OA17481A

OA17481A - Compounds and uses thereof for the modulation of hemoglobin.

Info

Publication number: OA17481A
Application number: OA1201500365
Authority: OA
Inventors: Brian W. Metcalf; Zhe Li; Jason R. Harris; Qing Xu; Stephen L. Ii Gwaltney; Calvin W. YEE
Original assignee: Global Blood Therapeutics, Inc.
Priority date: 2013-03-15
Filing date: 2014-03-10
Publication date: 2016-12-30

Abstract

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

Description

COMPOUNDS AND USES THEREOF FOR THE MODULATION OF

HEMOGLOBIN

FIELD OF THE INVENTION

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

STATE OF THE ART

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

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

SUMMARY OF THE INVENTION

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

[0005] In certain aspects of the invention, a compound of formula (I) is provided:

or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein L¹⁰ is optionally substituted methylene or, preferably, a bond;

each X and Y is independently (CR²⁰R^2I)_e, O, S, SO, SO2, or NR²⁰; e is 1 to 4, preferably 1; each R²⁰ and R²¹ independently is hydrogen or C1-C3 alkyl optionally substituted with 1-3 halo, OH, or Ci-Cô alkoxy, or CR²⁰R²¹ is C=O, provided that if one of X and Y is O, S, SO, SO₂, then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof;

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

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-Cô alkyl optionally substituted with 1-3 OH groups, or V⁵ is CO₂R⁶⁰, where each R⁶⁰ independently is C|-Cô alkyl or hydrogen; t is 0, 1,2, or 4; or CV’V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁸⁰ is optionally substituted Ci-Cô alkyl;

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

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

R⁸⁴ is optionally substituted C]-Cô alkyl;

provided that the compounds provided herein exclude those disclosed in U.S. patent application nos. 13/730,730 and 13/730,674; and provided that the compounds provided herein exclude those in Table 1 hereinbelow; and A, B, and C are defined as follows.

[0006] In one instance, ring A is Cô-Cioaryl, 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 aryl, or heteroaryl is optionally substituted, preferably with 1-4 Ci-Cô alkyl and/or Ci-Cô alkoxy groups;

ring B is:

wherein ring B' including the -N-CO- moiety is a 5-6 membered heterocycle containing up to 3 heteroatoms selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted, preferably with 1-4 Ci-Cô alkyl groups;

ring C is Cô-Cioaryl or a 5-10 membered heteroaryl 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, preferably with 1-4: halo, oxo, -OR¹, Ci-Cô alkyl, -COOR¹, and NR⁵R⁶,

R¹ is a hydrogen, Cj-Gs alkyl or a prodrug moiety; wherein the alkyl is optionally substituted with a 5-10 membered heteroaryl 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, which is optionally substituted with with a 5-10 membered heteroaryl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with Ci-Cô alkyl;

R⁵ and R⁶ are each independently hydrogen, optionally substituted Ci-Cô alkyl or -COOR³ ;

R³ is hydrogen or optionally substituted Ci-Cô alkyl;

with the proviso that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl;

and provided that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle.

[0007] In another instance:

ring A is Cô-Cio aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycle is optionally substituted, preferably with 1-4: halo, Ci-Cô alkyl, Ci-Cô alkoxy, and/or C3-C10 cycloalkyl, wherein the Ci-Cô alkyl is optionally substituted with 1-5 halo, Cj-Cô alkoxy, and/or C3-C10 cycloalkyl;

ring B is a 5-10 membered heteroaryl or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted, preferably with 1-4: halo, Cj-Cô alkyl and/or-CO-Ci-Cô alkyl, s

' is a single or a double bond;

ring C is Cg-Cio aryl or a 5-10 membered heteroaryl 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, preferably with 1-4: halo, oxo, -OR¹, Ci-Cô alkyl, -COOR¹, and/or Cj-Cè alkoxy, wherein the Ci-Cô alkyl is optionally substituted with 1-5 halo, Ci-Cô alkoxy and/or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; and

R¹ is hydrogen or a prodrug moiety;

provided that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl; then ring A excludes optionally substituted 5-10 membered heteroaryl; and provided that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle.

[0008] In certain aspects of the invention, a compound of formula (X-I) is provided:

(x-i) an N-oxide thereof, or a tautomer or each thereof, or a pharmaceutically acceptable sait of each of the preceding, wherein ring A is phenyl optionally substituted with 1-3 halo and/or Ci-Cô alkoxy, or is a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, optionally substituted, or is

wherein R⁷ is Cj-Cô alkyl, optionally substituted with 3-5 fluoro groups, or is

C3-C6 cycloalkyl;

ring B is selected from the group consisting of

JW

I

wherein R⁸ is Cj-Cô alkyl, -CO-Cj-C6 alkyl or a prodrug moiety and wherein the pyridyl ring is optionally substituted with a halo or an NR²⁵(CH2)₂N(R²⁵)2 group where each R²⁵ is independently hydrogen or Cj-C6 alkyl;

X is O, S, SO, or SO₂;

' is a single or a double bond;

ring C is phenyl or a 6 membered nitrogen-containing heteroaryl, each of which is optionally substituted with 1-4: halo, oxo, -OR¹, Cj-Cô alkyl, -COOR¹ and/or Cj-Cô alkoxy, wherein the Cj-Cô alkyl is optionally substituted with 1-5 halo, Cj-Cô alkoxy and/or 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; and each R¹ is hydrogen or a prodrug moiety R;

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

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is

or 2; each V⁵ is independently Ci-Cô alkyl or CO2R⁶⁰, where each R⁶⁰ independently is Ci-Cô alkyl or hydrogen; t is 1, 2, or 4; or CW² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

wherein R is optionally substituted Cj-Cô alkyl;

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

R⁸³ is hydrogen or optionally substituted Ci-Cô alkyl;

R⁸⁴ is optionally substituted Ci-Cô alkyl;

provided that when ring C is Cô-Cjo aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl;

provided that when ring C is Cô-Cæ aryl;

and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle;

provided that the compounds provided herein exclude those dîsclosed in U.S. patent application nos. 13/730,730 and 13/730,674; and provided that the compounds provided herein exclude those in Table 1 hereinbelow.

[0009] Preferably, V¹ and V² together with the carbon atom they are attachèd to form a ring of formula:

[0010] In some embodiments, V¹ and V² independently are Ci-Cé alkoxy; or V¹ and V² together with the carbon atom they are attachèd to form a ring of formula:

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one or V³ and V⁴ is S the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-Cô alkyl or CO2R⁶⁰, where each R⁶⁰ independently is C|-Cô alkyl or hydrogen; t is 0, 1,2, or 4; or CV'V² is C=V, wherein V is O, and wherein the remaining variables are defined herein.

[0011] In certain embodiments, a compound of fonnula (Π) is provided:

wherein the remaining variables are defined herein.

[0012] In certain embodiments, a compound selected from formulas (IIA), (IIB) and (HC) is provided:

HA ΠΒ HC wherein

R⁹ is hydrogen, -OR¹, Ci-Cô alkoxy optionally substituted with 1-3 Ci-Cé alkoxy or 410 membered heterocycle containing up to 5 ring heteroatoms selected from

N, O, S or oxidized forms thereof;

R¹⁰ is hydrogen, hydroxy, halo or Ci-Cô alkoxy;

R¹¹ is hydrogen or Ci-Cé alkyi; and

R¹² is -OR¹;

wherein R¹ is hydrogen or the prodrug moiety R.

[0013] In certain aspects of the invention, a compound of formula (I) is provided:

ring A is Cô-Cioaryl, 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 aryl, or heteroaryl is optionally substituted with 1-4 Ci-Ce alkyi and/or Ci-Cô alkoxy groups;

ring B is:

σννν' I

wherein ring B' including the -N-CO- moiety is a 5-6 membered heterocycle containing up to 3 heteroatoms selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1-4 Ci-C₆ alkyi groups;

each X and Y is independently (CR²⁰R²¹)e, O, S, SO, SO2, or NR²⁰; e is 1 to 4, preferably 1; each R²⁰ and R²¹ independently is hydrogen or C1-C3 alkyi optionally substituted with 1-3 halo, OH, or Ci-Cô alkoxy, or CR²⁰R²¹ is C=O, provided that if one of X and Y is O, S, SO, SO2, then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof;

ring C is Cô-Cio aryl or a 5-10 membered heteroaryl 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: halo, oxo, -OR¹, Ci-Cô alkyi, -COOR⁵, NR⁵R⁶,

R¹ is a hydrogen, Ci-Cô alkyl or a prodrug moiety; wherein the alkyl is optionally substituted with a 5-10 membered heteroaryl contaîning up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, which is optionally substituted with with a 5-10 membered heteroaryl contaîning up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with Cj-Cô alkyl;

R⁵ and R⁶ are each independently hydrogen, optionally substituted Cj-Cô alkyl or -COOR³ ;

R³ is hydrogen or optionally substituted Cj-Cô alkyl;

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

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-Cô alkyl optionally substituted with 1-3 OH groups, or V⁵ is CO₂R⁶⁰, where each R⁶⁰ independently is Cj-Cô alkyl or hydrogen; t is 0, 1,2, or 4; or CV’V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁸⁰ is optionally substituted Cj-Cô alkyl;

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

R⁸⁴ is optionally substituted Ci-Cô alkyl;

with the proviso that when ring C is G5-C10 aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl;

and provided that when ring C is Cô-Cæ aryl;

and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle.

[0014] In further aspects of the invention, a composition is provided comprising any of the 5 compounds described herein, and at least a pharmaceutically acceptable excipient.

[0015] In still 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.

[0016] In further aspects of the invention, a method is provided for treating oxygen deficiency associated with sickle cell anémia, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

DETAILED DESCRIPTION OF THE INVENTION

Définitions

[0017] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictâtes otherwise. Thus, for example, reference to “a solvent” includes a plurality of such solvents.

[0018] As used herein, the term “comprising” or “comprises” is intended to mean that the 20 compositions and methods include the recited éléments, but not excluding others.

“Consisting essentially of ’ when used to define compositions and methods, shall mean excluding other éléments of any essential significance to the combination for the stated purpose. Thus, a composition or process consisting essentially of the éléments as defined herein would not exclude other materials or steps that do not materially affect the basic and 25 novel characteristic(s) of the claimed invention. “Consisting of ’ shall mean excluding more than trace éléments of other ingrédients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

[0019] Unless otherwise indicated, ail numbers expressing quantities of ingrédients, reaction conditions, and so forth used in the spécification and claims are to be understood as 30 being modîfied in ail instances by the term “about.” Accordingly, unless indicated to the

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

[0020] As used herein, C_m-C_n, such as C1-C12, Ci-C₈, or Ci-Cô when used before a group refers to that group containing m to n carbon atoms.

[0021] The term “alkoxy” refers to -O-alkyl.

[0022] The term “alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 12 carbon atoms (i.e., C1-C12 alkyl) or 1 to 8 carbon atoms (i.e., Ci-C₈ alkyl), or 1 to 4 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH₃)₂CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH₃)₂CHCH₂-), sec-butyl ((CH3)(CH3CH₂)CH-), ί-butyl ((CEL^C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH₃)3CCH₂-).

[0023] The term “aryl” refers to a monovalent, aromatic mono- or bicyclic ring having 6-10 ring carbon atoms. Examples of aryl include phenyl and naphthyl. The condensed ring may or may not be aromatic provided that the point of attachment is at an aromatic carbon atom. For example, and without limitation, the following is an aryl group:

[0024] The term “-CO₂H ester” refers to an ester formed between the -CO₂H group and an alcohol, preferably an aliphatic alcohol. A preferred example included -CO2R^E, wherein R^Eis alkyl or aryl group optionally substituted with an amino group.

[0025] The term “chiral moiety” refers to a moiety that is chiral. Such a moiety can possess one or more asymmetric centers. Preferably, the chiral moiety is enantiomerically enriched, and more preferably a single enantiomer. Non limiting examples of chiral moieties include chiral carboxylic acids, chiral amines, chiral amino acids, such as the naturally occurring amino acids, chiral alcohols including chiral steroids, and the likes.

[0026] The term “cycloalkyl” refers to a monovalent, preferably saturated, hydrocarbyl mono-, bi-, or tricyclic ring having 3-12 ring carbon atoms. While cycloalkyl, refers preferably to saturated hydrocarbyl rings, as used herein, it also includes rings containing 1-2 carbon-carbon double bonds. Nonlimiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamentyl, and the like. The condensed rings may or may not be non-aromatic hydrocarbyl rings provided that the point of attachment is at a cycloalkyl carbon atom. For example, and without limitation, the following is a cycloalkyl group:

[0027] The term “halo” refers to F, Cl, Br, and/or I.

[0028] The term “heteroaryl” refers to a monovalent, aromatic mono-, bi-, or tricyclic ring having 2-16 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 5 ring atoms. Nonlimiting examples of heteroaryl include furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the like. The condensed rings may or may not be a heteroatom containing aromatic ring provided that the point of attachment is a heteroaryl atom. For example, and without limitation, the following is a heteroaryl group:

[0029] The term “heterocyclyl” 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, S, and P, provided that the ring contains at least 3 ring atoms. While heterocyclyl preferably refers to saturated ring Systems, it also includes ring Systems containing 1-3 double bonds, provided that the ring is non-aromatic. Nonlimiting examples of heterocyclyl include, azalactones, oxazoline, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl. The condensed rings may or may not contain a non-aromatic heteroatom containing ring provided that the point of attachment is a heterocyclyl group. For example, and without limitation, the following is a heterocyclyl group:

H

[0030] The term “hydrolyzing” refers to breaking an R^H-O-CO-, R^H-O-CS-, or an R^H-OSO₂- moiety to an R^h-OH, preferably by adding water across the broken bond. A hydrolyzing is performed using various methods well known to the skilled artisan, non limiting examples of which include acidic and basic hydrolysis.

[0031] The term “oxo” refers to a C=O group, and to a substitution of 2 geminal hydrogen atoms with a C=O group.

[0032] The term “optionally substituted,unless defined otherwise, refers to a substituted or unsubstituted group. The group may be substituted with one or more substituents, such as e.g., 1, 2, 3,4 or 5 substituents. Preferably, the substituents are selected from the group consisting of oxo, halo, -CN, NO₂, -N₂+, -CO₂R¹⁰⁰, -OR¹⁰⁰, -SR¹⁰⁰, -SOR¹⁰⁰, -SO2R¹⁰⁰, NR¹⁰¹R¹⁰², -CONR¹⁰¹R¹⁰², -SO2NR¹⁰¹R¹⁰², Ci-C6 alkyl, Ci-C6 alkoxy, -CR¹⁰⁰=C(R¹⁰⁰)2, CCR¹⁰⁰, C3-C10 cycloalkyl, C3-C10 heterocyclyl, C6-Ci2aryl and C2-Ci2 heteroaryl, wherein each R¹⁰⁰ independently is hydrogen or Ci-Cg alkyl; C3-C12 cycloalkyl; C3-C10 heterocyclyl; C6-Ci2aryl; or C₂-Ci₂ heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 halo, 1-3 Cj-Cô alkyl, 1-3 Ci-Cô haloalkyl or 1-3 Ci-Cô alkoxy groups. Preferably, the substituents are selected from the group consisting of chloro, fluoro, -OCH₃, methyl, ethyl, iso-propyl, cyclopropyl, vinyl, ethynyl, -CO₂H, CO₂CH₃, -OCF3, -CF₃ and -OCHF₂.

[0033] R¹⁰¹ and R¹⁰² independently is hydrogen; Ci-Cg alkyl, optionally substituted with CO2H or an ester thereof, Ci-Cô alkoxy, oxo, -CR¹⁰³=C(R¹⁰³)2, -CCR, C3-C10 cycloalkyl, C₃C10 heterocyclyl, Cô-Ci₂ aryl, or C₂-Ci₂ heteroaryl, wherein each R¹⁰³ independently is hydrogen or Cj-Cg alkyl; C₃-Ci₂ cycloalkyl; C3-C10 heterocyclyl; C6-Ci₂aryl; or C₂-Ci₂heteroaryl; wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halo groups, or R¹⁰¹ and R¹⁰² together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.

[0034] The term “pharmaceutically acceptable” refers to safe and non-toxic for in vivo, preferably, human administration.

[0035] The term “pharmaceutically acceptable sait” refers to a sait that is pharmaceutically acceptable.

φ [0036] The term “sait” refers to an ionic compound formed between an acid and a base.

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

[0037] The terms “treat”, “treating” or “treatment”, as used herein, include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting or suppressing the development of the disease or condition, relieving the disease or condition, causing régression of the disease or condition, relieving a condition caused by the disease or condition, or suppressing the symptoms of the disease or condition, and are intended to include prophylaxis. The terms also include relieving the disease or conditions, e.g., causing the régression of clînical symptoms. The terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant éradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the éradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual is still be afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0038] The terms “preventing” or “prévention” refer to a réduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clînical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet expérience or display symptoms of the disease). The terms further include causing the clînical φ 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.

[0039] The term “effective amount” refers to an amount that is effective for the treatment of a condition or disorder by an intranasal administration of a compound or composition described herein. In some embodiments, an effective amount of any of the compositions or dosage forms described herein is the amount used to treat a disorder mediated by hemoglobin or a disorder that would benefit from tissue and/or cellular oxygénation of any of the compositions or dosage forms described herein to a subject in need thereof.

[0040] The term “carrier” as used herein, refers to relatively nontoxic chemical compounds 10 or agents that facilitate the incorporation of a compound into cells, e.g., red blood cells, or tissues.

[0041] As used herein, a “prodrug” is a compound that, after administration, is metabolized or otherwise converted to an active or more active form with respect to at least one property. To produce a prodrug, a pharmaceutically active compound can be modîfied chemically to 15 render it less active or inactive, but the chemical modification is such that an active form of the compound is generated by metabolic or other biological processes. A prodrug may hâve, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity. For example, see the reference Nogrady, 1985, Médicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392. Prodrugs can 20 also be prepared using compounds that are not drugs.

[0042] In certain aspects of the invention, a compound of formula (I) is provided:

φ Compounds

(I) or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein L¹⁰ is optionally substituted methylene or, preferably, a bond;

ring A is Cô-Cioaryl, a C₃-Cg cycloalkyl, a 5-10 membered heteroaryl or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycle is optionally substituted with 1-4: halo, Ci-Cô alkyl, Ci-Cô alkoxy, and/or C3-C10 cycloalkyl, wherein the Ci-Cô alkyl is optionally substituted with 1-5 halo, Ci-Cô alkoxy, and/or C3-C10 cycloalkyl; or ring A is Cô-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 aryl, or heteroaryl is optionally substituted with 1-4 Ci-Cô alkyl and/or Ci-Cô alkoxy groups;

ring B is a 5-10 membered heteroaryl or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1-4: halo, Ci-Cô alkyl and/or -CO-Ci-Cô alkyl, or ring B is:

wherein ring B' including the -N-CO- moiety is a 5-6 membered heterocycle containing up to 3 heteroatoms selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1-4 Ci-Cô alkyl groups;

each X and Y is independently (CR²⁰R²¹)_e, O, S, SO, SO₂, or NR²⁰; e is 1 to 4, preferably 1; each R²⁰ and R²¹ independently is hydrogen or C1-C3 alkyl optionally substituted with 1-3 halo, OH, or Ci-Cô alkoxy, or CR²⁰R²¹ is C=O, provided that if one of X and Y is O, S, SO, SO₂, then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof;

ring C is Cô-Cio aryl or a 5-10 membered heteroaryl 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: halo, oxo, -OR¹, Ci-Cô alkyl, -COOR¹, and/or Ci-Cô alkoxy, wherein the Ci-Cô alkyl is optionally substituted with 1-5 halo, Cj-Cô alkoxy, and/or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; or ring C is Cô-Cioaryl or a 5-10 membered heteroaryl 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: halo, oxo, -OR¹, Cj-Cô alkyl, -COOR¹, NR⁵R⁶,

R¹ is a hydrogen, Ci-Cô alkyl or a prodrug moiety; wherein the alkyl is optionally substituted with a 5-10 membered heteroaryl 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, which is optionally substituted with with a 5-10 membered heteroaryl containing up to 5 ring heteroatoms, wherein

the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with Ci-Cô alkyl;

R³ is hydrogen or optionally substituted C|-Cô alkyl;

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-Cô alkyl optionally substituted with 1-3 OH groups, or V⁵ is COiR⁶⁰, where each R⁶⁰ independently is Cj-Cô alkyl or hydrogen; t is 0, 1,2, or 4; or CV’V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁸⁰ is optionally substituted Ci-Cô alkyl;

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

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

R⁸⁴ is optionally substituted Ci-Cô alkyl;

with the proviso that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl;

and provided that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle.

[0043] In certain aspects of the invention, a compound of formula (X-I) is provided:

or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein ring A is Cô-Cioaryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycle is optionally substituted with 1-4: halo, Ci-Cô alkyl, Ci-Cô alkoxy, and/or C3-C10 cycloalkyl, wherein the Ci-Cô alkyl is optionally substituted with 1-5 halo, Ci-Cô alkoxy, and/or C3-C10 cycloalkyl;

ring B is a 5-10 membered heteroaryl or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1-4: halo, Ci-Cô alkyl and/or -CO-Ci-Cô alkyl,

X is O, S, SO, or SO₂;

ring C is Cô-Cioaryl or a 5-10 membered heteroaryl 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: halo, oxo, -OR¹, Ci-Cô alkyl, -COOR¹, and/or Ci-Cô alkoxy, wherein the Cj-Cô alkyl is optionally substituted with 1-5 halo, Ci-Cô alkoxy and/or a 4-10 membered heterocycle containing up to 5 ring

heteroatoms, wherein the heteroatom is selected from the group consisting of

O, N, S, and oxidized forms of N and S; and

R¹ is hydrogen or a prodrug moiety;

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-Cô alkyl or CO2R⁶⁰, where each R⁶⁰independently is Ci-Cô alkyl or hydrogen; t is 0, 1,2, or 4; or CV'V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁸⁰ is optionally substituted Ci-Cô alkyl;

R⁸³ is hydrogen or optionally substituted Cj-Cô alkyl;

R⁸⁴ is optionally substituted Ci-Cô alkyl;

provided that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl;

and provided that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle.

[0044] In certain aspects of the invention, a compound of formula (X-I) is provided:

or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein ring A is phenyl optionally substituted with 1-3 halo and/or Ci-Cô alkoxy, or is a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, optionally substituted, or is

wherein R⁷ is Ci-Cô alkyl, optionally substituted with 3-5 fluoro groups, or is

C3-C6 cycloalkyl;

ring B is selected from the group consisting of

JW I

wherein R⁸ is Cj-Cô alkyl, -CO-Ci-Cô alkyl or a prodrug moiety;

X is O, S, SO, or SO₂;

ring C is phenyl or a 6 membered nitrogen-containing heteroaryl, each of which is optionally substituted with 1-4: halo, oxo, -OR¹, Ci-Cô alkyl, -COOR¹, and/or Ci-Cô alkoxy, wherein the Cj-Cô alkyl is optionally substituted with 1-5 halo, Ci-Cô alkoxyand/or 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; and each R¹ is hydrogen or a prodrug moiety R;

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-Cô alkyl or CO₂R⁶⁰, where each R⁶⁰independently is Ci-Cô alkyl or hydrogen; t is 0, 1,2, or 4; or CV’V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁸⁰ is optionally substituted Ci-Cô alkyl;

ΟΙ θ')

R and R independently are selected from the group consisting of hydrogen, optionally substituted Cj-Cô alkyl, COR⁸³, or CO₂R⁸⁴;

R⁸³ is hydrogen or optionally substituted Ci-Cô alkyl;

R⁸⁴ is optionally substituted Ci-Cô alkyl;

provided that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl;

and provided that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle.

[0045] Preferably, V and V together with the carbon atom they are attached to form a ring of formula:

[0046] In some embodîments, V¹ and V² independently are Cj-Cô alkoxy; or V¹ and V²together with the carbon atom they are attached to form a ring of formula:

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one or V³ and V⁴is S the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-Cô alkyl or CO₂R⁶°, where each R⁶⁰ independently is Ci-Cô alkyl or hydrogen; t is 0, 1,2, or 4; or CV¹ V² is C=V, wherein V is O, and wherein the remaining variables are defined herein.

[0047] In certain embodîments, a compound of formula (III) is provided:

or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein ring A is phenyl optionally substituted with 1-3 halo and/or Cj-Cô alkoxy, or is a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, optionally substituted, or is

? _e *7 wherein R is Cj-Cô alkyl, optionally substituted with 3-5 fluoro groups, or is

C₃-Cô cycloalkyl;

ring B is selected from the group consisting of

σνν I

wherein R⁸ is Cj-Cô alkyl, -CO-Cj-Cô alkyl or a prodrug moiety;

X is O, S, SO, or SO₂;

ring C is phenyl or a 6 membered nitrogen-containing heteroaryl, each of which is optionally substituted with 1-4: halo, oxo, -OR¹, Cj-Cô alkyl -COOR¹, and/or

Ci-Cô alkoxy, wherein the Ci-Cô alkyl is optionally substituted with 1-5 halo,

Ci-Cô alkoxy and/or 4-10 membered heterocycle contaîning up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; and each R¹ is hydrogen or a prodrug moiety R;

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

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-C₆ alkyl or CO2R⁶⁰, where each R⁶⁰independently is Ci-Cô alkyl or hydrogen; t is 0, 1, 2, or 4; or CV*V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁸⁰ is optionally substituted Ci-Cô alkyl;

R⁸³ is hydrogen or optionally substituted Ci-Cô alkyl;

R⁸⁴ is optionally substituted Ci-Cô alkyl;

provided that when ring C is C₆-Ci₀ aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl;

and provided that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle.

[0048] In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In one embodiment, —X-Y- is -CH2-O-. In another embodiment, -X-Y is -O-CH2-.

[0049] In certain embodiments, a compound selected from formulas (IHA), (IIIB) and (uIC) is provided:

IIIA IIIB HIC wherein

R⁹ is hydrogen, -OR¹, Ci-Ce alkoxy optionally substituted with 1-3 Ci-Cô alkoxy or 410 membered heterocycle containing up to 5 ring heteroatoms selected from N, O, S or oxidized forms thereof;

R¹⁰ is hydrogen, halo, hydroxy or Ci-Cô alkoxy;

R¹¹ is hydrogen or Ci-Cô alkyl; and

R¹² is -OR¹;

wherein R¹ is hydrogen or the prodrug moiety R.

[0050] In certain embodiments, ring A is phenyl substituted with 1-3 halo or Ci-Cô alkoxy, or

C3-C8 heterocyclyl containing 1-3 heteroatoms, wherein the heterocycle is optionally substituted with 1-3 halo.

[0051] In certain embodiments, ring A is pyridyl, optionally substituted as defined herein.

[0052] In certain embodiments, compounds of formulas (II), (ΙΠ), (ΙΠΑ), (IIIB) and (IHC) are provided, wherein

is selected from the group consisting of:

and

[0053] In certain embodiments, compounds of formulas (II), (III), (ΠΙΑ), (ΙΠΒ) and (IHC) are provided, wherein is

[0054] In certain embodiments, a compound is provided, wherein the compound selected from the group consisting of:

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

[0055] In certain embodiments, a compound is provided, wherein the compound selected from the group consisting of:

r₁₄

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

[0056] In certain aspects of the invention, a compound is provided, wherein the compound is selected from the group consisting of:

or a prodrug thereof, or a pharmaceuticlaly acceptable sait of each thereof. Other compounds of this invention are illustrated in the Examples section.

[0057] In certain aspects of the invention, a compound of formula (I) is provided:

ring A is Cô-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 aryl, or heteroaryl is optionally substituted with 1-4 Ci-Cô alkyl and/or Ci-Cô alkoxy groups;

ring B is:

k/VW' wherein ring B' including the -N-CO- moiety is a 5-6 membered heterocycle containing up to 3 heteroatoms selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1-4 Ci-Cô alkyi groups;

each X and Y is independently (CR²⁰R²¹)e, O, S, SO, SO2, or NR²⁰; e is 1 to 4, preferably 1; each R²⁰ and R²¹ independently is hydrogen or C1-C3 alkyi optionally substituted with 1-3 halo, OH, or Ci-Cô alkoxy, or CR²⁰R²¹ is C=O, 10 provided that if one of X and Y is O, S, SO, SO2, then the other is not CO, and

X and Y are both not heteroatoms or oxidized forms thereof;

ring C is Cô-Cioaryl or a 5-10 membered heteroaryl 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: halo, oxo, -OR¹, Cj-Cô alkyi, -COOR⁵, NR⁵R⁶,

R¹ is a hydrogen, Ci-Cô alkyi or a prodrug moiety; wherein the alkyi is optionally substituted with a 5-10 membered heteroaryl 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, which is optionally substituted with 20 with a 5-10 membered heteroaryl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with Cj-Cfi alkyi;

R⁵ and R⁶ are each independently hydrogen, optionally substituted Ci-Cô alkyi or

-COOR³ ;

R³ is hydrogen or optionally substituted Ci-Cô alkyi;

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Cj-Cô alkyl optionally substituted with 1-3 OH groups, or V⁵ is CO2R⁶⁰, where each R⁶⁰ independently is Cj-Cô alkyl or hydrogen; t is 0, 1,2, or 4; or CV'V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁸⁰ is optionally substituted Cj-Cô alkyl;

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

R⁸⁴ is optionally substituted Cj-Cô alkyl;

with the proviso that when ring C is Cô-Cjo aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl;

and provided that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle.

[0058] In certain aspects of the invention, a compound of formula (IV) is provided:

(IV) or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein ring A is Cô-Cjo 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 aryl or heteroaryl is optionally substituted with 1-4 Cj-Cô alkyl;

ring B is:

k/VW'

wherein ring B' including the -N-CO- moiety is a 5-6 membered heterocycle containing up to 3 heteroatoms selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1-4 Cj-Cô alkyl groups;

each X and Y is independently CR²⁰R²¹, O, S, SO, SO₂, or NR¹⁰; each R²⁰ and R²¹ independently is hydrogen or C1-C3 alkyl optionally substituted with 1-3 halo, OH, or Cj-Cô alkoxy, or CR²⁰R²¹ is C=O, provided that if one of X and Y is O, S, SO, SO₂, then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof;

ring C is Cô-Cioaryl or a 5-10 membered heteroaryl 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: halo, oxo, -OR¹, Cj-Cô alkyl, -COOR⁵, NR⁵R⁶,

R¹ is a hydrogen, Ci-Cô alkyl or a prodrug moiety; wherein the alkyl is optionally substituted with a 5-10 membered heteroaryl 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, which is optionally substituted with with a 5-10 membered heteroaryl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with C]-Cô alkyl;

R³ is hydrogen or optionally substituted Ci-Cô alkyl;

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-Cô alkyl optionally substituted with 1-3 OH groups, or V⁵ is CO2R⁶⁰, where each R⁶⁰ independently is Ci-Cô alkyl or hydrogen; t is 0, 1, 2, or 4; or CV’V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁸⁰ is optionally substituted Cj-Cô alkyl;

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

R⁸⁴ is optionally substituted Ci-Cô alkyl.

[0059] In certain embodiments, ring C is substituted with at least one substituent selected from with 1-4: halo, -OR¹, Ci-C₆ alkyl, -COOR⁵, NR⁵R⁶.

[0060] In certain embodiments, X is CH2, O, S, SO, SO₂ or NH. In certain embodiments, X is O, S, SO or SO₂. Preferably, X is O, and wherein the remaining variables are defîned herein.

[0061] In certain embodiments, Y is CR²⁰R²¹, O, S, SO, SO2, or NR¹⁰; wherein each R²⁰and R²¹ independently is hydrogen or C1-C3 alkyl. In certain embodiments, Y is CR²⁰R²¹wherein each R²⁰ and R²¹ independently is hydrogen or C1-C3 alkyl. Preferably, Y is CH2, and wherein the remaining variables are defîned herein.

[0062] In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3.

[0063] Preferably, CV'V² is C=V, wherein V is O, and wherein the remaining variables are defîned herein.

[0064] In certain embodiments, a compound of formula (V) is provided:

or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein ring A is Cô-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 aryl, or heteroaryl is optionally substituted with 1-4 Ci-Cô alkyl and/or Ci-Cô alkoxy groups;

ring B is:

X is O, S, SO or SO₂;

R¹ is a hydrogen, Ci-C₆ alkyl or a prodrug moiety R; wherein the alkyl is optionally substituted with a 5-10 membered heteroaryl 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, which is optionally substituted with with a 5-10 membered heteroaryl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with Cj-Cg alkyl;

R⁵ and R⁶ are each independently hydrogen, optionally substituted Ci-Cô alkyl or

-COOR³ ; and

R³ is hydrogen or optionally substituted Ci-Cô alkyl.

[0065] In certain embodiments, a compound of formula (VI) or (VII) is provided:

I t

(VI) (VII) or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein ring A is Cô-Cioaryl, 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 aryl, or heteroaryl is optionally substituted with 1-4 Ci-Cô alkyl;

ring B is Cô-Cioaryl, C3-C8 cycloalkyl, a 5-10 membered heteroaryl containing up to 5 ring heteroatoms or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of

O, N, S, and oxidized forms of N and S, wherein each of the aryl, heteroaryl, cycloalkyl or heterocycle is optionally substituted with 1-4: halo, Ci-Cô alkyl, or Ci-Cô alkoxy, wherein the Ci-Cô alkyl is optionally substituted with 1-5 halo, Ci-Cô alkoxy, and/or C3-C10 cycloalkyl;

R⁴is halo, oxo, -OR¹⁸, Ci-C₆ alkyl, Ci-C₆ alkoxy, -COOR⁵, and/or NR⁵R⁶;

R¹⁸ is hydrogen, subsitued Ci-Cô alkyl, or a prodrug moiety R;

R⁵ and R⁶ are each independently hydrogen, optionally substituted Ci-Cô alkyl or -COOR³ ; and

R³ is hydrogen, provided that the COOR³ is not joined to a nitrogen atom, or is optionally substituted Ci-Cô alkyl.

[0066] In one embodiment, R⁴ is -OH. In another embodiment, R⁴ is NH2. In one embodiment, R⁴is NH(CH3). In one embodiment, R⁴is N(CH3)2. In one embodiment, R⁴is NHC(O)OC(CH3)3. In one embodiment, R⁴ is COOH. In one embodiment, R⁴ is optionally

φ substituted dioxolan. In one embodiment, R⁴ is a substituted pyridine. As used herein, R³ is hydrogen, provided that the COOR³ is not joined to a nitrogen atom.

[0067] In certain embodiments, ring B is selected from the group consisting of:

N^i

JVW I

[0068] In certain embodiments, compounds of formula (V) are provided, wherein is

OH .

In certain embodiments, a compound of formula (IV) as disclosed above is

[0069] provided, with the proviso that:

when ring C is Cô-Cio aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl.

[0070] In certain embodiments, a compound is provided, wherein the compound is selected from the group consisting of:

or N oxides thereof, or a pharmaceutically acceptable sait of each thereof.

[0071] Compounds provided herein include those in the Examples section.

Prodrug Moiety

[0072] In one aspect, R is hydrogen, a phosphate or a diphosphate containîng moiety, or another promoiety or prodrug moiety. Preferably the prodrug moiety imparts at least a 2 fold, more preferably a 4 fold, enhanced solubility and/or bioavailability to the active moiety (where R is hydrogen), and more preferably is hydrolyzed in vivo. The promoieties are structurally and functionally defined herein.

[0073] In one embodiments, R is -COR⁹⁰, CO2R⁹¹, or CONR⁹²R⁹³ wherein

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

5-10 membered heteroaryl, each containîng at least 1 basic nitrogen moiety; and R⁹² and R⁹³ independently are Ci-Cô alkyl; C3-C8 cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, each containîng at least 1 basic nitrogen moiety; or R⁹² and R⁹³together with the nitrogen atom they are bonded to for a 4-9 member heterocycle substituted with at least 1 amino, Ci-Cô alkyl amino, or di Ci-Cô alkylamino group.

[0074] In certain embodiments, R is -C(O)R³¹, C(O)OR³¹, or CON(R¹³)₂, each R³¹ is independently a Ci-Cô alkyl; C3-C8 cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, containîng at least 1 basic nitrogen moiety; and each R¹³ independently is Ci-Cô alkyl; C3-C8 cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, containîng at least 1 basic nitrogen moiety; or both R¹³

together with the nitrogen atom they are bonded to for a 4-9 member heterocycle substituted with at least 1 amino, Ci-Cô alkyl amino, or di Ci-Cô alkylamino group.

[0075] In one aspect, R is C(O)OR³¹, C(S)OR³¹, C(O)SR³¹ or COR³¹, wherein R³¹ is as defined herein.

[0076] In one embodiment, R³¹ is a group of the formula (CR³²R³³)_eNR³⁴R³⁵, wherein each R³² and R³³ is independently H, a Ci-Cg alkyl, C3-C9 heterocyclyl, C3-C8 cycloalkyl, Cô-Cio aryl, C3-C9 heteroaryl or R³² and R³³ together with the carbon atom they are bond to form a C3-C8 cycloalkyl, Cô-Cio aryl, C3-C9 heterocyclyl or C3-C9 heteroaryl ring system, or 2 adjacent R³² moieties or 2 adjacent R³³ moieties together with the carbon atom they are bond to form a C3-C8 cycloalkyl, Cô-Cio aryl, C3-C9 heterocyclyl or C3-C9 heteroaryl ring system;

each R³⁴ and R³⁵ is a Ci-Cs alkyl, C3-C9 heterocyclyl, C3-C8 cycloalkyl, or R³⁴ and R³⁵together with the nitrogen atom they are bond to form a C3-C8 cycloalkyl or C3-C9 heterocyclyl ring system;

each heterocyclic and heteroaryl ring system is optionally substituted with C1-C3 alkyl, -OH, amino and carboxyl groups; and e is an integer of from 1 to 4.

[0077] In some less preferred embodîments R³⁴ and R³⁵ can be hydrogen.

[0078] In one embodiment, the subscript e is preferably 2 and each R and R is preferably independently selected from the group, H, CH3, and a member in which R³² and R³³ are joined together to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or l,l-dioxo-hexahydro-lA⁶-thiopyran-4-yl or tetrahydropyran-4-yl group.

[0079] With regard to the prodrug group, preferred embodîments are compounds wherein NR³⁴R³⁵ is morpholino.

[0080] In one embodiment, R is:

p32 R³³ wherein each R³² and R³³ is independently H, Ci-C₈ alkyl, or optionally, if both présent on the same substituent, may be joined together to form a C3-C8 cycloalkyl, Cô-Cio aryl, C3-C9 heterocyclyl or C3-C9 heteroaryl ring system.

[0081] Within this embodiment, each R³² and R³³ is independently, H, CH3, or are joined together to form a cyclopropyl, cyclopbutyl, cyclopentyl, cyclohexyl, 1,1-dioxo- hexahydrolX⁶-thiopyran-4-yl or tetrahydropyran-4-yl group.

[0082] In a preferred embodiment, linkage of the prodrug moiety to the rest of the active molécule is stable enough so that the sérum half life of the prodrug is from about 8 to about 24 hours.

[0083] 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 15 a morpholino group. This pKa range of 6.5 to 8.5 allows for significant concentrations of the basic neutral amine to be présent in the mildly alkaline small intestine. The basic, neutral form of the amine prodrug is lipophilie and is absorbed through the wall of the small intestine into the blood. Following absorption into the bloodstream, the prodrug moiety is cleaved by esterases which are naturally présent in the sérum to release an active compound.

[0084] Examples of R include, without limitation:

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

R	m	R³⁵	r³⁵	nr³⁴r³³
C(O)(CH₂)_mNR³⁴R³⁵	1	Me	Me
C(O)(CH₂)_mNR³⁴R³⁵	2	Me	Me
C(O)(CH₂)_mNR³⁴R³⁵	3	Me	Me
C(O)(CH₂)_mNR³⁴R³⁵	4	Me	Me
C(O)(CH₂)_mNR³⁴R^3:>	1			-^-n^___o
C(O)(CH₂)_mNR³⁴R³⁵	2			1 v\r ό
C(O)(CH₂)_mNR³⁴R^3S	3			-cj-r/ /°
C(O)(CH₂)_mNR³⁴R^3S	4			-%-N\ /0
C(O)O(CH₂)_mNR³⁴R^3:>	2	Me	Me
C(O)O(CH₂)_mNR³⁴R³⁵	3	Me	Me
C(O)O(CH₂)_mNR³⁴R^3S	4	Me	Me
C(O)O(CH₂)_mNR³⁴R³⁵	2			s -CN O * \—J
C(O)O(CH₂)_mNR³⁴R³⁵	3			* \J
C(O)O(CH₂)_mNR³⁴R³⁵	4			S -£-N\___G
P(O)(OH)₂
an N oxide thereof, or a pharmaceutically acceptable sait of each t	îereof.

[0085] In another aspect, R is,

wherein

R³⁶ is lower alkyl (e.g. Ci-Cô alkyl).

[0086] In yet another aspect, R is:

9 wherein X , Y and X are as defined herein.

[0087] In one embodiment, X¹ is selected from the group consisting of O, S and NR³⁷wherein R³⁷ is hydrogen or Ci-Cô alkyl;

Y¹ is -C(R³⁸)₂ or a sugar moiety, wherein each R³⁸ is independently hydrogen or

Ci-Cô alkyl, C3-C8 cycloalkyl, C3-C9 heterocyclyl, Cô-Cio aryl, or C3-C9 heteroaryl;

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

U is O or S; and

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

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

X⁴ is selected from the group consisting of O, S, S=O, and SO₂; and each R⁴⁰ is independently Cio-C₂₂ alkyl, C3-C8 cycloalkyl, C3-C9 heterocyclyl, C₆-C|₀aryl, or C3-C9 heteroaryl, CpCs alkylene, or Ci-Cs heteroalkylene.

[0088] Each heterocyclic and heteroaryl ring System is optionally substituted with C1-C3 alkyl, -OH, amino and carboxyl groups.

[0089] In one embodiment, the présent invention utilizes the following Y¹ groups: CH₂, CHMe, CH(isopropyl), CH(tertiarybutyl), C(Me)₂, C(Et)₂, C(isopropyl)₂, and C(propyl)₂.

[0090] In another embodiment, the présent invention utilizes the following X² groups:

-OMe, -OEt, -O-isopropyl, O-isobutyl, O-tertiarybutyl, -O-COMe, -O-C(=O)(isopropyl), -O-C(=O)(isobutyl), -O-C(=O)(tertiarybutyl), -O-C(=O)-NMe2,

-O-C(=O)-NHMe, -O-C(=O)-NH₂, -O-C(=O)-N(H)-CH(R⁴¹)-CO2Et wherein R⁴¹ is a side chain Cy-Cô alkyl, or C3-C9 heterocyclyl group selected from the side chain groups présent in essential amino acids; -O-P(=O)(OMe)2, -O-P(=O)(O-isopropyl)2, and -O-P(=O)(Oisobutyl)2· Each heterocyclic is optionally substituted with one or more, preferably, 1-3, CiC3 alkyl, -OH, amino and/or carboxyl groups.

[0091] In another embodiment, In one embodiment, R is:

wherein

X³ is independently Ci-Cô alkyl, C₃-Cs cycloalkyl, C3-C9 heterocyclyl, Cô-Cio aryl, or C3-C9 heteroaryl; and

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

Cô-Cio aryl, or C3-C9 heteroaryl.

[0092] Each heterocyclic is optionally substituted with one or more, preferably, 1-3, C1-C3 alkyl, -OH, amino and/or carboxyl groups.

[0093] In one embodiment, R is:

wherein each X³ is independently amino, hydroxyl, mercapto, Ci-Cô alkyl, C3-C8 cycloalkyl,

C3-C9 heterocyclyl, Cô-Cio aryl, or C3-C9 heteroaryl, Cj-Cô alkoxy, Ci-Cô alkylamino, Ci-Cô dialkylamino, Ci-Cô alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and -O-CH₂-CH(OR⁴⁰)CH₂X⁴R⁴⁰, wherein:

X⁴ is selected from the group consisting of O, S, S=O, and SO₂; and each R⁴⁰ is independently Cio-C₂₂ alkyl, C3-C8 cycloalkyl, C3-C9 heterocyclyl, C6-C10 aryl, C3-C9 heteroaryl, Ci-Cs alkylene, or Ci-Cs heteroalkylene; and

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

[0094] In some embodiments, R⁴² is independently hydrogen or Ci-Cô alkyl, C3-C8 cycloalkyl, C3-C9 heterocyclyl, Cô-Cio aryl, or C3-C9 heteroaryl; and each X³ independently is Ci-Cô alkyl, C3-C8 cycloalkyl, C3-C9 heterocyclyl, Cô-Cio aryl, or C3-C9 heteroaryl, Ci-Cô alkoxy, Ci-Cô alkylamino, Ci-Cô dialkylamino, or Ci-Cô alkylthio.

[0095] In some embodiments, R is represented by the following structures:

wherein, in the above examples, R⁴³ is C10-C22 alkyl or alkylene, R⁴⁴ is H or Ci-Cô alkyl and R⁴⁵ represents side chain alkyl groups présent in naturally occurring alpha amino acids;

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

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

[0096] In one embodiment, R is:

[0097] In one aspect, R is -C(R²⁰⁰R²⁰¹)O(R²⁰²R²⁰³)P(O)OR²⁰⁴NR²⁰⁵R²⁰⁶, wherein each R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, R²⁰⁴ R²⁰⁵ and R²⁰⁶ is independently H, a Ci-C₈ alkyl, C₃-C₉ heterocyclyl, C₃C₈ cycloalkyl, Cô-Cio aryl, C3-C9 heteroaryl, wherein each alkyl, heterocyclyl, cycloalkyl, aryl, and heteroaryl is optionally substituted.

[0098] In some embodiments, R is -CH(R²⁰¹)OCH2P(O)OR²⁰⁴NHR²⁰⁶, wherein R²⁰¹ is CjC8 alkyl, R²⁰⁴ is phenyl, optionally substituted. In one embodiment,R²⁰⁶ is -CHR²⁰⁷C(O)OR²⁰⁸wherein R²⁰⁷ is selected from the group consisting of the naturally occurring amino acid side chains and -CO2H esters thereof and R²⁰⁸ is Ci-C8 alkyl. In one embodiment, R²⁰⁶ is Ci-Cô alkyl, optionally susbtitued with 1-3, CO₂H, SH, NH₂, Cô-Cio aryl, and C₂-Cio heteroaryl.

[0099] In one embodiment, R is:

[0100] In one embodiment, R is:

PEG

VSaaT W^peg r = 0 to 12 ₅ or wherein Y¹ is -C(R³⁸)2, wherein each R³⁸ is independently hydrogen or Cj-Cô alkyl,

Cj-Cg cycloalkyl, C3-C9 heterocyclyl, Cô-Cj₀ aryl, or C3-C9 heteroaryl.

[0101] 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 in U.S. Patent

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

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

[0102] In one embodiment, R is

wherein

R⁵⁰ is -OH or hydrogen;

R⁵¹ is -OH, or hydrogen;

• Wis-CH(CH₃)W^l;

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

-P(O)(OR⁵²)(OH), -OP(O)(OR⁵²)(OH), and OSO₃H, wherein R⁵² is Ci-Cô alkyl, C₃-Cg cycloalkyl, C3-C9 heterocyclyl, Cô-Cio aryl, or C₃C9 heteroaryl.

[0103] Each heterocyclic and heteroaryl ring system is optionally substituted with one or more, preferably 1-3, Ci-C₃ alkyl, -OH, amino and/or carboxyl groups.

[0104] In one embodiment, R is:

wherein R⁵³ is H or Ci-Cô alkyl.

[0105] In another aspect, R is SO₃H.

[0106] In another aspect, R comprises a cleavable linker, wherein the term “cleavable linker” refers to a linker which has a short half life in vivo. The breakdown of the linker Z in a compound releases or generates the active compound. In one embodiment, the cleavable linker has a half life of less than ten hours. In one embodiment, the cleavable linker has a half life of less than an hour. In one embodiment, the half life of the cleavable linker is between one and fifteen minutes. In one embodiment, the cleavable linker has at least one connection with the structure: C*- C(=X*)X*-C* wherein C* is a substituted or unsubstituted methylene group, and X* is S or O. In one embodiment, the cleavable linker has at least one C*C(=O)O-C* connection. In one embodiment, the cleavable linker has at least one C*C(=O)S-C* connection. In one embodiment, the cleavable linker has at least one -C(=O)N*C*-SO2-N*-connection, wherein N* is -NH- or Ci-Cô alkylamino. In one embodiment, the cleavable linker is hydrolyzed by an esterase enzyme.

[0107] In one embodiment, the linker is a self-immolating linker, 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 substrate for enzymes. See generally Rooseboom et al., 2004, Pharmacol. Rev. 56:53-102.

Pharmaceutical Compositions

[0108] In further aspects of the invention, a composition is provided comprising any of the compounds described herein, and at least a pharmaceutically acceptable excipient.

[0109] In another aspect, this invention provides a composition comprising any of the compounds described herein, and a pharmaceutically acceptable excipient.

[0110] Such compositions can be formulated for different routes of administration. Although compositions suitable for oral delivery will probably be used most frequently, other routes that may be used include transdermal, intravenous, intraarterial, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous, intracranial, and subcutaneous routes. Suitable dosage forms for administering any of the compounds described herein include tablets, capsules, pills, powders, aérosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and émulsions. Sustained release dosage forms may also be used, for example, in a transdermal patch form. Ail dosage forms may be prepared using methods that are standard in the art (see e.g., Remington’s Pharmaceutical

Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).

[0111] Pharmaceutically acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefït of the compound of this invention. Such excipients may be any solid, liquid, semi-solid or, in the case of an aérosol composition, gaseous excipient that is generally available to one of skill in the art. Pharmaceutical compositions in accordance with the invention are prepared by conventional means using methods known in the art.

[0112] The compositions disclosed herein may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical préparations, e.g., talc, gum arabic, lactose, starch, magnésium stéarate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin dérivatives, glycols, etc. Coloring and flavoring agents may also be added to préparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as éthanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycérides, partial esters of glycerin and the like.

[0113] Solid pharmaceutical excipients include starch, cellulose, hydroxypropyl cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnésium stéarate, sodium stéarate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, éthanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, minerai oil, sesame oil, etc. In certain embodiments, the compositions provided herein comprises one or more of α-tocopherol, gum arabic, and/or hydroxypropyl cellulose.

[0114] In one embodiment, this invention provides sustained release formulations such as drug depots or patches comprising an effective amount of a compound provided herein. In another embodiment, the patch further comprises gum Arabic or hydroxypropyl cellulose separately or in combination, in the presence of alpha-tocopherol. Preferably, the hydroxypropyl cellulose has an average MW of from 10,000 to 100,000. In a more preferred embodiment, the hydroxypropyl cellulose has an average MW of from 5,000 to 50,000.

[0115] 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 be used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time. However, coadministration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such administration most advantageously proceeds by delivering both active ingrédients simultaneously in a novel pharmaceutical composition in accordance with the présent invention.

Methods of Treatment

[0116] In aspects of the invention, a method is provided for increasing tissue and/or cellular oxygénation, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

[0117] 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.

[0118] 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.

[0119] In further aspects of the invention, a method is provided for treating oxygen deficiency associated with sickle cell anémia, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

[0120] In further aspects of the invention, a method is provided for treating sickle cell disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the compounds or compositions described herein. In still further aspects of the invention, a method is provided for treating cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer s disease, acute respiratory disease syndrome, and a wound, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the compounds or compositions described herein.

Synthetic Methods

[0121] Certain methods for making the compounds described herein are also provided. The reactions are preferably carried out in a suitable inert solvent that will be apparent to the skilled artisan upon reading this disclosure, for a sufficient period of time to ensure substantial completion of the reaction as observed by thin layer chromatography, ’H-NMR, etc. If needed to speed up the reaction, the reaction mixture can be heated, as is well known to the skilled artisan. The final and the intermediate compounds are purified, if necessary, by various art known methods such as crystallization, précipitation, column chromatography, and the likes, as will be apparent to the skilled artisan upon reading this disclosure.

[0122] An illustrative and non-limiting method for synthesizing a compound of formula (I), is schematically shown below.

» A

In the following Schemes, «B ; > c î ' - ' and ' - ' refer to rings A, B and C as described herein;

A⁵ and B⁵ are independently NR¹⁴, O, S, S(O)x, NBoC, CH2, CHR¹⁴, C(R¹⁴)2 provided that when both A⁵ and B⁵ are présent in a ring, both are not CH2, CHR¹⁴, C(R¹⁴)2, and that when only 1 A⁵ or B⁵ is présent in a ring the A⁵ or B⁵ is not CH2, CHR¹⁴, C(R¹⁴)2;

R¹⁴ is Ci-Cô alkyl, COR¹⁵ or COOR¹⁵; wherein R¹⁵ is optionally substituted Ci-Cô alkyl, optionally substituted Cô-Cio aryl, optionally substituted 5-10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;

X, and X⁵ each represents a leaving group and are independently selected from Cl, Br, and I.

X⁶ represents CR, N, O, S(O)x ; wherein x is 0, 1, or 2;

• R⁷¹ is Ci-C₆ alkyl;

Y⁵ represents a leaving group selected from Cl, F, Br, I, OSCbR¹⁷ and OSChAr;

Ar is phenyl optionally substituted with 1-3 halo and/or C1-C4 alkyl; n is 0, 1, or 2; and

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

General Synthetic Schemes

Scheme 1

,î

4a or 4b

[0123] General method A (Scheme 1) for preparing aryloxy/heteroarylether analogs (4a/4b) from substituted methylene alcohol (1) and hydroxyl (hetero)aryl aldéhyde dérivatives (3a/3b). A hydroxyl (hetero)arylaldehyde dérivatives (3a/3b) (0.1-2 mmol) mixture with substituted methylene alcohol (1) (0.8 to 1.2eq) and PPh₃ (l-1.5eq) in anhydrous THF (1-lOmL) was stirred under nitrogen until complété dissolution. The solution was cooled to 0 °C on ice bath and DIAD or DEAD (1.1 eq) in THF or toluene was added dropwise over a 1-20 min period. The ice cooling 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

φ filtrâtes were evaporated and the residue was dried on highvac. The residue was purified by préparative HPLC or flash silica gel chromatography.

[0124] General method A (Scheme 1) for preparing aryloxy/heteroarylether analogs (4a/4b) from substituted methylene halide (2) and hydroxyl (hetero)aryl aldéhyde dérivatives (3a/3b). A mixture of hydroxyl (hetero)arylaldehyde dérivatives (3a/3b) (0.1-2 mmol, 1-4 eq.), substituted methylene chloride or bromide (2) (leq), and K2CO3 (2-5 eq.) (catalytic amount of Nal or BU4NI may also be added) in DMF or acetonitrile (1 to 10 mL) was stirred at RT or heating up to 120 °C for 0.5-8 h under nitrogen atmosphère. In workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to préparative HPLC or flash silica gel chromatography purification. In workup B (for products that did not precipïtate), diluted HCl or aqueous NH4CI was added at 0 °C to adjusted the pH to ~7, the reaction mixture was partitioned between ethyl acetate or dichloromethane and aqueous sodium chloride and the organic layer separated, dried, and solvent removed under vacuum to afford crude product which was purified by automated silica gel column chromatography using appropriate solvents mixture (e.g., ethyl acetate/hexanes).

[0125] General method C for preparing substituted methylene chloride (2a). To a solution of substituted methylene alcohol (1) (0.1 to 2 mmol) in DCM (1-10 mL) was added SOC1₂ dropwise (2eq to 5eq ) at 0 °C or RT. The reaction mixture was stirred at RT for

10min to 6 h, or until reaction is judged complété (LC/MS). The reaction mixture is concentrated to dryness over a rotavap. The crude chloride residue was suspended in toluene, sonicated and concentrated to dryness. The process was repeated three times and dried under vacuum to give the substituted methylene chloride (2), usually as an off-white solid, which was used for next step without further purification. Altematively, a solution of aqueous IN

Na₂CÛ3 is then added to produce a solution of pH~ 8. the mixture was extracted with DCM (3 xl0-50mL), dried over sodium sulfate, and concentrated to the crude substituted methylene chloride (2a), which is then purified by column chromatography on silica gel (0-100% ethyl acetate-hexanes).

[0126] General method D for preparing substituted methylene bromide (2b). To a solution of substituted methylene alcohol (1) (0.1 to 2 mmol) in DCM (1-10 mL) was added Ph3P Br₂ dropwise (2eq to 5eq ) at 0 °C or RT. The reaction mixture was stirred at RT for 10 min to 2 h, or until reaction is judged complété (LC/MS). The reaction mixture is

concentrated to dryness over a rotavap. The residue purified by column chromatography on silica gel (0-100% ethyl acetate-hexanes) to afford the pure bromide 2b.

Step2

Step4

Step3

Tf₂O

LAH or DIBAL

12-OH-trans

Step 9

13-X-trans 13-X-cis

[0127] General method E (Scheme 2) for preparing heterocyclic methylene dérivatives 5 9,10,12 and 13. Condensation of heterocyclic ketone analog 5 with chlorformate or dialkyl carbonate gives (hetero)cyclic beta-ketone ester 6 (Step 1). The ketone ester 6 is converted to the triflate intermediate 7 by treating with a triflating agent (e.g, triflic anhydride) in the presence of an organic base such as Hunig’s base (Step 2). Suzuki coupling of the triflate 7 with a boronic acid or ester affords heterocyclohexene carboxylate 8 (Step 3). Subséquent réduction of the ester group by LAH or DIBAL gives the corresponding alcohol 9-OH (Step 4). Further reaction of the alcohol 9-OH with thionyl chloride, Ph₃PBr₂ (or CBr4-Ph3P or PBr₃), or alkyl/aryl sufonyl chloride produces the corresponding 10-X chloride, bromide or sulfonate (Step 5).

[0128] Altematively, the double bond of heterocyclohexene carboxylate 8 is reduced to 15 give the cis-heterocyclohexane 11-cis carboxylate under palladium catalyzed hydrogénation

conditions (Step 6). Réduction of the ester group of 11-cis by LAH or DIB AL yields cisalcohol 12-OH-cis (Step 8). Conversion of the alcohol 12-OH-cis to its chloride, bromide or sulfonate (such as mesylate, tosylate) 13-X-cis can be achieved by reacting with thionyl chloride, or ΡΙίβΡΒ^, or sufonyl chloride (such as mesyl chloride or tosyl chloride) (Step 9).

The cM'-cyclohexane carboxylate 11-cis can also be isomerized to the thermodynamically more stable trans-isomer 11-trans by the treatment with an alcoholic alkoxide (e.g., ethoxide) solution. Analogously, transformation of 11-trans ester to 12-trans alcohol and 13-X-trans halide is accomplished by applying conditions of Step 8 and Step 9 (Scheme 2) similar to these for the corresponding cis-isomers.

Scheme 3

9-ΟΗ 12-OH-cis 12-OH-trans

Method A

3a or 3b

Method B

3a or 3b

[0129] Coupling of the (hetero)cyclic methylene dérivatives 9,10,12 and 13 with hydroxyl (hetero)arylaldehyde dérivatives (3a/3b) (Scheme 3) by general method A or B affords the corresponding aryloxy/heteroarylether analogs (4c and 4d).

[0130] Similarly, N-linked heterocyclic analogs (compound 5, Scheme 4) can also be synthesized from amination procedures developed by Buchwald and Hartwig.

X⁵

Method A

I /

[0131] Synthèses of the ester prodrugs start with the free carboxylic acid bearing the tertiary amine. The free acid is activated for ester formation in an aprotic solvent and then reacted with a free alcohol group in the presence of an inert base, such as triethyl amine, to provide the ester prodrug. Activating conditions for the carboxylic acid include forming the acid chloride using oxalyl chloride or thionyl chloride in an aprotic solvent, optionally with a catalytic amount of dimethyl formamide, followed by évaporation. Examples of aprotic solvents, include, but are not limited to methylene chloride, tetrahydrofuran, and the like. Altematively, activations can be performed in situ by using reagents such as BOP (benzotriazol-l-yloxytris(dimethylamino) phosphonium hexafluorolphosphate, and the like (see Nagy et al., 1993, Proc. Natl. Acad. Sci. USA 90:6373-6376) followed by reaction with the free alcohol. Isolation of the ester products can be affected by extraction with an organic solvent, such as ethyl acetate or methylene chloride, against a mildly acidic aqueous solution; followed by base treatment of the acidic aqueous phase so as to render it basic; followed by extraction with an organic solvent, for example ethyl acetate or methylene chroride; évaporation of the organic solvent layer; and recrystalization from a solvent, such as éthanol. Optionally, the solvent can be acidified with an acid, such as HCl or acetic acid to provide a pharmaceutically acceptable sait thereof. Altematively the crude reaction can be passed over an ion exchange column bearing sulfonic acid groups in the protonated form, washed with deionized water, and eluted with aqueous ammonia; followed by évaporation.

[0132] Suitable free acids bearing the tertiary amine are commercially available, such as 2(N-morpholino)-propionic acid, N,N- dimethyl-beta-alanine, and the like. Non- commercial acids can be synthesized in straightforward manner via standard literature procedures.

[0133] Carbonate and carbamate prodrugs can be prepared in an analogous way. For example, amino alcohols and diamines can be activated using activating agents such as phosgene or carbonyl diimidazole, to provide an activated carbonates, which in turn can react with the alcohol and/or the phenolic hydroxy group on the compounds utilized herein to provide carbonate and carbamate prodrugs.

[0134] 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.

[0135] Scheme 5 below provides a method of synthesizing an acyloxymethyl version of a prodrug by adapting a method from the reference Sobolev et al., 2002, J. Org. Chem. 67:401410.

Scheme 5

OH

I v/VX/VT

I

wherein R⁵¹ is Ci-Cô alkyl.

[0136] Scheme 6 below provides a method for synthesizing a phosphonooxymethyl version of a prodrug by adapting a method from Mantyla et al., 2004, J. Med. Chem. 47:188-195.

Scheme 6

NaH, DMF tetrabutylammonium bromide NaH, THF

I^OEt OEt

[0137] Scheme 7 below provides a method of synthesizing an alkyloxymethyl version of a prodrug

Scheme 7

wherein R⁵² is Cj-Cô alkyl, C3-C8 cycloalkyl, C3-C9 heterocyclyl, Cô-Cjo aryl, or C3C9 heteroaryl.

Scheme 8

Step 1

14a (R=H) 14b (R=alkyl)

Step

15c (R=Ar/HeteroAr)

[0138] Compounds of structure 17 can be synthesized via general synthetic scheme 8. Réduction of carboxylic acid dérivative 14 gives hydrxoymethyl analog, which can be N-derivativtized at via copper-mediated N-arylation reaction (Cul, Ar-I, base such as Ν,Ν-dimethylethylenediamine and potassium phosphate, heat) to give key hydroxymethyl intermediate 15. Coupling of 15 with phénol aldéhyde 16 produces the desired aldéhyde analog 17 via typical Mistunobu conditions using either triphenylphosphine or polymer supported triphenylphosphine.

[0139] General method step 1 - réduction of carboxylic acid dérivative 14 to methyl alcohol 15: To a suspension of carboxylic acid 14(l-10mmol) in MeOH or EtOH (2-10 mL) at 0 °C was added SOC1₂ (1.5eq). After stirred at room température for 1- 12h, it was concentrated to remove ail solvents, dried under high vacuum to give correspondîng methyl or ethyl ester. The ester was dissolved in MeOH or EtOH (5-30 mL), to this solution, was added NaBH₄ (l-4eq) at 0 °C, the mixture was warmed up to room température and stirred for additional 1-24 h. The mixture was quenched with Sat. NH₄C1, filtered off the insolubles and the filtrate was concentrated to give crude product, which was purified by flash silica gel chromatography to give the correspondîng hydroxymethylene compound 15.

φ [0140] General method step 2 - N-alkylation (14a to 14b): The carboxylate 14a (Ri=H) can be first alkylated and then reduced to give N-alkyl hydroxymethylene analog 14b (Ri=alkyl). In a typical procedure, the carboxylate 14a (l-10mmol) is first dissolved in DMF (2-20 mL); to this was then added a base such as NaH or CS2CO3 (l-1.2eq), followed by the addition of alkyl halide (eg, BnBr) (0.9-1.5eq). The reaction allowed to proceed at room température of heat at 40 to 115 °C for 0.5 to 24 h. In workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to préparative HPLC or flash silica gel chromatography purification. In workup B (for products that did not precipitate), diluted HCl or aqueous NH4CI was added at 0 °C to adjusted the pH to ~7, the reaction mixture was partitioned between ethyl acetate or dichloromethane and aqueous sodium chloride and the organic layer separated, dried, and solvent removed under vacuum to afford crude product which was purified by automated silica gel column chromatography, reaction appropriate solvents mixture (e.g., ethyl acetate/hexanes).

[0141] General method step 3 - Copper-mediated N-arylation from 15a to 15c: For cyclic amines (X=H, H), to a solution of hydroxymethylene compound 15a (1-10 mmol) and aryl/hetero iodide (1-1.5eq) in iPrOH (0.5-10 mL) was added ethylene diol (1.3eq) and Cul (6.7mol%), followed by K3PO4 (1.3eq), then it was degassed and heated at 88 °C for 6-24 h. Alternatively, for lactams (X=O), to a solution of hydroxymethylene compound 15a (120 lOmmol) and aryl/hetero iodide (l-1.5eq) in Dioxane (2-20 mL) was added Cul (0.17eq), Ν,Ν-dimethylethylenediamine (0.17eq), K3PO4 (1.7eq), then it was degassed and heated at 100 °C for 6-48 h.

[0142] Workup for both procedures: the reaction mixture was cooled to room température the mixture was diluted with EtOAc and water, organic layer was separated and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by flash silica gel chromatography to give N-aryl/heteroaryl compound 15c.

[0143] General method C -Mitsunobu conditions A hydroxyl (hetero)arylaldehyde dérivatives (17) (0.1-2 mmol) mixture with substituted methylene alcohol (16) (0.8 to 1.2eq) 30 and (polymer-supported) PPI13 (1-1.5eq) in anhydrous THF (1-lOmL) was stirred under nitrogen until complété dissolution. The solution was cooled to 0 °C on ice bath and DIAD or DE AD (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 2-20mL. The combined filtrâtes were evaporated and the residue was dried on highvac. The residue was purified by préparative HPLC or flash silica gel chromatography.

Scheme 9

X = halide, OTs Step ²

R1 = Aryl/heteroaryl

Y= halide, OTs, OMs

Y

[0144] General method step 1 (Scheme 9) for preparing substituted methylene alcohol (2) by Suzuki coupîing reaction. To a solution of (2-chloropyridin-3-yl)methanol or (2bromopyridin-3-yl)methanol (l-100mmol) and appreciate bronic acid or ester (0.8 to 1.5 eq) in dîoxane (2-200 mL) was added a solution of sodium bicarbonate (3 eq) in water (1-100 mL), followed by the addition of Pd(dppf)C12 (5 to 10mol%). After heating at 100 °C for 424 h, the reaction mixture was cooled and diluted with EtOAc, organic layer was washed with water, brine, dried and concentrated to give crude product, which was purified by column chromatography.

[0145] General method step 2 (Scheme 9) for preparing substituted methylene chloride (3a). To a solution of substituted methylene alcohol (2) (0.1 to 2 mmol) in DCM (1-10 mL) was added SOCI2 dropwise (2eq to 5eq ) at 0 °C or rt. The reaction mixture was stirred at rt for 10min to 6 h, or until reaction is judged complété (LC/MS). The reaction mixture is concentrated to dryness over a rotavap. The crude chloride residue was suspended in toluene, sonicated and concentrated to dryness. The process was repeated three times and dried under vacuum to give the substituted methylene chloride (3a), usually as an off-white solid, which was used for next step without further purification. Altematively, a solution of aqueous IN Na₂CO₃ is then added to produce a solution of pH~ 8. the mixture was extracted with DCM (3 xl0-50mL), dried over sodium sulfate, and concentrated to the crude substituted methylene chloride (3a), which is then purified by column chromatography on silica gel (0-100% ethyl acetate-hexanes).

φ [0146] General method 2 (Scheme 9) for preparing substituted methylene bromide (3b). To a solution of substituted methylene alcohol (2) (0.1 to 2 mmol) in DCM (1-10 mL) was added Ph₃P Br₂ dropwise (2eq to 5eq ) at 0 °C or rt. The reaction mixture was stirred at rt for 10 min to 2 h, or until reaction is judged complété (LC/MS). The reaction mixture is concentrated to dryness over a rotavap. The residue purified by column chromatography on silica gel (0-100% ethyl acetate-hexanes) to afford the pure bromide 3b.

[0147] General method step 3 (Scheme 9) for preparing aryloxy/heteroarylether analogs (5) from substituted methylene alcohol (2) and hydroxyl (hetero)aryl aldéhyde dérivatives (4). A hydroxyl (hetero)arylaldehyde dérivatives (4) (0.1-2 mmol) mixture with substituted methylene alcohol (2) (0.8 to 1.2eq) and (polymer-supported)/PPh₃ (1-1.5eq) in anhydrous THF (1-lOmL) was stirred under nitrogen until complété dissolution. The solution was cooled to 0 °C on ice bath and DIAD or DEAD (1.1 eq) in THF or toluene was added drop wise 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 filtrâtes were evaporated and the residue was dried on highvac. The residue was purified by préparative HPLC or flash silica gel chromatography.

[0148] General method step 4 (Scheme 9) for preparing aryloxy/heteroarylether analogs (5) from substituted methylene halide (3) and hydroxyl (hetero)aryl aldéhyde dérivatives (4). A mixture of hydroxyl (hetero)arylaldehyde dérivatives (4) (0.1-2 mmol, 1-4 eq.), substituted methylene chloride or bromide (3) (leq), and K₂CO₃ (2-5 eq.) (catalytic amount of Nal or Bu₄NI may also be added) in DMF, acetonitrile, NMP or DMSO (1 to 10 mL) was stirred at RT or heating up to 120 °C for 1-24 h under nitrogen atmosphère. In workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to préparative HPLC or flash silica gel chromatography purification. In workup B (for products that did not precipitate), diluted HCl or aqueous NH₄C1 was added at 0 °C to adjusted the pH to ~7, the reaction mixture was partitioned between ethyl acetate or dichloromethane and aqueous sodium chloride and the organic layer separated, dried, and solvent removed under vacuum to afford crude product which was purified by automated silica gel column chromatography using appropriate solvents mixture (e.g., ethyl acetate/hexanes).

φ Examples

[0149] In the examples below as well as throughout the application, the following abbreviations hâve the following meanings. If not defined, the terms hâve their generally accepted meanings.

°C = degrees Celsius

RT = Room température min = minute(s) h = hour(s) pL = Microliter mL = Milliliter mmol = Millimole eq = Equivalent mg = Milligram ppm = Parts per million atm = Atmospheric pressure

MS = Mass spectrometry

LC-MS = Liquid chromatography-mass spectrometry

HPLC = High performance liquid chromatography

NMR = Nuclear magnetic résonance

Sat./sat. Saturated

MeOH = Methanol

EtOH = Ethanol

EtOAc = Ethyl acetate

Et₃N = Triethylamine

ACN = Acetonitrile

AC2O = Acetic anhydride

Na(OAc)₃BH = Sodium triacetoxy borohydride

PBr₃ - phosphorus tribromide

Ph₃P = Triphenylphosphine

Ph₃PBr2 = Triphenylphosphine dibromide

CBr₄ Tetrabromomethane

DMF = N, N-Dimethylformamide

DCM = Dichloromethane

LAH/ LiAlH₄ =	= Lithium aluminum hydride
THF =	= Tetrahydrofuran
DIBAL =	= Diisobutylaluminium hydride
DIAD =	= Diisopropyl azodicarboxylate
DEAD =	= Diethyl azodicarboxylate
DIPEA =	= N,N-Diisopropylethylamine
Tf₂O =	= Trifluoromethanesulfonic (triflic) anhydride
Pd(dppf)Cl₂ --	= [1,1 '-Bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex

[0150] The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the présent invention in any fashion. The présent examples, along with the methods described herein are presently représentative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defîned by the scope of the claims will occur to those skilled in the art.

Experimental Procedures for Intermediates

[0151] (E)-l-(3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-310 (dimethylamino)prop-2-en-1 -one (INT-1)

INT-1

Step 1

O	imidazole	- π
		FF
bu γ^	TBSCI	Bf Y
ΌΗ		OTBS

[0152] To a mixture of (2-bromopyridin-3-yl)methanol (20.0 g, 106.4 mmol, 1 eq.; refer to example 14) and imidazole (14.5 g, 212.8 mmol, 2 eq.) in DMF (50.0 mL) was added TBSC1

(19.2 g, 150.7 mmol, 1.2 eq.) at RT. The mixture was stirred at RT for 1 h and diluted with a mixture of water (100 mL) and EtOAc (300 mL). The organic layer was washed with NH4Cl_(sat) solution and brine, dried over Na₂SÛ4, concentrated, and purified on silica gel using 10% EtOAc/hexanes as eluent to give 2-bromo-3-((tertbutyldimethylsilyloxy)methyl)pyridine (30.1 g, 94%) as a colorless oil. MS (ESI) m/z 302.0 [M+H]⁺.

Step 2

Zn(CN)₂

Pd(PPh₃)₄

[0153] A mixture of 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 100.0 mmol, 1 eq.) and Zn(CN)₂ ( 23.5 g, 200.0 mmol, 2.0 eq.) in DMF (100.0 mL) was purged with N₂ for 5 min and added Pd(PPh3)4 (5.78 g, 5.0 mmol, 0.05 eq.). The mixture was heated at 120 °C for 2 h under N₂, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tertbutyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82%) as a colorless oil. MS (ESI) m/z

249.1 [M+H]⁺.

Step 3:

MeMgBr

THF

[0154] Méthylmagnésium bromide (3M/ether, 41.0 mL, 123.4 mmol) was added to a stirred solution of 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82.25 mmol) in THF (100.0 mL) at -78 °C. The reaction mixture was warm to RT, quenched with aqueous citric acid solution, and extracted with EtOAc (50 mL) twice. The combined organic layers were washed with NaHCO3 (_Sat) solution and brine, dried over Na₂SO4, concentrated, and purified on silica gel using a mixture of EtOAc/hexanes as eluent to give l-(3-((tert-

butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (12.9 g, 59%) as a colorless oil. MS (ESI) m/z 266.2 [M+H]⁺.

Step 4:

[0155] l-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (10.8 g, 40.75 mmol) in dimethoxy-N,N-dimethylmethanamine (15.0 mL) was heated to reflux for 3 days. The mixture was concentrated and used for next step without further purification. MS (ESI) m/z 321.1 [M+H]⁺.

[0156] Préparation of 3-(chloromethyl)-2-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-510 yl)pyridine (INT-2).

Step 1:

HCl (12 N)

HCl HCl

70% wt inwater

[0157] To (3,3,3-trifluoroethyl)hydrazine (25 g, 50% wt in water, 153.5 mmol, 1 eq.) in a

RB flask (250 mL) was added HCl (12 N, 25.6 mL, 307.0 mmol, 2 eq.). The mixture was concentrated to give (3,3,3-trifluoroethyl)hydrazine dihydrochloride (1.07 g) as a yellow solid. MS (ESI) m/z 115.1 [M+H]⁺.

Step 2:

[0158] Το (E)- l-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3(dimethylamino)prop-2-en-l-one (crude above, 5.91 g, 18.44 mmol, 1 eq.) in EtOH (20 mL) was added (3,3,3-trifluoroethyl)hydrazine dihydrochloride (4.13 g, crude above, 22.13 mmol, 1.2 eq.) at RT. The mixture was heated at 80 °C for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO3(_sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(l-(3,3,3-trifluoroethyl)-lH-pyrazol5-yl)pyridine (5.90 g; 86% for 2 steps). MS (ESI) m/z 372.2 [M+H]⁺.

Step 3:

HCl

MeOH

[0159] To 3-((tert-butyldimethylsilyloxy)methyl)-2-(l-(3,3,3-trifluoroethyl)-lH-pyrazol-515 yl)pyridine (5.91 g, 15.93 mmol) in MeOH (20 mL) was added HCl (4 N, 8.0 mL). The mixture was stirred at RT for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO₃(_Sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SÛ4, and concentrated to give (2-(1-(3,3,3-trifluoroethyl)-lH-pyrazol-5-yl)pyridin-3-yl)methanol (4.1 g, quantitative yield) as colorless oil. 'H NMR (400 MHz, CDC1₃) δ 8.54 (dd, J = 4.7, 1.5 Hz,

IH), 7.92 (dd, J = 7.9, 1.2 Hz, IH), 7.57 (d, J= 1.9 Hz, 1H),7.3O (dd, J = 7.8, 4.8 Hz, IH),

φ 6.50 (d, J= 1.9 Hz, 1H), 5.09 (q, J= 8.6 Hz, 2H), 4.63 (s, 2H), 1.76 (s, 1H). MS (ESI) m/z

258.1 [M+H]⁺.

Step 4:

[0160] To (2-(1-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl)pyridin-3-yl)methanol (408 mg, 1.59 mmol) in DCM ( 5 mL) was added SOC1₂ (1.5 mL) at RT. The reaction mixture was stirred at RT for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl)pyridine hydrochloride (498 mg) as an off-white solid, which was used for next step without further purification.

[0161] Préparation of 3-(chloromethyl)-2-(l-(3,3,3-trifluoropropyl)-lH-pyrazol-5yl)pyridine (INT-3).

Step 1:

[0162] To a mixture of benzyl hydrazinecarboxylate (5.0 g, 30.3 mmol, 1 eq.) and DIEA (15.0 mL, 90.9 mmol, 3 eq.) in DMF (20 mL) was added 3,3,3-trifluoropropyl bromide (10.7 g 60.6 mmol, 2 eq.) at RT. The mixture was heated at 80 °C for 20 h, concentrated, and

purified on silica gel using a mixture of EtOAc and hexanes as eluent to benzyl 2-(3,3,3trifluoropropyl) hydrazinecarboxylate (4.2 g; 53%) as a white solid. Ή NMR (400 MHz, CDCI3) δ 7.33 - 7.17 (m, 5H), 6.11 (s, 1H), 5.01 (s, 2H),4.00 (s, 1H), 3.00 (dd, J= 12.2,7.1 Hz, 2H), 2.17 (qt, J= 10.8, 7.3 Hz, 2H). MS (ESI) m/z 263.1 [M+H]⁺.

Step 2:

[0163] To benzyl 2-(3,3,3-trifluoropropyl)hydrazinecarboxylate (1.7 g, 6.49 mmol, 1 eq.) in a mixture of EtOH (30 mL) were added Pd/C (1.0 g) and HCl (12 N, 2.0 mL). The mixture was charged with H2 (60 psi), stirred at RT for 1 h, fiîtered, and concentrated to give (3,3,3trifluoropropyl)hydrazine dihydrochloride (1.07 g) as a yellow solid. MS (ESI) m/z 129.1 [M+H]⁺.

Step 3:

[0164] To (£')-l-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3(dimethylamino)prop-2-en-l-one (crude above, 1.73 g, 5.41 mmol, 1 eq.) in EtOH (10 mL) was added (3,3,3-trifluoropropyl)hydrazine dihydrochloride (1.30 g, crude above, 6.49 mmol, 1.2 eq.) at RT. The mixture was heated at 80 °C for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO3(_Sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(l-(3,3,3-trifluoropropyl)-lH-

pyrazol-5-yl)pyridine ( 1.58 g; 76% for 2 steps). *H NMR (400 MHz, CDCI3) δ 8.53 (dd, J =

4.7, 1.6 Hz, 1H), 7.96-7.88 (m, 1H), 7.51 (d, J= 1.9 Hz, 1H),7.29 (dd, J = 7.9,4.7 Hz, 1H),

6.34 (d, J = 1.9 Hz, 1H), 4.62 (s, 2H), 4.45 - 4.33 (m, 2H), 2.82 - 2.61 (m, 2H), 0.85 (s, 8H), -0.00 (s, 5H). MS (ESI) m/z 386.2 [M+H]⁺.

Step 4:

HCl

MeOH

[0165] To 3-((tert-butyldimethylsilyloxy)methyl)-2-( 1-(3,3,3-trifluoropropyl)-lH-pyrazol5-yl)pyridine (1.58 g, 4.1 mmol) in MeOH (20 mL) was added HCl (4 N, 4.0 mL). The mixture was stirred at RT for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO3(_sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO₄, and concentrated to give (2-(1-(3,3,3-trifluoropropyl)-lH-pyrazol-5-yl)pyridin-3-yl)methanol (1.1 g, 99%) as colorless oil. 'H NMR (400 MHz, CDC1₃) δ 8.64 (dd, J = 4.7, 1.7 Hz, 1H), 8.00 (dd, J= 7.9, 1.7 Hz, 1H), 7.57 (d, J= 1.9 Hz, 1H), 7.38 (dd, 7= 7.9,4.8 Hz, 1H), 6.48 (d, J =

1.9 Hz, 1H), 4.69 (s, 2H), 4.51 - 4.43 (m, 2H), 2.85 - 2.72 (m, 2H), 2.70 (s, 1H). MS (ESI) m/z 272.1 [M+H]⁺.

Step 5:

[0166] To (2-(1-(2,2,2-trifluoropropyl)-lH-pyrazol-5-yl)pyridin-3-yl)methanol (140 mg, 0.52 mmol) in DCM ( 5 mL) was added SOCI2 (2.0 mL) at RT. The reaction mixture was stirred at RT for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum

φ to give 3-(chloromethyl)-2-(l-(2,2,2-trifluoropropyl)-lH-pyrazol-5-yl)pyridine hydrochloride (498 mg) as an off-white solid, which was used for next step without further purification.

[0167] Préparation of 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine (INT-4).

[0168] Step 1 : To a 500-mL flask containing the pyrazole boronate (9.0g, 38.Immol), 2chloropyridine (5.47g, 38.1mmol), Pd(dppf)C12 ([l,l-bis(diphenylphosphino)ferrocene] dichloropalladium) (1.39g, 1.91mmol, 5%mol), and sodium bicarbonate (9.61g, 114.4mmol, 3 equiv) was added 100 mL of dioxane and 30 mL of water. The mixture was heated under nitrogen at 100 °C for 12 hrs. Then solvents were removed on a rotavap at 40 oC undervacum. The resulting brown residue was suspended in 20%EtOAc/DCM (60mL), filtered through a pad of silica gel (15g); washed with 20%EtOAc/DCM (4x20mL). The combined filtrate were concentrated to afford a brown oil (13 g). The residue was dissolved 10% EtOAc/hexanes (20mL) and loaded on a Biotage 100g snap SiO2 column and eluted with 0-50% EtOAc. (2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol was obtained as a light brown oil (3.32 g, 40%). MS (ESI) m/z 218 [M+H]⁺.

[0169] Step 2: To a solution of (2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol) (440mg, 2.02mmol) in DCM (4 mL) was added SOCI2 (2eq) at 0 °C. The reaction mixture was stirred at RT for 15mins and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine hydrochloride (432 mg) as an off-white solid, which was used for next step without further purification. MS (ESI) m/z 236.5 [M+H]⁺.

[0170]

Préparation of 3-(chloromethyl)-2-(l-cyclopentyl-lH-pyrazol-5-yl)pyridine (INT5).

[)—NHNH;

—x HCl

INT-1

Step 1

OTBS

Step 2

INT-5

[0171] Step 1: To (E)-l-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3(dimethylamino)prop-2-en-l-one (crude,3.205g, 10.0 mmol, 1 eq.) in EtOH (30 mL) was added cyclopentylhydrazine HCl sait (1.639g, 12.0 mmol, 1.2eq) at RT. The mixture was heated at 80 °C for 2 h, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give a mixture of regio-isomers, the less polar (2-(l-cyclopentyl-lHpyrazol-5-yl)pyridin-3-yl)methanol was obtained as a light brown oil (440mg). MS (ESI) m/z

244.2 [M+H]⁺.

[0172] Step 2: To a solution of (2-(l-cyclopentyl-lH-pyrazol-5-yl)pyridin-3yl)methanol(301mg, 1.24mmol) in DCM ( 3 mL) was added SOC1₂ (3eq) at 0 °C. The reaction mixture was stirred at RT for 15mins (thew reaction was done in lOmins by LCMS) and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3(chloromethyl)-2-(l-cyclopentyl-lH-pyrazol-5-yl)pyridine hydrochloride (305 mg) as an offwhite solid, which was used for next step without further purification. MS (ESI) m/z 262.2 [M+H]⁺.

[0173] Préparation of 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (INT-6).

MeU.DIPA DMF

Step 4

INT-6 ‘O'0'

Step 1

[0174] To a solution of 6-(benzyloxy)pyridin-3-ol (2.0 g, 10 mmol, 1 eq.) in DMF (20 mL) was added NaH (60% in minerai oil; 0.6 g, 15 mmol, 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 chloromethyl methyl ether (0.88 g, 11 mmol, 1.1 eq.), stined at 0-5 °C for another 20 min, and quenched with NFUCl^at.) 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 Na₂SÛ4, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 2(benzyloxy)-5-(methoxymethoxy)pyridine (2.1 g, 87%) as a colorless oil. MS (ESI) m/z

246.1 [M+H]⁺.

Step 2

[0175] To 2-(benzyloxy)-5-(methoxymethoxy)pyridine (1.8 g, 8.71 mol) in EtOH was added Pd/C (1.0 g). The mixture was charged with H₂ (15 psi), stirred at RT for 45 min, 15 filtered, and concentrated to give 5-(methoxymethoxy)pyridin-2-ol (1.35 g, quantitative yield) as a pale yellow solid. MS (ESI) m/z 156.1 [M+H]⁺.

Step 3

[0176] To a mixture of 5-(methoxymethoxy)pyridin-2-ol (1.35 g, 8.71 mmol, 1 eq.) and

K₂CO₃ (6.01 g, 43.6 mmol, 5.0 eq.) in DMF (30.0 mL) was added l-bromo-2-methoxyethane

φ (3.61 g, 26.1 mmol, 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. *H

NMR (400 MHz, CDC1₃) δ 7.94 (d, J = 3.0 Hz, IH), 7.35 (ddd, J = 8.9, 3.0, 1.0 Hz, IH), 6.76 (dd, J= 8.9, 1.0 Hz, IH), 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 (ESI) m/z 214.1 [M+H]⁺.

Step 4

[0177] To a mixture of 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine (1.34 g, 6.3 mol, 1 eq.) and diisopropylamine (17.5 uL, 0.13 mmol, 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 HCl (12 N, 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 K2CO3. The aqueous layer was extracted with EtOAc (30 mL) twice. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give a mixture of 2-(2-methoxyethoxy)-5(methoxymethoxy)isonicotinaldehyde and 2-(2-methoxyethoxy)-520 (methoxymethoxy)nicotinaldehyde (5/1, 1.27 g, 83.6%) as a pale yellow oil. *H NMR (400 MHz, CDCh) δ 10.45 (s, IH), 8.23 (s, IH), 7.16 (s, IH), 5.27 (s, 2H), 4.46 (dd, J= 5.4, 3.9 Hz, 2H), 4.14 (q, J= 7.1 Hz, IH), 3.77 - 3.71 (m, 2H), 3.56 (s, 3H), 3.46 (s, 3H) and ’H NMR (400 MHz, CDC1₃) δ 10.41 (s, IH), 8.18 (d, J= 3.2 Hz, IH), 7.85 (d, J= 3.1 Hz, IH),

5.16 (s, 2H), 4.64-4.57 (m, 2H), 3.85 - 3.79 (m, 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

[0178] To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (1.27 g, 5.29 mol) in THF (5 mL) was added HCl (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 K2CO3 and the aqueous layer was extracted with EtOAc (100 mL) twice. The combined organic layers were dried over Na₂SÛ4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes to give 5-hydroxy-2-(2methoxyethoxy)isonicotinaldehyde (630 mg, 60%) and 5-hydroxy-2-(2methoxyethoxy)nicotinaldehyde (120 mg, 11%). Data for 5-hydroxy-2-(210 methoxyethoxy)isonicotinaldehyde: *H NMR (400 MHz, CDCI3) δ 9.98 (s, 1H), 9.50 (s, 1H), 8.07 (s, 1H), 7.02 (s, 1H), 4.51-4.39 (m, 2H), 3.81 - 3.72 (m, 2H), 3.47 (s, 3H). LRMS (M+H⁺) m/z 198.1. Data for and 5-hydroxy-2-(2-methoxyethoxy) nicotinaldehyde: ’H NMR (400 MHz, CDCI3) δ 10.3 (s, 1H), 7.99 (d, J= 3.2 Hz, 1H), 7.58 (d, J = 3.2 Hz, 1H), 7.18 7.07 (br, 1H), 4.54 (dd, J = 5.4, 3.7 Hz, 2H), 3.84 (dd, J = 5.4, 3.7 Hz, 2H), 3.49 (s, 3H); MS (ESI) m/z 198.1 [M+H]⁺.

[0179] Préparation of 2,6-dihydroxybenzaldehyde (INT-7).

[0180] Into a 3000-mL three neck round-bottom flask, was placed a solution of AICI3 (240 g, 1.80 mol, 3.00 equiv) in dichloromethane (1200mL). A solution of 2,620 dimethoxybenzaldehyde (100 g, 601.78 mmol, 1.00 equiv) in dichloromethane (800ml) was added to the reaction mixture dropwise at 0°C. The resulting solution was stirred overnight at room température, and then it was quenched with 200 mL of diluted HCl (2M). The resulting solution was extracted with 2x200 mL of dichloromethane. The combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl

acetate/petroleum ether (1:200-1:50) as eluent to fumish 40 g (48%) of 2,6dthydroxybenzaldehyde as a yellow solid.

*HNMR (300MHz, DMSO-J₆) δ 11.25(s, 2H), 10.25(s, 1H), 7.36(m, 1H), 6.36 (d, J=8.4Hz

2H); MS (ESI) m/z 139 [M+H]⁺.

[0181] Préparation of5-hydroxy-2-methoxyisonicotinaldehyde (INTS).

Step 1

OH

Step 3

HCl (3 N); THF

[0182] Step 1: To a solution of 6-methoxypyridin-3-ol (20 g, 0.16 mol) in DMF (200 mL) was added NaH (60% in minerai 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 chloromethyl methyl ether. The mixture was stirred at 0-5 °C for another 20 min and quenched with aqueous NH4Cl(_Sat.). The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layer was washed with water and brine, dried over Na2SO4, 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; CDC1₃) 7.97 (d, 1 H), 7.35 (dd, 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 [M+H]⁺.

[0183] Step 2: To a mixture of 2-methoxy-5-(methoxymethoxy)pyridine (30 g, 0.178 mol) and diisopropylamine (507 uL, 3.6 mmol) in THF (500 mL) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol) 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 followed by addition of DMF (24.7 mL, 0.32 mol) slowly. The mixture was then stirred at -40 °C for 1 h and quenched with a mixture of HCl (12 N, 120 mL) and THF (280 mL). Water (200 mL) was added and the pH of the mixture was adjusted to pH 89 with solid K2CO3. The mixture was extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na2SO4, 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; CD₃OD) 7.90 (s, 1 H), 6.92 (s, 1 H), 5.64 (s, 1 H), 5.20 (s, 2 H), 3.84 (s, 3 H), 3.48 (s, 3 H); MS (ESI) m/z 198.1 [M+H]⁺.

φ [0184] Step 3: Το a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g,

0.17 mol) in THF (150 mL) was added HCl (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 78 with solid K2CO3. The pale yellow solid was collected, washed with water, and dried in vacuum oven (40 °C) ovemight to give 5-hydroxy-2-methoxyisonicotinaldehyde (17.9 g, 74.6%). *H NMR (400 MHz; DMSO) δ= 10.31 (s, 1 H), 8.03 (s, 1 H), 6.89 (s, 1 H), 3.80 (s, 3 H); MS (ESI) m/z 154.0 [M+H]⁺.

Experimental procedures for Examples:

[0185] GBT527 Préparation of 2-methoxy-5-[[2-[ 1-(2,2,2-trifluoroethyl)pyrazol-310 yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde.

[0186] GTB527 was prepared using general method B from 5-hydroxy-2methoxyisonicotinaldehyde and INT-2.

[0187] GBT576 Préparation of 2-oxo-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-315 yl]methoxy] -1 H-pyridine-4-carbaldehyde

Step 1:

[0188] To (E)-l-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-35 (dimethylamino)prop-2-en-l-one (crude, 1.03 g, 3.22 mmol, 1 eq.; INT-1) in EtOH (10 mL) was added isopropylhydrazine hydrochloride (430 mg, 3.86 mmol, 1.2 eq.). The mixture was heated at 80 °C for 2 h, cooled, added HCl (6 N, 0.5 mL), and stirred O/N. The mixture was concentrated and diluted with EtOAc (80 mL) and NaHCO3(_Sat) (10 mL) solution. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined 10 organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using EtOAc as eluent to give (2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol (500 mg, 71%) and (2-(l-isopropyl-lH-pyrazol-3-yl)pyridin-5-yl)methanol (55 mg, 25%) as pale yellow oils.

Data for 2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol: 'H NMR (400 MHz, CDCI3) δ 8.67 (dd, J = 4.7, 1.5 Hz, 1H), 8.0 (d, J= 7.8 Hz, 1H), 7.61 (d, J= 1.8 Hz, 1H), 7.39 (dd, 7 = 15 7.8, 4.8 Hz, 1H), 6.37 (d, J= 1.8 Hz, 1H), 4.67 (s, 2H), 4.55 (sep, J = 6.6 Hz 1H), 1.98-2.05 (br, 1H), 1.47 (d, J = 6.6 Hz, 6H). LRMS (M+H⁺) m/z 218.1 Data for (2-(l-isopropyl-lHpyrazol-3-yl)pyridin-5-yl)methanol: *H NMR (400 MHz, CDCI3) δ 8.62 (dd, J = 4.8, 1.6 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 7.6,4.8 Hz, 1H), 6.99 (dd, J = 8.0, 6.5 Hz, 1H), 6.07 (t, J = 7.6 Hz, 1H), 4.67 (d, J = 7.6 Hz, 2H), 4.58 (sep, J = 6.7

Hz, 1H), 1.60 (d, J= 6.7 Hz, 1H). MS (ESI) m/z 218.1 [M+H]⁺.

Step 2:

HCl

[0189] To (2-(l-iospropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol (560 mg, 2.58 mmol) in DCM (10 mL) was added SOCI2 (3.0 mL) at RT. The reaction mixture was stirred at RT for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3(chloromethyl)-2-(l -isopropyl-lH-pyrazol-5-yl)pyridine hydrochloride (700 mg) as an offwhite solid, which was used for next step without further purification.

Step 3:

[0190] A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (395 mg, 2.58 mmol, 1 eq.),

3-(chloromethyl)-2-(l-isopropyl- lH-pyrazol-5-yl)pyridine hydrochloride (700 mg, 2.58 mmol, 1 eq.), and K2CO3 (1.4 g, 10.32 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70 °C for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(1 -isopropyl- lH-pyrazol-5-yl)pyridin-

3-yl)methoxy)-2-methoxyisonicotinaldehyde (590 mg, 65%) as an off-white solid. ’H NMR (400 MHz, CDCI3) δ 10.41 (s, 1H), 8.76 (dd, J = 4.7, 1.6 Hz, 1H), 8.04 (dd, J = 7.9, 1.6 Hz,

1H), 7.90 (s, 1H), 7.61 (d, J= 1.8 Hz, 1H), 7.44 (dd, J= 7.9,4.8 Hz, 1H), 7.10 (s, 1H), 6.37 (d, J = 1.8 Hz, 1H), 5.14 (s, 2H), 4.65 (sep, J = 6.6 Hz, 1H), 3.91 (s, 3H), 1.49 (d, J= 6.6 Hz, 6H); MS (ESI) m/z 353.1 [M+H]⁺.

[0191] To 5-((2-(1 -isopropyl-ΙΗ-pyrazol-5-yl)pyridin-3-yl)methoxy)-2methoxyisonicotinaldehyde (590 mg) suspened in water (5.0 mL) was added HCl (6 N, 4 mL). Once the mixture tumed into a homogeneous solution, it was frezee at -78 °C to an solid and pump under high vaccum O/N. The yellow solid was continued to pump at 45 °C

for 20 h, dîssolved in water (2.0 mL), and basified to pH 11 with NaOH (2 N). The aqueous layer was washed with DCM three times and the pH of the mixture was adjusted to pH 6-7. The solid was collected and dried to give 2-oxo-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3yl]methoxy]-lH-pyridine-4-carbaldehyde as a yellow solid. *H NMR (400 MHz, CDCI3) δ 10.3 (s, 1H), 8.8 (dd, J = 4.7, 1.6 Hz, 1H), 8.1 (dd, J = 7.9, 1.5 Hz, 1H), 7.6 (s, 1H),7.5 (d, J =

1.8 Hz, 1H), 7.1 (s, 1H), 7.0 (s, 1H), 6.6 (d, J = 1.8 Hz, 1H), 4.9 (s, 2H), 4.7 (sep, J = 6.6 Hz, 1H), 1.5 (d, J = 6.6 Hz, 6H); MS (ESI) m/z 339.4 [M+H]⁺.

[0192] GBT779 Préparation of 2-(2-morpholin-4-ylethoxy)-5-[[2-(2-propan-2-ylpyrazol-3yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde

[0193] GTB779 was prepared according to general method B from 5-hydroxy-2-(2morpholinoethoxy)isonicotinaldehyde and INT-4.

[0194] ’H NMR (400 MHz, Chloroform-d) δ 10.33 (s, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 7.95 (dd, J = 7.9, 1.7 Hz, 1H), 7.79 (s, 1H), 7.53 (d, J= 1.8 Hz, 1H), 7.36 (dd, J= 7.9, 4.7

Hz, 1H), 7.04 (s, 1H), 6.28 (d, J= 1.8 Hz, 1H), 5.06 (s, 2H), 4.57 (s, 0H), 4.32 (t, J= 5.7 Hz, 2H), 3.69 - 3.62 (m, 4H), 2.70 (t, J= 5.7 Hz, 2H), 2.53 - 2.45 (m, 4H), 1.41 (d, J= 6.6 Hz, 6H); MS (ESI) m/z 452 [M+H]⁺.

[0195] GBT832 Préparation of 2-(2-methoxyethoxy)-5-[[2-[2-(2,2,2trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde.

[0196] GTB832 was prepared according to general method B from 5-hydroxy-2-(2methoxyethoxy)isonicotinaldehyde (INT-5) and INT-2.

[0197] ’H NMR (400 MHz, CDC1₃) δ 10.32 (s, IH), 8.67 (dd, J = 4.8, 1.6 Hz, IH), 7.97 (dd, J = 7.9, 1.5 Hz, IH), 7.87 (s, IH), 7.59 (d, J = 1.9 Hz, IH), 7.38 (dd, J = 7.9,4.8 Hz, IH),

7.11 (s, IH), 6.47 (d, J = 1.9 Hz, IH), 5.17 (q, J = 8.6 Hz, 2H), 5.10 (s, 2H), 4.39 - 4.32 (m,

2H), 3.70 - 3.63 (m, 2H); MS (ESI) m/z 437 [M+H]⁺.

[0198] GBT835 Préparation of 6-methyl-3-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3yl] pyridin-3 -yl] methoxy] pyridine-2-carbaldehyde

[0199] GTB835 was prepared according to general method B from 3-hydroxy-6methylpicolinaldehyde and INT-2.

[0200] 'H NMR (400 MHz, CDC1₃) δ 10.23 (s, IH), 8.64 (dd, J = 4.7, 1.6 Hz, IH), 8.16 (dd, J = 7.9, 1.5 Hz, IH), 7.61 (d, J = 1.9 Hz, IH), 7.38 (dd, J = 7.9,4.8 Hz, IH), 7.21 (d, J =

8.6 Hz, IH), 7.10 (d, J = 8.6 Hz, IH), 6.47 (d, J = 1.9 Hz, IH), 5.19 (q, J = 8.6 Hz, 2H), 5.12 (d, J = 6.1 Hz, 2H), 2.51 (s, 3H); MS (ESI) m/z 377 [M+H]⁺.

[0201] GBT836 Préparation of 6-methyl-3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3yl]pyridin-3-yl]methoxy]pyridine-2-carbaldehyde

[0202] GTB836 was prepared according to general method B from 3-hydroxy-6methylpicolinaldehyde and INT-3.

[0203] ’H NMR (400 MHz, CDC1₃) δ 10.31 (s, IH), 8.75 (dd, J = 4.7, 1.7 Hz, IH), 8.27 (dd, J = 7.9, 1.6 Hz, IH), 7.62 (d, J = 1.9 Hz, IH), 7.49 (dd, J = 7.9, 4.8 Hz, IH), 7.33 (d, J = 8.6 Hz, IH), 7.24 (d, J = 8.6 Hz, IH), 6.46 (d, J = 1.9 Hz, IH), 5.18 (s, 2H), 4.61 -4.44 (m,

2H), 2.96 - 2.75 (m, 2H), 2.62 (s, 3H); MS (ESI) m/z 391 [M+H]⁺.

[0204] GBT839 Préparation of 3-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3yl] methoxy] pyridine-2-carbaldehyde

[0205] GTB839 was prepared according to general method B from 3hydroxypicolinaldehyde and INT-2.

[0206] 'H NMR (400 MHz, CDC1₃) δ 10.26 (s, IH), 8.65 (dd, J = 4.7, 1.5 Hz, IH), 8.38 (dd, J = 4.4, 1.0 Hz, IH), 8.19 (dd, J = 7.9, 1.0 Hz, IH), 7.61 (d, J = 1.9 Hz, IH), 7.43 - 7.33 (m, 2H), 7.21 (d, J = 8.6 Hz, IH), 6.48 (d, J = 1.9 Hz, IH), 5.19 (q, J = 8.6 Hz, 2H), 5.15 (s, 2H); MS (ESI) m/z 363.1 [M+H]⁺.

[0207] GBT840 Préparation of 3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3yl]methoxy]pyridine-2-carbaldehyde

[0208] GTB839 was prepared according to general method B from 3hydroxypicolinaldehyde and INT-3.

[0209] *H NMR (400 MHz, CDC1₃) δ 10.24 (s, 1H), 8.66 (dd, J = 4.7, 1.6 Hz, 1H), 8.39 (dd, J = 4.5, 1.1 Hz, 1H), 8.21 (dd, J = 7.9, 1.6 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.44-7.37 (m, 2H), 7.26 (d, J = 8.5 Hz, 1H), 6.37 (d, J = 1.9 Hz, 1H), 5.13 (s, 2H), 4.49 - 4.40 (m, 2H),

2.87 - 2.64 (m, 2H); MS (ESI) m/z 377.1 [M+H]⁺.

[0210] GBT841 Préparation of 3-chloro-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3yl] methoxy] pyridine-4-carbaldehyde.

[0211] GTB841 was prepared according to general method B from 3-chloro-510 hydroxyisonicotinaldehyde and INT-4.

[0212] ’H NMR (400 MHz, CDC1₃) δ 10.51 (s, 1H), 8.77 (dd, J = 4.7, 1.6 Hz, 1H), 8.41 (s,

1H), 8.28 (s, 1H), 8.13 (dd, J = 7.9, 1.5 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.47 (dd, J = 7.9,

4.8 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 5.23 (s, 2H), 4.66 (sep, J = 6.6 Hz, 1H), 1.49 (d, J = 6.6

Hz, 6H); MS (ESI) m/z 357 [M+H]⁺.

[0213] GBT844 Préparation of 3-chloro-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde.

[0214] GTB844 was prepared according to general method B from 3-chloro-5hydroxyisonicotinaldehyde and INT-2.

[0215] *H NMR (400 MHz, CDC1₃) δ 10.43 (s, 1H), 8.67 (dd, J = 4.7, 1.5 Hz, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.06 (dd, J = 7.9, 1.3 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 7.9,

4.8 Hz, 1H), 6.47 (d, J = 1.9 Hz, 1H), 5.21 - 5.10 (m, 4H); MS (ESI) m/z 397 [M+H]⁺.

[0216] GBT860 Préparation of tert-butyl 4-(((4-formyl-6-methoxypyridin-3yl)oxy)methyl)-5-( 1 -isopropyl-1 H-pyrazol-5-yl)-3,6-dihydropyridine-1 (2H)-carboxylate

[0217] Step 1 : To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-l,4-dicarboxylate (2.0g, 7.37 mmol) in DCM (45 mL) was added DIPEA (1.54 ml, 8.84 mmol) and Tf₂O (1.36 mL, 8.11 mmol) at -78 °C, then the température was warmed up to room température and the solution was stirred at RT for 1.5 h, the mixture was diluted with DCM (100 mL), organic layer was washed with Sat. NaHCO₃, brine, dried and concentrated to give 1-(tert-butyl) 4ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-l,4(2H)-dicarboxylate, which was used for next step without purification.

OTf O

PddppfCI₂

[0218] Step 2: To a solution of 1-tert-butyl 4-ethyl 3-(((trifluoromethyl)sulfonyl)oxy)-5,6dihydropyridine-l,4(2H)-dicarboxylate (1.49 g, 3.7 mmol) and (1-isopropyl-lH-pyrazol-5yl)boronic acid (0.57 g, 3.7 mmol) in dioxane (10 mL) was added Pd(dppf)Cl₂ (0.27 g, 0.37 mmol) and a solution of sodium carbonate (1.18g, 11.10) in water (3 ml), the mixture was degased with N₂ for 5 min, and was heated at 100 °C for 15 h, after cooling to room température the mixture was diluted with EtOAc and washed with Sat. NaHCÛ3 and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=3:l) to give desired product 830 mg (62%).

[0219] Step 3: To a solution of 1-(tert-butyl) 4-ethyl 5-(l-isopropyl-lH-pyrazol-5-yl)-3,6dihydropyridine-l,4(2H)-dicarboxylate (450 mg, 1.24 mmol) in THF (6 mL) was added LiAlH₄ (IM in THF, 1.49 mL, 1.49 mmol) at -20 °C, the reaction was stirred at -20 °C for 30 min, and was quenched with Sat. NH4CI, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc= 100:0 to 40:60) to give tert-butyl 4(hydroxymethyl)-5-( 1 -isopropyl-1 H-pyrazol-5-yl)-3,6-dihydropyridine-1 (2H)-carboxylate (370 mg, 91%).

PPh₃Br₂

[0220] Step 4: To a solution of give tert-butyl 4-(hydroxymethyl)-5-(l-isopropyl-1Hpyrazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (25 mg, 0.08 mmol) in DCM (1 mL) was added triphenylphosphine bromine adduct (40 mg, 0.09 mmol) at room température, after stirring for 30 min, it was diluted with DCM, washed with Sat. NaHCO3, brine, dried and concentrated to give crude product, which was purified by column to give tert-butyl 4(bromomethyl)-5-( 1 -isopropyl-1 H-pyrazol-5-yl)-3,6-dihydropyridine-1 (2H)-carboxylate (18 mg).

[0221] Step 5: To a solution of tert-butyl 4-(bromomethyl)-5-(l-isopropyl-lH-pyrazol-5yl)-3,6-dihydropyridine-l(2H)-carboxylate (18 mg, 0.05 mmol) and 5-hydroxy-2methoxyisonicotinaldehyde (10 mg, 0.06 mmol) in DMF (1 mL) was added K2CO3 (14 mg,

0.1 mmol). After stirred at room température for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concetrated to give crude product, which was purified by column (Hexanes/EtOAc=2:l) to give tert-butyl 4-(((4-formyl-6-methoxypyridin3-yl)oxy)methyl)-3-( 1 -isopropyl-1 H-pyrazol-5-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (7.2 mg). IH NMR (400 MHz, CDC1₃) (ppm) 10.39 (s, IH), 7.79 (s, IH), 7.56 (d, J= 1.6 Hz,

IH), 7.05(s, IH), 6.11 (d, J=1.6 Hz, IH), 4.40 (s, 2H), 4.38 (m, IH), 4.01 (s, 2H), 3.88 (s, 3H), 3.66 (bs, 2H), 2.46 (bs, 2H), 1.48 (s, 9H), 1.43 (d, 6.4 Hz, 6H). MS (ESI) m/z 457.3 [M+H]⁺.

[0222] GBT861 Préparation of 2-hydroxy-6-((5-(l-isopropyl-ΙΗ-p yrazol-5-yl)-3,615 dihydro-2H-pyran-4-yl)methoxy)benzaldehyde

φ [0223] Stepl : Το a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (1.0 g, 5.81 mmol)in DCM (30 mL) was added DIPEA (1.22 mL, 6.97 mmol) and Tf20 (1.08 mL, 6.39 mmol) at -78 °C, then it was warmed up to room température and stirred at room temeperature for 2 h, the solution was diluted with DCM, washed with Sat. NaHCO3, brine, dried and concentrated to give ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2Hpyran-4-carboxylate as crude product (2 g).

OTf O

PddppfCI2

Na₂CO₃

[0224] Step 2: To a solution of ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2Hpyran-4-carboxylate (crude from step 1) and l-isopropyl-5-(4,4,5,5-tetramethyl-l,3,210 dioxaborolan-2-yl)-lH-pyrazole (1.37 g, 5.82 mmol) in dioxane (20 ml) was added Pd(dppf)Cl₂ (430 mg, 0.58 mmol) and Na₂CO3 (1.85 g, 17.46 mmol) in water (6 mL), the mixture was degased with N2 for 5 min, and was heated at 100 °C for 15 h, after cooling to room température the mixture was diluted with EtOAc and washed with Sat. NaHCO₃ and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=3:1 ) to give ethyl 5-( 1 -isopropyl-1Hpyrazol-5-yl)-3,6-dihydro-2H-pyran-4-carboxylate (850 mg).

[0225] Step 3: To a solution of ethyl 5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydro-2Hpyran-4-carboxylate (600 mg, 2.27 mmol) in THF (10 mL) was added L1AIH4 (IM in THF,

2.72 mL, 2.72 mmol) at -20 °C, the reaction was stirred at -20 °C for 30 min, and was quenched with Sat. NH₄C1, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc= 100:0 to 20:80) to give (5-(l-isopropyl-lH-pyrazol-5yl)-3,6-dihydro-2H-pyran-4-yl)methanol (500 mg).

PPh₃Br₂

[0226] Step 4: To a solution of (5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4yl)methanol (300 mg, 1.35 mmol) in DCM (5 mL) was added dibromotriphenylphosphorane (630 mg, 1.35 mmol) at room température, after stirring for 30 min, it was diluted with DCM, 5 organic layer was washed with Sat. NaHCO₃, brine, dried and concentrated to give crude product, which was purified by column(Hexanes/EtOAc= 4:1) to give 5-(4-(bromomethyl)5,6-dihydro-2H-pyran-3-yl)-l-isopropyl-lH-pyrazole (360 mg).

OH O

K2CO3

DMF

69%

[0227] Step 5: To a solution of 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-l10 isopropyl-lH-pyrazole (110 mg, 0.38 mmol) and 2,6-dihydroxybenzaldehyde (100 mg, 0.76 mmol) in DMF (6 mL) was added K2CO3 (110 mg, 0.76 mmol). After stirred at room température for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc. Organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=l: 1) to give 2-hydroxy-6-((5-(l-isopropyl-lH-pyrazol-5-yl)-3,6-dihydro2H-pyran-4-yl)methoxy)benzaldehyde (90 mg). IH NMR (400 MHz, CDC1₃) δ (ppm) 11.89 (s, IH), 10.33 (s, IH), 7.53 (d, J= 1.6 Hz, IH), 7.33(t, J=8.8 Hz, IH), 6.51 (d, J=8.8 Hz, IH),

6.16 (d, J=8.0 Hz, IH), 6.08 (d, J=2.0 Hz, IH), 4.40 (dd, J = 12.8, 6.4 Hz, IH), 4.35 (s, 2H), 4.18 (s, 2H), 3.97 (t, J=5.2 Hz, 2H), 2.44 (s, 2H), 1.40 (d, J=6.4 Hz, 6H); MS (ESI) m/z 343.3

[M+H]⁺.

[0228] GBT863 Préparation of 2-methoxy-5-[[5-(2-propan-2-ylpyrazol-3-yl)-3,6-dihydro2H-pyran-4-yl]methoxy]pyridine-4-carbaldehyde

[0229] To a solution of 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-l-isopropyl- 1Hpyrazole (50 mg, 0.19 mmol) (see the synthesis of GBT861) and 5-hydroxy-25 methoxyisonicotinaldehyde (30 mg, 0.23 mmol) in DMF (1 mL) was added K2CO3 (50 mg, 0.38 mmol). After stirred at room température for 3 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concetrated to give crude product, which was purified by column (Hexanes/EtOAc=l:l) to give 5-((5-(l-isopropyl-lH-pyrazol-5-yl)-3,610 dihydro-2H-pyran-4-yl)methoxy)-2-methoxyisonicotinaldehyde (26 mg). 1H NMR (400 MHz, CDCI3) δ (ppm) 10.40 (s, 1H), 7.81 (s, 1H), 7.54 (d, J= 1.6 Hz, 1H), 7.05 (s, 1H), 6.08 (d, J=1.6 Hz, 1H), 4.42 (s, 2H), 4.40 (m, 1H), 4.19 (s, 2H), 3.98 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 2.47 (s, 2H), 1.41 (d, J=6.8 Hz, 6H); MS (ESI) m/z 358.4 [M+H]⁺.

[0230] GBT864 Préparation of 6-methyl-3-[[5-(2-propan-2-ylpyrazol-3-yl)-3,6-dihydro15 2H-pyran-4-yl]methoxy]pyridine-2-carbaldehyde

[0231] To a solution of 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-l-isopropyl-1Hpyrazole (50 mg, 0.19 mmol) (see the synthesis of GBT861) and 3-hydroxy-6methylpicolinaldehyde (30 mg, 0.24 mmol) in DMF (1 mL) was added K2CO3 (50 mg, 0.38 mmol). After stirred at room température for 3 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=40:60) to give 5-((5-(l-isopropyl-lH-pyrazol-5-yl)-3,6dihydro-2H-pyran-4-yl)methoxy)-2-methoxyisonicotinaldehyde (37 mg). IH NMR (400

MHz, CDCI3) δ (ppm) 10.30 (s, IH), 7.54 (d, J= 1.6 Hz, IH), 7.24 (d, J= 8.4 Hz, IH), 7.09 (d, J=9.2 Hz, IH), 6.08 (d, J=2.0 Hz, IH), 4.42 (m, IH), 4.38 (s, 2H), 4.18 (s, 2H), 3.98 (t, J=5.6 Hz, 2H), 2.56 (s, 3H), 2.51 (s, 2H), 1.39 (d, J=6.4 Hz, 6H); MS (ESI) m/z 342.4 [M+H]⁺.

[0232] GBT867 Préparation of 2-hydroxy-6-[(5-phenyl-3,6-dihydro-2H-pyran-4yl)methoxy]benzaldehyde

OTf O

PddppfCI₂

Na₂CO₃

[0233] Step 1: To a solution of ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2Hpyran-4-carboxylate (1.77 g, 5.81 mmol) and phenylboronic acid (1.42 g, 11.62 mmol) in dioxane (15 ml) was added Pd(dppf)C12 (430 mg, 0.58 mmol) and Na2CÜ3 (1.85 g, 17.46 mmol) in water (4.5 mL), the mixture was degased with N2 for 5 min, and was heated at 100 °C for 15 h, after cooling to room température the mixture was diluted with EtOAc and washed with Sat. NaHCO3 and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=4:l) to give ethyl 5-phenyl-3,6-dihydro-2H-pyran-4-carboxylate (1.05 g, 78%).

[0234] Step 2: To a solution of ethyl 5-phenyl-3,6-dihydro-2H-pyran-4-carboxylate (1.05 g, 4.52 mmol) in THF (20 mL) was added LÏA1H4 (IM in THF, 5.42 mL, 5.42 mmol) at -20 °C, the reaction was stirred at -20 °C for 30 min, and was quenched with Sat. NH4CI, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc= 100:0 to 35:65) to give (5-phenyl-3,6-dihydro-2H-pyran-4-yl)methanol (720 mg).

[0235] Step 3: To a solution of (5-phenyl-3,6-dihydro-2H-pyran-4-yl)methanol (360 mg, 1.89 mmol) in DCM (6 mL) was added dibromotriphenylphosphorane (880 mg, 2.08 mmol) at room température, after stirring for 30 min, it was diluted with DCM, organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give crude product, which was purified by column(Hexanes/EtOAc= 9:1) to give 4-(bromomethyl)-5-phenyl-3,6-dihydro2H-pyran (380 mg).

100

[0236] Step 4: To a solution of 4-(bromomethyl)-5-phenyl-3,6-dihydro-2H-pyran (110 mg, 0.45 mmol) and 2,6-dihydroxybenzaldehyde (120 mg, 0.90 mmol) in DMF (3 mL) was added K2CO3 (120 mg, 0.90 mmol). After stirred at room température for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc. Organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=3:l) to give 2-hydroxy-6-((5phenyl-3,6-dihydro-2H-pyran-4-yl)methoxy)benzaldehyde (120 mg). 1H NMR (400 MHz, CDCI3) δ (ppm) 11.92 (s, 1H), 10.36 (s, 1H), 7.35 (m, 4H), 7.18 (m, 2H), 6.49 (d, J=8.0 Hz,

1H), 6.13 (d, J=8.0 Hz, 1H), 4.48 (s, 2H), 4.32 (s, 2H), 3.95 (t, J=5.6 Hz, 2H), 2.41 (m, 2H);

MS (ESI) m/z 309.

[0237] GBT868 Préparation of 3-methoxy-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde

[0238] To a solution of 3-hydroxy-5-methoxyisonicotinaldehyde (0.13 g, 0.88 mmol) in DMF was added 3-(chloromethyl)-2-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl)pyridine (0.24 g, 0.88 mmol) (INT-2) and potassium carbonate (0.49 g, 3.52 mmol) and the reaction mixture

101 was heated (60 °C). After 3 hours, the reaction mixture was filtered through a plug of silica (MeOH/CfLCL, 0-20%). Purification of the resulting residue by Prep-HPLC, provided 2methoxy-6-((2-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (12 mg, 5% yield). ’H NMR (400 MHz, Chloroform-d) δ 10.54 (s, 1H), 8.71 (dd, J = 5.0, 1.8 Hz, 1H), 8.23 (s, 1H), 8.21 (ddd, J = 7.9, 1.7, 0.7 Hz, 1H), 8.10 (s, 1H), 7.67 (dd, J= 1.9, 0.5 Hz, 1H), 7.46 (dd, J= 8.0, 4.5 Hz, 1H), 7.26 (d, J = 0.5 Hz, 3H), 6.56 (dd, J= 1.9, 0.5 Hz, 1H), 5.23 (s, 2H), 5.28 - 5.15 (m, 2H), 4.04 (s, 3H); MS (ESI) m/z 393 [M+H]⁺.

[0239] GBT870 Préparation of 2-methoxy-5-[[2-(2-methoxyphenyl)pyridin-3yl]methoxy]pyridine-4-carbaldehyde

[0240] Step 1 : Into a 50-mL round-bottom flask, was placed a solution of (2-chloropyridin3-yl)methanol (500 mg, 3.48 mmol, 1.00 equiv) in a solvent mixture of dioxane and H₂O (10/10 mL). (2-Methoxyphenyl)boronic acid (532 mg, 3.50 mmol, 1.20 equiv), sodium bicarbonate (882 mg, 10.50 mmol, 3.00 equiv), and Pd(dppf)C12 (286 mg, 0.39 mmol, 0.10 equiv) were added to the reaction mixture. The resulting solution was stirred for 2 h at 100°C, and then it was diluted with 100 mL of H₂O. The resulting solution was extracted with 2x100 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent to fumish 650 mg (87%) of [2-(2-methoxyphenyl)pyridin-3-yl]methanol as a yellow solid.

[0241] Step 2: Into a 50-mL round-bottom flask, was placed a solution of [2-(2methoxyphenyl)pyridin-3-yl]methanol (600 mg, 2.79 mmol, 1.00 equiv) in thionyl chloride (10 mL). The resulting solution was heated to reflux for 2 hr, and then it was concentrated under vacuum. This resulted in 600 mg (92%) of 3-(chloromethyl)-2-(2methoxyphenyl)pyridine as a yellow solid.

102

[0242] Step 3: Into a 100-mL round-bottom flask, was placed a solution of 3 (chloromethyl)-2-(2-methoxyphenyl)pyndine (306 mg, 1.31 mmol, 1.00 equiv) in CH3CN (20 mL). 5-Hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), potassium carbonate (364 mg, 2.63 mmol, 2.00 equiv), and Kl (44 mg, 0.27 mmol, 0.20 equiv) were added to the reaction mixture. The resulting solution was stirred for 5 h at 60°C, and then it was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5um, 19*150mm,; mobile phase, water with 0.1%HCOOH and MeCN (10.0% MeCN up to 40.0% in 10 min, up to 95.0% in 2 min, down to 10.0% in 2 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 65 mg (9%) of 2-methoxy-5-[[2-(2methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid. The compound exhibited a melting point of 105-107°C. ¹HNMR(300MHz, CDCI3) δ 10.32 (s, 1H), 8.69 (s, 1H), 7.93 (m, 2H), 7.36(m, 3H), 6.99 (m, 3H), 5.35 (s, 2H),3.86(m, 6H); MS (ESI) m/z 351 [M+H]⁺.

[0243] GBT871 Préparation of 2-methoxy-5-[[2-(3-methoxyphenyl)pyridin-3yl]methoxy]pyridine-4-carbaldehyde

[0244] Step 1 : Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphère of nitrogen, was placed a solution of (3-methoxyphenyl)boronic acid (1.6 g, 10.53 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv), Pd(dppf)C12 (0.57 g, 0.10 equiv) in a solvent mixture of dioxane (10 mL) and water(10 mL). The resulting solution was stirred for

1.5 h at 100°C, and then it was diluted with 20 mL of H2O. The resulting solution was extracted with 2x50 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum

103 ether (1:50-1:1) as eluent to yield 1.3 g (87%) of [2-(3-methoxyphenyl)pyridin-3-yl]methanol as a colorless oil.

[0245] Step 2: Into a 50-mL round-bottom flask, was placed a solution of [2-(3methoxyphenyl)pyridin-3-yl]methanol (1 g, 4.65 mmol, 1.00 equiv) in thionyl chloride (20 mL). The resulting solution was stirred for 2 h at reflux. The resulting mixture was concentrated under vacuum to fumish 600 mg (55%) of 3-(chloromethyl)-2-(3methoxyphenyl)pyridine as a white solid.

[0246] Step 3: Into a 100-mL round-bottom flask, was placed a solution of 3(chloromethyl)-2-(3-methoxyphenyl)pyridine (234 mg, 1.00 mmol, 1.00 equiv), 5-hydroxy-2methoxypyridine-4-carbaldehyde (153 mg, 1.00 mmol, 1.00 equiv), and potassium carbonate (278 mg, 2.01 mmol, 2.00 equiv) in CH3CN (30 mL). The resulting solution was stirred for 4 h at 70°C, and then it was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column,5um, 19* 150mm,; mobile phase, water with 0.1%TFA and MeCN (20% MeCN up to 40% in 10 min, up to 95% in 2 min, down to 20% in 1 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 100.8 mg (17%) of 2-methoxy-5-[[2-(3methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid.

’HNMR(300MHz, DMSO-îZô) δ 10.01(s, 1H), 8.65 (m, 1H), 8.39(s, 1H), 8.10(m, 2H), 7.57 (d, J= 9Hz, 2H), 7.42 (m, 1H), 6.97 (m, 3H), 5.33 (s, 2H) 3.80 (m, 6H); MS (ESI) m/z 351 [M+H]⁺.

[0247] GBT874 Préparation of 2-hydroxy-6-[(l-methyl-5-phenyl-3,6-dihydro-2H-pyridin-

4-yl)methoxy]benzaldehyde

4M HCl

Dioxane

104

[0248] Step 1: To a solid of tert-butyl 4-(hydroxymethyl)-3-phenyl-5,6-dihydropyridinel(2H)-carboxylate (300 mg, 1.04 mmol) in round bottom flask was added 4N HCl in dtoxane (6 mL) at room température, after stirring for 1 h, the mixture was concentrated and dried under high vacuum to give (5-phenyl-l,2,3,6-tetrahydropyridin-4-yl)methanol as HCl sait.

HCHO

NaB(OAc)₃H AcCN

[0249] Step 2: To a solution of (5-phenyl-l,2,3,6-tetrahydropyridin-4-yl)methanol hydrochloride (230 mg, 1.04 mmol) in ACN (10 mL) was added Et₃N (0.15 mL, 1.04 mmol) followed by formalin (340 mg, 4.16 mmol). After stirred at room température for 10 min, it was added Na(OAc)₃BH (440 mg, 2.08 mmol) and was stirred for 30 min, the mixture was concentrated to remove most of the ACN, and the residue was diluted with CHC1₃, organic layer was washed with Sat. NaHCO₃, brine, dried and concentrated to give crude product, which was purified by column (DCM/MeOH=9:l) to give (l-methyl-5-phenyl-l,2,3,6tetrahydropyridin-4-yl)methanol (140 mg).

[0250] Step 3: To a solution of (l-methyl-5-phenyl-1,2,3,6-tetrahydropyridin-4yl)methanol (130 mg, 0.64 mmol) in DCM (4 mL) was added SOCI2 (1.16 mL, 16 mmol) at room température, after stirred at room température for 30 min, the mixture was concentrated, dried under high vacuum to give 4-(chloromethyl)-l-methyl-5-phenyl-l,2,3,6tetrahydropyridine as crude HCl sait.

OH O

K₂CO₃

DMF °C

105

[0251] Step 4: To a suspension of K2CO3 (350 mg, 2.56 mmol) and 2,6 dihydroxybenzaldehyde (180 mg, 1.28 mmol) in DMF (3 ml) was added a solution of 4(chloromethyl)-l-methyl-5-phenyl-l,2,3,6-tetrahydropyridine (140 mg, 0.64 mmol) in DMF (4 mL), the mixture was heated at 50 °C for 3 h, cooled to room température, and was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO3, brine, dried over Na₂SO4, and was concentrated to give crude oil, which was purified by column (Hexane/EtOAc= 1:1 followed by DCM/MeOH= 90:10) to give 2-hydroxy-6-((l-methyl-5-phenyl-l,2,3,6-tetrahydropyridin4-yl)methoxy)benzaldehyde (55 mg). IH NMR (400 MHz, CDCI3) δ (ppm) 11.92 (s, IH), 10.35 (s, IH), 7.34 (m, 5H), 7.19 (dd, J = 8.4,8.0 Hz, IH), 6.46 (d, J = 8.4 Hz, IH), 6.16 (d, J = 8.0 Hz, IH), 4.45 (s, 2H), 3.20 (s, 2H), 2.68 (t, J = 5.6 Hz, 2H), 2.47 (m, 2H), 2.42 (s, 3H); MS (ESI) m/z 324.3 [M+H]⁺.

[0252] GBT875 Préparation of 2-methoxy-5-[[2-(4-methoxyphenyl)pyridin-3yl]methoxy]pyridine-4-carbaldehyde

[0253] Step 1: Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphère of nitrogen, was placed a solution of (4-methoxyphenyl)boronic acid (1.6 g, 10.53 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv), Pd(dppf)Cl₂ (0.57 g, 0.10 equiv) in a solvent mixture of dioxane (10 mL) and water(10 mL). The resulting solution was stirred for

1.5 h at 100°C, and then it was diluted with 20 mL of H₂O. The resulting solution was extracted with 2x50 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50-1:1) as eluent to fumish 1 g (67%) of [2-(4-methoxyphenyl)pyridin-3-yl]methanol as a colorless oil.

106

[0254] Step 2: Into a 50-mL round-bottom flask, was placed a solution of [2-(4- methoxyphenyl)pyridin-3-yl]methanol (1 g, 4.65 mmol, 1.00 equiv) in thionyl chloride (20 mL). The resulting solution was stirred for 2 h at reflux. The resulting mixture was concentrated under vacuum to yield 600 mg (55%) of 3-(chloromethyl)-2-(4methoxyphenyl)pyridine as a white solid.

[0255] Step 3: Into a 50-mL round-bottom flask, was placed a solution of 3(chloromethyl)-2-(2-methoxyphenyl)pyridine (234 mg, 1.00 mmol, 1.00 equiv), 5-hydroxy-2methoxypyridine-4-carbaldehyde (153 mg, 1.00 mmol, 1.00 equiv), and potassium carbonate (278 mg, 2.01 mmol, 2.00 equiv) in CH3CN (20 mL). The resulting solution was stirred for 4 h at 70°C, and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column,5um,19*150mm; mobile phase, water with 0.1%TFA and MeCN (20.0% MeCN up to 50.0% in 10 min, up to 95.0% in 2 min,down to 20.0% in 1 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 265.1 mg (46%) of 2methoxy-5-[[2-(4-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a brown oil.

‘HNMR^OOMHz, DMSO-J₆) δ 10.08(s, 1H), 8.69 (m, 1H), 8.15(m, 2H), 7.50(m, 1H), 7.37(m, 1H), 7.18(m, 2H), 7.16(m, 1H), 6.99(m, 1H), 5.34(s, 2H), 3.86(s, 3H), 3.77(s, 3H); MS (ESI) m/z 351 [M+H]⁺.

[0256] GBT877 Préparation of 5-[[2-(2-chlorophenyl)pyridin-3-yl]methoxy]-2methoxypyridine-4-carbaldehyde

107

[0257] Step 1 : Into a 50-mL round-bottom flask, was placed a solution of (2 chlorophenyl)boronic acid (1.6 g, 10.23 mmol, 1.20 equiv), (2-chloropyndin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), Pd(dppf)C12 (570 mg, 0.78 mmol, 0.10 equiv), and sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water(10 mL). The resulting solution was stirred for 3 h at 70°C, and then it was diluted with 20 mL of H2O. The resulting solution was extracted with 2x20 mL of dichloromethane, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:5) as eluent to fumish 1 g (65%) of [2-(2-chlorophenyl)pyridin-3-yl]methanol as a white solid.

[0258] Step 2: Into a 25-mL round-bottom flask, was placed a solution of [2-(2chlorophenyl)pyridin-3-yl]methanol (1 g, 4.55 mmol, 1.00 equiv) in thionyl chloride (5 mL). The resulting solution was stirred for 1 h at reflux. The resulting mixture was concentrated under vacuum to yield 1 g (92%) of 3-(chloromethyl)-2-(2-chlorophenyl)pyridine as a white solid.

[0259] Step 3: Into a 50-mL round-bottom flask, was placed a solution of 3(chloromethyl)-2-(2-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmol, 1.50 equiv) in CH3CN (20 mL). The resulting solution was stirred for 4 h at 70°C, and then it was concentrated under vacuum. The residue was purified by prepHPLC. This resulted in 86.2 mg (11%) of 5-[[2-(2-chlorophenyl)pyridin-3-yl]methoxy]-2methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a brown oil.

*HNMR(300MHz, DMSO-J₆) δ 10.06(s, 1H), 8.69 (m, 1H), 8.19(m, 1H), 8.05(s, 1H), 7.56(m, 2H), 7.41(m, 3H), 6.92(s, 1H), 5.14(m, 2H), 3.81(s, 3H); MS (ESI) m/z 355 [M+H]⁺.

[0260] GBT878 Préparation of 2-[(l-acetyl-5-phenyl-3,6-dihydro-2H-pyridin-4yl)methoxy]-6-hydroxybenzaldehyde

ΌΗ

108

Et3N

Ac2O

[0261] Step 1 : To a solution of (5-phenyl-l,2,3,6-tetrahydropyridin-4-yl)methanol hydrochloride (90 mg, 0.38 mmol) in DCM (2 mL) at 0 °C was added Et3N (0.11 mL, 0.76 mmol) and a solution of Ac2O (0.04 mL, 0.38 mmol) in DCM (0.4 mL), after stirred for 15 min, it was diluted with Sat. NH4CI and EtOAc, organic layer was separated and the aqueous layer was further extracted with EtOAc, organic layers were combined, washed with Sat. NaHCO₃, brine, dried over Na₂SO₄, and was concentrated to give l-(4-(hydroxymethyl)-5phenyl-3,6-dihydropyridin-l(2H)-yl)ethan-l-one as crude product (95 mg).

[0262] Step 2: To a solution of l-(4-(hydroxymethyl)-3-phenyl-5,6-dihydropyridin-l(2H)yl)ethanone (86 mg, 0.37 mmol) in DCM (2 mL) was added SOC1₂ (0.67 mL, 9.25 mmol). After stirred at RT for 15 min, the mixture was concentrated and was diluted with Sat. NaHCO3 and EtOAc, organic layer was separated and the aqueous layer was extracted with EtOAc, organic layer ere combined, washed with brine, dried and concentrated to give crude oil, which was purifed by column ( Hexanes/EtOAc= 100:0 to 25:75) to give l-(4(chloromethyl)-5-phenyl-3,6-dihydropyridin-1 (2H)-yl)ethan- 1-one (35 mg).

[0263] Step 3: To a suspension of K₂CO₃ (40 mg, 0.28 mmol) and 2,6dihydroxybenzaldehyde (40 mg, 0.28 mmol) in DMF (1 mL) was added a solution of l-(420 (chloromethyl)-5-phenyl-3,6-dihydropyridin-l(2H)-yl)ethan- 1-one (35 mg, 0.14 mmol) in

DMF (1 mL), the mixture was heated at 50 °C for 3 h, cooled to room température, and was

109 diluted with EtOAc, organic layer was separated and aqueous layer was extracted with

EtOAc. EtOAc layers were combined, washed with Sat. NaHCO₃, brine, dried over Na₂SO₄, and was concentrated to give crude oil, which was purified by column (DCM/MeOH= 90:10) to give 2-(( l-acetyl-5-phenyl-l ,2,3,6-tetrahydropyridin-4-yl)methoxy)-6hydroxybenzaldehyde (17 mg). 1H NMR (400 MHz, CDC1₃, NMR shows rotamer exist, only one set of signal was reported) □ (ppm) 11.93 (s, 1H), 10.36 (s, 1H), 7.34 (m, 5H), 7.22 (m, 1H), 6.49 (d, J = 8.8 Hz, 1H), 6.10 (d, J = 8.8 Hz, 1H), 4.47 (s, 2H), 4.32 (s, 2H), 3.68 (t, J = 6.0 Hz, 2H), 2.47 (m, 2H), 2.18 (s, 3H); MS (ESI) m/z 352.5 [M+H]⁺.

[0264] GBT881 Préparation of 2-[(l-acetyl-4-phenyl-3,6-dihydro-2H-pyridin-5yl)methoxy]-6-hydroxybenzaldehyde

[0265] Step 1 : To a solution of 1-tert-butyl 3-methyl 4-oxopiperidine-l,3-dicarboxylate (2.50 g, 9.72 mmol) in DCM (50 mL) was added DIPEA (2.03 mL, 11.66 mmol) and Tf₂O (1.80 mL, 10.69 mmol) at -78 °C, and then it was warmed up to room température and stirred further for 2 h, the solution was diluted with DCM and the organic layer was washed with Sat. NaHCO₃, dried and concentrated to give 1-tert-butyl 3-methyl 4(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l,3(2H)-dicarboxylate as crude product (4.4 g).

B(OH)₂

Pd(dppf)CI2

----►

Na₂CO₃

[0266] Step 2: To a solution of 1-tert-butyl 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)5,6-dihydropyridine-l,3(2H)-dicarboxylate (1.95 g, 5 mmol) and phenylboronic acid (1.22 g,

110 mmol) in Dîoxane (20 ml) was added Pd(dppf)C12 and a solution of Na2CC>3 (3.18 g, 30 mmol) in water (6 mL), after degassed with N2 for 5 mm, the reaction was heated at 100 °C for 15 h, the mixture was cooled to room temeprature, diluted with EtOAc, organic layer was washed with water, brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc= 3:1) to give 1-tert-butyl 3-methyl 4-phenyl-5,6dihydropyridine-l,3(2H)-dicarboxylate (740 mg).

[0267] Step 3: To a solution of l-tert-butyl 3-methyl 4-phenyl-5,6-dihydropyridinel,3(2H)-dicarboxylate (740 mg, 2.33 mmol) in THF (7.2 mL) was added IM L1AIH4 in THF (2.80 mL, 2.80 mmol) at -20 °C dropwise, after stirring at -20 °C for 30 min, it was quenched with Sat. NH4CI, the mixture was extracted with EtOAc. Organic layers were combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc= 60:40) to give tert-butyl 5-(hydroxymethyl)-4-phenyl-3,6dihydropyridine-l(2H)-carboxylate (512 mg).

HCl

-----------*Dioxane

[0268] Step 4: To tert-butyl 3-(hydroxymethyl)-4-phenyl-5,6-dihydropyridine-l(2H)carboxylate (510 mg, 1.76 mmol) was added 4N HCl in Dioxane (3 ml), after stirring at room température for lh, it was concentrated to give (4-phenyl-1,2,5,6-tetrahydropyridin-3yl)methanol as HCl sait.

DIPEA

AC2O

[0269] Step 5: To a solution of (4-phenyl-1,2,5,6-tetrahydropyridin-3-yl)methanol hydrochloride (110 mg, 0.49 mmol) in DCM (2 mL) was added DIPEA (0.17 mL, 0.98 mmol) and AC2O (0.05 g, 0.49 mmol), 15 min later, it was diluted with water and extracted

111 with DCM. Organic layers were combined, dried and concentrated, the resulting crude oil was purified by column (EtOAc followed by DCM/MeOH =9:1) to give l-(5(hydroxymethyl)-4-phenyl-3,6-dihydropyridin-1 (2H)-yl)ethan-1 -one (88 mg).

SOCI₂

[0270] Step 6: To a solution of l-(3-(hydroxymethyl)-4-phenyl-5,6-dihydropyridin-l(2H)yl)ethanone (88 mg, 0.38 mmol) in DCM (2 mL) was added SOC1₂ (0.67 mL, 9.50 mmol) at 0 °C. After stirring at 0 °C for 15 min, the solution was concentrated to remove SOC1₂, dried under high vacuum to give l-(5-(chloromethyl)-4-phenyl-3,6-dihydropyridin-l(2H)-yl)ethan1-one as crude product.

[0271] Step 7: To a solution of l-(3-(chloromethyl)-4-phenyl-5,6-dihydropyridin-l(2H)yl)ethanone (100 mg, 0.40 mmol)and 2,6-dihydroxybenzaldehyde (110 mg, 0.80 mmol) in DMF (2.5 mL) was added K₂CO₃ (170 mg, 1.20 mmol), after heated at 50 degree for 2 h, the reaction was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO3, brine, dried over Na₂SO₄, and was concentrated to give crude oil, which was purified by préparative HPLC (eluted with ACN/H₂O) to give 2-((1-acetyl-4-phenyl-1,2,5,6-tetrahydropyridin-3yl)methoxy)-6-hydroxybenzaldehyde (26 mg). 1H NMR (400 MHz, CDCI3, NMR shows rotamers exist, only one set of signal was reported) Ô (ppm) 11.97 (s, 1H), 10.34 (s, 1H), 7.34 (m, 4H), 7.17 (m, 2H), 6.49 (d, J = 8.0 Hz, 1H), 6.11 (d, J = 8.8 Hz, 1H), 4.48 (s, 2H), 4.33 (s, 2H), 3.69 (t, J = 6.0 Hz, 2H), 2.55 (m, 2H), 2.18 (s, 3H); MS (ESI) m/z 352.3 [M+H]⁺.

[0272] GBT887 Préparation of 2-((2-(1-cyclopentyl-lH-pyrazol-5-yl)pyridin-3yl)methoxy)-6-hydroxybenzaldehyde

112

[0273] To a mixture of 3-(chloromethyl)-2-( 1 -cyclopentyl-1 H-pyrazol-5-yl)pyridine hydrochloride (44.7mg, 0.15mmol) and 2,6-dihydroxybenzaldehyde (83mg, 0.6mmol, 4eq) and potassium carbonate (41.5mg, 0.3mmol, 2eq) were added lmL anhydrous DMF. The mixture was heated to 80 oC for 40mins. The reaction was almost done by LCMS. Solvent was removed at 50 oC on a rotavap. Water 3mL and 0.3mL of formic acid were added to the resulting brown residue, the mixture was sonicated to make sure ail carbonate was neutralized. Solvents were then reomved at 45 oC on a rotavap. DCM (4x1 ml) was added to the yellow residue, the mixture was sonicated and filtered. The filtrate was concentrated to give the crude product as a yellow-light brown film. It contains the product, 2,6dihydroxybenzaldehyde, and some starting chloride, no bis-alkylation product was observed. The residue was taken up in 2ml DCM, filtered and loaded on a 4g ZAP SiO2 column. It was purified on Biotage Isolera One System eluted with 5%-100% EtOAc (the product came out around 25% EtOAc, 2nd peak; the lst peak is dihydroxybenzaldehyde). The product as a yellow film was ontained after removing solvents, the residue was re-dissolved in 0.3mL CH3CN and to this was added 0.5mL of water. This suspension was freezed and put on a lyophilizer over the weekend. The product was obtained as a light brown film (18.6mg, 34% yield). 'H NMR (400 MHz, CDC1₃-J) δ 11.94 (s, IH), 10.37 (s, IH), 8.75 (dd, J = 4.8, 1.7

Hz, IH), 7.97 (dd, J= 8.0, 1.4 Hz, IH), 7.59 (d, J = 2.0 Hz, IH), 7.42 (dd, 7 = 7.7,4.8 Hz, IH), 7.37 (t, J =8.3 Hz, IH), 6.56 (d, J =8.6 Hz, IH), 6.35 (d,J = 1.9 Hz, IH), 6.25 (d, J = 8.3 Hz, IH), 5.07 (s, 2H), 4.79-4.67 (m, IH), 2.18 - 1.95 (m, 4H), 1.95 - 1.84 (m, 2H), 1.66 - 1.50 (m, 2H); MS (ESI) m/z 364.3 [M+H]⁺.

[0274] GBT888 Préparation of 2-hydroxy-6-[[(2S)-l-phenylpyrrolidin-225 yl]methoxy]benzaldehyde

113

[0275] Step 1: To a solution of (S)-pyrrolidin-2-ylmethanol (1.52 g, 15 mmol) and Cul (190 mg, Immol) in iPrOH (10 mL) was added (CH2OH)₂ (1.11 mL, 20 mmol), iododbenzene (2.04 g, 20 mmol) and K3PO4 (4.25 g, 20 mmol), after degassed with N2, the mixture was heated at 88 °C for 15 h. Water and ether was added , organic layer was separated and aqueous layer was further extracted with ether. Organic layers were combined, concentrated and the resulting crude oil was purified by column (hexanes/EtOAc=2:l) to give (S)-(l-phenylpyrrolidin-2-yl)methanol (1.6 g).

[0276] Step 2: To a solution of (S)-(l-phenyIpyrrolidin-2-yl)methanol (45 mg, 0.23 mmol) and 2,6-dihydroxybenzaldehyde (60 mg, 0.46 mmol) in THF (1 ml) was added PPI13 (0.12 g, 0.46 mmol), followed by DIAD (90 mg, 0.46 mmol) at room température. After stirrer for 10 min, the mixture was concentrated and the residue was purified by column (Hexanes/EtOAc= 9:1) to give (S)-2-hydroxy-6-((l-phenylpyrrolidin-2-yl)methoxy)benzaldehyde (14 mg). 1H

NMR (400 MHz, CDC1₃ (ppm) 11.96 (s, 1H), 10.37 (s, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.25 (m, 2H), 6.73 (m, 3H), 6.53 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 9.2 Hz, 1H), 4.21 (m, 1H), 4.15 (d, J = 3.6 Hz, 1H), 3.83 (t, J= 8.0 Hz, 1H), 3.53 (m, 1H), 3.22 (m, 1H), 2.11 (m, 4H); MS (ESI) m/z 298.4

[0277] GBT892 Préparation of 5-[[2-(3-chlorophenyl)pyridin-3-yl]methoxy]-220 methoxypyridine-4-carbaldehyde

114

Stepl

[0278] Step 1: Into a 50-mL round-bottom flask, was placed a solution of (3chlorophenyl)boronic acid (1.6 g, 10.23 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), Pd(dppf)Cl₂ (570 mg, 0.78 mmol, 0.10 equiv), and sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water(10 mL). The resulting solution was stirred for 3 h at 70°C, and then it was diluted with 20 mL of H₂O. The resulting solution was extracted with 2x20 mL of dichloromethane, and the combined organic layers were concentrated under vacuum. The residue was applied onto 10 a silica gel column with ethyl acetate/petroleum ether (1:100-1:5) as eluent to yield 1.2 g (78%) of [2-(3-chlorophenyl)pyridin-3-yl]methanol as a white solid.

[0279] Step 2: Into a 50-mL round-bottom flask, was placed a solution of [2-(3chlorophenyl)pyridin-3-yl]methanol (600 mg, 2.73 mmol, 1.00 equiv) in thionyl chloride (10 mL). The resulting solution was stirred for 1 h at reflux. The resulting mixture was concentrated under vacuum. This resulted in 500 mg (77%) of 3-(chloromethyl)-2-(3chlorophenyl)pyridine as a white solid.

[0280] Step 3: Into a 50-mL round-bottom flask, was placed a solution of 3(chloromethyl)-2-(3-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate 20 (361 mg, 2.61 mmol, 2.00 equiv) in CH3CN (20 mL). The resulting solution was stirred for 4 h at 70°C, and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column,5um, 19* 150mm; mobile phase, water with 0.05%TFA and MeCN (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min);

Detector, Waters2545 UvDector 254&220nm. This resulted in 71 mg (9%) of 5-[[2-(3chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a yellow solid.

’HNMR (400MHz, DMSO-î/6) δ 10.07(s, IH), 8.72 (m, IH), 8.20(m, 2H), 7.79(s, IH), 7.60(m, 4H), 6.95(m, IH), 5.21(m, 2H), 3.85(s, 3H); MS (ESI) m/z 355 [M+H]⁺.

115

[0281] GBT893 Préparation of 5-[[2-(4-chlorophenyl)pyridin-3-yl]methoxy]-2methoxypyndine-4-carbaldehyde oh

dioxane, H₂0,100°C

Stepl

SOCI₂

Step2

CHO

Cl

[0282] Step 1: Into a 100-mL round-bottom flask, was placed a solution of (4chlorophenyl)boronic acid (1.6 g, 10.23 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), Pd(dppf)Cl₂ (570 mg, 0.78 mmol, 0.10 equiv), and sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water(10 mL). The resulting solution was stirred for 4 h at 70°C, and then it was diluted with 100 mL of H2O. The resulting solution was extracted with 2x200 mL of dichloromethane, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:5) as eluent to yield 1 g (65%) of [2-(4-chlorophenyl)pyridin-3-yl]methanol as a light yellow oil.

[0283] Step 2: Into a 25-mL round-bottom flask, was placed a solution of [2-(4chlorophenyl)pyridin-3-yl]methanol (1 g, 4.55 mmol, 1.00 equiv) in thionyl chloride (5 mL). The resulting solution was stirred for 1 h at reflux. The resulting mixture was concentrated under vacuum. This resulted in 1 g (92%) of 3-(chloromethyl)-2-(4-chlorophenyl)pyridine as a white solid.

[0284] Step 3: Into a 50-mL round-bottom flask, was placed a solution of 3(chloromethyl)-2-(4-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmol, 2.00 equiv) in CH3CN (20 mL). The resulting solution was stirred for 4 h at 70°C, and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column,5um, 19* 150mm; mobile phase, water with 0.05%TFA and MeCN

116 (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min);

Detector, Waters2545 UvDector 254&220nm. This resulted m 148.2 mg (20%) of 5-[[2-(4chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a yellow solid.

’HNMR (300MHz, DMSO-J₆) δ 10.05(s, 1H), 8.69 (m, 1H), 8.16(m, 2H), 7.64(m, 2H), 7.50(m, 3H), 5.32(s, 2H), 3.8l(s, 3H); MS (ESI) m/z 355 [M+H]⁺.

GBT903

(R)-2-hydroxy-6-((1-phenylpyrrolidin-2-yl)methoxy)benzaldehyde

[0285] GBT903 - Préparation of (R)-2-hydroxy-6-((l-phenylpyrrolidin-2yl)methoxy)benzaldehyde. The compound was prepared from (R)-pyrrolidin-2-ylmethanol and iodobenzene according to scheme 8, reaction steps 3 and 4. ^lH NMR (400 MHz, Chloroform-d) δ 11.96 (d, J = 0.4 Hz, 1H), 10.37 (s, 1H), 7.37 (td, J= 8.4, 0.4 Hz, 1H), 7.31 -7.18 (m, 2H), 6.77 - 6.64 (m, 3H), 6.53 (dt, J= 8.5, 0.7 Hz, 1H), 6.33 (dd, J= 8.3, 0.8 Hz, 1H), 4.25 - 4.12 (m, 2H), 3.88 - 3.78 (m, 1H), 3.53 (dt, J = 8.8, 4.4 Hz, 1H), 3.27 -3.16 (m, 1H), 2.11 (dqt, 7= 13.0, 6.4, 2.8 Hz, 4H). MS (M+H)+ found for Ci₈Hi₉NO₃: 298.2.

GBT904

2-hydroxy-6-((2-(1-methyl-1 /7-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

[0286] GBT904 - Préparation of 2-hydroxy-6-((2-(l-methyl-lH-pyrazol-5-yl)pyridin-3yl)methoxy)benzaldehyde. The compound was prepared from (2-chloropyridin-3yl)methanol and l-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole

117 according to scheme 9, reaction steps 1,2 and 4. In step 4, 2-hydroxy-6 (methoxymethoxy)benzaldehyde_was used; the MOM ether protecting group fell off after the reaction to give the final product. ’H NMR (400 MHz, Chloroform-J) δ 11.94 (s, IH), 10.36 (s, IH), 8.75 (dd, J = 4.8, 1.7 Hz, IH), 7.98 (d, J = 8.0 Hz, IH), 7.54 (d, J = 1.9 Hz, IH), 7.41 (dd, J = 8.0,4.0Hz, IH), 7.38 (t, J = 8.0 Hz, IH), 6.58 (dt, J = 8.5, 0.7 Hz, IH), 6.39 (d, J =

1.9 Hz, IH), 6.28 (dd, J= 8.3, 0.8 Hz, IH), 5.12 (s, 2H), 3.95 (s, 3H). MS (M+H) found for C₁₇Hi5N₃O3_;310.3.

GBT907 and GBT908

(S)-2-hydroxy-6-((1-(2-methoxyphenyl)pyrrolidin-2yl)methoxy)benzaldehyde

2-hydroxy-6-((1-(2-methoxyphenyl)piperidin-3yl)oxy)benzaldehyde

[0287] GBT907 and GBT908 - Préparation of (S)-2-hydroxy-6-((l-(2methoxyphenyl)pyrroIidin-2-yl)methoxy)benzaldehyde (GBT907) and 2-hydroxy-6-((l(2-methoxyphenyl)piperidin-3-yl)oxy)benzaldehyde (GBT908). The reaction of (S)pyrrolidin-2-ylmethanol with 2-iodoanisole, and subséquent Mitsunobu reaction, according to scheme 8, gave a mixture of GBT907 and GBT908 in 3:2 ratio, which were separated by reverse-phase prep HPLC.

[0288] GBT907- (S)-2-hydroxy-6-(( 1 -(2-methoxyphenyl)pyrrolidin-2yl)methoxy)benzaldehyde 'H NMR (400 MHz, Chloroform-J) δ 11.96 (d, J = 0.4 Hz, IH), 10.37 (d, J = 0.6 Hz, IH), 7.39 (td, J = 8.4, 0.4 Hz, IH), 7.04 - 6.87 (m, 3H), 6.84 (dd, J = 8.0, 1.4 Hz, IH), 6.52 (ddt, J = 13.7, 8.4, 0.7 Hz, 2H), 4.66 (tt, J = 8.2, 3.9 Hz, IH), 3.80 (s, 3H), 3.67 - 3.58 (m, IH), 3.29 (dt, J = 9.9,4.3 Hz, IH), 2.85 (dd, J = 11.3, 8.3 Hz, IH), 2.82 - 2.74 (m, IH), 2.20 (dd, J= 12.4,4.9 Hz, IH), 2.00 (dp, J= 13.0,4.6 Hz, IH), 1.94 - 1.79 (m, IH), 1.72 (dddd, J= 13.0, 10.7, 9.0,4.3 Hz, IH). MS (M+H)+ found for Ci₉H₂iNO₄: 328.3).

[0289] GBT908- 2-hydroxy-6-((l-(2-methoxyphenyl)piperidin-3-yl)oxy)benzaldehyde (40 mg, ’H NMR (400 MHz, Chloroform-J) δ 11.91 (s, IH), 10.09 (d, J = 0.6 Hz, IH), 7.32 (d, J = 8.4 Hz, IH), 6.93 - 6.80 (m, 4H), 6.46 (dt, J = 8.5, 0.7 Hz, IH), 6.23 (dd, J = 8.4, 0.8 Hz,

118

IH), 4.49 (tt, J = 7.2,4.7 Hz, IH), 4.06 (dd, J = 9.3,4.4 Hz, IH), 3.88 - 3.78 (m, IH), 3.80 (s, 3H), 3.63 (ddd, J = 9.1, 7.3, 6.3 Hz, IH), 3.21 - 3.11 (m, IH), 2.35-2.22 (m, IH), 2.091.86 (m, 3H), MS (M+H)+ found for Ci₉H₂iNO₄: 328.3).

GBT912

2-(((3S,4R)-1-acetyl-4-(2,5-difluorophenyl)pyrrolidin-3-yl)methoxy)-6-hydroxybenzaldehyde

[0290] GBT912- 2-(((3S,41î)-l-acetyl-4-(2,5-difluorophenyl)pyrrolidin-3-yl)methoxy)6-hydroxybenzaIdehyde. The compound was prepared from -(2,5-difluorophenyl)-4(hydroxymethyl)pyrrolidin-l-yl)ethan-l-one and 2,6-dihydroxybenzaldehyde (INT-7) using general method A (Mitsunobu conditions). 'H NMR (400 MHz, Chloroform-d) δ 11.90 (s, IH), 9.88 (s, IH), 7.37 (dd, J = 8.4, 6.4 Hz, IH), 7.01 (m, 3H), 6.53 (t, J = 8.6 Hz, IH), 6.27 (dd, J= 8.3, 0.8 Hz, IH), 4.02 (m, 4H), 3.55 (m, 3H), 2.96 (m, IH), 2.11 (s, 3H). MS (M+H)+ found for C20H19F2NO4: 376.3.

[0291] Préparation of -(2,5-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-l-yl)ethan-l-one

[0292] To a solution of ((3S,47?)-4-(2,5-difluorophenyl)pyrrolidin-3-yl)methanol hydrochloride (200 mg, 0.8 mmol) in DCM (2 mL) at 0 °C was added DIPEA (0.3 mL, 1.68 mmol) and Ac₂O (90 mg, 0.84 mmol), after stirred for 30 min, the solution was diluted with DCM, organic layer was washed with Sat. NaHCO₃, brine, dried over MgSO₄ and was concentrated to give 1-((3R,45)-3-(2,5-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-lyl)ethan-l-one as cmde product (175 mg).

119

GBT913 and GBT914

2-hydroxy-6-((1-(3-methoxyphenyl)piperidin-3yl)oxy)benzaldehyde (S)-2-hydroxy-6-((1-(3-methoxyphenyl)pyrrolidin-2yl)methoxy)benzaldehyde

[0293] GBT913 and GBT914 - Préparation of (S)-2-hydroxy-6-((l-(3methoxyphenyl)pyrrolidin-2-yl)methoxy)benzaldehyde (GBT913) and 2-hydroxy-6-((l(3-methoxyphenyl)piperidin-3-yl)oxy)benzaldehyde (GBT914). The reaction of (S)pyrrolidin-2-ylmethanol with 3-iodoanisole, and subséquent Mitsunobu reaction, according to scheme 8, gave a mixture of GBT913 and GBT914 in 5:4 ratio, which were separated by reverse-phase prep HPLC.

[0294] GBT913- (S)-2-hydroxy-6-((l-(3-methoxyphenyl)pyrrolidin-2yl)methoxy)benzaldehyde ’H NMR (400 MHz, Chloroform-J) δ 11.95 (s, 1H), 10.37 (t, J = 0.5 Hz, 1H), 7.42-7.31 (m, 1H), 7.16 (t, J= 8.2 Hz, 1H), 6.53 (dq, J=8.4, 0.6 Hz, 1H), 6.36 - 6.24 (m, 3H), 6.23 (t, J = 2.4 Hz, 1H), 4.23 - 4.12 (m, 2H), 3.79 (s, 4H), 3.50 (ddd, J = 9.0, 5.6, 3.5 Hz, 1H), 3.27 - 3.16 (m, 1H), 2.17 - 1.98 (m, 4H). MS (M+H)+ found for C19H21NO4: 328.3

GBT914 - 2-hydroxy-6-((l-(3-methoxyphenyl)piperidin-3-yl)oxy)benzaldehyde *H NMR (400 MHz, Chloroform-d) δ 11.94 (d, J = 0.4 Hz, 1H), 10.25 (d, J = 0.6 Hz, 1H), 7.39 (td, J = 8.4, 0.4 Hz, 1H), 7.19 - 7.08 (m, 1H), 6.51 (dt, J = 8.5, 0.7 Hz, 2H), 6.48 - 6.37 (m, 3H), 4.58 (m, 1H), 3.78 (m, 1H), 3.77 (s, 3H), 3.74-3.64 (m, 1H), 3.39 (d, J = 5.6 Hz, 1H), 3.17 (dd, J= 12.4, 7.6 Hz, 1H), 3.11 - 3.01 (m, 1H), 2.14(s, 1H), 2.02- 1.92 (m, 1H), 1.86-1.74 (m, 1H). MS (M+H)+ found for C19H21NO4: 328.4).

GBT916

120

[0295] GBT916 - 2-hydroxy-6-((2-(2-methoxyphenyl)pyridin-3 yl)methoxy)benzaldehyde. The compound was prepared from (2-chloropyridin-3yl)methanol and (2-methoxyphenyl)boronic acid according to scheme 9, reaction steps 1, 2 and 4. In step 4, alkylation with 2,6-dihydroxybenzaldehyde, the product of TFA sait was obtained after HPLC purification. ’HNMR (300MHz, DMSO, ppm): 11.71 (s, 1H), 9.99 (s, 1H), 8.65 (m, 1H), 8.13 (d, J=7.5Hz, 1H), 7.50 (m, 3H), 7.31 (m, 1H), 7.04 (m, 2H), 6.47 (m, 1H) 6.38 (m, d, J=8.4Hz, 1H), 5.00 (s, 2H), 3.73 (s, 3H); MS (ES, m/z): 336 [M+l]⁺.

GBT917

[0296] GBT917 - 2-hydroxy-6-((2'-methoxy-[2,3'-bipyridin]-3yl)methoxy)benzaldehyde. The compound was prepared from (2-chloropyridin-3yl)methanol and (2-methoxypyridin-3-yl)boronic acid according to scheme 9, reaction steps 1, 2 and 4. In step 4, alkylation with 2,6-dihydroxybenzaldehyde, the product TFA sait was obtained after HPLC purification.

’HNMR (300MHz, CDC13,ppm): 11.91 (s, 1H), 10.24 (s, 1H), 8.71 (t, 1H), 8.69 (m, 1H), 7.93 (d, 1H), 7.75 (d, 1H), 7.40 (m, 1H), 7.39 (m, 1H), 7.08 (m, 1H), 6.53 (d, 1H), 6.50 (d, 1H), 5.07 (s, 2H), 3.94 (s, 3H); MS (ES, m/z): 337 [M+l]⁺

[0297] GBT930- 2-((2-(l-cycIobutyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)-6hydroxybenzaldehyde. The compound was prepared by Mitsunobu reaction (scheme 9, step

3) of (2-(l-cyclobutyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol (A) with 2,6dihydroxybenzaldehyde (LNT3). The product was obtained as pale yellow solid. ’HNMR

121 (300MHz, CDC13, ppm): 11.95 (s, IH), 10.35 (s, IH), 8.75 (m, IH), 7.97 (d, J=7.2Hz, IH),

7.62 (m, IH), 7.45 (m, IH), 7.36 (m, IH), 6.56 (d, J=8.4Hz, IH), 6.38 (m, IH), 6.23 (d,

J=8.4Hz, IH), 5.07 (s, 2H), 4.85 (m, IH), 2.75 (m, 2H), 2.27 (m, 2H), 1.25 (m, 2H); (ES, m/z): 350 [M+l]⁺

[0298] Préparation of intermediate A. Intermediate A was prepared from pyrazole in three steps according scheme below.

[0299] Step 1: Into a 500-mL round-bottom flask, was placed a solution of lH-pyrazole (10 g, 146.89 mmol, 1.00 equiv), CS2CO3 (95.9 g, 294.33 mmol, 2.00 equiv), and bromocyclobutane (29.7 g, 220.00 mmol, 1.50 equiv) in CH3CN (150 mL). The resulting solution was stirred overnight at 80°C, and then it was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:400-1:200) as eluent to yield 8 g (45%) of 1-cyclobutyl-lH-pyrazole as a colorless liquid.

[0300] Step 2: Into a 250-mL round-bottom flask, was placed a solution of 1-cyclobutyllH-pyrazole (6.5 g, 53.21 mmol, 1.00 equiv) in tetrahydrofuran (100 ml). This was followed by the addition of BuLi (2.5 M, 22.7 mL, 1.10 equiv) dropwise with stirring at -30°C. The mixture was stirred for 30 min at the same température. To this was added 4,4,5,5tetramethyl-2-(propan-2-yloxy)-l,3,2-dioxaborolane (14.9 g, 80.08 mmol, 1.50 equiv) dropwise with stirring at -78°C. The resulting solution was stirred for 3 h at -78°C, and then it was quenched by the addition of 30 mL of water. The resulting solution was extracted with 2x200 mL of dichloromethane. The combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:200-1:30) as eluent to fumish 6.2 g (47%) of l-cyclobutyl-5-(tetramethyl-1,3,2dioxaborolan-2-yl)-lH-pyrazole as a colorless oil.

122

[0301] Step 3: Into a 100-mL round-bottom flask, was placed a solution of l-cyclobutyl-5(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (791 mg, 3.19 mmol, 2.00 equiv), (2bromopyridin-3-yl)methanol (500 mg, 2.66 mmol, 1.00 equiv), Pd(dppf)C12 (217 mg, 0.30 mmol, 0.10 equiv),and sodium carbonate (670 mg, 6.32 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water(10 mL). The resulting solution was stirred for 2 h at 80°C. The resulting solution was extracted with 3x20 mL of dichloromethane. The combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3-1:1) as eluent to provide 200 mg (33%) of [2(l-cyclobutyl-lH-pyrazol-5-yl)pyridin-3-yl]methanol as a yellow oil.

GBT934

[0302] GBT934- 2-((2 ' -ethoxy-[2,3' -bipyridin] -3-yl)methoxy)-6-hydroxybenzaldehyde The compound was prepared from (2-chloropyridin-3-yl)methanol and ((2-ethoxypyridin-3yl)boronic acid according to scheme 9, reaction steps 1, 2 and 4. In step 4, alkylation with 2,6-dihydroxybenzaldehyde (INT3), the product TFA sait as white solid was obtained after HPLC purification. ‘HNMR (400MHz, CDCl₃,ppm): 11.91 (brs, 1H), 10.29 (s, 1H), 8.97 (s, 2H), 8.97 (br s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 4.8 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J =6.8 Hz, 1H), 7.53 (t, J = 4.4 Hz, 1H), 7.12 (t, J = 6.0 Hz, 1H), 6.59 (d, 7=8.4 Hz, 1H), 6.14 (d, J = 8.4 Hz, 1H), 5.17 (s, 2H), 4.46 (q, J = 6.8 Hz, 2H), 1.32 (t, 7= 6.8 Hz, 3H); MS (ES, m/z:) 351.1 [M+l]⁺

GBT948

[0303] GBT948- 3-chloro-2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yI)pyridin-3yl)methoxy)benzaldehyde. The compound was prepared using general reaction step 4 of

123 scheme 9, by O-alkylation of 3-chloro-6-hydroxy-2-(methoxymethoxy)benzaldehyde (B) with 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine (A) and subséquent deprotection of the MOM ether by treating with aqueous 6N HCl in THF. ¹HNMR (400MHz,CDC1₃, ppm): 12.49(s, 1H), 10.34(s, 1H), 8.80(dd, J=3.6Hz, 1H), 8.00(dd, J=5.7Hz, 1H), 7.63(d, J=1.2Hz, lH),7.47(m, 2H), 6.36 (m, 2H) ,5.11 (d, J=10.8Hz, 2H), 4.70(m, 1H), 4.61(m, 1H), 1.53(d, J=4.5Hz, 6H); MS (ES, m/z): 372[M+1]⁺

A

1) K₂CO₃,KI DMSO

2) HCl

[0304] The MOM-protected phénol aldéhyde intermediate B was prepared according to the following synthetic scheme:

Step 1

MOMBr,K₂CO₃

Acetone

Step 2

BnBr,K₂CO₃

Acetone

OBn ^{Step 3}

LDA.DMF

OMOM ^THF

Cl

Step 4

Rh/C,H₂ ethyl acetate

[0305] Step 1 : Into a 2000-mL round-bottom flask, was placed a solution of 4chlorobenzene-l,3-diol (50.0 g, 345.89 mmol, 1.00 equiv) and potassium carbonate (95 g, 687.36 mmol, 2.00 equiv) in acetone (1000 mL). This was followed by the addition of MOMBr (40 g, 320.10 mmol, 0.90 equiv) dropwise with stirring. The resulting solution was stirred for 60 h at room température. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:2) as eluent to furnish 49 g (75%) of 4-chloro-3(methoxymethoxy)phenol as a colorless oil.

[0306] Step 2: Into a 1000-mL round-bottom flask, was placed a solution of 4-chloro-3(methoxymethoxy)phenol (49.0 g, 259.80 mmol, 1.00 equiv) and potassium carbonate (57.4 g, 415.31 mmol, 1.60 equiv) in acetone (500 mL). This was followed by the addition of BnBr (55 g, 321.58 mmol, 1.20 equiv) dropwise with stirring in 40 min. The resulting solution was stirred ovemight at room température. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:99-1:10-1:2) as eluent to furnish 40.0 g (55%) of 4-(benzyloxy)-lchloro-2-(methoxymethoxy)benzene as a colorless oil.

124

[0307] Step 3: Into a 500-mL three neck round-bottom flask, was placed a solution of bis(propan-2-yl)amine (29.7 g, 293.51 mmol, 5.00 equiv) in tetrahydrofuran (70 mL). This was followed by the addition of BuLi (100 mL, 3.00 equiv) dropwise with stirring at -78 °C. The mixture was stirred for 10 min at -78 °C, then stirred for 10 min at 0°C. To this was added a solution of 4-(benzyloxy)-l-chloro-2-(methoxymethoxy)benzene (23.3 g, 83.59 mmol, 1.00 equiv) in tetrahydrofuran (70 mL) dropwise with stirring at -78 °C. The mixture was stirred for 1 h at -40 °C. To the mixture was added N,N-dimethylformamide (18.3 g, 250.38 mmol, 3.00 equiv) dropwise with stirring at -78°C. The resulting solution was stirred for 30 min at -78 °C. The reaction was then quenched by the addition of 50 mL of NH4CI (aq). The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined and dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent. This resulted in 8.8 g (34%) of 6(benzyloxy)-3-chloro-2-(methoxymethoxy)benzaldehyde as a yellow soild.

[0308] Step 4: Into a 500-mL round-bottom flask, was placed a solution of 6-(benzyloxy)-

3-chloro-2-(methoxymethoxy)benzaldehyde (8.8 g, 28.69 mmol, 1.00 equiv) in ethyl acetate (100 mL). Rh/C (1.0 g) was added to the reaction. The resulting solution was stirred for 20 h at room température under 1 atm of hydrogen gas. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) as eluent. This resulted in 5.2 g (84%) of 3-chloro-6hydroxy-2-(methoxymethoxy)benzaldehyde as a light yellow solid.

GBT954

HO

[0309] GBT954- 4-hydroxy-2-((2-(l-isopropyl-lH-pyrazoI-5-yl)pyridin-3yl)methoxy)benzaldehyde. The compound was prepared by Mitsunobu reaction (scheme 9, step 3) of 2-hydroxy-4-(methoxymethoxy)benzaldehyde (A) with (2-(l-isopropyl-1Hpyrazol-5-yl)pyridin-3-yl)methanol (B) and subséquent deprotection of the MOM ether by treating with aqueous 6N HCl in THF according the scheme below. *HNMR (400MHz,

125

DMSO, ppm): 10.70 (s, 1H), 10.09 (s, 1H), 8.75 (m, 1H), 8.22 (d, J=8Hz, 1H), 7.59 (m, 3H),

6.52 (m, 3H), 5.16 (s, 2H), 4.65 (m, 1H), 1.37 (m, 6H); (ES, m/z): 338 [M+l]⁺

[0310] Préparation of intermediate 2-hydroxy-4-(methoxymethoxy)benzaldehyde

OH O A JJ	MOMBr	OH O A JJ
	_r 1
(A)	K₂CO₃, acetone _M0MCJ	U

[0311] Into a 100-mL round-bottom flask, was placed a solution of 2,4dihydroxybenzaldehyde (3 g, 21.72 mmol, 1.00 equiv), MOMBr (3.2 g, 25.60 mmol, 1.20 equiv), and potassium carbonate (3.9 g, 28.22 mmol, 1.30 equiv) in acetone (20 mL). The resulting solution was stirred ovemight at room température. The resulting solution was diluted with 30 mL of H₂O. The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50-1:30) as eluent to fumish 2.6 g (66%) of 2-hydroxy-4-(methoxymethoxy)benzaldehyde as a white solid.

[0312] GBT967- 2-((2',6^,-dimethoxy-[2,3'-bipyridin]-3-yl)methoxy)-6hydroxybenzaldehyde. The compound was prepared from (2-chloropyridin-3-yl)methanol and 2,6-dimethoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine according to scheme 9, reaction steps 1, 2 and 4. In step 4, alkylation with 2,6-dihydroxybenzaldehyde, the product of TFA sait as white solid was obtained after HPLC purification. ’HNMR (400MHz, DMSO, ppm): 10.04 (s, 1H), 8.65 (m, 1H), 8.14 (d, J=7.6Hz, 1H), 7.73 (d, J=8Hz, 1H), 7.51 (m, 2H), 6.50 (m, 3H), 5.16 (m, 2H), 3.91 (s, 1H), 3.86 (s, 1H); (ES, m/z): 367 [M+l]⁺

126

GBT000985

[0313] GBT985- 3-(difluoromethyl)-l-methyl-5-((2-(l-(2,2,2-trifliioroethyl)-lHpyrazol-5-yl)pyridin-3-yl)methoxy)-lH-pyrazole-4-carbaldehyde.

[0314] 3-(Difluoromethyl)-5-hydroxy-l-methyl-lH-pyrazole-4-carbaldehyde (100 mg, 0.568 mmol) was dissolved in DMF (2.8 ml). 3-(chloromethyl)-2-( 1-(2,2,2-trifluoroethyl)lH-pyrazol-5-yl)pyridine hydrochloride (0.195 g, 0.625 mmol) and potassium carbonate (0.235 g, 1.7 mmol) were then added and the mixture was stirred in a 60 °C heat block for 16 h. The reaction mixture was cooled and water (50 ml) and ethyl acetate (100 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic phases were washed with water (20 ml) and a saturated aqueous sodium chloride solution (20 ml). After drying over sodium sulfate and évaporation, the residue was purified by silica gel chromatography (5 - 50 % ethyl acetate/hexanes) to give 86 mg (36%) of 3-(difluoromethyl)-l-methyl-5-((2-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-5yl)pyridin-3-yl)methoxy)-lH-pyrazole-4-carbaldehyde as an off-white solid. *H NMR (400 MHz, CDC1₃) δ 9.97 (s, IH), 8.75 (d, J = 3.64 Hz, IH), 8.08 (d, J = 7.31 Hz, IH), 7.68 (d, J = 1.69 Hz, IH), 7.44 (dd, J = 4.66, 7.83 Hz, IH), 6.65 (t, J = 53.67 Hz, IH), 6.61 (d, J = 1.78 Hz, IH), 5.64 (s, 2H), 5.24 (q, J = 8.60 Hz, 2H), 3.54 (s, 3H). MS (ESI) m/z 416 [M+H]⁺.

127

GBT986

[0315] GBT986- l-methyl-5-((2-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl)pyridin-3yi)methoxy)-3-(trifluoromethyl)-lH-pyrazole-4-carbaldehyde

[0316] 5-Hydroxy-1 -methyl-3-(trifluoromethyl)-1 H-pyrazole-4-carbaldehyde ( 100 mg, 0.515 mmol) was dissolved in DMF (2.5 ml). ). 3-(chloromethyl)-2-( 1-(2,2,2-trifluoroethyl)lH-pyrazol-5-yl)pyridine hydrochloride (0.177 g, 0.567 mmol) and potassium carbonate (0.213 g, 1.545 mmol) were then added and the mixture was stirred in a 60 °C heat block for 16 h. The reaction mixture was cooled and water (50 ml) and ethyl acetate (100 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic phases were washed with water (20 ml) and a saturated aqueous sodium chloride solution (20 ml). After drying over sodium sulfate and évaporation, the residue was purified by silica gel chromatography (5 - 50 % ethyl acetate/hexanes) to give 86 mg (36%) of l-methyl-5-((2-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl)pyridin-3yl)methoxy)-3-(trifluoromethyl)-lH-pyrazole-4-carbaldehyde as an off-white solid. ’H NMR (400 MHz, CDCI3) δ 9.87 (s, 1H), 8.75 (d, J = 4.33 Hz, 1H), 8.08 (d, J = 7.73 Hz, 1H), 7.68 (d, J= 1.74 Hz, 1H), 7.45 (dd, J = 4.64, 7.84 Hz, 1H), 6.59 (d, J= 1.70 Hz, 1H), 5.63 (s, 2H), 5.24 (q, J= 8.60 Hz, 2H), 3.57 (s, 3H). MS (ESI) m/z 434 [M+H]⁺.

GBT1065

128

[0317] GBT1065 - 4-fluoro-7-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)2,3-dihydro-lH-inden-l-one bis(2,2,2-trifluoroacetate). The compound was prepared by Mitsunobu reaction of of 4-fluoro-7-hydroxy-2,3-dihydro-lH-inden-l-one with [2-[l5 (propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methanol according to scheme 9, reaction step 3. The product TFA sait as white solid was obtained after HPLC purification. ¹HNMR (300MHz, DMSO, ppm): 8.72 (m, 1H),8.23 (m, 1H), 7.56(m, 1H), 7.51(d, J=1.8Hz, 1H), 7.43(m, 1H), 6.93 (m, 1H), 6.58(d, J=1.8Hz, 1H), 5.08(s, 2H), 4.63(m, 1H), 3.03 (m, 2H), 2.61 (m, 2H), 1.33 (d, J=6.6Hz, 6H); MS (ES, m/z): 366[M+1]⁺

[0318] GBT1133- 2-(((2-(l-isopropyi-lH-pyrazol-5-yl)pyridin-3yl)oxy)methyl)benzaldehyde. The compound was prepared from ethyl 215 (bromomethyl)benzonitrile in 2 steps according to reaction scheme below.

[0319] Step 1: Into a 100-mL round-bottom flask, was placed a solution of 2(bromomethyl)benzonitrile (1.0 g, 5.10 mmol, 1.00 equiv) in dichloromethane (40 mL). This

129 φ was followed by the addition of DIBAL-H (5.5 mL, 1.10 equiv) at 0 °C. The resulting solution was stirred for 3.5 h at 0 °C. The reaction was then quenched by the addition of 10 mL of 5% HBr at 0 °C. The resulting solution was extracted with 3x30 mL of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate.

The residue was applied onto a silica gel column with ethyl acetate/petroleum ether ( 1:10) as eluent. This resulted in 500 mg (49%) of 2-(bromomethyl)benzaldehyde as a green oil.

[0320] Step 2: Into a 50-mL round-bottom flask, was placed a solution of 2(bromomethyl)benzaldehyde (150 mg, 0.75 mmol, 1.00 equiv) in CH₃CN (25 mL). 2-[l(Propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-ol (150 mg, 0.74 mmol, 1.00 equiv), potassium carbonate (210 mg, 1.52 mmol, 2.00 equiv), and Kl (40 mg, 0.30 equiv) were added to the reaction. The resulting solution was heated to reflux for 6 h, and then it was cooled to rt. The resulting solution was diluted with 20 mL of H2O, and then it was extracted with 3x20 mL of ethyl acetate. The combined organic layers were washed with 1x30 mL of brine and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column,5um, 19* 150mm,; mobile phase, water with 0.05%TFA and MeCN (38.0% MeCN up to 55.0% in 8 min); Detector, nm. This provided 98.6 mg (41%) of 2-[([2-[l-(propan-2yl)-lH-pyrazol-5-yl]pyridin-3-yl]oxy)methyl]benzaldehyde as a light yellow solid; ’HNMR (300MHz, CDCl₃,ppm): 10.01 (s, 1H), 8.43 (m, 1H), 7.88(m, 1H), 7.86 (m, 1H), 7.6120 7.79(m, 6H), 6.6l(d, J=2.1Hz, 1H), 5.60 (s, 2H), 4.69-4.78 (m, 1H), 1.46(d, J=6.6Hz, 6H);

(ES, m/z): 322 [M+l]⁺

GBT1197

[0321] GBT1197- 2-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-325 yl)methoxy)benzaldehyde. The compound was prepared by O-alkylation of 2hydroxybenzaldehyde with 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine (INT4). The product of TFA sait as white solid was obtained after HPLC purification. ’HNMR (300MHz, CDC1₃, ppm): 10.49(s, 1H), 8.78(m, 1H), 8.16(m, 1H), 7.88(m, 1H), 7.69(d,

130

Φ 7=6.0Ηζ, lH),7.54(m, 2H), 7.13(m, IH), 6.90(d, 7=8.4Hz, IH), 6.41(d, 7=1.8Hz, IH), 5.11 (s, 2H), 4.62 (m, IH); (ES, m/z): 322[M+1]⁺

GBT1252

[0322] GBT1252- 2-((6-bromo-2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)6-hydroxybenzaldehyde. The compound was prepared by Mitsunobu reaction of (6-bromo-

2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol (intermediate A) and 2,6dihydroxybenzaldehyde (INT-3) according to scheme 9, reaction step 3. The product as white 10 solid was obtained after flash column purification. ’HNMR (300MHz, DMSO, ppm): 11.70 (s, IH), 11.20 (s, IH), 8.17 (d, J = 8.1 Hz, IH), 7.81 (d, J = 8.1 Hz, IH), 7.57 (s, IH), 7.50 (t, J = 8.4 Hz, IH), 6.60 (s, IH), 6.55 (dd, J = 8.4 Hz, 3.6 Hz, IH), 5.19 (s, 2H), 4.65-4.55 (m, IH), 1.38 (d, J = 6.6 Hz, 6H); (ES, m/z:) 418.1 [M+l]⁺

[0323] Préparation of intermediate A. Intermediate A was prepared from 2,6dichloropyridine-3-carboxylic acid in five steps according to the synthetic scheme below.

131

Cl I	Step 1	OMe	Step 2
N Y	t-BuOK, MeOH		SOCI₂, MeOH
CI-V	cr	V
COOH		COOH

MeOOC

Step 4

POBr₃, H₃PO₄

PyHBr, C₆H₆

Step 5

LiBH₄, THF

[0324] Step 1 : Into a 500-mL round-bottom flask, was placed a solution of 2,6dichloropyridine-3-carboxylic acid (25 g, 130.21 mmol, 1.00 equiv) in methanol (350 mL). This was followed by the addition of t-BuOK (43.8 g, 390.34 mmol, 3.00 equiv), in portions at 0 °C. The resulting solution was heated to reflux for 3 days. The resulting mixture was concentrated under vacuum, and then it was diluted with 400 mL of water. The pH value of the solution was adjusted to 1 with hydrogen chloride aq. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This provided 20.5 g (84%) of 2-chloro-6-methoxypyridine-3-carboxylic acid as a white solid.

[0325] Step 2: Into a 100-mL round-bottom flask, was placed a solution of 2-chloro-6methoxypyridine-3-carboxylic acid (11.3 g, 60.24 mmol, 1.00 equiv) in methanol (50 mL). This was followed by the addition of SOC1₂ (26 mL, 5.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 1 h at room température and for an additional 2 h at reflux. The resulting solution was diluted with 100 mL of water. The pH value of the solution was adjusted to 10 with 2M sodium carbonate aq. The resulting solution was extracted with 3x80 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x150 mL of water and 1x100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) as eluent to fumish 7.8 g (64%) of methyl 2-chloro-620 methoxypyridine-3-carboxylate as a white solid.

[0326] Step 3: Into a 100-mL round-bottom flask, which was purged and maintained with an inert atmosphère of nitrogen, was placed methyl 2-chloro-6-methoxypyridine-3-

132 φ carboxylate (3.29 g, 16.32 mmol, 1.00 equiv), l-(propan-2-yl)-5-(tetramethyl-1,3,2dioxaborolan-2-yl)-lH-pyrazole (4.63 g, 19.61 mmol, 1.20 equiv), toluene (45 mL), éthanol (15 mL), sodium carbonate (2M in H₂O) (15 mL). This was followed by the addition of

Pd(dppf)(DCM)Cl₂ (665 mg, 0.05 equiv). The resulting solution was stirred for 20 h at 90 °C.

The reaction was then quenched by the addition of 20 mL of water and 100 mL of ethyl acetate. The resulting mixture was washed with 2x50 mL of water and 1x50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:25-1:15) as eluent to furnish 3.83 g (85%) of methyl 6-methoxy-2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridine-3-carboxylate as a light yellow oil.

[0327] Step 4: Into a 250-mL round-bottom flask, was placed methyl 6-methoxy-2-[l(propan-2-yl)-lH-pyrazol-5-yl]pyridine-3-carboxylate (3.6 g, 13.08 mmol, 1.00 equiv), CôHô (60 mL), Η3ΡΟ₄(85%) (150 mg, 1.53 mmol, 0.10 equiv), PyHBr (208 mg, 1.30 mmol, 0.10 equiv), ΡΟΒΓ3 (11.5 g, 40.11 mmol, 3.00 equiv). The resulting solution was heated to reflux for 40 h. The reaction mixture was cooled to 0 °C with an ice bath. The pH value of the solution was adjusted to 10 with potassium carbonate sat. The resulting solution was extracted with 3x80 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x50 mL of water and 1x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:8) as eluent. This provided 2.62 g (62%) of methyl 6-bromo-2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridine-3-carboxylate as a yellow oil.

[0328] Step 5: Into a 50-mL round-bottom flask, was placed methyl 6-bromo-2-[l-(propan2-yl)-lH-pyrazol-5-yl]pyridine-3-carboxylate (2.62 g, 8.08 mmol, 1.00 equiv), tetrahydrofuran (30 mL). This was followed by the addition of LiBH₄ (350 mg, 16.07 mmol, 2.00 equiv) at 0 °C. The resulting solution was stirred for 30 min at 0 °C and for an additional 1 h at room température. The reaction mixture was cooled to 0 °C with an ice bath. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3x60 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x50 mL of water and 1x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:8-1:5) as eluent to furnish 1.97 g

133 φ (82%) of [6-bromo-2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methanol as a light yellow solid.

GBT933

[0329] GBT933 - 4-(dimethylamino)-2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5yl)pyridin-3-yl)methoxy)benzaIdehyde

[0330] Step 1 : Into a 250-mL round-bottom flask, was placed a solution of 3,510 dimethoxyaniline (1) (4.6 g, 30.03 mmol, 1.00 equiv) and potassium carbonate (14.6 g,

105.64 mmol, 4.00 equiv) in N,N-dimethylformamide (80 mL). This was followed by the addition of SÛ2(OMe)2 (8.4 g, 66.67 mmol, 2.00 equiv) dropwise with stirring at 0 °C. The mixture was stirred for 2h at 0 °C. The resulting solution was stirred overnight at room température, and then it was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2x80 mL of ethyl acetate. The combined organic layers were washed with 1x50 mL of water and 1x50 mL of brine, dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with PE:EA (30:1-10:1) as eluent to fumish 2.8 g (51%) of 3,5-dimethoxy-N,N-dimethylaniline (2) as a white solid.

[0331] Step 2: Into a 50-mL round-bottom flask, was placed a solution of 3,5-dimethoxy20 N,N-dimethylaniline (2) (2.4 g, 13.24 mmol, 1.00 equiv) in N,N-dimethylformamide (25 mL). This was followed by the addition of POCI3 (2.57 g, 16.76 mmol, 1.30 equiv) dropwise

134 with stirring at 0 °C. The resulting solution was stirred for 15 min at 0 °C, and then it was quenched by the addition of 100 mL of sodium hydroxide (aq). The pH value of the solution was adjusted to 12 with sodium hydroxide (aq). The resulting solution was extracted with 3x60 mL of ethyl acetate. The combined organic layers were washed with 1x60 mL of water and 1x60 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1-1:0) as eluent to yield 2.08 g (75%) of 4-(dimethylamino)-2,6-dimethoxybenzaldehyde (3) as a white solid.

[0332] Step 3: Into a 50-mL round-bottom flask, was placed a solution of 4(dimethylamino)-2,6-dimethoxybenzaldehyde (3) (630 mg, 3.01 mmol, 1.00 equiv) in dichloromethane (25 mL). AICI3 (6 g, 45.11 mmol, 12.50 equiv) was added to the reaction. The resulting solution was heated to reflux for 24 h. The pH value of the solution was adjusted to 8-9 with sodium bicarbonate (aq). The resulting solution was extracted with 3x80 mL of ethyl acetate. The combined organic layers were washed with 1x60 mL of water and 1x60 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) as eluent to fumish 383 mg (70%) of 4-(dimethylamino)-2,6-dihydroxybenzaldehyde (4) as a light yellow solid.

[0333] Step 4: Into a 25-mL round-bottom flask, was placed a solution of [2-[l-(propan-2yl)-lH-pyrazol-5-yl]pyridin-3-yl]methanol (5) (132 mg, 0.61 mmol, 1.00 equiv), 4(dimethylamino)-2,6-dihydroxybenzaldehyde (4) (110 mg, 0.61 mmol, 1.00 equiv), PPI13 (207.3 mg, 0.79 mmol, 1.30 equiv) in tetrahydrofuran (10 mL). DIAD (160 mg, 0.79 mmol, 1.30 equiv) was added to the reaction dropwise dropwise at 0 °C. The resulting solution was stirred for 10 min at 0 °C and for an additional 2 h at room température. The reaction was then quenched with 10 mL of water. The resulting solution was extracted with 3x40 mL of ethyl acetate. The combined organic layers were washed with 3x20 mL of water and 1x20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5um, 19* 150mm,; mobile phase, water with 0.05%TFA and MeCN (30.0% MeCN up to 60.0% in 10 min, up to 95.0% in 4 min,down to 30.0% in 2 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 60 mg (26%)

135 φ of 4-(dimethylamino)-2-hydroxy-6-([2-[ l-(propan-2-yl)- lH-pyrazol-5-yl]pyridin-3yl]methoxy)benzaldehyde (GBT933) as a light yellow solid.

[0334] ’HNMR (400MHz, CDCl₃, ppm): 12.45 (br s, 1H), 9.87 (s, 1H), 8.70 (d, J = 4.0 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.58 (s, 1H), 7.42-7.39 (m, 1H), 6.32 (s, 1H), 5.68 (s, 1H), 5.43 (s, 1H), 4.94 (s, 2H), 4.58-4.51 (m, 1H), 2.96 (s, 6H), 1.40 (d, J= 6.8 Hz, 1H); MS (ES, m/z:) 381.2 [M-2CF₃COOH+1]⁺

GBT953

[0335] GBT953 - (S)-2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-310 yl)methoxy)benzaldehyde

[0336] Step 1 : Into a 250-mL round-bottom flask, was placed a solution of methyl 3hydroxybenzoate (3 g, 19.72 mmol, 1.00 equiv) in trifluoroacetic acid (100 mL). Urotropin (5.5 g, 39.29 mmol, 2.00 equiv) was added to the reaction. The resulting solution was heated to reflux for 2 hr. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether ( 1:5) as eluent to furnish 0.5 g (14%) of methyl 2-formyl-3-hydroxybenzoate as a yellow solid.

[0337] Step 2: Into a 100-mL round-bottom flask, was placed a solution of methyl 2formyl-3-hydroxybenzoate (400 mg, 2.22 mmol, 1.00 equiv) in CH3CN (30 mL). 3(Chloromethyl)-2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridine (523 mg, 2.22 mmol, 1.00 equiv), potassium carbonate (927 mg, 6.71 mmol, 3.00 equiv), and Kl (40 mg, 0.24 mmol, 0.10 equiv) were added to the reaction. The resulting solution was stirred for 2 h at 60°C, and then it was diluted with 200 ml of EA. The resulting mixture was washed with 2x100 mL of brine, and then it was concentrated under vacuum. This provided 500 mg (59%) of methyl 2formyl-3-([2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methoxy)benzoate as a yellow oil.

[0338] Step 3: Into a 100-mL round-bottom flask, was placed a solution of methyl 2formyl-3-([2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methoxy)benzoate (100 mg, 0.26 mmol, 1.00 equiv) in tetrahydrofuran (10 mL). This was followed by the addition of a

136 solution of sodium hydroxide (22 mg, 0.55 mmol, 2.00 equiv) in water (3 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 3 h at room température. The pH value of the solution was adjusted to 6 with hydrogen chloride (3 mol/L). The resulting solution was extracted with 2x100 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5um, 19* 150mm,; mobile phase, water with 0.05%TFA and MeCN (30% MeCN up to 60% in 10 min, up to 95% in 3 min, down to 30% in 2 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 30 mg (19%) of 2-formyl-3-([2-[l-(propan-2-yl)-lH-pyrazol-5yl]pyridin-3-yl]methoxy)benzoic acid; bis(trifluoroacetic acid) as a white solid. ’HNMR (300MHz, DMSO, ppm): 8.75(dd, J=4.8Hz, 1H), 8.15 (m, 2H), 7.59(m,3H), 7.40(d, J=7.8Hz, 1H), 7.33(d, J=8.1Hz, 1H), 6.66((d, J=7.8Hz, 1H), 6.60 (s, 1H), 5.18 (m, 2H), 4.70 (m, 1H), 1.35(m, 6H); MS (ES, w/z):366 [M+1J+

GBT963

[0339] GBT963 - (S)-2-hydroxy-6-((5-oxo-l-phenylpyrroIidin-2yl)methoxy)benzaldehyde

[0340] Step 1: To a suspension of (S)-5-(hydroxymethyl)pyrrolidin-2-one (230 mg, 2 mmol) and iodobenzene (0.49 g, 2.4 mmol) in Dioxane (4 mL) was added Cul (0.08 g, 0.4 mmol), N,N-dimethylethylenediamine (0.05 mL, 0.4 mmol), K2CO3 (0.55 g, 4 mmol). After heating at 100 °C for 24 h, the mixture was cooled and was diluted with EtOAc, insoluble material was filtered off, the filtrate was concentrated and purified by column ( Hexanes/EtOAc= 100:0 to 0:100) to give (S)-5-(hydroxymethyl)-l-phenylpyrrolidin-2-one (280 mg).

[0341] Step 2: To a solution of (S)-5-(hydroxymethyl)-l-phenylpyrrolidin-2-one (100 mg, 0.52 mmol) and 2,6-dihydroxybenzaldehyde (0.09 g, 0.65 mmol) in THF (5 mL) at 0 °C was added PPI13 (polymer supported, 650 mg, 0.78 mmol) and DIAD (0.16 mL, 0.78 mmol). After

137 stirred for 1 h, it was diluted with AcCN, the insoluble material was filtered off and the nitrate was concentrated and purified by préparative HPLC to give (S)-2-hydroxy-6-((5-oxol-phenylpyrrolidin-2-yl)methoxy)benzaldehyde (86 mg). *H NMR (400 MHz, Chloroform-d) δ 11.91 (d, J = 0.4 Hz, IH), 9.93 (d, J = 0.6 Hz, IH), 7.50-7.18 (m, 6H), 6.53 (dt,J=8.5, 0.7 Hz, IH), 6.21 (dd, J = 8.3, 0.8 Hz, IH), 4.70-4.59 (m, IH), 4.15-4.01 (m, 2H), 2.822.58 (m, 2H), 2.50 (ddt, J = 13.1,9.9, 8.3 Hz, IH), 2.16 (dddd, J= 13.6, 9.5, 5.1, 3.9 Hz, IH). MS found for Ci₈Hi₇NO₄: 312.3.

GBT998

[0342] GBT998 - (S)-2-hydroxy-6-((5-oxo-l-phenylpyrrolidin-2yl)methoxy)benzaldehyde

[0343] Step 1: To a suspension of (S)-5-(hydroxymethyl)pyrrolidin-2-one (230 mg, 2 mmol) and l-iodo-2-methoxybenzene (0.56 g, 2.4 mmol) in Dioxane (4 mL) was added Cul (0.08 g, 0.4 mmol), N,N-dimethylethylenediamine (0.05 mL, 0.4 mmol), K3PO4 (0.85 g, 4 mmol). After heating at 100 °C for 24 h, the mixture was cooled and was diluted with EtOAc, insoluble material was filtered off, the filtrate was concentrated and purified by column (Hexanes/EtOAc= 100:0 to 0:100) to give (S)-5-(hydroxymethyl)-l-(2methoxyphenyl)pyrrolidin-2-one (110 mg).

[0344] Step 2: To a solution of (S)-5-(hydroxymethyl)-l-phenylpyrrolidin-2-one (115 mg, 0.54 mmol) and 2,6-dihydroxybenzaldehyde (0.10 g, 0.70 mmol) in THF (4 mL) at 0 °C was added PPhj (polymer supported, 675 mg, 0.81 mmol) and DIAD (0.16 mL, 0.81 mmol). After stirred for 1 h, it was diluted with AcCN, the insoluble material was filtered off and the filtrate was concentrated and purified by column (100% EtOAc) to give (S)-2-hydroxy-6-((l(2-methoxyphenyl)-5-oxopyrrolidin-2-yl)methoxy)benzaldehyde (53 mg). ’H NMR (400 MHz, Chloroformé) δ 11.92 (s, IH), 9.68 (t, J = 0.5 Hz, IH), 7.38 - 7.30 (m, IH), 7.30 -

7.22 (m, IH), 7.14 (dd, J = 7.7, 1.7 Hz, IH), 6.99 - 6.89 (m, 2H), 6.50 (dq, J = 8.5, 0.6 Hz, IH), 6.25 - 6.18 (m, IH), 4.55 (dtd, J = 9.0, 5.1,4.0 Hz, IH), 4.10 - 3.94 (m, 2H), 3.73 (s,

138

3H), 2.75 - 2.55 (m, 2H), 2.48 (dddd, 7= 13.0, 9.6, 8.4,7.3 Hz, IH), 2.16 - 2.02 (m, IH).

MS found for Ci₉Hi₉NO₅: 342.3.

GBT1004

Boc2O,LiHMDS

Step 1

[0345] GBT1004 - 2-amino-4-((2-(l-isopropyl- lH-pyrazol-5-yl)pyridin-3-yl)methoxy) nicotinaldehyde

[0346] Step 1: Into a 250-mL round-bottom flask, was placed a solution of 4-chloropyridin2-amine (10 g, 77.78 mmol, 1.00 equiv) in tetrahydrofuran (150 mL). This was followed by the addition of LiHMDS(lM) (156 mL) dropwise with stirring at 0°C. The mixture was stirred for 20 min at 0 °C. To this was added Boc₂O (17.02 g, 77.98 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at 0 °C. The reaction was then quenched by the addition of 100 mL of NH4CI. The resulting solution was extracted with 2x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x150 mL of brine. The resulting mixture was concentrated under vacuum, washed with 2x20 mL of EA/hexane (3:7). This resulted in 12.5 g (70%) of tert-butyl N-(4-chloropyridin-2-yl)carbamate as a white solid.

[0347] Step 2: Into a 100-mL three neck round-bottom flask, was placed a solution of tertbutyl N-(4-chloropyridin-2-yl)carbamate (2 g, 8.75 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of BuLi (2.5M) (7.0 mL, 2.00 equiv) dropwise with stirring at -78 °C in 20 min. The mixture was stirred for 0.5h at -78 °C. To this was added N,N-dimethylformamide (2.0 mL, 3.00 equiv) dropwise with stirring at -78 °C in 5 min. The resulting solution was stirred for 1 h at -78 °C. The reaction was then quenched by the addition of 3 mL of hydrogen chloride (12M). The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 1x40 mL of 5% sodium bicarbonate and 1x30 mL of brine. The

139 resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1:4). This resulted in 1.46 g (65%) of tert-butyl N-(4-chloro-3formylpyridin-2-yl)carbamate as a yellow solid.

[0348] Step 3: Into a 100-mL round-bottom flask, was placed a solution of [2-[l-(propan-2yl)-lH-pyrazol-5-yl]pyridin-3-yl]methanol (500 mg, 2.30 mmol, 1.20 equiv) in Ν,Νdimethylformamide (50 mL). This was followed by the addition of sodium hydride (190 mg, 7.92 mmol, 2.50 equiv) at 0 °C. The mixture was stirred for 20 min at 0 °C. To this was added tert-butyl N-(4-chloro-3-formylpyridin-2-yl)carbamate (500 mg, 1.95 mmol, 1.00 equiv). The resulting solution was stirred ovemight at room température, and then it was quenched by the addition of 50 mL of water. The resulting solution was extracted with 8x20 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 506 mg (59%) of tert-butyl N-[3-formyl-4-([2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3yl]methoxy)pyridin-2-yl]carbamate as a yellow oil.

[0349] Step 4: Into a 100-mL round-bottom flask, was placed a solution of trifluoroacetic acid (10 mL) in dichloromethane (60 mL), tert-butyl N-[3-formyl-4-([2-[l-(propan-2-yl)-lHpyrazol-5-yl]pyridin-3-yl]methoxy)pyridin-2-yl]carbamate (500 mg, 1.14 mmol, 1.00 equiv). The resulting solution was stirred ovemight at room température. The resulting mixture was concentrated under vacuum. The crude product (500 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column,5um, 19* 150mm,; mobile phase, water with 0.05%TFA and MeCN (5.0% MeCN up to 26.0% in 10 min, up to 95.0% in 2 min,down to 5.0% in 2 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 122.9 mg (32%) of 2-amino-4-([2-[l-(propan-2-yl)lH-pyrazol-5-yl]pyridin-3-yl]methoxy)pyridine-3-carbaldehyde as a yellow solid. 'HNMR (300MHz, DMSO, ppm): 10.12(s, 1H), 8.79(m, 1H), 8.24(m, 2H), 7.59(m, 2H), 6.76(d, J=5.1Hz, 1H), 6.55(d, J=1.2Hz, 1H), 5.43(m,2H), 4.67(m,lH), 1.36(m, 6H); MS (ES, m/z); 338 [M+1-3CF₃COOH]⁺

140

GBT1006

Step 1

[0350] GBT1006 - 4-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)-2(methylamino)nicotinaldehyde

[0351] Step 1: Into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-(4chloropyridin-2-yl)carbamate (3.0 g, 13.12 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of sodium hydride (631 mg, 26.29 mmol, 1.20 equiv) at 0 °C. The mixture was stirred for 20 min at 0 °C. To this was added iodomethane (2.24 g, 15.78 mmol, 1.20 equiv) dropwise with stirring. The resulting solution was stirred for 6 h at room température. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 3.01 g (95%) of tert-butyl N-(4chloropyridin-2-yl)-N-methylcarbamate as a yellow oil.

[0352] Step 2: Into a 100-mL three neck round-bottom flask, was placed a solution of tertbutyl N-(4-chloropyridin-2-yl)-N-methylcarbamate (1.5 g, 6.18 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of BuLi (2.5M) (3.0 mL, 1.20 equiv) dropwise with stirring at -78 °C. The mixture was stirred for 30 mins at -78 °C. To this was added N,N-dimethylformamide (1.5 mL, 3.00 equiv) dropwise with stirring at -78 °C. The resulting solution was stirred for 1 h at -78 °C. The reaction was then quenched by the addition of 2.5 mL of hydrogen chloride (12M). The resulting mixture was concentrated under vacuum. The residue was dissolved in 40 mL of EA. The resulting mixture was washed with 1x30 mL of 5% sodium bicarbonate and 1x20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1:4). This resulted in 0.97 g (92%) of 4-chloro-2-(methylamino)pyridine-3-carbaldehyde as a yellow solid.

[0353] Steps 3 &4: Into a 100-mL round-bottom flask, was placed a solution of [2-[ 1(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methanol (1.15 g, 5.29 mmol, 1.00 equiv) in

141

Ν,Ν-dimethylformamide (40 mL). This was followed by the addition of sodium hydride (530 mg, 13.25 mmol, 2.50 equiv, 60%) at 0 C. The mixture was stirred for 15 min at 0 C. To this was added 4-chloro-2-(methylamino)pyridine-3-carbaldehyde (900 mg, 5.28 mmol, 1.00 equiv). The resulting solution was stirred ovemight at room température. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 5x30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (PrepHPLC-020): Column, SunFire Prep C18 OBD Column,5um, 19* 100mm,; mobile phase, water with 0.1%TFA and MeCN (3.0% MeCN up to 20.0% in 5 min, up to 95.0% in 2 min,down to 3.0% in 1 min); Detector, waters2489 254&220nm. This resulted in 107.1 mg (6%) of 2(methylamino)-4-([2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methoxy)pyridine-3carbaldehyde as a yellow solid. ’HNMR (400MHz, DMSO, ppm): 8.72 (m, IH), 8.17 (s, IH), 7.91 (m,lH), 7.52 (m, 3H), 6.56 (s, IH), 6.26(d, J=4.2Hz, IH), 6.15(d, J=3.3Hz, IH), 5.43 (m,lH), 5.12 (m,lH), 4.60 (m,lH), 2.87(d, J=3.3Hz, IH), 1.46(d, J=5.1Hz, IH), 1.35(d, J=5.1Hz, IH); (ES, m/z):352.1 [M+l]⁺

[0354] GBT1007- 2-(4-(hydroxymethyl)-l,3-dioxoIan-2-yl)-3-((2-(l-isopropyl-lHpyrazol-5-yl)pyridin-3-yl)methoxy)phenol

[0355] 2-Hydroxy-6-((2-( 1 -isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (0.4 g, 1.19 mmol) was dissolved in a solution of propane-1,2,3-triol (5.8 ml, 79 mmol) and DMF (5 ml). Amberlyst 15 resin (80 mg) and 3A molecular sieves (1 g) were added and the mixture was stirred in a heat block at 70 °C for 18 h. After cooling the mixture was filtered and taken up in ethyl acetate (200 ml) and water (100 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic phases

142 φ were washed with water (50 ml) and a saturated aqueous sodium chloride solution (50 ml), and dried over sodium sulfate. After évaporation, the residue was purified by silica gel chromatography (0 - 90% ethyl acetate/dichloromethane) to give 0.118 g (24%) of 2-(4(hydroxymethyl)-1,3-dioxolan-2-yl)-3-((2-( 1 -isopropyl-1 H-pyrazol-5-yl)pyridin-35 yl)methoxy)phenol as an off-white solid after lyophilization from acetonitrile/water. *H NMR (400 MHz, CDClj) δ 8.74 - 8.67 (m, 1H), 8.53 (s, 0.6H), 8.18 - 8.12 (m, 0.4H), 7.97 (d, J = 7.90 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.44 - 7.34 (m, 1H), 7.17 - 7.07 (m, 1H), 6.55 (d, J = SA! Hz, 1H), 6.42 - 6.36 (m, 1H), 6.31 - 6.23 (m, 1.6H), 5.95 - 5.89 (m, 0.4H), 4.98 (s, 2H), 4.71 -4.58 (m, 1H), 4.40-4.28 (m, 1.5H),4.24-4.17 (m, 0.6H), 4.10-4.01 (m, 1H),3.9910 3.92 (m, 0.6H), 3.73-3.65 (m, 0.6H), 3.56 (dd, J= 10.09, 20.18 Hz, 1H), 1.51 - 1.43 (m,

6H). MS (ESI) m/z 412 [M+H]⁺.

GBT1090

[0356] GBT1090 - (S)-2-((l-benzyl-5-oxopyrroIidin-2-yl)methoxy)-6hydroxybenzaldehyde

[0357] Step 1: To a solution of (S)-methyl 5-oxopyrrolidine-2-carboxylate (700 mg, 4.89 mmol) in DMF (5 mL) was added CS2CO3 (1.97 g, 5.99 mmol) and BnBr (0.59 mL, 4.99 mmol). After heated at 60 °C for 15 h, it was diluted with EtOAc, organic layer was washed with water, brine, dried and concentrated to give crude product which was purified by column (Hexanes/EtOAc=40:60) to give methyl (S)-l-benzyl-5-oxopyrrolidine-2-carboxylate (240 mg). To a solution of methyl (S)-l-benzyl-5-oxopyrrolidine-2-carboxylate (240 mg, 1.0 mmol) in THF ( 2mL) was added LiBH4 (IM in THF, lmL, Immol) at room température. After stirred at room température for 1 h, the solution was quenched with Sat. NH4C1, aqueous layer was extracted with EtOAc, EtOAc layer was combined, dried and concentrated to give crude product, which was purified by column (100% EtOAc) to give (S)-l-benzyl-5(hydroxymethyl)pyrrolidin-2-one (170 mg).

143

[0358] Step 2: To a solution of (S)-l-benzyl-5-(hydroxymethyl)pyrrolidin-2-one (170 mg,

0.83 mmol) and 2,6-dihydroxybenzaldehyde (0.15 g, 1.08 mmol) in THF (6 mL) was added PPh3 (polymer supported, 1.0 g, 1.25 mmol) and DIAD (0.24 mL, 1.25 mmol) at 0 °C. Then it was warmed up to room température and stirred for 1 h, AcCN was added to dilute the mixture, the insoluble material was filtered off, the filtrate was concentrated and was purified by préparative HPLC to give (S)-2-((l-benzyl-5-oxopyrrolidin-2-yl)methoxy)-6hydroxybenzaldehyde (95 mg). *H NMR (400 MHz, Chloroform-d) δ 11.93 (t, J - 0.4 Hz, 1H), 10.17 (t, J = 0.5 Hz, 1H), 7.39 - 7.29 (m, 1H), 7.29 - 7.18 (m, 5H), 6.54 (dt, J = 8.5, 0.7 Hz, 1H), 6.17 (dd, 7= 8.3,0.9 Hz, 1H), 4.85 (d, J= 15.2 Hz, 1H), 4.28 (d, J= 15.2 Hz, 1H), 3.99 (d, J = 4.0 Hz, 2H), 3.92 (td, J = 7.8, 7.2, 3.6 Hz, 1H), 2.68 - 2.45 (m, 2H), 2.33 - 2.19 (m, 1H), 2.10-1.96 (m, 1H). MS (M+H) found for Ci₉Hi₉NO₄: 326.4.

GBT1093 œO'Y^OH nh₂hci

CI^^CI

K₂CO₃

Step 1

[0359] GBT1093 - (S)-2-hydroxy-6-((5-oxo-4-phenylmorpholin-3yl)methoxy)benzaldehyde

[0360] Step 1: To a solution of (S)-benzyl 2-amino-3-hydroxypropanoate hydrochloride (5 g, 21.58 mmol) in THF-water (1/1, 80 mL) was added K2CO3 (8.95 g, 64.74 mmol) and chloroacetyl chloride (2.92 mL, 36.69 mmol). After stirred for 1 h, it was diluted with

EtOAc, organic layer was washed with water, brine, dried and concentrated to give benzyl (2chloroacetyl)-L-serinate (5 g).

[0361] Step 2: A solution of (5)-benzyl 2-(2-chloroacetamido)-3-hydroxypropanoate (2.55 g, 9.39 mmol) in iPrOH (20 mL) was added to KOtBu (3.16 g, 28.17 mmol) in iPrOH (15 mL) at room température. After stirred at room température for 1 h, the mixture was quenched with 6N HCl (10 mL) at 0 °C, extracted with EtOAc, organic layers were

144 combined, washed with brine, dried and concentrated to give isopropyl (2-chloroacetyl)-Lserinate as crude product.

[0362] Step 3: To a solution of (S)-benzyl 5-oxomorpholine-3-carboxylate in EtOH (7 mL) was added NaBEL (150 mg) at 0 °C, after stirred at room température for 3 h, it was quenched with NH4CI (220 mg in 0.6 mL water), and the insoluble material was filtered off, the filtrate was concentrated and was purified by column (DCM/MeOH= 100:0 to 80:20) to give (R)-5-(hydroxymethyl)morpholin-3-one (100 mg).

[0363] Step 4: To a suspension of (7?)-5-(hydroxymethyl)morpholin-3-one (100 mg, 2 mmol) and 3-iodopyridine (0.57 g, 2.8 mmol) in Dioxane (4 mL) was added Cul (0.08 g, 0.4 mmol), N,N-dimethylethylenediamine (0.05 mL, 0.4 mmol), K3PO4 (0.85 g, 4 mmol). After heating at 100 °C for 24 h, the mixture was cooled and was diluted with EtOAc, insoluble material was filtered off, the filtrate was concentrated and purified by column (Hexanes/EtOAc= 100:0 to 0:100) to give (S)-5-(hydroxymethyl)-l-(pyridin-3-yl)pyrrolidin2-one (55 mg).

[0364] Step 5: To a solution of (5)-5-(hydroxymethyl)-l-(pyridin-3-yl)pyrrolidin-2-one (55 mg, 0.29 mmol) and 2,6-dihydroxybenzaldehyde (0.05 g, 0.38 mmol) in THF (2 mL) was added PPh3 (polymer supported, 367 mg, 0.44 mmol) and DIAD (0.09 mL, 0.44 mmol) at 0 °C. Then it was warmed up to room température and stirred for 1 h, AcCN was added to dilute the mixture, the insoluble material was filtered off, the filtrate was concentrated and was purified by préparative HPLC to give (S)-2-hydroxy-6-((5-oxo-4-phenylmorpholin-3yl)methoxy)benzaldehyde (29 mg). *H NMR (400 MHz, Chloroform-d) δ 11.88 (d, J = 0.4 Hz, IH), 9.94 (d, J = 0.6 Hz, IH), 7.53 - 7.40 (m, 2H), 7.40 - 7.30 (m, 2H), 7.26 (s, 2H), 6.53 (dt, J = 8.5, 0.7 Hz, IH), 6.20 (dd, J = 8.3, 0.8 Hz, IH), 4.47 (dd, J = 16.9, 0.9 Hz, IH), 4.40-4.25 (m, 3H), 4.25-4.16 (m, IH), 4.15-4.07 (m, 2H). MS (M+H) found for

Ci₈Hi₇NO₅: 328.3.

145

φ GBT1123

Step 3

AICI₃DCM

[0365] GBT1123- terAbutyl (2-formyI-3-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridm-35 yl)methoxy)phenyl)carbamate

[0366] Step 1: fôrt-Butyl (3-methoxyphenyl)carbamate (0.517 g, 2.3 mmol) was dissolved in dry diethyl ether (12 ml) and cooled to -40 °C in a solvent bath. ί-Butyl lithium (4.1 ml of a 1.7 M pentane solution, 6.95 mmol) was added dropwise, the reaction was allowed to warm to -20 °C and stirred for 2 h more. The reaction was cooled to —78 °C, DMF (0.54 ml, 6.95 mmol) was added, and the reaction was allowed to gradually warm to 25 °C over 16 h. The reaction mixture was cooled in an ice bath and ammonium chloride solution (10 ml) was added. The reaction was extracted with ethyl acetate (3 x 80 ml), the combined organic phases were washed with a saturated aqueous sodium chloride solution (50 ml) and dried over sodium sulfate. After évaporation, the residue was purified by silica gel chromatography (0 - 30% ethyl acetate/hexanes) to give 0.46 g (79%) of tert-butyl (2-formyl-3methoxyphenyl)carbamate as a lightly-colored solid. MS (ESI) m/z 252 [M+H]⁺.

[0367] Step 2: tert-Butyl (2-formyl-3-methoxyphenyl)carbamate (0.38 g, 1.5 mmol) was dissolved in dichloromethane (10 ml) and added dropwise to a solution of aluminum chloride (1 g, 7.56 mmol) in dichloromethane (15 ml) while stirring in an ice bath. The yellowish solution was then stirred in a heat block at 50 °C. After 4 h, ice and water were added and the mixture stirred for 15 m. The reaction mixture was extracted with dichloromethane (3 x 50 ml), the combined organic phases were washed with water (30 ml) and a saturated aqueous

146 sodium chloride solution (30 ml), and dried over sodium sulfate. After évaporation the crude residue was carried directly into the next step. MS (ESI) m/z 138 [M+H] .

[0368] Step 3: 2-Amino-6-hydroxybenzaldehyde (0.207 g, 1.5 mmol) was dissolved in THF (4 ml). Di-terf-butyldicarbonate (0.726 g, 3.3 mmol) and 4-dimethylaminopyridine (37 mg, 0.3 mmol) were added and the reaction was stirred for 18 h. The solution was evaporated and the residue was purified by silica gel chromatography (0 - 40% ethyl acetate/hexanes) to give 50 mg (14%) of teri-butyl (2-formyl-3-hydroxyphenyl)carbamate. MS (ESI) m/z 238 [M+H]⁺.

[0369] Step 4: fôri-Butyl (2-formyl-3-hydroxyphenyl)carbamate (50 mg, 0.21 mmol) and 3(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-l-ium chloride (57 mg, 0.21 mmol) were dissolved in DMF (3 ml). The solution was purged with Ar gas. Potassium carbonate (116 mg 0.84 mmol) was added and the reaction mixture was stirred in a 60 °C heat block for 18 h. The reaction was cooled and water (50 ml) and ethyl acetate (50 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic phases were washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After évaporation the residue was purified by silica gel chromatography (5 - 50% ethyl acetate/hexanes) to give 5 mg (5%) of terr-butyl (2formyl-3-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)phenyl)carbamate as a white solid after lyophilization from acetonitrile/water. 'H NMR (400 MHz, CDCl·?) δ 10.51 (s, 1H), 8.74 (d, 7 = 4.81 Hz, 1H), 8.06 (d, 7 = 7.84 Hz, 1H), 7.60 (s, 1H), 7.48 (t, 7 =8.22 Hz, 1H), 7.44 - 7.39 (m, 1H), 6.91-6.81 (m, 2H), 6.36 (s, 1H), 5.10 (s, 2H),4.64 (d,7 = 6.51 Hz, 1H), 1.47 (d, 7 = 4.57 Hz, 6H), 1.41 (s, 9H). MS (ESI) m/z 437 [M+H]⁺.

GBT1131

[0370] GBT1131- (S)-2-hydroxy-6-((6-oxo-l-phenyIpiperidin-2 yl)methoxy)benzaldehyde

[0371] Step 1: To a suspension of (S)-6-oxopiperidine-2-carboxylic acid (1.0 g, 6.99 mmol) in EtOH (4 mL) at 0 °C was added SOCI2 (0.61 mL, 8.39 mmol). After stirred at room température for 3 h, it was concentrated to remove ail solvents, dried under high vacuum to

147 give corresponding ethyl ester. The ester was dîssolved in EtOH (15 mL) and was added

NaBH₄ (300 mg) at 0 C, the mixture was warmed up to room température and stirred for additional 15 h. The mixture was quenched with Sat. NH4C1, filtered off the insolubles and the filtrate was concentrated to give crude product, which was purified by column (DCM/MeOH=90:10) to give (S)-6-(hydroxymethyl)piperidin-2-one (450 mg) as white solid. [0372] Step 2: To a suspension of (S)-6-(hydroxymethyl)piperidin-2-one (150 mg, 1.16 mmol) and iodobenzene (0.35 g, 1.74 mmol) in Dioxane (2 mL) was added Cul (0.09 g, 0.46 mmol), N,N-dimethylethylenediamine (0.04 mL, 0.35 mmol), K₃PO₄ (0.49 g, 2.32 mmol). After heating at 100 °C for 24 h, the mixture was cooled and was diluted with EtOAc, organic layer was washed with brine, dried (Na₂SO₄) and concentrated to give crude product, which was purified by column (Hexanes/EtOAc= 100:0 to 0:100) to give (S)-6(hydroxymethyl)-l-phenylpiperidin-2-one (85 mg).

[0373] Step 3: To a solution of (S)-6-(hydroxymethyl)-l-phenylpiperidin-2-one (85 mg, 0.44 mmol) and 2,6-dihydroxybenzaldehyde (0.08 g, 0.57 mmol) in THF (5 mL) was added PPh3 (polymer supported, 550 mg, 0.66 mmol) and DLAD (0.13 mL, 0.66 mmol) at 0 °C. After warmed to room température and further stirred for 2 h, it was diluted with AcCN, the insoluble material was filtered off and the filtrate was concentrated and subjected to préparative HPLC to give (S)-2-hydroxy-6-((6-oxo-l-phenylpiperidin-2yl)methoxy)benzaldehyde (31 mg). ’H NMR (400 MHz, Chloroform-d) δ 11.90 (d, J = 0.4 Hz, 1H), 10.08 (d, J = 0.6 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.36 - 7.27 (m, 2H), 7.22 - 7.14 (m, 2H), 6.60 - 6.43 (m, 1H), 6.11 (dd, J = 8.3, 0.8 Hz, 1H), 4.25 (qd, J = 5.7, 4.2 Hz, 1H), 4.04 3.81 (m, 2H), 2.77 - 2.53 (m, 2H), 2.29 - 1.87 (m, 4H). MS (M+H) found for Ci₉Hi₉NO_4:326.5.

GBT001717

6-((2-(1-isopropyl-1/7-pyrazol-5-yl)pyridin-3-yl)methoxy)2,3-dimethoxybenzaldehyde

148 φ [0374] GBT1717- 6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)-2,3dimethoxybenzaldehyde. The compound was prepared by O-alkylation of 6-hydroxy-2,3dimethoxybenzaldehyde (A) and 3-(chloromethyl)-2-[l-(propan-2-yl)-lH-pyrazol-5yl]pyridine hydrochloride sait (INT-2) according to scheme 9, reaction step 4. The product as white solid was obtained after flash column purification. *H NMR (400 MHz, Chloroform-d) δ 10.49 (t, J = 0.4 Hz, IH), 8.69 (dd, J = 4.8, 1.7 Hz, IH), 8.29 (ddd, J = 8.0, 1.7, 0.9 Hz, IH), 7.61 (dd, J = 1.9, 0.5 Hz, IH), 7.44 (dd, J= 7.9, 4.8 Hz, IH), 7.03 (d, J = 9.0 Hz, IH), 6.52 (d, J= 7.9 Hz, IH), 6.36 (dd, J= 1.9,0.4 Hz, IH), 4.98 (s, 2H), 4.59 (hept, J= 6.7 Hz, IH), 3.95 (d, J = 0.4 Hz, 3H), 3.84 (s, 3H), 1.46 (d, J = 6.6 Hz, 6H). MS (M+H) found for 10 C₂iH₂3N₃O4_: 382.5.

Préparation of intermediate A

[0375] Step 1: To a suspension of 3,4-dimethoxyphenol (2.0 g, 12.97 mmol) in dihydropyran (2 mL, 21.87 mmol) at ambient température was added 1 drop of Conc. HCl. After stirred for 1 h, the solution was diluted with EtOAc, organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc = 65:35) to give 2-(3,4-dimethoxyphenoxy)tetrahydro-2H-pyran (2.9 g).

[0376] Step 2: To a solution of 2-(3,4-dimethoxyphenoxy)tetrahydro-2H-pyran (1.0 g, 4.2 mmol) in THF (6 mL) at 0 °C was added TMEDA (0.72 mL, 4.83 mmol) and BuLi (2.5 M, 2.02 mL, 5.05 mmol). After stirred for 1.5 h at 0 °C, it was added DMF (1.3 mL). After stirred for 1 h, the mixture was added 6N HCl (4 mL), and was stirred for 1 h at ambient température, additional 12N HCl (2 mL) was added to drive the reaction to completion. The

149 solution was diluted with EtOAc and water, organic layer was separated and washed with brine, dried and concentrated to give crude product, which was purified by column chromatography to give 6-hydroxy-2,3-dimethoxybenzaldehyde (490 mg).

GBT001659

2,3-dihydroxy-6-((2-(1-isopropyl-1 /-/-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

[0377] GBT1659- 2,3-dihydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3yl)methoxy)benzaldehyde.

[0378] To a solution of 6-((2-(1 -isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)-2,3dimethoxybenzaldehyde (24 mg, 0.05 mmol) was added BBr3 (IM, 0.5 mL), after stirred at ambient température for 30 min, the mixture was concentrated and the crude product was purified by préparative HPLC to give 2,3-dihydroxy-6-((2-(l-isopropyl-lH-pyrazol-515 yl)pyridin-3-yl)methoxy)benzaldehyde (10 mg). *H NMR (400 MHz, Chloroform-J) δ 12.01 (s, 1H), 10.32 (d, J = 0.5 Hz, 1H), 8.74 (dd, J = 4.8, 1.7 Hz, 1H), 8.00 - 7.92 (m, 1H), 7.60 (dd, J= 1.9, 0.6 Hz, 1H), 7.41 (dd, J= 7.9, 4.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.34 (d, J =

1.9 Hz, 1H), 6.19 (d, J= 8.8 Hz, 1H), 5.29 (s, 1H), 5.02 (s, 2H), 4.64 (hept, J= 6.6 Hz, 1H), 1.47 (d, J = 6.6 Hz, 6H). MS (M+H) found for Ci₉Hi₉N₃O4:354.4.

GBT001718

150

2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-3-methoxybenzaldehyde

[0379] GBT1718- 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3yl)methoxy)-3-methoxybenzaldehyde

BBr3

[0380] To a solution of 6-((2-( l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)-2,3dimethoxybenzaldehyde (50.00 mg; 0.13 mmol) in DCM (0.8 mL) at ambient température was added boron tribromide (0.13 ml; 1.00 mol/1). After stirred for 5 min, the red mixture was concentrated and the crude product was purified by préparative HPLC to give 2hydroxy-6-((2-( 1 -isopropyl-1 H-pyrazol-5-yl)pyridin-3-yl)methoxy)-3-methoxybenzaldehyde (15 mg). *H NMR (400 MHz, Chloroform-d) δ 12.15 (d, J = 0.6 Hz, 1H), 10.35 (s, 1H), 8.74 (dd, J = 4.8, 1.7 Hz, 1H), 7.97 (ddd, J = 7.9, 1.6, 0.7 Hz, 1H), 7.60 (dd, J= 1.8, 0.5 Hz, 1H), 7.41 (dd, J= 7.9,4.8 Hz, 1H), 6.98-6.94 (m, 1H), 6.34 (d,7 = 1.9 Hz, 1H), 6.18 (d, 7= 8.9

Hz, 1H), 5.02 (s, 2H), 4.72 - 4.57 (m, 1H), 3.84 (s, 3H), 1.47 (d, 7 = 6.6 Hz, 6H). MS (M+H) found for C2oH2iN304_:368.4.

GBT001723

151

[0381] GBT001723 - 2-((6-((2-(dimethylamino)ethyl)(methyl)amino)-2-(l-isopropyllH-pyrazoI-5-yl)pyridin-3-yl)methoxy)-6-hydroxybenzaldehyde. The compound was prepared by Mitsunobu coupling of (6-((2-(dimethylamino)ethyl)(methyl)amino)-2-(l5 isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol (A) with 2,6-dihydroxybenzaldehyde (INT3) according to scheme 9, reaction step 3. The product as green oil was obtained after flash column purification. ¹HNMR (400MHz, CDCI3, ppm): 11.87 (br s, 1H), 10.21 (s, 1H), 7.54(d, J= 8.8 Hz, 1H), 7.44 (s, 1H), 7.26 (t, J= 8.4 Hz, 1H), 6.50 (d, J= 8.8 Hz, 1H), 6.41 (d, J= 8.4 Hz, 1H), 6.20 (d, J= 8.4 Hz, 1H), 6.18 (s, 1H), 4.82 (s, 2H), 4.90-4.60 (m, 1H),

3.61 (t, y = 11.2 Hz, 2H), 3.03 (s, 3H), 2.43 (t, J = 11.2 Hz, 2H), 2.20 (s, 6H), 1.39 (d, 7=6.8

Hz, 6H); MS(ES, m/z:) 438.4 [M +1]⁺

[0382] Intermediate A was prepared followed the scheme below:

Step 2

LAH, THF

152

[0383] Step 1: Into a 25-mL round-bottom flask, was placed a solution of methyl 6-bromo2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridine-3-carboxylate (1.3 g, 4.01 mmol, 1.00 equiv) m tetrahydrofuran (15 mL). DIPEA (1.55 g, 3.00 equiv) and [2(dimethylamino)ethyl](methyl)amine (2.4 g, 23.49 mmol, 5.00 equiv) were added to the reaction mixture. The resulting solution was heated to reflux for 24 hr, and then it was quenched with 30 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate. The combined organic layers were washed with 1x80 mL of water and 1x80 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1-15:1) as eluent to fumish 1.22 g (88%) of methyl 6-[[2-(dimethylamino)ethyl](methyl)amino]-2-[l-(propan-2yl)-lH-pyrazol-5-yl]pyridine-3-carboxylate as a light yellow oil.

Step2. Into a 100-mL round-bottom flask, was placed a solution of methyl 6-[[2(dimethylamino)ethyl](methyl)amino]-2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridine-3carboxylate (1.2 g, 3.47 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of LAH (330 mg, 8.70 mmol, 2.50 equiv), in portions at 0 °C. The resulting solution was stirred for 4 h at room température. The reaction was quenched by the addition of 0.5 mL water, 0.5 mL 2.5M sodium hydroxide (aq.). The resulting solution was diluted with 50 mL of ethyl acetate. The solids were filtered out and washed with THF for 3 times. The resulting mixture was concentrated under vacuum. This resulted in 1.1 g (100%) of (6[ [2-(dimethylamino)ethyl] (methyl)amino] -2-[ 1 -(propan-2-yl)-1 H-pyrazol-5-yl]pyridin-3yl)methanol as a colorless oil.

[0384] From the foregoing it will be appreciated that, although spécifie embodiments of the invention hâve been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention.

[0385] 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.

[0256] As used herein, Table 1 includes compounds described below or tautomers or pharmaceutically acceptable salts thereof:

2-(imidazo[l_}2-a]pyridin-8-ylmethoxy>5-methoxybenzaldehyde,

2-(imidazo[ l ,2-a]pyridin-2-ylmethoxy)-5-methoxybcnzaldehyde,

153

2-( im idazo [ l, 5-a] py ridin-8-y lmethoxy)-5-me thoxy benzaldéhyde,

5-mcthoxy-2-(qiiinolin-5-yimethoxy)benzaldehyde,

5-methoxy-2-((l-methyI-lH-indazoi-4-yl)inethoxy)benzaldchyde,

5-methoxy-2-((8-methylimidazo[l,2-a]pyridÎn-2-yl)mcthoxy)benzaldehyde,

2-((lH-indazol-4-yl)methoxy)-5-methoxybenza]dehyde,

5-m ethoxy-2-(py rîd ίη-3-y Imethoxy )benzal dehyde,

2-((2-( l -isopropyl-1 H-pyrazol-5-yl)pyridin-3-yI)inethoxy)-5-methoxybenzaldehyde,

2-hydroxy-6-((2-( l -isopropyl-1 H-pyrazol-5-yl)pyridin-3-yi)mcthoxy)benzaldehyde,

2-((3“(2H-tctrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde,

2-((4-(2H-tctrazol-5-yi)benzyl)oxy)-6-hydroxybenzaldehydc, methyl 4-((2-lbnnylphenoxy)niethyl)benzoate,

4-((2-formylphenoxy)mcthyl)benzoic acid, methyl 3-((2-formylphenoxy)methyl)benzoate,

2-bromo-3-((2-(l-isopropyl-in-pyrazol-5-yl)pyridin-3-yl)methoxy)bcnzaldehyde,

2-hydroxy-6-((2-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl)pyridjn-3yl)methoxy)benzaldehydc,

2-hydroxy-6-((2-( 1-(3,3,3-trifluoropropyl)-1 H-pyrazol-5-yl)pyridin-3yl)methoxy)benzaldehyde,

2-fluoro-6-((2-( 1-(2,2,2-trifluoroethyl)-1 H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,

2-fluoro-6-((2-( 1 -(3,3,3-trîfluoropropyl)-1 H-pyrazol-5-yl)pyridin-3yl)methoxy)benza!dehydc,

2-fluoro-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehydc, and l-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylic acid, or a tautomer or phannaceutically acceptable sait thereof.

154

Compound	Structure	Name
1	Ό 0 φ^Η	2-(Îmidazo[l ,2-aJpyridin-8ylmethoxy)-5-mcthoxybenzaldeliyde
2	CO Ό 0	4-formy idazo[ 1,2-a] pyrid in-8- ylmethoxy)benzonitrile
3	cç Ό 0	2-(imidazo[ l,2-a]pyridîn-8ylmethoxy>4-methoxybcnza!dehyde
4 L	^ζδ Ό 0	2-(imidazo[l ,2-a]pyridin-6ylmethoxy>5-methoxy benzaldehyde i ___________________________________________________________________________________________J

155

5	Ο π Υ Οχ	2-(imidazo[ l,2-a]pyridin-2ylmethoxy)>5-meüioxybenzaldehyde
6	€Ο Ό 0	2-(imidazo[l ,5-a]pyridin-8ylmethoxyM-mcthoxybenzaldehyde
7	NJ* J Ό 0 çA Οχ	2-(imidazo[1,5-a]pyridïn-8' y lmethoxy>5-inethoxybenza Idehyde
8	/=\ _γ Ό Ο φΑ Οχ	2-(imidazo[ I_f2-a]py ridiri’7ylmethoxy)-5-methoxybenzaldehyde
9	Α\=ν ΑνΑ Υ θχ	2-(i m idazo[ l ,2-a]py rîd in-3ylmethoxy)-5-methoxybcnzaldehyde

156

ΙΟ	rO Ό 0	5-methoxy-2-(quinolin-5ylmethoxy)benzaldehyde
11	CO Ό 0 if Br	5-bromci-2-(iinidazo[l,2-a]pyridin-8- y lmethoxy)benzaldehyde
¹² :	CO Ό O _C\|LÎX^	4-chloro-2-(imidazo[l,2-a]pyridin-8- ylmethoxy)bcnzaldehyde
13	Vy¹ Ό 0 JO	2-(imidazo[ 1 _f2-a]pyridin-8y lmcthoxy)benzaldehyde
14	Vv ^kO 0	4-fluoro-2-(inuda2o[l,2-a]pyridin-8’ yltnetboxy)benzaldehyde t ____________________________________________________________________________________________________________________________1

157

15	CO Ό 0	2-(imidazo[ l,2-a]pyridin-8- ylmethoxy)-3-niethoxybenzaMehyde
16	Vy % 0 Y	2-(imidazo[ l,2-a]pyridin-8ylmcthüxy)-5-inethyfbenzaldchyde
17	νιγ Ό 0 ¢0	5-mcthoxy-2-(pyrro!o[ 1,2-a] pyrazin-4ylmethoxy)benzaldehyde
18	X τ Ό 0 ,χ·	2-(i midazo[l, 5-a] pyrid in-6y Imethoxyy 4-methoxy benzaldehyde
19	ο> Τ ⁰çO	2-(imidazo[ 1,5-a] pyrid in-5ylmcihoxy)-5-methoxybenzaldehyde

158

20	OO* A ί CN	3-fonnyl-4-(imidazo[l,5-a]pyridin-5y Imethoxy )benzûnitri le
21	Η Μ /^ΝΆ% Ό 0 ϊ <Α	2-(( 1 H-py rrolo(2,3-b ]py ridin-4yl)tnethoxy)-5-methoxybenzaldehydc
22	CO	5-ethyl-2-(imidazo[ 1,2-a]pyridirt-8- ylmethoxy)benzaldchyde
23 ί	\ ^NCO % ο <k	5-m ethoxy-2-(( 1 -methy 1-1 H-indazoI-4yl)methoxy)benzaldehyde
24	X A Ό 0 γ- A	5-methoxy-2-((8-methyl im idazo[ 1,2- a]pyrïdÎn-2-yl)methoxy)benzaldehyde

159

25	vXJ Ό 0 <Κ	2-(( l H-indazûl-4-yl)tnethoxy)-5methoxybenzaldehyde
26	/° Η -0	2-(( l H-py rrolo[23-b]pyrid in-4yl)methûxy)-5-methoxybenzaldehyde
27	PO Y CN	3-fonny l-4-(imidazo[ 1,2-a]pyridin-8ylmethoxy)benzonitrile
28	N^\ AnÇJ U 0	5-methoxy-2-(pyrrolo[ 1,2-a]py razin-6ylmethoxy)benzaldehyde
29 !	Ν==\ J-'nJX-cN Ό 0 X J	6-((2-fonnyl’4- tncthoxyphenoxy)methy l)pyirolo[ 1,2- a]pyrazine-7-carbonitrile

160

30	^Nsî\— ^'^tO^k'C0NH₂ Ό 0 X O-.	6-((2-fonnyl-4- methoxyphenoxy)methyl)pyrrolo[ l ,2- aJpyrazirie-7-carboxamide
31	Ν-Λ UJ X —0	2-(( l H-pyrazolo[3,4-b]pyridin-4- yl)methoxy)-5-methoxybenzaldehydc
32	V'N-N ^N^Y T ⁰ φ ^H	5-methoxy-2-(pyrazolo[ l ,5 -ajpyrazin- 3-y lmethoxy)benzaldehyde
33	Ç?ⁿ-^ cr o	5-inetho.xy-2-(pyaolo[ l ,2-a]pyrazin-6y lmcthoxy)benzaldehyde
34	n T cr a Y	2-(îmidazo[ l,5-aJpyridin-6- ylmethoxy)-5-methoxybeiizaldehyde

161

35	CT 0 CN	3 -formyl-4-( imidazof 1,2-aJpy ridin-8ylinethoxy)benzonitrile
36	OH CQ o <Λ“Ν	3-(imidazo[l,2-a]pyridin-8-ylmetliyl)- l ,3 -dihydroisobenzofiiran-1 -ol
37	co or o φ^	2-(imidazo[ 1,2-a]pyridin-5ylinethoxy)-5-methoxybenzaldehyde
38	CQ o hnO) ^ηΛΦ /0	N-(2-fc>rniyl-4methoxyphvny l)imidazo[ 1 fia]pyridïne-8-carboxaniide
39	ÇO O HN^O	N-(2-formy Ipheny l)imidazo[ l fiaJpyridinc-8-carboxamide
40	O_vNH_q O	2-fonny l-N-(imidazo[ 1,2-a ]py ridin-8yl)benzamide

162

41	Ο	5-methoxy-2-(pyridin-3ylmethoxy)benzaldehyde
Ό 0 I II
ΑΛ
Μ

Πϊ	O^OH % 0 <Χ;	4-((2-formyl-3- hydroxyphenoxy)methyl)benzoic ac id
43	^rAA W-_0H	2-hydroxy-6-((2-( l -isopropyl-1Hpyrazol-5-yl)pyr idin-3yl)methoxy)benzaldehyde
44	N*N l .^nh Çr ^N Ό 0 ôô	2-((3-(2H-tetrazol-5-yl)benzyl)oxy)-6- hydroxybcnzaldehyde
45	N-NH h ·< N^N (Γί Ό 0	2-((4-(2H-tctrazol-5-yl)benzyl)oxy)-6- hydroxybenzaldehyde

163

46	I 0^0 ίίη Sj 0 Y	methyl 4-((2- fonnylphenoxv)methyj)benzo;ile
47	Ο,χ,ΟΗ	4-((2-formy lphenoxy)methy l)benzoic acid
48	çA Ί3 0	methyl 3-((2- fonnylphcnoxy)methyl)bcnzoate
49	N'Y n\A) Â- 0	2-bromû-3-((2-( l -isopropyl-l IIpy razol-5-y l)py ridin-3yl)mcthoxy)benzaldchyde
50	k -, f'S «Y <ΓΎ CF ^OH	2- hydroxy-6-«2-( 1-(2,2,2trifluoroethy !)-111-py razoI-5-y 1 )pyridiii- 3- yl)methoxy)benzaldehyde

164

51	F x-x. C. t W Xs	2-hydroxy-6-((2-( 1-(3,3,3- trifluoropropyl)-1 H-pyrazol-5- yl)pyridin-3-yl)methoxy)benzatdchyde
T M V d	Λ) OH
52	Ν'			2-fluoro-6-((2-( 1 -(2,2,2-trifluoroethyl)-
	JL	Y		lH-pyrazol-5-yI)pyridin-3-
	N'N F-^f	% M	0	yl)methoxy)benzaldehyde
		*^A	^SF
53	Ν'			2-fluoro-6-((2-( 1-(3,3,3-
	Ί1			trifluoropropyl)-l H-pyrazol-5-
				y 1 )py ridin-3 -yl'Jmethoxy )bcnzaldehyde
	br’x φ	Ό Ai	0
	^F	kA	'F
i 54	N^Z	%·.		2-fluoro-6-((2-( 1 -isopropy t-111-
	JJ	x		pyrazol-5-yl)pyrïdin-3-
				y 1 )methoxy)benzaldchyde
	N-^Wy^,·	o	O	i
	Ar	^H
			'F
55	CkzOH o			1 -(2-fonnyl-3hydroxyphenelhy l)ptperidine-4carboxylic acid
		0
	Ar	^H
		ΌΗ

165

l	T Ό 0 Ν	4-(pyridîn-3- ylmethoxyjntcotinaldehyde
2	ν'Ύ 9 0 0 ΑΛη	3-(pyridin-3- y] methoxy)îsonicotinaldchyde
3	CO Ό Ο Ϋ	2-(imidazo [ l ,2-a]pyridi n-8ylmethoxy)ntcotinaldehyde
4	Ν*·γ Ό 0 Α+	3-(imidazo[ 1,2-a]pyridin-8ylmethoxy)picolinaldchyde
5	CC Ό 0 Α^ΛηNy» <k	5-(imidazo[ 1,2-a]pyridin-8ylmethoxy)-2medioxyîsonicotinaldehyde
6	CQ Ό 0 Λα_η	3-(imidazo [ 1,2-a ]pyr idin-8ylmethoxy)isonicotinaldehyde

166

7	νΆ Ό 0 A	3-(itnidazo[ 1 _s5-a]pyridin-8’ ylmethoxy)isonicotinaldehyde
8	p H ÇjA —o	2-mclhoxy-5-(pjTazolo[ 1,5 a_\|pyraziti-3ylmethoxy)isonicotinaldehyde
9	œJ^NH2 % H	8-((3 -formylpyridî n-2yloxy)mc(hyl)imidazo[ 1,2a]pyridine-6-cafboxaniide
10	0 ^Ν'^⁵γ^Λ'ΝΗ₂ Ί3 H ΛΛθ nA¹ <A	8-((4-formyl-6-methoxypyridin-3yloxy)methyl)imidazo[ 1,2ajpyridine-ô-carboxamide
II	CO Ό H -A 0	5-(imidazo[l ,2-a]pyridin-8ylmethoxy)-2-oxo-1,2dihydropyridine-4 -carbaldehyde i _

167

12	Z'N^l I ^H ^N II ⁰	2-(2-(imidazo[ l ,2-a]pyridin-8“ yl)ethyl)nicotinaldehyde
B	1 ^HΑΛ <k	5-(2-(imidazo[ 1,2-a]pyridin-8yl)ethyl)-2mcthoxyisonicotinaldchyde
14	CO 0Â —0	5-(( 1 H-pyrazolo[3,4-b]pyridin-4yl)methoxy)-2methoxyisonicoiinaldehydc
15	Vp η₂νΥΥ^ν -0	3-((4-fomiyl-6'inethûxypyridin-3yloxy)mdhyl)pyrazolo[1,5a]pyrazinc-2-carboxamide
16	? « nÇY° —O	5-((2-(1 H-pyrazol-5yl)pyrazolo[ 1,5-a]pyrazîn-3yl)me(hoxy)-2methoxyisonicotinaldchyde

168

17	Q γ 0 όΑ	2-(imidazo[l ,2-a]pyridïn-2ylmethoxy)nicotinaldchyde
18	ca ( H O^o -0	2- mcthoxy-5-((4,5,6,7tetrahydropyrazolo[ 1,5-aJpyrazin- 3- yl)mcthoxy)isonicotinaldehyde
19	CO Ό 0	2-(iniidazo[l ,2-a]pyridÎn-8ylmethoxy)nicotinaldehyde
20	cû Ό 0 J'	5-(iirnda*zo[ 1,2-a]pyridin-8 ylmethoxy)-2methylisoniœlinaldchydc
21	H M VAJ <A°	3-(( 1 H-pyrrolo [2,3-b]pyridin-4yl)methoxy)isonicotinaldehyde
22 ί	% 0	3-(imidazo[ 1,2-a]pyridin-8ylmcthoxy)isonicotinaldehyde

169

23	N^\	3-(jpyrrolo[ l ,2-a]pyrazin-6ylmethoxy)isonicotinaldehyde
	Ό 0 ô^Ah
24	Oy_cn Ό 0 AA N^A	6-((4-formylpyridin-3y ioxy)methy l)pyrrolo[ l ,2a]pyra2ine-7-carbonitrile
25	N^\ ^'O'-CONHj Ό 0 0^Λη	6-((4-formyl pyridin-3yloxy)mcthyl)pyrFolo[ l ,2-
	a]pyrazine-7 -carboxamide
26	H M <o p ^H	3-(( 11I-pyrazolo[3,4-b]pyridin-4yl)methoxy)isonicolinaldchyde
27	A%__N Mj Ό 0 Â	3-(pyrazolo[l ,5-a]pyrazin-3- yhnethoxy)isonicotinaldehyde
28	p ^HN il La	2-methoxy-5-((6-oxo-1,6- dihydropyridin-3yl)methoxy)isonicotinaldehyde
	Ό 0 ΛΑ_η Ny
	O\	J

170

29	H °V^NJ % 0 rîl ^H	2-methoxy-5-((2-oxo-1,2- dihydropyridin-4yl)methoxy)isonicotinaldehyde
30	/=* Ό 0 AA K	2-inethoxy-5-(oxa2ol-5- yl methoxy)isonÎcotinaIdehyde
31	/—N HN^J Ό O γ-	5-((lH-imidazol-5-yl)methoxy)-2- methoxyisonicotinaldehyde
32	f=\ HN^/N Ό O Y Oy	5-((lH-imÎdazol-2-yl)methoxy)-2- melhoxyisonicûtinaldchyde
33	p=N HhL^N Ό O ÂA J	5-((4H-1,2,4-triazol-3yl)methoxy)-2methoxyisonicotinaldehyde

171

34	N=N HN^N X Οχ	5-(( 1 H-tctrazol-5-yl)methoxy)-2methoxyisonicotinaldehyde
35	Ν=ι HfO Ό 0 θχ	5-((1 H-py razol-5-yl)methoxy)-2mcthoxyisonicotinaldehyde
36	N-NH ï 0 0 AA NssJ* Οχ	5-((1 H-pyrazol-4-y l)methoxv)-2methoxyisonicotinaldehyde
37	/το Ό 0 O^	2-methoxy-5-(oxazol-4- ylmethoxy)isonkotinaldehyde
38	JU Ό O Α^Λη Οχ	2-methoxy-5 -((2-methylpyridin-3 yl)methoxy)isonîcotinaldehyd e

172

39	NA Τ' ü 0 Νγ¹	2-methoxy-5-((4-methylpyridin-3yl)methoxy)isonicotinaldehyde
40	CF₃ Νη T 0 0 ΛΑ	2-methoxy-5-((6- (trifluoromethyl)pyridin-3yl)metlioxy)isonicotinaldehyde
41	NA T Ό O AA <K	2-mcihoxy-5-((6-methytpyridin-3yl)methoxy)isonicotinaldehyde
42	9 0 0 AA_h O-,	2-methoxy-5-(pyridin-3- ylmethoxy)isonicotinaldehyde
43	^N\|^Z^Y' Ό O <k	2-mcthoxy-5-((5-methylpyridin-3yl)methoxy)isonicotinaldehyde

44	ί	5-(ïsoquinolin' 1 -vlmethoxy)-2methoxyisonicotinaldehyde
	% 0 AA A
45	Ό O A A	2-methoxy-5-(quinolin-2- yltnethoxy)isonicotinaldehyde
46	Ç¹ Â	2-methoxy-5-(pyridi n-4yl methoxy)isonicotinaldehyde
47	JÔ Ό ? ΓΪΙ ^H K	2-methoxy-5’((3-methylpyridin-4- yl)mcthoxy)isonicotinaldehyde
48	Λ Br AA Ό O ,φτ^	5-((3-bromopyridin-4- yl)methoxy)-2- methoxyisonicotinaldehyde

174

49	CD cr o AA	3-(imidazo[ 1,2-a]pyridin-8ylmelhoxy)-6methyipicolinaldehyde
50	Cû ΟΓ OH	(5-(im idazo[ 1,2-a]pyridîn-5ylmclhoxy)-2-methoxypyridin-4yl)(mcthoxy)methanol
51	CD o hnD M	N-(4-formylpyridin“3- yl)imidazo[ 1,2-a]pyridine-8carboxomide
52	F₃C 0 A 0 O^{2 H}AA	2-methoxy-5-((6- (trifluoromcthyl)imidazo[l ,2a]pyridm-2- yl)methoxy) i son! cotinaldehydc
53	m M ° 0 Ό ^hJySi O/N CK	methyl 2-((4-iormyl-6methoxypyridin-3yloxy)methyl)imidazo[ 1.2a]pyridine-8-carboxylatc

175

54	I σ	2-inetlioxy-5 -(( 1 -methyl -2-οχο- 1,2-dihydropyridin-4yl)methoxy)isonicotinaldehydc
	% 0 A
55	A ΒγΆχ,Ν 0 0^ Μ	5-((3-bromoimidazo[ 1 _s2-a]pyridin- 2-yl)methoxy)-2- melhoxyisonicotinaldeliyde
56	^Β\ Ο π %/Ν ο <χ η^Α hyN	5-((6-bromoimidazo[l₍2-a]pyridin- 2-yl)mcthoxy)-2- methoxyisonicotinaldehyde
57	β_Γ π <yN Ο CT ^ΗΜ <k	5-((8-bromoimidazo[ 1,2-aJpyridin- 2-yi)methoxy)-2methoxyisonicotinaldchyde

176

58	or o iV^{H n}A x°	2-methoxy-5-((3 -mcthy l- [ l ,2,4]triazoIo[4,3-a]pyridin-8yl)methoxy)isonicotinaldehyde
59	Ô vn t» CT 0 A+ NyiJ χθ	5-((3-( ΙΗ-py razol-SyOimidazotl^-alpyridin^yl)methoxy)-2methoxyisonicotinaldehyde
60	H ,N o V1 y y ⁰ΔΑ Ν,Υ χθ	5-((6-(1 H-pyrazol-3yl)imidazo[ 1,2-a]pyridïn-2yl)methoxy)-2methoxyisonicotinaldehyde
61	lîA-ZA Or 0 [fAA'H N-A χθ	2-methoxy-5-((8-( 1 -methyl-111pyrazol-5-yl)imidazo[l ,2a]pyridin-2yl)methoxy)isônicotinaldehyde

177

62	CN J	5-((4-formyl-6-mcthoxypyridin-3- yloxy)methyl)picolinonitrile
	(λ 0 AA
63	Br-A^ cr o AA /0	5-((2-bromopyridin-3yl)mcthoxy)-2methoxyi sonicotinaldehyde
64	N'A. NcO¹ cr o rV^ /0	3-((4-formyl-6-mcthôxypyrïdin-3yloxy)methyl)picolinonitrile
65	«AU <JT 0 o AA Y	5-((2-( 1 H-pyrazol-5-yl) pyr idin-3yl)methôxy)-2methoxyisonicotïnaldehyde
66	N'V⁰' ? 0 0 AA nA	5-((5-bromopyridin-3yl)methoxy)-2methoxyisonicotinaldchyde

178

67	—0 ζΓΥ rO 0 VN γ CT 0-Λ Y χΟ	methyl 2-((4-(1,3-dioxolan-2-yl)6-methoxypyridïn-3yioxy)methyl)imidazo[l ,2a]pyridine-8-carboxylate
68	W Μ γ Ύ	2-((4-( 1,3-dioxolan-2-yl)-6methoxypyridin-3yloxy)methyl)imidazo[l ,2aJpyridme-8-carboxainide
69	οΆ-Ν Ο CT 0Λ ΧΛ, Λ	2-((4-(1,3-dioxolan-2-yl)-6incthoxypyridin-3-yloxy)methyl)- N-methyl imidazof l ,2-a]pyridine8-carbûxamide
70	ΗΝ'Ν, 0) 0 /Χπ /θ	5-((5-(111-pyrazol-5-yl)pyridin-3yl)methoxy)-2methoxyisonicotinaldchyde

179

71	η » Τ L? 0 0 ίίΐι ^Η	5-((4-(lH-pyrazol-5-yl)pyridin-3yl)methoxy)-2methoxyisonicotinaklehyde
72	~ΝΗ 7 ο Vn Ο ar oh Lv^oh	2-((4-(djhydroxymethyl)-6methoxypyridin-3 -yloxy) me thyl)N-methylimidazo [ 1,2-a]pyridine8-carboxamide
73	W NyJ CT OH ΛΑ* J>	2-((4-(dihydroxymethyl)-6methoxypyridin-3yloxy)methyl)imidazo[l ,2ajpyrid ine- 8-carboxamide
74	Μ ar o Y» A	2-methoxy-5-((5-( 1 -methyl-1Hpyrazol-5-y l)pyridin-3 yl)methoxy)isonicotinaldehyde

180

75	/ n-n qV A ΙίΆ^Η /0	2-meihoxy-5-((5-( l -methyl-1Hpyrazol-3-yl)pyridin-3yl)methoxy)isonicotinaldehyde
76	r^N.^H N (J 0 aa_h /0	5-((5-( 1 II-pyrazol-4-yl)pyridin-3yl)mcthoxy)-2- methoxyi sonicotinaldehy de
77	/ .-Λ Y 0 0 AA M /0	2-methoxy-5 -((5-( 1 -methyl-111py razoi-4-y l)py ridi n- 3 yi)methoxy)isonicotinaldchyde
78	o Y 0 o M /0	methyl 5-((4-formyl-6methoxypyridin-3y loxy)methyl)nÎco tinate

181

79	0 (j 0 AAh M /0	5-((4-ibnnyl-6-methoxypyridin-3- yloxy)mcthyl)nicotinic acid
80	jO n'V T CT 0 AA_h Νγ ^,0	2-methoxy-5-(qui nolïn-3 ylmethoxy)isonicotinaldehyde
SI	CT 0 Y	6-mcthyl-3 -(quinolin-3 - ylmcihoxyjpicolinaldehydc
82	Ct 0 iM nJ	5-(isoquinoIin-7-ylmethoxy)-2- methoxyisonicotinaldehyde

182

83	π Y ο⁷ ο ΛΑη γΝ	3-(isoquinolin-7-ylmethoxy)-6- methylpicolinaldehyde
84	bû <y ο «Y	2-methoxy-5-(( 1 -methyl-1 II· indazol-4yl)methoxy)isonicotinaldehyde
85	\ Μ 1 i σ o ¢0	6-methyl-3-(( 1 -methyl-1IIindazol-4yl)methoxy)picolinaldchyde
86 _	Ύ o^° œ b	tert-butyl 4-((2-formyl-6methylpyridin-3-yloxy)methyl )1 H-indazole-1 -carboxylate

183

87	H f H <y	5-(( 111-indazol-4-y l)methoxy)-2methoxyisonicotinaldchyde
	Ό 0 iY ιγ Οχ
88	H UJ Cf 0 (JA	3-((lH-indazol-4-yl)methoxy)-6methylpicolinaldehyde
89	-N. Y T cr o (Y A	6-methoxy-3-((1 -methyl-lHindazol-6- y l)methoxy)picoli naldehy de
90	<o Ç) 0 AA X	2-methoxy-5-((l -methyl-1Hindazol-7yl)methoxy)isonicotinaldehyde
91 .	Ns —n T CT 0 AA_h	6-methyl-3-((l -mcthyl-HIindazol-6yl)methoxy)picolinaldehyde

184

92	CO A Q7 0	6-mcthyl-3-(( 1 -methyl-1Hindazol-7yl)methoxy)picolinaldehyde
93	N cr o (V	3-(isoquinolin-l -ylmethoxy)-6methylpicolinaldehyde
94	d? cr o y	6-methy!-3-(quinolin-2ylmethoxy)picolinaldehyde
95	N F T ^HN CT O î¥ Ns> Οχ	5-((4-(1 H-pyrazol-4-yl)pyridin-3- yl)methoxy)-2- mcthoxyisonicotinaldehyde i
96	^ΒΓ vy <y o iY o^	5-((6-bromoimidazo[ 1,2-a]pyridin- 8-yl)methoxy)-2mcthoxyisonicotinaldehyde

185

97	αχ (Γ ρ ΛΑ νΑ À	8-((4-fonnyi’6’tnetiiQxypyridin-3yloxy)methyl)imidazo[ 1,2a]pyridine-6-carbonitrile
98	lÀ^CN cr ο AA A	5-((4-formyl-6-methoxypyridin-3- ylûxy)methyl)nicotinonitrilc
99	œ cJ o φ^Η	3-(benzo[d]oxazo!-4-ylniethoxy)- 6’methylpicol inaldchyde
ΙΟΟ	A cr o îV> M A	8-((4-formyl-6-mcthoxypyridin-3yloxy)methyl)imidazof 1,2- a] pyridine-6-carboxamide
ΙΟΙ	0 T <r o rSA A	5-((4-formyl-6*methoxypyridin-3- yloxy)metliyi)nicotinamide

186

102	_Λ L νη CF 0 ιΛΑ Οχ	5-((6-( 1 H-pyrazol-4- yl)imidazo[ 1,2-a]pyridin-8yl)methoxy)-2methoxyisonicotinaldehyde
103	œ QT 0 Χ^Λη 1 Οχ	5-(benzo[d]oxazol-4-ylmethoxy)- 2-methoxyisonicotinaldehyde
104	jPn «Tfl Η 0 ΑΛή Νγ¹ Οχ	5-((6-( 1 H-pyrazol-5yl)imidazo[l ,2-a]pyridin-8yl)methoxy)-2methoxyisonicotinaldchyde
105	Χ> /X J cr ο X-L NyL Οχ	5-(( 1,5-naphthyridin-4yl)methoxy)-2mcthoxyisonicolinaldchyde
106	Oô N y^ ο' Ρ ΛΑ	3-((1,5-naphthy ridin-4yl)methoxy)-6methylpicolinaldehyde

187

107	ν-νη CT 0 ΑΑ_η Οχ	5-(( I II-indazol-5-yl)methoxy)-2- methoxyisonicotinaldehyde
108	Ν-Ν^	6-methyl-3-(( l -methyl-1 H-
		indazol-5-
	(X 0	yl)methoxy)picolinaldehyde
	ίΐΊ'Π
109	ν-ν⁷ “Λϊ θ' Ο Α^η	3-((3-chloro-l -methyl-1 H-indazol-
	5-yl)methoxy)-6-
	methylpicol inaldehyde
HO	Ν—	2-methoxy-5-(( 1 -methyl-111-
		indazol-5-
	V fy·» Οχ	yl)mcthoxy)isomcotinaldehyde

188

111	kl ^Z n-n Y	5-((3-chloro-1 -methyl-11I-indazol- 5-yl)methoxy)-2- melhoxyisonicotinaldehyde
	or 0 Οχ
112	CO cOnh o Y	N-(4-formyl-6-methoxypyridin-3- yl)imidazü[ 1,2-a]pyridine-8carboxamide
113	Y o o ΛΑ Y/N	3-(( 1 _s3-dimethyl-1 H-pyrazolo [3,4bjpyridin-4-yl)mcthoxy)-6methylpicolinaldchyde
114	Y o o Y Οχ	5-((1,3-dimethyl-1 H-pyrazo!o[3,4b] pyridin-4-yl)mcthoxy)-2methoxyisonicotinal dchyde
115	N'Y YN-O-lY	3-((4-formyl-6-methoxypyridin-3- yloxy)methyl)picoiinamidc
	⁰ Ό 0	J
	AA Νγ Οχ	i i i l i 4

189

116	Vc, Ç) o ?	5-((2-chloroquinolin-3yI)methoxy)-2methoxyisonicotinaldehyde
117	1 1 h J 0 0 7~ L	5-((2-( 1 H-pyrazol-5-yl)quinolin-3yl)methoxy)-2methoxyisoriicotinaldehyde
118	Q. lU CT 0 L	2-methoxy“5-(quinoxalin-2ylmethoxy)îsônicotinaldeliyde
119	rΙΊ Ό 0 AA	6-methyl-3 -(quinolin-5ylmethoxy)pico!inaldehyde
120	LzJLJ Ό 0 A/'n nA /0	2-mcthoxy-5-(quînolîn-5 ylmethoxy)isonicotinaldehyde

190

121	Ν-ν/	6-methy 1-3-(( 1 -methyl-1Hpyrazolo[3,4-b] pyridin-5 yi)methoxy)picolinaldehyde

Π
T
Ό 0 1 il
ÂA
ΐίγΝ
122	Μ / N N	2-methoxy-5-((l-methyl-1II-
	< A	pyrazolo[3,4-bJpyri din-5-
	V Ό O liV^ N-A	yl)methoxy)isonicotinaldehyde
123		5-((7-( III-pyrazol-3-
	^N\-=A A	yl)imidazo[ l,5-a]pyridin-8-
	Y Y 7	yl)methoxy)-2-
	cr o ^N^NH N Y A	methoxyisonicotinaldehyde
124	nA	5 -((5 -(21I-tetrazol-5 -yl)pyridln-3-
	L NH 0*^ 0 Ατ^ΛηNsA A	yl)methoxy)-2-
	methoxyisonicotinaldehyde

191

125	n-n _Λ L NH (J 0 A Οχ	5-((6-(2H-tetrazol-5yl)imidazo[ l ,2-aJpyridm-8yl)methoxy)-2methoxyisonicotinaldehyde
126	s-\ ,0 Y	ethyl 2-(5-(inndazo[l,2-a]pyridin- 8-ylmethoxy)-2-mcthûxypyridin4-yl)thiazolidine-4-carboxylate
127	N^ CT 0 AA Ny» Οχ	2-methüxy-5-((2-( 1 -methyl -1Hpyrazol-4-yl)pyridin-3yl)methoxy)lsonicotinaldchyde
128	VA tj o NH a Οχ	5 -((2-( IH-py razol-4-y l)py r i din- 3 yl)methoxy)-2methoxyisonicotinaldehyde
129	Pï 1 JL? 0 0- (¥« Οχ	2-methoxy-5-((2-( 1-methyl-1Hpyrazol-5-yl)pyddin-3yl)methoxy)isonicotinaldehyde

192

130	Π τγ^Ν·_Ν0^ 0 AA N .A A	2-methoxy-5-((2-( 1 -methyl-1Hpyrazol-3-y l)py ri di n-3 yl)methoxy)isonicotinaldehyde
131	li^N >y;^nhor o ⁿ'ⁿ M	5-((2-(2H-tetrazûl-5-yl)pyridin-3yl)methoxy)-2methoxyisonicotinaldehyde
132	Q ; CT qHN~n AA Νγ A	2-methoxy-5-((2-(4-methyl-1Hpyrazol-5-yl)pyrîdtn-3y 1 )methoxy )isonîcotinaldehyde
133	\|q-NH >q q M /0	5-((3-(lH-pyrazol-5yl)isoquinolin-4-yl)methoxy)-2methoxyisonicotinaldehyde
134	nA ^Vn % 0 AA Y /0	5-((2-( 1 H-pyrazol-1 -yl)pyridin-3 yl)methoxy)-2methoxyisonicotinaldehyde

193

I35	N'Y	3 -((2-( 1 H-pyrazol-1 -y l)py ridin-3 yl)methoxy)-6methylpicolinaldehyde
O T ^Vn S> 0
Î\|Vb
Ln
136	N'Y	6-methyl-3-(pyridin-3-
	9 Ÿ	ylmethoxyjpicolmaldehyde
137	0	methyl 8-(((4-formyl-6-
		methoxypyridin-3-
	yl)oxy)methyl)imidazo[ 12-
	nYY Ό 0 ^NY	a]pyridinc-6-carboxylate
138	0	methyl 2-bromo-8-(((4-formyl-6-
	τΓ-νΎ^Ο^ Br—\ J J	methoxypyridin-3-
	yl)oxy)methyl)imidazo[ 1,2-
	νγ % 0 Y <K	a]pyridine-6-carboxylate
139		3-(imidazo[l₅5-a]pyridin-8-
	\Jy Ό 0 AA Y^N	ylmethoxy)-6methylpicolinaldehydc

194

MO	/Γ-ΝΆ ^NJJ Ό ο ΑΛ Μ	5-(imidazo[l,5-a]pyridin-8ylmethoxy)-2mcÎhoxyisonicotinaldehyde
I4l	0 î ? >0 ίίηρ ^H \ <K	(5-(methoxycarbonyl)pyridin-3yl)methyl 5-(((4-formyl-6melhoxypyndin-3yl)oxy)methyl)nicotînate
142	V\ % o rVH V 0-.	5-((2-( 1,4-dinwthyl-l H-pyrazoÎ-5yl)pyridîn-3-yl)mcthoxy)-2methoxyisonicotinaldehyde
Ï43	I I r i	5-((2-(1,5-dimelhyl-l H-pyrazol-4y l)pyridi n-3-yI)mcthoxy)-2melhûxyîsonicotinaldehyde
M4	O n-AA γΑ OH XA> <k	2- hydroxyethyl 5-(((4-(1,3dioxolan-2-yl)-6-rnethoxypyridïn- 3- yl)oxy)methyl)nicotinate

195

145	Ο	methyl 5-(((4-(1,3-dioxoIan-2-yl)ô-methoxypyridin-3yl)oxy)methyl)nicotinate

N U
	I Ό 0-Α Λ/ό
	Μ <k
146	0	methyl 5-(((4-(bîs(2-
	N^AcT ΗΟ ό ο⁷ιΑν^ο ^Νχτ A A ^ΟΗ	hydroxyethoxy)methyl)-6-
	methoxypyridin-3-
	yl)oxy)mcthyl)nicotinate
147	νΥ	5-((2-( 1,3-dimethyl-1 H-pyrazol-4-
	Al	yl Jpyrïdi n-3-yl)methoxy)-2-
	ν*\ % ο ΛΛη κγ τ Οχ.	mcthoxyi sonicotinaldehy de
148	νΥ	5-((2-( l ,3-dimethyl-1 H-pyrazol-5-
	>IL 0	yI)pvridin-3-yl)methoxy)-2-
	% Ο ΛΛ^η Νγ °χ	methoxyisonicotînaldehydc
149	N Y	5-((2-( 1 -ethyl-1 H-pyrazol-5-
	J1 xÿj	yl)pyridin-3-yl)methoxy)-2-
	ⁿ ^N\ A ο ^Ί ν Y Οχ	methoxyisonicotinaldehyde

196

150	^N’A ο Τγ. <κ	5-((2-( I -isopropyl-1 H-pyrazoi-5yl)pyridin-3-yl)methoxy)-2naethoxyisonicotinaldehyde
151	/Aï r^N % ο <Κ	2-mcthoxy-5-((2-(3-methyl-1Hpyrazol-1 -yl)pyridin-3yl)methoxy)i sonicotinaldehyde
152	0 Ν^Ά^Η ϊ ο ο-\ Αγ°	5 -(((4-( 1,3-dioxolan-2-yl)-6methoxypyridin-3yl)oxy)methyl)nicotinic acid
153	Α» % ν^ληαα <κ	(E)-2-niethoxy-5-((2-(4-methyl- 1 H-pyrazol-5-yl)pyridin-3yl)methoxy)isonicotinaldchyde oxime
154	νΆ τ % Ν-^0ΗΑΑ ^νΆ Οχ.	(E)-2-methoxy-5-(pyridin-3ylrnethoxy)isonicotinaldchyde oxime

197

155	co ÇJ ^H<k	2-(5-(imîdazo[ 1,2-a]pyridin-8ylmethoxy)-2-methoxypyridin-4yl)thiazoiidine
156	CO % S-A Aî y z^o	1 -(2-(5 -(imidazof 1,2-a]pyri din-8ylmethoxy)-2-methoxypyrid in-4yl)thiazolidîn-3-yl)ethanone
157	nA. j^N'A _h/_Y ^N^ u ° ^J rV N-X <K	5-((2-(4-( 1 H-pyrazol-3yl)piperazin- l-yl)pyridin-3yl)melhoxy)-2methoxyisonicotinaldehyde
158	CO Ό 0 âa_h ^Nv^ ΟγΡ F	2-(difluoromethoxy)-5(imidazo[l ,2-a]pyridin-8y]mcthoxy)isonicotinaldehyde
159	% o Xa <k	2-methoxy-5-((2-phenylpyridin-3yl)methoxy)isonicotinaldehyde

198

160	'f 1Π ⁿUÇj νΑο °χ	5-((3 -( 1 -i sopropy 1-1 H-pyrazol- 5 yl)pyridin-4-yl)methoxy)-2methoxyisonicotinaldehyde
I6l	Ν-γΥ 0 °χ	5-([2,3'-bipyridin]-3-ylmctht>xy)- 2-methoxyison.icotinaldehyde
162	1 ^ΝΧ,ϊή αχ <, Οχ	2- methoxy-5-((2-(o-tolyl)pyridin- 3- yl)methoxy)isonicotinaldehyde
163	^Χ0 _Ννφ V % 0 ÂA °χ	2-metlioxy-S-((2'-methoxy- [2,3 bipyridîn]-3yl)methoxy)isonicotinaldehyde
164	1 °^° 9 1	methyl 4-(((2-formylpyridin-3yl)oxy)methyl)benzoate

199

365	CK,OH Ο Ό 0 AA	4-(((2-formyl-6-methylpyridin-3- yl)oxy)methyl)benzoic acid
166	CkOH 0 Ό 0 AA^h	4-(((2-formylpyridin-3yl)oxy)methyl)benzoic acid
167	0 II	methyl 3-(((4-formylpyridin-3-
	qV Ό 0	yl)oxy)methyl)benzoate

168	0	methyl 3-(((2-formyl-6-
		methyIpyridin-3-
	Ό O AA^h	yl)oxy)mcthyl)benzoate
169	0 il	3-(((4-formylpyridin-3 -
	Çr ^OH ^0 0 AA	yl)oxy)metliyl)benzoic acid
	U

200

170	çA. Ό 0 ΑΛ Υ,Ν	3-(((2-fôrmyl-6-methylpyridin-3- yl)oxy)methyl)bcnzoîc acid
171	0	3-(((2-formy lpy ridin-3 -
	\|Υγ%Η Ό 0	yl)oxy)methyl)benzoic acid i
172	Y	2-methoxy-5-((2-( 1 -(2-
	JL xJ	methoxyethyl)-1 H-pyrazol-5-
	'r	yl)pyridin-3-
	“A % 0 - y- Οχ	yl)methoxy)isonicotinaldehyde
173	N Y	2-methoxy-5-((2-(l-propyl-1II-
	~ JL xJ	pyrazol-5-y l)pyridin-3 -
	ⁿ'ⁿ^ X> 0 AA Οχ	yl)methoxy)isonicotinaldehyde
174	nY	2-mcthoxy-5-((2-(l -(2,2,2-
	A xJ	trifluorocthyl)-1 H-pyrazol-5-
		yl)pyridin-3-
	A \> o ^F A ΛΥ y <A	yl)methoxy)isomcotinaldehyde ................ ..... - 1

201

175	N'A Vo ο a_f ιΛ^^η Οχ	5-((2-(1-(2,2-diiIuoroethyl)-1IIpyrazol-5-yl)pyridin-3yl)melhoxy)-2methoxyisonicotinaldehyde
176	^N ^NX^· Lq ο Γ AA Γιι ^ΗΑ-Ν	3-((2-( 1 -i sopropy 1-1 H-pyrazol-5yl)pyridin-3yl)methoxy)picolinaldehyde
177	νΑ ^N'^Nyio ο ÂA Αν	3-((2-( 1 -isopropyl-111-pyrazol-5yI)pyridin-3-yl)methoxy)-6methylpicol i naldehyde
178	N'A »Άθ 0 A OyF F	2-(difluoromethoxy)-5-((2-( 1 isopropyl-1 II-pyrazol-5yl)pyridin-3yl)methoxy)isonicotinaldehyde
179	CO CT ^a>--	5-(imîdazo[ l ,2-a]pyridin-8ylmethoxy )-2-(2metlioxyethoxy)isomcolinaldehyde

202

180	νΆ 'Ά 0	5-((2-( 1 -isopropyl-1 II-pyrazol-5- \| yl)pyridin-3 -yl)methoxy)-2-(2methoxycthoxy)ïsonicotinaldehyde
18I	Ύ Ο νΑυ Μ Ύ 0 ^NÇj^O °χ	5-((3 -( 1 -isopropyl-1 H-pyrazol-5yl)pyrazin-2-yl)methoxy)-2mcthoxy iso nicotinaldehyde
182	I Ζ-Δ□ A ~y~o Ο 'F-z ο X	3 -((4-formyl-6-methoxypyridin-3 yloxy)mcthyl)picolinate
183	N'y °H₀J <Α <	5 -((2-(2-hydroxypropan-2yl)pyridin-3 -yl)methoxy)-2methoxy i sonicotinaldehyde
184	1 ^NA n-AAJ MJ o nÇjA% A-x	2-(2-methoxyethoxy)-5-((2-(l methyl-1 H-pyrazol-5-yl)pyridin-3 yl)methoxy)isonicotinaldehyde

203

185	nA	2-(2-mcthoxycthoxy)-5 -((2-( 1 methyl-1 H-pyrazol-5 -y l)pyridin-3 yl)methoxy)nicotinaldehyde
	V Φν 0 0 u 1
186	A	nA	3-hydroxy-5-((2-(l -isopropyl-1 H-
	aJ	pyrazol’5-yl)pyridin-3-
	V		yl)methoxy)isonicotinaldehyde
		0^
	nJ%
		OH
187			3-(benzyloxy)-5-
	O		hydroxyisonicotinaldehyde
	% \|	0
	A	1 ^H
		X)H
188	A	nA	3-((2-( 1 -isopropyl-1 Il-pyrazol- 5 -
	aJ	y l)pyridin-3 -yl)methoxy)-5methoxyisonicoti naldehyde

	or
	C	jZA
		p
189	v	nA,	5-((2-(2-isopropyl-2H-1,2,4-
		aJ	triazol-3-yl)pyridin-3 -
	N' T	I	yl)methoxy)-2-
:	VN	cr	m ethoxy isonicotinaldehyde
	a	/%
	d
	\

204

Hw	M	AJ <r	5-((2-( 1 -isopropy 1-4-methy l-1Hpyrazol-5-yl)pyridtn-3yl)methoxy)-2methoxyisonicotinaldehyde

	O
	\
191		nO		5-((2-( 1 -(2-hydroxyelhy l> 111-
		âJ		pyrazoi-5-yl)pyridin-3 -
	V Z			yl)methoxy)-2-
	n-n	o 0 t II		melhoxyisonicotinaldehyde
	HO²	Y
		T
192		0 JOH		2,2,2-trifluoroacetic acid : 6-(((4- formylpyridin-3-
			yl)ôxy)rnethyl)picolinic acid (1:1)
	γ.	<N
	\|	CF3COOH
	or
	^νΆ
193		N M-		2-mcthoxy-5-((2-( 1-((2-
	Me₃Si^z		(trimcthylsilyl)ethoxy)incthyl)-1II-
	^NÂ T		pyrazol-5-yl )pyridin-3 -
			Ό O	yl)mcthoxy)isonicotinaldchyde
			rïr ^H
			M
			L
194		νΎ		5-((2-(4-mcthyl-1 H-pyrazol-5-
	rt Cr	AJ		yl)pyridin-3 -y 1 )methoxy)-2-oxo- 1,2-dihydropyridine-4-
	cr		carbaldehydc
	hnQo
	d

205

195	Νγ ιΗ'γλ) ο Ϋ <κ	5-((2-( l-cyclobutyl-l II-pyrazol-5yl)pyridin-3 -y l)mcthoxy)-2methoxyisonicotinaldehyde
196	Q.x NxJU v I 0 0 AA	5-((2-( 1 -cyclohexyl-111-pyrazol-5 yl)pyridki-3 -y l)mcthoxy)-2methoxyisonicotinaldehyde
197	N'Y Ό % _oδγ- Οχ	5-((2-( 1 -(cyclohexylmethyl)-l Hpyrazol-5-yl)pyridin-3yl)mcthoxy)-2mcthoxyisonïcotinaldehyde
198	Q Μζ Λλ^η Νγϋ θχ	5-((2-( 1 -cyclopentyl-1 H-pyrazol- 5-yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde
199 1	Ο ΗΟ-S Ή <Γ J Ο γ5^θ	2-(5-(3-((4-formyl-6- methoxypyridîn-3yloxy)methyl)pyridin-2-yl)-l Hpyrazol-l-yl)acetic acid

206

200	A J	methyl 3-(5-(3-(((4-formyl-6methoxypyridin-3yl)oxy)methyl)pyridm-2-yl)-l Hpyrazol-1 -yl)propanoate
NN V ^0	Ό 0 N^J³ °x
201		N%	3-(3-(3-((4-formyl-6-
		N. A J	methoxypyridin-3-
	U k / *<7 T V /Ά J I	yîoxy)mcthyl)pyrt din-2-yl)-111-
	/—7 X-sJ J HO O	pyrazol-l-yl)propanoic acid

		0
		\
202	N'	Ά	3-(5-(3-(((4-fomiyl-6-
	À	A	methoxypyridin-3-
	\\		yl)oxy)Tnethyl)pyridin-2-yl)-1 H-
	N-N	Ό 0	pyrazol-l-yOpropanoic acid
	V	AA^h
	HO
		°x
203	0		3-(((4-formyl-6-methoxypyridin-3-
	(Γί	ΌΗ	yl)oxy)methyl)benzoic acid
	LJ
	%	0
	r¥	Ύ

	<k
204	CN		6-(((4-formylpyridin-3-
			yl)oxy)methyl)nicotinon itri le
	il 1		2,2,2-trifluoroacetate
	cf₃cooh
	Ό	0 il
	rîr
	N<J«

207

205	CkOH HCl ^NU P	6-(((4-formylpyridin-3yl)oxy)methyl)nicotinic acid hydrochloride
206	H n Y lo il 1 2CF3COOH ΝΎ u O JJ	2,2,2-trifluoroacetic acid : 6-(((4formy lpyridin-3 -yl)oxy)methyl)N-(methylsulfonyl)nicotinamide (2:1)
207	N'Y ΑαΛ ^fA Qr ^H	2-(2-methoxy^rethoxy)-5-((2-( 1 (2,2,2-trifluoroethyl)-1 H-py ra201 5-yl)pyridin-3yl)methoxy)isonicotinaldehyde
208	Νγ A ^F Ν<γ O·-	2-methoxy-5-((2-( 1 -(3,3,3trifluoropropyl)-1 H-pyrazol-5yl)pyridin-3yl)methoxy)isonicotinaldehyde
209	N'Y A Y 0 r JA	2-(2-methoxyethoxy )-5-((2-( 1 (3,3,3-trifluoropropy 1)-1Hpyrazol-5-yl)pyridin-3yl)methoxy)isonicotinaldehyde

208

210	N'N λ If ? ? ^F Λ ιήρ NY	2-methyl-5-((2-(l-(2,2,2· trifluoroethyl)-l H-pyrazol-5yl)pyridin-3yl)methoxy)isonicotinaldehyde
211	à'Λα γ Ar ^HF X	2-methyl-5-((2-(l-(3,3,3- trifluoropropyl)-1 H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde
212	Αλχ fY_f(Wh	3-((2-(1 -(2,2,2-trifluorocthyl)-l Hpyrazol-5-yl)pyridin-3 y l)mcthoxy)i sonicotinal dehyde
213	^N'p X X) 0 T X	3 -((2-( 1-(3,3,3-tri Π uoropropy Ο- Ι H-pyrazol-5-yl)pyridin-3yl )methoxy)isonlcotinaldehyde
214	N'S ^N'^Ny- ό o Λ	3-chloro-5-((2-( l-isopropyl- i Hpyrazol-5-yl)pyridin-3yl)mcthoxy)isonïcotina!dehyde
215	^N'^NyA> o ΑΧ	3-((2-( 1 -isopropyl-1 H-pyrazol-5yl)pyridin-3-yl)methoxy)-5methylisonicotinaldehyde

209

216	N'Y Ya F N^. Jk	3-chloro-5-((2-(l-(3,3,3- triiluoropropyl)-11I-pyrazol-5yl)pyridin-3- yl)methoxy)i sonicotinaldehyde
217	A S 0 Lf ï I F Ύ	3-methyl-5-((2-(l-(2,2,2trifluoroethy 1)-1 H-pyrazol-5 yl)pyridin-3yl)methoxy)isonicotinaldchyde

The compound is selected from 5-hydroxy-2-(2methoxyethoxy)isonicotinaldehyde (Compound 218), 5-hydroxy-2-(2methoxyethoxy)nicotinaldehyde (Compound 219), 5-((2-(1-isopropyl-1 lI-pyrazol-5-yl)pyridin-

3-yl)methoxy)-2-oxo-l,2-dihydropyridine-4-carbaldehyde (Compound 220), 5-((2-(4-mcthyl-

H-pyrazol-5-yl)pyrÎdm-3-yl)methoxy)-2-oxo-1,2-dihydropyridme-4-carbaldehyde (Compound

221), or a tautomer or pharmaceutically acceptable sait thereof.

5-(imidazo[ 1,2-aJpyridin-8-ylmcthoxy)-2-methoxyisonicotinaldehyde,

2-methoxy-5-((5-methylpyridin-3-yl)inethoxy)isonicotinaldehyde,

5-(isoquinolin-1 -ylmethoxy)-2-methoxyisonicotinaldehyde,

2-methoxy-5-(quinolin-2-ylmethoxy)isonicotinaldehydc,

2- methoxy-5-(pyridin-4-ylmethoxy)isonicotinaldchyde,

3- (imidazo[l,2-a]pyridin-8-ylmcthoxy)-6-methylpicolinaldehyde, methyl 2-((4-forrnyl-6-melhoxypyridin-3-yloxy)mcthyl)imidazo[ 1,2-a]pyridine-8-carboxylate, 2-mcthoxy-5-((3-methyl-[l,2,4jtriazolo[4,3-a]pyridin-8-yl)methoxy)isonicotinaldehyde,

5-((2-bromopyridin-3-yl)mclhoxy)-2-methoxyisonicotinaldehyde,

5-((2-(lH-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde_f

5-((5-bromopyridin-3-yl)methoxy)-2-mcthoxyisonicotinaldehydc,

2-methoxy-5-((5-(l-methyl-ni-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldchyde, 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid, 2-methoxy-5-(quinolm-3-ylmethoxy)isonicotinaldehydc,

210

2- methoxy-5 -(( l -methyl-111-indazol-4-yl)mcthoxy)isomcotinaldehydc, tert-butyl 4-((2-foimyl-6-methylpyridin-3-yIoxy)methyl)-1 H-indazole-1 -carboxylate,

6-mclhy 1-3 -(( 1 -methyl-11I-îndazol-6-yl)methoxy)picolinaldehyde,

6-methyl-3-(( 1 -methyl-1 H-indazol-7-y l)methûxy)picolinaldehyde,

3- (isoquinolin-1 -ylmethoxy)-6-methylpicolinaldehyde,

5- (benzo[d]oxazol-4-ylmethoxy)-2-mcthoxyisonicotinaldehyde_f

3- (( 1,5-naphthyridin-4-yl)methoxy)-6-methylpicolinaldehyde,

6- mclhyl-3-((l-methyHH-indazol-5-yl)methoxy)picolinaldehyde, 6-mcthyl-3-(quinolin-5-ylmethoxy)picolinaldehyde, 2-methoxy-5-(quinolin-5-ylmethoxy)isonicotinaldehyde,

2-methoxy-5-((2-(l -methyl-1 H-pyrazol-5-yl)pyridin-3-yl)mcthoxy)isonicotinaldehyde, 2-methoxy-5-((2-(l-methyl-lH-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinal<iehyde, 5-((2-(2H-Îetrazol-5-yl)pyridin-3-yl)inethoxy)-2-rnethoxyisonicolina]dehyde, 2-methoxy-5-((2-(4-methyl-11I-pyrazol-5-yl)pyTidin-3-yl)metlioxy)i sonicotinaldehyde, 5-((3-( lII-pyrazol-5-yl)isoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldchyde,

5-((2-( IH-pyrazol-1 -yl)pyrjdin-3-yI)methoxy)-2-mcthoxyisonicotinaldehyde, 5-(imidazo[l,5-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde,

5-((2-( 1,5-dimethyl-1 H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldchy de, 5-((2-(l-elhyl-lH-pyrazol-5-yl)pyridin-3-yl)melhoxy)-2-methoxyisonicotinaldehyde,

-((2-( 1 -i sopropyl-1 H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehy de, 2-(difIuoromethoxy)-5-(imidazo[ 1,2-a] pyridin-8-ylmcthoxy)isonicotinaldehyde, 2-methoxy-5-((2-phenylpyridin-3-yl)methoxy)isonicotinaldehydc,

-((3-( 1 -isopropyl-1 H-pyrazol-5 -yl)pyridin-4-yl)methoxy)-2-methoxyisonîcotinaldchyde,

-([2,3 '-bipyridin]-3-ylmethoxy)-2-methoxyisonicotinaldehyde, 2-methoxy-5-((2-(o-tolyl)pyridin-3-yl)methoxy)isonicotinaldchyde,

2- methoxy'-5-((2'-methoxy-[2,3’-bÎpyridin]-3-yl)methoxy)isonicotinaldehyde,

4- (((2-formyl-6-methyIpyridin-3-yl)oxy)mclhyl)benzoic acid,

4-(((2-fonnylpyridin-3-yl)oxy)mcthyI)benzoic acid, methyl 3-(((4-formylpyridin-3-yl)oxy)methyl)benzoatc, methyl 3 -(((2-formyl-6-metliylpyridin-3 -yl)oxy)methyl)benzoate,

-(((4-formylpyridin-3-yl)oxy)methyl)benzoic acid,

3- (((2-ibrmyl-6-metliylpyridin-3-yl)oxy)mcthyl)benzoic acid,

211

3-(((2-ibmiylpyridin-3-yl)oxy)methyl)benzoic acid,

2-methoxy-5-((2-( 1 -(2-methoxyethyl)-1 H-pyrazol-5-yl)pyridin-3yl)methoxy)isonicotinaldehyde,

2-mcthoxy-5-((2-( I -propyl-111-pyrazol-5-y ijpyridin- 3 -y l)m ethoxy)isoni cotinaldehydc,

2- methoxy-5-((2-(l-(2,2,2-trifluorocthyl)-lH-pyrazol-5-yl)pyridin-3yl)methoxy)jsônicotmaldehyde,

5-((2 -( 1 -(2,2’difluoroethyl)-11I-pyrazol-5-yl)pyridin-3-y l)methoxy)-2methoxyisonicotinaldchydc,

3- ((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)mcthoxy)picolmaldehyde,

3-((2-(1-isopropyl-lli-pyrazol-5-yl)pyridin-3-yl)melhoxy)-6-methylpicolinaldchyde,

2- (difluoromethoxy )-5-((2-( 1 -isopropyl -1 H-pyrazol-5-yl)pyridin-3yl)methoxy)isonicotinaldehyde,

5-(imidazo[l,2-a]pyridin-8-ylmethoxy)-2-(2-mcthoxyethoxy)isonicotinaldehyde, 5-{(2-(l-ïsopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-(2methoxyethoxy)isoniçotinaldehyde,

-((3 -( 1 -isopropyl-1 H-pyrazûl-5 -y l)py razin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,

3- ((4-formyl-6-rncthoxypyridin-3-yloxy)methyl)picolinate,

5-((2-(2-hydroxypropan-2-yl)pyridin-3-yl)methoxy)-2-niethoxyisonicotinaldchyde,

2-(2-methoxyethoxy)-5-((2-( I -methyl-1 II-pyrazol-5-yl)pyridin-3yl)mcthoxy)isonicotinaldehyde,

2- (2-methoxyethoxy)-5-((2-(l-mcthyl-lH-pyrazol-5-yl)pyridm-3-yl)mcthoxy)nicotinaldehydc,

3- hydroxy-5-((2-(l-isopropyI-in-pyrazol-5-yl)pyridin-3-yl)tnethoxy)isonicotinaldehyde, 3-(bcnzyIoxy)-5-hydroxyisonicotinaldchydc,

3-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridîn-3-yl)inethoxy)-5-methoxyÎsonicotinaldehyde, 5-((2-(2-isopropyl-2H-l,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxyisônicotinaldehyde, 5-((2-(l-isopropyl-4-methyl-Ill-pyrazol-5-yl)pyridin-3-yl)niethoxy)-2methoxyisonicotinaldehyde,

5- ((2-(1-(2-hydroxyethyl)-l}I-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,

6- (((4-formylpyridin-3-yl)oxy)methyl)picolinic acid,

2,2,2-trifluoroacelic acid ; 6-(((4-formylpyridin-3-yl)oxy)methyl)picolinic acid (1:1), 2-rnethoxy-5-((2-(l-((2-(trimethylsilyl)cthoxy)methyl)-lH-pyrazol-5-yr)pyridin-3yl)methoxy)isonicotinaldehyde,

212

5-((2-(4-methyl-1 H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4carbaldehyde,

5-((2-(I-cydobuiyl-llLpyrazol-5-yl)pyrid!n-3-yl)meihoxy)-2- methoxyisonicotinaldehyde,

5-((2-( l-cyclohexyl-lH-pyrazûI-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,

5-((2-( 1 -(cyclohexylmethyl)-1 H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2methoxytsonicotinaldehyde,

5-((2-(l-cyclopentyl-lIÎ-pyrazol-5-yl)pyridin-3-y!)methoxy)-2-methoxyÎsonicotinaldehyde,

2- (5 -(3-((4-formy l-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1 H-pvrazol-1 -yl)acetic acid, methyl 3-(5-(3-(((4-formyl-6-mcthoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-lH-pyrazol-lyl)propanoate_}

3- (3-(3-((4-formyÎ-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-lH-pyrazol-l-yl)propanoic acid,

3-(5-(3-(((4-ibrmyl-6-methoxypyridin-3-yI)oxy)methyl)pyridin-2-yl)-lH-pyrazoI-l-yl)propanoic acid,

3-(((4-formyl-6-methoxypyri din-3 -yl)oxy)melhyl)benzoic acid,

6-(((4-fonnylpyridin-3-yl)oxy)methyl)nicotmonitrile 2,2,2-trifluoroacetatc,

6-(((4-formyl pyridin-3 -yl)oxy)mcthyl)mcotinic acid,

6-(((4-formylpyTidin-3 -yl)oxy)methyl)nicotinic acid hydrochloride,

6-(((4-fonny|pyridin-3-yl)oxy)methyl)-N-(methylsulfonyl)nicotinamide_i

2,2,2-trifluoroacetic acid : 6-(((4-formylpyridin-3-yl)oxy)methyl)-N(meihylsulfonyl)nicotinaintde (2:1), 2-(2-methoxyethoxy)-5-((2-(l-(2,2,2-trinuoroethyl)-lHpyrazol-5'yl)pyridin-3-yl)methoxy)isonicotinaldehyde,

2-methoxy-5-((2-(l-(3,3,3-trifluoropropyl)-lH-pyrazol-5-yl)pyridÎn-3 yl)methoxy)isonicQtinaIdehyde,

2-(2-mcîhoxyethoxy )-5-((2-( 1 -(3,3,3-trifluoropropyl)-l I I-pyrazol-5-yl)pyridin-3yl)methoxy)isonicotinaldehyde,

2-methyl-5-((2-( 1 -(2,2,2-trifluoroethyl)-111-pyrazol-5-yl)pyridin-3yl)methoxy)isonicotinaldehyde,

2- methyl-5*((2-(l-(3,3,3-trifluoropropyl)-lH-pyrazol-5-yl)pyridîn-3yl)methoxy)lsonieQtinaldehyde,

3- ((2-( 1 -(2,2,2-trifluorocthvl)-1 H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,

-((2-( 1-(3,3,3 -trifluoropropy 1)-1 H-py razol-5-y l)pyri di n-3 -yl)methoxy)isonicotinaldehy de,

213

3-chloro-5-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)inethoxy)isonicotÎnaldchyde_r

3-((2-( 1-isopropyl-1 H-pyrazol-5-yl)pyridin-3-yl)ine(hoxy)-5-methylisonicotinaldehyde_}

-chl oro-5-((2-( 1 -(3,3,3 -trifluoropropyl)-1 H-pyrazol-5-yl)pyridin-3 yl)methoxy)isonicotinaîdehyde, and

3-methyl-5-((2-( 1 -(2,2,2-trifluoroethyl)-l I I-pyrazol-5-yl)pyridin-3yl)metlioxy)isonicotinaldehyde, or a tautomer or pharmaceutically acceptable sait thereof.

Claims

214 or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein L¹⁰ is optionally substituted methylene or, preferably, a bond;

10 ring A is Cô-Cio aryl, a C₃-Cg cycloalkyl, a 5-10 membered heteroaryl or a 4-10 membered heterocycle contaîning up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycle is optionally substituted with 1-4: halo, Cj-Cô alkyl, Ci-Cô alkoxy,

15 and/or C₃-Cio cycloalkyl, wherein the Cj-Cô alkyl is optionally substituted with 1-5 halo, Ci-Cô alkoxy, and/or C₃-Cio cycloalkyl; or ring A is Cô-Cioaryl, 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 aryl, or heteroaryl is optionally substituted with 1-4 Ci-Cô 20 alkyl and/or Cj-Cô alkoxy groups;

ring B is a 5-10 membered heteroaryl or a 4-10 membered heterocycle contaîning up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the

215 heteroaryl and the heterocycle is optionally substituted with 1-4: halo, Ci-Cô alkyl and/or -CO-Ci-Cô alkyl, or ring B is:

wherein ring B' including the -N-CO- moiety is a 5-6 membered heterocycle containing up to 3 heteroatoms selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1-4 Ci-Cô alkyl groups;

each X and Y is independently (CR²⁰R²¹)_e, O, S, SO, SO₂, or NR²⁰; e is 1 to 4, preferably 1; each R²⁰ and R²¹ independently is hydrogen or C1-C3 alkyl optionally substituted with 1-3 halo, OH, or Ci-Cô alkoxy, or CR²⁰R²¹ is C=O, provided that if one of X and Y is O, S, SO, SO₂, then the other is not CO, and

X and Y are both not heteroatoms or oxidized forms thereof;

ring C is Cô-Cio aryl or a 5-10 membered heteroaryl 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: halo, oxo, -OR¹, Ci-Cô alkyl, -COOR¹, and/or Ci-Cô alkoxy, wherein the Ci-Cô alkyl is optionally substituted with 1-5 halo, Ci-Cô alkoxy and/or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; or ring C is Cô-Cio aryl or a 5-10 membered heteroaryl 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: halo, oxo, -OR¹, Ci-Cô alkyl, -COOR¹, NR^SR⁶,

R¹ is a hydrogen, Ci-Cô alkyl or a prodrug moiety; wherein the alkyl is optionally substituted with a 5-10 membered heteroaryl containing up to 5 ring

216 heteroatoms, wherein the heteroatom is selected from the group consisting of

O, N, S, and oxidized forms of N and S, which is optionally substituted with with a 5-10 membered heteroaryl containîng up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with Cj-Cô alkyl;

R⁵ and R⁶ are each independently hydrogen, optionally substituted Ci-Cô alkyl or -COOR³ ;

R³ is hydrogen or optionally substituted Ci-Cô alkyl;

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

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-Cô alkyl optionally substituted with 1-3 OH groups, or V⁵ is CO?R⁶⁰, where each R⁶⁰ independently is Ci-Cô alkyl or hydrogen; t is 0, 1,2, or 4; or CV’V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁸⁰ is optionally substituted Ci-Cô alkyl;

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

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

R⁸⁴ is optionally substituted Ci-Cô alkyl;

with the proviso that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl;

and provided that when ring C is Cô-Ciq aryl;

217 and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle.
2. A compound of formula (X-I):

or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein ring A is phenyl optionally substituted with 1-3 halo and/or Ci-Cô alkoxy, or is a 4-10 membered heterocycle contaîning up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, optionally substituted, or is wherein R⁷ is Cj-Cô alkyl, optionally substituted with 3-5 fluoro groups, or is C3-C6 cycloalkyl;

ring B is selected from the group consisting of ν''Ά

JW I wherein R⁸ is Cj-Cô alkyl, -CO-Ci-Cô alkyl or a prodrug moiety and wherein the pyridyl ring is optionally substituted with a halo or an NR²⁵(CH2)2N(R²⁵)2 group where each R²⁵ is independently hydrogen or Cj-Cô alkyl;

218 ring C is phenyl or a 6 membered nitrogen-containing heteroaryl, each of which is optionally substituted with 1-4: halo, oxo, -OR¹, Cj-Cô alkyl, -COOR¹, and/or

Ci-Cô alkoxy, wherein the C1-C5 alkyl is optionally substituted with 1-5 halo,

Ci-Cô alkoxy and/or 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of

X is O, S, SO, or SO₂;

O, N, S, and oxidized forms of N and S; and each R¹ is hydrogen or a prodrug moiety R;

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

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Cj-Cô alkyl or CO2R⁶⁰, where each R⁶⁰independently is Ci-Cô alkyl or hydrogen; t is 1, 2, or 4; or CV¹ V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

wherein R⁸⁰ is optionally substituted Ci-Cô alkyl;

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

R⁸³ is hydrogen or optionally substituted Ci-Cô alkyl;

R⁸⁴ is optionally substituted C]-C₆ alkyl;

provided that when ring C is Cô-Cæ aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl;

and provided that when ring C is Cô-Cio aryl;

and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle.

219

19 1
3. The compound of claim 2, wherein V and V independently are Ci-Cô alkoxy; or V and V² together with the carbon atom they are attached to form a ring of formula:

5 wherein each V³ and V⁴ are independently O, S, or NH, provided that when one or V³ and V⁴is S the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Ci-Cô alkyl or CO2R⁶⁰, where each R⁶⁰ independently is Ci-Cô alkyl or hydrogen; t is 1, 2, or 4; or CV*V² is C=V, wherein V is O, and wherein the remaining variables are defmed as in claim.
4. The compound of claim 3, of formula:

(Π) wherein the remaining variables are defined as in claim 2.

220
5. A compound of claim 3 or 4 selected from formulas (HA), (HB) and (HC):

wherein

R⁹ is hydrogen, -OR¹, Ci-Cô alkoxy optionally substituted with 1-3 Ci-Cô alkoxy or 410 membered heterocycle containing up to 5 ring heteroatoms selected from

N, O, S or oxidized forms thereof;

R¹⁰ is hydrogen, halo, hydroxy, or Cj-Cô alkoxy;

R¹¹ is hydrogen or Ci-Cô alkyl; and

R¹² is -OR¹;

wherein R¹ is hydrogen or the prodrug moiety R.
6. The compound of claim 4, wherein ring A is phenyl substituted with 1-3 halo or Ci-Cô alkoxy, or

C3-C8 heterocyclyl containing 1-3 heteroatoms, wherein the heterocycle is optionally substituted with 1-3 halo.
7. The compound of any one of claims 3-6, wherein is selected from the group consisting of:

221 jw\r \^·^Ν and
8. The compound of any one of claims 3-6, wherein is

222
9. A compound of claim 1 wherein:

ring A is Cô-Cio aryl, or a 5-10 membered heteroaryl, wherein the heteroatom is

5 selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl, or heteroaryl is optionally substituted with 1-4: CiCô alkyl and/or Ci-C₆ alkoxy;

ring B is:

σννν'
10 wherein ring B' including the -N-CO- moiety is a 5-6 membered heterocycle contaîning up to 3 heteroatoms selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1-4 Cj-Cô alkyl groups;

each X and Y is independently CR²⁰R²¹, O, S, SO, SO₂, or NR²⁰; each R²⁰ and R²¹

15 independently is hydrogen or C1-C3 alkyl optionally substituted with 1-3 halo,

OH, or Ci-Cô alkoxy, or CR²⁰R²¹ is C=O, provided that if one of X and Y is O, S, SO, SO₂, then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof;

ring C is Cô-Cæ aryl or a 5-10 membered heteroaryl contaîning up to 5 ring

20 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: halo, oxo, -OR¹, Cj-Cô alkyl, -COOR⁵, NR⁵R⁶,

R¹ is a hydrogen, Ci-C₆ alkyl or a prodrug moiety; wherein the alkyl is optionally substituted with a 5-10 membered heteroaryl contaîning up to 5 ring

223 heteroatoms, wherein the heteroatom is selected from the group consisting of

O, N, S, and oxidized forms of N and S, which is optionally substituted with with a 5-10 membered heteroaryl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with Cj-Cô alkyl;

R⁵ and R⁶ are each independently hydrogen, optionally substituted Cj-Cô alkyl or -COOR³ ;

R³ is hydrogen or optionally substituted Ci-Cô alkyl;

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

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one of V³and V⁴ is S, the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently Cj-Cô alkyl optionally substituted with 1-3 OH groups, or V⁵ is CO2R⁶⁰, where each R⁶⁰ independently is Cj-Cô alkyl or hydrogen; t is 0, 1,2, or 4; or CX^V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;

R⁸⁰ is optionally substituted Cj-Cô alkyl;

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

R⁸³ is hydrogen or optionally substituted Cj-Cô alkyl; and

R⁸⁴ is optionally substituted Cj-Cô alkyl;

with the proviso that when ring C is Cô-Cjo aryl;

and ring B is optionally substituted 4-10 membered heterocyclyl;

then ring A excludes optionally substituted 5-10 membered heteroaryl;

and provided that when ring C is Cô-Cjq aryl;

224 and ring B is optionally substituted 5-10 membered heteroaryl;

then ring A is not optionally substituted 4-10 membered heterocycle.

10. The compound of claim 9, wherein CV'V² is C=V, wherein V is O, and wherein the remaining variables are defined as in claim 10.
11. The compound of claim 10, of formula:

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

10 wherein the remaining variables are defmed as in claim 9.

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

225 ring A is Cô-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 aryl, or heteroaryl is optionally substituted with 1-4 Cj-Cô alkyl;

ring B is Cô-Cio aryl, C3-C8 cycloalkyl, a 5-10 membered heteroaryl containing up to

5 ring heteroatoms or a 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl, heteroaryl, cycloalkyl or heterocycle is optionally substituted with 1-4: halo, Ci-Cô alkyl, or Cj-Cô alkoxy, wherein the Cj-Cô alkyl is optionally substituted with 1-5 halo, Cj-Cô alkoxy, and/or C3-C10 cycloalkyl;

R⁴is halo, oxo, -OR¹⁸, Ci-Cô alkyl, Ci-Cô alkoxy, -COOR⁵, and/or NR⁵R⁶;

R¹⁸ is hydrogen, subsitued Cj-Cô alkyl, or a prodrug moiety R;

R⁵ and R⁶ are each independently hydrogen, optionally substituted Cj-Cô alkyl or -COOR³ ; and

R³ is hydrogen, provided that the COOR³ is not joined to a nitrogen atom, or optionally substituted Cj-Cô alkyl.
13. The compound of claim 12, wherein ring B is selected from the group consisting of:

N^l

JVW

I
14. A compound of claim 1 selected from the group consisting of:

226

227

228

229

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

5
15. A compound of claim 1 selected from the group consisting of:

231

5 or N oxides thereof, or a pharmaceutically acceptable sait of each thereof.

232 *
16. A composition comprising a compound of any one of claims 3-8 and 10-15, and at least one pharmaceutically acceptable excipient.
17. Use of a compound of any one of claims 3-8 and 10-15 in the manufacture of a

5 composition for increasing oxygen affinity of hemoglobin S in a subject.
18. Use of a compound of any one of claims 3-8 and 10-15 in the manufacture of a composition for treating oxygen deficiency associated with sickle cell anémia.