WO2009001127A1 - Cyanocyclopropylcarboxamides as cathepsin inhibitors - Google Patents

Cyanocyclopropylcarboxamides as cathepsin inhibitors Download PDF

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WO2009001127A1
WO2009001127A1 PCT/GB2008/050483 GB2008050483W WO2009001127A1 WO 2009001127 A1 WO2009001127 A1 WO 2009001127A1 GB 2008050483 W GB2008050483 W GB 2008050483W WO 2009001127 A1 WO2009001127 A1 WO 2009001127A1
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mmol
cyanocyclopropyl
carbonyl
cyclohexanecarboxamide
compound
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PCT/GB2008/050483
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French (fr)
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James John Crawford
Alexander Graham Dossetter
Jonathan Erle Finlayson
Nicola Murdoch Heron
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2009001127A1 publication Critical patent/WO2009001127A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity.
  • the compounds are reversible inhibitors of cysteine proteases, including cathepsins B, K, C, F, H, L, O, S, W and X.
  • cathepsins B, K, C, F, H, L, O, S, W and X are reversible inhibitors of cysteine proteases, including cathepsins B, K, C, F, H, L, O, S, W and X.
  • diseases associated with Cathepsin K are diseases associated with Cathepsin K.
  • this invention also discloses processes for the preparation of such inhibitors.
  • Cathepsin K is a member of the papain superfamily of cysteine proteases, which also encompasses Cathepsins B, C, F, H, L, O, S, W and X.
  • Cathepsin K is a lysosomal collagenase like enzyme, highly expressed in osteoclast cells and plays a key role in turnover and degradation of the bone organic matrix in skeletal growth and development, but also in diseases.
  • inhibitors of cathepsin K may be useful agents in the treatment of but not limited to, osteoporosis, osteoarthritis, asthma, rheumatoid arthritis, metastatic bone disease, osteolytic bone cancer and bone related neuropathic pain.
  • the present invention therefore provides a compound of formula (I)
  • A is a 5- to 7- membered aliphatic ring optionally containing a double bond and optionally comprising an oxygen atom as a ring member and optionally being substituted by up to three substituents each independently selected from halogen and C3_4carbocyclyl;
  • R is hydrogen or C 1-6 alkyl
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- to 7- membered monocyclic saturated heterocyclic ring, which ring can optionally comprise up to three additional heteroatoms each independently selected from O, S or N atoms, and which ring can be optionally substituted by up to three substituents each independently selected from phenyl, benzyl, naphthyl, Ci -6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, cyano, halogen, COOR 3 , COR 3 , NO 2 , OR 4 , CONR 5 R 6 , NR 6 R 7 , monocyclic heteroaryl comprising up to 7 ring atoms, and bicyclic heteroaryl comprising up to 12 carbon atoms, and wherein
  • phenyl, naphthyl, C 1-6 alkyl, C 2-6 arkenyl, C 2-6 arkynyl and benzyl are optionally further substituted by up to three substituents each independently selected from halogen, NR 6 R 7 , SO 2 R 3 , CONR 5 R 6 , cyano, OR 3 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 , Ci -6 alkyl and C 3- vcarbocyclyl, wherein Ci -6 alkyl and C 3-7 carbocyclyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from methyl, and halogen, cyano, SO 2 R 3 , NR 6 R 7 , OR 3 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 and CONR 5 R 6 , and
  • monocyclic or bicyclic heteroaryl are optionally further substituted by up to three substituents each independently selected from halogen, NR 6 R 7 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 , CONR 5 R 6 , SO 2 R 3 , cyano, CO 2 R 3 , OR 3 , Ci -6 alkyl and C 3-7 carbocyclyl, wherein Ci -6 alkyl and C 3-7 carbocyclyl are optionally substituted with up to three substituents independently selected from methyl, halogen, cyano, SO 2 R 3 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 , NR 6 R 7 , OR 3 , CONR 5 R 6 and CO 2 R 3 and wherein phenyl is optionally substituted with up to three substituents selected from halogen groups, SO 2 R 3 , Ci -6 alkyl and C 3-7 carbocyclyl, wherein Ci
  • R 3 is hydrogen, NR 6 R 7 , phenyl, C 3-7 carbocyclyl, a 4-7 membered monocyclic saturated heterocyclic ring comprising up to three heteroatoms each independently selected from O, S or N atoms, or R 3 is Ci -6 alkyl optionally substituted by up to five substituents independently selected from halogen, 0-Ci -3 alkyl and NR 6 ⁇ R7 ;.
  • R >4 is hydrogen, Ci -6 alkyl or phenyl, wherein Ci -6 alkyl or phenyl can be optionally substituted by up to three groups independently selected from halogen, cyano, CONR 5 R 6 , NR 6 R 7 , SO 2 NR 6 R 7 , NSO 2 R 3 and SO 2 R 3 ;
  • R 5 is hydrogen, Ci -6 alkyl or phenyl
  • R 6 and R 7 are independently hydrogen, Ci -6 alkyl, COR 3 , monocyclic heteroaryl comprising up to 7 ring atoms or bicyclic heteroaryl comprising up to 12 ring atoms or together with the nitrogen to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring optionally comprising up to three additional hetetoatoms each independently selected from O, S or N atoms and optionally substituted by C 1-6 alkyl optionally substituted by NR 8 R 9 ;
  • R 8 and R 9 are independently hydrogen or Ci -6 alkyl; and pharmaceutically acceptable salts or solvates thereof.
  • an alkyl, alkenyl or alkynyl group or an alkyl, alkenyl or alkynyl moiety in a substituent group may be linear or branched.
  • references to individual alkyl groups such as "propyl” are specific for the straight chain version only and references to individual branched-chain alkyl groups such as t-butyl are specific for the branched chain version only.
  • Ci-3alkyl includes methyl, ethyl, propyl and isopropyl and examples of "Chalky!" include the examples of “Ci-3alkyl”and additionally t-butyl, pentyl, 2,3-dimethylpropyl, 3- methylbutyl and hexyl.
  • Examples of "Ci-salkyl” include the examples of “Ci-6alkyl” and additionally heptyl, 2,3-dimethylpentyl, 1-propylbutyl and octyl.
  • C 2 - 6 alkenyl includes vinyl, allyl, 1-propenyl , 2- butenyl, 3-butenyl, 3-methylbut-l-enyl, 1-pentenyl and 4-hexenyl and examples of
  • C 2 - 6 alkynyl includes ethynyl, 1-propynyl, 3-butynyl, 2-pentynyl and l-methylpent-2- ynyl.
  • C3-4carbocyclyl is a saturated, partially saturated or unsaturated, monocyclic ring containing 3 to 4 carbon ring atoms wherein a -CH 2 - group can optionally be replaced by a -C(O)-.
  • Suitable examples of "C3-4carbocyclyl” are cyclopropyl and cyclobutyl.
  • C3-7carbocyclyl is a saturated, partially saturated or unsaturated, monocyclic ring containing 3 to 7 carbon ring atoms wherein a -CH 2 - group can optionally be replaced by a -C(O)- Suitable examples of “C3-7carbocyclyl” are cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, 4-oxocyclohex-l-yl and S-oxocyclohept-S-en-l-yl.
  • Aryl groups include phenyl and naphthyl.
  • “Monocyclic heteroaryl” or “bicyclic heteroaryl” groups comprising up to 7 or up to 12 ring atoms respectively include 5- or 6-membered, 5,6- or 6,6-fused aromatic rings containing up to 5 ring heteroatoms each independently selected from N, S, O.
  • Examples include pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyridazinyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, benzimidazolyl, triazolyl, benzfuranyl, benzothiophenyl, indolyl, indazolyl, benzoxazolyl, benzfuranyl, quinoxalinyl, benzothiazolyl, furo[3,2-c]pyridinyl, 6,7-dihydro-4H-pyrano[4,3- ⁇ i][l,3]thiazolyl, [l,3]thiazolo[5,4- ⁇ ]pyridinyl, [l,3]thiazolo[4,5- ⁇ ]pyridinyl, 5,6-dihydro-4H- cyclopenta[d][l,3]thi
  • Heteroaryl groups include pyridinyl, thiazolyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, furo[3,2- c]pyridinyl, 6,7-dihydro-4H-pyrano[4,3- ⁇ i][l,3]thiazolyl, [l,3]thiazolo[5,4- ⁇ ]pyridinyl, [l,3]thiazolo[4,5- ⁇ ]pyridinyl, 5,6-dihydro-4H-cyclopenta[ ⁇ i][l,3]thiazolyl, benzimidazole and especially pyridin-2-yl, pyridin-6-yl, thiazole-2-yl, quinoxalin-2-yl, quinoxalin-3-yl, benzothiazol-2-yl, benzoxazol-2-yl, furo[3,2-c]pyridin-2-yl, 6,7-dihydro-4H-
  • Examples of "a 5- to 7-membered monocyclic saturated heterocyclic ring” include pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, homo-morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 1 ,4-diazepanyl and homopiperazinyl.
  • Particular examples of a 5-, 6- or 7-membered monocyclic saturated heterocyclic ring optionally containing one or more O, S or N atoms include pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, 1 ,4-diazepanyl and especially pyrrolidin-1-yl, piperidin-1- yl, piperazin-1-yl, homopiperazin-1-yl and 1,4-diazepan-l-yl.
  • Examples of "a 4-7 membered monocyclic saturated heterocyclic ring” include azetidinyl pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, homo- morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 1 ,4-diazepanyl and homopiperazinyl.
  • Particular examples of a 5-, 6- or 7-membered monocyclic saturated heterocyclic ring optionally containing one or more O, S or N atoms include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, 1 ,4-diazepanyl and especially azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl, and 1,4- diazepan-l-yl.
  • halo refers to fluoro, chloro, bromo and iodo; such as for example fluoro, chloro, bromo; chloro and fluoro; chloro and bromo; fluoro and bromo.
  • tautomerism may affect any heterocyclic groups that bear 1 or 2 oxo substituents.
  • present invention includes in its definition any such tautomeric form, or a mixture thereof, which possesses the above-mentioned activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings or named in the Examples.
  • a suitable pharmaceutically-acceptable salt of a compound of the Formula (I) is, for example, an acid-addition salt of a compound of the Formula (I), for example an acid- addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric, para-toluenesulphonic, methanesulphonic, tartaric or maleic acid; or, for example, a salt of a compound of the Formula (I) which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt.
  • an acid-addition salt of a compound of the Formula (I) for example an acid- addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric, para-toluenesulphonic, methanesulphonic, tartaric or maleic acid
  • a further suitable pharmaceutically acceptable salt of a compound of the Formula (I) is, for example, a salt formed within the human or animal body after administration of a compound of the Formula (I).
  • the compounds of the invention may be administered in the form of a pro-drug that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • pro-drugs examples include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I) and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I).
  • the present invention includes those compounds of the Formula (I) as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I) may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzvmology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.
  • Bundgaard Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113- 191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al, Chem. Pharm. Bull. 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the Formula (I) containing a carboxy group is, for example, a pharmaceutically-acceptable ester, which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters such as methyl, ethyl and tert-butyl, (l-6C)alkoxymethyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-l,3- dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and (1- 6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether, which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include (1-1 OC) alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-lOC) alkoxycarbonyl groups such as ethoxycarbonyl, N,N-[di-( ⁇ - 4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • (1-1 OC) alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
  • (1-lOC) alkoxycarbonyl groups such as ethoxycarbonyl, N,N-[di-( ⁇ - 4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, 7V,7V-dialkylaminomethyl, morpholinomethyl, piperazin- 1 -ylmethyl and 4-(l -4C)alkylpiperazin- 1 -ylmethyl.
  • Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include ⁇ - acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, 7V,7V-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-ylmethyl.
  • the in vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I). As stated hereinbefore, the in vivo effects of a compound of the Formula (I) may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • each individual species or substituent species and any convenient or more convenient combination of species and/or substituent species represents an independent embodiment of the invention.
  • A is a 5-7-membered aliphatic ring optionally containing a double bond and optionally comprising an oxygen atom as a ring member and optionally being substituted by up to 3 substituents independently selected from halogen and C 3- 4 carbocyclyl.
  • a double bond is conveniently present in any suitable position of the ring A.
  • An oxygen atom can be present in any suitable position of the ring A, in addition to a double bond if desired.
  • A is a 5-7-membered aliphatic ring optionally being substituted by up to three substituents each independently selected from halogen and C 3-4 carbocyclyl. More conveniently, A is selected from any one of cyclopentane, norpinane, cycloheptane and cyclohexane. More conveniently, A is cyclohexane.
  • R is hydrogen or C 1-4 alkyl. Conveniently R is hydrogen, methyl, ethyl or propyl. More conveniently, R is hydrogen.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring, which ring may optionally comprise up to three N atoms and can be optionally substituted by up to three substituent groups as defined herein.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form any one of a pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or 1 ,A- diazepanyl ring, wherein the pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or 1 ,A- diazepanyl ring can optionally be substituted by up to three substituent groups as defined herein.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring, which ring can optionally comprise up to three additional heteroatoms each independently selected from O, S or N atoms and can be optionally substituted by up to three substituents independently selected from phenyl, benzyl, naphthyl, Ci -6 alkyl, cyano, halogen, COOR 3 , COR 3 , NO 2 , OR 4 , CONR 5 R 6 , NR 6 R 7 , monocyclic heteroaryl comprising up to 6 ring atoms or bicyclic heteroaryl comprising up to 10 ring atoms, wherein the phenyl, benzyl, naphthyl, Ci -6 alkyl, monocyclic or bicyclic heteroaryl can be optionally further substituted as defined herein.
  • the phenyl, naphthyl, Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl and benzyl groups stated in part (i) of the definition or R 1 and R 2 above, can be optionally substituted further by 1 or 2 substituents independently selected from halogen, NR 6 R 7 , SO 2 R 3 , CONR 5 R 6 , cyano, OR 3 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 , Ci -6 alkyl and C 3-7 carbocyclyl, wherein Ci -6 alkyl and C3 -7 carbocyclyl can themselves be optionally substituted with up to three substituents independently selected from halogen, cyano, SO 2 R 3 , NR 6 R 7 , OR 3 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 or CONR 5 R 6 .
  • the phenyl, naphthyl, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and benzyl groups stated in part (i) of the definition or R 1 and R 2 above, can be optionally substituted further by 1 or 2 substituents independently selected from halogen, NR 6 R 7 , SO 2 R 3 , CONR 5 R 6 , cyano, OR 3 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 , Ci -6 alkyl and C 3-7 carbocyclyl, wherein Ci -6 alkyl and C 3-7 carbocyclyl can themselves be optionally with 1 or 2 substituents independently selected from halogen, cyano, SO 2 R 3 , NR 6 R 7 , OR 3 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 or CONR 5 R 6 .
  • the monocyclic or bicyclic heteroaryl groups stated in part (ii) of the definition or R 1 and R 2 above, can be optionally substituted further by 1 or 2 substituents independently selected from halogen, NR 6 R 7 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 , CONR 5 R 6 , SO 2 R 3 , cyano, OR 3 , phenyl itself optionally substituted with up to three halogen groups or SO 2 R 3 , Ci -6 alkyl and C 3-7 carbocyclyl, wherein Ci -6 alkyl and C 3-7 carbocyclyl can themselves be optionally itself optionally substituted with up to three substituents independently selected from halogen, cyano, SO 2 R 3 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 , NR 6 R 7 , OR 3 , C 3-7 carbocyclyl or CONR 5 R 6 .
  • the monocyclic or bicyclic heteroaryl groups stated in part (ii) of the definition or R 1 and R 2 above, can be optionally substituted further by 1 or 2 substituents independently selected from halogen, NR 6 R 7 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 , CONR 5 R 6 , SO 2 R 3 , cyano, OR 3 , phenyl itself optionally substituted with halogen, SO 2 R 3 C 1-6 alkyl and 5 C3_7carbocyclyl, wherein Ci -6 alkyl and C3_7carbocyclyl can themselves be optionally itself optionally substituted with up to three substituents each independently selected from halogen, cyano, SO 2 R 3 , SO 2 NR 6 R 7 , NSO 2 R 3 , NR 8 COR 9 , NR 6 R 7 , OR 3 , C 3-7 carbocyclyl and CONR 5 R 6 .
  • R 3 is hydrogen, NR 6 R 7 , phenyl, cyclopropyl, cyclobutyl, a 4-7o membered monocyclic saturated heterocyclic ring containing one or more O, S or N atoms or or R 3 is Ci -6 alkyl optionally substituted by up to three substituents independently selected from halogen, 0-Ci -3 alkyl and NR 6 R 7 .
  • R 3 is hydrogen, NR 6 R 7 , phenyl, cyclopropyl, cyclobutyl, oxetanyl or Ci -6 alkyl itself optionally substituted by up to three halogen groups, OCH 3 ,s OCH 2 CH 3 and NR 6 R 7 .
  • R 6 and R 7 are independently hydrogen, Ci -6 alkyl, COR 3 , monocyclic or bicyclic heteroaryl or together with the nitrogen to which they are attached form a 5 or 6 membered monocyclic saturated heterocyclic ring optionally containing up to three heteroatoms each independently selected from O, S or N atoms, and optionally substitutedo with C 1-6 alkyl which may itself be optionally substituted with NR 8 R 9 .
  • R 6 and R 7 are independently hydrogen, Ci -6 alkyl, COR 3 , monocyclic or bicyclic heteroaryl or together with the nitrogen to which they are attached form a 5 or 6 membered monocyclic saturated heterocyclic ring optionally containing up to three heteroatoms each independently selected from O or N atoms and optionally substituted5 with C 1-6 alkyl which may itself be optionally substituted with NR 8 R 9 .
  • the chiral cyclic 1 ,2-diacid (VI) may be dehydrated with a suitable reagent such as acetic anhydride, acetyl chloride, dicyclohexylcarbodiimide (DCC), thionylchloride and the such like, preferably acetic anhydride at a temperature between room temperature and 100 0 C, then removal of excess dehydrating agent yields a bi-cyclic- anhydride of the type (VII).
  • a suitable reagent such as acetic anhydride, acetyl chloride, dicyclohexylcarbodiimide (DCC), thionylchloride and the such like, preferably acetic anhydride at a temperature between room temperature and 100 0 C, then removal of excess dehydrating agent yields a bi-cyclic- anhydride of the type (VII).
  • the anhydride (VII) is reactive towards secondary amines of the type (V) in the presence or absence of a suitable base such as triethylamine, diethylisopropylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the such like or ionic bases such as potassium carbonate, in a suitable aprotic solvent such as dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformamide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene.
  • a suitable base such as triethylamine, diethylisopropylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the such like or ionic bases such as potassium carbonate
  • a suitable aprotic solvent such as dichloromethane (DCM),
  • a coupling agent such as O-(7-azabenzotriazol-l-yl)- ⁇ /, ⁇ /,N',N'-tetramethyluronium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC) / hydroxylbenzotriazole (HOBt), 1 -benzotriazolyoxy-tris-dimethylamino-phosphonium hexafluorophosphate (BOP), benzotriazolyoxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), ⁇ /, ⁇ /-dimethylaminoethylcyclohexylcarbodiimide (EDC), 4-(4,6-dimethoxy-l,3,5-triazin-2- yl)-4-methylmorpholinium chloride (DMTMM), t
  • DHC dicyclohexylcarbodiimide
  • HOBt hydroxylbenz
  • the chiral cyclic 1,2-diacid of the type (VI) can be produced by methods as shown in the literature - WO2004000825, Eur. J. Org. Chem. 2002, 2948-2952, which include chiral resolution, chiral separation by chromatographic methods, de-symmetrisation using esterase enzymes, such as pig liver esterase as generalised below.
  • the preferred i?,i?-cyclohexyl-l,2-dicarboxylic acid can be produced by a resolution of commercially available racemic diacid by a resolution process using chiral amines bases to form diastereomeric salts and recystallisation of the single enantiomers, as outlined by Eur. J. Org. Chem. 2002, 2948-2952.
  • the ester group is now represented by the group PG, as this is formally a protecting group masking the acid.
  • a free acid of the type (VIII) can be coupled with an appropriately substituted 1-aminocyclopropylcarbonitrile (III) by the use of a coupling agent such as HATU, PyBOP, EDC, DCC / HOBt, BOP, PyBOP, EDC, DMTMM, trichloroacetyl chloride, by the formation of an active ester in the presence of a suitable bases triethylamine, diethylisopropylamine, DBU and the such like, or suitable ionic bases such as potassium carbonate, in an appropriate solvent dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformaide (DMF), dimethylacet
  • DCM dichloromethane
  • THF tetrahydrofuran
  • DMF dimethylformaide
  • An alternative method would be by conversion to an acid chloride with a suitable reagent such as oxalylchloride, thionyl chloride, and the such like, then addition of the secondary amine (V) in the presence of a bases as listed above.
  • a suitable reagent such as oxalylchloride, thionyl chloride, and the such like
  • V secondary amine
  • a combination of HATU or PyBOP in either DMF or DCM between room temperature and 50 0 C is preferred.
  • the protecting group can be removed from compounds of the type (IX) to reveal an acid of the type (IV) by the methods described in Green and Wuts, Protective groups in Organic synthesis, 1991, John Wiley.
  • a suitable catalyst such as palladium on carbon (5 to 10% loading), palladium hydroxide, and the such like
  • palladium (II) acetate and ammonium formate in a suitable solvent such as methanol, ethanol, ethylacetate and the such like
  • the appropriate secondary amine (V) (HMUR2) can then be coupled with with acids of type (IV) by the use of a coupling agent such as HATU, PyBOP, EDC, DCC /HOBt, BOP, PyBOP, EDC, DMTMM, by the formation of an active ester in the presence of a suitable bases triethylamine, diethylisopropylamine, DBU and the such like, or suitable ionic bases such as potassium carbonate, in an appropriate solvent dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformaide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene at a temperature between 0 0 C and 100 0 C to yield compounds of the type (I).
  • a coupling agent such as HATU, PyBOP, EDC, DCC /HOBt, BOP, PyBOP, EDC, DMTMM
  • a combination of HATU or PyBOP in either DMF or DCM between room temperature and 50 0 C is preferred.
  • Many of the secondary amines used in the synthesis of examples below are from commercially available sources or from routes described previously in the literature. In general terms, the compounds can be made by the routes described below.
  • Secondary amines of the type (XIII), where there is a linking heteroatom Y between two rings, which is either oxygen or nitrogen, can be synthesised by the route outlined in scheme 4.
  • An approach of using the Y atom as a nucleophile and displacement of a halogen from an aromatic ring such as (X) can be used to form the carbon heteroatom bond, and thus compounds of the type (XII).
  • the representative secondary amine ring is a piperadine such as (XI). This approach would also be applicable with pyrrolidine and azetine rings as well.
  • a mixture of the two ring compound (X), and (XI) are reacted in the presence of a suitable base and inert solvent
  • bases would include potassium carbonate, potassium tert-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP.
  • a suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0 C and 100 0 C.
  • Another approach would be to use a palladium catalysed coupling reaction to combine the two rings. This is particularly useful where the aromatic ring of (X) is too electron rich to enable a nucleophilic substitution reaction.
  • a suitable palladium source would be palladium (II) chloride, palladium acetate, Pd 2 (dba) 3 and the such like, and appropriate phosphine lingand, such triphenyl phosphine, 2- biphenyl-diphenyl phosphine and the such like in presence of a base such as potassium carbonate, potassium tert-butoxide, cesium carbonate, potassium phosphate, and strong amine bases such as DIPEA, DBU in an inert solvent such as THF, DMF, DMA, and toluene at a temperature between 25 0 C and 100 0 C.
  • a base such as potassium carbonate, potassium tert-butoxide, cesium carbonate, potassium phosphate, and strong amine bases
  • DIPEA inert solvent
  • DMF DMF
  • DMA toluene
  • PG protecting group
  • BOC tert-butyl carbamate
  • cbz benzyl carbamate
  • benzyl and trifiuoroacetyl Conditions to remove these protecting groups can be found in Greene Wuts Protective groups in Organic synthesis, 1991, John Wiley, to reveal the secondary amine of type (XIII).
  • Directly linked rings can be synthesised by the combining an aromatic ring of the type (XIV), and attack on a piperidone, with a protecting group PG, to yield of tertiary alcohol of the type (XV).
  • the aromatic ring (XIV) is activated by conversion into a nucleophile such as an organolithium, by reacting with n-butyl lithium in an appropriate solvent such as THF at low temperature, or into a Grignard reagent by reacting the aromatic halogen with magnesium metal in an inert solvent such as diethyl ether and THF. Addition of the piperidone at a low temperature such as -50 0 C to 0 0 C, and allowing the temperature to rise to room temperature would complete the reaction.
  • the tertiary alcohol can be eliminated by the addition of a mineral acid such as a sulphuric acid, hydrochloric acid or activation with a conversion to an group to eliminate for example mesyl chloride or tosyl chloride in the presence of amine bases such as DIPEA, DBU, triethylamine in an inert solvent such as DCM, dichloroethane. Heat may be required to complete the elimination to yield the unsaturated bicycle (XVI).
  • the double bond can be removed by hydrogenation by treatment with hydrogen gas in the presence of a metal catalyst such palladium on carbon, or platinum oxide and the such like in an inert solvent such as THF, DCM, ethanol or ethylacetate.
  • the protecting group PG can be removed as the same time, for example when the group is Cbz or benzyl.
  • a BOC group can be removed by strong acid such as trifiuoroacetic acid, hydrochloric acid in an appropriate acid such as methanol or dioxane at room temperature to yield the amine (XVII).
  • Secondary amines of the type (XX) can be synthesised by the route outlined in scheme 6, where the nucleophilic nitrogen of piperazine directly displaces the halogen from an aromatic ring such as (XIV).
  • the representative secondary amine ring is a piperazine such as (XVIII), but this approach would also be applicable with homopiperazine.
  • bases would include potassium carbonate, potassium tert-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP.
  • a suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0 C and 100 0 C.
  • an excess of piperazine is used to stop dimerisation, which could be up to 10 equivalents, which directly yields the desire secondary amine.
  • a protecting group such as tert-butyl carbamate (BOC), benzyl carbamate (cbz), benzyl and trifiuoroacetyl and the such like, can be employed to yield compounds of the type (XIX), and a subsequently deprotection step yields the desired secondary amine (XX) by method described in Greene Wuts Protective groups in Organic synthesis, 1991, John Wiley.
  • the tert-butyl carbamate (BOC) is used and deprotected using by strong acid such as trifluoroacetic acid, hydrochloric acid in an appropriate acid such as methanol or dioxane at room temperature to yield the amine (XX).
  • thiazole piperazine and benzothiazole piperazine of the type (XXIV) can be synthesised by the route outlined in scheme 7, where the nucleophilic nitrogen of piperazine directly displaces the halogen from an aromatic ring such as (XXII).
  • the representative secondary amine ring is a piperazine such as (XVIII), but this approach would also be applicable with homopiperazine.
  • a suitable base and inert solvent such bases would include potassium carbonate, potassium tert-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP.
  • a suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0 C and 100 0 C.
  • a protecting group such as tert-butyl carbamate (BOC), benzyl carbamate (cbz), benzyl and trifiuoroacetyl and the such like, can be employed to yield compounds of the type (XVIII), and a subsequently deprotection step yields the desired secondary amine (XXIV) by method described in Greene Wuts Protective groups in Organic synthesis, 1991, John Wiley.
  • the tert- butyl carbamate (BOC) is used and deprotected using by strong acid such as trifluoroacetic acid, hydrochloric acid in an appropriate acid such as methanol or dioxane at room temperature to yield the amine (XXIV).
  • Thiazole piperazine can also be synthesised by thiazole ring formation between a thiourea of the type (XXVI), where PG is a protecting group selected from tert-butyl carbamate (BOC), benzyl carbamate (cbz), benzyl and trifluoroacetyl, and an ⁇ -haloketone such as (XXV).
  • PG is a protecting group selected from tert-butyl carbamate (BOC), benzyl carbamate (cbz), benzyl and trifluoroacetyl, and an ⁇ -haloketone such as (XXV).
  • a suitable solvent such as ethanol, n-Butanol, toluene and xylene between 50 0 C and 150 0 C, will affect ring closure to form the thiazole product (XXIII). Deprotection as described yields the appropriate secondary amine (XXIV).
  • Sulphone-aryl-piperazines of the type (XXXII) can be synthesised by the steps outlined in scheme 9.
  • An appropriately substituted thiophenol bearing a halogen atom of fluoro or chloro can be alkylated using an alkyl chloride, bromide or iodide in the presence of a suitable base and inert solvent, such bases would include potassium carbonate, potassium tert-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP.
  • a suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0 C and 100 0 C.
  • the subsequent sulphide is oxidised to a sulphone using a suitable oxidising agent such as met ⁇ -chloroperbenxoic acid, trifluoroperacetic acid, dimethyldioxirane, oxone, and the such like in an inert solvent, to yield the sulphone (XXIX).
  • a suitable oxidising agent such as met ⁇ -chloroperbenxoic acid, trifluoroperacetic acid, dimethyldioxirane, oxone, and the such like in an inert solvent
  • XXIX oxidising agent
  • PG H
  • a suitable base and inert solvent such bases would include potassium carbonate, potassium t ⁇ t-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP.
  • a suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0 C and 100 0 C. If a protecting group has been used the is removed as described above to yield the secondary amine (XXXII).
  • Alkylsubstituted aryl piperazines of the type (XXXVI), can be synthesised by the route described in scheme 10.
  • a halo-substituted aryl of the type (XXXII) can be directly substituted with the alkyl group, which contains an electron withdrawing group by the method described by Caron, S. et al. J.Am.Chem.Soc, 2000, 712, to yield substituted compounds of the type (XXXIV)
  • the group can be attached by palladium coupling methods such as described by Verkade et alJ. Org. Chem. 2003, 63, 8003 to yield the same intermediate (XXXIV).
  • a simple alkylated aryl such as (XXXIII) can be di-alkylated using methyl iodide, alkyl bromides or alkyl iodides by treatment with a suitable base and inert solvent, such bases would include potassium carbonate, potassium t ⁇ t-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP.
  • a suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0 C and 100 0 C.
  • Coupling with piperazine (XXXV) or another di-amine ring such as homo-piperazine can be achieved using palladium catalysis conditions using a suitable palladium source would be palladium (II) chloride, palladium acetate, Pd 2 (dba)3 and the such like, and appropriate phosphine lingand, such triphenyl phosphine, 2-biphenyl-diphenyl phosphine, PEPPSI-IEt [Aldrichimica Acta, 39, 2006, 97 and method described within] and the such like, or BINOL in presence of a bases potassium carbonate, potassium ter t-butoxide, cesium carbonate, potassium phosphate, and strong amine bases such as DIPEA, DBU in an inert solvent such as THF, DMF, DMA, and toluene at a temperature between 25 0 C and 100 0 C, to yield the secondary amine (XXXVI).
  • a method for producing inhibition of a cysteine protease in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of a cysteine protease in a warm blooded animal, such as man.
  • the compounds of the invention are useful in the treatment of inflammation and immune disorders such as, but not limited to, osteoporosis, rheumatoid arthritis, osteoarthritis, metastatic bone disease, osteolytic bone disease and bone related neuropathic pain.
  • the invention provides the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of Cathepsin K in a warm blooded animal, such as man.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in the inhibition of a cysteine protease, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition, which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule, which contains between 1 mg and 1 g of the compound of this invention.
  • composition of the invention is one suitable for intravenous, subcutaneous, intramuscular or intra-articular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg "1 to 100 mgkg "1 of the compound, preferably in the range of 0.1 mgkg "1 to 20 mgkg "1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose, which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • the invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • the compounds of the invention may be combined with agents listed below.
  • Non-steroidal anti-inflammatory agents including nonselective cyclo-oxygenase COX-I / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramus
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin-like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signal
  • the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B- Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).
  • B- Lymphocytes such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRl for the C-X 3 - C family.
  • a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, M
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.
  • a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • a proton pump inhibitor such as omeprazole
  • a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochlor
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • Ml, M2, and M3 antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.
  • a beta-adrenoceptor agonist including beta receptor subtypes 1-4
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically- applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
  • immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcripta
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase);
  • - or B.sub2. -receptor antagonist for example colchicine;
  • anti-gout agent for example colchicine;
  • xanthine oxidase inhibitor for example allopurinol;
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone;
  • growth hormone secretagogue for example transforming growth factor (TGF ⁇ );
  • PDGF platelet-derived growth factor
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NK.
  • NKP-608C sub 1. or NK.sub3.
  • receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418;
  • elastase inhibitor such as UT-77 or ZD-0892;
  • TACE TNF-alpha converting enzyme inhibitor
  • iNOS induced nitric oxide synthase
  • chemoattractant receptor-homologous molecule expressed on TH2 cells such as a CRTH2 antagonist
  • inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
  • agent modulating the activity of purinergic receptors such as P2X7; or
  • inhibitor of transcription factor activation such as NFkB, API, or STATS.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer
  • suitable agents include: (i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fiuorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubic
  • a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5 ⁇ -reductase such as finasteride;
  • an antioestrogen for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene
  • an agent which inhibits cancer cell invasion for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function
  • an inhibitor of growth factor function for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as ⁇ /-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), ⁇ /-(3-ethynylphenyl)-6
  • an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354
  • a compound that works by another mechanism for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin
  • vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
  • an agent used in antisense therapy for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • an agent used in a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as trans fection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • GDEPT gene-directed enzyme pro-drug
  • Microwave reactions were performed in a Smith Synthesiser (300 Kwatts) on either the normal or high setting using appropriate tubes recommended by the manufacturer.
  • Purification by column chromatography was typically performed using silica gel (Merck 7734 grade) and solvent mixtures and gradients are recorded herein. Purification by reverse phase high performance chromatography was typically performed using a Perkin Elmer instrument using UV detection at 254 nm and a Cl 8 1500 x 21.2 mm Phenomenex column 100 A. Acidic conditions (0.1 to 0.5% formic acid) or basic conditions (ammonia to pHIO) were used with gradiant solvent mixtures of acetonitrile and water. SCX columns were supplied from International Sorbent Technology and used as directed in this specification.
  • DMTMM 4-(4,6-dimethoxy-l,3,5-t5riazin-2-yl)-4-methylmorpholinium chloride HATU O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the solid was purified by loading onto an SCX cartridge (20 g) and eluting with methanol. Increased polarity to IM ammonia in MeOH (2 x 15 mL) furnished the desired compound as a white solid (300 mg, 58% yield).
  • the diastereomers can be separated by chiral HPLC using Merck 50mm 20 ⁇ m Chiralpak AS - No ASVOOSC BD004 Packed 31-03-03, eluent iso- Hexane/(EtOH/MeOH50/50) 95/5, flow 40mL/min, 210, 230 nm) to yield each diastereomer as characterised by 1 H NMR.
  • the reaction mixture was diluted with DCM (100 mL) and washed with IN HCl (100 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were washed with brine (50 mL) and dried (MgSO 4 ) to give a dark crude oil.
  • the crude material was purified by flash chromatography (isohexane to 20 % DCM) to furnish the desired compound as an orange oil (0.78 g, 20 % yield) which was used crude in the next step.
  • 6-methylsulfonyl-2-piperazin-l-yl-benzothiazole (446 mg; 1.5 mmol) and (3aR,7aR)- 3a,4,5,6,7,7a-hexahydroisobenzofuran-l,3-dione (231 mg; 1.5 mmol) were stirred in DMF (10 mL) at room temperature for 3 hours.
  • LCMS analysis indicated complete conversion to the intermediate acid.
  • 1 -amino- 1-cylcopropanecarbonitrile-HCl (213 mg, 1.80 mmol), DIPEA (1046 uL ; 6.00 mmol) and HATU (684 mg; 1.80 mmol) were added and the mixture allowed to stir overnight.
  • the resulting solution was stirred at room temperature for 16 hours.
  • the reaction mixture was diluted with DCM (100 mL), and washed with water (50 mL).
  • the organic layer was passed through a phase separator and evaporated to afford crude product.
  • the crude product was purified by preparative HPLC (Waters XBridge Prep Cl 8 OBD column, 5 ⁇ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% NH 3 ) and CH 3 CN as eluents.
  • 2-Bromo-5-chloroanisole (1.77 g, 8.00 mmol), potassium phosphate (5.94 g, 28.0 mmol), tricyclohexylphosphine (0.224 g, 0.800 mmol) and cyclopropylboronic acid (0.893 g, 10.4 mmol) were suspended in toluene (32 mL) and water (1.6 mL) added followed by palladium(II) acetate (0.090 g, 0.40 mmol). The mixture was heated to 100 0 C for 3 hours and then allowed to cool.

Abstract

The present invention relates to compounds of formula (I) for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases, including cathepsins B, K, C, F, H, L, O, S, W and X. Of particular interest are diseases associated with Cathepsin K.

Description

CYANOCYCLOPROPYLCARBOXAMIDES AS CATHEPSIN INHIBITORS
The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases, including cathepsins B, K, C, F, H, L, O, S, W and X. Of particular interest are diseases associated with Cathepsin K. In addition this invention also discloses processes for the preparation of such inhibitors.
Cathepsin K is a member of the papain superfamily of cysteine proteases, which also encompasses Cathepsins B, C, F, H, L, O, S, W and X. Cathepsin K is a lysosomal collagenase like enzyme, highly expressed in osteoclast cells and plays a key role in turnover and degradation of the bone organic matrix in skeletal growth and development, but also in diseases. In this respect inhibitors of cathepsin K may be useful agents in the treatment of but not limited to, osteoporosis, osteoarthritis, asthma, rheumatoid arthritis, metastatic bone disease, osteolytic bone cancer and bone related neuropathic pain.
The present invention therefore provides a compound of formula (I)
Figure imgf000002_0001
(I) in which:
A is a 5- to 7- membered aliphatic ring optionally containing a double bond and optionally comprising an oxygen atom as a ring member and optionally being substituted by up to three substituents each independently selected from halogen and C3_4carbocyclyl; R is hydrogen or C1-6 alkyl
R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 7- membered monocyclic saturated heterocyclic ring, which ring can optionally comprise up to three additional heteroatoms each independently selected from O, S or N atoms, and which ring can be optionally substituted by up to three substituents each independently selected from phenyl, benzyl, naphthyl, Ci-6 alkyl, C2-6alkenyl, C2-6alkynyl, cyano, halogen, COOR3, COR3, NO2, OR4, CONR5R6, NR6R7, monocyclic heteroaryl comprising up to 7 ring atoms, and bicyclic heteroaryl comprising up to 12 carbon atoms, and wherein
(i) phenyl, naphthyl, C1-6 alkyl, C2-6arkenyl, C2-6arkynyl and benzyl are optionally further substituted by up to three substituents each independently selected from halogen, NR6R7, SO2R3, CONR5R6, cyano, OR3, SO2NR6R7, NSO2R3, NR8COR9, Ci-6 alkyl and C3- vcarbocyclyl, wherein Ci-6 alkyl and C3-7carbocyclyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from methyl, and halogen, cyano, SO2R3, NR6R7, OR3, SO2NR6R7, NSO2R3, NR8COR9 and CONR5R6, and
(ii) monocyclic or bicyclic heteroaryl are optionally further substituted by up to three substituents each independently selected from halogen, NR6R7, SO2NR6R7, NSO2R3, NR8COR9, CONR5R6 , SO2R3, cyano, CO2R3, OR3, Ci-6 alkyl and C3-7carbocyclyl, wherein Ci-6 alkyl and C3-7carbocyclyl are optionally substituted with up to three substituents independently selected from methyl, halogen, cyano, SO2R3, SO2NR6R7, NSO2R3, NR8COR9, NR6R7, OR3, CONR5R6 and CO2R3 and wherein phenyl is optionally substituted with up to three substituents selected from halogen groups, SO2R3, Ci-6 alkyl and C3-7carbocyclyl, wherein Ci-6 alkyl and C3-7carbocyclyl are optionally substituted with up to three substituents independently selected from halogen, cyano, SO2R3, SO2NR6R7, NSO2R3, NR8COR9, NR6R7, OR3, C3-7carbocyclyl,CONR5R6 and CO2R3;
R3is hydrogen, NR6R7, phenyl, C3-7carbocyclyl, a 4-7 membered monocyclic saturated heterocyclic ring comprising up to three heteroatoms each independently selected from O, S or N atoms, or R3 is Ci-6 alkyl optionally substituted by up to five substituents independently selected from halogen, 0-Ci-3 alkyl and NR 6π R7 ;. R >4 is hydrogen, Ci-6 alkyl or phenyl, wherein Ci-6 alkyl or phenyl can be optionally substituted by up to three groups independently selected from halogen, cyano, CONR5R6, NR6R7, SO2NR6R7, NSO2R3 and SO2R3;
R5 is hydrogen, Ci-6 alkyl or phenyl;
R6 and R7 are independently hydrogen, Ci-6 alkyl, COR3, monocyclic heteroaryl comprising up to 7 ring atoms or bicyclic heteroaryl comprising up to 12 ring atoms or together with the nitrogen to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring optionally comprising up to three additional hetetoatoms each independently selected from O, S or N atoms and optionally substituted by C1-6 alkyl optionally substituted by NR8R9;
R8 and R9 are independently hydrogen or Ci-6 alkyl; and pharmaceutically acceptable salts or solvates thereof. In the context of the present specification, unless otherwise indicated, an alkyl, alkenyl or alkynyl group or an alkyl, alkenyl or alkynyl moiety in a substituent group may be linear or branched. However references to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched-chain alkyl groups such as t-butyl are specific for the branched chain version only. For example, "Ci-3alkyl" includes methyl, ethyl, propyl and isopropyl and examples of "Chalky!" include the examples of "Ci-3alkyl"and additionally t-butyl, pentyl, 2,3-dimethylpropyl, 3- methylbutyl and hexyl. Examples of "Ci-salkyl" include the examples of "Ci-6alkyl" and additionally heptyl, 2,3-dimethylpentyl, 1-propylbutyl and octyl. An analogous convention applies to other terms, for example "C2-6alkenyl" includes vinyl, allyl, 1-propenyl , 2- butenyl, 3-butenyl, 3-methylbut-l-enyl, 1-pentenyl and 4-hexenyl and examples of
"C2-6alkynyl" includes ethynyl, 1-propynyl, 3-butynyl, 2-pentynyl and l-methylpent-2- ynyl.
"C3-4carbocyclyl" is a saturated, partially saturated or unsaturated, monocyclic ring containing 3 to 4 carbon ring atoms wherein a -CH2- group can optionally be replaced by a -C(O)-. Suitable examples of "C3-4carbocyclyl" are cyclopropyl and cyclobutyl.
"C3-7carbocyclyl" is a saturated, partially saturated or unsaturated, monocyclic ring containing 3 to 7 carbon ring atoms wherein a -CH2- group can optionally be replaced by a -C(O)- Suitable examples of "C3-7carbocyclyl" are cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, 4-oxocyclohex-l-yl and S-oxocyclohept-S-en-l-yl. Aryl groups include phenyl and naphthyl.
"Monocyclic heteroaryl" or "bicyclic heteroaryl" groups comprising up to 7 or up to 12 ring atoms respectively include 5- or 6-membered, 5,6- or 6,6-fused aromatic rings containing up to 5 ring heteroatoms each independently selected from N, S, O. Examples include pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyridazinyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, benzimidazolyl, triazolyl, benzfuranyl, benzothiophenyl, indolyl, indazolyl, benzoxazolyl, benzfuranyl, quinoxalinyl, benzothiazolyl, furo[3,2-c]pyridinyl, 6,7-dihydro-4H-pyrano[4,3-<i][l,3]thiazolyl, [l,3]thiazolo[5,4-ό]pyridinyl, [l,3]thiazolo[4,5-ό]pyridinyl, 5,6-dihydro-4H- cyclopenta[d][l,3]thiazolyl and benzimidazole. Particular examples of Heteroaryl groups include pyridinyl, thiazolyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, furo[3,2- c]pyridinyl, 6,7-dihydro-4H-pyrano[4,3-<i][l,3]thiazolyl, [l,3]thiazolo[5,4-ό]pyridinyl, [l,3]thiazolo[4,5-ό]pyridinyl, 5,6-dihydro-4H-cyclopenta[<i][l,3]thiazolyl, benzimidazole and especially pyridin-2-yl, pyridin-6-yl, thiazole-2-yl, quinoxalin-2-yl, quinoxalin-3-yl, benzothiazol-2-yl, benzoxazol-2-yl, furo[3,2-c]pyridin-2-yl, 6,7-dihydro-4H-pyrano[4,3- <i][l,3]thiazol-2-yl, [l,3]thiazolo[5,4-ό]pyridin-2-yl, [l,3]thiazolo[4,5-ό]pyridine-2-yl, 5,6- dihydro-4H-cyclopenta[J][l,3]thiazol-2-yl, benzimidazole -2 -yl, 4,5,6,7- tetrahydrothiazolo[5,4-c]pyridinyl, 2,2-difluoro-l,3-benzodioxole, [l,3]dioxolo[4,5- ό]pyridinyl , 3-methyl-l,2-benzoxazolyl; 2,3-dimethylquinoxalinyl; 1,4- dimethylphthalazinyl; 4-methyl-2,3-dihydro-l,4-benzoxazinyl; l,3-dimethyl-lH-indazol-6- yl; l,3-dimethyl-lH-indazol-5-yl.
Examples of "a 5- to 7-membered monocyclic saturated heterocyclic ring" include pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, homo-morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 1 ,4-diazepanyl and homopiperazinyl. Particular examples of a 5-, 6- or 7-membered monocyclic saturated heterocyclic ring optionally containing one or more O, S or N atoms include pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, 1 ,4-diazepanyl and especially pyrrolidin-1-yl, piperidin-1- yl, piperazin-1-yl, homopiperazin-1-yl and 1,4-diazepan-l-yl.
Examples of "a 4-7 membered monocyclic saturated heterocyclic ring" include azetidinyl pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, homo- morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 1 ,4-diazepanyl and homopiperazinyl. Particular examples of a 5-, 6- or 7-membered monocyclic saturated heterocyclic ring optionally containing one or more O, S or N atoms include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, 1 ,4-diazepanyl and especially azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl, and 1,4- diazepan-l-yl.
The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo; such as for example fluoro, chloro, bromo; chloro and fluoro; chloro and bromo; fluoro and bromo.
Where optional substituents are chosen from "up to three" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups. An analogous convention applies to substituents chosen from "1 or 2", "1, 2, or 3", or "1, 2, 3, or 4" groups.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates.
It is to be understood that certain compounds of Formula I defined above may exhibit the phenomenon of tautomerism. In particular, tautomerism may affect any heterocyclic groups that bear 1 or 2 oxo substituents. It is to be understood that the present invention includes in its definition any such tautomeric form, or a mixture thereof, which possesses the above-mentioned activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings or named in the Examples.
It is also to be understood that certain compounds of formula (1) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
A suitable pharmaceutically-acceptable salt of a compound of the Formula (I) is, for example, an acid-addition salt of a compound of the Formula (I), for example an acid- addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric, para-toluenesulphonic, methanesulphonic, tartaric or maleic acid; or, for example, a salt of a compound of the Formula (I) which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt. A further suitable pharmaceutically acceptable salt of a compound of the Formula (I) is, for example, a salt formed within the human or animal body after administration of a compound of the Formula (I). The compounds of the invention may be administered in the form of a pro-drug that is a compound that is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I) and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I).
Accordingly, the present invention includes those compounds of the Formula (I) as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I) may be a synthetically-produced compound or a metabolically-produced compound.
A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzvmology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113- 191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al, Chem. Pharm. Bull. 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987. A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the Formula (I) containing a carboxy group is, for example, a pharmaceutically-acceptable ester, which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters such as methyl, ethyl and tert-butyl, (l-6C)alkoxymethyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-l,3- dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and (1- 6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.
A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether, which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include (1-1 OC) alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-lOC) alkoxycarbonyl groups such as ethoxycarbonyl, N,N-[di-(\- 4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, 7V,7V-dialkylaminomethyl, morpholinomethyl, piperazin- 1 -ylmethyl and 4-(l -4C)alkylpiperazin- 1 -ylmethyl. Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include α- acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, 7V,7V-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-ylmethyl.
The in vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I). As stated hereinbefore, the in vivo effects of a compound of the Formula (I) may also be exerted by way of metabolism of a precursor compound (a pro-drug).
By way of clarification in the following convenient and more convenient embodiments of the invention each individual species or substituent species and any convenient or more convenient combination of species and/or substituent species represents an independent embodiment of the invention.
Conveniently A is a 5-7-membered aliphatic ring optionally containing a double bond and optionally comprising an oxygen atom as a ring member and optionally being substituted by up to 3 substituents independently selected from halogen and C3- 4carbocyclyl. A double bond is conveniently present in any suitable position of the ring A. An oxygen atom can be present in any suitable position of the ring A, in addition to a double bond if desired.
Conveniently, A is a 5-7-membered aliphatic ring optionally being substituted by up to three substituents each independently selected from halogen and C3-4carbocyclyl. More conveniently, A is selected from any one of cyclopentane, norpinane, cycloheptane and cyclohexane. More conveniently, A is cyclohexane.
Conveniently, R is hydrogen or C1-4alkyl. Conveniently R is hydrogen, methyl, ethyl or propyl. More conveniently, R is hydrogen.
Conveniently, R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring, which ring may optionally comprise up to three N atoms and can be optionally substituted by up to three substituent groups as defined herein.
Conveniently, R1 and R2 together with the nitrogen atom to which they are attached form any one of a pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or 1 ,A- diazepanyl ring, wherein the pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or 1 ,A- diazepanyl ring can optionally be substituted by up to three substituent groups as defined herein. Conveniently, R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring, which ring can optionally comprise up to three additional heteroatoms each independently selected from O, S or N atoms and can be optionally substituted by up to three substituents independently selected from phenyl, benzyl, naphthyl, Ci-6 alkyl, cyano, halogen, COOR3, COR3, NO2, OR4, CONR5R6, NR6R7, monocyclic heteroaryl comprising up to 6 ring atoms or bicyclic heteroaryl comprising up to 10 ring atoms, wherein the phenyl, benzyl, naphthyl, Ci-6 alkyl, monocyclic or bicyclic heteroaryl can be optionally further substituted as defined herein. Conveniently, the phenyl, naphthyl, Ci-6 alkyl, C2-6alkenyl, C2-6alkynyl and benzyl groups stated in part (i) of the definition or R1 and R2 above, can be optionally substituted further by 1 or 2 substituents independently selected from halogen, NR6R7, SO2R3, CONR5R6, cyano, OR3, SO2NR6R7, NSO2R3, NR8COR9, Ci-6 alkyl and C3-7carbocyclyl, wherein Ci-6 alkyl and C3-7carbocyclyl can themselves be optionally substituted with up to three substituents independently selected from halogen, cyano, SO2R3, NR6R7, OR3, SO2NR6R7, NSO2R3, NR8COR9 or CONR5R6.
Conveniently, the phenyl, naphthyl, Ci-6 alkyl, C2-6alkenyl, C2-6alkynyl and benzyl groups stated in part (i) of the definition or R1 and R2 above, can be optionally substituted further by 1 or 2 substituents independently selected from halogen, NR6R7, SO2R3, CONR5R6, cyano, OR3, SO2NR6R7, NSO2R3, NR8COR9, Ci-6 alkyl and C3-7carbocyclyl, wherein Ci-6 alkyl and C3-7carbocyclyl can themselves be optionally with 1 or 2 substituents independently selected from halogen, cyano, SO2R3, NR6R7, OR3, SO2NR6R7, NSO2R3, NR8COR9 or CONR5R6.
Conveniently, the monocyclic or bicyclic heteroaryl groups stated in part (ii) of the definition or R1 and R2 above, can be optionally substituted further by 1 or 2 substituents independently selected from halogen, NR6R7, SO2NR6R7, NSO2R3, NR8COR9, CONR5R6 , SO2R3, cyano, OR3, phenyl itself optionally substituted with up to three halogen groups or SO2R3, Ci-6 alkyl and C3-7carbocyclyl, wherein Ci-6 alkyl and C3-7carbocyclyl can themselves be optionally itself optionally substituted with up to three substituents independently selected from halogen, cyano, SO2R3, SO2NR6R7, NSO2R3, NR8COR9, NR6R7, OR3, C3-7carbocyclyl or CONR5R6. Conveniently, the monocyclic or bicyclic heteroaryl groups stated in part (ii) of the definition or R1 and R2 above, can be optionally substituted further by 1 or 2 substituents independently selected from halogen, NR6R7, SO2NR6R7, NSO2R3, NR8COR9, CONR5R6 , SO2R3, cyano, OR3, phenyl itself optionally substituted with halogen, SO2R3 C1-6 alkyl and 5 C3_7carbocyclyl, wherein Ci-6 alkyl and C3_7carbocyclyl can themselves be optionally itself optionally substituted with up to three substituents each independently selected from halogen, cyano, SO2R3, SO2NR6R7, NSO2R3, NR8COR9, NR6R7, OR3, C3-7carbocyclyl and CONR5R6.
Conveniently, R3 is hydrogen, NR6R7, phenyl, cyclopropyl, cyclobutyl, a 4-7o membered monocyclic saturated heterocyclic ring containing one or more O, S or N atoms or or R3 is Ci-6 alkyl optionally substituted by up to three substituents independently selected from halogen, 0-Ci-3 alkyl and NR6R7.
More conveniently, R3 is hydrogen, NR6R7, phenyl, cyclopropyl, cyclobutyl, oxetanyl or Ci-6 alkyl itself optionally substituted by up to three halogen groups, OCH3,s OCH2CH3 and NR6R7.
Conveniently, R6 and R7 are independently hydrogen, Ci-6 alkyl, COR3, monocyclic or bicyclic heteroaryl or together with the nitrogen to which they are attached form a 5 or 6 membered monocyclic saturated heterocyclic ring optionally containing up to three heteroatoms each independently selected from O, S or N atoms, and optionally substitutedo with C1-6 alkyl which may itself be optionally substituted with NR8R9.
Conveniently, R6 and R7 are independently hydrogen, Ci-6 alkyl, COR3, monocyclic or bicyclic heteroaryl or together with the nitrogen to which they are attached form a 5 or 6 membered monocyclic saturated heterocyclic ring optionally containing up to three heteroatoms each independently selected from O or N atoms and optionally substituted5 with C1-6 alkyl which may itself be optionally substituted with NR8R9.
It is to be understood that convenient compounds of the invention include each exemplified compound selected independently and pharmaceutically acceptable salts, in vivo hydrolysable esters thereof.
It is also to be understood that each of the following compounds and o pharmaceutically acceptable salts, in vivo hydrolysable esters thereof, taken alone or in any combination of compounds represents an independent aspect of the invention: ( \R,2R)-N-(\ -cyanocyclopropyl)-2-( {4-[4-(methylsulfonyl)phenoxy]piperidin- 1 - yl}carbonyl)cyclohexanecarboxamide
( \R,2R)-N-( 1 -cyanocyclopropyl)-2- { [4-(4-fluorophenoxy)piperidin- 1 - yl]carbonyl}cyclohexanecarboxamide ( 1R,2R)-N-(1 -cyanocyclopropyl)-2-( {4-[4-(methylsulfonyl)phenyl]piperazin- 1 - yl}carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({2,5-dimethyl-4-[4-(methylsulfonyl)phenyl]piperazin-
1 -yl} carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({2,2-dimethyl-4-[4-(methylsulfonyl)phenyl]piperazin- 1 -yl} carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-({(2i?,65)-2,6-dimethyl-4-[4-
(methylsulfonyl)phenyl]piperazin- 1 -yl} carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-({(2i?)-2-methyl-4-[4-
(methylsulfonyl)phenyl]piperazin- 1 -yl} carbonyl)cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-({(25)-2-methyl-4-[4-
(methylsulfonyl)phenyl]piperazin- 1 -yl} carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({4-[4-(methylsulfonyl)phenyl]-l,4-diazepan-l- yl}carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(piperidin-l-ylcarbonyl)cyclohexanecarboxamide (li?,2i?)-2-[(4-benzylpiperidin- 1 -yl)carbonyl]-7V-(l - cyanocyclopropyl)cyclohexanecarboxamide
( \R,2R)-N-( 1 -cyanocyclopropyl)-2- { [4-(4-fluorophenyl)piperazin- 1 - yl]carbonyl}cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({4-[3-(dimethylamino)propyl]piperazin-l- yl} carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(4-pyrrolidin-l-ylpiperidin-l- yl)carbonyl]cyclohexanecarboxamide
( \R,2R)-N-(\ -cyanocyclopropyl)-2- { [4-(3-methylpyridin-2-yl)piperazin- 1 - yl]carbonyl}cyclohexanecarboxamide ( \R,2R)-N-(\ -cyanocyclopropyl)-2-( {4-[4-(phenylsulfonyl)phenyl]piperazin- 1 - yl}carbonyl)cyclohexanecarboxamide ( \R,2R)-N-( 1 -cyanocyclopropyl)-2-( {4- [4-(methylsulfonyl)- 1 -naphthyljpiperazin- 1 - yl}carbonyl)cyclohexanecarboxamide
(li?,2i?)-2-({4-[3-chloro-4-(methylsulfonyl)phenyl]piperazin-l-yl}carbonyl)-Λ/-(l- cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-[(4-{4-[(3,3,3- trifluoropropyl)sulfonyl]phenyl}piperazin-l-yl)carbonyl]cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({3-[2-(trifluoromethyl)phenyl]pyrrolidin-l- yl}carbonyl)cyclohexanecarboxamide
( \R,2R)-N-( 1 -cyanocyclopropyl)-2-( {3 - [3 -(trifluoromethyl)phenyl]pyrrolidin- 1 - yl} carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({3-[4-(trifluoromethyl)phenyl]pyrrolidin-l- yl}carbonyl)cyclohexanecarboxamide
(li?,2i?)-2-{[3-(2-chlorophenyl)pyrrolidin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-2-{[3-(3-chlorophenyl)pyrrolidin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-2-{[3-(4-chlorophenyl)pyrrolidin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-7V-(l-cyanocyclopropyl)-2-{[3-(2-fluorophenyl)pyrrolidin-l- yljcarbonyl} cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-{[3-(3-fluorophenyl)pyrrolidin-l- yljcarbonyl} cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-{[3-(4-fluorophenyl)pyrrolidin-l- yljcarbonyl} cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-{[(3i?)-3-phenylpyrrolidin-l- yljcarbonyl} cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-{[(35)-3-phenylpyrrolidin-l- yljcarbonyl} cyclohexanecarboxamide
(li?,2i?)-7V-(l-cyanocyclopropyl)-2-{[3-(2-methoxyphenyl)pyrrolidin-l- yljcarbonyl} cyclohexanecarboxamide
( \R,2R)-2- { [4-( 1 ,3-benzothiazol-2-yl)piperazin- 1 -yl]carbonyl} -N-(I - cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-2-{[4-(4-chloro-l,3-benzothiazol-2-yl)piperazin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
( \R,2R)-2- { [4-(6-bromo- 1 ,3-benzothiazol-2-yl)piperazin- 1 -yl]carbonyl} -N-(I - cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-{[4-(4,6-difluoro-l,3-benzothiazol-2-yl)piperazin-l- yl]carbonyl}cyclohexanecarboxamide
(li?,2i?)-2-{[4-(6-chloro-l,3-benzothiazol-2-yl)piperazin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-2-{[4-(l,3-benzoxazol-2-yl)piperazin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
( \R,2R)-N-( 1 -cyanocyclopropyl)-2- { [4-(2-cyanophenyl)piperazin- 1 - yl]carbonyl}cyclohexanecarboxamide
N- {!-[(( \R,2R)-2- { [( 1 -cyanocyclopropy^amino] carbonyl} cyclohexyl)carbonyl]piperidin-
4-yl}benzamide (li?,2i?)-2-({4-[l,3-benzothiazol-2-yl(methyl)amino]piperidin-l-yl}carbonyl)-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-({4-[5-methyl-4-(trifluoromethyl)-l,3-thiazol-2- yl]piperazin- 1 -yl} carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-({4-[5-(morpholin-4-ylmethyl)-l,3-thiazol-2- yljpiperazin- 1 -yl} carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-{[4-(5-cyano-l,3-thiazol-2-yl)piperazin-l- yl]carbonyl}cyclohexanecarboxamide
(li?,2i?)-2-({4-[5-chloro-4-(trifluoromethyl)-l,3-thiazol-2-yl]piperazin-l-yl}carbonyl)-N-
( 1 -cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({4-[3-fluoro-4-(methylsulfonyl)phenyl]piperazin-l- yl}carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({4-[4-(ethylsulfonyl)-2-fluorophenyl]piperazin-l- yl}carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({4-[2-fluoro-4-(methylsulfonyl)phenyl]piperazin-l- yl} carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({4-[4-(trifluoromethyl)-l,3-thiazol-2-yl]piperazin-l- yl}carbonyl)cyclohexanecarboxamide ( lR,2R)-2- { [4-( lH-benzimidazol-2-yl)piperazin- 1 -yl]carbonyl} -N-(I - cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({4-[3-cyano-6-(4-fluorophenyl)pyridin-2-yl]piperazin-
1 -yl} carbonyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({4-[3-cyano-6-(trifluoromethyl)pyridin-2- yl]piperazin- 1 -yl} carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({4-[3-(trifluoromethyl)quinoxalin-2-yl]piperazin-l- yl}carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(4-furo[3,2-c]pyridin-4-ylpiperazin-l- yl)carbonyl]cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-{[4-(l,3-thiazol-2-yl)piperazin-l- yl]carbonyl}cyclohexanecarboxamide
( lR,2R)-2- { [4-(4-tert-butyl- 1 ,3-thiazol-2-yl)piperazin- 1 -yl]carbonyl} -N-(I - cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[4-(6-methylsulfonylbenzothiazol-2-yl)piperazine-l- carbonyljcyclohexane- 1 -carboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[4-(4-tert-butylphenyl)piperazine-l- carbonyljcyclohexane- 1 -carboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-{[4-(6,7-dihydro-4H-pyrano[4,3-J][l,3]thiazol-2- yl)piperazin- 1 -yljcarbonyl} cyclohexanecarboxamide
( \R,2R)-N-(\ -cyanocyclopropyl)-2-( {4-[4-(l -cyano- 1 -methylethyl)phenyl]piperazin- 1 - yl}carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(4-[l,3]thiazolo[5,4-/)]pyridin-2-ylpiperazin-l- yl)carbonyl]cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-{[4-(5,6-dihydro-4H-cyclopenta[(i][l,3]thiazol-2- yl)piperazin- 1 -yljcarbonyl} cyclohexanecarboxamide
(\R,2R)-N-(\ -cyanocyclopropyl)-2-[(3-pyridin-2-ylpyrrolidin- 1 - yl)carbonyl]cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(4-{4-[(cyclopropylmethyl)sulfonyl]phenyl}piperazin- 1 -yl)carbonyl] cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-{[4-(4-cyclopropyl-l,3-thiazol-2-yl)piperazin-l- yljcarbonyl} cyclohexanecarboxamide ( \R,2R)-N-( 1 -cyanocyclopropyl)-2- { [3 -(3 -methoxyphenyl)pyrrolidin- 1 - yl]carbonyl}cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(4-[l,3]thiazolo[4,5-ό]pyridin-2-ylpiperazin-l- yl)carbonyl]cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(3-pyridin-3-ylpyrrolidin-l- yl)carbonyl]cyclohexanecarboxamide
( lR,2R)-N-( 1 -cyanocyclopropyl)-2- { [4-(4-methoxyphenyl)piperazin- 1 - yl]carbonyl}cyclohexanecarboxamide
(li?,2i?)-2-{[4-(4-cyano-l,3-benzothiazol-2-yl)piperazin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
(1R,2R)-N-(1 -cyanocyclopropyl)-2-[(4- {4-[4-(methylsulfonyl)phenyl]- 1 ,3-thiazol-2- yl}piperazin-l-yl)carbonyl]cyclohexanecarboxamide
( \R,2R)-2- { [(2R)-4-( 1 ,3-benzothiazol-2-yl)-2-methylpiperazin- 1 -yl]carbonyl} -N-(I - cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-2-{[(3i?)-4-(l,3-benzothiazol-2-yl)-3-methylpiperazin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(5-(2-cyanopropan-2-yl)pyridin-2-yl)piperazine-l- carbonyl)cyclohexanecarboxamide benzyl 2-(4-(( 1 R,2R)-2-( 1 -cyanocyclopropylcarbamoyl)cyclohexanecarbonyl)piperazin- 1 ■ yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(6-(2-cyanopropan-2-yl)-4-methylpyridin-3- yl)piperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-2-(4-(3-chloro-4-(2-cyanopropan-2-yl)phenyl)piperazine-l-carbonyl)-N-(l- cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(6-(2-cyanopropan-2-yl)pyridin-3-yl)piperazine-l- carbonyl)cyclohexanecarboxamide
(\R,2R)-N-(\ -cyanocyclopropyl)-2-(4-(4-( 1 -cyanocyclopropy^pheny^piperazine- 1 - carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-(4-(4-(2-cyanopropan-2-yl)-2- methylphenyl)piperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(4-(2-ethoxypropan-2-yl)phenyl)piperazine-l- carbonyl)cyclohexanecarboxamide (li?,2i?j-2-(4-(3-chloro-4-(l -cyanocyclopropy^pheny^piperazine- 1 -carbonyl)-7V-(l - cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(4-(2-cyanopropan-2-yl)-2-fluorophenyl)piperazine- l-carbonyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(4-(2-cyanopropan-2-yl)-2-
(trifluoromethyl)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-(4-(4-(2-cyanopropan-2-yl)-2-
(trifluoromethoxy)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide
( li?,2i?)-2-(4-(4-( 1 -carbamoylcyclopropy^pheny^piperazine- 1 -carbonyl)-7V-( 1 - cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-2-(4-(4-(l-amino-2 -methyl- l-oxopropan-2-yl)-3-chlorophenyl)piperazine-l- carbonyl)-7V-( 1 -cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-(4-(4-(2-cyanopropan-2-yl)-3,5- difluorophenyl)piperazine- 1 -carbonyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(4-(2-cyanopropan-2-yl)-3-
(trifluoromethyl)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-(4-(3-methoxy-4-(2- morpholinoethoxy)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-(4-(4-methoxy-3-(2- morpholinoethoxy)phenyl)piperazine- 1 -carbonyl)cyclohexanecarboxamide
(\R,2R)-N-(\ -cyanocyclopropyl)-2-(4-(4-( 1 -(dimethylamino)-2-methyl- 1 -oxopropan-2- yl)phenyl)piperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-(4-(3-methoxy-4-(3- morpholinopropoxy)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(3-methoxy-4-methylphenyl)piperazine-l- carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(4-(2-cyanopropan-2-yl)-3- methylphenyl)piperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(4-(2-cyanopropan-2-yl)phenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-2-(4-(4-(l-amino-2 -methyl- l-oxopropan-2-yl)-3-methylphenyl)piperazine-l- carbonyl)-N-(l-cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-2-(4-(4-cyano-3-methoxyphenyl)piperazine-l-carbonyl)-Λ/-(l- cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(4-cyclobutyl-3-methoxyphenyl)piperazine-l- carbonyl)cyclohexanecarboxamide 5 ( lR,2R)-N-( 1 -cyanocyclopropyl)-2-(4-(4-(2 -methyl- 1 -(methylamino)- 1 -oxopropan-2- yl)phenyl)piperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)piperazine-l- carbonyl)cyclohexanecarboxamide
(li?,2i?)-7V-(l-cyanocyclopropyl)-2-(4-(4-(2-cyanopropan-2-yl)-3- i o methoxyphenyl)piperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(4-cyclopropyl-3-methoxyphenyl)piperazine-l- carbonyl)cyclohexanecarboxamide
( \R,2R)-N-( 1 -cyanocyclopropyl)-2-((i?)-4-(3 ,4-dimethoxyphenyl)-2-methylpiperazine- 1 - carbonyl)cyclohexanecarboxamide 15 ( li?,2i?)-2-(4-(4-( 1 -amino-2 -methyl- 1 -oxopropan-2-yl)-3 -methoxyphenyl)piperazine- 1 - carbonyl)-N-(l-cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-ethoxy-3-methoxyphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-7V-(l-cyanocyclopropyl)-2-(4-(4-ethoxy-3-methoxyphenyl)piperazine-l- 20 carbonyl)cyclohexanecarboxamide
( \R,2R)-N-(\ -cyanocyclopropyl)-2-(4-phenylpiperazine- 1 - carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(4-ethoxy-2-fluoro-5-methoxyphenyl)piperazine-l- carbonyl)cyclohexanecarboxamide 25 (li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(2,2-difluorobenzo[J][l,3]dioxol-5-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(2,2-difluorobenzo[(/][l,3]dioxol-5-yl)piperazine-l- carbonyl)cyclohexanecarboxamide
(li?,2i?)-7V-(l-cyanocyclopropyl)-2-((i?)-4-(4-cyclopropyl-3-methoxyphenyl)-2- 30 methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-7V-(l-cyanocyclopropyl)-2-((i?)-4-(4-ethoxy-2-fluoro-5-methoxyphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide ( \R,2R)-N-( 1 -cyanocyclopropyl)-2-((i?)-4-(3 ,4-dimethoxyphenyl)-2-ethylpiperazine- 1 - carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(2,4-dimethoxyphenyl)-2-methylpiperazine-l- carbonyl)cyclohexanecarboxamide 5 ( 1R,2R)-N-(1 -cyanocyclopropyl)-2-((i?)-2-methyl-4-(2,3 ,4-trimethoxyphenyl)piperazine- 1 - carbonyl)cyclohexanecarboxamide
( \R,2R)-2-((R)-4-(4-( 1 -amino-2-methyl- 1 -oxopropan-2-yl)-3-methoxyphenyl)-2- methylpiperazine- 1 -carbonyl)-7V-(l -cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(3-methoxy-4-methylphenyl)-2- i o methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-(2-cyanopropan-2-yl)-3-methoxyphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
( \R,2R)-N-( 1 -cyanocyclopropyl)-2-(4-(2-fluoro-3 ,4-dimethoxyphenyl)piperazine- 1 - carbonyl)cyclohexanecarboxamide 15 ( 1R,2R)-N-(1 -cyanocyclopropyl)-2-(4-(2,4-dimethoxyphenyl)piperazine- 1 - carbonyl)cyclohexanecarboxamide
( \R,2R)-N-(\ -cyanocyclopropyl)-2-(4-(2,3 ,4-trimethoxyphenyl)piperazine- 1 - carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(3-methoxyphenyl)-2-methylpiperazine-l- 20 carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(3,4-difluoro-5-methoxyphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(2-fluoro-3,4-dimethoxyphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide 25 (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(3-ethoxyphenyl)-2-methylpiperazine-l- carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(3-(difluoromethoxy)phenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-2-methyl-4-phenylpiperazine-l- 30 carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-2-methyl-4-(3-(l, 1,2,2- tetrafluoroethoxy)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-ethoxy-3-ethylphenyl)-2-methylpiperazine-l- carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(3-ethyl-4-methoxyphenyl)-2-methylpiperazine- l-carbonyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-2-methyl-4-(pyridin-4-yl)piperazine-l- carbonyl)cyclohexanecarboxamide
(li?,2i?)-2-((i?)-4-(2-chloro-5-methoxyphenyl)-2-methylpiperazine-l-carbonyl)-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-2-((i?)-4-(3-butoxyphenyl)-2-methylpiperazine-l-carbonyl)-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(4-ethoxy-3-ethylphenyl)piperazine-l- carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(3-ethyl-4-methoxyphenyl)piperazine-l- carbonyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-(difluoromethoxy)-3-methoxyphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(5-methoxy-2-methylphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(4-fluoro-3-methoxyphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(3-isopropoxyphenyl)-2 -methylpiperazine- 1- carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-2-methyl-4-(3-
(trifluoromethoxy)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(3-(2-methoxyethoxy)phenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
( \R,2R)-N-( 1 -cyanocyclopropyl)-2-((i?)-4-(3 ,4-dimethoxyphenyl)-2-isopropylpiperazine- 1 - carbonyl)cyclohexanecarboxamide
(li?,2i?)-2-(4-(4-chloro-3-methoxyphenyl)piperazine-l-carbonyl)-Λ/-(l- cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(5,6-dimethoxypyridin-2-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-2-(4-(4-chlorophenyl)-3-oxopiperazine-l-carbonyl)-7V-(l- cyanocyclopropyl)cyclohexanecarboxamide 5 (li?,2i?)-2-((i?)-4-(4-chloro-3-methoxyphenyl)-2-methylpiperazine-l-carbonyl)-Λ/-(l- cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-ethoxy-3-fluorophenyl)-2-methylpiperazine- l-carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-methoxy-3-(trifluoromethoxy)phenyl)-2- i o methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-ethoxy-3-(trifluoromethoxy)phenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
( \R,2R)-N-( 1 -cyanocyclopropyl)-2-((i?)-4-(3 ,4-difluorophenyl)-2-methylpiperazine- 1 - carbonyl)cyclohexanecarboxamide is (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-fluoro-3-methylphenyl)-2-methylpiperazine- l-carbonyl)cyclohexanecarboxamide
(\R,2R)-2-((R)-4-(3 ,4-bis(difluoromethoxy)phenyl)-2-methylpiperazine- 1 -carbonyl)-N-(l - cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-2-((i?)-4-(3-chloro-4-methoxyphenyl)-2-methylpiperazine-l-carbonyl)-Λ/-(l- 20 cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(3-ethoxy-4-fluorophenyl)-2 -methylpiperazine- l-carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(3-ethoxy-4-methoxyphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide 25 (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-(difluoromethoxy)-3-fluorophenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(5-cyclopropyl-6-methoxypyridin-2-yl)piperazine-l- carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(6-methoxypyridin-2-yl)piperazine-l- 30 carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(4-methoxy-3-methylphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-methoxy-3-(methylsulfonyl)phenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(3-fluoro-2,4-dimethoxyphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide 5 (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(2-fluoro-4,5-dimethoxyphenyl)piperazine-l- carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(2-fluoro-4,5-dimethoxyphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-7V-(l-cyanocyclopropyl)-2-((i?)-4-(5-cyclopropyl-6-methoxypyridin-2-yl)-2- i o methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(5-cyclopropyl-4-methoxypyridin-2-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-ethyl-3-methoxyphenyl)-2 -methylpiperazine- l-carbonyl)cyclohexanecarboxamide is (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(3-fluoro-4-methylphenyl)-2-methylpiperazine- l-carbonyl)cyclohexanecarboxamide
( 1R,2R)-N-(1 -cyanocyclopropyl)-2-(4-methylpiperazine- 1 - carbonyl)cyclohexanecarboxamide
(li?,2i?)-7V-(l-cyanocyclopropyl)-2-((i?)-4-(5-cyclopropyl-4-methoxypyrimidin-2-yl)-2- 20 methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(l,3-dimethyl-lH-indazol-6-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
( \R,2R)-N-( 1 -cyanocyclopropyl)-2-(4-cyclohexylpiperazine- 1 - carbonyl)cyclohexanecarboxamide 25 (li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(l,3-dimethyl-lH-indazol-5-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-2-((i?)-4-([l,3]dioxolo[4,5-/)]pyridin-6-yl)-2-methylpiperazine-l-carbonyl)-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
(li?,2i?)-7V-(l-cyanocyclopropyl)-2-((i?)-4-(3-methoxy-4-(l-methylcyclopropyl)phenyl)-2- 30 methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(3-methoxy-4-(methylsulfonyl)phenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide ( \R,2R)-N-( 1 -cyanocyclopropyl)-2-((i?)-4-(3 ,4-diethoxyphenyl)-2-methylpiperazine- 1 - carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(4-(ethylsulfonyl)-2-fluorophenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide (li?,2i?)-7V-(l-cyanocyclopropyl)-2-((i?)-2-methyl-4-(2-oxo-l,2-dihydropyridin-4- yl)piperazine- 1 -carbonyl)cyclohexanecarboxamide
( \R,2R)-N-( 1 -cyanocyclopropyl)-2-((i?)-4-( 1 -cyclopropyl-2-oxo- 1 ,2-dihydropyridin-4-yl)-
2-methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(2-methoxypyridin-4-yl)-2-methylpiperazine-l- carbonyl)cyclohexanecarboxamide
(1R,2R)-N-(1 -cyanocyclopropyl)-2-((i?)-4-( 1 -ethyl-2-oxo- 1 ,2-dihydropyridin-4-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-2-methyl-4-(3-methylbenzo[d]isoxazol-6- yl)piperazine- 1 -carbonyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-ethoxy-3-methylphenyl)-2-methylpiperazine- l-carbonyl)cyclohexanecarboxamide
(li?,2i?)-7V-(l-cyanocyclopropyl)-2-((i?)-4-(l-isopropyl-2-oxo-l,2-dihydropyridin-4-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(3-fluoro-4-(methylsulfonyl)phenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(2-isopropoxypyridin-4-yl)-2-methylpiperazine- l-carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-2-methyl-4-(3-methyl-4-
(methylsulfonyl)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(5-fluoro-2-(methylsulfonyl)phenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
( \R,2R)-N-(l -cyanocyclopropyl)-2-((i?)-2-methyl-4-(2-oxo- 1 -propyl- 1 ,2-dihydropyridin-4- yl)piperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(4-(2-methoxyethoxy)-3-methylphenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(5-cyclopropyl-6-methoxypyrazin-2-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(l,4-dimethylphthalazin-6-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(3-cyclopropyl-6-methoxypyrazin-2-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(2,3-dimethylquinoxalin-6-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(3-methoxy-4-(oxetan-3-yloxy)phenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-2-methyl-4-(3-methyl-4-(oxetan-3- yloxy)phenyl)piperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-cyclopropoxyphenyl)-2-methylpiperazine-l- carbonyl)cyclohexanecarboxamide
( \R,2R)-2-((R)-4-(3 ,4-bis(methoxymethyl)phenyl)-2-methylpiperazine- 1 -carbonyl)-7V-(l - cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(6-methoxy-5-methylpyridin-3-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(6-ethoxy-5-methylpyridin-3-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(3-methoxy-4-(2-methoxyethoxy)phenyl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(5-ethoxy-6-methylpyridin-2-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(5-(2-methoxyethoxy)-6-methylpyridin-2-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(5-methoxy-6-methylpyridin-2-yl)-2- methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide
(li?,2i?)-2-[4-(l,3-benzodioxol-5-yl)piperazine-l-carbonyl]-N-(l- cyanocyclopropyl)cyclohexane- 1 -carboxamide
(li?,2i?)-2-((i?)-4-(3-chloro-4-methoxyphenyl)-2-methylpiperazine-l-carbonyl)-Λ/-(l- cyanocyclopropyl)cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-[(2i?)-4-[3-(hydroxymethyl)-4-
(trifluoromethyl)phenyl]-2-methyl-piperazine-l-carbonyl]cyclohexane-l-carboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(2i?)-4-(3,4-dimethylphenyl)-2-methyl-piperazine-l- carbonyljcyclohexane- 1 -carboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-[(2i?)-4-(3-fluoro-4-methoxy-phenyl)-2-methyl- piperazine- 1 -carbonyljcyclohexane- 1 -carboxamide
(li?,2i?)-2-[(2i?)-4-(4-chloro-3-methyl-phenyl)-2-methyl-piperazine-l-carbonyl]-N-(l- cyanocyclopropyl)cyclohexane- 1 -carboxamide
(li?,2i?)-2-[(2i?)-4-(l,3-benzodioxol-5-yl)-2-methyl-piperazine-l-carbonyl]-N-(l- cyanocyclopropyl)cyclohexane-l -carboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(2i?)-4-(3,4-dichlorophenyl)-2-methyl-piperazine-l- carbonyljcyclohexane- 1 -carboxamide
(li?,2i?)-2-[(2i?)-4-(3-chloro-4-fluoro-phenyl)-2-methyl-piperazine-l-carbonyl]-N-(l- cyanocyclopropyl)cyclohexane- 1 -carboxamide (li?,2i?)-2-[(2i?)-4-(4-chloro-3-fluoro-phenyl)-2-methyl-piperazine-l-carbonyl]-N-(l- cyanocyclopropyl)cyclohexane- 1 -carboxamide
(li?,2i?)-2-[(2i?)-4-(3-chloro-4-methyl-phenyl)-2-methyl-piperazine-l-carbonyl]-N-(l- cyanocyclopropyl)cyclohexane- 1 -carboxamide
(li?,2i?)-2-[(2i?)-4-(3-tert-butyl-4-methoxy-phenyl)-2-methyl-piperazine-l-carbonyl]-N-(l- cyanocyclopropyl)cyclohexane- 1 -carboxamide
(li?,2i?)-N-(l-cyanocyclopropyl)-2-[(2i?)-2-methyl-4-(4-methyl-2,3-dihydro-l,4- benzoxazin-7-yl)piperazine- 1 -carbonyljcyclohexane- 1 -carboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[4-[4-(l-cyano-l-methyl-ethyl)-3-fluoro- phenyljpiperazine- 1 -carbonyljcyclohexane- 1 -carboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[4-(2-quinolyl)piperazine-l -carbonyljcyclohexane- 1- carboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[4-[4-(l-cyano-l-methyl-ethyl)-2-methoxy- phenyljpiperazine- 1 -carbonyljcyclohexane- 1 -carboxamide
(\R,2R)-N-(\ -cyanocyclopropyl)-2-[4-[4-(2,2,2-trifluoro- 1 -hydroxy- 1 -methyl- ethy^phenyljpiperazine-l-carbonyljcyclohexane-l -carboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[4-[4-(l-hydroxycyclobutyl)phenyl]piperazine-l- carbonyljcyclohexane- 1 -carboxamide (li?,2i?)-7V-(l-cyanocyclopropyl)-2-[4-[4-(l -hydroxy- l-methyl-ethyl)phenyl]piperazine-l- carbonyljcyclohexane- 1 -carboxamide
(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[4-(3-methoxyphenyl)piperazine-l- carbonyljcyclohexane- 1 -carboxamide.
Compounds of formula (I) may be prepared by any one of the following routes:
Route A
Figure imgf000026_0001
(H) (IH) (I)
Route B
Figure imgf000026_0002
(IV) (V) (I)
These routes are further illustrated by the following schemes:
Figure imgf000026_0003
(V) (VI) (in) (I) SCHEME 1
Compounds of the type (I) can be synthesised by combining three building blocks as outlined above. A secondary amine of the type represented by structure (V) coupled with a single enantiomer of cyclic 1,2- diacid of the type (VI), then an appropriately substituted 1-aminocyclopropylcarbonitrile (III) is coupled to the remaining acid.
Dehydrating agent
Figure imgf000027_0001
Figure imgf000027_0002
R,R-enantiomer
VIl)
Vi)
Figure imgf000027_0003
N)
SCHEME 2
In more detail the chiral cyclic 1 ,2-diacid (VI) may be dehydrated with a suitable reagent such as acetic anhydride, acetyl chloride, dicyclohexylcarbodiimide (DCC), thionylchloride and the such like, preferably acetic anhydride at a temperature between room temperature and 100 0C, then removal of excess dehydrating agent yields a bi-cyclic- anhydride of the type (VII). The anhydride (VII) is reactive towards secondary amines of the type (V) in the presence or absence of a suitable base such as triethylamine, diethylisopropylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the such like or ionic bases such as potassium carbonate, in a suitable aprotic solvent such as dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformamide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene. The subsequent acid is combined with an appropriately substituted 1-aminocyclopropylcarbonitrile by the use of a coupling agent such as O-(7-azabenzotriazol-l-yl)-Λ/,Λ/,N',N'-tetramethyluronium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC) / hydroxylbenzotriazole (HOBt), 1 -benzotriazolyoxy-tris-dimethylamino-phosphonium hexafluorophosphate (BOP), benzotriazolyoxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), Λ/,Λ/-dimethylaminoethylcyclohexylcarbodiimide (EDC), 4-(4,6-dimethoxy-l,3,5-triazin-2- yl)-4-methylmorpholinium chloride (DMTMM), trichloroacetyl chloride, by the formation of an active ester in the presence of a suitable bases triethylamine, diethylisopropylamine, DBU, and the such like or ionic bases such as potassium carbonate, in the presence or absence of an activating base such as Λ/,Λ/-dimethyl-4-amino-pyridine (DMAP) in a suitable solvent dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformamide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene at a temperature between 0 0C and 60 0C to yield compounds of type (I). A combination of HATU or PyBOP in either DMF or DCM at a temperature between room temperature and 50 0C is preferred.
The chiral cyclic 1,2-diacid of the type (VI) can be produced by methods as shown in the literature - WO2004000825, Eur. J. Org. Chem. 2002, 2948-2952, which include chiral resolution, chiral separation by chromatographic methods, de-symmetrisation using esterase enzymes, such as pig liver esterase as generalised below.
resolving enzyme
Figure imgf000028_0001
Figure imgf000028_0002
(+/-) racemic R,R-enantiomer
n tion
Figure imgf000028_0004
Figure imgf000028_0003
(+/-) racemic Chiral amine R,R-enantiomer
The preferred i?,i?-cyclohexyl-l,2-dicarboxylic acid can be produced by a resolution of commercially available racemic diacid by a resolution process using chiral amines bases to form diastereomeric salts and recystallisation of the single enantiomers, as outlined by Eur. J. Org. Chem. 2002, 2948-2952.
Figure imgf000029_0001
VII) VIII) III)
Figure imgf000029_0002
SCHEME 3
An alternative synthesis of compounds of the type (I) can be made by the route outlined in scheme 3 above. The previously described chiral 1,2-diacid can be reacted with a suitable alcohol such as benzyl alcohol, substituted benzyl alcohol (for example 4- methoxybenzyl alcohol), ethanol, methanol, propan-1-ol, isopropanol, butan-1-ol, at room temperature to 50 0C in a suitable unreactive solvent such as THF, DCM, DMF and the such like to yield an ester-acid of the type (VIII). The reaction with benzyl and substituted benzyl alcohols is preferred. The ester group is now represented by the group PG, as this is formally a protecting group masking the acid. Descriptions of suitable protecting groups in organic synthesis can be found in Green and Wuts Protective groups in Organic synthesis, 1991, John Wiley. In a similar manner to that described above a free acid of the type (VIII) can be coupled with an appropriately substituted 1-aminocyclopropylcarbonitrile (III) by the use of a coupling agent such as HATU, PyBOP, EDC, DCC / HOBt, BOP, PyBOP, EDC, DMTMM, trichloroacetyl chloride, by the formation of an active ester in the presence of a suitable bases triethylamine, diethylisopropylamine, DBU and the such like, or suitable ionic bases such as potassium carbonate, in an appropriate solvent dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformaide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene at a temperature between O 0C and 100 0C to yield compounds of the type (IX). An alternative method would be by conversion to an acid chloride with a suitable reagent such as oxalylchloride, thionyl chloride, and the such like, then addition of the secondary amine (V) in the presence of a bases as listed above. A combination of HATU or PyBOP in either DMF or DCM between room temperature and 50 0C is preferred. The protecting group can be removed from compounds of the type (IX) to reveal an acid of the type (IV) by the methods described in Green and Wuts, Protective groups in Organic synthesis, 1991, John Wiley. In the preferred case of benzyl group group (PG = CH2-phenyl) this can be removed by treatment with hydrogen gas and a suitable catalyst such as palladium on carbon (5 to 10% loading), palladium hydroxide, and the such like or by transferred hydrogenation using such systems as palladium (II) acetate and ammonium formate in a suitable solvent such as methanol, ethanol, ethylacetate and the such like, and heating between 0 0C and 100 0C. The appropriate secondary amine (V) (HMUR2) can then be coupled with with acids of type (IV) by the use of a coupling agent such as HATU, PyBOP, EDC, DCC /HOBt, BOP, PyBOP, EDC, DMTMM, by the formation of an active ester in the presence of a suitable bases triethylamine, diethylisopropylamine, DBU and the such like, or suitable ionic bases such as potassium carbonate, in an appropriate solvent dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformaide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene at a temperature between 0 0C and 100 0C to yield compounds of the type (I). A combination of HATU or PyBOP in either DMF or DCM between room temperature and 50 0C is preferred. Many of the secondary amines
Figure imgf000031_0001
used in the synthesis of examples below are from commercially available sources or from routes described previously in the literature. In general terms, the compounds can be made by the routes described below.
Figure imgf000031_0002
X) Xl) XII)
Figure imgf000031_0003
XIII)
SCHEME 4
Secondary amines of the type (XIII), where there is a linking heteroatom Y between two rings, which is either oxygen or nitrogen, can be synthesised by the route outlined in scheme 4. An approach of using the Y atom as a nucleophile and displacement of a halogen from an aromatic ring such as (X) can be used to form the carbon heteroatom bond, and thus compounds of the type (XII). In this case the representative secondary amine ring is a piperadine such as (XI). This approach would also be applicable with pyrrolidine and azetine rings as well. In general a mixture of the two ring compound (X), and (XI) are reacted in the presence of a suitable base and inert solvent, such bases would include potassium carbonate, potassium tert-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP. A suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0C and 100 0C. Another approach would be to use a palladium catalysed coupling reaction to combine the two rings. This is particularly useful where the aromatic ring of (X) is too electron rich to enable a nucleophilic substitution reaction. In this case a suitable palladium source would be palladium (II) chloride, palladium acetate, Pd2(dba)3 and the such like, and appropriate phosphine lingand, such triphenyl phosphine, 2- biphenyl-diphenyl phosphine and the such like in presence of a base such as potassium carbonate, potassium tert-butoxide, cesium carbonate, potassium phosphate, and strong amine bases such as DIPEA, DBU in an inert solvent such as THF, DMF, DMA, and toluene at a temperature between 25 0C and 100 0C. In both approaches a protecting group (PG) maybe required such groups could be tert-butyl carbamate (BOC), benzyl carbamate (cbz), benzyl and trifiuoroacetyl. Conditions to remove these protecting groups can be found in Greene Wuts Protective groups in Organic synthesis, 1991, John Wiley, to reveal the secondary amine of type (XIII).
Figure imgf000032_0001
X = Cl, Br
Z = CH or N Y = O
XiV) XV)
Figure imgf000032_0002
XVII) XVI)
SCHEME 5
Directly linked rings can be synthesised by the combining an aromatic ring of the type (XIV), and attack on a piperidone, with a protecting group PG, to yield of tertiary alcohol of the type (XV). The aromatic ring (XIV) is activated by conversion into a nucleophile such as an organolithium, by reacting with n-butyl lithium in an appropriate solvent such as THF at low temperature, or into a Grignard reagent by reacting the aromatic halogen with magnesium metal in an inert solvent such as diethyl ether and THF. Addition of the piperidone at a low temperature such as -50 0C to 0 0C, and allowing the temperature to rise to room temperature would complete the reaction. The tertiary alcohol can be eliminated by the addition of a mineral acid such a sulphuric acid, hydrochloric acid or activation with a conversion to an group to eliminate for example mesyl chloride or tosyl chloride in the presence of amine bases such as DIPEA, DBU, triethylamine in an inert solvent such as DCM, dichloroethane. Heat may be required to complete the elimination to yield the unsaturated bicycle (XVI). The double bond can be removed by hydrogenation by treatment with hydrogen gas in the presence of a metal catalyst such palladium on carbon, or platinum oxide and the such like in an inert solvent such as THF, DCM, ethanol or ethylacetate. In certain circumstances the protecting group PG can be removed as the same time, for example when the group is Cbz or benzyl. In a preferred option a BOC group can be removed by strong acid such as trifiuoroacetic acid, hydrochloric acid in an appropriate acid such as methanol or dioxane at room temperature to yield the amine (XVII).
Figure imgf000033_0001
X = Cl, Br Z = CH or N
XIV) XVIII) XIX)
Figure imgf000033_0002
XX)
SCHEME 6
Secondary amines of the type (XX) can be synthesised by the route outlined in scheme 6, where the nucleophilic nitrogen of piperazine directly displaces the halogen from an aromatic ring such as (XIV). In this case the representative secondary amine ring is a piperazine such as (XVIII), but this approach would also be applicable with homopiperazine. In general a mixture of the two ring compound (XIV), and (XVIII) are reacted in the presence of a suitable base and inert solvent, such bases would include potassium carbonate, potassium tert-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP. A suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0C and 100 0C. In the case of the starting piperazine where no protecting group PG is used, an excess of piperazine is used to stop dimerisation, which could be up to 10 equivalents, which directly yields the desire secondary amine. However a protecting group such as tert-butyl carbamate (BOC), benzyl carbamate (cbz), benzyl and trifiuoroacetyl and the such like, can be employed to yield compounds of the type (XIX), and a subsequently deprotection step yields the desired secondary amine (XX) by method described in Greene Wuts Protective groups in Organic synthesis, 1991, John Wiley. In the preferred case the tert-butyl carbamate (BOC), is used and deprotected using by strong acid such as trifluoroacetic acid, hydrochloric acid in an appropriate acid such as methanol or dioxane at room temperature to yield the amine (XX).
Figure imgf000034_0001
XXIII)
Figure imgf000034_0002
Figure imgf000034_0003
XXIV)
SCHEME 7
In a similar and preferred example thiazole piperazine and benzothiazole piperazine of the type (XXIV) can be synthesised by the route outlined in scheme 7, where the nucleophilic nitrogen of piperazine directly displaces the halogen from an aromatic ring such as (XXII). In this case the representative secondary amine ring is a piperazine such as (XVIII), but this approach would also be applicable with homopiperazine. In general a mixture of the two ring compounds (XXII), and piperazine are reacted in the presence of a suitable base and inert solvent, such bases would include potassium carbonate, potassium tert-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP. A suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0C and 100 0C. In the case of the starting piperazine where no protecting group PG is used and excess of piperazine is used to stop dimerisation, which is upto 10 equivalents, which directly yield the desire secondary amine. However a protecting group such as tert-butyl carbamate (BOC), benzyl carbamate (cbz), benzyl and trifiuoroacetyl and the such like, can be employed to yield compounds of the type (XVIII), and a subsequently deprotection step yields the desired secondary amine (XXIV) by method described in Greene Wuts Protective groups in Organic synthesis, 1991, John Wiley. In the preferred case the tert- butyl carbamate (BOC), is used and deprotected using by strong acid such as trifluoroacetic acid, hydrochloric acid in an appropriate acid such as methanol or dioxane at room temperature to yield the amine (XXIV).
Figure imgf000035_0001
X = Cl, Br
XXV) XXVI) XXIII)
Figure imgf000035_0002
XXIV)
SCHEME 8 Thiazole piperazine can also be synthesised by thiazole ring formation between a thiourea of the type (XXVI), where PG is a protecting group selected from tert-butyl carbamate (BOC), benzyl carbamate (cbz), benzyl and trifluoroacetyl, and an α-haloketone such as (XXV). Usually heating of these two compounds in a suitable solvent such as ethanol, n-Butanol, toluene and xylene between 50 0C and 150 0C, will affect ring closure to form the thiazole product (XXIII). Deprotection as described yields the appropriate secondary amine (XXIV).
Figure imgf000036_0001
X = F, Cl X = F, Cl XXVIII) XXVII)
[Oxidation agent]
Figure imgf000036_0002
X = F, Cl
XXIX) XXX) XXXI)
Deprotection
Figure imgf000036_0003
XXXII)
SCHEME 9
Sulphone-aryl-piperazines of the type (XXXII) can be synthesised by the steps outlined in scheme 9. An appropriately substituted thiophenol bearing a halogen atom of fluoro or chloro can be alkylated using an alkyl chloride, bromide or iodide in the presence of a suitable base and inert solvent, such bases would include potassium carbonate, potassium tert-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP. A suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0C and 100 0C. The subsequent sulphide is oxidised to a sulphone using a suitable oxidising agent such as metø-chloroperbenxoic acid, trifluoroperacetic acid, dimethyldioxirane, oxone, and the such like in an inert solvent, to yield the sulphone (XXIX). To join the two rings the sulphone (XXIX), and piperazine (PG = H) or with a protecting group, are reacted in the presence of a suitable base and inert solvent, such bases would include potassium carbonate, potassium tøt-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP. A suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0C and 100 0C. If a protecting group has been used the is removed as described above to yield the secondary amine (XXXII).
Figure imgf000037_0001
X = CI, Br X = CI, Br
EWG = CN, NO2, CO2Et EWG = CN, NO2, CO2Et
XXXIV) XXXV) XXXVI)
SCHEME 10
Alkylsubstituted aryl piperazines of the type (XXXVI), can be synthesised by the route described in scheme 10. A halo-substituted aryl of the type (XXXII) can be directly substituted with the alkyl group, which contains an electron withdrawing group by the method described by Caron, S. et al. J.Am.Chem.Soc, 2000, 712, to yield substituted compounds of the type (XXXIV) In a similar way the group can be attached by palladium coupling methods such as described by Verkade et alJ. Org. Chem. 2003, 63, 8003 to yield the same intermediate (XXXIV). Alternatively a simple alkylated aryl such as (XXXIII), can be di-alkylated using methyl iodide, alkyl bromides or alkyl iodides by treatment with a suitable base and inert solvent, such bases would include potassium carbonate, potassium tøt-butoxide, strong amine bases such as DIPEA, DBU and the such like, and phosphene amine bases such as BEMP. A suitable solvent would be THF, DMF, DMA, dichloromethane and dichloroethane, as a temperature between 25 0C and 100 0C. Coupling with piperazine (XXXV) or another di-amine ring such as homo-piperazine can be achieved using palladium catalysis conditions using a suitable palladium source would be palladium (II) chloride, palladium acetate, Pd2(dba)3 and the such like, and appropriate phosphine lingand, such triphenyl phosphine, 2-biphenyl-diphenyl phosphine, PEPPSI-IEt [Aldrichimica Acta, 39, 2006, 97 and method described within] and the such like, or BINOL in presence of a bases potassium carbonate, potassium ter t-butoxide, cesium carbonate, potassium phosphate, and strong amine bases such as DIPEA, DBU in an inert solvent such as THF, DMF, DMA, and toluene at a temperature between 25 0C and 100 0C, to yield the secondary amine (XXXVI). According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a therapeutic agent.
According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a therapeutic agent, where it is desirable to have inhibition of Cathepsin K. According to a further feature of the present invention there is provided a method for producing inhibition of a cysteine protease in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of a cysteine protease in a warm blooded animal, such as man. In particular the compounds of the invention are useful in the treatment of inflammation and immune disorders such as, but not limited to, osteoporosis, rheumatoid arthritis, osteoarthritis, metastatic bone disease, osteolytic bone disease and bone related neuropathic pain. In particular the invention provides the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of Cathepsin K in a warm blooded animal, such as man. In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in the inhibition of a cysteine protease, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition, which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule, which contains between 1 mg and 1 g of the compound of this invention.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous, intramuscular or intra-articular injection.
Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg"1 to 100 mgkg"1 of the compound, preferably in the range of 0.1 mgkg"1 to 20 mgkg"1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose, which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
The invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
In particular, for the treatment of (but not restricted to) osteoporosis, rheumatoid arthritis, osteoarthritis, metastatic bone disease, osteolytic bone disease and bone related neuropathic pain, the compounds of the invention may be combined with agents listed below.
Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including nonselective cyclo-oxygenase COX-I / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin-like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline. In addition the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B- Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15). The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CRl for the C-X3- C family.
The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4. selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab). The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically- applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
A compound of the present invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-B.subl. - or B.sub2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK. sub 1. or NK.sub3. receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS.
A compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include: (i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fiuorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin);
(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5α-reductase such as finasteride;
(iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as Λ/-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), Λ/-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-/V-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;
(v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin);
(vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as trans fection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
The invention will now be illustrated by the following examples, in which standard techniques known to the skilled chemist and techniques analogous to those described by these Examples were used as appropriate. I H NMR spectra were recorded using a Bruker DPX300 FT spectrometer or via
Flow NMR process using an AVANCE 500 FT spectrometer, and using d6- dimethylsulphoxide (d6-DMSO) or deuterated chloroform (CDCl3) with the data expressed as chemical shifts in ppm from internal standard TMS on the δ scale and with multiplicity (b=broad, s=singlet, d=doublets, t=triplet, q=quartet, qn=quintet, sx=sextet, h= heptet), and integration.
Low resolution mass spectra were obtained using a Waters liquid chromatography mass spectrometry system, where purity was determined by UV absorption at a wavelength of 254 nm, and the mass ion was determined by electrospray ionisation (Micromass instrument). The reverse phase column used was a 4.6 mm x 50 mm Phenomenex Synergi Max-RP 80A and the solvent system was water containing 0.1% formic acid and acetonitrile unless otherwise stated. A typical run was 5.5 minutes with a 4.0 minute gradient from 0 - 95% acetonitrile.
Microwave reactions were performed in a Smith Synthesiser (300 Kwatts) on either the normal or high setting using appropriate tubes recommended by the manufacturer.
Purification by column chromatography was typically performed using silica gel (Merck 7734 grade) and solvent mixtures and gradients are recorded herein. Purification by reverse phase high performance chromatography was typically performed using a Perkin Elmer instrument using UV detection at 254 nm and a Cl 8 1500 x 21.2 mm Phenomenex column 100 A. Acidic conditions (0.1 to 0.5% formic acid) or basic conditions (ammonia to pHIO) were used with gradiant solvent mixtures of acetonitrile and water. SCX columns were supplied from International Sorbent Technology and used as directed in this specification.
High purity and dry solvents were supplied from Aldrich and used as delivered. The following abbreviations are used herein:
BOP 1 -benzotriazolyoxy-tris-dimethylamino-phosphonium hexafluorophosphate
PyBOP benzotriazolyoxy-tris-pyrrolidino-phosphonium hexafluorophosphate
EDC Λ/,Λ/-dimethylaminoethylcyclohexylcarbodiimide
DMTMM 4-(4,6-dimethoxy-l,3,5-t5riazin-2-yl)-4-methylmorpholinium chloride HATU O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
NMP l-methyl-2-pyrrolidinone
DMAP Λ/,Λ/-dimethyl-4-amino-pyridine
DIPEA di-zsø-propylethylamine HPLC high performance liquid chromatography
TBAF tetrα-butylammonium fluoride
LCMS liquid Chromatraphy / Mass Spectrometry
DMF di-methylformamide
TFA trifiuoroacetic acid NaHMDS sodium hexamethyldisilylamide
DMA dimethylacetamide
DEAD diethylazodicarboxylate mCPBA meto-chloroperbenzioc acid
DMSO dimethylsulphoxide DBU l,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane
Reagent 10 1.0M Hydrochloric acid solution in methanol Example 1
(lR,2R)-Λ/-(l-cyanocyclopropyl)-2-({4-[4-(methylsulfonyl)phenoxy]piperidin-l- yl}carbonyl)cyclohexanecarboxamide
Figure imgf000049_0001
1) (l/f,2R)-2-({4-[4-(methylsulfonyl)phenoxy]piperidin-l- yl} carbonyl)cyclohexanecarboxylic acid (li?,2i?)-cyclohexane-l,2-dicarboxylic acid (878 mg, 5.10 mmol) was suspended in acetic anhydride (20 mL) and heated at 80 0C for 1 hour. The mixture was cooled and concentrated under reduced pressure to yield a white solid which was dissolved in DMF (30 mL), treated with 4-[4-(methylsulfonyl)phenoxy]piperidine1 (1.30 g, 5.10 mmol) and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the crude material partitioned between DCM (30 mL) and potassium carbonate solution (20 mL). The aqueous layer was acidified (aqueous HCl solution (2N)) and the product extracted into DCM (2 x 30 mL). The solvent was removed under reduced pressure to afford the desired product as a white solid (1.60 g), which was used directly in the next step. MS (+ve ESI) : 410 (M+H)+
2) (lR,2R)-Λ/-(l-cyanocyclopropyl)-2-({4-[4-(methylsulfonyl)phenoxy]piperidin-l- yl}carbonyl)cyclohexanecarboxamide
( \R,2R)-2-( {4-[4-(methylsulfonyl)phenoxy]piperidin- 1 - yl}carbonyl)cyclohexanecarboxylic acid (418 mg, 1.02 mmol), PyBOP (586 mg, 1.12 mmol), DIPEA (0.53 mL, 3.07 mmol) and 1-aminocyclopropanecarbonitrile (13 mg, 1.10 mmol) were dissolved in DMF (10 mL) and the reaction stirred for 48 hours at room temperature. Water (20 mL) and DCM (50 mL) were added, the layers separated and organics washed with a saturated solution of potassium carbonate (100 mL). The solvent was removed under reduced pressure and the residue dissolved in DMF (5 mL). The mixture was filtered and purified using HPLC (0.1% formic acid/water: acetonitrile; λ=254nm) to furnish the desired product as a white solid (63.0 mg, 13 % yield). MS (+ve ESI) : 472 (M+H)+
1R NMR (400.13 MHz, CDCl3) δl.16 (3H, m), 1.30 (2H, m), 1.41 (IH, m), 1.44 - 1.46 (IH, m), 1.52 (IH, m), 1.60 (IH, m), 1.82 (3H, m), 1.85-2.10 (4H, m), 2.54 (IH, m), 2.93 (IH, m), 3.03 (3H, s), 3.44 (IH, m), 3.64 - 3.68 (IH, m), 3.82 (IH, m), 4.03 (IH, m), 4.74 (IH, m), 6.69 (IH, s), 7.01 (2H, d), 7.86 (2H, d) ! WO2003018556
Example 2
(lR,2R)-ΛL(l-cyanocyclopropyl)-2-{[4-(4-fluorophenoxy)piperidin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000050_0001
1) (l/?,2/?)-2-{[4-(4-fluorophenoxy)piperidin-l-yl]carbonyl}cyclohexanecarboxylic acid
Following Example 1, but using 4-[(4-fluorocyclohexyl)oxy]piperidine1 (1.00 g, 5.15 mmol) furnished the desired intermediate as a white solid (1.80 g). MS (+ve ESI) : 350 (M+H)+
2) (l/f,2/f)-Λ/-(l-cyanocyclopropyl)-2-{[4-(4-fluorophenoxy)piperidin-l- yl] carbonyl} cyclohexanecarboxamide Following Example 1 part (2), but using (li?,2i?)-2-{[4-(4-fluorophenoxy)piperidin- l-yl]carbonyl}cyclohexanecarboxylic acid (355 mg, 1.02 mmol) furnished the desired product as a colourless gum (100 mg, 26 % yield). MS (+ve ESI) : 414 (M+H)+ 1R NMR (400.13 MHz, CDCl3) δl.10-1.195 (3H, m), 1.32-1.54 (4H, m), 1.61-1.65 (2H, m), 1.79 -1.85 (2H, m), 1.87-1.91 (IH, m), 1.91-1.95 (IH, m), 1.99-2.05 (IH, m), 2.56- 2.62 (IH, m), 2.85 - 2.91 (IH, m), 3.44-3.60 (4H, m), 3.76-3.81 (IH, m), 3.89-3.94 (IH, 5 m), 4.42-4.51 (IH, m), 6.79 (IH, s), 6.82-6.87 (2H, m), 6.96-6.94 (2H, m) 1 WO2003018556
Example 3
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-({4-[4-(methylsulfonyl)phenyl]piperazin-l- i o yl} carbonyl)cyclohexanecarboxamide
Figure imgf000051_0001
l) (lR,2R)-2-({4-[4-(methylsulfonyl)phenyl]piperazin-l- yl} carbonyl)cyclohexanecarboxylic acid
Following Example 1, but using l-[4-(methylsulfonyl)phenyl]piperazine (1.23 g, is 5.15 mmol) furnished the desired intermediate as a white solid (1.98 g) MS (+ve ESI) : 395 (M+H)+
2) (l/f,2R)-ΛL(l-cyanocyclopropyl)-2-({4-[4-(methylsulfonyl)phenyl]piperazin-l- yl}carbonyl)cyclohexanecarboxamide
20 Following Example 1, part (2) but using (\R,2R)-2-({4-[4-
(methylsulfonyl)phenyl]piperazin-l-yl}carbonyl)cyclohexanecarboxylic acid (400 mg, 1.02 mmol) furnished the desired compound as a colourless gum (165 mg, 35 % yield). MS (+ve ESI) : 459 (M+H)+ 1U NMR (400.13 MHz, CDCl3) δl.12 - 1.20 (2H, m), 1.32 (IH, d), 1.36 - 1.45 (2H, m),
25 1.46 -1.52 (2H, m), 1.60 (IH, m), 1.83 -1.85 (4H, m), 2.51 - 2.58 (IH, m), 2.94 - 3.02 (IH, m), 2.97 - 3.01 (3H, s), 3.14 - 3.19 (IH, m), 3.39 (2H, m), 3.47 (2H, m), 3.65 - 3.68 (IH, m), 3.87-3.98 (2H, m), 6.76 (IH, s), 6.91 (2H, m), 7.76 - 7.80 (2H, m) Example 4
(lR,2R)-N-(l-cyanocyclopropyl)-2-({2,5-dimethyl-4-[4-
(methylsulfonyl)phenyl]piperazin-l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000052_0001
1) (li?,2i?)-cyclohexane-l,2-dicarboxylic acid (78 mg, 0.45 mmol) was suspended in acetic anhydride (20 mL) and heated at 800C for 1 hour. The mixture was cooled and concentrated under reduced pressure to yield a white solid, which was dissolved in DMF (30 mL), treated with 2,5-dimethyl-l-[4-(methylsulfonyl)phenyl]piperazine (120 mg, 0.45 mmol) and stirred at room temperature for 3 hours. PyBOP (350 mg, 0.67 mmol), DIPEA (0.3 mL, 1.79 mmol) and 1-aminocyclopropanecarbonitrile (78 mg, 0.67 mmol) were added and the reaction stirred for 16 hours at room temperature. Water (20 mL) and DCM (50 mL) were added, the layers separated and organics washed with a saturated solution of potassium carbonate (100 mL). The solvent was removed under reduced pressure and the residue dissolved in DMF (5 mL). The mixture was filtered and purified using HPLC (0.1% formic acid/water: acetonitrile; λ=254nm) to furnish the desired product as a colourless gum (17.0 mg, 7 % yield). MS (+ve ESI) : 487 (M+H)+ 1U NMR (400.13 MHz, CDCl3) δl.05 - 1.5 (14H, m), 1.53 (4H, m), 2.6-2.82 (2H, m ), 3.00 (3H, s), 3.20-4.9 (6H, m), 6.18-6.5 (IH, m), 6.86 - 6.90 (2H, m), 7.74 - 7.78 (2H, m)
2) 2,5-dimethyl- 1- [4-(methylsulfonyl)phenyl] piperazine l-fiuoro-4-(methylsulfonyl)benzene (871 mg, 5 mmol), trans-2,5-dimethylpiperazine
(1.71 g, 15 mmol) and K2CO3 (2.07 g, 15 mmol) were heated to 100 0C in DMF (10 mL) and stirred for 4 hours. The mixture was cooled and concentrated under reduced pressure to yield a yellow oil. This was dissolved in water (20 mL) and extracted with EtOAc (6 x 20 mL). The organic extracts were combined, washed with H2O (20 mL) then brine (20 mL) and dried using magnesium sulphate. The solution was concentrated and the residue dissolved in MeOH (10 mL) and loaded onto an SCX column. The SCX column was washed with MeOH to remove any non amine impurities. Ammonia solution (7N in MeOH, 15 mL) was then passed through the column and the solvent removed under reduced pressure to furnish the desired product as a colourless oil (0.60 g, 45 % yield). MS (+ve ESI) : 269 (M+H)+
Example 5 (lR,2R)-N-(l-cyanocyclopropyl)-2-({2,2-dimethyl-4-[4-
(methylsulfonyl)phenyl]piperazin-l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000053_0001
Following Example 4, but starting with 3,3-dimethyl-l-[4- (methylsulfonyl)phenyl]piperazine (280 mg, 1.04 mmol) furnished the desired compound as a colourless gum (81.0 mg, 16 % yield). MS (+ve ESI) : 487 (M+H)+
1H NMR (400.13 MHz, CDCl3) δl.13 - 1.16 (IH, m), 1.27 (IH, m), 1.34 (IH, m), 1.42 - 1.47 (4H, m), 1.52 (3H, s), 1.58 (IH, s), 1.82 - 1.85 (2H, m), 2.50 (2H, m), 2.88 (2H, m), 3.01 (3H, s), 3.52 (3H, m), 3.65 (2H, m), 3.85 (2H, m), 4.02 (2H, m), 6.64 (IH, s), 6.71 (2H, d), 7.76 (2H, d)
3,3-dimethyl-l-[4-(methylsulfonyl)phenyl]piperazine
Following Example 4, part (2) but using 2,2-dimethylpiperazine (1.14 g, 10 mmol) furnished the desired product as a white solid (1.20 g, 89 % yield). MS (+ve ESI) : 269 (M+H)+ Example 6
(lR,2R)-N-(l-cyanocyclopropyl)-2-({(2R,6S)-2,6-dimethyl-4-[4-
(methylsulfonyl)phenyl]piperazin-l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000054_0001
Following Example 4 but starting with (3i?,55)-3,5-dimethyl-l-[4-
(methylsulfonyl)phenyl]piperazine (280 mg, 1.04 mmol) furnished the desired compound as a colourless gum (20.0 mg, 4 % yield). MS (+ve ESI) : 487 (M+H)+
1U NMR (400.13 MHz, CDCl3) δl.15 (2H, d), 1.31 and 1.35 (3H, d), 1.42 and 1.50 (3H, d), 1.60 (IH, m), 1.80-1.85 (5H, m), 2.45 and 2.60 (IH, m), 2.84 (2H, m), 3.01 and 3.02 (3H, s), 3.08 - 3.11 (IH, m), 3.13 - 3.18 (2H, m), 3.28-3.42 (IH, m), 3.64 - 3.70 (2H, m), 4.01 and 4.61 (2H, m), 4.50 and 4.79 (IH, m), 6.63 and 6.75 (IH, s), 6.89 - 6.94 (2H, m), 7.75 - 7.80 (2H, m)
(3R,5S)-3,5-dimethyl-l-[4-(methylsulfonyl)phenyl]piperazine
Following Example 4, part (2) but using 2,6-dimethylpiperazine (3.27 g, 28.7 mmol) furnished the desired product as a yellow solid (3.20 g, 83 % yield). MS (+ve ESI) : 269 (M+H)+
Example 7
(lR,2R)-N-(l-cyanocyclopropyl)-2-({(2R)-2-methyl-4-[4-
(methylsulfonyl)phenyl]piperazin-l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000055_0001
Following Example 4 but starting with (3i?)-3-methyl-l-[4-
(methylsulfonyl)phenyl]piperazine (250 mg, 0.98 mmol) furnished the desired compound as a white solid (56.0 mg, 12 % yield). 5 MS (+ve ESI) : 473 (M+H)+
1H NMR (400.13 MHz, CDCl3) δl.13 -1.52 (9H, m), 1.21 and 1.40 (3H, d), 1.7 (IH, m), 1.76 - 1.84 (4H, m), 2.57 (IH, m), 2.81-2.98 (IH, m), 3.00 (3H, s), 3.14 - 3.20 (IH, m), 3.55-3.80 (2H, m), 4.41 and 4.85 (IH, m), 3.91 and 4.48 (IH, m), 6.38 and 6.46 (IH, s), 6.84 (2H, m), 7.75 (2H, m) i o (3R )-3-methyl- 1- [4-(methylsulfonyl)phenyl] piperazine
Following Example 4 part (2) but using R-2-methylpiperazine (1.50 g, 15.0 mmol) furnished the desired product as a white solid (0.96 g, 76 % yield). MS (+ve ESI) : 255 (M+H)+
is Example 8
(lR,2R)-N-(l-cyanocyclopropyl)-2-({(25)-2-methyl-4-[4- (methylsulfonyl)phenyl]piperazin-l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000055_0002
Following Example 4 but starting with (35)-3-methyl-l-[4-
20 (methylsulfonyl)phenyl]piperazine (250 mg, 0.98 mmol) furnished the desired compound as a white solid (45.0 mg, 10 % yield). MS (+ve ESI) : 473 (M+H)+
1R NMR (400.13 MHz, CDCl3) δl.14 -1.52 (9H, m), 1.23 and 1.33 (3H, d), 1.62 (IH, d), 1.80 - 1.83 (4H, m), 2.5 (IH, m), 2.81-2.98 (IH, m), 3.00 (3H, s), 3.15 - 3.19 (IH, m), 3.59-3.80 (2H, m), 3.65 and 4.31 (IH, m), 4.45 and 4.73 (IH, m), 6.38 and 6.46 (IH, s), 6.86 (2H, m), 7.77 (2H, m)
(3S)-3-methyl- 1- [4-(methylsulfonyl)phenyl] piperazine
Following Example 4, part (2) but using (S)-2-methylpiperazine (1.50 g, 15 mmol) furnished the desired product as a white solid (1.05 g, 83 % yield). MS (+ve ESI) : 255 (M+H)+
Example 9
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-({4-[4-(methylsulfonyl)phenyl]-l,4-diazepan-l- yl}carbonyl)cyclohexanecarboxamide
Figure imgf000056_0001
Following Example 4 but starting with l-[4-(methylsulfonyl)phenyl]-l,4-diazepane
(250 mg, 0.98 mmol) furnished the desired compound as a white solid (78.0 mg, 17 % yield).
MS (+ve ESI) : 473 (M+H)+ 1H NMR (400.13 MHz, CDCl3) δ 1.11 - 1.15 (IH, m), 1.16 - 1.27 (IH, m), 1.31-1.35 (IH, m), 1.38 - 1.40 (IH, m), 1.42 - 1.46 (2H, m), 1.51 - 1.53 (IH, m), 1.62-1.75 (2H, m), 1.81 (IH, m), 2.00-2.02 (IH, m), 2.04-2.16 (IH, m), 2.21 (IH, m), 2.51-2.53 (IH, m), 2.82 (2H, m), 3.01 (3H, s), 3.20-3.36 (IH, m), 3.42 - 3.47 (IH, m), 3.53 - 3.80 (2H, m), 3.86 (2H, d), 3.90-3.97 (IH, m), 4.10 (IH, d), 6.50-6.58 (IH, s), 6.74 (2H, d), 7.72 - 7.75 (2H, m) l-[4-(methylsulfonyl)phenyl]-l,4-diazepane Following example 4 part (2) but using homopiperazine (1.50 g, 15 mmol) furnished the desired product as a white solid (900 mg, 71 % yield). MS (+ve ESI) : 255 (M+H)+
Example 10
(lR,2R)-N-(l-cyanocyclopropyl)-2-(piperidin-l-ylcarbonyl)cyclohexanecarboxamide
Figure imgf000057_0001
Following Example 4 but starting with piperidine 0.086 mL, 0.87 mmol.
Purification by flash column chromatography on silica gel (elution with 0-100 % ethyl acetate/isohexane) furnished the desired compound as a white solid (119 mg, 33 % yield).
MS (+ve ESI) : 304 (M+H)+
1H NMR (400 MHz, DMSO) δ 1.0 (m, 2H), 1.2-1.8 (m, 16H), 2.4 (t, IH), 2.9 (t, IH), 3.5 (m, 4H), 8.6 (s, IH)
Example 11
(l/f,2/f)-2-[(4-benzylpiperidin-l-yl)carbonyl]-Λ/-(l-cyanocyclopropyl) cyclohexanecarboxamide
Figure imgf000057_0002
Following Example 4 but starting with 4-benzylpiperidine (0.51 mL, 2.9 mmol). Purification by reverse phase HPLC (0.1% formic acid/water: acetonitrile), furnished the desired compound as a white solid (75.0 mg, 33 % yield). MS (+ve ESI) : 394 (M+H)+
1U NMR (400.132 MHz, DMSQ) δ 0.89 - 1.51 (m, HH), 1.52 - 1.80 (m, 7H), 2.33 - 2.49 (m, 3H), 2.78 - 3.00 (m, 2H), 3.95 (m, IH), 4.30 (m, IH), 7.18 (m, 3H), 7.28 (m, 2H), 8.61 (d, IH)
Example 12
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-{[4-(4-fluorophenyl)piperazin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000058_0001
Following Example 4 but starting with l-(4-fluorophenyl)piperazine (1.10 g, 6.10 mmol). The compound was purified by flash column chromatography on silica gel (elution with 30 % ethyl acetate/isohexane increase to 100 % ethyl acetate). The residue was dissolved in EtOAc (75 mL) and washed with water (3 x 20OmL). The organics were dried
(magnesium sulphate) and concentrated to furnish the desired compound as a cream solid
(1.25 g, 54 % yield).
MS (+ve ESI) : 399.6 (M+H)+
1R NMR (400.132 MHz, DMSQ) δ 0.92 - 1.04 (m, 2H), 1.15 - 1.44 (m, 6H), 1.65 - 1.82 (m, 4H), 2.45 (m, IH), 2.87 - 3.15 (m, 5H), 3.46 - 3.75 (m, 4H), 6.97 (m, 2H), 7.06 (m,
2H), 8.66 (s, IH)
Example 13
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-({4-[3-(dimethylamino)propyl]piperazin-l- yl} carbonyl)cyclohexanecarboxamide
Figure imgf000059_0001
Following Example 4 but starting with l-(3-dimethylaminopropyl)-piperizine (221 mg, 1.3 mmol), furnished the desired compound as a white solid (72.0 mg, 14 % yield). LCMS retention time 0.47 MS (-ve ESI) : 390 (M+H)+
Example 14
(lR,2R)-ΛL(l-cyanocyclopropyl)-2-[(4-pyrrolidin-l-ylpiperidin-l- yl)carbonyl]cyclohexanecarboxamide
Figure imgf000059_0002
Following Example 4 but starting with 4-(l-pyrrolidinyl)-piperidine (200 mg, 1.3 mmol), furnished the desired compound as a colourless gum (198 mg, 41 % yield). LCMS retention time 0.52 MS (-ve ESI) : 373 (M+H)+
Example 15
(lR,2R)-Λ/-(l-cyanocyclopropyl)-2-{[4-(3-methylpyridin-2-yl)piperazin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000060_0001
A mixture of l-(3-methylpyridin-2-yl)-piperizine (115 mg, 0.65 mmol) and (3ai?,7ai?)-hexahydro-2-benzofuran-l,3-dione (100 mg, 0.65 mmol) in DCM (3 mL) was stirred at room temperature for 18 hours. N-methylmorpholine (0.2ImL, 1.95 mmol) and 1- aminocyclopropanecarbonitrile (lOOmg, 0.84 mmol) were added followed by dropwise addition of isobutyl chloro formate (0.093 mL, 0.71 mmol). The reaction mixture was stirred for 48 hours, diluted with DCM (50 mL) and washed with water (30 mL). The organics were passed through a phase separation cartridge and concentrated to give a gum. Purification by reverse phase HPLC ((0.1% formic acid/water: acetonitrile) furnished the desired compound as a colourless gum (57.0 mg, 22% yield).
1U NMR (400.132 MHz, DMSO) δ 0.86 - 1.71 (m, 10H), 2.26 (s, 3H), 3.32 (m, 4H), 3.56 (m, 2H), 3.66 (m, 2H), 3.79 (m, 4H), 6.95 (m, IH), 7.52 (d, IH), 8.11 (m, IH), 8.27 (s, IH)
Example 16 (l/f,2R)-ΛL(l-cyanocyclopropyl)-2-({4-[4-(phenylsulfonyl)phenyl]piperazin-l- yl}carbonyl)cyclohexanecarboxamide
Figure imgf000060_0002
Following Example 4, but starting with l-[4-(phenylsulfonyl)phenyl]piperazine (302 mg, 1 mmol) furnished the desired compound as a white foam (120 mg, 23 % yield). MS (+ve ESI) : 521 (M+H)+
1R NMR (400.132MHz, CDCl3) δ 1.12 (2H, m), 1.28-1.50 (4H, m), 1.55-1.75 (2H, m), 1.82 (4H, m), 2.60 (IH, t), 2.90 (IH, t), 3.38 (4H, m), 3.62 (2H, m), 3.88 (2H, m), 6.75 (IH, s), 6.85 (2H, d), 7.48 (3H, m), 7.80 (2H, d), 7.90 (2H, d)
l-[4-(phenylsulfonyl)phenyl]piperazine
To a slurry of piperazine (2.76 g, 32.0 mmol), sodium tert-butoxide (1.54 g, 16.0 mmol), BINAP (126 mg, 0.20 mmol), and Pd2(dba)3 (116 mg, 0.12 mmol) in toluene (21 mL) was added l-bromo-4-(phenylsulfonyl)benzene (2.38 g, 8.00 mmol) and the reaction mixture heated to 80 0C under an atmosphere of argon for 19 hours. The dark brown mixture was allowed to cool to ambient temperature, filtered to remove any large deposits and the filtrate evaporated to dryness. The resultant residue was purified by use of a SCX cartridge (50 g), flushing through first with methanol (30 mL) and then eluting with a IM NH3 in MeOH (2 x 20 mL) solution afforded a waxy solid. The solid was dissolved in EtOAc, washed with water (3 x 20 mL), dried over magnesium sulphate and then concentrated in vacuo to furnish the desired compound as a waxy orange solid (1.56 g, 64 % yield). MS (+ve ESI) : 303 (M+H)+
1U NMR (400.132MHz, CDCl3) δ 3.00 (4H, m), 3.28
(4H, m), 6.88 (IH, d), 7.48 (5H, m), 7.78 (2H, d), 7.90 (2H, d)
Example 17 (IR, 2R )-iV-(l-cyanocy clopropyl)-2-({4-[4-(methylsulfonyl)-l-naphthyl]piperazin-l- yl}carbonyl)cyclohexanecarboxamide
Figure imgf000062_0001
Following Example 4 but starting with l-[4-(methylsulfonyl)-l-naphthyl]piperazine (290 mg, 1.00 mmol) furnished the desired compound as a colourless film (30.0 mg, 6 % yield).
MS (+ve ESI) : 509 (M+H)+
1U NMR (400.132MHz, CDCl3) δ 1.18 (2H, m), 1.30-1.55 (4H, m), 1.60-1.70 (2H, m), 1.82 (6H, m), 2.64 (IH, t), 2.98 (IH, t), 3.20 (7H, s), 3.80 (IH, m), 3.95 (IH, m), 6.75 (IH, s), 7.12 (IH, d), 7.60 (IH, t), 7.70 (IH, t), 8.26 (2H, m), 8.70 (IH, d) l-[4-(methylsulfonyl)-l-naphthyl]piperazine
To a stirred mixture of piperazine (3.08 g, 35.8 mmol) and potassium carbonate (1.24 g, 8.95 mmol) in DMF (36 mL), was added 4-fluoro-naphthalene-l-methylsulfone (401 mg, 1.79 mmol) and the mixture heated to 100 0C for one hour. Allowing the mixture to cool to room temperature followed by concentration in vacuo produced a white crystalline solid, which was dissolved in water and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed with water (2 x 20 mL), brine (2 x 20 mL) and dried over magnesium sulphate to furnish a white solid. The solid was purified by loading onto an SCX cartridge (20 g) and eluting with methanol. Increased polarity to IM ammonia in MeOH (2 x 15 mL) furnished the desired compound as a white solid (300 mg, 58% yield).
MS (+ve ESI) : 291 (M+H)+
1H NMR (400.132MHz, CDCl3) δ 3.18 (HH, m), 7.10 (IH, d), 7.59 (IH, t), 7.69 (IH, t), 8.28 (2H, m), 8.70 (IH, d) Example 18
(l/f,2R)-2-({4-[3-chloro-4-(methylsulfonyl)phenyl]piperazin-l-yl}carbonyl)-ΛL(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000063_0001
Following Example 4, but starting with l-[3-chloro-4-
(methylsulfonyl)phenyl]piperazine (274 mg, 1 mmol) furnished the desired compound as a white solid (69.0 mg, 28 % yield).
MS (+ve ESI) : 493 (M+H)+
1R NMR (400.132MHz, CDCl3) δ 1.09 - 1.68 (8H, m), 1.83 (4H, m), 2.57 (IH, m), 2.90 (IH, m), 3.21 (3H, s), 3.42 (4H, m), 3.61 (2H, m), 3.88 (IH, m), 3.98 (IH, m), 6.52 (IH, s), 6.77 (IH, m), 6.89 (IH, d), 7.94 (IH, d) l-[3-chloro-4-(methylsulfonyl)phenyl]piperazine i) 2-Chloro-4-fluoro-l-(methylsulfonyl)benzene (1.63 g, 7.84 mmol) was added to a mixture of piperazine (13.4 g, 157 mmol) and potassium carbonate (5.40 g, 39.2 mmol) in DMF (140 mL) and the resultant mixture heated to 100 0C for 4 hours. The reaction mixture was cooled and concentrated to afford a white solid which was subsequently dissolved in water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water (2 x 20 mL), brine (2 x 20 mL) and dried over magnesium sulphate and concentrated to afford the desired product as a waxy white solid which was used directly in the next step. (1.88 g, 88 % yield).
MS (+ve ESI) : 275 (M+H)+
1U NMR (400.132MHz, CDCl3) δ 3.00 (4H, m), 3.20 (3H, s), 3.32 (4H, m), 6.78 (IH, d),
6.90 (IH, s), 7.92 (IH, d) ii) 2-Chloro-4-fluorobenzenesulfbnyl chloride (6.20 g, 27.0 mmol) was added to a solution of sodium sulfite (3.4 g, 27 mmol) and sodium hydrogen carbonate (6.30 g, 81.0 mmol) in water at 75 0C and the resultant mixture stirred at 75 0C for lhr. Chloroacetic acid (3.83 g, 40.5 mmol) was added portionwise followed by sodium hydroxide (1.65 g, 41.5 mmol) and the colourless solution was heated to reflux overnight. The resultant pale yellow solution containing a white precipitate was allowed to cool to room temperature and was then acidified to pH 1 with 2M HCl. The resultant white precipitate was filtered, washed with water (c.f. 20 mL) and allowed to dry to yield a fine white solid (1.63 g, 29 % yield) which was used directly in the next step. 1R NMR (400.132MHz, CDCl3) δ 3.25 (3H, s), 7.18 (IH, t), 7.32 (IH, d), 8.20 (IH, dd)
Example 19
(lR,2R)-N-(l-cyanocyclopropyl)-2-[(4-{4- [(3,3,3- trifluoropropyl)sulfonyl]phenyl}piperazin-l-yl)carbonyl]cyclohexanecarboxamide
Figure imgf000064_0001
Following Example 4, but starting with l-{4-[(3,3,3- trifluoropropyl)sulfonyl]phenyl}piperazine (322 mg, 1.00 mmol) furnished the desired compound as a colourless foam (10.0 mg, 2 % yield). MS (+ve ESI) : 541 (M+H)+ 1U NMR (400.132MHz, CDCl3) δ 1.15 (2H, m), 1.30-1.50 (4H, m), 1.82 (4H, d), 2.52 (3H, m), 2.90 (IH, t), 3.22 (3H, m), 3.45 (5H, m), 3.62 (2H, m), 3.88 (IH, m), 3.95 (IH, m), 6.40 (IH, s), 6.90 (2H, d), 7.75 (2H, d) l-{4-[(3,3,3-trifluoropropyl)sulfonyl]phenyl}piperazine l-fluoro-4-[(3,3,3-trifluoropropyl)sulfonyl]benzene (1.42 g, 5.50 mmol) was added to a slurry of piperazine (9.55 g, 111 mmol) and potassium carbonate (3.80 g, 27.7 mmol) in DMF (100 mL) and the mixture heated to 100 0C for 18 hr. The resultant solution was allowed to cool and concentrated in vacuo to yield a white crystalline solid. The compound was dissolved in water and extracted with ethyl acetate (3 x 20 mL). The combined organics were washed with water (1 x 20 mL), brine (1 x 20 mL), dried over magnesium sulphate and concentrated in vacuo to give a fine white crystalline solid (880 mg, 49 % yield).
1R NMR (400.132MHz, CDCl3) δ 2.55 (2H, m), 3.02 (4H, m), 3.22 (2H, m), 3.35 (4H, m), 6.92 (2H, d), 7.72 (2H, d)
Example 20
(^{^^-^-(l-cyanocyclopropylJ-l-dS-Il-^rifluoromethylJphenylJpyrrolidin-l- yl}carbonyl)cyclohexanecarboxamide
Figure imgf000065_0001
Following Example 4, but starting with 3-[2-(trifluoromethyl)phenyl]pyrrolidine hydrochloride (102 mg, 0.47 mmol) furnished the desired compound as a white solid (43.0 mg, 21 % yield). MS (+ve ESI) : 434 (M+H)+
1R NMR (400.13 MHz, CDCl3) δl.05 - 1.15 1.78 (9H, m), 1.81 -1.93 (4H, m), 2.40 - 2.47 (IH, m), 2.50-2.91 (2H), 3.65-4.10 (4H, m), 5.20-5.63 (IH, m), 6.54-6.77 (IH, m), 7.08- 7.70 (4H, m)
Example 21 (l/f,2/f)-Λ/-(l-cyanocyclopropyl)-2-({3-[3-(trifluoromethyl)phenyl]pyrrolidin-l- yl}carbonyl)cyclohexanecarboxamide
Figure imgf000066_0001
Following Example 4, but starting with 3-[3-(trifluoromethyl)phenyl]pyrrolidine hydrochloride (102 mg, 0.47 mmol) furnished the desired compound as a white solid (95.0 mg, 44 % yield). MS (+ve ESI) : 434 (M+H)+
1U NMR (400.13 MHz, CDCl3) δl.12 - 1.15 (IH, m), 1.20 (IH, m), 1.26 - 1.30 (2H, m), 1.33 (IH, m), 1.38 - 1.44 (2H, m), 1.50 (IH, m), 1.65 (IH, t), 1.80 -1.84 (4H, m), 1.90-2.39 (IH, m), 2.51 (IH, m), 2.69 (IH, m), 3.42 (IH, m), 3.60 (IH, m), 3.61-4.12 (3H, m), 6.57 and 6.58 (IH, s), 7.41 - 7.43 (IH, m), 7.47 (2H, d), 7.50-7.52 (IH, m).
Example 22
(l/f,2/f)-Λ/-(l-cyanocyclopropyl)-2-({3-[4-(trifluoromethyl)phenyl]pyrrolidin-l- yl}carbonyl)cyclohexanecarboxamide
Figure imgf000066_0002
Following Example 4, but starting with 3-[4-(trifluoromethyl)phenyl]pyrrolidine hydrochloride (102 mg, 0.47 mmol) furnished the desired compound as a white solid (61.0 mg, 34 % yield).
MS (+ve ESI) : 434 (M+H)+
1R NMR (400.13 MHz, CDCl3) δl.26- 1.53 (8H, m), 1.62 (IH, t), 1.79-1.84 (4H, m), 1.90- 2.38 (IH, m), 2.50 (IH, m), 2.71 (IH, m), 3.36-3.61 (2H, m), 3.62-4.13 (3H, m), 6.50 (IH, m), 7.35 (IH, m), 7.39 (IH, m), 7.56 (IH, m), 7.58 (IH, m) Example 23
(lR,2R)-2-{[3-(2-chlorophenyl)pyrrolidin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000067_0001
Following Example 4, but starting with 3-(2-chlorophenyl)pyrrolidine hydrochloride (100 mg, 0.55 mmol) and using 4 equivalents of DIPEA furnished the desired compound as a white solid (85.0 mg, 45 % yield).
MS (+ve ESI) : 400 (M+H)+
1H NMR (400.13 MHz, CDCl3) δl.11 - 1.16 (IH, m), 1.16 - 1.23 (IH, m), 1.31 (2H, d), 1.37 - 1.45 (2H, m), 1.46 - 1.55 (2H, m), 1.66 (IH, t), 1.83 (4H, m), 2.04-2.49 (IH, m), 2.51-2.59 (IH, m), 2.66 - 2.74 (IH, m), 3.40 - 3.61 (3H, m), 3.76 - 3.84 (IH, m), 3.89 - 3.93 (IH, m), 6.76 and 6.77 (IH, s), 7.15 - 7.23 (2H, m), 7.34 - 7.40 (2H, m)
Example 24 (lR,2R)-2-{[3-(3-chlorophenyl)pyrrolidin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000067_0002
Following Example 4, but starting with 3-(3-chlorophenyl)pyrrolidine hydrochloride (100 mg, 0.55 mmol) and using 4 equivalents of DIPEA furnished the desired compound as a white solid (98.0 mg, 52 % yield). MS (+ve ESI) : 400 (M+H)+
1H NMR (400.13 MHz, CDCl3) δl.11 - 1.16 (IH, m), 1.13 - 1.21 (IH, m), 1.33 (2H, d), 1.38 - 1.45 (2H, m), 1.46 - 1.51 (2H, m), 1.62 (IH, t), 1.80 (4H, m), 1.98-2.45 (IH, m), 2.53-2.59 (IH, m), 2.66 - 2.73 (IH, m), 3.35 - 4.10 (5H, m), 6.69 and 6.70 (IH, s), 7.10 - 7.29 (4H, m)
Example 25 (lR,2R)-2-{[3-(4-chlorophenyl)pyrrolidin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000068_0001
Following Example 4, but starting with 3-(4-chlorophenyl)pyrrolidine hydrochloride (100 mg, 0.55 mmol) and using 4 equivalents of DIPEA furnished the desired compound as a white solid (72.0 mg, 38 % yield). MS (+ve ESI) : 400 (M+H)+
1U NMR (400.13 MHz, CDCl3) δl.09 - 1.20 (2H, m), 1.30 (2H, m), 1.36 - 1.44 (2H, m), 1.48 - 1.53 (2H, m), 1.64 (IH, t), 1.83 (4H, m), 1.91 - 2.40 (IH, m), 2.53 - 2.58 (IH, m), 2.65 - 2.76 (IH, m), 3.27 - 3.35 (IH, m), 3.47 - 3.58 (IH, m), 3.62 - 4.11 (3H, m), 7.01- 7.16 (IH, m), 7.21 - 7.32 (4H, m)
Example 26
(lR,2R)-ΛL(l-cyanocyclopropyl)-2-{[3-(2-fluorophenyl)pyrrolidin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000068_0002
Following Example 4, but starting with 3-(2-fluorophenyl)pyrrolidine hydrochloride (99.0 mg, 0.60 mmol) and using 4 equivalents of DIPEA furnished the desired compound as a colourless gum (69.0 mg, 30 % yield). MS (+ve ESI) : 384 (M+H)+
1H NMR (400.13 MHz, CDCl3) δl.10 - 1.15 (IH, m), 1.16 - 1.20 (2H, m), 1.26 - 1.41 (2H, m), 1.42 - 1.45 (IH, m), 1.48 - 1.52 (2H, m), 1.63 (IH, m), 1.82 (4H, m), 2.10-2.42 (IH, m), 2.55 (IH, m), 2.70 (IH, m), 3.44-4.08 (5H, m), 6.64 and 6.65 (IH, s), 7.00 - 7.09 (IH, m), 7.13 (IH, m), 7.18 - 7.22 (IH, m), 7.30 (IH, m)
The diastereomers can be separated by chiral HPLC using Merck 50mm 20μm Chiralpak AS - No ASVOOSC BD004 Packed 31-03-03, eluent iso- Hexane/(EtOH/MeOH50/50) 95/5, flow 40mL/min, 210, 230 nm) to yield each diastereomer as characterised by 1H NMR.
1: 1U NMR (400.13 MHz, CDCl3) δl.12- 1.15 (IH, m), 1.16 - - 1.41 (4H, m), 1.42 (IH, m), 1.46 - 1.56 (2H, m), 1.60 (IH, m), 1.83 (4H, m), 2.05-2.40 (IH, m), 2.52 (IH, m), 2.69 (IH, m), 3.44-4.08 (5H, m), 6.63 and 6.65 (IH, s), 7.01 - 7.09 (IH, m), 7.11 (IH, m), 7.17 - 7.20 (IH, m), 7.28 (IH, m)
2: 1H NMR (400.13 MHz, CDCl3) δl.10 - 1.16 (IH, m), 1.16 - 1.23 (2H, m), 1.25 - 1.40 (2H, m), 1.43 - 1.44 (IH, m), 1.49 - 1.50 (2H, m), 1.64 (IH, m), 1.82-1.85 (4H, m), 2.10- 2.39 (IH, m), 2.52-2.54 (IH, m), 2.70-2.72 (IH, m), 3.45-4.10 (5H, m), 6.65 and 6.66 (IH, s), 7.00 - 7.08 (IH, m), 7.12 (IH, m), 7.18 - 7.21 (IH, m), 7.30 (IH, m)
Example 27 (l/f,2R)-ΛL(l-cyanocyclopropyl)-2-{[3-(3-fluorophenyl)pyrrolidin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000069_0001
Following Example 4, but starting with 3-(3-fluorophenyl)pyrrolidine hydrochloride (99.0 mg, 0.60 mmol) and using 4 equivalents of DIPEA furnished the desired compound as a colourless gum (96.0 mg, 53 % yield). MS (+ve ESI) : 384 (M+H)+ 1H NMR (400.13 MHz, CDCl3) δl.10 - 1.15 (IH, m), 1.16 - 1.23 (IH, m), 1.31 (2H, m), 1.35 - 1.41 (2H, m), 1.4 - 1.54 (2H, m), 1.61 (IH, t), 1.79 (4H, m), 1.95-2.44 (IH, m), 2.51 (IH, m), 2.64 (IH, m), 3.38 (IH, m), 3.49-4.10 (4H, m), 6.61 and 6.65 (IH, m), 6.90 - 6.94 (IH, m), 7.00 (IH, m), 7.01 (IH, m), 7.28 (IH, m)
Example 28
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-{[3-(4-fluorophenyl)pyrrolidin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000070_0001
Following Example 4, but starting with 3-(4-fluorophenyl)pyrrolidine hydrochloride (99.0 mg, 0.60 mmol) and using 4 equivalents of DIPEA furnished the desired compound as a colourless gum (85.0 mg, 47 % yield). MS (+ve ESI) : 384 (M+H)+
1R NMR (400.13 MHz, CDCl3) δl.09 - 1.16 (IH, m), 1.17 - 1.23 (IH, m), 1.30 (2H, m), 1.35 - 1.38 (2H, m), 1.39 - 1.44 (2H, m), 1.64 (IH, m), 1.79 - 1.88 (4H, m), 194-2.39 (IH, m), 2.54 - 2.59 (IH, m), 2.66 - 2.70 (IH, m), 3.38 (IH, m), 3.50 - 3.57 (IH, m), 3.58-4.10 (3H, m), 6.81 an 6.82 (IH,), 6.97 - 7.02 (2H, m), 7.16 - 7.23 (2H, m)
Example 29
(lR,2R)-N-(l-cyanocyclopropyl)-2-{[(3R)-3-phenylpyrrolidin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000070_0002
Following Example 4, but starting with (3i?)-3-phenylpyrrolidine hydrochloride (103 mg, 0.70 mmol) and using 4 equivalents of DIPEA furnished the desired compound as a colourless gum (69.0 mg, 40 % yield). MS (+ve ESI) : 366 (M+H)+ 1R NMR (400.13 MHz, CDCl3) δl.10 - 1.65 (8H, m), 1.80- 1.88(4H, m), 2.01 (IH, m), 2.21 - 2.41 (IH, m), 2.54 (IH, m), 2.71 - 2.81 (IH, m), 3.39 - 3.57 (3H, m), 3.71 (IH, m), 3.8-4.18 (IH, m 7.20 - 7.30 (3H, m), 7.30 - 7.35 (2H, m)
Example 30 (l/f,2/f)-Λ/-(l-cyanocyclopropyl)-2-{[(3S)-3-phenylpyrrolidin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000071_0001
Following Example 4, but starting with (3S)-3-phenylpyrrolidine hydrochloride (103 mg, 0.70 mmol) and using 4 equivalents of DIPEA furnished the desired compound as a colourless gum (18.0 mg, 7 % yield). MS (+ve ESI) : 366 (M+H)+
1R NMR (400.13 MHz, CDCl3) δl.08 - 1.56 (8H, m), 1.78- 1.89(4H, m), 2.02 - 2.41 (2H, m), 2.53 (IH, m), 2.65 - 2.71 (IH, m), 3.35 - 3.71 (4H, m), 3.81-4.15 (IH, m), 6.82 (IH, s), 7.18-7.45 (5H, m),
Example 31
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-{[3-(2-methoxyphenyl)pyrrolidin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000072_0001
Following Example 4, but starting with 3-(2-methoxyphenyl)pyrrolidine (100 mg, 0.56 mmol) and using 4 equivalents of DIPEA furnished the desired compound as a white solid (96.0 mg, 44 % yield). MS (+ve ESI) : 396 (M+H)+
1R NMR (400.13 MHz, CDCl3) δl.07 - 1.23 (2H, m), 1.28-1.30 (3H, m), 1.36 - 1.53 (3H, m), 1.62 (IH, m), 1.8- 1.87 (4H, m), 2.13 - 2.30 (IH, m), 2.53 - 2.62 (IH, m), 2.68 - 2.73 (IH, m), 3.30 - 3.74 (4H, m), 3.85 and 3.86 (3H, 2 x s), 4.01-4.11 (IH, m), 6.87 - 6.96 (2H, m), 6.85 - 6.97 (IH, m), 7.19 -7.26 (IH, m)
Example 32
(lR,2R)-2-{[4-(l,3-benzothiazol-2-yl)piperazin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000072_0002
Following Example 4, but starting with 2-piperazin-l-yl-l,3-benzothiazole (876 mg, 4.00 mmol) furnished the desired compound as a white foam (107 mg, 24 % yield). MS (+ve ESI) : 438 (M+H)+
1U NMR (400.13 MHz, CDCl3) δ 1.05 - 1.98 (HH, m), 2.51 - 2.66 (IH, m), 2.91 (IH, m), 3.26 - 3.87 (8H, m), 3.94 (IH, m), 6.55 (IH, m), 7.09 (IH, m), 7.31 (IH, m), 7.58 (2H, m) Example 33
(lR,2R)-2-{[4-(4-chloro-l,3-benzothiazol-2-yl)piperazin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000073_0001
Following Example 4, but starting with 4-chloro-2-piperazin-l-yl-l,3- benzothiazole (214 mg, 0.84 mmol) furnished the desired compound as a white gum (233 mg, 60 % yield). MS (+ve ESI) : 470, 472
1U NMR (400.13 MHz, CDCl3) δl.04 - 1.85 (HH, m), 2.54 - 2.61 (IH, m), 2.92 (IH, m), 3.73 (8H,m), 3.94 - 3.98 (IH, m), 6.54 (IH, s), 7.00 (IH, t), 7.31 - 7.33 (IH, m), 7.47 - 7.50 (IH, m)
Example 34
(l/f,2/f)-2-{[4-(6-bromo-l,3-benzothiazol-2-yl)piperazin-l-yl] carbonyl}-iV-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000073_0002
Following Example 4, but starting with 6-bromo-2-piperazin-l-yl-l,3- benzothiazole (252 mg, 0.84 mmol) furnished the desired compound as a white foam (191 mg, 44 % yield). MS (+ve ESI) : 517 (M+H)+
1R NMR (400.13 MHz, CDCl3) δl.09 - 1.20 (2H, m), 1.45 (6H, m), 1.82 - 1.85 (4H, m), 2.54 - 2.61 (IH, m), 2.88 - 2.95 (IH, m), 3.57 - 3.74 (6H, m), 3.83 (IH, m), 3.96 - 4.01 (IH, m), 6.55 (IH, s), 7.37 - 7.42 (2H, m), 7.71 (IH, m) Example 35
(lR,2R)-ΛL(l-cyanocyclopropyl)-2-{[4-(4,6-difluoro-l,3-benzothiazol-2-yl)piperazin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000074_0001
Following Example 4, but starting with 4,6-difluoro-2-piperazin-l-yl-l,3- benzothiazole (216 mg, 0.84 mmol) furnished the desired compound as a white foam (215 mg, 54 % yield). MS (+ve ESI) : 474 (M+H)+
1R NMR (400.13 MHz, CDCl3) δ 1.09 - 1.20 (2H, m), 1.48 (1OH, cm), 2.54 - 2.61 (IH, m), 2.92 (IH, m), 3.57 - 3.76 (6H, m), 3.81 - 3.86 (IH, m), 3.99 (IH, m), 6.56 (IH, s), 6.81 - 6.87 (IH, m), 7.11 - 7.14 (IH, m)
Example 36
(lR,2R)-2-{[4-(6-chloro-l,3-benzothiazol-2-yl)piperazin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000074_0002
Following Example 4, but starting with 6-chloro-2-piperazin-l-yl-l,3- benzothiazole (214 mg, 0.84 mmol) furnished the desired compound as a white foam (246 mg, 62 % yield).
MS (+ve ESI) : 471, 473 (M+H)+
1R NMR (400.13 MHz, CDCl3) δl.08 - 1.20 (2H, m), 1.62 (1OH, bm), 2.54 - 2.60 (IH, m), 2.88 (IH, m), 3.50 - 3.86 (7H, m), 3.98 (IH, m), 6.61 (IH, s), 7.23 - 7.26 (IH, m), 7.42 - 7.46 (IH, m), 7.55 - 7.57 (IH, m) Example 37
(lR,2R)-2-{[4-(l,3-benzoxazol-2-yl)piperazin-l-yl]carbonyl}-JV-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000075_0001
Following Example 4, but starting with 2-piperazin-l-yl-l,3-benzoxazole (146 mg, 0.71 mmol) furnished the desired compound as a white foam (51.0 mg, 17 % yield). MS (+ve ESI) : 420, 422 (M+H)+
1R NMR (400.13 MHz, CDCl3) δl.09 - 1.76 (8H, m), 1.83 (4H, d), 2.55 - 2.62 (IH, m), 2.85 - 2.95 (IH, m), 3.53 - 3.83 (7H, m), 3.96 - 4.00 (IH, m), 6.54 (IH, s), 7.02 - 7.06 (IH, m), 7.15 - 7.19 (IH, m), 7.274 (IH, m), 7.35 - 7.38 (IH, m)
Example 38
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-{[4-(2-cyanophenyl)piperazin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000075_0002
Following Example 4, but starting with 2-piperazin-l-ylbenzonitrile (183 mg, 0.97 mmol) furnished the desired compound as a white solid (173 mg, 44 % yield). MS (+ve ESI) : 406 (M+H)+
1R NMR (400.13 MHz, CDCl3) δ 1.37 (8H, bm), 1.83 - 1.86 (4H, m), 2.60 - 2.66 (IH, m), 2.90 - 2.96 (IH, m), 3.08 - 3.44 (5H, m), 3.57 - 3.64 (IH, m), 3.95 (IH, d), 4.26 (IH, d), 6.80 (IH, s), 7.02 - 7.07 (2H, m), 7.47 - 7.52 (IH, m), 7.57 - 7.59 (IH, m) Example 39
N-{l-[((lR,2R)-2-{[(l- cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]piperidin-4-yl}benzamide
Figure imgf000076_0001
Following Example 4, but starting with 7V-piperidin-4-ylbenzamide (199 mg, 0.97 mmol) furnished the desired compound as a colorless gum (183 mg, 44 % yield). MS (+ve ESI) : 423 (M+H)+
1U NMR (400.13 MHz, CDCl3) δ 1.40 (1 IH, bm), 1.59 (IH, m), 1.99 - 2.03 (IH, m), 2.50 2.65 (2H, m), 2.85 - 2.91 (IH, m), 3.18 (4H, m), 4.00 (IH, m), 4.26 - 4.37 (IH, m), 4.58 (IH, m), 6.79 (IH, m), 6.92 (IH, s), 7.29 - 7.41 (3H, m), 7.65 - 7.72 (2H, m)
Example 40 (lR,2R)-2-({4-[l,3-benzothiazol-2-yl(methyl)amino]piperidin-l-yl}carbonyl)-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000076_0002
Following Example 4, but starting with 7V-methyl-7V-piperidin-4-yl- 1,3- benzothiazol-2-amine hydrochloride6 (100 mg, 0.35 mmol) and DIPEA (306 Dl, 1.75 mmol) furnished the desired compound as a colorless gum (58.0 mg, 36 % yield). MS (+ve ESI) : 466 (M+H)+
1U NMR (400.13 MHz, CDCl3) δ 1.10 - 2.04 (16H, m), 2.53 - 2.79 (2H, m), 2.91 (IH, m), 3.03 (3H, s), 3.16 - 3.29 (IH, m), 4.09 (IH, m), 4.54 (IH, m), 4.74 (IH, m), 6.66 - 6.94 (IH, m), 7.01 - 7.08 (IH, m), 7.28 - 7.31 (IH, m), 7.52 - 7.60 (2H, m) 6WO 2005003127 Example 41
(lR,2R)-N-(l-cyanocyclopropyl)-2-({4-[5-methyl-4-(trifluoromethyl)-l,3-thiazol-2- yl]piperazin-l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000077_0001
Following Example 4, but starting with l-[5-methyl-4-(trifluoromethyl)-l,3- thiazol-2-yl]piperazine hydrochloride (173 mg, 0.6 mmol) furnished the desired compound as a cream solid (222 mg, 79 % yield). MS (+ve ESI) : 470 (M+H)+
1H NMR (400.132 MHz, DMSOδ 0.98 (m, 2H), 1.14 - 1.45 (m, 6H), 1.64 - 1.81 (m, 4H), 2.37 - 2.48 (m, 4H), 2.90 (m, IH), 3.21 (m, IH), 3.36 - 3.49 (m, 4H), 3.55 - 3.80 (m, 3H), 8.76 (s, IH) l-[5-methyl-4-(trifluoromethyl)-l,3-thiazol-2-yl]piperazine hydrochloride To a mixture of tert-butyl 4-(aminocarbonothioyl)piperazine-l-carboxylate (200 mg, 0.82 mmol) and 3-bromo-l,l,l-trifluorobutan-2-one (204 mg, 0.99 mmol) in xylene (20 mL) was added triethylamine (454 μl, 3.26 mmol). The reaction mixture was refluxed (140 0C) for 16 hours and concentrated in vacuo. Purification by column chromatography eluting with isohexane to 25% ethyl acetate / isohexane gave a cream solid (210 mg). This was stirred in methanol reagent 10 (15 mL) at room temperature for 16 hours. Reaction mixture was concentrated to dryness to give a pale yellow solid (230 mg) which was used crude directly in the next step (230 mg, > 100 % yield) MS (-ve ESI) : 252 (M-H)+ Example 42
(lR,2R)-N-(l-cyanocyclopropyl)-2-({4-[5-(morpholin-4-ylmethyl)-l,3-thiazol-2- yl]piperazin-l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000078_0001
Following Example 4, but starting with 4-[(2-piperazin-l-yl-l,3-thiazol-5- yl)methyl]morpholine dihydrochloride (173 mg, 0.6 mmol) and 7V,7V-diisopropylethylamine (146 μl, 0.84 mmol, 2 equivalents) furnished the desired compound as a white solid (822 mg, 40 % yield). MS (-ve ESI) : 485 (M-H)+ 1U NMR (400.132 MHz, DMSO) δ 0.92 - 1.04 (m, 2H), 1.15 - 1.44 (m, 6H), 1.65 - 1.81 (m, 4H), 2.36 (m, 4H), 2.44 (m, IH), 2.91 (m, IH), 3.22 (m, IH), 3.31 - 3.47 (m, 4H), 3.50 - 3.79 (m, 9H), 7.01 (s, IH), 8.69 (s, IH) 4-[(2-piperazin-l-yl-l,3-thiazol-5-yl)methyl]morpholine dihydrochloride
To a solution of bis(dibenzylideneacetone)palladium (86 mg, 0.15 mmol) and tri-t- butylphosphonium tetrafluoroborate (23.0 mg, 0.08 mmol) in anhydrous toluene (6 mL) under an argon atmosphere was added 4-[(2-chloro-l,3-thiazol-5-yl)methyl]morpholine (656 mg, 3.00 mmol) followed by sodium tert-butoxide (317 mg, 3.30 mmol) then tert- butyl piperazine-1-carboxylate (558 mg, 3.00 mmol). The reaction mixture was heated at 8O0C under an argon atmosphere for 24 hours. The reaction mixture was diluted with EtOAc (100 mL), water (100 mL) and the layers separated. The aqueous layer was extracted with EtOAc (100 mL), the combined organics washed with water (100 mL) and dried (MgSO4) to give a crude gum. The crude material was purified by flash column chromatography (isohexane to ethyl acetate) to give pale yellow solid (157 mg). This was dissolved in methanol reagent 10 (10 mL) and allowed to stir at room temperature for 16 hours. Concentration in vacuo furnished the desired compound as a yellow gum (143 mg, 18% yield). MS (+ve ESI) : 269 (M+H)+
Example 43
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-{[4-(5-cyano-l,3-thiazol-2-yl)piperazin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000079_0001
Following Example 4, but starting with 2-piperazin-l-yl-l,3-thiazole-5-carbonitrile hydrochloride (165 mg, 0.71 mmol) furnished the desired compound as a white solid (167 mg, 62 % yield).
MS (+ve ESI) : 413 (M+H)+
1U NMR (400.132 MHz, DMSQ) δ 0.99 (m, 2H), 1.17 - 1.44 (m, 6H), 1.65 - 1.82 (m, 4H),
2.44 (m, IH), 2.92 (m, IH), 3.33 - 3.50 (m, 2H), 3.51 - 3.87 (m, 6H), 8.05 (s, IH), 8.72 (s,
IH) 2) 2-piperazin-l-yl-l,3-thiazole-5-carbonitrile i) To a solution of palladium (II) trifluoroacetate (66.0 mg, 0.20 mmol) and tri-t- butylphosphonium tetrafluoroborate (58.0 mg, 0.20 mmol) in anhydrous toluene (10 mL) under an argon atmosphere was added 2-bromo-l,3-thiazole-5-carbonitrile (756 mg, 4.00 mmol) followed by potassium phosphate tribasic (934 mg, 4.40 mmol) then tert-butyl piperazine-1-carboxylate (3.00 g, 16.00 mmol). The reaction mixture was heated at 8O0C for 16 hours. The reaction mixture was diluted with EtOAc (100 mL), water (100 mL) and the layers separated. The aqueous layer was extracted with EtOAc (100 mL), the combined organics washed with water (100 mL) and dried (MgSO4) to give a crude gum. The crude material was purified by flash column chromatography (isohexane to 50 % ethyl acetate then to ethyl acetate) to furnish the desired compound as a white solid (1.00 g, 85 % yield). MS (+ve ESI) (des Boc material) : 195 (M+H)+
1R NMR (400.13 MHz, CDCl3) δ 1.48 (s, 9H), 3.57 (m, 8H), 7.69 (s, IH) ii) A solution of tert-butyl 4-(5-cyano-l,3-thiazol-2-yl)piperazine-l-carboxylate (0.30 g, 1.02 mmol) in methanol reagent 10 (15 mL) was allowed to stir at room temperature for 64 hours. The reaction mixture was concentrated to furnish the desired compound as a white solid (308 mg, >100% yield). MS (+ve ESI) : 195 (M+H)+
Example 44 (l/f,2R)-2-({4-[5-chloro-4-(trifluoromethyl)-l,3-thiazol-2-yl]piperazin-l-yl}carbonyl)- iY-(l-cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000080_0001
Following Example 4, but starting with l-[5-chloro-4-(trifluoromethyl)-l,3-thiazol- 2-yl]piperazine hydrochloride (200 mg, 0.65 mmol) furnished the desired compound as a white solid (220 mg, 69 % yield).
MS (+ve ESI) : 490, 492 (M+H)+
1U NMR (400.132 MHz, DMSQ) δ 0.94 - 1.04 (m, 2H), 1.16 - 1.45 (m, 6H), 1.64 - 1.83
(m, 4H), 2.44 (m, IH), 2.91 (m, IH), 3.26 (m, IH), 3.37 - 3.54 (m, 4H), 3.57 - 3.84 (m, 3H), 8.71 (s, IH) l-[5-chloro-4-(trifluoromethyl)-l,3-thiazol-2-yl]piperazine
Following Example 43 part 2, but using 2-bromo-5-chloro-4-(trifluoromethyl)-l,3- thiazole (780 mg, 2.8 mmol) furnished the desired compound as a yellow solid (474 mg, 62
% yield). MS (+ve ESI) : 272, 274 (M+H)+ 2-br omo-5-chlor o-4-(trifluoromethyl)- 1 ,3-thiazole
To a solution of 5-chloro-4-(trifluoromethyl)-l,3-thiazol-2-amine (3.00 g, 14.81 mmol) in anhydrous acetonitrile (25 mL) at 0 0C under an argon atmosphere was slowly added (5 mins) tert-butyl nitrite and the reaction mixture allowed to stir for 10 mins at 0 0C. To the cooled reaction mixture was added copper (II) bromide (4.0O g, 17.8 mmol) portionwise and the reaction mixture was allowed to warm to room temperature then heated at 80 0C under an argon atmosphere for 90 mins. The reaction mixture was diluted with DCM (100 mL) and washed with IN HCl (100 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were washed with brine (50 mL) and dried (MgSO4) to give a dark crude oil. The crude material was purified by flash chromatography (isohexane to 20 % DCM) to furnish the desired compound as an orange oil (0.78 g, 20 % yield) which was used crude in the next step.
Example 45 (l/f,2R)-ΛL(l-cyanocyclopropyl)-2-({4-[3-fluoro-4-(methylsulfonyl)phenyl]piperazin- l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000081_0001
Following Example 4, but starting with l-[3-fluoro-4- (methylsulfonyl)phenyl]piperazine hydrochloride (162 mg, 0.55 mmol) in DMF (15 mL) furnished the desired compound as a white solid (20.0 mg, 8 % yield).
MS (+ve ESI) : 477 (M+H)+
1H NMR (400.13 MHz, CDCl3) δl.13 - 1.17 (IH, m), 1.26 (IH, m), 1.32 (2H, m), 1.38 -
1.46 (2H, m), 1.49 - 1.52 (IH, m), 1.61 (IH, m), 1.80 - 1.83 (4H, m), 2.55 (IH, t), 2.88 (IH, t), 3.15 (3H, s), 3.16 - 3.19 (IH, m), 3.39 (2H, m), 3.45 (2H, m), 3.61 (2H, m), 3.81-
4.00 (IH, m), 6.35 (IH, s), 6.53 - 6.57 (IH, dd), 6.62 - 6.65 (IH, dd), 7.74 (IH, dd) 2) l-[3-fluoro-4-(methylsulfonyl)phenyl]piperazine
2,4-difluoro-l-(methylsulfonyl)benzene (1.00 g, 5.21 mmol) , tert-butyl piperazine- 1-carboxylate (1.00 g, 5.7 mmol) and K2CO3 (863 mg, 6.2 mmol) were heated to 100 0C in dry DMF (20 mL) for 18 hours. The mixture was cooled and concentrated under reduced pressure to yield a white solid. This was dissolved in water (80 mL) and extracted with EtOAc (2 x 80 mL). The organic extracts were combined, washed with H2O (40 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo to yield a white solid (1.07 g, 57 % yield). The solid was stirred in a solution of HCl in MeOH (reagent 10) (25 mL) for 3 hours. The solution was filtered and the resultant solid washed with methanol (5 mL) to furnish the desired compound as a white solid (610 mg, 40 % yield) that was used directly in the next reaction. MS (+ve ESI) : 259 (M+H)+
Example 46
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-({4-[4-(ethylsulfonyl)-2-fluorophenyl]piperazin-l- yl}carbonyl)cyclohexanecarboxamide
Figure imgf000082_0001
Following Example 4, but starting with l-[4-(ethylsulfonyl)-2- fluorophenyljpiperazine hydrochloride (31.0 mg, 0.1 mmol) furnished the desired compound as a white solid (10.0 mg, 20 % yield). MS (+ve ESI) : 491 (M+H)+
1U NMR (400.13 MHz, CDCl3) δ 1.14 (IH, m), 1.16 (IH, m), 1.25 - 1.32 (8H, m), 1.33 (IH, m), 1.42 - 1.43 (IH, m), 1.49-1.61 (2H, m), 1.82 (4H, m), 2.52 (IH, m), 2.89 (IH, m), 3.08 (2H, q), 3.10-3.26 (2H, m), 3.28 (IH, m), 3.51-3.63 (IH, m), 3.82-4.10 (IH, m), 6.39 (IH, s), 6.99 (IH, m), 7.51 - 7.52 (IH, m), 7.55 - 7.60 (IH, m) 2) l-[4-(ethylsulfonyl)-2-fluorophenyl]piperazine
Following Example 45, part 2, but starting with 3,4-difluorophenyl ethyl sulfone (1.07 g, 5.21 mmol) furnished the desired compound as a white solid (790 mg, 55 % yield) that was used directly in the next reaction. MS (+ve ESI) : 273 (M+H)+
Example 47
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-({4-[2-fluoro-4-(methylsulfonyl)phenyl]piperazin- l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000083_0001
Following Example 4, but starting with l-[2-fluoro-4- (methylsulfonyl)phenyl]piperazine hydrochloride (162 mg, 0.55 mmol) furnished the desired compound as a white solid (47.0 mg, 18 % yield). MS (+ve ESI) : 477 (M+H)+
1U NMR (400.13 MHz, CDCl3) δl.12 - 1.18 (2H, m), 1.26 (2H, m), 1.42 - 1.44 (2H, m), 1.51 (IH, m), 1.60 (IH, m), 1.82 (4H, m), 2.51 (IH, t), 2.89 (IH, t), 3.02 (3H, s), 3.17 (IH, d), 3.25 - 3.29 (3H, m), 3.45-3.62 (2H, m), 3.86-4.10 (IH, m), 6.44 (IH, s), 7.00 (IH, dd), 7.60 (IH, dd), 7.61 (IH, dd)
2) l-[2-fluoro-4-(methylsulfonyl)phenyl]piperazine hydrochloride
Following example 45 part 2, but starting with 3,4-difluorophenyl methyl sulfone (1.05 g, 5.21 mmol) furnished the desired compound as a white solid (640 mg, 55 % yield) that was used directly in the next reaction. MS (+ve ESI) : 259 (M+H)+ Example 48
(lR,2R)-Λ/-(l-cyanocyclopropyl)-2-({4-[4-(trifluoromethyl)-l,3-thiazol-2-yl]piperazin- l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000084_0001
Following Example 4, but starting with l-[4-(trifluoromethyl)-l,3-thiazol-2- yl]piperazine hydrochloride (151 mg, 0.55 mmol) furnished the desired compound as a white solid (48.0 mg, 27 % yield).
MS (+ve ESI) : 456 (M+H)+
1U NMR (400.13 MHz, CDCl3) δ 1.10 -1.62 (8H, m), 1.82 (4H, m), 2.52 - 2.59 (IH, m), 2.96 (IH, m), 3.49 - 3.65 (6H, m), 3.81 (IH, m), 3.90 - 3.95 (IH, m), 6.65 (IH, s), 7.01 -
7.01 (IH, m)
2) l-[4-(trifluoromethyl)-l,3-thiazol-2-yl]piperazine hydrochloride
4-(4-trifluoromethyl-thiazol-2-yl)-piperazine-l-carboxylic acid tert-butyl ester (201 mg, 0.82 mmol), l,l,l-trifiuoro-3-bromoacetone (107 μl, 1.03 mmol) and triethylamine (474 μl, 3.28 mmol) in xylene (20 mL) were refiuxed for 18 hours. The solution was cooled to room temperature and the solvent removed under reduced pressure. The product was purified by HPLC (the compound was diluted with Acetonitrile/H2θ; filtered; pH adjusted to >9 with NH3, injected onto a Waters 100mm x 19mm XBridge C18 5μ column; flow 16mLs/min; Solvent A = 0.1%NH3/Water, Solvent B = CH3CN; λ=230nm) to afford the desired compound as a brown solid (151 mg). This compound was stirred in Methanol
10 (15 mL) for 6 hours and the solvent was removed under reduced pressure to furnish the desired compound as an off-white solid (107 mg, 54 % yield).
MS (+ve ESI) : 239 (M+H)+ 1H NMR (400.13 MHz, CDCl3) 53.38 (4H, m), 3.92 (4H, m), 7.12 (IH, s), 10.18 (2H, s)
Example 49
(lR,2R)-2-{[4-(lH-benzimidazol-2-yl)piperazin-l-yl]carbonyl}-JV-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000085_0001
Following Example 4, but starting with 2-piperazin-l-yl-lH-benzimidazole (213 mg, 1.05 mmol) furnished the desired compound as a white solid (108 mg, 25 % yield). MS (+ve ESI) : 421 (M+Η)+
1U NMR (400.13 MHz, CDCl3) δl.08 - 1.19 (2H, m), 1.25 -1.50 (7H, m), 1.80 - 1.84 (4H, m), 2.54 - 2.60 (IH, m), 2.88 - 2.94 (IH, m), 3.55 - 3.63 (2H, m), 3.66 (IH, m), 3.67 (IH, s), 3.77 - 3.78 (IH, m), 3.92 - 3.97 (IH, m), 6.64 (IH, s), 7.08 (2H, m), 7.28 (2H, m)
Example 50
(lR,2R)-ΛL(l-cyanocyclopropyl)-2-({4-[3-cyano-6-(4-fluorophenyl)pyridin-2- yl]piperazin-l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000085_0002
To a solution of (3ai?,7ai?)-hexahydro-2-benzofuran-l,3-dione (0.10 g, 0.65 mmol) in DCM (3 mL) was added 6-(4-fluorophenyl)-2-piperazin-l-ylnicotinonitrile hydrochloride (207 mg, 0.65 mmol) and Λ/-methylmorpholine (71 μl, 0.65 mmol, 1 equivalent). This was allowed to stir at room temperature for 2 hours. To the reaction mixture was added N-methylmorpholine (0.21 mL, 1.95 mmol), isobutyl chloro formate (93 μl, 0.71 mmol) dropwise and l-aminocyclopropanecarbonitrile (0.10 g, 0.84 mmol). The reaction mixture was heated in the microwave at 120 0C for 45 mins. The reaction mixture was diluted with DCM (50 mL), washed with water (30 mL), then the organic layer was passed through a phase separation cartridge and concentrated in vacuo to give a crude gum. The crude gum was purified by reverse phase HPLC (0.1% formic acid/water: acetonitrile; λ=254nm t) to give a white solid (72 mg, 22 % yield). MS (+ve ESI) : 501 (M+H)+
1R NMR (400.132 MHz, DMSQ) δ 0.95 - 1.77 (m, 12H), 2.33 (m, IH), 3.15 (m, IH), 3.49 - 3.87 (m, 8H), 7.36 (t, 2H), 7.56 (d, IH), 8.16 - 8.24 (m, 3H), 8.35 (s, IH)
2) 6-(4-fluorophenyl)-2-piperazin-l-ylnicotinonitrile hydrochloride i) To a solution of 2-chloro-6-(4-fiuorophenyl)nicotinonitrile (337 mg, 1.45 mmol) and tert-butyl piperazine-1-carboxylate (297 mg, 1.60 mmol) in DMSO (1 mL) was added N, 7V-diisopropylethylamine (0.50 mL, 2.90 mmol) and the reaction mixture heated at 75 0C for 16 hours. The reaction mixture was diluted with water and the precipitate was filtered off and washed with water. The precipitate was redissolved in DCM, dried by passing through a phase separation cartridge and concentrated in vacuo to furnish the desired compound as a yellow solid (528 mg, 95 % yield). 1R NMR (400.13 MHz, CDCl3) δ 1.49 (s, 9H), 3.63 (m, 4H), 3.78 (m, 4H), 7.16 (t, 2H), 7.22 (d, IH), 7.85 (d, IH), 8.01 (m, 2H) ii) Tert-butyl 4-[3-cyano-6-(4-fluorophenyl)pyridin-2-yl]piperazine- 1 -carboxylate (528 mg, 1.45 mmol) in methanol reagent 10 (25 mL) was allowed to stir at room temperature for 5 days, and then heated at 60 0C for 2 hours. The reaction mixture was concentrated to give a pale yellow solid (481 mg, >100 % yield).
Example 51
(l/f,2/f)-Λ/-(l-cyanocyclopropyl)-2-({4-[3-cyano-6-(trifluoromethyl)pyridin-2- yl]piperazin-l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000087_0001
Following Example 4 but starting with 2-piperazin-l-yl-6-
(trifluoromethyl)nicotinonitrile hydrochloride (190 mg, 0.65 mmol) furnished the desired compound as a white solid (71 mg, 23 % yield). MS (+ve ESI) : 475 (M+H)+
1U NMR (400.132 MHz, DMSQ) δ 0.95 - 1.11 (m, 2H), 1.22 - 1.83 (m, 10H), 2.33 (m, IH), 3.13 (m, IH), 3.45 - 3.89 (m, 8H), 7.34 (d, IH), 8.35 (s, IH), 8.39 (d, IH)
2) 2-piperazin-l-yl-6-(trifluoromethyl)nicotinonitrile hydrochloride Following Example 50 part 2 but starting with 2-chloro-6-
(trifluoromethyl)nicotinonitrile (300 mg, 1.45 mmol) furnished the desired compound as a yellow solid (420 mg, 99 % yield)
MS (+ve ESI) : 257 (M+H)+
1R NMR (400.132 MHz, DMSQ) δ 3.25 (m, 4H), 3.91 (m, 4H), 7.45 (d, IH), 8.46 (d, IH), 9.57 (m, 2H)
Example 52 (lRjlRJ-N^l-cyanocyclopropylJ-l-^-β-^rifluoromethylJquinoxalin-Z-yllpiperazin- l-yl}carbonyl)cyclohexanecarboxamide
Figure imgf000087_0002
Following Example 4 but starting with 2-piperazin-l-yl-3-
(trifluoromethyl)quinoxaline hydrochloride (207 mg, 0.65 mmol) furnished the desired compound as a yellow gum (204 mg, 62 % yield). MS (+ve ESI) : 501 (M+H)+ 1R NMR (400.132 MHz, DMSQ) δ 0.88 - 1.11 (m, 2H), 1.15 - 1.54 (m, 6H), 1.59 - 2.04 (m, 4H), 2.34 - 2.49 (m, IH), 2.95 (m, IH), 3.32 (m, IH), 3.36 - 3.83 (m, 7H), 7.75 (m, IH), 7.92 (m, 2H), 8.09 (d, IH), 8.74 (s, IH) 2) 2-piperazin-l-yl-3-(trifluoromethyl)quinoxaline hydrochloride
Following Example 50 part 2, but starting with 2-chloro-3- (trifluoromethyl)quinoxaline (337 mg, 1.45 mmol) furnished the desired compound as a yellow solid (447 mg, 96 % yield) MS (+ve ESI) : 283 (M+H)+
1U NMR (400.132 MHz, DMSQ) δ 3.28 (s, 4H), 3.61 (t, 4H), 7.80 (m, IH), 7.95 (m, 2H), 8.13 (d, IH), 9.36 - 9.70 (m, 2H)
Example 53
(lR,2R)-ΛL(l-cyanocyclopropyl)-2-[(4-furo[3,2-c]pyridin-4-ylpiperazin-l- yl)carbonyl]cyclohexanecarboxamide
Figure imgf000088_0001
Following Example 4 but starting with 4-piperazin-l-ylfuro[3,2-c]pyridine (132 mg, 0.65 mmol) furnished the desired compound as a white solid (144 mg, 53 % yield). MS (+ve ESI) : 422 (M+H)+
1R NMR (400.132 MHz, DMSQ) δ 0.92 - 1.05 (m, 2H), 1.18 - 1.45 (m, 6H), 1.66 - 1.81 (m, 4H), 2.44 (m, IH), 2.92 (m, IH), 3.53 (d, 2H), 3.61 - 3.78 (m, 6H), 7.07 (m, IH), 7.20 (m, IH), 7.98 (m, 2H), 8.73 (s, IH) Example 54
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-{[4-(l,3-thiazol-2-yl)piperazin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000089_0001
Following Example 4 but starting with l-(l,3-thiazol-2-yl)piperazine hydrochloride
(133 mg, 0.65 mmol) furnished the desired compound as a white solid (90.0 mg, 36 % yield).
MS (+ve ESI) : 388 (M+H)+
1H NMR (400.13 MHz, DMSO) δ 0.93 - 1.03 (m, 2H), 1.15 - 1.43 (m, 6H), 1.65 - 1.82 (m, 4H), 2.45 (m, IH), 2.92 (m, IH), 3.26 (m, IH), 3.35 - 3.53 (m, 4H), 3.56 - 3.80 (m, 3H),
6.88 (d, IH), 7.19 (d, IH), 8.69 (s, IH)
Example 55
(lR,2R)-2-{[4-(4-fert-butyl-l,3-thiazol-2-yl)piperazin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000089_0002
To a solution of anhydride (99 mg, 0.64 mmol) in DCM (4 mL) was added thiazole piperazine hydrochloride (168 mg, 0.64 mmol) followed by 7V,7V-diisopropylethylamine (112 uL, 0.64 mmol, 1 equivalent) and allowed to stir at room temperature for 16 hours. LCMS shows reaction gone to completion (MH+ 378). To the reaction mixture was added HATU (341 mg, 0.90 mmol) and 7V,7V-diisopropylethylamine (334 ul, 1.92 mmol) followed by cyclopropyl nitrile hydrochloride (99 mg, 0.83 mmol), the allowed to stir at room temperature for 16 hours. LCMS shows reaction gone to completion. The reaction mixture was diluted with DCM (50 mL), washed with water (30 mL), then the organic layer was passed through a phase separation cartridge and concentrated in vacuo to give a crude gum. The crude gum was purified by reverse phase HPLC (basic) to give a white solid (186 mg, 66%).
MS (+ve ESI) : 444.3 (M+H)+
1R NMR (400.132 MHz, DMSQ) δ 0.92 - 1.07 (m, 2H), 1.22 (s, 9H), 1.24 - 1.46 (m, 6H),
1.64 - 1.81 (m, 4H), 2.44 (m, IH), 2.90 (m, IH), 3.21 (m, IH), 3.31 (m, IH), 3.39 - 3.53
(m, 3H), 3.59 - 3.76 (m, 3H), 6.41 (s, IH), 8.74 (s, IH) l-(4-tørM)utyl-l,3-thiazol-2-yl)piperazine
Figure imgf000090_0001
To a mixture of tert-butyl 4-(aminocarbonothioyl)piperazine-l-carboxylate (0.20 g, 0.82 mmol) and 1-bromopinacolone (134 uL, 0.99 mmol) in xylene (20 mL) was added triethylamine (454 ul, 3.26 mmol). The reaction mixture was refluxed (140 0C) for 16 hours. The reaction mixture was concentrated in vacuo and the residue purified by reverse phase HPLC (basic) to give a light brown solid (207 mg,Yield 78%). MS (+ve ESI) : 326.3 (M+H)+
1R NMR (400.132 MHz, CDCl3.) δ 1.26 (s, 9H), 1.48 (s, 9H), 3.43 (m, 4H), 3.55 (m, 4H), 6.16 (s, IH) tert-butyl 4-(4-tøfγ-butyl-l,3-thiazol-2-yl)piperazine-l-carboxylate
Figure imgf000090_0002
A solution of l-(4-tøt-butyl-l,3-thiazol-2-yl)piperazine (207 mg, 0.64 mmol) in methanol reagent 10 (15 mL) was allowed to stir at room temperature for 16 hours. Reaction mixture was concentrated in-vacuoϊo dryness to give a dark green solid (187 mg).
Yield 100%.
MS (+ve ESI) : 226 (M+H)+
Examples 56
(lR,2R)-N-(l-cyanocyclopropyl)-2-[4-(6-methylsulfonylbenzothiazol-2-yl)piperazine- l-carbonyl]cyclohexane-l-carboxamide
Figure imgf000091_0001
6-methylsulfonyl-2-piperazin-l-yl-benzothiazole (446 mg; 1.5 mmol) and (3aR,7aR)- 3a,4,5,6,7,7a-hexahydroisobenzofuran-l,3-dione (231 mg; 1.5 mmol) were stirred in DMF (10 mL) at room temperature for 3 hours. LCMS analysis indicated complete conversion to the intermediate acid. 1 -amino- 1-cylcopropanecarbonitrile-HCl (213 mg, 1.80 mmol), DIPEA (1046 uL ; 6.00 mmol) and HATU (684 mg; 1.80 mmol) were added and the mixture allowed to stir overnight. The solution was partitioned between brine (50 mL) and ethyl acetate (80 mL), organic extract dried (Na2SO4), filtered and evaporated to an oil, this was purified by flash chromatography on a 2Og silica column eluting with CH2Cl2 to 5% MeOH/CH2Cl2 to give (li?,2i?)-7V-(l-cyanocyclopropyl)-2-[4-(6- methylsulfonylbenzothiazol-2-yl)piperazine- 1 -carbonyljcyclohexane- 1 -carboxamide (762 mg; 91% based on 93% strength) as a white foam MS (+ve ESI) : 516 (M+H)+ 2-bromo-6-methylsulfonyl-benzothiazole
Figure imgf000091_0002
To a solution of tert-Butyl Nitrite (3.84 mL;32.9 mmol) and copper bromide (5.87g; 26.3 mmol) in anhydrous acetonitrile (50 mL) at 60 0C was added 6- methylsulfonylbenzothiazol-2-amine (5.00 g, 21.9 mmol) portion wise. The reaction was then heated at 60 0C for 3 hours. The reaction was allowed to cool, partitioned between dichloromethane (300 mL) and IM hydrochloric acid (100 mL), filtered to remove insoluble material, organic extract dried (Na2SO4), filtered and evaporated to give 2- bromo-6-methylsulfonyl-benzothiazole (2.15 g; 33%) as a yellow crystalline solid. MS (+ve ESI) : 293 (M+H)+ IH NMR (400.13 MHz, DMSO-d6) 53.30 (3H, s), 8.05 - 8.07 (IH, m), 8.24 (IH, d), 8.82 (IH, d)
6-methylsulfonyl-2-piperazin-l-yl-benzothiazole
Figure imgf000092_0001
To a suspension of 2-bromo-6-methylsulfonyl-benzothiazole (2.10 g; 7.19 mmol) in
IPA (50 mL) was added piperazine (3.09 g; 36.0 mmol) and the reaction heated at 100 0C for 2 hours, reaction complete by LCMS. The reaction was evaporated to a paste, partitioned with ethyl acetate (100 mL) and water (50 mL), organic extract washed with a saturated solution of sodium bicarbonate (50 mL), organic extract dried (Na2SO4) filtered and evaporated to give 6-methylsulfonyl-2-piperazin-l-yl-benzothiazole (1.86g ; 87%) MS (+ve ESI) : 298 (M+H)+
IH NMR (400.13 MHz, DMSO-d6) 52.82 - 2.84 (4H, m), 3.19 (3H, s), 3.57 (4H, m), 7.57 (IH, d), 7.76 - 7.78 (IH, m), 8.37 (IH, d)
Example 57
(lR,2R)-N-(l-cyanocyclopropyl)-2-[4-(4-tert-butylphenyl)piperazine-l- carbonyl]cyclohexane-l-carboxamide
Figure imgf000093_0001
Following Example 4 except using l-(4-tert-butylphenyl)piperazine (225 mg, 1.03 mmol) and (3aR,7aR)-3a,4,5,6,7,7a-hexahydroisobenzofuran-l,3-dione (159 mg, 1.03 mmol) were stirred in DMF (5mL) at 50 0C for 3 hours, gave (1R,2R)-7V-(1- cyanocyclopropyl)-2-[4-(4-tert-butylphenyl)piperazine-l-carbonyl]cyclohexane-l- carboxamide (145 mg ; 32%) as a cream foam, after purification.
MS (+ve ESI) : 437 (M+H)+
IH NMR (400.13 MHz, CDC13) δl.10 - 1.5 (1OH, m), 1.29 (9H, s), 2.58 (IH, m), 2.89 (IH, m), 3.10 - 3.23 (4H, m), 3.63 - 3.80 (4H, m), 6.61 (IH, s), 6.86 - 6.88 (2H, m), 7.28 -
7.30 (2H, m)
Example 58
(lR,2R)-N-(l-cyanocyclopropyl)-2-{[4-(6,7-dihydro-4H-pyrano[4,3-</] [l,3]thiazol-2- yl)piperazin-l-yl]carbonyl}cyclohexanecarboxamide
Figure imgf000093_0002
Following Example 4 expect using 8-piperazin-l-yl-3-oxa-9-thia-7- azabicyclo[4.3.0]nona-7,10-diene (390 mg, 1.73 mmol) and (3aR,7aR)-3a,4,5,6,7,7a- hexahydroisobenzofuran-l,3-dione (267 mg, 1.73 mmol) were stirred in DMF (5 mL) at room temperature for 2 hours. 1 -Amino- 1-cylcopropanecarbonitrile-HCl (247 mg, 2.08 mmol), DIPEA (1.21 mL; 6.93 mmol) and HATU (791 mg; 2.08 mmol) were added and the mixture allowed to stir overnight to give (lR,2R)-7V-(l-cyanocyclopropyl)-2-[4-(3- oxa-9-thia-7-azabicyclo[4.3.0]nona-7, 10-dien-8-yl)piperazine-l -carbonyl]cyclohexane-l - carboxamide (330 mg ; 43%) as a foam after purification MS (+ve ESI) : 444 (M+H)+
1R NMR (400.13 MHz, CDCl3) δl.39 (12H, m), 2.54 - 2.61 (IH, m), 2.70 - 2.72 (2H, m), 2.86 - 2.92 (IH, m), 3.43 - 3.89 (8H, m), 3.98 (2H, t), 4.66 (2H, t), 6.57 (IH, s) 4-(6,7-Dihydro-4H-pyrano [4,3-d] thiazoH-ylJ-piperazine-l-carboxylic acid tert-butyl ester
Figure imgf000094_0001
4-Thiocarbamoyl-piperazine-l-carboxylic acid tert-butyl ester (500 mg; 2.04 mmol) and 3-bromo-tetrahydro-pyran-4-one (446 mg; 2.49 mmol) [WO 2004/041161] were stirred in toluene (10 mL) and triethylamine (1.13 mL; 8.15 mmol) added, the reaction was heated at 110 0C until reaction complete by LCMS analysis. The reaction was evaporated to dryness and the residue purified by flash chromatography on a 1Og silica Isolute eluting with 10-20% ethyl acetate in hexane to yield 4-(6,7-dihydro-4H-pyrano[4,3- d]thiazol-2-yl)-piperazine-l-carboxylic acid tert-butyl ester (505mg ; 76%) MS (+ve ESI) : 326 (M+H)+ 1R NMR (400.13 MHz, CDCl3) δl.48 (9H, s), 2.70 - 2.73 (2H, m), 3.40 - 3.43 (4H, m), 3.54 - 3.56 (4H, m), 3.98 (2H, t), 4.66 (2H, t) 2-Piperazin- l-yl-6,7-dihydro-4H-pyrano [4,3-d] thiazole
Figure imgf000094_0002
4-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-piperazine-l-carboxylic acid tert- butyl ester (500 mg; 1.54 mmol) was stirred in HCl in methanol (about 1OM; 10 mL) for 18 hours, reaction evaporated and the residue taken up in DCM (100 mL) and washed with a saturated bicarbonate solution (50 mL), organic extract dried (Na2SO4), filtered and evaporated to give 2-piperazin-l-yl-6,7-dihydro-4H-pyrano[4,3-d]thiazole (394 mg; 20% DCM; 91% yield based on strength). MS (+ve ESI) : 226 (M+H)+
1R NMR (400.13 MHz, CDCl3) 52.00 (IH, s), 2.70 - 2.73 (2H, m), 2.98 - 3.00 (4H, m), 3.41 - 3.44 (4H, m), 3.98 (2H, t), 4.66 (2H, t)
Example 59
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-({4-[4-(l-cyano-l-methylethyl)phenyl]piperazin-l- yl}carbonyl)cyclohexanecarboxamide
Figure imgf000095_0001
(3aR,7aR)-3a,4,5,6,7,7a-hexahydroisobenzofuran-l,3-dione (2.00 g, 13.0 mmol) (\R,2R)-2-( {4-[4-( 1 -cyano- 1 -methylethyl)phenyl]piperazin- 1 - yl}carbonyl)cyclohexanecarboxylic acid (2.98 g, 13.0 mmol) were stirred in DMF (20 mL) at room temperature for 3 hours. The solvent was removed under reduced pressure to give the desired product as a white solid (4.80 g). DMF (30 mL) was added then 1-Amino-l- cyclopopancarbonitrile (2.07 g, 17.5 mmol), mmol), DIPEA (8.7 mL, 50 mmol) and HATU (6.65 g, 17.5 mmol) were the added and the reaction were allowed to stir at room temperature overnight. The solution subjected to HPLC (x 3 runs block 14 large scale baseprep, Solvent A = 0.1%NH3/Water, Solvent B = CH3CN; λ=230 nm). The product fractions were combined and the solvent removed under reduced pressure to afford the desired product as a white foam (3.00g, 51%). MS (+ve ESI) : 448 (M+H)+ 1H NMR ^OO- B MHZ5 CDCI3) OI .09 - 1.20 (2H, m), 1.32 (2H, m), 1.39 - 1.45 (2H, m), 1.48 - 1.51 (IH, m), 1.53-1.62 (2H, m), 1.69 (6H, s),1.84 (3H, m), 2.60 (IH, t), 2.87 - 2.94 (IH, t), 3.18 (3H, m), 3.25 - 3.30 (IH, m), 3.64 - 3.69 (2H, m), 3.76 - 3.81 (IH, m), 3.84 - 3.90 (IH, m), 6.65 (IH, s), 6.91 (2H, dd), 7.35 (2H, dd) (l/?,2/?)-2-({4-[4-(l-cyano-l-methylethyl)phenyl]piperazin-l- yl}carbonyl)cyclohexanecarboxylic acid was synthesized in the following manner. 2-(4-bromophenyl)-2-methylpropanenitrile
Figure imgf000096_0001
To a solution of sodium hydride (60%, 5.50 g, 137.9 mmol) in THF (50 mL) at 00C was slowly added 4-bromophenylacetonitrile (10.0 g, 51.0 mmol) followed by methyl iodide (8.58 mL, 137.8 mmol). The reaction was allowed to warm to room temperature and stirred overnight. The starting material had disappeared so magnesium sulphate (10 g) was added to the mixture and the solids filtered off. The solvent was removed in vacuo and the resultant solid partitioned between ethyl acetate (200 mL) and water (150 mL). The organic layer separated and the solvent removed under reduced pressure to afford a yellow oil, this was subjected to flash column chromatography (30-50% ethyl acetate in isoheaxane). The fractions were reduced under reduced pressure to afford the desired product as a yellow oil (8.06 g, 71%). 1U NMR (400.13 MHz, CDCl3) δl.70 (6H, s), 7.33 - 7.36 (2H, m), 7.49 - 7.52 (2H, m) 2-methyl-2-(4-piperazin-l-ylphenyl)propanenitrile
Figure imgf000096_0002
A mixture of 2-(4-bromophenyl)-2-methylpropanenitrile (8.00 g, 36.0 mmol), piperazine (19.3 g, 108 mmol), sodium-tert-butoxide (4.84 g, 50.4 mmol), Pd2(dba)3 (659 mg, 0.72 mmol) and BINAP (1.12 g, 1.80 mmol) in toluene (100 mL) was heated to 80 0C under argon. The mixture was stirred for 18 hours. The mixture was allowed to cool to room temperature and the solid removed by filtration. The solvent was removed under reduced pressure and the resultant crude mixture dissolved in DCM and purified by flash column chromatography (x 2 batches, 120 g silica columns, 1-35% MeOH in DCM). The relevant fractions were combined and the solvent removed under reduced pressure to 5 afford the desired product as a yellow solid (6.30 g, 76%). LCMS retention time 1.78 min (+ve ESI) : 230 (M+H)+
Example 60
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-[(4-[l,3]thiazolo[5,4-6]pyridin-2-ylpiperazin-l- i o yl)carbonyl] cyclohexanecarboxamide
Figure imgf000097_0001
In a similar manner to example 59 except starting with 2-piperazin-l- yl[l,3]thiazolo[5,4-ό]pyridine yielded the example compound as a white foam. (21.0 mg, is 24%).
MS (+ve ESI) : 439 (M+H)+
1R NMR (400.13 MHz, CDCl3) δ 1.10 - 1.22 (3H, m), 1.25 (IH, t), 1.33 (IH, m), 1.44 - 1.46 (2H, m), 1.51 - 1.54 (IH, m), 1.84 (4H, m), 2.54 - 2.59 (IH, m), 2.91 (IH, t), 3.58 - 3.67 (3H, m), 3.72 - 3.75 (IH, m), 3.76 - 3.83 (2H, m), 3.78 - 3.85 (IH, m), 3.99 - 4.03
20 (IH, m), 6.42 (IH, s), 7.21 - 7.25 (IH, m), 7.71 - 7.73 (IH, m), 8.20 - 8.21 (IH, m) 2-piperazin-l-yl[l,3]thiazolo[5,4-6]pyridine was synthesized by the method below. 2-(methylsulfonyl) [ 1 ,3] thiazolo [5,4-6] pyridine
Figure imgf000097_0002
To a solution of 8-methylsulfanyl-7-thia-5,9-diazabicyclo[4.3.0]nona-l,3,5,8- tetraene (100 mg; 0.55 mmol) in acetic acid (2.5 mL) was added a solution of potassium permanganate (174 mg; 1.10 mmol) in water (1.5 mL) maintaining a temperature of 10-20 0C with an ice bath. After the addition a saturated solution of sodium sulphite (1 mL) was
5 added followed by 20% ammonium hydroxide (5 mL), filtered to remove insoluble and extracted with ethyl acetate (10 mL), organic extract dried (Na2SO4), filtered and evaporated to give 2-(methylsulfonyl)[l,3]thiazolo[5,4-ό]pyridine (65 mg ; 30%) IH NMR (400.13 MHz, CDC13) 53.43 (3H, s), 7.61 - 7.64 (IH, m), 8.47 - 8.49 (IH, m), 8.79 - 8.81 (IH, m) i o 2-piperazin- 1-yl [ 1 ,3] thiazolo [5,4-6] pyridine
Figure imgf000098_0001
2-(methylsulfonyl)[l,3]thiazolo[5,4-ό]pyridine (65.0 mg, 0.30 mmol) and piperazine (258 mg, 3 mmol) were stirred in DMF (5 mL) at 60 0C for 18 hours. The solvent was removed under reduced pressure and the resultant solid subjected to flash column is chromatography (1-10% MeOH in DCM) to yield the product as an off- white solid (45 mg).
Example 61
(lR,2R)-N-(l-cyanocyclopropyl)-2-{[4-(5,6-dihydro-4H-cyclopenta[(/] [l,3]thiazol-2- 20 yl)piperazin-l-yl]carbonyl}cyclohexanecarboxamide
In a similar manner to Example 59, except starting with 2-piperazin-l-yl-5,6-dihydro-
4H-cyclopenta[J][l,3]thiazole (72.0 mg, 0.29 mmol) to give a white/colourless glass/film
(76.0 mg, 46%)
MS (+ve ESI) : 428 (M+H)+ 1R NMR (400.132 MHz, DMSO) δ 0.91 - 1.04 (m, 2H), 1.13 - 1.45 (m, 7H), 1.63 - 1.81
(m, 4H), 2.30 (m, 2H), 2.43 (m, IH), 2.58 (t, 2H), 2.74 (t, 2H), 2.91 (m, IH), 3.18 (m, IH),
3.42 (m, 3H), 3.59 (m, IH), 3.71 (m, 2H), 8.74 (s, IH)
2-piperazin-l-yl-5,6-dihydro-4H-cyclopenta[(/] [l,3]thiazole was synthesized in the following manner: tert-butyl 4-(aminocarbonothioyl)piperazine-l-carboxylate
Figure imgf000099_0001
To a solution of l,l '-thiocarbonyldiimidazole (2.20 g, 12.3 mmol) in anhydrous TΗF (30 mL) was added tert-butyl 1-piperazinecarboxylate (2.00 g, 10.7 mmol) and allowed to stir at room temperature for 2 hours then heated at 55 0C for 1 hour. The reaction mixture was concentrated in vacuo to about half the volume. To the remaining reaction mixture was added a 2M solution of ammonia in methanol (20 mL) and allowed to stir at room temperature for 64 hours. The reaction mixture was concentrated in vacuo and the residue was triturated with diethyl ether to give a cream solid (1.13 g, 43.0%). MS (+ve ESI) : 244 (M+Η)+
1R NMR (400.132 MHz, CDCl3.) δ 1.47 (s, 9H), 3.55 (m, 4H), 3.85 (s, 4H), 5.82 (s, 2H) tert-butyl 4-(5,6-dihydro-4H-cyclopenta[</] [l,3]thiazol-2-yl)piperazine-l-carboxylate
Figure imgf000100_0001
To a mixture of tert-butyl 4-(aminocarbonothioyl)piperazine-l-carboxylate (0.20 g,
0.82 mmol) and 2-chlorocyclopentanone (100 μL, 0.99 mmol) in xylene (20 mL) was added triethylamine (454 μL, 3.26 mmol). The reaction mixture was refiuxed (140 0C) for
16 hours. The reaction mixture was concentrated in vacuo and the residue purified by flash column chromatography (silica, isohexane to 25% ethyl acetate/isohexane) to give a white solid (152 mg, 59.9%).
MS (+ve ESI) : 310 (M+H)+ 1U NMR (400.132 MHz, CDCl3.) δ 1.48 (s, 9H), 2.38 (m, 2H), 2.70 (m, 2H), 2.79 (m, 2H),
3.42 (m, 4H), 3.54 (t, 4H)
2-piperazin-l-yl-5,6-dihydro-4H-cyclopenta[(/] [l,3]thiazole
Figure imgf000100_0002
A solution of tert-butyl 4-(5,6-dihydro-4H-cyclopenta[J][l,3]thiazol-2-yl)piperazine-
1-carboxylate (30.0 mg, 0.10 mmol) in 4M hydrogen chloride in dioxane (5 mL) was allowed to stir at room temperature for 3 hours. The reaction mixture was concentrated in- vacuo to dryness to give a crude gum (-30 mg).
Example 62
(lR,2R)-ΛL(l-cyanocyclopropyl)-2-[(3-pyridin-2-ylpyrrolidin-l- yl)carbonyl]cyclohexanecarboxamide
Figure imgf000101_0001
In a similar manner to Example 59 except using 2-pyrrolidin-3-ylpyridine (96.0 mg, 0.65 mmol) yielded the compound as a a white solid (132 mg, 55%). MS (+ve ESI) : 367.4 (M+H)+ 1R NMR (400.132 MHz, DMSO) δ 0.90 - 1.37 (m, 9H), 1.43 (m, 2H), 1.90 - 2.44 (m, 4H), 2.67 (m, IH), 3.41 - 3.77 (m, 4H), 3.80 - 4.10 (m, IH), 7.22 - 7.40 (m, 2H), 7.75 (m, IH), 8.53 (m, IH), 8.74 (m, IH)
Example 63 (l/f,2R)-ΛL(l-cyanocyclopropyl)-2-[(4-{4-[(cyclopropylmethyl)sulfonyl] phenyl} piperazin-l-yl)carbonyl]cyclohexanecarboxamide
Figure imgf000101_0002
In a similar manner to Example 59 except using l-{4- [(cyclopropylmethyl)sulfonyl]phenyl}piperazine (420.0 mg, 1.50 mmol) yielded the compound as a a white solid (129 mg, 17%). MS (+ve ESI) : 498 (M+H)+
1H NMR (400.132 MHz, CDC13) δ 0.14 (2H, m),0.55 (2H, m),0.99 (IH, m),1.16 (2H, m),1.24 - 1.68 (6H, m),1.82 (4H, m),2.58 (IH, m),2.91 (IH, m),2.97 (2H, d),3.34 - 3.52 (4H, m),3.66 (2H, m),3.86 (IH, m),3.95 (IH, m),6.62 (IH, s),6.90 (2H, d),7.76 (2H, d) l-{4-[(cyclopropylmethyl)sulfonyl]phenyl}piperazine was synthesized in the following manner: l-[(cyclopropylmethyl)sulfbnyl]-4-fluorobenzene
Figure imgf000102_0001
To a solution of 21% sodium ethoxide in ethanol at 0 0C was added the 4-fluoro thiophenol (1.06 mL, 10.0 mmol) dropwise. The ice bath was removed and the reaction stirred for 1 hour. The mixture was cooled to 0 0C and the cyclopropylmethyl bromide (1.36 g, 10.0 mmol) in ethanol (10 mL) and the ice bath removed and the reaction stirred for 4 hours and then concentrated in vacuo. Partitioned with water / DCM (50 / 50 mL) and the organic layer cooled to 0 0C and mCPBA (2.00 g, 11.6 mmol) added portionwise, the reaction was left to stir over 48hours. Diluted with DCM (100 mL) and washed with 2M NaOH (50 mL), dried (MgSO4), filtered and concentrated in vacuo. (1.9Ig, 92%) Material was used crude.
1H NMR (400.132 MHz, CDC13) δ 0.13 (2H, m),0.58 (2H, m),1.00 (IH, m),3.03 (2H, d),7.25 (2H, m),7.96 (2H, m) l-{4-[(cyclopropylmethyl)sulfonyl]phenyl}piperazine
Figure imgf000102_0002
A mixture of the l-[(cyclopropylmethyl)sulfonyl]-4-fiuorobenzene (1.07g, 5.00 mmol), piperazine (8.6Og, 100 mmol) and potassium carbonate (3.46g, 25.0 mmol) in DMF (50 mL) was heated at 100 0C for 3 hours and then allowed to cool, concentrated in vacuo. Partitioned with DCM / water (50 / 50 mL) and the organic layer washed with further water (2 x 50 mL), dried over (MgSO4), filtered and concentrated in vacuo. (1.30 g 93%). Material used crude.
1H NMR (400.132 MHz, CDC13) δ 0.15 (2H, m),0.56 (2H, m),1.00 (IH, m),2.97 (4H, d),2.97 (2H, d),3.03 (4H, m),3.32 (4H, m),6.93 (2H, m),7.75 (2H, m) Example 64
(lR,2R)-N-(l-cyanocyclopropyl)-2-{[4-(4-cyclopropyl-l,3-thiazol-2-yl)piperazin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000103_0001
In a similar manner to Example 59 except using l-(4-cyclopropyl-l,3-thiazol-2- yl)piperazine. hydrobromide (117 mg, 0.040 mmol) yielded the compound as a cream solid (222 mg, 79%).
LCMS rentention time 2.40 min. MS (+ve ESI) : 470.2 (M+H)+ l-(4-cyclopropyl-l,3-thiazol-2-yl)piperazine hydrobromide was synthesized in the following manner. 2,5-dibr omo-4-cyclopr opyl- 1 ,3-thiazole
Figure imgf000103_0002
To a solution of tert-butyl nitrite (1.60 mL, 13.3 mmol) and copper (II) bromide (2.40 g, 10.6 mmol) in anhydrous acetonitrile (20 mL at 60 C was added 4-cyclopropyl-l,3- thiazol-2-ylamine (1.24 g, 8.84 mmol) portionwise. The reaction mixture was then heated at 80 0C for 2 hours. The reaction mixture was diluted with DCM (100 mL) and washed with IN HCl (100 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were washed with brine (50 mL) and dried (MgSO4) to give a dark crude oil. The crude material was purified by flash column chromatography (silica, eluting with isohexane to 10% DCM) gave a yellow oil (293 mg, 16%). 1U NMR (400.132 MHz, CDCl3) δ 0.99 (m, 4H), 2.05 (m, IH) l-(4-cyclopropyl-l,3-thiazol-2-yl)piperazine hydrobromide
Figure imgf000104_0001
To a solution of 2,5-dibromo-4-cyclopropyl-l,3-thiazole (290.0 mg, 12.0 mmol) in xylene (10 mL) was added piperazine (63.0 mg, 0.73 mmol) and heated at 140 0C for 60 minutes in the microwave The reaction was concentrated in-vacuo then diluted with DCM (50 mL), washed with water (50 mL) and dried (MgSO4) to give a crude gum. The crude was purified by reverse phase HPLC (basic) to give a white solid (124 mg, 42%). 1R NMR (400.132 MHz, CDCl3.) δ 0.81 - 0.93 (m, 4H), 1.93 (m, IH), 2.93 (t, 4H), 3.33 (t, 4H) The white solid (124 mg) was dissolved in ethanol ( 5 mL) and treated with hydrogen gas at 1 atm in the presence of 10% palladium on carbon (20 mg) for 4 hours. The solids were removed by filtration to yield the title compound as a white solid (85.0 mg 95%).
Example 65 (l/f,2R)-ΛL(l-cyanocyclopropyl)-2-{[3-(3-methoxyphenyl)pyrrolidin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000104_0002
In a similar manner to Example 59 except using 3-(3-methoxyphenyl)pyrrolidine Hydrochloride (104 mg, 0.49 mmol) to yield (lR,2R)-N-(l-cyanocyclopropyl)-2-[3-(3- methoxyphenyl)pyrrolidine-l -carbonyl] cyclohexane-1-carboxamide (131 mg, 68%) as a white solid. MS (+ve ESI) : 396.4 (M+H)+ 1U NMR (500.13 MHz, CDCl3) 1.09 - 1.86 (14H, cm), 2.53 - 2.72 (2H, m), 3.67 (8H, cm), 6.74 - 6.85 (3H, m), 6.96 (IH, d), 7.19 - 7.24 (IH, m)
Example 66 (l/f,2R)-ΛL(l-cyanocyclopropyl)-2-[(4-[l,3]thiazolo[4,5-6]pyridin-2-ylpiperazin-l- yl)carbonyl]cyclohexanecarboxamide
Figure imgf000105_0001
In a similar manner to Example 59 except using 2-piperazin-l-yl[l,3]thiazolo[4,5- όjpyridine (104 mg, 0.49 mmol) to yield the title compound (208 mg, 73%) as a cream solid.
MS (+ve ESI) : 439.2 (M+H)+
1R NMR (400.132 MHz, DMSO) δ 0.94 - 1.04 (m, 2H), 1.14 - 1.45 (m, 6H), 1.66 - 1.82
(m, 4H), 2.44 (m, IH), 2.95 (m, IH), 3.46 (m, 2H), 3.61 - 3.89 (m, 6H), 7.06 (m, IH), 8.21 (m, IH), 8.32 (m, IH), 8.78 (s, IH)
2-piperazin- 1-yl [ 1 ,3] thiazolo [4,5-6] pyridine
Figure imgf000105_0002
To a solution of 2-(methylthio)[l,3]thiazolo[4,5-ό]pyridine [K. Walcynski et al, Eurpoean Journal of Medicinal Chemistry 40 (2005) 15] (0.20 g, 1.10 mmol) in IPA (3 mL) was added piperazine (378 mg, 4.39 mmol) and heated in the microwave at 160 0C for 2 hours. LCMS shows reaction gone about 87% and increasing amounts of bis material. The reaction mixture was concentrated in-vacuo to give a crude solid which was purified by reverse phase HPLC (basic) to give a white solid (185 mg, 76%). MS (+ve ESI) : 221 (M+H)+
1R NMR (400.132 MHz, DMSQ) δ 2.82 (t, 4H), 3.55 (t, 4H), 7.02 (m, IH), 8.15 (m, IH), 8.29 (m, IH)
Example 67
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-[(3-pyridin-3-ylpyrrolidin-l- yl)carbonyl]cyclohexanecarboxamide
Figure imgf000106_0001
In a similar manner to Example 59 except using 3-pyrrolidin-3-ylpyridine (96.0 mg, 0.65 mmol) yielded the compound as a a white solid (123 mg, 52%). MS (+ve ESI) : 367.4 (M+H)+ 1R NMR (400.132 MHz, DMSQ) δ 0.92 - 1.38 (m, 6H), 1.45 (m, 2H), 1.60 - 2.08 (m, 5H), 2.16 - 2.47 (m, 2H), 2.68 (m, IH), 3.16 - 3.33 (m, 2H), 3.40 - 4.13 (m, 3H), 7.32 (m, IH), 7.69 - 7.79 (m, IH), 8.42 - 8.56 (m, 2H), 8.74 (m, IH).
Example 68 (l/f,2R)-ΛL(l-cyanocyclopropyl)-2-{[4-(4-methoxyphenyl)piperazin-l- yl] carbonyl} cyclohexanecarboxamide
Figure imgf000106_0002
In a similar manner to Example 59 except using l-(4-methoxyphenyl)piperazine (259 uL, 1.50 mmol) yielded the compound as a a white solid (407 mg, 67%). MS (+ve ESI) : 411 (M+H)+ 1R NMR (400.13 MHz, CDCl3) δ 1.10 - 1.20 (2H, m), 1.32 (IH, m), 1.36 -1.50 (4H, m), 1.51-1.61 (IH, m), 1.84 (4H, m), 2.64 - 2.68 (IH, t), 2.93 - 2.97 (IH, t), 2.99 - 3.06 (3H, m), 3.15 (IH, m), 3.63 - 3.72 (2H, m), 3.77 (3H, s), 3.78 - 3.85 (2H, m), 6.82 - 6.86 (2H, m), 6.89 - 6.93 (2H, m), 7.37 (IH, s).
Example 69
(l/?,2/?)-2-{[4-(4-cyano-l,3-benzothiazol-2-yl)piperazin-l-yl] carbonyl}-iV-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000107_0001
In a similar manner to Example 59 except using crude 2-piperazin-l-yl-l,3- benzothiazole-4-carbonitrile (100 mg, 0.25 mmol) yielded the compound as a a white solid (5.00 mg, 5%). MS (+ve ESI) : 463 (M+H)+ 1H NMR (400.13 MHz, CDCl3) δl.13 - 1.19 (3H, m), 1.22 - 1.25 (IH, m), 1.33 (IH, m), 1.42 (IH, m), 1.43 - 1.47 (IH, m), 1.51 - 1.54 (IH, m), 1.82-1.85 (4H, m), 2.57 (IH, t), 2.89 (IH, t), 3.55 - 3.61 (IH, m), 3.63 - 3.68 (2H, m), 3.75 - 3.89 (2H, m), 3.82 - 3.86 (2H, m), 4.05 (IH, m), 6.46 (IH, s), 7.10 (IH, dd), 7.56 - 7.58 (IH, m), 7.75 - 7.78 (IH, m) 2-piperazin-l-yl-l,3-benzothiazole-4-carbonitrile was synthesized in the following manner. tert-bntyl 4-{[(2-cyanophenyl)amino]carbonothioyl}piperazine-l-carboxylate
Figure imgf000108_0001
2-cyanoisothiocyanate (1.00 g, 6.25 mmol) and boc-piperazine (1.40 g, 7.50 mmol) were stirred in DMF (20 mL) at room temperature for 18 h. The solvent was removed under reduced pressure and the crude material subjected to flash column chromatography (silica, 1% MeOH in DCM). The relevant fractions were combined and the solvent removed under reduced pressure to afford the desired product as a yellow oil (1.30 g, 60%). LCMS retention time 1.85 min MS (+ve ESI) : 347 (M+H)+ tert-bntyl 4-(4-cyano-l,3-benzothiazol-2-yl)piperazine-l-carboxylate
Figure imgf000108_0002
To a solution of tert-butyl 4-{[(2-cyanophenyl)amino]carbonothioyl}piperazine-l- carboxylate (1.30 g, 3.76 mmol) in DCM (20 mL) was slowly added bromine (194 uL, 3.76 mmol) and the reaction heated to reflux. Acetic acid (5 mL) was added to the reaction reluxed for 4 hours. The solvent was removed under reduced pressure and the material used crude in the next step.
LCMS retention time 2.61 min MS (+ve ESI) : 345 (M+H)+ 2-piperazin-l-yl-l,3-benzothiazole-4-carbonitrile
Figure imgf000109_0001
tert-butyl 4-(4-cyano- 1 ,3-benzothiazol-2-yl)piperazine- 1 -carboxylate (1.26 g, crude from previous reaction) was stirred in a solution of hydrochloric acid in methanol (reagent 10, 20 mL) at room temperature for 18 hours. The solvent was removed under reduced pressure to afford a mixture of the desired product and a product with bromine attached (815 mg). These appeared difficult to separate so the mixture was used directly in the next reaction. LCMS retention time 0.86 min MS (+ve ESI) : 463 (M+H)+
Example 70
(lR,2R)-N-(l-cyanocyclopropyl)-2-[(4-{4-[4-(methylsulfonyl)phenyl]-l,3-thiazol-2- yl}piperazin-l-yl)carbonyl]cyclohexanecarboxamide
Figure imgf000109_0002
In a similar manner to Example 59 except using crude l-{4-[4- (methylsulfonyl)phenyl]-l,3-thiazol-2-yl}piperazine (387 mg, mmol) yielded the compound as a a white solid (387 mg, 90%). MS (+ve ESI) : 542 (M+H)+ 1U NMR (400.13 MHz, CDCl3) δl.10 - 1.85 (12H, m), 2.56 - 2.62 (IH, m), 2.93 (IH, m), 3.07 (3H, s), 3.60 (6H, m), 3.81 - 3.85 (IH, m), 3.93 - 3.99 (IH, m), 6.58 (IH, s), 6.99 (IH, s), 7.92 - 7.95 (2H, m), 8.00 - 8.02 (2H, m) l-{4-[4-(methylsulfonyl)phenyl]-l,3-thiazol-2-yl}piperazine was synthesized in the following manner. 4-(4-Phenyl-thiazol-2-yl)-piperazine-l-carboxylic acid tert-butyl ester
Figure imgf000110_0001
4-Thiocarbamoyl-piperazine-l-carboxylic acid tert-butyl ester (200 mg; 0.82 mmol) and 2-bromo-l-(4-methanesulfonyl-phenyl)-ethanone (276 mg; 0.99 mmol) were stirred in xylene (10 mL) and triethylamine (455 uL; 3.26 mmol) added, the reaction was heated at
110 0C. The reaction was evaporated to dryness and the residue chromatographed (silica,
10-20% ethyl acetate in hexane) to give 4-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]- piperazine-1-carboxylic acid tert-butyl ester (312 mg; 89%).
MS (+ve ESI) : 424 (M+H)+ 1H NMR (400.13 MHz, CDCl3) δl.49 (9H, s), 3.07 (3H, s), 3.53 - 3.56 (4H, m), 3.59 - 3.61
(4H, m), 6.98 (IH, s), 7.92 - 7.95 (2H, m), 8.00 - 8.03 (2H, m) l-{4-[4-(methylsulfonyl)phenyl]-l,3-thiazol-2-yl}piperazine
Figure imgf000111_0001
4-(4-Phenyl-thiazol-2-yl)-piperazine-l-carboxylic acid tert-butyl ester (255 mg; 0.74 mmol) was stirred in HCl in Methanol (about 1OM; 5 mL) for 18 hours, reaction evaporated and the residue azeotroped with toluene to give l-[4-(4-methanesulfonyl- phenyl)-thiazol-2-yl]-piperazine.HCl which was used in the next reaction without further purification.
Example 71
(lR,2R)-2-{[(2R)-4-(l,3-benzothiazol-2-yl)-2-methylpiperazin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000111_0002
In a similar manner to example 59 except using 2-[(3i?)-3-methylpiperazin-l-yl]-l,3- benzothiazole (241 mg, 0.89 mmol) yielded the compound as a white solid (213 mg, 53%). MS (+ve ESI) : 452 (M+H)+ 1U NMR (400.132 MHz, DMSO) δ 0.80 - 0.97 (m, 2H), 1.00 (d, 2H), 1.04 - 1.36 (m, 5H), 1.57 - 1.80 (m, 4H), 2.79 - 3.02 (m, 2H), 3.17 - 3.49 (m, 5H), 3.69 - 3.82 (m, IH), 3.94 - 4.36 (m, 3H), 7.01 (t, IH), 7.22 (t, IH), 7.41 (d, IH), 7.71 (d, IH), 8.71 (d, IH) tert-butyl (2/f)-4-(l,3-benzothiazol-2-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000112_0001
The 2-bromo-l,3-benzothiazole (536 mg , 250 mmol) and (R)-l-N-boc-2 -methyl piperazine (501 mg, 2.50 mmol) were dissolved in DMF (5 mL) under argon and the DIPEA (872 uL, 5.00 mmol) added. The reaction was heated to 100 0C overnight to about 70% completion. The product was isolated by flash column chromatography (silica, 0-30% EtOAc in hexane). to give colourless oil which crystallised on standing (401 mg, 48%). MS (+ve ESI) : 334 (M+H)+
IH NMR (400.132 MHz, DMSO) δ 1.18 (d, 3H), 1.44 (s, 9H), 2.88 - 3.36 (m, 3H), 3.75 - 3.91 (m, 2H), 3.93 - 4.11 (m, IH), 4.22 - 4.32 (m, IH), 7.08 (t, IH), 7.28 (t, IH), 7.47 (d, IH), 7.78 (d, IH)
2- [(3R )-3-methylpiper azin- 1-yl] - 1 ,3-benzothiazole
Figure imgf000112_0002
The (i?)-4-benzothiazol-2-yl-2-methyl-piperazine-l-carboxylic acid tert-butyl ester (401mg, 1.20 mmol) in DCM (3 mL) was treated with the 4M HCl in dioxane (1 mL) with stirring. Immediate evolution of gas was observed and after 10 min a yellow semicrystalline precipitate formed. The reaction was allowed to continue for Ih when the solvent was decanted and the residue triturated with ether (x 2). After drying obtained pale yellow solid (264 mg, 82%). MS (+ve ESI) : 234 (M+H)+ IH NMR (400.132 MHz, DMSO) δ 1.42 (d, 3H), 3.09 (q, IH), 3.21 - 3.37 (m, 3H), 3.54 (t, IH), 4.04 (d, IH), 4.44 - 4.53 (m, IH), 7.13 (t, IH), 7.32 (t, IH), 7.52 (d, IH), 7.83 (d, IH), 9.30 - 9.43 (m, IH), 9.77 - 9.92 (m, IH).
Example 72
(lR,2R)-2-{[(3R)-4-(l,3-benzothiazol-2-yl)-3-methylpiperazin-l-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000113_0001
In a similar manner to Example 59 except using 2-((i?)-2-methyl-piperazin-l-yl)- benzothiazole (91.0 mg, 0.34 mmol) yielded the compound as a a white solid (62.0 mg,
40%).
MS (+ve ESI) : 452 (M+H)+
1U NMR (400.132 MHz, DMSO) δ 0.88 - 1.06 (m, 2H)*, 1.09 (d, 2H), 1.13 - 1.45 (m, 4H), 1.31 (d, IH)*, 1.65 - 1.86 (m, 4H), 2.54 - 3.21 (m, 6H), 3.85 (q, IH), 3.98 - 4.08
(m, 2H), 4.25 (d, IH), 4.53 (d, IH), 7.08 (t, IH), 7.29 (t, IH), 7.46 (d, IH), 7.78 (d,
IH), 8.73 (d, IH).
2-[(2/?)-2-methylpiperazin-l-yl]-l,3-benzothiazole was synthesized in the following manner. tert-butyl (3/f)-4-(l,3-benzothiazol-2-yl)-3-methylpiperazine-l-carboxylate
Figure imgf000113_0002
The 2-bromo-l,3-benzothiazole (123 mg, 0.57 mmol), (R)-2-N-boc-2 -methyl piperazine (115 mg, 0.57 mmol) and the potassium carbonate (236 mg) in DMF (3 mL) were heated in a microwave to 120 0C for 30 min. The bulk of the DMF was evaporated and the residue partitioned between water (100 mL) and ethyl acetate (100 mL). The organic phase combined with a further extract was dried (MgSO4) and evaporated to give a yellow oil. The oil was purified by flash chromatographed (silica, eluting with 0-50% EtOAc in hexane) to a white solid on standing. (156mg). MS (+ve ESI) : 334 (M+H)+ 1H NMR (400.132 MHz, CDC13) δ 1.24 (d, 3H), 1.49 (s, 9H), 3.15 - 3.31 (m, 2H), 3.43 (q, IH), 3.81 (d, IH), 4.04 (q, 2H), 4.40 (s, IH), 7.09 (t, IH), 7.30 (t, IH), 7.55 (d, IH), 7.60 (d, IH). 2-[(2/?)-2-methylpiperazin-l-yl]-l,3-benzothiazole
Figure imgf000114_0001
The ((i?)-4-benzothiazol-2-yl-3-methyl-piperazine-l-carboxylic acid tert-butyl ester (154 mg, 0.46 mmol) in DCM (1 mL) was treated with the 4.0M HCl in dioxane (0.5 mL) with stirring. Immediate evolution of gas was observed and after Ih a white precipitate formed. The solid was filtered off and washed with ether (2 x 5 mL). After drying obtained mg white solid. (91.0 mg, 73%) MS (+ve ESI) : 234 (M+H)+
1R NMR (400.132 MHz, DMSO) δ 1.33 (d, 3H), 3.10 - 3.24 (m, IH), 3.31 (q, IH), 3.35 - 3.48 (m, 2H), 3.49 - 3.59 (m, IH), 4.12 (q, 2H), 7.14 (t, IH), 7.33 (t, IH), 7.52 (d, IH), 7.84 (d, IH), 9.43 - 9.70 (m, 2H).
Example 73
(l/f,2/f)-2-[4-(3,4-Dimethoxy-phenyl)-piperazine-l-carbonyl]-cyclohexanecarboxylic acid (l-cyano-cyclopropylj-amide
Figure imgf000115_0001
l-(3,4-Dimethoxy-phenyl)-piperazine.HCl (194 mg, 0.75 mmol) and (3aR,7aR)- 3a,4,5,6,7,7a-hexahydroisobenzofuran-l,3-dione (116 mg, 0.75 mmol) were stirred in DMF (5 mL) and DIPEA (523 DL;3.00 mmol) for 2 hours. 1-amino-l- cyclopropanrcarbonitrlie-HCl (107 mg; 0.90 mmol) and HATU (342 mg; 0.90 mmol) were added and the mixture allowed to stir overnight. The solution was subjected to HPLC preparative chromatography as follows: Compound diluted with Acetonitrile/H2O; filtered; pH adjusted to >9 with NH3, injected onto a Waters 100mm x 19mm XBridge C18 5m column; flow 2 lmls/min; Solvent A = 0.1 %NH3/Water, Solvent B = CH3CN; l=230nm. The product fractions were combined and then partitioned between diethyl ether (30 mL) and brine (30 mL), organic extract dried (Na2SO4), filtered and solvent removed under reduced pressure to give (7i?,2i?)-2-[4-(3,4-Dimethoxy-phenyl)-piperazine-l-carbonyl]- cyclohexanecarboxylic acid (l-cyano-cyclopropyl)-amide (193 mg; 58%) as a white foam. MS (+ve ESI) : 441 (M+H)+
1U NMR (400.13 MHz, CDCl3) δ 1.10-1.86 (12H, d), 2.56 - 2.62 (IH, m), 2.86 - 2.92 (IH, m), 3.10 (4H, m), 3.59 - 3.91 (4H, m), 3.83 (3H, s), 3.86 (3H, s), 6.44 - 6.47 (IH, m), 6.57 (IH, s), 6.58 (IH, d), 6.78 (IH, d)
Example 74
(l/f,2/f)-Λ/-(l-cyanocyclopropyl)-2-((/f)-4-(3,4-dimethoxyphenyl)-2-methylpiperazine- l-carbonyl)cyclohexanecarboxamide
Figure imgf000116_0001
(3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (191 mg, 1.24 mmol) was added to (R)-I- (3,4-dimethoxyphenyl)-3-methylpiperazine, HCl (338 mg, 1.24 mmol) and in DCM (10 mL) at room temperature. The resulting solution was stirred at room temperature for 3 days. To the reaction mixture was added HATU (660 mg, 1.73 mmol), 1-amino-l- cyclopropanecarbonitrile HCl (191 mg, 1.61 mmol) and 7V,7V-diisopropylethylamine (1.08 mL, 6.20 mmol). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (100 mL), and washed with water (50 mL). The organic layer was passed through a phase separator and evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% NH3) and CH3CN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (li?,2i?)-7V-(l-cyanocyclopropyl)-2-((i?)-4- (3 ,4-dimethoxyphenyl)-2-methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide (320mg, 56.7%) as a cream solid.
MS (+ve ESI) : Rt = 2.00 min, 455.57 (M+H)+
1H NMi? (400.132 MHz, DMSO) δ 0.91 - 1.47 (12H, m), 1.64 - 1.82 (4H, m), 2.37 (IH, m), 2.54 - 2.96 (3H, m), 3.37 - 3.54 (2H, m), 3.68 (3H, s), 3.75 (3H, s), 3.91 - 4.67 (2H, m), 6.41 (IH, m), 6.60 (IH, m), 6.82 (IH, d)4, 8.69 (IH, d).
METHOD A
The synthesis of (i?)-l-(3,4-dimethoxyphenyl)-3-methylpiperazine.HCl is a representative example of the general two step method of making secondary amine building blocks of the type (V) using a palladium coupling reaction. (R)-tert-bntyl 4-(3,4-dimethoxyphenyl)-2-methylpiperazine-l-carboxylate
Figure imgf000117_0001
Palladium(II) acetate (0.052 g, 0.230 mmol) and (R)-(+)-2,2'-bis(diphenylphosphino)-l,l?- binaphthyl (0.115 g, 0.180 mmol) were added to 4-bromoveratrole (0.662 mL, 4.61 mmol), (R)-\-N-boc-2 -methyl piperazine (0.923 g, 4.61 mmol) and sodium tert-butoxide (0.664 g, 6.91 mmol) in anhydrous toluene (12 mL) under argon. The resulting solution was stirred at reflux for 16 hours. The reaction mixture was diluted with Et2O and filtered through celite. The resulting mixture was evaporated to dryness to afford crude (R)-tert-butyl 4- (3,4-dimethoxyphenyl)-2-methylpiperazine-l-carboxylate. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(3,4-dimethoxyphenyl)-2- methylpiperazine-1-carboxylate (0.871 g, 56.2 %) as a beige solid. MS (+ve ESI) : Rt = 2.57 min, 337.31 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.33 (3H, d), 1.49 (9H, s), 2.67 (IH, m), 2.85 (IH, m), 3.24 (2H, m), 3.37 (IH, d), 3.84 (3H, s), 3.88 (3H, s), 3.94 (IH, m), 4.34 (IH, s), 6.43 (IH, m), 6.54 (IH, d), 6.79 (IH, d)
(R)-l-(3,4-dimethoxyphenyl)-3-methylpiperazine.HCl
Figure imgf000117_0002
(R)-tert-buty{ 4-(3,4-dimethoxyphenyl)-2-methylpiperazine-l-carboxylate (0.400 g, 1.19 mmol) was added to hydrochloric acid in methanol (methanol reagent 10) (15 mL, 1.19 mmol) and the resulting solution was stirred at room temperature for 16 hours. The resulting mixture was evaporated to dryness and the residue was azeotroped with DCM to afford crude (i?)-l-(3,4-dimethoxyphenyl)-3-methylpiperazine (100 %). MS (+ve ESI) : Rt = 1.22 min, 237.30 (M+H)+ Example 75
(lR,2R)-ΛL(l-cyanocyclopropyl)-2-((R)-4-(4-cyclopropyl-3-methoxyphenyl)-2- methylpiperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000118_0001
To a solution of (i?)-l-(4-cyclopropyl-3-methoxyphenyl)-3-methylpiperazine (0.123 g, 0.50 mmol) in DCM (5ml) was added (3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (0.077 g, 0.5 mmol) and triethylamine (0.070 ml, 0.50 mmol) and the reaction stirred for 3 hours, HATU (0.209 g, 0.55 mmol), 1 -amino- l-cyclopropanecarbonitrile HCl (0.065 g, 0.55 mmol) and triethylamine (0.139 ml, 1.00 mmol) were added and the reaction stirred for 41 hours then diluted with DCM (50 mL) and washed sequentially with water (2 x 50 mL) and 2M NaOH (50 mL), dried over MgSO4, filtered and evaporated. X-Bridge Base Prep HPLC/LCMS details: Compounds were purified using 0.1% NH3 modified water/MeCN on a Waters X-Bridge Cl 8 (5μ silica, 19 mm diameter, 100 mm length) column. Fractions containing the desired compound were lyophilised to dryness to afford a white foam (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-cyclopropyl-3-methoxyphenyl)-2- methylpiperazine-l-carbonyl)cyclohexanecarboxamide (0.111 g, 47.8 %) as a white solid MS (+ve ESI) : Rt = 1.22 min, 465 (M+H)+ 1H NMi? (400.132 MHz, CDC13) δ 0.56 (2H, m), 0.84 (2H, m), 1.04 - 1.88 (15H, m), 2.02 (IH, m), 2.56 - 4.87 (9H, m), 3.85 (3H, s), 6.37 - 6.43 (2H, m), 6.54 - 6.62 (IH, m), 6.72 - 6.78 (IH, m)
METHOD B The synthesis of (i?)-l-(4-cyclopropyl-3-methoxyphenyl)-3-methylpiperazine is a representative example of the general method of making secondary amine building blocks of the type (V) using [l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ii) dichloride [PEPPSI] catalytic cross coupling reaction. 4-Chloro-l-cyclopropyl-2-methoxybenzene
Figure imgf000119_0001
2-Bromo-5-chloroanisole (1.77 g, 8.00 mmol), potassium phosphate (5.94 g, 28.0 mmol), tricyclohexylphosphine (0.224 g, 0.800 mmol) and cyclopropylboronic acid (0.893 g, 10.4 mmol) were suspended in toluene (32 mL) and water (1.6 mL) added followed by palladium(II) acetate (0.090 g, 0.40 mmol). The mixture was heated to 100 0C for 3 hours and then allowed to cool. Poured into water (100 mL) and extracted with EtOAc (3 x 50 mL), the combined organics layers were dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% Et20 in isohexane. Pure fractions were evaporated to dryness to afford 4-chloro-l-cyclopropyl- 2-methoxybenzene (1.380 g, 94 %) as a yellow oil.
1H NMi? (400.132 MHz, CDC13) δ 0.57 - 0.64 (2H, m), 0.86 - 0.95 (2H, m), 2.03 - 2.13
(IH, m), 3.85 (3H, s), 6.74 (IH, d), 6.79 - 6.85 (2H, m)
(R)-tert-butyl 4-(4-cyclopropyl-3-methoxyphenyl)-2-methylpiperazine-l-carboxylate
Figure imgf000119_0002
4-Chloro-l-cyclopropyl-2-methoxybenzene (1.38 g, 7.56 mmol), PEPPSI (0.103 g, 0.150 mmol) and potassium tøt-butoxide (1.017 g, 9.07 mmol) were suspended in DME (3 mL) under a blanket of Ar and the mixture stirred for a minute. (R)-\-N-boc-2 -methyl piperazine (1.51 g, 7.56 mmol) in DME (4 mL) was added and the mixture warmed to 50 0C for 18 hours allowed to cool and evaporated to dryness and partitioned with water (50 mL) and DCM (50 mL). The oragnic layer was washed with water (50 ml) and the aqueous layers washed with DCM (50 mL), the combined organic layers were dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(4-cyclopropyl-3-methoxyphenyl)-2-methylpiperazine-l- carboxylate (1.220 g, 46.6 %) as a yellow oil which solidified on standing. MS (+ve ESI) : 347 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 0.53 - 0.60 (2H, m), 0.81 - 0.89 (2H, m), 1.30 (3H, d), 1.48 (9H, s), 1.98 - 2.05 (IH, m), 2.71 (IH, m), 2.91 (IH, m), 3.19 - 3.54 (3H, m), 3.86 (3H, s), 3.93 (IH, d), 4.33 (IH, s), 6.38 - 6.44 (2H, m), 6.76 (IH, d) (R)-l-(4-cyclopropyl-3-methoxyphenyl)-3-methylpiperazine
Figure imgf000120_0001
(R)-tert-butyl 4-(4-cyclopropyl-3-methoxyphenyl)-2-methylpiperazine- 1 -carboxylate (1.22 g, 3.52 mmol) was suspended in 4M hydrogen chloride (35.2 ml, 140.8 mmol) in dioxane. The reaction was stirred for 2 hours and then evaporated. Partitioned with 2M NaOH (25 ml) and DCM (50 ml) and aqueous layer extracted with further DCM (25 mL), the combined organic layers were dried over MgSO4, filtered and evaporated to give (R)-I- (4-cyclopropyl-3-methoxyphenyl)-3-methylpiperazine (0.852 g, 98.0 %) as a brown oil MS (+ve ESI) : 247 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 0.54 - 0.60 (2H, m), 0.81 - 0.87 (2H, m), 1.14 (3H, d), 2.03 (IH, m), 2.35 (IH, m), 2.71 (IH, m), 2.94 - 3.16 (3H, m), 3.45 (IH, d), 3.64 (IH, m), 3.76 (IH, t), 3.85 (3H, s), 6.41 - 6.48 (2H, m), 6.75 (IH, d)
Example 76
(l/f,2R)-Λ/-(l-cyanocyclopropyl)-2-((R)-4-(2,4-dimethoxyphenyl)-2-methylpiperazine- l-carbonyl)cyclohexanecarboxamide
Figure imgf000121_0001
(3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (220 mg, 1.43 mmol) was added to (R)-I- (2,4-dimethoxyphenyl)-3-methylpiperazine (281 mg, 1.19 mmol) in DMF (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. DIPEA (0.983 mL, 5.95 mmol), HATU (814 mg, 2.14 mmol) and 1-amino-l- cyclopropanecarbonitrile.HCL (254 mg, 2.14 mmol) were then added and the resulting solution was stirred at room temperature for 20 hours. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(2,4-dimethoxyphenyl)-2- methylpiperazine-l-carbonyl)cyclohexanecarboxamide (96.0 mg, 17.8 %) as a white solid. MS (+ve ESI) : Rt = 2.17 min, 455 (M+H)+ 1H NMi? (400.13 MHz, CDC13) δ 1.07 - 1.53 (1 IH, m), 1.66 -1.68 (IH, m), 1.62 - 2.00 (4H, m), 2.60 - 2.66 (2H, m), 2.72 - 2.82 (IH, m), 3.13 - 3.17 (IH, m), 3.22 (IH, d), 3.54 and 4.42 (2 x IH, m), 3.76 - 3.77 (4H, m), 3.82 (3H, s), 4.00 and 4.72 (2 x IH, m), 6.40 - 6.42 (IH, m), 6.46 - 6.48 (IH, m), 6.61-6.62 (IH, m), 6.76 - 6.81 (IH, m) In a similar manner to Method A (i?)-l-(2,4-dimethoxyphenyl)-3-methylpiperazine was synthesised as outlined below: - (R)-tert-bntyl 4-(2,4-dimethoxyphenyl)-2-methylpiperazine-l-carboxylate
Figure imgf000121_0002
Palladium(II) acetate (0.056 g, 0.25 mmol) and (i?)-(+)-2,2'-bis(diphenylphosphino)-l,r- binaphthyl (0.124 g, 0.20 mmol) were added to l-bromo-2,4-dimethoxybenzene (1.01 g, 4.99 mmol), (R)-\-N-boc-2 -methyl piperazine (1.00 g, 4.99 mmol) and sodium tert- butoxide (0.720 g, 7.49 mmol) in anhydrous Toluene (12 mL) under argon. The resulting solution was stirred at reflux for 16 hours, to yield (R)-tert-butyl 4-(2,4-dimethoxyphenyl)- 2-methylpiperazine-l-carboxylate. This was used directly in the next reaction. (R)-l-(2,4-dimethoxyphenyl)-3-methylpiperazine
Figure imgf000122_0001
(R)-tert-buty{ 4-(2,4-dimethoxyphenyl)-2-methylpiperazine-l-carboxylate (1.60 g, 4.76 mmol) was added to hydrochloric acid (9.51 ml, 19.0 mmol) in methanol (10 ml) at 230C under air to afford (i?)-l-(2,4-dimethoxyphenyl)-3-methylpiperazine (0.281 g, 25.0 %) as a brown solid after workup.
MS (+ve ESI) : Rt = 1.41 min, 237 (M+H)+
Example 77
(lR,2R)-N-(l-cyanocyclopropyl)-2-((R)-4-(3,4-dimethoxyphenyl)-2- isopropylpiperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000122_0002
Following example 73 (3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (0.079 g, 0.51 mmol) was added to (i?)-l-(3,4-dimethoxyphenyl)-3-isopropylpiperazine (0.135 g, 0.51 mmol) in DCM (3 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. To the reaction mixture was added HATU (0.272 g, 0.71 mmol), 1-amino-l- cyclopropanecarbonitrile HCl (0.079 g, 0.66 mmol) and 7V,7V-diisopropylethylamine (0.267 mL, 1.53 mmol). The resulting solution was stirred at room temperature for 16 hours to yield (li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-4-(3,4-dimethoxyphenyl)-2- isopropylpiperazine-l-carbonyl)cyclohexanecarboxamide (162 mg, 66.1%) as a white solid after work up and isolation.
MS (+ve ESI) : Rt = 2.30 min, 483.63 (M+H)+
1H NMi? (400.132 MHz, DMSO) δ 0.71 (2H, d), 0.91 - 1.06 (6H, m), 1.10 - 1.44 (6H, m),
1.64 - 1.85 (4H, m), 2.23 - 2.48 (2H, m), 2.53 - 3.00 (3H, m), 3.29 (IH, m), 3.40 - 3.58
(2H, m), 3.68 (3H, s), 3.75 (3H, s), 3.94 - 4.38 (2H, m), 6.42 (IH, m), 6.57 (IH, m), 6.82
(IH, m), 8.65 (IH, d)
Synthesis of (R)-l-(3,4-dimethoxyphenyl)-3-isopropylpiperazine
(R)-tert-bntyl 4-(3,4-dimethoxyphenyl)-2-isopropylpiperazine-l-carboxylate.
Figure imgf000123_0001
In a similar manner to method A 4-bromoveratrole (0.331 mL, 2.30 mmol) was reacted with (i?)-2-isopropyl-piperazine-l-carboxylic acid tert-butyl ester (0.526 g, 2.30 mmol) to afford (R)-tert-buty{ 4-(3,4-dimethoxyphenyl)-2-isopropylpiperazine-l-carboxylate (0.423 g, 50.4 %) as a yellow gum. MS (+ve ESI) : Rt = 2.96 min, 365.60 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 0.90 (3H, d), 1.03 (3H, d), 1.48 (9H, s), 2.41 (IH, m), 2.67 (2H, m), 3.03 - 3.78 (4H, m), 3.84 (3H, s), 3.87 (3H, s), 3.99 (IH, m), 6.43 (IH, m), 6.53 (IH, d), 6.79 (IH, d) (R)-l-(3,4-dimethoxyphenyl)-3-isopropylpiperazine
Figure imgf000123_0002
In a similar manner to method A (R)-tert-butyl 4-(3,4-dimethoxyphenyl)-2- isopropylpiperazine-1-carboxylate (0.423 g, 1.16 mmol) was added to hydrochloric acid in methanol (methanol reagent 10) (10 mL, 1.16 mmol) to afford (i?)-l-(3,4- dimethoxyphenyl)-3-isopropylpiperazine (90 %) as a tan solid. MS (+ve ESI) : Rt = 1.61 min, 265.67 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.01 (6H, t), 1.70 (IH, m), 2.43 (IH, t), 2.63 (IH, m), 2.71 (IH, m), 3.03 (IH, m), 3.18 (IH, m), 3.37 (IH, m), 3.45 (IH, m), 3.84 (3H, s), 3.88 (3H, s), 6.448 (41H, m), 6.59 (IH, d), 6.80 (IH, d).
Example 78
(l/f,2R)-Λ/-(l-cyanocyclopropyl)-2-((R)-4-(5,6-dimethoxypyridin-2-yl)-2- methylpiperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000124_0001
In a similar manner to example 73 (3ai?,7ai?)-Hexahydroisobenzofuran-l,3-dione (0.109 g, 0.710 mmol) was added to (i?)-l-(5,6-dimethoxypyridin-2-yl)-3-methylpiperazine (0.168 g, 0.710 mmol) in DCM (3 mL) at room temperature. The resulting solution was stirred at room temperature for 3 days. To the reaction mixture was added HATU (0.377 g, 0.990 mmol), 1 -amino- 1-cyclopropanecarbonitrile HCl (0.109 g, 0.920 mmol) and N,7V- diisopropylethylamine (0.370 mL, 2.12 mmol). The resulting solution was stirred at room temperature for 16 hours to afford (li?,2i?)-7V-(l-cyanocyclopropyl)-2-((i?)-4-(5,6- dimethoxypyridin-2-yl)-2-methylpiperazine- 1 -carbonyl)cyclohexanecarboxamide (241 mg, 74.7 %) as a cream solid. MS (+ve ESI) : Rt = 2.09min, 456.57 (M+H)+ 1U NMi? (400.132 MHz, DMSO) δ 0.89 - 1.46 (1 IH, m), 1.64 - 1.83 (4H, m), 2.45 (IH, m), 2.74 - 2.94 (3H, m), 3.32 (IH, m), 3.67 (3H, s), 3.82 (3H, s), 3.84 - 4.67 (4H, m), 6.24 (IH, m), 7.21 (IH, d), 8.69 (IH, d)
Synthesis of (R)-l-(5,6-dimethoxypyridin-2-yl)-3-methylpiperazine. 2-Bromo-6-iodopyridin-3-ol
Figure imgf000124_0002
Iodine (4.59 g, 18.10 mmol) was added to 2-bromo-3-hydroxypyridine (3.00 g, 17.2 mmol) and potassium carbonate (4.77 g, 34.4 mmol) in water (40 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was cooled to 5 0C and carefully adjusted to pH 6 with 2M HCl. The precipitate was collected by filtration, washed with water (100 mL) and dried under vacuum to afford 2-bromo-6-iodopyridin-3- ol (4.68 g, 90 %) as a tan solid, which was used without further purification. IH NMi? (400.132 MHz, CDC13) δ 5.50 (IH, s), 6.99 (IH, d), 7.56 (IH, d) 2-Bromo-6-iodo-3-methoxypyridine
Figure imgf000125_0001
Methyl iodide (3.40 mL, 54.6 mmol) was added to 2-bromo-6-iodopyridin-3-ol (4.68 g, 15.6 mmol) and potassium carbonate (2.37 g, 17.1 mmol) in DMF (10 mL) under argon. The resulting solution was stirred at 100 0C for 2 hours. The reaction mixture was diluted with water (35 mL). The precipitate was collected by filtration, washed with water (75 mL), dried under vacuum, then redissolved in DCM passed through a phase separator and concentrated to afford 2-bromo-6-iodo-3-methoxypyridine (4.76 g, 97 %) as a brown solid, which was used without further purification.
1H NMi? (400.132 MHz, CDC13) δ 3.90 (3H, s), 6.84 (IH, d), 7.59 (IH, d) 6-Iodo-2,3-dimethoxypyridine
Figure imgf000125_0002
Sodium methoxide (1.18 g, 21.9 mmol) was added to 2-bromo-6-iodo-3-methoxypyridine (4.75 g, 15.1 mmol) in DMF (10 mL) under argon. The resulting suspension was stirred at 100 0C for 2 hours. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with saturated NaHCO3 (100 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% DCM in isohexane. Pure fractions were evaporated to dryness to afford 6-iodo-2,3- dimethoxypyridine (1.86 g, 46.3 %) as a white solid. MS (+ve ESI) : Rt = 2.19min, 266.37 (M+H)+M+ 1U KiMR (400.132 MHz, CDCB) δ 3.85 (3H, s), 4.00 (3H, s), 6.74 (IH, d), 7.23 (IH, d) (R)-tert-butyl 4-(5,6-dimethoxypyridin-2-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000126_0001
In a similar manner to method A 6-iodo-2,3-dimethoxypyridine (0.500 g, 1.89 mmol) was added to (i?)-l-7V-BOC-2-methyl piperazine (0.483 g, 2.26 mmol) to yield after reaction and work up (R)-tert-butyl 4-(5,6-dimethoxypyridin-2-yl)-2-methylpiperazine-l- carboxylate (0.505 g, 79 %) as a yellow gum.
MS (+ve ESI) : Rt = 2.80 min, 338.51 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.23 (3H, d), 1.48 (9H, s), 2.79 (IH, m), 2.99 (IH, m), 3.22 (IH, m), 3.79 (3H, s), 3.84 - 4.02 (6H, m), 4.33 (IH, m), 6.06 (IH, d), 7.04 (IH, d)
(R)-l-(5,6-dimethoxypyridin-2-yl)-3-methylpiperazine
Figure imgf000126_0002
In a similar manner to method A (i?)-tert-butyl 4-(5,6-dimethoxypyridin-2-yl)-2- methylpiperazine-1-carboxylate (0.505 g, 1.50 mmol) was added to hydrochloric acid in methanol (methanol reagent 10) (10 mL, 1.50 mmol) and the resulting solution was stirred at room temperature for 16 hours to afford (i?)-l-(5,6-dimethoxypyridin-2-yl)-3- methylpiperazine (95 %) as an orange oil after work up.
MS (+ve ESI) : Rt = 1.44 min, 238.52 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.17 (3H, d), 2.39 (IH, m), 2.74 (IH, m), 2.92 - 3.04 (2H, m), 3.13 (IH, m), 3.80 (3H, s), 3.93 - 4.01 (5H, m), 6.09 (IH, d), 7.04 (IH, d)
Example 79
(l/f,2R)-2-(4-(4-chlorophenyl)-3-oxopiperazine-l-carbonyl)-N-(l- cyanocyclopropyl)cyclohexanecarboxamide
Figure imgf000127_0001
In a similar manner to example 73 a solution of (3ai?,7ai?)-hexahydroisobenzofuran-l,3- dione (6.15 mg, 0.04 mmol) and l-(4-chlorophenyl)piperazin-2-one [WO 2007080382](8.40 mg, 0.04 mmol) in DMF (2 mL) was stirred at ambient temperature for 3 hours. HATU (16.68 mg, 0.04 mmol) was then added, followed by 1- aminocyclopropanecarbonitrile hydrochloride (5.20 mg, 0.04 mmol) and N- ethyldiisopropylamine (0.034 mL, 0.20 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours to afford (li?,2i?)-2-(4-(4-chlorophenyl)-3- oxopiperazine-l-carbonyl)-Λ/-(l-cyanocyclopropyl)cyclohexanecarboxamide (8.00 mg, 46.8 %) as a white solid after work up and isolation. MS (+ve ESI) : Rt = 1.84 min, 427.35 (M+H)+
Example 80
(lR,2R)-N-(l-cyanocyclopropyl)-2-((R)-4-(l,3-dimethyl-lH-indazol-6-yl)-2- methylpiperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000127_0002
In a similar manner to example 73 (3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (0.237 g, 1.54 mmol) was added to (i?)-l,3-dimethyl-6-(3-methylpiperazin-l-yl)-lH-indazole (0.376 g, 1.54 mmol) in DMF (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. DIPEA (1.02 mL, 6.16 mmol), HATU (0.703 g, 1.85 mmol) and 1 -amino- 1-cyclopropanecarbonitrile. HCL (0.219 g, 1.85 mmol) were then added and the resulting solution was stirred at room temperature for 20 hours to obtain (li?,2i?)-N-(l- cyanocyclopropyl)-2-((i?)-4-(l,3-dimethyl-7H-indazol-6-yl)-2-methylpiperazine-l- carbonyl)cyclohexanecarboxamide (600mg, 84 %) as a white solid after work up and isolation.
MS (+ve ESI) : Rt = 1.97 min, 463.29 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.07 - 1.91 (13H, m), 2.50 (3H, d), 2.64 (IH, t), 2.73 -
3.07 (3.5H, m), 3.19 - 3.28 (0.5H, m), 3.44 - 3.67 (4H, m), 3.88 - 3.97 (0.5H, m), 3.92 (3H, s), 4.12 - 4.20 (0.5H, m), 4.47 (0.5H, d), 4.84 - 4.91 (0.5H, m), 6.56 - 6.61 (IH, m), 6.71
(0.5H, s), 6.78 - 6.84 (1.5H, m), 7.46 - 7.52 (IH, m)
Synthesis of (R)-l,3-dimethyl-6-(3-methylpiperazin-l-yl)-lH-indazole l-(4-Bromo-2-hydroxyphenyl)ethanone
Figure imgf000128_0001
Aluminum chloride (6.94 g, 52.0 mmol) was added portionwise to a solution of 3- bromophenol (6 g, 34.6 mmol) in 1 ,2-dichloroethane (25 mL) at ambient temperature under argon with a 2M NaOH scrubber attached (some gas evolution - small exotherm). To the resulting orange solution was added acetyl chloride (2.47 mL, 34.7 mmol) dropwise (exotherm here and gas evolution). The resulting dark brown solution was heated to reflux temperature (blast shield as a precaution) for 5 hours and then allowed to cool to room temperature under argon. The mixture was then added slowly to a ~1M HCl ice/water mixture (150 mL) and then extracted with dichlorome thane (15OmL). The organic layer was dried (Na2SO4), filtered and concentrated at reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 5 to 30% EtOAc in isohexane.
Pure fractions were evaporated to dryness to afford l-(4-bromo-2-hydroxyphenyl)ethanone
(4.10 g, 55.0 %) as a yellow oil which solidified on standing.
MS (+ve ESI) : Rt = 1.70 min, 215.29 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 2.61 (3H, s), 7.03 - 7.06 (IH, m), 7.18 (IH, d), 7.58 (IH, d), 12.35 (IH, s)
2-Acetyl-5-bromophenyl methanesulfonate
Figure imgf000128_0002
Methanesulfonyl chloride (0.40 mL, 5.12 mmol) was added dropwise to a solution of l-(4- bromo-2-hydroxyphenyl)ethanone (1.00 g, 4.65 mmol) and triethylamine (1.30 mL, 9.30 mmol) in DCM (30 mL) at 0 0C. After 1 hour allowed to warm to room temperature and was stirred for a further 2 hours. The reaction was quenched with IM HCl (2OmL), diluted with DCM (2OmL) and the layers separated by phase transfer cartridge. Concentrated organic layer at reduced pressure and purified by flash silica chromatography, elution gradient 5 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 2-acetyl-5-bromophenyl methanesulfonate (1.36 g, 100 %) as a colourless oil which solidified on standing. MS (+ve ESI) : Rt = 2.00 min, 229.33 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 2.61 (3H, s), 3.28 (3H, s), 7.53 - 7.57 (IH, m), 7.61
(IH, d), 7.64 (IH, d)
6-Bromo-l,3-dimethyl-lH-indazole
Figure imgf000129_0001
Methylhydrazine (0.428 mL, 7.98 mmol) was added to a solution of 2-acetyl-5- bromophenyl methanesulfonate (1.17 g, 3.99 mmol) and Ammonium acetate (0.769 g, 9.98 mmol) in xylenes (6 mL) at ambient temperature. The resulting solution was heated to 135 0C for 26 hours with Dean-Stark apparatus attached so to enable water removal. The reaction mixture was cooled to room temperature and concentrated and diluted with toluene (75 mL), and washed sequentially with 2M HCl (50 mL) and water (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 6-bromo-l,3- dimethyl-lH-indazole (0.770 g, 86.0 %) as a yellow solid. MS (+ve ESI) : Rt = 2.20 min, 225.34 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 2.54 (3H, s), 3.96 (3H, s), 7.18 - 7.22 (IH, m), 7.48 -
7.52 (2H, m)
(R)-tert-butyl 4-(l,3-dimethyl-lH-indazol-6-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000130_0001
In a similar manner to method B (R)-tert-butyl 2-methylpiperazine-l-carboxylate (654 mg, 3.27 mmol), potassium 2-methylpropan-2-olate (419 mg, 3.73 mmol) and PEPPSI (42.4 mg, 0.06 mmol) were suspended in DME (3 mL) and the mixture stirred for 1 minute under a blanket of argon, 6-bromo-l,3-dimethyl-lH-indazole (700 mg, 3.11 mmol) in DME (3 mL) was added and the reaction heated to 50 0C for 18 hours and then allowed to cool to afford {R)-tert-bvXy\ 4-(l,3-dimethyl-iH-indazol-6-yl)-2-methylpiperazine-l- carboxylate (840 mg, 78 %) as a colourless gum after work up. MS (+ve ESI) : Rt = 2.53 min, 345.28 (M+H)+ 1H NMi? (400.132 MHz, CDC13) δ 1.34 (3H, d), 1.50 (9H, s), 2.50 (3H, s), 2.77 - 2.85
(IH, m), 2.96 - 3.02 (IH, m), 3.26 - 3.34 (IH, m), 3.43 - 3.48 (IH, m), 3.54 - 3.60 (IH, m), 3.92 (3H, s), 3.98 (IH, d), 4.38 (IH, s), 6.57 (IH, d), 6.80 - 6.84 (IH, m), 7.49 (IH, d) (R)-l,3-dimethyl-6-(3-methylpiperazin-l-yl)-lH-indazole
Figure imgf000130_0002
In a similar manner to method B trifiuoroacetic acid (2.15 mL, 27.9 mmol) was added to a solution of (R)-tert-butyl 4-(l,3-dimethyl-iH-indazol-6-yl)-2-methylpiperazine-l- carboxylate (800 mg, 2.32 mmol) in dichloromethane (5 mL) at ambient temperature to afford (i?)-l,3-dimethyl-6-(3-methylpiperazin-l-yl)-lH-indazole (490 mg, 86 %) as a yellow gum after work up. MS (+ve ESI) : Rt = 1.49 min, 245.29 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.15 (3H, d), 1.92 (IH, s), 2.40 (IH, t), 2.49 (3H, s), 2.71 - 2.80 (IH, m), 2.97 - 3.16 (3H, m), 3.58 (2H, d), 3.91 (3H, s), 6.59 (IH, d), 6.84 - 6.88 (IH, m), 7.47 (IH, d) Example 81
(lR,2R)-N-(l-cyanocyclopropyl)-2-((R)-4-(l,3-dimethyl-lH-indazol-5-yl)-2- methylpiperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000131_0001
In a similar manner to example 73 (3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (0.065 g, 0.42 mmol) was added to (i?)-l,3-dimethyl-5-(3-methylpiperazin-l-yl)-lH-indazole (0.103 g, 0.42 mmol) in DCM (3 mL) at room temperature. The resulting solution was stirred at room temperature for 5 hours. To the reaction mixture was added HATU (0.224 g, 0.59 mmol), 1 -amino- l-cyclopropanecarbonitrile HCl (0.065 g, 0.55 mmol) and N,N- diisopropylethylamine (0.220 mL, 1.26 mmol). The resulting solution was stirred at room temperature for 3 days to afford (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(l,3-dimethyl- 7H-indazol-5-yl)-2-methylpiperazine-l-carbonyl)cyclohexanecarboxamide (68.7 %) as a cream solid after work up and isolation. MS (+ve ESI) : Rt = 1.97 min, 463.55 (M+H)+ 1R NMi? (400.132 MHz, DMSO) δ 0.91 - 1.08 (2H, m), 1.12 - 1.48 (9H, m), 1.65 - 1.84 (4H, m), 2.41 (3H, s), 2.54 (IH, m), 2.60 - 3.00 (3H, m), 3.38 (IH, m), 3.40 - 3.55 (2H, m), 3.90 (3H, s), 3.95 - 4.72 (2H, m), 7.04 (IH, m), 7.20 (IH, m), 7.45 (IH, d), 8.70 (IH, d) Synthesis of (R)-l,3-dimethyl-5-(3-methylpiperazin-l-yl)-lH-indazole 5-Bromo-l,3-dimethyl-lH-indazole
Figure imgf000131_0002
Sodium hydride 60% dispersion (0.171 g, 4.26 mmol) was added to 5 -bromo-3 -methyl- IH- indazole (0.750 g, 3.55 mmol) in anhydrous DMF (15 mL) under argon. The resulting suspension was stirred at room temperature for 15 minutes. To the reaction was added methyl iodide (0.299 mL, 4.80 mmol) and stirred at room temperature for a further 3 days. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (3 x 50 mL), the organic layers were combined and washed with saturated brine (2 x 50 mL), dried over MgSO4, filtered and evaporated to afford orange oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% Et2O in isohexane. Pure fractions were evaporated to dryness to afford 5-bromo-l,3-dimethyl-lH-indazole (0.448 g, 56.0 %) as a yellow oil.
MS (+ve ESI) : Rt = 2.19 min, 225.33 (M+H)+
IH NMi? (400.132 MHz, CDC13) δ 2.51 (3H, s), 3.98 (3H, s), 7.19 (IH, d), 7.42 (IH, d), 7.78 (IH, s) (R)-tert-Bntyl 4-(l,3-dimethyl-lH-indazol-5-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000132_0001
In a similar manner to method A 5 -bromo- 1,3 -dimethyl- lΗ-indazole (0.448 g, 1.99 mmol) was reacted with (i?)-l-7V-Boc-2-methyl piperazine (0.399 g, 1.99 mmol) to afford (R)- tert-butyl 4-(l,3-dimethyl-iH-indazol-5-yl)-2-methylpiperazine-l-carboxylate (0.363 g, 52.9 %) as a white solid after isolation and work up. MS (+ve ESI) : Rt = 2.58 min, 345.55 (M+Η)+
1H NMi? (400.132 MHz, CDC13) δ 1.37 (3H, d), 1.50 4(9H, s), 2.52 (3H, s), 2.72 (IH, m), 2.88 (IH, m), 3.25 - 3.33 (2H, m), 3.41 (IH, d), 3.96 (3H, s), 3.99 (IH, m), 4.37 (IH, s), 7.00 (IH, d), 7.14 (IH, m), 7.25 (41H, d) (R)-l,3-dimethyl-5-(3-methylpiperazin-l-yl)-lH-indazole
Figure imgf000132_0002
In a similat manner to method A (R)-tert-butyl 4-(l,3-dimethyl-ii/-indazol-5-yl)-2- methylpiperazine-1-carboxylate (0.363 g, 1.05 mmol) was added to hydrochloric acid in methanol (methanol reagent 10) (15 mL, 1.05 mmol) and the resulting solution was stirred at room temperature for 16 hours to afford (i?)-l,3-dimethyl-5-(3-methylpiperazin-l-yl)- iϋ-indazole (80 %) as a yellow gum after work up and isolation.
MS (+ve ESI) : Rt = 1.27 min, 245.50 (M+H)+
IH NMi? (400.132 MHz, CDC13) δ 1.21 (3H, d), 2.05 (IH, s), 2.44 (IH, t), 2.53 (3H, s),
2.78 (IH, m), 3.07 - 3.22 (3H, m), 3.45 (2H, m), 3.96 (3H, s), 7.03 (IH, d), 7.18 (IH, m),
7.25 (IH, d)
Example 82
(l/f,2R)-Λ/-(l-cyanocyclopropyl)-2-((R)-4-(3,4-diethoxyphenyl)-2-methylpiperazine-l- carbonyl)cyclohexanecarboxamide
Figure imgf000133_0001
In a similar manner to example 73 (3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (0.071 g, 0.460 mmol) was added to (i?)-l-(3,4-diethoxyphenyl)-3-methylpiperazine (0.121 g, 0.460 mmol) in DCM (3 mL) at room temperature. The resulting solution was stirred at room temperature for 16 hours. To the reaction mixture was added HATU (0.244 g, 0.64 mmol), 1 -amino- 1-cyclopropanecarbonitrile HCl (0.071 g, 0.60 mmol) and N, N- diisopropylethylamine (0.239 mL, 1.37 mmol). The resulting solution was stirred at room temperature for 3 days to afford (li?,2i?)-7V-(l-cyanocyclopropyl)-2-((i?)-4-(3,4- diethoxyphenyl)-2-methylpiperazine-l-carbonyl)cyclohexanecarboxamide (186 mg, 84 %) as a white solid. MS (+ve ESI) : Rt = 2.35min, 483.53 (M+H)+
1U NMi? (400.132 MHz, DMSO) δ 0.92 - 1.06 (2H, m), 1.14 - 1.44 (15H, m), 1.65 - 1.81 (4H, m), 2.40 (IH, m), 2.57 - 2.95 (3H, m), 3.26 (IH, m), 3.33 - 3.50 (2H, m), 3.93 (2H, m), 3.99 - 4.67 (3H, m), 4.20 (IH, d), 6.41 (IH, 4m), 6.58 (IH, m), 6.82 (IH, d), 8.64 (IH, s). (R)-l-(3,4-diethoxyphenyl)-3-methylpiperazine was synthesised in the following manner. 4-Bromo-l,2-diethoxybenzene
Figure imgf000134_0001
Iodoethane (0.935 mL, 11.6 mmol) was added to 4-bromobenzene-l,2-diol (1.00 g, 5.29 mmol) and Potassium carbonate (1.76 g, 12.7 mmol) in acetone (40 mL). The resulting suspension was stirred at 50 0C for 18 hours. The reaction mixture was evaporated to dryness and redissolved in Et2O (100 mL), and washed sequentially with water (100 mL),
2M NaOH (100 mL), and saturated brine (75 mL). The organic layer was dried over
MgSO4, filtered and evaporated to afford crude product.
MS (+ve ESI) : Rt = 2.29min, no mass ion IH NMi? (400.132 MHz, CDC13) δ 1.41 - 1.47 (6H, m), 4.03 - 4.09 (4H, m), 6.74 (IH, d),
6.97 - 7.01 (2H, m)
(R)-tert-butyl 4-(3,4-diethoxyphenyl)-2-methylpiperazine-l-carboxylate
Figure imgf000134_0002
Following method A 4-bromo-l,2-diethoxybenzene (0.500 g, 2.04 mmol) was reacted with (i?)-l-7V-Boc-2-methyl piperazine (0.409 g, 2.04 mmol) to afford (R)-tert-butyl 4-(3,4- diethoxyphenyl)-2-methylpiperazine-l-carboxylate (0.358 g, 48.2 %) as a pink oil after workup and isolation.
MS (+ve ESI) : Rt = 3.06 min, 365.49 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.32 (3H, d), 1.38 - 1.46 (6H, m), 1.48 (9H, s), 2.65 (IH, m), 2.83 (IH, m), 3.19 - 3.27 (2H, m), 3.35 (IH, m), 3.93 (IH, d), 4.00 - 4.13 (4H, m), 4.33 (IH, s), 6.41 (IH, m), 6.53 (IH, d), 6.81 (IH, 4d)
(R)-l-(3,4-diethoxyphenyl)-3-methylpiperazine
Figure imgf000135_0001
Following method A (R)-tert-butyl 4-(3,4-diethoxyphenyl)-2-methylpiperazine-l- carboxylate (0.358 g, 0.98 mmol) was added to hydrochloric acid in methanol (methanol reagent 10) (10 mL, 0.98 mmol) and the resulting solution was stirred at room temperature for 16 hours to afford (i?)-l-(3,4-diethoxyphenyl)-3-methylpiperazine (93 %) as a beige gum after work up and isolation. MS (+ve ESI) : Rt = 1.62 min, 265.51 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.24 (3H, d), 1.38 - 1.47 (6H, m), 2.48 (IH, t), 2.81 (IH, m), 3.04 - 3.24 (4H, m), 3.39 (2H, d), 4.00 - 4.11 (4H, m), 6.45 (IH, m), 6.57 (IH, d), 6.81 (IH, d).
Example 83
(lR,2R)-N-(l-cyanocyclopropyl)-2-((R)-4-(4-ethoxy-3-methylphenyl)-2- methylpiperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000135_0002
In a similar manner to example 73 (3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (0.120 g, 0.780 mmol) was added to (i?)-l-(4-ethoxy-3-methylphenyl)-3-methylpiperazine (0.182 g, 0.78 mmol) in DMF (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. DIPEA (0.515 mL, 3.11 mmol), HATU (0.414 g, 1.09 mmol) and 1 -amino- 1-cyclopropanecarbonitrile. HCL (0.129 g, 1.09 mmol) were then added and the resulting solution was stirred at room temperature for 20 hours to obtain (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(4-ethoxy-3-methylphenyl)-2-methylpiperazine- l-carbonyl)cyclohexanecarboxamide (291mg, 83 %) as a white solid after work up and isolation.
MS (+ve ESI) : Rt = 2.45min, 453.22 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.05 - 1.89 (18H, m), 2.20 (3H, d), 2.54 - 2.67 (1.5H, m), 2.74 - 2.89 (2.5H, m), 3.09 - 3.52 (3H, m), 3.83 (0.5H, d), 3.93 - 4.01 (2H, m), 4.04 -
4.12 (0.5H, m), 4.43 (0.5H, d), 4.77 - 4.84 (0.5H, m), 6.62 - 6.77 (4H, m)
(R)-l-(4-ethoxy-3-methylphenyl)-3-methylpiperazine was synthesised in the following manner. l-Ethoxy-4-iodo-2-methylbenzene
Figure imgf000136_0001
Iodoethane (0.789 mL, 9.87 mmol) was added to a mixture of 4-iodo-2-methylphenol (2.10 g, 8.97 mmol) and Potassium carbonate (3.72 g, 26.92 mmol) in DMF (20 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with water (2 x 50 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford desired product l-ethoxy-4-iodo-2-methylbenzene (2.30 g, 98 %). MS (+ve ESI) : Rt = 2.92 min, no mass ion
IH NMi? (400.132 MHz, CDC13) δ 1.41 (3H, t), 2.16 (3H, s), 3.99 (2H, q), 6.56 (IH, d), 7.39 - 7.43 (2H, m) (R)-tert-butyl 4-(4-ethoxy-3-methylphenyl)-2-methylpiperazine-l-carboxylate
Figure imgf000136_0002
Following method B (R)-tert-butyl 2-methylpiperazine-l-carboxylate (481 mg, 2.40 mmol) was reacted with l-ethoxy-4-iodo-2-methylbenzene (600 mg, 2.29 mmol) in DME (5 mL) was added and the reaction heated to 50 0C to afford (R)-tert-butyl 4-(4-ethoxy-3- methylphenyl)-2-methylpiperazine-l-carboxylate (550 mg, 71.8 %) as a colourless gum. MS (+ve ESI) : Rt = 3.10min, 335.30 (M+H)+ 1H NMi? (400.132 MHz, CDC13) δ 1.32 (3H, d), 1.39 (3H, t), 1.48 (9H, s), 2.21 (3H, s), 2.58 - 2.67 (IH, m), 2.77 - 2.83 (IH, m), 3.17 - 3.24 (2H, m), 3.30 - 3.36 (IH, m), 3.89 - 4.01 (IH, m), 3.97 (2H, q), 4.28 - 4.36 (IH, m), 6.66 - 6.70 (IH, m), 6.72 - 6.78 (2H, m) (R)-l-(4-ethoxy-3-methylphenyl)-3-methylpiperazine
Figure imgf000137_0001
In a similar manner to method B trifluoroacetic acid (1.437 mL, 18.66 mmol) was added to a solution of (i?)-tert-butyl 4-(4-ethoxy-3-methylphenyl)-2-methylpiperazine-l-carboxylate (520 mg, 1.55 mmol) in dichloromethane (5 mL) at ambient temperature. The resulting solution was stirred at ambient temperature for 5 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3ZMeOH and pure fractions were evaporated to dryness to afford (i?)-l-(4-ethoxy-3-methylphenyl)-3-methylpiperazine (364 mg, 100 %) as a yellow gum. MS (+ve ESI) : Rt = 2.00 min, 235.28 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.12 (3H, d), 1.39 (3H, t), 1.55 (IH, s), 2.21 (3H, s), 2.27 (IH, t), 2.59 - 2.66 (IH, m), 2.95 - 3.13 (3H, m), 3.33 - 3.40 (2H, m), 3.97 (2H, q), 6.69 - 6.81 (3H, m)
Example 84
(lR,2R)-N-(l-cyanocyclopropyl)-2-((R)-2-methyl-4-(3-methyl-4-
(methylsulfonyl)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000137_0002
In a similar manner to example 73 (3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (0.238 g, 1.55 mmol) was added to (i?)-3 -methyl- 1 -(3 -methyl-4-(methylsulfonyl)phenyl)piperazine (0.415 g, 1.55 mmol) in DMF (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. DIPEA (1.02 mL, 6.19 mmol), HATU (1.06 g, 2.78 mmol) and 1 -amino- l-cyclopropanecarbonitrile. HCL (0.330 g, 2.78 mmol) were then added and the resulting solution was stirred at room temperature for 20 hours to afford (li?,2i?)-N-(l-cyanocyclopropyl)-2-((i?)-2-methyl-4-(3-methyl-4-
(methylsulfonyl)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide (51.8 %) 390 mg as a colourless gum after work up and isolation.
MS (+ve ESI) : Rt = 1.88 min, 487 (M+H)+
1H NMi? (400.13 MHz, CDC13) δ 0.94 - 0.95 (IH, m), 1.08 - 1.24 (3H, m), 1.26 - 1.53 (6H, m), 1.62 - 1.67 (IH, m), 1.77 - 1.84 (4H, m), 2.57 - 2.64 (4H, m), 2.77 - 2.99 (IH, m),
3.02 (3H, d), 3.16 - 3.30 (2H, m), 3.51 - 3.76 (3H, m), 3.89 - 4.84 (2H, m), 6.46 and 6.51
(2 x IH, m), 6.64 - 6.72 (2H, m), 7.84 - 7.88 (IH, m)
(R)-3-methyl-l-(3-methyl-4-(methylsulfonyl)phenyl)piperazine was synthesised in the following manner. (R)-tert-butyl 2-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)piperazine-l- carboxylate
Figure imgf000138_0001
(i?)-l-7V-BOC-2-methyl piperazine (3.83 g, 19.1 mmol) was added to 4-fluoro-2-methyl-l- (methylsulfonyl)benzene (3.00 g, 15.9 mmol) and potassium carbonate (2.64 g, 19.1 mmol) in DMF (200 mL) at 18 0C under air. The resulting mixture was stirred at 130 0C for 72 hours. The solvent was removed under reduced pressure to afford a brown gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 2- methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)piperazine-l-carboxylate (1.02 g, 17.4 %) as a white solid.
MS (+ve ESI) : Rt = 2.44 min, 369 (M+H)+ (R)-3-methyl-l-(3-methyl-4-(methylsulfonyl)phenyl)piperazine
Figure imgf000139_0001
(R)-tert-Butyl 2-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)piperazine- 1 -carboxylate (1.50 g, 4.07 mmol) was added HCl (0.124 mL, 4.07 mmol) in methanol (100 mL) room temeprature. The resulting solution was stirred at room temperature for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NHVMeOH and pure fractions were evaporated to dryness to afford (i?)-3-methyl-l-(3-methyl-4- (methylsulfonyl)phenyl)piperazine (0.830 g, 76 %) as a yellow gum. MS (+ve ESI) : Rt = 1.36 min, 269 (M+H)+
Example 85
(lR,2R)-N-(l-cyanocyclopropyl)-2-((R)-4-(4-(2-methoxyethoxy)-3-methylphenyl)-2- methylpiperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000139_0002
Following example 73, to a solution of (i?)-l-(4-(2-methoxyethoxy)-3-methylphenyl)-3- methylpiperazine (0.132 g, 0.500 mmol) in DCM (5 ml) was added (3aR,7aR)- hexahydroisobenzofuran-l,3-dione (0.077 g, 0.500 mmol) and triethylamine (0.070 ml, 0.500 mmol) and the reaction stirred for 4 hours, HATU (0.209 g, 0.55 mmol), 1-amino-l- cyclopropanecarbonitrile HCl (0.083 g, 0.70 mmol) and triethylamine (0.139 ml, 1.00 mmol) were added and the reaction stirred for 18 hours to give (li?,2i?)-Λ/-(l- cyanocyclopropyl)-2-((i?)-4-(4-(2-methoxyethoxy)-3-methylphenyl)-2-methylpiperazine-l- carbonyl)cyclohexanecarboxamide (0.149 g, 61.7 %) as a white foam after work up and isolation.
MS (+ve ESI) : 483 (M+H)+ 1H NMi? (400.132 MHz, CDC13) δ 1.05 - 1.87 (15H, m), 2.22 (3H, s), 2.55 - 2.66 (2H, m),
2.73 - 2.87 (2H, m), 3.08 - 3.51 (3H, m), 3.45 (3H, s), 3.71 - 3.75 (2H, m), 3.79 - 3.86 and
4.39 - 4.47(1H, m), 4.04 - 4.08 (2H, m), 4.07 - 4.12 and 4.77 - 4.85 (IH, m), 6.57 - 6.78
(4H, m)
(R)-l-(4-(2-methoxyethoxy)-3-methylphenyl)-3-methylpiperazine was synthesised in the following manner.
4-Bromo-l-(2-methoxyethoxy)-2-methylbenzene
Figure imgf000140_0001
To a mixture of 4-bromo-2-methylphenol (1.870 g, 10.0 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in acetone (50 mL) was added l-bromo-2-methoxyethane (1.88 mL, 20 mmol) and the reaction heated at reflux for 17 hours, further l-bromo-2-methoxyethane (0.470 mL, 5.00 mmol) added and the reaction heated for 7 hours. Partitioned with water (100 mL) and DCM (100 mL) and the organic layer washed with further water (100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Semi-pure fractions were evaporated to dryness and then dissolved in DCM (50 mL) and washed with 2M NaOH (2 x 50 mL), dried over MgSO4, filtered and evaporated to give 4-bromo-l-(2- methoxyethoxy)-2-methylbenzene (2.13 g, 67 %-from both reactions) as a yellow oil. MS (+ve ESI) : Rt = 2.66 min, no mass ion observed. 1H NMi? (400.132 MHz, CDC13) δ 2.21 (3H, s), 3.45 (3H, s), 3.75 (2H, t), 4.08 (2H, t), 6.69 (IH, d), 7.20 - 7.25 (2H, m)
(R)-tert-butyl 4-(4-(2-methoxyethoxy)-3-methylphenyl)-2-methylpiperazine-l- carboxylate
Figure imgf000140_0002
In a similar manner to method B (R)-tert-Butyl 2-methylpiperazine-l-carboxylate (506 mg, 2.53 mmol) was reacted with 4-bromo-l-(2-methoxyethoxy)-2-methylbenzene (590 mg, 2.41 mmol) in DME (4 mL) at 60 0C for 20 hours to afford (R)-tert-buty\ 4-(4-(2- methoxyethoxy)-3-methylphenyl)-2-methylpiperazine-l-carboxylate (520 mg, 59.3 %) as a yellow oil after work up and isolation. MS (+ve ESI) : 365 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.31 (3H, d), 1.48 (9H, s), 2.59 - 2.68 (IH, m), 2.78 - 2.84 (IH, m), 3.17 - 3.24 (2H, m), 3.33 (IH, d), 3.45 (3H, s), 3.73 (2H, t), 3.89 - 3.96 (IH, m), 4.06 (2H, t), 4.27 - 4.35 (IH, m), 6.65 - 6.69 (IH, m), 6.73 - 6.78 (2H, m) (R)-l-(4-(2-methoxyethoxy)-3-methylphenyl)-3-methylpiperazine
Figure imgf000141_0001
In a similar manner to method B (R)-tert-butyl 4-(4-(2-methoxyethoxy)-3-methylphenyl)- 2-methylpiperazine-l-carboxylate (520 mg, 1.43 mmol) was dissolved in hydrogen chloride (4M in dioxane) (14 ml, 56.0 mmol) and the reaction stirred for 1 hour to afford (i?)-l-(4-(2-methoxyethoxy)-3-methylphenyl)-3-methylpiperazine (370 mg, 98 %) as a brown oil after work up and isolation. MS (+ve ESI) : 265 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.11 (3H, d), 2.22 (3H, s), 2.28 (IH, t), 2.58 - 2.67 (IH, m), 2.93 - 3.12 (3H, m), 3.32 - 3.41 (2H, m), 3.45 (3H, s), 3.71 - 3.76 (2H, m), 4.02 - 4.10 (2H, m), 6.68 - 6.80 (3H, m)
Example 86
(l/f,2R)-Λ/-(l-cyanocyclopropyl)-2-((R)-4-(3-methoxy-4-(oxetan-3-yloxy)phenyl)-2- methylpiperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000141_0002
In a similar manner to Example 73, to a solution of (i?)-l-(3-methoxy-4-(oxetan-3- yloxy)phenyl)-3-methylpiperazine (90.0 mg, 0.320 mmol) in DCM (3 mL) was added (3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (49.8 mg, 0.320 mmol) and triethylamine (0.045 ml, 0.320 mmol) and the reaction stirred for 3 hours, HATU (135 mg, 0.360 mmol), 1 -amino- l-cyclopropanecarbonitrile HCl (53.7 mg, 0.450 mmol) and triethylamine (0.090 ml, 0.650 mmol) were added and the reaction stirred for 22 hours to give (1R,2R)-N-(1- cyanocyclopropyl)-2-((i?)-4-(3-methoxy-4-(oxetan-3-yloxy)phenyl)-2-methylpiperazine-l- carbonyl)cyclohexanecarboxamide (30.0 mg, 18.68 %) as pale yellow dry film after work up and isolation. MS (+ve ESI) : Rt = 497 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.06 - 1.86 (HH, m), 2.56 - 2.95 (4H, m), 3.12 - 3.54 (3H, m), 3.80 - 3.87 (4H, m), 3.82 - 3.85 and 4.06 - 4.13 (IH, m), 3.85 (3H, d), 4.41 - 4.48 (IH, m), 4.79 - 4.92 (4H, m), 5.07 - 5.15 (IH, m), 6.32 - 6.39 (IH, m), 6.43 - 6.54 (3H, m) (R)-l-(3-methoxy-4-(oxetan-3-yloxy)phenyl)-3-methylpiperazine was synthesised in the following manner.
(R)-tert-butyl 4-(4-(benzyloxy)-3-methoxyphenyl)-2-methylpiperazine-l-carboxylate
Figure imgf000142_0001
In a similar manner to method B l-(benzyloxy)-4-bromo-2-methoxybenzene (2.93 g, 10.0 mmol) was reacted with (R)-tert-butyl 2-methylpiperazine-l-carboxylate (2.10 g, 10.5 mmol to afford (R)-tert-butyl 4-(4-(benzyloxy)-3-methoxyphenyl)-2-methylpiperazine-l- carboxylate (2.35 g, 57.0 %) as a yellow solid after work up and isolation.
MS (+ve ESI) : Rt = 413 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.31 (3H, d), 1.48 (9H, s), 2.62 - 2.70 (IH, m), 2.80 -
2.89 (IH, m), 3.18 - 3.26 (2H, m), 3.32 - 3.41 (IH, m), 3.87 (3H, s), 3.89 - 3.97 (IH, m), 4.28 - 4.37 (IH, m), 5.07 (2H, s), 6.33 - 6.39 (IH, m), 6.53 (IH, d), 6.80 (IH, d), 7.27 -
7.45 (5H, m)
(R)-tert-butyl 4-(4-hydroxy-3-methoxyphenyl)-2-methylpiperazine-l-carboxylate
Figure imgf000143_0001
(R)-tert-buty{ 4-(4-(benzyloxy)-3 -methoxyphenyl)-2-methylpiperazine- 1 -carboxylate (2.35 g, 5.70 mmol) was suspended in ethanol (57 mL) and palladium hydroxide (0.800 g, 5.70 mmol) added. The system was stirred under a H2 atmosphere for 18 hours and then filtered through celite and evaporated, azeotroped with toluene twice to give (R)-tert-butyl A-(A- hydroxy-3-methoxyphenyl)-2-methylpiperazine-l -carboxylate (1.66 g, 90 %) as a purple oil.
MS (+ve ESI) : Rt = 323 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.32 (3H, d), 1.48 (9H, s), 2.66 (IH, t), 2.80 - 2.87 (IH, m), 3.12 - 3.35 (3H, m), 3.88 (3H, s), 3.89 - 3.97 (IH, m), 4.28 - 4.38 (IH, m), 5.23 (IH, s), 6.40 - 6.45 (IH, m), 6.49 - 6.51 (IH, m), 6.82 (IH, d)
(R)-tert-bntyl 4-(3-methoxy-4-(oxetan-3-yloxy)phenyl)-2-methylpiperazine-l- carboxylate
Figure imgf000143_0002
(R)-tert-buty{ 4-(4-hydroxy-3-methoxyphenyl)-2-methylpiperazine-l -carboxylate (0.645 g, 2.00 mmol) was dissolved in NMP (5 mL) and sodium hydride (0.088 g, 2.20 mmol) added portionwise and the reaction stirred for 10 minutes. Oxetan-3-yl A- methylbenzenesulfonate (0.548 g, 2.40 mmol) was added in one portion and the reaction was heated to 120 0C for 17 hours and then allowed to cool. Poured into water (50 ml) and extracted with EtOAc (3 x 50 mL), the combined organic extracts were washed with water (100 mL) and then saturated brine (100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-bvXy\ A- (3-methoxy-4-(oxetan-3-yloxy)phenyl)-2-methylpiperazine-l-carboxylate (0.306 g, 40.4
%) as a cream solid.
MS (+ve ESI) : Rt = 2.46 min, 379 (M+H)+
IH NMi? (400.132 MHz, CDC13) δ 1.31 (3H, d), 1.48 (9H, s), 2.63 - 2.72 (IH, m), 2.83 -
2.89 (IH, m), 3.19 - 3.25 (2H, m), 3.33 - 3.40 (IH, m), 3.86 (3H, s), 3.90 - 3.97 (IH, m),
4.29 - 4.38 (IH, m), 4.83 (2H, t), 4.89 (2H, t), 5.08 - 5.15 (IH, m), 6.33 - 6.37 (IH, m),
6.48 (IH, d), 6.52 (IH, d)
(R)-l-(3-methoxy-4-(oxetan-3-yloxy)phenyl)-3-methylpiperazine
Figure imgf000144_0001
(R)-tert-butyl 2-methyl-4-(3-methyl-4-(oxetan-3-yloxy)phenyl)piperazine- 1 -carboxylate (492 mg, 1.36 mmol) was dissolved in TFA (14 mL) and the reaction aged for 30 minutes and then evaporated. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3ZMeOH and pure fractions were evaporated to dryness to afford (R)-3 -methyl- 1 -(3- methyl-4-(oxetan-3-yloxy)phenyl)piperazine (315 mg, 88 %) as a brown gum. MS (+ve ESI) : 279 (M+H)+
Example 87
(lR,2R)-N-(l-cyanocyclopropyl)-2-((R)-2-methyl-4-(3-methyl-4-(oxetan-3- yloxy)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000144_0002
In a similar manner to Example 73, to a solution of (i?)-3 -methyl- 1 -(3 -methyl-4-(oxetan-3- yloxy)phenyl)piperazine (0.131 g, 0.500 mmol) in DCM (5 mL) was added (3ai?,7ai?)- hexahydroisobenzofuran-l,3-dione (0.077 g, 0.500 mmol) and triethylamine (0.070 mL, 0.50 mmol) and the reaction stirred for 3 hours, HATU (0.209 g, 0.550 mmol), 1 -amino- 1- cyclopropanecarbonitrile HCl (0.083 g, 0.700 mmol) and triethylamine (0.139 mL, 1.00 mmol) were added and the reaction was stirred for 17 hours to give (1R,2R)-N-(1- cyanocyclopropyl)-2-((i?)-2-methyl-4-(3-methyl-4-(oxetan-3-yloxy)phenyl)piperazine-l- carbonyl)cyclohexanecarboxamide (0.086 g, 35.8 %) as a white solid. M+H=481 1H NMi? (400.132 MHz, CDC13) δ 1.05 - 1.87 (15H, m), 2.23 (3H, d), 2.54 - 2.89 (4H, m), 3.09 - 3.52 (3H, m), 3.80 - 3.86 and 4.40 - 4.46 (IH, m), 4.04 - 4.12 and 4.78 - 4.87 (IH, m), 4.75 (2H, t), 4.94 (2H, t), 5.09 - 5.17 (IH, m), 6.25 - 6.31 (IH, m), 6.53 - 6.64 (2H, m), 6.77 (IH, d) (R)-3-methyl-l-(3-methyl-4-(oxetan-3-yloxy)phenyl)piperazine was synthesised in the following manner.
(i?)-tert-butyl 4-(4-(benzyloxy)-3-methylphenyl)-2-methylpiperazine- 1 -carboxylate
Figure imgf000145_0001
In a manner similar to method B (R)-tert-butyl 2-methylpiperazine-l -carboxylate (1.25 g,
6.28 mmol) was reacted with l-(benzyloxy)-4-bromo-2-methylbenzene (1.66 g, 5.98 mmol) to afford (R)-tert-butyl 4-(4-(benzyloxy)-3-methylphenyl)-2-methylpiperazine-l- carboxylate (1.78 g, 75 %) as a yellow oil.
MS (+ve ESI) : 397 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.31 (3H, d), 1.48 (9H, s), 2.26 (3H, s), 2.58 - 2.68
(IH, m), 2.78 - 2.85 (IH, m), 3.17 - 3.37 (3H, m), 3.88 - 3.96 (IH, m), 4.27 - 4.37 (IH, m), 5.02 (2H, s), 6.64 - 6.70 (IH, m), 6.76 - 6.82 (2H, m), 7.27 - 7.45 (5H, m)
(R)-tert-bntyl 4-(4-hydroxy-3-methylphenyl)-2-methylpiperazine-l-carboxylate
Figure imgf000146_0001
(R)-tert-butyl 4-(4-(benzyloxy)-3-methylphenyl)-2-methylpiperazine-l-carboxylate (890 mg, 2.24 mmol) was suspended in ethanol (22 mL) and dihydroxypalladium (20% wt on carbon) (158 mg, 0.220 mmol) added. The system was stirred under a H2 atmosphere for 18 hours and then filtered through celite and evaporated and azeotroped with toluene twice to give (R)-tert-buty{ 4-(4-hydroxy-3-methylphenyl)-2-methylpiperazine-l-carboxylate
(633 mg, 92 %) as a purple oil.
MS (+ve ESI) : Rt = 2.17 min, no mass ion (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.31 (3H, d), 1.48 (9H, s), 2.22 (3H, s), 2.56 - 2.66 (IH, m), 2.73 - 2.84 (IH, m), 3.11 - 3.34 (3H, m), 3.88 - 3.97 (IH, m), 4.25 - 4.36 (IH, m),
6.60 - 6.74 (3H, m)
(R)-tert-bntyl 2-methyl-4-(3-methyl-4-(oxetan-3-yloxy)phenyl)piperazine-l- carboxylate
Figure imgf000146_0002
(R)-tert-butyl 4-(4-hydroxy-3-methylphenyl)-2-methylpiperazine-l-carboxylate (0.613 g, 2 mmol) was dissolved in NMP (6 mL) and sodium hydride (0.096 g, 2.40 mmol) added portionwise and the reaction stirred for 10 minutes. Oxetan-3-yl A- methylbenzenesulfonate (0.593 g, 2.60 mmol) was added in one portion and the reaction was heated to 120 0C for 17 hours and then allowed to cool. Poured into water (50 mL) and extracted with EtOAc (3 x 50 mL), the combined orgainc extracts were washed with water (100 mL) and then saturated brine (100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Semi-pure fractions were evaporated to dryness to afford (R)-tert-butyl 2-methyl-4-(3 -methyl-4-(oxetan-3 -yloxy)phenyl)piperazine- 1 - carboxylate (0.492 g, 67.9 %) as a orange solid. MS (+ve ESI) : Rt = 363 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.31 (3H, d), 1.48 (9H, s), 2.24 (3H, s), 2.63 (IH, t), 2.78 - 2.85 (IH, m), 3.16 - 3.24 (2H, m), 3.29 - 3.37 (IH, m), 3.81 - 3.96 (IH, m), 4.27 - 4.36 (IH, m), 4.73 - 4.78 (2H, m), 4.94 (2H, t), 5.10 - 5.17 (IH, m), 6.29 (IH, d), 6.59 - 6.64 (IH, m), 6.76 - 6.80 (IH, m) (R)-3-Methyl-l-(3-methyl-4-(oxetan-3-yloxy)phenyl)piperazine
Figure imgf000147_0001
(R)-tert-butyl 2-methyl-4-(3-methyl-4-(oxetan-3-yloxy)phenyl)piperazine- 1 -carboxylate (492 mg, 1.36 mmol) was dissolved in TFA (14 mL) and the reaction aged for 30 minutes and then evaporated. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3ZMeOH and pure fractions were evaporated to dryness to afford (i?)-3 -methyl- 1 -(3- methyl-4-(oxetan-3-yloxy)phenyl)piperazine (315 mg, 88 %) as a brown gum. MS (+ve ESI) : 263 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.11 (3H, d), 2.24 (3H, s), 2.58 - 2.67 (IH, m), 2.93 - 3.13 (4H, m), 3.32 - 3.38 (2H, m), 4.75 (2H, t), 4.94 (2H, t), 5.10 - 5.17 (IH, m), 6.29 (IH, d), 6.62 - 6.66 (IH, m), 6.81 (IH, d)
EXAMPLE 88
(lR,2R)-ΛL(l-cyanocyclopropyl)-2-((R)-4-(4-cyclopropoxyphenyl)-2- methylpiperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000148_0001
In a similar manner to example 73 (3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (119 mg,
0.77 mmol), (i?)-l-(4-cyclopropoxyphenyl)-3-methylpiperazine (180mg, 0.77 mmol) and
7V-ethyldiisopropylamine (0.268 mL, 1.55 mmol) were stirred in DMF (2.5 mL) for 2 hours. 1 -Amino- l-cyclopropanecarbonitrile HCl (101 mg, 0.85 mmol) and HATU (295 mg, 0.77 mmol) were added and the mixture allowed to stir overnight to give (IR,2R)-N-
( 1 -cyanocyclopropyl)-2-((i?)-4-(4-cyclopropoxyphenyl)-2-methylpiperazine- 1 - carbonyl)cyclohexanecarboxamide (247 mg, 70.8 %).
MS (+ve ESI) : Rt = 2.43 min, 451. 51 (M+H)+ 1U NMR (400.13 MHz, CDCl3) δ 0.74 (4H, t), 1.07 - 1.75 (1 IH, m), 1.75 - 1.90 (4H, m),
2.57 - 2.89 (4H, m), 3.11 - 3.52 (3H, m), 3.66 - 4.83 (3H, m), 6.57 (0.5H, s), 6.63 (0.5H, s),
6.85 (2H, d), 6.94 - 6.98 (2H, m)
(i?)-l-(4-cyclopropoxyphenyl)-3-methylpiperazine was synthesised in the following manner. l-Bromo-4-(vinyloxy)benzene
Figure imgf000148_0002
Sodium 2-methylpropan-2-olate (3.57 g, 37.2 mmol) was added in one portion to 1-bromo- 4-(2-chloroethoxy)benzene (7g, 29.8 mmol) in tetrahydrofuran (45 mL). The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with saturated brine (100 mL), water (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-bromo- 4-(vinyloxy)benzene (5.21 g, 88 %) as a colourless liquid. 1H NMi? (400.13 MHz, CDC13) δ 4.45 - 4.47 (IH, m), 4.75 - 4.79 (IH, m), 6.55 - 6.60 (IH, m), 6.86 - 6.90 (2H, m), 7.39 - 7.44 (2H, m) l-Bromo-4-cyclopropoxybenzene
Figure imgf000149_0001
To diethylzinc (IM Solution in hexanes) (15.1 mL, 15.1 mmol) in DCE (25 mL) under a blanket of argon at 0 0C was added chloroiodomethane (2.20 mL, 30.1 mmol) and the mixture stirred for 5 minutes. l-bromo-4-(vinyloxy)benzene (1.50 g, 7.54 mmol) in DCE (15 mL) was added and the reaction stirred and allowed to warm to ambient temperature for 90 minutes. Saturated NH4CI (5 ml) was added and the mixture partitioned with Et2O (50 mL), and saturated NH4CI (50 ml), the organic layer was washed with further saturated NH4CI (50 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford l-bromo-4-cyclopropoxybenzene (0.650 g, 40.5 %) as a colourless oil.
1H NMi? (400.13 MHz, CDC13) δ 0.72 - 0.80 (4H, m), 3.67 - 3.72 (IH, m), 6.90 - 6.94 (2H, m), 7.35 - 7.41 (2H, m) (R)-tert-butyl 4-(4-cyclopropoxyphenyl)-2-methylpiperazine-l-carboxylate
Figure imgf000149_0002
In a similar manner to method A (R)-tert-butyl 2-methylpiperazine-l-carboxylate (1.480 g, 7.39 mmol), l-bromo-4-cyclopropoxybenzene (1.50 g, 7.04 mmol) were reacted to afford (R)-tert-buty\ 4-(4-cyclopropoxyphenyl)-2-methylpiperazine-l-carboxylate (0.635 g, 27.1 %) as a pale yellow oil that solidified on standing. MS (+ve ESI) : Rt = 3.18 min, 333.47 (M+H)+
1H NMi? (400.13 MHz, CDC13) δ 0.72 - 0.74 (4H, m), 1.31 - 1.32 (3H, d), 1.48 (9H, t), 2.62 - 2.68 (IH, m), 2.81 - 2.85 (IH, m), 3.19 - 3.27 (2H, m), 3.32 - 3.35 (IH, m), 3.66 - 3.71 (IH, m), 3.93 (IH, d), 4.32 (IH, bs), 6.84 - 6.88 (2H, m), 6.95 - 6.99 (2H, m) (R)-l-(4-cyclopropoxyphenyl)-3-methylpiperazine
Figure imgf000150_0001
Hydrochloric acid in methanol (methanol reagent 10) (5000 μl, 1.90 mmol) was added to (R)-tert-buty\ 4-(4-cyclopropoxyphenyl)-2-methylpiperazine-l-carboxylate (630 mg, 1.90 mmol) and the resulting solution was stirred at room temperature for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NHVMeOH and pure fractions were evaporated to dryness to afford (i?)-l-(4-cyclopropoxyphenyl)-3-methylpiperazine (83 %) as a yellow oil which was used without further purification. MS (+ve ESI) : Rt = 1.79 min, 234.46 (M+H)+ 1U NMR (400.13 MHz, CDCl3) δ 1.07 - 1.75 (1 IH, m), 1.75 - 1.90 (4H, m), 2.57 - 2.89 (4H, m), 3.11 - 3.52 (3H, m), 3.81 (3H, s), 3.81 - 4.85 (2H, m), 6.58 (0.5H, s), 6.65 (0.5H, s), 6.75 - 6.79 (IH, m), 6.83 - 6.87 (IH, m), 6.96 (IH, q)
Example 89
(l/f,2/f)-Λ/-(l-cyanocyclopropyl)-2-((/f)-4-(3-methoxy-4-(2-methoxyethoxy)phenyl)-2- methylpiperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000150_0002
In a similar manner to example 73, to a solution of (i?)-l-(3-methoxy-4-(2- methoxyethoxy)phenyl)-3-methylpiperazine (40.0 mg, 0.140 mmol) in DCM (2 mL) was added (3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (22.0 mg, 0.140 mmol) and triethylamine (0.020 ml, 0.140 mmol) and the reaction stirred for 4 hours, HATU (108 mg, 0.29 mmol), 1 -amino- 1-cyclopropanecarbonitrile HCl (50.7 mg, 0.43 mmol) and triethylamine (0.040 ml, 0.290 mmol) were added and the reaction stirred for 18 hours to give (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-((i?)-4-(3-methoxy-4-(2-methoxyethoxy)phenyl)- 2-methylpiperazine-l-carbonyl)cyclohexanecarboxamide (57.0 mg, 80.0 %) as a white foam.
MS (+ve ESI) : 499 (M+H)+
1H NMi? (400.132 MHz, CDCB) δ 1.07 - 1.88 (15H, m), 2.57 - 2.94 (4H, m), 3.10 - 3.47 (3H, m), 3.44 (3H, s), 3.71 - 3.77 (2H, m), 3.84 (3H, d), 3.82 -3.86 and 4.41 - 4.46 (IH, m)
4.08 - 4.13 (2H, m), 4.08 - 4.13 and 4.81 - 4.86 (IH, m), 6.37 - 6.44 (IH, m), 6.49 - 6.52
(IH, m), 6.65 (IH, d), 6.83 - 6.87 (IH, m)
(R)-l-(3-methoxy-4-(2-methoxyethoxy)phenyl)-3-methylpiperazine was synthesised in the following manner. (R)-tert-bntyl 4-(3-methoxy-4-(2-methoxyethoxy)phenyl)-2-methylpiperazine-l- carboxylate
Figure imgf000151_0001
To (R)-tert-buty{ 4-(4-hydroxy-3-methoxyphenyl)-2-methylpiperazine-l-carboxylate (380 mg, 1.18 mmol) in DMF (12 mL) was added sodium hydride (33.9 mg, 1.41 mmol) and the reaction stirred for 20 minutes, l-bromo-2-methoxyethane (0.222 mL, 2.36 mmol) was added and the reaction stirred for 17 hours. Further l-bromo-2-methoxyethane (0.222 mL, 2.36 mmol) was added and the reaction stirred for 30 minutes and then further sodium hydride (17.0 mg, 0.70 mmol) was added and the reaction stirred for 90 minutes and then evaporated. Partitioned with Et2θ/water (50 mL/ 50 mL), the organic layer was washed with 2M NaOH (50 mL), dried over MgSO4, filtered and evaporated.The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(3- methoxy-4-(2-methoxyethoxy)phenyl)-2-methylpiperazine-l-carboxylate (156 mg, 34.8 %) as a yellow oil.
MS (+ve ESI) : Rt = 2.52 mins 381.45 (M+H)+ 1H NMi? (400.132 MHz, CDCB) δ 1.32 (3H, d), 1.48 (9H, s), 2.63 - 2.72 (IH, m), 2.83 - 2.89 (IH, m), 3.19 - 3.25 (2H, m), 3.33 - 3.39 (IH, m), 3.43 (3H, s), 3.71 - 3.75 (2H, m), 3.84 (3H, s), 3.90 - 3.96 (IH, m), 4.09 - 4.14 (2H, m), 4.29 - 4.37 (IH, m), 6.38 - 6.42 (IH, m), 6.50 (IH, d), 6.86 (IH, d) (R)-l-(3-methoxy-4-(2-methoxyethoxy)phenyl)-3-methylpiperazine
Figure imgf000152_0001
(R)-tert-butyl 4-(3 -methoxy-4-(2-methoxyethoxy)phenyl)-2-methylpiperazine- 1 - carboxylate (153 mg, 0.400 mmol) was dissolved in hydrogen chloride (4M in dioxane) (8.00 ml, 32.0 mmol) and the reaction stirred for 1 hour and then evaporated. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3ZMeOH and pure fractions were evaporated to dryness to afford (i?)-l-(3-methoxy-4-(2-methoxyethoxy)phenyl)-3- methylpiperazine (80 mg, 71.0 %) as a brown oil. MS (+ve ESI) : 281 (M+H)+ Methyl 2-methyl-2-(4-(piperazin-l-yl)phenyl)propanoate
Figure imgf000152_0002
To a slurry of methyl 2-(4-bromophenyl)-2-methylpropanoate (2.57 g, 10 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.28 g, 0.30 mmol) and i?ACEMIC-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (0.249 g, 0.40 mmol) in toluene (50 mL) was added piperazine (2.58 g, 30.00 mmol) and sodium tert-butoxide (1.35 g, 14.00 mmol). The mixture was heated at 80 0C for 18 hours and then the reaction mixture was evaporated and diluted with DCM (100 mL), and washed with water (100 mL), the aqueous layer was washed with DCM (100 mL) and the combined organic layers washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The compound was purified using 0.1% NH3 modified water/MeCN on a Waters X-Bridge C18 (lOμ silica, 50 mm diameter, 150 mm length) column. Fractions containing the desired compound were evaporated to dryness to afford an off- white gum.methyl 2-methyl-2-(4-(piperazin-l-yl)phenyl)propanoate (0.368 g, 14.0 %) MS (+ve ESI) : Rt = 1.99 min, 417.31 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.55 (6H, s), 3.02 (4H, m), 3.12 (4H, m), 3.63 (3H, s), 6.87 (2H, d), 7.23 (2H, d) Methyl 2-(4-(4-((lR,2R)-2-(l- cyanocyclopropylcarbamoyl)cyclohexanecarbonyl)piperazin-l-yl)phenyl)-2- methylpropanoate
Figure imgf000153_0001
To a solution of the methyl 2-methyl-2-(4-(piperazin-l-yl)phenyl)propanoate (368 mg, 1.40 mmol) in DCM (14 mL) was added (3ai?,7ai?)-hexahydroisobenzofuran-l,3-dione (216 mg, 1.40 mmol) and triethylamine (0.391 mL, 2.81 mmol) and the mixture stirred under a blanket of argon for 2 hours. 2,4,6-Trichlorobenzoyl chloride (0.307 mL, 1.96 mmol) and 4-Dimethylaminopyridine (42.8 mg, 0.35 mmol) were added and the reaction stirred for 2.5 hours, 1 -amino- 1-cyclopropanecarbonitrile HCl (233 mg, 1.96 mmol) and triethylamine (0.782 mL, 5.61 mmol) were added and the reaction stirred for 1 hour.The reaction mixture was diluted with DCM (50 mL), and washed sequentially with saturated NH4Cl (2 x 50 mL), and saturated NaHCO3 (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4-(4-((li?,2i?)-2-(l- cyanocyclopropylcarbamoyl)cyclohexanecarbonyl)piperazin-l-yl)phenyl)-2- methylpropanoate (42.3 %) as a yellow gum. MS (+ve ESI) : Rt = 1.99 min, 417.31 (M+H)+ 1H NMi? (400.132 MHz, CDC13) δ 1.06 - 1.70 (8H, m), 1.55 (6H, s), 1.82 (4H, m), 2.57 (IH, m), 2.87 (IH, m), 3.07 - 3.28 (4H, m), 3.57 - 3.87 (4H, m), 3.63 (3H, s), 6.47 (IH, s), 6.85 (2H, d), 7.23 (2H, d)
2-(4-(4-((lR,2R)-2-(l-cyanocyclopropylcarbamoyl)cyclohexanecarbonyl)piperazin-l- yl)phenyl)-2-methylpropanoic acid
Figure imgf000154_0001
The methyl 2-(4-(4-(( \R,2R)-2-( 1 -cyanocyclopropylcarbamoyl)cyclohexanecarbonyl) piperazin-l-yl)phenyl)-2-methylpropanoate (280 mg, 0.58 mmol) was dissolved in THF (6 mL) and lithium hydroxide- 1 -hydrate (122 mg, 2.91 mmol) in water (6.00 mL) was added and the reaction stirred for 48 hours. The mixture was acidified with 2M HCl to pHl and extracted with EtOAc (2 x 50 mL) and the combined organics dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford 2-(4-(4-((li?,2i?)-2-(l-cyanocyclopropylcarbamoyl)cyclohexanecarbonyl)piperazin- l-yl)phenyl)-2-methylpropanoic acid (69.0 mg, 25.4 %) as a yellow oil. MS (+ve ESI) : Rt = 2.04 min, 481.25 (M+H)+
1H NMi? (400.132 MHz, CDC13) δ 1.03 - 1.70 (9H, m), 1.57 (6H, d), 1.80 (4H, m), 2.55 (IH, t), 2.92 (IH, t), 3.05 - 3.28 (4H, m), 3.52 - 3.84 (4H, m), 6.85 (2H, m), 7.30 (2H, d)
Example 90
(l/f,2R)-ΛL(l-cyanocyclopropyl)-2-(4-(4-(l-(dimethylamino)-2-methyl-l-oxopropan-2- yl)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide
Figure imgf000154_0002
To a solution of 2-(4-(4-((li?,2i?)-2-(l-cyanocyclopropylcarbamoyl)cyclohexanecarbonyl) piperazin-l-yl)phenyl)-2-methylpropanoic acid (69 mg, 0.15 mmol) and HATU (79 mg, 0.21 mmol) in DMF (1 mL) was added Λ/,Λ/-diisopropylethylamine (0.077 mL, 0.44 mmol) followed by dimethylamine (0.370 mL, 0.74 mmol) and the reaction stirred for 18 hours. The reaction mixture was purified directly. Compounds were purified using 0.1% NH3 modified water/MeCN on a Waters X-Bridge Cl 8 (lOμ silica, 50 mm diameter, 150 mm length) column. Fractions containing the desired compound were lyophilised to dryness to afford a gum (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(4-(4-(l-(dimethylamino)-2-methyl-l- oxopropan-2-yl)phenyl)piperazine-l-carbonyl)cyclohexanecarboxamide (48.0 mg, 65.8
%).
MS (+ve ESI) : Rt = 1.85 min, 494.72 (M+H)+
1H NMi? (400.132 MHz, CDCB) δ 1.06 - 1.69 (8H, m), 1.54 (6H, d), 1.82 (4H, m), 2.47
2.99 (8H, m), 3.11 - 3.28 (4H, m), 3.57 - 3.89 (4H, m), 6.54 (IH, s), 6.86 (2H, d), 7.10
(2H, d)
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
1U NMR data
Example 91: IH NMR (400.13 MHz, CDC13) δ 1.08 - 1.20 (2H, m), 1.32 (2H, q), 1.47 - 1.50 (2H, m), 1.39 - 1.44 (IH, m), 1.60 - 1.66 (IH, m), 1.64 (IH, d), 1.70 - 1.75 (6H, m), 1.79- 1.85 (4H, m), 2.54 - 2.60 (IH, m), 2.84 - 2.90 (IH, m), 3.53 - 3.63 (4H, m), 3.64 - 3.67 (2H, m), 3.73 - 3.76 (IH, m), 3.82 - 3.88 (IH, m), 6.38 (IH, s), 6.63 (IH, d), 7.57 (IH, dd), 8.28 (IH, d)
Example 93: IH NMR (400.132 MHz, CDC13) δ 1.10 - 1.75 (8H, m), 1.72 (6H, s), 1.84 (4H, m), 2.33 (3H, s), 2.60 (IH, t), 2.85 - 3.14 (5H, m), 3.59 - 3.89 (4H, m), 6.62 (IH, s), 7.36 (IH, d), 8.23 (IH, s)
Example 94: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.88 (12H, m), 1.82 (6H, s), 2.57 (IH, t), 2.90 (IH, t), 3.17 - 3.33 (4H, m), 3.63 (2H, m), 3.75 - 3.93 (2H, m), 6.52 (IH, s), 6.76 (IH, d), 6.93 (IH, s), 7.31 (IH, d) Example 95: IH NMR (400.132 MHz, CDCB) δ 1.08 - 1.88 (12H, m), 1.73 (6H, s), 2.59 (IH, t), 2.92 (IH, t), 3.18 - 3.34 (4H, m), 3.64 (2H, m), 3.84 (IH, m), 3.95 (IH, m), 6.63 (IH, s), 7.19 (IH, d), 7.43 (IH, d), 8.27 (IH, s)
Example 96: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.54 (1 IH, m), 1.83 (4H, m), 2.60 (IH, t), 2.91 (IH, t), 3.11 - 3.31 (5H, m), 3.60 - 3.87 (4H, m), 6.72 (IH, s), 6.88 (2H, d), 7.31 (2H, d)
Example 97: IH NMR (400.132 MHz, CDC13) δ 1.10 - 1.56 (8H, m), 1.69 (6H, s), 1.78 - 1.90 (4H, m), 2.33 (3H, s), 2.61 (IH, m), 2.78 - 3.04 (5H, m), 3.55 - 3.93 (4H, m), 6.71 (IH, s), 7.00 (IH, d), 7.23 (IH, m), 7.28 (IH, d)
Example 98: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.64 (8H, m), 1.13 (3H, t), 1.50 (6H, s), 1.83 (4H, m), 2.60 (IH, m), 2.91 (IH, m), 3.12 - 3.30 (4H, m), 3.17 (2H, t), 3.58 - 3.87 (4H, m), 6.72 (IH, s), 6.88 (2H, d), 7.31 (2H, d)
Example 99: IH NMR (400.132 MHz, CDC13) δ 1.06 - 1.70 (12H, m), 1.81 (4H, m), 2.56 (IH, t), 2.88 (IH, t), 3.15 - 3.33 (4H, m), 3.62 (2H, m), 3.78 (IH, m), 3.88 (IH, m), 6.48 (IH, s), 6.71 (IH, m), 6.91 (IH, d), 7.18 (IH, d)
Example 100: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.72 (8H, m), 1.68 (6H, s), 1.77 - 1.87 (4H, m), 2.59 (IH, t), 2.89 (IH, t), 3.01 - 3.15 (4H, m), 3.58 (2H, m), 3.82 (IH, m), 4.01 (IH, m), 6.54 (IH, s), 6.92 (IH, t), 7.14 (2H, m)
Example 101: IH NMR (400.132 MHz, CDC13) δ 1.10 - 1.69 (8H, m), 1.72 (6H, s), 1.82 (4H, m), 2.63 (IH, t), 2.83 - 3.05 (5H, m), 3.31 (IH, t), 3.50 (IH, t), 3.86 (IH, d), 4.22 (IH, d), 6.67 (IH, s), 7.45 (IH, d), 7.62 (IH, m), 7.69 (IH, m)
Example 102: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.67 (9H, m), 1.69 (6H, s), 1.82 (4H, m), 2.60 (IH, t), 2.89 (IH, t), 2.99 - 3.15 (4H, m), 3.42 - 3.60 (2H, m), 3.83 (IH, m), 4.07 (IH, m), 6.54 (IH, s), 7.02 (IH, d), 7.33 (IH, d) Example 103: IH NMR (400.132 MHz, CDC13) δ 1.04 (2H, q), 1.07 - 1.69 (1OH, m), 1.82 (4H, m), 2.58 (IH, t), 2.90 (IH, t), 3.22 (4H, m), 3.62 (2H, m), 3.80 (IH, m), 3.90 (IH, m), 5.40 (2H, m), 6.72 (IH, s), 6.87 (2H, d), 7.31 (2H, d)
Example 104: IH NMR (400.132 MHz, CDC13) δ 1.08 - 1.67 (8H, m), 1.60 (6H, s), 1.82 (4H, m), 2.58 (IH, m), 2.89 (IH, m), 3.23 (4H, m), 3.62 (2H, m), 3.79 (IH, m), 3.90 (IH, m), 5.22 (2H, s), 6.59 (IH, s), 6.79 (IH, d), 6.92 (IH, s), 7.34 (IH, d)
Example 105: IH NMR (400.132 MHz, CDC13) δ 1.06 - 1.88 (12H, m), 1.82 (6H, s), 2.57 (IH, m), 2.88 (IH, m), 3.25 (4H, m), 3.60 (2H, m), 3.80 (IH, m), 3.90 (IH, m), 6.36 (2H, m), 6.46 (IH, s)
Example 106: IH NMR (400.132 MHz, CDC13) δ 1.06 - 1.87 (12H, m), 1.82 (6H, s), 2.57 (IH, m), 2.89 (IH, m), 3.29 (4H, m), 3.64 (2H, m), 3.82 (IH, m), 3.92 (IH, m), 6.47 (IH, s), 6.99 (IH, m), 7.22 (IH, d), 7.56 (IH, d)
Example 107: IH NMR (400 MHz, DMSO) δ 1.0 (m, 2H), 1.152-1.4 (m, 6H), 1.75 (m, 4H), 2.45 (m, 6H), 2.65 (t, 2H), 2.9-3.1 (m, 4H), 3.25 (m, IH), 3.5-3.7 (m, 7H), 3.75 (s, 3H), 4.0 (t, 2H), 6.4 (d, IH), 6.6 (s, IH), 6.85 (d, IH), 8.65 (s, IH).
Example 108: IH NMR (400 MHz, DMSO) δ 1.0 (m, 2H), 1.15-1.4 (m, 6H), 1.75 (m, 4H), 2.45 (m, 4H), 2.65 (t, 2H), 2.9-3.1 (m, 5H), 3.5-3.7 (m, 9H), 3.75 (s, 3H), 4.05 (t, 2H), 6.4 (d, IH), 6.65 (s, IH), 6.8 (d, IH), 8.65 (s, IH).
Example 109: IH NMR (400 MHz, DMSO) δ 1.0 (m, 2H), 1.15-1.4 (m, 6H), 1.75 (m, 6H), 2.4 (m, 8H), 2.9-3.1 (m, 5H), 3.5-3.7 (m, 7H), 3.75 (s, 3H), 3.9 (t, 2H), 6.4 (d, IH), 6.6 (s, IH), 6.85 (d, IH), 8.65 (s, IH).
Example 110: IH NMR (400.132 MHz, CDC13) δ 1.06 - 1.71 (8H, m), 1.82 (4H, m), 2.13 (3H, s), 2.59 (IH, m), 2.88 (IH, m), 3.04 - 3.26 (4H, m), 3.58 - 3.88 (4H, m), 3.81 (3H, s), 6.42 (2H, m), 6.54 (IH, s), 7.00 (IH, d) Example 112: IH NMR (400.132 MHz, CDC13) δ 1.06 - 1.68 (8H, m), 1.74 (6H, s), 1.82 (4H, m), 2.58 (IH, m), 2.60 (3H, s), 2.89 (IH, m), 3.13 - 3.31 (4H, m), 3.56 - 3.89 (4H, m), 6.53 (IH, s), 6.71 (IH, m), 6.75 (IH, d), 7.18 (IH, d)
Example 112: IH (400.13 MHz, CDC13) δ 1.08 - 1.21 (2H, m), 1.26 - 1.29 (2H, m), 1.31
- 1.43 (3H, m), 1.44 - 1.53 (4H, m), 1.69 (6H, m), 1.66 - 1.71 (IH, d), 1.77 - 1.88 (3H, m), 2.58 - 3.04 (4H, m), 3.15 - 3.22 (0.5H, m), 3.38 - 3.60 (2.5H, m), 3.85 - 3.92 (0.5H, m), 4.08 - 4.16 (0.5H, m), 4.41 - 4.46 (0.5H, m), 4.80 - 4.88 (0.5H, m), 6.59 - 6.66 (IH, m),
6.85 - 6.90 (2H, m), 7.32 - 7.37 (2H, m)
Example 113: IH NMR (400.132 MHz, CDC13) δ 1.05 - 1.72 (3H, m), 1.55 (7H, s), 1.60 (3H, s), 1.82 (4H, m), 2.30 (3H, s), 2.58 (IH, t), 2.90 (IH, t), 3.13 - 3.29 (4H, m), 3.55 - 3.92 (4H, m), 5.23 (2H, s), 6.70 (3H, m), 6.73 (IH, s), 7.30 (IH, d)
Example 114: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.67 (8H, m), 1.76 - 1.87 (4H, m), 2.57 (IH, t), 2.90 (IH, t), 3.31 - 3.49 (4H, m), 3.57 - 3.67 (2H, m), 3.82 - 3.99 (2H, m), 3.89 (3H, s), 6.29 (IH, d), 6.41 (IH, m), 6.57 (IH, s), 7.38 (IH, d)
Example 115: IH NMR (400.132 MHz, CDC13) δ 1.05 - 1.70 (8H, m), 1.75 - 1.88 (4H, m), 1.90 - 2.12 (4H, m), 2.26 (2H, m), 2.59 (IH, t), 2.89 (IH, t), 3.04 - 3.27 (4H, m), 3.58 -
3.86 (5H, m), 3.78 (3H, s), 6.42 (IH, d), 6.47 (IH, m), 6.59 (IH, s), 7.09 (IH, d)
Example 116: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.69 (8H, m), 1.53 (6H, s), 1.77
- 1.87 (4H, m), 2.58 (IH, m), 2.70 (3H, d), 2.90 (IH, m), 3.14 - 3.29 (4H, m), 3.57 - 3.69 (2H, m), 3.79 (IH, m), 3.90 (IH, m), 5.16 (IH, s), 6.59 (IH, s), 6.88 (2H, d), 7.25 (2H, d)
Example 117: IH NMR (400.13 MHz, CDC13) δ 1.07 - 1.68 (8H, m), 1.80 - 1.84 (4H, m), 2.55 - 2.61 (IH, m), 2.84 - 2.91 (IH, m), 2.95 - 3.14 (4H, m), 3.70 (4H, m), 4.19 - 4.24 (4H, m), 4.19 - 4.27 (IH, m), 6.44 (2H, m), 6.59 (IH, s), 6.76 - 6.78 (IH, m) Example 118: IH NMR (400.132 MHz, CDCB) δ 1.08 - 1.68 (8H, m), 1.72 (6H, s), 1.78 - 1.87 (4H, m), 2.58 (IH, m), 2.91 (IH, m), 3.15 - 3.23 (3H, m), 3.28 (IH, m), 3.59 - 3.73 (2H, m), 3.75 - 3.89 (2H, m), 3.90 (3H, s), 6.42 - 6.50 (2H, m), 6.62 (IH, s), 7.18 (IH, d)
Example 119: IH NMR (400.132 MHz, CDC13) δ 0.58 (2H, m), 0.85 (2H, m), 1.07 - 1.69 (8H, m), 1.78 - 1.88 (4H, m), 2.04 (IH, m), 2.59 (IH, m), 2.90 (IH, m), 3.06 - 3.26 (4H, m), 3.59 - 3.84 (4H, m), 3.85 (3H, s), 6.42 (IH, m), 6.46 (IH, d), 6.67 (IH, s), 6.75 (IH, d)
Example 120: IH NMR (400.132 MHz, CDC13) δ 1.08 - 1.88 (12H, m), 1.50 (6H, s), 2.58 (IH, t), 2.91 (IH, t), 3.13 - 3.31 (4H, m), 3.57 - 3.97 (4H, m), 3.80 (3H, s), 5.02 - 5.27 (2H, m), 6.47 (2H, m), 6.74 (IH, s), 7.22 (IH, d)
Example 121: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.54 (14H, m), 1.77 - 1.86 (4H, m), 2.57 - 2.94 (4H, m), 3.09 - 3.55 (3H, m), 3.84 (IH, m), 3.86 (3H, d), 4.43 and 4.04 (IH, m), 4.84 and 4.10 (IH, m), 6.41 (IH, m), 6.52 (IH, d), 6.66 (IH, d), 6.79 (IH, m)
Example 122: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.69 (8H, m), 1.43 (3H, t), 1.78 - 1.88 (4H, m), 2.59 (IH, m), 2.89 (IH, m), 3.00 - 3.20 (4H, m), 3.57 - 3.91 (4H, m), 3.86 (3H, s), 4.04 (2H, q), 6.44 (IH, m), 6.57 (IH, d), 6.68 (IH, s), 6.79 (IH, d)
Example 123: IH NMR (400.13 MHz, CDC13) δ 1.07 - 1.21 (2H, m), 1.25 - 1.66 (6H, d), 1.78 - 1.88 (4H, m), 2.57 - 2.63 (IH, m), 2.88 - 2.95 (IH, m), 3.11 - 3.31 (4H, m), 3.62 - 3.86 (4H, m), 6.78 (IH, s), 6.87 - 6.94 (3H, m), 7.25 - 7.30 (2H, m)
Example 124: IH NMR (400.13 MHz, CDC13) δ 1.09 - 1.20 (2H, m), 1.25 - 1.37 (2H, m), 1.40 - 1.45 (5H, m), 1.47 - 1.52 (IH, m), 1.60 - 1.69 (IH, m), 1.77 - 1.86 (4H, m), 2.56 -
2.62 (IH, m), 2.84 - 2.91 (IH, m), 2.96 - 3.07 (4H, m), 3.49 - 3.60 (2H, m), 3.76 - 3.81 (IH, m), 3.81 (3H, s), 4.00 - 4.07 (IH, m), 4.02 (2H, q), 6.54 (IH, s), 6.57 - 6.59 (IH, m),
6.63 - 6.66 (IH, m)
Example 125: IH NMR (400.132 MHz, CDC13) δ 1.06 - 1.87 (15H, m), 2.53 - 3.55 (7H, m), 3.86 and 4.44 (IH, m), 4.11 and 4.86 (IH, m), 6.53 (2H, m), 6.66 (IH, s), 6.91 (IH, m) Example 126: IH NMR (400.132 MHz, CDCB) δ 1.06 - 1.71 (8H, m), 1.77 - 1.86 (4H, m), 2.58 (IH, t), 2.88 (IH, t), 3.01 - 3.19 (4H, m), 3.54 - 3.97 (4H, m), 6.49 (IH, s), 6.57 (IH, m), 6.69 (IH, d), 6.92 (IH, d)
Example 127: IH NMR (400.13 MHz, CDC13) δ 1.07 - 1.52 (14H, m), 1.60 - 1.87 (4H, m), 2.55 - 2.94 (4H, m), 3.06 - 3.25 (2.5H, m), 3.50 - 3.57 (0.5H, m), 3.78 - 3.84 (3.5H, m), 3.99 - 4.05 (2.5H, m), 4.41 - 4.47 (0.5H, m), 4.82 - 4.87 (0.5H, m), 6.49 - 6.66 (3H, m)
Example 128: IH NMR (400.132 MHz, DMSO) δ 0.77 (2H, t), 0.91 - 1.05 (4H, m), 1.11
- 1.46 (6H, m), 1.59 - 1.91 (6H, m), 2.46 (IH, m), 2.55 - 2.99 (3H, m), 3.36 - 3.53 (2H, m), 3.68 (3H, s), 3.75 (3H, s), 3.84 - 4.00 (IH, m), 4.23 - 4.52 (IH, m), 6.41 (IH, m), 6.58 (IH, m), 6.82 (IH, d), 8.67 (IH, d)
Example 129 AZ12886714: IH NMR (400.13 MHz, CDC13) δ 1.08 - 1.54 (1 IH, m), 1.62
- 1.72 (IH, m), 1.80 - 1.84 (4H, m), 2.51-2.89 (4H, m), 3.11-2.40 (2H, m), 3.50 and 4.42 (2 x IH, m), 3.80 - 3.82 (3H, m), 3.87 - 3.90 (6H, m), 4.03 and 4.82 (2 x IH, m) 6.57 - 3.60 (3H, m)
Example 130: IH NMR (400.132 MHz, CDC13) δ 1.08 - 1.69 (9H, m), 1.51 (6H, d), 1.82 (4H, m), 2.57 - 3.05 (4H, m), 3.20 (IH, m), 3.35 - 3.62 (3H, m), 3.80 (3H, d), 4.56 (4H, d), 6.40 - 6.49 (2H, m), 6.69 (IH, d), 7.18 - 7.24 (2H, m)
Example 131: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.69 (1OH, m), 1.77 - 1.86 (4H, m), 2.13 (3H, d), 2.57 - 2.71 (2H, m), 2.74 - 2.96 (2H, m), 3.17 (IH, m), 3.29 - 3.55 (3H, m), 3.81 (3H, d), 3.86 and 4.43 (IH, d), 4.11 and 4.82 (IH, m), 6.37 - 6.43 (2H, m), 6.70 (IH, d), 7.00 (IH, m)
Example 132: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.56 (7H, m), 1.61 (6H, s), 1.72 (3H, d), 1.75 - 1.87 (4H, m), 2.61 (IH, m), 2.70 - 3.07 (3H, m), 3.20 (IH, m), 3.35 - 3.63 (3H, m), 3.88 and 4.43 (IH, d), 3.90 (3H, d), 4.12 and 4.85 (IH, m), 6.40 - 6.47 (2H, m), 6.61 (IH, d), 7.17 (IH, m) Example 133: IH NMR (400.13 MHz, CDCB) δ 1.31 (8H, m), 1.82 - 1.84 (4H, m), 2.56 - 2.63 (IH, m), 2.86 - 3.04 (5H, m), 3.49 - 3.62 (2H, m), 3.79 - 3.84 (4H, m), 3.92 (3H, s), 3.99 . 4.04 (IH, m), 6.57 - 6.68 (3H, m)
Example 134: IH NMR (400.13 MHz, CDC13) δ 1.09 - 1.20 (2H, m), 1.26 - 1.52 (5H, m), 1.60-1.69 (IH, m), 1.82-1.86 (4H, m), 2.58 - 2.64 (IH, m), 2.86 - 2.93 (2H, m), 3.00 - 3.05 (3H, m), 3.27-3.33, (2H, m), 3.77 - 3.79 (4H, m), 3.84 (3H, s), 3.91 - 3.96 (IH, m), 6.40 - 6.43 (IH, m), 6.48 (IH, d), 6.71 (IH, s), 6.84 (IH, d)
Example 135: IH NMR (400.13 MHz, CDC13) δ 1.10 - 1.53 (8H, m), 1.82 - 1.84 (4H, m),
2.58 (IH, t), 2.86 (IH, t), 2.95 - 3.00 (3H, m), 3.09 (IH, d), 3.56 - 3.74 (4H, m), 3.82 (3H, s), 3.88 (3H, s), 3.91 (3H, s), 6.48 (IH, s), 6.57 - 6.59 (2H, m)
Example 141: IH NMR (400.13 MHz, CDC13) δ 1.07 - 1.21 (2H, m), 1.25 - 1.53 (8H, m), 1.63 - 1.70 (IH, m), 1.76 - 1.88 (4H, m), 2.57 - 3.01 (4H, m), 3.13 - 3.22 (0.5H, m), 3.37 -
3.59 (2.5H, m), 3.83 - 3.90 (0.5H, m), 4.07 - 4.15 (0.5H, m), 4.44 (0.5H, d), 4.79 (0.5H, m), 6.60 - 6.66 (IH, m), 6.86 - 6.91 (3H, m), 7.24 - 7.29 (2H, m)
Example 143: IH NMR (400.13 MHz, CDC13) δ 1.07 - 1.54 (16H, m), 1.63 - 1.87 (5H, m), 2.56 - 2.86 (6H, m), 3.11 - 3.52 (3H, m), 3.79 - 3.86 (0.5H, m), 3.95 - 4.01 (2H, m), 4.04 - 4.12 (0.5H, m), 4.40 - 4.47 (0.5H, m), 4.77 - 4.85 (0.5H, m), 6.58 - 6.63 (IH, m),
6.66 - 6.69 (IH, m), 6.73 - 6.77 (2H, m)
Example 144: IH NMR (400.13 MHz, CDC13) δ 1.08 - 1.21 (5H, m), 1.27 - 1.54 (8H, m),
1.67 - 1.84 (5H, m), 2.56 - 2.86 (6H, m), 3.11 - 3.52 (3H, m), 3.77 - 3.79 (3H, m), 3.80 - 3.87 (0.5H, m), 4.09 (0.5H, d), 4.44 (0.5H, d), 4.76 - 4.86 (0.5H, m), 6.65 - 6.78 (4H, m)
Example 145: IH NMR (400.132 MHz, CDC13) δ 1.06 - 1.62 (1OH, m), 1.75 - 1.86 (4H, m), 2.54 - 2.65 (IH, m), 2.72 - 3.00 (2H, m), 3.12 - 3.32 (2H, m), 3.46 - 3.80 (3H, m), 3.86 - 4.85 (2H, m), 6.54 (IH, d), 6.61 (2H, t), 8.27 (2H, t) Example 148: IH NMR (400.13 MHz, CDCB) δ 1.08 - 1.20 (5H, m), 1.30 - 1.52 (8H, m), 1.60 - 1.88 (5H, m), 2.56 - 2.64 (3H, m), 2.85 - 3.15 (5H, m), 3.60 - 3.83 (4H, m), 3.98 (2H, q), 6.59 (IH, s), 6.69 - 6.81 (3H, m)
Example 149: IH NMR (400.13 MHz, CDC13) δ 1.13 (6H, d), 1.26 - 1.85 (9H, m), 2.56 - 2.63 (3H, m), 2.86 - 3.16 (5H, m), 3.60 - 3.85 (7H, m), 6.63 (IH, s), 6.71 - 6.81 (3H, m)
Example 150: IH NMR (400.132 MHz, DMSO) δ 0.92 - 1.05 (2H, m), 1.11 - 1.47 (9H, m), 1.65 - 1.83 (4H, m), 2.48 (IH, m), 2.65 - 2.98 (3H, m), 3.38 - 3.68 (3H, m), 3.82 (3H, s), 3.92 - 4.67 (2H, m), 6.46 (IH, m), 6.68 (IH, d), 6.85 (IH, m), 7.01 (IH, d), 8.69 (IH, d)
Example 153: IH NMR (400.132 MHz, DMSO) δ 0.90 - 1.06 (2H, m), 1.14 - 1.45 (6H, m), 1.64 - 1.80 (4H, m), 2.43 (IH, m), 2.86 - 3.26 (5H, m), 3.51 (IH, m), 3.58 - 3.76 (3H, m), 3.84 (3H, s), 6.51 (IH, m), 6.68 (IH, d), 7.21 (IH, d), 8.72 (IH, s)
Example 157: IH NMR (400.132 MHz, DMSO) δ 0.91 - 1.06 (2H, m), 1.11 - 1.46 (1OH, m), 1.65 - 1.82 (4H, m), 2.45 (IH, m), 2.65 - 2.98 (3H, m), 3.38 - 3.71 (2H, m), 3.84 (3H, s), 3.92 - 4.66 (2H, m), 6.50 (IH, m), 6.63 (IH, m), 7.20 (IH, m), 8.70 (IH, d)
Example 158: IH NMR (400.13 MHz, CDC13) δ 1.08 - 1.52 (17H, m), 1.67 - 1.69 (IH, m), 1.80 - 1.86 (4H, m), 2.58 - 2.65 (IH, m), 2.75 - 2.92 (2H, m), 3.11 - 3.50 (3H, m), 3.80 - 3.89 (IH, m), 4.02 - 4.09 (2H, m), 4.44 - 4.46 (IH, m), 5.81 - 5.89 (IH, m), 6.48 (IH, s), 6.54 - 6.58 (IH, m), 6.65 - 6.69 (IH, m), 6.85 - 6.91 (IH, m)
Example 160: IH NMR (400.13 MHz, CDC13) δ 1.08 - 1.84 (18H, m), 2.57 - 2.93 (4H, m), 3.12 - 3.52 (3H, m), 3.84 - 4.11 (3H, m), 4.45 (0.5H, d), 4.81 - 4.89 (0.5H, m), 6.56 - 6.62 (IH, m), 6.74 - 6.80 (2H, m), 6.88 - 6.92 (IH, m)
Example 161: IH NMR (400.13 MHz, CDC13) δ 1.08 - 1.22 (2H, m), 1.26 - 1.70 (9H, m), 1.77 - 1.84 (4H, m), 2.58 - 2.99 (4H, m), 3.13 - 3.52 (3H, m), 3.89 and 4.44 (IH x 2, d), 4.11 and 4.85 (IH x 2, s), 6.51 - 6.57 (2H, m), 6.64 - 6.70 (IH, m), 6.99 - 7.08 (IH, m) Example 162: IH NMR (400.13 MHz, CDCB) δ 0.94 - 1.55 (1OH, m), 1.65 - 1.70 (IH, m), 1.83 - 1.87 (4H, m), 2.58 - 2.91 (4H, m), 3.12 - 3.45 (3H, m), 3.49 - 3.50 (3H, m), 3.85 and 4.44 (IH, d), 4.09 and 4.49 (IH, m), 6.53 - 6.59 (IH, m), 6.64 - 6.72 (2H, m), 6.87 - 6.92 (IH, m)
Example 163: IH NMR (400.132 MHz, DMSO) δ 0.90 - 1.45 (12H, m), 1.64 - 1.82 (4H, m), 2.43 (IH, m), 2.75 - 2.98 (3H, m), 3.38 - 3.68 (2H, m), 3.93 - 4.67 (2H, m), 6.79 - 7.39 (5H, m), 8.70 (IH, d)
Example 168: IH NMR (400.132 MHz, CDC13) δ 0.49 - 0.57 (2H, m), 0.79 - 0.86 (2H, m), 0.99 - 1.94 (12H, m), 2.53 - 2.63 (IH, m), 2.85 - 2.95 (IH, m), 3.37 - 3.84 (9H, m), 3.92 (3H, s), 6.07 (IH, d), 6.66 (IH, s), 7.02 (IH, d)
Example 169: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.90 (12H, m), 2.56 - 2.65 (IH, m), 2.86 - 2.95 (IH, m), 3.44 - 3.88 (8H, m), 3.86 (3H, s), 6.08 - 6.17 (2H, m), 6.70 (IH, s), 7.41 (IH, t)
Example 170: IH NMR (400.132 MHz, DMSO) δ 0.91 - 1.06 (2H, m), 1.13 - 1.46 (1OH, m), 1.64 - 1.82 (4H, m), 2.12 (3H, s), 2.37 (IH, m), 2.53 - 2.93 (3H, m), 3.40 (2H, m), 3.71 (3H, s), 3.90 - 4.68 (2H, m), 6.71 (IH, m), 6.81 (2H, d), 8.68 (IH, d)
Example 172: IH NMR (400.13 MHz, CDC13) δ 0.96 - 1.68 (1OH, m), 1.81 - 1.83 (4H, m), 2.56 - 2.84 (3H, m), 2.99 - 3.53 (3H, m), 3.84 (3H x 2, s), 3.92 (3H x 2, s), 3.81 - 5.89 (2H, m), 6.53 - 6.64 (3H, m)
Example 173: IH NMR (400.13 MHz, CDC13) δ 1.11 - 1.20 (3H, m), 1.27 - 1.85 (9H, m), 2.58 - 2.65 (IH, m), 2.87 - 3.06 (5H, m), 3.47 - 3.61 (3H, m), 3.82 - 3.86 (6H, m), 4.04 - 4.10 (IH, m), 6.59 (IH, d), 6.65 (IH, d), 6.75 (IH, s).
Example 174: IH NMR (400.13 MHz, CDC13) δ 1.06 - 1.54 (1 IH, m), 1.75 - 1.87 (4H, m), 2.59 - 2.93 (4H, m), 3.06 - 3.26 (2.5H, m), 3.52 - 3.59 (0.5H, m), 3.82 - 3.84 (6.5H, m), 4.01 - 4.10 (0.5H, m), 4.45 (0.5H, d), 4.82 - 4.89 (0.5H, m), 6.50 - 6.57 (IH, m), 6.63 - 6.68 (IH, m), 6.62 - 6.72 (IH, m)
Example 175: IH NMR (400.132 MHz, CDC13) δ 0.49 - 0.54 (2H, m), 0.79 - 0.86 (2H, m), 1.03 - 1.93 (13H, m), 2.62 (IH, t), 2.73 - 3.47 (5H, m), 3.49 (2H, d), 3.79 - 4.86 (4H, m), 3.91 (3H, s), 6.05 (IH, t), 6.73 (IH, d), 6.98 - 7.05 (IH, m)
Example 176: IH NMR (400.132 MHz, CDC13) δ 0.53 - 0.61 (2H, m), 0.77 - 0.86 (2H, m), 1.04 - 1.89 (13H, m), 2.57 - 2.66 (IH, m), 2.73 - 3.26 (4H, m), 3.44 - 3.52 (IH, m), 3.49 (2H, s), 3.81 - 4.83 (4H, m), 3.86 (3H, s), 6.02 (IH, d), 6.74 (IH, d), 7.67 (IH, s)
Example 177: IH NMR (400.132 MHz, CDC13) δ 0.99 - 1.88 (15H, m), 2.50 - 2.71 (4H, m), 2.75 - 2.97 (3H, m), 3.13 - 3.23 (IH, m), 3.31 - 3.56 (2H, m), 3.49 (2H, d), 3.81 (3H, d), 3.83 - 4.87 (2H, m), 6.39 - 6.46 (2H, m), 6.69 (IH, d), 6.99 - 7.05 (IH, m)
Example 178: IH NMR (400.132 MHz, DMSO) δ 0.90 - 1.06 (2H, m), 1.09 - 1.45 (9H, m), 1.64 - 1.82 (4H, m), 2.12 (3H, s), 2.45 (IH, m), 2.65 - 2.84 (2H, m), 2.90 (IH, m), 3.35 - 3.62 (3H, m), 3.90 - 4.66 (2H, m), 6.64 - 6.75 (2H, m), 7.09 (IH, t), 8.69 (IH, d)
Example 179: IH NMR (400.132 MHz, DMSO) δ 1.00 - 1.09 (2H, m), 1.18 - 1.44 (4H, m), 1.46 - 1.51 (2H, m), 1.68 - 1.86 (4H, m), 2.38 - 2.84 (6H, m), 2.88 - 2.98 (IH, m), 3.18 - 3.80 (6H, m), 8.79 (IH, s)
Example 180: IH NMR (400.132 MHz, DMSO) δ 0.55 (2H, m), 0.76 (2H, m), 0.89 - 1.04 (4H, m), 1.13 - 1.46 (9H, m), 1.62 - 1.85 (4H, m), 2.65 - 2.82 (2H, m), 2.86 - 3.09 (2H, m), 3.89 (3H, s), 4.14 - 4.67 (4H, m), 7.80 (IH, s), 8.70 (IH, d)
Example 181: IH NMR (400.132 MHz, CDC13) δ 1.02 - 1.52 (1OH, m), 1.54 - 1.67 (2H, m), 1.72 - 1.90 (1OH, m), 2.22 - 2.32 (IH, m), 2.45 - 2.67 (5H, m), 2.81 - 2.91 (IH, m), 3.39 - 3.50 (2H, m), 3.60 - 3.68 (IH, m), 3.71 - 3.78 (IH, m), 7.11 (IH, s) Example 182: IH NMR (400.132 MHz, CDCB) δ 1.07 - 1.87 (13H, m), 2.55 - 3.55 (9H, m), 3.82 - 4.90 (2H, m), 6.03 (2H, d), 6.57 - 6.68 (IH, m), 6.72 - 6.78 (IH, m), 7.18 - 7.24 (IH, m)
Example 183: IH NMR (400.132 MHz, CDC13) δ 0.55 - 0.61 (2H, m), 0.64 - 0.70 (2H, m), 0.94 - 1.01 (IH, m), 1.06 - 1.87 (12H, m), 1.60 (3H, s), 2.55 - 3.47 (6H, m), 3.49 (3H, d), 3.55 and 4.42 (IH, d), 3.85 (3H, d), 4.06 - 4.14 and 4.78 - 4.87(1H, m), 6.36 - 6.41 (2H, m), 6.60 (IH, d), 7.08 - 7.14 (IH, m)
Example 184: IH NMR (400.132 MHz, CDC13) δ 1.08 - 1.89 (14H, m), 2.55 - 2.65 (IH, m), 2.74 - 2.91 (IH, m), 2.96 - 3.05 (IH, m), 3.16 (3H, d), 3.19 - 3.38 (2H, m), 3.48 - 3.78 (3H, m), 3.89 - 4.86 (2H, m), 3.96 (3H, d), 6.28 - 6.34 (IH, m), 6.41 - 6.47 (IH, m), 6.59 (IH, d), 7.75 - 7.81 (IH, m)
Example 185: IH NMR (400.132 MHz, CDC13) δ 1.07 - 1.87 (18H, m), 2.55 - 3.62 (9H, m), 3.91 and 4.48 (IH, d), 4.11 and 4.90 (IH, m), 6.59 (IH, d), 6.93 - 7.03 (IH, m), 7.48 - 7.64 (2H, m)
Example 190: IH NMR (400.132 MHz, CDC13) δ 1.00 - 1.88 (15H, m), 2.50 (3H, d), 2.57 - 2.67 (IH, m), 2.76 - 2.92 (1.5H, m), 3.06 - 3.15 (IH, m), 3.18 - 3.31 (IH, m), 3.46 - 3.72 (2.5H, m), 3.90 - 3.97 (0.5H, m), 4.12 - 4.20 (0.5H, m), 4.39 - 4.47 (0.5H, m), 4.81 - 4.89 (0.5H, m), 6.61 (0.5H, s), 6.68 (0.5H, s), 6.83 - 6.92 (2H, m), 7.43 (IH, t)
Example 196: IH NMi? (400MHz, DMSO) d 0.8 (m, 4H), 0.9-1.4 (m, 9H), 1.45 (m, 2H), 1.75 (m, 4H), 2.15 (m, IH), 2.7-3.1 (m, 4H), 3.4 (m, IH), 3.9 (s, 3H), 4.0 (m, IH), 4.1-4.6 (m, 3H), 7.6 (m, IH), 8.65 (m, IH).
Example 197: IH NMR (400MHz, DMSO) d 1.0 (m, 2H), 1.2-1.5 (m, 9H), 1.8 (m, 4H), 2.8 (s, 3H), 2.85 (s, 3H), 2.9-3.3 (m, 4H), 3.6-4.1 (m, 3H), 4.25-4.7 (m, 2H), 7.2 (m, IH), 7.7 (m, IH), 8.05 (m, IH), 8.7 (m, IH). Example 198: IH NMR (400MHz, DMSO) d 1.0 (m, 6H), 1.3-1.5 (m, 10HO, 1.75 (m, 4H), 2.1 (m, IH), 2.45 (m, IH), 2.65-3.05 (m, 3H), 3.5-4.0 (m, 5H), 4.3-4.7 (m, 2H), 7.7 (s, IH), 8.6 (m, IH).
Example 199: IH (400MHz, DMSO) d 1.0-1.5 (m, HH), 1.75 (m, 4H), 2.45 (m, IH), 2.6 (m, 6H), 2.7-3.2 (m, 4H), 3.5-4.1 (m, 3H), 4.2-4.7 (m, IH), 7.15 (d, IH), 7.55 (t, IH), 7.8 (d, IH), 8.65 (m, IH).
Example 200: IH NMR (400.13 MHz, CDC13) δ 1.06 - 1.20 (2H, m), 1.27 - 1.53 (9H, m), 1.62 - 1.70 (IH, m), 1.83 - 1.84 (4H, m), 2.58 - 3.00 (4H, m), 3.13 - 3.21 (IH, m), 3.33 - 3.34 (3H, m), 3.41 (3H, d), 3.43 - 3.60 (2H, m), 3.89 and 4.45 (IH x 2, m) 4.11 and 4.88 (IH x 2, s), 4.42 (2H, s), 4.50 (2H, s), 6.57 - 6.63 (IH, m), 6.74 - 6.78 (IH, m), 6.94 - 6.96 (IH, m), 7.20 - 7.23 (IH, m)
Example 201: IH NMR (400.13 MHz, CDC13) δ 1.09 - 1.53 (9H, m), 1.76 - 1.87 (6H, m), 2.16 (3H, d), 2.58 - 2.96 (4H, m), 3.11 - 3.38 (3H, m), 3.83 - 3.90 (0.5H, m), 3.91 (3H, d),
4.06 - 4.14 (0.5H, m), 4.42 - 4.48 (0.5H, m), 4.81 - 4.87 (0.5H, m), 6.65 - 6.75 (IH, m),
7.07 - 7.11 (IH, m), 7.57 - 7.61 (IH, m)
Example 202: IH NMR (400.13 MHz, CDC13) δ 1.08 - 1.52 (14H, m), 1.73 - 1.87 (4H, m), 2.16 (3H, m), 2.58 - 3.38 (6H, m), 3.49 (IH, s), 3.82 - 3.88 + 4.06 - 4.14 (IH, m), 4.31 (2H, q), 4.41 - 4.47 + 4.80 - 4.87 (IH, m), 6.64 - 6.73 (IH, m), 7.06 - 7.10 (IH, m), 7.55 - 7.59 (IH, m)
Example 203: IH NMR (400.13 MHz, CDC13) δ 1.11 - 1.48 (14H, m), 1.79 - 2.93 (4H, m), 2.38 (3H, s), 2.62 -4.81 (Hm), 3.94 (2H, q), 6.35 - 6.42 (IH, m), 6.50and 6.56 (2 x IH, s), 7.02 - 7.04 (IH, m)
Example 204: IH NMR (400MHz, DMSO) d 0.9-1.4 (m, 1 IH), 1.75 (m, 4H), 2.25 (s, 3H), 2.45 (m, 2H), 2.8 (m, 3H), 3.3 (s, 3H), 3.65 (m, 2H), 3.9-4.6 (m, 6H), 6.6 (m, IH), 7.25 (d, IH), 8.65 (m, IH). Example 206: IH NMR (400.132 MHz, DMSO) δ 0.90 - 1.09 (3H, m), 1.13 - 1.46 (8H, m), 1.65 - 1.82 (4H, m), 2.26 (3H, s), 2.46 (IH, m), 2.66 - 2.94 (3H, m), 3.38 (IH, m), 3.72 (3H, s), 3.85 - 4.67 (4H, m), 6.63 (IH, m), 7.25 (IH, d), 8.67 (IH, d)
Example 207: 1H NMR (400.132 MHz, DMSO) δ 0.91 - 1.05 (m, 2H), 1.14 - 1.46 (m, 6H), 1.64 - 1.81 (m, 4H), 2.44 (m, IH), 2.83 - 3.11 (m, 5H), 3.49 (m, IH), 3.54 - 3.73 (m, 3H), 5.92 (s, 2H), 6.36 (m, IH), 6.69 (d, IH), 6.77 (d, IH), 8.65 (s, IH)
Example 220: IH NMR (400.13 MHz, CDCl3) δ 1.12 - 1.49 (8H, m), 1.75 (6H, s), 1.81 - 1.83 (4H, m), 2.60 (IH, m), 2.92 (IH, m), 3.12 - 3.30 (4H, m), 3.61 - 3.88 (4H, m), 6.58 - 6.64 (2H, m), 6.80 (IH, s), 7.31 (IH, t)
Example 221 IH (400.13 MHz, CDCl3) δ 1.12 - 1.83 (12H, m), 2.63 (IH, t), 2.93 (IH, t), 3.68 - 3.84 (8H, m), 6.86 (IH, s), 6.94 - 6.97 (IH, m), 7.21 - 7.28 (IH, m), 7.54 (IH, t), 7.61 (IH, d), 7.71 (IH, d), 7.90 - 7.93 (IH, m)
Example 222:% NMR (400.132 MHz, CDC13) δ 1.08 - 1.87 (l lH, m),1.70 (6H, s),2.58 (IH, m),2.83 - 3.25 (7H, m),3.62 (2H, m),3.79 (IH, m),3.90 (3H, s),3.95 (IH, m),6.87 (IH, d),6.97 (2H, m)
Example 223:% NMR (400.132 MHz, CDC13) δ 7.45 (2H, d),6.89 (2H, d),6.58 (IH, s),3.58 - 3.87 (4H, m),3.14 - 3.38 (4H, m),2.89 (IH, t),2.57 (2H, m),1.82 (4H, m),1.75 (3H, s),1.05 - 1.70 (7H, m)
Example 224: % NMR (400.132 MHz, CDC13) δ 1.13 (2H, m),1.24 - 1.89 (9H, m),1.97 (2H, m),2.34 (2H, m),2.56 (3H, m),2.89 (IH, t),3.16 (4H, m),3.27 (IH, m),3.59 - 3.89 (4H, m),6.62 (IH, s),6.91 (2H, d),7.40 (2H, d)
Example 225:% NMR (400.132 MHz, CDC13) δ 1.06 - 1.69 (8H, m), 1.56 (6H, s), 1.82 (4H, m), 2.58 (IH, m), 2.89 (IH, m), 3.15 (3H, m), 3.25 (IH, m), 3.57 - 3.88 (4H, m), 6.60 (IH, s), 6.88 (2H, d), 7.39 (2H, d) Example 226: 1R NMR (400.132 MHz, DMSO) δ 0.93 - 1.03 (2H, m), 1.16 - 1.43 (6H, m), 1.65 - 1.82 (4H, m), 2.44 (IH, m), 2.91 (IH, m), 2.98 - 3.22 (4H, m), 3.50 (IH, m), 3.56 - 3.72 (3H, m), 3.73 (3H, s), 6.40 (IH, m), 6.47 (IH, t), 6.54 (IH, m), 7.13 (IH, t), 8.66 (IH, s)
The secondary amines used for the synthesis of example compound above were prepared by the following methods 2-Methyl-2-(6-piperazin-l-ylpyridin-3-yl)propanenitrile
Figure imgf000204_0001
The 2-(6-chloropyridin-3-yl)-2-methylpropanenitrile [US2008039457] (1.23 g, 6.80 mmol), piperazine (1.76 g, 20.4 mmol) and di-isopropylethyl amine (4.74 mL, 27.2 mmol) were combined in DMF (20 mL) and heated to 85 0C overnight. Allowed to cool then partitioned between EtOAc (100 mL) and sat NH4Cl (aq) (100 mL), back extracted with EtOAc (100 mL) and the combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and reduced to yield a low-melting crystalline solid which was triturated with hexanes then passed through a 10 g SCX acidic resin cartridge, washing with MeOH and then 1 :2 7 N NH3 in MeOH / MeOH. This yielded a mixture which was purified by flash column chromatography (silica, eluting with DCM to 5% MeOH / DCM to 9:1 ratio of 5% MeOH / DCM : 7N NH3 in MeOH) to obtain a clear golden oil (146 mg, 9.0%). MS (+ve ESI) : Rt = 1.58 min, 231.34 (M+H)+
1R NMR (400.13 MHz, CDCl3) δ 1.70 (6H, s), 2.35 (IH, br s), 2.98 - 3.00 (4H, m), 3.53 - 3.58 (4H, m), 6.64 (IH, d), 7.55 - 7.58 (IH, m), 8.28 (IH, d) Benzyl 2-piperazin-l-yl-6,7-dihydro[l,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate was synthesized in the following manner.
Benzyl 2- [4-(tør*-butoxycarbonyl)piperazin-l-yl] -6,7-dihydro [1,3] thiazolo [5,4- c] pyridine-5(4H)-carboxylate
Figure imgf000205_0001
To a mixture of tert-butyl 4-(aminocarbonothioyl)piperazine-l-carboxylate (0.31 g, 1.26 mmol) and benzyl 3-bromo-4-oxopiperidine-l-carboxylate (481 mg, 1.54 mmol) in xylene
(20 mL) was added triethylamine (704 ul, 5.05 mmol). The reaction mixture was refluxed (140 0C) for 64 hours. The reaction mixture was concentrated in vacuo and the residue purified by flash column chromatography (isohexane to 50% ethyl acetate/isohexane) to give an orange gum (366 mg, 11.6%).
MS (+ve ESI) : Rt = 2.88 min, 459.23 (M+H)+
1R NMR (400.132 MHz, DMSO) δ 1.42 (9H, s), 2.57 (2H, m), 3.33 (4H, m), 3.44 (4H, m), 3.69 (2H, t), 4.48 (2H, s), 5.12 (2H, s), 7.30 - 7.41 (5H, m)
Benzyl 2-piperazin-l-yl-6,7-dihydro[l,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
Figure imgf000205_0002
A solution of (366 mg, 0.800 mmol) in benzyl 2-[4-(tøt-butoxycarbonyl)piperazin-l-yl]- 6,7-dihydro[l,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate methanol reagent 10 (15 mL) was allowed to stir at room temperature for 16 hours. Reaction mixture was concentrated to dryness to give a pale brown solid(287 mg, 90.8%). MS (+ve ESI) : Rt = 1.90 min, 359.23 (M+Η)+ l-(4-(Piperazin-l-yl)phenyl)cyclopropanecarboxamide
Figure imgf000205_0003
l-(4-(Piperazin-l-yl)phenyl)cyclopropanecarbonitrile (954 mg, 4.20 mmol) was suspended in sulfuric acid (20 mL). The resulting mixture was stirred at ambient temperature for 45 hours and then poured onto ice, the mixture was basified with 1OM NaOH and then 2M
NaOH (cf. 10 mL), extracted with DCM (3 x 40 mL) and then the organic layer was dried over MgSO4, filtered and evaporated to afford crude product.
Compound were purified by prep HPLC using 0.1% NH3 modified water/MeCN on a Waters X-Bridge Cl 8 (5μ silica, 50 mm diameter, 150 mm length) column. Fractions containing the desired compound were evaporated to dryness. To give l-(4-(piperazin-l- yl)phenyl)cyclopropanecarboxamide (193 mg, 18.7%) as a white solid
MS (+ve ESI) : Rt = 1.05 min, 246.32 (M+H)+
1U NMR (400.132 MHz, CDC13) δ 1.03 (2H, q), 1.56 (2H, q), 2.57 (IH, m), 3.03 (4H, m), 3.15 (4H, m), 5.35 - 5.62 (2H, m), 6.89 (2H, d), 7.30 (2H, d)
2-(2-Chloro-4-(piperazin-l-yl)phenyl)-2-methylpropanamide
Figure imgf000206_0001
2-(2-Chloro-4-(piperazin-l-yl)phenyl)-2-methylpropanenitrile (227 mg, 0.860 mmol) was suspended in sulfuric acid (5 mL). The resulting mixture was stirred at ambient Temperature for 16 hours and then poured onto ice, the mixture was basified with 1OM NaOH and then 2M NaOH (cf. 10 mL), extracted with DCM (3 x 40 mL) and then the organic layer was dried over MgSO4, filtered and evaporated to afford crude product 2-(2- chloro-4-(piperazin-l-yl)phenyl)-2-methylpropanamide (243 mg, 81 %) as a white foam. MS (+ve ESI) : Rt = 0.70 min, 282.24 (M+H)+ 1U NMR (400.132 MHz, CDC13) δ 1.61 (6H, s), 3.02 (4H, m), 3.15 (4H, m), 5.20 (2H, m), 6.81 (IH, m), 6.94 (IH, d), 7.34 (IH, d) 2-Methyl-2-(2-methyl-4-(piperazin-l-yl)phenyl)propanamide
Figure imgf000206_0002
2-Methyl-2-(2-methyl-4-(piperazin-l-yl)phenyl)propanenitrile (0.730 g, 3.00 mmol) was suspended in sulfuric acid (10 mL) and the mixture stirred for 66 hours. The reaction was poured into ice and then basified to pH12, initially with 1OM NaOH and then 2M NaOH (cf 20 mL) and extracted with DCM (2 x 100 mL), dried over MgSO4, filtered and evaporated. Gave crude 2-methyl-2-(2-methyl-4-(piperazin-l-yl)phenyl)propanamide (0.705 g, 90 %) as a yellow foam. MS (+ve ESI) : 262 (M+H)+
1R NMR (400.132 MHz, CDCB) δ 1.56 (6H, s), 2.31 (3H, s), 3.05 - 3.10 (4H, m), 3.15 -
3.22 (4H, m), 5.11 - 5.26 (2H, m), 6.73 (2H, m), 7.30 (IH, d)
2-(2-Methoxy-4-(piperazin-l-yl)phenyl)-2-methylpropanamide
Figure imgf000207_0001
2-(2-Methoxy-4-(piperazin-l-yl)phenyl)-2-methylpropanenitrile (136 mg, 0.520 mmol) was suspended in sulfuric acid (5ml). The resulting mixture was stirred at ambient temperature for 16 hours and then poured onto ice, the mixture was basified with 1OM NaOH and then 2M NaOH (c.f. 20 mL), extracted with DCM (3 x 100 mL) and then the organic layer was dried over MgSO4, filtered and evaporated to afford semi pure product. 2-(2-methoxy-4-(piperazin-l-yl)phenyl)-2-methylpropanamide (83.8 mg, 57.8 %) as a white foam.
MS (+ve ESI) : 278 (M+H)+ 1R NMR (400.132 MHz, CDC13) δ 1.53 (6H, s), 3.02 - 3.09 (4H, m), 3.13 - 3.20 (4H, m), 3.80 (3H, s), 4.89 - 5.27 (2H, m), 6.46 - 6.51 (2H, m), 7.20 - 7.25 (IH, m)
(if)-2-(2-Methoxy-4-(3-methylpiperazin-l-yl)phenyl)-2-methylpropanamide
Figure imgf000207_0002
(R)-tert-Butyl 4-(4-(2-cyanopropan-2-yl)-3-methoxyphenyl)-2-methylpiperazine-l- carboxylate (193 mg, 0.520 mmol) was suspended in sulfuric acid (10 mL). The resulting mixture was stirred at ambient temperature for 65 hours and then poured onto ice, the mixture was basified with 1OM NaOH and then 2M NaOH to pH12, extracted with DCM (3 x 50 mL) and then the organic layer was dried over MgSO4, filtered and evaporated to afford semi pure product (i?)-2-(2-methoxy-4-(3-methylpiperazin-l-yl)phenyl)-2- methylpropanamide (85.0 mg, 56.5 %) as a yellow foam. MS (+ve ESI) : 292 (M+H)+ iV-2-Dimethyl-2-(4-(piperazin-l-yl)phenyl)propanamide was synthesized in the following manner. tert-butyl 4-(4-(2-methyl-l-(methylamino)-l-oxopropan-2-yl)phenyl)piperazine-l- carboxylate
Figure imgf000208_0001
To a slurry of 2-(4-(4-(tert-butoxycarbonyl)piperazin-l-yl)phenyl)-2-methylpropanoic acid (266 mg, 0.760 mmol) and HATU (319 mg, 0.84 mmol) in DCM (3.8 mL) was added N- ethyldiisopropylamine (0.396 ml, 2.29 mmol) followed by methylamine (1.15 mL, 2.29 mmol) and the reaction stirred for 18 hours. The mixture was diluted with DCM (50 mL) and washed sequentially with water (2 x 50 mL) and saturated NaHCO3 (2 x 50 mL), dried over MgSO4, filtered and evaporated to give tert-butyl 4-(4-(2 -methyl- l-(methylamino)-l - oxopropan-2-yl)phenyl)piperazine-l-carboxylate (274 mg, 99 %) as a yellow solid. MS (+ve ESI) : 362 (M+H)+
1H NMR (400.132 MHz, CDC13) δ 6.90 (2H, d), 7.26 (2H, d), 5.16 (IH, s), 3.55 - 3.60 (4H, m), 3.11 - 3.16 (4H, m), 2.70 (3H, d), 1.48 (9H, s), 1.54 (6H, s) ΛL2-Dimethyl-2-(4-(piperazin-l-yl)phenyl)propanamide
Figure imgf000208_0002
A 4M solution of hydrogen chloride (7.6ml, 30.4 mmol) in dioxane was added to tert-butyl 4-(4-(2 -methyl- 1 -(methylamino)- 1 -oxopropan-2-yl)phenyl)piperazine- 1 -carboxylate (274 mg, 0.760 mmol) and the mixture stirred , DCM (ca 5 mL) was added to aid solubility and the reaction stirred for 2 hours and Et2O (10 mL) added and the precipitate was collected by filtration, washed with Et2O (10 mL) and dried under vacuum to afford 7V-2-dimethyl-2- (4-(piperazin-l-yl)phenyl)propanamide (221 mg, 100 %) as a white solid, which was used without further purification. MS (+ve ESI) : 262 (M+H)+ 1U NMR (400.132 MHz, DMSO) δ 1.46 (6H, s), 2.59 (3H, d), 3.22 - 3.29 (4H, m), 3.37 - 3.44 (4H, m), 6.99 (2H, d), 7.25 (2H, d), 9.33 (2H, s) tert- Butyl 4-(6-methoxypyridin-2-yl)piperazine-l-carboxylate
Figure imgf000209_0001
To a solution of l-(6-methoxypyridin-2-yl)piperazine (865 mg, 4.48 mmol) in DCM (22 mL) was added di-tert-butyl dicarbonate (1075 mg, 4.92 mmol) and the reaction stirred for 18 hours and then diluted with DCM (50 mL) and washed with 2M NaOH (2x50 mL), water (50 mL), dried over MgSO4, filtered and evaporated to give pure tert-butyl 4-(6- methoxypyridin-2-yl)piperazine-l-carboxylate (1360 mg, 104 %) as a brown solid.
MS (+ve ESI) : Rt = 2.78 min, 238.45 (M+H-boc)+
1R NMR (400.132 MHz, CDC13) δ 1.49 (9H, s), 3.48 - 3.57 (8H, m), 3.87 (3H, s), 6.11 (IH, d), 6.16 (IH, d), 7.42 (IH, t) tert-Bntyl 4-(5-bromo-6-methoxypyridin-2-yl)piperazine-l-carboxylate and tert-Bntyl 4-(3-bromo-6-methoxypyridin-2-yl)piperazine-l-carboxylate
Figure imgf000209_0002
To a solution of tert-butyl 4-(6-methoxypyridin-2-yl)piperazine-l-carboxylate (0.147 g, 0.500 mmol) in chloroform (5 mL) at 0 0C was added l-bromopyrrolidine-2,5-dione (0.089 g, 0.500 mmol) and the reaction stirred and allowed to warm to ambient temperature over 3 hours. Diluted with DCM (50 mL) and washed with water (2 x 50 mL), dried over MgSO4, filtered and evaporated. Purified by HPLC.
The crude product was purified by preparative HPLC Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. The aqueous mixture were extracted with DCM (2 x 50 mL) and the combined organics dried over MgSO4, filtered and evaporated. This gave tert-butyl 4-(5-bromo-6-methoxypyridin-2-yl)piperazine-l- carboxylate (0.108 g, 58.0 %) as a white solid (1st eluted) and tert-butyl 4-(3-bromo-6-methoxypyridin-2-yl)piperazine-l-carboxylate (0.025 g, 13.4 %) as a colourless oil. tert-butyl 4-(5-bromo-6-methoxypyridin-2-yl)piperazine-l-carboxylate
MS (+ve ESI) : Rt = 3.16 min, 272.23 (M+H-boc)+ 1R NMR (400.132 MHz, CDC13) δ 1.48 (9H, s), 3.46 - 3.56 (8H, m), 3.94 (3H, s), 6.08 (IH, d), 7.55 (IH, d) tert-butyl 4-(3-bromo-6-methoxypyridin-2-yl)piperazine-l-carboxylate
MS (+ve ESI) : Rt = 3.15 min, no mass ion (M+H)+
1H NMR (400.132 MHz, CDC13) δ 1.48 (9H, s), 3.46 (4H, m), 3.30 (4H, m), 3.87 (3H, s), 6.25 (IH, d), 7.61 (IH, d)
tert-Butyl 4-(5-cyclopropyl-6-methoxypyridin-2-yl)piperazine-l-carboxylate
Figure imgf000210_0001
tert-Butyl 4-(5-bromo-6-methoxypyridin-2-yl)piperazine-l-carboxylate (108 mg, 0.290 mmol), potassium phosphate (216 mg, 1.02 mmol), tricyclohexylphosphine (8.14 mg, 0.03 mmol) and cyclopropylboronic acid (32.4 mg, 0.380 mmol) were suspended in toluene (2 mL) and water (0.06 mL) added followed by palladium(II) acetate (3.26 mg, 0.01 mmol).
The mixture was heated to 100 0C for 4 hours and then allowed to cool. Poured into water
(50 mL) and extracted with EtOAc (2 x 50 mL), the combined organics layers were dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(5-cyclopropyl-6-methoxypyridin-2- yl)piperazine-l-carboxylate (72.0 mg, 74.4 %) as a orange oil.
MS (+ve ESI) : Rt = 3.23 min, 334 (M+H)+ 1R NMR (400.132 MHz, CDC13) δ 0.49 - 0.56 (2H, m), 0.80 - 0.87 (2H, m), 1.48 (9H, s),
1.85 - 1.93 (IH, m), 3.41 - 3.47 (4H, m), 3.50 - 3.56 (4H, m), 3.92 (3H, s), 6.09 (IH, d),
7.03 (IH, d) l-(5-Cyclopropyl-6-methoxypyridin-2-yl)piperazine
Figure imgf000211_0001
tert-Butyl 4-(5-cyclopropyl-6-methoxypyridin-2-yl)piperazine-l-carboxylate (72.0 mg, 0.22 mmol) was dissolved in hydrogen chloride (4M in dioxane) (2.20 mL, 8.80 mmol) and the reaction stirred for 2 hours and then evaporated. Partitioned with 2M NaOH (50 mL) and DCM (50 mL) and the aqueous layer washed with further DCM (25 mL), the combined organic layers were dried over MgSO4, filtered and evaporated to afford l-(5- cyclopropyl-6-methoxypyridin-2-yl)piperazine (42.0 mg, 83 %) as a orange solid. MS (+ve ESI) : Rt = 3.23 min, 334 (M+H)+
1R NMR (400.132 MHz, CDC13) δ 0.55 (2H, m), 0.87 (2H, m), 1.87 (IH, m), 2.85 - 3.10 (4H, m), 3.45 (2H, m), 3.60 - 3.85 (2H, m), 3.95 (3H, s), 6.05 (2H, m), 7.05 (IH, d) (R)-tert-Butyl 4-(6-methoxypyridin-2-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000211_0002
(i?)-l-7V-Boc-2-methyl piperazine (1.05 g, 5.25 mmol), PEPPSI (0.068 g, 0.10 mmol), 2- chloro-6-methoxypyridine (0.718 g, 5.00 mmol) and potassium tert-butoxide (0.673 g, 6.00 mmol) were suspended in DME (5mL) and the mixture stirred and heated to 50 0C for 5 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (2 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 15 % EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(6- methoxypyridin-2-yl)-2-methylpiperazine-l-carboxylate (1.220 g, 79 %) as a colourless oil.
MS (+ve ESI) : Rt = 3.23 min, 334 (M+H)+ 1U NMR (400.132 MHz, CDCB) δ 1.20 (3H, d), 1.48 (9H, s), 2.87 - 2.97 (IH, m), 3.11 - 3.27 (2H, m), 3.86 (3H, s), 3.88 - 3.95 (IH, m), 3.98 - 4.04 (IH, m), 4.08 - 4.14 (IH, m), 4.27 - 4.35 (IH, m), 6.06 (IH, d), 6.12 (IH, d), 7.40 (IH, t) (R)-tert-butyl 4-(5-bromo-6-methoxypyridin-2-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000212_0001
To a solution of (R)-tert-butyl 4-(6-methoxypyridin-2-yl)-2-methylpiperazine-l- carboxylate (0.922 g, 3.00 mmol) in chloroform (30 mL) at 0 0C was added 1- bromopyrrolidine-2,5-dione (0.534 g, 3.00 mmol) and the reaction stirred and allowed to warm to ambient temperature over 3 hours. Diluted with DCM (50 mL) and washed with water (2 x 50 mL), dried over MgSO4, filtered and evaporated. Purified by HPLC. The crude product was purified by preparative HPLC Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. The aqueous mixture were extracted with DCM (2 x 50 mL) and the combined organics dried over MgSO4, filtered and evaporated. This gave (R)-tert-butyl 4-(5-bromo-6-methoxypyridin-2-yl)-2-methylpiperazine-l- carboxylate (0.555 g, 47.9 %) as a yellow oil. MS (+ve ESI) : Rt = 3.27 min, 386 (M+H)+
(R)-tert-bntyl 4-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-methylpiperazine-l- carboxylate
Figure imgf000212_0002
(R)-tert-Butyl 4-(5-bromo-6-methoxypyridin-2-yl)-2-methylpiperazine- 1 -carboxylate (555 mg, 1.44 mmol), potassium phosphate (1.07 g, 5.03 mmol), tricyclohexylphosphine (40.3 mg, 0.14 mmol) and cyclopropylboronic acid (160 mg, 1.87 mmol) were suspended in toluene (10 mL) and water (0.30 mL) added followed by palladium(II) acetate (16.13 mg, 0.07 mmol). The mixture was heated to 100 0C for 5 hours and then allowed to cool.
Poured into water (5OmL) and extracted with EtOAc (2 x 50 mL), the combined organics layers were dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(5-cyclopropyl-6-methoxypyridin-2- yl)-2-methylpiperazine-l-carboxylate (327 mg, 65.5 %) as a orange oil.
MS (+ve ESI) : Rt = 3.45 min, 348.54 (M+H)+
1U NMR (400.132 MHz, CDC13) δ 0.49 - 0.55 (2H, m), 0.79 - 0.85 (2H, m), 1.20 (3H, d),
1.48 (9H, s), 1.84 - 1.92 (IH, m), 2.79 - 2.89 (IH, m), 3.02 - 3.09 (IH, m), 3.15 - 3.25 (IH, m), 3.88 - 4.00 (2H, m), 3.92 (3H, s), 4.03 - 4.10 (IH, m), 4.27 - 4.37 (IH, m), 6.05 (IH, d), 7.01 (IH, d)
(if)-l-(5-cyclopropyl-6-methoxypyridin-2-yl)-3-methylpiperazine
Figure imgf000213_0001
(R)-tert-buty{ 4-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-methylpiperazine- 1 -carboxylate (322 mg, 0.930 mmol) was dissolved in hydrogen chloride (4M in dioxane) (10 mL, 40.0 mmol) and the reaction stirred for 1 hour and then evaporated. Partitioned with 2M NaOH (50 mL) and DCM (50 mL) and the aqueous layer washed with further DCM (25 mL), the combined organic layers were dried over MgSO4, filtered and evaporated to afford (R)-I- (5-cyclopropyl-6-methoxypyridin-2-yl)-3-methylpiperazine (230 mg, 100 %) as a yellow solid.
MS (+ve ESI) : Rt = 1.16 min, 248.49 (M+H)+
1U NMR (400.132 MHz, CDC13) δ 0.49 - 0.56 (2H, m), 0.79 - 0.86 (2H, m), 1.16 (3H, d), 1.84 - 1.93 (IH, m), 2.37 - 2.45 (IH, m), 2.72 - 2.81 (IH, m), 2.87 - 3.01 (2H, m), 3.07 - 3.14 (IH, m), 3.93 (3H, s), 4.06 (2H, t), 6.08 (IH, d), 7.02 (IH, d) (R)-tert-Butyl 4-(4-methoxypyridin-2-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000214_0001
(R)-I -JV-Boc-2-methyl piperazine (1.05 g, 5.25 mmol), PEPPSI (0.068 g, 0.10 mmol), 2- chloro-4-methoxypyridine (1.00 g, 5.25 mmol) and potassium tert-butoxide (0.673 g, 6.00 mmol) were suspended in DME (5 mL) and the mixture stirred and heated to 50 0C for 6 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (2 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50 % EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(4- methoxypyridin-2-yl)-2-methylpiperazine-l-carboxylate (1.26 g, 82 %) as a yellow oil. MS (+ve ESI) : Rt = 1.11 min, 308.52 (M+H)+
1H NMR (400.132 MHz, CDC13) δ 1.21 (3H, d), 1.48 (9H, s), 2.91 - 3.00 (IH, m), 3.18 - 3.30 (2H, m), 3.81 (3H, s), 3.89 - 3.95 (2H, m), 4.02 - 4.08 (IH, m), 4.26 - 4.35 (IH, m), 6.05 (IH, d), 6.24 - 6.27 (IH, m), 8.02 (IH, d) (R)-tert-butyl 4-(5-bromo-4-methoxypyridin-2-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000214_0002
To a solution of (R)-tert-butyl 4-(4-methoxypyridin-2-yl)-2-methylpiperazine-l- carboxylate (0.922 g, 3 mmol) in chloroform (30 mL) at 0 0C was added 1- bromopyrrolidine-2,5-dione (0.534 g, 3.00 mmol) and the reaction stirred and allowed to warm to ambient temperature over 3 hours. Diluted with DCM (50 mL) and washed with water (2 x 50 mL), dried over MgSO4, filtered and evaporated.The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(5-bromo-4- methoxypyridin-2-yl)-2-methylpiperazine-l-carboxylate (1.03 g, 89 %) as a yellow oil.
MS (+ve ESI) : Rt = 2.31 min, 388.36 (M+H)+
1R NMR (400.132 MHz, CDC13) δ 1.20 (3H, d), 1.48 (9H, s), 2.95 - 3.05 (IH, m), 3.21 -
3.32 (2H, m), 3.89 - 3.96 (2H, m), 3.91 (3H, s), 3.97 - 4.04 (IH, m), 4.26 - 4.35 (IH, m),
6.03 (IH, s), 8.08 (IH, s)
(R)-tert-Bntyl 4-(5-cyclopropyl-4-methoxypyridin-2-yl)-2-methylpiperazine-l- carboxylate
Figure imgf000215_0001
(R)-tert-Butyl 4-(5-bromo-4-methoxypyridin-2-yl)-2-methylpiperazine-l-carboxylate (1.03 g, 2.66 mmol), potassium phosphate (1.98 g, 9.30 mmol), tricyclohexylphosphine (0.074 g, 0.27 mmol) and cyclopropylboronic acid (0.297 g, 3.45 mmol) were suspended in toluene (20 mL) and water (0.60 mL) added followed by palladium(II) acetate (0.030 g, 0.13 mmol). The mixture was heated to 100 0C for 5 hours and then allowed to cool. Poured into water (50 mL) and extracted with EtOAc (2 x 50 mL), the combined organics layers were dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford {R)-tert -butyl 4-(5-cyclopropyl-4-methoxypyridin-2-yl)-2- methylpiperazine-1-carboxylate (0.716 g, 78 %) as a yellow oil. MS (+ve ESI) : Rt = 3.45 min, 348.54 (M+H)+
1U NMR (400.132 MHz, CDC13) δ 0.54 - 0.60 (2H, m), 0.79 - 0.84 (2H, m), 1.22 (3H, d), 1.48 (9H, s), 1.75 - 1.85 (IH, m), 2.87 - 2.96 (IH, m), 3.13 - 3.29 (2H, m), 3.87 (3H, s), 3.87 - 4.06 (3H, m), 4.27 - 4.35 (IH, m), 6.02 (IH, s), 7.69 (IH, s) (if)-l-(5-Cyclopropyl-4-methoxypyridin-2-yl)-3-methylpiperazine
Figure imgf000215_0002
(R)-tert-buty{ 4-(5-cyclopropyl-4-methoxypyridin-2-yl)-2-methylpiperazine- 1 -carboxylate
(716 mg, 2.06 mmol) was dissolved in hydrogen chloride (4M in dioxane) (21 mL, 84.0 mmol) and the reaction stirred for 2 hours and then evaporated. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NHVMeOH and pure fractions were evaporated to dryness to afford (i?)-l-(5-cyclopropyl-4-methoxypyridin-2-yl)-3-methylpiperazine (502 mg, 98 %) as a yellow oil.
MS (+ve ESI) : Rt = 1.16 min, 248.54 (M+H)+
1U NMR (400.132 MHz, CDC13) δ 0.54 - 0.60 (2H, m), 0.78 - 0.85 (2H, m), 1.14 (3H, d), 1.76 - 1.85 (IH, m), 2.38 - 2.46 (IH, m), 2.76 - 3.00 (3H, m), 3.08 - 3.15 (IH, m), 3.87
(3H, s), 3.98 - 4.11 (2H, m), 6.07 (IH, s), 7.70 (IH, s)
(i?)-l-(4-Ethyl-3-methoxyphenyl)-3-methylpiperazine was synthesised in the following manner. l-(4-Bromo-2-methoxyphenyl)ethanone
Figure imgf000216_0001
To a slurry of l-(4-bromo-2-hydroxyphenyl)ethanone (2.15 g, 10.0 mmol) and potassium carbonate (1.81 mL, 30.0 mmol) in DMF (10 mL) at 0 0C was added iodomethane (0.747 mL, 12.0 mmol) and the reaction stirred and allowed to warm to ambient temperature for 5 hours. The mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL), the combined organic extracts dried over MgSO4, filtered and evaporated. The residue was dissolved in EtOAc (50 mL) and washed with water (3 x 50 mL), brine (50 mL), dried over MgSO4, filtered and evaporated to give l-(4-bromo-2-methoxyphenyl)ethanone (2.15 g, 94
%)
MS (+ve ESI) : Rt = 2.25 min, 231.31 (M+H)+ 1R NMR (400.132 MHz, CDC13) δ 2.58 (3H, s), 3.92 (3H, s), 7.12 - 7.17 (2H, m), 7.63 (IH, d) (R)-tert-Bntyl 4-(4-acetyl-3-methoxyphenyl)-2-methylpiperazine-l-carboxylate
Figure imgf000217_0001
l-(4-Bromo-2-methoxyphenyl)ethanone (0.687 g, 3 mmol), PEPPSI (0.041 g, 0.06 mmol),(i?)-l-7V-Boc-2-methyl piperazine (0.631 g, 3.15 mmol) and potassium tert- butoxide (0.404 g, 3.60 mmol) were suspended in DME (3 mL) and the mixture stirred and heated to 50 0C for 18 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (2 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40 % EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(4-acetyl-3 -methoxyphenyl)-2-methylpiperazine- 1 -carboxylate (0.542 g, 51.9 %) as a yellow solid.
MS (+ve ESI) : Rt = 2.56 min, 349.47 (M+H)+
1R NMR (400.132 MHz, CDC13) δ 1.25 (3H, d), 1.49 (9H, s), 2.56 (3H, s), 2.96 - 3.05 (IH, m), 3.16 - 3.24 (IH, m), 3.26 - 3.36 (IH, m), 3.50 - 3.57 (IH, m), 3.64 - 3.71 (IH, m), 3.90 (3H, s), 3.90 - 3.97 (IH, m), 4.29 - 4.38 (IH, m), 6.26 (IH, s), 6.44 (IH, d), 7.81 (IH, d)
(2R)-tert-Bntyl 4-(4-(l-hydroxyethyl)-3-methoxyphenyl)-2-methylpiperazine-l- carboxylate
Figure imgf000217_0002
(R)-tert-Butyl 4-(4-acetyl-3-methoxyphenyl)-2-methylpiperazine-l -carboxylate (542 mg, 1.56 mmol) was dissolved in THF (16 mL) under a blanket of argon and borane-methyl sulfide complex (1.71 mL, 3.42 mmol) added. The reaction was stirred for 2 hours and then methanol (2 mL) added, cautiously. The mixture was evaporated and then purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(4-(l-hydroxyethyl)-3- methoxyphenyl)-2-methylpiperazine-l-carboxylate (352 mg, 64.6 %) as a yellow oil.
MS (+ve ESI) : Rt = 2.44min, 351.53 (M+H)+
1H NMR (400.132 MHz, CDC13) δ 1.30 (3H, d), 1.49 (9H, s), 1.49 (3H, d), 2.51 (IH, d),
2.71 - 2.81 (IH, m), 2.92 - 2.98 (IH, m), 3.21 - 3.30 (IH, m), 3.35 (IH, d), 3.50 (IH, d),
3.86 (3H, s), 3.94 (IH, d), 4.30 - 4.39 (IH, m), 4.98 - 5.07 (IH, m), 6.42 (IH, d), 6.44 -
6.49 (IH, m), 7.20 (IH, d)
(R)-tert-Bntyl 4-(4-ethyl-3-methoxyphenyl)-2-methylpiperazine-l-carboxylate
Figure imgf000218_0001
A mixture of (R)-tert-butyl 4-(4-(l-hydroxyethyl)-3-methoxyphenyl)-2-methylpiperazine- 1-carboxylate (332 mg, 0.95 mmol) and triethylsilane (0.184 mL, 1.14 mmol) in DCM (9.5 mL) under a blanket of argon was cooled to -78 0C and boron trifluoride diethyl etherate (0.120 mL, 0.95 mmol) added dropwise. The bath was removed and the mixture was allowed to warm to ambient temperature for 30 minutes. Poured into saturated NaHCO3 (25 mL) and extracted with DCM (2 x 25 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4- (4-ethyl-3-methoxyphenyl)-2-methylpiperazine-l-carboxylate (221 mg, 69.8 %) as a colourless oil which solidified on standing
MS (+ve ESI) : Rt = 3.33 min, 335.54 (M+H)+
1R NMR (400.132 MHz, CDC13) δ 1.15 (3H, t), 1.31 (3H, d), 1.48 (9H, s), 2.55 (2H, q), 2.67 - 2.77 (IH, m), 2.87 - 2.93 (IH, m), 3.20 - 3.35 (2H, m), 3.43 - 3.50 (IH, m), 3.82 (3H, s), 3.90 - 3.97 (IH, m), 4.30 - 4.38 (IH, m), 6.41 - 6.46 (2H, m), 7.02 (IH, d) (i?)-l-(4-Ethyl-3-methoxyphenyl)-3-methylpiperazine
Figure imgf000219_0001
(R)-tert-Butyl 4-(4-ethyl-3-methoxyphenyl)-2-methylpiperazine-l-carboxylate (211 mg,
0.63 mmol) was dissolved in hydrogen chloride (4M in dioxane) (6.3 mL, 25.2 mmol) and the reaction stirred for 2 hours and then evaporated. Partitioned with 2M NaOH (50 mL) and DCM (50 mL) and the aqueous layer washed with further DCM (25 mL), the combined organic layers were dried over MgSO4, filtered and evaporated to afford (R)-I-
(4-ethyl-3-methoxyphenyl)-3-methylpiperazine (151 mg, 102 %) as a yellow oil.
MS (+ve ESI) : Rt = 1.22 min, 235.54 (M+H)+
1U NMR (400.132 MHz, CDC13) δ 1.11 - 1.18 (6H, m), 2.34 (IH, t), 2.55 (2H, q), 2.65 - 2.74 (IH, m), 2.94 - 3.15 (3H, m), 3.44 - 3.50 (2H, m), 3.82 (3H, s), 6.44 - 6.49 (2H, m),
7.02 (IH, d)
(if)-5-Cyclopropyl-4-methoxy-2-(3-methylpiperazin-l-yl)pyrimidine was synthesised in the following manner.
(R)-tert-Bntyl 4-(5-bromo-4-methoxypyrimidin-2-yl)-2-methylpiperazine-l- carboxylate
Figure imgf000219_0002
5-Bromo-2-chloro-4-methoxypyrimidine (1.00 g, 4.48 mmol), (R)-tert-butyl 2- methylpiperazine-1 -carboxylate (0.941 g, 4.70 mmol) and DIPEA (1.56 mL, 8.95 mmol) were suspended in ethanol (7 mL) and sealed into a microwave tube. The reaction was heated to 150 0C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was evaporated to dryness and redissolved in DCM (100 mL), and washed sequentially with water (100 mL) and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(5-bromo-4- methoxypyrimidin-2-yl)-2-methylpiperazine-l-carboxylate (1.65 g, 95 %) as a colourless gum.
MS (+ve ESI) : Rt = 3.09 min, 389.36 (M+H)+
1R NMR (400.132 MHz, CDC13) δ 1.13 (3H, d), 1.48 (9H, s), 3.00 (IH, m), 3.09 - 3.21
(2H, m), 3.91 (IH, m), 3.96 (3H, s), 4.32 (IH, s), 4.42 (IH, d), 4.51 (IH, m), 8.11 (IH, s)
(R)-tert-bntyl 4-(5-cyclopropyl-4-methoxypyrimidin-2-yl)-2-methylpiperazine-l- carboxylate
Figure imgf000220_0001
Palladium(II) acetate (0.013 g, 0.06 mmol) was added to cyclopropylboronic acid (0.204 g, 2.38 mmol), tricyclohexylphosphine (0.033 g, 0.12 mmol), potassium phosphate (0.882 g, 4.16 mmol) and (R)-tert-butyl 4-(5-bromo-4-methoxypyrimidin-2-yl)-2-methylpiperazine- 1-carboxylate (0.460 g, 1.19 mmol) in toluene (15 mL) and water (0.4 mL) under argon. The resulting suspension was stirred at 100 0C for 5 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 75 mL). The organic layers were combined and washed with saturated brine (50 mL), dried over MgSO4, filtered and evaporated to afford a crude yellow gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% Et2O in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(5-cyclopropyl-4-methoxypyrimidin-2-yl)- 2-methylpiperazine-l-carboxylate (0.309 g, 74.7 %) as a yellow gum. MS (+ve ESI) : Rt = 1.95 min, 349.54 (M+H)+
1R NMR (400.132 MHz, CDC13) δ 0.54 (2H, m), 0.80 (2H, m), 1.14 (3H, d), 1.48 (9H, s), 1.70 (IH, m), 2.95 (IH, m), 3.13 (2H, m), 3.89 (IH, m), 3.93 (3H, s), 4.31 (IH, s), 4.44 (IH, m), 4.54 (IH, m), 7.75 (IH, s) (if)-5-Cyclopropyl-4-methoxy-2-(3-methylpiperazin-l-yl)pyrimidine
Figure imgf000220_0002
(R)-tert-Butyl 4-(5-cyclopropyl-4-methoxypyrimidin-2-yl)-2-methylpiperazine-l- carboxylate (0.309 g, 0.89 mmol) was added to hydrochloric acid in methanol (methanol reagent 10) (10 mL, 0.89 mmol) and the resulting solution was stirred at room temperature for 16 hours. The resulting mixture was evaporated to dryness and the residue was azeotroped with DCM to afford crude product as di HCL salt. The crude product was purified by ion exchange chromatography, using an SCX2 column. The desired product was eluted from the column using 2M NH3ZMeOH and pure fractions were evaporated to dryness to afford (i?)-5-cyclopropyl-4-methoxy-2-(3-methylpiperazin-l-yl)pyrimidine (100 %) as a colourless gum. MS (+ve ESI) : Rt = 1.96 min, 249.49 (M+H)+
1U NMR (400.132 MHz, CDC13) δ 0.53 (2H, m), 0.80 (2H, m), 1.14 (3H, d), 1.70 (IH, m), 1.95 (IH, s), 2.52 (IH, m), 2.78 - 2.92 (3H, m), 3.07 (IH, m), 3.94 (3H, s), 4.54 (2H, m), 7.75 (IH, s) 4-(2-chloropyridin-4-yl)-2-methylpiperazine
Figure imgf000221_0001
(i?)-2-methylpiperazine (1.63 g, 16.0 mmol) was added to 2-chloro-4-fluoropyridine (2.00 g, 15.2 mmol) in DMF (10 mL). The resulting solution was stirred at 80 0C for 3 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product which was used without further purification. MS (+ve ESI) : Rt = 0.35 min, 212.43 (M+H)+ (R)-tert-Butyl 4-(2-chloropyridin-4-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000221_0002
Di-tert-Butyl dicarbonate (3.97 g, 18.2 mmol) was added to a stirred solution of (i?)-l-(2- chloropyridin-4-yl)-3-methylpiperazine (3.50 g, 16.5 mmol) and 4-Dimethylaminopyridine (0.202 g, 1.65 mmol) in THF (30 mL) at room temperature, then added triethylamine (2.30 mL, 16.5 mmol) and the solution was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with DCM (50 mL), and washed with saturated NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product which was used without further purification. (R)-tert-Bntyl 4-(2-(benzyloxy)pyridin-4-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000222_0001
Sodium hydride (1.02 g, 25.6 mmol) was added to benzyl alcohool (2.56 mL, 24.8 mmol) in DMF (30 mL) under argon. The resulting suspension was stirred at room temperature for 30 minutes and then added a solution of (R)-tert-butyl 4-(2-chloropyridin-4-yl)-2- methylpiperazine-1-carboxylate (5.14 g, 16.5 mmol) in DMF (20 mL), the reaction was stirred at room temperature for 4 hours, reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with saturated brine (100 mL), water (100 mL), and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography on a 4Og Biotage silica column, eluting with 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(2-(benzyloxy)pyridin- 4-yl)-2-methylpiperazine-l-carboxylate (3.35 g, 52.9 %) as a colourless oil and (i?)-benzyl 4-(2-(benzyloxy)pyridin-4-yl)-2-methylpiperazine-l-carboxylate (1.15 g, 16.7 %) as a colourless oil.
MS (+ve ESI) : Rt = 3.02 min, 384.53 (M+H)+
(R)-tert-Butyl 2-methyl-4-(2-oxo-l,2-dihydropyridin-4-yl)piperazine-l-carboxylate
Figure imgf000223_0001
(R)-tert-Butyl 4-(2-(benzyloxy)pyridin-4-yl)-2-methylpiperazine-l-carboxylate (2.30 g, 6.00 mmol) was hydrogenated over 10% Pd/C cartridge in the H-Cube at 10 bar in methanol (150 mL), flow rate 1 mL/min. The methanol was evaporated to dryness and the resulting white solid filtered from ether to give (R)-tert-butyl 2-methyl-4-(2-oxo-l,2- dihydropyridin-4-yl)piperazine-l-carboxylate (1.20 g, 68.2 %) MS (+ve ESI) : Rt = 1.53 min, 292.49 (M+H)+ (if)-fert-Butyl-2-methyl-4-(2-oxo-l-propyl-4-pyridyl)piperazine-l-carboxylate
Figure imgf000223_0002
(R)-tert-Butyl 2-methyl-4-(2-oxo-l,2-dihydropyridin-4-yl)piperazine-l-carboxylate
(250mg, 0.85 mmol) was added to sodium hydride (40.9 mg, 1.02 mmol) in NMP (5 mL) under argon. The resulting solution was stirred at Room Temperature for 20 minutes and then added 1-iodopropane (145 mg, 0.85 mmol) and the solution stirred at room temperature for 18 hours, the crude product was diluted with EtOAc (10 mL), and washed sequentially with water (15 mL), saturated brine (15 mL), and water (15 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude, (R)-tert-Butyl-2- methyl-4-(2-oxo-l-propyl-4-pyridyl)piperazine-l-carboxylate used without further purification. (if)-4-(3-methylpiperazin-l-yl)-l-propylpyridin-2(lH)-one
Figure imgf000223_0003
Hydrochloric acid in methanol (methanol reagent 10) (3.0 mL, 30.0 mmol) was added to (R)-tert-butyl 2-methyl-4-(2-oxo- 1 -propyl- 1 ,2-dihydropyridin-4-yl)piperazine- 1 - carboxylate (0.285 g, 0.85 mmol) and the resulting solution was stirred at room temperature for 18 hours. The crude product was purified by preparative HPLC Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compounds were lyophilised to dryness to give (i?)-4-(3- methylpiperazin-l-yl)-l-propylpyridin-2(lH)-one (9.63 %). MS (+ve ESI) : Rt = 1.11 min, 236.49 (M+H)+ (i?)-4-(3-methylpiperazin-l-yl)pyridin-2(lH)-one
Figure imgf000224_0001
(i?)-Benzyl 4-(2-(benzyloxy)pyridin-4-yl)-2-methylpiperazine-l-carboxylate (1.10 g, 2.63 mmol) was hydrogenated over 10% Pd/C cartridge in the H-Cube at 10 bar in Methanol (85 mL), flow rate lml/min. The methanol was evaporated to dryness and the crude product was purified by preparative HPLC Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compounds were lyophilised to dryness to give (R)-4-(3-methylpiperazin-l-yl)pyridin-2(lH)-one (0.215 g, 42.2 %) and (i?)-benzyl 2-methyl-4-(2-oxo-l,2-dihydropyridin-4-yl)piperazine-l- carboxylate (0.547 g, 63.4 %)
MS (+ve ESI) : Rt = 0.69 min, 194.44 (M+H)+
1R NMR (400.132 MHz, CDC13) δ 1.14 (3H, d), 1.20 (2H, b), 2.52 (IH, m), 2.78 - 2.92 (3H, m), 3.07 (IH, m), 3.65 (2H, m), 5.67 (IH, s), 5.98 (IH, d), 7.15 (IH, d) (R)-tert-bntyl 4-(l-cyclopropyl-2-oxo-l,2-dihydropyridin-4-yl)-2-methylpiperazine-l- carboxylate
Figure imgf000225_0001
Copper(II) acetate (279 mg, 1.53 mmol) was added to dioxane (2 mL) and the resulting suspension was stirred at room temperature for 10 minutes. (R)-tert-butyl 2-methyl-4-(2- oxo-l,2-dihydropyridin-4-yl)piperazine-l-carboxylate (300mg, 1.02 mmol), cyclopropylboronic acid (176 mg, 2.05 mmol) and cesium carbonate (333 mg, 1.02 mmol) were added and the resulting suspension was heated to 80 0C for 6 hours. The crude product was purified by preparative HPLC Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound was evaporated to dryness to give (R)-tert-butyl 4-(l-cyclopropyl-2-oxo-l,2- dihydropyridin-4-yl)-2-methylpiperazine-l-carboxylate (187 mg, 54.8 %) MS (+ve ESI) : Rt = 1.87 min, 255.57 (M+H)+
1U NMR (400.13 MHz, CDC13) δ 0.78 - 0.83 (2H, m), 1.04 - 1.09 (2H, m), 1.17 (3H, d), 1.48 (9H, s), 2.94 - 3.01 (IH, m), 3.14 - 3.28 (3H, m), 3.46 (IH, d), 3.60 (IH, d), 3.84 - 3.89 (IH, m), 4.28 (IH, s), 5.66 (IH, d), 5.80 - 5.83 (IH, m), 7.10 (IH, d) (if)-l-Cyclopropyl-4-(3-methylpiperazin-l-yl)pyridin-2(lH)-one
Figure imgf000225_0002
Hydrochloric acid in methanol (methanol reagent 10) (405 μl, 4.05 mmol) was added to (R)-tert-butyl 4-(l-cyclopropyl-2-oxo-l,2-dihydropyridin-4-yl)-2-methylpiperazine-l- carboxylate (135 mg, 0.40 mmol) and the resulting solution was stirred at room temperature for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3ZMeOH and pure fractions were evaporated to dryness to afford (R)-I- cyclopropyl-4-(3-methylpiperazin-l-yl)pyridin-2(lH)-one (92 %) as a yellow oil which was used without further purification. MS (+ve ESI) : Rt = 0.96 min, no mass ion (M+H)+
(if)-l-(2-methoxypyridin-4-yl)-3-methylpiperazine was synthesised in the following manner.
(R)-tert-Butyl 4-(2-methoxypyridin-4-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000226_0001
(R)-tert-Butyl 4-(2-chloropyridin-4-yl)-2-methylpiperazine-l-carboxylate (800 mg, 2.57 mmol) and sodium methanolate (693 mg, 12.8 mmol) were suspended in methanol (5 mL) and sealed into a microwave tube. The reaction was heated to 130 0C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (10 mL), and washed with water (10 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford crude product which was used without further purification. MS (+ve ESI) : Rt = 2.33 min, 308.52 (M+H)+ (if)-l-(2-methoxypyridin-4-yl)-3-methylpiperazine
Figure imgf000226_0002
Hydrochloric acid in methanol (methanol reagent 10) (1.53 ml, 15.3 mmol) was added to (R)-tert-buty{ 4-(2-methoxypyridin-4-yl)-2-methylpiperazine-l-carboxylate (470 mg, 1.53 mmol) and the resulting solution was stirred at room temperature for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3ZMeOH and pure fractions were evaporated to dryness to afford (i?)-l-(2-methoxypyridin-4-yl)-3-methylpiperazine (86 %) as a yellow oil which was used without further purification. MS (+ve ESI) : Rt = 1.17 min, 208.47 (M+H)+
(R)-tert-Bntyl 4-(l-ethyl-2-oxo-l,2-dihydropyridin-4-yl)-2-methylpiperazine-l- carboxylate
Figure imgf000227_0001
(R)-tert-Butyl 2-methyl-4-(2-oxo- 1 ,2-dihydropyridin-4-yl)piperazine- 1 -carboxylate (293 mg, 1.00 mmol) was added to sodium hydride (47.9 mg, 1.20 mmol) in NMP (5 mL) under argon. The resulting solution was stirred at room temperature for 20 minutes and then added iodoethane (0.096 mL, 1.20 mmol) and the solution stirred at room temperature for 18 hours, the crude product was purified by preparative HPLC Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were lyophilised to dryness to give (R)-tert-butyl 4-(l-ethyl-2-oxo-l,2- dihydropyridin-4-yl)-2-methylpiperazine-l -carboxylate (105 mg, 32.7 %) as a colourless oil.
MS (+ve ESI) : Rt = 1.78 min, no mass ion (M+H)+ (i?)-l-Ethyl-4-(3-methylpiperazin-l-yl)pyridin-2(lH)-one
Figure imgf000227_0002
Hydrochloric acid in methanol (methanol reagent 10) (560 μl, 5.60 mmol) was added to (R)-tert-buty{ 4-( 1 -ethyl-2-oxo- 1 ,2-dihydropyridin-4-yl)-2-methylpiperazine- 1 -carboxylate (180 mg, 0.56 mmol) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was applied directly to an ion exchange SCX column. The desired product was eluted from the column using 7M NH3ZMeOH and pure fractions were evaporated to dryness to afford (i?)-l-ethyl-4-(3-methylpiperazin-l-yl)pyridin-2(lH)-one (97 %) as a colourless oil which was used without further purification. MS (+ve ESI) : Rt = 0.93 min, 222.49 (M+H)+
(i?)-l-isopropyl-4-(3-methylpiperazin-l-yl)pyridin-2(lH)-one and (R)-I-(I- isopropoxypyridin-4-yl)-3-methylpiperazine were synthesised in the following manner. (R)-tert-butyl 4-(l-isopropyl-2-oxo-l,2-dihydropyridin-4-yl)-2-methylpiperazine-l- carboxylate and (R)-tert-butyl 4-(2-isopropoxypyridin-4-yl)-2-methylpiperazine-l- carboxylate
Figure imgf000228_0001
(R)-tert-Butyl 2-methyl-4-(2-oxo- 1 ,2-dihydropyridin-4-yl)piperazine- 1 -carboxylate (200 mg, 0.68 mmol) was added to sodium hydride (32.7 mg, 0.82 mmol) in NMP (5 mL) under argon. The resulting solution was stirred at room temperature for 20 minutes and then added iodomethane (74.9 μl, 1.20 mmol) and the solution stirred at room temperature for 18 hours, the crude product was purified by preparative HPLC Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compounds were lyophilised to dryness to give (R)-tert-butyl 4-(l-isopropyl-2- oxo-l,2-dihydropyridin-4-yl)-2-methylpiperazine-l -carboxylate (58.0 mg, 25.4 %) as a colourless oil and (R)-tert-butyl 4-(2-isopropoxypyridin-4-yl)-2-methylpiperazine-l- carboxylate (149 mg, 65.2 %) as a colourless oil.
(R)-tert-buty{ 4-(l-isopropyl-2-oxo-l,2-dihydropyridin-4-yl)-2-methylpiperazine-l- carboxylate
MS (+ve ESI) : Rt = 1.93 min, 336.48 (M+H)+
(R)-tert-butyl 4-(2-isopropoxypyridin-4-yl)-2-methylpiperazine- 1 -carboxylate MS (+ve ESI) : Rt = 2.74 min, 336.48 (M+H)+
(if)-l-isopropyl-4-(3-methylpiperazin-l-yl)pyridin-2(lH)-one
Figure imgf000228_0002
Hydrochloric acid in methanol (methanol reagent 10) (328 μl, 3.28 mmol) was added to (R)-tert-buty{ 4-(l-isopropyl-2-oxo-l,2-dihydropyridin-4-yl)-2-methylpiperazine-l- carboxylate (55.0 mg, 0.16 mmol) and the resulting solution was stirred at room temperature for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3ZMeOH and pure fractions were evaporated to dryness to afford (R)-I- isopropyl-4-(3-methylpiperazin-l-yl)pyridin-2(lH)-one as a yellow oil which was used without further purification. MS (+ve ESI) : Rt = 1.12 min, 236.48 (M+H)+ (R)-l-(2-isopropoxypyridin-4-yl)-3-methylpiperazine
Figure imgf000229_0001
Hydrochloric acid in methanol (methanol reagent 10) (432 μl, 4.32 mmol) was added to (R)-tert-buty{ 4-(2-isopropoxypyridin-4-yl)-2-methylpiperazine-l -carboxylate (145 mg, 0.43 mmol) and the resulting solution was stirred at room temperature for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3ZMeOH and pure fractions were evaporated to dryness to afford (i?)-l-(2-isopropoxypyridin-4-yl)-3-methylpiperazine (96 %) as a yellow oil which was used without further purification. MS (+ve ESI) : Rt = 1.63 min, 236.48 (M+H)+ (R)-tert-Butyl 4-(6-methoxypyrazin-2-yl)-2-methylpiperazine-l-carboxylate
Figure imgf000229_0002
PEPPSI (141 mg, 0.21 mmol) was added to 2-chloro-6-methoxypyrazine [US
2005288299] (500 mg, 3.46 mmol), (R)-tert-butyl 2-methylpiperazine-l -carboxylate (1.39 g, 6.92 mmol) and potassium tert-butoxide (0.57 mL, 4.15 mmol) in DME (15 mL) under argon. The resulting suspension was degassed with argon for 15 minutes. It was stirred at 70 0C under argon for 18 hours. It was cooled to room temperature and concentrated in vacuo. The residue was taken up in DCM (50 mL) and treated with 50% brine (25 mL), dried (sodium sulphate), concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(6- methoxypyrazin-2-yl)-2-methylpiperazine-l-carboxylate (309 mg, 29.0 %) as a brown gum.
MS (+ve ESI) : Rt = 2.43 min, 309.52 (M+H)+
(R)-tert-bntyl 4-(3-bromo-6-methoxypyrazin-2-yl)-2-methylpiperazine-l-carboxylate and (R)-tert-bntyl 4-(5-bromo-6-methoxypyrazin-2-yl)-2-methylpiperazine-l- carboxylate
Figure imgf000230_0001
7V-Bromosuccinimide (0.09 mL, 1.00 mmol) was added to (R)-tert-butyl 4-(6- methoxypyrazin-2-yl)-2-methylpiperazine-l -carboxylate (309 mg, 1.00 mmol) in chloroform (10 mL). The resulting solution was stirred and allowed to warm to room temperature over 18 hours. It was concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4- (5-bromo-6-methoxypyrazin-2-yl)-2-methylpiperazine-l -carboxylate (102 mg, 26 %) as a white solid and (R)-tert-butyl 4-(3-bromo-6-methoxypyrazin-2-yl)-2-methylpiperazine-l- carboxylate (100 mg, 26 %) as a colourless gum. MS (+ve ESI) : Rt = 2.92 min, 389.36 (M+H)+
(R)-tert-Bntyl 4-(5-cyclopropyl-6-methoxypyrazin-2-yl)-2-methylpiperazine-l- carboxylate
Figure imgf000231_0001
Palladium(II) acetate (7.48 mg, 0.03 mmol) was added to (R)-tert-butyl 4-(5-bromo-6- methoxypyrazin-2-yl)-2-methylpiperazine-l-carboxylate (258 mg, 0.67 mmol), cyclopropylboronic acid (114 mg, 1.33 mmol), tricyclohexylphosphine (18.68 mg, 0.07 mmol) and tripotassium phosphate (495 mg, 2.33 mmol) in toluene (10 mL) and water (0.3 mL). The resulting suspension was degassed with argon for 10 minutes and stirred at 100 0C for 18 hours. It was cooled to room temperature and partitioned between water (20 mL) and ethyl acetate (2 x 40 mL). Combined organics were dried (sodium sulphate), concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(5-cyclopropyl-6-methoxypyrazin-2-yl)-2- methylpiperazine-1-carboxylate (198 mg, 85 %) as a colourless gum. MS (+ve ESI) : Rt = 2.86 min, 349.21 (M+H)+ 1R NMR (400MHz, DMSO) d 0.8 (m, 4H), 1.1 (d, 3H), 1.4 (s, 9H), 2.15 (m, IH), 2.9 (m, IH), 3.1 (m, 2H), 3.8 (m, IH), 3.9 (s, 3H), 4.05 (m, 2H), 4.2 (m, IH), 7.6 (s, IH). 2-Cyclopropyl-3-methoxy-5-[(3R)-3-methylpiperazin-l-yl]pyrazine
Figure imgf000231_0002
Trifluoroacetic acid (2.00 mL, 26.12 mmol) was added to (R)-tert-butyl 4-(5-cyclopropyl- 6-methoxypyrazin-2-yl)-2-methylpiperazine-l-carboxylate (195 mg, 0.56 mmol) in DCM (20 mL). The resulting solution was stirred at 20 0C for 2 hours. It was concentrated in vacuo and azeotroped once with toluene. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3ZMeOH and pure fractions were evaporated to dryness to afford (R)-2- cyclopropyl-3-methoxy-5-(3-methylpiperazin-l-yl)pyrazine (123 mg, 89 %) as a colourless gum.
MS (+ve ESI) : Rt = 0.97 min, 249.30 (M+H)+
1R NMR (400MHz, DMSO) d 0.8 (m, 4H), 1.05 (d, 3H), 2.15 (m, IH), 2.35 (m, IH), 2.7 (m, 3H), 2.95 (m, IH), 3.85 (s, 3H), 4.0 (d, 2H), 7.6 (s, IH).
(R)-tert-bntyl 4-(3-cyclopropyl-6-methoxypyrazin-2-yl)-2-methylpiperazine-l- carboxylate
Figure imgf000232_0001
Palladium(II) acetate (9.42 mg, 0.04 mmol) was added to (R)-tert-butyl 4-(3-bromo-6- methoxypyrazin-2-yl)-2-methylpiperazine-l-carboxylate (325 mg, 0.84 mmol), cyclopropylboronic acid (144 mg, 1.68 mmol), tricyclohexylphosphine (23.5 mg, 0.08 mmol) and potassium phosphate (623 mg, 2.94 mmol) in toluene (15 mL) and water (0.45 mL) under argon. The resulting suspension was degassed with argon for 10 minutes and stirred at 100 0C for 18 hours. It was cooled to room temperature and partitioned between water (20 mL) and ethyl acetate (2 x 40 mL). Combined organics were dried (sodium suphate), concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(3-cyclopropyl-6- methoxypyrazin-2-yl)-2-methylpiperazine-l-carboxylate (224 mg, 77 %) as a colourless gum.
MS (+ve ESI) : Rt = 3.21min, 349.54 (M+H)+ 2-Cyclopropyl-5-methoxy-3-[(3R)-3-methylpiperazin-l-yl]pyrazine
Figure imgf000232_0002
Trifluoroacetic acid (1.00 mL, 13.0 mmol) was added to (R)-tert-butyl 4-(3-cyclopropyl-6- methoxypyrazin-2-yl)-2-methylpiperazine-l-carboxylate (220 mg, 0.63 mmol) in DCM (10 mL). The resulting solution was stirred at 20 0C for 18 hours. It was concentrated in vacuo and azeotroped once with toluene. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NHβ/MeOH and pure fractions were evaporated to dryness to afford (R)-2- cyclopropyl-5-methoxy-3-(3-methylpiperazin-l-yl)pyrazine (151 mg, 96 %) as a brown gum MS (+ve ESI) : Rt = 1.01 min, 249.49 (M+H)+ (R)-tert-Butyl 4-(3-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazine-l- carboxylate and (R)-tert-Butyl 4-(5-fluoro-2-(methylsulfonyl)phenyl)-2- methylpiperazine-1-carboxylate
Figure imgf000233_0001
2,4-Difluoro-l-(methylsulfonyl)benzene (1.00 g, 5.20 mmol), (R)-tert-buty\ 2- methylpiperazine-1-carboxylate (1.15 g, 5.72 mmol) and DIPEA (1.29 ml, 7.81 mmol) were dissolved in DMF and sealed into a microwave tube. The reaction was heated to 60 0C for 1 hour in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (50 mL), and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC Waters XBridge Prep Cl 8 OBD column, lOμ silica, 50 mm diameter, 150 mm length, using decreasingly polar mixtures of water (containing 0.2% NH3) and MeCN as eluents. Fractions containing the desired compounds were Lyopholised to dryness to give (R)-tert-butyl 4-(3-fluoro-4-(methylsulfonyl)phenyl)-2- methylpiperazine-1-carboxylate (0.425 g, 21.93 %) and (R)-tert-butγl 4-(5-fluoro-2- (methylsulfonyl)phenyl)-2-methylpiperazine-l-carboxylate (0.494 g, 25.5 %) (if)-l-(5-fluoro-2-(methylsulfonyl)phenyl)-3-methylpiperazine.HCl
Figure imgf000233_0002
Hydrochloric acid in methanol (methanol reagent 10) (3.00 mL, 30.00 mmol) was added to (i?)-tert-butyl 4-(5 -fluoro-2-(methylsulfonyl)phenyl)-2-methylpiperazine- 1 -carboxylate (490 mg, 1.32 mmol) and the resulting solution was stirred at room temperature for 18 hours. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford crude (i?)-l-(5-fluoro-2-(methylsulfonyl)phenyl)-3- methylpiperazine.HCl (98 %), used without further purification. MS (+ve ESI) : Rt = 1.49 min, 273.42 (M+H)+ (if)-l-(3-Fluoro-4-(methylsulfonyl)phenyl)-3-methylpiperazine
Figure imgf000234_0001
Hydrochloric acid in methanol (methanol reagent 10) (6 mL, 60.0 mmol) was added to (R)- tert-butyl 4-(3-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazine- 1 -carboxylate (420mg, 1.13 mmol) and the resulting solution was stirred at room temperature for 18 hours. The reaction was evaporated to dryness to give the product as the hydrochloride salt, used without further purification. MS (+ve ESI) : Rt = 1.37 min, 273.42 (M+H)+
2- [(3R )-3-Methylpiperazin- 1-yl] -6,7-dihydr o-4H-pyr ano [4,3-d] thiazole was synthesised in the following manner.
(R)-tert-Butyl 4-carbamothioyl-2-methylpiperazine-l-carboxylate
Figure imgf000234_0002
To a solution of 1 , l'-thiocarbonyldiimidazole (3.07 g, 17.23 mmol) in anhydrous THF (30 mL) was added (R)-tert-butyl 2-methylpiperazine-l -carboxylate (3.00 g, 14.98 mmol) and allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to half the volume. To the remaining reaction mixture was added a 2M solution of ammonia in methanol (120 mL) which was thenallowed to stir at room temperature for 16 hours. LCMS shows reaction gone almost to completion. The reaction mixture was concentrated in vacuo and the residue was triturated with diethyl ether to give (R)-tert- butyl 4-carbamothioyl-2-methylpiperazine-l-carboxylate (2.38 g, 61.3 %) as a white solid, m/z (ESI-) (M-H)- = 258; HPLC tR = 1.63 min.
(R)-tert-Butyl 4-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2-methylpiperazine-l- carboxylate
Figure imgf000235_0001
(R)-tert-butyl 4-carbamothioyl-2-methylpiperazine-l -carboxylate (2.30 g, 8.87 mmol) was added to 3-bromodihydro-2H-pyran-4(3H)-one (1.27 g, 7.09 mmol) and triethylamine (3.96 mL, 28.38 mmol) in toluene (25 mL). The resulting solution was stirred at 110 0C for 6 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed with water (150 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford (R)- tert-butyl 4-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2-methylpiperazine- 1 -carboxylate (quant.) which was used without further purification, m/z (ESI+) (MH+)- = 340.23; HPLC tR = 2.24 min. 2- [(3R )-3-Methylpiperazin- 1-yl] -6,7-dihydro-4H-pyrano [4,3-d] thiazole
Figure imgf000235_0002
Hydrochloric acid in methanol (20.0 mL, 200 mmol) was added to (R)-tert-bvXy\ 4-(6,7- dihydro-4H-pyrano[4,3-J]thiazol-2-yl)-2-methylpiperazine-l-carboxylate (3.00 g, 8.84 mmol) and the resulting solution was stirred at room temperature for 18 hours The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3ZMeOH and pure fractions were evaporated to dryness to afford crude product as a brown oil. 360 mg of crude material was removed and used without further purification. The remaining material was treated with a IM hydrochloric Acid in Ether solution to precipitate a beige solid as (R)-2-(3- methylpiperazin-l-yl)-6,7-dihydro-4H-pyrano[4,3-J]thiazole hydrochloride (1.75 g, 57.4 %). m/z (ESI+) (M+H)+ = 458.47; HPLC tR = 1.73 min.
In a similar manner to methods A and B the following building blocks were synthesised starting with an appropriate ayrl halide and either piperazine, N-tert-Boc-pvperazinQ, (R)-I- 7V-Boc-2-methyl piperazine and (i?)-l-7V-Boc-2-ethyl piperazine.
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
-2.07 d),
(IH, q),
Figure imgf000243_0001
Figure imgf000244_0001
-
(IH,
(IH, d)
Figure imgf000245_0001
s),
Figure imgf000246_0001
(IH,
Figure imgf000247_0001
Figure imgf000248_0002
(IH,
Figure imgf000248_0001
4-bromo-2- (R)-l-(3-ethyl- A 94.0 (M+H)+ ethyl-1- 4- 235.52, methoxy methoxyphenyl) 1.88.
Figure imgf000249_0001
benzene -3 -methyl piperazine
Figure imgf000249_0002
4- (R)-3-methyl-l- B 89% chloropyridine (pyridin-4-yl) hydrochloride piperazine
Figure imgf000249_0003
Figure imgf000249_0004
IH NMR (400.132 MHz, CDC13) δ 1.15 (3H, d), 2.40 - 2.51 (IH, m), 2.77 - 3.00 (3H, m), 3.12 (IH, m), 3.65 - 3.73 (2H, m), 6.65 (2H, d), 8.26 (2H, d)
2-bromo-l- (R)-l-(2-chloro- A 68.7 (M+H)+ chloro-4- 5- 241.51, methoxy methoxyphenyl) 1.02
Figure imgf000249_0005
benzene -3 -methyl piperazine
Figure imgf000249_0006
IH NMR (400.13 MHz, CDC13) δ 1.15 - 1.17 (3H, m), 2.39 - 2.44 (IH, m), 2.70 - 2.77 (IH, m), 3.10 - 3.18 (3H, m), 3.27 - 3.33 (2H, m), 3.79 (3H, s), 6.51 - 6.54 (IH, m), 6.59 (IH, d), 7.25 (IH, d)
3-butoxy-l- (R)-l-(3- A 35.7 (M+H)+ bromobenzene butoxyphenyl)- 248.36, 3 -methyl 1.34 piperazine
Figure imgf000249_0007
-
(3H,
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
If not otherwise stated above the aryl halide used in the synthesis of the appropriate secondary amines can be made by the following methods.
l-Bromo-4-(l-ethoxy-l-methylethyl)benzene
Figure imgf000263_0002
To a slurry of the sodium hydride (2.01 mg, 7.00 mmol) in DMF (20 mL) at 0 0C under a blanket of Ar was added the l-bromo-(l -hydroxy- 1 -me thylethyl)benzene (151 mg, 7.00 mmol) in DMF (10 mL) and the reaction allowed to warm to ambient temperature for 1 hour, heated to 40 0C so all NaH reacted and then allowed to cool for 30 mins. Ethyl iodide (0.56 mL, 7.00 mmol) was added and the reaction stirred overnight and then concentrated in vacuo. The mixture was partitioned with DCM/ water (50 mL) and then dried over magnesium sulphate, filtered and concentrated in vacuo. Used crude. MS (+ve ESI) : Rt = 2.73 min, no mass ion (M+H)+
1H NMR (400.132 MHz, CDC13) δ 1.15 (3H, t),1.50 (6H, s),1.52 (7H, s),3.20 (2H, q),7.29
(2H, m),7.45 (2H, m)
2 -(4-Chloro-3-fluorophenyl)-2-methylpropanenitrile
Figure imgf000264_0001
A solution of 4-chloro-3-fluorophenylacetonitrile (1.70 g, 10.0 mmol) in DMF (5 mL) was added dropwise to Sodium hydride (1.00 g, 41.7 mmol) and iodomethane (1.87 mL, 30.0 mmol) in DMF (10 mL) at O0C under a blanket of argon. The resulting slurry was stirred and allowed to warm to ambient temperature for 2 hours. The mixture was concentrated and diluted with ethyl acetate and water and the organic layer washed with further water and the organic layer washed with saturated brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 2-(4-chloro-3-(trifluoromethoxy)phenyl)-2-methylpropanenitrile as a yellow oil which solidified on standing.
MS (+ve ESI) : Rt = 2.51 min, no mass ion (M+H)+ 1U NMR (400.132 MHz, CDC13) δ 1.71 (6H, s), 7.20 - 7.28 (3H, m), 7.42 (IH, t) 2- [4-Chloro-3-(trifluoromethyl)phenyl] -2-methylpropanenitrile
Figure imgf000264_0002
In a similar method to that described above, a solution of 4-chloro-3- (trifluoromethyl)phenylacetonitrile (2.20 g, 10.0 mmol) in DMF (5 mL) was added dropwise to sodium hydride (1.00 g, 41.7 mmol) and iodomethane (1.87 mL, 30 mmol) in DMF (10 mLi at 0 0C under a blanket of argon . The resulting slurry was stirred and allowed to warm to ambient temperature for 2 hours to afford 2-(4-chloro-3- (trifluoromethyl)phenyl)-2-methylpropanenitrile (53.3 %) as a yellow oil which solidified on standing.
1R NMR (400.132 MHz, CDC13) δ 1.75 (3H, s), 7.54 (IH, d), 7.62 (IH, m), 7.74 (IH, m)
2-(4-Chloro-2,6-difluorophenyl)-2-methylpropanenitrile
Figure imgf000265_0001
In a similar method to that described above, a solution of 4-chloro-2,6-difluoro- phenylacetonitrile (1.88 g, 10.0 mmol) in DMF (5 mL) was added dropwise to sodium hydride (1.00 g, 41.7 mmol) and iodomethane (1.87 mL, 30 mmol) in DMF (10 mL » at 0 0C under a blanket of argon . The resulting slurry was stirred and allowed to warm to ambient temperature for 2 hours to afford 2-(4-chloro-2,6-difluorophenyl)-2- methylpropanenitrile (1.07g, 53.3 %) as a yellow oil which solidified on standing.
MS (+ve ESI) : Rt = 2.51 min, 196.20 (M+H)+
1R NMR (400.132 MHz, CDC13) δ 1.87 (6H, t), 6.97 (2H, d)
2-(4-Chloro-3-(trifluoromethoxy)phenyl)-2-methylpropanenitrile
Figure imgf000265_0002
In a similar method to that described above a solution of 4-chloro-3- (trifluoromethoxy)phenylacetonitrile (2.36 g, 10.0 mmol) in DMF (5 mL) was added dropwise to sodium hydride (1.00 g, 41.7 mmol) and iodomethane (1.87 mL, 30.0 mmol) in DMF (10ml) at 0 0C under a blanket of argon to afford 2-(4-chloro-3- (trifluoromethoxy)phenyl)-2-methylpropanenitrile (1.44 g, 55.0 %) as a yellow oil. 1R NMR (400.132 MHz, CDC13) δ 1.73 (6H, s), 7.39 (2H, m), 7.51 (IH, m) 2-(4-Chloro-2-(trifluoromethyl)phenyl)-2-methylpropanenitrile
Figure imgf000265_0003
In a similar method to that described above a solution of 4-chloro-2- (trifluoromethyl)phenylacetonitrile (2.20 g, 10.0 mmol) in DMF (5 mL) was added dropwise to sodium hydride (1.00 g, 41.7 mmol) and iodomethane (1.87 mL, 30.0 mmol) in DMF (10ml) at 0 0C under a blanket of argon to afford 2-(4-chloro-2-
(trifluoromethyl)phenyl)-2-methylpropanenitrile (1.44 g, 62.2 %) as a yellow oil.
MS (+ve ESI) : Rt = 2.68 min, 228.20 (M+H)+
1R NMR (400.132 MHz, CDC13) δ 1.87 (6H, s), 7.55 (IH, m), 7.69 (IH, d), 7.77 (IH, d)
2-(4-Bromo-2-methylphenyl)-2-methylpropanenitrile
Figure imgf000266_0001
In a similar method to that described above a solution of 2-(4-bromo-2- methylphenyl)acetonitrile (2.82 g, 10.0 mmol) in DMF (5 mL) was added dropwise to sodium hydride (1.00 g, 41.7 mmol) and iodomethane (1.87 mL, 30.0 mmol) in DMF
(10ml) at 0 0C under a blanket of argon to afford 2-(4-chloro-2-(trifiuoromethyl)phenyl)-
2-methylpropanenitrile (2.77 g, 87.0 %) as a yellow oil.
1U NMR (400.132 MHz, CDC13) δ 1.76 (6H, s), 2.62 (3H, s), 7.16 (IH, d), 7.33 (IH, m),
7.38 (IH, m) 2-(4-Bromophenyl)-2-methylpropanenitrile
Figure imgf000266_0002
In a similar method to that described above a solution of 4-bromophenylacetonitrile (10.0 g g, 51.0 mmol) in THF (50 mL) was added dropwise to sodium hydride (4.08 g, 102 mmol) and iodomethane (9.53 mL, 153 mmol) at 0 0C under a blanket of argon to afford 2-(4- bromophenyl)-2-methylpropanenitrile 2-(4-chloro-2-(trifiuoromethyl)phenyl)-2- methylpropanenitrile (2.77 g, 87.0 %) as a colourless oil after work up and isolation. 1U NMR (400.13 MHz, CDC13) δ 1.71 (6H, s), 7.33 - 7.37 (2H, m), 7.50 - 7.53 (2H, m) 4-(2-(4-Bromo-2-methoxyphenoxy)ethyl)morpholine
Figure imgf000266_0003
4-(2-Chloroethyl)morpholine hydrochloride (916 mg, 4.93 mmol) was added to A- bromoguaiacol (500 mg, 2.46 mmol) and potassium carbonate (1.02 g, 7.39 mmol) in acetone (30 mL). The resulting suspension was stirred at reflux for 2 hours. Sodium iodide (738 mg, 4.93 mmol) was added and the reflux continued overnight. Triethylamine (0.687 mL, 2.0 equivalent) was added and the reflux continued overnight. The mixture was allowed to cool and the inorganic solid removed by filtration. The filtrate was concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(2-(4-bromo-2-methoxyphenoxy)ethyl)morpholine (445 mg, 57%) as a yellow oil.
MS (+ve ESI) : Rt = 1.04 min, 316.20 (M+H)+ 1U NMR (400 MHz, DMSO) d 2.4 (m, 3H), 2.7 (m, 2H), 3.6 (m, 5H), 3.8 (s, 3H), 4.05 (t, 2H), 6.95 (d, IH), 7.05(d, IH), 7.1 (s, IH).
4-(2-(5-Iodo-2-methoxyphenoxy)ethyl)morpholine
Figure imgf000267_0001
4-(2-Chloroethyl)morpholine hydrochloride (744 mg, 4.00 mmol) was added to 5-iodo-2- methoxyphenol (500 mg, 2.00 mmol), potassium carbonate (829 mg, 6.00 mmol) and sodium iodide (599 mg, 4.00 mmol) in acetone (30 mL) at 20 0C. Triethylamine (0.557ml, 4.00 mmol) was added. The resulting suspension was stirred at 60 0C for 18 hours. The suspension was allowed to cool and inorganic residues removed by filtration and the filtrate concentrated in vacuo and adsorbed onto silica for purification by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(2-(5-iodo-2-methoxyphenoxy)ethyl)morpholine as a colourless oil (413 mg, 57%).
MS (+ve ESI) : Rt = 1.05 min, 364.15 (M+H)+
1R NMR (400 MHz, DMSO) d 2.45 (t, 4H), 2.7 (t, 2H), 3.6 (m, 4H), 3.75(s, 3H), 4.05 (t, 2H), 6.85 (d, IH), 7.25(d, IH), 7.3 (s, IH). 4-(3-(4-Bromo-2-methoxyphenoxy)propyl)morpholine
Figure imgf000267_0002
4-(3-Chloropropyl)morpholine (806 mg, 4.93 mmol) was added to 4-bromo-2- methoxyphenol (500 mg, 2.46 mmol), potassium carbonate (1.02 g, 7.39 mmol) and sodium iodide (738 mg, 4.93 mmol) in acetone (30 mL). Triethylamine (0.726 mL, 4.93 mmol) was added. The resulting suspension was stirred at 60 0C for 35 hours. It was allowed to cool and the inorganic residues removed by filtration. The filtrate was concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(3-(4-bromo-2-methoxyphenoxy)propyl)morpholine as a colourless oil (395mg, 48.6%) .
MS (+ve ESI) : Rt = 1.10 min, 332.13 (M+H)+
1U NMR (400 MHz, DMSO) d 1.85 (m, 2H), 2.35 (m, 6H), 3.6 (m, 4H), 3.8 (s, 3H), 4.0 (t, 2H), 6.9(d, IH), 7.05 (d, IH), 7.1 (s IH). 4-Bromo-l-ethoxy-2-methoxybenzene
Figure imgf000268_0001
To a slurry of 4-bromoguaiacol (8.12 g, 40.0 mmol) and potassium carbonate (4.83 g, 80.0 mmol) in acetone (80 mL) was added ethyl iodide (4.80 mL, 60.0 mmol) and the reaction stirred at ambient temperature for 30 minutes. The reaction was not proceeding so heated to 40 0C for 4 hours, further ethyl iodide (1.60 ml, 20.0 mmol) was added and the reaction stirred for 90 minutes at 40 0C , further ethyl iodide (3.20 ml, 40.0 mmol) was added and the reaction heated for 1 hour and then allowed to stand overnight. The solid was filtered off and washed with further acetone (50 ml) and the filtrate evaporated. The residue was dissolved in Et2O (100 mL) and washed sequentially with water (50 mL), 2M NaOH (2 x 50 mL), water (50 mL), dried over MgSO4, filtered and evaporated to give pure 4-bromo- l-ethoxy-2-methoxybenzene (8.81 g, 95 %) as an off- white solid. 1R NMR (400.132 MHz, CDC13) δ 1.46 (3H, t), 3.86 (3H, s), 4.07 (2H, q), 6.74 (IH, d), 6.99 (IH, d), 7.01 (IH, m) l-Bromo-4-ethoxy-2-fluoro-5-methoxybenzene
Figure imgf000268_0002
To a slurry of 4-bromo-5-fluoro-2-methoxyphenol (2.00 g, 9.05 mmol) and sodium hydride
(0.543 g, 13.6 mmol) in DMF (9.05 mL) was added ethyl iodide (1.45 mL, 18.1 mmol) and the reaction stirred at ambient temperature for 16 hours. The reaction mixture was quenched with water (5 mL), diluted with EtOAc (50 mL) and washed sequentially with 2M NaOH (25 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford desired product l-bromo-4-ethoxy-2-fiuoro-5- methoxybenzene (2.15 g, 95 %) as a brown solid.
MS (+ve ESI) : Rt = 2.49 min, no mass ion (M+H)+
1U NMR (400.13 MHz, CDC13) δ 1.47 (3H, t), 3.84 (3H, s), 4.05 (2H, q), 6.68 - 6.71 (IH, m), 6.96 (IH, d) l-Bromo-2-fluoro-3,4-dimethoxybenzene was synthesized in the following manner.
4-Bromo-3-fluorobenzene-l,2-diol
Figure imgf000269_0001
Fluoroboric acid (1.08 mL, 7.81 mmol) were added dropwise to 3-fiuorocatechol (1.00 g, 7.81 mmol) in acetonitrile (10 mL) at -30 0C over a period of 5 minutes under argon. N- Bromosuccinimide (1.39 g, 7.81 mmol) was then added portionwise to the reaction mixture. The resulting solution was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was poured into water (50 mL) and extracted with EtO2 (3 x 20 mL). The organic portion was washed with brine (2 x 50 mL), dried over Na2SO4 and the solvent evaporated to afford crude product as a grey-brown oil wich solidified on standing. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-bromo- 3-fiuorobenzene-l,2-diol (1.43 g, 88 %) as a cream oil which solidified on standing. MS (+ve ESI) : Rt = 1.57 min, 207.24 (M+H)+ 1R NMR (500.13 MHz, DMSO-d6) δ 6.58 - 6.60 (2H, m), 6.87 - 6.90 (IH, m) l-Bromo-2-fluoro-3,4-dimethoxybenzene
Figure imgf000269_0002
Iodomethane (0.860 mL, 13.8 mmol) was added to 4-bromo-3-fluorobenzene-l,2-diol (1.43 g, 6.91 mmol) and potassium carbonate (1.91 g, 13.8 mmol) in acetone (30 mL) at 25 0C. The resulting suspension was stirred at reflux for 2 hours. The reaction was incomplete and further potassium carbonate (0.90 g, 6.90 mmol) and iodomethane (0.430 mL, 6.90 mmol) were added and the suspension was stirred at reflux for a further 1 hour. The reaction mixture was filtered and the solid washed. The washings and filtrate were combined, evaporated and redissoved in Et2O (70 mL). The organic layer was washed with Brine (2 x 50 mL), dried over Na2SO4 and evaporated to afford crude product as a yellow oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 15% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford l-bromo-2- fluoro-3,4-dimethoxybenzene (0.880 g, 54.2 %) as a colourless oil. MS (+ve ESI) : Rt = 2.37 min, no mass ion (M+H)+
1U NMR (400.13 MHz, CDC13) δ 3.86 (3H, s), 3.93 (3H, d), 6.59 - 6.62 (IH, m), 7.15 - 7.19 (IH, m) 4-Bromo-l-ethoxy-2-ethylbenzene
Figure imgf000270_0001
To a slurry of 4-bromo-2-ethylphenol (0.500 g, 2.49 mmol) and sodium hydride (0.149 g, 3.73 mmol) in DMF (2.49 mL) cooled to 0 0C was added ethyl iodide (0.398 mL, 4.97 mmol). The reaction mixture solidified so DMF (1.97 mL) was added and the reaction stirred at ambient temperature for 16 hours. The reaction mixture was quenched with 2M NaOH (25 mL), diluted with EtOAc (75 mL) and washed sequentially with 2M NaOH (25 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-bromo-l-ethoxy-2-ethylbenzene (0.428 g, 75 %) as a colourless oil.
MS (+ve ESI) : Rt = 3.30 min, 193.51 (M+H)+
1R NMR (400.13 MHz, CDC13) δ 1.18 (3H, t), 1.41 (3H, t), 2.60 (2H, q), 4.00 (2H, q), 6.66 - 6.69 (IH, m), 7.21 - 7.24 (2H, m) 4-Bromo-2-ethyl-l-methoxybenzene
Figure imgf000271_0001
To a slurry of 4-bromo-2-ethylphenol (0.500 g, 2.49 mmol) and sodium hydride (0.149 g, 3.73 mmol) in DMF (2.487 mL) cooled to 0 0C was added iodomethane (0.310 mL, 4.97 mmol). The reaction mixture solidified so DMF (1.970 ml) was added and the reaction stirred at ambient temperature for 16 hours. The reaction mixture was quenched with 2M NaOH (25 mL), diluted with EtOAc (75 mL) and washed sequentially with 2M NaOH (25 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-bromo-2-ethyl-l-methoxybenzene (0.485 g, 91 %) as a colourless oil.
MS (+ve ESI) : Rt = 3.03 min, no mass ion (M+H)+ 1H NMR (400.13 MHz, CDC13) δ 1.17 (3H, t), 2.60 (2H, q), 3.80 (3H, s), 6.68 - 6.71 (IH, m), 7.24 - 7.26 (2H, m)
4-Bromo-l-(difluoromethoxy)-2-methoxybenzene
Figure imgf000271_0002
Sodium chlorodifiuoroacetate (0.826 g, 5.42 mmol) was added to 4-bromoguaiacol (1.00 g, 4.93 mmol) and potassium carbonate (0.817 g, 5.91 mmol) in DMF (10 mL) under argon. The resulting suspension was stirred at 90 0C for 16 hours. The reaction mixture was quenched with water (100 mL), extracted with Et2O (3 x 100 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% Et2O in isohexane. Pure fractions were evaporated to dryness to afford 4-bromo-l-(difluoromethoxy)-2- methoxybenzene (0.445 g, 35.7 %) as a colourless oil. MS (+ve ESI) : Rt = 2.55 min, no mass ion (M+H)+ 1U NMR (400.132 MHz, CDC13) δ 3.87 (3H, s), 6.50 (IH, t), 7.01 - 7.10 (3H, m) 4-Bromo-l-methoxy-2-(trifluoromethoxy)benzene
Figure imgf000272_0001
To a slurry of 4-bromo-2-(trifluoromethoxy)phenol (200 mg, 0.780 mmol) and sodium hydride (46.7 mg, 1.17 mmol) in DMF (2 mL) cooled to 0 0C was added iodomethane (100 μl, 1.56 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with water, diluted with DCM (50 mL)and washed sequentially with water (25 mL) and saturated brine (50 mL). The organic filtered through a phase separator and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 5% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-bromo-l-methoxy-2- (trifluoromethoxy)benzene (90.0 mg, 42.7 %) as a colourless oil. MS (+ve ESI) : Rt = 2.84 min, no mass ion (M+H)+
1H NMR (400.13 MHz, CDCB) δ 3.87 (3H, s), 6.88 (IH, t), 7.36 - 7.39 (2H, m) 4-Bromo-l-ethoxy-2-(trifluoromethoxy)benzene
Figure imgf000272_0002
To a slurry of 4-bromo-2-(trifluoromethoxy)phenol (200 mg, 0.78 mmol) and sodium hydride (46.7 mg, 1.17 mmol) in DMF (2 mL) cooled to 0 0C was added iodoethane (62.5 μl, 0.78 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with water, diluted with DCM (50 mL)and washed sequentially with water (25 mL) and saturated brine (50 mL). The organic filtered through a phase separator and evaporated to afford crude product. TLC indicated a new, less polar spot. The crude product was purified by flash silica chromatography, elution gradient 2 to 5% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-bromo-l- ethoxy-2-(trifluoromethoxy)benzene (177 mg, 80 %) as a colourless oil. MS (+ve ESI) : Rt = 3.07 min, no mass ion (M+H)+ 1H NMR (400.13 MHz, CDCB) δ 1.43 (3H, t), 4.07 (2H, q), 6.86 (IH, s), 7.33 - 7.37 (2H, m) 4-Bromo- 1 ,2-bis(difluoromethoxy)benzene
Figure imgf000273_0001
Difluoroiodomethane (1.04 g, 5.82 mmol) was added to 4-bromobenzene-l,2-diol (0.50 g, 2.65 mmol) and potassium carbonate (0.877 g, 6.35 mmol) in acetone (20 mL). The resulting suspension was stirred at 50 0C for 18 hours. The reaction mixture was evaporated to dryness and redissolved in Et2O (100 mL), and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% DCM in isohexane. Pure fractions were evaporated to dryness to afford 4-bromo-l,2- bis(difiuoromethoxy)benzene (0.251 g, 32.8 %) as a colourless oil. MS (+ve ESI) : Rt = 2.68 min, no mass ion (M+H)+ 1R NMR (400.132 MHz, DMSO) δ 7.04 - 7.48 (3H, m), 7.54 (IH, m), 7.62 (IH, d) 4-Bromo-l-ethoxy-2-fluorobenzene
Figure imgf000273_0002
To a slurry of 4-bromo-2-fiuorophenol (1.00 g, 5.24 mmol) and potassium carbonate (1.45 g, 10.5 mmol) in DMF (5 mL) was added ethyl iodide (0.423 mL, 5.24 mmol) and the reaction stirred at room temperature overnight. The solid was filtered off , washed with acetone (50 mL) and the filtrate evaporated. The residue was dissolved in Et2O (100 mL) and washed sequentially with water (50 mL), 2M NaOH (2 x 50 mL), water (50 mL), dried over MgSO4, filtered and evaporated to give pure 4-bromo-l-ethoxy-2-fiuorobenzene (1.14 g, 99 %) as a yellow gum. MS (+ve ESI) : Rt = 2.68 min, no mass ion (M+H)+ 1R NMR (400.13 MHz, DMSO-d6) δ 1.33 (3H, t), 4.09 (2H, q), 7.13 (IH, t), 7.30 - 7.34 (IH, m), 7.50 - 7.53 (IH, m) 4-Bromo-l-(difluoromethoxy)-2-fluorobenzene
Figure imgf000274_0001
To a slurry of 4-bromo-2-fluorophenol (I g, 5.24 mmol) and potassium carbonate (1.45 g,
10.5 mmol) in DMF (5 mL) was added iododifluoromethane (0.932 g, 5.24 mmol) and the reaction stirred at ambient temperature overnight. The solid was filtered off, washed with
DCM (50 mL) and the filtrate washed with NaOH solution (2N, 50 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give pure 4-bromo-l-
(difluoromethoxy)-2-fiuorobenzene (0.809 g, 64.1 %) as an off-white low melting point solid. MS (+ve ESI) : Rt = 2.68 min, no mass ion (M+H)+
1R NMR (400.13 MHz, DMSO-d6) δ 7.07 - 7.26 (IH, t), 7.37 (IH, m), 7.47 - 7.50 (IH, m), 7.77 - 7.80 (IH, m)
4-Chloro-l-cyclobutyl-2-methoxybenzene was synthesized in the following manner. l-(4-Chloro-2-methoxyphenyl)cyclobutanol
Figure imgf000274_0002
To a slurry of 2-bromo-5-chloroanisole (7.07 g, 31.9 mmol) in THF (50 mL) at -78 0C under an atmosphere of argon was added n-butyllithium (12.8 ml, 31.9 mmol), dropwise keeping the temperature below -60 0C. The reaction was stirred at -78 0C for 1 hour and then cyclobutanone (2.46 g, 35.1 mmol) added dropwise. The reaction was stirred at -78 0C and then allowed to warm to ambient temperature over 2 hours. The reaction was poured into saturated NH4Cl (100 mL) and washed with EtOAc (2 x 10OmL), the comined organic extracts were washed with saturated brine (100 mL) dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% Et2O in isohexane. Pure fractions were evaporated to dryness to afford l-(4-chloro-2-methoxyphenyl)cyclobutanol (2.63 g, 38.8 %) as a yellow oil.
1R NMR (400.132 MHz, CDC13) δ 1.64 (IH, m), 2.05 (IH, m), 2.34 (2H, m), 2.47 (2H, m), 3.88 (3H, s), 6.89 (IH, d), 6.94 (IH, m), 7.22 (IH, d) 4-Chloro-l-cyclobutyl-2-methoxybenzene
Figure imgf000275_0001
A mixture of l-(4-chloro-2-methoxyphenyl)cyclobutanol (1.50 g, 7.05 mmol) and triethylsilane (1.37 mL, 8.46 mmol) in DCM (17.5 mL) under a blanket of argon was cooled to -78 0C and boron trifiuoride diethyl etherate (0.90 mL, 7.05 mmol) added dropwise. The mixture was allowed to warm to -40 0C over 3 hours and stirred at -40 0C for a further 2 hours before being poured into a 10% solution OfKHCO3 in water (100 mL). The mixture was extracted with DCM (3 x 100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-chloro-l-cyclobutyl-2-methoxybenzene (1.21 g, 87 %) as a colourless oil.
1R NMR (400.132 MHz, CDC13) δ 1.81 (IH, m), 2.03 (3H, m), 2.29 (2H, m), 3.65 (IH, m), 3.78 (3H, s), 6.78 (IH, d), 6.90 (IH, m), 7.10 (IH, d)
EXAMPLE METHOD C
4-Bromo-2-chloro-l-(2-cyano-2-methyl)ethylbenzene
Figure imgf000275_0002
To a solution of the 4-bromo-2-chloro-l-fluorobenzene (2.1Og, 10.0 mmol) in toluene (15 mL) was added the isobutyronitrile (3.64 mL) followed by KHMDS (0.5 M solution in toluene, 15 mL, 7.50 mmol). Reaction heated at 60 0C for 10 mins and then cooled to 0 0C, poured into IM HCl (5 mL) and extracted with ethyl acetate (2 x 30 mL), orgs washed with brine (10 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. Residue was purified by flash column chromatography (silica, 0 to 50 % EtOAc / hexanes) to yield a brown solid (970 mg, 38%). MS (+ve ESI) : Rt = 2.46 min, no mass ion (M+H)+ 1H NMR (400.132 MHz, CDC13) δ 1.85 (6H, s),7.35 (IH, d),7.43 (IH, m),7.61 (IH, d) 2-(5-chloro-4-methylpyridin-2-yl)-2-methylpropanenitrile
Figure imgf000276_0001
In a similar manner to method C above except using 5-chloro-2-fluoro-4-picoline (1.46 g, 10.0 mmol) yielded 2-(5-chloro-4-methylpyridin-2-yl)-2-methylpropanenitrile (1.51 g, 78%) as a colourless oil after work up and isolation. MS (+ve ESI) : Rt = 2.21 min, 195 (M+H)+
1H NMR (400.132 MHz, CDCB) δ 1.76 (6H, s),2.42 (3H, s),7.46 (IH, s),8.47 (IH, s) 2-(5-Chloropyridin-2-yl)-2-methylpropanenitrile
Figure imgf000276_0002
In a similar manner to method C above except using 5-chloro-2-fiuoropyridine (1.32 g, 10.0 mmol) yielded 2-(5-chloropyridin-2-yl)-2-methylpropanenitrile (0.945 g, 53 %) as a colourless oil after work up and isolation.
1H NMR (400.132 MHz, CDC13) δ 1.75 (6H, s),7.56 (IH, d),7.70 (IH, d),8.55 (IH, s) 2-(4-Chloro-3-methylphenyl)-2-methylpropanenitrile
Figure imgf000276_0003
In a similar manner to method C above except using 2-chloro-5-fiuoro toluene (1.45 g, 10.0 mmol) yielded 2-(4-chloro-3-methylphenyl)-2-methylpropanenitrile (720 mg, 37%) as a yellow oil. MS (+ve ESI) : Rt = 2.19 min, no mass ion (M+H)+
1H NMR (400.132 MHz, CDC13) δ 1.70 (6H, s),2.40 (3H, s),7.21 (IH, m),7.34 (2H, m) 2-(4-Bromo-2-methoxyphenyl)-2-methylpropanenitrile
Figure imgf000276_0004
In a similar manner to method C above except using 3-bromo-6-fluoroanisole (2.05 g, 10.0 mmol) yielded 2-(4-bromo-2-methoxyphenyl)-2-methylpropanenitrile (0.402 g, 15.8%) as a yellow oil.
1R NMR (400.132 MHz, CDC13) δ 1.74 (6H, s), 3.92 (3H, s), 7.09 (2H, m), 7.20 (IH, d)
4-Chloro-l-methoxy-2-(methylsulfonyl)benzene
Figure imgf000277_0001
l,4-Dichloro-2-(methylsulfonyl)benzene (950 mg, 4.22 mmol), sodium methanolate (1140 mg, 21.1 mmol) were suspended in methanol (5 mL) and sealed into a microwave tube. The reaction was heated to 120 0C for 10 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (30 mL), and washed sequentially with water (30 mL) and saturated brine (30 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-chloro-l-methoxy-2-(methylsulfonyl)benzene (663 mg, 71.2 %) as a white solid. MS (+ve ESI) : 220 (M+H)+
1R NMR (400.132 MHz, CDC13) δ 3.32 (3H, s), 4.00 (3H, s), 7.00 (IH, d), 7.55 (IH, d), 7.95 (IH, s) 2-Fluoro-4-iodo-l,3-dimethoxybenzene was synthesised in the following manner. 2-Fluoro- 1 ,3-dimethoxy-4-nitrobenzene
Figure imgf000277_0002
A solution of freshly prepared sodium methoxide [sodium (1.45 g, 63.0 mmol) in methanol (25 mL)] was added dropwise to a stirred solution of l,2,3-trifluoro-4-nitrobenzene (3.24 mL, 28.24 mmol) in methanol (75 mL) at 50C. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was quenched with 0. IM citric acid solution (1.5 mL), evaporated to dryness and redissolved in Et2O (200 mL), and washed sequentially with IM citric acid solution (200 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. MS (+ve ESI) : Rt = 2.52, no mass ion (M+H)+
1R NMR (400.132 MHz, CDCB) δ 3.98 6(3H, s), 4.08 (3H, d), 6.74 (IH, m), 7.75 (IH, m)
3-Fluoro-2,4-dimethoxyaniline
Figure imgf000278_0001
2-Fluoro-l,3-dimethoxy-4-nitrobenzene (5.82 g, 28.9 mmol) and 10% palladium on carbon (0.72 g, 6.77 mmol) in a mixture of ethanol (45 mL) and ethyl acetate (45.0 mL) was stirred under an atmosphere of hydrogen at 5 atm and 25 0C for 18 hours. The reaction mixture was filtered through celite and the resulting filtrate was evaporated to dryness to afford crude 3-fiuoro-2,4-dimethoxyaniline (4.82 g, 97 %). MS (+ve ESI) : Rt = 1.35, no mass ion (M+H)+
1R NMR (400.132 MHz, CDC13) δ 3.64 (2H, s), 3.82 (3H, s), 3.93 (3H, s), 6.42 (IH, m), 6.54 (IH, t) 2-Fluoro-4-iodo-l,3-dimethoxybenzene
Figure imgf000278_0002
Sodium nitrite (0.652 g, 9.45 mmol) in water (2 mL) was added to 3-fluoro-2,4- dimethoxyaniline (1.54 g, 9.00 mmol), in water (15.0 mL) and water (15 mL) at O0C over a period of 5 minutes under air. The resulting solution was stirred at 0 0C for 15 minutes, and then potassium iodide (1.51 g, 9.09 mmol) in water (5 ml) was added. The reaction was stirred at room temperature for 3 hours. The reaction mixture was diluted with Et2O (100 mL), and the organic layer washed sequentially with sodium metabisulfate (20 mL), water (50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford pure product. The crude product was purified by flash silica chromatography, elution gradient 5 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 2-fluoro-4-iodo-l,3-dimethoxybenzene (1.90 g, 74.9 %) as a brown gum. MS (+ve ESI) : Rt = 2.52, no mass ion (M+H)+ 1U NMR (400.13 MHz, CDCB) δ 3.87 (3H, s), 3.94 - 3.94 (3H, m), 6.50 - 6.54 (IH, m),
7.41 - 7.44 (IH, m) l-Bromo-2-fluoro-4,5-dimethoxybenzene
Figure imgf000279_0001
To a slurry of 4-bromo-5-fluoro-2-methoxyphenol (2.00 g, 9.05 mmol) and sodium hydride (0.543 g, 13.8 mmol) in DMF (9.05 mL) was added methyl iodide (1.13 mL, 18.1 mmol) and the reaction stirred at ambient temperature for 30 minutes. The reaction was heated to 40 0C for 4 hours then further methyl iodide (1.13 mL, 18.1 mmol) was added. The reaction was reheated at 40 0C for 1 hour and allowed to cool. The reaction mixture was quenched with water (5 mL), diluted with EtOAc (50 mL) and washed sequentially with 2M NaOH (25 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford a biphasic oil. This was clean by NMR and LCMS, but it was purified by flash silica chromatography, elution gradient 5 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford l-bromo-2-fluoro-4,5- dimethoxybenzene (1.81 g, 85 %) as a orange oil. MS (+ve ESI) : Rt = 2.22, no mass ion (M+H)+ 1U NMR (400.13 MHz, CDC13) δ 3.86 (3H, s), 3.86 (3H, s), 6.69 - 6.72 (IH, m), 6.96 (IH, d) 4-Bromo-2-methoxy-l-(prop-l-en-2-yl)benzene
Figure imgf000279_0002
To μ-chloro-μ-methylenebis(cyclopentadienyl)titaniumdimethylaluminum (13.4 mL, 6.67 mmol) was added at 0 0C, under argon, the l-(4-bromo-2-methoxyphenyl)ethanone (1.39 g, 6.07 mmol) in tetrahydrofuran (6 mL), slowly. The mixture was stirred and allowed to warm to ambient temperature for 1 hour. 2M NaOH (ca ImL) was added dropwise over 30 minutes and MgSO4 was added. The mixture was filtered through celite and washed with Et2O. The filtrate was evaporated and the crude product was purified by flash silica chromatography, elution gradient 0 to 2% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-bromo-2-methoxy-l-(prop-l-en-2-yl)benzene (0.815 g, 59.1 %) as a orange oil.
MS (+ve ESI) : Rt = 2.98, no mass ion (M+H)+
1R NMR (400.132 MHz, CDCB) δ 2.08 (3H, s), 3.83 (3H, s), 5.05 (IH, s), 5.15 (IH, s), 7.00 (IH, s), 7.04 (2H, s)
4-Bromo-2-methoxy-l-(l-methylcyclopropyl)benzene
Figure imgf000280_0001
To diethylzinc (IM Solution in hexanes) (4.00 mL, 4.00 mmol) in DCE (6.5 mL) under a blanket of argon at 0 0C was added chloroiodomethane (0.583 mL, 8.00 mmol) and the mixture stirred for 5 minutes. 4-bromo-2-methoxy-l-(prop-l-en-2-yl)benzene (0.454 g, 2 mmol) in DCE (3.5 mL) was added and the reaction stirred and allowed to warm to ambient temperature for 90 minutes. Saturated NH4CI (5 mL) was added and the mixture partitioned with Et2O (50 mL), and saturated NH4CI (50 mL), the organic layer was washed with further saturated NH4CI (50 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with isohexane. Pure fractions were evaporated to dryness to afford 4-bromo-2-methoxy-l-(l- methylcyclopropyl)benzene (0.369 g, 77 %) as a colourless oil. MS (+ve ESI) : Rt = 2.98, no mass ion (M+H)+ 1R NMR (400.132 MHz, CDC13) δ 0.61 - 0.65 (2H, m), 0.66 - 0.70 (2H, m), 1.27 (3H, s), 3.85 (3H, s), 6.95 (IH, s), 6.99 (IH, d), 7.10 (IH, d) 4-Bromo-2-methoxy-l-(methylsulfonyl)benzene
Figure imgf000280_0002
(4-Bromo-2-methoxyphenyl)(methyl)sulfane [WO 2000002859] (2.41 g, 10.3 mmol) was dissolved in DCM (50 mL) at 0 0C and 3-chlorobenzoperoxoic acid (5.61 g, 22.7 mmol) was added portionwise. The reaction was allowed to warm to ambient temperature and stirred for 5 hours. Diluted with DCM (100 mL) and washed with 2M NaOH (3 x 100 mL), dried over MgSO4, filtered and evaporated to give 4-bromo-2-methoxy-l- (methylsulfonyl)benzene (2.20 g, 80 %) as a pretty pure yellow solid. MS (+ve ESI) : Rt = 1.73, no mass ion (M+H)+
1R NMR (400.132 MHz, CDC13) δ 3.20 (3H, s), 4.01 (3H, s), 7.21 (IH, d), 7.25 - 7.29 (IH, m), 7.84 (IH, d)
6-Bromo-3-methylbenzo[</]isoxazole was synthesised in the following manner. l-(4-Bromo-2-hydroxyphenyl)ethanone oxime
Figure imgf000281_0001
Hydroxylamine hydrochloride (1.87 g, 27.0 mmol) was added to a solution of l-(4-bromo- 2-hydroxyphenyl)ethanone (1.16 g, 5.39 mmol) and pyridine (5.89 mL, 72.8 mmol) in ethanol (30 mL) at ambient temperature. The resulting solution was heated to reflux temperature for 4 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc (125 mL), and washed with 2M HCl (50 mL) and water (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford desired product (E)- l-(4-bromo-2-hydroxyphenyl)ethanone oxime (1.20 g, 97 %). MS (+ve ESI) : Rt = 1.06, 230.06 (M+H)+ 1U NMR (400.132 MHz, CDC13) δ 2.34 (3H, s), 7.02 - 7.05 (IH, m), 7.15 (IH, d), 7.26 - 7.29 (IH, m), 11.33 (IH, s) l-(4-Bromo-2-hydroxyphenyl)ethanone O-acetyl oxime
Figure imgf000281_0002
Acetic anhydride (1.0 ml, 10.9 mmol) was added in one portion to l-(4-bromo-2- hydroxyphenyl)ethanone oxime (500 mg, 2.17 mmol). The mixture was stirred for 10 minutes (formed a solution then a solid precipitated out). Added water (10 mL) and stirred for a further 2 minutes then filtered and washed with water. Solid was dissolved in EtOAc and dried over Na2SO4, filtered and concentrated at reduced pressure to give l-(4-bromo-2- hydroxyphenyl)ethanone O-acetyl oxime (490 mg, 83 %) as a white solid. MS (+ve ESI) : Rt = 1.19, no mass ion (M+H)+
1H NMR (400.132 MHz, CDC13) δ 2.26 (3H, s), 2.43 (3H, s), 7.03 - 7.07 (IH, m), 7.22 (IH, d), 7.31 (IH, d), 11.47 (IH, s) 6-Bromo-3-methylbenzo [d\ isoxazole
Figure imgf000282_0001
A solution of l-(4-bromo-2-hydroxyphenyl)ethanone O-acetyl oxime (450 mg, 1.65 mmol) in pyridine (5.35 ml, 66.2 mmol) was heated to reflux temperature for 3 hours. The resulting yellow solution was cooled and was diluted with Et2O (150 mL), and washed with 2M HCl (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 1 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 6-bromo-3-methylbenzo[J]isoxazole (270 mg, 77 %) as a white solid.
MS (+ve ESI) : Rt = 2.11, no mass ion (M+H)+
1R NMR (400.132 MHz, CDC13) δ 2.57 (3H, s), 7.41 - 7.45 (IH, m), 7.49 (IH, d), 7.74
(IH, d)
6-Chloro-l,4-dimethylphthalazine
Figure imgf000282_0002
l,r-(4-chloro-l,2-phenylene)diethanone [J Chem. Soc. (1947), 232-7] (2.14 g, 10.9 mmol) in ethanol (100 mL) was added to hydrazine hydrate (0.582 mL, 12.0 mmol) in ethanol (100 mL) at 0 0C over a period of 5 minutes under argon. The resulting solution was stirred and allowed to warm to room temperature with the argon source removed over 18 hours. It was concentrated in vacuo into 15 mL of toluene. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-chloro-l,4-dimethylphthalazine (1.93 g, 92 %) as a sand coloured solid. MS (+ve ESI) : Rt = 0.88, 193.38 (M+H)+ 1H NMR (400MHz, DMSO) d 2.85 (s, 6H), 7.95 (d, IH), 8.2 (m, 2H). 4-Bromo-l,2-bis(methoxymethyl)benzene
Figure imgf000283_0001
Sodium hydride (1.70 g, 42.6 mmol) was added to iodomethane (2.87 mL, 46.12 mmol) and (4-bromo-l,2-phenylene)dimethanol [J Med. Chem. (1995), 38(22), 4529-37] (3.85 g, 17.7 mmol) in THF (71 mL) at O0C over a period of 10 minutes under argon. The resulting mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. DCM (150 mL) and sodium hydroxide solution (2N, 150 mL) were added and the organic layer separated. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to afford 4-bromo-l,2- bis(methoxymethyl)benzene as a yellow oil (2.80 g, 64%). 1U NMR (400.13 MHz, MeOD) δ 3.39 (3H, s), 3.42 (3H, s), 4.49 (2H, s), 4.52 (2H, s), 7.30 (IH, d), 7.43 - 7.46 (IH, m), 7.57 (IH, d) S-Chloro-l-ethoxy-S-methyl-pyridine
Figure imgf000283_0002
Ethyl iodide (0.808 mL, 10.0 mmol) was added dropwise to a stirred suspension of 5- chloro-3-methylpyridin-2-ol (1.44 g, 10.0 mmol) and silver carbonate (3.86 g, 14.0 mmol) in a mixture of THF (33.3 mL) and toluene (6.67 mL) at room temperature, over a period of 5 minutes under argon. The resulting suspension was stirred at room temperature for 3 days. A black semi-solid was obtained after this time. The suspension was filtered, washing with EtOAc (300 mL). The organics were washed with 2N NaOH (200 mL) and brine (200 mL), dried over sodium sulphate and reduced in vacuo. The crude product was purified by flash chromatography, elution gradient 10 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 5-chloro-2-ethoxy-3-methylpyridine (0.128 g, 7.7 %) as a yellow oil. MS (+ve ESI) : Rt = 2.78, 194.45 (M+H)+ 1U NMR (400.13 MHz, CDC13) δ 1.38 (3H, t), 2.16 (3H, s), 4.34 (2H, q), 7.34 - 7.35 (IH, m), 7.91 (IH, d) 6-Bromo-3-(2-methoxyethoxy)-2-methylpyridine
Figure imgf000284_0001
Potassium carbonate (441 mg, 3.19 mmol) was added to 6-bromo-2-methylpyridin-3-ol [Bioorg Med. Chem. Letters (2005), 15(6), 1721-1724] (400 mg, 2.13 mmol) and 2- Bromoethyl methyl ether (0.20 mL, 2.13 mmol) in acetone (20 mL). The resulting suspension was stirred at 60 0C for 2 hours. The reaction was incomplete and further 2- bromoethyl methyl ether (0.20 mL, 2.13 mmol) and sodium iodide (319 mg, 2.13 mmol) were added and the resulting suspension maintained at 60 0C for 2 hours. The reaction was incomplete and further sodium iodide (319 mg, 2.13 mmol), Potassium carbonate (441 mg, 3.19 mmol) and 2-bromoethyl methyl ether (2.0 mL, 21.30 mmol) were added and the temperature maintained at 60 0C for 18 hours. A further 10 equivalents of 2-bromoethyl methyl ether (2.0 mL) was then added and the temperature maintained at 60 0C for 8 hours. It was cooled to room temperature and the inorganic residue removed by filtration. The filtrate was concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 6-bromo-3-(2-methoxyethoxy)-2- methylpyridine (347 mg, 66.3 %) as a colourless oil. MS (+ve ESI) : Rt = 1.78, 248.36 (M+H)+
1U NMR (400MHz, DMSO) δ 2.35 (s, 3H), 3.35 (s, 3H), 3.7 (t, 2H), 4.15 (t, 2H), 7.35 (m,
2H).
4,6-Dibromo-2-methylpyridin-3-ol
Figure imgf000284_0002
l-Bromopyrrolidine-2,5-dione (1.31 g, 7.33 mmol) was added to 2-methylpyridin-3-ol
(0.400 g, 3.67 mmol) in acetonitrile (30 mL). The resulting suspension was stirred at reflux for 2 hours. The resulting mixture was evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% Et2O in isohexane. Pure fractions were evaporated to dryness to afford 4,6-dibromo-2- methylpyridin-3-ol (0.823 g, 84 %) as a cream solid. MS (+ve ESI) : Rt = 1.81, 268.23 (M+H)+
IH NMR (400.132 MHz, CDC13) δ 2.52 (3H, s), 5.51 (IH, s), 7.45 (IH, s) 6-Bromo-2-methylpyridin-3-ol
Figure imgf000285_0001
n-Butyllithium (1.6M in hexanes) (25.6 mL, 40.9 mmol) was added to 4,6-dibromo-2- methylpyridin-3-ol (5.46 g, 20.5 mmol) in anhydrous THF (100 mL) at -78 0C under argon. The resulting solution was stirred at -78 0C for 2 hours. To the reaction mixture water (3.69 mL, 204 mmol) was added and the solution was stirred and allowed to warm to room temperature. The reaction mixture was concentrated and diluted with saturated NH4Cl (100 mL), extracted with EtOAc (3 x 150 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford yellow waxy solid. The crude product was purified by flash silica chromatography (dry loaded), elution gradient 0 to 50% Et2O in isohexane. Pure fractions were evaporated to dryness to afford 6-bromo-2-methylpyridin- 3-ol (2.76 g, 71.8 %) as a white solid. MS (+ve ESI) : Rt = 1.29, 190.25 (M+H)+
1R NMR (400.132 MHz, CDC13) δ 2.48 (3H, s), 4.95 (IH, d), 6.96 (IH, d), 7.19 (IH, d) 6-Bromo-3-methoxy-2-methylpyridine
Figure imgf000285_0002
Methyl iodide (0.12 mL, 1.91 mmol) was added to 6-bromo-2-methylpyridin-3-ol (0.300 g, 1.60 mmol) and potassium carbonate (0.287 g, 2.07 mmol) in acetone (15 mL). The resulting suspension was stirred at 50 0C for 2 hours. The reaction mixture was evaporated to dryness and redissolved in Et2O (100 mL), and washed sequentially with water (100 mL) and 2M NaOH (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. MS (+ve ESI) : Rt = 1.82, 204.31 (M+H)+ 1U NMR (400.132 MHz, CDCB) δ 2.44 (3H, s), 3.83 (3H, s), 6.97 (IH, d), 7.25 (IH, d) 2-(4-Bromophenyl)-l,l,l-trifluoropropan-2-ol
Figure imgf000286_0001
To a slurry of 1 ,4-dibromobenzene (7.53 g, 31.9 mmiol) in THF under a blanket of argon was added n-BuLi (1.6M, 20 mL), dropwise at -78 0C so as to keep the temperature below -550C. The reaction was stirred for 30 mins at -780C then 1,1,1-trifluoroacetone (3.43 mL, 38.3 mmol) was added (keeping temp below -550C). The reaction was then stirred at -780C for 1 hour and then allowed to warm to ambient temperature overnight. The reaction was quenched with water and then extracted with ethyl acetate (100 mL x 2), the organics washed with brine, dried over magnesium sulphate, filtered and concentrated in vacuo. Used crude (5.25 g, 61%).
Assay for the identification of cathepsin K inhibitors
QFRET Technology (Quenched Fluorescent Resonance Energy Transfer) was used to measure the inhibition by test compounds of cathepsin K-mediated cleavage of the synthetic peptide Z-Phe-Arg-AMC. Compounds were screened at twelve concentrations (3.5x10-8 - lOuM), on two separate occasions and the mean pIC50 values reported. 0.5nM [final] rhuman cathepsin K in phosphate buffer was added to a 384-well black micro titre plate containing investigative compounds. The enzyme and compound were pre-incubated at room temperature for 30 minutes before the addition of 5OmM [final] Z-Phe-Arg-AMC synthetic substrate in phosphate buffer. The plates were covered and incubated for Ih at room temperature, protected from light. Following the incubation the reaction was stopped with 7.5% [final] acetic acid. Relative fluorescence was measured using the Ultra plate reader at a wavelength of 360nm excitation and 425nm emission.
Data was corrected for background fluorescence (minimum controls without enzyme). This data was used to plot inhibition curves and calculate pIC50 values by non- linear regression using a variable slope, offset=zero model in Origin 7.5 analysis package. Reproducibility of data was assessed using a quality control statistical analysis package whereby internal variability of the assayed indicated a repeat testing (n=3) if pIC50 SD was > 0.345.
The compounds of the Examples have Cat K FRET competitive binding as measured by the assay described above at pIC50 > 5.5.

Claims

1. A compound of formula (I)
Figure imgf000288_0001
(I) in which:
A is a 5- to 7- membered aliphatic ring optionally containing a double bond and optionally comprising an oxygen atom as a ring member and optionally being substituted by up to three substituents each independently selected from halogen and
Figure imgf000288_0002
R is hydrogen or C1-6 alkyl;
R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 7- membered monocyclic saturated heterocyclic ring, which ring can optionally comprise up to three additional heteroatoms each independently selected from O, S or N atoms, and which ring can be optionally substituted by up to three substituents each independently selected from phenyl, benzyl, naphthyl, Ci-6 alkyl, C2-6alkenyl, C2-6alkynyl, cyano, halogen, COOR3, COR3, NO2, OR4, CONR5R6, NR6R7, monocyclic heteroaryl comprising up to 7 ring atoms, and bicyclic heteroaryl comprising up to 12 carbon atoms, and wherein (i) phenyl, naphthyl, Ci-6 alkyl, C2-6alkenyl, C2-6alkynyl and benzyl are optionally further substituted by up to three substituents each independently selected from halogen, NR6R7, SO2R3, CONR5R6, cyano, OR3, SO2NR6R7, NSO2R3, NR8COR9, Ci-6 alkyl and C3- 7carbocyclyl, wherein Ci-6 alkyl and C3-7carbocyclyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from methyl, halogen, cyano, SO2R3, NR6R7, OR3, SO2NR6R7, NSO2R3, NR8COR9 and CONR5R6, and (ii) monocyclic or bicyclic heteroaryl are optionally further substituted by up to three substituents each independently selected from halogen, NR6R7, SO2NR6R7, NSO2R3, NR8COR9, CONR5R6 , SO2R3, cyano, CO2R3, OR3, Ci-6 alkyl and C3-7carbocyclyl, whereinCi-6 alkyl and C3-7carbocyclyl are optionally substituted with up to three 5 substituents independently selected from methyl, halogen, cyano, SO2R3, SO2NR6R7,
NSO2R3, NR8COR9, NR6R7, OR3, CONR5R6 and CO2R3 , and wherein phenyl is optionally substituted with up to three substituents selected from halogen groups, SO2R3, Ci-6 alkyl and C3-7carbocyclyl, wherein Ci-6 alkyl and C3-7carbocyclyl are optionally substituted with up to three substituents independently selected from halogen, cyano, SO2R3, SO2NR6R7,o NSO2R3, NR8COR9, NR6R7, OR3, C3-7carbocyclyl, CONR5R6 and CO2R3;
R3is hydrogen, NR6R7, phenyl, C3-7carbocyclyl, a 4-7 membered monocyclic saturated heterocyclic ring comprising up to three heteroatoms each independently selected from O, S or N atoms, or R3 is Ci-6 alkyl optionally substituted by up to five substituents independently selected from halogen, 0-Ci-3 alkyl and NR6R7; s R4 is hydrogen, Ci-6 alkyl or phenyl, wherein Ci-6 alkyl or phenyl can be optionally substituted by up to three groups independently selected from halogen, cyano, CONR5R6, NR6R7, SO2NR6R7, NSO2R3 and SO2R3;
R5 is hydrogen, Ci-6 alkyl or phenyl;
R6 and R7 are independently hydrogen, Ci-6 alkyl, COR3, monocyclic heteroarylo comprising up to 7 ring atoms or bicyclic heteroaryl comprising up to 12 ring atoms or together with the nitrogen to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring optionally comprising up to three additional hetetoatoms each independently selected from O, S or N atoms and optionally substituted by Ci-6 alkyl optionally substituted by NR8R9; 5 R8 and R9 are independently hydrogen or Ci-6 alkyl, and pharmaceutically acceptable salts or solvates thereof.
2. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein A is a 5 -7-membered aliphatic ring optionally being substituted by up to three0 substituents independently selected from halogen and C3-4carbocyclyl.
3. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is hydrogen or C1-4alkyl.
4. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring, which ring can optionally contain one or more N atoms and can be optionally substituted by up to three substituent groups as defined in claim 1.
5. A process for the preparation of a compound of formula (I) or pharmaceutically acceptable salt thereof as defined in claim 1 which comprises: (a) treating a compound of formula (II):
Figure imgf000290_0001
(H) wherein R1 and R2 are as defined in claim 1, with a compound of formula (III):
≡N
H-N
R
(in) wherein R is as defined in claim 1 , in the presence of a coupling agent, or
(b) treatment of a compound of formula (IV):
Figure imgf000290_0002
(IV) wherein R is as defined in claim l,with a compound of formula (V):
R1N
N-H R27
(V)
wherein R1 and R2 are as defined in claim 1 , in the presence of a coupling agent, and optionally after (a) or (b) forming a pharmaceutically acceptable salt thereof.
6. A compound of formula (I) as defined in any one of claims 1 to 5 for use in therapy.
7. A compound of formula (I) as defined in any one of claims 1 to 5 for use in therapy, where it is desirable to have inhibition of Cathepsin K.
8. A compound of formula (I) as defined in any one of claims 1 to 5 for use in the treatment of osteoporosis, rheumatoid arthritis, osteoarthritis, metastatic bone disease, osteolytic bone disease or bone related neuropathic pain.
9. A compound of formula (I) as defined in any one of claims 1 to 5 for use in the treatment of rheumatoid arthritis or osteoarthritis.
10. A pharmaceutical composition which comprises a compound of the formula (I) as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
11. A method for producing inhibition of a cysteine protease in a mammal in need of such treatment, which comprises administering to said mammal an effective amount of a compound as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.
12. Use of a compound of the formula (I) as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of Cathepsin K in a warm blooded animal.
PCT/GB2008/050483 2007-06-26 2008-06-24 Cyanocyclopropylcarboxamides as cathepsin inhibitors WO2009001127A1 (en)

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