WO2006055245A2 - Process for preparing pyrazolopyridine compounds - Google Patents

Process for preparing pyrazolopyridine compounds Download PDF

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Publication number
WO2006055245A2
WO2006055245A2 PCT/US2005/039571 US2005039571W WO2006055245A2 WO 2006055245 A2 WO2006055245 A2 WO 2006055245A2 US 2005039571 W US2005039571 W US 2005039571W WO 2006055245 A2 WO2006055245 A2 WO 2006055245A2
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het
pyrimidin
methylthio
cycloalkyl
pyrazolo
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PCT/US2005/039571
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French (fr)
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WO2006055245A3 (en
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Kristjan Gudmundsson
Brian A. Johns
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Smithkline Beecham Corporation
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Publication of WO2006055245A3 publication Critical patent/WO2006055245A3/en

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    • 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
    • C07D471/02—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

Definitions

  • the present invention relates to a novel process for preparing pyrazolopyridine compounds.
  • Pyrazolopyridine compounds which may be prepared using the processes of the present invention are described in PCT Publication Nos. WO02/48148, published 20 June 2002, WO02/48147, published 20 June 2002, WO02/72581 , published 19 September 2002, and WO02/088124, published 7 November 2002, all to SmithKline Beecham Corp., together with pharmaceutical formulations containing the same, therapeutic uses thereof and other processes for their preparation.
  • the present invention provides processes for preparing a compound of formula (I):
  • R 1 is aryl or heteroaryl
  • R 2 is selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, Ay, Het, -OR 7 , -OAy, -OHet, -OR 10 Het, -S(O) n R 9 ,
  • R 7 and R 8 are the same or different and are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkenyl, -C(O)R 9 , -CO 2 R 9 , -C(O)NR 9 R 11 , -C(S)NR 9 R 11 , -C(NH)NR 9 R 11 , -SO 2 R 10 , - SO 2 NR 9 R 11 , -R 10 cycloalkyl, -R 10 OR 9 , -CH(R 10 OR 9 ) 2 , -R 10 C(O)R 9 , -R 10 CO 2 R 9 , -R 10 C(O)NR 9 R 11 , -R 10
  • R 3 and R 4 are the same or different and are each independently selected from the group consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, -OR 7 , -OAy, - C(O)R 7 , C(O)Ay, -CO 2 R 7 , -CO 2 Ay, -SO 2 NHR 9 , -NR 7 R 8 , -NR 7 Ay, -NHHet, -
  • each R 6 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, - OR 7 , -OAy, -OHet, -OR 10 Ay, -OR 10 Het, -C(O)R 9 , -C(O)Ay, -C(O)Het, -CO 2 R 9 , -C(O)NR 7 R 8 , -C(O)NR 7 Ay, -C(O)NHR 10 Ay,
  • R 2 is -S-CH 3 ; c) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt or solvate thereof; and d) optionally converting the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof into a different compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound selected from the group consisting of: 2-(4-Fluorophenyl)-7-(4-methylphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5- a]pyridine; 2-(4-Fluorophenyl)-7-(3-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5- a]pyridine; 2-(4-Fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]-7-pyridin-3-ylpyrazolo[1 ,5- a]pyridine;
  • a compound of the invention or "a compound of formula (I)” means a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the phrase "a compound of formula (number)” means a compound having that formula and pharmaceutically acceptable salts and solvates thereof.
  • alkyl refers to straight or branched hydrocarbon chains containing from 1 to 8 carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, and tert-butyl.
  • alkylene as used herein include, but are not limited to, methylene, ethylene, propylene, butylene, and isobutylene.
  • Alkyl also includes substituted alkyl. The alkyl groups may be optionally substituted with one or more substituents selected from the group consisting of mercapto, nitro, cyano and halo. Perhaloalkyl, such as trifluoromethyl is one particular alkyl group.
  • cycloalkyl refers to a non-aromatic carbocyclic ring having from 3 to 8 carbon atoms and no carbon-carbon double bonds.
  • Cycloalkyl includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Cycloalkyl also includes substituted cycloalkyl.
  • the cycloalkyl may be optionally substituted on an available carbon with one or more substituents selected from the group consisting of mercapto, nitro, cyano, halo and alkyl.
  • alkenyl refers to straight or branched hydrocarbon chains containing from 2 to 8 carbon atoms and at least one and up to three carbon-carbon double bonds.
  • alkenyl as used herein include, but are not limited to ethenyl and propenyl.
  • Alkenyl also includes substituted alkenyl.
  • the alkenyl groups may optionally be substituted on an available carbon with one or more substituents selected from the group consisting of mercapto, nitro, cyano, halo and alkyl.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring having from 3 to 8 carbon atoms (unless otherwise specified) and up to 3 carbon- carbon double bonds.
  • Cycloalkenyl includes by way of example cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • Cycloalkenyl also includes substituted cycloalkenyl.
  • the cycloalkenyl may optionally be substituted on an available carbon with one or more substituents selected from the group consisting of mercapto, nitro, cyano, halo and alkyl.
  • alkynyl refers to straight or branched hydrocarbon chains containing from 2 to 8 carbon atoms and at least one and up to three carbon-carbon triple bonds.
  • alkynyl as used herein include, but are not limited to ethynyl and propynyl.
  • Alkynyl also includes substituted alkynyl.
  • alkynyl groups may optionally be substituted on an available carbon with one or more substituents selected from the group consisting of mercapto, nitro, cyano, halo and alkyl.
  • halo or halogen refers to the elements fluorine, chlorine, bromine and iodine.
  • aryl refers to monocyclic carbocyclic groups and fused bicyclic carbocyclic groups having from 5 to 12 carbon atoms and having at least one aromatic ring. Examples of particular aryl groups include but are not limited to phenyl and naphthyl. "Aryl” also includes substituted aryl.
  • Aryl groups may optionally be substituted on an available carbon with one or more substituents selected from the group consisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido.
  • substituents selected from the group consisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido.
  • heterocyclic refers to a monocyclic saturated or unsaturated non-aromatic groups and fused bicyclic non-aromatic groups, having the specified number of members and containing 1 , 2, 3 or 4 heteroatoms selected from N, O and S.
  • heterocyclic groups include but are not limited to tetrahydrofuran, dihydropyran, tetrahydropyran, pyran, oxetane, thietane, 1 ,4-dioxane, 1 ,3-dioxane, 1 ,3-dioxalane, piper ⁇ dine, piperazine, tetrahydropyrimidine, pyrrolidine, morpholine, thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
  • Heterocyclic also includes substituted heterocyclic.
  • the heterocyclic groups may optionally be substituted on an available carbon or heteroatom with one or more substituents selected from the group consisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido.
  • substituents selected from the group consisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azid
  • heteroaryl refers to aromatic monocyclic groups and aromatic fused bicyclic groups having the specified number of members and containing 1 , 2, 3, or 4 heteroatoms selected from N, O and S.
  • heteroaryl groups include but are not limited to furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, and indazole.
  • Heteroaryl also includes substituted heteroaryl.
  • the heteroaryl groups may optionally be substituted on an available carbon or heteroatom with one or more substituents selected from the group consisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido.
  • heteroaryl groups include but are not limited to pyridine, furan, thiophene, pyrrole, imidazole, pyrazole and pyrimidine, and substituted variants thereof.
  • the term "members" (and variants thereof e.g., “membered") in the context of heterocyclic and heteroaryl groups refers to the total atoms, carbon and heteroatoms N, O and/or S, which form the ring.
  • an example of a 6-membered heterocyclic ring is piperidine and an example of a 6-membered heteroaryl ring is pyridine.
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and events that do not occur.
  • the present invention provides processes for preparing compounds of formula (I):
  • R 1 is aryl or heteroaryl
  • R 2 is selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, Ay, Het, -OR 7 , -OAy, -OHet, -OR 10 Het, -S(O) n R 9 ,
  • Ay is aryl
  • Het is a 5- or 6-membered heterocyclic or heteroaryl group; each R 7 and R 8 are the same or different and are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkenyl,
  • Y is N or CH
  • R 3 and R 4 are the same or different and are each independently selected from the group consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, -OR 7 , -OAy, - C(O)R 7 , C(O)Ay 1 -CO 2 R 7 , -CO 2 Ay, -SO 2 NHR 9 , -NR 7 R 8 , -NR 7 Ay, -NHHet, -
  • each R 6 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, - OR 7 , -OAy, -OHet, -OR 10 Ay, -OR 10 Het, -C(O)R 9 , -C(O)Ay, -C(O)Het, -CO 2 R 9 , -C(O)NR 7 R 8 , -C(O)NR 7 Ay, -C(O)NHR 10 Ay,
  • R 1 is Ay.
  • R 1 is phenyl or substituted phenyl (i.e., phenyl substituted one or more times with a substituent(s) selected from the group consisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido).
  • a substituent(s) selected from the group consisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, car
  • R 1 is 5- or 6-membered heteroaryl. In one embodiment, R 1 is a 5-6 membered heteroaryl including 1 , 2 or 3 heteroatoms selected from N, O and S or substituted 5-6 membered heteroaryl including 1 , 2 or 3 heteroatoms selected from N, O and S (i.e,.
  • R 1 is a 5-6 membered heteroaryl including 1 heteroatom selected from N, O and S or substituted 5-6 membered heteroaryl including 1 heteroatom selected from N, O and S.
  • R 1 is selected from the group consisting of furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, and substituted variants thereof.
  • R 1 is selected from the group consisting of pyridine, furan, thiophene, pyrrole, imidazole, pyrazole and pyrimidine, and substituted variants thereof.
  • R 2 is selected from the group consisting of Het, -OR 7 , -OAy 1 -OHet, -OR 10 Het, -S(O) n R 9 , -S(O) n Ay, -NR 7 R 8 , -N(R 7 )Ay, -NHHet and -NHR 10 Het, or any subset thereof. More particularly, R 2 is selected from the group consisting of Het, -S(O) n R 9 , -NR 7 R 8 , -N(R 7 )Ay, -NHHet and NHR 10 Het, or any subset thereof. In one embodiment, R 2 is selected from the group consisting of Het, -OR 7 , -OAy 1 -OHet, -OR 10 Het, -S(O) n R 9 , -S(O) n Ay, -NR 7 R 8 , -N(R 7 )Ay, -NHHet and
  • R 2 is -NR 7 R 8 .
  • R 2 is -N(R 7 )Ay.
  • R 2 is -S(O) n R 9 .
  • R 2 is selected from the group consisting of -S-alkyl, -NH 2 , -NH- alkyl, -NH-cycloalkyl, -N(alkyl)(alkyl), -N(H)Ay, -N(alkyl)Ay, Het (e.g., pyrrolidine), - NHHet and -NH-alkyl-Het, or any subset thereof. More particularly, R 2 is selected from the group consisting of -S-alkyl, -NH-alkyl, -NH-cycloalkyl, -N(H)Ay and -N(alkyl)Ay, or any subset thereof.
  • R 2 groups are selected from the group consisting of -S-methyl, -NH 2 , -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, - NH-cyclopropyl, -NH-butyl, -NH-isobutyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH- cyclohexyl, -N(H)phenyl, -NH(CH 2 ⁇ OCH 3 , and pyrrolidine (e.g., pyrrolidine bonded through N).
  • pyrrolidine e.g., pyrrolidine bonded through N.
  • R 7 and R 8 are each the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl,
  • R 7 and R 8 are each the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl and R 10 -cycloalkyl, or any subset thereof.
  • R 7 and R 8 are each the same or different and are independently selected from the group consisting of H, alkyl and cycloalkyl or any subset thereof.
  • R 9 and R 11 refers to a linear PEG-like chain.
  • R 9 and R 11 are each the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, and -R 10 - cycloalkyl, or any subset thereof. More particularly, R 9 and R 11 are each the same or different and are each independently selected from the group consisting of H and alkyl, or any subset thereof.
  • R 10 is alkyl or cycloalkyl; more particularly alkyl.
  • Y is CH. In another class of compounds of formula (I), Y is N.
  • R 3 is selected from the group consisting of H, halo, alkyl, Ay, - OR 7 , -CO 2 R 7 , -NR 7 R 8 , -R 10 OR 7 and -R 10 NR 7 R 8 , or any subset thereof. More particularly, R 3 is selected from the group consisting of H, halo, alkyl, -OR 7 and -NR 7 R 8 , or any subset thereof. In one particular embodiment R 3 is H or alkyl. In one embodiment R 3 is H.
  • R 4 is selected from the group consisting of H, halo, alkyl, Ay, - OR 7 , -CO 2 R 7 , -NR 7 R 8 , -R 10 OR 7 and -R 10 NR 7 R 8 , or any subset thereof. More particularly R 4 is selected from the group consisting of H, halo, alkyl, OR 7 and - NR 7 R 8 , or any subset thereof. In one particular embodiment, R 4 is H or alkyl. In one embodiment R 4 is H.
  • q is 0, 1 or 2. In one particular embodiment, q is 0. In another particular embodiment, q is 1. In one embodiment, q is 2 and optionally two adjacent R 5 groups together with the atoms which they are bonded, they form a Cs-6 cycloalkyl or aryl.
  • the phrase "two adjacent R 5 groups" refers to two R 5 groups, each bonded to adjacent carbon atoms on the phenyl ring. In the embodiment where two adjacent R 5 groups together with the atoms to which they are bonded form a cycloalkyl or aryl, q is typically 2, 3, 4 or 5; more typically 2.
  • R 5 may be in the ortho, meta and/or para position.
  • each R 5 group may be the same or different and is typically selected from the group consisting of alkyl and alkenyl.
  • two adjacent R 5 groups are alkyl and together with the atoms to which they are bonded, they form a cycloalkyl group such as:
  • each R 5 group is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, Ay, Het, -OR 7 , -OAy, - CO 2 R 9 , -C(O)NR 7 R 8 , -C(O)NR 7 Ay, -S(O) 2 NR 7 R 8 , -NR 7 R 8 , -NR 7 Ay, -NHR 10 Ay, cyano, nitro and azido, or any subset thereof. More particularly, each R 5 group is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, Ay, Het, -OR 7 ,
  • each R 5 group is the same or different and is independently selected from the group consisting of halo, alkyl, -OR 7 , -NR 7 R 8 and cyano, or any subset thereof.
  • the compounds of formula (I) are defined where R 5 is H, halo (e.g., fluoro, chloro or bromo), alkyl (e.g., methyl), O-alkyl (e.g., O-methyl, O-isobutyl, and ), " cy%no ⁇ NH-CH 3 , and
  • p is 0, 1 or 2, more particularly 0 or 1.
  • R may be in the 4, 5 or 6 position.
  • p is 1 and R is in the C-5 position.
  • p is 1 and R 6 is in the C-6 position.
  • p is 2 and one R 6 is in the C-5 position and one R 6 is in the C-6 position (thus defining a class of compounds of formula (I) having two adjacent R 6 groups). In the embodiments where two adjacent R 6 groups together with the atoms to which they are bonded form a C 5 .
  • each R 6 group may be the same or different and is typically selected from the group consisting of alkyl, alkenyl, -OR 7 , -NR 7 R 8 and - S(O) n R 9 .
  • two adjacent R 6 groups are -OR 7 and together with the atoms to which they are bonded, they form a heterocyclic group such as:
  • two adjacent R 6 groups are alkyl and together with the atoms to which they are bonded, they form a cycloalkyl group such as:
  • two adjacent R 6 groups are defined as -OR 7 , -NR 7 R 8 respectively and together with the atoms to which they are bonded, they form a heterocyclic group such as:
  • two R 6 groups together with the atoms to which they are bonded do not form a C 5-6 cycloalkyl or a 5- or 6-membered heterocyclic group.
  • each R 6 is the same or different and is independently selected from the group consisting of halo, alkyl, Ay, Het, -OR 7 , -OAy, -OHet, -C(O)Het, - CO 2 R 9 , -C(O)NR 7 R 8 , -C(O)NR 7 Ay, -C(O)NHR 10 Het, -NR 7 R 8 , -NR 7 Ay, -NHHet, -NHR 10 Ay, -NHR 10 Het, -R 10 OR 9 and cyano, or any subset thereof. More particularly, each R 6 is the same or different and is independently selected from the group consisting of halo, alkyl, -OR 7 ,
  • each R 6 is the same or different and is independently selected from the group consisting of halo, alkyl, -C(O)NR 7 R 8 , -NR 7 R 8 , -NR 7 Ay, -NHHet, -NHR 10 Ay, and -NHR 10 Het, or any subset thereof.
  • R 6 is selected from the group consisting of Cl, Br, -O-alkyl, -O-alkyl-O-alkyl, -S-alkyl, -NH 2 , -NH-alkyl, -NHR 10 OR 9 , -NH-cycloalkyl, and -NH-SO 2 -alkyl, or any subset thereof.
  • R 6 is selected from the group consisting of Cl, Br, -O-CH 3 , -O-(CH 2 ) 2 -O-CH 3 , -S-CH 3 , -NH 2 , -NHCH(CH 3 ) 2 , -NHcyclopropyl, -NHcyclopentyl, -NH(CH 2 ) 2 -O-CH 3 and -NH-SO 2 -CH 3 , or any subset thereof.
  • R 6 is halo, such as Cl or Br.
  • R 6 is trifluoromethyl.
  • the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof.
  • the pharmaceutically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium salts.
  • suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like.
  • the compounds of formula (I) are in the form of the mesylate salt.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N 1 N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts.
  • solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula (I)) and a solvent.
  • Solvents include water, methanol, ethanof, or acetic acid.
  • Certain compounds of formula (I) may exist in stereoisomer ⁇ forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism).
  • the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.
  • the present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted.
  • the compounds of formula (I) are useful as pharmaceutically active agents.
  • X is halo or triflate
  • Me is methyl
  • LDA lithium diisopropylamide
  • 9-BBN-OMe 9-methoxy-9-borabicyclo[3.3.1]nonane; and all other variables are as defined above.
  • the process comprises the steps of: a) with a hindered amide base to produce an anion and reacting the anion with 9- methoxy-9-borabicyclo[3.3.1]nonane; b) adding a compound of formula R 1 -X in the presence of a palladium catalyst to prepare a compound of formula (I) wherein R 2 is -S-CH 3 ; c) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt or solvate thereof; and d) optionally converting the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof into a different compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of formula (I) is prepared by a Suzuki coupling process.
  • the compound of formula (II) is deprotonated with a hindered amide base and the anion so produced is reacted with 9-methoxy-9-borabicyclo[3.3.1]nonane to prepare the borinate intermediate in situ.
  • the reaction is typically carried out in a solvent, such as for example tetrahydrofuran.
  • the reaction may be carried out at a temperature of from about -78°C to about room temperature.
  • a suitable hindered amide base is lithium diisopropylamide, others will be apparent to those skilled in the art.
  • the compounds of formula (II) may be prepared by processes known in the art, including those described in PCT Publication Nos.
  • the coupling of the aryl, heteroaryl or heterocyclic group is achieved by addition of R 1 -X in the presence of a palladium (0) catalyst.
  • This step is conveniently carried out in situ, without isolation of the borinate intermediate.
  • This step can be conveniently performed in an inert solvent, optionally with heating.
  • the reaction is performed by reacting equimolar amounts of the reactants or optionally adding an excess of the halide compound.
  • the palladium catalyst is typically present in 1-10 mol% compared to the compound of formula (II).
  • Palladium catalysts that may be used may include, but are not limited to, tetrakistriphenylphosphine palladium (0) dichlorobis(triphenylphosphine)palladium(ll), and bis(diphenylphosphino- ferrocene)palladium (II) dichloride.
  • the palladium (0) catalyst is bis(diphenylphosphinoferrocene)-palladium (II) dichloride.
  • Inert solvents for use in the reaction include but are not limited to, ⁇ /, ⁇ £dimethylformamide, toluene, tetrahydrofuran, dioxane, and 1 -methyl-2-pyrrolidinone. In one preferred embodiment, the solvent is ⁇ /, ⁇ Adimethylformamide.
  • the reaction may be facilitated by adding a base in a proportion equivalent to, or greater than, that of the halide compound.
  • suitable bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium phosphate, potassium carbonate, sodium bicarbonate, sodium methoxide, and cesium fluoride.
  • the step of adding the halide compound further comprises the presence of a base.
  • the base is potassium phosphate.
  • a wide variety of halide compounds of formula R 1 -X are commercially available.
  • the availability of aryl halides and heteroaryl halides offers an advantage of the present invention over the conventional Suzuki coupling processes previously disclosed.
  • Conventional Suzuki coupling process for preparing pyrazolopyridines of formula (I) require metal compounds of formula Ay-M or heteroaryl-M, wherein Ay and heteroaryl are as defined above and M is B(OH) 2 , B(Ra) 2 , B(ORa) 2 , Sn(Ra) 3 , Zn- halide, Zn-Ra or Mg-halide.
  • the conventional method also requires the pyrazolopyridine coupling partner to contain a halogen or triflate to serve as the electrophile in the synthesis.
  • the current method contained herein effectively accomplishes an umpolung by reversing the electrophile and transmetalation partner further increasing the usefulness of the Suzuki coupling reaction in the context of the pyrazolopyridine ring system.
  • the process of the present invention may be carried out in situ, in a single reaction vessel, thus providing efficiencies which may facilitate the preparation of commercial quantities of the compounds of formula (I). Further, the process of the present invention does not require the isolation of the borinate intermediate, further simplying the synthesis of the compounds of formula (I) and adding efficiency. Additional advantages of the process of the present invention will be apparent to those skilled in the art.
  • one method of converting a compound of formula (I-A) to a different compound of formula (I) comprises a) oxidizing the compound of formula (I-A) to prepare a compound of formula (I-B) and then b) optionally reacting a compound of formula (I-B) with an oxygen or amine nucleophile selected from the group consiting of Het bonded through N, -OR 7 , -OAy, -OHet, -OR 10 Het, -NR 7 R 8 , -NHHet, -NHR 10 Ay and -NHR 10 Het to produce a compound of formula I wherein R 2 is selected from the group consisting of Het bonded through N, -OR 7 , -OAy, -OHet, -OR 10 Het, -NR 7 R 8 , -NHHet, -NHR 10 Ay and -NHR 10 Het; n' is 1 or 2; and all other variables are as defined above.
  • compounds of formula (I) can be prepared by reacting a compound of formula (I-B) (i.e., compounds of formula I wherein R 2 is S(O) n R 9 where n 1 is 1 or 2) with an oxygen or amine nucleophile selected from the group consisting of Het bonded through N, -OR 7 , -OAy, -OHet,
  • the reaction may be carried out neat or in a suitable solvent and may be heated to 50-150 0 C.
  • the solvent is a lower alcohol such as methanol, ethanol, isopropanol and the like or solvent such as ⁇ /,/V-dimethylformamide or tetrahydrofuran, and the like.
  • a base may be used to facilitate the reaction.
  • the base can be potassium carbonate, or an amine base such as triethylamine.
  • Compounds of formula (I-B) may be conveniently prepared by oxidizing a compound of formula (I-A) (i.e., compounds of formula I wherein R 2 is S(O) n R 9 where n is 0) with an oxidizing agent in an inert solvent, optionally in the presence of a base.
  • a compound of formula (I-A) i.e., compounds of formula I wherein R 2 is S(O) n R 9 where n is 0
  • an oxidizing agent in an inert solvent, optionally in the presence of a base.
  • Suitable solvents include but are not limited to, dichloromethane, chloroform and the like.
  • Example 1 2-(4-FluorophenvO-7-(4-methylphenyO-342-(methylthio)pyrimidin-4- yl
  • Example 3 2-(4-Fluorophenyl)-3-f2-(methylthio)pyrimidin-4-yl]-7-pyridin-3- ylpyrazoloH ,5-alpyridine.
  • Example 4 1-(4- ⁇ 2-(4-Fluorophenyl)-3-[2-(methylthio)pyrimidin-4-vnpyrazolo[1 ,5- alpyridin-7-yl ⁇ phenyl)ethanone.
  • Example 6 7-(3-Methoxyphenyl)-2-(4-methoxypheny ⁇ -3-[2-(methylthio)pyrimidin-4- ylipyrazoloH ,5-alpyridine.
  • Example 7 4- ⁇ 2-(4-Methoxyphenv ⁇ -3-[2-(methylthio)pyrimidin-4-yllpyrazolo ⁇ ,5- aiPVridin-7-yl)phenylamine.
  • Example 8 2-(4-Methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl1-7-tr ⁇ ien-3- ylpyrazolop ,5--?]pyridine.
  • Example 2 In a similar manner to Example 1 , from 4- ⁇ [4-(cyclopropylmethoxy)phenyl]ethynyl ⁇ - 2-(methylthio)pyrimidine (600 mg, 2.0 mmol), 1-aminopyridinium iodide (585 mg, 2.65 mmol), and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL, 3.0 mmol) in acetonitrile 20 mL) was formed 2-[4-(cyclopropylmethoxy)phenyl]-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine (556 mg, 71 %) as a white solid.
  • Example 10 2-f4-(Cvclopropylmethoxy)phenyl]-7-(4-fluorophenyl)-3-[2- (methylthio)pyrimidin-4-yllpyrazolof1 ,5-a]pyridine.
  • Example 11 2-f4-(Cvclopropylmethoxy)phenyl1-7-(4-methoxyphenyl)-3-
  • Example 12 2-[4-(Cyclopropylmethoxy)phenvn-7-(3-methylphenyl)-3-[2- (methylthio)pyrimidin-4-v ⁇ pyrazolo[1 ,5-a]pyridine.
  • Example 14 1- ⁇ 4-f3-[2-(Cvclopentylamino)pyrimidin-4-vn-2-(4- fluorophenyl)pyrazolo[1 ,5-alpyridin-7-yl]phenyl)ethanone.
  • Example 15 ⁇ ACyclopentyl-4-
  • Example 16 yV-Cvclopentyl-4-[2-(4-fl ⁇ orophenv ⁇ -7-(4-methylphenyl)pyrazolof 1 ,5- a]pyridin-3-vnpyrimidin-2-amine.

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Abstract

The present invention provides a process for preparing pyrazolopyridine compounds.

Description

PROCESS FOR PREPARING PYRAZOLOPYRIDINE COMPOUNDS
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for preparing pyrazolopyridine compounds. Pyrazolopyridine compounds which may be prepared using the processes of the present invention are described in PCT Publication Nos. WO02/48148, published 20 June 2002, WO02/48147, published 20 June 2002, WO02/72581 , published 19 September 2002, and WO02/088124, published 7 November 2002, all to SmithKline Beecham Corp., together with pharmaceutical formulations containing the same, therapeutic uses thereof and other processes for their preparation.
BRIEF SUMMARY OF THE INVENTION
The present invention provides processes for preparing a compound of formula (I):
Figure imgf000002_0001
wherein:
R1 is aryl or heteroaryl; R2 is selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, Ay, Het, -OR7, -OAy, -OHet, -OR10Het, -S(O)nR9,
-S(O)nAy, -S(O)nHe-, -S(O)nNR7R8, -NR7R8, -N(R7)Ay, -NHHet,
-NHR10Ay, -NHR10Het, -R10NR7R8 and -R10NR7Ay; Ay is aryl; Het is a 5- or 6-membered heterocyclic or heteroaryl group; each R7 and R8 are the same or different and are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkenyl, -C(O)R9, -CO2R9, -C(O)NR9R11, -C(S)NR9R11, -C(NH)NR9R11, -SO2R10, - SO2NR9R11, -R10cycloalkyl, -R10OR9, -CH(R10OR9)2, -R10C(O)R9, -R10CO2R9, -R10C(O)NR9R11, -R10C(S)NR9R11, -R10C(NH)NR9R11, -R10SO2R10, -R10SO2NR9R11, -R10SO2NHCOR9, -R10NR9R11, -R10NHCOR9, -R10NHSO2R9 and -R10NHC(NH)NR9R11; each R9 and R11 are the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, -R10cycloalkyl, -R10OH, -R10(OR10)W where w is 1-10, and -R10NR10R10; each R10 is the same or different and is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl; n is O, 1 or 2; Y is N or CH;
R3 and R4 are the same or different and are each independently selected from the group consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, -OR7, -OAy, - C(O)R7, C(O)Ay, -CO2R7, -CO2Ay, -SO2NHR9, -NR7R8, -NR7Ay, -NHHet, -
NHR10Het -R10OR7, -R10OAy, -R10NR7R8 and -R10NR7Ay; q is O, 1, 2, 3, 4 or 5; each R5 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, - OR7, -OAy, -OHet, -C(O)R9, -C(O)Ay, -C(O)Het, -CO2R9,
-C(O)NR7R8, -C(O)NR7Ay, -C(O)NHR10Het, -C(S)NR9R11, -C(NH)NR7R8, -C(NH)NR7Ay, -S(O)nR9, -S(O)2NR7R8, -S(O)2NR7Ay, -NR7R8, -NR7Ay, -NHHet, -NHR10Ay, -NHR10Het, -R10cycloalkyl, -R10OR9, -R10C(O)R9, -R10CO2R9, -R10C(O)NR9R11, -R10C(S)NR9R11, -R10C(NH)NR9R11, -R10SO2R9, -R10SO2NR9R11, -R10SO2NHCOR9,
-R10NR7R8, -R10NR7Ay, -R10NHC(NH)NR9R11, cyano, nitro and azido; or two adjacent R5 groups together with the atoms to which they are bonded form a Cs-6 cycloalkyl or aryl; p is O, 1, 2 or 3; and each R6 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, - OR7, -OAy, -OHet, -OR10Ay, -OR10Het, -C(O)R9, -C(O)Ay, -C(O)Het, -CO2R9, -C(O)NR7R8, -C(O)NR7Ay, -C(O)NHR10Ay, -C(O)NHR10Het, -C(S)NR9R11, -C(NH)NR7R8, -C(NH)NR7Ay, -S(O)nR9, - S(O)nAy, -S(O)nHet, -S(O)2NR7R8, -S(O)2NR7Ay1 -NR7R8, -NR7Ay, -NHHet, -NHR10Ay, -NHR10Het, -R10cycloalkyl, -R10Ay, -R10Het, -R10OR9, -R10O-C(O)R9, -R10-O-C(O)Ay, -R10-O-C(O)Het, -R10-O-S(O)nR9, -R10C(O)R9, -R10CO2R9, -R10C(O)NR9R11,
-R10C(S)NR9R11, -R10C(NH)NR9R11, -R10SO2R9, -R10SO2NR9R11, -R10SO2NHCOR9, -R10NR7R8, -R10NR7Ay, -R10NHC(NH)NR9R11, cyano, nitro and azido; or two adjacent R6 groups together with the atoms to which they are bonded form a Cs-6 cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms; and pharmaceutically acceptable salts and solvates thereof.
In a first aspect of the invention there is provided a process for preparing a compound of formula (I) comprising the steps of: a) reacting a compound of formula (II):
Figure imgf000004_0001
with a hindered amide base to produce an anion and reacting the anion with 9- methoxy-9-borabicyclo[3.3.1 ]nonane; b) adding a compound of formula R1-X, wherein X is is halo or triflate, in the presence of a palladium catalyst to prepare a compound of formula (I), wherein
R2 is -S-CH3; c) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt or solvate thereof; and d) optionally converting the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof into a different compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In a second aspect the present invention provides a compound selected from the group consisting of: 2-(4-Fluorophenyl)-7-(4-methylphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5- a]pyridine; 2-(4-Fluorophenyl)-7-(3-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5- a]pyridine; 2-(4-Fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]-7-pyridin-3-ylpyrazolo[1 ,5- a]pyridine;
1-(4-{2-(4-Fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridin-7- yl}phenyl)ethanone;
7-(4-Fluorophenyl)-2-(4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5- ajpyridine; 7-(3-Methoxyphenyl)-2-(4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-a]pyridine; 4-{2-(4-Methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5--?]pyridin-7- yl}phenylamine; 2-(4-Methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]-7-thien-3-ylpyrazolo[1 ,5- ajpyridine;
2-[4-(Cyclopropylmethoxy)phenyl]-7-(4-methylphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1,5-a]pyridine;
2-[4-(Cyclopropylmethoxy)phenyl]-7-(4-fluorophenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-c?]pyridine; 2-[4-(Cyclopropylmethoxy)phenyl]-7-(4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-a]pyridine; 2-[4-(Cyclopropylmethoxy)phenyl]-7-(3-methylphenyl)-3-[2-(methyIthio)pyrimidin-4- yl]pyrazolo[1 ,5-a]pyridine; ΛACyclopentyl-4-[2-(4-fluorophenyl)-7-pyridin-3-ylpyrazolo[1 ,5-a]pyridin-3- yl]pyrimidin-2-amine;
1-{4-[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridin- 7-yl]phenyl}ethanone;
ΛACyclopentyl-4-[2-(4-fluorophenyl)-7-(3-methoxyphenyl)pyrazolo[1 ,5-a]pyridin-3- yl]pyrimidin-2-amine; /V-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(4-methylphenyl)pyrazolo[1 ,5-a]pyridin-3- yl]pyrimidin-2 -amine; and pharmaceutically acceptable salts and solvates thereof.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, "a compound of the invention" or "a compound of formula (I)" means a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Similarly, with respect to isolatable intermediates such as for example, compounds of formula (VIII), (IX), (XVI), (XX), and (XXII), the phrase "a compound of formula (number)" means a compound having that formula and pharmaceutically acceptable salts and solvates thereof.
As used herein, the terms "alkyl" (and alkylene) refer to straight or branched hydrocarbon chains containing from 1 to 8 carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, and tert-butyl. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, propylene, butylene, and isobutylene. "Alkyl" also includes substituted alkyl. The alkyl groups may be optionally substituted with one or more substituents selected from the group consisting of mercapto, nitro, cyano and halo. Perhaloalkyl, such as trifluoromethyl is one particular alkyl group.
As used herein, the term "cycloalkyl" refers to a non-aromatic carbocyclic ring having from 3 to 8 carbon atoms and no carbon-carbon double bonds. "Cycloalkyl" includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. "Cycloalkyl" also includes substituted cycloalkyl. The cycloalkyl may be optionally substituted on an available carbon with one or more substituents selected from the group consisting of mercapto, nitro, cyano, halo and alkyl.
As used herein, the term "alkenyl" (and alkenylene) refers to straight or branched hydrocarbon chains containing from 2 to 8 carbon atoms and at least one and up to three carbon-carbon double bonds. Examples of "alkenyl" as used herein include, but are not limited to ethenyl and propenyl. "Alkenyl" also includes substituted alkenyl. The alkenyl groups may optionally be substituted on an available carbon with one or more substituents selected from the group consisting of mercapto, nitro, cyano, halo and alkyl.
As used herein, the term "cycloalkenyl" refers to a non-aromatic carbocyclic ring having from 3 to 8 carbon atoms (unless otherwise specified) and up to 3 carbon- carbon double bonds. "Cycloalkenyl" includes by way of example cyclobutenyl, cyclopentenyl and cyclohexenyl. "Cycloalkenyl" also includes substituted cycloalkenyl. The cycloalkenyl may optionally be substituted on an available carbon with one or more substituents selected from the group consisting of mercapto, nitro, cyano, halo and alkyl.
As used herein, the term "alkynyl" (and alkynylene) refers to straight or branched hydrocarbon chains containing from 2 to 8 carbon atoms and at least one and up to three carbon-carbon triple bonds. Examples of "alkynyl" as used herein include, but are not limited to ethynyl and propynyl. "Alkynyl" also includes substituted alkynyl.
The alkynyl groups may optionally be substituted on an available carbon with one or more substituents selected from the group consisting of mercapto, nitro, cyano, halo and alkyl.
The term "halo" or "halogen" refers to the elements fluorine, chlorine, bromine and iodine.
The term "aryl" refers to monocyclic carbocyclic groups and fused bicyclic carbocyclic groups having from 5 to 12 carbon atoms and having at least one aromatic ring. Examples of particular aryl groups include but are not limited to phenyl and naphthyl. "Aryl" also includes substituted aryl. Aryl groups may optionally be substituted on an available carbon with one or more substituents selected from the group consisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido. Particular aryl groups according to the invention include but are not limited to phenyl and substituted phenyl. The term "heterocyclic" (or "heterocycle") refers to a monocyclic saturated or unsaturated non-aromatic groups and fused bicyclic non-aromatic groups, having the specified number of members and containing 1 , 2, 3 or 4 heteroatoms selected from N, O and S. Examples of particular heterocyclic groups include but are not limited to tetrahydrofuran, dihydropyran, tetrahydropyran, pyran, oxetane, thietane, 1 ,4-dioxane, 1 ,3-dioxane, 1 ,3-dioxalane, piperϊdine, piperazine, tetrahydropyrimidine, pyrrolidine, morpholine, thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran, tetrahydrothiophene, and the like. "Heterocyclic" also includes substituted heterocyclic. The heterocyclic groups may optionally be substituted on an available carbon or heteroatom with one or more substituents selected from the group consisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido. Particular heterocyclic groups according to the invention include but are not limited to pyrrolidine, piperidine, morpholine, thiomorpholine and piperazine and substituted variants thereof.
The term "heteroaryl" refers to aromatic monocyclic groups and aromatic fused bicyclic groups having the specified number of members and containing 1 , 2, 3, or 4 heteroatoms selected from N, O and S. Examples of particular heteroaryl groups include but are not limited to furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, and indazole. "Heteroaryl" also includes substituted heteroaryl. The heteroaryl groups may optionally be substituted on an available carbon or heteroatom with one or more substituents selected from the group consisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido. Particular heteroaryl groups according to the invention include but are not limited to pyridine, furan, thiophene, pyrrole, imidazole, pyrazole and pyrimidine, and substituted variants thereof. The term "members" (and variants thereof e.g., "membered") in the context of heterocyclic and heteroaryl groups refers to the total atoms, carbon and heteroatoms N, O and/or S, which form the ring. Thus, an example of a 6-membered heterocyclic ring is piperidine and an example of a 6-membered heteroaryl ring is pyridine.
As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and events that do not occur.
The present invention provides processes for preparing compounds of formula (I):
Figure imgf000009_0001
wherein:
R1 is aryl or heteroaryl;
R2 is selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, Ay, Het, -OR7, -OAy, -OHet, -OR10Het, -S(O)nR9,
-S(O)nAy, -S(O)nHet, -S(O)nNR7R8, -NR7R8, -N(R7)Ay, -NHHet,
-NHR10Ay, -NHR10Het, -R10NR7R8 and -R10NR7Ay; Ay is aryl;
Het is a 5- or 6-membered heterocyclic or heteroaryl group; each R7 and R8 are the same or different and are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkenyl,
-C(O)R9, -CO2R9,
Figure imgf000009_0002
, -C(S)NR 99rR->1"1, -C(NH)NR ,99nR1"1, -SO2R -.10 SO2NR9R11, -R10cycloalkyl, -R10OR9, -CH(R10OR9)2, -R10C(O)R9, -R10CO2R9, -R10C(O)NR9R11, -R10C(S)NR9R11, -R10C(NH)NR9R11, -R10SO2R10, -R10SO2NR9R11, -R10SO2NHCOR9, -R10NR9R11, -R10NHCOR9, -R10NHSO2R9 and -R10NHC(NH)NR9R11-; each R9 and R11 are the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, -R10cycloa!kyl, -R10OH, -R10(OR10)W where w is 1-10, and -R10NR10R10; each R10 is the same or different and is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl; n is O, 1 or 2;
Y is N or CH;
R3 and R4 are the same or different and are each independently selected from the group consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, -OR7, -OAy, - C(O)R7, C(O)Ay1 -CO2R7, -CO2Ay, -SO2NHR9, -NR7R8, -NR7Ay, -NHHet, -
NHR10Het -R10OR7, -R10OAy, -R10NR7R8 and -R10NR7Ay; q is O, 1 , 2, 3, 4 or 5; each R5 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, - OR7, -OAy, -OHet, -C(O)R9, -C(O)Ay, -C(O)Het, -CO2R9,
-C(O)NR7R8, -C(O)NR7Ay, -C(O)NHR10Het, -C(S)NR9R11, -C(NH)NR7R8, -C(NH)NR7Ay, -S(O)nR9, -S(O)2NR7R8, -S(O)2NR7Ay, -NR7R8, -NR7Ay, -NHHet, -NHR10Ay, -NHR10Het, -R10cycloalkyl, -R10OR9, -R10C(O)R9, -R10CO2R9, -R10C(O)NR9R11, -R10C(S)NR9R11, -R10C(NH)NR9R11, -R10SO2R9, -R10SO2NR9R11, -R10SO2NHCOR9,
-R10NR7R8, -R10NR7Ay, -R10NHC(NH)NR9R11, cyano, nitro and azido; or two adjacent R5 groups together with the atoms to which they are bonded form a Cs-6 cycloalkyl or aryl; p is 0, 1 , 2 or 3; and each R6 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, - OR7, -OAy, -OHet, -OR10Ay, -OR10Het, -C(O)R9, -C(O)Ay, -C(O)Het, -CO2R9, -C(O)NR7R8, -C(O)NR7Ay, -C(O)NHR10Ay, -C(O)NHR10Het, -C(S)NR9R11, -C(NH)NR7R8, -C(NH)NR7Ay, -S(O)nR9, - S(O)nAy, -S(O)nHet, -S(O)2NR7R8, -S(O)2NR7Ay, -NR7R8, -NR7Ay,
-NHHet, -NHR10Ay, -NHR10Het, -R10cycloalkyl, -R10Ay, -R10Het, -R10OR9, -R10-O-C(O)R9, -R10-O-C(O)Ay, -R10-O-C(O)Het, -R10-O-S(O)πR9, -R10C(O)R9, -R10CO2R9, -R10C(O)NR9R11, -R10C(S)NR9R11, -R10C(NH)NR9R11, -R10SO2R9, -R10SO2NR9R11, -R10SO2NHCOR9, -R10NR7R8, -R10NR7Ay, -R10NHC(NH)NR9R11, cyano, nitro and azido; or two adjacent R6 groups together with the atoms to which they are bonded form a C5-6 cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms; and pharmaceutically acceptable salts and solvates thereof.
In one embodiment, R1 is Ay. In one particular embodiment, R1 is phenyl or substituted phenyl (i.e., phenyl substituted one or more times with a substituent(s) selected from the group consisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido).
In one embodiment, R1 is 5- or 6-membered heteroaryl. In one embodiment, R1 is a 5-6 membered heteroaryl including 1 , 2 or 3 heteroatoms selected from N, O and S or substituted 5-6 membered heteroaryl including 1 , 2 or 3 heteroatoms selected from N, O and S (i.e,. heteroaryl substituted one or more times with a substituent(s) selected from the halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido). In one embodiment, R1 is a 5-6 membered heteroaryl including 1 heteroatom selected from N, O and S or substituted 5-6 membered heteroaryl including 1 heteroatom selected from N, O and S.
In one embodiment, R1 is selected from the group consisting of furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, and substituted variants thereof. In one particular embodiment, R1 is selected from the group consisting of pyridine, furan, thiophene, pyrrole, imidazole, pyrazole and pyrimidine, and substituted variants thereof. In one embodiment, R2 is selected from the group consisting of Het, -OR7, -OAy1 -OHet, -OR10Het, -S(O)nR9, -S(O)nAy, -NR7R8, -N(R7)Ay, -NHHet and -NHR10Het, or any subset thereof. More particularly, R2 is selected from the group consisting of Het, -S(O)nR9, -NR7R8, -N(R7)Ay, -NHHet and NHR10Het, or any subset thereof. In one embodiment, R2 is selected from the group consisting of Het, -
S(O)nR9, -NR7R8, -N(R7)Ay, and -NHHet, or any subset thereof. In one embodiment, R2 is -NR7R8. In one embodiment, R2 is -N(R7)Ay. In one embodiment, R2 is -S(O)nR9.
In one embodiment, R2 is selected from the group consisting of -S-alkyl, -NH2, -NH- alkyl, -NH-cycloalkyl, -N(alkyl)(alkyl), -N(H)Ay, -N(alkyl)Ay, Het (e.g., pyrrolidine), - NHHet and -NH-alkyl-Het, or any subset thereof. More particularly, R2 is selected from the group consisting of -S-alkyl, -NH-alkyl, -NH-cycloalkyl, -N(H)Ay and -N(alkyl)Ay, or any subset thereof.
Specific examples of some particular R2 groups are selected from the group consisting of -S-methyl, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, - NH-cyclopropyl, -NH-butyl, -NH-isobutyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH- cyclohexyl, -N(H)phenyl, -NH(CH2^OCH3, and pyrrolidine (e.g., pyrrolidine bonded through N).
In one embodiment, R7 and R8 are each the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl,
R10-cycloalkyl, -R10OR9, -R10NR9R11, -C(O)R9, and R10CO2R9, or any subset thereof. More particularly, R7 and R8 are each the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl and R10-cycloalkyl, or any subset thereof. In one embodiment, R7 and R8 are each the same or different and are independently selected from the group consisting of H, alkyl and cycloalkyl or any subset thereof.
The group -R10(OR10)W in the definition of R9 and R11 refers to a linear PEG-like chain. In one embodiment, R9 and R11 are each the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, and -R10- cycloalkyl, or any subset thereof. More particularly, R9 and R11 are each the same or different and are each independently selected from the group consisting of H and alkyl, or any subset thereof.
In one embodiment, R10 is alkyl or cycloalkyl; more particularly alkyl.
In one class of compounds of formula (I), Y is CH. In another class of compounds of formula (I), Y is N.
In one embodiment, R3 is selected from the group consisting of H, halo, alkyl, Ay, - OR7, -CO2R7, -NR7R8, -R10OR7 and -R10NR7R8, or any subset thereof. More particularly, R3 is selected from the group consisting of H, halo, alkyl, -OR7 and -NR7R8, or any subset thereof. In one particular embodiment R3 is H or alkyl. In one embodiment R3 is H.
In one embodiment, R4 is selected from the group consisting of H, halo, alkyl, Ay, - OR7, -CO2R7, -NR7R8, -R10OR7 and -R10NR7R8, or any subset thereof. More particularly R4 is selected from the group consisting of H, halo, alkyl, OR7 and - NR7R8, or any subset thereof. In one particular embodiment, R4 is H or alkyl. In one embodiment R4 is H.
In one embodiment q is 0, 1 or 2. In one particular embodiment, q is 0. In another particular embodiment, q is 1. In one embodiment, q is 2 and optionally two adjacent R5 groups together with the atoms which they are bonded, they form a Cs-6 cycloalkyl or aryl. The phrase "two adjacent R5 groups" refers to two R5 groups, each bonded to adjacent carbon atoms on the phenyl ring. In the embodiment where two adjacent R5 groups together with the atoms to which they are bonded form a cycloalkyl or aryl, q is typically 2, 3, 4 or 5; more typically 2.
R5 may be in the ortho, meta and/or para position.
In the embodiments where two adjacent R5 groups together with the atoms to which they are bonded form a cycloalkyl or aryl, each R5 group may be the same or different and is typically selected from the group consisting of alkyl and alkenyl. For example, in one embodiment, two adjacent R5 groups are alkyl and together with the atoms to which they are bonded, they form a cycloalkyl group such as:
> . From this example, additional embodiments, including those where two adjacent R5 groups together with the atoms to which they are bonded form an aryl group, can be readily ascertained by those skilled in the art. In one preferred embodiment, the compounds of formula (I) are defined wherein two adjacent R5 groups together with the atoms to which they are bonded do not form a C5-6 cycloalkyl or aryl.
In one embodiment, each R5 group is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, Ay, Het, -OR7, -OAy, - CO2R9, -C(O)NR7R8, -C(O)NR7Ay, -S(O)2NR7R8, -NR7R8, -NR7Ay, -NHR10Ay, cyano, nitro and azido, or any subset thereof. More particularly, each R5 group is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, Ay, Het, -OR7,
-NR7R8, -NR7Ay, cyano, nitro and azido, or any subset thereof. In one particular embodiment, each R5 group is the same or different and is independently selected from the group consisting of halo, alkyl, -OR7, -NR7R8 and cyano, or any subset thereof.
More specifically, in one embodiment, the compounds of formula (I) are defined where R5 is H, halo (e.g., fluoro, chloro or bromo), alkyl (e.g., methyl), O-alkyl (e.g., O-methyl, O-isobutyl, and ),"cy%no^NH-CH3, and
-N(CH3):?, or any subset thereof.
In one embodiment, p is 0, 1 or 2, more particularly 0 or 1.
R may be in the 4, 5 or 6 position. In one embodiment, p is 1 and R is in the C-5 position. In one embodiment, p is 1 and R6 is in the C-6 position. In one embodiment p is 2 and one R6 is in the C-5 position and one R6 is in the C-6 position (thus defining a class of compounds of formula (I) having two adjacent R6 groups). In the embodiments where two adjacent R6 groups together with the atoms to which they are bonded form a C5.6 cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms, each R6 group may be the same or different and is typically selected from the group consisting of alkyl, alkenyl, -OR7, -NR7R8 and - S(O)nR9. For example, in one embodiment two adjacent R6 groups are -OR7 and together with the atoms to which they are bonded, they form a heterocyclic group such as:
Figure imgf000015_0001
In another embodiment, two adjacent R6 groups are alkyl and together with the atoms to which they are bonded, they form a cycloalkyl group such as:
Figure imgf000015_0002
In another embodiment two adjacent R6 groups are defined as -OR7, -NR7R8 respectively and together with the atoms to which they are bonded, they form a heterocyclic group such as:
°y .
From these examples, additional embodiments can be readily ascertained by those skilled in the art. In one particular embodiment, two R6 groups together with the atoms to which they are bonded do not form a C5-6 cycloalkyl or a 5- or 6-membered heterocyclic group.
In one embodiment, each R6 is the same or different and is independently selected from the group consisting of halo, alkyl, Ay, Het, -OR7, -OAy, -OHet, -C(O)Het, - CO2R9, -C(O)NR7R8, -C(O)NR7Ay, -C(O)NHR10Het, -NR7R8, -NR7Ay, -NHHet, -NHR10Ay, -NHR10Het, -R10OR9 and cyano, or any subset thereof. More particularly, each R6 is the same or different and is independently selected from the group consisting of halo, alkyl, -OR7,
-C(O)Het, -C(O)NR7R8, -C(O)NHR10Het, -NR7R8, -NR7Ay, NHHet, -NHR10Ay, -NHR10Het, -R10OR9 and cyano, or any subset thereof. In one particular embodiment, each R6 is the same or different and is independently selected from the group consisting of halo, alkyl, -C(O)NR7R8, -NR7R8, -NR7Ay, -NHHet, -NHR10Ay, and -NHR10Het, or any subset thereof.
More specifically, in one embodiment, R6 is selected from the group consisting of Cl, Br, -O-alkyl, -O-alkyl-O-alkyl, -S-alkyl, -NH2, -NH-alkyl, -NHR10OR9, -NH-cycloalkyl, and -NH-SO2-alkyl, or any subset thereof. In one embodiment, R6 is selected from the group consisting of Cl, Br, -O-CH3, -O-(CH2)2-O-CH3, -S-CH3, -NH2, -NHCH(CH3)2, -NHcyclopropyl, -NHcyclopentyl, -NH(CH2)2-O-CH3 and -NH-SO2-CH3, or any subset thereof. In one embodiment, R6 is halo, such as Cl or Br. In one embodiment R6 is trifluoromethyl.
It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove.
Specific compounds of formula (I) which can be made by the processes of the present invention include but are not limited to those compounds identified in the Example section which follows.
It will be appreciated by those skilled in the art that the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof. The pharmaceutically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. In one embodiment, the compounds of formula (I) are in the form of the mesylate salt. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N1N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts.
The term "solvate" as used herein refers to a complex of variable stoichiometry formed by a solute (a compound of formula (I)) and a solvent. Solvents, by way of example, include water, methanol, ethanof, or acetic acid.
Processes for preparing pharmaceutically acceptable salts and solvates of the compounds of formula (I) are conventional in the art. See, e.g., Burger's Medicinal Chemistry And Drug Discovery 5th Edition, Vo1 1 : Principles And Practice.
As will be apparent to those skilled in the art, in the processes described below for the preparation of compounds of formula (I), certain intermediates, may be in the form of pharmaceutically acceptable salts or solvates of the compound. Those terms as applied to any intermediate employed in the process of preparing compounds of formula (I) have the same meanings as noted above with respect to compounds of formula (I). Processes for preparing pharmaceutically acceptable salts and solvates of such intermediates are known in the art and are analogous to the process for preparing pharmaceutically acceptable salts and solvates of the compounds of formula (I).
Certain compounds of formula (I) may exist in stereoisomer^ forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted.
Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
The compounds of formula (I) are useful as pharmaceutically active agents.
Pharmaceutical compositions and therapeutic uses for the compounds of formula (I) are described in PCT Publication Nos. PCT Publication Nos. WO02/48148, published 20 June 2002, WO02/48147, published 20 June 2002, WO02/72581 , published 19 September 2002, and WO02/088124, published 7 November 2002, to
SmithKline Beecham Corp, the subject matter of which is incorporated herein by reference in their entirety.
Compounds of formula (I) wherein may be conveniently prepared by the process outlined in Scheme 1 below.
Scheme 1
Figure imgf000018_0001
wherein:
X is halo or triflate;
Me is methyl;
LDA is lithium diisopropylamide; 9-BBN-OMe is 9-methoxy-9-borabicyclo[3.3.1]nonane; and all other variables are as defined above.
Generally, the process comprises the steps of: a) with a hindered amide base to produce an anion and reacting the anion with 9- methoxy-9-borabicyclo[3.3.1]nonane; b) adding a compound of formula R1-X in the presence of a palladium catalyst to prepare a compound of formula (I) wherein R2 is -S-CH3; c) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt or solvate thereof; and d) optionally converting the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof into a different compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
More specifically, the compound of formula (I) is prepared by a Suzuki coupling process. The compound of formula (II) is deprotonated with a hindered amide base and the anion so produced is reacted with 9-methoxy-9-borabicyclo[3.3.1]nonane to prepare the borinate intermediate in situ. The reaction is typically carried out in a solvent, such as for example tetrahydrofuran. The reaction may be carried out at a temperature of from about -78°C to about room temperature. One example of a suitable hindered amide base is lithium diisopropylamide, others will be apparent to those skilled in the art. The compounds of formula (II) may be prepared by processes known in the art, including those described in PCT Publication Nos. PCT Publication Nos. WO02/48148, published 20 June 2002, WO02/48147, published 20 June 2002, WO02/72581 , published 19 September 2002, and WO02/088124 , published 7 November 2002, to SmithKline Beecham Corp. 9-Methoxy-9- borabicyclo[3.3.1]nonane is commercially available.
The coupling of the aryl, heteroaryl or heterocyclic group is achieved by addition of R1-X in the presence of a palladium (0) catalyst. This step is conveniently carried out in situ, without isolation of the borinate intermediate. This step can be conveniently performed in an inert solvent, optionally with heating. In one embodiment, the reaction is performed by reacting equimolar amounts of the reactants or optionally adding an excess of the halide compound. The palladium catalyst is typically present in 1-10 mol% compared to the compound of formula (II). Palladium catalysts that may be used may include, but are not limited to, tetrakistriphenylphosphine palladium (0) dichlorobis(triphenylphosphine)palladium(ll), and bis(diphenylphosphino- ferrocene)palladium (II) dichloride. In one preferred embodiment, the palladium (0) catalyst is bis(diphenylphosphinoferrocene)-palladium (II) dichloride. Inert solvents for use in the reaction include but are not limited to, Λ/,Λ£dimethylformamide, toluene, tetrahydrofuran, dioxane, and 1 -methyl-2-pyrrolidinone. In one preferred embodiment, the solvent is Λ/,ΛAdimethylformamide.
In certain embodiments, the reaction may be facilitated by adding a base in a proportion equivalent to, or greater than, that of the halide compound. Examples of suitable bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium phosphate, potassium carbonate, sodium bicarbonate, sodium methoxide, and cesium fluoride. In one embodiment, the step of adding the halide compound further comprises the presence of a base. In one particular embodiment, the base is potassium phosphate.
A wide variety of halide compounds of formula R1-X are commercially available. The availability of aryl halides and heteroaryl halides offers an advantage of the present invention over the conventional Suzuki coupling processes previously disclosed. Conventional Suzuki coupling process for preparing pyrazolopyridines of formula (I) require metal compounds of formula Ay-M or heteroaryl-M, wherein Ay and heteroaryl are as defined above and M is B(OH)2, B(Ra)2, B(ORa)2, Sn(Ra)3, Zn- halide, Zn-Ra or Mg-halide. Fewer of said aryl and heteroaryl metal compounds are commercially available, thus limiting the choice of convenient reactants and/or requiring the synthesis of specialty metal compounds to achieve certain compounds of formula (I). In addition, the conventional method also requires the pyrazolopyridine coupling partner to contain a halogen or triflate to serve as the electrophile in the synthesis. The current method contained herein effectively accomplishes an umpolung by reversing the electrophile and transmetalation partner further increasing the usefulness of the Suzuki coupling reaction in the context of the pyrazolopyridine ring system.
As a further advantage, the process of the present invention may be carried out in situ, in a single reaction vessel, thus providing efficiencies which may facilitate the preparation of commercial quantities of the compounds of formula (I). Further, the process of the present invention does not require the isolation of the borinate intermediate, further simplying the synthesis of the compounds of formula (I) and adding efficiency. Additional advantages of the process of the present invention will be apparent to those skilled in the art.
It will also be apparent to those skilled in the art that the compounds of formula (I-A) may be converted to other compounds of formula (I) using techniques well known in the art, including those described in PCT Publication Nos. PCT Publication Nos. WO02/48148, published 20 June 2002, WO02/48147, published 20 June 2002, WO02/72581 , published 19 September 2002, and WO02/088124, published 7 November 2002, to SmithKline Beecham Corp. For example, one method of converting a compound of formula (I-A) to a different compound of formula (I) comprises a) oxidizing the compound of formula (I-A) to prepare a compound of formula (I-B) and then b) optionally reacting a compound of formula (I-B) with an oxygen or amine nucleophile selected from the group consiting of Het bonded through N, -OR7, -OAy, -OHet, -OR10Het, -NR7R8, -NHHet, -NHR10Ay and -NHR10Het to produce a compound of formula I wherein R2 is selected from the group consisting of Het bonded through N, -OR7, -OAy, -OHet, -OR10Het, -NR7R8, -NHHet, -NHR10Ay and -NHR10Het; n' is 1 or 2; and all other variables are as defined above.
Figure imgf000022_0001
More specifically, compounds of formula (I) can be prepared by reacting a compound of formula (I-B) (i.e., compounds of formula I wherein R2 is S(O)n R9 where n1 is 1 or 2) with an oxygen or amine nucleophile selected from the group consisting of Het bonded through N, -OR7, -OAy, -OHet,
-OR10Het, -NR7R8, -NHHet, -NHR10Ay and -NHR10Het. The reaction may be carried out neat or in a suitable solvent and may be heated to 50-1500C. Typically the solvent is a lower alcohol such as methanol, ethanol, isopropanol and the like or solvent such as Λ/,/V-dimethylformamide or tetrahydrofuran, and the like. Optionally a base may be used to facilitate the reaction. Typically the base can be potassium carbonate, or an amine base such as triethylamine.
Compounds of formula (I-B) may be conveniently prepared by oxidizing a compound of formula (I-A) (i.e., compounds of formula I wherein R2 is S(O)nR9 where n is 0) with an oxidizing agent in an inert solvent, optionally in the presence of a base.
Typically the oxidizing agent is a peracid such as /77-chloroperbenzoic acid or the like optionally with a base such as sodium bicarbonate. Careful monitoring of the stoichiometry between the oxidizing agent and the substrate allows the product distribution between sulfoxide (n=1), and sulfone (n=2) to be controlled. Suitable solvents include but are not limited to, dichloromethane, chloroform and the like.
Based upon the knowledge in the art, this disclosure and the examples contained herein one skilled in the art can readily convert a compound of formula (I) (including a compounds of formula (I-A) and (I-B)) or a pharmaceutically acceptable salt or solvate thereof into a different compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way, the invention being defined by the claims which follow.
Reagents are commercially available or are prepared according to procedures in the literature. Example numbers refer to those compounds listed in the tables above. 1H and 13C NMR spectra were obtained on Varian Unity Plus NMR spectrophotometers at 300 or 400 MHz, and 75 or 100 MHz respectively. 19F NMR were recorded at 282 MHz. Mass spectra were obtained on Micromass Platform, or ZMD mass spectrometers from Micromass Ltd. Altrincham, UK, using either Atmospheric Chemical Ionization (APCI) or Electrospray Ionization (ESI). Analytical thin layer chromatography was used to verify the purity of some intermediates which could not be isolated or which were too unstable for full characterization, and to follow the progress of reactions. Unless otherwise stated, this was done using silica gel (Merck Silica Gel 60 F254). Unless otherwise stated, column chromatography for the purification of some compounds, used Merck Silica gel 60 (230-400 mesh), and the stated solvent system under pressure. All compounds were characterized as their free-base form unless otherwise stated. On occasion the corresponding hydrochloride salts were formed to generate solids where noted. Example 1 : 2-(4-FluorophenvO-7-(4-methylphenyO-342-(methylthio)pyrimidin-4- yl|pyrazolof1 ,5-alpyridine.
Figure imgf000024_0001
a) 4-[(4-Fluorophenyl)ethynyl]-2-(methylthio)pyrimidine To a solution of 4-iodo-2-(methylthio)pyrimidine (15.0 g, 0.0673 mol) in tetrahydrofuran (90 mL) was added triethylamine (12.2 mL, 0.0875 mol). Dichlorobis(triphenylphosphine)palladium(ll) (1.90 g, 2.69 mmol) and copper iodide (769 mg, 4.04 mmol) were added simultaneously. A solution of 1-ethynyl-4- fluorobenzene (8.50 mL, 0.0740 mol) in tetrahydrofuran (10 mL) was added dropwise and the reaction mixture was stirred at room temperature for 6 hours. Water (20 mL) was added and the resulting solution was concentrated in vacuo to remove the excess tetrahydrofuran. The predominantly aqueous mixture was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate. Filtration and concentration , followed by flash chromatography (100% dichloromethane) provided 4-[(4-fluorophenyl)ethynyl]-2- (methylthio)pyrimidine (12.0 g, 73%) as a pale yellow solid. Rf 0.85 (49:1 dichloromethane:methanol). 1H NMR (300 MHz, CDCI3) δ 8.52 (d, J= 5.1 Hz, 1 H), 7.62 (dd, J= 8.5, 5.5 Hz, 2 H), 7.13-7.06 (m, 3 H), 2.60 (s, 3 H); MS m/z245 (M+H)+.
b) 2-(4-Fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine
To a cold (0 0C) solution of 4-[(4-fluorophenyl)ethynyl]-2-(methylthio)pyrimidine (4.00 g, 16.4 mmol) and 1-aminopyridinium iodide (3.63 g, 16.4 mmol) in acetonitrile (100 mL) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (2.45 mL, 16.4 mmol). The reaction mixture was warmed to room temperature and stirred for 3 days. The reaction mixture was quenched with water and concentrated in vacuo to remove the excess acetonitrile. The resultant mass was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (20% to 25% ethyl acetate in hexanes) provided 2-(4-fluorophenyl)-3-[2-(rhethylthio)-4- pyrimidinyl]pyrazolo[1 ,5-a]pyridine (4.34 g, 79%) as a pale yellow solid. Rf 0.20 (4:1 hexanes:ethyl acetate); 1H NMR (400 MHz1 CDCI3) δ 8.52 (d, J= 6.8 Hz, 1 H), 8.47 (d, J= 8.9 Hz, 1 H), 8.24 (d, J = 5.5 Hz, 1 H), 7.59 (dd, J= 8.6, 5.3 Hz, 2 H), 7.39 (m, 1 H), 7.17 (t, J= 8.7 Hz, 2 H), 6.96 (td, J= 6.9, 1.1 Hz, 1 H), 6.70 (d, J= 5.5 Hz, 1 H), 2.61 (s, 3 H); MS m/z337 (M+H)+; Anal. Calcd for C18H13FN4S: C, 64.27; H, 3.90; N, 16.66. Found: C, 64.35; H, 3.87; N, 16.70.
c) 2-(4-Fluorophenyl)-7-(4-methylphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-a]pyridine. A fresh stock solution of lithium diisopropylamide (0.36 M in tetrahydrofuran) was prepared by adding /7-butyllithium (6.25 ml_, 1.6 M in hexanes, 10 mmol) to a cold (0 0C) solution of diisopropylamine (1.39 mL, 10 mmol) in tetrahydrofuran (20 ml_) and stirred for 15 minutes prior to use. To a cold (-78 0C) solution of 2-(4-Fluorophenyl)- 3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine (100 mg, 0.30 mmol) in tetrahydrofuran (10 mL) was added lithium diisopropylamide (2.1 mL, 0.36 M in tetrahydrofuran, 0.75 mmol) dropwise. The resultant solution was stirred at -78 0C for 1 hour. 9-Methoxy-9-borabicyclo[3.3.1]nonane (£-OMe-9-BBN) (0.75 mL, 1.0 M in hexanes, 0.75 mmol) was then added and the mixture was warmed to room temperature. After 1 hour, potassium phosphate (K3PO4) (0.25 mL, 3.0 M aqueous, 0.75 mmol) was added followed by /V.Mdimethylformamide (5 mL), 4-iodotoluene (84 mg, 0.39 mmol) and [1 ,1 '-bis(diphenylphosphino)ferrocene]- dichloropalladium(ll), complex with dichloromethane (1 :1) (PdCI2(dppf);CH2CI2) (12 mg, 0.014 mmol). The resultant solution was stirred for 24 hours. Water was added followed by ethyl acetate and the layers were separated. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics dried over Na2SO4. Filtration and concentration followed by purification by flash chromatography on silica gel provided the title compound (84 mg, 67%) as a white solid. 1H NMR (400 MHz, CDCI3) δ 8.44 (dd, J= 9.0, 1.2 Hz, 1 H), 8.25 (d, J= 5.3 Hz1 1 H), 7.86 (d, J= 8.2 Hz, 2 H), 7.59 (dd, J= 8.6, 5.6 Hz, 2 H), 7.44 (dd, J= 8.8, 7.0 Hz, 1 H), 7.33 (d, J= 7.8 Hz, 2 H), 7.11 (dd, J= 8.6, 8.6 Hz, 2 H), 7.01 (dd, J= 7.2, 1.4 Hz, 1 H), 6.73 (d, J= 5.5 Hz, 1 H), 2.63 (s, 3 H), 2.44 (s, 3 H); MS /77/z427 (M+1). Example 2: 2-(4-Fluorophenyl)-7-(3-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4- yllpyrazolofi ,5-alpyridine.
Figure imgf000026_0001
In a similar manner to that described in Example 1 , from of 2-(4-fluorophenyl)-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine (200 mg, 0.60 mmol) and 3- iodoanisole (0.11 ml_, 0.89 mmol) was formed 2-(4-fluorophenyl)-7-(3- methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine (152 mg, 58%) as a white solid. 1H NMR (300 MHz, CDCI3) δ 8.47 (dd, J = 9.1 , 1.1 Hz1 1 H)1 8.26 (d, J = 5.4 Hz, 1 H), 7.59 (dd, J= 8.8, 5.3 Hz, 2 H), 7.54 (dd, J= 12.0, 9.5 Hz, 2 H), 7.47-7.40 (m, 2 H), 7.12 (dd, J= 8.6, 8.6 Hz, 2 H), 7.04 (dd, J= 7.1, 1.5 Hz, 2 H), 6.74 (d, J = 5.5 Hz, 1 H), 3.87 (s, 3 H), 2.63 (s, 3 H); 19F NMR (CDCI3) δ -112.89; .MS /77/z443 (M+1).
Example 3: 2-(4-Fluorophenyl)-3-f2-(methylthio)pyrimidin-4-yl]-7-pyridin-3- ylpyrazoloH ,5-alpyridine.
Figure imgf000026_0002
In a similar manner to that described in Example 1, from of 2-(4-Fluorophenyl)-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (200 mg, 0.60 mmol) and 3- iodopyridine (183 mg, 0.89 mmol) was formed 2-(4-fluorophenyl)-3-[2- (methylthio)pyrimidin-4-yl]-7-pyridin-3-ylpyrazolo[1 ,5-a]pyridine (90 mg, 37%) as a greenish solid. 1H NMR (300 MHz, CDCI3) δ 9.12 (br, 1 H), 8.71 (br, 1 H), 8.49 (d, J= 8.7 Hz, 1 H), 8.38 (d, J= 8.1 Hz, 1 H), 8.26 (d, J= 5.2 Hz, 1 H), 7.57 (dd, J= 8.3, 5.5 Hz, 2 H), 7.49-7.43 (m, 2 H), 7.14-7.04 (m, 3 H), 6.73 (d, J= 5.5 Hz, 1 H), 2.61 (s, 3 H); 19F NMR (CDCI3) δ -112.47; . MS m/zAΛA (M+1).
Example 4: 1-(4-{2-(4-Fluorophenyl)-3-[2-(methylthio)pyrimidin-4-vnpyrazolo[1 ,5- alpyridin-7-yl}phenyl)ethanone.
Figure imgf000027_0001
In a similar manner to that described in Example 1, from of 2-(4-Fluorophenyl)-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine (200 mg, 0.60 mmol) and 4- iodoacetophenone (219 mg, 0.89 mmol) was formed 1-(4-{2-(4-fluorophenyl)-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridin-7-yl}phenyl)ethanone (160 mg, 59%) as a yellow solid. 1H NMR (300 MHz, CDCI3) δ 8.52 (dd, J = 8.7, 1.1 Hz, 1 H), 8.29 (d, J= 5.4 Hz, 1 H)1 8.12 (d, J= 8.6 Hz, 4 H), 8.09 (d, J= 8.6 Hz, 1 H), 7.60 (dd, J= 8.6, 5.4 Hz, 2 H), 7.48 (dd, J= 8.9, 7.1 Hz, 1 H), 7.17-7.08 (m, 3 H), 6.75 (d, J = 5.5 Hz, 1 H), 2.68 (s, 3 H)1 2.64 (s, 3 H); 19F NMR (CDCI3) δ -112.62; MS m/z 455 (M+1).
Example 5: 7-(4-Fluorophenyl)-2-(4-methoxyphenyl)-3-f2-(methyltriio)pyrimidin-4- yl]pyrazolo[1 ,5-ajpyridine
Figure imgf000027_0002
a) 4-[(4-Methoxyphenyl)ethynyl]-2-(methylthio)pyrimidine.
In a similar manner to Example 1 , from 4-iodo-2-(methylthio)pyrimidine and 1- ethynyl-4-methoxybenzene was formed 4-[(4-methoxyphenyl)ethynyl]-2-
(methylthio)pyrimidine in 89 % yield. 1H NMR (CDCI3) δ 8.42 (d, 1H), 7.52 (d, 2H), 7.02 (d, 1 H), 6.86 (d, 2H), 3.83 (s, 3H), 2.58 (s, 3H); MS m/z251 (M+1). b) 2-(4-Methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine. In a similar manner to Example 1 , from 4-[(4-methoxyphenyl)ethynyl]-2- (methylthio)pyrimidine and 1-aminopyridinium iodide was formed 2-(4- methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine in 73 % yield. 1H NMR (CDCI3) δ 8.53-8.47 (m, 2H), 8.22 (d, 1 H)1 7.53 (d, 2H), 7.36 (m 1 H), 7.01- 6.91 (m, 3H), 7.76 (d, 1 H), 3.88 (s, 3H), 2.64 (s, 3H); MS /7?/z349 (M+1). c) 7-(4-Fluorophenyl)-2-(4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-a]pyridine.
In a similar manner to Example 1, from 2-(4-methoxyphenyl)-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine and 1 -fluoro-4-iodobenzene was formed 7-(4-fluorophenyl)-2-(4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-a]pyridine in 42% yield. 1H NMR (CDCI3) δ 8.49 (dd, 1 H), 8.42 (d, 1 H), 7.99-7.96 (m, 2H), 7.53 (d, 2H), 7.43 (m, 1 H), 7.22-7.17 (m, 2H), 6.99-6.94 (m, 3H), 6.78 (d, 1 H), 3.86 (s, 3H), 2.65 (s, 3H); MS m/z443 (M+1).
Example 6: 7-(3-Methoxyphenyl)-2-(4-methoxyphenyπ-3-[2-(methylthio)pyrimidin-4- ylipyrazoloH ,5-alpyridine.
Figure imgf000028_0001
In a similar manner to Example 1 , from 2-(4-methoxyphenyl)-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine and 1-iodo-3-methoxybenzene was formed 7-(3-methoxyphenyl)-2-(4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-a]pyridine in 59% yield. 1H NMR (CDCI3) δ 8.47 (d, 1 H), 8.23 (d, 1 H), 7.57-7.50 (m, 4H), 7.42-7.38 (m, 2H), 7.03-6.98 (m, 2H), 6.94 (d, 2H), 6.79 (d, 1 H), 6.83 (s, 3H), 3.84 (s, 3H), 2.65 (s, 3H); MS m/z455 (M+1).
Example 7: 4-{2-(4-Methoxyphenvπ-3-[2-(methylthio)pyrimidin-4-yllpyrazoloπ ,5- aiPVridin-7-yl)phenylamine.
Figure imgf000029_0001
In a similar manner to Example 1, from 2-(4-methoxyphenyl)-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine and 4-iodoaniline was formed 4-{2- (4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridin-7- yl}phenylamine in 24% yield. 1H NMR (CDCI3) δ 8.41 (d, 1 H), 8.21 (d, 1 H), 7.83 (d, 2H), 7.54 (d, 2H), 7.39 (t, 1 H), 6.95 (d, 3H), 6.78-6.74 (m, 3H), 3.90 (s, 2H), 3.86 (s, 3H), 2.65 (s, 3H); MS m/z440 (M+1).
Example 8: 2-(4-Methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl1-7-trιien-3- ylpyrazolop ,5--?]pyridine.
Figure imgf000029_0002
In a similar manner to Example 1, from 2-(4-methoxyphenyl)-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine and 3-iodothiophene was formed 2-(4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]-7-thien-3-ylpyrazolo[1 ,5- a]pyridine in 79% yield. 1H NMR (CDCI3) δ 8.79 (d, 1 H)1 8.47 (d, 1 H), 8.24 (d, 1 H), 7.79 (d, 1 H), 7.60 (d, 2H), 7.46-7.40 (m, 2H), 7.28 (m, 1 H), 6.99 (d, 2H), 6.81 (d, 1 H), 3.89 (s, 3H), 2.65 (s, 3H); MS /τ?/z431 (M+1). Example 9: 2-f4-(Cvclopropylmethoxy)phenyl]-7-(4-methylphenyl)-3-f2- (methvlthio)pvrimidin-4-vllpvrazolo[1 ,5-a1pyridine.
Figure imgf000030_0001
a) 1 -(Cyclopropylmethoxy)-4-iodobenzene. To a cold (0 0C) solution of 4-iodophenol (1.0 g, 4.54 mmol), cyclopropylmethanol (0.37 mL, 4.54 mmol) and triphenylphosphine (1.31 g, 4.99 mmol) in tetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (DIAD) (0.98 mL, 4.99 mmol) dropwise. The mixture was then allowed to warm to room temperature and stirred overnight. Celite was added and the solution was concentrated in vacuo. The residue was filtered through a pad of silica gel (4:1 hexanes-ether gradient to 100 % ether). This material was further purified by crystallization (twice) of by-products using hexanes and ether. Concentration of the mother liquor then gave 1- (cyclopropylmethoxy)-4-iodobenzene (12.5 g, 99%) which solidified upon standing. 1H NMR (300 MHz, CDCI3) δ 7.55 (d, J= 8.8 Hz, 2 H), 6.69 (d, J= 8.9 Hz, 2 H), 3.77 (d, J= 7.0 Hz, 2 H), 1.26 (m, 1 H), 0.65 (m, 2 H), 0.35 (m, 2 H). b) 2-(Methylthio)-4-[(trimethylsilyl)ethynyl]pyrimidine.
To a cold (o 0C) solution of 4-chloro-2-(methylthio)pyrimidine (2.17 mL, 18.7 mmol) in tetrahydrofuran was added dichlorobistriphenylphosphine palladium (II) PdCI2(PPh3)2 (655 mg, 0.93 mmol), triethylamine (7.8 mL, 56.0 mmol) and copper (I) iodide (355 mg, 1.86 mmol) followed by trimethylsilylacetylene (3.95 mL, 28.0 mmol). The resultant solution was stirred overnight. Following a standard aqueous workup, the residue was purified by flash chromatography on silica gel to give 2- (methylthio)-4-[(trimethylsilyl)ethynyl]pyrimidine (2.69 g, 65%) as an oil. 1H NMR (400 MHz, CDCI3) δ 8.47 (d, J= 5.2 Hz, 1 H), 7.02 (d, J= 5.0 Hz, 1 H), 2.56 (s, 3 H), 0.27 (s, 9 H); MS m/z222> (M+1). c) 4-Ethynyl-2-(methylthio)pyrimidine.
To a cold (0 0C) solution of 2-(methylthio)-4-[(trimethylsilyl)ethynyl]pyrimidine (2.65 g, 11.9 mmol) in methanol (50 mL) was added potassium carbonate (1.8 g, 13.1 mmol). The mixture was stirred at 0 0C for 1 hour and then concentrated in vacuo. Ether and water were added and the organics were washed with brine. The aqueous layer was extracted with ether and dried over Na2SO4. Filtration and concentration provided 4-ethynyl-2-(methylthio)pyrimidine (1.81 g, 99%) of approximately 90% purity. This material was used without further purification. 1H NMR (300 MHz,
CDCI3) δ 8.51 (d, J= 5.1 Hz, 1 H), 7.07 (d, J= 5.0 Hz, 1 H), 3.34 (s, 1 H), 2.58 (s, 3 H); MS /77/Z 151 (M+1). d) 4-{[4-(Cyclopropylmethoxy)phenyl]ethynyl}-2-(methylthio)pyrimidine To a cold (0 0C) solution of 4-ethynyl-2-(methylthio)pyrimidine (1.81 g, 11.9 mmol, ~90% pure) in tetrahydrofuran (50 mL) was added 1 -(cyclopropylmethoxy)-4- iodobenzene (3.26 g, 11.9 mmol), dichlorobistriphenylphosphine palladium (II) PdCI2(PPh3)2 (417 mg, 0.59 mmol), triethylamine (4.97 mL, 35.7 mmol) and copper (I) iodide (226 mg, 1.19 mmol). The mixture was allowed to warm to room temperature and stirred overnight. Water and ether were added and the layers separated. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over Na2SO4. Filtration and concentration followed by purification by flash chromatography on silica gel provided 4-{[4-(cyclopropylmethoxy)phenyl]ethynyl}-2-(methylthio)pyrimidine. 1H NMR (300 MHz1 CDCI3) δ 8.48 (d, J= 4.9 Hz, 1 H), 7.55 (d, J= 8.8 Hz, 2 H), 7.07 (d, J= 5.2 Hz, 1 H), 6.91 (d, J= 8.9 Hz, 2 H), 3.85 (d, J= 7.3 Hz, 2 H), 2.60 (s, 3 H), 1.29 (m, 1 H), 0.68 (m, 2 H), 0.38 (m, 2 H); MS m/z297 (M+1). e) 2-[4-(Cyclopropylmethoxy)phenyl]-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5--?]pyridine.
In a similar manner to Example 1 , from 4-{[4-(cyclopropylmethoxy)phenyl]ethynyl}- 2-(methylthio)pyrimidine (600 mg, 2.0 mmol), 1-aminopyridinium iodide (585 mg, 2.65 mmol), and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL, 3.0 mmol) in acetonitrile 20 mL) was formed 2-[4-(cyclopropylmethoxy)phenyl]-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine (556 mg, 71 %) as a white solid. 1H NMR (300 MHz, CDCI3) δ 8.54-8.49 (m, 2 H), 8.23 (d, J= 5.3 Hz, 1 H), 7.53 (d, J= 8.9 Hz, 2 H), 7.38 (m, 1 H), 7.03-6.92 (m, 3 H), 6.77 (d, J= 5.5 Hz, 1 H), 3.89 (d, J= 6.9 Hz, 2 H), 2.65 (s, 3 H), 1.32 (m, 1 H), 0.69 (m, 2 H), 0.40 (m, 2 H); MS m/z389 (M+1). f) 2-[4-(Cyclopropylmethoxy)phenyl]-7-(4-methylphenyl)-3-[2-
(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine.
In a similar manner to Example 1 , from 2-[4-(cyclopropylmethoxy)phenyl]-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine and 4-iodotoluene was formed 2- [4-(cyclopropylmethoxy)phenyl]-7-(4-methylphenyl)-3-[2-(methyIthio)pyrimidin-4- yl]pyrazolo[1 ,5-a]pyridine in 87% yield. 1H NMR (CDCI3) δ 8.46 (dd, 1 H), 8.22 (d, 1 H), 7.87 (d, 2H), 7.51 (d, 2H), 7.41 (m, 1 H), 7.31 (d, 2H), 6.99-6.93 (m, 3H), 6.78 (d, 1H), 3.84 (d, 2H), 2.65 (s, 3H), 2.43 (s, 3H), 1.29 (m, 1 H), 0.66 (q, 2H), 0.37 (2H); MS m/z479 (M+1 ).
Example 10: 2-f4-(Cvclopropylmethoxy)phenyl]-7-(4-fluorophenyl)-3-[2- (methylthio)pyrimidin-4-yllpyrazolof1 ,5-a]pyridine.
Figure imgf000032_0001
In a similar manner to Example 1 , from 2-[4-(cyclopropylmethoxy)phenyl]-3-[2- (methylthio)pyrirnidin-4-yl]pyrazolo[1 ,5-a]pyridine and 1 -fluoro-4-iodobenzene was formed 2-[4-(cyclopropylmethoxy)phenyl]-7-(4-fluorophenyl)-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine in 73% yield. 1H NMR (CDCI3) δ 8.48 (d, 1 H)1 8.23 (d, 1 H), 7.99-7.97 (m, 2H), 7.51 (d, 2H), 7.42 (m, 1 H), 7.22-7.17 (m, 2H), 6.96-6.94 (m, 3H), 6.78 (d, 1 H), 3.85 (d, 2H), 2.65 (s, 3H), 1.29 (m, 1H), 0.66 (q, 2H), 0.37 (2H); MS m/_?483(M+1).
Example 11 : 2-f4-(Cvclopropylmethoxy)phenyl1-7-(4-methoxyphenyl)-3-|2- (methylthio)pyrimidin-4-yllpyrazoloπ ,5-g|pyridine.
Figure imgf000033_0001
In a similar manner to Example 1 , from 2-[4-(cyclopropylmethoxy)phenyl]-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine and 4-iodoanisole was formed 2- [4-(cyclopropylmethoxy)phenyl]-7-(4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-a]pyridine in 25% yield. 1H NMR (CDCI3) δ 8.44 (d, 1 H), 8.21 (d, 1 H), 7.95 (d, 2H)1 7.52 (d, 2H), 7.41 (m, 1 H), 7.04-6.93 (m, 5H), 6.78 (d, 1 H), 3.88-3.84 (m, 5H), 2.65 (s, 3H), 1.29 (m, 1 H), 0.66 (q, 2H), 0.37 (2H); MS m/z 495(M+1).
Example 12: 2-[4-(Cyclopropylmethoxy)phenvn-7-(3-methylphenyl)-3-[2- (methylthio)pyrimidin-4-vπpyrazolo[1 ,5-a]pyridine.
Figure imgf000033_0002
In a similar manner to Example 1 , from 2-[4-(cyclopropylmethoxy)phenyl]-3-[2- (methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine and 3-iodotoluene was formed 2- [4-(cyclopropylmethoxy)phenyl]-7-(3-methylphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-φyridine in 80% yield. 1H NMR (CDCI3) δ 8.47 (d, 1 H), 8.22 (d, 1 H), 7.77 (d, 1 H), 7.72 (s 1 H), 7.51 (d, 2H), 7.43-7.37 (m, 2H), 7.28 (d, 1 H), 6.98- 6.93 (m, 3H), 6.78 (d, 1 H), 3.84 (d, 2H), 2.65 (s, 3H), 2.44 (s, 3H), 1.26 (m, 1 H), 0.66 (q, 2H), 0.37 (2H); MS m/z479 (M+1). Example 13: yV-Cvclopentyl-4-[2-(4-fluorophenyl)-7-pyridin-3-ylpyrazolo[1 ,5-a|pyridin- 3-vπpyrimidin-2-amine
Figure imgf000034_0001
To a solution of 2-(4-fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]-7-pyridin-3- ylpyrazolo[1 ,5-a]pyridine (83 mg, 0.20 mmol) in dichloromethane (10 mL) was added acetic acid (0.1 mL) and /77-chloroperbenzoic acid (mCPBA) (53 mg, ~65% purity, 0.20 mmol). The resulting solution was stirred at room temperature for 30 minutes at which time the reaction was judged complete. Aqueous solutions of Na2S2C»3 and sodium bicarbonate were added with vigorous stirring. The layers were separated and the organic layer washed with brine. After extraction of the aqueous layer, the combined organics were dried over Na2SO4 and concentrated in vacuo to produce the corresponding sulfoxide which was used without further purification. This material was taken up in cyclopentylamine neat (4 mL) and heated in a sealed tube at 120 0C overnight. Upon cooling to room temperature, the mixture was concentrated in vacuo and the residue was taken up in ether, washed with aqueous sodium bicarbonate and brine. After extraction of the aqueous layer, the combined organics were dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography produced the title compound (69 mg, 76%) as a yellow solid. 1H NMR (300 MHz, CDCI3) δ 9.12 (d, J= 1.9 Hz, 1 H), 8.69 (dd, J= 4.9, 1.8 Hz, 1 H), 8.44-8.36 (m, 2 H), 8.08 (d, J= 5.3 Hz, 1 H), 7.61 (dd, J= 8.7, 5.4 Hz, 2 H), 7.43 (dd, J= 8.0, 5.0 Hz, 1 H), 7.37 (dd, J= 9.1 , 6.9 Hz, 1 H), 7.08 (t, J= 8.6 Hz, 2 H), 6.98 (dd, J= 6.8, 1.5 Hz, 1 H), 6.35 (d, J= 5.3 Hz, 1 H), 5.36 (d, J= 7.4 Hz, 1 H), 4.35 (m, 1 H), 2.07 (m, 2 H), 1.80-1.48 (m, 6 H); 19F NMR δ -113.09; MS /77/_r451 (M+1).
Example 14: 1-{4-f3-[2-(Cvclopentylamino)pyrimidin-4-vn-2-(4- fluorophenyl)pyrazolo[1 ,5-alpyridin-7-yl]phenyl)ethanone.
Figure imgf000035_0001
In a similar manner to that described in Example 13, from of 1 -(4-{2-(4-fluorophenyl)- 3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridin-7-yl}phenyl)ethanone (146 mg, 0.32 mmol) was formed 1 -{4-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4- fluorophenyl)pyrazolo[1 ,5-a]pyridin-7-yl]phenyl}ethanone (131 mg, 83%) as a yellow solid. 1H NMR (300 MHz, CDCI3) δ 8.43 (d, J= 9.0 Hz, 1 H), 8.15-8.02 (m, 5 H), 7.61 (t, J= 6.7 Hz, 2 H), 7.38 (dd, J= 8.9, 7.2 Hz, 1 H), 7.09 (t, J= 8.4 Hz, 2 H), 7.01 (d, J = 7.2 Hz, 1 H)1 6.36 (d, J= 5.2 Hz, 1 H), 5.28 (d, J= 7.2 Hz, 1 H), 4.36 (m, 1 H), 2.65 (s, 3 H), 2.09 (m, 2 H), 1.82-1.49 (m, 6 H); 19F NMR δ -1 13.17; MS /7?/z492 (M+1).
Example 15: ΛACyclopentyl-4-|2-(4-f)uorophenyl)-7--(3-rnethoxyphenyl)pyrazolo[1 ,5- 3lpyridin-3-vπpyrimidin-2-amine.
Figure imgf000035_0002
In a similar manner to that described in Example 1, from of 2-(4-fluorophenyl)-7-(3- methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (149 mg, 0.34 mmol) was formed ΛAcyclopentyl-4-[2-(4-fluorophenyl)-7-(3- methoxyphenyl)pyrazolo[1 ,5-3]pyridin-3-yl]pyrimidin-2-amine (137 mg, 85%) as a solid. 1H NMR (300 MHz, CDCI3) δ 8.40 (d, J= 8.9 Hz, 1 H), 8.08 (d, J= 5.0 Hz, 1 H), 7.67-7.49 (m, 4 H), 7.44-7.34 (m, 2 H), 7.12-6.97 (m, 4 H), 6.36 (d, J= 5.3 Hz, 1 H), 5.38 (d, J= 6.3 Hz, 1 H), 4.36 (m, 1 H), 3.86 (s, 3 H), 2.08 (m, 2 H), 1.82-1.50 (m, 6 H); 19F NMR δ -113.45; MS m/z480 (M+1). Example 16: yV-Cvclopentyl-4-[2-(4-flυorophenvπ-7-(4-methylphenyl)pyrazolof 1 ,5- a]pyridin-3-vnpyrimidin-2-amine.
Figure imgf000036_0001
In a similar manner to that described in Example 1 , from of 2-(4-fluorophenyI)-7-(4- methylphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridine (80 mg, 0.19 mmol) was formed ΛAcyclopentyl-4-[2-(4-fluorophenyl)-7-(4- methylphenyl)pyrazolo[1 ,5-φyridin-3-yl]pyrimidin-2-amine (56 mg, 65%) as a yellow solid. 1H NMR (400 MHz, CDCI3) δ 8.37 (d, J= 8.9 Hz, 1 H), 8.07 (d, J= 4.8 Hz, 1 H)1 7.86 (d, J= 8.0 Hz, 2 H), 7.62 (dd, J= 8.6, 5.8 Hz, 2 H), 7.37 (dd, J= 8.7, 7.1 Hz, 1 H), 7.32 (d, J= 8.0 Hz, 2 H), 7.08 (t, J= 8.7 Hz, 2 H), 6.96 (d, J= 7.2 Hz, 1 H), 6.35 (d, J= 5.3 Hz, 1 H), 5.13 (d, J= 7.0 Hz, 1 H), 4.36 (m, 1 H), 2.43 (s, 3 H), 2.09 (m, 2 H), 1.76 (m, 2 H), 1.66 (m, 2 H), 1.56 (m, 2 H); 19F NMR δ -113.63; MS m/z464 (M+1).

Claims

CLAIMS 1. A process for preparing a compound of formula (I):
Figure imgf000037_0001
wherein: R1 is aryl or heteroaryl;
R2 is selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, Ay, Het, -OR7, -OAy, -OHet, -OR10Het, -S(O)nR9, -S(O)nAy1 -S(O)nHeT, -S(O)nNR7R8, -NR7R8, -N(R7)Ay, - NHHet, -NHR10Ay, -NHR10HeI, -R10NR7R8 and -R10NR7Ay; Ay is aryl;
Het is a 5- or 6-membered heterocyclic or heteroaryl group; each R7 and R8 are the same or different and are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkenyl, - C(O)R9, -CO2R9, -C(O)NR9R11, -C(S)NR9R11, -C(NH)NR9R11, -SO2R10, -SO2NR9R11,
-R10cycloalkyl, -R10OR9, -CH(R10OR9)2, -R10C(O)R9, -R10CO2R9, -R10C(O)NR9R11, -R10C(S)NR9R11, -R10C(NH)NR9R11, -R10SO2R10, -R10SO2NR9R11, -R10SO2NHCOR9, -R10NR9R11, -R10NHCOR9, -R10NHSO2R9 and - R10NHC(NH)NR9R11; each R9 and R11 are the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, -R10cycloalkyl, -R10OH, -R10(OR10)W where w is 1-10, and -R10NR10R10; each R10 is the same or different and is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl; n is 0, 1 or 2; Y is N or CH; R3 and R4 are the same or different and are each independently selected from the group consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, -OR7,
-OAy, -C(O)R7, C(O)Ay, -CO2R7,
-CO2Ay, -SO2NHR9, -NR7R8, -NR7Ay, -NHHet, -NHR10Het -R10OR7, -R10OAy, -R10NR7R8 and -R10NR7Ay; q is O, 1 , 2, 3, 4 or 5; each R5 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay,
Het, -OR7, -OAy, -OHet, -C(O)R9, -C(O)Ay, -C(O)Het, -CO2R9, -C(O)NR7R8, -C(O)NR7Ay, -C(O)NHR10Het,
-C(S)NR9R11, -C(NH)NR7R8, -C(NH)NR7Ay, -S(O)nR9,
-S(O)2NR7R8, -S(O)2NR7Ay, -NR7R8, -NR7Ay, -NHHet,
-NHR10Ay, -NHR10HeI, -R10cycloalkyl, -R10OR9, -R10C(O)R9,
-R10CO2R9, -R10C(O)NR9R11, -R10C(S)NR9R11, -R10C(NH)NR9R11, -R10SO2R9, -R10SO2NR9R11,
-R10SO2NHCOR9, -R10NR7R8, -R10NR7Ay, -R10NHC(NH)NR9R11, cyano, nitro and azido; or two adjacent R5 groups together with the atoms to which they are bonded form a Cs-6 cycloalkyl or aryl; p is O, 1 , 2 or 3; and each R6 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay,
Het, -OR7, -OAy, -OHet, -OR10Ay, -OR10Het,
-C(O)R9, -C(O)Ay, -C(O)Het, -CO2R9, -C(O)NR7R8, -C(O)NR7Ay, - C(O)NHR10Ay, -C(O)NHR10Het, -C(S)NR9R11, -C(NH)NR7R8,
-C(NH)NR7Ay, -S(O)nR9, -S(O)nAy, -S(O)nHet, -S(O)2NR7R8,
-S(O)2NR7Ay, -NR7R8, -NR7Ay, -NHHet, -NHR10Ay, -NHR10Het,
-R10cycloalkyl, -R10Ay, -R10Het, -R10OR9, -R10-O-C(O)R9,
-R10-O-C(O)Ay; -R10-O-C(O)Het, -R10-O-S(O)nR9, -R10C(O)R9, -R10CO2R9, -R10C(O)NR9R11, -R10C(S)NR9R11,
-R10C(NH)NR9R11, -R10SO2R9, -R10SO2NR9R11,
-R10SO2NHCOR9, -R10NR7R8, -R10NR7Ay, -R10NHC(NH)NR9R11, cyano, nitro and azido; or two adjacent R6 groups together with the atoms to which they are bonded form a C5-6 cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms; and pharmaceutically acceptable salts and solvates thereof said process comprising the steps of: a) reacting a compound of formula (II):
Figure imgf000039_0001
with a hindered amide base to produce an anion and reacting the anion with 9- methoxy-9-borabicyclo[3.3.1]nonane; b) adding a compound of formula R1-X, wherein X is is halo or triflate, in the presence of a palladium catalyst to prepare a compound of formula (I), wherein R2 is -S-CH3; c) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt or solvate thereof; and d) optionally converting the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof into a different compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
2. The process according to claim 1 , wherein said hindered amide base is lithium diisopropylamide.
3. The process according ot claim 1 , wherein said palladium catalyst is bis(diphenylphosphinoferrocene)palladium (II) dichloride.
4. The process according to claim 1 , wherein said step (a) is carried out in tetrahydrofuran.
5. The process according to claim 1 , wherein said step (b) is carried out in dimethyl formamide.
6. A compound selected from the group consisting of: 2-(4-Fluorophenyl)-7-(4-methylphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5- ajpyridine;
2-(4-Fluorophenyl)-7-(3-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5- ajpyridine;
2-(4-Fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]-7-pyridin-3-ylpyrazolo[1 ,5- ajpyridine; 1-(4-{2-(4-Fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridin-7- yl}phenyl)ethanone; 7-(4-Fluorophenyl)-2-(4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5- a]pyridine; 7-(3-Methoxyphenyl)-2-(4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-a]pyridine;
4-{2-(4-Methoxyphenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1 ,5-a]pyridin-7- yl}phenylamine;
2-(4-Methoxyphenyl)-3-[2-(methylthio)pyrimidin-4"yl]-7-thien-3-ylpyrazolo[1 ,5- ajpyridine; 2-[4-(Cyclopropylmethoxy)phenyl]-7-(4-methylphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-a]pyridine; 2-[4-(Cyclopropylmethoxy)phenyl]-7-(4-fluorophenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ^-^pyridine; 2-[4-(Cyclopropylmethoxy)phenyl]-7-(4-methoxyphenyl)-3-[2-(methylthio)pyrimidin-4- yl]pyrazolo[1 ,5-ajjpyridine;
2-[4-(Cyclopropylmethoxy)phenyl]-7-(3-methylphenyl)-3-[2-(methylthio)pyrimidin-4- yljpyrazoiofi.δ-ailpyrjdine;
ΛACyclopentyl-4-[2-(4-fluorophenyl)-7-pyridin-3-ylpyrazolo[1 ,5-a]pyridin-3- yI]pyrimidin-2 -amine; 1-{4-[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridin-
7-yl]phenyl}ethanone; ΛACyclopentyl-4-[2-(4-fluorophenyl)-7-(3-methoxyphenyl)pyrazolo[1 ,5-a]pyridin-3- yl]pyrimidin-2-amine; Λ{-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(4-methylphenyl)pyrazolo[1 ,5-a]pyridin-3- yl]pyrimidin-2-amine; and pharmaceutically acceptable salts and solvates thereof.
PCT/US2005/039571 2004-11-17 2005-11-01 Process for preparing pyrazolopyridine compounds WO2006055245A2 (en)

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EP2402335A1 (en) 2010-06-29 2012-01-04 Basf Se Pyrazolopyridine compounds
EP2402336A1 (en) 2010-06-29 2012-01-04 Basf Se Pyrazolopyridine compounds
JP2014528961A (en) * 2011-10-06 2014-10-30 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ Heterocyclylpyri (mi) dinylpyrazole

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EP2402335A1 (en) 2010-06-29 2012-01-04 Basf Se Pyrazolopyridine compounds
EP2402336A1 (en) 2010-06-29 2012-01-04 Basf Se Pyrazolopyridine compounds
JP2014528961A (en) * 2011-10-06 2014-10-30 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ Heterocyclylpyri (mi) dinylpyrazole

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