹ L ² R ³ ;

wherein Z and -CV ^H are joined to adjacent atoms on ring C;

V ¹ and V ² inciepersdently are d-Ce afkoxy; or V ¹ and V ² together with the carbon atom they are attached to form a ring of formula :

wherein each V° and V are independently 0, S, or NH, provided that when one of V* and V' is S, the other is NH, and provided that V ³ and V ⁴ are both not NH; q is 1 or 2; each V ⁵ is independently C C ₆ aINyl or C0 ₂ R ^b!) , where each R ^b0 independently is Cx-Q a iky I or hydrogen; t is 0, 1, 2, or 4; or CV ¹ '* ' is C=V, wherein V is O, NOR ⁸⁰ , or NNR ^8l R ⁸² ;

R ⁴ is OH, halo, Ci-C,:, alkoxy, - cycloalkoxy or OR, where R is a prodrug moiety, wherein, the C rQ _> alkoxy is optionally substituted with 1-5 halo; R ' is optiona!iy substituted CrQ alkyl;

R ⁸¹ and R* ² independently are selected from the group consisting of hydrogen; optionally substituted C Q alkyl.. COR ⁸³ and C0 ₂ R ⁸⁴ ;

R ⁸³ is hydrogen or optionally substituted Q-Q alkyl; and

R ⁸⁴ is optionally substituted C C ₆ alkyl.

and R ³ , B, and C are defined as follows.

[0040J In one instance,.

R ^~ is Ci-Cr, a!kyl, C ₃ -Q cycloalkyl, C C _& alkoxy, C _¾ -Q cycloalkoxy, or -NR ^l R ² ;

each R ^l and R ² independently is hydrogen, CrQ alkyl, C ₃ -C ₈ cycloalkyl, Q-C ₁₀ aryi, 4- 10 membered heterocycie or 5-10 membered heteroaryi, each containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, , S, and oxidized forms of N and S, wherein each alkyl, cycloalkyl, heterocycie, aryi or heteroaryi is optionally substituted, or R ¹ and R ² together with the nitrogen atom they are attached to form an optionally substituted 4-7 membered heterocycie;

ring B is a optionally substituted Q-Qo aryi, optionally substituted 5-10 membered heteroaryi having 1-3 nitrogen atoms or oxidized forms of N, or optionally substituted 4-10 membered heterocycie 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; and

ring C is a optionally substituted C _e -Ci _C . aryi or optionally substituted 5- 10 membered heteroaryi containing 1-3 nitrogen atoms, or an oxidized form of N;

[0041] In another instance, ^' ϊ' is Cg-Cjo aryl, or a 5- 10 membered heteroaryl, wherein the heteroatom is selected from the group consisting of 0, N, S, and oxidized forms of N and S, wherein each of the aryl, or heteroaryi is optionaiiy substituted with 1-4 C .-C ₆ aiky! ; ring 8 is a optionaiiy substituted 4-10 membered heterocycfe containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, , S, and oxidized forms of N and S;

ring C is C _ir C _i0 ary! or a 5-10 membered heteroaryl containing up to 5 ring

heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and 5, each of which is optionally substituted with 1-4; halo, oxo, -OR ¹⁹ , C C ₆ alky I, and/or C C _s aikoxy, wherein the C _r Q, alkyl is optionally substituted with 1-5 halo, C C ₆ aikoxy and/or a 4-10 membered heterocycle containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of 0, N, S, and oxidized forms o? N and S; and

R ^l9 is hydrogen or a prodrug moiety R.

[0042] in certain embodiments, L ^l is a bond.

10043] In certain embodiments, L ⁴ is C=0. In certain embodiments, is SO _? .

[0044] !n one embodiment,, ring C is phenyl which is optionally substituted with 1-4; halo, oxo, -OR ² , Ci-C _f c alky! and/or Cv-C ₆ aikoxy,

[0045] In certain aspects of the invention, a compound of Formu la (!!; is provided :

or a tautomer th ereof, or pharmaceutica!ly acceptable salt of each o f thereof or a pharmaceutically acceptable salt thereof, wherein

s is C.t- -6 aikyi, C ₃ -Q cycioafkyl, Ci-C _b alkoxy, C ₃ -Cg cycloa!koxy, or - R ¹ R ^Z ;

each R ¹ and ² independentl is hydrogen, d-Cg alkyl, C ₃ -C ₃ cycloalkyl, Cg-do aryl, 4- 10 roembered heterocycle or 5- 10 membered heteroaryl, each containing u p 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 each alkyl, cycloalkyl, heterocycle, aryi or heteroaryl is optionally substituted, or R ¹ and R" together with the n itrogen atom they are attached to form an optionally substituted 4-7 membered heterocycle;

L ¹ is a bond or is N R ⁷⁰ , O. S, or (CR^ ⁷² )^ wherein each R ^/U , R ^;1 , and R ⁿ

independently are hydrogen or C i-Q alkyl;

d is 1, 2, or 3;

ring B is a optionally substituted C ₆ ~Ci ₀ aryl, optionally substituted 5-10 mem bered heteroaryl having 1-3 nitrogen atoms or oxidized forms of , or optionally su bstituted 4-10 mem bered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, , S, and oxidized forms of N and S;

each Y and Z is independently CR ¹⁰ R" O, S, SO, S0 _2, or NR ¹⁰ ; each ⁰ and R ^N

independently is hydrogen or C _r C ₃ alky! option ally substituted with 1-3 halo, OH, or CrC& alkoxy, or CP °R ^" is C=0, provided that if one of Y and 2 is 0, S, SO, S0 ₂ , then the other is not CO, and Y and Z are both not heteroatorns or oxidized forms thereof;

wherein Y is a or β substituted relative to the -LCOR ³ ;

ring C is a optionally substituted Cg-Cto aryi or optionally substituted 5-10 membered heteroaryl containing 1-3 nitrogen atoms, or an oxidized form of N;

wherein Z and -CV H are joined to adjacent atoms on ring C;

V ^s and independently are C C ₆ aikoxy; or V ¹ and V"' together with the carbon atom they are attached to form a rin of formula:

wherein each V ³ and V ⁴ are independently 0, S, or NH, provided that when one of V ³ and y ⁴ is S, the other is NH, and provided that V ³ and V ⁴ are both not NH; q is 1 or 2; each V ^s is independently C _r C ₆ alky! or C0 ₂ ⁶ °, where each R ⁶⁰ independently is C -C ₆ alky! or hydrogen; t is 0, 1. 2, or 4; or CVV ² is OV, wherein V is O, NOR ⁸⁰ , or NNR ⁸¹ R ⁸² ;

R" is OH, haio, Ci-C ₆ alkoxy, C ₃ -C ₆ cycioaikoxy or O-R, where R is a prodrug moiety, wherein the C C ₆ alkoxy is optionally substituted with 1-5 haio;

R ⁸⁰ is optionally substituted C C ₆ aikyf;

R ⁸¹ and R ⁸² independently are selected from the group consisting of hydrogen;

optionally substituted C C ₆ afkyl, COR ⁸³ and C0 ₂ R ^S4 ;

R ⁰³ is hydrogen or optionally substituted Ci- aikyf; and

R ⁸⁴ is optionally substituted C C _& aikyi.

[0046j in certain embodiments, t is 0. in certain embodiments, t is 1. in certain embodiments, t is 2. in certain embodiments, t is 3.

[0047] As used herein, P. ^' " ^' ' can be hydrogen, provided that the COOR ^'"} is not joined to a nitrogen atom.

[0048] Preferably, in certain embodiments, Y and Z are both not a heteroatom or a heteroatom containing moiety. Preferably, 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 alkyiene, and Z is a heteroatom or a heteroatom containing moiety, whic h, yet more preferably is oxygen.

{0049] Preferably, V ¹ and V ^* " together with the carbon atom they are attached to form a ring of formula :

[OOSO] In some embodiments, V ^A and V ^" independentiy are C _r C ₆ alkoxy; or V ¹ and V together with the ca rbon atom they are tached to form a ring of formula:

wherein each V ³ and V are independently 0, S, or NH, provided that when one or V ^s and V ⁴ is S the other is N H, and provided that V ³ and V' ⁴ a re both not N H; q is 1 or 2; each V ^s is independently Ci-C ₆ aikyl or C0 ₂ R ^6& , where each R°° independently is C C ₆ alkyi or hyd rogen; t is 0, 1 _, , 2, or 4; or CVV is C=V, wherein V is 0.

[0051] In certain aspects of the Invention, the compound of Formula (If ) is of Formula (l i!);

c : (ill)

wherein Y-Z is - ^~ CH ₂ 0- or -CH?CH and the remaining subststuents are as defined herein .

[0052] In some embodiments, R ⁴ and -CHO are joined to adjacent atoms on ring C.

[0053J in certain aspects of the invention., the compound of Formula {!!) is of Formula (ll!A):

MA

wherein ring B is a optionally substituted C ₆ -Ci ₀ aryi, optionally substituted 5-10 membered heteroaryi having 1-3 nitrogen atoms or oxidized forms of N; Β ^ΰ is hydrogen, C _r C _b alky! or 3 prodrug moiety R;

R" is halo, C C ₆ alkyi, C ₃ -C ₅ cydoalkyl, Ci-C ₆ alkoxy, C ₃ --C ₆ cycfoalkoxy, wherein the Ci-Ce alkyi is optionally substituted with 1-5 halo; and p is 0, 1, 2 or 3.

[0054] in some embodiments., the compound is of Formula iiiB, IMC, or ii!D:

III UiC

w er in

are optionally substituted 4-10 membered heterocycle as defined herein;

R ^s is hydrogen, C C ₅ a iky I or a prodrug moiety;

R ^b is halo, C C _& aikyi, C C ₆ a!koxy, wherein the C _r C _t alkyl is optionally substituted with 1-5 halo; and p is 0, 1, 2 or 3,

[0055] In some embodiments, ring B is substituted with 1-3: halo, C C ₆ alkyl, COR ¹⁵ , or COOP. ¹⁵ ; and P ^J is Ci-Cs alkyl, Cj-Q cycloalkyl, C ₆ -Ci ₀ aryl, 5-10 membered heteroaryl or a 4-10 mem bered heterocyde 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, '//herein the alkyl, aryf, heteroaryl or heterocyciyi is optionally substituted .

[0056] In certain aspects of the in vention, a compound of formula (IV) is provided:

or a tautomer thereof, or a pharmaceutically acceptable salt of each thereo f, wh erein

R ³ is C ₆ -C ₁₀ aryl, or a 5-10 membered heteroaryi, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized for ms of and S, wherein each of the aryl, or heteroaryl is optionally substituted with 1-4 C C ₆ alkyl;

L ^l is a bond or is N R. ⁷⁰ , O, S, or (CR ⁷¹ R ⁷² ) _d ; wherein each R ⁷⁰ , R ⁷¹ , and R ⁷²

independently are hyd rogen or Q-Ce alkyl;

d is 1, 2, or 3;

L ² is OO or S0 ₂ ;

r ing B is a optionally substituted 4-10 membered heterocyde contain ing up to 5 ring h eteroatoms, wherein the heteroatom is selected from the group consisting of O, M , S, and oxidized forms of N and 5;

each Y and Z is independently CR ¹⁰ R", O, S, SO, S0 ₂ or NR ¹⁰ ; each R ¹⁰ and R ^u

independently is hydrogen or C _r C-< alkyl option ally substituted with 1-3 halo, OH, or C C _b aikoxy, or CR ¹⁰ R ^U is OO, provided that if one of Y a nd Z is O, S, SO, S0 ₂ , then the other is not CO, and Y and Z are both not heteroatoms or oxidized forms thereof;

wherein Y is a or β substituted relative to the ~-L ^: L ² PV ^l ;

ring C is Cs-Cio aryi or a 5- 10 membered heteroaryf containing up to 5 ring

heteroatoms, wherein the heteroatorn is selected from the group consisting of 0, , 5, and oxidized forms of and S, each of which is optionally substituted with 1-4: halo, oxo, -OR ¹⁹ , C C ₆ alkyi, arid/or C C ₆ alkoxy, wherein the Ci-Cg a'M is optionaiiy substituted with 1-5 halo, C C ₆ alkoxy and/or a 4-10 membered heterocycie containing up to 5 nng heteroatoms, wherein the heteroatorn is selected from the group consisting of O, , S, and oxidized forms of and S;

FT ^' is hydrogen or a prodrug moiety R; and

wherein Z and -CV ^' V ^' H are attached to adjacent atoms on ring C;

V ¹ and V ² independently are C _r C ₆ alkoxy; or V ¹ and V ^" together with the carbon atom they are attached to form a rin of formula:

wherein each V ³ and V ⁴ are independently 0, S, or NH, provided that when one of V ^! and V ⁴ is S, the other is NH, and provided that V ³ and V ⁴ are both not NH; q is 1 or 2; each V ⁵ is independently C _{r 6} alkyi or COjR ⁶⁰ . where each R ⁵⁰ independently is Ci-C ₆ alkyl or hydrogen; t is 0, 1, 2. or 4; or CV\' is C=V, wherein V is 0, NOR ⁸⁰ , or NNR ^sl R ⁸² ;

R ⁸⁰ is optionally substituted C _r C ₆ alkyl;

R ⁸¹ and R ¹ " Independently are selected from the group consisting of hydrogen;

optionally substituted C C _t , alkyl, COR ⁸³ and Ci¾R ^¾ ;

R ⁸³ is hydrogen or optionaiiy substituted C s alkyl; and

R ⁸⁴ is optionally substituted C,-C ₆ alkyl.

[0057] n certain embodiments,. Z is CH ₂ , 0, S, SO, S0 ₂ or NH. In certain embodiments, Z is O, S, SO or S0 ₂ . Preferably, Z is O, and wherein the remaining variables are defined herein. {0058J In certain embodiments, Y is CR ^:I 'R , 0, S, SO, S0 ₂ or NR ^H' ; wherein each R ¹⁰ and 1 ¹ independently is hydrogen or C C ₃ alkyl. In certain embodiments, Y is CR ^K1 R" wherein each R ⁱ⁰ and R ¹¹ independently is hydrogen or C1-C3 alkyl. Preferably, Y is CH ₂ , and wherein the remaining variables are defined herein.

[0059J in certain embodiments, t is 0. in certain embodiments, t is 1. in certain embodiments, t is 2. in certain embodiments, t is 3,

[0060] Preferably, CVfy* is C~V, wherein V is O, and wherein the remaining variables are defined herein.

[006.1] In certain embodiments, a compound of formula {V) is provided: i B

L ²

1

-CHO

C

or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein

R ⁵ is Ce-Cio aryl, or a 5-10 membered heteroaryl, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryi, or heteroaryl is optionally substituted with 1- 4 Cy-Cg alkyi;

L ¹ is 3 bond or is NR ⁷⁰ , O, S, or (CR ⁷ⁱ R ⁷² ) _rJ ; wherein each R ⁷⁰ , R ⁷¹ , and R ⁷²

independently are hydrogen or C Cs aikyl;

d is 1, 2, or 3;

L ² is C=0 or SO.;

ring B is a optionaify substituted 4-10 membered heterocycle containing up to 5 ring neteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;

2 is O, S, SO or SO;,; ring C is Cg- io aryl or a 5-10 membered heteroaryi 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 of which is optionally substituted with 1-4 : haio, oxo, -OR ^w , C Cg a!ky!, and/or C _r C ₆ alkoxy, wherein the Q-Cs alkyi is optionally substituted with 1-5 halo, C _r C<, aikoxy and/or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of 0, N, S, and oxidized forms of N and S; and

R ^1" is hydrogen or a prodrug moiety R. in certain embodiments, a compound of formula (VI) is provided :

or a tautomer thereof,, or a pharmaceutically acceptable salt of each thereof, wherein

FT is C ₆ -Ci ₀ aryl _; or a 5-10 membered heteroaryi, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of and S, wherein each of the aryl. or heteroaryi is optionally substituted with 1-4 Ct-Ce alkyi;

L ¹ is a bond or is NR ⁷⁰ , 0, S, or (CR ⁷¹ R ⁷² ) _d ; wherein each ^/0 , R ⁷¹ , and R ⁷²

independently are hydrogen or C C _e a!kyl;

d is 1, 2, or 3;

I is C=0 or SO;.; ring B is a opilorsaiiy substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of 0, N, S, and oxidized forms of and S;

R ⁴ is -OR ¹⁹ or Ci-Cg alkoxy; and

R ' ^" is hydrogen or a prodrug moiety R.

[0063} in one embodiment, R ^'1 is -OH.

[0064] in certain embodiments, R ³ is optionally substituted phenyl, in other

embodiments, R ^* is optionally substituted pyridine, in certain embodiments, R ³ is optionally substituted pyrazole.

[0065] in certain embodiments, R ³ is selected from the group consistin of:

In certain embodiments, compounds of formulas (IV) and (V) are provided, wherein

[0067] in one embodiment, ring B is a 5-6 membered heterocycle containing a heteroatom selected from N, S, or O. In one embodiment, ring B Is a 5-6 membered heterocycle containing a N as the heteroatom. In certain embodiments ring B is selected from the group consisting of:

[0069] in certain embodiments, L ¹ is a bond.

] in certain embodiments, L ^' is C=0. in certain embodiments, 1/ 2 i :s, SO?.

[0071J in one embodiment, ring C is phenyl which is optionally substituted with 1-4: halo, oxo, -OFT ^' , C Q alkyl and/or C C _s alkoxy,

or an N ide thereof, wherein is a single or a double bond;

each P and Q is independently selected from CHR ¹⁷ , NCOR ¹⁵ , NC0 ₂ R ¹⁵ ; N-O, 0, S, SO, and S0 ₂ ;

each R ¹ and R ² independently is hydrogen, C C ₆ alkyi, a C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or a 4-10 membered heterocycie containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the alkyi, aryi, heteroaryl or heterocyc!yl is optionally substituted, together R ¹ and R" can form a 3-7 membered ring, preferably a 4-7 membered ring with 1-2 hetero atoms ;

R ¹³ is d-Ce alkyi, C ₆ -C ₁₀ aryl,. 5-10 membered heteroaryl or a 4-10 membered

heterocycie containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the alkyi, aryi, heteroaryl or heterocyclyl is optionally substituted;

R ¹ ' is Ci-Q aikyl, Cg-Cio ary!, 5-10 membered heteroaryl or a 4-10 membered

heterocycie containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of and S, wherein the alkyi, aryi, heteroaryl or heterocyclyl is optionally substituted; and r is 0, 1, or 2. in certain embodiments of the invention,, a compound is provided of formula

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

[0074] In certain embodiments of the invention, a compound is provided of formu

or an N oxide thereof, or a pharmaceutically acceptable sait of each thereof. [0075] Compounds provided herein include those in the Examples section.

Prodrug Moiety

[0076J in one aspect, R is hydrogen, a phosphate or a diphosphate containing moiety, or another promoiety or prodr ug moiety. Preferably the prodrug moiety imparts at least a 2 fold, more preferably a 4 fold, enhanced solubility and/or bioavailability to the active moiety (where R is hydrogen), and more preferably is hydrolyzed in vivo. The promoieties are structurally and functionally defined herein.

10077] In one embodiments, R is -COR ⁹⁰ , or CONR ^S2 R ⁹³ wherein

R ⁶ and R ⁹¹ independently are C _r C ₆ aSkyl. C ₃ -C« cycioalkyi, 4-9 membered heterocycle, or a

5-10 membered heteroaryl, each containing at least 1 basic nitrogen moiety; and R ^ai and R ⁹ * independently are Ci-C ₆ alkyi, C^ cycloalkyi, 4-9 membered heterocycie, or a 5- 10 membered heteroary!, each containing at least 1 basic nitrogen moiety; or R ^¾ and R ⁹³ together with the nitrogen atom they are bonded to for a 4-9 member heterocycie substituted with at least 1 amino, Ci-Cg alky! amino, or di C _r C ₅ aikyiamino group,

[0078] In certain embodiments, R is -C(G}R ³ \ C(0)OR ³¹ , or CON(R ⁱ³ ) _; .,

each R ³¹ is independently a C C ₆ alkyi; C ₃ -C _a cycloalkyi, 4-9 membered heterocycie, or a 5-10 membered heteroaryl, containing at least 1 basic nitrogen moiety: and

each R" Independently is d- alkyi; C3-C3 cycloalkyi, 4-9 membered heterocycie, or a 5-10 membered heteroaryl, containing at least 1 basic nitrogen moiety; or 2 R ¹³ together with the nitrogen atom they are bonded to for a 4-9 member heterocycie substituted with at least 1 amino, C _r C ₆ alkyi amino, or di C C ₆ aSky!atnino group.

[0079] In one aspect R is C(0)OR ³¹ , C(S}OR ³¹ , C(0)SR ³¹ or COR ³¹ ,, wherein R ³¹ is as defined herein.

[0080] In one embodiment, R ³¹ is a group of the formula (CR ³² R ³³ ) _e NR ³⁴ R ³⁵ , wherein

each " and R ³ⁱ is Independently H, a C C ₈ alkyi, C3-C9 heterocyclyl, C ₃ -C ₃ cycloalkyi, Ce-Cio ary!, C3-C9 heteroaryl or R ^iZ and R" together with the carbon atom they are bond to form a C ₃ -Cg cycloalkyi, C ₆ -C; ₀ aryi, C3- C9 heterocyclyl or C3-C9 heteroaryl ring system, or 2 adjacent " moieties or 2 adjacent R ³³ moieties together with the carbon atom they are bond to form a C ₃ -C ₈ cycloalkyi, Cg-Cxo aryi, C3-C9 heterocyclyl or C3-C9 heteroaryl ring system;

each R ³⁴ and R ^3S is a C _r Q alkyi, C _r C ₉ heterocyclyl, C ₃ -C ₈ cycloalkyi, or R ³⁴ and R ⁵⁵ together with the nitrogen atom they are bond to form a C ₃ -C ₃ cycloalkyi or C3-C3

heterocyclyl ring system :

each heterocyclic and heteroaryl ring system is optionally substituted with C1-C3 alky!, -OH, amino and carboxy! groups; and

e is an integer of from 1 to 4.

[0081] in some less preferred embodiments R ³ " and R ³⁵ can be hydrogen.

[0082] In one embodiment, the subscript e is preferably 2 and each R ^~'J and R ³³ is preferably independently selected from the group. H, CH ₃ , and a member in which and R ^" are joined together to form a cydopropyi, cyclobutyl, cyclopentyl, cyclohexyl, or i,l-dioxo-hexahydro-IA ⁶ -thiopyran-4-yl or tetrahydropyran-4-yl group.

[0083] With regard to the prodrug group,, preferred embodiments are compounds wherein NR ³ V ⁵ is morpholino.

[0084] in one embodiment, R is:

wherein

each R ³² and R ³³ is independently H, C Cg alkyl, or optionally, if both present on the same substituent, may be joined together to form a Ca-Cg cyctoalkyi, C&-C10 aryl, C3-C9 heterocyclyi or C3-C9 heteroary! ring system.

[0085] Within this embodiment, each R ^il and R ⁵³ is independently,, H, CH ₃ , or are joined together to form a cydopropyi _. , cyclopbuty!, cyclopentyl, cyclohexyl, 1,1 -dioxo- hexahydro- l?v ^U -thiopyra»4-yl or tetrahydropyran-4-yl group.

[0086] In a preferred embodiment, linkage of the prodrug moiety to the rest of the active molecule is stabie enough so that the serum half life of the prodrug is from about 8 to about 24 hours.

[0087] in an embodiment of the 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 present in the mildly alkaline small intestine. The basic, neutral form of the amine prodrug is lipophilic and is absorbed through the wail of the small intestine into the blood. Following absorption into the bloodstream, the prodrug moiety is cleaved by esterases which are naturally present i n the serum to release an active compound.

[0088] Examples of include, without limitation:

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

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

[0089] in another aspect, R is,

wherein R ^s is lower alky! {e.g. _r C ₆ aikyi), aspect,. R is: wherein X ¹ , Y" and X ² are as defined herein.

[0091] in one embodiment, X ¹ is selected from the group consisting of O, S and NR ³ ' wherein P ' is hydrogen or Cj -Cg aikyi;

Y ¹ is or a sugar moiety, wherein each R~'° is independentiy hydrogen or C _r Cs aikyi, C3-C3 cycloaikyi, C ₃ -C ₉ heterocyclyl, C ₆ -C ₁₀ aryi, or C3-C9 heteroaryi;

X ² is selected from the group consisting of halogen, d-Cg aikoxy, diacyigiycerol, amino, C _r Q; alkyiamino, Ci-Ce dia!kylamino, Q-Cg alkylthio, a PEG moiety, a bile acid moiety, 3 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 C ₆ alkyl, C ₃ -Cg cycloaikyi, C3-C9

heterocyciyi, C ₆ --C ₁₀ aryl, C3-C9 heteroaryi, C(W ^Z )X ³ , PO(X¾, and S0 ₂ X ³ ;

wherein W ² is 0 or NR ³⁹

wherein R ^i& is hydrogen or C C ₆ aikyi, C ₃ -C ₈ cycloaikyi, C3-C9 hetrocyciyi, C ₅ -Ci ₀ aryi, or C3-C9 heteroaryi; and

each X ³ is independentiy amino, hydroxyl, mercapto, Ci-Q aikyi, heteroa!kyl, cycloaikyi, hetrocyciyi, aryi, or heteroaryi, C _r C ₆ alkoxy, C _r C ₆ alkyiamino, C Ce diaikylamino,

C C ₆ alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and

-O-CH -CH(OR ⁴⁰ )CH _? X ⁴ R ⁴⁰ ,

wherein:

X ⁴ Is selected from the group consisting of 0, S, S=0, and SO _? ; and

each R ° is independently C10-C22 alkyl, C ₃ -C ₈ cycloaikyi, C3-C9 heterocyciyi, C ₆ -Cio aryi, or C3-C9 heteroaryi, C C _s a!ky!ene, or C Cs heteroaikylene, [0092] Each heterocyclic and heteroaryl ring system is optiona lly substitu ted with C C ₃ alkyl, -OH, a mino and carboxy! groups.

[0093] in one embodiment, the present invention utilizes the following Y ⁱ groups: CH ₂ , CH e, CH(isopropyl), CH(tertiarybutyl), C( e} ₂ , C(Et) ₂ , C(isopropyI) ₂ , and C(propyi) _? .

[00943 in a nother embodiment, the present invention utilizes the following groups:

-O e, -OBt, -O-isopropyi, O-isobutyl, O-tertiarybutyl, -O-CO e, -0-C{=0)(isopropyl), -0-C(=0)(isobutyl), -0-C(=0}(tertiarybutyl), -0-C(=0)-NMe ₂ , -0-C{=0)-NH e, -0-C(=0)-NH ₂ , -0-C(=0)-N{H)-CH( ¹ }-C0 ₂ Et wherein R ⁴¹ is a side chain C _r C ₆ alkyl, or C ₃ -C ₃ heterocyclyl group selected from the side chain groups present in essential amino acids; -0-P(-0)(OMe) ₂ . -0-P(=0)(0-isopropy!) ₂ , and -0-P{=0)(0-isobutyi)2. Each heterocyclic is optionally substituted with one or more, preferably, 1-3, C1-C3 a!kyl, -OH, amino and/or carboxy! grou s.

[00353 l ⁿ another embodiment,. In one embodiment, R Is:

wherein

X" is independently C _r C ₆ alkyl, Cj-C ₈ cycioalkyL C3-C5 heterocyclyl, C _t -C _;0 aryl, o r C Co heteroaryl; and

R ^{4 ~} is independently hydrogen or CrCg alkyl, C ₃ -C ₈ cycloalkyl, C3-C9 heterocyclyl, C5-C10 aryi, or C Cq heteroaryl, [0096] Each heterocyclic is optionally substituted with one or more, preferably, 1-3, C C ₃ alkyl, -OH, amino and/or carboxy! groups.

[0097] In one embodiment, R Is:

wherein

each X ^s is independently amino, hydroxy!,, mercapto, C _r -C ₆ alkyl, C ₃ -C _G cycloaikyl, C ₃ - C ₉ heterocyciyl, C ₆ -Cio aryl, or C ₃ -C ₃ heteroaryl, C Ce alkoxy, Ci-Ce alkylamino, C-.-Cs dialky!amino, C C ₆ alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and -0-CH CH{OR' ^iCi }CH ₂ X ⁰ ,

wherein:

X' is selected from the group consisting of O, S, S-Q, and S0 ₂ ; and

each R ⁴⁰ is independently C10- 22 alkyl, Cj-Cg cycloaikyl, C3-C9 heterocyciyl, C ₆ -C ₁₀ aryl,

C3-C9 heteroaryl, C C _s alkyiene, or C _r C _s heteroalkylene; and

R ⁱ is independently hydrogen or C O _c , alkyl, C ₃ -C ₈ cycloaikyl, C3-C9 heterocyclyi,

Cg-Cio aryl, or C ₃ -C ₉ heteroaryl,

[0098] In some embodiments, R ⁴ ' is independently hydrogen or C C ₆ alkyl, -Cg cycloaikyl, C ₃ -C ₉ heterocyciyl,, C ₆ -C ₁₀ aryl, or C3-C3 heteroaryl; and each X ³ independently is Ci-Q, alkyl. C ₃ -C ₈ cycloaikyl, C3-C9 heterocyciyl, C&-CIQ aryl, or C3-C9 heteroaryl, C Q alkoxy, C _;r C(, a!kylarnirto, C _r Q dialkylamino, or C Co alkylthio. [0099] in some embodiments, R is represented by the following structures:

COjE wherein,, in the above examples,, R ⁴³ is C _i0 -C22 alky! or aikyiene, R ⁴⁴ is H or C _r C ₆ a lky! and FT ^s represents side chairs aikyl groups present in naturally occu rring alpha amino acids;

wherein ^4t: is (CH ₂ ) _n , f=2-4, and CO-R ^/ - H? represents an aminoacy! group; or

wherein R ⁴⁶ is (CH ₂ ) _n , n=2-4, R ⁴⁷ is (CH ₂ ) _n , n=l~3 and R ⁴⁹ is 0 or NMe. [0100] In one embodiment, R is:

[0101] in one aspect, R is -C(R ²⁰⁰ R ²⁰¹ )O(R ²⁰² R ^2C8 )P{O)OR ²⁰ NR ²⁰⁵ R ²⁰⁶ _; wherein each R ²⁰⁰ , R ²⁰¹ , ²⁰² , R ²⁰³ , R ²⁰⁴ P. ²⁰⁵ and R ²⁰⁶ is independently H, a C _r C ₈ aikyl, C _r C heterocyclyi, C ₃ -C ₈ eycioalkyt, C ₆ -C ₁₀ aryl, C3-C9 heteroaryl, wherein each aikyl, heterocyclyi, cycloalkyi, aryl, and heteroaryl is optionaily substituted.

[0102] In some embodiments, R is - C H ( R ²⁰¹ ) O C H ₂ P ( Q ) Q R ²⁰⁴ H R ²⁰⁶ , wherein R ²⁰¹ is C C ₈ aikyl, R ¹⁰⁴ is phenyl, optionally substituted, in one e bodiment^ ²⁰⁶ is -CHR ²⁰ ' ^' C(O)OR ²⁰⁸ wherein R ² ° ^; is selected from the group consisting of the naturally occurring amino acid side chains and -C0 ₂ H esters thereof and R ^20S is C _:l -Cg aikyl. in one embodiment, R ²⁰⁶ is C Ce aikyl,. optionally susbtitued with 1-3, CO2H, SH, NH ₂ , C&-C ₁₀ aryl, and C2-C10 heteroaryl.

[0103] in one embodiment, R is:

[0104] In one embodiment,

r = υ to , or wherein Y ¹ is -C(R ³⁸ ) ₂ , wherein each R ^'8 is independently hydrogen or C C ₆ alkyl, C ₃ - C ₃ cycloalkyi, C3-C9 heterocyciyl, C ₃ -C ₁₀ aryl, or C3-C9 heteroaryi.

[0105] Various polyethylene glycol (PEG) moieties and synthetic methods related to them that can be used or adapted to make compounds of the invention are described Irs U.S. Patent Nos. 6,608,075; 5,395,266; 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.

[0106] In one embodiment, R is

wherein FT ¹ ' is -OH or hydrogen;

FT ^'1 is -OH, or hydrogen;

W is- CH(CH ₃ )W ^! ;

wherein W ¹ is a substituted C C ₈ aikyt group containing a moiety which is optionally negatively charged at physiological pH,

said moiety is selected from the group consisting of CQ ₂ H, SO _¾ H, S0 ₂ H,

-P{0)(OR ^5Z )(OH), -OP(0)(O ⁵² )(OH), and OS0 ₃ H,

wherein R ^a<£ is C _r C ₆ a!kyi, C ₃ -C ₈ cycloaiky!, C3-C9 beterocyclyl, C ₆ -C _[0 aryl, or C3-C9 heteroaryl.

[0107] Each heterocyclic and heteroaryl ring system is optionally substituted with one or more, preferably 1-3, -C3 aikyl, -OH, amino and/or carboxyi groups.

[0108] In one embodiment,. R is:

wherein R ^" is H or Ci-Ce aikyl. [0109] In another aspect, R is SC½H.

[0110] 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 brea kdown of the linker Z in a compound releases or generates the active compound, in one ernbocismerst, the cleavable lin ker has a half life of less than ten hours, in one embodiment, the cleavable li nker has a h alf life of less than an hou r. I n one embodiment, the half life of th e cleavable l in ker is between one and fifteen minutes. In one embodiment, the cleavable linker has at least one connection with the structu re: C*- C(~X*)X*-C* wherein C* Is a substituted or unsubstituted methylene group, and X* is S or 0. in one embodiment, the cleavable Sinker has at least one €*-€(=G)0-C* connection. In one embodiment, the cleavable linker has at least, one C*- C(=0)S-C* con nection. In one embod iment, the cleavable linker h as at least on e -C{=0)N*- C*-S0 ₂ -N *-connection, wherein N * is -NH- or C C _s al kylamino. In one embod i ment, the cleavabie lin ker is hydro!yzed by an esterase enzyme.

[0111] In one embodiment, the lin ker is a self-immolating lin ker, such as that disclosed in 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 su bstrate for enzymes, See gen erally Rooseboom et a! , , 2004, Pharmacol. Rev. 55:53-102.

Pharmaceutical Compositions

[0112] In further aspects of the invention , a com position is provided comprising a ny of the compounds described herein, and at least a pharmaceutically acceptable excipient.

[0113] In another aspect, this invention provides a composition comprising any of the compounds described herein, and a pharmaceutically acceptable excipient.

[0114J Such compositions can be formulated for different routes of ad ministration.

Although com positions su itable for oral delivery will probably be used most freq uently, other routes that may be used include transdermal, Intravenous, intraa rterial, pulmon a ry, rectal, nasal, vaginal, lingual, intramuscu lar, intraperitoneal, intracutaneous, Intracranial, and subcutaneous routes. Suitable dosage forms for ad ministering any of the compounds described herein include tablets, capsu les, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions,, solutions and emulsions. Sustained release dosage forms may aiso 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, Eastern Pa. 1980).

[0115] 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 aerosol composition, gaseous exciplent 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.

[0116] The compositions disclosed herein may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc,, gum arabic, lactose,, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1, 2- propy!ene glycol, polyglycois, dimethyisulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like.

[0117] Solid pharmaceutical excipients include starch, cellulose, hydroxypropy! cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate., sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. In certain embodiments, the compositions provided herein comprises one or more of a-tocopherol, gum arabic, and/or hydroxypropy! cellulose.

[0118] Irs 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 hydroxypropy! cellulose separately or in combination, in the presence of alpha-tocophero!. Preferably, the hydroxypropyl cellulose has an average fvlW of from 10,000 to 100,000. in a more preferred embodiment, the hydroxypropyl cellulose has an average W of from 5,000 to 50,000.

[0119 J Compounds and pharmaceutical compositions of this invention maybe used alone or in combination with other compounds. When administered with another agent, the coadministration 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 he used for administration of both the compound of this invention and the other agent or that the two agents he 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 ingredients simultaneously in a novel pharmaceutical composition in accordance with the present Invention.

Methods of Treatment

[0120] in aspects of the invention, a method is provided for increasing tissue

and/or cellular oxygenation, the method comprising administering to a subject in

need thereof a therapeutically effective amount of any of the compounds or

compositions described herein.

[0121] 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.

[0122] In aspects of the invention, a method is provided for treating 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.

[0123] In further aspects of the invention, a method is provided for treating oxygen deficiency associated with sickle ceil anemia, the method comprising administering to a subject in need thereof 3 thera peutically effective amount of any of the compounds or compositions described herein,

{0124] 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 ad ministering to a subject in need thereof a therapeutically effective amount of a compound of any of the compounds or compositions described herein.

Synthetic Methods

[0125] Certa in methods for making the compounds described herein are aiso provided. The reactions are preferabiy carried out in a suitable inert solvent that will be apparent to the skilled artisan upon reading th is disclosure, for a sufficient period of time to ensure substantial completion of the reaction as observed by th in layer chromatography, ^: H-fM M R, etc. If needed to speed u p the reaction, the reaction mixture can he heated, as is well known to the skilled artisan . Th e final and the intermediate compou nds are pu rified, if necessary, by various a rt known methods such as crystallization, precipitation , colum n chromatogra phy, and the !ikes, as will be apparent to the skilled artisa n upon reading this disclosu re.

[0126] An illustrative and non-limiting method for synthesizing a compound of formula (I), is schematica lly shown below.

In the following Schemes, - - ' and " refer to rings B and C as described he ei : L, R ³ and R ^; " are as described herein;

A ^s and 8 ^s are independently R ¹ , O, 5, S(0}x, NBoC, CH ₂ , CH ¹⁴ , C(R ^l ) ₂ provided that when both A* and S ³ are present in a ring, both are not CH _2; CHR ¹⁴ , C( R ⁱ⁴ } ₂ , and provided that if on ly a single A ⁵ or B ^¾ is present in a ring, that A ^b or B is not CH ₂ , CH R ¹⁴ , C(R ⁱ⁴ ) ₂ ; ^w is C C ₆ aikyl, COR ¹⁵ or COO ¹⁵ ; wherein R ^iS is optionally substituted C Q, aikyl. optionaify su bstituted Q-Cto aryl, optionally su bstituted 5- 10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4-10 membered heterocycie containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of Q, N, S, and oxidized forms of N and S;

X, and X ^s each represents a leaving group and are independently selected from O, Br, and i,

X° represents CR, N, 0, S(0)x ; wherein x is 0,. 1, or 2;

Y ^¾ represents a leaving group selected from C!, F, Br, I, OS0 ₂ R ^/:L and OS0 ₂ Ar; R ⁷¹ is C Cg alkyi;

Ar is phenyl optionally substituted with 1-3 halo and /or Ci-C ₄ ai kyl groups; n is 0, 1, or 2.

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 Method A

Method C &D

3a o! 3 b sr 4fc

Aiky!ation

Method B

o

A.

R ³

2 X

[0127] Genera! method A for preparing aryioxy/heteroarylether analogs (4a/4b) from substituted methylene alcohol flj and hydroxy! (hetero)aryf aldehyde derivatives (3a/3b). A hydroxy! (hetero)ary!aidehyde derivatives (3a/3b) (0.1-2 mmol) mixture with substituted methylene alcohol (1) (0.8 to 1.2eq) and PPh ₃ {1-1.5eq) in anhydrous THF (1-lOmL) was stirred under nitrogen until complete 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 stirred for 10 min, then filtered through a pad of silica. The silica was washed with ethyl acetate 2-20ml. The combined filtrates were evaporated and the residue was dried on high vac. The residue was purified by preparative HPLC or flash silica gel chromatography.

[01281 Seneral method 8 for preparing aryloxy/heteroarylether analogs (4a/4h) from substituted methylene halide (2) and hydroxy! {heterojaryi aldehyde derivatives (3a/3b). A mixture of hydroxy! (hetero)arylaidehyde derivatives (3a/3b) (0.1-2 mmol, 1.-4 eq.), substituted methylene chloride or bromide (2) (leq), and ₂ CO _¾ (2-5 eq.) (catalytic amount of Nal or Bu ₄ IMI may also be added) in D F or acetonitri!e { 1 to 10 ml.) was stirred at RT or heating up to 120 °C for 0.5-8 h under nitrogen atmosphere. In workup A, water was added to the reaction mixture, the precipitated product was collected,, washed with water,, and then subjected to preparative HPLC or flash silica ge! chromatography purification, fn workup B (for products that did not precipitate , diluted HCi or aqueous NH ₄ Ci 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 pu rified by automated silica gel column chromatography using appropriate solvents mixture (e.g.,. ethyl

acetate/hexanes).

[0129] General method C for preparing substituted methylene chloride (2a), To a solution of substituted methylene alcohol (1) (0.1 to 2 mmol) in DClvl ( 1-10 ml) was added SOCi ₂ dropwise (2eq to 5eq ) at 0 °C or RT, The reaction mixture was stirred at RT for lOmin to 6 h, or until reaction is judged complete (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. Alternatively,, a solution of aqueous IN Na ₂ C0 ₃ is then added to produce a solution of pH~ 8. the mixtu re was extracted with DCM (3 xlO~5QmL), dried over sodium sulfate, and concentrated to the crude substituted methylene chloride (2a), which is then purified by coiumn chromatography on si lica gel (0- 100% ethyl acetate-hexanes).

[01303 Genera! method D for preparing substituted methylene bromide (2b}„ To a solution of substituted meth ylene alcohol (1} (0.1 to 2 m moi) in DCM (1- 10 ml) was added Ph ₃ P Br dropwise (2eq to 5eq ) at 0 "C or RT, The reaction mixture was stirred at RT for 10 rnin to 2 h, or unti l reaction is judged complete (LC/ ^' S). The reaction m ixture is

concentrated to dryness over a rotavap. The residue purified by column ch romatography on si lica gel (0-100% ethyl acetate-hexanes) to afford the pure brom ide 2b.

Step4

[0131] Genera! method E for preparing heterocyclic methylene derivatives 9, 10, 12 and

13, Red uction of the ester group of heterocyciohexene carboxyiate 8 by LAH or DiBAI. gives th e correspond i ng alcohol 9-OH (Step 4). F urther reaction of the alcohol 9-OH with thionyi chloride, ΡΗ ₃ ΡΒί ^' 2 (or CBrvPh ₃ P or PBr ₃ ), or alkyl/aryl sufonyl chloride produces the corresponding 10-X chloride, bromide or sulfonate (Step 5).

[0132] Alternatively,, the double bond of heterocyciohexene carboxyiate 8 is reduced to give the c/s-heterocyclohexane 11-cis carboxyiate under palladium catalyzed hydrogenation conditions (Step 6). Reduction of the ester group of 11-cis by LAH or D! BAL yields cis-alcohol 12-GH-ess (Step 8), Conversion of the alcohol 12-OH-cis to its chloride, bromide or sulfonate (such as mesylate,, tosyiate) 13-X-cis can be achieved by reacting with thionyi chloride, or Ph ₃ PBr ₂ , or sufonyl chloride (such as mesyl chloride or tosyl ch loride) (Step 9). The cis- cyclohexane carboxyiate 11-cis can also be isomerized to the thermodynamicaliy more stabfe trans-isomer 11-trans by the treatment with an alcoholic alkoxide (e.g., ethoxide) solution. Analogously, transformation of 11-trarts ester to 12-trans alcohol and 13-X-trans halide is accom plished by applying conditions of Step 8 and Step 9 similar to these for the corresponding cis-isomers.

[0.133] Coupling of the (heterocyclic methylene derivatives 9, 10, 12 and 13 with hydroxyl (hetero)aryfaldehyde derivatives (3a/3b) by general method A or B affords the

corresponding ary!oxy/heteroaryiether analogs (4c and 4d).

[0134] General method F for preparing heterocyclic methylene derivatives IS, 19., 20 and 21. The ketone ester 14 is converted ΐο the inflate intermediate 15 by treating with a trifiating agent (e.g, triflic anhydride) in the presence of an organic base such as Hunig's base (Step 1). Suzuki coupling of the trifiate 15 with a boronic acid or ester affords

heterocyclo carboxy!ate 16 (Step 2). Subsequent reduction of the ester group by LAH or D!BAL gives the corresponding alcohol 18 (Step 3). Further reaction of the alcohol 18 with thiony! chloride, Ph _; ;PBr _. > (or CBr ₄ -Ph ₃ P or PBr-j, or alkyl/aryi sufonyl chloride produces the corresponding 19 chloride, bromide or sulfonate (Step 4),

[0135] Alternatively, the double bond of 16 is reduced to give the saturated heterolic analog 17 under palladium catalyzed hydrogenation conditions (Step 5). Reduction of the ester group of 17 by LAH or DiBAL yields a!cohoi 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 Ph jPBr?, or sufonyl chloride (such as mesyl chloride or tosyl chloride) (Step 8).

[0136] Coupling of the (heterocyclic methylene derivatives 18, 19, 20 and 21 with hydroxy! (hetero)arylaldehyde derivatives (3a/3b) by general method A or B affords the corresponding aryloxy/heteroaryioxyether analogs (4e and 4f), [0137] Chiral pyrrolidine methylene derivatives 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 aikene 22 with azomethine-yiide generated in situ from formaldehyde and amino add 23 aikene (Stepl). Subsequent reduction of the ester to alcohol 24 and further conversion 25 are accornpiished by anaiogous methods described herein. If a chiral auxiiiary group such as chiral oxazolidinone derivative 22a is used, optically active pyrrolidine derivatives 25 and 26 can also be obtained. Cou pling of 25 and 26 with hydroxy!

(hetero)aryialdehyde derivatives (3a/3b) by general method A or B affords the

corresponding aryloxy/heteroaryloxyether analogs (4).

3 . I Method A

22a ^R?2 Method B

[0138] Separate from the general synthesis of tetrahydrothiophenes {i.e., 20 and 21, A=S) described herein . Also described is a different synthetic approach to this class of analogs.

[0139] Other heterocyclic analogs (compound 5) with C-N linkage are synthesized by- applying Buchwald/Hartwig amination conditions, Many of the cyclic amines (1) are available commercially (e.g., la, lb, lc, Id, and le).

[0140] Protected amides of formula -CO HR ^{" J} and -CONHOR ^{1 "} can be converted e.g. _. , hydro!yzed to the corresponding amides according to methods known to the skilled artisan.

(R A /H A

[0141] Compounds of structure 4 can be synthesized via genera! synthetic scheme 1. Reduction of carboxyiic acid derivative 1 gives hydrxoym ethyl analog 2, which can he N- derivativtized at via copper-mediated N-ary!ation reaction (Cul, AM, base such as N, - dimethylethylenediamine and potassium phosphate, heat) to give key hydroxymethyl intermediate 3. Coupling of 3 with phenol aldehyde 4 produces the desired aldehyde analog 5 via typicai Mistunobu conditions using either triphenyiphosphine or polymer supported tripheny!phosphine. A _:i is a heteroatom or a hydrocarbyl moiety as defined herein.

[0142] General method step 1 - reduction of carboxyiic acid derivative 1 to methyl aicohoi 2: To a suspension of carboxyiic acid l(l- lOmmoi) sn McOH or EtOH (2-10 mL) at 0 °C was added SOCI _? (l,5eq). After stirred at room temperature for l-12h, it was

concentrated to remove all solvents, dried under high vacuum to give corresponding methyl or ethyl ester. The ester was dissolved in MeOH or EtOH (5-30 rriL), to this solution, was added NaBH^ (l-4eq) at 0 "C, the mixture was warmed up to room temperature and stirred for additional 1-24 h. The mixture was quenched with Sat. H I, 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 hydroxymethyiene compound 2.

[0143] Genera! method step 2 - N-alkyiation (la to lb): The carboxyiate la (R|=H) can be first alkylated and then reduced to give N-alkyl hydroxymethyiene analog lb (R > =alkyi). In a typical procedure, the carboxyiate la (1- lOrnmol) 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 alky! halide (eg, BnBr) (0.9-1, 5eq). The reaction allowed to proceed at room temperature 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 preparative HPLC or flash silica gel chromatography purification, Irs workup B (for products that did not precipitate), diluted HCI or aqueous NH4CI was added at 0 °C to adjusted the pH to "'7, the reaction mixture was partitioned between ethyl acetate or dich!oromethane 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).

[0144j General method step 3 - Copper-mediated N-arylation from 2a to 2c: For cyclic amines (X=H, H), to a solution of hydroxymethyiene compound 2a (1-10 mmol) and

aryl/hetero iodide (1-1.5eq ) in iPrOH (0.5-10 ml.} was added ethylene diol (1.3eq) and Cui (6,7moi%), followed by 3PO4 (1.3eq), then it was degassed and heated at 88 X for 6-24 h.

[0145] Alternatively,, for lactams (X=0), to a solution of hydroxymethyiene compound 2a (1-lOmmol) and aryl/hetero iodide (1-1.5eq) in Dioxane (2-20 snL) was added Cui (0.17eq), , -dirnethylethy'lenediamine (0.1?eq), K3PO4 (l,7eq),. then it was degassed and heated at 100 X for 6-48 h.

[0146] Workup for both procedures: the reaction mixture was cooled to room

temperature 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 chr omatography to give N-aryl/heteroaryl compound 2c.

[0147] General method C -Mitsunobu conditions A hydroxy! (hetero)aryialdehyde derivatives (4) (0.1-2 mmo!) mixture with substituted methylene alcohol (3) (0.8 to l,2eq) and (polymer-supported) PPh ₃ (1-1.5eq) in anhydrous THF (1-lOmL) was stirred under nitrogen until complete dissolution. The solution was cooled to 0 ^C C on ice hath 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 2- 20niL. The combined filtrates were evaporated and the residue was dried on highvac. The residue was purified by preparative HPLC or flash siiica gel chromatography

[0148J Compounds of structure 5 can be synthesized via general synthetic scheme 1. Reduction of carboxylic acid derivative 1 gives hydrxoymethyl analog 2, which can he - alkylated by simple a Iky I ha!lde (base, RiX, heat) or aryl halide (ArX) via copper-mediated - arylation reaction (Cul, Ar-i, base such as Ν,Ν-dimethyIethylenediamine and potassium phosphate, heat) to give key hydroxymethyl Intermediate 3. Coupling of 3 with phenol aldehyde 4 produces the desired aldehyde analog 5 via typical Mistunobu conditions using either trtphenylphosphine or polymer supported tripheny!phosphine. A _a is a heteroatom or a hydrocarby! moiety as defined herein.

[0149] General method step 1 - reduction of carboxylic acid derivative 1 to nrsethy! alcohol 2: To a suspension of carboxylic acid l(l-lOmmol) in fvleOH or EtOH (2- 10 mL} at 0 "C was added SOC!? (l.Seq). After stirred at room temperature for l- 12h, it was concentrated to remove all solvents, dried under high vacuum to give corresponding methyl or ethyl ester. The ester was dissolved in eOH or EtOH (5-30 ml), to this solution, was added NaBH ₄ (l-4eq) at 0 °C, the mixture was warmed up to room temperature and stirred for additional 1- 24 h. The mixture was quenched with Sat. NH ₄ CI, 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 2.

[0150] General method step 2 - Copper-mediated N-ary!atiort: For cyclic amines (X=H, H), to a solution of hydroxymethylene compound 2 (1-10 mrrsoi) and aryl/hetero iodide ( 1- l ,5eq) in iPrOH (0.5- 10 ml.) was added ethylene dio! (l.Seq) and Cu! (6,7rool ), followed by i< PO. _; (l.Seq), then it was degassed and heated at 88 T for 6-24 h.

Alternatively, for lactams (X--0), to a solution of hydroxymethylene compound 2 (1-lOmmol) and aryl/hetero iodide (1- l.Seq) in Dioxane (2-20 mL) was added Cut (0.17eq), N,N- dimethylethy!enediamine (0.17eq), 3PO4 (1.7eq), then it was degassed and healed at 100 "C for 6-48 h.

[0151] Workup for both procedures: the reaction mixture was cooled to room

temperature the mixture was diluted with EtOAc and water, organic layer was separated and the aqueous layer was extracted with EtQAc, 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-ary!/heteroaryl compound 3.

[0152] General method step 2b - N-alkylation: T he carboxyiate 1 can be first alkylated and then reduced to give N-alkyi hydroxymethylene analog 3. in a typical procedure, the carboxyiate 1 (1- lOmmoi) 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 alky! hafide (eg, BnBr) (0,9- 1.5eq}. The reaction allowed to proceed at room temperature of heat at 40 to 115 ^C C for 0.5 to 24 h. !n workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to preparative HPLC or flash silica gel chromatography purification. In workup B (for products that did not precipitate), diluted HC! or aqueous H CI 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). [0153] Genera! method C - itsunobu conditions A hydroxy! (hetero)arylaldehyde derivatives (4) (0.1- 2 mmoi) mixture with substituted methylene alcohol (3) (0.S to 1.2eq) and (polymer-supported) PPh ₃ (1-l.Seq) in an hydrous THF (1-lQmL) was stirred under nitrogen until complete dissolution. The solution as 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 T for 2-48 hours. The mixture was filtered through a pad of silica. The silica was washed with ethyl acetate 2- 20mL The combined filtrates were evaporated and the residue was dried on highvac. The residue was purified by preparative HPLC or flash silica gel chromatography.

Prodrug Synthesis

[0154] Syntheses of the ester prodrugs start with the free carboxylic acid hearing 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 oxaiyi chloride or thionyl chloride in an aprotic solvent, optionally with a catalytic amount of dimethyl formamide, followed by evaporation. Examples of aprotic solvents, include, but are not limited to methylene chloride, tetrahydrofuran, and the like. Alternatively, activations can be performed in situ by using reagents such as BOP

(benzotriazol-I-yloxytris(dimethylamino) phosphonium nexafiuoroiphosphate, and the like (see Nagy et a!„ 1993, Proc. Natl. Acad . Sci. USA 90:6373-6376) followed by reaction with the free alcohol. solation 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; evaporation of the organic solvent layer; and recrystaiization from a solvent _, , such as ethanol. Optionally, the solvent can be acidified with an acid, such as HCI or acetic acid to provide a pharmaceutically acceptable salt 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 evaporation. [0.1553 Suitable free acids bearing the tertiary amine are commercially available, such as 2- (N- orphoIino)-prapionic acid, N,N- dlmethyl-beta-alanine, and the like. Non~ commercial acids can be synthesized in straightforward manner via standard literature procedures.

[0156] 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 carbonyi diimidazoie, 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.

[0157] 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.

[0158] Provided herein is a method of synthesizing an acyloxymethy! version of a prodrug by adapting a method from the reference Sobolev et al., 2002, J. Org. Chem. 67:401-410.

R ⁵¹ is Cj-Cg alkyl.

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

[0160] Provided herein is a method of synthesizing an alkyloxymethyl version of a prodrug

R ^"' - is Ci-Ce alkyl, C ₃ -C ₃ cydoalkyi, C3-C9 heterocyciyl, C5-C10 aryl, or C3-C9 heteroaryl

[0161] The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention m any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exempiary, and are not intended as limitations on the scope of the Invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.

[0162] In the examples below as well as throughout, the application., the following abbreviations have the following meanings, if not defined, the terms have their generally accepted meanings.

degrees Celsius

RT Room temperature

min = minute(s)

h hour(s)

μί - Microliter

m l = Milliliter

mmoi = Milii nole

eq = Equivalent

mg illigram

ppm = Parts per million

atm - Atmospheric pressure

MS Mass spectrometry

LC-MS Liquid chromatography-mass spectrometry High performance liquid chromatography

Nuclear magnetic resonance

Saturated

Methanol

Et ano!

Ethy! acetate

Triethyiamine

Acetic anhydride

Sodium triacetoxy borohydride

phosphorus tribromide

T ^' riphenyiphosphine

Triphenylphosphine dibromide

Teixabromornethane

N, N-Dimethylformamide

Dichloromethane

Lithium a!uminum hydride

Tetrahydrofurari

Diisobutylaluminium hydride

Diisopropyi azodscarboxylate

Diethyl azodicarboxylate

, N - D i i s o p to p y I et h y ! a m i n e

[l,l'-Sis(diphenylphosphino)ferrocene]

dichloropal!adium{ii), complex

[0163] The following representative B-ring and C-ring intermediates may be incorporated into the compounds of the invention by methods that are commonly known to the skilled artisan. Ϊ164] Preparation of5-hydroxy-2-(2-methoxyethoxy)i$onicotmaldehyde).

S'ep 4

Step 1

[0165] To a solution of 6-(benzy!oxy)pyridin-3-o! (2.0 g, 10 rnmol, 1 eq.) in DM F (20 m l) was added NaH (60% in mineral oil; 0.6 g, 15 rnmol, 1.5eq. ) at 0-5 °C portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5 °C for 15 min, added chiorornethyl methyi ether (0.88 g, 11 mmoi, 1.1 eq.), stirred at 0-5 °C for another 2.0 min, and quenched with NH^C!,^., solution. The aqueous layer was extracted with EtOAc (3 x 20 ml) and the combined organic layers were washed with water and brine, dried over 3 ₂ $0 ₄ , concentrated, and purified on silica gel using 25% EtOAc/h ex an.es as eluent to give 2- (benzyioxy)-5-(nr»ethoxymethoxy)pyridine (2.1 g, 87%) as a colorless oil. MS (ESI) m/z 246.1

[ + Mj ⁺ .

Step 2

[0166] To 2-(benzyloxy)-5-(niethoxymethoxy)pyridine (1.8 g, 8.71 mol) in EtOH was added Pd/C (1.0 g). The mixture was charged with H ₂ (15 psi), stirred at RT for 45 min, filtered, and concentrated to give 5-imethoxymethoxy)pyridin-2-o! ( 1.35 g, quantitative yield) a a pale ye!io solid, MS {ESI) m/z 156.1 [ +Hf .

Step 3

[0167] To a mixture of 5-(rnethoxymethoxy)pyridin-2-ol (1.35 g, 8.71 mmoi, 1 eq.) and K ₂ C0 ₃ (6.01 g, 43.6 mmoi, 5.0 eq.) In DMF (30.0 ml.) was added l-bromo-2-methoxyethane (3.61 g, 26.1 m rnol, 3eq.). The mixture was heated at 60 °C for 2 h, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-{2-methoxyethoxy)-5-(methoxymethoxy)pyridine (500 mg, 27%) as a colorless oil. ^l NMR (400 MHz, CDCI ₃ ) δ 7.94 (d, J = 3.0 Hz, 1H), 7.35 (ddd,. J = 8.9, 3.0, 1.0 Hz, 1H), 6.76 (del, J = 8.9, 1.0 Hz, 1H), 5.11 (s, 2H), 4.48 - 4.40 (m, 2H), 3.79-3.71 (m, 2H), 3.50 (s, 3H), 3.45 (s, 3H), MS (ESS) m/z 214.1 [M+Hf. iep

[01681 To a mixture of 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine (1.34 g, 6.3 mol, 1 eq. ) and diisopropylamine (.17.5 ii L, 0.13 mmoi, 0.02 eq.) in THF (50 ml) was added methyl lithium (1.6 M/THF, 7 mL, 11.3 mol, 1.8 eq.) at -40 °C. Upon the completion of addition, the mixture was warmed to 0 °C, continued to stir at 0 °C for 3 h, cooled back down to -40 °C, and added DMF (0.83 ml, 11,3 mol, 1.8 eq. ) slowly. The mixture was then stirred at -40 °C for 1 h, quenched with a mixture of HCI (12 , 12 mL) and THF (28 mL), warmed to RT , and added water (20 ml). The pH of the mixture was adjusted to pH 8- 9 with solid K ₂ C0 ₃ . The aqueous layer was extracted with EtOAc (30 mL) twice. The combined organic layers were dried over Ν3 ₂ 50 ₄ , concentrated,, and purified on silica gel using a mixture of EtOAc and hexanes as eiuent to give a mixture of 2-{2-methoxyethoxy)-5- (methoxymethoxy)isonicotinaldehyde and 2-{2-methoxyethoxy)-5 - (methoxymethoxy)nicot!naldehyde (5/ 1, 1.27 g, 83.6%) as a pale yellow oil. , NMR (400 MHz, CDCij) 5 10.45 (s, IH), 8.23 is, 1H), 7.16 (s, IH), 5.27 (s, 2H), 4.46 {dd, J = 5.4, 3.9 Hz, 2H), 4.14 iq, J = 7.1 Hz, I H), 3.77 - 3,71 (m, 2H), 3.56 (s, 3H), 3.46 (s, 3H} and ^a H NM R (400 MHz, CDCIj) δ 10.41 (s, 1H), 8.18 (d, J = 3.2 Hz, 1H), 7.85 (d, J = 3.1 Hz, 1H), 5.16 (s, 2H), 4.64 - 4.57 (m, 2H), 3.85 - 3.79 fm, J = 5.4, 4.0 Hz, 2H), 3.50 (s, 3H), 3.46 (s, 3H); MS (ESi ) m/z 242.1 [M+H] ⁺ .

Step 5

[0169] To a solution of 2-methoxy-5-{methoxymethoxy)isonicotinaldehyde (1.27 g, 5.29 mo!) in THF (5 mL) was added HCI (3 N, 4 mL). The reaction was stirred at 50 °C for 1 h, cooled to RT, and diluted with water (5 ml.}. The mixture was neutralized to pH 7-8 with solid ₂ C0 ₃ and the aqueous layer was extracted with EtOAc (100 mL) twice. The combined organic layers were dried over a ₂ S0 ₄ , concentrated,, and purified on silica gel using a mixture of EtOAc and hexanes to give 5-hydroxy-2-(2-methoxyethoxy)isonicotinaidehyde (630 mg, 60%) and 5-hydroxy-2-(2-methoxyethoxy)r»icotinafdehyde (120 mg, 11%). Data for 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde: ^: H NM R (400 M Hz, CDCk) 6 9.98 (s, 1H), 9.50 {s, 1H), 8.07 (s, IH}, 7.02 (s, IH), 4.51 - 4.39 (m, 2H), 3.81 - 3.72 (m, 2H), 3.47 is, 3H). LRMS (M r IT ) m/z 198.1. Data for and 5-hydroxy-2-(2-methoxyethoxy) nicoiina!dehyde: ^; Ή N MR (400 MHz, CDCi ₃ ) 6 103 (s, IH), 7.99 (d, J = 3,2 Hz, IH), 7.58 (d, J = 3.2 Hz, IH), 7.18 - 7.07 (br, H), 4.54 (dd, J = 5.4, 3.7 Hz, 2H), 3.84 (dd, J = 5.4, 3.7 Hz, 2H), 3.49 is, 3H); MS (ESI) m/z 198.1 [M+Hf. [0170] Preparation of 2,6-dihydroxybenzaldehyde.

[0171] Into a 3000-mL three neck round-bottom flask, was placed a solution of AiC (240 g, 1.80 moi, 3.00 equiv) in dichioromethane (1200ml.). A solution of 2,6- dimethoxyhenzaidehyde (100 g, 601.78 mmol, 1.00 eq) in dichioromethane (800ml) was added to the reaction mixture dropwise at Q°C. The resulting solution was stirred overnight at room temperature,, and then it was quenched with 200 mL of diluted HCi (2 ). The resulting solution was extracted with 2x200 mL of dichioromethane. The combined organic layers were concentrated under vacuum. The residue was appiied onto a silica gel column with ethyf acetate/petroleum ether (1:200-1:50) as e!uent to furnish 40 g (48%) of 2,6- dihydroxybenzaldehyde as a yellow solid.

¹ HNMR (300MHz, DMSO-efe) 6 11.25(5, 2H), 10.25(s, 1H), 7.36(m, 1H), 6.36 (d, J=8.4Hz 2H); MS (ESI ) m/z 139 [M+H]\

[0172] Preparation of5-hydroxy-2- ethoxyisonicotinaidehyde.

[0173] Step 1: To a solution of 6-methoxypyridin-3-oI (20 g, 0.16 mol) in D F (200 mL) was added NaH (60% in mineral oil; 9,6 g, 0.24 mol) at 0-5 °C portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5 °C for 15 min followed by additional of chioromethyl methyl ether. The mixture was stirred at 0-5 °C for another 20 min and quenched with aqueous NH _fl CI ₍₄₃ t}. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layer was washed with water and brine, dried over Na ₂ SO/|, and concentrated under reduced pressure. The residue was purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)pyridine (24.1 g, 89.3%) as a colorless oil. H NMR (400 MHz; CDCI3) 7,97 (d, 1 H), 7.35 (όά, 1 H), 6.70 (d, 1 H), 5.12 (s, 2 H), 3.91 (s, 3 H), 3.51 (s, 3 H); MS (ESI) m/z 170.1 [ +H]*.

[0174J Step2: To a mixture of 2-methoxy-5-(methoxymethoxy)pyrldlne (30 g. 0.178 moi) and diisopropylamine (507 uL, 3.5 mrool) in THF (500 ml) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 moi) at -40 °C. Upon the completion of addition, the mixture was warmed to 0 °C and continued to stir at 0 °C for 3 h. The reaction mixture was then cooled back down to -40 ^C' C followed by addition of BMF (24.7 mL, 0.32 mo!) slowly, The mixture was then stirred at -40 ^U C for 1 h and quenched with a mixture of HCI (12 N, 120 mL) and THF (280 nit). Water (200 ml.) was added and the pH of the mixture was adjusted to pH 8-9 with solid K2CO3. The mixture was extracted with EtOAc 300 mL) twice. The organic layer was combined, dried over a ₂ S0 ₄ , and concentrated to give 2-methoxy-5- (methoxymethoxy)isonicotinaldehyde (33.5 g, 95.7%) as a brown solid, which was used for next step without further purification, ^: H NMR (400 MHz; CD ₃ OD) 7.90 (s, 1 H), 6.92 (s, 1 H), 5.64 (s, 1 h ^' ),, 5.20 (s, 2 Hi, 3.84 (s, 3 H), 3.48 (s, 3 H); MS (ESI) m/z 198.1 [M+Hf .

{0175] Step 3; To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 0.17 moi) in THF (150 mL) was added HCI (3 N, 250 mL). The reaction was stirred at 50 °C for 1 h, cooled to RT and diluted with water (500 mL). The mixture was neutralized to pH 7-8 with soiid K _? CO}. The pale yellow solid was collected, washed with water, and dried in vacuum oven (40 °C) overnight to give 5-hydroxy-2-methoxyisonicotinaldehyde (17,9 g, 74.6%). ^l H NMR (400 MHz; DMSO) = 10.31 (s, 1 H), 3.03 (s, 1 H), 6.89 (s, 1 H), 3.80 (s, 3 H); MS (ESI) m/z 154.0 [M+Hf.

GBT915

(S)-2-((1 -benzoyipyrroiidin-2-yi)methoxy)-6- hydroxybenzaidehyde [0176] GBT915- {S}-2-f{l-ben?.oylpyfro idin-2-yS)methoxy)-6-hydroxybenzaidehyde.

[0177] Step 1 : To a solution of (S)-pyrrolidin-2-ylmethanol (700 mg, 6.92 mmol) and D!PEA (1.20 mL, 6,92 mmoi) in DCEV1 ( 12 ml) at 0 X was added benzoyl chloride (0.80 ml, 6.92 mmoi), 30 min later it was diluted with more DC and was washed with Sat. aHCG-¾, brine, dried over MgS0 ₄ , concentrated to give crude product, which was purified by column {EtOAc 0-100%) to give (S)-(2-(hydroxymethyl)pyrro!idin-l-yl)(phenyl)methanone (1.2 g).

[017SJ Step 2: To a solution of (S)-(2-{hydroxymethyl)pyrrolidin-l-yl)(phenyl)methanone (100 mg, 0.49 mmoi) and 2,6-dihydroxybenzaldehyde (90 rng, 0.64 mmoi) in THF (I rnL) was added PPh ₃ ( 190 rng, 0.73 mmoi) and DiAD {0.15 ml, 0.73 mmol) at room temperature, 30 min later, it was concentrated and the residue was purified by column

(Hexanes/EtOAc=100:0 to 1:1) to give (5)-2-((l-benzoylpyrroltdin-2-y!)methoxy)-6- hydroxybenza!dehyde (65 mg). ^X H MR (400 M Hz, Chloroform-rf) 6 11.90 (s, IH), 10.40 (s, IH), 7.51 - 7.31 (m, 6H), 6.53 (t, J = 9.2 Hz, 2H), 4.65 (s, IH), 4.38 (d _; J = 6.1 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.29 - 1.90 (m, 2H), 1.79 (d, ./ « 36.4 Hz, IH), 1.31 - 1.18 (m, 1H). MS found for

-benzoyipiperidin-2-yi)meihoxy)--6- hydroxybenzaldehyde [0179] GBT952- {S)-2-{(l-berszoylpIperidin-2-yf)methoxy)--6-hydroxybenzaSde hyd8

[0180] Step 1: To a suspension of {S)-ptperidin-2-y!methanol hydrochloride (0.11 g, 0.70 mmo!) in DCM (2 mL) was added D!PEA (0.27 ml, 1.54 mmol) and benzoyl chloride (0.08 m 0.70 rnmol) at room temperature, after stirred for 30 min, it was diluted with DCM and washed with Sat. NH4CI, brine, dried over gS0 ₄ and was concentrated to give crude product, which was purified by coiumn (Hexanes/EtOAc- 0:100) to give (S}-(2- (hydroxymethyl)pipertdin-l-yl)(phenyl)methanone (84 mg).

[0181] Step 2 : To a solution of 2,6-dihydroxybenzaIdehyde (110 nig, 0.80 rnmol) and (S)-(. (hydrOxymeihyl)piperidin-l-yl)(pheny!)methanone (0.23 g, 1.04 mmoi} in THF (1.5 mL) was added PPh ₃ (310 mg, 1.20 rnmol) and DIAD (0.23 ml, 1.20 mmo!) at 0 "C, then it was warmed up to room temperature and stirred for 1 h. The mixture was concentrated and purified by column (hexanes/EtOAc=60:40) to give (S)-2-((l-benzoyipiperidin-2-yl)methoxy) 6-hydroxybenzaldehyde 62 mg. ^X H NMR (400 MHz, Ch!oroform-c ) 6 11,98 (s, 1H), 10.29 (s, 1H), 7.45-7.28 (m, 5H), 6.58-6.50 (rn, 2H), 6.40 (dt, J = 8.1, 0.3 Hz, 1H), 4.32 (t, J * 8.5 Hz, 1H), 4.18 (s, IN), 3.04 (s, 1H), 1.94 - 1.76 (m, 3H), 1,73 - 1,58 (m, 3H), 1.26 (dt, J = 7.0, 3, 1 Hz, 2H). MS found for C20H21 O ₄ : 340.2.

GBT961

I a

0

O

(S)-2-hydroxy-6-{(i-nicoWnoyipyrroiidin-2-yi)methoxy)ben2 a!dehyde 0182] GBT961- S)-2-hydroxy-6-{fl-iiicotfnoyipyrroydirs-2-yijmethOKyJberi2a idehyde

[0183] Step 1: To a solution of (S)-pyrroiidin-2-ylmethano! (500 mg, 4.94 mmol) in DCM (10 mL) was added D1PEA (1.89 ml, 10.87 mmol), followed by nicotinyl chloride (0.92 g, 5.19 mmol) at 0 "C, after stirred for 30 min, it was diluted with DCM, washed with aqueous Sat. N aHC0 _3; brine, dried and concentrated to give crude product, which was pu rified by column (DC /MeOH=100:0 to 80:20) to give {S)-(2-{hydroxymethyl)pyrroIidin-l-yl)(pyridin-3- yl)methanone (900 mg).

[0184] Step 2: To a solution of {S)-{2-(hydroxymethyl}pynO!idin-l-yl)(pyridin-3- yljmethanone ( 150 mg.. 0,73 m mol) and 2,6-dihydroxybenzaldehyde (0.13 g, 0.91 mmol) in TH F ( 1.5 mL) was added PPh ₃ (0.29 g, 1.1 mmol) and DIAD (0.21 mL, 1.1 mmol) at 0 °C and stirred at room temperature for 2 h, It was subseq uently concentrated, the resu lting residue was purified by colum n (hexanes/EtOAc=100:0 to 40:60 to DCM/MeOH=100:0 to 90: 10) to give a mixtu re of prod ucts, wh ich was fu rther pu ri fied by preparative HPLC to give (S)-2 - hydroxy-6-{(l-nicotinoyIpyrrolidin-2-yl)methoxy)ben2a!dehyde (68 mg) . Hi R (400 M Hz, Ch!oroform-d) δ 11.90 (s, 1H), 10.40 (s, IN), 8.78 - 8.72 (rn, 1H), 8.68 (dd, ./ = 4.9, 1 ,7 Hz, 1H), 7.82 (dt, J = 7.9, 2 ,0 Hz, 1H ), 7.40 (t, J - 8.3 Hz, 1H), 7.36 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H ), 6.53 (dd, J = 8.5, 4.9 Hz, 2H), 4.66 (d, J - 11.1 Hz, 1H), 4.38 (d, J = 5.8 Hz, 2H), 3.54 (t, J = 7.6 Hz, 2H), 2.2.6 (dtd, J = .12.8, 7.6, 5.3 Hz, 1H), 2.19 - 2.10 (m, 1H), 2.10 - 1.98 (m, 1H), 1.88 (dt, J = 12.5, 7.8 Hz, 1H). MS found for CigH . sNaO : 327.4.

GBT962

(S)-2-hydroxy-6-(( 1 sonicotinoylp rTolidin-2-yl)meihoxy) enzaidehyde

[0185] GBT962- {Si-2-hydroxy-6-( l-isonfcotinoy!pyrroiidiri-2-yi}methoxy)bers2a!dehyde

10186] Step 1: To a solution of (S)-pyrrolidin-2-y!methanol (500 mg, 4.94 mmol) in DCM (10 ml) was added DIPEA (1.89 rnL, 10.87 mmol), followed by nicotinyi chloride (0.88 g, 4.94 mmol) at 0 °C, after stirred for 30 min, it was diluted with DCM, washed with aqueous Sat. NaHCGj, brine,, dried and concentrated to give crude product, which was purified by column (DCM/MeOH=100:0 to 80:20) to give (S)-{2-(hydroxymethyl)pyrroiidin-l-yi){pyridin-4- yl)methanorte (900 mg).

[0187J Step 2: To a solution of (S}-(2-{hydroxymethyl)pyrrolidin-l-yl)(pyridin-3- yUmetbanone (150 mg, 0,73 mmol) and 2,6-dibyriroxybenzaidehyde (0.13 g, 0.91 mmol) in THF (1.5 rnL) was added PPh ₃ (0.29 g, 1.1 mmol) and DIAD (0.21 rnL, l.i mmoi) at 0 °C and stirred at room temperature for 2 h, it was subsequently concentrated, the resulting residue was purified by column {hexanes/EtOAc=100:0 to 40:60 to DCM/ eOH=100:0 to 90:10) to give a mixture of products, which was further purified by preparative HPLC to give (S}-2- hydroxy-6-((l-isonicotinoylpyrro!tdin-2-yi)methoxy)benzaideh yde (36 mg). ^l H MR (400 MHz, Chloroform-^} δ 11.88 (s, 1H), 10.38 (s, 1H), 8.72 - 8.63 (m, 2H), 7.39 (t, J = 8.4 Hz, 1H), 7.35 - 7.24 (m, 2H), 6.52 (t, J = 8.6 Hz, 2H), 4.63 (dq, J = 8.4, 5.1 Hz, 1H), 4.42 - 4.29 (m, 2H), 3.46 (hept, J 6.3, 5.4 Hz, 2H), 2.24 (dtd, J = 13.3, 7.7, 5.5 Hz, 1H), 2.13 (dq, ./ = 13.0, 6.8 Hz, 1 H), 2.03 (dt, J = 12.4, 6.3 Hz, 1H ), 1.95 - 1.79 (m, 1H). MS found for C ₁₈ H _{ls 2} 0 ₄ i 327.4.

GBT379

(S)-2-hydroxy^(1 -picolinoyipyrroiidin-2-yl)methoxy)berizaidehyde

[0188] Step 1 : To a solution of {5}-pyrro!idirt-2-ylrnethanol ( 500 mg, 4.94 mmol) in DCM (10 ml.} was added DI PEA (1.89 mL, 10.87 mmoi), followed by isonicotlnyl ch loride- (0.88 g, 4.94 mmol) at 0 *C, after stirred for 30 min, it was diluted with DCM, washed with aqueous Sat. NaHCC'3, brine, d ried and concentrated to give cr ude prod uct, wh ich was p urified by colu mn (DC / eOH=100:0 to 80:20) to give (S)-(2-(hydroxymethyl}pyrrolidin-l-yl)(pyridin-2- yi ^' jnietha none (900 mg).

J0189] Step 2: To a solution of (S)-(2 ^{^} (hyxiroxymethy!)pyrrolidin-l-yi)(pyridin-2-- yl)methanone ( 100 mg, 0.48 mmol) and 2,6-dihydroxybenzaldehyde (0.08 g, 0, 6 mmoi) in TH F (5 mL) was added PPh ₃ (polymer supported, 600 mg, 0.72 mmol) and DIAD (0.15 m l, 0.72 m moi) at room temperature. After stirred at room tem per atu re for 3 h . the mixture was diluted with AcCN, the insoluble material was filtered off, the nitrate was concentrated to give crude produc which was pu rified by prepa rative HPLC to give (5)-2- hydroxy-6-({l- picolinoylpyrrolidin-2-yl)methoxy)benzaidehyde (15 mg). ^X H NMR (400 MHz, Chloroform -d) 6 11.92 (s, 1H ), 10.39 (d, J - 0.6 Hz, 1H), 8.55 (ddt, J = 40.7, 4.9, 1.1 Hz, 1H), 7.89 - 7.74 (m, 2H), 7.40 (t, J = 8.4 Hz, 1H), 7.37 -7.23 (m, 1H), 6.60- 6.46 {m, 2H), 4.76-4.65 (m, 1H), 4.48 (dd, J ~ 9.5, 3.3 Hz, 1H), 4.32 - 4.18 (m, 1H), 3.99 - 3.81 (m, 1H), 3.81 - 3.67 (m, 1H , 2.25 - 1.83 (m, 4H). MS found for G _g H _ls N ₂ 04: 327.3.

GBT1064

-2-h droxy-6-((1-(1-isopropy -1 H-pyrazo!e-5-carbony!)pyrroiidii

yi)meihoxy)benzaldehyde

10.1.90] GST1064 (S)-2-hydro y-6-i(l-¾l-isopropyi-lH-pyrazo!e-5-carboryI}pyrrolidin-2- Yl)methoxy)benzaidehyde

[0191] Step 1: To a solution of (S)-pyrrolidin-2-yimethanol {100 mg, 1 mmoi) and 1- isopropyl-lH-pyrazoie-5-carboxylic acid (0.15 g, lmmol) in DMF (2 mL) was added HATU (0.38 g, 1 mmoi) and then the mixture was stirred until finished, it was diluted with water and extracted with EtOAc, organic layer was dried and concentrated to give crude product, which was purified by column (100% EtOAc) to give (S)-(2-(hydroxymethyl)pyrrolidin-l-yI)(l- isopropyi-lH-pyrazo!-5~y!)methanone (120 mg).

f0192] Step 2: To a solution of (S)-(2-{hydroxymethyl)pyrrolidin-l-yl){l-isopropyl-lH- pyrazoi-5-yl)methanone (120 mg, 0.51 mmoi) and 2,6-dihydroxybenzaidehyde (0.09 g, 0.66 mmoi) in THF (4 mL) waas added PPh ₃ (Polymer supported, 640 mg, 0.77 mmoi) and DIAD (0.16 mL, 0.77 mmoi) at 0 °C. After stirred at room temperature for 1 h, it was diluted with AcCN, the insoluble materia! was filtered off and the filtrate was concentrated to give crude product, which was purified by preparative HPLCto give (S)-2-hydroxy-6-((l-(l-isopropyi lH- pyrazole-5-carbonyl)pyrrolidin-2-yl)methoxy}benzaldehyde (46 mg). ^X NMR (400 MHz,

77 Chforoform-or) δ 11.90 (s, IH), 10.37 (s, IH), 7.55 (d, J = 2.0 Hz, 1H), 7,41 (t, J - 8.4 Hz, IH), 6.54 (d, J - 8.5 Hz, IH), 6.48 (d, ; = 83 Hz, 1 H], 6.37 (d, J = 2.0 Hz, I H), 5.03 - 4.94 (m, I H), 4,65 (s, IH), 4.37 (d, J = 5.4 Hz, 2H), 3.67 (s, IH), 3.60 - 3,45 (m, IH), 2.25 (dd, J = 13.1, 6.1 Hz, IH), 2.11 (deft, 7 = 30.4, 12.0, 6.4 Hz, 2H), 1.93 (s, IH), 1.53 {d, J = 6.6 Hz, 3H), 1.46 (d, / = 6.7 Hz, 3H). MS (M+H) found for CuHaNsGi: 358,3.

GBT1118

( S)-2-hydroxy-6-{( 1 -ni >tinoylpiperidin-2-yl)methoxy) ert2aldehyde

[0193] GBT1118- (S)"2-hydroxy-6-{(l-nicotinoyipiperidin-2-v! meihoKy)benzaidehyde

[0194] Step 1&2: To a solid sample of (5)- tert-butyl 2-(hydroxymethyl)piperidine-l- carboxy!ate (2.15 mg, 1.02 mrnoi) was added 4N HCI in dioxane (1 ml.). After stirred for 30 min, it was concentrated to give (S)-piperidin-2-yimethartoi HCi salt. To a suspension of (Si- piperidin-2-yImethanol HCi salt in DC (3 ml.) at 0 X was added DIPEA (0.39 mL, 2.24 mmol) and nicotinyi chloride (0.2 g, 1.12 mrnoi). After stirred for 30 min, it was diluted with DCM, washed with aqueous Sat, NaHC03, brine, dried and concentrated to give crude product, which was purified by column (DCM/MeOH=90:10) to give (5)-(2·

(hydroxymethyI)piperidin-l-yi)(pyridin-3-yl)methanone (130 mg).

[0195J Step 2: To a solution of (S)-(2-(hydroxymethyl)piperidin-l-yi)(pyridin-3- yl imethanone (130 mg, 0.59 mrnoi) and 2,6-dihydroxybenzaldehyrie (0.11 g, 0.77 mmol) in THF {4 mL) was added PPh ₃ (polymer supported, 0, 74 g, 0,89 mmoi) and OiAD (0.17 ml, 0.83 mmoi) at 0 "C and stirred at room temperature for 2 h . it was subsequently concentrated, the resulting residue was purified by preparative HPLC to give (S)-2-hydroxy-6-((l- nicotitioylpiperidin-2-yl)metboxy)benzaidehyde (30 mg). ^X H R (400 MHz, Ch ioroform-c ) δ 11.95 (s, 1H), 10.29 (s, 1H), 8.66 {dd, = 4.9, 1.7 Hz, 1H), 8.65 - 8.62 (m, 1H), 7.73 (dt, J = 7.8, 2,0 Hz, IH}, 7,41 (d., J « 8,4 Hz, 1H), 7.37 (ddd, J - 7.8, 4.9,, 0.9 Hz, 1H), 6.59 ~ 6.54 (m, 1 H), 6.40 id, J = 7.0 Hz, 1H), 4.39 - 4,30 (m, 2H), 4.19 (s, 2H), 3.15 ($, 1H ), 1.97 - 1.78 (m, 4H), 1.72 - 1.56 ! m, 2H) MS found for C _: ^Η. , , .0 , : 341,3.

6BT001579

(S)-2- y'droxy~6-((1 -{6"methyinicotlnoyr!p!peridin-2

yl)methoxy)benzaldehyde

[0196] GBTlS79- {S)-2-hydroxy-6-f{l-{6-methy!nicotinoyf)pIperidin-2- yiJmethoxy beruaSdehyde

[0197] Steps 1&2: To a suspension of 6-methyinicotinic acid (270 mg, zmmoi) i n DCM (5 mL) was added oxaiy! chloride (0.34 m L, 4mmof) at 0 °C followed by a drop of D F, after stirred for 2 hour at room temperature, the solution was concentrated to give crude acid chloride.

To the above crude acid chloride in DCM (4 m L; was added (S)-pipend in-2-y!methanoi hyd rochloride (300 mg, 1.98 mmoi) and DI PEA ( 1.04 ml, 5.94 mmoi) at 0 X, after stirred at room temperature for 2 h, more DIPEA was added to drive the reaction to completion. The

^' 4 reaction was diiuted with DCM.. washed with Sat. NaHCCB, brine, dried and concentrated to gsve crude product, which was purified by column (DCM/MeOH=90:iO) to give desired (SJ- (2-(hydroxymethyl piperidin-l-yl)(6-methylpyridin-3-yl)methanone (100 mg).

[0198] Step 3: To a solution of (S)-(2- hydroxymethyl)piperidin- l-yI)(6-methyIpyridin-3- yi)niethanone ( 100 mg, 0.43 mm of) and 2,6-dfhydroxybenzaldehyde (30 mg, 0.56 mmol) in THF (2.5 ml) at 0 °C was added polymer supported triphenyiphosphine (435 mg, 0,52 rnmoi) and DIAD (0.11 rnL, 0.52 rnmoi), after stirred for 4 hour at room temperature, the solution was filtered, the filtrate was concentrated and was purified by prep HPLC to give (S)-2- hydroxy-6-{(l-(6-methylnicotinoyi)piperidin-2-yI)methoxy)ben 2aIdehyde (29 mg). ^l H NMR (400 M Hz, Chioroform-d) δ 11.95 is,. IN), 10.2.8 (s, 1H), 3,53 (d, J = 2.2 Hz, 1H), 7.62 (dd, J - 8,0, 2.3 Hz, 1H), 7.39 (t, J■ 8.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.55 (dd, J - 8.5, 0.8 Hz, 1H), 6.40 (s, 1H), 4.33 (t, J ~ 8.6 Hz, 2H), 4, 19 (s, 1H), 3.09 (s, 2H), 2.59 (s, 3H), 1.73 (m, 6H). MS (M+H) found for C20H22 2O4: 355.3.

GBT001580

(S)-2-bydroxy-6-((1-(2-methylnicotinoyi)pipendin-2- yl)methoxy)benza!dehyde

[0199] GBT1580- (S)-2-hydro «: y-6-(fl~{2-roethy1nico†isioy!} piperidin-2- y methoxylbertxaidehyde

[0200] Step 1&2: To a suspension of 2- methyinicotinic acid (300 nig, 2, 19 mmo!) in DC (5 ml.) was added oxalyl chloride (0.28 ml, 3.3 mmoi) at 0 °C and was further stirred for 2 hour at room temperature, then the solution was concentrated to give crude acid chloride.

[0201] To the acid chloride in DCM (5 mi.) was added ($)-piperidin-2-ylmethanol

hydrochloride (250 mg, 1.65 mmol) and triethylamine (0.69 mL, 4.95 mmoi) at 0 ^* C and was further stirred for 30 min at room temperature, the solution was diluted with more DCM and the organic layer was washed with Sat, NaHC03 and brine, dried and concentrated to give crude product, which was purified by column (DCM/MeOH=95:5) to give (S)-(2- {hydroxymethyl)piperidin-l-yl)(2-methylpyridin-3-yi)methanon e (200 mg).

[0202] Step 3: To a solution of (S)-(2-{hydroxymethyl)piperidin-l-yl)(2-methylpyridin-3- yi imethanone (180 mg, 0.77 mmol) and 2,6-dihydroxybenzaldehyde (140 mg, 1.0 mmol) in THF (5 mL) at 0 °C was added polymer supported tripheny!phosphine (1.0 g, 1.16 mmoi) and DIAD (0.21 mL, 1.08 mmol), after stirred for 15 hour at room temperature, the solution was filtered, the filtrate was concentrated and was purified by prep HPLC to give (5)-2-hydroxy- 6-((l-{2-methylnicotinoyl)piperidin-2-yi)methoxy)benzaIdehyd e (129 mg). Ή NMR (400 MHz, Chloroform -d) δ 11.99 (s„ IH), 10.40 (s, H), 8, 53 (m, IH),. 7.42 (t, J = 8.4 Hz, IH), 7.32 (m, IH), 7.20 (m, IH), 6.55 (d, J = 8.4 Hz, IH), 6.47 (d, J ~- 8.3 Hz, IH), 5.39 (s, IH), 4.38 (t, J > 8.8 Hz, IH), 4,2,1 (dd, J = 9.5, 6.6 Hz, IH), 3.36 (d, J = 13.5 Hz, IH), 3.14 (m, IH), 2.52 (s, 3H), 2.10 - 1 35(m, 6H). MS (M+H) found for C ₂ oH ₂₂ N ₂ 0 ₄ ; 355.3.

GBT1124

(8}-2-{( ^ηζο^Γηο ΗοΙίη-3-^)ιη ^β ΙΗοχν)-6-ΗγάΓθ νΐ3βη ^ζ 3^ ^β Η^β [0203] GBT1124- {S)-2-|{4-ben2oyimof ?hoiin^-yi)methoKy)-6-hydroxybenzaldehyde

[0204] Step 1&2: To a solid sample of (/?)-tert-butyl 3-{hydroxymethyi)morpholine-4- carboxylate (150 rng,. 0.69 mmol) was added 4N HCi in dioxane (1.5 mL). After stirred for 30 min, it was concentrated to give ( )-(3-(hydroxymethyl)morpholino){phenyl)methanone as HCI salt. To a suspension of { )-{3-{hydroxymethyl)morphorino)(phenyl)methanone HCI salt in DCM (2 mL) at 0 "C was added DiPEA {0.36 mL, 2.07 mmol) and benzoyl chloride (0,08 mL, 0.69 mmol). After stirred for 30 min, it was diluted with DCM, washed with aqueous Sat. NaHC03, brine, dried and concentrated to give crude product, which was purified by column (100% EtOAc) to give {R)-(3-(hydroxymethyl)morphoiino)(phenyl)methanone (120 mg). Step 3, To a solution of (R)-(3-(hydroxymethyl)morphonno)(pheny!imethanone (80 mg, 0.36 mmol) and 2,6-dihydroxybenzaldehyde (0.06 g,. 0.47 mmol) in THF (2 mL) was added PPh ₃ (polymer supported, 0.45 g, 0.54 mmol) and D!AD (0.11 mL, 0.54 mmol) at 0 °C and stirred at room temperature for 2 h, it was subsequently concentrated, the resulting residue was purified by preparative HPLC to give {S}-2-((4-ben2oylmorphoiin-3-yl)methoxy)-6- hydroxybenzaldehyde (20 mg). ^X H NMR (400 MH∑, Chloroform-cr) δ 11.96 (s., 1H), 10.28 (s, 1H), 7.50 - 7.35 (m, 7H , 6.61 - 6,41 (m, 1H), 4.37 (s, 2H), 4.07 (s, 1H), 3.39 (s, 1H), 3,76 (dd, J = 12.2, 3,2 Hz, 1H), 3.55 (s, 2H), 3.39 (s, 1H), 1.35 - 1.18 (m, 1 H). MS found for C ₁₉ H _i9 N0 ₅ : 342.3,

GBT1126

(S)-2- ydroxy-8-((1-(phen¥lsulfonyl)pyiTolfdin-2--yl)me [0205] GBT1126- (S}-2-hydroxy-6-{( l-{pheny!sulfoiiyl)pyrrolidtn-2- yI)methoxy)henzaidehyde

[0206] Step !: To a solution of (5)-pyrrolidin-2-ylmethanol (500 mg, 4,94 in itio!) in DC ( 10 ml.) at 0 "C was added TEA ( 1.04 m l, 7.41 mmol) followed by benzenesuffonyl chloride (0,63 m L, 4.94 mmol). After stirred for 30 min, it was diluted with DCM,, washed with aqueous Sat, a HCOS,, brine, dried and concentrated to give crude product, which was purified by column to (S)-( l-(phenySsulfonyl)pyrroiidin-2-yi}methanol.

[0207] Step 2 : To a solution of (S)-(l-(phenylsulfonyi)pyrroIidin-2-y!)methanoi (125 mg, 0.54 m mol) and 2,6-dihydroxybenzaldehyde (0.1 g, 0, 7 rn rnoi) in THF (2 ml ) was added ΡΡη¾ (0.21 g, 0.81 mmol) and Di.AD (0.16 m L, 0.81 m mol) at 0 °C and stirred at room tem peratu re for 2 h, it was subsequently concen trated, the r esulting residue was purified by preparative H PLC to give {S)-2-hydroxy-6-({l-(phenylsuifonyi)pyrrolidin-2-yl)methoxy) benzaldehyde (37 mg), ^] H MR (400 MHz, Chloroform-d) δ 11.90 (d, J = 0.4 Hz,. 1H), 10.28 (d, J = 0.6 Hz, 1H), 7.93 - 7.76 (m, 2H), 7,65 - 7,56 (m, 1H), 7.56 - 7,47 (m, 2H), 7.43 (td, J « 8.4, 0.4 Hz, 1.H), 6.55 (dt, J = 8.5, 0.7 Hz, 1 H), 6.48 (dd, ./ = 8.3, 0.8 Hz, 1H ), 4.42 - 4.31 (m, 1H), 4.08 - 3.95 (m, 2H), 3.56 - 3.45 (m, 1 H), 3.20 (ddd, J = 10.0, 8.0, 7.0 Hz, 1H ), 2.03 - 1.83 (m, 2H)„ 1.81 - 1.50 (m, 2H). MS found for C ₁₃ H ₁₉ !M0 ₅ S : 362.4.

GBT1128

(S}-2-hydroxy-6-(( 1-(pyridin-3-y!8ulfony!)py^

[0208] GBT1128- fS)-2-hYdrOKY-6-{(l-{pyrId!!i-3-y!su!fonYi)pyrrolidm-2- yl)methoxY)ben2aldehY le

[0203] Stepl: To a solution of (S?-pyrrolidin-2-yimethanol (320 mg, 3.16 mmoii in DCM (6 rnL) at 0 "C was added TEA (0.97 mL, 6.95 mmol) fo!iowed by pyridine-3-sulfonyl chloride (0.68 g, 3.16 mmol). After stirred for 30 rnin, it was diluted with DCM, washed with aqueous Sat. aHC'03, brine, dried and concentrated to give crude product, which was purified by column to give (S)-(l-(pyridin-3-ylsulfonyl)pyrroiidin-2-yi)methanoi (66 mg).

[0210] Step 2: To a solution of ^SHl-(py ^r 'din-3-ylsutfonyl)pyrrolidin-2-yl)methanol (65 mg, 0.29 mmoij and 2,6-dihydroxybenzaldehyde (0.06 g, 0.41 mmol) in THF (2 mL) was added PPh ₃ (polymer supported,. 0.37 g, 0,44 mmol) arid DIAD (0.09 mL,. 0.44 mmo!) at 0 °C and stirred at room temperature for 2 h, it was subsequently diluted with AcCN, the insoluble material was filtered off, the filtrate was concentrated, the resulting residue was purified by preparative HPLC to give (S)-2-hydroxy-6-((l-(pyridin-3-ylsuifonyi)pyrroIidin-2- yi)methoxy)benzafdehyde {17 mg). ^X H N R {400 MHz, Chloroform- /} δ 11.90 (s, 1H), 10.29 (d,. J = 0.6 Hz,. 1H), 9.08 (dd, J = 2.3, 0.9 Hz, IB), 8.83 (dd, J = 4.9,. 1.6 Hz, 1H), 8. IS - 8.09 {m, 1H), 7.53 - 7.46 (m, 1H), 7.44 ft, J = 8.4 Hz, 1H), 6.61 - 6.54 (m, 1H),. 6.50 - 6.44 (m, 1H), 4.40 - 4.31 (m, 1H), 4.12 - 3.96 (m, 2H), 3.56 (ddc = 10.5, 7.1, 4, 2 Hz, IHj, 3.21 (dt, i = 10 1, 7.4 Hz, 1H), 2.08 - 1.88 (m, 214), 1.37 - 1.66 (m, 2H). MS (M+H) found for C ₁₇ H _1S N _; 0 ₅ S: 363.4.

[0211] From the foregoing it vviil he appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention,

[0212] 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.