Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

• This invention provides compounds and pharmaceutical compositions suitable as allosteric modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.
• Sickle cell disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent.
• the basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin (Hb).
• Hemoglobin transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through conformational changes.
• Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing HbS to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels.
• US 7, 160,910 discloses compounds that are allosteric modulators of hemoglobin. However, a need exists for additional therapeutics that can treat disorders that are mediated by Hb or by abnormal Hb such as HbS.
• This invention relates generally to compounds and pharmaceutical compositions suitable as allosteric modulators of hemoglobin. In some aspects, this invention relates to methods for treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation. In certain aspects of the invention, a compound of formula (I) is provided:
• ring A is an optionally substituted 4-10 membered cycloalkyi or 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;
• ring B is a C 6 -Ci 0 aryl or 5-10 membered heteroaryl having 1-3 nitrogen atoms,
• aryl or heteroaryl is optionally substituted; is a single or a double bond;
• each Y and Z is independently CR 10 R n , O, S, SO, S0 2, or NR 12 ; each R 10 and R 11
• R 12 is hydrogen or Ci-C 6 alkyl; provided that if one of Y and Z is O, S, SO, S0 2 , then the other is not CO, and provided that Y and Z are both not heteroatoms or oxidized forms thereof;
• ring C is C 6 -Ci 0 aryl, optionally substituted
• V 1 and V 2 independently are Ci-C 6 alkoxy; or V 1 and V 2 together with the carbon atom they are attached to form a ring of formula:
• R 80 is optionally substituted Ci-C 6 alkyi
• R 81 and R 82 independently are selected from the group consisting of hydrogen, optionally substituted C C 6 alkyi, COR 83 , or C0 2 R 84 ;
• R is hydrogen or optionally substituted Ci-C 6 alkyi
• R is optionally substituted Ci-C 6 alkyi.
• a compound of formula (IA) is provided:
• R 5 is hydrogen, Ci-C 6 alkyi or a prodrug moiety R, wherein the Ci-C 6 alkyi is optionally substituted with 1-5 halo;
• R 6 is halo, Ci-C 6 alkyi, Ci-C 6 alkoxy, Ci-C 6 alkylthio, Ci-C 6 S(O)-, Ci-C 6 S(0) 2 -,wherein the Ci-C 6 alkyi is optionally substituted with 1-5 halo; or
• R 6 is 4-10 membered cycloalkyl or heterocycle substituted with an R'R'N- moiety wherein each R' is independently C1-C6 alkyi or hydrogen; k is 0 or 1;
• p 0, 1, 2 or 3; and the remaining variables are defined as above.
• 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.
• compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
• compositions and methods 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 terms are within the scope of this invention.
• C m -C n such as C1-C12, Ci-C 8 , or Ci-C 6 when used before a group refers to that group containing m to n carbon atoms.
• alkoxy refers to -O-alkyl.
• alkylthio is -S-alkyl.
• alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 30 carbon atoms (i.e., Ci-C 30 alkyl) or 1 to 22 carbon atoms (i.e., C1-C22 alkyl), 1 to 8 carbon atoms (i.e., Ci-C 8 alkyl), or 1 to 4 carbon atoms.
• This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH3CH2-), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), i-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH2CH 2 CH2- ), and neopentyl ((CH 3 ) 3 CCH 2 -).
• linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH3CH2-), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (
• 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:
• -CO2H ester refers to an ester formed between the -CO2H group and an alcohol, preferably an aliphatic alcohol.
• chiral moiety refers to a moiety that is chiral. Such a moiety can possess one or more asymmetric centers. Preferably, the chiral moiety is enantiomerically enriched, and more preferably a single enantiomer.
• Non limiting examples of chiral moieties include chiral carboxylic acids, chiral amines, chiral amino acids, such as the naturally occurring amino acids, chiral alcohols including chiral steroids, and the likes.
• cycloalkyl refers to a monovalent, preferably saturated, hydrocarbyl mono-, bi-, or tricyclic ring having 3-12 ring carbon atoms. While cycloalkyl, refers preferably to saturated hydrocarbyl rings, as used herein, it also includes rings containing 1- 2 carbon-carbon double bonds. Nonlimiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamentyl, and the like. The condensed rings may or may not be non-aromatic hydrocarbyl rings provided that the point of attachment is at a cycloalkyl carbon atom. For example, and without limitation, the following is a cycloalkyl group:
• halo refers to F, CI, Br, and/or I.
• heteroaryl refers to a monovalent, aromatic mono-, bi-, or tricyclic ring having 2-16 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 5 ring atoms.
• Nonlimiting examples of heteroaryl include furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the like.
• the condensed rings may or may not be a heteroatom containing aromatic ring provided that the point of attachment is a heteroaryl atom.
• heterocyclyl refers to a non-aromatic, mono-, bi-, or tricyclic ring containing 2-12 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 3 ring atoms. While heterocyclyl preferably refers to saturated ring systems, it also includes ring systems containing 1-3 double bonds, provided that the ring is non-aromatic.
• heterocyclyl examples include, azalactones, oxazoline, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl.
• the condensed rings may or may not contain a non-aromatic heteroatom containing ring provided that the point of attachment is a heterocyclyl group.
• the following is a hetero
• hydrolyzing refers to breaking an R H -0-CO-, 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.
• a hydrolyzing is performed using various methods well known to the skilled artisan, non limiting examples of which include acidic and basic hydrolysis.
• the term "optionally substituted” refers to a substituted or unsubstituted group.
• the group may be substituted with one or more substituents, such as e.g., 1, 2, 3, 4 or 5 substituents.
• the substituents are selected from the group consisting of chloro, fluoro, -OCH 3 , methyl, ethyl, / ' so-propyl, cyclopropyl, vinyl, ethynyl, -C0 2 H, -C0 2 CH 3 , -OCF 3 , -CF 3 and -OCHF 2 .
• pharmaceutically acceptable salt refers to a salt that is
• 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, NH 4 , Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids.
• salts include, without limitation, salts of organic acids, such as carboxylic 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 include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisalfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.
• 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
• the terms also include relieving the disease or conditions, e.g., causing the regression of clinical symptoms.
• the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
• therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
• 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.
• 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.
• preventing refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a su bject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
• the terms further include causing the clinical symptoms not to develop, for example in a su bject at risk of suffering from such a disease or disorder, thereby su bstantially averting onset of the disease or disorder.
• 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 su bject 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 meta bolic sta bility or transport characteristics, fewer side effects or lower toxicity. For example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford U niversity Press, New York, pages 388-392.
• Prodrugs can also be prepared using compounds that are not drugs.
• ring A is an optionally substituted 4-10 membered cycloalkyi or 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom selected from the group consisting of O, N, S, and oxidized forms of N and ring B is a C 6 -Ci 0 aryl or 5-10 membered heteroaryl having 1-3 nitrogen atoms,
• aryl or heteroaryl is optionally substituted; is a single or a double bond;
• each Y and Z is independently CR 10 R n , O, S, SO, S0 2, or N R 12 ; each R 10 and R 11
• R 12 is hydrogen or Ci-C 6 alkyl; provided that if one of Y and Z is O, S, SO, S0 2 , then the other is not CO, and provided that Y and Z are both not heteroatoms or oxidized forms thereof;
• ring C is C6-C10 aryl
• V 1 and V 2 independently are Ci-C 6 alkoxy; or V 1 and V 2 together with the carbon atom they are attached to form a ring of formula:
• R 5 is hydrogen, Ci-C 6 alkyi or a prodrug moiety R, wherein the Ci-C 6 alkyi is optionally substituted with 1-5 halo;
• R 6 is halo, Ci-C 6 alkyi, Ci-C 6 alkoxy, Ci-C 6 alkylthio, Ci-C 6 S(O)-, Ci-C 6 S(0) 2 -,wherein the Ci-C 6 alkyi is optionally substituted with 1-5 halo; or
• R 6 is 4-10 membered cycloalkyl or heterocycle substituted with an R'R'N- moiety wherein each R' is independently C1-C6 alkyi or hydrogen;
• R 80 is optionally substituted Ci-C 6 alkyi
• R 81 and R 82 independently are selected from the group consisting of hydrogen, optionally substituted C C 6 alkyi, COR 83 , or C0 2 R 84 ;
• R 83 is hydrogen or optionally substituted Ci-C 6 alkyi
• R 84 is optionally substituted Ci-C 6 alkyi
• k is 0 or 1
• p 0, 1, 2 or 3.
• t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3.
• Y and Z are both not a heteroatom or a heteroatom containing moiety.
• one of Y and Z is a methylene or substituted methylene and the other is a heteroatom or a heteroatom containing moiety.
• Y is an alkylene
• Z is a heteroatom or a heteroatom containing moiety, which, yet more preferably is oxygen.
• V 1 and V 2 together with the carbon atom they are attached to form a ring of formula:
• V 1 and V 2 independently are Ci-C 6 alkoxy; or V 1 and V 2 together with the carbon atom they are attached to form a ring of formula:
• the compound of Formula (I) is of Formula (II):
• the compound of Formula (I) is of Formula (MA):
• ring A is optionally substituted with 1-3: halo, Ci-C 6 alkyl, COR 15 and/or COOR 15 ; wherein R 15 is optionally substituted Ci-C 6 alkyl, optionally substituted C 6 -Ci 0 aryl, optionally substituted 5-10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.
• ring B is optionally substituted with 1-3: halo, Ci-C 6 alkyl COR 15 and/or COOR 15 ; wherein R 15 is optionally substituted C1-C6 alkyl, optionally substituted C6-Ci 0 aryl, optionally substituted 5-10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.
• the compound is selected from the group consisting of
• R 14 is Ci-Ce alkyl, C 3 -C 8 cycloalkyl, COR 15 or COOR 15 ;
• R 15 is optionally substituted Ci-C 6 alkyl, optionally substituted C 6 -Ci 0 aryl, optionally substituted 5-10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; x is 0, 1, or 2;
• p 0, 1, and 2;
• n 0, 1 or 2.
• 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 bioavailability to the active moiety (where R is hydrogen), and more preferably is hydrolyzed in vivo.
• the promoieties are structurally and functionally defined herein.
• R is -COR 90 , C0 2 R 91 , or CON R 92 R 93 wherein
• R 90 and R 91 independently are Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, 4-9 membered heterocycle, or a
• R 92 and R 93 independently are Ci-C 6 alkyl; C 3 -C 8 cycloalkyl, 4-9 membered heterocycle, or a 5-
• R is -C(0)R 31 , C(0)OR 31 , or CON(R 13 ) 2 ,
• each R 31 is independently a C1-C6 alkyl; C3-C8 cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, containing at least 1 basic nitrogen moiety; and
• each R 13 independently are Ci-C 6 alkyl; C 3 -C 8 cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, containing at least 1 basic nitrogen moiety; or 2 R 13 together with the nitrogen atom they are bonded to for a 4-9 member heterocycle su bstituted with at least 1 amino, Ci-C 6 alkyl amino, or di Ci-C 6 alkylamino group.
• R is C(0)OR 31 , C(S)OR 31 , C(0)SR 31 or COR 31 , wherein R 31 is as defined herein.
• R 31 is a group of the formula (CR 32 R 33 ) e N R 34 R 35 , wherein
• each R 32 and R 33 is independently H, a Ci-C 8 alkyl, C 3 -C 9 heterocyclyl, C 3 -C 8 cycloalkyl, C 6 -Cio aryl, C 3 -C 9 heteroaryl or R 32 and R 33 together with the carbon atom they are bond to form a C 3 -C 8 cycloalkyl, C 6 -Ci 0 aryl, C 3 -C 9 heterocyclyl or C 3 -C 9 heteroaryl ring system, or 2 adjacent R 32 moieties or 2 adjacent R 33 moieties together with the carbon atom they are bond to form a C 3 -C 8 cycloalkyl, C 6 -Ci 0 aryl, C 3 -C 9 heterocyclyl or C 3 -C 9 heteroaryl ring system;
• each R 34 and R 35 is a Ci-C 8 alkyl, C 3 -C 9 heterocyclyl, C 3 -C 8 cycloalkyl, or R 34 and R 35 together with the nitrogen atom they are bond to form a C 3 -C 8 cycloalkyl or C 3 -C 9 heterocyclyl ring system;
• each heterocyclic and heteroaryl ring system is optionally su bstituted with Ci-C 3 alkyl, -OH, amino and carboxyl groups;
• e is an integer of from 1 to 4.
• R 34 and R 35 can be hydrogen.
• the subscript e is preferably 2 and each R 32 and R 33 is prefera bly independently selected from the group, H, CH 3 , and a member in which R 32 and R 33 are joined together to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or l, l-dioxo-hexahydro-IA 6 -thiopyran-4-yl or tetrahydropyran-4-yl group.
• preferred embodiments are compounds wherein NR 34 R 35 is morpholino.
• R is:
• each R 32 and R 33 is independently H, Ci-C 8 alkyl, or optionally, if both present on the same substituent, may be joined together to form a C 3 -C 8 cycloalkyl, C 6 -Ci 0 aryl, C 3 -C 9 heterocyclyl or C 3 -C 9 heteroaryl ring system.
• each R 32 and R 33 is independently, H, CH 3 , or are joined together to form a cyclopropyl, cyclopbutyl, cyclopentyl, cyclohexyl, 1,1-dioxo- hexahydro- I 6 -th iopyran-4-yl or tetrahydropyran-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 morpholino group. This pKa range of 6.5 to 8.5 allows for significant concentrations of the basic neutral amine to be present in the mildly alkaline small intestine.
• the basic, neutral form of the amine prodrug is lipophilic and is absorbed through the 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 include, without limitation:
• R is as tabulated below:
• R is,
• R is lower alkyl (e.g. Ci-C 6 alkyl).
• pect, R is: wherein X 1 , Y 1 and X 2 are as defined herein.
• X 1 is selected from the group consisting of O, S and NR 37 wherein R 37 is hydrogen or Ci-C 6 alkyl;
• Y 1 is -C(R 38 ) 2 or a sugar moiety, wherein each R 38 is independently hydrogen or Ci-C 6 alkyl, C 3 -C 8 cycloalkyi, C 3 -C 9 heterocyclyl, C 6 -Ci 0 aryl, or C 3 -C 9 heteroaryl;
• X 2 is selected from the group consisting of halogen, Ci-C 6 alkoxy, diacylglycerol, amino, Ci-C 6 alkylamino, Ci-C 6 dialkylamino, Ci-C 6 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 Ci-C 6 alkyl, C 3 -C 8 cycloalkyi, C 3 -C 9
• W 2 is O or NR 39
• R 39 is hydrogen or Ci-C 6 alkyl, C 3 -C 8 cycloalkyi, C 3 -C 9 hetrocyclyl, C 6 -Ci 0 aryl, or C 3 -C 9 heteroaryl;
• each X 3 is independently amino, hydroxyl, mercapto, Ci-C 6 alkyl, heteroalkyl, cycloalkyi, hetrocyclyl, aryl, or heteroaryl, Ci-C 6 alkoxy, Ci-C 6 alkylamino, Ci-C 6 dialkylamino, C1-C6 alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and
• each R 40 is independently Ci 0 -C 22 alkyl, C 3 -C 8 cycloalkyi, C 3 -C 9 heterocyclyl, C 6 -Ci 0 aryl, or C 3 -C 9 heteroaryl, Ci-C 8 alkylene, or Ci-C 8 heteroalkylene.
• Each heterocyclic and heteroaryl ring system is optionally substituted with C alkyl, -OH, amino and carboxyl groups.
• the present invention utilizes the following Y 1 groups: CH CHMe, CH(isopropyl), CH(tertiarybutyl), C(Me)2, C(Et)2, C(isopropyl)2, and C(propyl)2.
• the present invention utilizes the following X 2 groups
• R is:
• X 3 is independently Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -Ci 0 aryl, or C 3 -
• RR 4422 iiss iinnddeeppendently hydrogen or Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -Cio aryl, or C 3 -C 9 heteroaryl.
• Each heterocyclic is optionally substituted with one or more, preferably, 1-3, Ci-C 3 alkyl, -OH, amino and/or carboxyl groups.
• R is:
• each X 3 is independently amino, hydroxyl, mercapto, C1-C6 alkyl, C3-C8 cycloalkyi, C 3 - C 9 heterocyclyl, C 6 -Ci 0 aryl, or C 3 -C 9 heteroaryl, Ci-C 6 alkoxy, Ci-C 6 alkylamino, Ci-C 6
• 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 C10-C22 alkyl, C 3 -C 8 cycloalkyi, C 3 -C 9 heterocyclyl, C 6 -Ci 0 aryl,
• R 42 is independently hydrogen or Ci-C 6 alkyl, C 3 -C 8 cycloalkyi, C 3 -C 9 heterocyclyl,
• R 42 is independently hydrogen or Ci-C 6 alkyl, C 3 -C 8
• R is represented by the following structures:
• R is:
• R is -C(R 200 R 201 )O(R 202 R 203 )P(O)OR 204 N R 205 R 206 , wherein each R 200 , R 201 , R 202 , R 203 , R 204 R 205 and R 206 is independently H, a C C 8 alkyl, C 3 -C 9 heterocyclyl, C 3 -C 8 cycloalkyl, C 6 -Ci 0 aryl, C 3 -C 9 heteroaryl, wherein each alkyl, heterocyclyl, cycloalkyl, aryl, and heteroaryl is optionally substituted.
• R is -CH(R 201 )OCH 2 P(O)OR 204 N HR 206 , wherein R 201 is Ci-C 8 alkyl, R 204 is phenyl, optionally substituted.
• R 206 is -CH R 207 C(O)OR 208 wherein R 207 is selected from the group consisting of the naturally occurring amino acid side chains and C0 2 H esters thereof and R 208 is Ci-C 8 alkyl.
• R 206 is Ci-C 6 alkyl, optionally susbtitued with 1-3, C0 2 H, SH, NH 2 , C 6 -Ci 0 aryl, and C 2 -Ci 0 heteroaryl.
• R is:
• R is:
• Y 1 is -C(R 38 ) 2 , wherein each R 38 is independently hydrogen or Ci-C 6 alkyl, C 3 - C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -Ci 0 aryl, or C 3 -C 9 heteroaryl.
• R is
• R is -OH, or hydrogen
• W is- CHiCHsjW 1 ;
• W 1 is a substituted Ci-C 8 alkyl group containing a moiety which is optionally negatively charged at physiological pH
• said moiety is selected from the group consisting of C0 2 H, S0 3 H, S0 2 H,
• R 52 is Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -Ci 0 aryl, or C 3 -C 9 heteroaryl.
• Each heterocyclic and heteroaryl ring system is optionally substituted with one or more, preferably 1-3, C1-C3 alkyl, -OH, amino and/or carboxyl groups.
• R is:
• R comprises a cleavable linker, wherein the term "cleavable linker” refers to a linker which has a short half life in vivo. The breakdown of the linker Z in a compound releases or generates the active compound.
• the cleavable linker has a half life of less than ten hours. In one embodiment, the cleavable linker has a half life of less than an hour. In one embodiment, the half life of the cleavable linker is between one and fifteen minutes.
• the cleavable linker is hydrolyzed by an esterase enzyme.
• the linker is a self-immolating linker, such as that disclosed in U.S. patent publication 2002/0147138, to Firestone; PCT Appl. No. US05/08161 and PCT Pub. No. 2004/087075.
• the linker is a substrate for enzymes. See generally Rooseboom et al., 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. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16 th ed., A. Oslo editor, Easton Pa. 1980).
• 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 excipients commonly employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2- propylene glycol, polyglycols, 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, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, 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 hydroxypropyl cellulose has an average MW of from 10,000 to 100,000.
• the hydroxypropyl cellulose has an average MW of from 5,000 to 50,000.
• Compounds and pharmaceutical compositions of this invention maybe used alone or in combination with other compounds. When administered with another agent, the coadministration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time.
• co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time.
• co-administration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such
• administration most advantageously proceeds by delivering both active ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention.
• 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.
• a method for treating a condition associated with oxygen deficiency 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 in need thereof a therapeutically effective amount of a compound of any of the compounds or compositions described herein.
• X and X 5 each represent a leaving group and are independently selected from CI, F, Br, and I.
• X s represents CHR 14 , NR 14 , O, S(0)x ; wherein x is 0, 1, or 2;
• Y 5 represents a leaving group selected from CI, F, Br, I, OS0 2 R 17 and OS0 2 Ar;
• R 17 is Ci-C 6 alkyl; n is 0, 1, or 2; Ar is phenyl optionally substituted with 1-3 halo or C1-C4 alkyl groups.
• the ice cooling bath was allowed to expire over 90 min and the mixture was stirred at RT for 2-48 hours.
• the mixture was stirred for 10 min, then filtered through a pad of silica.
• the silica was washed with ethyl acetate 2- 20mL The combined filtrates were evaporated and the residue was dried on highvac.
• the residue was purified by preparative HPLC or flash silica gel chromatography.
• N-linked heterocyclic analogs (compound 5) can also be synthesized from amination procedures developed by Buchwald and Hartwig.
• Step 1 Condensation of heterocyclic ketone analog 5 with chlorformate or dialkyi carbonate gives (hetero)cyclic beta-ketone ester 6 (Step 1).
• the ketone ester 6 is converted to the triflate intermediate 7 by treating with a triflating agent (e.g, triflic anhydride) in the presence of an organic base such as Hunig's base (Step 2).
• a triflating agent e.g, triflic anhydride
• Suzuki coupling of the triflate 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).
• Conversion of the alcohol 12-OH-cis to its chloride, bromide or sulfonate (such as mesylate, tosylate) 13-X-cis can be achieved by reacting with thionyl chloride, or Ph 3 PBr 2 , or sufonyl chloride (such as mesyl chloride or tosyl chloride) (Step 9).
• the cis- cyclohexane carboxylate 11-cis can also be isomerized to the thermodynamically more stable trans-isomer 11-trans by the treatment with an alcoholic alkoxide (e.g., ethoxide) solution.
• transformation of 11-trans ester to 12-trans alcohol and 13-X-trans halide is accomplished by applying conditions of Step 8 and Step9 (Scheme 2) similar to these for the corresponding cis-isomers.
• the solution was cooled to 0 °C on ice bath and DIAD or DEAD (1.1 eq) in THF or toluene was added drop wise over a 1-20 min period.
• Step 2 The ice cooling bath was allowed to expire over 90 min and the mixture was stirred at RT for 2- 48 hours. The mixture was stirred for 10 min, then filtered through a pad of silica. The silica was washed with ethyl acetate 2-20mL The combined filtrates were evaporated and the residue was dried on highvac. The residue was purified by preparative HPLC or flash silica gel chromatography. [0111] Step 2.
• Compound 25 can be prepared from 2-halonicotinate through a series organic transformations that involve displacement with cyclic amine and reduction of ester to give hydroxymethylene derivative 22 (step 1).
• the final product can be synthesized via either direct Mitsunobu reaction of 22 with phenol aldehyde 24 or conversion of the alcohol 22 to halide 23 followed by O-alkylation of phenol 24 with 23.
• 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
• Isolation of the ester products can be affected by extraction with an organic solvent, such as ethyl acetate or methylene chloride, against a mildly acidic aqueous solution; followed by base treatment of the acidic aqueous phase so as to render it basic; followed by extraction with an organic solvent, for example ethyl acetate or methylene chroride; evaporation of the organic solvent layer; and recrystalization from a solvent, such as ethanol.
• the solvent can be acidified with an acid, such as HCI 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-morpholino)-propionic acid, N,N- dimethyl-beta-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.
• R bl is Ci-C 6 alkyl.
• R 52 is Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -Ci 0 aryl, or C 3 -C 9 heteroaryl. Examples
• Step 1 (R)-ethyl 2-(3-fluoropyrrolidin-l-yl)nicotinate.
• ethyl 2- fluoronicotinate 0.074 g, 0.48 mmol
• DM F 0.3 m L
• diisopropylethyl amine 0.25 m L, 1.4 mmol
• (/?)-3-fluoropyrrolidine 0.090 g, 0.72 mmol.
• the resulting mixture was irradiated with microwaves (100 °C) for lh and loaded directly onto a silica column.
• Step 2 ( ?)-(2-(3-fluoropyrrolidin-l-yl)pyridin-3-yl)methanol.
• a solution of (/?)-methyl 2-(3-fluoropyrrolidin-l-yl)nicotinate in TH F 5 m L
• a solution of lithium aluminum hydride (1M in TH F)
• the reaction mixture was stirred for lh and then 20 ⁇ of H 2 0 was added followed by 20 ⁇ of 15% NaOH (aq) and then 60 ⁇ of additional water.
• the slurry was stirred for lh and filtered and the resulting residue was washed with ether.
• Step 3 ( ?)-3-(chloromethyl)-2-(3-fluoropyrrolidin-l-yl)pyridine.
• SOCI 2 (0.450 g, 3.8 mmol
• Step 4 ( ?)-2-((2-(3-fluoropyrrolidin-l-yl)pyridin-3-yl)methoxy)-6- hydroxybenzaldehyde.
• (/?)-3-(chloromethyl)-2-(3-fluoropyrrolidin-l- yl)pyridine (0.080 g, 0.35 mmol) and 2,6-dihydroxybenzaldehyde (0.130 g, 0.94 mmol) in DM F was added potassium carbonate (0.190 g, 1.4 mmol) and the reaction mixture was heated (60 °C). After 30 minutes, the DMF was removed and the resulting residue was reconstituted in CH 2 CI 2 and filtered through a plug of silica (EtOAc/hexanes, 1:1).
• GBT883- ( ?)-2-((2-(3-fluoropyrrolidin-l-yl)pyridin-3-yl)methoxy)-6- hydroxybenzaldehyde.
• the compound was prepared from ethyl 2-fluoronicotinate and (/?)- 3-fluoropyrrolidine according to scheme 5, reaction steps 1, 3 and 4.
• Step la To a solution of ethyl 2-fluoronicotinate (0.074 g, 0.48 mmol) in DM F (0.3 mL) was added diisopropylethyl amine (0.25 mL, 1.4 mmol), and (/?)-3-fluoropyrrolidine (0.090 g, 0.72 mmol). The resulting mixture was irradiated with microwaves (100 °C) for lh and loaded directly onto a silica column. Eluting the column with EtOAc/hexanes (0-100%) provided (/?)-ethyl 2-(3-fluoropyrrolidin-l-yl)nicotinate as a clear oil (0.100 g, 94% yield). MS (ES) for C12H15FN2O2: 225 (MH + ).
• Step lb To a cooled (0 °C) solution of (/?)-methyl 2-(3-fluoropyrrolidin-l- yl)nicotinate in THF (5 mL) was added a solution of lithium aluminum hydride (1M in THF). The reaction mixture was stirred for lh and then 20 ⁇ of H20 was added followed by 20 ⁇ of 15% NaOH (aq) and then 60 ⁇ of additional water. The slurry was stirred for lh and filtered and the resulting residue was washed with ether. The combined organic layers were dried over MgSC and concentrated in vacuo.
• Step 3 To a cooled (0 °C) solution of (/?)-(2-(3-fluoropyrrolidin-l-yl)pyridin-3- yl)methanol (0.081 g, 0.38 mmol) in dichloromethane was added SOCI 2 (0.450 g, 3.8 mmol) and the reaction mixture was allowed to warm to am bient temperature.
• Step 4 To a solution of (/?)-3-(chloromethyl)-2-(3-fluoropyrrolidin-l-yl)pyridine (0.080 g, 0.35 mmol) and 2,6-dihydroxybenzaldehyde (0.130 g, 0.94 mmol) in DM F was added potassium carbonate (0.190 g, 1.4 mmol) and the reaction mixture was heated (60 °C). After 30 minutes, the DM F was removed and the resulting residue was reconstituted in CH 2 CI 2 and filtered through a plug of silica ( EtOAc/hexanes, 1: 1).
• the compound was prepared from ethyl 2-fluoronicotinate and 8- oxa-3-azabicyclo[3.2.1]octane according to reaction scheme below. Step 1a
• Step la To a solution of ethyl 2-fluoronicotinate (0.15 g, 0.97 mmol) in N MP (0.5 mL) was added diisopropylethyl amine (0.50 mL, 2.9 mmol), and 8-oxa-3- azabicyclo[3.2.1]octane (0.17 g, 0.72 mmol). The resulting mixture was irradiated with microwaves (100 °C) for lh and loaded directly onto a silica column.
• Step lb To a cooled (0 °C) solution of 2-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)nicotinate (0.10 g, 0.40 mmol) in THF (5 mL) was added a solution of lithium aluminum hydride (1.2 mL, 1M in THF). The reaction mixture was stirred for lh and then 20 ⁇ of H 2 0 was added followed by 20 ⁇ of 15% NaOH (aq) and then 60 ⁇ of additional H 2 0. The slurry was stirred for lh, filtered and the resulting residue was washed with ether.
• Step 2 To a cooled (0 °C) solution of (2-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyridin-3-yl)methanol (0.070 g, 0.32 mmol) in dichloromethane was added SOCI 2 (0.23 mL, 3.2 mmol) and the reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was concentrated and azeotroped with toluene three times to provide 3-(3-(chloromethyl)pyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.075 g, 98%) as a clear oil.
• Step 3 To a solution of provide 3-(3-(chloromethyl)pyridin-2-yl)-8-oxa-3- azabicyclo[3.2.1]octane (0.080 g, 0.35 mmol) and 5-hydroxy-2,2-dimethyl-4H- benzo[d] [l,3]dioxin-4-one (0.061 g, 0.31 mmol) in DMF was added cesium carbonate (0.307 g, .94 mmol) and the reaction mixture was heated (60 °C). After 30 minutes, the reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate and the aqueous layer was extracted two times with EtOAc.
• Step 4 To a cooled (-78 °C) solution of 5-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)pyridin-3-yl)methoxy)-2,2-dimethyl-4H-benzo[d] [l,3]dioxin-4-one (0.11 g, 0.28 mmol) in CH 2 CI 2 was added DIBAL-H (0.85 mL, 1M in CH 2 CI 2 ) and reaction mixture was allowed to warm to ambient temperature over 3 hours. The reaction mixture was then cooled (-78 °C) and MeOH was added followed by saturated potassium sodium tartrate solution (300 ⁇ ).
• GBT911 2-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methoxy)-6- hydroxybenzaldehyde.
• the compound was prepared from ethyl 2-fluoronicotinate and (5)- 3-fluoro rrolidine according to reaction scheme below.
• Step la To a solution of ethyl 2-fluoronicotinate (0.090 g, 0.58 mmol) in DMF (0.3 mL) was added diisopropylethyl amine (0.51 mL, 2.9 mmol), and (5)-3-fluoropyrrolidine (0.10 g, 1.2 mmol). The resulting mixture was irradiated with microwaves (100 °C) for lh and loaded directly onto a silica column. Eluting the column with EtOAc/hexanes (0-100%) provided (S)-ethyl 2-(3-fluoropyrrolidin-l-yl)nicotinate as a clear oil (0.100 g, 46% yield). MS (ES) for C12H15FN2O2: 225 (MH + ).
• Step lb To a cooled (0 °C) solution of (S)-methyl 2-(3-fluoropyrrolidin-l- yl)nicotinate (0.20 g, 0.87 mmol) in THF (5 mL) was added a solution of lithium aluminum hydride (2.6 mL, 1M in THF). The reaction mixture was stirred for lh and then 20 ⁇ of H 2 0 was added followed by 20 ⁇ of 15% NaOH (aq) and then 60 ⁇ of additional H 2 0. The slurry was stirred for lh, filtered and the resulting residue was washed with ether. The combined organic layers were dried over MgS0 4 and concentrated in vacuo.
• Step 2 To a cooled (0 °C) solution of (S)-(2-(3-fluoropyrrolidin-l-yl)pyridin-3- yl)methanol (0.081 g, 0.77 mmol) in dichloromethane was added SOCI 2 (0.92 g, 7.7 mmol) and the reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was concentrated and azeotroped with toluene to provide (S)-3- (chloromethyl)-2-(3-fluoropyrrolidin-l-yl)pyridine (0.180 g, 99%) as a clear oil. MS (ES) for C10H12CI FN2: 215 (MH + ).
• Step 3 To a solution of provide (5)-3-(chloromethyl)-2-(3-fluoropyrrolidin-l- yl)pyridine (0.085 g, 0.40 mmol) and 5-hydroxy-2,2-dimethyl-4H-benzo[d] [l,3]dioxin-4-one (0.12 g, 0.59 mmol) in DMF was added cesium carbonate (0.39 g, 0.12 mmol) and the reaction mixture was heated (60 °C). After 30 minutes, the reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate and the aqueous layer was extracted two times with EtOAc.
• Step 4 To a cooled (-78 °C) solution of (S)-5-((2-(3-fluoropyrrolidin-l-yl)pyridin-3- yl)methoxy)-2,2-dimethyl-4H-benzo[d][l,3]dioxin-4-one (0.085 g, 0.23 mmol) in CH 2 CI 2 was added DIBAL-H (0.68 mL, 1M in CH 2 CI 2 ) and reaction mixture was allowed to warm to ambient temperature over 3 hours. The reaction mixture was then cooled (-78 °C) and MeOH was added followed by saturated potassium sodium tartrate solution (300 ⁇ ). This mixture was stirred for 2 hours at ambient temperature and filtered over Celite.
• GBT1028 Z-hydroxy-e-iiZ' ⁇ ' ⁇ ' ⁇ '-tetramethyl-l' ⁇ ' ⁇ ' ⁇ '-tetrahydro-lZ ⁇ '- bipyridin]-3-yl)methoxy)benzaldehyde.
• the compound was prepared by Suzuki coupling of 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6- tetrahydropyridine and 2-((2-bromopyridin-3-yl)methoxy)-6-
• GBT1045-2 hydroxy-6-((2-(4-methylpiperazin-l-yl)pyridin-3- yl)methoxy)benzaldehyde.
• the compound was prepared from methyl 2-chloronicotinate
• Step la Into a 100-m L round-bottom flask, was placed a solution of methyl 2- chloropyridine-3-carboxylate (2.0 g, 11.66 mmol, 1.00 equiv) in N,N-dimethylformamide m L). 1-methylpiperazine (1.75 g, 17.47 mmol, 1.50 equiv), potassium carbonate (3.30 g, 23.88 mmol, 2.00 equiv), 18-crown-6 (200 mg, 0.06 equiv) were added to the reaction. The resulting solution was stirred overnight at 100°C. The reaction mixture was cooled to room temperature. The resulting solution was diluted with 30 mL of H 2 0, and then it was extracted with 5x30 mL of ethyl acetate. The com bined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with
• Step lb Into a 100-m L round-bottom flask, was placed a solution of methyl 2-(4- methylpiperazin-l-yl)pyridine-3-carboxylate (1.3 g, 5.53 mmol, 1.00 equiv) in
• Step 2 Into a 50-m L round-bottom flask, was placed a solution of [2-(4- methylpiperazin-l-yl)pyridin-3-yl] methanol (200 mg, 0.96 mmol, 1.00 equiv) in
• the crude product (200 mg) was purified by Prep-H PLC with the following conditions ( Prep-H PLC-010): Column, Sun Fire Prep C18 OBD Column, 5um, 19* 150mm,; mobile phase, water with 0.05%TFA and MeCN (25.0% MeCN up to 42.0% in 13 min, up to 95.0% in 2 min, down to 25.0% in 2 min); Detector, Waters2545 UvDector 254&220nm.
• GBT1249 2-((2-chloropyridin-3-yl)methoxy)-6-(methoxymethoxy)benzaldehyde.
• the compound was prepared by O-alkylation of 2-hydroxy-6-
• the compound was prepared by Suzuki coupling of 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane and 2-((2-bromopyridin-3-yl)methoxy)-6- (methoxymethoxy)benzaldehyde according to scheme 4, reaction step 2; the MOM ether protecting group was removed by treating with cone HQ (2eq) in TH F. The product was obtained as light brown solid after silica gel chromatography. 1 H N M R (400 M Hz,
• GBT1063 2-hydroxy-6-((2-(4-methyl-l,4-diazepan-l-yl)pyridin-3- yl)methoxy)benzaldehyde.
• the compound was prepared from methyl 2-chloronicotinate and l-meth l-l,4-diazepane according to scheme 5, reaction steps 1 and 2.
• Step la Into a 100-m L round-bottom flask, was placed a solution of methyl 2- chloropyridine-3-carboxylate (2.0 g, 11.66 mmol, 1.00 equiv) in N,N-dimethylformamide (40 m L). l-methyl-l,4-diazepane (2.0 g, 17.51 mmol, 1.50 equiv), potassium carbonate (3.3 g, 23.88 mmol, 2.00 equiv), and 18-crown-6 (200 mg, 0.06 equiv) were added to the reaction. The resulting solution was stirred overnight at 100°C. The reaction mixture was cooled to room temperature, and then it was diluted with 40 mL of H 2 0.
• Step lb Into a 100-mL round-bottom flask, was placed a solution of methyl 2-(4- methyl-l,4-diazepan-l-yl)pyridine-3-carboxylate (1.2 g, 4.81 mmol, 1.00 equiv) in tetrahydrofuran (40 mL). This was followed by the addition of LiAIH 4 (500 mg, 13.18 mmol, 2.00 equiv) at 0°C. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 0.5 mL of water, 1.5 mL of 15% NaOH,0.5 mL of H 2 0. The solids were filtered out.
• LiAIH 4 500 mg, 13.18 mmol, 2.00 equiv
• Step 2 Into a 50-mL round-bottom flask, was placed a solution of [2-(4-methyl-l,4- diazepan-l-yl)pyridin-3-yl]methanol (300 mg, 1.36 mmol, 1.00 equiv) in tetrahydrofuran (25 mL). 2,6-Dihydroxybenzaldehyde (280 mg, 2.03 mmol, 1.50 equiv) and PPh 3 (532 mg, 2.03 mmol, 1.50 equiv) were added to the reaction. This was followed by the addition of DIAD (410 mg, 2.03 mmol, 1.50 equiv) at 0°C.
• DIAD 410 mg, 2.03 mmol, 1.50 equiv
• GBT1121 2-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)methoxy)-6- hydroxybenzaldehyde.
• the compound was prepared from methyl 2-fluoronicotinate and 2- oxa-6-azaspiro[3.3]heptane according to scheme 5, reaction steps 1 and 2.
• Step la Methyl 2-fluoronicotinate (0.3 g, 1.93 mmol) and 2-oxa-6- azaspiro[3.3]heptane oxalate (0.55 g, 2.9 mmol) were combined with DMF (3 ml). N,N- diisopropylethylamine (2 ml, 11.6 mmol) was added and the mixture was heated in a microwave reactor (120 °C, 1 h). Ethyl acetate (100 ml) and water (50 ml) were added to the cooled solution and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 x 50 ml).
• Step lb Methyl 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinate (0.26 g, 1.1 mmol) was dissolved in TH F (5 ml) and stirred in an ice bath. Lithium aluminum hydride (2.2 ml of a 1M THF solution) was added dropwise. The reaction was stirred to 25 °C over 2 h. Water (0.084 ml) was carefully added followed by 15% aqueous sodium hydroxide solution (0.084 ml) and water (0.25 ml).
• Step 2 2-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)methanol (0.12 g, 0.582 mmol) 2,6-dihydroxybenzaldehyde (96 mg, 0.7 mmol) and triphenylphosphine-polystyrene resin (0.63 g, 0.76 mmol) were combined with THF (3 ml), and stirred in an ice bath.
• GBT1122- 2-Hydroxy-6-((2-morpholinopyridin-3-yl)methoxy)benzaldehyde The compound was prepared from ethyl 2-fluoronicotinate and morpholine according to a
• Step la To a solution of ethyl 2-fluoronicotinate (0.40 g, 2.6 mmol) in DMF (0.3 mL) was added diisopropylethyl amine (1.8 mL, 10 mmol), and morpholine (0.45 g, 5.2 mmol). The resulting mixture was irradiated with microwaves (100 °C) for lh and loaded directly onto a silica column. Eluting the column with EtOAc/hexanes (0-100%) Methyl 2- morpholinonicotinate as a clear oil (0.36 g, 62% yield). MS (ES) for Ci 2 Hi 6 N 2 0 3 : 237 (MH + ).
• Step lb To a cooled (0 °C) solution of Methyl 2-morpholinonicotinate (0.36 g, 1.6 mmol) in THF (5 mL) was added a solution of lithium aluminum hydride (4.9 mL, 1M in TH F). The reaction mixture was stirred for lh and then 180 ⁇ of H20 was added followed by 180 ⁇ of 15% NaOH (aq) and then 540 ⁇ of additional water. The slurry was stirred for lh and filtered and the resulting residue was washed with ether. The combined organic layers were dried over MgS0 4 and concentrated in vacuo.
• Step 3 To a cooled (0 °C) solution of provided (2-morpholinopyridin-3-yl)methanol (0.100 g, 0.51 mmol) in dichloromethane was added SOCI 2 (0.50 mL, 6.9 mmol) and the reaction mixture was allowed to warm to ambient temperature.
• Step 4 To a solution of 4-(3-(chloromethyl)pyridin-2-yl)morpholine (0.11 g, 0.50 mmol) and 2-hydroxy-6-(methoxymethoxy)benzaldehyde (0.09 g, 0.50 mmol) in DM F was added potassium carbonate (0.210 g, 1.5 mmol) and the reaction mixture was heated (60 °C). After 30 minutes, the reaction mixture was partitioned between EtOAc and saturated NaHC0 3 and the aqueous layer was extracted twice with EtOAc.
• Step 5 To a solution of 2-(methoxymethoxy)-6-((2-morpholinopyridin-3- yl)methoxy)benzaldehyde (0.120 g, 0.33 mmol) in THF (5 mL) was added concentrated HCI (0.5 mL, 6 mmol). After stirring at ambient temperature for 3 hours, the mixture was partitioned between EtOAc and saturated aqueous NaHC0 3 and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgS0 4 and concentrated in vacuo.

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