WO2014150276A1 - Compounds and uses thereof for the modulation of hemoglobin - Google Patents

Compounds and uses thereof for the modulation of hemoglobin Download PDF

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Publication number
WO2014150276A1
WO2014150276A1 PCT/US2014/022789 US2014022789W WO2014150276A1 WO 2014150276 A1 WO2014150276 A1 WO 2014150276A1 US 2014022789 W US2014022789 W US 2014022789W WO 2014150276 A1 WO2014150276 A1 WO 2014150276A1
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WIPO (PCT)
Prior art keywords
optionally substituted
ring
alkyl
dkt
independently
Prior art date
Application number
PCT/US2014/022789
Other languages
French (fr)
Inventor
Brian W. Metcalf
Zhe Li
Qing Xu
Stephen L. II. GWALTNEY
Jason R. Harris
Calvin W. YEE
Original Assignee
Global Blood Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US13/815,770 external-priority patent/US9422279B2/en
Priority to BR112015021982-9A priority Critical patent/BR112015021982B1/en
Priority to JP2016501067A priority patent/JP6463327B2/en
Priority to KR1020157024780A priority patent/KR102293060B1/en
Priority to EA201591430A priority patent/EA037091B1/en
Priority to AU2014237348A priority patent/AU2014237348C1/en
Priority to EP21185435.1A priority patent/EP3919056A1/en
Priority to CN201480015926.6A priority patent/CN105051044A/en
Priority to KR1020197010691A priority patent/KR20190041548A/en
Priority to MX2015011448A priority patent/MX2015011448A/en
Priority to KR1020177015283A priority patent/KR101971385B1/en
Priority to ES14768317T priority patent/ES2890077T3/en
Application filed by Global Blood Therapeutics, Inc. filed Critical Global Blood Therapeutics, Inc.
Priority to CA2903022A priority patent/CA2903022C/en
Priority to SG11201507349TA priority patent/SG11201507349TA/en
Priority to EP14768317.1A priority patent/EP2970308B1/en
Priority to AP2015008722A priority patent/AP2015008722A0/en
Priority to US14/776,603 priority patent/US9981939B2/en
Publication of WO2014150276A1 publication Critical patent/WO2014150276A1/en
Priority to IL241037A priority patent/IL241037B/en
Priority to SA515361021A priority patent/SA515361021B1/en
Priority to US15/445,878 priority patent/US10017491B2/en
Priority to US15/941,433 priority patent/US10829470B2/en
Priority to AU2018260809A priority patent/AU2018260809C1/en
Priority to US17/026,690 priority patent/US11530191B2/en
Priority to US17/981,140 priority patent/US20230322704A1/en

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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • This invention provides compounds and pharmaceutical compositions suitable as allosleric 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.
  • Sickle ceil disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent.
  • the basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin (Hb),
  • Hemoglobin transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through
  • Sickle hemoglobin contains a point mutation where glutamic acid is replaced with valine, aliowing HbS to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape.
  • the sickled ceils are also more rigid than normal red blood ceils, and their lack of flexibility can lead to blockage of blood vessels.
  • U.S. 7, 160,910 discloses compounds that are ailosteric
  • This invention relates generally to compounds and pharmaceutical compositions suitable as ailosteric modulators of hemoglobin. In some aspects, this invention relates to methods for treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.
  • L 10 is optionally substituted methylene or, preferably, a bond; is a single or a double bond;
  • each X and Y is independently (CR 2 V) e , O, S, SO, S0 2 or NR 20 ; e is 1 to 4,
  • each R' ' ° and R"' independently is hydrogen or C-.- . ; alkyl optionally substituted with 1-3 halo, OH, or C
  • V ! and V independently are Ci-C 6 alkoxy; or V ! and V 2 together with the carbon
  • each V J and V are independently O, S, or NH, provided that when one of V " and V 4 is S, the other is NH, and provided that V 1 and V are both not NH; q is 1 or 2; each V° is independently C] -C 6 aikyl optionally substituted with 1 -3 OH groups, or V" is CC ⁇ " 0 , where each R 60 independently is C ; -C 6 alkyl or hydrogen; t is 0, 1 , 2, or 4; or CV 'V 2 is OV, wherein V is O, NOR 80 , or Atty. Dkt. No. : 104592-021 0
  • R "J is optionally substituted Ci-C 6 alkyl
  • R Sl and R 8 independently are selected from the group consisting of hydrogen,
  • R" is hydrogen or optionally substituted C
  • R K is optionally substituted C i -Q alkyl
  • ring A is Ce-Ci o aryl, or a 5- 10 membered heteroaryl . wherein the heteroatom is
  • ring B is:
  • 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, wiierein each of the heteroaryl and the heterocycle is optionally substituted, preferably with 1 -4 Ci -Ce alkyl groups;
  • ring C is C Ci o a l or a 5- 1 0 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
  • R ! is a hydrogen, C ⁇ -C(, alkyl or a prodrug moiety; wherein the alkyl is optionally
  • 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 io 5 ring heteroatonis, wherem 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-C 6 alky I;
  • R 3 and R 6 are each independently hydrogen, optionally substituted C
  • Ci-Q alkyl is hydrogen or optionally substituted Ci-Q alkyl
  • ring B is optionally substituted 4-10 membered heterocyclyl
  • ring A excludes optionally substituted 5-10 membered heteroaryl
  • ring B is optionally substituted 5-10 membered heteroaryl:
  • ring A is not optionally substituted 4-10 membered heterocycle. in another instance:
  • ring A is C/ 0 -C;o aryl. a C ' 3-C's cycloa!kyl, 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, cyeloalkyl, or heterocycle is optionally substituted, preferably with 1 -4: halo, C
  • 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 and S, wherein each of the heteroaryl and the heterocycle is optionally substituted, preferably with 1 -4: halo, Cj-C f , alkyl and/or --CO-Cj-Q, alkyl , is a single or a double bond; Atty. Dkt. No.: 1 04592-0210 ring C is Cs-C io ary!
  • heteroatom selected from the group consisting of O, N, S. and oxidized forms of N and S, each of which is optionally
  • R 1 is hydrogen or a prodrug moiety
  • ring B is optionally substituted 4- 10 membered heierocyc!yi;
  • ring A excludes optionally substituted 5- 10 membered heieroaryl
  • ring B is optional ly substituted 5- 1 0 membered heteroaryi
  • ring A is not optionally substituted 4- 10 membered heterocycie.
  • ring A is phenyl optionally substituted with 1 -3 halo and/or ⁇ ⁇ C f , aikoxy, or is a 4-10 membered heterocycie containing up to 5 ring heteroaioms, wherein the heieroatom is selected from the group consisting of O, N, S, and oxidized forms of and S. optionally substituted, or is
  • R' is Q-Q alkyl, optionally substituted with 3-5 fluoro groups, or i s C3-C cycloalkyl;
  • ring B is selected from the group consisting of
  • R' is -Q alkyl, -CO-C1-C6 alkyi or a prodrug moiety and wherein the pyridy! ring is optionally substituted with a halo or an NR AS (CH2)_ (R 25 )2 group where each R 25 is independently hydrogen or C-.-Cf, alkyi;
  • ring C is phenyl or a 6 membered nitrogen-containing heteroaryl, each of which is optionally substituted with 1-4: halo, oxo, -OR', Q ⁇ Q, alkyl, -COOR ! and/or Ci-C- alkoxy, wherein the C]-Q > alkyi is optionally substituted with 1 -5 halo, Ci- ; alkoxy and/or 4- 10 membered heterocycie containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; and
  • each R 1 is hydrogen or a prodrug moiety R
  • V' and V 2 independently are Ci-C 6 alkoxy; or V 1 and V 2 together with the carbon atom they are attached to fon formula:
  • each V " and V 4 are independently O, S, or NH, provided that when one of V and V 4 is S, the other is NH, and provided that V J and V 4 are both not NH; q is Atty. Dkt. No.: 104592-0210
  • R U is optionally substituted Cj-Ce alkyl ;
  • R and R* 2 independently are selected from the group consisting of hydrogen
  • R is hydrogen or optionally substituted ⁇ ⁇ C(, alkyl
  • R 84 is optionally substituted ⁇ ⁇ (. ' ,, alkyl
  • ring B is optionally substituted 4- 10 membered heterocyclyl
  • ring A excludes optionally substituted 5- 10 membered heteroaryl
  • ring B is optionally substituted 5-10 membered heteroaryl
  • ring A is not optionally substituted 4-10 membered heterocycle; provided that the compounds provided herein exclude those disclosed in U .S. patent application nos. 13/730,730 and 1 3/730,674; and provided that tire compounds provided herein exclude those in able 1 hereinbclow.
  • V ! and V 2 together with the carbon atom they are attached to form a ring of formula:
  • V 1 and V 2 independently are C ⁇ -Ce alkoxy; or V s and ⁇ > together with the carbon atom they are attached to form a ring of formula:
  • each V 3 and V 4 are independently O, 8, or NH, provided that when one or V and V is S the oilier is NH, and provided that V 3 and V 4 are both not NH; q is 1 or 2; each V 5 is independently C -. -C alkyl or C0 2 R 60 , where each R 6 independently is Ci-Ce alk l or hydrogen; t is 0, 1 , 2, or 4; or CV'V is 0 : V, wherein V is O, and wherein the remaining variables are defined herein.
  • a compound of formula (i l) is provided :
  • a compound selected from formulas (HA), (11B) and (DC) is provided :
  • R 9 is hydrogen, -OR 1 , Cj-CV, alkoxy optionally substituted with 1 -3 Cj-Ce alkoxy or 4- 1 0 rnembered heterocycle containing up to 5 ring heteroatoms selected from N, O, S or oxidized forms thereof; -0G57.1 8 Atty. Dkt. No.: 1 04592-0210
  • R ' is hydrogen, hydroxy, halo or d-Ce alkoxy
  • R ! ! is hydrogen or Ci- a!kyl
  • R 1 is -OR ! ;
  • R ! is hydrogen or the prodrug moiety R.
  • a compound of formula ⁇ ) is provided: or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein
  • L'° is optionally substituted methylene or, preferably, a bond
  • ring A is C b -C i o a yl , or a 5- 10 membered heteroaryl, wherein the heteroatom is
  • each of the aryl, or heteroaryl is optionally substituted with 1 -4 Ci-C 6 alkyl and/or Ci -C 6 alkoxy groups;
  • ring B is:
  • ring B' including the -N-CO moiety is a 5-6 membered heteroc cle
  • each of the heteroaryl and the heterocycle is optionally substituted with 1 -4 C
  • each R 2 and R zl independently is hydrogen or C 1 -C3 alkyl optionally substituted with 1-3 halo, OH, or Cj -Cr, alkoxy, or CR 20
  • ring C is C io aryi 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
  • R is a hydrogen, Ci -Ce alkyl or a prodrug moiety; wherein the aikyl is optionally
  • heteroaloms wherein the heieroatom 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 u to 5 ring heteroatoms, wherein the heieroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroarvl is optionally substituted with Ci-Ce aikyl;
  • R and R" are each independently hydrogen, optionally substituted C i -Q, alkyl or
  • R 3 is hydrogen or optionally substituted Ci-Q aikyl
  • V 1 and V 2 independently are CrQ alkoxy; or V 1 and V 2 together with the carbon
  • R m is optionally substituted Q-Ce alkyl
  • R 8 ' and R 82 independently are selected from the group consisting of hydrogen,
  • R Sj is hydrogen or optionally substituted Ci-Ce alkyl
  • R 84 is optionally substituted Cj-C 6 alkyl
  • ring B is optionally substituted 4-10 membered heterocyclyl
  • ring A excludes optionally substituted 5-10 membered heteroaryl ; . Dkt. No.: 104592-0210 and provided Ihat when ring C is C 6 -Cio aryl;
  • ring B is optionally substituted 5-10 membered heleroaryl
  • ring A is not optionally substituted 4-10 membered heteroeycle.
  • composition comprising any of the compounds described herein, and at least a pharmaceutically acceptable excipient.
  • a method for increasing oxygen affinity of hemoglobin S in a subject comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.
  • a method for treating oxygen deficiency associated with sickle cell anemia comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.
  • a solvent includes a plurality of such solvents
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
  • compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition or process consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terras are within the scope of this invention.
  • C m -C n such as C1-C12, CpCg, or C]-C 6 when used before a group refers to that group containing m to n carbon atoms.
  • alkyl refers to monovalent saturated aliphatic hydrocarbyi groups having from 1 to 12 carbon atoms (i.e., CpC; 2 aikyl) or 1 to 8 carbon atoms (i.e., CpQ aikyl), or 1 to 4 carbon atoms.
  • This term includes, by way of example, linear and branched hydrocarbyi groups such as methyl (CH3-), ethyl (CH3CH2-), w-propyl (CH3CH2CH2-), isopropyl
  • aryl refers to a monovalent aromatic mono- or bicyclic ring having 6- 10 ring carbon atoms.
  • 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,
  • -C0 2 H ester refers to an ester formed between the ⁇ C0 2 H group and an alcohol, preferably an aliphatic alcohol.
  • a preferred example included - C0 2 R h , wherein R L* is aikyl or aryl group optionally substituted with an amino group.
  • 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 enantiomericailv enriched, and more preferably a single enantiomer.
  • Non limiting examples of chiral moieties include chiral carbox lic acids, chiral amines, chiral amino acids, such as the naturally occurring amino acids, chiral alcohols including chiral steroids, and the likes,
  • cycloalkyl refers to a monovalent, preferably saturated, hydrocarbyi mono-, bi-, or tricyclic ring having 3-12 ring carbon atoms. While cycloalkyl, refers
  • Dkt, No, : 104592 preferably to saturated hydrocarbyl rings, as used herein, it also includes rings containing carbon-carbon double bonds,
  • Nonlimiting examples of cycloalkyl include cyclopropyi, 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.
  • halo refers to F, CI, Br, and/or 1.
  • heteroaryl refers to a monovalent, aromatic mono-, bi-, or tricyclic ring having 2- 16 ring carbon atoms and 1 -8 ring heieroatoms 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, oxazoic, pyridine, quinoline, and the like.
  • the condensed rings may or may not be a heteroatom containing aromauc ring provided that the point of attachment is a heteroaryl atom.
  • heterocyclyP 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 heterocyelyl preferably refers to saturated ring systems, it also includes ring systems containing 1-3 double bonds, provided that the ring is non-aromatic.
  • heterocyelyl examples include, azalactones, oxazoline, piperidinyl, piperaziny!, pyrrol idinyl, 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 heterocyelyl group.
  • the following is a heterocyelyl group: Atty. Dkt. No.: 104592-0210
  • hydrolyzing refers to breaking an R H -0-CC R H -0-CS-, or an R H -0- S0 2 - moiety to an R H -OH, preferably by adding water across the broken bond.
  • hydrolyzing is performed using various methods well known to the skilled artisan, non limiting examples of which include acidic and basic hydrolysis.
  • the group may be substituted with one or more substituents, such as e.g., 1 , 2, 3, 4 or 5 substituents.
  • the substituents are selected from the group consisting of oxo, halo, -CN, N0 2 , -N 2 +, -CO 2 R U 0 , -OR 100 , -SR i °, -SOR ! °, -SO 2 R !0 °, ⁇ ⁇ NR l01 R i02 , -CONR.
  • each R 100 independently is hydrogen or Ci-C& alkyl; C3-Cn cycloalkyl; C3-C 10 heterocyclyl; CVCi 2 aryl; or C 2 -C ; 2 heteroaryl; wherein each alky!, cycloalkyl, heterocyclyl, aryi, or heteroaryl is optionally substituted with 1-3 halo, 1-3 C 3 ⁇ 4 -C 6 alkyl, 1-3 Cj-C 6 haloalkyl or 1-3 Ci-C
  • the substituents are selected from the group consisting of chloro, f!uoro, -OCH 3 , methyl, ethyl, so-propyl, cyclopropyl, vinyl, ethyny!, -C0 2 H, - C0 2 CH3 ⁇ 4, -OCF3, -CF 3 and ⁇ ( )( . HF 2 .
  • pharmaceutically acceptable salt refers to a salt that is pharmaceutically acceptable.
  • salt ' ' refers to an ionic compound formed between an acid and a base.
  • salts include- without limitation, alkali metal , alkaline earth metal, and ammonium salts
  • 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, N! L- ; , Ca, Ba, imicazoliuni, and ammonium cations based on naturally occurring amino acids.
  • salts include, without limitation, salts of organic acids, such as caroboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
  • organic acids such as caroboxylic acids and sulfonic acids
  • mineral acids such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
  • exemplary and non-limiting anions useful in pharmaceutically acceptable salts incl ude oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisalfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the iikes.
  • treat 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 regression of the disease or condition, relieving a condition caused by the disease or condition, or suppressing the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms also include relieving the disease or conditions, e.g., causing the regression of clinical symptoms.
  • the terras further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • 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.
  • the terms " 'preventing” or “prevention” refer to a reduction in risk of acquiring a disease or disorder (i. e. , causing at least one of the cl inical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • the terms further include causing the clinical condition
  • an 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.
  • an effective amount of any of the compositions or dosage forms described herein is the amount used to treat a disorder mediated by hemoglobin or a disorder that would benefit from tissue and/or cellular oxygenation of any of the
  • compositions or dosage forms described herein to a subject in need thereof.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells, e.g., red blood cells, or tissues.
  • 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.
  • a pharmaceutically active compound can be modified chemically to render it less active or inactive, but the chemical modification is such that an active form of the compound is generated by metabolic or other biological processes.
  • a prodrug may have, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity. For example, see the reference Nogrady, 1 85, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392.
  • Prodrugs can also be prepared using compounds thai are not drugs.
  • L i 0 is optionally substituted methylene or, preferably, a bond
  • ring A is C Cio aryl, a C Ca eycloaikyi, a 5- 10 membered heieroaryi or a 4- 1 0
  • 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, heteroarvl, cycloalkyl, or
  • heterocycle is optionally substituted with 1 -4: halo, C i-C f , alkyl, Ci-C b alkoxy, and/or C3-C 10 cycloalkyl, wherein the Cj-C 6 alkyl is optionally substituted with 1 -5 halo, Cj -Cf, alkoxy, and/or C 3 -Cso cycloalkyl; or ring A is Cg-Cio aryl, or a 5- 10 membered heteroarvl, wherein the heteroatom is
  • each of the aryl, or heteroaryl is optionally substituted with 1 -4 Cj-Ce alkyl and/or C i ⁇ C,3 ⁇ 4 alkoxy groups;
  • ring B is a 5- 1 0 membered heteroarvl or a 4- 1 0 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 heteroarvl and the heterocycle is optionally substituted with 1 -4: halo, C ; -C 6 alkyl and/or -CO-C ⁇ . - €(, alkyl, or
  • ring B is:
  • ring B' including the -N-CO- moiety is a 5-6 mernbered heterocyele containing up to 3 heteroatorns selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocyele is optionally substituted with 1 -4 Cj-Ce alky] groups;
  • each X and Y is independently (CR 20 R 2! ) e , O, S, SO, S0 2, or NR 20 : e is 1 to 4,
  • each R iJ and R z! independently is hydrogen or Cj-C 3 alkyl optionally substituted with 1 -3 halo, OH, or Ci-C-6 alkoxy, or CR 0 R 21 is CTM0, provided thai if one of X and Y is O, S, SO, S0 2 , then the other is not CO, and X and Y are both not heteroatorns or oxidized forms thereof;
  • ring C is Cg-Cjo aryl or a 5-10 mernbered heteroaryl containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, each of which is optionally
  • heteroatorns wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; or
  • ring C is Ce-Cio aryl or a 5- 10 mernbered heteroaryl containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, , S. and oxidized forms of N and S, each of which is optionally
  • R 1 is a hydrogen, C
  • heteroatorns wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and 8, which is optionally substituted with with a 5- 10 mernbered heteroaryl containing up to 5 ring heteroatorns, wherein
  • heteroatom is selected frorn the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with C]-C & alkyl;
  • R “1 and R 6 are each independently hydrogen, optionally substituted Ci-C 6 alkyl or
  • R ' is hydrogen or optionally substituted C i-Ce alkyl
  • V 1 and V 2 independently are C ; -Cf. alkoxy; or V 5 and V 2 together with the carbon
  • each V and V 4 are independently O, S, or NH, provided that when one of V ! and V 4 is S, the other is NH, and provided that V J and V 4 are both not NH; q is 1 or 2; each V* is independently C i -Ct alkyl optionally substituted with 1 -3 OH groups, or V " is CO ⁇ " 0 , where each R 6 " independently is Ci-Cg alkyl or hydrogen; t is 0, 1 , 2, or 4; or CV'V 2 is OV, wherein V is O, OR 80 , or NNR 8 i R. 82 ;
  • R 80 is optionally substituted C-.-C 6 alkyl
  • R 6i and R 8 " 4 independently are selected frorn the group consisting of hydrogen
  • R 5 ' is hydrogen or optionally substituted C
  • R s4 is optionally substituted C ⁇ -Ct, alkyl
  • ring B is optionally substituted 4-10 membered heterocyclyl
  • ring A excludes optionally substituted 5- 10 membered heteroaryl ;
  • ring B is optionally substituted 5-10 membered heteroaryl
  • ring A is not optionally substituted 4- 10 membered heterocycie, Atty. Dkt. No.: 104592-0210
  • ring A is C 6 -Cjo aryl, a Cj-Cs cycloalkyl, a 5-10 membered heteroaiyl or a 4-10
  • heterocycle containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms ofN and S, wherein each of the aryl, heteroaiyl, cycloalkyl, or
  • heterocycle is optionally substituted with 1 -4: halo, C r-Cf, alkyl, Q -Cs alkoxy and/or CN-Ci o cycloalkyl, wherein the C j-C,, alkyl is optionally substituted with 1 -5 halo, Ci -Ce 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 heteroatorns, 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, C ⁇ -C & alkyi and/or -CO-C pCe alkyl,
  • ' is a single or a double bond
  • X is O, S, SO, or S0 2 ;
  • ring C is C Cio aryl or a 5-10 membered heteroaryl containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, each of which is optionally
  • Ci -Cf, alkyl is optionally substituted with 1 -5 halo, CVC f , alkoxy and/or a 4-10 membered heterocycle containing up to 5 ring
  • R' is hydrogen or a prodrug moiety :
  • V 1 and V 4 independently are Ci-C ⁇ 3 ⁇ 4 alkoxy; or V 1 and V 2 together with the carbon
  • each V " and V 4 are independently O, S. or NH, provided that when one of V and V is S, the other is NH, and provided that V 3 and V 4 are both not NH; q is 1 or 2; each V 3 is independently C ⁇ -Ce alkyl or CO 2 R 00 , where each R 611 independently is Cj-Gs alkyl or hydrogen; t is 0, 1 , 2, or 4; or CV ! V * is C ::: V, wherein V is O, NOR 80 , or NNR i R 82 ;
  • R so is optionally substituted Cj-C 6 alkyl
  • R 8 ' and R 8'2 independently are selected from the group consisting of hydrogen,
  • G-Cs alkyl optionally substituted G-Cs alkyl, COR 8'5 , or CG 2 R 84 ;
  • R B ' is hydrogen or optionally substituted C
  • R* 4 is optionally substituted Cj-Q alkyl
  • ring B is optionally substituted 4- 10 merabered heterocyclyl:
  • ring A excludes optionally substituted 5-10 membcrcd heteroaryl
  • ring B is optionally substituted 5-10 membered heteroaryl
  • ring A is not optionally substituted 4-10 merabered heterocycle.
  • ring A is phenyl optionally substituted with 1-3 halo and/or G -C 6 alkoxy, or is a 4-1 0 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
  • R ' is C[-C 6 alkyl, optionally substituted with 3-5 fluoro groups, or is C -C cycloalkyl;
  • ring B is selected from the group consisting of
  • R is Ci-Cg alkyl, -CO-CrCe alkyl or a prodrug moiety
  • ring C is phenyl or a 6 raembered nitrogen-containing heteroaryl. each of which is
  • Ci-C 6 aikyl is optionally substituted with 1 -5 halo, Ci-Cft alkoxyand/or 4-10 mcmbered heterocycle containing up to 5 ring heieroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; and
  • each R 1 is hydrogen or a prodrug moiety R ;
  • V 1 and V 2 independently are C C 6 alkoxy: or V 1 and V" together with the carbon
  • each V° and V 4 are independently O, S, or NH, provided that when one of V and V 4 is S. the other is NI L and provided that V 3 and V 4 ar hnth not H ⁇ ⁇ 1 '- '
  • each V 5 is independently ⁇ -C$ aikyl or CO 2 R 00 , where each R 60 independently is Cj -Cc, aik l or hydrogen; t is 0. 1 , 2, or 4; or CV 1 V z is ( V. wherein V is O, NOR 80 , or NNR 8 I R 82 ; Dkt. No. : 104592-021 0
  • R ' is optionally substituted C i -C 5 alkyi
  • R 8i and R s ⁇ independently are selected from the group consisting of hydrogen,
  • R 83 is hydrogen or optionally substituted CY-CV, alkyl
  • R " is optionally substituted Ci-Cg alkyl
  • ring B is optionally substituted 4- 10 merabered heterocyclyl
  • ring A excludes optionally substituted 5- 10 membered heteroaryl
  • ri ng B is optionally substituted 5- 1 0 membered heteroaryl
  • ring A is not optionally substituted 4- 1 0 membered heterocycle.
  • V 1 and V 2 together with the carbon atom they are attached to form a ring of formula:
  • ring A is phenyl optionally substituted with 1 -3 halo and/or CpQ aikoxy, or is a 4-10 membered heterocycle containing up to 5 ring hetcroatoms, wherein the heteroatom is selected from the groiip consisting of O, N, S, and oxidized forms of N and S, optionally substituted, or is
  • R 7 is C
  • ring B is selected from the group consisting of
  • ring C is phenyl or a 6 membered nitrogen-containing heteroaryi, each of which is
  • each R' is hydrogen or a prodrug moiety R
  • V' and V 2 independently are C; -C alkoxy; or V 1 and V " together with the carbon
  • each V 3 and V 4 are independently O, S, or NH, provided that when one of V ' and V 4 is S, the other is NH, and provided that V ⁇ ! and V 4 are both not NH; q is 1 or 2; each V* is independently Q-Ce alkyl or C0 2 R 6 ", where each R 60
  • R 80 is optionally substituted C r C 6 alkyl
  • R 81 and R 8 ' independently are selected from the group consisting of hydrogen,
  • R 8"5 is hydrogen or optionally substituted CVC 6 alkyl
  • R* 4 is optionally substituted Ci-Ce alkyl
  • ring B is optionally substituted 4- 10 membered heterocyclyl
  • ring A excludes optionally substituted 5- 1 0 membered heteroaryl
  • ring B is optional!y substituted 5- 1 0 membered heteroaryl
  • ring A is not optionally substituted 4- 1 0 membered heterocycle.
  • t is 0, In certain embodiments, t is 1. in certain
  • t is 2. in certain embodiments, t is 3. In one embodiment,— X-Y- is - ⁇ C3 ⁇ 4-0-. In another embodiment, -X-Y is -0-CH 2 -.
  • R is hydrogen, -OR', C
  • R" ' is hydrogen, halo, hydroxy or CyCe, alkoxy
  • R' 1 is hydrogen or C
  • R 12 is -OR' ;
  • R ! is hydrogen or the prodrug moiety R
  • ring A is
  • ring A is pyridy!. optionally substituted as defined herein.
  • Dkt No. : 104592-0210 is selected from the group consisting of:
  • a compound is provided, wherein the compound selected from the group consisting of:
  • a compound is provided, wherein the compound selectee from the group consisting of:
  • a compound is provided, wherein the compound is selected from the group consisting of:
  • L'° is optionally substituted methylene or, preferably, a bond
  • ring A is Cs-C i o aryl, or a 5-10 membered heteroaryl, wherein the heteroatom is
  • each of the aryl, or heteroaryl is optionally substituted with 1 -4 C ; -Cf, alkyi and/or CrQ, alkoxy groups;
  • 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 heieroaryl and the heterocycle is optionally substituted with 1-4 C i-Cg alkyl groups;
  • each X and Y is independently (CR 20 R 21 ) C , O, S, SO, S0 2 , or NR 20 ; e is 3 to 4,
  • each R 0 and R 21 independently is hydrogen or C C 3 alkyl optionally substituted with 1 -3 halo, OH, or C ( -C 0 aikoxy, or CR 20 R 2 i is CO, provided that if one of X and Y is O, S, SO, SO 2 , then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof;
  • ring C is Q-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
  • R ' is a hydrogen, Ci-Cg alkyl or a prodrug moiety; wherein the alkyl is optionally
  • 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 , -C 6 alkyl ;
  • R 5 and R" are each independently hydrogen, optionally substituted C 1-C alkyl or
  • R 3 is hydrogen or optionally substituted Cj-C t , alkyl
  • V 1 and ⁇ independently are Ci-Ce alkoxy; or V 1 and V 2 together with the carbon
  • each V 3 and V 4 are independently Q, S, or NH, provided that when one of
  • R 8 is optionally substituted C Ce alky]
  • R 81 and R S/' independently are selected from the group consisting of hydrogen,
  • R 83 is hydrogen or optionally substituted C
  • R 84 is optionally substituted C i-Cs alkyl
  • ring B is optionally substituted 4-1 0 membered heterocyclyl
  • ring A excludes optionally substituted 5-10 membered heteroaryl
  • ring B is optionally substituted 5- 10 membered heteroaryl
  • ring A is not optionally substituted 4- 10 membered heterocycie.
  • ring A. is C Cio a yl, or a 5- 10 membered heteroaryi, wherein the heteroatora is
  • ring B is:
  • 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 heteroaryi and the heterocycle is optionally substituted with 1-4 Ci -C 6 alkyl groups;
  • each X and Y is independently CR 20 R 21 , O, S, SO, S0 2, or NR 10 ; each R 20 and R :? i
  • 104592-0210 ring C is Cg-Cio aryl or a 5- 10 membered keteroaryl containing up to 5 ring
  • heteroatoms wherein the heteroatom is selected from the group consisiing of O, N, S, and oxidized forms of N and S, each of which is optionally
  • R l is a hydrogen, C ⁇ -C alkyl or a prodrug moiety; wherein the alkyi is optionally
  • heteroatoms wherein the heteroatom is selected from the group consisiing of O, , 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 consisiing of O, N, 8, and oxidized fonns of N and S, wherein the heteroaryl is optionally substituted with Ci-C 6 alkyl;
  • R 5 and R 6 are each independently hydrogen, optionally substituted C f -Ce alkyl or
  • IV is hydrogen or optionally substituted Ci-C 3 ⁇ 4 alkyl
  • V and V" independently are Ci-C 6 alkoxy; or V and V together with the carbon
  • R s0 is optionally substituted Ci -C'e alkyl ;
  • R 6 i and R S2 independently are selected from the group consisting of hydrogen,
  • R 8j is hydrogen or optionally substituted Ci -Ce alkyl:
  • R 84 is optionally substituted CrC 6 alkyl. Atty. Dkt. No.: 104592-021
  • ring C is substituted with at least one substituent selected from with 1-4: halo, -OR 1 , C.-C 6 alkyl, -COOR 5 , NR 5 R 6 .
  • X is CI i 2 , O, S, SO, S0 2 or NH. In certain embodiments, is O, S, SO or S0 2 . Preferably, X is O, and wherein the remaining variables are defined herein.
  • Y is CR 20 R 2i , O, 5. SO, S0 2( or NR 10 ; wherein each R 20 and R 2! independently is hydrogen or C 1 -C3 alkyl.
  • Y is CR 20 ! ⁇ ' 1 wherein each R' '0 and R 2 ' independently is hydrogen or Ci-C 3 alkyl.
  • Y is CH 2 , and wherein the remaining variables are defined herein.
  • t is 0. In certain embodiments, t is 1 , In certain
  • t is 2. In certain embodiments, t is 3.
  • CV 'V 2 is C :::: V, wherein V is O, and wherein the remaining variables ar defined herein.
  • ring A is Ce-Cio aryl, or a 5-10 membered heteroaryl, wherein the heteroatom is
  • each of the aryl, or heteroaryl is optionally substituted with 1-4 Cj-Ce alkyl and/or CpCe alkoxy groups;
  • rina B is:
  • ring B ' including Ihe -N-CO- moiety is a 5-6 membered heterocycie containing up to 3 heteroatoms selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroary! and the heterocycie is optionally substituted with 1-4 C i -Cs alkyl groups;
  • X is O, S, SO or S0 2 ;
  • ring C is C Cjo 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
  • R' is a hydrogen, ;-(?. ⁇ . . alkyl or a prodrug moiety R; wherein the alkyl is optionally substituted with a 5- 10 membered heteroary! 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 optionall substituted with with a 5-10 membered heteroaryl containing up to 5 ring heteroatoms.
  • ihe 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 CrC ' 6 alkyl;
  • R 5 and R 6 are each independently hydrogen, optionally substituted C-i-Ce alkyl or
  • R 3 is hydrogen or optionally substituted Cj-C 6 alkyl.
  • ring B is CV-Cio ar !, CVC* cycloalkyl, a 5-10 membered heteroaryi containing up to 5 ring hctcroaioms or a 4- 1 0 membered iieterocycle containing up to 5 ring neteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryi, heteroaryi, cycloalkyl or heierocycle is optionally substituted with 1 -4: halo, C] ⁇ C(, alkyi, or C pCf, alkoxy, wherein the C pC,, alkyi is optionally substituted with 1 -5 halo, C i
  • R is halo, oxo, -OR 18 , C , -C 6 alkyi, C s -C 6 alkoxy, -COOR 5 , and/or R 5 R 6 ;
  • R ' is hydrogen, subsitued Ci-C-6 alkyi, or a prodrug moiety R;
  • R 5 and R 6 are each independently hydrogen, optionally substituted Cj-Q alkyi or
  • R J is hydrogen, provided that the COOR 3 is not joined to a nitrogen atom, or is
  • R 4 is -OH. In another embodiment, R is N H 2 . In one
  • R 4 is NH(CH 3 ). In one embodiment, R 4 is N(CH 3 )2. in one embodiment, R 4 is NHC(0)OC(CH 3 ) 3 . In one embodiment, R 4 is COOH. In one embodiment, R 4 is optionally -0057.1 40 Atty. Dkt. No,: 304592-0210 substituted dioxolan. In one embodiment, R 4 is a substituted pyridine. As used herein, R 3 is hydrogen, provided that the COOR 3 is not joined to a nitrogen atom.
  • ring B is selected from the group consisting of:
  • ring B is optionally substituted 4-10 membered heieroeyelyl
  • ring A excludes optionally substituted 5-10 membered heieroaryl.
  • a compound is provided, wherein the compound is selected from the group consisting of:
  • R is hydrogen, a phosphate or a diphosphate containing moiety, or another promoiety or prodrug moiety.
  • the prodrug moiety imparts at least a 2 fold, more preferably a 4 fold, enhanced solubility and/or bioavailabi lity to the active moiety
  • R is -COR 90 , C0 2 R S , or CONR 92 R 93 wherein
  • R 90 and R 9 ' independently are Ci-Ce alkyi, C3-C8 cyeloalkyl, 4-9 membered heteroeycle, or a
  • R 2 and R 9 independently are C
  • heteroaryl each containing at least I basic nitrogen moiety; or R 92 and R 9 ⁇ together with the nitrogen atom they are bonded to for a 4-9 member heteroeycle substituted with at least 1 amino, Ci-C 6 alkyl amino, or di C
  • R is -C(0)R 3 ! , C(0)OR 31 , or CONi R 13 ),
  • each R i is independently a Q-Co alkyi; C 3 -Cg cyeloalkyl, 4-9 membered heteroeycle, or a 5- 10 membered heteroaryl, containing at least 1 basic nitrogen moiety; and
  • each R 13 independently is Cj -Q alkyl; C3-C8 cyeloalkyl , 4-9 membered heteroeycle, or a 5- 10 membered heteroaryl, containing at least 1 basic nitrogen moiety; or both R I J
  • R is C(0)OR 3 ⁇ C(S)OR 31 , C(0)SR 3i or COR 3* ', wherein R 3 ! is as defined herein.
  • R' 1 is a group of the formula (CR ' R 33 ) t; NR ⁇ R 35 .
  • each R 3 and R 3j is independently H, a Cs-Cg alkyl, C3-C9 hcterocyclyl, Cs-Cg cycloalkyl, Cg-Cjo aryl, C3-C9 heteroaryl or R° 2 and R 33 together with the carbon atom they axe bond to form a C ⁇ -Cg cycloalkyl, Cg-Cio aryl, C3-C9 lieterocyclyl or C3-C9 heteroaryl ring system, or 2 adjacent R 3 " ' moieties or 2, adjacent R 33 moieties together with the carbon atom they are bond to form a C3-C8 cycloalkyl, Cc-Cio aryl, C3-C9 heterocyclyl or C3-C9 heteroaryl ring system;
  • each R 34 and R 35 is a C,-C 8 alkyl, C3-C9 heterocyclyl, C 3 -C 8 cycloalkyl, or R 3'4 and R 35 together with the nitrogen atom they are bond to form a C3-C & cycloalkyl or C3-C9
  • each heterocyclic and heteroaryl ring system is optionally substituted with C1-C3 alkyi, -OH, amino and carboxyl groups;
  • e is an integer of from 1 to 4.
  • R 14 and R 35 can be hydrogen.
  • the subscript e is preferably 2 and each Ji and R >J is
  • R 32 and R j3 are joined together to form a cyclopropyl, cyclobutyl, cyclopentyi, cyclohcxyl, or
  • preferred embodiments are compounds wherein NR ⁇ R 35 is morpholino.
  • R is:
  • each R 3'1 and R' ' ' is independently H, Ci-Cs alky;, or optionally, if both present on the same substituent, may be joined together to form a C3-C8 cycloaikyl, Ce-Cio aryl, C3-C9 heterocyelyl or C3-C9 heteroaryl ring system.
  • each R 32 and R JJ is independently, H, CH 3 , or are joined together to form a cyclopropy], cyclopbutyl, cyclopentyl, cyclohexyl, 1,1 -dioxo- hexahydro- L ⁇ (, -thiopyran-4 ⁇ yi or tctrahydropyran-4-yl group,
  • linkage of the prodrug moiety to the rest of the active molecule is stable enough so that the serum half life of the prodrug is from about 8 to about 24 hours.
  • the prodrug moiety comprises a tertiary amine having a pKa near the physiological pH of 7,5. Any amines having a pKa within 1 unit of 7.5 are suitable alternatives amines for this purpose.
  • the amine may be provided by the amine of a morpbolino group. This pKa range of 6.5 to 8.5 allows for significant concentrations of the basic neutral amine to be present in the mildly alkaline small intestine.
  • the basic, neutral form of the amine prodrug is lipophilic and is absorbed through the wall of the small intestine into the blood. Following absorption into the bloodstream, the prodrug moiety is cleaved by esterases which are naturally present in the serum to release an active compound.
  • R examples include, without limitation:
  • R is as tabulated below:
  • R is.
  • R JC is lower aik l (e.g. C;-Cr, alkyl). 0086] fn yet another aspect, R is: wherein X 1 . Y ' and X" are as defined herein.
  • X' is selected from the group consisting of O, S and NR wherein Rr ' is hydrogen or -C alkyl; -0057 1 48 Atty. Dki. No. : 104592-0210
  • Y 1 is -C(R i5 ) 2 or a sugar moiety, wherein each R 58 is independently hydrogen or
  • X z is selected from the group consisting of halogen, Ci-C alkoxy, diacvlgiycerol, amino, alkylamino, CrQ, dialkylamino, C]-C & 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
  • V is selected from the group consisting of C 1 -C5 alkyl, Cs-Cg cyeloalkyi, C3-C9 heterocyclyl, C 6 -C f o aryl, C3-C9 heteroaryl, C'iW ⁇ X', PO(X 3 ) 2 , and SCbX " ;
  • W ' is O or NR 39
  • R 39 is hydrogen or C
  • each X '3 is independently amino, hydroxy!, inereapto, C ⁇ -C(, alkyl, heteroalkyl, cyeloalkyi, hetrocyclyl, aryl. or heteroaryl, C i -C,-, alkoxy, CyCi, alkylamino, C pC,
  • dialkylamino Ci-C 6 alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and -O-CH 2 -CH(OR 40 )CH 2 X 4 R 40 ,
  • each R 40 is independently C1 -C22 alkyl, C -C8 cyeloalkyi, C3-C9 heterocyclyl, Ce-Cio aryl, or C3-C9 heteroaryl. Ct-Cg a!kylene, or Ci- g heteroalkyiene.
  • Each heterocyclic and heteroaryl ring system is optionally substituted with C i -C;, alkyl, -OH, amino and carboxyl groups.
  • the present invention utilizes the following Y 1 groups: CH 2 , CHMe, CH(isopropyl), CH(tertiarybutyi), C(Me ⁇ 2, C(Et)>, C(isopropy!);,, and C(propyl) 2 .
  • the present invention utilizes the following X 2 groups:
  • Each heterocyclic is optionally substituted with one or more, preferably, 1 -3, Cj - Cx alky], -OH, amino and/or carboxy] groups.
  • R is :
  • X 3 is independently C i-Cc alky], C'3- g cvcloaikyl, C3-C9 heterocyclyl. C KI aryl , or C3-C9 heieroary! ; and
  • R ' ⁇ is independently hydrogen or C i -Cg alkyl, Cj-Cg cycloalkyl, C3-C9 heterocyclyl, C f) -Cio aryl. or C3-C9 heleroary!.
  • Each heterocyclic is optionally substituted with one or more, preferably, 1 -3, C 1-C3 alkyl, -OH, amino and/or carboxy] groups.
  • R is:
  • each X 3 is independently amino, hydroxy;, mercapto, € ⁇ ) - €(, alkyl, C 3 -C $ cycloalkyh C3-C9 heterocyciyi. CV €>o aryi, or C3-C9 heteroaryl, C )-Q alkoxy, Cj -Ce aiky!amino, CVC ( , diaikylamirso, C-.-C f , alkykhio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and -O-CH 2 -CH(OR 0 CH 2 X 4 R 40 ,
  • X 4 is selected from the group consisting of O, S, S ), and S0 2 ;
  • each IV 0 is independently Cj ⁇ >-C 22 alkyl, C 3 -Cg cycloalkyL C3-C9 heterocyciyi, Ce,-C
  • R 42 is independently hydrogen or C
  • R 42 is independently hydrogen or C ⁇ ⁇ C alkyl, C 3 -Cg eyeioaikyl, C3-C9 heterocyciyi, Cg-Cio aryl, or C3-C9 heteroaryl; and each X s independently is Ci-C alkyl, C 3 -Cs cvcloalkyi, C3-C9 heterocyciyi, C 6 -Cio aryl, or C3-C9 heteroaryl, C i-Q alkoxy, C-.-Ct, alkylammo, C1 -C6 dialkylamino, or Cj-Ce a!kylthio.
  • R is represented by the following structures:
  • R is C10-C22 alkyl or alkyiene
  • R 44 is H or C f -C aikyl
  • R ' represents side chain a!kyl groups present in naturally occurring alpha arnir 10 acids
  • R is;
  • R is -C(R 2n °R 20 l )O(R 20:! R 20i )P(O)OR 204 NR 205 R 206 , wherein each R 2 0 , R 20 i , R 202 , R 203 , R 204 R 205 and R 206 is independently H, a C , -C 8 aikyi, C 3 -C 9 hcierocyelyl, C 3 - Cg cycloalkyl, C 6 -Cio aryi, C3-C9 heteroaryl, wherein each alkyi, heterocyc!yl, cycloalkyl, aryl and heteroaryl is optionaliy substituted,
  • R is -CH(R 20, )OCH ? P(O)OR 204 NHR m , wherein R 201 is d- C g aikyi, R 204 is phenyl, optionaliy substituted, in one embodiment ⁇ 206 is -CHR 207 C(O)OR 208 wherein R" " is selected from the group consisting of the naturally occurring amino acicl side chains and --CCbH esters thereof and R' :0a is C
  • R 2b is C i -Ce aikyi, optionally susbtitued with 1 -3, C0 2 H, SH, Nl3 ⁇ 4, C 6 -C: o aryl, and C2-C 10 heteroaryl.
  • R is:
  • R is:
  • Y is -C(R" ) 2 .
  • R "' ' is independently hydrogen or Cj-Cg alkyl, Cj-Cg cyeloalky], C3-C heterocyclyl, aryl, or C3-C9 heteroary!.
  • R is
  • R ,IJ is -Oi l or hydrogen
  • R is -OH, or hydrogen
  • W is- CH(CH 3 )W' ;
  • W ! is a substituted C rC3 ⁇ 4 alley! group containing a moiety which is optional!) negatively charged at physiological pH
  • said moiety is selected from the group consisting of C0 2 H, SO3H, S0 2 H, -P(0)(OR 52 )(OH), -OP(0)(OR 52 )(OH), and OSO 3 H,
  • R 52 is C f -C 6 alkyi, Cs-Cg cycloalkyl, C3-C9 heterocyclyl, C -C10 aryl, or C 3 - C9 heieroaryi.
  • Each heterocyclic and heteroaryi ring system is optionally substituted with one or more, preferably 1 -3, C1 -C3 alkyL -OH, amino and/or carboxyl groups.
  • R is:
  • R" is 1 ! or O-Cg alkvi.
  • R is S0 3 H.
  • R comprises a cleavable linker, wherein the term "cleavable linker"' refers to a linker wh ich 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.
  • the linker is a self- immolating linker, such as that disclosed in U.S. patent publication 2002/01471 38, to Firestone; PCT Appl . No. US05/08161 and PCT Pub, No, 2004/087075.
  • the linker is a substrate for enzymes. See generally Rooseboom et a!., 2004, Pharmacol. Rev, 56:53-102.
  • composition comprising any of the compounds described herein, and at least a pharmaceutically acceptable excipient.
  • this invention provides a composition comprising any of the compounds described herein, and a pharmaceutically acceptable excipient.
  • compositions can be formulated for different routes of administration.
  • 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, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. 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 cd., A. Oslo editor, Easton Pa. 1980).
  • excipicnts are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this invention.
  • Such excipicnts may be any solid, liquid, semi-solid or, in the case of an aerosol 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,
  • compositions disclosed herein may be used in conjunction with any of the vehicles and excipicnts commonly employed in pharmaceutical preparations, e.g., talc, gum arable, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, ,2-propylene glycol, po!ygiycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like.
  • Solid pharmaceutical excipients include starch, cellulose, hydroxypropyl cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, eihanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oi l, soybean oil, mineral oil, sesame oil, etc.
  • the compositions provided herein comprises one or more of a-tocopherol, gum arabic. and/or hydroxypropyl cellulose.
  • this invention provides sustained release formulations such as drug depots or patches comprising an effective amount of a compound provided herein.
  • the patch further comprises gum Arabic or hydroxypropyl cellulose separately or in combination, in the presence of alpha-tocopherol.
  • the patch further comprises gum Arabic or hydroxypropyl cellulose separately or in combination, in the presence of alpha-tocopherol.
  • 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.
  • Compounds and pharmaceutical compositions of this invention maybe used al one or in combination with other compounds.
  • the coadministration can be in any manner in which the pharmacological effec ts of both are
  • co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration he used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time.
  • 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 ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention.
  • the method comprising administering to a subject in
  • a method for increasing oxygen affinity of hemoglobin S in a subject comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.
  • the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or
  • a method for treating oxygen deficiency associated with sickle cell anemia comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.
  • a method for treating sickle cell disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the compounds or compositions described herein.
  • a method 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 comprising administering to a subject
  • 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, precipitation, column chromatography, and the l ikes, as will be apparent to the skilled artisan upon reading this disclosure.
  • a 5 and B 5 are independently NR.' 4 , O, S, S(0)x, NBoC, CI ! 2 , CM R M , C(R I ) 2 provided that when both A 5 and B 5 are present in a ring, both are not Ci3 ⁇ 4, CHR' 4 , C(R 14 )., and that when only I A 3 or B 5 is present in a ring the A 5 or B 5 is not CH?, CHR i4 , C(R ,4 ) 2 ;
  • R' 4 is C t -C 6 alkyl, COR , s or COOR 15 ; wherein IV 5 is optionally substituted Cj -C 6 alkyl, optionally substituted Cg-Cio aryi, optionally substituted 5- 10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4- 10 membered heterocycie containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;
  • X, and X 5 each represents a leaving group and are independently selected from CI, Br, a d L
  • R ! is C
  • Y 5 represents a leaving group selected from CI, F, Br, 1, OSO 2 R 1 ' and OSG 2 Ar; -0057 1 60 . Dkt. No. ; 104592-0 '
  • Ar is phenyl optionally substituted with 1 -3 halo and/or C 1 -C4 alkyl; n is 0, 1 , or 2; and
  • Step 4 Subsequent reduction 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, Ph 3 PBr 2 (or CBr 4 -Pb 3 P or PBr , or aikyl/aryl sufonyl chloride produces the corresponding 10-X chloride, bromide or sulfonate (Step 5).
  • the double bond oi heterocyclohexene carboxylate 8 is reduced to give the «-heterocyc3ohexane ll-cis carboxylate under palladium catalyzed hydrogenation conditions (Step 6).
  • Reduction of the ester group of l l-cis by LAH or DIBAL yields cis- aicohoi 12-OH-cis (Step 8).
  • sulfonate such as mesylate, tosylate
  • 13-X-cis can be achieved by reacting with thionyl chloride, or Ph 3 PBr 2 , or sufonyl chloride (such as mesyl chloride or tosyi chloride) (Step 9).
  • the cw-cyclohexane carboxylate 11-cis can also be isomerized to the thermodynamically raore stable trans-isomer 11 -trans by the treatment with an alcoholic alkoxide (e.g., ethoxide) solution.
  • 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.
  • N-linked heterocyclic analogs (compound 5, Scheme 4) can also be synthesized from animation procedures developed by Buchwaid and Hartwig. ⁇ B
  • Syntheses 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 evaporation.
  • aprotic solvents include, but are not limited to methylene chloride, tetrahydrofuran, and the like.
  • activations can be performed in situ by using reagents such as BOP
  • 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 methy lene chroride;
  • organic solvent such as ethyl acetate or methylene chloride
  • the solvent can be acidified with an acid, such as HC1 or acetic acid to provide a pharmaceutically acceptable salt thereof.
  • the crude reaction can be passed over an ion exchange column bearing sulfonic acid groups in the protonated form, washed with deionized water, and eluted with aqueous ammonia; followed by evaporation.
  • Suitable free acids bearing the tertiary amine are commercially available, such as 2- (N -morphoJ ino)-propi onic acid, N,N- dimethyl-bcta-alanine, and the like, Non- commercial acids can be synthesized in straightforward manner via standard literature procedures.
  • Carbonate and carbamate prodrugs can be prepared in an analogous way.
  • 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.
  • Scheme 5 below provides a meihod of synthesizing an acyioxymethyl version of a prodrug by adapting a method from the reference Sobolev et al., 2002, J. Org. Chem. 67:401- 410.
  • R S ! is C] -Cf, aikyl.
  • Scheme 6 below provides a method for synthesizing a phosphonooxyniethyl version of a prodrug by adapting a method from Mantyla et al., 2004-, J. Med. Chem. 47: 188- 195.
  • Scheme 7 provides a method of synthesizing an alkyloxymethyl version oi a prodrug
  • R 52 is Ci-Ce alky L, C 3 -Cg cycloalkyi, C3-C heterocyclyi, Cg-C f o aryl, or Cj- C heteroaryl.
  • the mixture was filtered through a pad of silica.
  • the silica was washed with ethyl acetate 2-20mL.
  • the combined filtrates were evaporated and the residue was dried on highvac.
  • the residue was purified by preparative HPLC or flash silica gel chromatography,
  • the ice cooling bath was allowed to expire over 90 min and the mixture was stirred at RT for 2-48 hours.
  • the mixture was stirred for 10 min, then filtered through a pad of silica.
  • the silica was washed with ethyl acetate 2-20mL.
  • the combined filtrates were evaporated and die residue was dried on highvac.
  • the residue was purified by preparative HPLC or flash silica gel chromatography.
  • Li --MS Liquid chromatography-mass spectrometry
  • ACN Acetonitriie
  • LAH/ L1AIH4 Lithium aluminum hydride
  • DIBAL Diisobutylaluminium hydride
  • DIAD Diisopropyl azodicarboxylate
  • DLPEA ⁇ , ⁇ -Diisopropylethylamine
  • Step 3
  • Step 1
  • Step 1 To a 500-mL flask containing the pyrazole boronate (9.0g, 38. 1 mrnol), 2- chloropyridine (5.47g, 38. Irnmol), Pd(dppf)Cl2 ([1,1 -bis(diphenylphosphino)f errocene] dichloropalladium) (i .39g, 1.91 mmol, 5%raol), and sodium bicarbonate (9.6 lg, 1 14.4mmoI, 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
  • Step 2° To a solution of ⁇ 2 ⁇ (l ⁇ isopropyl ⁇ rH ⁇ pyrazol-5-yl)pyridin-3-yl)methanoi ⁇ (440mg, 2.02mmol) in DCM (4 mL) was added SOCl 2 (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.
  • Step 1 To (E)-l-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yI)-3- (dimethylamino)prop-2-en- 1 -one (crude,3.205g, 10.0 mmoL 1 eq.) in EtOH (30 mL) was added cyclopentylhydrazine 11C1 salt (1.639g, 12.0 mmol, 1.2eq) at RT.
  • Step 2 To a solution of (2-(l-cyclopentyl-lH-pyrazol-5-yl)pyridin-3- yl)methanol(301mg, 1.24mmol) in DCM ( 3 mL) was added SOCl 2 (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.
  • Step 1 To a solution of 6-methoxypyridin-3-ol (20 g, 0.16 mol) in DMF (200 mL) was added NaH (60% in mineral oil; 9,6 g, 0.24 mol) at 0-5 U C portion-wise. Upon die completion of addition, the mixture was continued to stir at 0-5 °C for 15 rnin followed by additional of chioromethyl methyl ether. The mixture was stirred at 0-5 °C for another 20 min and quenched with aqueous UC ijsat .
  • Step 2 To a mixture of 2-mcthoxy-5-(methoxymethoxy)pyridine (30 g f 0. i 78 rno! and diisopropylamine (507 uL, 3.6 mmoi) 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.
  • DMF 24.7 mL, 0.32 mol
  • GTB527 was prepared using general method B from 5-bydroxy-2- methoxyisonicotinaldehyde and INT-2.
  • Step 1
  • Step 2 -0057.1 86 Atty. Dkt. No.: 104592-0210
  • methoxyisonicotinaldefiyde (590 mg) suspened in water (5.0 mL) was added HCI (6 N, 4 mL), Once the mixture turned into a homogeneous solution, it was frezee at -78 °C to an solid and pump under high vaecurn O/N. The yellow solid was continued to pump at 45 °C -0057.1 87 Ally. Dkt. No,: 104592-021 0 for 20 h, dissolved in water (2.0 raL), and basified to p! 1 I ⁇ 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.
  • GTB779 was prepared according to general method B from 5-hydroxy-2-(2- morpholinoethoxyjisonicotinaldehyde and iNT-4,
  • GBT832 Preparation of 2-(2-methoxyethoxy)-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridrae-4-carba]dehyde.
  • GTB8.32 was prepared according to general method B from 5-hydroxy-2-(2- methoxyethoxy)isonicotinaldehyde (l ' NT-5) and INT-2.
  • GTB835 was prepared according to general method B from 3-hydroxy-6- methyipicolinaldehyde and iNT-2.
  • GTB836 was prepared according to general method B from 3-hydroxy-6- methylpicolinaldehyde and INT-3.
  • GTB839 was prepared according to general method B from 3- hydroxypicoiinaidehyde and INT-2.
  • GTB839 was prepared according to general method B from 3- hydroxypicolinaldehyde and INT-3,
  • GTB844 was prepared according to general method B from 3-chloro-5- hydroxyisonicotinaldehyde and iNT-2.
  • Step 1 To a solution of l-tert-butyl 4-ethyl 3-Qxopiperidine- 1 ,4-dicarboxylate
  • Step 2 To a solution of 1 -tert-butyl 4-ethyl 3-(((trifluorometliy] ⁇ 8u]fbnyl)oxy)-5,6- dihydropyridine-l ,4(2H)-dicarboxylate (1 ,49 g, 3.7 mmol) and ( 1 -isopropy 1 - 1 H-pyrazol-5 - yl)boronic acid (0.57 g, 3,7 mmol) in dioxane (10 mL) was added Pd(dppf)C.2 (0.27 g, 0.37 mmol) and a solution of sodium carbonate (1.18 g, 1 1.10) in water (3 ml), the mixture was degased with No for 5 min, and was heated at i 00 °C for 15 h, after cooling to room
  • Step 3 To a solution of l-(terl-butyl) 4-ethyl 5-(l -isopropyi- 1 H-pyrazo]-5-yl)-3,6- dihydropyridme- 1 4 4 ⁇ 2H)-dicarboxylate (450 mg, 1.24 mmol) in THF (6 mL) was added
  • Step 5 To a solution of tert-butyl 4-(bromomethyl)-5-( l-isopropyi-3 H-pyrazol-5- yl)-3,6-dihydropyridine- 1 (2H)-carboxylate (18 mg, 0.05 mmol) and 5-hydroxy-2- niethoxyisonicotmaldehyde (10 mg, 0,06 mmol) in DMF (1 mL) was added K 2 C()3 (14 mg, 0.1 mmol).
  • Step 1 To a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (1.0 g, 5.81 mmol)in DCM (30 mL) was added DIPEA (1.22 mL, 6.97 mmol) and Tf20 ( 1.08 mL, 6.39 -0057.1 94 Dkt. No. : 104592-0210 mmoi) at -78 °C, then it was warmed up to room temperature and stirred at room
  • Step 2 To a solution of ethyl 5 -(((trifluoromethyl)sulfonyl)oxy)-3 ,6-dihydro-2H- pyran-4-carboxylate (crude from step 1) and 1 -isopropyi-5 -(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)- 1 H-pyrazote ( 1 .37 g, 5.82 ramo! in dioxanc (20 ml) was added
  • Step 3 To a solution of ethyl 5-(l-isopropyl-lH-pyfazol-5-yl)-3,6-dihydro-21 I- pyran-4-carbox late (600 mg, 2.27 mmoi) in THF (10 mL) was added LiA!H 4 (1 M in THF. 2.72 mL, 2.72 mmoi) at -20 °C, the reaction was stirred at -20 °C for 30 min, and was quenched with Sat. NH 4 CI.
  • Step 4 To a solution of (5-(l -isopropyl-1 H-pyrazol-5-yl)-3,6-dihydro-2H-pyraQ-4- yl)methanol (300 mg, 1.35 ramoi) in DCM (5 rsiL) was added dibromotriphenylphosphorane (630 mg, 1.35 mmol) at room temperature, after stirring for 30 min, it was diluted with DCM. organic layer was washed with Sat.
  • Step 5 To a solution of 5-(4-(bromomet.hyl)-5,6-dihydro-2H-pyran-3-yl)- l - isopropy!- 1 H-pyrazolc (1 10 mg, 0.38 mmol) and 2,6-dihydroxybenzaldehyde (100 mg. 0.76 mmol) in DMF (6 niL) was added K 2 C0 3 (i 10 mg, 0.76 mmol), After stirred at room
  • Step 1 To a solution of ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H- pyran-4-carboxyiate (1.77 g, 5.81 mmol) and phenylboronic acid (1.42 g, 11.62 mmol) in
  • Step 2 To a solution of ethyl 5-phenyl-3,6-dihydro-2H-p>Tan-4-carboxylate (1.05 g. 4.52 mmol) in THF (20 mL) was added L1AIH4 (1M 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.
  • Step 1 into a 50-mL round- bottom flask, was placed a solution of (2-chloropyridin- 3-yl)methanol (500 rag, 3.48 mmol, 1.00 equiv) in a solvent mixture of dioxane and 3 ⁇ 40 ( 10/10 mL).
  • (2-Methoxyphenyl)boromc acid (532 mg, 3.50 mmol, 1.20 equiv)
  • sodium bicarbonate (882 mg. 10,50 mmol, 3.00 equiv
  • PdtdppfiCL 286 mg, 0.39 mmol, 0.10 equiv

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

Dkt. No.: 104592-02
COMPOUNDS AND USES THEREOF FOR THE MODULATION OF
HEMOGLOBIN
FIELD OF THE INVENTION
[0001 ] This invention provides compounds and pharmaceutical compositions suitable as allosleric modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.
STATE OF THE ART
{0002J Sickle ceil disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent. The basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin (Hb),
[0003] Hemoglobin (Hb) transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through
conformational changes. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, aliowing HbS to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled ceils are also more rigid than normal red blood ceils, and their lack of flexibility can lead to blockage of blood vessels. U.S. 7, 160,910 discloses compounds that are ailosteric
modulators of hemoglobin. However, a need exists for additional therapeutics that can treat disorders that arc mediated by Hb or by abnormal Hb such as HbS.
SU MARY OF THE INVENTION
[0004] This invention relates generally to compounds and pharmaceutical compositions suitable as ailosteric modulators of hemoglobin. In some aspects, this invention relates to methods for treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.
-0057.1 1 . Dkt. No.: 104592-02 ! I in certain aspects of the invention, a compound of formula (I) is provided:
Figure imgf000003_0001
or a tautorner thereof, or a pharmaceutically acceptable salt of each thereof wherein
L10 is optionally substituted methylene or, preferably, a bond; is a single or a double bond;
each X and Y is independently (CR2V)e, O, S, SO, S02 or NR20; e is 1 to 4,
preferably I ; each R''° and R"' independently is hydrogen or C-.- .; alkyl optionally substituted with 1-3 halo, OH, or C|-C6 alkoxy, or CR^R^ is OO, provided that if one of X and Y is O, S, SO, SO?, then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof;
V! and V independently are Ci-C6 alkoxy; or V! and V2 together with the carbon
atom they are attached to form a ring of formula:
Figure imgf000003_0002
wherein each VJ and V are independently O, S, or NH, provided that when one of V" and V4 is S, the other is NH, and provided that V 1 and V are both not NH; q is 1 or 2; each V° is independently C] -C6 aikyl optionally substituted with 1 -3 OH groups, or V" is CC^ "0, where each R60 independently is C ; -C6 alkyl or hydrogen; t is 0, 1 , 2, or 4; or CV 'V2 is OV, wherein V is O, NOR80, or Atty. Dkt. No. : 104592-021 0
R"J is optionally substituted Ci-C6 alkyl;
RSl and R8 independently are selected from the group consisting of hydrogen,
optionally substituted C C6 alkyl, COR , or C02R ;
R" is hydrogen or optionally substituted C | -C6 alkyl ; and
RK is optionally substituted C i -Q alkyl;
provided that the compounds provided herein exciude 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 Ce-Ci o aryl, or a 5- 10 membered heteroaryl . wherein the heteroatom is
selected from the group consisting of O, N , $,, and oxidized forms of N and S, wherein each of the aryl, or heteroaryl is optionally substituted, preferably with 1 -4 C i -Cf, alkyl and/or Q- alkoxy groups; ring B is:
Figure imgf000004_0001
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, wiierein each of the heteroaryl and the heterocycle is optionally substituted, preferably with 1 -4 Ci -Ce alkyl groups;
ring C is C Ci o a l or a 5- 1 0 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 , C \ -C alkyl, -COOR1, and
R! is a hydrogen, C\-C(, alkyl or a prodrug moiety; wherein the alkyl is optionally
substituted with a 5 - 10 membered heteroaryl containing up to 5 ring
4314-3854-0057.1 3 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 io 5 ring heteroatonis, wherem 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-C6 alky I;
R3 and R6 are each independently hydrogen, optionally substituted C|-C6 alky! or -COOR3 ;
is hydrogen or optionally substituted Ci-Q alkyl;
with the proviso that when ring C is C 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 Q-Cio aryl;
and ring B is optionally substituted 5-10 membered heteroaryl:
then ring A is not optionally substituted 4-10 membered heterocycle. in another instance:
ring A is C/0-C;o aryl. a C'3-C's cycloa!kyl, 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, cyeloalkyl, or heterocycle is optionally substituted, preferably with 1 -4: halo, C |-C(; alkyl, Ci-Cf, alkoxy, and/or CJ-CJO cyeloalkyl, wherein the Cj-Cg alkyl is optionally substituted with 1-5 halo, Ct-Q alkoxy, and/or C3-C10 cyeloalkyl;
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 and S, wherein each of the heteroaryl and the heterocycle is optionally substituted, preferably with 1 -4: halo, Cj-Cf, alkyl and/or --CO-Cj-Q, alkyl , is a single or a double bond; Atty. Dkt. No.: 1 04592-0210 ring C is Cs-C io ary! or a 5- 1 0 membered heieroaryl containing up to 5 ring heteroaioms, 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, -OR! , C ] -C6 aikyi, -COOR 1 , and/or Ci-Cs aikoxy, wherein the
Figure imgf000006_0001
alkyl is optionally substituted with 1 -5 halo,
Figure imgf000006_0002
aikoxy and/or a 4-10 membered heterocycie containing up to 5 ring heteroaioms, 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 Co-C'ic aryi;
and ring B is optionally substituted 4- 10 membered heierocyc!yi;
then ring A excludes optionally substituted 5- 10 membered heieroaryl;
and provided that when ring C is Ce-C io aryl;
and ring B is optional ly substituted 5- 1 0 membered heteroaryi;
then ring A is not optionally substituted 4- 10 membered heterocycie.
[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 salt of each of the preceding, wherein
ring A is phenyl optionally substituted with 1 -3 halo and/or \ ~Cf, aikoxy, or is a 4-10 membered heterocycie containing up to 5 ring heteroaioms, wherein the heieroatom is selected from the group consisting of O, N, S, and oxidized forms of and S. optionally substituted, or is
4814-3854-0057.1 5 . Dkt. No,: 104592-02
Figure imgf000007_0001
wherein R' is Q-Q alkyl, optionally substituted with 3-5 fluoro groups, or i s C3-C cycloalkyl;
ring B is selected from the group consisting of
Figure imgf000007_0002
wherein R' is -Q alkyl, -CO-C1-C6 alkyi or a prodrug moiety and wherein the pyridy! ring is optionally substituted with a halo or an NRAS(CH2)_ (R25)2 group where each R25 is independently hydrogen or C-.-Cf, alkyi;
, S, SO, or S02; 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, -OR', Q~Q, alkyl, -COOR! and/or Ci-C- alkoxy, wherein the C]-Q> alkyi is optionally substituted with 1 -5 halo, Ci- ; alkoxy and/or 4- 10 membered heterocycie containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; and
each R 1 is hydrogen or a prodrug moiety R;
V' and V2 independently are Ci-C6 alkoxy; or V 1 and V2 together with the carbon atom they are attached to fon formula:
Figure imgf000007_0003
wherein each V" and V4 are independently O, S, or NH, provided that when one of V and V4 is S, the other is NH, and provided that VJ and V4 are both not NH; q is Atty. Dkt. No.: 104592-0210
1 or 2; each V5 is independently Ci -C6 alkyl or CO2R60, where each R°° independently is Ci-Ce alkyl or hydrogen; t is 1 , 2, or 4; or CV'V2 is C=V, wherein V is O, NOR80, or NNRS !R82;
wherein R U is optionally substituted Cj-Ce alkyl ;
R and R*2 independently are selected from the group consisting of hydrogen,
optionally substituted C C6 alkyl, COR83, or C02RM;
R is hydrogen or optionally substituted \~C(, alkyl;
R84 is optionally substituted < ■(.',, alkyl;
provided that when ring C is C C io 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 Ce-Cio 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 disclosed in U .S. patent application nos. 13/730,730 and 1 3/730,674; and provided that tire compounds provided herein exclude those in able 1 hereinbclow.
0009] Preferably, V! and V2 together with the carbon atom they are attached to form a ring of formula:
Figure imgf000008_0001
2
[0010] In some embodiments, V1 and V2 independently are C\-Ce alkoxy; or Vs and λ> together with the carbon atom they are attached to form a ring of formula:
Figure imgf000008_0002
-0057, 1 Dkt. No. : 104592-0210 wherein each V3 and V4 are independently O, 8, or NH, provided that when one or V and V is S the oilier is NH, and provided that V3 and V4 are both not NH; q is 1 or 2; each V5 is independently C -. -C alkyl or C02R60, where each R6 independently is Ci-Ce alk l or hydrogen; t is 0, 1 , 2, or 4; or CV'V is 0:V, wherein V is O, and wherein the remaining variables are defined herein.
[0011] in certain embodiments, a compound of formula (i l) is provided :
Figure imgf000009_0001
(II)
wherein the remaining variables are defined herein.
[0012] In certain embodiments, a compound selected from formulas (HA), (11B) and (DC) is provided :
Figure imgf000009_0002
ΪΪΑ IIB nc
wherein
R9 is hydrogen, -OR1 , Cj-CV, alkoxy optionally substituted with 1 -3 Cj-Ce alkoxy or 4- 1 0 rnembered heterocycle containing up to 5 ring heteroatoms selected from N, O, S or oxidized forms thereof; -0G57.1 8 Atty. Dkt. No.: 1 04592-0210
R ' is hydrogen, hydroxy, halo or d-Ce alkoxy;
R! ! is hydrogen or Ci- a!kyl; and
R1 is -OR! ;
wherein R! is hydrogen or the prodrug moiety R. ] In certain aspects of the invention, a compound of formula Π) is provided: or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein
L'° is optionally substituted methylene or, preferably, a bond;
ring A is Cb-C i o a yl , 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-C6 alkyl and/or Ci -C6 alkoxy groups;
ring B is:
Figure imgf000010_0001
wherein ring B' including the -N-CO moiety is a 5-6 membered heteroc cle
containing up to 3 heteroatoms selected from nitrogen, oxygen, and sul fur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1 -4 C | -Cf, alkyl groups; each X and Y is independently (CR 0R2 l)e, G, S, SO, S02, or MR20; e is I to 4,
preferably 1 ; each R2 and Rzl independently is hydrogen or C1-C3 alkyl optionally substituted with 1-3 halo, OH, or Cj -Cr, alkoxy, or CR20R23 is O=:0, provided that if one of X and Y is O, S, SO, SO ?, then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof;
ring C is C io aryi 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, CrC6 alkyl, -COOR5, NR5R6, . Dkt. No,: 104592-0210
R is a hydrogen, Ci -Ce alkyl or a prodrug moiety; wherein the aikyl is optionally
substituted with a 5- 10 membered heteroarvl containing up to 5 ring
heteroaloms, wherein the heieroatom 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 u to 5 ring heteroatoms, wherein the heieroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroarvl is optionally substituted with Ci-Ce aikyl;
R and R" are each independently hydrogen, optionally substituted C i -Q, alkyl or
-COOR3 ;
R3 is hydrogen or optionally substituted Ci-Q aikyl;
V1 and V2 independently are CrQ alkoxy; or V1 and V2 together with the carbon
atom they are attached to form a ring of formula:
Figure imgf000011_0001
wherein each V3 and V are independently O, S, or NH, provided that when one of V and V'1 is S, the other is NH, and provided that V3 and V4 are both not NH; q is 1 or 2; each V3 is independently Ci -C6 alkyl optionally substituted with 1-3 OH groups, or V5 is C02R6°, where each R60 independently is C C6 alkyl or hydrogen; t is 0, 1 , 2, or 4; or CV 'V2 is C=V, wherein V is O, NOR80, or NNR81 R82;
Rm is optionally substituted Q-Ce alkyl;
R8' and R82 independently are selected from the group consisting of hydrogen,
optionally substituted CrC6 alkyl, COR83, or C02Rg4:
RSj is hydrogen or optionally substituted Ci-Ce alkyl; and
R84 is optionally substituted Cj-C6 alkyl;
with the proviso that when ring C is Ce-C io aryl;
and ring B is optionally substituted 4-10 membered heterocyclyl;
then ring A excludes optionally substituted 5-10 membered heteroaryl ; . Dkt. No.: 104592-0210 and provided Ihat when ring C is C6-Cio aryl;
and ring B is optionally substituted 5-10 membered heleroaryl;
then ring A is not optionally substituted 4-10 membered heteroeycle.
[0014] In further aspects of the invention, a composition is provided comprising any of the compounds described herein, and at least a pharmaceutically acceptable excipient.
[0015] In still farther 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.
[0016J in further aspects of the invention, a method is provided for treating oxygen deficiency associated with sickle cell anemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[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 dictates 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 compositions and methods include the recited elements, but not excluding others.
"Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition or process consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terras are within the scope of this invention.
[0019] Unless otherwise indicated, ail numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term ''about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached
4814-3854-0057. 1 1 Atty. Dkt. No.: 104592-0210 claims are approximations. Each numerical parameter should at least he construed in light of the number of reported significant digits and by applying ordinary rounding techniques. The term ''about" when used before a numerical designation, e.g., temperature, time, amount, and concentration, including range, indicates approximations which may vary by ( + ) or ( - ) 10
%, 5 % or 1 %
[0020] As used herein, Cm-Cn, such as C1-C12, CpCg, or C]-C6 when used before a group refers to that group containing m to n carbon atoms.
[002 If The term "aikoxy" refers to -O-alky!,
0022] The term "aikyl" refers to monovalent saturated aliphatic hydrocarbyi groups having from 1 to 12 carbon atoms (i.e., CpC;2 aikyl) or 1 to 8 carbon atoms (i.e., CpQ aikyl), or 1 to 4 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyi groups such as methyl (CH3-), ethyl (CH3CH2-), w-propyl (CH3CH2CH2-), isopropyl
((CH. 2CH-X w-butyl (CH3CH?Ci-I2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl
((CH3)(CH3Ct l2)CH-), r-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ίΐΠ Ι. 'Π !_·- >·
[0023] The terra "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:
Figure imgf000013_0001
[0024] The term "-C02H ester" refers to an ester formed between the ~C02H group and an alcohol, preferably an aliphatic alcohol. A preferred example included - C02Rh, wherein RL* is aikyl 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 enantiomericailv enriched, and more preferably a single enantiomer. Non limiting examples of chiral moieties include chiral carbox lic acids, chiral amines, chiral amino acids, such as the naturally occurring amino acids, chiral alcohols including chiral steroids, and the likes,
[00261 The term "cycloalkyl" refers to a monovalent, preferably saturated, hydrocarbyi mono-, bi-, or tricyclic ring having 3-12 ring carbon atoms. While cycloalkyl, refers
4814-3854-0057.1 12 Λΐιν. Dkt, No, : 104592 preferably to saturated hydrocarbyl rings, as used herein, it also includes rings containing carbon-carbon double bonds, Nonlimiting examples of cycloalkyl include cyclopropyi, 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:
Figure imgf000014_0001
[0027] The term "halo" refers to F, CI, Br, and/or 1.
[0028] The term "heteroaryl" refers to a monovalent, aromatic mono-, bi-, or tricyclic ring having 2- 16 ring carbon atoms and 1 -8 ring heieroatoms 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, oxazoic, pyridine, quinoline, and the like. The condensed rings may or may not be a heteroatom containing aromauc ring provided that the point of attachment is a heteroaryl atom. For example, and without limitation, the following is a heteroaryl group:
Figure imgf000014_0002
[0029] The term "heterocyclyP 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 heterocyelyl 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 heterocyelyl include, azalactones, oxazoline, piperidinyl, piperaziny!, pyrrol idinyl, 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 heterocyelyl group. For example, and without limitation, the following is a heterocyelyl group: Atty. Dkt. No.: 104592-0210
Figure imgf000015_0001
[0030] The term "hydrolyzing" refers to breaking an RH-0-CC RH-0-CS-, or an RH-0- S02- moiety to an RH-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=0 group, and to a substitution of 2 geminal hydrogen atoms with a C=0 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, N02, -N2+, -CO2RU 0, -OR 100, -SRi °, -SOR! °, -SO2R!0°,■· NRl01Ri02, -CONR.i 0 iRi02, -SO2N R!0iR'02, C . -C6 alkyl, O-Q, aikoxy, -CR! ii0-C(Rl 00)2, - CCRHl°, C3-C 10 cycloalkyl, C3-C 10 heterocyclyl, Q-C^ r l and C2-C|2 heteroaryl, wherein each R 100 independently is hydrogen or Ci-C& alkyl; C3-Cn cycloalkyl; C3-C 10 heterocyclyl; CVCi2 aryl; or C2-C ;2 heteroaryl; wherein each alky!, cycloalkyl, heterocyclyl, aryi, or heteroaryl is optionally substituted with 1-3 halo, 1-3 C¾-C6 alkyl, 1-3 Cj-C6 haloalkyl or 1-3 Ci-Cfc aikoxy groups. Preferably, the substituents are selected from the group consisting of chloro, f!uoro, -OCH3, methyl, ethyl, so-propyl, cyclopropyl, vinyl, ethyny!, -C02H, - C02CH¾, -OCF3, -CF3 and ·( )(. HF2.
[0033] Rl 0! and R1"2 independently is hydrogen; Cj-Cg alkyl, optionally substituted with - C02H or an ester thereof, C,-C6 aikoxy, oxo, -CRI03=C(RI 03)2, -CCR, C -C I 0 cycloalkyl, C3- Cio heterocyclyl, C6-C12 aryl, or C2-C12 heteroaryl, wherein each RklJ independently is hydrogen or CpCg alkyl; C3-C12 cycloalkyl; C C R) heterocyclyl; Ce-Cn aryl; or C2-C12 heteroaryl; wherein each cycloalkyl heterocyclyl, aryl , or heteroaryl is optionally substituted with 1 -3 alkyl groups or 1 -3 halo groups, or R101 and RUl' together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
j0O34] The term ''"pharmaceutically acceptable" rerei'S to safe and non -toxic for in vivo, preferably, human administration.
[0035] The term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable.
4814-3854-0057.1 14 Aitv. Dkt. o.: 104592 -1)2
[0036] The term "salt'' 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 metal , alkaline earth metal, and ammonium salts, As used herein, ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases. Exemplary, and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, N! L-;, Ca, Ba, imicazoliuni, 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 mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes. Exemplary and non-limiting anions useful in pharmaceutically acceptable salts incl ude oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisalfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the iikes.
[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 regression of the disease or condition, relieving a condition caused by the disease or condition, or suppressing the symptoms of the disease or condition, and are intended to include prophylaxis. The terms also include relieving the disease or conditions, e.g., causing the regression of clinical symptoms. The terras further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual is still be afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
[0038] The terms "'preventing" or "prevention" refer to a reduction in risk of acquiring a disease or disorder (i. e. , causing at least one of the cl inical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). The terms further include causing the clinical
4314-3854-0057.1 15 Dkt. No. : 104592-0210 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 oxygenation 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 or agents that facilitate the incorporation of a compound into cells, e.g., red blood cells, or tissues.
[ΘΘ41] As used herein, a "prodrug" is a compound that, after administration, is metabolized or otherwise converted to an active or more active form with respect to at least one property. To produce a prodrug, a pharmaceutically active compound can be modified chemically to render it less active or inactive, but the chemical modification is such that an active form of the compound is generated by metabolic or other biological processes. A prodrug may have, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity. For example, see the reference Nogrady, 1 85, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392. Prodrugs can also be prepared using compounds thai are not drugs.
481 -3854-0057.1 16 Atty. Dkt, No,: 104592-0210
Figure imgf000018_0001
[0042] In certain aspects of the invention, a compound of formula (I) is provided:
Figure imgf000018_0002
or a tautomer thereof, or a pharmaceutically acceptable sait of each thereof, wherein Li 0 is optionally substituted methylene or, preferably, a bond;
ring A is C Cio aryl, a C Ca eycloaikyi, a 5- 10 membered heieroaryi or a 4- 1 0
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, heteroarvl, cycloalkyl, or
heterocycle is optionally substituted with 1 -4: halo, C i-Cf, alkyl, Ci-Cb alkoxy, and/or C3-C 10 cycloalkyl, wherein the Cj-C6 alkyl is optionally substituted with 1 -5 halo, Cj -Cf, alkoxy, and/or C3-Cso cycloalkyl; or ring A is Cg-Cio aryl, or a 5- 10 membered heteroarvl, 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-Ce alkyl and/or C i~C,¾ alkoxy groups;
ring B is a 5- 1 0 membered heteroarvl or a 4- 1 0 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 heteroarvl and the heterocycle is optionally substituted with 1 -4: halo, C ; -C6 alkyl and/or -CO-C■. -€(, alkyl, or
ring B is:
4314-385Λ-0057 1 17 AUy. Dk No.: 104592-021 0
Figure imgf000019_0001
wherein ring B' including the -N-CO- moiety is a 5-6 mernbered heterocyele containing up to 3 heteroatorns selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocyele is optionally substituted with 1 -4 Cj-Ce alky] groups;
each X and Y is independently (CR20R2! )e, O, S, SO, S02, or NR20: e is 1 to 4,
preferably 1 ; each RiJ and Rz! independently is hydrogen or Cj-C3 alkyl optionally substituted with 1 -3 halo, OH, or Ci-C-6 alkoxy, or CR 0R21 is C™0, provided thai if one of X and Y is O, S, SO, S02, then the other is not CO, and X and Y are both not heteroatorns or oxidized forms thereof;
ring C is Cg-Cjo aryl or a 5-10 mernbered heteroaryl containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, each of which is optionally
substituted with 1-4: halo, oxo, -OR1 , Ci-G, alkyl, -COOR1, and/or C rC6 alkoxy, wherein the CVCv, alkyl is optionally substituted with 1 -5 halo. C pC, alkoxy, and/ or a 4- 10 mernbered heterocyele containing up to 5 ring
heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; or
ring C is Ce-Cio aryl or a 5- 10 mernbered heteroaryl containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, , S. and oxidized forms of N and S, each of which is optionally
substituted with 1 -4: halo, oxo, -OR1, C C6 alkyl, -COOR1, NR5R6,
R1 is a hydrogen, C|-C6 alkyl or a prodrug moiety; wherein the alky! is optionally
substituted with a 5- 10 mernbered heteroaryl containing up to 5 ring
heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and 8, which is optionally substituted with with a 5- 10 mernbered heteroaryl containing up to 5 ring heteroatorns, wherein
4814-3854-0057. 1 8 Dkt. No.: 104592-0210 the heteroatom is selected frorn the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with C]-C& alkyl;
R"1 and R6 are each independently hydrogen, optionally substituted Ci-C6 alkyl or
-COOR3 ;
R' is hydrogen or optionally substituted C i-Ce alkyl;
V1 and V2 independently are C ;-Cf. alkoxy; or V5 and V2 together with the carbon
atom they are attached to form a ring of formula:
Figure imgf000020_0001
wherein each V and V4 are independently O, S, or NH, provided that when one of V ! and V4 is S, the other is NH, and provided that VJ and V4 are both not NH; q is 1 or 2; each V* is independently C i -Ct alkyl optionally substituted with 1 -3 OH groups, or V" is CO^"0, where each R6" independently is Ci-Cg alkyl or hydrogen; t is 0, 1 , 2, or 4; or CV'V2 is OV, wherein V is O, OR80, or NNR8 iR.82;
R80 is optionally substituted C-.-C6 alkyl;
R6i and R8"4 independently are selected frorn the group consisting of hydrogen,
optionally substituted ( >( '., alkyl, COR83, or C02Rs4;
R5 ' is hydrogen or optionally substituted C|-C6 alkyl; and
Rs4 is optionally substituted C \ -Ct, alkyl;
with the proviso that when ring C is Ce-Cio ary!;
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 C¾-C io aryi;
and ring B is optionally substituted 5-10 membered heteroaryl;
then ring A is not optionally substituted 4- 10 membered heterocycie, Atty. Dkt. No.: 104592-0210
[00431 In certain aspects of the invention, a compound of formula (X-I) is provided:
B i A ;
c
(X-I)
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is C6-Cjo aryl, a Cj-Cs cycloalkyl, a 5-10 membered heteroaiyl or a 4-10
membered heterocycle containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms ofN and S, wherein each of the aryl, heteroaiyl, cycloalkyl, or
heterocycle is optionally substituted with 1 -4: halo, C r-Cf, alkyl, Q -Cs alkoxy and/or CN-Ci o cycloalkyl, wherein the C j-C,, alkyl is optionally substituted with 1 -5 halo, Ci -Ce 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 heteroatorns, 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, C \-C& alkyi and/or -CO-C pCe alkyl,
' is a single or a double bond;
X is O, S, SO, or S02;
ring C is C Cio aryl or a 5-10 membered heteroaryl containing up to 5 ring heteroatorns, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, each of which is optionally
substituted with 1 -4: halo, oxo, -OR 1, C'i~C& alkyl, -COOR', and/or C1-C5 alkoxy, wherein the Ci -Cf, alkyl is optionally substituted with 1 -5 halo, CVCf, alkoxy and/or a 4-10 membered heterocycle containing up to 5 ring
4814-3854-006' 20 Atty. Did. No.: 104592-0210 heteroatonis, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; and
R' is hydrogen or a prodrug moiety :
V1 and V4 independently are Ci-C<¾ alkoxy; or V1 and V2 together with the carbon
atom they are attached to form a ring of formula:
Figure imgf000022_0001
wherein each V" and V4 are independently O, S. or NH, provided that when one of V and V is S, the other is NH, and provided that V3 and V4 are both not NH; q is 1 or 2; each V3 is independently C \-Ce alkyl or CO2R00, where each R611 independently is Cj-Gs alkyl or hydrogen; t is 0, 1 , 2, or 4; or CV ! V* is C:::V, wherein V is O, NOR80, or NNR iR82;
Rso is optionally substituted Cj-C6 alkyl;
R8' and R8'2 independently are selected from the group consisting of hydrogen,
optionally substituted G-Cs alkyl, COR8'5, or CG2R84;
RB' is hydrogen or optionally substituted C |-Cg alkyl;
R*4 is optionally substituted Cj-Q alkyl;
provided that when ring C is C&-Cio aryl;
and ring B is optionally substituted 4- 10 merabered heterocyclyl:
then ring A excludes optionally substituted 5-10 membcrcd heteroaryl;
and provided that when ring C is Cs-Qo aryl;
and ring B is optionally substituted 5-10 membered heteroaryl;
then ring A is not optionally substituted 4-10 merabered heterocycle.
[0044] In certain aspects of the invention, a compound of formula (X-I) is provided:
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is phenyl optionally substituted with 1-3 halo and/or G -C6 alkoxy, or is a 4-1 0 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
-0057.1 Atty. Dkt. No. : 104592-0210
Figure imgf000023_0001
wherein R ' is C[-C6 alkyl, optionally substituted with 3-5 fluoro groups, or is C -C cycloalkyl;
ring B is selected from the group consisting of
Figure imgf000023_0002
wherein R: is Ci-Cg alkyl, -CO-CrCe alkyl or a prodrug moiety;
, S, SO, or S02; is a single or a double bond;
ring C is phenyl or a 6 raembered nitrogen-containing heteroaryl. each of which is
optionally substituted with 1 -4: halo, oxo, -OR1, Ci-C6 alkyl, -COOR1, and/or C j -Ce alkoxy, wherein the Ci-C6 aikyl is optionally substituted with 1 -5 halo, Ci-Cft alkoxyand/or 4-10 mcmbered heterocycle containing up to 5 ring heieroatoms, 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 ;
V 1 and V2 independently are C C6 alkoxy: or V1 and V" together with the carbon
atom they are attached to for formula:
Figure imgf000023_0003
wherein each V° and V4 are independently O, S, or NH, provided that when one of V and V4 is S. the other is NI L and provided that V3 and V4 ar hnth not H■ Π 1 '-'
1 or 2; each V5 is independently \ -C$ aikyl or CO2R00, where each R60 independently is Cj -Cc, aik l or hydrogen; t is 0. 1 , 2, or 4; or CV1 Vz is ( V. wherein V is O, NOR80, or NNR8 IR82; Dkt. No. : 104592-021 0
R ' is optionally substituted C i -C5 alkyi;
R8i and Rs~ independently are selected from the group consisting of hydrogen,
optionally substituted C|-C6 alky], COR83, or C02R84;
R83 is hydrogen or optionally substituted CY-CV, alkyl;
R " is optionally substituted Ci-Cg alkyl;
provided that when ring C is C<;-C [o aryl;
and ring B is optionally substituted 4- 10 merabered heterocyclyl;
then ring A excludes optionally substituted 5- 10 membered heteroaryl;
and provided that when ring C is C¾-C ;0 aryl:
and ri ng B is optionally substituted 5- 1 0 membered heteroaryl;
then ring A is not optionally substituted 4- 1 0 membered heterocycle.
[00451 Preferably, V 1 and V2 together with the carbon atom they are attached to form a ring of formula:
Figure imgf000024_0001
wherein each VJ and V are independently O, S, or NH, provided that when one or V" and V is S the other i s NH, and provided that V3 and V4 are both not NH; q is 1 or 2; each \'° is independently C i- Y, alkyl or C02R60, where each Ra'J independently is Ci-C6 alky! or hydrogen; t is 0, 1 , 2, or 4: or CV'V2 is C=V. wherein V is (), and wherein the remaining variables are defined herein.
[0047] In certain embodiments, a compound of formula (III) is provided:
4814-3854-0057.1 23 Arty, Dkl. No.: 104592-0210
Figure imgf000025_0001
(in)
or a lautomer thereof, or a phannaceutically accep table salt of each thereof, wherein ring A is phenyl optionally substituted with 1 -3 halo and/or CpQ aikoxy, or is a 4-10 membered heterocycle containing up to 5 ring hetcroatoms, wherein the heteroatom is selected from the groiip consisting of O, N, S, and oxidized forms of N and S, optionally substituted, or is
Figure imgf000025_0002
wherein R7 is C| -C(1 alkyl, optionally substituted with 3-5 fluoro groups, or is C -C6 cycloaikyl;
ring B is selected from the group consisting of
Figure imgf000025_0003
wherein is CpCg aikyl, -CO-Ci -Ce alkyl or a prodrug moiety;
, S, SO, or S02; is a single or a double bond;
ring C is phenyl or a 6 membered nitrogen-containing heteroaryi, each of which is
optionally substituted with 1 -4: halo, oxo, -OR' , Cj-Cg alkyl -COOR1, and/or C] -C(, aikoxy, wherein the C i-C-, alkyl is optionally substituted with 1 -5 halo. Dkt. No.: 104592-021 0
Ci-C-6 alkoxy and/or 4-10 merabered 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 R' is hydrogen or a prodrug moiety R;
V' and V2 independently are C; -C alkoxy; or V1 and V" together with the carbon
atom they are attached to form a ring of formula:
Figure imgf000026_0001
wherein each V3 and V4 are independently O, S, or NH, provided that when one of V' and V4 is S, the other is NH, and provided that V~! and V4 are both not NH; q is 1 or 2; each V* is independently Q-Ce alkyl or C02R6", where each R60
1 2
independently is C]-C& alkyl or hydrogen; t is 0, 1 , 2, or 4; or CV V is C=V, wherein V is O, NOR80, or NRS ,RS2;
R80 is optionally substituted CrC6 alkyl;
R81 and R8 ' independently are selected from the group consisting of hydrogen,
optionally substituted CrC6 alkyl, COR83, or C02R84;
R8"5 is hydrogen or optionally substituted CVC6 alkyl;
R*4 is optionally substituted Ci-Ce alkyl;
provided that when ring C is Cg-Ci aryl;
and ring B is optionally substituted 4- 10 membered heterocyclyl;
then ring A excludes optionally substituted 5- 1 0 membered heteroaryl;
and provided that when ring C is C6-CJO aryl;
and ring B is optional!y substituted 5- 1 0 membered heteroaryl;
then ring A is not optionally substituted 4- 1 0 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 -~C¾-0-. In another embodiment, -X-Y is -0-CH2-.
-0057/ In certain embodiments, a compound selected from formulas (IIIA), (IIIB) and (IIIC) is provided:
Figure imgf000027_0001
IIIA IIIB IIIC
wherein
R is hydrogen, -OR', C| -C6 alkoxy optionally substituted with 1-3 C; ~C6 a!koxy or 4 10 membered heterocycle containing up to 5 ring heteroatoms selected from
N. O, S or oxidized forms thereof;
R" ' is hydrogen, halo, hydroxy or CyCe, alkoxy;
R' 1 is hydrogen or C | -C6 alkyl; and
R12 is -OR' ;
wherein R! is hydrogen or the prodrug moiety R,
in certain embodiments, ring A is
phenyl substituted with 1 -3 halo or Ci-C6 alkoxy, or
C3-Cg heterocyclyl containing 1-3 heteroatoms, wherein the heterocycle is optionally substituted with i -3 halo.
[005.1 J In certain embodiments, ring A is pyridy!. optionally substituted as defined herein.
[0052] In certain embodiments, compounds of formulas (II), (III), (ΠΙΑ), (IIIB) and (IiiC) are provided, wherein
Figure imgf000027_0002
-0057.1 26 . Dkt No. : 104592-0210 is selected from the group consisting of:
Figure imgf000028_0001
[0053] in certain embodiments, compounds of formulas (II), (Hi), (Ί11Α), (IIIB) and (IITC) are provided, wherein
Figure imgf000028_0002
4814-3854-0057.1 2.7 Atty. Dkt. No.: 104592-0210
Figure imgf000029_0001
[0054] In certain embodiments, a compound is provided, wherein the compound selected from the group consisting of:
Figure imgf000029_0002
Figure imgf000029_0003
-0057. 28 Atty. Dkt. No.: 104592-0210
Figure imgf000030_0001
057.1 29 Atty. Dkt. No.: 104592-0210
Figure imgf000031_0001
Figure imgf000031_0002
or an N oxides thereof, or a pharmaceutically acceptable salt of each thereof.
[0055] in certain embodiments, a compound is provided, wherein the compound selectee from the group consisting of:
Figure imgf000031_0003
-0057.1 30 Arty. Dkt. No. : 104592-0210
Figure imgf000032_0001
or an N oxides thereof, or a pharmaceutically acceptable salt of each thereof,
|0056'j In certain aspects of the invention, a compound is provided, wherein the compound is selected from the group consisting of:
Figure imgf000032_0002
4-0057.1 31 Atty. Dkt.No.: 104592-0210
Figure imgf000033_0001
Atty. Dkt. No.: 104592-0210
Figure imgf000034_0001
or a prodrug thereof, or a pharmaceutic! al acceptable salt 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:
Figure imgf000034_0002
(I)
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein L'° is optionally substituted methylene or, preferably, a bond;
ring A is Cs-C i o 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 C ; -Cf, alkyi and/or CrQ, alkoxy groups;
4814-3854-0057.1 33 Atty. Dkt. No.: 104592-0210 ring B is:
Figure imgf000035_0001
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 heieroaryl and the heterocycle is optionally substituted with 1-4 C i-Cg alkyl groups;
each X and Y is independently (CR20R21)C, O, S, SO, S02, or NR20; e is 3 to 4,
preferably i ; each R 0 and R21 independently is hydrogen or C C3 alkyl optionally substituted with 1 -3 halo, OH, or C(-C0 aikoxy, or CR20R2 i is CO, 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 Q-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, -OR! , Ci-C6 alkyl, -COOR3, NR5R°,
R ' is a hydrogen, Ci-Cg 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 , -C6 alkyl ;
R5 and R" are each independently hydrogen, optionally substituted C 1-C alkyl or
-COOR3 ;
R3 is hydrogen or optionally substituted Cj-Ct, alkyl;
4814-3854-0057.1 34 Atty. Dkt. No.: 104592-0210
V1 and \; independently are Ci-Ce alkoxy; or V1 and V2 together with the carbon
atom they are attached to form a ring of formula:
Figure imgf000036_0001
wherein each V3 and V4 are independently Q, S, or NH, provided that when one of
and V4 is S, the other is H, and provided that VJ and V4 are both not NH; q is 1 or 2; each V3 is independently Cj-Ce alky! optionally substituted with 1 -3 OH groups, or V3 is CO2R00, where each R60 independently is C 1 -C<s alkyl or hydrogen; t is 0, 1 , 2, or 4; or CV !V2 is C=V, wherein V is O, NOR80, or
NNR8 iR82;
R8 is optionally substituted C Ce alky];
R81 and RS/' independently are selected from the group consisting of hydrogen,
optionally substituted CrC6 alkyl, COR83, or CO?R8 ;
R83 is hydrogen or optionally substituted C|-C6 alkyi ; and
R84 is optionally substituted C i-Cs alkyl;
with the proviso that when ring C is Ct-C io aryl;
and ring B is optionally substituted 4-1 0 membered heterocyclyl;
then ring A excludes optionally substituted 5-10 membered heteroaryl;
and provided that when ring C is C C io aryl;
and ring B is optionally substituted 5- 10 membered heteroaryl;
then ring A is not optionally substituted 4- 10 membered heterocycie.
Dkt. No.: 104592-0210
JOSS] In certain aspects of the invention, a compound of formula (IV) is provided:
Figure imgf000037_0001
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A. is C Cio a yl, or a 5- 10 membered heteroaryi, wherein the heteroatora is
selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryi or heteroaryi is optionally substituted with 1-4 C\-C(, alkyl; ring B is:
Figure imgf000037_0002
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 heteroaryi and the heterocycle is optionally substituted with 1-4 Ci -C6 alkyl groups;
each X and Y is independently CR20R21, O, S, SO, S02, or NR10; each R20 and R:? i
independently is hydrogen or C1-C3 alkyl optionally substituted with 1 -3 halo, OH, or Ci-C6 alkoxy, or CR20R2! is C=0, provided that if one of X and Y is O, S, SO, S02, then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof;
4814-3854-0057. 36 . Dkt. No.: 104592-0210 ring C is Cg-Cio aryl or a 5- 10 membered keteroaryl containing up to 5 ring
heteroatoms, wherein the heteroatom is selected from the group consisiing of O, N, S, and oxidized forms of N and S, each of which is optionally
substituted with 1 -4: halo, oxo, -OR1, Cj~C6 alkyi, -CGOR5, NR5R6,
Rl is a hydrogen, C\-C alkyl 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 consisiing of O, , 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 consisiing of O, N, 8, and oxidized fonns of N and S, wherein the heteroaryl is optionally substituted with Ci-C6 alkyl;
R5 and R6 are each independently hydrogen, optionally substituted Cf-Ce alkyl or
-COOR3 ;
IV is hydrogen or optionally substituted Ci-C¾ alkyl;
V and V" independently are Ci-C6 alkoxy; or V and V together with the carbon
atom they are attached to form a ring of formula:
Figure imgf000038_0001
wherein each V"' and V are independently O, S, or i, provided that when one of V ,3 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-Ce alkyl optionally substituted with 1-3 OH groups, or V5 is C02R6°, where each R6u independently is Ci -Cg alkyi or hydrogen; t is 0, 1 , 2, or 4; or CV' V2 is C=V, wherein V is O, NOR80, or NNR81 R82;
Rs0 is optionally substituted Ci -C'e alkyl ;
R6 i and RS2 independently are selected from the group consisting of hydrogen,
optionally substituted CrC6 alkyl, COR83, or C02R84;
R8j is hydrogen or optionally substituted Ci -Ce alkyl: and
R84 is optionally substituted CrC6 alkyl. Atty. Dkt. No.: 104592-021
[005 1 in certain embodiments, ring C is substituted with at least one substituent selected from with 1-4: halo, -OR1 , C.-C6 alkyl, -COOR5, NR5R6.
[0060] In certain embodiments, X is CI i2, O, S, SO, S02 or NH. In certain embodiments, is O, S, SO or S02. Preferably, X is O, and wherein the remaining variables are defined herein.
[0061] In certain embodiments, Y is CR20R2i, O, 5. SO, S02( or NR10; wherein each R20 and R2! independently is hydrogen or C1-C3 alkyl. In certain embodiments, Y is CR20!^' 1 wherein each R''0 and R2' independently is hydrogen or Ci-C3 alkyl. Preferably, Y is CH2, and wherein the remaining variables are defined 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 ar defined herein.
[0064] In certain embodiments, a compound of formula (V) is provided:
Figure imgf000039_0001
(V)
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is Ce-Cio aryl, or a 5-10 membered heteroaryl, wherein the heteroatom is
selected from the group consisting of O, N, S, and oxidized forms of N and S. wherein each of the aryl, or heteroaryl is optionally substituted with 1-4 Cj-Ce alkyl and/or CpCe alkoxy groups;
rina B is:
481 -3854-005?.1 38 Atly. Dkt. No.: 104592-0210
Figure imgf000040_0001
wherein ring B' including Ihe -N-CO- moiety is a 5-6 membered heterocycie containing up to 3 heteroatoms selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroary! and the heterocycie is optionally substituted with 1-4 C i -Cs alkyl groups;
X is O, S, SO or S02;
ring C is C Cjo 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 , CyQ, alkyl -COOR\ NR3R6,
R' is a hydrogen, ;-(?.·.. alkyl or a prodrug moiety R; wherein the alkyl is optionally substituted with a 5- 10 membered heteroary! 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 optionall substituted with with a 5-10 membered heteroaryl containing up to 5 ring heteroatoms. wherein ihe 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 CrC'6 alkyl;
R5 and R6 are each independently hydrogen, optionally substituted C-i-Ce alkyl or
-COOR3 ; and
R3 is hydrogen or optionally substituted Cj-C6 alkyl.
[0065] In certain embodiments, a compound of formula (VI) or (VII) is provided:
4814-3864-0057.1 39 ·. kl . No. 104592-0210
Figure imgf000041_0001
(VI) (VII) or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is Q-Cio ary!, or a 5- 10 membered heteroaryi , wherein the heteroatom is
selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the ary!, or heteroaryi is optional ly substituted with 1 -4 C rCf, alkyi; ring B is CV-Cio ar !, CVC* cycloalkyl, a 5-10 membered heteroaryi containing up to 5 ring hctcroaioms or a 4- 1 0 membered iieterocycle containing up to 5 ring neteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryi, heteroaryi, cycloalkyl or heierocycle is optionally substituted with 1 -4: halo, C]~C(, alkyi, or C pCf, alkoxy, wherein the C pC,, alkyi is optionally substituted with 1 -5 halo, C i -Cb alkoxy, and/or C.yCio cycloalkyl;
R is halo, oxo, -OR 18, C , -C6 alkyi, C s -C6 alkoxy, -COOR5, and/or R5R6;
R ' is hydrogen, subsitued Ci-C-6 alkyi, or a prodrug moiety R;
R5 and R6 are each independently hydrogen, optionally substituted Cj-Q alkyi or
-COOR3 ; and
RJ is hydrogen, provided that the COOR3 is not joined to a nitrogen atom, or is
optionally substituted C i -Ct. alkyi .
[0066j In one embodiment, R4 is -OH. In another embodiment, R is N H2. In one
embodiment, R4 is NH(CH3). In one embodiment, R4 is N(CH3)2. in one embodiment, R4 is NHC(0)OC(CH3)3. In one embodiment, R4 is COOH. In one embodiment, R4 is optionally -0057.1 40 Atty. Dkt. No,: 304592-0210 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:
Figure imgf000042_0001
In certain embodiments, compounds of formula (V) are provided, wherein
Figure imgf000042_0002
[0069] In certain embodiments, a compound of formula (IV) as disclosed above is
provided, with the proviso that:
when ring C is C Ci aryl;
and ring B is optionally substituted 4-10 membered heieroeyelyl;
then ring A excludes optionally substituted 5-10 membered heieroaryl.
[0070] In certain embodiments, a compound is provided, wherein the compound is selected from the group consisting of:
4814-3854-005!'. 41 Aity. Dkt. No.: 104592-0210
Figure imgf000043_0001
4814-3854-0057.1 42 Atty. Dkt. No.: 104592-0210
Figure imgf000044_0001
or N oxides thereof, or a pharmaceutically acceptable salt 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 containing moiety, or another promoiety or prodrug moiety. Preferably the prodrug moiety imparts at least a 2 fold, more preferably a 4 fold, enhanced solubility and/or bioavailabi lity to the active moiety
(where R is hydrogen), and more preferably is hydrolyzed in vivo. The promoieties are structurally arid functionally defined herein.
[0073] In one embodiments, R is -COR90, C02R S, or CONR92R93 wherein
R90 and R9' independently are Ci-Ce alkyi, C3-C8 cyeloalkyl, 4-9 membered heteroeycle, or a
5-10 membered heteroaryl, each containing at least 1 basic nitrogen moiety; and
R 2 and R9 independently are C |-C() alkyl; C-j-Cg cyeloalkyl, 4-9 membered heteroeycle, or a
5-10 membered heteroaryl , each containing at least I basic nitrogen moiety; or R92 and R9~ together with the nitrogen atom they are bonded to for a 4-9 member heteroeycle substituted with at least 1 amino, Ci-C6 alkyl amino, or di C|-C6 a!kylamino group,
[00741 n certain embodiments, R is -C(0)R3 !, C(0)OR31, or CONi R13),,
each R i is independently a Q-Co alkyi; C3-Cg cyeloalkyl, 4-9 membered heteroeycle, or a 5- 10 membered heteroaryl, containing at least 1 basic nitrogen moiety; and
each R13 independently is Cj -Q alkyl; C3-C8 cyeloalkyl , 4-9 membered heteroeycle, or a 5- 10 membered heteroaryl, containing at least 1 basic nitrogen moiety; or both R I J
4814-3854-0057. 1 43 Atty. Dkt. No.; 104592-0210 together with the nitrogen atom they are bonded to for a 4-9 member heterocvcle substituted with at least 1 amino, CpC6 alkyi amino, or di Cj-Qj alkylamino group.
[0075] In one aspect, R is C(0)OR3 \ C(S)OR31, C(0)SR3i or COR3*', wherein R3 ! is as defined herein.
[0076] in one embodiment, R'1 is a group of the formula (CR' R33)t;NR^R35. wherein
each R3 and R3j is independently H, a Cs-Cg alkyl, C3-C9 hcterocyclyl, Cs-Cg cycloalkyl, Cg-Cjo aryl, C3-C9 heteroaryl or R°2 and R33 together with the carbon atom they axe bond to form a C^-Cg cycloalkyl, Cg-Cio aryl, C3-C9 lieterocyclyl or C3-C9 heteroaryl ring system, or 2 adjacent R3"' moieties or 2, adjacent R33 moieties together with the carbon atom they are bond to form a C3-C8 cycloalkyl, Cc-Cio aryl, C3-C9 heterocyclyl or C3-C9 heteroaryl ring system;
each R34 and R35 is a C,-C8 alkyl, C3-C9 heterocyclyl, C3-C8 cycloalkyl, or R3'4 and R35 together with the nitrogen atom they are bond to form a C3-C& cycloalkyl or C3-C9
heterocyclyl ring system;
each heterocyclic and heteroaryl ring system is optionally substituted with C1-C3 alkyi, -OH, amino and carboxyl groups; and
e is an integer of from 1 to 4.
[0077] In some less preferred embodiments R14 and R35 can be hydrogen.
[0078] in one embodiment, the subscript e is preferably 2 and each Ji and R >J is
preferably independently selected from the group, H, CJ¾, and a member in which R32 and Rj3 are joined together to form a cyclopropyl, cyclobutyl, cyclopentyi, cyclohcxyl, or
1 , 1 -dioxo-hexahydro-lA6-thiopyran-4-yl or tetrahydropyran-4-yl group.
[0079] With regard to the prodrug group, preferred embodiments are compounds wherein NR^R35 is morpholino.
[0080] In one embodiment, R is:
-0057.1 44 Atty. Dkt. No,: 1 04592-021 0
Figure imgf000046_0001
wherein
each R3'1 and R''' is independently H, Ci-Cs alky;, or optionally, if both present on the same substituent, may be joined together to form a C3-C8 cycloaikyl, Ce-Cio aryl, C3-C9 heterocyelyl or C3-C9 heteroaryl ring system.
[0081] Within this embodiment, each R32 and RJJ is independently, H, CH3, or are joined together to form a cyclopropy], cyclopbutyl, cyclopentyl, cyclohexyl, 1,1 -dioxo- hexahydro- L\(,-thiopyran-4~yi or tctrahydropyran-4-yl group,
[0082] in a preferred embodiment, linkage of the prodrug moiety to the rest of the active molecule is stable enough so that the serum 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 a morpbolino group. This pKa range of 6.5 to 8.5 allows for significant concentrations of the basic neutral amine to be present in the mildly alkaline small intestine. The basic, neutral form of the amine prodrug is lipophilic and is absorbed through the wall of the small intestine into the blood. Following absorption into the bloodstream, the prodrug moiety is cleaved by esterases which are naturally present in the serum to release an active compound.
[0084] Examples of R include, without limitation:
Figure imgf000046_0002
-0057. 45 Arty. Dkt. No.: 104592-0210
Figure imgf000047_0001
4814-3854-0057 1 46 Atty. Dki. No.: 104592-0210
[0001] In another embodiment, R is as tabulated below:
Figure imgf000048_0001
an N ox e t ereo , or a pharmaceutca y acceptable salt of each thereof.
[0085] In another aspect, R is.
4-0057.1 47 At!) . Dkt. No.: 104592-0210
Figure imgf000049_0001
wherein
RJC is lower aik l (e.g. C;-Cr, alkyl). 0086] fn yet another aspect, R is:
Figure imgf000049_0002
wherein X1. Y ' and X" are as defined herein.
[0087] In one embodiment. X' is selected from the group consisting of O, S and NR wherein Rr ' is hydrogen or -C alkyl; -0057 1 48 Atty. Dki. No. : 104592-0210
Y1 is -C(Ri5)2 or a sugar moiety, wherein each R58 is independently hydrogen or
Cj-Ce aikyl, C3-C8 cyeloalkyi, C3-C9 heterocyclyl, Q-C10 aryl, or C3-C9 heteroaryl;
Xz is selected from the group consisting of halogen, Ci-C alkoxy, diacvlgiycerol, amino, alkylamino, CrQ, dialkylamino, C]-C& alkylthio, a PEG moiety, a bile acid moiety, a sugar moiety, an amino acid moiety, a di-or tri-peptide, a PEG carboxylic acid, and — U-V wherein
U is O or S; and
V is selected from the group consisting of C 1 -C5 alkyl, Cs-Cg cyeloalkyi, C3-C9 heterocyclyl, C6-Cfo aryl, C3-C9 heteroaryl, C'iW^X', PO(X3)2, and SCbX" ;
wherein W' is O or NR39
wherein R39 is hydrogen or C |-C6 alkyl, s-Cg cyeloalkyi, C3-C9 hetrocyclyl, Cg-Cto aryl, or C3-C9 heteroaryl; and
each X'3 is independently amino, hydroxy!, inereapto, C\-C(, alkyl, heteroalkyl, cyeloalkyi, hetrocyclyl, aryl. or heteroaryl, C i -C,-, alkoxy, CyCi, alkylamino, C pC,
dialkylamino, Ci-C6 alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and -O-CH2-CH(OR40)CH2X4R40,
wherein:
X4 is selected from the group consisting of O, S, S=0, and SG¾ and
each R40 is independently C1 -C22 alkyl, C -C8 cyeloalkyi, C3-C9 heterocyclyl, Ce-Cio aryl, or C3-C9 heteroaryl. Ct-Cg a!kylene, or Ci- g heteroalkyiene.
[0088] Each heterocyclic and heteroaryl ring system is optionally substituted with C i -C;, alkyl, -OH, amino and carboxyl groups.
[0089] In one embodiment, the present invention utilizes the following Y1 groups: CH2, CHMe, CH(isopropyl), CH(tertiarybutyi), C(Me}2, C(Et)>, C(isopropy!);,, and C(propyl)2.
[0090] In another embodiment, the present invention utilizes the following X2 groups:
4814-3854-0057.1 49 Attv. Dkt. No. : 104592-0210
Figure imgf000051_0001
-OMe, -OEt, -O-isopropyl, O-isobuty!, O-iertiarybuty!, -O-COMe,
-0-C(=0)(isopropyl , -0-C(=0)(isobutyl), -0-C(=0)(tertiarybutyl), -0-C(=0)-NMe2.
-0-C(=0)-NHMe, -0-C(=0)-NH2, -0-C(=0)-N(H)-CH(R'u)-C02Et wherein R ! is a side chain C i -Ce alky!, or C3-C9 hetcrocyclyl group selected from the side chain groups present in essentia] amino acids; -0-P(=0)(OMe)2, -0-P(=0)(0-isopropyl)2, and 0~Ρ(Ο)(Ό- isobutyl)?. Each heterocyclic is optionally substituted with one or more, preferably, 1 -3, Cj - Cx alky], -OH, amino and/or carboxy] groups.
In another embodiment, In one embodiment, R is :
Figure imgf000051_0002
wherein
X3 is independently C i-Cc alky], C'3- g cvcloaikyl, C3-C9 heterocyclyl. C KI aryl , or C3-C9 heieroary! ; and
R'^ is independently hydrogen or C i -Cg alkyl, Cj-Cg cycloalkyl, C3-C9 heterocyclyl, Cf)-Cio aryl. or C3-C9 heleroary!.
[0092] Each heterocyclic is optionally substituted with one or more, preferably, 1 -3, C 1-C3 alkyl, -OH, amino and/or carboxy] groups.
[00931 in one embodiment, R is:
-0057.1 50 Ally. Dkt. No.: 104592-0210
Figure imgf000052_0001
wherein
each X3 is independently amino, hydroxy;, mercapto,€■) -€(, alkyl, C3-C$ cycloalkyh C3-C9 heterocyciyi. CV€>o aryi, or C3-C9 heteroaryl, C )-Q alkoxy, Cj -Ce aiky!amino, CVC(, diaikylamirso, C-.-Cf, alkykhio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and -O-CH2-CH(OR 0 CH2X4R40,
wherein:
X4 is selected from the group consisting of O, S, S ), and S02; and
each IV0 is independently Cj<>-C22 alkyl, C3-Cg cycloalkyL C3-C9 heterocyciyi, Ce,-C|<> aryi, C3-Cy heteroaryl, Cj-Cs alkylene, or C|-Cg heteroalkylene; and
R42 is independently hydrogen or C|-C6 a!kyl, C3-Cg cvcloalkyi, C3-C9 heterocyciyi,
Cft-Cso aryl, or C3-C9 heteroaryl.
[0094] In some embodiments. R42 is independently hydrogen or C\~C alkyl, C3-Cg eyeioaikyl, C3-C9 heterocyciyi, Cg-Cio aryl, or C3-C9 heteroaryl; and each Xs independently is Ci-C alkyl, C3-Cs cvcloalkyi, C3-C9 heterocyciyi, C6-Cio aryl, or C3-C9 heteroaryl, C i-Q alkoxy, C-.-Ct, alkylammo, C1 -C6 dialkylamino, or Cj-Ce a!kylthio.
[0095] in some, embodiments, R is represented by the following structures:
-0057 1 51 Att . Dkt. No.: 104592-0210
Figure imgf000053_0001
4814-3854-0057.1 52 Arty. Dkt. No.: 104592-0210
Figure imgf000054_0001
Figure imgf000054_0002
W /!herein, in the above examples, R is C10-C22 alkyl or alkyiene, R44 is H or Cf -C aikyl and R ' represents side chain a!kyl groups present in naturally occurring alpha arnir 10 acids;
Figure imgf000054_0003
Atty. Dkt. No.: 104592-021 0 wherein R46 is (CH?)n, f;;:2~4, and CG-R 7-NH2 represents an aminoacyl group; or
Figure imgf000055_0001
wherein R46 is (CH2)„, n=2-4, R47 is (Ci i2);i. n=l-3 and R49 is O or NMe. [0096] In one embodiment, R is;
Figure imgf000055_0002
[0097] In one aspect, R is -C(R2n°R20 l)O(R20:!R20i)P(O)OR204NR205R206, wherein each R2 0, R20 i, R202, R203, R204 R205 and R206 is independently H, a C , -C8 aikyi, C3-C9 hcierocyelyl, C3- Cg cycloalkyl, C6-Cio aryi, C3-C9 heteroaryl, wherein each alkyi, heterocyc!yl, cycloalkyl, aryl and heteroaryl is optionaliy substituted,
{0098] In some embodiments, R is -CH(R20,)OCH?P(O)OR204NHRm, wherein R201 is d- Cg aikyi, R204 is phenyl, optionaliy substituted, in one embodiment^206 is -CHR207C(O)OR208 wherein R"" is selected from the group consisting of the naturally occurring amino acicl side chains and --CCbH esters thereof and R':0a is C|-Cg alkyi. In one embodiment, R2b is C i -Ce aikyi, optionally susbtitued with 1 -3, C02H, SH, Nl¾, C6-C: o aryl, and C2-C 10 heteroaryl.
[0099] in one embodiment, R is:
Figure imgf000055_0003
|0100] In one embodiment, R is:
4814-3854-0057. 54 W 201
Atty. Dkt, No.: 104592-0210
Figure imgf000056_0001
wherein Y is -C(R" )2. wherein each R"' ' is independently hydrogen or Cj-Cg alkyl, Cj-Cg cyeloalky], C3-C heterocyclyl,
Figure imgf000056_0002
aryl, or C3-C9 heteroary!.
[OlOlj 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, 1 1 1 ,107; 5,965,566;
5,880,1 31 ; 5,840,900; 6,01 1 ,042 and 5,681 ,567.
[0102] In one embodiment, R is
Figure imgf000056_0003
wherein
R,IJ is -Oi l or hydrogen;
R is -OH, or hydrogen;
4814-3854-0057.1 55 W
Atty. Dkt. No.: 104592-0210
W is- CH(CH3)W' ;
wherein W! is a substituted C rC¾ alley! group containing a moiety which is optional!) negatively charged at physiological pH,
said moiety is selected from the group consisting of C02H, SO3H, S02H, -P(0)(OR52)(OH), -OP(0)(OR52)(OH), and OSO3H,
wherein R52 is Cf -C6 alkyi, Cs-Cg cycloalkyl, C3-C9 heterocyclyl, C -C10 aryl, or C3- C9 heieroaryi.
[0103} Each heterocyclic and heteroaryi ring system is optionally substituted with one or more, preferably 1 -3, C1 -C3 alkyL -OH, amino and/or carboxyl groups.
[0104} in one embodiment, R is:
Figure imgf000057_0001
wherein R" is 1 ! or O-Cg alkvi.
[0105] In another aspect, R is S03H.
431 -3854-0057. ' D Atty. Dkt. No.: 104592-0210
[0106] in another aspect, R comprises a cleavable linker, wherein the term "cleavable linker"' refers to a linker wh ich 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. I n 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(=0)0-C* connection. In one embodiment, the cleavable linker has at least one C*- C(::"0}S-C* connection. In one embodiment, the cleavable linker has at least one -C(=Q)N*- C*-S02*N*-connection, wherein N* is -NH- or Ci-Ca alkylammo. in one embodiment, the cleavable linker is hydrolyzcd by an esterase enzyme.
[0107] in one embodiment, the linker is a self- immolating linker, such as that disclosed in U.S. patent publication 2002/01471 38, 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 a!., 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, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. 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 cd., A. Oslo editor, Easton Pa. 1980).
4814-3854-0057. 1 57 Atty. I )!·. ! . No. : 1 04592-02 10
[0111] Pharmaceutically acceptable excipicnts are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this invention, Such excipicnts may be any solid, liquid, semi-solid or, in the case of an aerosol 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 excipicnts commonly employed in pharmaceutical preparations, e.g., talc, gum arable, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, ,2-propylene glycol, po!ygiycols, dimethylsulfoxide, fatty alcohols, triglycerides, 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, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, eihanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oi l, soybean oil, mineral oil, sesame oil, etc. In certain embodiments, the compositions provided herein comprises one or more of a-tocopherol, gum arabic. and/or 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 al one or in combination with other compounds. When administered with another agent, the coadministration can be in any manner in which the pharmacological effec ts of both are
4814-3854-0057.1 58 Atty. Dkt. No,: 104592-0210 manifest in the patient at the same time. Thus, co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration he used for administration of both the compound of this invention and the other agent or that the two agents 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 ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention.
Methods of Treatment
(0116] In aspects of the invention, a method is provided for increasing tissue
and/or cellular oxygenation, the method comprising administering to a subject in
need thereof a therapeutically effective amount of any of the compounds or
compositions described herein.
(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.
[01 18} 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 anemia, 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
4814-3654-0057.1 59 Atty. Dk No,: 104592-0210 in need thereof a therapeutically effecti ve 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 ski l led 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, precipitation, column chromatography, and the l ikes, 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.
, ' ~ , ' ~ , ' ~
1 A ' ' B ' C
In the following Schemes, v - "- ' , and refer to rings A, B and C as described herein;
A5 and B5 are independently NR.'4, O, S, S(0)x, NBoC, CI !2, CM RM, C(RI )2 provided that when both A5 and B5 are present in a ring, both are not Ci¾, CHR'4, C(R14)., and that when only I A3 or B5 is present in a ring the A5 or B5 is not CH?, CHRi4, C(R,4)2;
R'4 is Ct-C6 alkyl, COR , s or COOR15; wherein IV5 is optionally substituted Cj -C6 alkyl, optionally substituted Cg-Cio aryi, optionally substituted 5- 10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4- 10 membered heterocycie containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;
X, and X5 each represents a leaving group and are independently selected from CI, Br, a d L
R ! is C | -C(, alkyl;
Y5 represents a leaving group selected from CI, F, Br, 1, OSO2R1' and OSG2Ar; -0057 1 60 . Dkt. No. ; 104592-0'
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
' B '
A
OH
Method
Figure imgf000062_0001
[0123] General method A (Scheme 1 } for preparing aryloxy/heteroarylether analogs (4a/4b) from substituted methylene alcohol (1) and hydroxy! (hetero)aryl aldehyde derivatives (3a/3b). A hydroxyl (hetero)aryi aldehyde derivatives (3a/3b) (0.1-2 mmol) mixture with substituted methylene alcohol (1) (0.8 to 1 ,2eq) and PPh ¾ ( 1 - 1 .5eq) in anhydrous THF (1-1 OmL) was stirred under nitrogen until complete dissolution. The solution was cooled to 0 °C on ice bath and DIAD or DEAD ( 1.1 eq) in THF or toluene was added dropwise over a 1-20 min period. The ice cooling bath was allowed to expire over 90 min and the mixture was stirred at RT for 2-48 hours. The mixture was stirred for 1 0 min, then filtered through a pad of silica. The silica was washed with ethyl acetate 2-20mL. The combined filtrates were evaporated and the residue was dried on highvac. The residue was purified by preparative HPLC or flash silica gel chromatography.
-0057 1 61 Diet o, : 104592-021 0
[0124] General method A (Scheme 1} for preparing aryloxy/heteroarylether analogs (4a/4b) from substituted methylene halide (2) and hydroxy! (hetero)aryl aldehyde derivatives (3a/3b). A mixture of hydroxy! (lietero)aryialdehyde derivatives (3a 3b) (0.1 -2 mmol, 1-4 eq.). substituted methylene chloride or bromide (2) (Icq), and K2C03 (2-5 eq.) (catalytic amount ofNal or B114NI 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 atmosphere. In workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to preparative HPLC or flash silica 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 dichtoromethane 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 SOC-2 dropwise (2eq to 5eq ) at 0 °C or RT, The reaction mixture was stirred at RT for
1 Ornin to 6 h, or until reaction is judged complete (LC/MS). The reaction mixture is
concentrated to dryness over a rotavap. The cmde chloride residue was suspended in toluene, sonicated and concentrated to dryness. The process was repeated three times and dried under vacuum to give the substituted methylene chloride (2), usually as an off-white solid, which was used for next step without further purification. Alternatively, a solution of aqueous I N NazCOj 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 -1 0 mL) was added PI13P 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 complete (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. -0057.1 62 . Dkt. No. : 104592-0210
Figure imgf000064_0001
Figure imgf000064_0002
13-X -trans 13-X-cis
| 127| i.cneral method E (Scheme 2) for preparing heterocyclic methylene derivatives 9, 10, 12 and 13, Condensation of heterocyclic ketone analog 5 with chlorfbrmats or diaiky! carbonate gives (hetero)cyclic beta-ketone ester 6 (Step 1 ). The ketone ester 6 is converted to the inflate intermediate 7 by treating with a Inflating agent (e.g, triflic anhydride) in the presence of an organic base such as Hunig's base (Step 2), Suzuki coupling of the trifiate 7 with a boronic acid or ester affords heterocyclohexene carboxylate 8 (Step 3). Subsequent reduction 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-Pb3P or PBr , or aikyl/aryl sufonyl chloride produces the corresponding 10-X chloride, bromide or sulfonate (Step 5).
[0128] Alternatively, the double bond oi heterocyclohexene carboxylate 8 is reduced to give the «-heterocyc3ohexane ll-cis carboxylate under palladium catalyzed hydrogenation conditions (Step 6). Reduction of the ester group of l l-cis by LAH or DIBAL yields cis- aicohoi 12-OH-cis (Step 8). Conversion of the alcohol 12-OH-cis to its chloride, bromide or Dkt. No.: 104592-02 sulfonate (such as mesylate, tosylate) 13-X-cis can be achieved by reacting with thionyl chloride, or Ph3PBr2, or sufonyl chloride (such as mesyl chloride or tosyi chloride) (Step 9). The cw-cyclohexane carboxylate 11-cis can also be isomerized to the thermodynamically raore 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
Figure imgf000065_0001
13-X-cis
13-X-trarts
Figure imgf000065_0002
[ )129] Coupling of the (hetero)cyclic methylene derivatives 9, 10, 12 and 13 with hydroxy! (hetero)arylaldehyde derivatives (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 animation procedures developed by Buchwaid and Hartwig. λ B
K c
Figure imgf000065_0003
Method B
Figure imgf000065_0004
814-3854-0057.1 64 Aity. Dkt. No.: 104592-0210
[0131] Syntheses 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 evaporation. Examples of aprotic solvents, include, but are not limited to methylene chloride, tetrahydrofuran, and the like.
Alternatively, activations can be performed in situ by using reagents such as BOP
(benzotriazol-l-yloxytiis(dimethylamino) phosphonium hexafluoro!phosphate, and the like (see Nagy et ai., 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 methy lene chroride;
evaporation of the organic solvent layer; and reerystalization from a solvent, such as ethanol. Optionally, the solvent can be acidified with an acid, such as HC1 or acetic acid to provide a pharmaceutically acceptable salt thereof. Alternatively the crude reaction can be passed over an ion exchange column bearing sulfonic acid groups in the protonated form, washed with deionized water, and eluted with aqueous ammonia; followed by evaporation.
[0132] Suitable free acids bearing the tertiary amine are commercially available, such as 2- (N -morphoJ ino)-propi onic acid, N,N- dimethyl-bcta-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 j 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- VCR Zurich, 41 9-534 and Beaumont et al, Curr. Drug Metab. 2003. 4:461 -85.
4814-3854-0057.1 65 . Dki. No.: i 04592 -0210
[0135] Scheme 5 below provides a meihod of synthesizing an acyioxymethyl version of a prodrug by adapting a method from the reference Sobolev et al., 2002, J. Org. Chem. 67:401- 410.
Scheme 5
Figure imgf000067_0001
wherein RS ! is C] -Cf, aikyl.
[0136] Scheme 6 below provides a method for synthesizing a phosphonooxyniethyl version of a prodrug by adapting a method from Mantyla et al., 2004-, J. Med. Chem. 47: 188- 195.
Figure imgf000067_0002
0137] Scheme 7 below provides a method of synthesizing an alkyloxymethyl version oi a prodrug
Scheme 7
Figure imgf000067_0003
wherein R52 is Ci-Ce alky L, C3-Cg cycloalkyi, C3-C heterocyclyi, Cg-Cfo aryl, or Cj- C heteroaryl.
4814-3854-0057.1 66 Arty, Dkt. No.: 104592-0210
Scheme 8
Figure imgf000068_0001
15c (R-Ar/HeteroAr)
[0138] Compounds of structure 17 can be synthesized via general synthetic scheme 8.
Reduction of carboxyiic acid derivative 14 gives hydrxoymethyl analog, which can be
N-derivativtized at via copper-mediated N-arylation reaction (Cul, Ar-I, base such as
Ν,Ν-dimethyl ethylenediamine and potassium phosphate, heat) to give key hydroxymethyl intermediate 15. Coupling of 15 with phenol aldehyde 16 produces the desired aldehyde analog 17 via typical Mistunobu conditions using either triphenylphosphine or polymer supported triphenylphosphine.
[0139] General method step 1 - reduction of carboxyiic acid derivative 14 to methyl alcohol 15: To a suspension of carboxyiic acid 14(l - 10mmoi) in MeOH or EtOH (2-10 mL) at 0 °C was added SOCl2 (1 .5eq). After stirred at room temperature for 1 - 12h, it was
concentrated to remove all solvents, dried under high vacuum to give corresponding methyl or ethyl ester. The ester was dissolved in MeOH or EtOH (5-30 mL), to this solution, was added NaBI-l* (l -4eq) at 0 °C, the mixture was warmed up to room temperature and stirred for additional 1 -24 h. The mixture was quenched with Sat. NH4CI, filtered off the insolubles and the filtrate was concentrated to give crude product, which was purified by flash silica gel chromatography to give the corresponding hydroxym ethylene compound 15.
[0140] General method step 2 - N-alkyiatioii (14a to 14b); The carboxylate 14a ( : =H) can be first alkylated and then reduced to give N-a!kyl hydroxymethyiene analog 14b
(R]=aikyl). in a typical procedure, the carboxylate 14a (1 -lOmmol) is first dissolved in DMF (2-20 mL); to this was then added a base such as Mali or CS2CO3 (1- 1.2eq). followed by the
-1.5eq). The reaction allowed to proceed at room
Figure imgf000068_0002
reaction mixture, the precipitated product was collected, washed with water, and then subjected to preparative HPLC or flash silica gel chromatography purification, in workup B (for products that did not precipitate), diluted HQ or aqueous NH4CI was added at 0 °C to
4814-3S54 -0057.1 67 Atty. Dkt. No.: 104592-0210 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).
[0Ι4Ϊ ] General method step 3 - Copper-mediated N-arylation from 15a to 15c: For cyclic amines (X=H, H). to a solution of hydroxymethy!ene compound 15a ( 1 - 10 mrnoi) and aryl/hetero iodide (1 -1 , 5eq) in iPrOH (0.5- 10 mL) was added ethylene diol (1.3eq) and Cul (6.7moi%), followed by K3P04 (1.3eq), then it was degassed and heated at 88 °C for 6-24 h. Alternatively, for lactams (X:;;:0), to a solution of hydroxymethylene compound 15a (1 - lOmmol) and aryl/hetero iodide (1 - 1.5eq) in Dioxane (2-20 mL) was added Cul (0.17eq), Ν,Ν-dimemylethylenediarnine (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 temperature the mixture was diluted with EtOAc and water, organic layer was separated and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by flash silica gel chromatography to give N-aryl heteroaryl compound 15c.
[0143] General method C -Mitsunobu conditions Λ hydroxy! (hetero)arylaldehyde derivatives (17) (0.1-2 mmoi) mixture with substituted methylene alcohol (16) (0.8 to 1.2eq) and (polymer-supported) PPh.3 (i -1.5eq) in anhydrous THF (1 - l OmL) was stirred under nitrogen until complete dissolution. The solution was cooled to 0 °C on ice bath and DIAD or DEAD (1.1 eq) in THF or toluene was added dropwise over a i -20 rnin period. The ice cooling bath was allowed to expire over 90 rnin and the mixture was stirred at RT tor 2-48 hours. The mixture was filtered through a pad of silica.. The silica was washed with ethyl acetate 2-20mL. The combined filtrates were evaporated and the residue was dried on highvac. The residue was purified by preparative HPLC or flash silica gel chromatography,
4814-3854-0057.1 68 Arty. Dkt No,: 104592-0210
Scheme 9
Figure imgf000070_0001
[0144] General method step 1 (Scheme 9) for preparing substituted methylene alcohol (2) by Suzuki coupling reaction. To a solution of (2-chloropyridin-3-yl)methanol or (2- bromopyridin-3 -yl)methanol (1- l OOmmoi) and appreciate bronic acid or ester (0.8 to 1.5 eq) in dioxane (2-200 mL) was added a solution of sodium bicarbonate (3 eq) in water (1-100 mL), followed by the addition of Pd(dppf)Ci2 (5 to 10mol%). After heating at 100 °C for 4- 24 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 SOCl2 dropwise (2eq to 5eq ) at 0 °C or rt. The reaction mixture was stirred at rt for lOmin to 6 h, or until reaction is judged complete (LC/MS). The reaction mixture is concentrated to dryness over a rotavap. The crude chloride residue was suspended in toluene, sonicated and concentrated to dryness. The process was repeated three times and dried under vacuum to give the substituted methylene chloride (3a), usually as an off-white solid, which was used for next step without further purification. Alternatively, a solution of aqueous IN Na2C03 is then added to produce a solution of pH~ 8. the mixture was extracted w ith 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).
[0146] General method 2 (Scheme 9) for preparing substituted methylene hroirside (3b). To a solution of substituted methylene alcohol (2) (0.1 to 2 mmol) in DCM ( 1 -10 mL) was added Ph3P Br? dropwise (2eq to 5eq ) at 0 "C or rt. The reaction mixture was stirred at -0057. 1 69 Atty. Dkt. No. : 104592-0210 rt for 10 min to 2 h, or until reaction is judged complete (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] Genera! method step 3 (Scheme 9) for preparing aryloxy/heteroarylether
analogs (5) from substituted meihyiene alcohol (2) and hydroxyl (hetero)aryl akiehyde derivatives (4). A hydroxy! (hetero)arylaldehyde derivatives (4) (0.1 -2 mmo!) mixture with substituted methylene alcohol (2) (0.8 to 1.2eq) and (polymer-supported)/PPh3 (1- 1.5eq) in anhydrous THF (I -l OmL) was stirred under nitrogen until complete dissolution. The solution was cooled to 0 JC on ice bath and DT AD or DEAD (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 filtrates were evaporated and die residue was dried on highvac. The residue was purified by preparative HPLC or flash silica gel chromatography.
[0148] General method step 4 (Scheme 9) for preparing aryloxy/heteroarylether
analogs (5) from substituted methylene iialide (3) and hydroxyl (hetero)aryl aldehyde derivatives (4). A mixture of hydroxyl (hetero)arylaldehyde derivatives (4) (0.1 -2 mrooi, 1 -4 eq.), substituted methylene chloride or bromide (3) (l eq). and 2CO3 (2-5 eq.) (catalytic amount of NaT or BU4NI may also be added) in DMF, acetonitnle, NMP or DMSO (1 to 10 mL) was stirred at RT or heating up to 120 °C for 1 -24 h under nitrogen atmosphere. In workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to preparative HPLC or flash silica gel
chromatography purification, in workup B (for products that did not precipitate), diluted HQ 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).
481 -1-3854-0057.1 70 . Dkt. No. : 104592-021 0
Examples
{0149] in the examples below as well as throughout the applicaiion, the following
abbreviations have the following meanings, if not defined, the terras have their generally accepted meanings.
°c = degrees Celsius
RT = Room temperature
min - minute(s)
h hour(s)
~ Microliter
mL = Milliliter
mrnol Millimole
eq = Equivalent
mg = Milligram
ppm = Parts per million
aim = Atmospheric pressure
MS Mass spectrometry
Li --MS = Liquid chromatography-mass spectrometry
HPLC = High performance liquid chromatography
NMR Nuclear magnetic resonance
Sat. /sat. Saturated
MeOH - Methanol
EtOH = Ethanol
EtOAc Ethyl acetate
Et3N = Tri ethyl amine
ACN = Acetonitriie
Ac20 = Acetic anhydride
Na(OAc)3BH Sodium triacetoxv borohydride
PB1-3 phosphorus tri bromide
Pli3P = Triphenylphosphine
Ph',PBr- — Triphenylphosphine dibromide
CBr4 Tetrabromomethane
DMF N. N-Dimethylformaraide
DCM = Dichloromethane
4814-3854 -0C57.1 71 Dkt. No.: 104592-02 !
LAH/ L1AIH4 = Lithium aluminum hydride
THF = Tetrahydrofuran
DIBAL = Diisobutylaluminium hydride
DIAD = Diisopropyl azodicarboxylate
DEAD = Diethyl azodicarboxylate
DLPEA = Ν,Ν-Diisopropylethylamine
] !;;( = Triiluoromethanesulfonic (tritlic) anhydride
Pd(dppf)Cl2 [ 1 J '-Bis(dipheny]phosphino)ferroeerie]
dichl oropal ladi um(II), comp lex
[0150] The following examples are given tor the purpose of illustrating various
embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative 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 defined 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)-3- (dimethylarnino)prop-2-en- 1 -one (INT-1)
Figure imgf000073_0001
Step 1
Figure imgf000073_0002
[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 niL) was added TBSC1
4814-3854-0057.1 Atty. Dkt. No,: 104592-0210
(1 .2 g, 1 50.7 mmol, 1.2 eq.) at RT. The mixture was stirred at RT for 1 h and diluted with a mixture of water (1 00 mL) and EtOAc (300 mL). The organic layer was washed with
NlTiCifsa!.) solution and brine, dried over Na2S04, concentrated, and purified on silica gel using 10% EtOAc/hexanes as eluent to give 2-bromo-3-((tert- buty]dimethylsilyloxy)raeihyl)pyridine (30.1 g, 94%) as a colorless oil, MS (ESI) m/z 302,0
[M+Hf.
Step 2
Figure imgf000074_0001
[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 N2s cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert- butyldimethylsilyioxy)methyl)picoiinonitrile (20.4 g, 82%) as a colorless oil. MS (ESI) m z 249.1 [M+H .
Step 3 :
Figure imgf000074_0002
[0154] Methylmagnesium bromide (3M/ether, 41.0 mL, 123.4 mmol) was added to a stirred solution of 3-((tert-buty3dimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82.25 mmol) in THE (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 NaHC03 (Sao solution and brine, dried over Na2S04, concentrated, and purified on silica gel using a mixture of EtOAc/hexanes as eluent to give 1 -(3-((tert-
4814-3854-0057.1 73 . Dkt. No. : 1 04592-0210 butyldimethy3sily]oxy)methyl)pyridin-2-y])ethanone (12.9 g, 59%) as a colorless oil. MS (ESI) m/z 266.2 i H j .
Step 4:
Figure imgf000075_0001
[0155] 1 -(3-((tert-butyldimethylsilyloxy)niethy!)pyridin-2-yl)ethanone (1 0.8 g, 40.75 mraol) 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)
Figure imgf000075_0002
0156] Preparation of3-(chloromethyl)-2-(l-(2, 2,2-irifluoroethyl)-lH-pyrazol-5- y' pyridine (INJ-2).
Figure imgf000075_0003
Step 1 :
Figure imgf000075_0004
HCi
70% wt inwater
[0157] To (3,3 ,3-trtfluoroethyl)hydrazme (25 g, 50% wt in water, 153.5 mmol, 1 eq.) in a RB flask (250 mL) was added HCI (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 1 1 5. ! [M+Hf.
4814-3864-0057.1 74 ', Dkt. No.: 104592-0210
Step 2:
Figure imgf000076_0001
[0158] To (¾ -l-(3-((tert-butyidimethylsilyloxy)methyl)pyridin-2-yi)-3- (diniethylamino)prop-2-en- 1 -one (crade above, 5.91 g, 18.44 mmol, 1 eq.) in EtOH (20 mL) was added (3,3 ,3 -trifluoroethyl)hydrazine dihydrochloride (4.1 3 g, crude above, 22.33 mmol, 1 .2 eq.) at RT. The mixture was heated at 80 °C for 1 h, concentrated, and diluted with
EtOAc (50 mL) and NaHC03(S3t) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na^SO*}, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethyisilyloxy)met^
5-yl)pyridine (5.90 g; 86% for 2 steps). MS (EST) m/z 372.2 [ +H .
Step 3:
Figure imgf000076_0002
[0159] To 3-{(tert-butyldimethyisiM
y pyridine (5.91 g, 15.93 mmol) in MeOH (20 mL) was added HCI (4 N, 8.0 mL). The mixture was stirred at RT for 1 h, concentrated, and diluted with EtOAc (50 mL) and
NaHC03(5at) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2S04, and
concentrated to give (2-( l-(3,3,3-trifluoroethyi)-lH-pyrazol-5-yl)pyridm-3-yl)methano (4.1 g, quantitative yield) as colorless oil. !H NMR (400 MHz, CDCij) δ 8.54 (dd, J~ 4.7, 1.5 Hz, 1H), 7.92 (dd, J= 7.9, 1.2 Hz, IH), 7.57 (d, J = 1,9 Hz, 1H), 7.30 (dd, J= 7.8, 4.8 Hz, IH), -0057.1 75 Atty. Dkt. No. : 104592-0210
6.50 id. ./ ' 1 .9 Hz, I H), 5.09 (q, ./ .6 Hz, 2H), 4.63 (s, 2H), 1.76 (s, I H). MS (ESI) m/z 258.1 [M+H]+.
Step 4:
Figure imgf000077_0001
|0160] To (2-(l 2,2,2 rifluoroe l) H^yrazol-5-yl)pyridin-3-yl)inethanol (408 nig, 1.59 mraol) in DCM ( 5 mL) was added SOC32 (1.5 mL) ai 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-(chloromeihyl)-2-(l-(2,2,2-trifluorocthyl)-l H-pyrazol-5-yl)pyridine hydrochloride (498 mg) as an off-white solid, which was used for next step without further purification.
[0161] Preparation of 3-(chloromeihyl)-2-(l-(3, 3, 3-trifluoropropyl)-lH-pyrazol-5- yljpyridine (ΪΝΤ-3),
Figure imgf000077_0002
Step
Figure imgf000077_0003
[0162] To a mixture of benzyl hydrazinecarboxylate (5.0 g, 30.3 mmoi, 1 eq.) and DIEA (15.0 mL, 90.9 mmoi, 3 eq.) in DMF (20 mL) was added 3 ,3,3-trifluoropropyl bromide (10.7 g 60.6 mmoi, 2 eq.) at RT. The mixture was heated at 80 °C for 20 h, concentrated, and purified on silica gel using a mixture ofEtOAc and hexanes as eluent to benzyl 2-(3,3,3- -0057. 76 . Dkt. No. : 104592-0210 trifluoropropyl) hydrazinecarboxylate (4.2 g; 53%) as a white solid. !H NMR (400 MHz, CDC13) 5 7.33 - 7.17 (m, 5H), 6.11 (s, 1 H), 5.01 (s, 2H), 4.00 (s, 1H), 3.00 (dd, J ::: 12,2, 7. 1 Hz, 2H), 2.1 7 (qt, J= 10.8, 7.3 Hz, 2H). MS (ESI) m/z 263.1 [M+H] \
Figure imgf000078_0001
[0163] To benzyl 2-(3,3,3-trifluoropropyl)hydrazinecarboxylate (1 .7 g, 6.49 mmol, 1 eq.) in a mixture of EtOH (30 raL) were added Pd/C (1 ,0 g) and HCi (12 N, 2.0 mL). The mixture was charged with ¾ (60 psi), stirred at RT for 1 h, filtered, and concentrated to give (3,3,3- trifluoropropyl)hydrazine dihydrochloride (1 .07 g) as a yellow solid. MS (ESI) m/z 129.1 | H i .
Step 3:
Figure imgf000078_0002
[0164] To (E)~ \ -(3 -((tert-butyldimethylsi3yloxy)methyl)pyridin-2-yl)-3- (dimethylami no)prop-2-en- 1 -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 NaHC03(Sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over NaiSO/j, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluetit to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(l-(3,3,3-trifluoropropyl)-lH- pyrazoi-5-yl)pyridine ( 1.58 g; 76% for 2 steps). jH NMR (400 MHz, CDCI3) δ 8.53 (dd, J = Atty. Dkt. No.: 104592-0210
4.7, 1 .6 Hz, Hi), 7.96 - 7.88 (m, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.29 (dd, ./ = 7.9, 4.7 Hz, 1 H). 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:
Figure imgf000079_0001
To 3-((tert-butyldimethylsilyloxy)methyi)-2-(l -(3?3.3-triflu
5-yI)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
NaHC03(S8[) solution (10 mL). The layers were separated and aqueous layer was extraeted with EtOAc three times. The combined organic layers were dried over Na2SC)4, and
concentrated to give (2-( l -(3,3,3-trilluoropropyl)-l H-pyrazoi-5-yl)pyridin-3-yl)methanol ( 1 . g, 99%) as colorless oil. Ή 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, ./ = 1.9 Hz, H I), 7.38 (dd, ,/ = 7.9, 4.8 Hz, H I), 6.48 (d, J = 3.9 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]+.
Figure imgf000079_0002
[01661 To (2-( 1 -(2,2,2-trifluoropropyl)- i H-pyrazo!-5-yl)pyridin-3-yl)methanol (140 mg, 0.52 mmol) in DCM ( 5 mL) was added SOCL (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 repealed three times and dried under vacuum
4814-3864-0057.1 78 Atty. Dkt. No.: 104592-0210 to give 3-(chloromethyl)-2-( 1 -(2,2,2-trifluoropropyl)- 1 H^yrazol-5-yl)pyridine hydrochloride (498 mg) as an off-white solid, which was used for next step without further purification.
<7j Preparation of3-(chloromethyl)-2~(1 sopropyl-lH-pyrazol-5-yl)pyridine (INT-4).
Figure imgf000080_0001
[0168] Step 1 : To a 500-mL flask containing the pyrazole boronate (9.0g, 38. 1 mrnol), 2- chloropyridine (5.47g, 38. Irnmol), Pd(dppf)Cl2 ([1,1 -bis(diphenylphosphino)f errocene] dichloropalladium) (i .39g, 1.91 mmol, 5%raol), and sodium bicarbonate (9.6 lg, 1 14.4mmoI, 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
undervacurn. The resulting brown residue was suspended in 20%EtOAc/DCM (60niL), filtered through a pad of silica gel (1 5g); washed with 20%EtOAc/DCM (4x20mL). The combined filtrate were concentrated to afford a brown oil (33 g). The residue was dissolved l O /o EtOAc/hexanes (20raL) and loaded on a Biotage l OOg snap SiC)2 column and eluted with 0-50% EtOAc. (2-(l -isopropyl- 1 H-pyrazol-5-yi)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~ rH~pyrazol-5-yl)pyridin-3-yl)methanoi} (440mg, 2.02mmol) in DCM (4 mL) was added SOCl2 (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-( 1 -isopropyl- 1 H-pyrazoI~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]L
-0057.1 79 Atty. Dkt. No.: 104592-0210
Preparation of 3-(ch romeihyl)-2-(l-cyclopeiityl-lH-pyr∑ol-5-yl)pyridiiie (INT-
Figure imgf000081_0001
[01711 Step 1 : To (E)-l-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yI)-3- (dimethylamino)prop-2-en- 1 -one (crude,3.205g, 10.0 mmoL 1 eq.) in EtOH (30 mL) was added cyclopentylhydrazine 11C1 salt (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-( 1 -cyclopentyl - 1 H- pyrazol-5-yl)pyridin-3-yl)methanol was obtained as a light brown oil (440rag). MS (ESI) m/z 244.2 [ ··Η | ' .
[0172] Step 2; To a solution of (2-(l-cyclopentyl-lH-pyrazol-5-yl)pyridin-3- yl)methanol(301mg, 1.24mmol) in DCM ( 3 mL) was added SOCl2 (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- (chlorornethyl)-2-( 1 -cyclopentyl- 1 H-pyrazol-5-yl)pyridine hydrochloride (305 mg) as an off- white solid, which was used for next step without further purification. MS (ESI) m/z 262.2
[M+Hf.
[0173] Preparation of 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (INT-6).
Figure imgf000081_0002
Figure imgf000081_0003
Step
4814-3854-0057.1 80 Atty. Dkt. No.: 104592-0210
Figure imgf000082_0001
[0174] To a solution of 6-(benzyloxy)pyridin-3-ol (2.0 g, 10 mmol, 1 eq.) in DMF (20 ITIL) was added NaH (60% in mineral 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 1 5 min. added chioromethyl methyl ether (0,88 g, 1 1 mmol, 1.1 eq.), stirred at 0-5 °C for another 20 min, and quenched with NH4CI;S1J! , 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 Na2SC>4, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 2- (benzj'loxy)-5-(methoxymethoxy)pyridine (2.1 g, 87%) as a colorless oil. MS (ESI) m/z
246.1 i M - i i i ' .
Step 2
Figure imgf000082_0002
[0175] To 2-(benzyioxy)-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, filtered, and concentrated to give 5 -(methoxymethoxy)py ri din-2-o ! ( 1 .35 g, quantitative yield) as a pale yellow solid. MS (ESI) m/z 156.1 [M+Hf.
Step 3
Figure imgf000082_0003
[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 1 -bromo-2-methoxyethane -0057.1 81 Arty. Dkt. No.; 104592-0210
(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 ofEtOAc and hexanes as eluent to give 2-(2-raethoxyethoxy)-5-(methoxymethoxy)pyridine (500 mg, 27%) as a colorless oil. Ή NMR (400 MHz, CDC13) δ 7.94 (d, J = 3.0 Hz, 1 H), 7.35 (ddd, ./= 8.9, 3.0, 1 .0 Hz, ! H), 6.76 (dd, .7 = 8.9, 1 .0 Hz, 1H), 5.1 1 (s, 211), 4.48 - 4.40 (m, 2H), 3.79-3.71 (m, 2H)5 3.50 (s, 3H), 3.45 (s, 3H). MS (ESI) ra/z 214.1 [M+H] .
Step 4
Figure imgf000083_0001
[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, 1 1.3 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, 1 1 .3 mol, 1 .8 eq.) slowly. The mixture was then stirred at -40 °C for 1 h, quenched with a mixture of HC1 (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
2CO3. The aqueous Layer was extracted with EtOAc (30 ml.) twice. The combined organic layers were dried over Na2S04, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give a mixture of 2-(2--methoxyethoxyV5- (methoxymethoxy)isonicotinaldehyde and 2-(2-methoxyethoxy)-5-
(methoxymethoxy)nicotinaldehyde (5/1 , 1 .27 g, 83.6%) as a pale yellow oil. Ή NMR (400 MHz, CDCij) δ 10.45 (s, 1H), 8.23 (s, IH), 7.16 (s, IH), 5.27 (s, 2H), 4.46 (dd, 7 = 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 Ή
NMR (400 MHz, CDCI3) δ 10.41 (s, 1 I I), 8.1 8 id, J = 3.2 Hz, I H), 7.85 (d, J = 3.1 Hz, I H), 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 i ' .
4814-3354-0057.1 82 Atty. Dkt. No.: 104592-021 0
Figure imgf000084_0001
[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 2CO3 and the aqueous layer was extracted with EtOAc (100 mL) twice. The
combined organic layers were dried over Na2S04, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes to give 5-hydroxy-2-(2- methoxyethoxy)isonicotinaidehyde (630 mg, 60%) and 5-hydroxy-2-{2- methoxyethoxy)mcotinaldehyde (120 mg, 1 1 %). Data for 5-hydroxy-2-(2- mcthoxyeihoxy)isonieotinaidehyde: fH NMR (400 MHz, CDCI3) δ 9.98 (s, 1 H), 9.50 (s, 1H), 8.07 (s, 1 H), 7.02 (s, 1 H), 4.51 - 4.39 (m, 2H), 3.81 - 3.72 (m, 2H), 3.47 (s, 3H). LRMS (Μ+ΤΓ) m/z 198.1. Data for and 5-hydroxy-2-(2-methoxyethoxy) nicotinaldehyde: Ή NMR (400 MHz, CDCI3) δ 10.3 (s, HI), 7.99 (a, .7 = 3.2 Hz, 1H), 7.58 (d, J= 3.2 Hz, 1 H), 7.1 8 - 7.07 (br, 1 H), 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] Preparation of 2, 6-dihydroxybenzaldehyde (TNT-7).
Figure imgf000084_0002
INT-7
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 2,6- 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 temperature, and then it was quenched with 200 mL of diluted HCI (2M), The resul ting 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 Dkt. No .: 304592-0210 acetate/petroleum ether (1 :200-l :50) as ehient to furnish 40 g (48%) of 2,6- dihydroxybenzaldehyde as a yellow solid.
!HNMR (300MHz, DMSO- δ 1 1.25(s, 2H), 10.25(s, 1H), 7.36(m, 1H), 6.36 (d, J=8.4Hz 2H); MS (ESI) m/z 139 [M+Hf.
[0181] Preparation of5-hydroxy-2-methoxyisonicotinaldehyde (1NT-8).
Figure imgf000085_0001
[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 mineral oil; 9,6 g, 0.24 mol) at 0-5 UC portion-wise. Upon die completion of addition, the mixture was continued to stir at 0-5 °C for 15 rnin followed by additional of chioromethyl methyl ether. The mixture was stirred at 0-5 °C for another 20 min and quenched with aqueous UC ijsat. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layer was washed with water and brine, dried over Na2SC> , and concentrated under reduced pressure. The residue was purified on silica gel with 25% EtOAc/hexanes as eiuent to give 2-methoxy-5-(methoxymethoxy)pyridine (24.1 g, 89.3%) as a colorless oil. Ή NMR (400 MHz; CDC13) 7.97 (d, 1 H), 7.35 (dd, 1 H), 6.70 (d, 1 H), 5.12 (s, 2 I I), 3.91 (s, 3 H), 3.51 (s, 3 H); MS (ESI) m/z 170.1 [M+H]L
[0183] Step 2: To a mixture of 2-mcthoxy-5-(methoxymethoxy)pyridine (30 gf 0. i 78 rno!) and diisopropylamine (507 uL, 3.6 mmoi) 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 wanned 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 HCI (12 N, 120 mL) and THF (280 mL). Water (200 mL) was added and the pH of the mixture was adjusted to pH 8- 9 with solid K2C03. The mixture was extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na2S0 , and concentrated to give 2-metboxy-5- (methoxymethoxy)isonicotinaldehyde (33.5 g, 95,7%) as a brown solid, which was used for next step without further purification. Ή 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!+.
-0057.1 84 . Dkt. o.: 104592-021 0
JO184| Step 3: To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 0.17 mol) in THF (150 mL) was added HC1 (3 N, 250 mL). The reaction was stirred at 50 °C for 1 h, cooled to RT and diluted with water {500 mL). The mixture was neutralized to pH 7- 8 with solid K2CO3. The pale yellow solid was collected, washed with water, and dried in vacuum oven (40 UC) overnight to give 5-hydroxy-2-methoxyisonicotinaldehyde (17.9 g, 74.6%). 5H NM (400 MHz; DMSO) 8- 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 ! H i .
Experimental procedures for Examples:
[0185] GBT527 Preparation of 2-methoxy-5-[[2-[ l-(2,2,2-trifluoroethyl)pyrazol-3- yi]pyridin-3-yrjmethoxy]pyridine-4-carbaldehyde.
(0186] GTB527 was prepared using general method B from 5-bydroxy-2- methoxyisonicotinaldehyde and INT-2.
Figure imgf000086_0001
[0187] GBT576 Preparation of 2-oxo-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3- yljmethoxy]- 1 H-pyridine-4-carbaldehyde
Figure imgf000086_0002
Atty. Dkt. No.: 104592-0210
Figure imgf000087_0001
on
Ste 3 "Ύ^°
Figure imgf000087_0002
Step 1 :
Figure imgf000087_0003
[0188] To £ l-(3-i tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3- (dimethyiamino)prop-2-en-l -one (crude, 1.03 g, 3.22 mmol, 1 eq.; ΙΝΤ-ί) in EtOH (10 mL) was added isopropylhydra/ine hydrochloride (430 rng, 3.86 mmol, 1.2 eq.). The mixture was heated at 80 °C for 2 h, cooled, added HCI (6 N, 0.5 mL), and stirred O/N. The mixture was concentrated and diluted with EtOAc (80 mL) and NaHC k^ao (10 mL) solution. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2S0 > concentrated, and purified on silica gel using EtOAc as eluent to give (2-(l-isopropyi-I H-pyrazol-5-yl)pyridin-3-yl)methanol (500 rng, 71%) and (2-(l-tsopropyH H-pyra2»l-3-yl)pyridin-5-yl)methanoi (55 mg, 25%) as pale yellow oils, Data for 2-(l-isopropyHH-pyrazol-5-yl)pyridin-3-yl)methano{: Ή NMR (400 MHz, CDC13) δ 8.67 (dd, ./ 4.7, 1.5 Hz, 1 H), 8.0 (d, ,/ 7.8 Hz, 1H), 7.61 i d. ./ · 1.8 Hz, IH), 7.39 (dd, ./ 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+) mix 218.1 Data for (2-(l-isopropyl-lH- pyrazol-3-yl)pyridin-5-y[)methanol: TT NMR (400 MHz, CDC13) δ 8.62 (dd, 4.8, 1.6 Hz, 111). 7.72 (d. J = 7.6 Hz. 1 H). 7.55 (d, J - 2.4 Hz, I I ), 7.23 {dd, J- ----- 7.6, 4.8 Hz, 1 H). 6.99
(dd, J= 8.0, 6.5 Hz, IH), 6.07 (t, J~ 7.6 Hz, 1H), 4.67 (d, J- 7.6 Hz, 2H), 4.58 (sep, ./ = 6.7 Hz, IH), 1.60 (d, J= 6.7 Hz, IH). MS (ESI) m/z 218.1 [M+Hj+.
Step 2: -0057.1 86 Atty. Dkt. No.: 104592-0210
Figure imgf000088_0001
[0189] To (2-(l -iospropyl- Ϊ H-p Tazol-5-yl)pyridin-3-yl)methanol (560 mg, 2.58 mmol) in DCM ( 10 mL) was added SOCl2 (3.0 niL) 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- (chJoromethyl)-2-(l -isopropyl- 1 H-pyrazol-5-yl)pyridine hydrochloride (700 mg) as an off- white solid, which was used for next step without further purification.
Step 3:
Figure imgf000088_0002
[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 K2C03 (1.4 g, 10.32 mmo!, 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- 1 H-pyrazol-5-yl)pyridin- 3-yl)methoxy)-2-raethoxyisonicotinaldehyde (590 nig, 65%) as an off-white solid, 'H NMR (400 MHz, CDC!3) δ 10.41 (s, 1 H), 8.76 (dd, J = 4.7, 1.6 Hz, 1 H), 8.04 (dcL J = 7.9, 1 .6 Hz, 1 H), 7.90 (s, 1 H), 7.61 (df J = 1.8 Hz, 1 H), 7.44 i d. J 7.9, 4.8 Hz, 1 H), 7.10 (s, 1 H), 6.37 (d, J= 1.8 Hz, I S ! ;. 5.14 (s, 21 1 ). 4.65 (sep, ./ 6.6 Hz, 1H), 3.91 (s, 3H), 1.49 (d, ./ 6.6 Hz, 6H); MS (ESI) m/z 353.1 [M+H]+.
[01 1] To 5 --((2-( 1 -isopropyl- 1 H-pyrazol-5 -yl)pyridin-3 -yl)methoxy)■ 2■■
methoxyisonicotinaldefiyde (590 mg) suspened in water (5.0 mL) was added HCI (6 N, 4 mL), Once the mixture turned into a homogeneous solution, it was frezee at -78 °C to an solid and pump under high vaecurn O/N. The yellow solid was continued to pump at 45 °C -0057.1 87 Ally. Dkt. No,: 104592-021 0 for 20 h, dissolved in water (2.0 raL), and basified to p! 1 I ί 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-y[)pyridin-3- l]mcthoxy]-l H-pyridine-4-carbaIdehyde as a yellow solid. Ή NMR (400 MHz, CDCh) δ 10.3 (s, 1H), 8,8 (dd, J = 4.7, 1.6 Hz, 1 H), 8.1 (dd, i =: 7.9, 1 .5 Hz, 1 H), 7.6 (s, 1H),7.5 (d, J = 1.8 Hz. 1H), 7.1 (s, 1H), 7.0 (s, 1 M), 6.6 (d, J « 1.8 Hz, 1 H), 4.9 (s, 2H), 4.7 (sep, J - 6.6 Hz, 111}, 1.5 (d, J - 6.6 Hz. 6H); MS (ESI) mix 339.4 [M+Hf.
[0192] GBT779 Preparation of 2-(2-morpholm-4-ylethoxy)-5-[[2-(2-propan-2-ylpyrazoi-3- yI)pyridin-3-yr]rneihoxy]pyridine-4-earbaldehyde
[0193] GTB779 was prepared according to general method B from 5-hydroxy-2-(2- morpholinoethoxyjisonicotinaldehyde and iNT-4,
Figure imgf000089_0001
[01941 Ή NMR (400 MHz. Chloroform-;/) δ 10.3.3 (s, IHj, 8.68 (dd, ./ 4.8, 1 .7 Hz, I Hj, 7.95 (dd, ./ = 7.9, 1 .7 Hz, 1 11), 7.79 (s, 1 ί i), 7.53 (d, J ------ 1 .8 Hz. 1 Hj, 7.36 (dd, J= 7.9, 4.7
Hz, H I), 7.04 (s, 1 H), 6.28 (d, J ::: 1.8 Hz, 1 H), 5.06 (s. 2H), 4.57 (s, OH), 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 Preparation of 2-(2-methoxyethoxy)-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridrae-4-carba]dehyde.
[0196] GTB8.32 was prepared according to general method B from 5-hydroxy-2-(2- methoxyethoxy)isonicotinaldehyde (l'NT-5) and INT-2.
! 4-3854-0057.1 88 Arty. Dkt. No. : 104592-021 0
Figure imgf000090_0001
"'
|0197] SH NMR (400 MHz, CDC13) δ 10.32 (s, 1 H), 8,67 (dd, J - 4.8, 1.6 Hz, IH), 7.97 (dd, J = 7.9, 1.5 Hz, 1H), 7.87 (s, IH), 7.59 (d, J - 1.9 Hz, IH), 7.38 (dd, J = 7.9, 4.8 Hz, 1 H), 7.1 1 (s, IH), 6.47 i d. j = 1.9 Hz, I H), 5.17 (q. J - 8.6 Hz, 21 ! ·. 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 Preparation of 6-methyl-3- [2-[2-(2,2,2-trifluoroethyl)pyrazol-3- yljpyridin - 3 · y 1 ] methoxy] pyridine-2-carbaldehyde
[0199] GTB835 was prepared according to general method B from 3-hydroxy-6- methyipicolinaldehyde and iNT-2.
Figure imgf000090_0002
[0200] lll NMR (400 MHz, CDC13) δ 10.23 (s, H), 8.64 (dd, J = 4.7, 1.6 Hz, I H), 8.16 (dd, J = 7.9, 1.5 Hz, 1 H), 7.61 (d, J = 1 .9 Hz, 1 H), 7.38 (dd, J = 7.9, 4.8 Hz, I H), 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. 1 (s, F iji MS (ESI) m z 377 [ X 1 · Π ) ' .
[0201] GBT836 Preparation of 6-methy 1-3 - [[2 - [2-(3 ,3,3 -trifluoropropyl )pyrazol -3 - y!]pyridin-3-yl]meihoxy]pyridine-2-carbaldehyde
[0202] GTB836 was prepared according to general method B from 3-hydroxy-6- methylpicolinaldehyde and INT-3.
4814-3854-0057.1 89 . Dkt. No.: 104592-0210
Figure imgf000091_0001
[0203] !H NMR (400 MHz, CDC13) δ 10.31 (s, 1H), 8.75 (dd, J = 4.7, 1.7 Hz, IH), 8.27 (dd, J - 7.9, 1.6 Hz, I H), 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, I H), 6.46 (d. J = 1.9 Hz, I H), 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+Hf .
[0204] GBT839 Preparation of 3-[[2-(2-(2,2,2-trinuoroeth l)pyrazol-3-yi]pyridin-3- yl]methoxy]pyridine-2-carbaklehyde
[0205] GTB839 was prepared according to general method B from 3- hydroxypicoiinaidehyde and INT-2.
Figure imgf000091_0002
[0206] !H NMR (400 MHz, CDC13) δ 10.26 i s, IH), 8.65 (dd, J = 4.7, 1.5 Hz, 1 H), 8
(dd, J = 4.4, 1 .0 Hz, IH), 8.19 (dd, J = 7.9, 1.0 Hz, I H), 7.63 (d, J - 1.9 Hz, I H), 7.43
(m, 2H), 7.21 (d, J = 8.6 Hz, I H), 6.48 (d, J - 3 .9 Hz, I H), 5.19 (q, J = 8.6 Hz, 2H), 5.
2H): MS (ESI) m/z 363.1 [M+Hf.
[0207] GBT840 Preparation of 3-[[2-[2-(3,3,3-trifluoropropyl)pyrazoI-3-yl]pyridin- yi]methoxy]pyridine-2-earbaldehyde
[0208| GTB839 was prepared according to general method B from 3- hydroxypicolinaldehyde and INT-3,
4814-3854-0057.1 90 Atty. Dki. No.: 1 04592-0210
Figure imgf000092_0001
[0209] Ή NMR (400 MHz, CDC13) δ 10.24 (s, 1 H), 8.66 (del, J = 4.7, 1.6 Hz, I H), 8.39 (dd, J - 4.5, 1 .1 Hz, 1 H), 8.21 (dd, J - 7.9, 1.6 Hz, I II), 7.53 (d, J - 1.9 Hz. S H), 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+Hf .
[O2J0] GBT841 Preparation of 3-chloro-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridiri-3- y]]methoxy]pyridine-4-carbaidehyd .
[021 1 j GTB841 was prepared according to general method B from 3-cbloro-5- hydroxyisonicotinaldehycle and ΪΝΤ-4,
Figure imgf000092_0002
[0212] ! NMR (400 MHz, CDC!j) δ 10.51 (s, 1 11), 8.77 (dd, J = 4.7, 1.6 Hz, 1 H), 8.41 (s. 1H), 8.28 (s, 1 H), 8.13 (dd, J = 7.9, 1.5 Hz, lH), 7.63 (d, J = 1.8 Hz, 1 H), 7.47 (dd, J ----- 7.9, 4.8 Hz, S H), 6.37 (d, J = 1.8 Hz, IH), 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+I-l .
[02131 GBT844 Preparation of 3-chloro-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazoi-3- yl]pyridin-3-y3]rnethoxy]pyridine-4-carbaldehyde.
[0214] GTB844 was prepared according to general method B from 3-chloro-5- hydroxyisonicotinaldehyde and iNT-2.
-0057.1 91 Atty. Dkt. No.: 104592-0210
Figure imgf000093_0001
[02151 H NMR (400 MHz, CDC13) δ 10.43 (s, 1 H), 8.67 (dd, J = 4.7, 1.5 Hz, 1 H), 8.35 (s, 1 H), 8.26 is, 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, I H), 6.47 (d, J - 1 .9 Hz, 1 H), 5.21 - 5.10 (m, 4H): MS (ESI) m/z 397 [M+H]+.
GBT860 Preparation of tert- utyl 4-(((4-formyl-6-methoxypyri din-3 - yl)oxy)methyl)-5-( 1 -isopropyi- 1 H-pyrazol-5-yl)-3,6-dihydropyridine- 1 (2H)-carboxylate
Figure imgf000093_0002
[0217] Step 1 : To a solution of l-tert-butyl 4-ethyl 3-Qxopiperidine- 1 ,4-dicarboxylate
(2.0g, 7.37 mmol) in DCM (45 mL) was added DIPEA (1.54 ml, 8.84 romoJ) and Tf20 (1.36 mL, 8.1 1 mmol) at -78 °C, then the temperature was warmed up to room temperature 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. NaHC(¾, brine, dried and concentrated to give l -(tert-butyl) 4- ethyi 5-(((trifluoromethyi)sulfonyl)oxy)-3,6-dib.ydropyridine-l ,4(2H)-d)carboxylate, which was used for next step without purification.
Figure imgf000093_0003
-0057.1 92 Attv. Dki. No.: 104592-0210
[0218] Step 2; To a solution of 1 -tert-butyl 4-ethyl 3-(((trifluorometliy]}8u]fbnyl)oxy)-5,6- dihydropyridine-l ,4(2H)-dicarboxylate (1 ,49 g, 3.7 mmol) and ( 1 -isopropy 1 - 1 H-pyrazol-5 - yl)boronic acid (0.57 g, 3,7 mmol) in dioxane (10 mL) was added Pd(dppf)C.2 (0.27 g, 0.37 mmol) and a solution of sodium carbonate (1.18 g, 1 1.10) in water (3 ml), the mixture was degased with No for 5 min, and was heated at i 00 °C for 15 h, after cooling to room
temperature the mixture was diluted with EtOAc and washed with Sat. NaHC0 and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc^S : 1 ) to give desired product 830 mg
62%)
Figure imgf000094_0001
[0219] Step 3: To a solution of l-(terl-butyl) 4-ethyl 5-(l -isopropyi- 1 H-pyrazo]-5-yl)-3,6- dihydropyridme- 144{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, NH CI, 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- 1 0:0 to 40:60) to give tert-butyl 4- (hydroxymethyl)-5-(l -isopropyi- H-pyrazo^
(370 mg, 91 %).
Figure imgf000094_0002
[9220] Step 4; To a solution of give tert-butyl 4~(hydroxymethyl)-5-(l-isopropy3-l H- pyrazol-5-yl)-3,6-dihydropyridine-l (2HVcarboxylate (25 mg, 0.08 mmol) in DCM (i mL) was added triphenylpiiosphine bromine adduct (40 mg, 0.09 mmol) at room temperature, after stirring for 30 min, it was diluted with DCM, washed with Sat, NaHC03, brine, dried and concentrated to give crude product, which was purified by column to give tert-butyl 4- (bromomethyl)-5-( 1 -isoprop i- 1 i ! -pyrazol-5 -yl)-3 ,6-dihydropyridine- 1 (2H)-carboxylate ( 1 8
4814-3854-0057.1 93 Atty. Dkt. No. : 104592-0210
Figure imgf000095_0001
[Θ221] Step 5: To a solution of tert-butyl 4-(bromomethyl)-5-( l-isopropyi-3 H-pyrazol-5- yl)-3,6-dihydropyridine- 1 (2H)-carboxylate (18 mg, 0.05 mmol) and 5-hydroxy-2- niethoxyisonicotmaldehyde (10 mg, 0,06 mmol) in DMF (1 mL) was added K2C()3 (14 mg, 0.1 mmol). After stirred at room temperature 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/EtOAe=2: 1 ) to give tert-butyl 4-(((4-formyl-6-methoxypyridin- 3-yi)oxy)methyl)-3-(l -isopropyl-l H-pyr^
(7.2 mg), I H R (400 MHz, CDC13) (ppm) 10.39 (s, IH), 7.79 (s. I H), 7.56 (d, J= l .6 Hz, 1 l i s 7.05(s, I H), 6.1 1 (d, J-1.6 Hz, I H), 4.40 (s, 2H), 4.38 (m, 3 H), 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
[0222] GBT861 Preparation of 2-hydroxy-6-((5-( l -isopropyl-lH-pvrazol-5-yl)-3,6- dihydro-2H-pyraii-4»yi)methoxy)ben/.aldehyde
Figure imgf000095_0002
[0223] Step 1 : To a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (1.0 g, 5.81 mmol)in DCM (30 mL) was added DIPEA (1.22 mL, 6.97 mmol) and Tf20 ( 1.08 mL, 6.39 -0057.1 94 Dkt. No. : 104592-0210 mmoi) at -78 °C, then it was warmed up to room temperature and stirred at room
temeperature for 2 h, the solution was diluted with DC , washed with Sat, NaHC03, brine, dried and concentrated to give ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H- pyran-4-carboxylate as crude product (2 g),
Y'
Figure imgf000096_0001
[0224] Step 2: To a solution of ethyl 5 -(((trifluoromethyl)sulfonyl)oxy)-3 ,6-dihydro-2H- pyran-4-carboxylate (crude from step 1) and 1 -isopropyi-5 -(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)- 1 H-pyrazote ( 1 .37 g, 5.82 ramo!) in dioxanc (20 ml) was added
Pd(dppf)Cl2 (430 mg, 0.58 mmoi) and Na2C03 (1 .85 g, 17.46 mmoi) in water (6 rnL), the mixture was degased with N2 for 5 min, and was heated at 100 °C for 1 5 h, after cooling to room temperature the mixture was diluted with EtOAc and washed with Sat. NaHC03 and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes EtO Ac=3 : 1 ) to give ethyl 5-(l-isopropyl-lH- pyrazoi-5-yl)-356-dihydro-2H-pyran-4-carboxylate (850 mg).
Figure imgf000096_0002
[0225] Step 3: To a solution of ethyl 5-(l-isopropyl-lH-pyfazol-5-yl)-3,6-dihydro-21 I- pyran-4-carbox late (600 mg, 2.27 mmoi) in THF (10 mL) was added LiA!H4 (1 M in THF. 2.72 mL, 2.72 mmoi) at -20 °C, the reaction was stirred at -20 °C for 30 min, and was quenched with Sat. NH4CI. the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc= 100:0 to 20:80) to give (5-(1 -isopropyl-lH-pyrazol-5- yl)-3,6~dihydro-2H-pyran-4-yl)methanol (500 mg).
4814-3854-0057.' 95 . Dkt. No.: 104592-0210
Figure imgf000097_0001
[0226] Step 4: To a solution of (5-(l -isopropyl-1 H-pyrazol-5-yl)-3,6-dihydro-2H-pyraQ-4- yl)methanol (300 mg, 1.35 ramoi) in DCM (5 rsiL) was added dibromotriphenylphosphorane (630 mg, 1.35 mmol) at room temperature, after stirring for 30 min, it was diluted with DCM. organic layer was washed with Sat. NaliCCh, brine, dried and concentrated to give crude product, which was purified by coiumn(Hexanes/EtOAc= 4: 1) to give 5-(4-(bromomethyi 5,6-dihydro-2H-pyran~3-yl)-l -isopropyl- 1 H-pyrazole (360 mg).
Figure imgf000097_0002
[0227] Step 5: To a solution of 5-(4-(bromomet.hyl)-5,6-dihydro-2H-pyran-3-yl)- l - isopropy!- 1 H-pyrazolc (1 10 mg, 0.38 mmol) and 2,6-dihydroxybenzaldehyde (100 mg. 0.76 mmol) in DMF (6 niL) was added K2C03 (i 10 mg, 0.76 mmol), After stirred at room
temperature 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= 1 : 1 ) to give 2-hydroxy-6-((5-( 1 -isopropyl- 1 H-pyrazol-5-y i)-3 ,6-dihy dro- 2H-pyran-4-yl)methoxy)benzaldehyde (90 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 1 1 .89
(s, H i), 10.33 (s, I H), 7.53 (d, J=1.6 Hz, 1H), 7.33(t, J=8.8 Hz, I H), 6.51 (d, J=8.8 Hz. I H), 6.1 6 (d, J=8.0 Hz, IH), 6.08 (d, J=2.0 Hz, IH), 4.40 (cld, 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 is, 2H), 1.40 (d, J=6.4 Hz, 6H); MS (ESI) m/z 343.3
[Θ228] GBT863 Preparation of 2-meth.oxy-5-[[5-(2-propan-2-ylpyrazol-3-yl)-356-diliydro- 2H-pyran-4-yi]methoxy]pyridine-4-carbaldeliyde
4614-3854-0057.1 96 Atty. Dkt. No,: 104592-0210
Figure imgf000098_0001
[0229] To a solution of 5-(4-(bromomethyl)-5,6-dthydro-2H-pyran-3-yl)-l-isopropyl-i H- pyrazole (50 mg, 0.19 mmol) (see the .synthesis of GBT861) and 5-hydroxy-2- nicthoxyisonicotinaidehyde (30 mg, 0.23 mmol) in DMF ( 1 mL) was added f 2C03 (50 mg, 0.38 mmol). After stirred at room temperature 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/EtO Ac= 1 : 1 ) to give 5-((5-(l-isopropyl-l M-pyrazol-5-yl)-3,6- dihydro-2H-pyran-4-yl)methoxy)-2-methoxyisonicotinaldehyde (26 mg). I H NMR (400 MHz, CDCl3) δ (ppm) 10.40 (s, I H), 7.81 (s, IH), 7.54 (d, J-1.6 Hz. I H), 7.05 (s, I H), 6.08 (d, J-1 .6 Hz, I H), 4.42 (s, 2H), 4.40 (m, I H), 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) rn/z 358.4 [M+H]'\
[0230] GBT864 Preparation of 6-methyi-3-i[5-(2-propan-2-ylpyrazo3-3-y3)-3,6-dihydro- 2H-pyran-4-yl]methoxyjpyridinc-2-carbaldehyde
Figure imgf000098_0002
4814-3 54-0057.1 97 Did. No.: 104592-0210
Figure imgf000099_0001
∑31] To a solution of 5-(4-(bromomethyl)-5>6-dihydro-2H-pyran-3-yl)- l-isopropyl-lH- pyrazole (50 mg, 0.19 mmol) (see the synthesis of G.BT861) and 3-hydroxy-6- methylpicolinaldehyde (30 mg, 0,24 mmol) in DMF (1 mL) was added K2CO3 (50 mg, 0,38 mmol). After stirred at room temperature 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-l H-pyrazol-5-yl)-3,6- dihydro-2H-pyran-4-yl)methoxy)-2-methoxyisonicotinaldehyde (37 mg). I H NMR (400 MHz, CDCh) δ (pp ) 10.30 (s, IH), 7.54 (d, J-1.6 Hz, I H), 7.24 (d, J- 8.4 Hz, I H), 7.09 (d, J=9.2 Hz, I H), 6.08 (d, J=2.0 Hz, IH), 4.42 (ms IH), 4,38 (s, 2H), 4.1 8 (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 Preparation of 2-hydroxy-6-[(5 -phenyl-3 ,6-di hydro-2 H -pyran-4- y3)methoxy]benzaldehyde
Figure imgf000099_0002
[0233] Step 1 : To a solution of ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H- pyran-4-carboxyiate (1.77 g, 5.81 mmol) and phenylboronic acid (1.42 g, 11.62 mmol) in
4814-3854-0057 1 98 Arty. Dkt. No. : 104592-0210 lioxane ( 15 ml) was added Pd(dppi)Cl2 (430 mg, 0.58 mmol) and Na;CG (1 .85 g, 1 7.46 mmol) in water (4.5 ml,), the mixture was degased with N2 for 5 rain, and was heated at 100 °C for 15 h, after cooling to room temperature the mixture was diluted with EtOAc and washed with Sat. NaHCC and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes EtO Ac=4: 1 ) to give ethyl 5-pheny1-3,6-dihydro-2H-pyraa-4-carboxylate (1.05 g,
Figure imgf000100_0001
[0234] Step 2: To a solution of ethyl 5-phenyl-3,6-dihydro-2H-p>Tan-4-carboxylate (1.05 g. 4.52 mmol) in THF (20 mL) was added L1AIH4 (1M 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, winch was purified by column ( Hexanes/EtO Ac- 100:0 to 35:65) to give (5-phenyl-3,6-dihydro-2H-pyran-4-yl)methanol (720 mg).
Figure imgf000100_0002
0235| Step 3: To a solution of (5-phenyl-3,6-dihydro-2H-pyran-4-y!)m.ethanoi (360 mg, 1 .89 mmol) in DCM (6 mL) was added dibromotriphenylphosphorane (880 mg, 2.08 mmol) at room temperature, after stirring for 30 min, it was diluted with DCM. organic layer was washed with Sat. NaHC03, brine, dried and concentrated to give crude product, which was purified by column(Hexanes/EtOAc:= 9: 1 ) to give 4-(bromamethyl)-5-phenyl-3,6-dibydro- 2H-pyran (380 mg).
Figure imgf000100_0003
-0057.1 99 Atty. Dkt. No.: 1 04592-0210
(0236J Step 4: To a solution of 4-(bromomethyl)-5-phenyl-3,6-dihydro-2H-pyran (1 10 mg, 0.45 mmol) and 2,6-dihydroxybenzaldehyde (120 mg, 0.90 mmol) in DMF (3 niL) was added K2CO3 (120 mg. 0.90 mmol). After stirred at room temperature 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/ElO Ac-=3 : 1 ) to give 2-hydroxy-6-((5- phenyi-3,6-dihydro-2H-pyran-4-yl)methoxy)ben2aldehyde (120 mg). IH NMR (400 MHz, CDCI3) δ (ppm) 1 1 .92 (s, IH), 10.36 (s, I H), 7.35 (m, 4H), 7.18 (m, 2H), 6.49 (d, J=8.0 Hz, I H), 6.13 (d, J-8.0 Hz, IH), 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 Preparation of 3-methoxy-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3- yi]pyridin-3-y! jmethoxy]pyridine-4-earbaldehyde
Figure imgf000101_0001
[0238] To a solution of 3-hydroxy-5-methoxyisonicotinaldehyde (0.13 g. 0,88 mmol) in
DMF was added 3-(chloromethyl)-2-( 1 -(2,2,2-trifluoroethy!)- 1 H-pyrazol-5-yi)p}'ridine (0.24 g, 0.88 mmof) (ΪΝΤ-2) and potassium carbonate (0.49 g, 3.52 mmol) and the reaction mixture was heated (60 °C ). After 3 hours, the reaction mixture was filtered through a plug of silica (MeOH/CH2Cl2, 0-20%). Purification of the resulting residue by Prep-HPLC, provided 2- !bo v-6 2-( 1 -(2,2.2-trifluoroethvl)-lH-pYrazoi-5-v!)pvridin-3-Yl)methoxy)benza!dehyde ( 12 mg, 5% yield). Ή NMR (400 MHz, Chlorofomwf) δ 10.54 (s, IH), 8.71 (dd, J- 5.0, 1 .8 Hz, IH), 8.23 (s, I H), 8.21 (ddd, J - 7.9, 1.7, 0.7 Hz, l H), 8.10 (s, I H). 7.67 (dd, ,/ - 1 .9, 0.5
4814-3854-0057.1 100 Dkt. No.: 104592-0210
Hz, 1H), 7.46 (dd, J= 8.0, 4.5 Hz, 1 H), 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) ra/z 393 [M+H]4.
|0239] GBT870 Preparation of 2-methoxy-5 - [[2-(2-methoxy phenyl)pyridin-3 - yijmethoxylpyridine-4-carbaldehyde
Figure imgf000102_0001
[0240] Step 1 : into a 50-mL round- bottom flask, was placed a solution of (2-chloropyridin- 3-yl)methanol (500 rag, 3.48 mmol, 1.00 equiv) in a solvent mixture of dioxane and ¾0 ( 10/10 mL). (2-Methoxyphenyl)boromc acid (532 mg, 3.50 mmol, 1.20 equiv), sodium bicarbonate (882 mg. 10,50 mmol, 3.00 equiv), and PdtdppfiCL (286 mg, 0.39 mmol, 0.10 equiv) were added to the reaction mixture. The resulting solution was stirred for 2 h at 1 00°C, and then it was diluted with 1 00 mL of H2O. The resulting solution was extracted with 2 100 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 el ent to furnish 650 mg (87%) of [2-(2-methoxyphenyl)pyrid'in-3-yl]methanol as a yellow solid.
[0241] Step 2: Into a 50-mL round-bottom flask, was placed a solution of [2-(2- methoxyphenyl)pyridin-3-yi]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 nig (92%) of 3-(chloromethyl)-2-(2- meihoxyphenyl)pyridme as a yellow solid.
[0242] Step 3: Into a 1 00-mL round-bottom flask, was placed a solution of 3- (chloromethyi)-2-(2-methoxyphenyl)pyridine (306 mg, 1.31 mmol, 1.00 equiv) in C¾CN (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 KT (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 S -3S54-0057.1 101 Atty. Dkt. No. : 1 04592-0210
Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C 1 8 GBD Column, Sum, 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 rain); Detector, Waters2545 UvDector 254&220nm. This resulted in 65 rog (9%) of 2-methoxy-5-[[2-(2- methoxyphenyl)pyridin-3-yl3methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid. The compound exhibited a meiting point of 1 05-107°C. 'HNMRQOO HZ.
CDClj) δ 30.32 (s, 1H), 8.69 (s, 1 H), 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+Hf .
[0243] GBT871 Preparation of 2-methoxy-5-ff2-(3-methoxyphenyl)pyridm-3- yl]nieihoxy]pyridine-4~carbaidehyde
Figure imgf000103_0001
Step ! feP -O- 0244] Step 1 : Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (3-methoxyphenyl)boronic acid (1 .6 g, 10.53 mmol, 1.20 equiv), (2-cMoropyridm-3-yl)methanol ( 1 g, 6.97 mmol, 1.00 equiv), sodium bicarbonate (1 ,7 g, 20.24 mmol, 3.00 equiv), Pd(dppf)CL (0.57 g, 0.10 equiv) in a solvent mixture of dioxane (10 mL) and waierfl O mL). The resulting solution was stirred for 1.5 h at J 00°C, and then it was diluted with 20 mL of H20. 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 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-(3- methoxyphenyl)pyridm-3-yl]methanol (1 g, 4.65 mmol, 1.00 equiv) in thionyi chloride (20 mL). T he resulting solution was stirred for 2 h at reflux. The resulting mixture was
4814-3854-0057.1 102 Atty. Dkt. No,: 104592-021 0 concentrated under vacuum to furnish 600 mg (55%) of 3-(chloromethyi)-2-(3- methoxyphenyl)pyridine as a white solid.
[0246] Step 3: Into a 100-mL round-bottom flask, was placed a solution of 3- (chloromethyl)-2-(3-raeihoxyphenyl)pyridjne (234 mg, 1.00 mrnol, 1.00 equiv), 5-hydroxy-2- raethoxypyridme-4-carbaldehyde (153 mg, 1.00 mmoi, 1 ,00 equiv), and potassium carbonate (278 mg, 2.01 mraol, 2,00 equiv) in CHjCN (30 raL). The resulting solution was stirred tor 4 h at 7G°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 C 18 OBD Column uin, 19* 150mm,; mobile phase, water with 0.1%TFA and MeCN (20% MeCN up to 40% in 10 rain, up to 95% in 2 min, down to 20% in 1 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 100.8 mg (37%) of 2-methoxy-5-[[2-(3- methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid.
!HNMR(300MHz, DMSO-<¾) δ 10.01 (5, 1 H), 8.65 (m, 1H. 8.39(s, 1 H), 8.10(ra, 2H), 7.5" (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
[ +Hf.
[0247] GBT874 Preparation of 2-hydroxy-6- [( 1 -methyi-5-phenyl-3 ,6-dihydro-2H-pyridin-
4-yl)methoxy]benzaldehyde
Figure imgf000104_0001
1: To a solid of tert-butyl 4-(hydroxymethyl)-3~pheny]-5,6-dthydropyridine-
1121 [)-carboxv!ate (300 mg. 1 .04 mnioi) in round bottom flask was added 4N HCI in dioxane (6 nil.) at room temperature, after stirring for 1 h, the mixture was concentrated, and dried under high vacuum to give (5-phenyl- l.,2,3,6-tetrahydropyridiri-4-yl)meihanol as HCi salt.
4814-3854-0057.1 103 Any. Dkt. No. : 104592-0210
Figure imgf000105_0001
[0249] Step 2: To a solution of (5-phenyl- 1 ,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 temperature 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 CHCij, organic layer was washed with Sat. NaHCO-j, brine, dried and concentrated to give crude product, which was purified by column (DCM/MeOH=9: i) to give (l-methyl-5-phenyl-l , 2,3,6- tetra ydropyridin-4-yl)methanol (140 mg).
Figure imgf000105_0002
[0250] Step 3: To a solution of (l-methyl-5-pheny{-l ,2,3>6-tetrahydropyridin-4- yl)methanoi (1 30 mg, 0.64 mmol) in SX'.Yi (4 mL) was added SQCL (1.16 mL, 16 mmol) at room temperature, after stirred at room temperature for 30 min, the mixture was concentrated, dried under high vacuum to give 4-(chloromethyl)- 1 -tnethyl-5-phenyl- 1 ,2,3 ,6- tetrahydropyridine as crude HCi salt.
Figure imgf000105_0003
[02511 Step 4: To a suspension of 2C03 (350 mg, 2.56 mmol) and 2,6- dihydroxybenzaldehyde ( 180 mg, 1 .28 mmol) in DMF (3 mi) was added a solution of 4- (chlorornethyl)-l -inethyl-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 temperature, and was diluted -0057 1 104 Dkt. No.: 104592-0210 with EiOAc, organic layer was separated and aqueous layer was extracted with ΕίΟΛα
EtOAc layers were combined, washed with Sat. NaHCCb, brine, dried over Ma2504. and was concentrated to give crude oil, which was purified by column (Hexane/EtOAc- 1 : 1 followed by DCM/MeOH= 90: J O) to give 2-hydroxy-6-((l -methyl-5-phenyI- 1 ,2,3,6-tetrahydropyridin- 4-yl)methoxy)benzaldehyde (55 mg). 1 H NMR (400 MHz, CDC33) δ (ppm) 11.92 (s. 1 H), 10.35 (s, 1 H), 7.34 (m, 5H), 7.19 (dd, I ~ 8,4 , 8.0 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1 H), 6.16 (d, j - 8.0 Hz, 1 H), 4.45 (s, 2H), 3.20 (s, 2H), 2.68 (t, J = 5.6 Hz, 2H), 2.47 (ra, 2H), 2.42 (s, 3H); MS (EST) m/z 324.3 [M+H]+.
[0252] GBT875 Preparation of 2-methoxy-5-[[2-(4-methoxypheny1)pyridin-3- yl]methoxy]pyridine-4 -carbaidehyde
Figure imgf000106_0001
[0253 j Step 1 : Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere 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)Cl (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 10()"C, and then it was diluted with 20 mL of H20. 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 furnish 1 g (67%) of [2-(4-methoxyphenyl)pyridin-3-yl]methanol as a colorless oil.
[025 j Step 2' Into a 50-mL round -bottom flask, was placed a solution of [2-(4- methoxyphenyl)pyridin-3-yi]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
4814-3854-0057,- 105 Atty. Dkt. No.: 104592-021 0 concentrated under vacuum to yield 600 mg (55%) of 3-(chloromethyl)-2-(4- methoxyphenyi)pyridine as a white solid.
[0255] Step 3: Into a 50-mL round-bottom flask, was placed a solution of 3- (chloromethyl)-2-(2-methoxyphenyI)pyridine (234 mg, 1.00 mmol, 1.00 equiv), 5-hydroxy-2- methoxypyridine-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 nig) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SimFire Prep C 18 ΟΒΓ) Column, Sum, 19* 150mm; mobile phase, water with 0.1 TFA and MeCN (20.0% MeCN up to 50.0% in 30 rain, 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 2- methoxy-5-[[2-(4«methox>phenyl)pyridin-3-yl]raethoxy]pyridinc-4-carbaldchyde;
bis(trifluoroacetic acid) as a brown oil,
!HNMR(300MHz, DMSO-c¾) δ 10.08(s, I I I ). 8.69 (m, 1 1 Π. 8.15(m, 2R ). 7.50(m, H i).
7.37(m, 1H), 7.18(m, 2H), 7.16(ra, 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 Preparation of 5-[[2-(2-chlorophenyl)pyridin-3-yl]raet oxy]-2- methoxypyridine-4-carba!dehyde
Figure imgf000107_0001
Figure imgf000107_0002
[0257] Step 1 : Into a 50-mL round -bottom flask, was placed a solution of (2- chlorophenyl)boromc 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)(¾ (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 rnL). The resulting solution was stirred for 3 h at 70°C, and then it was di luted with S14-3854-0057 1 j Ally. Dkt. No. ; 104592-02 10
20 mL of ¾0. The resulting solution was extracted with 2x20 rnL of dichlorornethane, 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 furnish 1 g (65%) of [2-(2-chloiOphenyl)pyridin-3-yi]niethanol as a white sol id.
[0258] Step 2: Into a 25-mL round-bottom flask, was placed a solution of [2-(2- chlorophenyi)pyridin-3-yl]methanol (5 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-raL round-bottom flask, was placed a solution of 3- (chloromethyl)-2-(2-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2- mcthoxypyridine-4-carbaidehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2,61 mmol, 1.50 equiv) in CH.¾CN (20 mL). The resulting solution was stirred for 4 h at 70°C, and then it was concentrated under vacuum. The residue was puri fied by prep- HPLC. This resulted in 86.2 mg ( 1 1 %) of 5-[[2-(2-chlorophenyl)pyridin-3-yl]methoxy]-2- methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a brown oil.
! H MR.(300MHz, DMSO-«¾ δ 10.06(s, 1H), 8.69 (m, Hi), 8.19(m, 1H), 8.05(s, 1H),
7.56(m, 2H), 7.4 l(m, 3H), 6.92(s, 1H), 5.14(m, 2H), 3.81 (s, 3H); MS (ESI) m/z 355 [M+H] ''. 0260] GBT878 Preparation of 2-[(l -acctyl-5-pheny]-3,6-dihydro-2PI-pyridin-4- yl')methoxy] -6-hydroxybenzaldeh v de
Figure imgf000108_0001
-0057. 107 Atty. Dkt. No.: 104592-0210 f 0261] Step 1 : To a solution of (5-phenyl- 1 ,2,3,6-tetrahydropyridin-4-yl)methanol hydrochloride (90 rng, 0.38 mmol) in DCM (2 mL) at 0 °C was added Et3N (0.1 1 raL, 0.76 mmol) and a solution of Ac20 (0.04 mL, 0.38 mmol) in DCM (0.4 mL), after stirred for 15 min, it was diluted with Sat. NH CI and EtOAc, organic layer was separated and the aqueous layer was further extracted with EtOAc, organic lay ers were combined, washed with Sat.
NaHC(¾, brine, dried over Na2S04, and was concentrated to give l-(4-{hydroxymethyl)-5- phenyl-3,6-dihydropyridin- 1 (2H)-yl)ethan- 1 -one as crude product (95 rag).
Figure imgf000109_0001
[0262] Step 2; To a solution of l-(4-(hydroxymethyl)-3-phenyl-5,6-dihydropyridin-l(2H)- yl)cthanone (86 mg, 0.37 mmol) in DCM (2 mL) was added SOCb (0.67 mL, 9.25 mmol).
After stirred at RT for 15 min. the mixture was concentrated and was diluted with Sat.
NaHC03 and EtOAc, organic iayer was separated and the aqueous layer was extracted with EtOAc, organic laver ere combined, washed with brine, dried and concentrated to give crude oil, which was purifed by column ( Hexanes/EtOAc=l 00:0 to 25:75) to give l-(4- (chloromcthyl)-5-phenyl-3.6-dihydropyridin- l(2H)-yl)ethan-l -one (35 mg).
Figure imgf000109_0002
[0263] Step 3: To a suspension of K?CO¾ (40 mg, 0.28 mmol ) and 2,6- dihydroxybenzaidehyde (40 mg, 0.28 mmol) in DMF (1 mL) was added a solution of {-(4- (chloromethyl)-5-phenyl-3,6-dihydropyridin-l(2H)-yl)ethan-l-one (35 mg, 0.14 mmol) in DMF (1 mL), the mixture was heated at 50 °C for 3 h, cooled to room temperature, and was diluted with EtOAc. organic layer was separated and aqueous layer was extracted with
EtOAc. EtOAc layers were combined, washed with Sat. NaHCOj. brine, dried over Na2SQ , and was concentrated to give crude oil, which was purified by column (DCM/MeOH= 90:10) to give 2-(( 1 -acctyi-5-phenyi- 1 ,2,3 ,6-tetrahydropyridi n-4-yl )methoxy)-6-
4814-3854-0057 1 108 Dkt. No.i 104592-0210 hydroxybenzaldehyde (17 rag). 1 H NMR (400 MHz, CDCU, NMR shows rotamer exist, only one set of signal was reported)□ (ppm) 1 1.93 (s, 1H). 10.36 (s, 1 H), 7.34 (m, 5H), 7.22 (rn, 1H), 6.49 (d, J = 8,8 Hz, 1H), 6.10 (d, J = 8.8 Hz, 1 H), 4.47 (s, 2H), 4.32 (s, 2H), 3.68 (t, J === 6.0 Hz, 2H)5 2.47 (m, 2H), 2.18 (s, 3H); MS (ESI) mix 352.5 [M+Hf.
[0264| GBT881 Preparation of 2-[( 1 -acetyl-4-phenyl-3,6-dihydro-2H-pyridin-5- yl imethoxyJ-6-hydroxybenzaldehyde
Figure imgf000110_0001
65] Step 1: To a solution of 1-tert-butyl 3 -methyl 4-oxopiperidine- 1 ,3-dicarboxyiate (2.50 g, 9.72 mmol) in DCM (50 mL) was added DIPEA (2,03 raL. 1 1 .66 mmol) and Tf20 (1.80 mL, 10.69 mmol) at -78 °C, and then it was warmed up to room temperature and stirred further for 2 h, the solution was diluted with DCM and the organic layer was washed with Sat. NaHCOj, dried and concentrated to give 1-tert-butyl 3-methyl 4-
(((trifluoromethyl)st}ltbnyl)oxy)-5,6-dihydropyridine-i ,3(2H)-dicarboxylate as crude product
Figure imgf000110_0002
[Θ266| Step 2: To a solution of 1 -tert-butyl 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)- 5,6-dihydropyridine- 1 ,3(2H)-dicarboxylate (1 ,95 g, 5 mmol) and phenylboronic acid (1,22 g, 10 mmol) in Dioxane (20 ml} was added Pd(dppf)Cl2 and a solution of a2CQ3 (3.18 g, 30 mmol) in water (6 mL), after degassed with N2 for 5 mm, the reaction was heated at 100 °C for 1 h, the mixture was cooled to room temepraiure. diluted with EtOAc. organic layer was washed with water, brine, dried and concentrated to give crude product, which was purified -0057.1 109 Atty. Dkt. No.: 104592-0210 by column (Hexanes/EtOAc= 3: 3) to give 1 -tert -butyl 3-methyS 4-phenyl-5,6- dihydropyridme-l ,3(2H)-dicarboxylate (740 mg).
Figure imgf000111_0001
[0267] Step 3: TO a solution of 1-tert-butyl 3-methyl 4-phenyi-5,6-dihydropyridine~ l ,3(2H)-dicarboxylate (740 mg, 2.33 mraol) in THF (7.2 mL) was added IM LiAlH4 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 (Hcxanes/EtOAc= 60:40) to give tert-buty! 5 -(hyd roxymethyl )-4-pheny 1-3 ,6- dihydropyridirie-1 (2H)-carboxylate (512 mg).
Figure imgf000111_0002
Step 4; To tert-butyl 3-(hydroxymcthyl)-4-phenyl-5,6-dihydropyridine-'i (2] I)~ carboxylase (510 mg, 1 ,76 mraol) was added 4N HCI in Dioxane (3 ml), after stirring at room temperature for Ih, it was concentrated to give (4-phenyl- 1 ,2,5 ,6-tetrahydropyridin-3 - yl)methanoi as HCi salt.
Figure imgf000111_0003
[0269] Step 5: To a solution of (4-phenyl- 1 ,2,5,6-tetrahydropyridin-3-yi)methanol hydrochloride (110 mg, 0.49 mmol) in DCM (2 mL) was added DIPEA (0.17 mL, 0.98 mmol) and Ac 0 (0.05 g, 0,49 mmol), 15 min later, it was diluted with water and extracted 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).
4814-3854-0057.1 1 10 Atty, Dkt. No. : 104592-0210
Figure imgf000112_0001
[0270] Step 6: To a solution of l -(3-(hydroxymethyl)-4-phenyl-5,6-dihydropyridin-l (2H)- yl)ethanone (88 rag, 0.38 mmol) in DCM (2. mL) was added SOC ; · (0.67 mL, 9.50 mmol) at
0 °C. After stirring at 0 °C for 15 rain, the solution was concentrated to remove SOCL, dried under high vacuum to give 1 -(5 -(chloromethyl)-4-phenyl-3 ,6-dihydropyridin- 1 (2H)-yx)ethan-
1 -one as crude product.
Figure imgf000112_0002
[0271] Step 7: To a solu ion of 1 -(3-(chloromethyl)-4-p enyl-5,6-dihydropyridin-l (2H)- yl)ethanone (100 mg, 0.40 mmol)and 2,6-dihydroxybenzaldehyde (1 10 rag, 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. NaHCOj, brine, dried over Na2S(¼, and was concentrated to give crude oil. w hich was purified by preparative HPLC (eluted with ACN/H?0) to give 2-(( 1 -acety 1-4-phenyl- 1 ,2,5,6-tetrahydropyridin-3- yl)methoxy)-6-hydroxybenzaldehyde (26 mg). 1 H NMR (400 MHz, CDC13, NMR shows rotaraers exist, only one set of signal was reported) δ (ppm) 11.97 (s, 1H), 10.34 (s, 1H), 7.34 (m, 4H), 7.17 (m, 2H), 6.49 (d, J = 8.0 Hz, 1 H), 6.1 1 (d, J = 8.8 Hz, 1 H), 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+Hf.
|0272] GBT887 Preparation of 2-((2-(l -cyclopeotyl-lH-pyrazol-5-yl)pyridin-3- yl)methoxy)-6-hydroxybenzaldehyde
Figure imgf000112_0003
-0057.1 H i Atty. Dkt. No.: 104592-02
Figure imgf000113_0001
10273 J To a mixture of 3-(chloromethyl)-2-(l -cyclopentyl-1 H-pyrazol-5-yl)pyridine hydrochloride (44.7mg, O.l Smmol) and 2,6-dihydroxybenzaldehyde (83mg, 0,6mmol, 4eq) and potassium carbonate (41.5mg, OJmmol, 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 (4 1 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, 2,6- dihydroxybenzaidehyde, 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 Si02 column. It was purified on Biotage isoiera One system eluted with 5%- ! 00% EtOAc (the product came out around 25% EtOAc, 2nd peak; the 1 st peak is dihydroxybenzaidehyde). The product as a yello film was ontained after removing solvents, the residue was re-dissolved in 0.3mL CIHCN 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 ( 8.6mg. 34% yield). 'H NMR (400 MHz, COCA3-d) 8 1 1.94 (s, I H), 10.37 (s, 1H), 8.75 (dd, J = 4.8, 1.7 Hz, 1 H), 7.97 (dd, J- 8.0, 1.4 Hz. I H), 7.59 (d, J = 2.0 Hz, 1 H), 7.42 (dd, J= 7.7, 4.8 Hz, 1 H), 7.37 (i, .7 - 8.3 Hz, 1 H), 6.56 (d, J = 8.6 Hz, 1 H), 6.35 (d, J = 1.9 Hz, 1 H), 6.25 (d, J - 8.3 Hz, 111), 5.07 (s, 2H), 4.79 - 4.67 (m, I H), 2.1 8 - 1 ,95 (m, 4H), 1.95 1 .84 (rn, 2H), 1.66 - 1.50 (m, 2H); MS ( LSI) m/z 364.3 [M M If.
|0274] GBT888 Preparation of 2-hydroxy-6-[[(2S)- l -phenylpyrrolidirt-2- yl] methoxyjbenzaidehyde
Figure imgf000113_0002
-0057.1 1 12 . Dkt. No.: 104592-021 0
HO'
Figure imgf000114_0001
[0275] Step I : To a solution of (S)-pyrrolidin-2-ylmet anol (1.52 g, 15 mmol) and Cul ( 190 rag, lmmol) in iPrOH (10 mL) was added (CH2OH)2 (1.1 1 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: 1 ) to give (S)-(l-phenylpyrrolidin-2-yl)methanol ( 1.6 g).
[0276] Step 2: To a solution of (S)-( 1 -phenylpyrrolidin-2-yl)methanol (45 mg, 0.23 rnmol) and 2,6-dihydrox benzaldehyde (60 mg, 0.46 ramol) in THF (1 ml) was added PPh3 (0.12 g, 0.46 mmol), followed by DTAD (90 mg, 0.46 mmol) at room temperature. 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 -phenylpynO!idin-2-yl)melhoxy)benzaldehyde (14 mg). 1H NMR (400 MHz, CDCK (ppm) 1 1.96 (s. IH), 10.37 (s. I H), 7.35 (t. J = 8.0 Hz, 1 H), 7.25 (m, 2H). 6.73 (m, 3H), 6.53 (d, J - 8.4 Hz, I H), 6.33 (d, J = 9.2 Hz. IH), 4.21 (m, I H), 4.15 (d, J - 3.6 Hz, I H), 3.83 (t, J= 8,0 Hz, IH), 3.53 (m, I H). 3.22 (m, I H), 2.1 1 (m, 4H); MS (ESI) m/z 298.4
[0277] GBT892 Preparation of 5-f{2-(3-chlorophenyl)pyridin-3-yl]methoxy]-2- methoxypyridine-4-carbaldehyde
Figure imgf000114_0002
Figure imgf000114_0003
, Dki. No.; 104592-0210
[0278] Step 1 : Into a 50-mL round-bottom flask, was placed a solution of (3- chlorophcnyl)boronic acid (1.6 g, 10.23 mmoi, 1.20 equiv), (2-ch]oropyridin-3-yl)methano! (1 g, 6.97 mmoi, 1.00 equiv), Pd(dppi)Cl2 (570 rng, 0.78 rnmoi, 0.10 equiv), and sodium bicarbonate (3.7 g, 20.24 mmoi, 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 H20. 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 yield 1.2 g (78%) of [2-(3-chloropheny3)pyridin-3-yl]methanol as a white solid.
[0279] Step 2; Into a 50-mL round-bottom flask, was placed a solution of [2-(3- chlorophenyl)pyridin-3-yl]methanol (600 mg, 2.73 mmoi. 1.00 equiv) i 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-(3 - ch!oropheny 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 mmoi, 1 .00 equiv), 5-hydroxy-2- methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmoi, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmoi, 2.00 equiv) in C¾CN (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 CI S 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 i min);
Detector, Waters2545 UvDector 254&220nm. This resulted in 71 mg (9%) of 5-[[2-(3- chlorophenyl)pvrtdin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a yellow solid.
'HNM (400MHz, DMSO-i d) δ 10.07(s, 1H), 8.72 (m, 1 H), 8.20(m, 2H), 7.79(s, 1H)S
7.60(m, 4H), 6.95(m, 1H), 5.21(m, 2H), 3.85(s, 3H); MS (ESI) m/z 355 [M+H]+.
[0281 ] GBT893 Preparation of 5-[[2-(4-chlorophenyl)pyridin-3-yl]methoxy]-2- methoxypyridi ne-4-carbai dehyde
-0057.1 1 14 Atty. Dkt. No.: 104592-0210
Figure imgf000116_0001
[0282] Step 1 : into a 100-mL round-bottom flask, was placed a solution of (4- chlorophenyl)boronic acid ( 1 .6 g, 10.23 nimol, 1 .20 equiv), (2-chloropyridin-3 -yl)methanol ( 1 g, 6.97 ramol, 1.00 equiv), Pd(dppf)C (570 rag, 0.78 mmo!, 0. 30 equiv). and sodium bicarbonate (1.7 g, 20.24 mmo!, 3.00 equiv) in a solvent mixture of dioxane ( 10 niL) and water(10 niL). The resulting solution was stirred for 4 h at 70°C, and then it was diluted with 3 00 mL of H20. The resulting solution was extracted with 2x200 mL of dichJoromethane, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyi acetate/petroleum ether (1:100-1 :5) as eluent to yield 1 g (65%) of [2-(4-ehlorophenyl)pyridin-3-yl]mcthanol as a light yellow oil.
[0283] Step 2: nto a 25-mL round-bottom flask, was placed a solution of [2-(4- chlorophenyl)pyridin-3-yi]raethanol (1 g, 4.55 mmol, 1.00 equiv) in thionyl chloride {5 mL). The resulting solution was stirred for 3 h at reflux. The resulting mixture was concentrated under vacuum. This resulted in 1 g (92%) of 3-(chloromet yl)-2-(4-chlorophenyl)pyridine as a white solid.
|0284| Step 3: into a 50-mL round-bottom flask, was placed a solution of 3- (cbJoromethyi)-2-(4-chlorophenyl)pyridine (309 mg, 1.30 mmol. 1 .00 equiv), 5-hydroxy-2- methoxypyridine-4-carbaldehyde (200 mg, 3 .31 mmol, 1 .00 equiv). and potassium carbonate (361 mg, 2.61 mmol, 2.00 equiv) in CHjCN (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 148.2 mg (20%) of 5-[[2-(4- chlorophenyl)p Tidjn-3-yJ]methoxy]-2-mcthoxypyridine-4-carbaldehyde; bis(trifluoroacetic -0057 1 1 15 . Dkt. No,: 1 04592-02 acid) as a yellow solid.
'HNMR (300MHz, DM80--<¾) δ ] 0.05(s, 1H), 8.69 (m, 1 H), 8.16(m, 2H), 7.64(m, 2H), 7.50(m, 3H), 5.32(s, 211), 3.81 (s, 3 FT); MS (ESI) m/z 355 [M+H]+,
GBT903
Figure imgf000117_0001
{R)-2-hydroxy-6-((1 -phenylpyrroildin-2-yl)methoxy)benzaldehyde
[0285] GBT903 - Preparation of (R)-2-hydroxy-6-((l-phenylpyrrolidlin-2- yl)methoxy)benzaldehyde. The compound was prepared from (/f)-pyrrolidin-2-yitnethanoi and iodobenzene according to scheme 8, reaction steps 3 and 4. Ή NMR (400 MHz,
Chloroform-cf) δ 1 1.96 (d, J = 0.4 Hz, 1H), 10.37 (s, 1H), 7.37 (td, J= 8.4, 0.4 I !z, IH), 7.3 1 - 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, 1 H), 4.25 - 4.12 (m, 2H), 3.88 - 3.78 (m, ΪΗ), 3.53 (dt J= 8.8, 4.4 Hz, 1 H), 3.27 - 3.16 (tn, I H), 2.1 1 (dqt, J = 1 3.0, 6.4, 2.8 Hz. 4H). MS (M÷H)4 found for CisH! 9N03: 298.2.
Figure imgf000117_0002
2-hydroxy-6-{(2-( 1 -methyi-1 H-pyrarot-5-yl pyrtdip.-3-vl)metho v)benzal<ie y(ie
[0286] GBT904 - Preparation of 2-hydroxy-6-((2-(l -methyl-lH-pyrazol-5-yl)pyridin-3- yl)methoxy)benzaldehyde. The compound was prepared from (2 -chloropyridin-3- y])methanoI and 1 -methyl-5-(4,4>5,5-tetramethyl-l,3,2-dioxaboroian-2-yl)-3 H-pyrazo!e according to scheme 9, reaction steps 1 , 2 and 4. In step 4. 2-hydroxy-6- (methoxymethoxy)benzaldehyde.was used; die MOM ether protecting group fell off after the reaction to give the final product. !H NMR (400 MHz, Chloroforrn-cf) δ 1 1 .94 (s, 1H), 10.36 -0057. 1 16 . Dkt.No.: 104592-0210
(s, 1H), 8.75 (dd,J = 4.8, 1.7 Hz, IH), 7.98 (d,J=8.0Hz, IH), 7.54 (d, J - 1.9 Hz, IH), 7.41 (dd, J = 8.0, 4.0Hz, 1H), 7.38 (t, J- 8.0 Hz, 1H), 6.58 (dt, ./= 8.5, 0.7 Hz, 1H)56.39 (d, J= 1.9 Hz, HI), 6.28 (dd, J= 8.3, 0,8 Hz, lii).5.12 is, 2H), 3.95 (s.311). MS (.VI r ! 1) found for C,7Hi5N3O3:310.3.
CiBT907
Figure imgf000118_0001
2-hydroxy-6-(1-f>2-methoxypheny!;piperidin-3- (S)-2-hydroxy-6-(( 1 -(2-methoxyphenyi)pyrroiidin-2- yi)oxy)benz3idehyde
yl)methoxy)benzaldehyde
[0287] GBT907 and G8T908 - Preparation of (5)-2-hydroxy-6-((l-(2- raethoxyphenyl)pyrrolidin-2-yl)methoxy)benzaldehyde (GBT907) and 2~hydroxy-6-((l- (2-methoxyphenyI)piperidin-3-yi)oxy)beQzaldehyde (GBT908). The reaction of (S)- pyrrolidin-2-ylmethanol with 2-iodoanisole, and subsequent Mitsunobu reaction, according to scheme 8, gave a mixture of GBT9 7 and GBT908 in 3:2 ratio, which were separated by reverse-phase prep HPLC.
[0288] GBT907- (S)-2-hydroxy-6-(( 1 -(2 -methoxyphenyl)pyrrolidin-2- yl)methoxy)benza!dehyde Ή NMR (400 MHz, Chloroform-*/) δ 11.96 (d, J = 0.4 Hz, H), 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, 1H),3.80 (s, 3H), 3.67 - 3.58 (m, I H), 3.29 (dt,./- 9.9,4.3 Hz, IH), 2,85 (dd, J = 11.3, 8.3 Hz, 1H),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 Cf9H2iN04:
.328.3).
10289] GBT908- 2-hydroxy-6-((l-(2-methoxyphenyl)piperidin-3-yi)oxy)benzaldehyde (40 mg, Ή NMR (400 MHz, Chloroform-^) 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.
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), 2.09 - 1.86 (m, 3H), MS (M+H)+ found for C19H21NO : 328.3). -0057.1 117 . Dkt. No.: 104592-0210
GBT912
Figure imgf000119_0001
2-{((3S,4R)-1 -acetyi-4-(2,5-difluorophenyl)p^^
[0290] GBT912- 2-(((3S,4ii)-l-acetyI-4-(2,5~difiuorophenyl)pyrro!idin-3-yl)meihox.y)- ό-hydroxybeiizaldehyde. The compound was prepared from -(2,5-difluorophenyl)-4- (hydroxymethyl)pyrro1idin- 1 -yl)ethan- 1 -one and 2,6-dihydroxybenzaldehyde (INT-7) using genera] method A (Mitsunobu conditions). Ή NMR (400 MHz, Chiorofonri-i } δ 1 1.90 (s, 1H). 9.88 (s, 1H), 7.37 (dd, J= 8.4, 6.4 Hz, I H), 7.01 (m, 3H), 6.53 (t, J- 8.6 Hz, !H), 6.27 (dd, ,7= 8.3, 0.8 Hz, I H), 4.02 (ra, 4H), 3.55 (m, 3H). 2.96 (m, I H), 2.1 1 (s, 3H). MS
(M+H)+ found for C20H 19F2NO4: 376,3.
0291] Preparation of -(255-difluorophenyl)-4-(hydroxymethyl)pyrroiidin-l -y])ethan- 1 -one
Figure imgf000119_0002
[0292] To a solution of ((35,4 ?)-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 niL. 1.68 mmol) and AcjO (90 mg, 0.84 mmol), after stirred for 30 niin, the solution was diluted with DCM, organic layer was washed with Sat. NaHCC , brine, dried over MgS04 and was concentrated to give l-((3i?,4S)-3-(2,5-difluorophenyl)-4-(hydroxymethyI)pyrroIidin-l.- yl)cthan-l-one as crude product (175 mg).
GBT913 and GBT91
-0057.1 1 1 8 . Dkt. No.: 1 04592-0210
Figure imgf000120_0001
-hydroxy-6- (1 - 3-methoxypheny!)piperidit
-hydroxy-6-((1-(3-methoxypheny!)pyrrolidin- yl)oxy)benzaidehyde
yl)methoxy)benzaldshyde
[0293] GBT913 and GBT914 - Preparation of (S)-2-hydroxy-6-((l-(3- methoxyphenyl)pyrroIidin-2-yl)rnethoxj')benzaIdehyde (GBT913) and 2-hydroxy-6-((l- (3-methoxyphenyl)piperjdin-3-yl)oxy)bciizaldehyde (GBT914). The reaction of (5)- pyrrolidin-2-ylmet anol with 3-iodoanisole, and subsequent 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-methoxyphenyi)pyrrolidin-2- yl)methoxy)benzaldehyde Ή NMR (400 MHz, Chloroform-i/} δ 1 1.95 (s, 111), 10.37 (ΐ, J ------
0.5 Hz, lH), 7.42 - 7.31 (m, 1 H), 7.16 (t, J= 8.2 Hz, 1H), 6.53 (dq, J = 8.4, 0.6 Hz, I H), 6.36 - 6,24 (m, 3H), 6.23 (t, J= 2.4 Hz, IH), 4.23 - 4.12 (m, 2H), 3.79 (s, 4H), 3.50 (ddd, J- 9.0, 5.6, 3.5 Hz, I H), 3.27 - 3.16 (m, 1H), 2.17 ~ 1.98 (m, 4H). MS (M+H)+ found for
Figure imgf000120_0002
GBT914 - 2 -hydroxy-6-(( 1 -(3 -methoxypbenyl )piperid in-3 -yl)oxy )benza! deh de Ί ! N .M R (400 MHz, Chloroform-i/) δ 1 1 .94 (d, 0,4 Hz, I H), 10.25 (d, ./ 0.6 H. , IH), 7,39 (td, J = 8.4, 0.4 Hz, IH), 7.19 - 7.08 (m, IH), 6.51 (dt, J= 8.5, 0.7 Hz, 2H), 6.48 - 6,37 (m, 3H), 4.58 (m, I H), 3.78 (m, I H), 3, 77 (s, 3H), 3.74 - 3.64 (m, 1 1 !), 3.39 (d, J= 5.6 Hz, IH), 3.17 (dd, J= 12.4, 7.6 Hz, IH), 3.1 1 - 3.01 (m, I H), 2.14 (s, IH), 2.02 - 1.92 (m, IH), 1.86 - 1.74 (m, I H). MS (M+H)+ found for C9H21 O4: 328.4).
Figure imgf000120_0003
[0295] GBT916 - 2-hydroxy-6-((2-(2-methoxyphenyl)pyrtdin-3- yl)raethoxy)benzaldehydc. The compound was prepared from (2-chloropyridin-3-
4814-386 -005Γ. 1 39 . Dkt No.: 104592-02 yJ)meihanol and (2-methoxyphenyl)boronic acid according to scheme 9, reaction steps I, 2 and 4. In step 4, aikyiation with 2,6-dihydroxybenzaldehyde, the product of TFA salt 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, IH), 7.50 (m, 3H), 7.3 ί (m, IK), 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, /z): 336 M+l .
BT 17
Figure imgf000121_0001
[0296S GBT91 - 2-hydroxy-6-((2'-methoxy-[2^'-bipyridin|-3- yI)methoxy)bcnzaldehyde. The compound was prepared from (2-chloropyridin-3- yl)meihanoI and (2-raethoxypyridin-3-yi)boronic acid according to scheme 9. reaction steps 1, 2 and 4. In step 4, aikyiation with 2,6-dihydroxybenzaldehyde, the product TFA salt was obtained after HPLC purification.
'HNMR (300MHz, CDC ,ppm): 11.91 (s, H), 10.24 (s, IH), 8.71 (t, IH), 8.69 (m, IH), 7.93 (d, 1H), 7.75 (d, 1H), 7.40 (m, IH), 7.39 (m.1H), 7.08 (m, 1H), 6.53 (l.1H).6,50 (d, IH), 5.07 (s, 2H), 3.94 (s, 311;·: MS (ES, m/z): 337 [M+lf
Figure imgf000121_0002
10297] GBT930-2-((2-(l-cyclobutyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)-6- hyd roxybenzaldehy de> The compound was prepared by Mitsunobu reaction (scheme 9. step 3) of (2-(l-cycIobutyl-lH-pyrazol-5-yl)pyridin-.3-yi)methanoi (A) with 2,6- dihydroxybenzaldehyde (INT3). The product was obtained as pale yellow solid, 'HNMR (300MHz, CDCI3, ppm): 11.95 (s, IH), 10.35 (s, IH), 8.75 (m, HI), 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 (ra, IH), 6.23 (d,
4814-3854-0057.1 120 Dkt. No.: 104592-0210
J=8.4Hz, I H), 5.07 (s, 2H), 4.85 (m, 1 H), 2.75 (m, 2H), 2.27 (m, 2H), 1 .25 (m, 2H); (E8, m/z ) : 350 (M- l | '
Figure imgf000122_0001
?8] Preparation of intermediate A. intermediate A was prepared from pyrazole in three steps according scheme below.
Figure imgf000122_0002
[0299] Step I : Into a 500-mL round-bottom flask, was placed a solution of ! H-pyrazoie ( 1 0 g, 146,89 mmol, 1 .00 equiv), Cs2C03 (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 80CC, 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 S g (45%) of 1 -cyclobutyl- 1 H-pyrazole as a colorless liquid.
Step 2: Into a 250-mL round-bottom flask, was placed a solution of 1 -cyclobutyl- IH-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 -3()°C. The mixture was stirred for 30 min at the same temperature. To this was added 4,4,5,5- tetramethy]-2-(propan-2-yioxy)-l ,3,2-dioxaborolane (14.9 g, 80.08 mmol, 1.50 equiv) dropwise with stirring at -7S°C. The resulting solution was stirred tor 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 clichloromethane. The combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :200-l :30) as eluent to furnish 6.2 g (47%) of l-cyc!obutyl-5-(tetn 1 "t
dioxaborolan-2-yl)-l H-pyrazole as a colorless oil.
Step 3 : into a 100-mL round-bottom flask, was placed a solution of 1-cyclobtityl- (tetramethyl- 1 ,3,2-dioxaboro1an-2-yl)~l H-pyrazole (791 mg, 3.19 mmol, 2.00 equiv), (2-
4814-3854-0057.1 . Dkt. No.: 104592-0210 bromopyridin-3 -yl)methanol (500 rag, 2,66 mmol, 1.00 equiv), Pd(dppf)C]2 (217 rag, 0.30 mmol, 0.10 equiv),and sodium carbonate (670 mg, 6.32 rnmol, 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 nig (33%) of [2- ( l-cyclobutyl-1 H-pyrazol-5-yI)pyridin-3-yI]methanol as a yellow oil.
Figure imgf000123_0001
[0302] GBT934- 2-((2>-ethox -[23,-bipyridin]-3-yl)methoxy)-6-hydroxybenzaldehyde
The compound was prepared from (2-chloropyridin-3 -yl)raethanol and ((2-ethoxypyridin-3 - yl)boronic acid according to scheme 9, reaction steps 1 , 2 and 4. In step 4, alkylation with 2 ,6-dihydroxybenzaldehyde (INT3), the product TFA salt as white solid was obtained alter HPLC purification. !HN MR (400MHz, CDC13, ppm): 1 1.91 (br s. 1 H), 10.29 (s, 1H), 8.97 (s, 2H), 8.97 (br s, 1 H), 8.46 id, J = 8.0 Hz, lH), 8.40 (d, ./ 4.8 Hz, 1 H), 7.87 (s, 1 H), 7,81 (d, J = 6.8 Hz, 1 H), 7.53 (t, J - 4.4 Hz, 1H), 7.12 (t, J = 6.0 Hz, 1H), 6.59 (d, J= 8.4 Hz, 1 H), 6.14 (d, J = 8.4 Hz, I H), 5.17 (s, 2H), 4.46 (q, J - 6.8 Hz, 2H), 1.32 (t, J™ 6.8 Hz, 3H); MS (E$, m/∑) 35 1.1 [M+l]+
Figure imgf000123_0002
[0303] GBT948- 3-chloro-2-hydroxy-6-((2-(l-isopropyl-lH-pyraz;oi-5-yI)pyridin-3- yl)methoxy)benzaidehyde. The compound was prepared using general reaction step 4 of 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 subsequent -0057.1 j 22 Dkt. No.: 104592-0210 deprotection of the MOM ether by treating with aqueous 6N HQ in THF. 'HNMR
(400MHz,CDCl3> Jfip/n): 12.49(s, 1 H), 10.34(s, 1H), 8.80(dd, J-3.6Hz, 1 H), 8.00(dd
J=5.7IJz, 1 H), 7.63(d, J-l .2Hz, lH),7.47(m, 2H), 6.36 (m, 2H) ,5.1 1 (d, J=10.8Hz, 2H) 4.70(m, 1H), 4.6 l (m, 1H), 1.53(d, J-4.5Hz, 6H); MS (ES, m/z): 372[M+1]~
Figure imgf000124_0001
The MOM-protected phenol aldehyde intermediate B was prepared according to the following synthetic scheme; .M
Figure imgf000124_0002
|6305] Step 1 : Into a 2000-mL round-bottom flask, was placed a solution of 4- ehlorobenzene-1 ,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 temperature. 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- (rnethoxymethoxy)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 overnight at room temperature. 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)- 1 - chloro-2-(methoxymethoxy)benzene as a colorless oil.
4814-3854-0057 123 Atty. Diet. No.: 1 04592-0210
10307 j Step 3: Into a 500-rnL three neck round-bottom flask, was placed a solution of bis(propan-2-yl)amme (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) drop-wise 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)bcnzene (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-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 3x 100 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 gei column with ethyl acetate/petroleum ether (1 :5) as eluent. This resulted in 8.S g (34%) of 6- (benz>4oxy)-3-ch!oro-2-(methoxymethoxy)benzaldehyde as a yellow soild.
[0308] Step 4: Into a 500-mL round-bottom flask, was placed a solution of 6-(henzyloxy)- 3-chloro-2-(raethoxymethoxy)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 temperature under 1 aim 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-6- hydroxy-2-(methoxymethoxy)benzaldehyde as a light yellow solid.
GBT954
Figure imgf000125_0001
[0309] GBT954- 4-hydroxy-2-((2-(I-isopropyl-l H-pyrazol-5-yl)pyridin-3- yi)methoxy)beiizaideh'yde. The compound was prepared by itsunobu reaction (scheme 9, step 3) of 2-hydroxy-4-(methoxymethoxy)benzaldehyde (A) with (2-(1 -isopropyHH- pyrazo3-5-yl)pyridin-3-yl)methanol (B) and subsequent deproteetion of the MOM ether by- treating with aqueous 6 HC! in THF according the scheme below. ' llNMR (400MHZ,
4314-3854-0057.1 124 Atty. Dkt. No. : 104592-0210
DM SO. ppm): 10.70 (s, i ! i ). 10,09 (s, i l l ). 8.75 (m, 1H), 8.22 (d, J H S I/. I H), 7.59 (m, 3H),
+
Figure imgf000126_0001
[0310] Preparation of intermediate 2-h droxy-4-(methoxymethoxy)benzaldehyde
Figure imgf000126_0002
|0311] Into a 100-raL round-bottom flask, was placed a solution of 2,4- dihydroxybenzaldebyde (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 rnL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 30 mL of H20. The resulting solution was extracted with 3x20 raL of
dichioromethane 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) eluent to furnish 2.6 g (66%) of 2-hydroxy-4-(methoxymethoxy)benzaldehyde as a while solid.
C;BT967
Figure imgf000126_0003
[0312] C BT967- 2-((2',6'-dimethoxy-[2r3,-bipyridin]-3-yl)methoxy)-6- hydroxyhenzalde yde. The compound was prepared from (2-chloropyridin-3-yi)methanol and 2,6-dimethoxy-3--(4,4,5,5-tetramethyl- i ,3,2-dioxaboroian-2-yl)pyridine according to scheme 9. reaction steps 1 , 2 and 4. In step 4, alkylalion with 2,6-dihydroxybenzaldehyde, the product of TFA salt as white solid was obtained after HPLC purification. !H MR (400MHz, DMSO, ppm): 10.04 (s, 1H), 8,65 (m, 1H), 8.14 (d, J=7.6Hz, I H), 7.73 (d, J=8Hz, 5H), 7.51 (m, 2H), 6.50 (m, 3H), 5.16 (m, 2H), 3.91 (s, I H), 3.86 (s, IH); (ES, m/z): 367 [M+l ]+ -0057 1 125 Dkt. No , : 104592-0210
GBT000985
Figure imgf000127_0001
[0313] GBT985- 3-(difluoromethyl)-l-mcthyl-5-((2-(l-(2,2,2-triflluoroethyl)-l H- pyraz l-5-yl)pyridin-3-yl)aieihoxy)-lH-pyrazo{e-4-earbaidehyde.
Figure imgf000127_0002
[0314 ] 3-(DifluoromethyI)-5 -hydroxy- 1 -methyl- 1 H-pyrazo !e-4-carbaldehyde ( 100 mg, 0.568 mmol) was dissolved in DMF (2.8 mi). 3-(ch!oromethyl)-2-( 1 -(2,2,2-trifluoroethyi)- l H-pyrazol-5-yI)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 1 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 evaporation, the residue was purified by silica gel chromatography (5 - 50 % ethyl acetate/hexanes) to give 86 mg (36%) of 3 -(diHuoromeihyl)- 1 -methyi-5-((2-( 1 -(2,2,2-trif! uoroethyl)- 1 H-pyrazol-5- yi)pyridin-3 -yl)methoxy)- l H-'pyrazoie-4--carbaldehyde as an off-white solid. Ή NMR (400 MHz, CDCI ¾) o 9.97 (s, 1 H), 8.75 (d, J = 3.64 Hz, 1 H), 8.08 (d, J = 7.3 1 Hz, 1 H), 7.68 (d, J = 1.69 Hz, 1 H), 7.44 (dd, J = 4.66, 7.83 Hz, 1 H), 6.65 (i, J = 53.67 Hz, 1 H), 6.61 (d, J - 1 .78 Hz, 1 H), 5.64 (s, 2H), 5.24 (q, J - 8,60 Hz, 2H), 3.54 (s, 3 H). MS (ESI) m/z 41 6 [M+H]+. -0057.1 [ 26 Atty. Dkt. No.: 104592-021
GBT986
Figure imgf000128_0001
[0315| GBT986- l-methyl-S-((2-(l-(2,2,2-trifluoroethyI)-lH-pyrazoI-S-yI)pyridin-3- yi)methoxy)-3-(trifluoromethyl)-lH-pyrazoIe-4-carba!dehyde
Figure imgf000128_0002
[0316] 5-Hydroxy- 1 -methyl -3 -(trifluoromethyl)- 1 H-pyrazole-4-carbaldehyde ( 100 m g, 0.515 mmol) was dissolved in DMF (2.5 ml). ). 3 -(chloromethyl)-2-( 1 -(2,2,2-trifluoroethyi)- 1 H-pyrazoi-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 UC 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 mi) and a saturated aqueous sodium chloride solution (20 mi). After drying over sodium sulfate and evaporation, the residue was purified by silica gel chromatography (5 - 50 % ethyl acetate/hexanes) to give 86 mg (36%) of ί -methyl-5-((2-( 1 -(2,2,2-trifluoroethyl)- lH-pyrazol-5 -yl)pyridin-3 - yl)methoxy)-3 -(trifluoromethyl)- 1 } l-pyrazoie-4-carbaidehyde as an off-white solid. Ή N R
(400 MHz, CDC13) 8 9.87 (s, J H), 8.75 (d, J - 4.33 Hz, 1H), 8.08 (d, J- 7.73 Hz, 1 H), 7.68 (d, J = 1.74 Hz, 1H), 7.45 (dd, J = 4.64, 7.84 Hz, ] H), 6.59 (d, 1.70 Hz, 1 H), 5.63 (s. 2H), 5.24 (q, J= 8,60 Hz, 2H), 3.57 (s, 3H). MS (ESi) m/z 434 [M+Hf.
G B -0057. 127 Dkt. No.: 104592-0210
Figure imgf000129_0001
[0317] GBT1065 - 4-iluoro-7-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridiin-3-yl)meihoxy)- 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-[l- (propan-2-yl)- 1 H-pyrazol-5-yl]pyridin-3-yl]methanol according to scheme 9, reaction step 3, The product TFA sail as white solid was obtained after HFLC purification. 5HNMR
(300MHz, DMSCX ppm): 8.72 (m, 1 H),8.23 (m, 1 H), 7.56(ra, 1H), 7.5 l (d, J=1 .8Hz, 1 H), 7.43(m. 1H), 6.93 (m, 1 H), 6.58(d, J LSI !/. 1 H), 5.08(s, 2H), 4.63(m, \ H), 3.03 (m, 21 1), 2.61 irn. 2H), 1.33 id. J o.6f ix. 6H); MS (ES, w z): 366[M+l
Figure imgf000129_0002
|0318j GBT1133- 2-(((2-(l-isopropyl-lH-pyrazoi~5-yl)pyridin-3- yl)oxy)methyl)benzaldehyde. The compound was prepared from ethyl 2- (bromomethyl)benzonitrile in 2 steps according to reaction scheme below.
Step 2
Figure imgf000129_0003
[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 dich!oromethane (40 mL). This
4814-3354-0057.1 128 Atty. Dkt. No.: 104592-0210 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% 1 IBr 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-(bromomethyi)benzaldehyde as a green oil.
[0320] Step 2: Into a 50-mL round-bottom flask, was placed a solution of 2- (bromomethyl)benzaldehyde (1 50 mg, 0.75 mmol, 1 ,00 equiv) in CLLCN (25 mL). 2-[l - (Propan-2-yi)-lH-pyrazo!-5-ylJpyridin-3-ol (150 mg, 0.74 mmol, 1.00 equiv), potassium carbonate (210 mg, 1 ,52 mmol, 2.00 equiv), and I (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 H20, and then it was extracted with 3x20 mL of ethyl acetate. The combined organic layers were washed with 1 x30 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 C I 8 OBD
Coiumn,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-[1 -(propan~2- yl)-l H-pyrazoi-5-yi]pyridin-3-yl]oxy)methyl]benzaldehyde as a light yellow solid; 'HNMR (300MHz, CDC , ppm): 10.01 (s, I H), 8.43 (m, I H), 7.88(m. 1H), 7.86 (m, 1 H), 7.61 - 7.79(m, 6H , 6.61(d, ,/ 2. 1 H/. 1 H), 5.60 (s, 2H), 4.69-4.78 (m, 1 H), 1 ,46(d, ,/ -6.M 1/. 6H); (ES, /z): 322 [M+l
Figure imgf000130_0001
[0321 ] GBT1197- 2-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3- yi)methoxy)benzaidehyde. The compound was prepared by O-alkyfation of 2- hvdroxvbenzaidehvde with
Figure imgf000130_0002
(IN 1 - 4). The product of IF A salt as white solid was obtained after HPLC purification. 'HNMR (300MHz, CDC , ppm): 10.49(s, I H), 8.78(m, 1H), 8, 16(m, i l l ). 7.88(m, 1 H), 7.69(d,
4814-3654-0057.1 129 Ally. Dkt. No.: 104592-0210
J=6.0Hz, lH),7.54(m, 2H), 7.13(m, 3 H) , 6.90(d, J=8.4Hz, 1H), 6.4 l(d, J=1.8Hz, 1 H)5 5.1 1 (s, 2H), 4.62 (m, 1H); (ES, m/z): 322[M+lf
GBT1252
Figure imgf000131_0001
[0322] GBT1252- 2-((6-bromo-2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yI)methoxy)-
6-hydroxybenzaidehyde. The compound was prepared by Mitsunobu reaction of (6-bromo- 2-(l -isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol (intermediate A) and 2,6- dihydroxybenzaidehyde (INT-3) according to scheme 9, reaction step 3. The product as white solid was obtained after flash column purification. 'l-lNMR (300MHz. DMSO, ppm): 1 1.70 (s, I H), 11.20 (s, 1H), 8. 1 7 id. . I 8.1 Hz, 1H), 7.81 (d, J = 8.1 Hz, IH), 7.57 (s, IH), 7.50 (t, J - 8.4 Hz, IH), 6.60 (s, I H), 6.55 (dd, J = 8.4 Hz, 3.6 Hz, IH), 5.19 (s, 211), 4.65-4.55 (m, I H), 1.38 (d, j = 6.6 Hz, 6H); (ES, m/z ) 418. i [M l f
Figure imgf000131_0002
[0323] Preparation of intermediate A. intermediate A was prepared from 2,6- diehloropyridine-3-carboxy!ic acid in five steps according to the synthetic scheme below.
4814-3854-0057.1 130 . Dkt. No.: 104592-021 0
Step 3
Figure imgf000132_0001
cooH COQMe
Figure imgf000132_0002
[0324] Step 1 : Into a 500-mL round-bottom flask, was placed a solution of 2,6- dichloropyridine-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 mmo!, 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-methoxyp>Tidine-3 -carboxyl ic acid as a white solid.
[0325] Step 2: Into a 100-mL round-bottom flask, was placed a solution of 2-chloro-6- rnethoxypyridine-3-carboxylic acid ( 1 1 .3 g, 60.24 mmol. 1.00 equiv) in methanol (50 mL). This was followed by the addition of SOCb (26 mL, 5.00 equiv) dropwise with stirring as 0 °C. The resulting solution was stirred for 1 h at room temperature 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 1x 150 mL of water and 1x 100 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 furnish 7.8 g (64%) of methyl 2-chloro-6- methoxypyridine-3-carboxy!ate as a white solid.
[0326] Step 3 : Into a ! 00-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed methyl 2-chloro-6-methoxypyridine-3-
4814-3854-0057.1 13 1 Atty. Dkt No.: 104592-0210 carboxylate (3.29 g, 16.32 mraol, 1 .00 equiv), 1 -(propan-2-yl)-5-(tetramethyl- 1 ,3,2- dioxaboroian-2-yl)- 1 I i-pyrazole (4.63 g, 19.63 mmol. 1 .20 equiv), toluene (45 mL), ethanol (15 mL), sodium carbonate (2M in H20) (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 X. The reaction was then quenched by the addition of 20 mL of water and 1 00 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-l : 15) as eluent to furnish 3.83 g (85%) of methyl 6-methoxy-2-[l-(propan-2-yl)- lH-pyrazol-5-yi]pyridine-3-carboxylate as a light yellow oil.
[0327] Step 4: Into a 250-tnL round-bottom flask, was placed methyl 6-methoxy-2-[ l - (propan-2-yl)- 1 H-pyrazol-5-yl]pyridine-3-carboxy!ate (3.6 g, 1 3,08 rnmol, 1.00 equiv), Cell*, (60 mL), H3P04(85%) (150 mg, 1.53 mmol, 0.10 equiv), PyllBr (208 mg, 1 .30 rnmol, 0.1 0 equiv), ΡΟϊ¾ (1 1.5 g, 40.1 1 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-[ 1 -(propan-2-yl)- 1 H-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-[ 1 -(propan- 2-yl)- i H-pyrazo)-5-yi]pyridine-3-earboxylatc (2.62 g, 8.08 mmol, 1 .00 equiv),
tetrahydrofuran (3(3 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 temperature. 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 1 50 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-l :5) as eluent to furnish 1 .97 g -0057. 132 . Dkt. No. : 104592-0210 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 1 x60 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 elucnt to yield 2.08 g (75%) of 4-(diraethylamino)-2,6-dimeihoxybenzaldehyde (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 mmoi, 1.00 equiv) in dichloromeihane (25 mL). AICI3 (6 g, 45.1 i mmoi, 12.50 equiv) was added to the reaction. The resulting solution was heated to reflux for 24 h. The pH value of the soiution 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 1 x60 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 furnish 383 mg (70%) of 4-(dimethy3amino)-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-2- yi)- l H-pyrazoL5-yl]pyridin-3-yl]methanoi (5) (132 rag, 0.61 mmoi, 1.00 equiv). 4- (dimethylamino)-2,6-dihydroxybenzaldehydc (4) (1 10 mg. 0.61 mmoi, 1 .00 equiv), ΡΡ1¾ (207.3 mg, 0.79 mmoi, 1.30 equiv) in tetrahydrofuran (10 mL). DIAD (160 mg, 0.79 mmoi, 1.30 equiv) was added to the reaction dropwise drop ise at 0 L'C. The resulting soiution was stirred for 10 min at 0 °C and for an additional 2 h at room temperature. The reaction was then quenched with 10 mL of water. The resulting solution was extracted with 3x40 mL of ethy l acetate. The combined organic layers were washed with 3x20 mL of water and 1 x20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HP LC with the following conditions (Prep-HPLC-01 0):
Column, SunFire Prep C S OBD Column, 5urn, l 9* 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%) of 4-(dimethyiamino)-2-hydroxy-6-( [2- [ 1 -(propan-2-y f)- 1 H-pyrazol-5-y ]]pyridin-3 - yljmeihoxyjbenzaldehyde (GBT933) as a light yellow solid. -0057.1 134 Atty. Dkt. No.: 1 04592-0210
(82%) of [6-bromo-2- [ 1 -(propan-2 -yl)- 1 H-pyrazoi-5 -yl]pyridin-3-yl]methanol as a light yellow solid.
GBT933
Figure imgf000135_0001
[0329] GBT933 - 4-(dhnethylaraino)-2-hydroxy-6-((2-(l-isopropyI-lH-pyrazoi-S- yl)pyridin-3-yl)methoxy)benzaldehyde
10330] Step 1 : Into a 250-mL round-bottom flask, was placed a solution of 3,5- dimethoxyaniline (1 ) (4.6 g, 30.03 mmol, 1 .00 equiv) and potassium carbonate (14.6 g,
105.64 mmol, 4.00 equiv) in Ν,Ν-dimethylformamide (80 mL). This was followed by the addition of S02(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 temperature, and then it was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2x80 ml , of ethyi acetate. The combined organic layers were washed with 1 x50 mL of water and 1 x50 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 furnish 2.8 g ( 1%) 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-dimethoxy- 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 mmoi, 1.30 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 15 min at 0 °C, and then it was
4814-3854-0057.1 133 Dkt. No.: 104592-0210
HNMR (400MHz, CDCh,ppm): 12.45 (br s, IH), 9.87 (s, I H), 8.70 (d, J = 4.0 Hz, 1H), 7.96 (d, J ::: 7.2 Hz, IH), 7.58 (s, IH), 7.42-7.39 (m, I H), 6.32 (s, I H), 5.68 (s, 1H), 5.43 (s, IH), 4.94 (s, 2H), 4.58-4.51 (m, IH), 2.96 (s, 6H), 1.40 (d, 7= 6.8 Hz, I H); MS (ES,
/z-) 381.2 [M-2CF3COOH+I]
GBT953
Figure imgf000136_0001
[0335] GBT953 - (S)-2-hydroxy-6-((2-(l-isopropyl-lH-pyrazoi-5-yl)pyridin-3- yl)methoxy)henzaldehyde
[0336] Step 1 : into a 250-raL round-bottom flask, was placed a solution of methyl 3- hydroxybenzoate (3 g, 1 9.72 mmol, i .00 cquiv) 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 I QO-mL round-bottom flask, was placed a solution of methyl 2- formyl-3-bydroxybenzoate (400 mg, 2.22 mmol, 1.00 equiv) in CH3CN (30 mL), 3- (Chloromethyl)-2-[ l -(propan-2-yl)- l H-pyrazol-5-yl]pyridine (523 mg, 2.22 mmol, 1.00 equiv), potassium carbonate (927 mg, 6.71 mmol, 3.00 equiv), and KI (40 mg, 0.24 mmol, 0.10 equiv) were added to the reaction. The resulting solution was stirred for 2 h at 60UC, and then it was diluted with 200 ml of EA. The resulting mixture was washed with 2x 100 mL of brine, and then it was concentrated under vacuum. 'This provided 500 ng (59%) of methyl 2- formyl-3-({2-[l -^ropan-2-yl)-lH-pyrazoi-5-yljpyridin-3-yl]methoxy)benzoate as a yellow oil.
[0338] Step 3: into a 100-mL round-bottom flask, was placed a solution of methyl 2- formyl-3 -([ 2- [ 1 -(propan-2-yl)- 1 H-pyrazol-5-yl jpyridin-3-yl jmethoxy )benzoate (100 mg, 0.26 mmol, 1.00 equiv) in tetrahydrofuran (10 mL). This was followed by the addition of a solution of sodium hydroxide (22 rag, 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 temperature. The pH value of the solution was adjusted to 6 with hydrogen chloride (3 mol/L). The resulting solution
4814-3854-0057.1 1 35 Aity. Dkt. No.: 104592-0210 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-RPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C I 8 OBD Column. Sum, 19* 150mm,; mobile phase, water with 0.05%TFA and MeCN (30% MeCN up to 60% in 10 rain, up to 95% in 3 min, down to 30% in 2 rain); Detector, Waters2545 UvDector
254&220nm. This resulted in 30 n g (19%) of 2-fonnyl-3-([2-[l-(propan-2-yl)- l !-I-p razol-5- yl]pyridin -3-yl]methoxy)benzoie acid; bis(trifluoroacetic acid) as a white solid. ' l INMR
(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=8.1 Hz5 1H), 6.66((d, J=7.8Hz, IH) , 6.60 (s, IH), 5.18 (m, 2H), 4.70 (m, 1H), 1 ,35(m, 6H); MS (ES, m. ):366 [M+ l ]+
GBT963
Figure imgf000137_0001
btep Step 2
[0339] GBT963 - (S)-2-h droxy-6-((5-oxo-i-p enylpyrr«HdSn-2-
Step 1 : To a suspension of (1S)-5-(hydroxymethyl)pyrrolidin-2-one (230 nig, 2 mmol) and iodobenzene (0.49 g, 2.4 mmol) in Dioxane (4 mL) was added Cul (0.08 g, 0.4 mraol), N.N-dimethylethylenediamine (0.05 mL, 0.4 mmo!), 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^l 00:0 to 0: 100) to give (S')-5-(hydroxymethy!)-1 -phenylpyrroiidin-2-one (280 mg).
[0341] Step 2: To a solution of (S -5-(hydroxymethy!)-l-phenylpyrro3idin-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 PP1¾ (polymer supported, 650 mg, 0.78 mmol) and DiAD (0.16 mL, 0.78 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 preparative HPLC to give (S)-2-hydroxy-6-(( 5-oxo- l -phenylpyiTolidin-2-yi)methox>')benzaIdehyde (86 mg). 'H NMR (400 MHz, Chioroform-if) -0057. 136 , Dkt. No,: 104592-02 δ 11.91 (d,J = 0.4 Hz, IH), 9.93 (d,J = 0.6 Hz, 3H), 7.50-7.18 (rn, 6H), 6.53 (dt,J=8.5, 0.7 Hz, 111), 6.21 (dd, J= 8.3, 0.8 Hz, 1H), 4.70 - 4.59 (m, IH), 4.15 - 4.01 (m, 2H), 2.82 - 2.58 (m, 2H), 2.50 (ddt, J= 13.1, 9.9. S.3 Hz, IH), 2,16 (dddd, J= 13.6, 9.5, 5.1, 3.9 Hz, IH). MS found for C|gH)7N04: 312.3.
Figure imgf000138_0001
[0342] GBT998 - (S)-2-h droxy-6-((5-oxo-l-phenylpyrrolidin-2- yi)methoxy)benzaIdehydc
(0343] Step 1 : To a suspension of (S)-5-(hydrox.ymethyi)pyriOlidin-2-one (230 mg, 2 mmol) and 1 -iodo-2-methoxybenzene (0,56 g, 2.4 mmol) in Dioxane (4 ml.) was added Cul (0,08 g, 0,4 mmol), N,N-dimcthylethylenediamine (0.05 ml,, 0.4 mmol), K3P04 (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/F.tOAc=l00:0 to 0:100) to give (S)-5-(hydroxymethyl)- 1 -(2- methoxyphenyI)pyrrolidin-2-one (110 mg).
[0344] Step 2: To a solution of (S)-5-(hydroxymethyl)-l-phenylpyrrolidin-2-one (115 mg, 0,54 rnmol) and 2,6-dihydroxybenzaldehyde (0,10 g, 0.70 mmol) in THF (4 mL) at 0 °C was added PPh:, (polymer supported, 675 mg, 0.81 mmol) and DIAD (0.16 mL, 0.81 rnmol). 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-oxopyrTo]idin-2-yl)raethoxy)bcnzaldehyde (53 mg). l NMR (400 MHz, Chloroform-*/) 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, 3H), 2.75 2.55 (m, 2H), 2.48 (dddd. J~ 13.0,9.6,8.4,7.3 Hz, IH), 2.16 - 2.02 (rn, IH). MS found for Ο,.,ίΙΛΟ,: 342.3.
-0057.1 137 Atty. Dkt. No,: 104592-0230
Figure imgf000139_0001
δ (X = Boc)
J TF.Ai
G8T1004 - DC
Step 4
[0345] GBT1004 - 2-amino-4-((2-(l -isopropyl- 1 H-pyrazol-5-yl)pyridin-3-yl)methoxy) nicotinaldehyde
Step 1 : Into a 250-mL round-bottom flask, was placed a solution of 4-chloropyridin- 2-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 Boc20 (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 NH4C3. The resulting solution was extracted with 2x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x150 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-butyi N-(4-chloropyridin-2-yl)carbarnate as a white solid,
[0347] Step 2: Into a 100-mL three neck round-bottom flask, was placed a solution of tert- butyl 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-dimcthylformami de (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 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-3- formylpyridm-2-yl)carbamate as a yellow solid. -0057.1 Dkt. No. : 104592-02 10
[0348] Step 3 : Into a 100-mL round-bottom flask, was placed a solution of [2-[l -(propan-2- yl)- 1 H-pyrazol-5-yl]pyridin-3 -yI]methanol (500 mg, 2,30 mmol, 1 ,20 equiv) in NJSf- dimethylformamide (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 overnight at room temperature, and then it was quenched by the addition of 50 raL 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) H^yrazol-5-yl]pyridin-3- yl]methoxy)pyridin-2-yl]carbamate as a yellow oil.
[0349] Step 4: into a 100-mL round-bottom flask, was placed a solution of trifiuoroaceiic acid (10 mL) in dichloromethane (60 mL), tert-butyl N-[3-formyl-4-([2-[l-(propan-2-yl)-l H- p>Tazol-5-yl]pyridin-3-yl]methoxy)pyridin-2-yl]carbamate (500 mg, 1.14 mmol. 1.00 equiv). The resulting solution was stirred overnight at room temperature. 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 C 8 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)- l TI-pyrazol-5-yl]pyridin-3-yl]methoxy)pyridine-3-carbaldehyde as a yellow solid, 'HNMR (300MHz, OMSO, ppm): 10.1 2(s, 1 H), 8.79(m, 1 H), 8.24(m, 2H), 7.59(m, 2H), 6.76(d,
J-5.3 HZ, I H), 6.55(d, J=1 .2Hz, 1 H), 5.43(m,2H), 4.67(m, l H) , 1.36(m, 6H); MS (ES, m/z): 338 [M+l-3CF3COOH]+
Figure imgf000140_0001
5a (X = Boc>--i TF/V
GBT1006 '— 1 DC! !
Step 4
[0350] GBT1006 - 4-((2-{l -isopropyl- 1 H-pyrazol~5-yI)pyridin-3-yl)niethoxy)-2-
4814-3854-0057.1 139 Atty. Dkt. No.: 104592-0210
[0351 j Step 1 : Into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-(4- chloropyridin-2-yl)carbamate (3.0 g, 13.12 mmo!, 1 .00 equiv) in tetrahydro uran (50 mL ).
This was followed by the addition of sodium hydride (63 1 rag, 26.29 mmol, 1.20 equiv) at 0 °C. The mixture was stirred for 20 min at 0 °C. To this was added iodomeihane (2.24 g, 1 5.78 rnmol, 1 .20 equiv) dropwise with stirring. The resulting solution was stirred for 6 h at room temperature. 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-buty l N~(4~ cMoropyridin-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 tert- butyl N-(4-chloropyridin-2-yl)-N-methy!carbamate (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 rains 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 ( 12.M). 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 arid 1 x20 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-(methy!amino)pyridine-3-carbaldehyde as a yellow solid.
[0353] Steps 3 &4: Into a 100-mL round-bottom flask, was placed a solution of [2-[l- (propan-2-yl)-lH-pyrazol-5-y1]pyridirj-3-yl]rnethanol (1 .15 g, 5.29 mmol. 1 .00 equiv) in N,N-dimethylformamide (40 mL). This was followed by the addition of sodium hydride (530 trig, 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-(methyiamino)pyridine-3-carbaldehyde (900 mg, 5.28 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. 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 (Prep- i iPLC-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 nig (6%) of 2-
4814-3354-0057.1 1 40 Atty. Dkt. No,: 104592-0210
(methyIarmno)-4 [2-[l
Figure imgf000142_0001
carbaidehyde as a yellow solid. !HNMR (400MHz, DMSO, ppm): 8.72 (m, 1H), 8.17 is, I I I), 7.91 (m, lH), 7.52 (m, 3H), 6.56 (s, 1H), 6,26(d, J-4.2Hz, 1H), 6.15(d, J~3,3Hz, 1 H), 5.43 (m, l H), 5.12 (m,lH), 4.60 (m,lH), 2.87(d, J=3.3Hz, 1H), 1.46(d, ,/==5.1 Hz, 1H), 1.35(d, J=5.1 Hz, 1H); (ES, /w z):352.1 [M+l f
Figure imgf000142_0002
)354] GBT1007- 2-(4-(hydroxymethyI)-l,3-dioxolan-2-yl)-3-((2-(l-isopropyi-lH- -5-yl)pyridin-3~yI)methoxy)phenoi
Figure imgf000142_0003
[0355] 2-Hydroxy-6-((2-( 1 -isopropyl- 1 H-pyrazol-5-yl)pyridin-3-yl)raethoxy)benzaldehyde (0.4 g, 1.19 mraol) was dissolved in a solution of propane- 1, 2,3 -trioi (5.8 ml, 79 mmol) and DMF (5 ml). Amberlysi 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 were washed with water (50 ml) and a saturated aqueous sodium chloride solution (50 ml), and dried over sodium sulfate. After evaporation, the residue was puri fied by silica gei chromatography (0 - 90% ethyl acetate/dichloromethane) to give 0.1 38 g (24%) of 2-(4- (hydroxyraethyl)- 1 ,3 -dioxolan-2-yl)-3 -((2-( 1 -isopropyl- 1 H-pyrazol-5-yl)pyridin-3- yl)rnethoxy)phenol as an off-white solid after iyophilization from acetonitrile/water. Ή NM (400 MHz, CDC13) δ 8.74 - 8.67 (rn, 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 (rn, 1 H), 7.44 - 7.34 (m, 1 H), 7.1 7 - 7.07 (m, 1 H), 6.55 (d, ./ = 8.47 Hz, 1H), 6.42 - 6.36 (ra, 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, 1 H), 3.99 - 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 ! j \
4814-3854-0057.1 141 . Dkt, No.: 104592-021
GBT1090
Figure imgf000143_0001
[0356| GBT1090 - (S)-2-((l-ben3E l-5-oxopyrrolidin-2-yl)inethoxy)-6-
Step 1 : To a solution of (S)-methyl 5-oxopyrrolidine-2-carboxylate (700 rng, 4,89 ramol) in DMF (5 mL) was added Cs2C03 (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 (1M in THF, lmL, Immol) at room temperature. After stirred at room temperature for 1 h, the solution was quenched with Sat. NI 14C1, 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)-'i -benzyl-5- (hydroxymethyl)pyrroUdin-2-one (170 mg).
[0358] Step 2; To a solution of (S)-l-bcnzyl-5-(hydroxymethy3)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 temperature 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 preparative HPLC to give (S)-2-((l -benzyl-5-oxopyrrolidin-2-yl)methoxy)-6- hydroxybenza!dehyde (95 mg). Ή NM (400 MHz, Chloroform-^ δ 1 3 .93 (t, ./ « 0.4 Hz, 1 H), 10.17 0, J- 0.5 Hz, 1H), 7.39 - 7.29 (m, 1H), 7.29 - 7.18 (m, 5H), 6.54 (dL J~ 8.5, 0.7 Hz, 1 H), 6.17 (dd, J = 8.3, 0.9 Hz, 1 H), 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 {id, J - 7.8, 7.2, 3.6 Hz, I H), 2.68 - 2.45 (m, 2H), 2.33 - 2.19 (m, I H), 2.30 - 1 .96 (m, 1H). MS (M+H) found for C ,Η,ΝΟ ,: 326.4.
: 4-3854-0057.1 142 Attv. Dkt. No.: 104592-02 ! 0
Figure imgf000144_0001
[0359] GBT.1093 - (5)-2-hydroxy~6-((5-oxo-4-phenylmorpholin-3-
Step 1 : To a solution of (5 benzyl 2-amino-3-hydroxypropanoate hydrochloride (5 g, 21.58 mmol) in THF-water (1/1. 80 mL) was added K2C03 (8.95 g, 64.74 mmol) and chloroacetyl chloride (2.92 mL, 36.69 mmol). After stirred for 1 h, it was di luted with
EtOAc, organic layer was washed with water, brine, dried and concentrated to give benzyl (2- chioroacctyi)-L-scrinatc (5 g).
[03613 Step 2: A solution of (S)-benzyi 2-(2-chloroacetamido)-3-hydroxypropanoate (2.55 g, 9.39 mmol) in iPrOH (20 mL) was added to OtBu (3.16 g, 28.17 mmol) in iPrOH (15 mL) at room temperature. After stirred at room temperature for 1 h, the mixture was
quenched with 6N HQ (10 mL) at 0 °C, extracted with EtOAc, organic layers were
combined, washed with brine, dried and concentrated to give isopropyi (2-chloroacetyl)-L- serinate as crude product.
[0362] Step 3 : To a solution of (S -benzyi 5-oxomorpholine-3-carboxylate in EtOH (7 mL) was added NaBH4 (150 mg) at 0 °C, after stirred at room temperature for 3 h, it was
quenched with NH4CI (220 rag in 0,6 mL water), and the insoluble material was filtered off, the filtrate was concentrated and was purified by column (DCM/MeOH=I 00:0 to 80:20) to give (R)-5-(hydroxymethyl)morpholin-3-one (100 mg).
[0363] Step 4: To a suspension of (ii)-5-(hydroxymeihyl)morpholin-3-one (100 mg, 2 mmol) and 3-iodopyridinc (0.57 g, 2.8 mmol) in Dioxane (4 mL) was added Cui (0.08 g, 0.4 mmol), N,N-dirnethylethylenediamine (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
4814-3854-0057.1 143 Atty. Dkt, No.: 10 592-0210
(Hexanes/EtOAc=100:0 to 0: 100) to give (S)-5-(hydroxymethyl)- 1 -(pyridin-3-yl)pyrrolidin- 2-one (55 mg).
|0364] Step 5: To a solution of (S)-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 D1AD (0.09 mL, 0.44 mmol) at 0 °C. Then it was warmed up to room temperature and stirred for 1 h, AcCN was added to diiutc the mixture, the insoluble material was filtered off, the filtrate was concentrated and was purified by preparative HPLC to give (8)~2~1ι\^ΐΌΧ}'-6-((5-οχο-4-ρ1ιεη Γ1ΐΉθ 1ιο1ίη-3- yl)methoxy)benzaldehyde (29 mg). Ή NMR (400 MHz, CWoroforn ) 5 1 1 .88 (d, J- 0.4 Hz, 1 H), 9.94 (d, ./ 0.6 Hz, 1 H), 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, 1 H), 6.20 (dd, J— 8.3, 0,8 Hz, 1 H), 4.47 (dd. J = 16.9, 0.9 Hz, 1H), 4.40 - 4.25 (m, 3H), 4.25 - 4.16 (m, 1 H), 4.15 - 4.07 (m, 2H). MS (M+H) found for
Ci 8H17N05: 328.3.
Figure imgf000145_0001
Figure imgf000145_0002
[0365] GBTI 123- tert-butyl (2-formyl-3-((2-(i-isopropyl-lH-pyrazol-S-yl)pyridin-3- y )methoxy)phenyl)carban!iatc
[0366] Step 3 : tert-Bulyl (3-raeihoxyphenyl)carbamate (0.51 7 g, 2.3 mmol) was dissolved in dry diethyl ether (32 ml) and cooled to -40 °C in a solvent bath. /-Butyl lithium (4.1 ml of a 1.7 M pentane solution, 6.95 mmol) was added dropwsse, the reaction was ailowed to warm to -20 °C and stirred for 2 h more. The reaction was cooled to— 78 °C, DMF (0.54 mi, 6.95
4814-3854-0057 144 . Dkt. No.: 104592-0210 mraol) 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. T he reaction was extracted with ethyl acetate (3 x 80 ml), the combined organic- phases were washed with a saturated aqueous sodium chloride solution (50 nil) and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (0 - 30% ethyl acetate/hexanes) to give 0.46 g (79%) of /er/-butyl (2-fonnyl-3- methoxyphenyl)carbamate as a lightly-colored solid. MS (ESI) m/z 252 [M+H]+.
10367] Step 2: terf-Butyl (2-formyl-3-methoxyphenyl)carbamate (0.38 g, 1.5 rnmol) was dissolved in dichlorornethane (10 nil) and added dropwise to a solution of aluminum chloride (1 g, 7.56 rnmol) in dichlorornethane (15 mi) 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 dichlorornethane (3 x 50 ml), the combined organic phases were washed with water (30 ml) and a saturated aqueous sodium chloride solution (30 ml), and dried over sodium sulfate. After evaporation 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 rnmol) was dissolved in THE (4 ml). Di-rerZ-butyldicarbonate (0.726 g, 3.3 mmol) and 4-dimethyiaminopyridine (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 tert-butyl (2-formyl-3-hydroxyphenyl)carbamate. MS (ESI) m/z 238
[M+H]+.
[0369] Step 4: tert-Buty] (2-formyl-3 -hydroxyphenyl)carbamate (50 mg, 0.21 mmol) and 3- (chloromethyl)-2-( 1 -isopropyl- 1 H-pyrazol-5 -yl)pyridin- 1 -iura chloride (57 mg, 0.21 mmol) were dissolved in DMF (3 ml). The solution was purged with Ar gas. Potassium carbonate ( 1 16 mg 0.84 mmol) was added and the reaction mixture was stirred in a 60 '"'C heat block tor 18 h. The reaction was cooled and water (50 ml) and ethyl acetate (50 mi) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 mi).
The combined organic phases were washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation the residue was purified by silica gel chromatography (5 - 50% ethyl acetate/hexanes) to give 5 mg (5%) of tert-buty] (2- formyl-3-((2-(l -isopropyl-l H-pyrazol-5-yl)pyridin-3'yl)methoxy)phenyl)earbamate as a white solid after lyophilization from acetonitrile/water. !H NMR (400 MHz, CDC13) 6 10.51 (s, 1 H), 8.74 (d, J = 4.81 Hz, l !T), 8.06 (d, J = 7.84 Hz, 1 H), 7.60 is, 1H), 7.48 (t, J = 8.22 -0057.1 145 Dkt. No.: 104592-0210
Hz, 1H), 7,44 - 7.39 (ra, 1H), 6.91 - 6.81 (m, 2H), 6.36 (s, 1H), 5.10 (s, 2H), 4.64 (d, J = 6.51 Hz, 1H), 1.47 (d, J = 4.57 Hz, 6H), 1.41 (s, 9H). MS (ESI) m/z 437 r\ f H i .
GBTU31
Figure imgf000147_0001
[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 SOCl2 (0.61 ml ., 8.39 mmol). After stirred at room temperature for 3 h, it was concentrated to remove all solvents, dried under high vacuum to give corresponding ethyl ester. The ester was dissolved in EtOH (15 mL) and was added NaBEU (300 mg) at 0 °C, the mixture was warmed up to room temperature and stirred for additional 15 h. The mixture was quenched with Sat. NH4C1, filtered off the insolubles and the filtrate was concentrated to gi e 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 (5 -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 (Na2S04) and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=l 00:0 to 0:100) to give (S)-6- (hydroxymeihyi)- 1 -phenylpiperidin-2-one (85 mg).
[0373] Step 3 : To a solution of (S)-6-(hydroxymethyl)- 1 ~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 DIAD (0.13 mL, 0.66 mmol) at 0 ° .
After warmed to room temperature and further stirred for 2 b, it was diluted with AcCN, the insoluble materia] was filtered off and the filtrate was concentrated and subjected to
preparative HPLC to give (S)-2-hydroxy-6-((6-oxo- 1 -phen lpiperidin-2- yl)methoxy)bcnzaldehyde (31 mg). Ή NMR (400 MHz, Chloroform-^) 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, 211), 7.22 - 7.14 (m, -0057.1 146 Atty. Dkt. No.: 1 04592-02
2H), 6.60 - 6.43 (m, 1H), 6.11 (dd, J= 8.3, 0.8 Hz, I H), 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 Ci 9Hi9N04:
326.5.
GBT001717
Figure imgf000148_0001
6-({2-( 1 -isopropyl-1 H-pyrazol-5-y!)pyridin-3-yl)methoxy)- 2,3-dimethoxybenzaidehyde
[0374] GBT1717- 6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yI)methoxy)-2,3- dimethoxybenzaldehyde. The compound was prepared by O-alkylation of 6-hydroxy-2,3- dirnetboxybenzaldehyde (A) and 3-(chloromeihyl)-2-[ l-(propan-2-yl)- lH-pyrazol-5~ yfjpyridine hydrochloride salt (INT-2) according to scheme 9, reaction step 4. The product as white solid was obtained after flash column purification. Ή NMR (400 MHz, Chloroform-rf) δ 10.49 (t, J = 0.4 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, IH), 8.29 (ddd, J= 8.0, 1.7, 0.9 Hz, 1 H), 7.61 (dd, J = 1.9, 0.5 Hz, I H), 7.44 (dd, J === 7.9, 4.8 Hz, I H), 7.03 (d, .7= 9.0 Hz, 1 H), 6.52 (d, J ~ 7.9 Hz, IH), 6.36 (dd, J - 1.9, 0.4 Hz, I H), 4.98 (s, 2H), 4.59 (hept, J= 6.7 Hz, 1H), 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 C2iH23N304. 382.5.
Figure imgf000148_0002
Preparation of intermediate A
-0057.1 147 Atty. Dkt. No. : 104592-021 0
Figure imgf000149_0001
15) Step 1 : To a suspension of 3 ,4-dimethoxyphenoi (2,0 g, 1 2.97 mraol) in
dihydropyran (2 mL. 21.87 mmoi) at ambient temperature was added 1 drop of Cone. HCI. After stirred for 1 h, the solution was diluted with EtOAc, organic layer was washed with Sat. NaHC03, brine, dried and concentrated io 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 3 .5 h at 0 °C, it was added DMF (1 .3 mL), After stirred for 1 h, the mixture was added 6N HCI (4 mL), and was stirred tor 1 h at ambient temperature, additional 12N HCI (2 mL) was added to drive the reaction to completion. The 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
chromatograph to give 6-hydroxy-2.3-dimethoxybenzaldehyde (490 mg).
GBT0016S9
Figure imgf000149_0002
2,3-dihydroxy-6-((2-( 1 -isopropy!-1 H-pv^zot-5-yl}pynd',n-3-vl)(xi thOKv) enzaldehv<ie
[0377] GBT1659- 2,3-dihydroxy-6-((2-(l-isopropyl-lH-pyrazoI-5-y in~3~
yl)methoxy)henzaIdehyde.
4814-3854-0057. S 48 . Dkt. No,: 104592-0210
Figure imgf000150_0001
[0378] To a solution of 6-{{2-( l -isopropyl-3H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2,3- dimeihoxybenzaldehyde (24 mg, 0.05 mraol) was added BBrj (1M, 0.5 mL), after stirred at ambient temperature for 30 min, the mixture was concentrated and the crude product was purified by preparative HPLC to give 2,3-dihydroxy-6-((2-( 1 -isopropyl - 1 H-pyrazol-5- yi)pyridin-3-yl)rnethoxy)benzaidehyde (10 mg). !H NMR (400 MHz, Chloroform-^) δ 12,01 (s, ilit 10.32 id../- - 0.5 Hz, 1 Hi.8.74 (dd, J- 4.8, 1.7 Hz, 1H), 8.00 - 7.92 (m, 111), 7.60 (dd, J = 1.9, 0.6 Hz, 1 H), 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, !H), 6.19 (d,J= 8.8 Hz, 1H), 5.29 (s, 1H), 5.02 (s, 21 i), 4.64 (hept, .7=6.6 Hz, 1H), 1.47 (d, J= 6.6 Hz, 6H). MS (M+H) found for 1';.·! f ! X= ..354.4.
Figure imgf000150_0002
2-hydrox ^-((2-{14sopropyl-1H-pyrazo!-5-y!)pyridin-3-yi)me1r!Oxy)-3-methoxybenzaidehyd.
[0379] GBT1718- 2-hydroxy-6-(2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3- y)iiiet oxy)-3-raeih xyb njaIdeIi de
Figure imgf000150_0003
S14-3SS4-0057.1 149 Dkt. No.: 104592-0210
[0380] To a solution of 6-((2-(l -isopropyl-1 H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2,3- dimethoxybenzaidehyde (50.00 mg; 0.13 mmol) in DCM (0.8 niL) at ambient temperature was added boron tribromide (0.13 ml; 1.00 moi/1). After stirred for 5 min, the red mixture was concentrated and the crude product was purified by preparative HPLC to give 2- hydroxy-6-((2-(l-isopropyl-lH^yrazol-5-yl)pyridin-3-yl)methoxy)-3-methoxybenzaldehyde (15 mg). Ή NMR (400 MHz, Chloroforrn-if) δ 12.15 id../ 0.6 Hz, 1H), 10.35 (s, 3H), 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=7.9s4.8Hz, 1H), 6.98 - 6.94 (m, 11!).6.34 (d, J= 1.9 Hz, 1H), 6.18 (d,J= 8.9 Hz, 1H), 5.02 (s, 2H)S 4.72 - 4.57 (m, 1H), 3.84 (s, 3H), 1.47 (d,J = 6.61 Iz, 6H). MS (M+H) found for C20H21N3O4: 368.4.
GBT001723
Figure imgf000151_0001
[0381] GBT001723 - 2~((6-((2-(dimethylamino)ethyl)(methyl)amino)-2-(l -isopropyl- lH-pyrazol-5-yl)pyridra-3-yl)methoxy)-6-hydroxybenzaldehyde. The compound was prepared by Mitsunobu coupling of (6-((2-(dimetbylammo)ethyl)(methyi)arnino)-2-(l - isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol (A) with 2,6-dihydroxybenzaldehyde (INT- 3) according to scheme 9, reaction step 3. The product as green oil was obtained after flash column purification. !HNMR (400MHz, COC , ppm): 11.87 (br s, 1H), 10.21 (s, 1H), 7.54(d, J= 8.8 Hz, 1H), 7.44 (3, 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, 211), 4.90-4.60 (m, 1H), 3.61 (t,J- 11.2 Hz, 2H), 3.03 (s, 3H), 2.43 (t,J=11.2 Hz, 2H), 2.20 (s, 6H), 1.39 (d,J- 6.8 Hz, 6H); MS(ES, m/z:) 438.4 [M+l]4"
4814-3854-0057. 1 0 Atty. Dkt. No. : 104592-0210
Figure imgf000152_0001
[0383] Step 1 : Into a 25-mL round-bottom flask, was placed a solution of methyl 6-bromo- 2-[ 1 -(propan-2-yJ)- 1 H-pyrazol-5-yi]pyridine-3-carboxyiate (1.3 g, 4.01 mmol, 1.00 equiv) in tetrahydrofuran (15 mL). DIPEA (1.55 g, 3.00 equiv) and [2-
(dimethyiamino)ethyl](methyl)aniine (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 rnL 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/rnethanol (30: 1-15: 1 ) as eluent to furnish 1 .22 g (88%) of methyl 6-[i2-(dimcthylamino)ethyl](methyl)amino]-2-[ i-(propan-2- yl)-lH-pyrazoi-5-yl]pyridine-3-carboxylate as a light yellow oil.
Step2. into a 1 00-mL round-bottom flask, was placed a solution of methyl 6-[[2- (djmethylamino)ethyl](methyl)arainoJ-2-[l -(propan-2-y!)-lH-pyrazol-5-yl]pyridinc-3- carboxylate (1.2 g, 3.47 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by j.!.„ . .i ®r>
JC UUU UIOIl ui
Figure imgf000152_0002
i iic i raum ug
solution was stirred for 4 h at room temperature. 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 ethv! acetate. The solids were filtered out and washed with THF for 3 limes. -O057.1 15 1 Atty. Dkt. No.: 104592-0210
The resulting mixture was concentrated under vacuum. This resulted in 1 , 1 g ( 100%) of (6- [ f 2-(dimethylarnino)ethyl](methy])amino]-2-f 1 -(propan-2-yl)- 1 H-pyrazol-5-yl ]pyridin-3- y!)methanol as a colorless oil.
[Θ384] From the foregoing it will be appreciated that, although specific embodiraents of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention.
[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.
|0256J As used herein. Table 1 includes compounds described below or tautoniers or pharmaceutically acceptable salts thereof:
2 imidaa.o[ 1 ,2-a]pyridin-8-ylmetl >xy 5-mettoxyben3i lde >¾lef
2 imidazol 1 ^-aJpyridin-a-yJmethoxy^S-methoxybcnzaldehyde,
-0057.1 152 Arty, Dirt. No.: 104592-021 0
2-(imidazo[ 1 ,5-a pyridin'8-y lmethoxy)-5-meilmybeRza1 idiydc, 5 -methoxy-2-(quinoi in- 5 -ylmethoxy)benzafdehyde , 5-methoxy*2-<( I -raethyl-1 H-tndazoi-^-y^-netho j beRZ-sldehyde, 5-meihoxy-2~((8-methyHmidazo^ 2'((lH-indaEol-4-yi)methoxy)-5-raethox>^e∞aWehy<te, 5-methoxy-2-(pyridtn-3-ybnethoxy)ben2ald«hyde>
2.((2'(l-i^propyi-lH-pyra2ol-5-yi)pyridjn-3-yl)meihoxy)-5-met oxybenz3idehyde, 2-hydroxy-6-({2~( 1 -isopropy!- ί H-pyrazol-5-y!)pyridin-3-yI)methoxy)bcnzaldehyde,
2-((4.(2H-teirazGi-5«yl)be»;^ methyl 4-((2-f iwiylphenoxy)raet yl)ben2oate,
4»((2-foroi}'iphenoxy)HiCt yf) eozoic acid, methyl 3-((,2-forroyIphen xy)methyi)benzoate,
2-bj omO"3-(i2'( l -isopropyi- i H-pyrazo!-5-yI)pyridin
2-liydroxy-6-((2-( I -(2,2,2-trifluoroethyl)- 1 H'pyiazol-5-yI)pyridin-3- y l)iB©thoxy)benzaldehydes
2-hydroxy-6~i(2--( l -(3,3 3~trifluotx;propyi ! H-pyrazol-5-y])pyridm-3«
yl)oiethoxy)benzalde hyde,
2-fluoro-6-((2~( 1 -(2,2,2-trifluoroethy! - 1 H-pyrazol-S^y pyridin^-y!^tiethoxy^benzafdehydsif,
2-fiuofO-6~((2-( 1 -(3,3,3·- tsiflitoropropyi}- 1 H-pyrazoi-5*yl)pyridin-3- yl)methoxy)beazaidehydc,
2-fluo!'o-6-((2-( 1 -isopropyl- 1 H-pyra2oI-5»yl)p>^din-3-yl)tnethoxy)beozaIdehyde, and l -(2'formyl-3-hydToxypJien thyl)piperidiTO-4^ftrbox.yiic acid, or a tautomer or
pharmaceutically acceptable salt thereof. Attv. Dki, No,: 104592-02
Figure imgf000155_0001
Αίΐγ, Dkt.No.: 104592-0210
Figure imgf000156_0001
Atty. Dki. No.: 104592-0210
Figure imgf000157_0001
14022789
Dkt. No.: 104592-0210
Figure imgf000158_0002
Figure imgf000158_0001
4314-3854-00571 1 ^7 Atty. Dkt. No.: 104592-0210
Figure imgf000159_0001
Atty. Dkt. No.: 104592-0210
Figure imgf000160_0001
Atty. Dkt. No,: 104592-0210
Figure imgf000161_0001
4814-3854-0057.1 Ally. Dkt. No.: 104592-0210
Figure imgf000162_0001
7. Arty. Dkt. No.: 104592-0210
Figure imgf000163_0001
Atty. Dkt. No.: 104592-0210
Figure imgf000164_0001
Attv. Dkt. No.: 104592-0210
Figure imgf000165_0001
4022789
Atty. Dkt. No.; 104592-0210
Figure imgf000166_0002
Figure imgf000166_0001
4022789
Atty. Dkt. No.: 104592-0210
Figure imgf000167_0001
Atty. Dkt. No.: 104592-0210
Figure imgf000168_0001
4814-3854-00571 167 Atty.Dkt. No.: 104592-0210
Figure imgf000169_0001
U2014/022789
Atty. Dkt.No.: 104592-0210
Figure imgf000170_0001
Atty. Dkt. No.: 104592-0210
Figure imgf000171_0001
4814-3854-0057.1 170 Atty. Dkt.No.: 104592-0210
Figure imgf000172_0001
Figure imgf000172_0002
Ally. Dkt. No.: 104592-0210
Figure imgf000173_0001
057.1 . Dkt. No,: 104592-0210
Figure imgf000174_0001
Atty. Dki. No.: 104592-0210
Figure imgf000175_0001
4814-3854-00571 174 Atty. Dkt. No.: 104592-0210
Figure imgf000176_0001
Ally. Dkt. No.: 104592.-0210
Figure imgf000177_0001
Atty. Dkt, No,: 104592-0210
Figure imgf000178_0001
0057.1 377 Arty. Dkt. No.: 104592-0230
Figure imgf000179_0001
. Dkt. No.: 104592-0210
Figure imgf000180_0001
Figure imgf000180_0002
7.1 Atty. Dkt.No.: 104592-0210
Figure imgf000181_0001
4314-3854-0067.1 180 Atty. Dkt No,: 104592-0210
Figure imgf000182_0001
,1 Atty. Dkt. No.: 104592-0210
Figure imgf000183_0001
Atty. Dkt, No.: 104592-0210
Figure imgf000184_0001
.1 Atty. Dkt. No.: 104592-0210
Figure imgf000185_0001
Atty. Dkt. No.: 104592-0210
Figure imgf000186_0001
:4-3854-0057.1 185 Atty. Dkt.No.: 104592-0210
Figure imgf000187_0001
Atty. Dki. No.: 104592-0210
Figure imgf000188_0001
57.1 Dkl.No.: 104592-0210
Figure imgf000189_0001
481 -3S54-0057.1 188 Atty. Dkt. No,: 104592-0210
Figure imgf000190_0001
Atty. Dkt. No.: 104592-0210
Figure imgf000191_0001
Ally. Dkt. No.: 104592-0210
Figure imgf000192_0001
7.1 Atty. Dkt. No.: 104592-0210
Figure imgf000193_0001
.1 . Dkt. No.: 104592-0210
Figure imgf000194_0001
4814-3854-0057.1 193 Atty. Dkt. No.: 104592-0210
Figure imgf000195_0001
.94 Atty. Dkt, No.: 104592-0210
Figure imgf000196_0001
.1 Dkt. No.: 104592-0210
Figure imgf000197_0001
4814-3S54-0Q57.1 196 Atty. Dkt. No,: 104592-0210
Figure imgf000198_0001
Atty. Dkt. No.: 104592
Figure imgf000199_0001
Attv. Dkt. No.: 104592-0210
Figure imgf000200_0001
Atty. Dkt, No.: 104592-02
Figure imgf000201_0001
057.1 200 Atty. Dkt. No.: 104592-0210
Figure imgf000202_0001
057.1 201 Atty. Dkt. No.: 104592-0210
Figure imgf000203_0001
.1 Atty. Dkt. No.: 104592-0210
Figure imgf000204_0001
Figure imgf000204_0002
Aity. Dkt. No.: 104592-0210
Figure imgf000205_0001
Dkt. No.: 104592-0210
Figure imgf000206_0001
7.1 2.05 Atty. Dkt. No. : 104592-0210
Figure imgf000207_0001
4814-3854-0057.1 Atty. Dkt. No.: 104592-0210
Figure imgf000208_0001
4814-3854-0057.1 207 Atty. Dkt. No.: 104592-0210
Figure imgf000209_0001
Atty. Dkt. No,: 104592-0210
Figure imgf000210_0001
The compound is selected from 5-faydroxy-2-{2- e!hoxycihoxy)isonicotittaidehyde (Compound 218), 5-hydroxy-2-(2- ffi^thoxyethoxy)nic»tisaldehyde (Compound 2 I 9), 5-({2-{ 1 -i soprapyl H~pyma]-5-yl)pyridin- 3-yl)methoxy)-2-ox0»l ,2-<!ihydropyridine-4-carba3dc¾yds (Compound 220).5-(i2-( -nicihyl- 1 H-pyr3zoi"5-yl)pyridin~3-yi ^^ (Compound 221), or & tautomer or phantna cutically acceptable salt thereof
5-(im3dazaiI
Figure imgf000210_0002
2-rrteihoxy-5n((S'-niethyipyridiiv3-yl)metliox
5 -(i scMju itiolin-t -yl nethoxy }-2-nieihoxy ison icotiiiaidehy de .
2-methoxy-5-(q«iDojin-2-yIfKeihoxy}isoBkotinaldc!iyde,
2- meihox ridiii-4- lm^^
3- (imidazo[ !,2-a]pyiidin-8-y!racihoxy)-6-rnethytpicoliaaI<ichydc,
methyl 2-({4^foj^W-me¾oxypyridin-3'yloxy)me»byl)irojdaw| 1 ,2-a]pytidrae arboxyliUe,
2 melh xy-5"((3'-inelhyl' 1,2,4]triaz.ole[4,3-3]pyridk
5H'{2-broQi pyridin-3*yi}methoxy}-2-methoxyisonico
5-{{2«ClH-pyra:«i~5-yl}pyr
Figure imgf000210_0003
2'inethoxy.5- {5-( 1 -iBcrtryl - 1 H-pyrazol-5-yl)pyridin«3-^^^
5 ^( 'form l^n«rt o p^ acid,
Figure imgf000210_0004
0057.1 209 Atty. Dkt. No.: 104592-0210
2- mcthoxy-HO -methyl-l H nd^l^yi)met^xy)isonicotinaMehyde>
iert-butyl 4-({2-forinyS-6-methylpyridin-3-yl xy )metyl) H-mdaxoIe- I-c-arboxyiaie,
6-mcthyi-3-(ii«methyl H-inda2o3-0-yl ^^
6-metliy!-3-((l-iTiethyi. ί H.-inda¾;ol-7-yi3roCiIioxy)picoiinaidehydeJ
3- {isoqttim>Jin-l -ylme&K>xy)-6-meihylpicoliBakl©hyde,
5- (beTOo[d]Gxazol~4-yimethoxy 2-:^
Figure imgf000211_0001
6- methyi-3-{(J-meihyUl .H-iridaz l-5-yI)metho y)pECo!!naidehyd«,
6-mcihy! »{q«moUa-5-ylmedjoxy)picolii»aliehyde,
2-methoxy-5-({2-(l-methyi-S H'-pyt^ol-5-yl}pyridin-3-yI)methoxy)isonicotms3idehyde,
Figure imgf000211_0002
5 ~((2-{2H-tetrazei-5-yl)pyridin - -yl)met ox.y)-2 -methoxysonscoijiisaldehyde,
2-naethoKy-5 -{{2-(4-methy 3- 11 l-pyrazoi- 5 - yl )pyn di n-3 -y l)meSf ioxy)isonicoli.nald hyde,
5 (MlHi»yrazol-5- l)isoq<^
Figure imgf000211_0003
5--{imida 0i 1 , 5-a jpyr i d m~S - tae!ho^
5 ~{( ~( K5 -d i methy M H-py f > I -4 -yl)pyrid.in-3 -y I )methoxy)-2-m«ihaxyisonicoiinaldehyde>
5~({2-il~eihyi-IH-pyraz0l-5-y^
5-('(2~( 1 -tsopropyl- 1 E-pyrazol-5-yl )pwidm-3-yI)raeihoxy)-2-ms 30xyts nicoti.iiaidc yde,
2 -(di 'fhioromethoxy)- 5 -( Ί mida¾o[ 1 ,2-a ] pyridin- 8 -y Sir ttHhoxy)isonicotinatdehydc,
2- ffi thoxy (2-phenyipyrIdiEi-3-yl)msih0xy)
5 -((3 -( 1 -isopropyl - ί H-pyras:ol-5-y i)pyridm-4-yl)fflet oxy)-2-fnethoxyisonicoliiialdehyde,
5-([2,3'-bipyridin|-3-yimcthoxy 2-methoxyi.s^^
2'-rBet osy-5-<(2~(o-toyl)pyndi«-3-yl)mei oxy)isoni
2«meax)x -5-((2'-mep½ ^
Figure imgf000211_0004
4- ({(2-¾ffnylpyridi«-3-y!}oxy)msi yl)laRZolc acid,
methyl 3-(({4-fomTylpyTidiii-3-yl)oxy)rneliiyi)b«nxiac,
methyl 3 ((2-foro l-6Hneihyi^^
3^((44i^yl^yn^ ^'yi) xy)m^ f mmic acid,
3- <{(2-fOTOyl^metbylpyndto-3-yl)oxy)me l)ben2oic acid,
057.1 210 Atty. Dkt. No.: 10459
3-({(2-&rniy[pyrid!n-3-yi)osy):ncthyi)benzo:C acid,
2-iM«ihoxy~5-({2-i 1 -(2-methoxyethyi)- 1 H-pyrasx)i-5-yi)pyridifv-3- yl)njeihoxy)isonicoiiniiiclehyde,
2-rnethoxy-5-((2-( I -propyl-! H-pyrazoi-S-y pyridin-S-ylJmethoxy^sanicQiBaidchyde,
2-!nethoxy -((2-(I -(2,2,2-irifluorocthyl)- 1 H-pyraz !-5-yl)pyridia-3- vdJmsthos jiaHsitotiiaidc!iyde,
Figure imgf000212_0001
nsethoxyisoBicoiinalddiyde,
3 -({ 2 -(l-isopropyl- 1 H-pyrazol-5-yl)pyridin- 3 -yl)nwthoxy)picolinaWchydc,
-i(2-f 1 -isopropyl- 11 ί -pyrazol- 5-yl)pyridin-3 -yl^ethoxyJ-^-mcibylpicoiinaidkihydc,
2^difluoromet oxy)-5-{(2<l sop«>pyl-IH-pyfazol-5-y{)pyTidin-3- yi}methoxy)isoiHCotir»¾idebyde,
S-CimidazoU
Figure imgf000212_0002
5-{{2-(] -isopropyl- ! H- yrazol-5-y!)pyridiB-3-yl)raeilioxy)-2-{2- methoxyei¾ijxy isi>aicoits¾ak!ehyde,
5 (3-(1 sopro UlH- yi^ol-5*>¾p ^^
3 -((4-formyl -6-meth oxypynds n-3-y!osy)oiet: yi )pk*oiioaie,
SHp-^-hydrox ro ar^- ^
2-(2-mgtiioxyethoxy)-5-{{2-(l-m thy]-1 H-pyrazol-5-yi)pyridii!-3- y])ractf¾oxy)isonicoTinaidehyde,
2- (2-rneihoxvethoxy)-5-ii2-{j -methyl- 1 H-pyfa2ol-5->1)pyrid-in-3-y))itwthoxy)iiico1.irialdehydc,
3 iydrc¾y.5 (2HHsopr©py
3- (bni'yloxy)-5-hydroxylsctRicotinaideliyde,
3-((:2 -( 1 -isopropyl- 1 H-pyraaei -S-y!)pyridtn -3 -yI)niethoxy)- 5 -meihoxyi sonicotiaaldehydc,
5^{2-(2 ^ro yl~2IW,2Au az»W-y^
5-({2.-(l -is propyl-4-mei y] - 111-p>nra2oi-5-yl)pyndm-3-yl)metJ )xy)-2- mettioxyisonicotina!dehytlc,
5-(2-{iH2 iydroxyi0i l)--u^
(C^f°^ ^^^3- l)ox )m«thyi^icollntc acid,
Figure imgf000212_0003
2-meaioxy-5-((2HK(2-<traneth>½il^ 3 H-pyrazol-S-yiipyridiB-S- yl)raethoxy)is nicotinald*hyde,
057.1 211 Atty, Dkt. No.: 104592-0210
Figure imgf000213_0001
earbaldehyde,
!Hi2-(i-i^ilo u.t ]~lH~ yrazoi-5^ methoxyso eotinajdehyde,
5 - ((2--( 1 -cy clohexy I- S H-pyrazoi-S -yl)pyxid .in-3-y 1 )m«i-oxy)-2-n¾cihosyisonicoiiitalclehyde:t
Figure imgf000213_0002
met hoxy mm cot j naldehy de>
5- i(2-(i-ey iopeni MH~^
acid,
Figure imgf000213_0003
y ropanoate,
3 - {3 -(3 -{(4-formy! -6-niethoxypyTk!iti- 3 -y loxy)m€ih>1}pynd5n-2-yl)-lH-pyraa»]--i-yl)propanoic acid,
3-(5 3HX(4-iwmyi--6-methoxypyndo 3-y!)oxy
acid,
3<{( -fomi l-^^<rtboxy yridm-3-ytox )mc D^zoic acid,
6- (Ci4-fomiyIpyridin~3-) )oxy}ineth>1}r5icoiit^ 2,2,2-trifuoroacetale,
^(<4-foTiiiyIpytidiiv3-yl)oxy)roe<b^)wcodiiic acd,
6-(((4~i rmylpyridin -vl)oxy)me*^^ acid hydrochloride,
Figure imgf000213_0004
2.2,24rifltforoacetic acid ; i> ((4 nriy!py din -yI>oxy)n3elhyi)-N-
{melhylsulfonyj)nicottnaratde (2: 1 ), 2-{2-mcl¾ xyethox> -5-((2-(l-(2>2)2-irinu£}roesi'sy]}-Ui- pyrazoi-5-yl) yfidi.n-3-yl)meihosy)tSGi3S£OCHialdch
2-methoxy~5-{(2-(l -(3,3,3-tftfiuoropropyl)- 1 H-pyrazo!-5~yt)pyridi!¾-3-- yJlnicthoxylisonicotisialdehyde,
2~{2-mcthoxyethoxy)-5-{<2-( I -(3,3 ,3 rifluoropropy!) Il-pyTa2ol-5-yl}pyri.din-3- yl)rEietlKixy)isoiiic0tkaidebyde7
2-rBsthyl-5«((2 ! -(2,2,2- triftuorocihyl)-! Hi>yrazQ.i-5-yl)pyridm-3- yl)methcxy)isonicotinaldehyde,
2- methyl-5-((2-(l-{3,3,3-irlt¾ior<pr(jpyi> t H-pyrazo!-5-yJ)pyfiKn-3- yl)m€tbojy)i.sonicoti a!dehy{c,
3- {(2 H2,2,24riiluoroethyl)-IH-pyr^^
Figure imgf000213_0005
Atty. Dkt. No.: 104592-0210
3-e 3oexv5-(C2-i 1 -½opropyl- 1 H- yra^
3-¾24l sopropyMH~pyraz I-S-y^
3-cWom-5-((2-( ! ^3,3 -trifluoropropyi lH-pyimol-5-yi)pyridin-3- yI)raetoxy)isoDicotiBaldehy{ie, and yl)mellioxy)isonicoti.rjaidehyde,
or ataulomer or jAanuaccuticeily aecepteble salt thereof.
4814-3854 0057 213

Claims

What is claimed is:
1 . A compound of formula (I):
Figure imgf000215_0001
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein L10 is optionally substituted methylene or, preferably, a bond;
ring A is C6-Cio aryi, a C3-Cs cycioalkyl, a 5 - 10 membered heteroaryl or a 4-10
n embered hctcrocycle containing up to 5 ring heteroatoras, wherein the heteroaiom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl heteroaryl, cycioalkyl, or heterocycle is optionally substituted with 1-4: halo, Ci-C6 alkyl, Ci-Ce alkoxy, and/or C3-C10 cycioalkyl, wherein the Ci- alkyl is optionally substituted with 1-5 halo, CVQ, alkoxy, and/or C3-C10 cycioalkyl; or ring A is Ce-Cio aryl, or a 5-10 membered heteroaryl, wherein the heteroatom is
selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl, or heteroaryl is optionally substituted with 1 -4 C j -G, alkyl and/or Ci-Ce alkoxy groups;
ring B is a 5-10 membered heteroaryl or a 4-10 membered heterocycle containing up to 5 ring heteroatoras, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the
4814-3854-0057 1 14
. Dkt. No.i 104592-0210 heteroaryl and the heterocycle is optionally substituted with 1 -4: halo, Cj-C6 alkyl and/or -CO-CrC6 alkyl, or
ring B is:
Figure imgf000216_0001
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 forrns of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1 -4 Cj-Ce alkyl groups; ■'' is a single or a double bond;
each X and Y is independently (CR¾2,)e, O, S, SO, S02) or R20; e is 1 to 4, preferably 1 ; each R"° and R ' independently is hydrogen or C1-C3 alkyl optionally substituted with 1-3 halo, OH, or Ci -C& alkoxy, or CR20R ! is C=0, provided that if one of X and Y is O, S, SO, S02, then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof;
ring C is C^-Cio ar l or a 5- 1 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, -OR' , Cj-Cf, alkyl, -COOR1, and/or Cj-C6 alkoxy, wherein the C|-C6 alkyl is optionally substituted with 1-5 halo, -Ce 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 C6-Cio aryi or a 5- 10 membered heteroaryl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of j, is, o, dim OAiui c iuiiits ui I cuiu o, ca ii ui wui u is cpuouaiiy
substituted with 1-4: halo, oxo, -OR1, C C6 alkyl, -COOR1, NR5R6,
R! is a hydrogen, Cj-C6 alkyl or a prodrug moiety; wherein the alkyl is optionally
substituted with a 5- 10 membered heteroaryl containing up to 5 ring : 4-3854-0057.1 215 Atty. Dkt. No. : 104592-0210 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 heleroaloms, wherein the heteroatom is selected from the group consisting of (). N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally subsiituted with Cj-Cfi alkyl;
R5 and R'J are each independently hydrogen, optionally substituted
Figure imgf000217_0001
alkyl or
-COOR3 ;
RJ is hydrogen or optionally substituted C|-C6 alkyl;
V and Vz independently are C ;-C() alkoxy; or V and V~ together with the carbon
atom they are attached to form a ring of formula:
Figure imgf000217_0002
wherein each VJ and V4 are independently 0, S, or NH, provided that when one of VJ and V4 is S, the other is NH, and provided that V° and V'1 are both not NH; q is 1 or 2; each V5 is independently Cj-Cg alkyl optionally substituted with 1-3 OH groups, or V3 is CO2R60, where each R60 independently is C1-C6 alkyl or hydrogen; t is 0, 3 , 2, or 4; or CV' V2 is C=V, wherein V is O, NOR80, or NNRS!RS2;
R80 is optionally substituted C 1 -C0 alkyl;
R8i and R*2 independently are selected from the group consisting of hydrogen,
optionally substituted C | -C6 alkyl, COR83, or CQ2RM;
RSJ is hydrogen or optionally substituted C'rCs alkyl; and
R¾4 is optionally substituted Cj-Cg alkyl;
with the proviso that when ring C is C6-Cio aryl;
and ring 13 is optionally substituted 4-10 membered heterocyclyl;
then ring A excludes optionally substituted 5- 10 membered heteroaryl;
and provided that when ring C is C<,-C io aryl;
and ring B is optionally substituted 5-10 membered heteroaryl, Atty. Dkt. No,: 104592-0210 then ring A is not optionally substituted 4-10 membered heterocycle,
A compound of formula (X-I):
B
A
CV1V2H
or a lautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is phenyl, optionally substituted with 1 -3 halo and/or C : -C,-, alkoxy, or is a 4- 30 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroaiom is selected from the group consisting of O, N, S, and oxidized forms of N and S, optionally substituted, or is
Figure imgf000218_0001
wherein R ' is C Q alkyl, optionally substituted with 3-5 fluoro groups, or is C3-C6 cyeloa!ky!;
ring B is selected from the group consisting of
Figure imgf000218_0002
the pyridyl ring is optionally substituted with a halo or an NR^(CH2)2N(R^)2 group where each is independently hydrogen or Ci-C6 alkyl:
X is O, S, SO, or SO?;
4814-3854-0057. 1 217 Atty. Dkt. No.: 104592-0210 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, Ci-C6 alkyl, -COOR1, and/or Cj-Ce aikoxy, wherein the C[-C6 alkyl is optionally substituted with I -5 halo, C j-C6 aikoxy and/or 4-10 membered heterocyci e 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 R' is hydrogen or a prodrug raoiety R;
V1 and V' independently are C .-C aikoxy; or V1 and V" together with the carbon
atom they are attached to form a tins, of formula:
Figure imgf000219_0001
wherein each VJ and V are independently O, S, or NH, provided that when one of VJ 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-C6 alkyl or CQ2R<k', where each R6 independently is CyC alkyl or hydrogen; t is 1 , 2, or 4: or CV'V2 is C wherein V is O, NOR80, or N R8 i 82;
wherein Rg0 is optionally substituted Q-Q alkyl;
RSi and Rs2 independently are selected from the group consisting of hydrogen,
optionally substituted CrC6 alkyl, COR83, or C02R84:
hydrogen or optionally substituted C. -Ce alkyl;
R is optionally substituted Q-Cs alkyl;
provided that when ring C is C6-Cio aryk
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 C0-Ci o aryl;
and ring B is optionally substituted 5-10 membered heteroaryl;
then ring A is not optionally substituted 4-10 membered heterocycle. Dkt, No. : 104592-021 0
3 , The compound of claim 2, wherein V 1 and V independently are C | -C& alkoxy: or V 1 and V2 together with the carbon atom they are attached to form a ring of formula:
Figure imgf000220_0001
wherein each V3 and V4 are independently O, S, or NH, provided that when one or VJ and V'1 is S the other is NH, and provided that V3 and V4 are both not NH; q i s 1 or 2; each V5 is independently Ci -Q alkyl or CO2R60, where each R6" independently is CpCe alky! or hydrogen: t is 1 , 2, or 4; or CV' V2 is C=V. wherein V is O, and wherein the remaining variables are defined as in claim.
4. The coniDound of claim 3 , of formula;
Figure imgf000220_0002
(Π)
wherein the remaining variables are defined as i n clai m
4814-3854-0067.1 219 Atty. Dkt. No.: 104592-0210
Figure imgf000221_0001
ΠΑ ΠΒ IIC
wherein
R'i is hydrogen, -OR1. Ci-C,-, aikoxy optionally substituied with 1-3 C|-C& aikoxy or 4- 1 0 mernhered helerocycie containing up to 5 ring heteroatoms selected from N, O, S or oxidized forms thereof;
R, J is hydrogen, halo, hydroxy, or C|-C'6 a!koxy;
R1 1 is hydrogen or C|-C6 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 Cj-Q aikoxy, or
Cj-Cg heierocyclyl 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
Figure imgf000221_0002
is selected from the group consisting of:
4814-3554-0057 22'
Figure imgf000222_0001
8, The compound of any one of claims 3-6, wherein
Figure imgf000222_0002
JS
854-0057.1 Dkt. No. : 104592-0210
Figure imgf000223_0001
9. A compound of claim 1 wherein:
ring A is CV io aryl, or a 5-10 membered heteroaryl, wherein the heteroatom is
selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryi, or heteroaryl is optionally substituted with 1-4: CV C-6 alkyl and/or C ; -C¾ alkoxy;
ring B is:
Figure imgf000223_0002
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 8, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1 -4 C -.-C^ alkyl groups;
each X and Y is independently CR20R21, O, S, SO, S02, or NR20; each R20 and R2!
independently is hydrogen or Ci-C3 alkyl optionally substituted with 1 -3 halo, OH, or Ci-Cfi alkoxy, or CR20R21 is C=0, provided that if one of X and Y is O, S, SO, SO , then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof;
ring C is C Cio a yl or a 5- 10 membered heteroaryl containing up to 5 ring
consisting of
Figure imgf000223_0003
substituted with 1-4: halo, oxo, -OR1, C,-C6 alkyl, -COOR5, NR5R6,
Figure imgf000223_0004
4814-3854-0057.1 22.2 Dki. No.: 104592-0210 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- alkyl;
R'1 and R6 are each independently hydrogen, optionally substituted C ; -Q alkyl or
-COOR3 ;
R3 is hydrogen or optionally substituted C ; -C6 alkyl;
V1 and V" independently are Ci-C6 alkoxy; or V 1 and V2 together with the carbon
atom they are attached to form a ring of formula:
Figure imgf000224_0001
wherein each i and V4 are independently O, S, or NH, provided that when one of VJ and V4 is S, the other is NH; and provided that V3 and V' are both not. NH; q is 1 or 2; each V3 is independently C;-Cs alkyl optionally substituted with 1-3 OH groups, or V5 is C02R60, where each R60 independently is C C6 alkyl or hydrogen; t is 0. 1 , 2, or 4; or CV 'v ' is =V, wherein V is O, NOR81', or NNR ! R*2;
R '"' is optionally substituted C\-C(, a!kyi;
RS ! and R8-4 independently are selected from the group consisting of hydrogen,
optionally substituted CrC6 alkyl, COR83, or C02R84:
R8 i is hydrogen or optionally substituted
Figure imgf000224_0002
alkyl ; and
R84 is optionally substituted C \ -C alkyl;
with the proviso that when ring C is C -Cio aryl;
and ring B is optionally substituted 4- 10 membered heterocyclyl;
then ring A excludes opiionaliy substituted 5-10 membered heteroaryl;
and provided that when ring C is Cg-Cio aryl;
and ring B is optionally substituted 5-10 membered heteroaryl;
. Dkt. No.: 104592-0210 then ring A is not optionally substituted 4-10 rnembered heterocycie.
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.
1 1 , The compound of claim 10, of formula:
Figure imgf000225_0001
(V)
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, where
wherein the remaining variables are defined as in claim 9.
12. A compound of claim 10 or 1 1 of formula (Vi) or (VII):
Figure imgf000225_0002
Am Α/ΤΓ, or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof wherein ring A is C6-Cio aryj, or a 5-10 membered heieroaryl , wherein the heteroatom is
selected from the group consisting of O, N, S, and oxidized forms of N and S,
4814-3354-0057.1 224 Atty. Dkt. No.: 104592-0210 wherein each of the aryl, or heteroaryl is optionall substituted with 1 -4 Ci-Ce alkyi;
ring B is Q-Cio aryl, C3-C8 cycioaikyi, a 5-10 membered heteroaryl containing up to 5 ring heteroatoms or a 4- i 0 membered heterocycle containing up to 5 ring heteroatoms, wherein the hetcroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl, heteroaryl, cycioaikyi or heterocycle is optionally substituted with 1 -4: halo, Ci-Ce alkyl, or C | -Ce alkoxy, wherein the Q-Ce alkyl is optionally substituted with 1 -5 halo, C-.-Cfi alkoxy, and/or C3-C10 cycioaikyi;
R4 is halo, oxo, -OR18, C rC6 alkyl, C C6 alkoxy, -COOR5, and/or NR5R6;
R is hydrogen, subsitued Ci-Cg alkyl, or a prodrug moiety R;
R5 and R° are each independently hydrogen, optionally substituted C C6 alkyl or
-COOR3 ; and
RJ is hydrogen, provided that the COOR3 is not joined to a nitrogen atom, or
optionally substituted C| -C6 alkyl.
13. The compound of claim 12, wherein ring B is selected from the group consisting of:
Figure imgf000226_0001
14. A compound of claim 1 selected from the group consisting of:
Figure imgf000226_0002
4814-3854-0057.1
. !)k:. No.: 104592-0210
Figure imgf000227_0001
Figure imgf000227_0002
Figure imgf000227_0003
4814-3854-0057 226 Ally. Dkt. No.: 1045924)210
Figure imgf000228_0001
Figure imgf000228_0002
57.1 Atty. Dkt. No.; 104592-0210
Figure imgf000229_0001
4814-3854-0057.1 228 Atty. Dkt. No.: 104592-0210
Figure imgf000230_0001
4814-3854-0057.1 229 Atty. Dkt. No,: 104592-0210
Figure imgf000231_0001
a prodrug thereof, or a pharmaceuticlaly acceptable salt of each thereof.
15. A compound of claim 1 selected from the group consisting of:
Figure imgf000231_0002
4814-3854-0057 1 230 Any. Di t. No.: 104592-0210
Figure imgf000232_0001
or N oxides thereof, or a pharmaceutically acceptable salt of each thereof.
16. A composition comprising a compound of any one of claims 3-8 and 10-15, and at least one pharmaceutically acceptable excipient.
4814-3854-0057.1
. Dkt. No,: 104592-021 0
1 7. A method 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 a compound of any one of claims 3-8 and 10- 15 or the composition of claim 16.
1 8. A method for treating oxygen deficiency associated with sickle cell anemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 3-8 and 10-15 or the composition of claim 1 6.
4814-3854-0057.1
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