WO2018047983A1 - Indane derivatives useful as modulators of mglur7 - Google Patents

Indane derivatives useful as modulators of mglur7 Download PDF

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WO2018047983A1
WO2018047983A1 PCT/JP2017/033368 JP2017033368W WO2018047983A1 WO 2018047983 A1 WO2018047983 A1 WO 2018047983A1 JP 2017033368 W JP2017033368 W JP 2017033368W WO 2018047983 A1 WO2018047983 A1 WO 2018047983A1
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Prior art keywords
inden
carboxamide
dihydro
oxo
mmol
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PCT/JP2017/033368
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French (fr)
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Gemma LIWICKI
Stephen Mack
Anne STEPHENSON
Martin Teall
Kathryn WHITE
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Takeda Pharmaceutical Company Limited
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Publication of WO2018047983A1 publication Critical patent/WO2018047983A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
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    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61P25/32—Alcohol-abuse
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom
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    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
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    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
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    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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    • 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
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to indane derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly for use in treating disorders associated with changes in one or both of the glutamatergic and GABAergic signalling pathways regulated in full or in part by metabotropic glutamate receptor 7 (mGluR7).
  • mGluR7 metabotropic glutamate receptor 7
  • WO 2008/151211 discloses substituted benzoylamino-indan-2-carboxylic acids and related compounds which have CXCR5 inhibitory activity.
  • L-Glutamate is the major neurotransmitter in the mammalian central nervous system and activates both ionotropic and metabotropic glutamate receptors. L-Glutamate plays a central role in numerous physiological functions such as learning and memory ( 1 ). sensory perception, development of synaptic plasticity, motor control, respiration and regulation of cardiovascular function. Thus an imbalance in glutamatergic neurotransmission often underlies many neuropathological conditions.
  • the metabotropic glutamate receptors arc a family of G protein-coupled receptors that have been divided into three groups on the basis of sequence homology, putative signal transduction mechanisms and pharmacologic properties.
  • Group I includes niGluRl and mGluR5 and these receptors have been shown to activate phospholipase C.
  • Group II includes mGluR2 and mGluR3 whilst Group III includes mGluR4.
  • mGluR7 and mGluR8 Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities.
  • mGluR7 is an inhibitory GPCR expressed pre-synaptically at the synaptic cleft on
  • mGluR7 modulators would be expected to be useful in treating a wide variety of neurological and psychiatric disorders such as Parkinson's disease (2. 3); dementia associated with Parkinson's disease (3. 4); Alzheimer's disease (5); Huntington's Chorea (6); amyotrophic lateral sclerosis and multiple sclerosis; bipolar disorder (6. 7); psychiatric
  • ISA/EP diseases such as schizophrenia, post-traumatic stress disorder, anxiety disorders and depression (1,4, 6, 8-11); and addiction. They may also be useful in treating age-related hearing loss/tinnitus (12).
  • the present invention provides modulators of mGluR7.
  • n O or 1;
  • R and R may together form a C2-C 3 alkylene chain, or
  • Z is >CHR 6a
  • Y is >NR 6b
  • R 6a represents hydrogen, (halo)C 1 -C 6 alkyl, (halo)C 3 -C 6 cycloalkyl or (halo)phenyl and R represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkylmethyl, or
  • R represents either a C 3 -C 6 cycloalkyl group, or, a C 1 -C 6 alkyl group optionally substituted by at least one substituent independently selected from C 1 -C 6 alkoxy and C 3 -C 6 cycloalkyl, or
  • X is >CH 2
  • Y is >CH 2
  • Z is >NR 8 , >NC(O)R 9 , >NC(O)NHR 9 or
  • R represents hydrogen or a C 1 -C 6 alkyl group optionally substituted by at least one substituent independently selected from halogen, C 3 -C 6 cycloalkyl and a 5- to 6-membered saturated or unsaturated heterocycle, wherein the heterocycle is optionally substituted by at least one
  • R represents a C 1 -C 6 alkoxy group, a C 3 -C 6 cycloalkyl group, or a C ⁇ -C$ alkyl group optionally substituted by at least one substituent independently selected from halogen, cyano, C 1 -C 6 alkoxy and C 3 -C 6 cycloalkyl, or
  • X is >CH 2
  • Z is >NR 10
  • R 10 represents a C 1 -C 6 alkyl group optionally substituted by at least one substituent independently selected from halogen, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, phenyl or a S- to
  • R , R and R each independently represent hydrogen or halogen
  • R represents hydrogen, halogen or is joined to R as defined above;
  • D represents >C(R J V or, when Z is >CH 2 , D may additionally represent a nitrogen atom;
  • R 11 represents hydrogen, halogen or C 1 -C 6 alkyl
  • R represents hydrogen, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulphonyl or
  • R and R each independently represent hydrogen, C 1 -C 6 alkylcarbonyl, C 3 -C 6 cycloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, or C 1 -C 6 alkyl optionally substituted by at least one substituent independently selected from halogen, CyC$ cycloalkyl or a S- to 6- membered saturated or unsaturated heterocycle, or
  • R and R together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing a further ring heteroatom selected from nitrogen and oxygen, wherein the heterocyclic ring is optionally substituted by at least one substituent independently selected from halogen, cyano, C 1 -C 6 alkyl and
  • R 15 represents hydrogen or halogen
  • R 16 represents hydrogen or halogen.
  • an "alkyl” substituent group or an “alkyl” moiety in a substituent group may be linear or branched.
  • Examples of C 1 -C 6 alkyl groups/moieties include methyl, ethyl, propyl,
  • a “cycloalkyl” substituent group or a “cycloalkyl” moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 8 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • a "haloalkyl", “halocycloalkyl” or “halophenyl” substituent group/moiety comprises at least one halogen atom, e.g. one, two, three, four or five halogen atoms. Examples of such groups/moieties include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4-fluorocyclohexyl and 4-fluorophenyl.
  • a "5- to 6-membered saturated or unsaturated heterocycle” means a saturated, partially unsaturated or fully unsaturated hydrocarbyl group containing 5 to 6 ring atoms in which one or more (e.g. one, two, three or four) ring carbon atoms are replaced by a
  • heterocycles independently selected from nitrogen, oxygen and sulphur, particularly nitrogen and oxygen.
  • heterocycles include tetrahydrofuranyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl (oxanyl), morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furyl, furazanyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl and tetrazinyl.
  • R and R form a 4- to 6-membered saturated heterocyclic ring which is substituted, it should be understood that the substituent(s) may be attached to any suitable ring atom.
  • the invention does not encompass any unstable ring or other structures (e.g. >NCH 2 N ⁇ , >NCH 2 0- or aminal groupings of the type
  • n is 0.
  • R , R and R each independently represent hydrogen, fluorine or chlorine.
  • R , R and R each represent hydrogen.
  • one of R , R and R represents halogen and the remaining two represent hydrogen.
  • R represents halogen (particularly fluorine) and R and R both represent hydrogen.
  • two of R , R and R independently represent halogen and the remaining one represents hydrogen.
  • R and R each independently represent halogen and R represents hydrogen.
  • R represents hydrogen or halogen
  • R represents hydrogen
  • R represents either a C 3 -C 6 , or C 4 -C 6 , or C 5 -C 6 cycloalkyl group, or, a
  • C 1 -C 6 or C 1 -C 4 , or C 1 -C 2 alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from
  • X is >CH 2
  • Y is >CH 2
  • Z is >NR 8 , >NC(O)R 9 , >NC(O)NHR 9 or
  • R represents hydrogen or a C 1 -C 6 , or C 1 -C 4 , or
  • C 1 -C 2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from halogen, C 3 -C 6 , or C 4 -C 6 , or C 5 -C 6 cycloalkyl and a 5- to 6-membered saturated or unsaturated heterocycle, wherein the heterocycle is optionally substituted by at least one C 1 -C 3 alkyl substituent (e.g. one, two or three
  • R represents a C ⁇ -CQ, or C 1 -C 4 , or C 1 -C 2 alkoxy group, a C 3 -C 6 , or C 4 -C 6 , or C 5 -C 6 cycloalkyl group, or a C 1 -C 6 , or C 1 -C 4 , or
  • C 1 -C 4 , or C 1 -C 2 alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from halogen, C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkoxy, C 3 -C 6 , or C 4 -C 6 , or C 5 -C 6 cycloalkyl, phenyl or a 5- to 6-membered saturated or unsaturated heterocycle.
  • substituent e.g. one, two or three substituents
  • R 5 represents hydrogen, C 1 -C 2 alkyl, cyclopropyl or cyclopropylmethyl.
  • R represents hydrogen, C 1 -C 2 alkyl, cyclopropyl or (halo)phenyl.
  • -R- - represents hydrogen or halophenyl (e:g: fluorophenyl):
  • R 6b represents hydrogen, C 1 -C 2 alkyl, cyclopropyl or
  • R 6b represents hydrogen or, preferably, methyl. 7
  • R represents either a cyclopropyl group, or, a C 1 -C 2 alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from C 1 -C 2 alkoxy and cyclopropyl.
  • R represents either a cyclopropyl group, or, a methyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from methoxy and cyclopropyl.
  • R represents hydrogen or a C 1 -C 2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from fluorine, cyclopropyl and a 5- to 6-membered saturated or unsaturated heterocycle, wherein the heterocycle is optionally substituted by at least one C 1 -C 3 alkyl substituent (e.g. one, two or three C 1 -C 3 alkyl substituents which may be the same as, or different to, one another).
  • R represents hydrogen or a C 1 -C 2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from fluorine, cyclopropyl and a 5- to 6-membered unsaturated heterocycle (e.g. thiazolyl, pyrazolyl or pyrimidinyl), wherein the heterocycle is optionally substituted by at least one methyl substituent.
  • substituent e.g. one, two, three, four or five substituents
  • a substituent e.g. one, two, three, four or five substituents
  • a 5- to 6-membered unsaturated heterocycle e.g. thiazolyl, pyrazolyl or pyrimidinyl
  • R represents a C 1 -C 4 or C 1 -C 2 alkoxy group, a cyclopropyl group, or a C 1 -C 2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from fluorine, cyano,
  • R represents a C 1 -C 4 or C 1 -C 2 alkoxy group, a cyclopropyl group, or a C 1 -C 2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from fluorine, cyano and methoxy.
  • substituent e.g. one, two, three, four or five substituents
  • R*° represents a C 1 -C 3 alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from fluorine, C 1 -C 2 alkoxy, cyclopropyl, phenyl or a 5- to 6-membered saturated or unsaturated heterocycle.
  • R represents a C 1 -C 3 alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from fluorine, methoxy, cyclopropyl, phenyl or a 5- to 6-membered saturated or unsaturated heterocycle (e.g. pyridinyl, oxanyl or pyrrolidinyl), specific examples of which are cyclopropylmethyl and 3-fluoropropyl (-CH2CH2CH2F).
  • D represents >C(R )- where R represents hydrogen, halogen or C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl.
  • R represents hydrogen, halogen or C 1 -C 2 alkyl such that D represents, for example, >CH, >CF or >C(CH3).
  • R represents hydrogen, hydroxy., C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkoxy, C 1 -C 6 , or C 1 -C 4 ,
  • R represents hydrogen, hydroxy!, C 1 -C 2 alkoxy, C 1 -C 4 , or C 1 -C 3 ,
  • R represents hydrogen, C 1 -C 2 alkoxy or NR R .
  • R and R each independently represent hydrogen, C 1 -C 6 , or
  • R and R each independently represent hydrogen
  • substituent e.g. one, two, three, four or five substituents
  • R and R each independently represent hydrogen
  • substituent e.g. one, two, three, four or five substituents
  • R and R each independently represent hydrogen, cyclopropylcarbonyl, C 1 -C 4 alkoxycarbonyl, or C 1 -C 3 alkyl optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from fluorine, cyclopropyl or oxanyl.
  • substituents e.g. one, two, three, four or five substituents
  • R and R may together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing a further ring heteroatom selected from nitrogen and oxygen (e.g. azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl), wherein the heterocyclic ring is optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from halogen (e.g. fluorine) cyano, C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl and C 1 -C 6 , or C 1 -C 4 , or
  • R 15 represents hydrogen or fluorine, in particular hydrogen. In an embodiment of the invention R represents hydrogen or fluorine, in particular hydrogen.
  • R 10 represents cyclopropylmethyl or 3- fluoropropyl (-CH2CH2CH2F).
  • Examples of compounds of the invention include:
  • the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises reacting a compound of formula (II) or a salt (e.g. hydrochloride salt) thereof,
  • n, X, Y, Z, D, R , R , R and R are as defined in formula (I) above, with a compound of formula ( ⁇ ) or a salt (e.g. hydrochloride salt) thereof,
  • the above process may conveniently be carried out by combining the carboxylic acid of " formula ( ⁇ ) with the amine of formula (III) in the presence bf a coupling reagent suctfas " "
  • EDC l-emyl-3-(3-dimemylanxtnopropyl)carbomimide
  • HOAt 7-aza-l- hydroxybenzotriazole
  • a compound of formula (I) may be converted into another compound
  • R represents an optionally substituted C 1 -C 6 alkyl group by reacting the
  • R is cyclopropyl) in the presence of a base (such as triethylamine) and an aprotic solvent (such as dichloromethane, tetrahydrofuran or acetonitrile).
  • a base such as triethylamine
  • an aprotic solvent such as dichloromethane, tetrahydrofuran or acetonitrile
  • hydrochloride hydrobromide
  • benzenesulphonate besylate
  • saccharin e.g.
  • the compounds of formula (I) are in the form of a hydrochloride salt.
  • compounds of formula (I) may bear one or more radiolabels.
  • radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of formula (I), or may be introduced by coupling the compounds of formula (I) to chelating moieties capable of binding to a radioactive metal atom.
  • radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.
  • any atom specified herein may also be an isotope of said atom.
  • hydrogen encompasses l H, 2 H and 3 H.
  • carbon atoms are to be understood to include 12 C, l3 C and 14 C, nitrogen atoms are to be understood to include 14 N and 1S N, and oxygen atoms are to be understood to include 16 0, 17 0 and I8 0.
  • compounds of formula (I) may be isotopically labelled.
  • an “isotopically labelled" compound is one in which the abundance of a particular nuclide at a particular atomic position within the molecule is increased above the level at which it occurs in nature.
  • Compounds of formula (I) and their salts may be in the form of hydrates or solvates which form an aspect of the present invention.
  • Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
  • Compounds of formula (I) and their salts may be amorphous or in a polymorphic form or a mixture of any of these, each of which forms an aspect of the present invention.
  • the present invention provides a compound offormula (I)-or a. pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy, in particular for the treatment of conditions associated with metabotropic glutamate receptor 7.
  • the present invention also provides the use of a compound of formula (I) or a
  • the present invention still further provides a method of treating a condition associated with metabotropic glutamate receptor 7 which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question.
  • Persons at risk of developing a particular disorder or condition generally include those having a family history of the disorder or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disorder or condition or those in the prodromal phase of a disorder.
  • treat include improvement of the conditions described herein.
  • the terms “treat”, “treatment” and “treating” include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition.
  • the terms “treat”, “treatment,” and “treating” are intended to include therapeutic as well as prophylactic treatment of such conditions.
  • condition As used herein the terms “condition,” “disorder,” and “disease” relate to any unhealthy or abnormal state.
  • conditions associated with metabotropic glutamate receptor 7 includes conditions, disorders and diseases in which the modulation of mGluR7 may provide a therapeutic benefit, examples of which include:
  • Nervous system disorders Parkinson's disease, including dementia associated with Parkinson's disease; Alzheimer's disease; Huntington's Chorea; amyotrophic lateral sclerosis; multiple sclerosis; bipolar disorder; and psychiatric disorders such as schizophrenia, post-traumatic stress disorder, anxiety disorders and depression (e.g. major depressive disorder);
  • Hearing disorders hearing loss and/or tinnitus caused by age, noise or trauma;
  • Schizophrenia is a debilitating psychiatric disorder characterised by a combination of negative symptoms (such as social withdrawal, anhedonia, avolition and apathy) and positive symptoms (including hallucinations, delusions and paranoia) as well as marked cognitive deficits (such as impairment of executive function).
  • the executive function (EF) has been defined as "a set of abilities, which allows us to invoke voluntary control of our behavioral responses.
  • EF includes divided attention and sustained attention, working memory (WM), set-shifting, flexibility, planning, and the regulation of goal directed behavior and can be defined as a brain function underlying the human faculty to act or think not only in reaction to external events but also in relation with internal goals and states" (Orellana G. and Slachevsky A., 2013. Executive Functioning in Schizophrenia. Front. Psychiatry, 4, 35).
  • the present invention also provides a method of treating, a.negative.symptom,- a positive symptom and/or a cognitive deficit associated with a psychiatric disorder, especially schizophrenia, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight fag/kg) to 100 micrograms per kilogram body weight ⁇ g/kg).
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight fag/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Therefore the present invention further provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention still further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
  • carboxymethylcellulose polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred.
  • the pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically acceptable adjuvants, diluents or carriers.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • the suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable diluents and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.
  • compositions of the invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • the pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the compounds of the invention may also be aa ⁇ inistered in ⁇ njunction withjother. compounds- used for the treatment of the above conditions.
  • the invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents for the treatment of one or more of the conditions previously indicated.
  • therapeutic agents may be selected from the following:
  • anti-addiction drugs including, for example, acamprosate, disulfiram, naltrexone and nalmefene for alcohol dependency, and gabapentin, modafinil, topiramate, vigabatrin and baclofen for drug, particularly ***e, addiction;
  • antidepressants such as amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robaizotan, sertraline, sibutramine, tianeptine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine, vortioxetine and equivalents and pharmaceutically active isomers) and/or metabolite(s) thereof;
  • antidepressants such as amitriptyline, amoxapine, bupropion, citalopram, clomipramine,
  • antipsychotics including, for example, amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, brexpiprazole, carbamazepine, cariprazine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, fluphenazine, haloperidol, iloperidone, lamotrigine, loxapine, lurasidone, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutlypiperidine, pimozide, prochlorperazine, quetiapine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trim
  • anxiolytics including, for example, alnespirone, azapirones, benzodiazepines, barbiturates, and equivalents and pharmaceutically active isomers) and/or metabolite(s) thereof.
  • Example anxiolytics include adinazolam, alprazolam, balezepam, _bentazepam, .
  • anticonvulsants including, for example, carbamazepine, valproate, lamotrigine, levetiracetam and gabapentin, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • Alzheimer's therapies including, for example, donepezil, galantamine, memantine, rivastigmine, tacrine, and equivalents and pharmaceutically active isomers) and/or metabolite(s) thereof;
  • Parkinson's therapies including, for example, L-dopa, ropinirole, pramipexole, monoamine oxidase type B (MAO-B) inhibitors such as deprenyl, selegiline and rasagiline, catechol-O-methyl transferase (COMT) inhibitors such as entacapone or tolcapone, adenosine A- 2 inhibitors, dopamine re-uptake inhibitors, NMDA antagonists, Nicotine agonists, and Dopamine agonists and inhibitors of neuronal nitric oxide synthase, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • MAO-B monoamine oxidase type B
  • COMP catechol-O-methyl transferase
  • entacapone or tolcapone adenosine A- 2 inhibitors
  • dopamine re-uptake inhibitors NMDA antagonists
  • Nicotine agonists and Do
  • migraine therapies including, for example, almotriptan, amantadine, botulinum toxin A, bromocriptine, butalbital, cabergoline, dichloralphenazone, dihydroergotamine, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, topiramate, zolmitriptan, and zomitriptan, and equivalents and
  • (ix) stroke therapies including, for example, abciximab, activase, citicoline,
  • urinary incontinence therapies includingjibr example, darafenacin, duloxetine, - falvoxate, mirabegron, oxybutynin, propiverine, robalzotan, solifenacin, and tolterodine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • neuropathic pain therapies including, for example, capsaicin, gabapentin, lidoderm, and pregabalin, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • nociceptive pain therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, and paracetamol, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • insomnia therapies including, for example, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, eszopiclone, etomidate, glutethimide, halazepam, hydroxyzine, lorediplon, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ralmeteon, roletamide, suvorexant, triclofos, secobarbital, zaleplon, and Zolpidem, zopiclone and equivalents and pharmaceutically active isomers) and/or metabolite(s) thereof; (xiv) mood stabilizers including, for example,
  • SHT1B ligands such as, for example, compounds disclosed in WO 99/05134 and WO 02/08212;
  • alpha 7 nicotinic agonists such as, for example, compounds disclosed in
  • (xix) delta opioid agonists such as, for example, compounds disclosed in WO 97/23466 and WO 02/094794.
  • Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges.
  • Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated and at 300.3K, 298.2K or 293K unless otherwise stated; the chemical shifts ( ⁇ ) are reported in parts per million.
  • Spectra were recorded using a Bruker (trade mark) 400 A VANCE instrument fitted with a 5mm BBFO probe with instrument controlled by Bruker TopSpin 2.1 software, or by a Bruker 400 AVANCE- ⁇ HD instrument fitted with a 5mm BBFO smart probe or a 5mm BBFO probe with instrument controlled by Bruker TopSpin 3.2 software, or by a Bruker 400 AVANCE-III instrument fitted with a 5mm BBFO probe with instrument controlled by Bruker Topspin 3.0 software or by a Bruker 300MHz AVANCE II instrument fitted with a 5mm DUL probe with instrument controlled by Bruker TopSpin 1.3 software, or 5mm BBFO probe controlled by Bruker Topspin 3.2 software.
  • Ultra Performance Liquid Chromatography with UV (photodiode array) detection over a wide range of wavelengths, normally 220-450 run, using a Waters (trade mark) Acquity UPLC system equipped with Acquity UPLC BEH, HSS or HSS T3 CI 8 columns (2.1mm id x 50mm long) operated at 50 or 60 °C.
  • Mobile phases typically consisted of acetonitrile mixed with water containing either 0.1% formic acid, 0.1% trifluoroacetic acid (TFA) or 0.025% ammonia.
  • Mass spectra were recorded with a Waters SQD single.quadrupole mass-spectrometer using atmospheric pressure ionisation.
  • Preparative HPLC was performed using Agilent Technologies (trade mark) 1100 Series system or a Waters autopurification LC/MS system or a Shimadzu semi prep HPLC system, typically using Waters 19 mm id x 250 mm long CI 8 columns such as XBridge (trade mark) or SunFire (trade mark) 5 um materials at room temperature.
  • Mobile phases typically consisted of acetonitrile mixed with water containing either 0.1% formic acid or 0.1% ammonia, unless otherwise stated.
  • Super Critical Fluid Chromatography (SFC) chiral separations were performed on a Waters prep30/MS system, using a flow rate of 30 mL/min, temperature of 40 °C and a pressure of 100 bar.
  • Mobile phases typically consisted of supercritical C0 2 and a polar solvent such as methanol, ethanol or isopropanol. Column type and eluent are detailed for individual examples.
  • 'Room temperature' as used in the present specification, means a temperature in the range from about 18 °C to about 25 °C.
  • BINAP 2,2 -Bis(diphenylphosphino)- 1 , 1 '-binaphthalene
  • HATU 1 -[Bis(dimethylamino)methylene]- 1H- 1 ,2,3-triazolo[4,5-6]pyridinium 3- oxid hexafluorophosphate
  • HOAt 1 -Hydroxy- 7-azabenzotriazole
  • NFSI N-Fluorobenzenesulfonimide
  • T3P Propylphosphonic Anhydride
  • the reaction was heated to 60 °C for 5 h then stirred at room temperature for 18 h.
  • the suspension was filtered through diatomaceous earth and concentrated in vacuo.
  • the crude product was purified by column chromatography on silica, eluted with 0- 10% EtO Ac/petroleum ether to afford the title compound.
  • T3P 50% in EtOAc
  • TEA 0.332 mL, 2.446 mmol
  • 2-cyclopropanecarbonyl- 1,2,3 ,4-tetrahydroisoquinoline-l- carboxylic acid (0.200 g, 0.815 mmol
  • fer/-butyl ((lS,2S)-2-amino-2,3-dihydro-1H- inden-l-yl)carbamate (0.202 g, 0.815 mmol) in DCM (5 mL) and stirred for 30 min.
  • 2-tert-butyl 4-methyl l,2,3,4-tetrahydroisoquinoline-2,4- dicarboxylate 1.5 g, 5.15 mmol
  • THF:H 2 0 (1:1) 40 mL
  • LiOH 0.634 g, 15.4 mmol
  • the reaction mixture was then stirred at 80 °C for 30 min.
  • the reaction mixture was cooled to room temperature, diluted with cold water and acidified with IN HC 1 to pH 4.
  • Aqueous layer was extracted with EtOAc.
  • the organic layer was washed with brine, dried over sodium sulphate and concentrated in vacuo to afford the title compound.
  • Sodium hydride 60 % dispersion in mineral oil, 0.6S1 g, 27.1 mmol
  • a cooled (0 °C) solution of methyl 2-oxo-2,4-dihydro-1H-3,l-benzoxazine-4-carboxylate (Intermediate 23, 2.81 g, 13.6 mmol) in DMF (100 mL) under nitrogen.
  • the reaction was stirred at 0 °C for 10 min.
  • Methyl iodide (1.27 mL, 20.3 mmol) was added to the reaction mixture.
  • the reaction was stirred at 0 °C for 30 min, then allowed to warm to room temperature and stirred for 18 h.
  • the reaction was diluted with sat. aqueous NH 4 C 1 and extracted with EtOAc. The phases were separated, the organic washed twice with 50% sat. aqueous NaCl, dried (Na 2 S0 4 ) and concentrated in vacuo.
  • the crude product was purified by column chromatography on silica, eluted with 0-100% EtO Ac/petroleum ether to afford the title compound.
  • Lithium hydroxide (0.022 g, 0.94 mmol) was added to a solution of methyl l-methyl-2- oxo-2,4-(hhydro-1H-3,l-benzoxazine-4-carboxylate (0.200 g, 0.90 mmol) in MeOH (4 mL) and water (1 mL). The reaction was stirred at room temperature overnight. Further lithium hydroxide (0.06 g, 0.2S mmol) was added to the reaction mixture. The reaction was stirred at room temperature for a further 2 h. The mixture was concentrated in vacuo to afford the title compound.
  • Manganese(in) acetate dihydrate (1.104 g, 4.12 mmol) was added to a solution of diethyl 2-(2-(indolin-l-yl)-2-oxoethyl)malonate (0.263 g, 0.824 mmol) in acetic acid (20 mL). The mixture was heated at reflux in air for 3 h. The mixture was concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 30-100% EtOAc/petroleum ether to afford the title compound.
  • Manganese(in) acetate dihydrate (5.97 g, 22.3 mmol) was added to a solution of 1,3- diethyl 2- ⁇ [(2-fluorophenyl)(methyl)carbamoyl]methyl ⁇ propanedioate (3.62 g, 11.1 mmol) in acetic acid (30 mL).
  • the mixture was heated at 100 °C in air for 30 rain, then at reflux for 1 hour. After cooling, the reaction mixture was filtered, washing with diethyl ether. The filtrate was concentrated in vacuo and dissolved in ethanol (30 mL).
  • Manganese(III) acetate dihydrate (2.36 g, 8.80 mmol) was added to a solution of 1,3- diethyl 2- ⁇ [(3,5-difluorophenyl)(methyl)carbamoyl]methyl ⁇ propanedioate (1.51 g, 4.40 mmol) in acetic acid (15 mL). The mixture was heated at 120 °C in air for 30 min. After cooling, the reaction mixture was concentrated in vacuo.
  • 1,3-dimethyl propanedioate (2.72 g, 20.6 mmol) was added drop wise over 5 min to an ice- water bath cooled mixture of 4-acetamidobenzene-l-sulfonyl azide (5.0 g, 20.8 mmol) and TEA (3.07 mL, 22.0 mmol) in MeCN (30 mL).
  • the reaction was stirred at 0 °C for 1 hour, then allowed to warm to room temperature and stirred overnight.
  • the reaction mixture was filtered, washing with a mixture of hexane and diethyl ether (1:1) and the filtrate concentrated in vacuo.
  • the residue was stirred in a mixture of hexane and diethyl ether (1:1, 70 mL) for 5 min and then filtered.
  • the filtrate was concentrated in vacuo to afford the title compound.
  • MeOH 1,3-dimethyl 2-diazopropanedioate
  • MeOH 1,3-dimethyl 2-diazopropanedioate
  • MeOH MeOH
  • benzyl(methyl)amine 0.100 g, 0.82 mmol
  • silver(I) oxide 0.21 g, 0.091 mmol
  • pentamethylcyclopentadienylrhodium(III) chloride dimer 0.013 g, 0.021 mmol
  • T3P (50% in EtOAc) (0.272 mL, 0.457 mmol) was added to a stirred solution of TEA (0.093 mL, 0.685 mmol), 6-fluoro-2-[(2-methyl-l,3-thiazol-4-yl)methyl]-l,2,3,4- tetrahydroisoquinoline-1-carboxylic acid (0.070 g, 0.228 mmol) and tert-butyl ((lS,2S)-2- amino-2,3-dihydro-1H-inden-l-yl)carbamate (0.057 g, 0.228 mmol) in DCM (2 mL) and stirred for 30 min.
  • Reaction 1 2,2- difluoroethyl methanesulfonate (0.298 g, 1.862 mmol) was added to a stirred suspension of ethyl 1,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (0.300 g, 1.241 mmol) and K2CO3 (0.343 g, 2.482 mmol) in MeCN (10 mL) and heated to 60°C for 18h.
  • Reaction 2 2,2-difluoroethyl methanesulfonate (0.331 g, 2.069 mmol) was added to a vial containing a solution of ethyl 1,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (0.100 g, 0.414 mmol) and DEPEA (0.361 mL, 2.069 mmol) in MeCN (2 mL). The reaction was heated in the microwave to 160°C for 30 min. The reaction was heated for a further 30 min at 160°C.
  • Reaction 3 l,l-difluoro-2-iodoethane (1.00 g, S.21 mmol) was added to a vial containing a suspension of ethyl 1,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (0.2S2 g, 1.042 mmol) and DIPEA (0.910 mL, S.21 mmol) in MeCN (S mL), and this was heated in the microwave to 160 °C for 30 min.
  • reaction mixtures of the three reactions were combined and partitioned between DCM and water.
  • the organic phase was dried (phase separator) and concentrated in vacuo prior to purification by column chromatography on silica, eluted with 0 - 50% EtOAc/petroleum ether to afford the title compound.
  • T3P (50% in EtOAc) (3.22 mL, 5.41 mmol) was added to a solution of 2-(/eri- butoxycarbonyl)-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (1.00 g, 3.61 mmol),(trans)- l-methoxy-2,3-dihydro-1H-inden-2-amine (Intermediate 2, 0.647 g, 3.97 mmol) and TEA (0.754 mL, 5.41 mmol) in DCM (20 mL). The reaction was stirred at room temperature for 1.5 h. The mixture was partitioned between DCM and saturated NaHCCh, dried (phase separator) and concentrated in vacuo.
  • NBS (25.2 g, 141 mmol) was added portion wise to a solution of 1H-indene (15.0 mL, 129 mmol) in THF (150 mL) and water (150 mL). The reaction was stirred at room temperature over 4 days open to the air. The mixture concentrated in vacuo then partitioned between EtOAc and water. The phases were separated and the aqueous extracted twice with EtOAc. The combined organics were washed with saturated Na2S 2 0 3 , brine, dried (MgSC ⁇ ) and concentrated in vacuo. The crude material was triturated with diethyl ether to afford the title compound.
  • the reaction mixture was heated to 60°C for a further 24 h. After that time, the mixture was cooled to room temperature and poured onto water. The mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried (Na 2 S0 4 ), filtered and concentrated in vacuo. The crude material was purified by column chromatography on silica, eluted with 10% EtOAc/hexane to afford the title compound.
  • the mixture was partitioned between ethyl acetate and saturated NaHCCh. The phases were separated and the aqueous extracted with ethyl acetate. The combined organics were dried (phase separator) and concentrated in vacuo. The crude product was loaded onto a cation exchange cartridge, washed with methanol and eluted with 2M ammonia/methanol solution then concentrated in vacuo to the title compound.
  • T3P (50% in EtOAc) (0.344 mL, 0.392 mmol) was added to a solution of 1 -methyl- 1,2,3,4- tetrahydroquinoline-4-carboxylic acid (0.05 g, 0.261 mmol), 2,3-dihydro-1H-inden-2- amine (0.037 mL, 0.288 mmol) and TEA (0.055 mL, 0.392 mmol) in DCM (2 mL) under nitrogen. The reaction was stirred at room temperature for 1.5 h. The mixture was diluted with DCM and washed with saturated bicarb, dried (phase separator) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC to afford the title compound.
  • HATU (0.120 g, 0.315 mmol) was added to a solution of l-methyl-2-oxo-l,2,3,4- tetrahydroquiooline-4-carboxylic acid (0.062 g, 0.3 mmol) and DEPEA (0.0S8 mL, 0.330 mmol) in DMF (0.5 mL). The mixture was stirred for 5 min, then 2,3-dihydro-1H-inden-2- amine (0.040 g, 0.3 mmol) was added and stirring continued for 5 min. The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound.
  • Example 2 N-(2,3-dihydro- 1 H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3 ,4-tetrahydroquinoline-4- carboxamide (Example 2) was purified by chiral SFC (40% isopropanol, ID column) to afford the title compounds. Absolute stereochemistry confirmed by X-ray crystallography. Example 4 - 1" eluting peak
  • Example 15 l-methyl-N-[(lS,2S)-l- ⁇ [(oxan-4-yl)methyl]amino ⁇ -2,3-dihydro-1H- inden-2-yl]-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide
  • Example 23 N-(2,3-dihydro- 1 H-inden-2-yl)-2-(2-methoxyacetyl)- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 - carboxamide (Example 23) was purified by chiral SFC (40% isocratic IP A, IA column) to afford the title compounds.
  • Example 28 2-(cyclopropylmethyl)-N-(2 r 3-dihydro-1H-inden-2-yl)-l,2,3,4- tetrahydroisoquinoline-l-carboxamide
  • the reaction mixture was diluted with MeOH and loaded onto a cation exchange cartridge, washed with MeOH and eluted with 2M NH 3 /MeOH solution then concentrated in vacuo with the washings.
  • the crude product was purified by reverse phase chromatography on CI 8 silica eluted with 5-95% MeCN/water (with 0.05% NH 3 ) to afford the title compound.
  • Example 33 N-[(1S,2S)-l-amino-2,3-dihvdro-1H-inden-2-vll-6-chloro-2- cyclopropanecarbonyl-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomer)
  • Example 30 N-[( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]-2-cyclopropanecarbonyl- 1 ,2,3,4- tetrahydroisoquinoline-l-carboxamide (Example 30) was purified by chiral SFC (34% isocratic EtOH+0.5% DEA, Lux-C 4 column) to afford the title compounds.
  • TEA (0.138 g, 1.3 mmol) was added to a solution of N-(2,3-dihydro-1H-inden-2-yl)- l,2,3,4-tetrahydroisoquinoline-4-carboxamide hydrochloride salt (Intermediate 10, 0.100 g, 0.3 mmol) in DCM (3 mL) and stirred for 20 min. Cyclopropyl carbonyl chloride (0.0S3 g, 0.S1 mmol) was added at 0 °C and stirred for 3 h at room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude compound was purified by column chromatography on silica, eluted at 0-80% EtOAc/hexane to afford the title compound.

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Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein n, X, Y, Z, D, R1, R2, R3, R4, R12, R15nd R16 are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them and their use as modulators of mGluR7.

Description

DESCRIPTION
Title of Invention : INDANE DERIVATIVES USEFUL AS MODULATORS OF MGLUR7 The present invention relates to indane derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly for use in treating disorders associated with changes in one or both of the glutamatergic and GABAergic signalling pathways regulated in full or in part by metabotropic glutamate receptor 7 (mGluR7).
WO 2008/151211 discloses substituted benzoylamino-indan-2-carboxylic acids and related compounds which have CXCR5 inhibitory activity.
L-Glutamate is the major neurotransmitter in the mammalian central nervous system and activates both ionotropic and metabotropic glutamate receptors. L-Glutamate plays a central role in numerous physiological functions such as learning and memory ( 1 ). sensory perception, development of synaptic plasticity, motor control, respiration and regulation of cardiovascular function. Thus an imbalance in glutamatergic neurotransmission often underlies many neuropathological conditions.
The metabotropic glutamate receptors arc a family of G protein-coupled receptors that have been divided into three groups on the basis of sequence homology, putative signal transduction mechanisms and pharmacologic properties. Group I includes niGluRl and mGluR5 and these receptors have been shown to activate phospholipase C. Group II includes mGluR2 and mGluR3 whilst Group III includes mGluR4. mGluR6. mGluR7 and mGluR8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. mGluR7 is an inhibitory GPCR expressed pre-synaptically at the synaptic cleft on
GABAergic and glutamatergic neurons. Depending on the location it can inhibit or disinhibit synaptic activity and can therefore be seen as a modulator of neuronal function. Therefore. mGluR7 modulators would be expected to be useful in treating a wide variety of neurological and psychiatric disorders such as Parkinson's disease (2. 3); dementia associated with Parkinson's disease (3. 4); Alzheimer's disease (5); Huntington's Chorea (6); amyotrophic lateral sclerosis and multiple sclerosis; bipolar disorder (6. 7); psychiatric
RECTIFIED SHEET (RULE 91) ISA/EP diseases such as schizophrenia, post-traumatic stress disorder, anxiety disorders and depression (1,4, 6, 8-11); and addiction. They may also be useful in treating age-related hearing loss/tinnitus (12).
There is a need for treatment of the above conditions and others described herein with compounds that are mGluR7 modulators. The present invention provides modulators of mGluR7.
In accordance with the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof
Figure imgf000003_0001
wherein
n is O or 1;
X, Y and Z have the following meanings:
(i) Z is >α¼, >CHCH3 or >0, Y is >CH2 or >C=O and X is >NR5 where R5 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or
5 4
C3-C6 cycloalkylmethyl or, alternatively, R and R may together form a C2-C3 alkylene chain, or
(ii) Z is >CHR6a, X is >C=O and Y is >NR6b where R6a represents hydrogen, (halo)C1-C6 alkyl, (halo)C3-C6 cycloalkyl or (halo)phenyl and R represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkylmethyl, or
(iii) Z is >CH2, X is >CH2 and Y is >NR7, >NC(O)R7 or >NS02R? where
7
R represents either a C3-C6 cycloalkyl group, or, a C1-C6 alkyl group optionally substituted by at least one substituent independently selected from C1-C6 alkoxy and C3-C6 cycloalkyl, or
(iv) Z is >C=O, X is >CH2 and Y is >NR7, or
(v) X is >CH2, Y is >CH2 and Z is >NR8, >NC(O)R9, >NC(O)NHR9 or
9 8
>NS02R where R represents hydrogen or a C1-C6 alkyl group optionally substituted by at least one substituent independently selected from halogen, C3-C6 cycloalkyl and a 5- to 6-membered saturated or unsaturated heterocycle, wherein the heterocycle is optionally substituted by at least one
9
C1-C3 alkyl substituent, and R represents a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, or a C\-C$ alkyl group optionally substituted by at least one substituent independently selected from halogen, cyano, C1-C6 alkoxy and C3-C6 cycloalkyl, or
(vi) X is >CH2, Y is >C=O and Z is >NR10 where R10 represents a C1-C6 alkyl group optionally substituted by at least one substituent independently selected from halogen, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl or a S- to
6-membered saturated or unsaturated heterocycle;
1 2 3
R , R and R each independently represent hydrogen or halogen;
4 5
R represents hydrogen, halogen or is joined to R as defined above;
D represents >C(RJ V or, when Z is >CH2, D may additionally represent a nitrogen atom;
R11 represents hydrogen, halogen or C1-C6 alkyl; 12
R represents hydrogen, hydroxyl, C1-C6 alkoxy, C1-C6 alkylsulphonyl or
NR,3R14;
13 14
R and R each independently represent hydrogen, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, C1-C6 alkoxycarbonyl, or C1-C6 alkyl optionally substituted by at least one substituent independently selected from halogen, CyC$ cycloalkyl or a S- to 6- membered saturated or unsaturated heterocycle, or
13 14
R and R together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing a further ring heteroatom selected from nitrogen and oxygen, wherein the heterocyclic ring is optionally substituted by at least one substituent independently selected from halogen, cyano, C1-C6 alkyl and
C1-C6 alkoxy;
R15 represents hydrogen or halogen; and
R16 represents hydrogen or halogen.
In the context of the present specification, unless otherwise stated, an "alkyl" substituent group or an "alkyl" moiety in a substituent group (such as an alkoxy group) may be linear or branched. Examples of C1-C6 alkyl groups/moieties include methyl, ethyl, propyl,
2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l -butyl, 2-methyl-3- butyl, 2,2-dimethyl-l -propyl, 2-methyl-pentyl, 3-methyl-l -pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyI, 2-ethyl-l -butyl, n-butyl, tert-butyl, n-pentyl, and n-hexyl.
A "cycloalkyl" substituent group or a "cycloalkyl" moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 8 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "halogen" includes fluorine, chlorine, bromine and iodine. A "haloalkyl", "halocycloalkyl" or "halophenyl" substituent group/moiety comprises at least one halogen atom, e.g. one, two, three, four or five halogen atoms. Examples of such groups/moieties include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4-fluorocyclohexyl and 4-fluorophenyl.
A "5- to 6-membered saturated or unsaturated heterocycle" means a saturated, partially unsaturated or fully unsaturated hydrocarbyl group containing 5 to 6 ring atoms in which one or more (e.g. one, two, three or four) ring carbon atoms are replaced by a
corresponding number of ring heteroatoms independently selected from nitrogen, oxygen and sulphur, particularly nitrogen and oxygen. Examples of such heterocycles include tetrahydrofuranyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl (oxanyl), morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furyl, furazanyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl and tetrazinyl.
13 14
When R and R form a 4- to 6-membered saturated heterocyclic ring which is substituted, it should be understood that the substituent(s) may be attached to any suitable ring atom.
For the purposes of the present invention, where a combination of moieties is referred to as one group, for example, cycloalkylmethyl or alkoxycarbonyl, the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule.
When any chemical group or moiety in formula (I) is described as substituted, it will be appreciated that the number and nature of substituents will be selected so as to avoid sterically undesirable combinations.
Further, it will be appreciated that the invention does not encompass any unstable ring or other structures (e.g. >NCH2N<, >NCH20- or aminal groupings of the type
>C(NRaRb)(NRcRd)) or any 0-0 or S-S bonds. In a preferred embodiment of the invention, n is 0. In one embodiment, R , R and R each independently represent hydrogen, fluorine or chlorine.
1 2 3
In another embodiment, R , R and R each represent hydrogen.
1 2 3
In still another embodiment, one of R , R and R represents halogen and the remaining two represent hydrogen.
3 1 2
In yet another embodiment, R represents halogen (particularly fluorine) and R and R both represent hydrogen.
1 2 3
In a further embodiment, two of R , R and R independently represent halogen and the remaining one represents hydrogen.
1 3 2 In a still further embodiment, R and R each independently represent halogen and R represents hydrogen.
4
In an embodiment of the invention, R represents hydrogen or halogen.
4
In another embodiment, R represents hydrogen.
X, Y and Z have the following meanings:
(i) Z is >CH2, >CHCH3 or >0, Y is >CH2 or >C=O and X is >NR5 where R5 represents hydrogen, C1-C6, or C1-C4, or C1-C2 alkyl, C3-C6, or C4-C6, or C5-C6 cycloalkyl or C3-C6, or C4-C6, or
5 4
C5-C6 cycloalkylmethyl or, alternatively, R and R may together form a C2-C3 alkylene chain, or (ii) Z is >CHR6a, X is >C=O and Y is >NR6b where R6a represents hydrogen,
(halo)C1-C6, or C1-C4, or C1-C2 alkyl, (halo)C3-C6, or C4-C6, or
6b
C5-C6 cycloalkyl or (halo)phenyl and R represents hydrogen, C1-C6, or
C1-C4, or C1-C2 alkyl, C3-C6, or C4-C6, or C5-C6 cycloalkyl or
C3-C6, or C4-C6, or C5-C6 cycloalkylmethyl, or
(iii) Z is >CH2, X is >CH2 and Y is >NR7, >NC(O)R7 or >NS02R7 where
7
R represents either a C3-C6, or C4-C6, or C5-C6 cycloalkyl group, or, a
C1-C6, or C1-C4, or C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from
C1-C6, or C1-C4, or C1-C2 alkoxy and C3-C6, or C4-C6, or
C5-C6 cycloalkyl, or
(iv) Z is >C=O, X is >CH2 and Y is >NR7, or
(v) X is >CH2, Y is >CH2 and Z is >NR8, >NC(O)R9, >NC(O)NHR9 or
9 8
>NS02R where R represents hydrogen or a C1-C6, or C1-C4, or
C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from halogen, C3-C6, or C4-C6, or C5-C6 cycloalkyl and a 5- to 6-membered saturated or unsaturated heterocycle, wherein the heterocycle is optionally substituted by at least one C1-C3 alkyl substituent (e.g. one, two or three
C1-C3 alkyl substituents which may be the same as, or different to, one
9
another), and R represents a C\-CQ, or C1-C4, or C1-C2 alkoxy group, a C3-C6, or C4-C6, or C5-C6 cycloalkyl group, or a C1-C6, or C1-C4, or
C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from halogen, cyano, C1-C6, or C1-C4, or C1-C2 alkoxy and C3-C6, or C4-C6, or C5-C6 cycloalkyl, or (vi) X is >CH2, Y is >C=O and Z is >NR where R represents a C1-C6, or
C1-C4, or C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from halogen, C1-C6, or C1-C4, or C1-C2 alkoxy, C3-C6, or C4-C6, or C5-C6 cycloalkyl, phenyl or a 5- to 6-membered saturated or unsaturated heterocycle.
In an embodiment of the invention, R5 represents hydrogen, C1-C2 alkyl, cyclopropyl or cyclopropylmethyl.
6a
In an embodiment, R represents hydrogen, C1-C2 alkyl, cyclopropyl or (halo)phenyl.
6a
In anotherembodiment,-R- - represents hydrogen or halophenyl (e:g: fluorophenyl):
In one embodiment, R6b represents hydrogen, C1-C2 alkyl, cyclopropyl or
cyclopropylmethyl.
According to a further embodiment, R6b represents hydrogen or, preferably, methyl. 7
In one embodiment, R represents either a cyclopropyl group, or, a C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from C1-C2 alkoxy and cyclopropyl.
7
In another embodiment, R represents either a cyclopropyl group, or, a methyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from methoxy and cyclopropyl. In an embodiment, R represents hydrogen or a C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from fluorine, cyclopropyl and a 5- to 6-membered saturated or unsaturated heterocycle, wherein the heterocycle is optionally substituted by at least one C1-C3 alkyl substituent (e.g. one, two or three C1-C3 alkyl substituents which may be the same as, or different to, one another). g
In another embodiment, R represents hydrogen or a C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from fluorine, cyclopropyl and a 5- to 6-membered unsaturated heterocycle (e.g. thiazolyl, pyrazolyl or pyrimidinyl), wherein the heterocycle is optionally substituted by at least one methyl substituent.
9
In one embodiment, R represents a C1-C4 or C1-C2 alkoxy group, a cyclopropyl group, or a C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from fluorine, cyano,
C1-C2 alkoxy and cyclopropyl.
9
According to a further embodiment, R represents a C1-C4 or C1-C2 alkoxy group, a cyclopropyl group, or a C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from fluorine, cyano and methoxy.
In an embodiment of the invention, R*° represents a C1-C3 alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from fluorine, C1-C2 alkoxy, cyclopropyl, phenyl or a 5- to 6-membered saturated or unsaturated heterocycle. In another embodiment, R represents a C1-C3 alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from fluorine, methoxy, cyclopropyl, phenyl or a 5- to 6-membered saturated or unsaturated heterocycle (e.g. pyridinyl, oxanyl or pyrrolidinyl), specific examples of which are cyclopropylmethyl and 3-fluoropropyl (-CH2CH2CH2F).
In an embodiment of the invention, D represents >C(R )- where R represents hydrogen, halogen or C1-C6, or C1-C4, or C1-C2 alkyl.
In one aspect, R represents hydrogen, halogen or C1-C2 alkyl such that D represents, for example, >CH, >CF or >C(CH3).
R represents hydrogen, hydroxy., C1-C6, or C1-C4, or C1-C2 alkoxy, C1-C6, or C1-C4,
13 14
or C1-C2 alkylsulphonyl or NR R .
In one embodiment, R represents hydrogen, hydroxy!, C1-C2 alkoxy, C1-C4, or C1-C3,
13 14
or C1-C2 alkylsulphonyl or NR R .
In another embodiment, R represents hydrogen, C1-C2 alkoxy or NR R .
In one embodiment R and R each independently represent hydrogen, C1-C6, or
C1-C4, or C1-C2 alkylcarbonyl, C3-C6, or C4-C6, or C5-C6 cycloalkylcarbonyl,
C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl, or C1-C6, or C1-C4, or C1-C2 alkyl optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from halogen, C3-C6, or C4-C6, or C5-C6 cycloalkyl or a 5- to 6- membered saturated or unsaturated heterocycle. In a particular aspect, R and R each independently represent hydrogen,
C1-C4, or C1-C3, or C1-C2 alkylcarbonyl, cyclopropylcarbonyl,
C1-C4, or C1-C3, or C1-C2 alkoxycarbonyl, or C1-C4, or C1-C3, or C1-C2 alkyl optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from halogen, cyclopropyl or a 5- to 6-membered saturated or unsaturated heterocycle.
13 14
In a further aspect, R and R each independently represent hydrogen,
C1-C2 alkylcarbonyl, cyclopropylcarbonyl, C1-C4, or C1-C3, or C1-C2 alkoxycarbonyl, or C1-C4, or C1-C3, or C1-C2 alkyl optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from fluorine, cyclopropyl or a 5- to 6-membered saturated heterocycle.
13 14
In a still further aspect, R and R each independently represent hydrogen, cyclopropylcarbonyl, C1-C4 alkoxycarbonyl, or C1-C3 alkyl optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from fluorine, cyclopropyl or oxanyl.
13 14
Alternatively, R and R may together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing a further ring heteroatom selected from nitrogen and oxygen (e.g. azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl), wherein the heterocyclic ring is optionally substituted by at least one substituent (e.g. one, two, three, four or five substituents) independently selected from halogen (e.g. fluorine) cyano, C1-C6, or C1-C4, or C1-C2 alkyl and C1-C6, or C1-C4, or
C1-C2 alkoxy.
In an embodiment of the invention R15 represents hydrogen or fluorine, in particular hydrogen. In an embodiment of the invention R represents hydrogen or fluorine, in particular hydrogen.
A preferred subset of compounds of formula (I) are those in which n is 0, X is >€¾, Y is >C=O and Z is >NR10. In one embodiment, R10 represents cyclopropylmethyl or 3- fluoropropyl (-CH2CH2CH2F).
Examples of compounds of the invention include:
N-(2,3-dihydro- 1 H-inden-2-yl)- 1 -methyl- 1 ,2,3 ,4-tetrahydroquinoline-4-carboxamide;
N-(2,3-dihydro- 1H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3,4-tetrahydroquinoline-4- carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-2-methyl-l-oxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide;
(4S)-N-(2,3-dihydro- 1H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3,4-tetrahydroquinoline-4- carboxamide;
(4R)-N-(2,3-dihydro- 1H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3,4-tetrahydroquinoline-4- carboxamide;
(4S)-N-((/ra/w)- 1 -methoxy-2,3-dihydro- 1 H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3 ,4- tetrahydroquinoline-4-carboxamide;
(4S)-N-((trans)- 1 -ethoxy-2,3-dihydro- 1 H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3,4- tetrahydroquinoline-4-carboxamide;
tert-butyl N-[(lS,2S)-2-(l-methyl-2-oxo-l,2,3,4-tetrahydroqumoline4-amido)-2,3 dihydro- 1 H-inden- 1 -yl]carbamate;
N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide;
1 -methyl-2-oxo-N-[( 1 S,2S)- 1 -[(propan-2-yl)amino]-2,3-dihydro- 1 H-inden-2-yl]- 1 ,2,3 ,4-tetrahydroquinoline-4-carboxamide;
N-[(lS,2S>l-[(cyclopropylme*yl)arr^
1 ,2,3 ,4-tetrahydroquinoline-4-carboxamide;
l-methyl-N-[(lS,2S)-l-{[(oxan-4-yl)me*yl]armno}-2,3-dihydro-1H-m^
1 ,2,3 ,4-tetrahydroquinoline-4-carboxamide; N-[(lS,2S)-l-cyclopropaneamido-2,3-dihydro-1H-inde
tetrahydroquinoline-4-carboxamide;
N-[(lS,2S)-l-(dimemylamino)-2,3-dihydro^^
tetrahydroquinoline-4-carboxamide;
N-(2,3-dihydro-1H-inden-2-yl>l-ethyl-2-oxo-l,2,3,44etrahydroquinoline-4^ carboxamide
ter/-butyl l-[(2,3-dihydro-1H-inden-2-yl)carb.-moyl]-l,2,3,4-te1rahydroisoquinoline-2- carboxylate;
N-(2,3-dihydro-1H-inden-2-yl)- 1 ,2,3, 4-tetrahydroisoquinoline- 1 -carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-2-(2-methoxyacetyl)- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 - carboxamide;
2-cyclopropanecarbonyl-N-(2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide;
N2-cyclopropyl-N 1 -(2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 ,2- dicarboxamide;
2-(cyclopropylmemyl)-N-(2,3-dihydro-1H-inden-2-yl)-l,2,3,4-tetrahydroisoquinoline- 1 -carboxamide;
2-(cyclopropanesulfonyl)-N-(2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3 ,4- tetrahydroisoquinoline- 1 -carboxamide;
N-[(l S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]-2-cyclopropanecarbonyl- 1 ,2,3 ,4- tetrahydroisoquinoline- 1 -carboxamide;
N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-2-cyclopropanecarbonyl-6-fluoro- 1,2,3,4-tetrahydroisoquinoline-l-carboxamide;
N-[( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]-6-chloro-2-cyclopropanecarbonyl- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide;
2-cyclopropanecarbonyl-N-(2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3 ,4-tetrahydroisoquinoline- 4-carboxamide;
N-(2,3-dmydro-1H-inden-2-yl)-2-(2-meto^^
carboxamide;
2-(2-cyclopropylacetyl)-N-(2,3-(hhydro-1H-inden-2-yl)-l,2,3,4-tetrahyd^
4-carboxamide;
2-(cyclopropanesulfonyl)-N-(2,3-dihydro-1H-inden-2-yl)-l,2,3,4- tetrahydroisoquinoline-4-carboxamide; 2-(cyclopropylmethyl)-N-(2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3,4-tetrahydroisoquinoline- 4-carboxamide;
N-(2,3-dihycko-1H-inden-2-yl)-2-meftyl-3- carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-2-(2-methoxyethyl)-3-oxo-l>2,3>4- tetrahydroisoquinoline- 1 -carboxamide;
2-(cyclopropylmethyl)-N-(2,3-dihydro- 1 H-inden-2-yl)-3-oxo- 1 ,2,3,4- tetrahydroisoquinoline- 1 -carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-2-ethyl-3-oxo- 1 ,2,3,4-tetrahydroisoquinoline- 1 - carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-3-oxo-2-[(p^
tetrahydroisoquinoline- 1 -carboxamide;
N-(2,3-dihydro- 1H-inden-2-yl)-2-[(oxan-4-yl)methyl]-3-oxo- 1 ,2,3,4- tetrahydroisoquinoline- 1 -carboxamide;
_. N_{2,3-dihydro-m^
tetrahydroisoquinoline- 1 -carboxamide;
N-[( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]-2-(cyclopropylmethyl)-3-oxo- 1 ,2,3 ,4- tetrahydroisoquinoline- 1 -carboxamide;
N-[( 1 S,2S>1 -amino-2,3-dihydro- 1H-iden-2-yl]-2-benzyl-3-oxo- 1 ,2,3,4- tetrahydroisoquinoline- 1 -carboxamide;
N-[( 1 S,2S> 1 -amino-2,3-dihydro- 1 H-inden-2-yl]-2-[(oxan-4-yl)methyl]-3-oxo- 1 ,2,3 ,4- tetrahydroisoquinoline- 1 -carboxamide;
N-(2,3-dmydro-1H-inden-2-yl)-7-fluoro-2-oxo-l^^
carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-7-fluoro- 1 -methyI-2-oxo- 1 ,2,3,4-tetrahydroquinoline-4- carboxamide;
N-(2,3-dmydro-1H-inden-2-yl)-7-fluoro-l,4-<iimethyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide;
N-(2,3-dmy<ko-1H-inden-2-yl)-6-fluoro-2-oxo-l,2,3,4-tetrahydroq
carboxamide;
N-(2,3-dmydro-1H-inden-2-yl)-6^fluoro-l-memyl-2-oxo-l,2,3,4-tetrahy(lroqum carboxamide; N-(2,3-dihydro- 1 H-inden-2-yl)-6-fluoro- 1 ,4-dimethyl-2-oxo- 1 ,2,3 ,4- tetrahydroquinoline-4-carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-4-methyl-3-oxo-l,2,3,4-tetrahydroquinoxali carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-l^
carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-4-oxo-2,4,5,6-tetrahydro- 1 H-pyrrolo[3 ,2, 1 -ij]quinoline- 6-carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-8-fluoro- 1 -methyl-2-oxo- 1 ,2,3 ,4-tetrahydroquinoline-4- carboxamide;
N-(2,3 -dihydro- 1 H-inden-2-yl)-5-fluoro- 1 -methyl-2-oxo- 1,2,3 ,4-tetrahydroquinoline-4- carboxamide;
8-bromo-N-(2,3-dihydro-1H-inden-2-yl)-5-fluoro-l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide;
N-(2,3-dihydro- 1HrMen-2-yl)T5,7Hdifluoro.r lrmethyl-2-oxo.- 1 ,2,3,4- tetrahydroquinoline-4-carboxamide;
1 -cyclopropyl-N-(2,3-dihydro- 1H-inden-2-yl)-2-oxo- 1 ,2,3,4-tetrahydroquinoline-4- carboxamide;
N-[( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]- 1 -cyclopropyl-2-oxo- 1 ,2,3 ,4- tetrahydroquinoline-4-carboxamide;
N-[( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]-8-fluoro- 1 -methyl-2-oxo- 1 ,2,3,4- tetrahydroquinoline-4-carboxamide;
N-(2,3-d&ydro-1H-inden-2-yl)-2-memyI-3-oxo-l,2,3^^
carboxamide;
N-(2,3-dihy(lro4H-inden-2-yl)^fluoro-2-memyl-3-oxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide;
N-(2,3-dmydro-1H-mden-2-yl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H4-^
carboxamide;
2-cyclopropanecarbonyl-N-((/rani)- 1 -methoxy-2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3 ,4- tetrahydroisoquinoline- 1 -carboxamide;
N-[(lS,2S>l-amino-2,3-flhydro-1H-m^
yl)methyl] -1,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide;
Figure imgf000017_0001
2-(cyclopropylmethyl)-N-((/ra«i)-l-methanesulfonyl-2,3-dihydro-1H-m
oxo- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide;
( 1 S)-2-(cyclopropylmethyl)-3 -oxo-N-[(trans)- 1 -(propane-2-sulfonyl)-2,3-dihydro- 1 H- inden-2-yl]-l,2,3,4-tetrahydroisoquinoline-l-carboxamide;
2-(3-fluoropropanoyl)-N-((/ra¾s)- 1 -methoxy-2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3 ,4- tetrahydroisoquinoline- 1 -carboxamide;
2-(cyclopropylmethyl)-N-(trans)-[(iro7ij)-7-fluoro-l-(methylmino)-2,3-dih inden-2-yl]-3-oxo- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-3-(4-fluorophenyl)-2-methyl- 1 -οχο- 1 ,2,3 ,4- tetrahydroisoquinoline-4-carboxamide;
(lS)-2-(3-fluoropropyl)-N-((/ra«i)-l-methoxy-2,3-dihydro-1H-inden-2-yl)-3-oxo- 1,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide; and enantiomers, diastereoisomers and mixtures thereof; and pharmaceutically acceptable salts of any of the foregoing.
It should be noted that each of the chemical compounds listed above represents a particular and independent aspect of the invention.
The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises reacting a compound of formula (II) or a salt (e.g. hydrochloride salt) thereof,
(<?¾)„
Figure imgf000018_0001
"OH (II)
1 2 3 4
in which n, X, Y, Z, D, R , R , R and R are as defined in formula (I) above, with a compound of formula (ΙΠ) or a salt (e.g. hydrochloride salt) thereof,
Figure imgf000019_0001
in which R , R and R are as defined in formula (I) above; and optionally thereafter carrying out one or more of the following procedures:
■ converting a compound of formula (I) into another compound of formula (I) • removing any protecting groups
■ forming a pharmaceutically acceptable salt.
The above process may conveniently be carried out by combining the carboxylic acid of "formula (Π) with the amine of formula (III) in the presence bf a coupling reagent suctfas" "
(1) EDC (l-emyl-3-(3-dimemylanxtnopropyl)carbomimide) and HOAt (7-aza-l- hydroxybenzotriazole) with triethylamine in dichloromethane at room temperature to 60°C, or
(2) HATU (l-|¾is(dimemylamino)memylene]-1H-l,2,3-triazolo[4,5-b]pyridm^ 3-oxid hexafluorophosphate) with triethylamine in dichloromethane at room temperature to 60°C; or
(3) HATU with N^N-diisopropylethylamine in dimethylformamide at room temperature to 60°C;
or
(4) Propylphosphonic anhydride with triethylamine in dichloromethane at room temperature to 60°C; followed, if necessary, to remove any protecting groups (e.g. a tert-butyloxycarbonyl group 12 13 14
ifR is a -NR R group such as -NH2), by reaction with hydrochloric acid in an organic solvent, e.g. a polar solvent such as 1,4-dioxane, at a temperature in the range from, for example, room temperature to 100°C. Compounds of formulae (II) and (ΙΠ) are known compounds or may be prepared according to processes known in the art.
In one embodiment, a compound of formula (I) may be converted into another compound
12
of formula (I). For example, a compound of formula (I) in which R represents -NH2
12
may be converted into a corresponding compound of formula (I) in which R represents 14 14
-NHR where R represents an optionally substituted C1-C6 alkyl group by reacting the
14 former with a suitable aldehyde or ketone (e.g. cyclopropanecarbaldehyde where R is a cyclopropylmethyl group), in the presence of a reducing agent such as sodium
triacetoxyhydroborate and a protic solvent such as methanol. g
Further, a compound of formula (I) in which X is CH2, Y is CH2 and Z is >NR
g
where R is hydrogen may be converted to a corresponding compound of formula
9 9
(I) in which Z is >NC(O)R where R represents a C3-C6 cycloalkyl group by reacting the former with a suitable acyl halide (e.g. cyclopropanecarbonyl chloride where 9
R is cyclopropyl) in the presence of a base (such as triethylamine) and an aprotic solvent (such as dichloromethane, tetrahydrofuran or acetonitrile).
It will be appreciated by those skilled in the art that in the process of the present invention certain functional groups such as phenol, hydroxyl or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the introduction and/or removal of one or more protecting groups.
The protection and deprotection of functional groups is described, for example, in
"Protective Groups in Organic Chemistry1, edited by J.W.F. McOmie, Plenum Press (1973); 'Greene's Protective Groups in Organic Synthesis', 4th edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (2007); and 'Protecting Groups', 3rd edition, P. J. Kocienski, Thieme (200S). The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a formate, hemi-formate,
hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g.
monosaccharin), trifluoroacetate, sulphate, nitrate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, l-hydroxy-2-napthoate (xinafoate), methanesulphonate or p-toluenesulphonate salt. In one embodiment of the invention, the compounds of formula (I) are in the form of a hydrochloride salt.
In one aspect of the invention, compounds of formula (I) may bear one or more radiolabels. Such radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of formula (I), or may be introduced by coupling the compounds of formula (I) to chelating moieties capable of binding to a radioactive metal atom. Such radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.
Unless stated otherwise, any atom specified herein may also be an isotope of said atom. For example, the term "hydrogen" encompasses lH, 2H and 3H. Similarly carbon atoms are to be understood to include 12C, l3C and 14C, nitrogen atoms are to be understood to include 14N and 1SN, and oxygen atoms are to be understood to include 160, 170 and I80.
In a further aspect of the invention, compounds of formula (I) may be isotopically labelled. As used herein, an "isotopically labelled" compound is one in which the abundance of a particular nuclide at a particular atomic position within the molecule is increased above the level at which it occurs in nature.
Compounds of formula (I) and their salts may be in the form of hydrates or solvates which form an aspect of the present invention. Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
Where compounds of formula (I) are capable of existing in stereoisomeric forms, it will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also forms an aspect of the present invention. Enantiomerically pure forms are particularly desired. "Enantiomerically pure" denotes the presence of at least 75%w, in particular at least 90%w and, more particularly, at least 95%w of one of the two possible enantiomers of a compound.
Compounds of formula (I) and their salts may be amorphous or in a polymorphic form or a mixture of any of these, each of which forms an aspect of the present invention.
The compounds of formula (I) and their pharmaceutically acceptable salts Jiave activity as pharmaceuticals and may be used in treating conditions or disorders associated with changes in one or both of the glutamatergic and GABAergic signalling pathways regulated in full or in part by metabotropic glutamate receptor 7.
Thus, the present invention provides a compound offormula (I)-or a. pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy, in particular for the treatment of conditions associated with metabotropic glutamate receptor 7.
The present invention also provides the use of a compound of formula (I) or a
pharmaceutically acceptable salt thereof as hereinbefore defined for the preparation of a medicament for the treatment of conditions associated with metabotropic glutamate receptor 7.
The present invention still further provides a method of treating a condition associated with metabotropic glutamate receptor 7 which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof as hereinbefore defined.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and
"therapeutically" should be construed accordingly. Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question. Persons at risk of developing a particular disorder or condition generally include those having a family history of the disorder or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disorder or condition or those in the prodromal phase of a disorder.
The terms "treat", "treatment" and "treating" include improvement of the conditions described herein. The terms "treat", "treatment" and "treating" include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition. The terms "treat", "treatment," and "treating" are intended to include therapeutic as well as prophylactic treatment of such conditions.
As used herein the terms "condition," "disorder," and "disease" relate to any unhealthy or abnormal state. The term "conditions associated with metabotropic glutamate receptor 7" includes conditions, disorders and diseases in which the modulation of mGluR7 may provide a therapeutic benefit, examples of which include:
(1) Nervous system disorders: Parkinson's disease, including dementia associated with Parkinson's disease; Alzheimer's disease; Huntington's Chorea; amyotrophic lateral sclerosis; multiple sclerosis; bipolar disorder; and psychiatric disorders such as schizophrenia, post-traumatic stress disorder, anxiety disorders and depression (e.g. major depressive disorder);
(2) Addiction disorders: alcohol, drug or nicotine addiction;
(3) Hearing disorders: hearing loss and/or tinnitus caused by age, noise or trauma; and
(4) Others: idiopathic autism; severe neonatal encephalopathy; autism spectrum disorder (ASD); X-linked intellectual disability (also known as X-linked mental retardation); epilepsy; cerebral ischemias; eye disorders; and pain (e.g. inflammatory pain or neuropathic pain). Schizophrenia is a debilitating psychiatric disorder characterised by a combination of negative symptoms (such as social withdrawal, anhedonia, avolition and apathy) and positive symptoms (including hallucinations, delusions and paranoia) as well as marked cognitive deficits (such as impairment of executive function). The executive function (EF) has been defined as "a set of abilities, which allows us to invoke voluntary control of our behavioral responses. These functions enable human beings to develop and cany out plans, make up analogies, obey social rules, solve problems, adapt to unexpected circumstances, do many tasks simultaneously, and locate episodes in time and place. EF includes divided attention and sustained attention, working memory (WM), set-shifting, flexibility, planning, and the regulation of goal directed behavior and can be defined as a brain function underlying the human faculty to act or think not only in reaction to external events but also in relation with internal goals and states" (Orellana G. and Slachevsky A., 2013. Executive Functioning in Schizophrenia. Front. Psychiatry, 4, 35).
Accordingly, the present invention also provides a method of treating, a.negative.symptom,- a positive symptom and/or a cognitive deficit associated with a psychiatric disorder, especially schizophrenia, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight fag/kg) to 100 micrograms per kilogram body weight ^g/kg). Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight fag/kg) to 100 milligrams per kilogram body weight (mg/kg).
The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Therefore the present invention further provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention still further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceutics - The Science of Dosage Form Design", M. E. Aulton, Churchill Livingstone, 1988.
Pharmaceutically acceptable adjuvants, diluents or carriers that may_be used.in the_. — pharmaceutical compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred. The pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically acceptable adjuvants, diluents or carriers. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable diluents and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.
The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
The compounds of the invention (that is, compounds of formula (I) and pharmaceutically acceptable salts thereof) may also be aa^inistered in^njunction withjother. compounds- used for the treatment of the above conditions.
The invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents for the treatment of one or more of the conditions previously indicated. Such therapeutic agents may be selected from the following:
(i) anti-addiction drugs including, for example, acamprosate, disulfiram, naltrexone and nalmefene for alcohol dependency, and gabapentin, modafinil, topiramate, vigabatrin and baclofen for drug, particularly ***e, addiction;
(ii) antidepressants such as amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robaizotan, sertraline, sibutramine, tianeptine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine, vortioxetine and equivalents and pharmaceutically active isomers) and/or metabolite(s) thereof;
(iii) antipsychotics including, for example, amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, brexpiprazole, carbamazepine, cariprazine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, fluphenazine, haloperidol, iloperidone, lamotrigine, loxapine, lurasidone, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutlypiperidine, pimozide, prochlorperazine, quetiapine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, zicronapine, ziprasidone, and equivalents and pharmaceutically active isomers) and/or metabolite(s) thereof;
(iv) anxiolytics including, for example, alnespirone, azapirones, benzodiazepines, barbiturates, and equivalents and pharmaceutically active isomers) and/or metabolite(s) thereof. Example anxiolytics include adinazolam, alprazolam, balezepam, _bentazepam, . _ bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, prazosin, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, and zolazepam; and equivalents and pharmaceutically active isomers) and/or metabolite(s) thereof;
(v) anticonvulsants including, for example, carbamazepine, valproate, lamotrigine, levetiracetam and gabapentin, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
(vi) Alzheimer's therapies including, for example, donepezil, galantamine, memantine, rivastigmine, tacrine, and equivalents and pharmaceutically active isomers) and/or metabolite(s) thereof;
(vii) Parkinson's therapies including, for example, L-dopa, ropinirole, pramipexole, monoamine oxidase type B (MAO-B) inhibitors such as deprenyl, selegiline and rasagiline, catechol-O-methyl transferase (COMT) inhibitors such as entacapone or tolcapone, adenosine A- 2 inhibitors, dopamine re-uptake inhibitors, NMDA antagonists, Nicotine agonists, and Dopamine agonists and inhibitors of neuronal nitric oxide synthase, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
(viii) migraine therapies including, for example, almotriptan, amantadine, botulinum toxin A, bromocriptine, butalbital, cabergoline, dichloralphenazone, dihydroergotamine, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, topiramate, zolmitriptan, and zomitriptan, and equivalents and
pharmaceutically active isomer(s) and/or metabolite(s) thereof;
(ix) stroke therapies including, for example, abciximab, activase, citicoline,
desmoteplase, , and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
(x) urinary incontinence therapies includingjibr example, darafenacin, duloxetine, - falvoxate, mirabegron, oxybutynin, propiverine, robalzotan, solifenacin, and tolterodine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
(xi) neuropathic pain therapies including, for example, capsaicin, gabapentin, lidoderm, and pregabalin, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
(xii) nociceptive pain therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, and paracetamol, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
(xiii) insomnia therapies including, for example, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, eszopiclone, etomidate, glutethimide, halazepam, hydroxyzine, lorediplon, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ralmeteon, roletamide, suvorexant, triclofos, secobarbital, zaleplon, and Zolpidem, zopiclone and equivalents and pharmaceutically active isomers) and/or metabolite(s) thereof; (xiv) mood stabilizers including, for example, carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, and verapamil, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
(xv) SHT1B ligands such as, for example, compounds disclosed in WO 99/05134 and WO 02/08212;
(xvi) mGluR2 agonists;
(xvii) alpha 7 nicotinic agonists such as, for example, compounds disclosed in
WO 96/006098, WO 97/030998, WO 99/003859, WO 00/042044, WO 01/029034, WO 01/60821, WO 01/36417, WO 02/096912, WO 03/087102, WO 03/087103,
WO 03/087104, WO 2004/016617, WO 2004/016616, and WO 2004/019947;
(xviii) chemokine receptor CCR1 inhibitors; and
(xix) delta opioid agonists such as, for example, compounds disclosed in WO 97/23466 and WO 02/094794.
Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges.
The present invention will now be further explained by reference to the following illustrative examples, in which the starting materials and reagents used are available from commercial suppliers or prepared via literature procedures.
Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated and at 300.3K, 298.2K or 293K unless otherwise stated; the chemical shifts (δ) are reported in parts per million. Spectra were recorded using a Bruker (trade mark) 400 A VANCE instrument fitted with a 5mm BBFO probe with instrument controlled by Bruker TopSpin 2.1 software, or by a Bruker 400 AVANCE-ΠΙ HD instrument fitted with a 5mm BBFO smart probe or a 5mm BBFO probe with instrument controlled by Bruker TopSpin 3.2 software, or by a Bruker 400 AVANCE-III instrument fitted with a 5mm BBFO probe with instrument controlled by Bruker Topspin 3.0 software or by a Bruker 300MHz AVANCE II instrument fitted with a 5mm DUL probe with instrument controlled by Bruker TopSpin 1.3 software, or 5mm BBFO probe controlled by Bruker Topspin 3.2 software.
Purity was assessed using one or more of the following:
• Ultra Performance Liquid Chromatography (UPLC) with UV (photodiode array) detection over a wide range of wavelengths, normally 220-450 run, using a Waters (trade mark) Acquity UPLC system equipped with Acquity UPLC BEH, HSS or HSS T3 CI 8 columns (2.1mm id x 50mm long) operated at 50 or 60 °C. Mobile phases typically consisted of acetonitrile mixed with water containing either 0.1% formic acid, 0.1% trifluoroacetic acid (TFA) or 0.025% ammonia. Mass spectra were recorded with a Waters SQD single.quadrupole mass-spectrometer using atmospheric pressure ionisation.
• UPLC with UV (photodiode array) detection over a wide range of wavelengths, normally 220 - 450 nm, using Shimadzu (trade mark) Nexera X2 UPLC controlled by Lab Solution software equipped with Acquity UPLC BEH, HSS or HSS T3 C18 columns (2.1mm id x 50mm long) operated at 50 °C. Mobile phases typically consisted of acetonitrile mixed with water containing either 0.1% formic acid, 0.1% TFA or 0.025% ammonia. Mass spectra were recorded with a Shimadzu single quadrupole mass spectrometer using DUIS ionisation.
Compounds were purified using normal phase chromatography on silica, using Biotage (trade mark) KP-Sil cartridges, Interchim (trade mark) PuriFlash cartridges or Kinesis (trade mark) Telos silica cartridges, or on basic silica using Biotage KP-NH cartridges, or by reverse phase chromatographic methods using Biotage KP-C18-HS cartridges or by Biotage Isolute SCX-2 or Phenomenex (trade mark) Strata ABW catch-release cartridges, or by preparative high performance liquid chromatography (HPLC).
Preparative HPLC was performed using Agilent Technologies (trade mark) 1100 Series system or a Waters autopurification LC/MS system or a Shimadzu semi prep HPLC system, typically using Waters 19 mm id x 250 mm long CI 8 columns such as XBridge (trade mark) or SunFire (trade mark) 5 um materials at room temperature. Mobile phases typically consisted of acetonitrile mixed with water containing either 0.1% formic acid or 0.1% ammonia, unless otherwise stated.
Super Critical Fluid Chromatography (SFC) chiral separations were performed on a Waters prep30/MS system, using a flow rate of 30 mL/min, temperature of 40 °C and a pressure of 100 bar. Mobile phases typically consisted of supercritical C02 and a polar solvent such as methanol, ethanol or isopropanol. Column type and eluent are detailed for individual examples.
'Room temperature', as used in the present specification, means a temperature in the range from about 18 °C to about 25 °C.
Abbreviations
AcOH: Acetic acid
ADBN: Azobisisobutyronitrile
BINAP: 2,2 -Bis(diphenylphosphino)- 1 , 1 '-binaphthalene
COMU: ( 1 -Cyano-2-euoxy-2-oxoemylidenaminooxy)dimemylamino-morpholinO'
carbenium hexafluorophosphate
DCM: Dichloromethane
DEA: Diethylamine
DIPEA: NjN-Diisopropylethylamine
DMF: Dimethylformamide
DMSO: Dimethylsulfoxide
EDC: N-Ethyl-N-iS-dimethylaminopropyOcarbodiimide
Et20: diethyl ether
EtOAc: Ethyl acetate
EtOH: Ethanol
FA: Formic acid
h: hours
HATU: 1 -[Bis(dimethylamino)methylene]- 1H- 1 ,2,3-triazolo[4,5-6]pyridinium 3- oxid hexafluorophosphate HOAt: 1 -Hydroxy- 7-azabenzotriazole
HOBt: 1 -Hydroxy-benzotriazole
HPLC: High-Performance Liquid Chromatography
IPA: Isopropyl alcohol
mCPBA: meta Chloroperbenzoic Acid
MeCN: Acetonitrile
MeOH: Methanol
min: minutes
NBS: N-bromosuccinamide
NFSI: N-Fluorobenzenesulfonimide
TEA: Triethylamine
THF: Tetrahydrofuran
T3P: Propylphosphonic Anhydride
Figure imgf000033_0003
Xphos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
1. Intermediates
Intermediate 1: (4S)-l-methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxylic acid - 2nd eluting peak, single enantiomer
Figure imgf000033_0001
l-methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxylic acid was purified by chiral SFC (14% isocratic EtOH + 0.5% FA, AD column) to afford the title compound.
1H NMR (300 MHz, DMSCwfc) δ ppm 2.64 - 2.81 (m, 2 H) 3.22 (s, 3 H) 3.71 - 3.94 (m, 1 H) 6.94 - 7.16 (m, 2 H) 7.22 - 7.50 (m, 2 H) 12.68 (br. s., 1 H)
Intermediate 2: (trans)-l-methoxy-2,3-dihydro-1H-inden-2-amine
Figure imgf000033_0002
Step (i): (ire/is)-2-azido-l-methoxy-2,3-dihydro-1H-indene Methyl iodide (1.43 mL, 22.83 mmol) was added to a suspension of (frowj)-2-azido-2,3- dihydro-1H-inden-1-ol ((synthesis described in Tetrahedron: Asymmetry, 1995, 5, 7, 1535, using racemic cis starting material) 1.6 g, 9.13 mmol) and silver oxide (2.S4 g, 10.96 mmol) in MeCN (25 mL). The reaction was stirred at room temperature for 48 h in a sealed flask in the dark. The reaction was heated to 60 °C for 5 h then stirred at room temperature for 18 h. The suspension was filtered through diatomaceous earth and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0- 10% EtO Ac/petroleum ether to afford the title compound.
'H NMR (400 MHz, CDC13) δ ppm 2.86 - 2.95 (m, 1 H) 3.34 - 3.42 (m, 1 H) 3.60 (s, 3 H) 4.14 - 4.20 (m, 1 H) 4.70 - 4.74 (m, 1 H) 7.21 - 7.33 (m, 3 H) 7.37 - 7.42 (m, 1 H)
Step (ii): (/rfl/ts)-l-methoxy-2,3-dihydro-1H-inden-2-amine
A suspension of (/raw)-2-azido-l-methoxy-2,3-dihydro-1H-indene (1.36 g, 7.19 mmol) and 10% palladium on activated carbon powder (0.765 g, 0.719 mmol) in EtOH (50 mL) was evacuated and purged with nitrogen three times,. then.stirred under-an atmosphere of- - hydrogen for 18 h. The suspension was filtered through diatomaceous earth and
concentrated in vacuo. The product was loaded onto a cation exchange cartridge, washed with methanol and eluted with 2M N¾/MeOH solution then concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, CDCI3) δ ppm 1.46 (br. s., 2 H) 2.55 - 2.64 (m, 1 H) 3.27 - 3.36 (m, 1 H) 3.55 (s, 3 H) 3.68 - 3.74 (m, 1 H) 4.45 - 4.49 (m, 1 H) 7.20 - 7.26 (m, 3 H) 7.37 - 7.42 (m, 1 H)
Intermediate 3: (trans)-l-methoxy-2,3-dihydro-1H-inden-2-amine
Figure imgf000034_0001
rac-trans rac-trans rac-trans
Step (i): (/ra/w)-2-azido-l-ethoiy-2,3-dihydro-1H-indene
Iodoethane (1.826 mL, 22.83 mmol) was added to a suspension of (trans)-2-azido-2,3- dihydro-1H-inden-l-ol ((synthesis described in Tetrahedron: Asymmetry, 1995, 5, 7, 1535, using racemic cis starting material) 1.6 g, 9.13 mmol) and silver oxide (2.54 g, 10.96 mmol) in MeCN (25 mL). The reaction was stirred at room temperature for 48 h in a sealed flask in the dark. The reaction was heated to 60 °C for 5 h. Further portions of iodoethane (1.826 mL, 22.83 mmol) and silver oxide (2.S4 g, 10.96 mmol) were added and the reaction stirred at room temperature for 18 h, then heated in a sealed flask at 70 °C for 4 h and room temperature for 72 h. The suspension was heated to 70 °C for 4 h. The suspension was filtered through diatomaceous earth and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-10%
EtOAc/petroleum ether to afford the title compound.
lH NMR (400 MHz, CDC13) δ ppm 1.28 - 1.34 (m, 1 H) 2.84 - 2.93 (m, 1 H) 3.32 - 3.40 (m, 1 H) 3.74 - 3.89 (m, 2 H) 4.13 - 4.19 (m, 1 H) 4.81 (d, J=4.95 Hz, 1 H) 7.20 - 7.31 (m, 3 H) 7.35 - 7.41 (m, 1 H)
Step (ii): (trans)-l-methoxy-2,3-dihydro-1H-inden-2-aniine
A suspension of (/ra«j)-2-azido-l-ethoxy-2,3-dihydro-1H-indene (1.40 g, 6.89 mmol) and 10% palladium on activated carbon powder (0.733 g, 0.689 mmol) in EtOH (SO mL) was evacuated and purged with nitrogen three times, then stirred under an atmosphere of hydrogen for 2 h. The suspension was filtered through diatomaceous earth and
concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, CDC13) 8ppm 1.29 (t, J=6.97 Hz, 3 H) 1.43 (br. s., 2 H) 2.53 - 2.64 (m, 1 H) 3.26 - 3.35 (m, 1 H) 3.64 - 3.74 (m, 1 H) 3.74 - 3.83 (m, 2 H) 4.55 (d, J=4.59 Hz, 1 H) 7.18 - 7.26 (m, 3 H) 7.33 - 7.41 (m, 1 H)
Intermediate 4; l-ethyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid
Figure imgf000035_0001
Step (i): ethyl l-ethyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylate
Ethyl iodide (0.088 mL, 1.095 mmol) was added to a solution of ethyl 2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxylate (200 mg, 0.912 mmol) in acetone (4 mL) under nitrogen with CS2CO3 (357 mg, 1.095 mmol). Stirred at room temperature overnight. More ethyl iodide (0.088 mL, 1.095 mmol) was added and stirring continued overnight. Reaction mixture was filtered, the filtrate concentrated in vacuo and purified by column chromatography on silica, eluted with 0-50% EtOAc/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 - 1.15 (m, 6 H) 2.75 - 2.81 (m, 2 H) 3.78 - 4.10 (m, 4 H) 4.27 - 4.47 (m, 1 H) 7.01 - 7.09 (m, 1 H) 7.16 (s, 0 H) 7.23 - 7.41 (m, 2 H)
Step (ii): l-ethyl-2-oxo-l,2,3,4-tetrahydroquinotine-4-carboxylic acid
LiOH (126 mg, 5.26 mmol) was added to a stirred solution of ethyl 1 -ethyl- 2-oxo- 1,2,3 ,4- tetrahydroquinoline-4-carboxylate (130 mg, 0.526 mmol) in dioxane (2 mL) and water (2 mL). After 4 hours, reaction mixture was acidified with 2N HC1 (to pH~l) and extracted with EtOAc. Organics passed through a phase separation cartridge and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% formic acid) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (t, J= 7.06 Hz, 3 H), 2.75 (d, J = 4.77 Hz, 2
H), 3.83 - 3.94 (m, 3 H), 7.00 - 7.07 (m, 1 H), 7.12 - 7.18 (m, 1 H), 7.30 (d, J= 7.34 Hz, 2
H), 12.60 (br. s, 1 H)
Intermediate 5; ferf-butyl N-[(lS,2S)-2-(2-cyclopropanecarbonyl-l,2,3,4- tetrahydroisoquinoline-l-carboxamido)-2,3-dihydro-1H-inden-l-yl]carbamate
Figure imgf000036_0001
Step (i): ethyl 2-cyclopropanecarbonyl-l,2,3,4-tetrahydroisoquinoline-l-carboxylate Cyclopropanecarbonyl chloride (0.5 mL, S.S1 mmol) was added to a solution of ethyl 1,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (1.075g, 4.45 mmol) and TEA (1.7 mL, 12.20 mmol) in DCM (40 mL) and stirred for 1 hour. The reaction mixture was washed with water, dried (phase separator) and purified by column chromatography on silica, eluted with 0-100% EtO Ac/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.62 - 0.92 (m, 4 H) 1.03 - 1.16 (m, 3 H) 2.03 - 2.20 (m, 1 H) 2.69 - 3.06 (m, 2 H) 3.88 - 4.19 (m, 4 H) 5.57 - 6.19 (m, 1 H) 7.13 - 7.32 (m, 3 H) 7.42 - 7.53 (m, 1 H)
Step (ii): 2-cyclopropanecarbonyl-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid LiOH (0.526 g, 21.95 mmol) was added to a solution of ethyl 2-cyclopropanecarbonyl- 1,2,3,4-tetrahydroisoquinoline-l-carboxylate (0.60 g, 2.195 mmol) in dioxane (10 mL) and water (10 mL) and stirred for 18 h. The reaction mixture was acidified with cone. HC1 and extracted with EtOAc. The organics were dried (phase separator) and concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSCwfc) δ ppm 0.66 - 0.88 (m, 4 H), 2.01 - 2.16 (m, 1 H), 2.71 - 3.06 (m, 2 H), 3.87 - 4.05 (m, 2 H), 5.55 - 6.05 (m, 1 H), 7.10 - 7.35 (m, 3 H), 7.39 - 7.56 (m, 1 H), 12.52 - 13.01 (m, 1 H)
Step (iii): tert-butyl N-[(lS,2S)-2-(2-cyclopropanecarbonyl-l,2,3,4- tetrahydroisoquinoline-l-carboxamido)-2,3-dihydro-1H-inden-l-yl]carbamate T3P (50% in EtOAc) (0.971 mL, 1.631 mmol) was added to a stirred solution of TEA (0.332 mL, 2.446 mmol), 2-cyclopropanecarbonyl- 1,2,3 ,4-tetrahydroisoquinoline-l- carboxylic acid (0.200 g, 0.815 mmol) and fer/-butyl ((lS,2S)-2-amino-2,3-dihydro-1H- inden-l-yl)carbamate (0.202 g, 0.815 mmol) in DCM (5 mL) and stirred for 30 min. The reaction mixture was washed with sodium bicarbonate solution, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-100% EtO Ac/petroleum ether to afford the title compound.
MS ES+: 476
Intermediates 6 and 7: /erf-butyl ((lS,2S)-2-(2-(cyclopropanecarbonyl)-6-fluoro- 1,2,3,4-tetrahydroisoquinoIine-l-carboxamido)-2,3-dihydro-1H-inden-l-yl)carbamate (single stereoisomers)
Figure imgf000038_0001
Prepared as described for /erf-butyl N-[(lS,2S)-2-(2-cyclopropanecarbonyl-l,2,3,4- tetrahydroisoquinoline- 1 -amido)-2,3-dihydro- 1 H-inden- 1 -yl]carbamate (Intermediate 5) using ethyl 6-fluoro-l,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (0.400 g, 1.S40 mmol) to afford the title compounds.
Intermediate 6, l" eluted peak
1H NMR (300 MHz, DMSO-d6) δ ppm 0.65 - 0.92 (m, 4 H) 1.32 - 1.49 (m, 9 H) 2.57 - 3.19 (m, 4 H) 3.60 - 3.95 (m, 2 H) 4.12 - 4.37 (m, 2 H) 4.96 - 5.16 (m, 1 H) 5.57 - 5.86 (m, 1 H) 6.87 - 7.56 (m, 8 H) 8.40 - 8.97 (m, 1 H)
Intermediate 7, 2nd eluted peak
1H NMR (300 MHz, DMSO-d6) δ ppm 0.62 - 0.87 (m, 4 H) 1.27 - 1.50 (m, 9 H) 2.60 - 3.19 (m, 4 H) 3.62 - 3.98 (m, 2 H) 4.09 - 4.36 (m, 2 H) 4.85 - 5.16 (m, 1 H) 5.56 - 5.90 (m, 1 H) 6.85 - 7.60 (m, 8 H) 8.48 - 8.91 (m, 1 H)
Intermediates 8 and 9; /erf-butyl ((lS,2S)-2-(6-chloro-2-(cyclopropanecarbonyl>- l,2^3,4-tetrahydroisoquinoline-l-carboxamido)-2,3-dihydro-1H-inden-l-yl)carbamate (single stereoisomers)
Figure imgf000038_0002
Prepared as described for ter/-butyl N-[(lS,2S)-2-(2-<^clopropanecarbonyl-l,2,3,4- tetrahydroisoquinoline-l-amido)-2,3-dihyd
using ethyl 6^chloro-l,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (0.400 g, 1.448 mmol) to afford the title compounds. Intermediate 8, l" eluted peak
'H NMR (400 MHz, DMSO--d6) δ ppm 0.65 - 0.90 (m, 4 H) 1.41 (s, 9 H) 2.55 - 3.14 (m, 4 H) 3.62 - 4.00 (m, 2 H) 4.07 - 4.45 (m, 2 H) 4.99 - 5.17 (m, 1 H) 5.60 - 5.88 (m, 1 H) 7.31 (s, 7 H) 7.43 - 7.56 (m, 1 H) 8.53 - 8.94 (m, 1 H)
Intermediate 9, 2nd eluted peak
1H NMR (400 MHz, DMSO-d6) δ ppm 0.71 - 0.90 (m, 4 H) 1.34 - 1.51 (m, 9 H) 2.66 - 3.24 (m, 4 H) 3.77 - 4.35 (m, 4 H) 4.83 - 5.13 (m, 1 H) 5.63 - 5.90 (m, 1 H) 6.96 - 7.59 (m, 8 H) 8.50 - 8.74 (m, l H)
Intermediate 10; N-(2,3-dihydro-1H-inden-2-yl)-1,2,3,4-tetrahydroisoquinoline-4- carboxamide hydrochloride
Figure imgf000039_0001
Step (i): 2-terf-butyl 4-methyl 1^^4~tetrahydroisoquinoline-2,4-dicarboxylate TEA (4.0 mL, 28.57 mmol) was added to a suspension of methyl 1,2,3,4- tetrahydroisoquinoline-4-carboxylate hydrochloride (1.30 g, 5.7 mmol) in DCM (20 mL) and stirred for 20 min. Di-/er/-butyl dicarbonate (2.50 g, 11.4 mmol) was added and stirred for 3 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried (Na2S04) and concentrated in vacuo to afford the title compound. 'Η NMR (400 MHz, DMSO-i/e) 6 ppm 1.41 (s, 9 H) 3.40 - 3.52 (m, 1 H) 3.56 - 3.72 (m, 3 H) 3.87 - 3.98 (m, 1 H) 4.17 - 4.51 (m, 2 H) 4.61 - 4.88 (m, 1 H) 7.06 - 7.36 (m, 4 H) MS ES+: 292
Step (ii): 2-[(/er/-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid To a stirred solution of 2-tert-butyl 4-methyl l,2,3,4-tetrahydroisoquinoline-2,4- dicarboxylate (1.5 g, 5.15 mmol) in THF:H20 (1:1) (40 mL) was slowly added LiOH (0.634 g, 15.4 mmol). The reaction mixture was then stirred at 80 °C for 30 min. The reaction mixture was cooled to room temperature, diluted with cold water and acidified with IN HC1 to pH 4. Aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulphate and concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9 H) 3.39 - 3.48 (m, 1 H) 3.72 - 3.82 (m, 1 H) 4.08 - 4.89 (m, 3 H) 7.07 - 7.42 (m, 4 H) 12.57 (s, 1 H)
MS ES+: 278
Step (iii): ferf-butyl 4-[(2,3-dihydro-1H-inden-2-yl)carbamoyI]-l,2,3,4- tetrahydroisoquinoline-2-carboxylate
To a stirred solution of 2-[(ter/-butoxy)carbonyl]- 1,2,3 ,4-tetrahydroisoquinoline-4- carboxylic acid (0.6 g, 2.11 mmol) and 2,3-dihydro-1H-inden-2-amine (0.29 g, 2.11 mmol) in DMF (15 mL) was added EDC.HC1 (0.624 g, 3.2 mmol), HOBt (0.35 g, 2.6 mmol) and N-methyl morpholine (1.1 g, 10.8 mmol) sequentially at room temperature. The reaction mixture was stirred for 5 h. The reaction mixture was poured into ice-water and the resulting solid was filtered, washing with cold water and dried in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9 H) 2.78 - 2.87 (m, 2 H) 3.14 - 3.27 (m, 2 H) 3.54 - 3.86 (m, 3 H) 4.36 - 4.67 (m, 3 H) 6.93 - 7.33 (m, 8 H) 8.48 - 8.64 (m, 1 H) MS ES+: 393
Step (iv): N-(2,3-dihydro-1H-inden-2-yl)-1,2,3,4-tetrahydroisoquinoline-4- carboxamide hydrochloride
HC1 (4N in dioxane) (7 mL) was added to a solution of tert-butyl 4-[(2,3-dihydro-1H- inden-2-yl)carbamoyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate (0.68 g, 1.7 mmol) in DCM (IS mL) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and triturated with n-pentane to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 2.74 - 2.95 (m, 2 H) 3.11 - 3.28 (m, 2 H) 3.36 -
3.47 (m, 1 H) 3.52 - 3.56 (m, 1 H) 3.89 - 3.98 (m, 1 H) 4.18 - 4.57 (m, 3 H) 7.08 - 7.49 (m,
8 H) 8.74 - 8.93 (m, 1 H) 9.14 (d, J=7.02 Hz, 1 H) 9.56 - 9.77 (m, 1 H)
MS ES+: 293
Intermediate 11: ethyl 2-bromo-2-[2-(2-ethoxy-2-oxoethyl)phenyl] acetate
Figure imgf000041_0001
Step (i): ethyl 2-[2-(2-ethoxy-2-oxoethyl)phenyl]acetate
A solution of 2-[2-(carboxymethyl)phenyl]acetic acid (25 g, 0.128 mmol) in EtOH (500 mL) with concentrated sulphuric acid (1.5 mL) was heated tp_reflux_for 3. h and allowed to cool to room temperature. The reaction was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic phase was dried over Na2S04 and concentrated in vacuo to afford the title compound.
'H NMR (400 MHz, CDC13) δ ppm 1.24 (t, J=7.08 Hz, 6 H) 3.70 (s, 4 H) 4.13 (q, J=7.08 Hz, 4 H) 7.00 - 7.49 (m, 4 H)
Step (ii): ethyl 2-bromo-2-[2-(2-ethoxy-2-oxoethyl)phenyl]acetate
NBS (0.712 g, 4 mmol) was added to a solution of ethyl 2-[2-(2-ethoxy-2- oxoethyl)phenyl]acetate (1.00 g, 4 mmol) in CCI4 (15 mL). AD3N (66 mg, 0.4 mmol) was added and the reaction heated to 60°C overnight. After cooling to room temperature, the reaction mixture was filtered and the filtrate concentrated in vacuo to afford the title compound.
lK NMR (400 MHz, CDC13) δ ppm 1.03 - 1.35 (m, 6 H) 3.44 - 3.81 (m, 2 H) 4.00 - 4.38 (m, 4 H) 5.52 - 5.86 (m, 1 H) 7.02 - 7.86 (m, 4 H)
Intermediate 12: 2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid jo
Br
Step (i) Step (ii)
Figure imgf000042_0001
Figure imgf000042_0002
o^o^
Figure imgf000042_0003
"OH
Step (i): ethyl 2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-l-carboxylate ethyl 2-bromo-2-[2-(2-ethoxy-2-oxoethyl)phenyl]acetate (0.5 g, 1.52 mmol), K2CO3 (0.42 g, 3.04 mmol), methylamine hydrochloride (0.103 g, 1.52 mmol) and DMF (2 mL) were combined in a tube, sealed and heated to 100°C for 18 h. Reaction mixture allowed to cool to room temperature, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica, eluted with 0-20% EtOAc/toluene to afford the title compound.
1H NMR (400 MHz, CDCI3) δ ppm 1.21 (t, J=7.22 Hz, 3 H) 3.07 (s, 3 H) 3.51 - 3.84 (m, 2 H) 4.06 - 4.23 (m, 2 H) 4.99 (s, 1 H) 7.15 (d, J=7.36 Hz, 1 H) 7.22 - 7.33 (m, 2 H) 7.38 (d, J=7.63 Hz, 1 H)
MS ES+: 234
Step (ii): 2-methyl-3-oxo-l,23,4-tetrahydroisoquinoline-l-carboxylic acid
LiOH.H20 (0.66 g, 16.1 mmol) was added to a solution of ethyl 2-methyl-3-oxo-l,2,3,4- tetrahydroisoquinoline-l-carboxylate (3.4 g, 14.6 mmol) in THF (75 mL) and water (25 mL) and stirred overnight. Reaction was concentrated in vacuo. HC1 was added to pH7 and the resulting solid filtered, azeotroped with toluene and dried in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.85 (s, 3 H) 3.20 - 3.34 (m, 1 H) 3.39 - 3.51 (m, 1 H) 3.60 - 3.74 (m, 1 H) 4.58 (s, 1 H) 7.02 - 7.11 (m, 1 H) 7.12 - 7.20 (m, 2 H) 7.30 - 7.42 (m, 1 H)
ES": 204
Intermediate 13: 2-(2-methoxyethyl)-3-oxo-l,2,3,4-tetrahydroisoquinoline-l carboxylic acid
Figure imgf000042_0004
O' ΌΗ Prepared as described for 2-methyl-3-oxo-l,2,3>4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 12) using ethyl 2-bromo-2-[2-(2-ethoxy-2-oxoethyl)phenyl]acetate
(Intermediate 11, 8.5 g, 2S.88 mmol) and 2-methoxyethylamine (2.7 mL, 30.96 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-£¾) δ ppm 2.93 - 3.06 (m, 1 H) 3.12 - 3.22 (m, 4 H) 3.29 (d, J=18.80 Hz, 1 H) 3.33 - 3.40 (m, 2 H) 3.73 (d, J=18.53 Hz, 1 H) 3.83 - 4.00 (m, 1 H) 4.72 (s, 1 H) 7.02 - 7.09 (m, 1 H) 7.11 - 7.19 (m, 2 H) 7.30 - 7.40 (m, 1 H)
ES": 248
Intermediate 14; 2-(cyclopropylmethyl)-3-oxo-1,2,3,4-tetrahydroisoquinoline-l- carboxylic aeid
Figure imgf000043_0001
O' ΌΗ
Prepared as described for 2-methyl-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 12) using ethyl 2-bromo-2-[2-(2-ethoxy-2-oxoethyl)phenyl]acetate
(Intermediate 11, 8.S g, 25.88 mmol) and (aminomethyl)cyclopropane (2.6 g, 36.48 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.05 - 0.50 (m, 4 H) 0.86 - 1.02 (m, 1 H) 2.63 - 2.79 (m, 1 H) 3.12 - 3.31 (m, 2 H) 3.63 - 3.85 (m, 2 H) 4.78 (s, 1 H) 7.02 - 7.19 (m, 3 H) 7.33 - 7.43 (m, 1 H)
ES-: 244
Intermediate IS: 2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinoIine-l-carboxylic acid
Figure imgf000043_0002
Prepared as described for 2-memyl-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 12) using ethyl 2-bromo-2-[2-(2-ethoxy-2-oxoethyl)phenyl]acetate
(Intermediate 11, 10 g, 30.4 mmol) and ethylamine.HCl (4.95 g, 60.755 mmol) to afford the title compound. 'Η NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.22 Hz, 3 H) 2.94 - 3.08 (m, 1 H) 3.14 - 3.29 (m, 2 H) 3.57 - 3.84 (m, 2 H) 4.64 (s, 1 H) 7.02 - 7.19 (m, 3 H) 7.30 - 7.42 (m, 1 H) ES": 218
Intermediate 16: 3-oxo-2-[(pyridin-2-yl)methyl]-l,2,3,4-tetrahydroisoquinoline-l- carboxylic acid
Figure imgf000044_0001
ΌΗ
Prepared as described for 2-rnethyl-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 12) using ethyl 2-bromo-2-[2-(2-ethoxy-2-oxoethyl)phenyl]acetate (Intermediate 11, 10 g, 30.4 mmol) and 2-picolylamine (3.94 g, 36.S mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-c¾) δ ppm 3.34 - 3.45 (m, 2 H) 3.77 - 3.97 (m, 2 H) 4.59 (s, 1 H) 5.34 (d, J=15.80 Hz, 1 H) 7:01 ^7.32 (mT 6 H) 7160 "7.71 (m7 l H) 8.47 (¾ J=4.36 Hz," 1 H)
MS ES+: 283
Intermediate 17: 2-[(oxan-4-yl)metbyl]-3-oxo-l ,2,3,4-tetrahydroisoquinoline-l- carboxylic acid
Figure imgf000044_0002
Prepared as described for 2-methyl-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 12) using ethyl 2-bromo-2-[2-(2-ethoxy-2-oxoethyl)phenyl]acetate (Intermediate 11, 10 g, 30.4 mmol) and 4-(arninomethyl)tetrahydro-2H-pyran (4.2 g, 36.5 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 - 1.26 (m, 2 H) 1.31 - 1.44 (m, 1 H) 1.49 - 1.59 (m, 1 H) 1.75 - 1.90 (m, 1 H) 2.68 - 2.81 (m, 1 H) 3.08 - 3.29 (m, 4 H) 3.62 - 3.84 (m, 4 H) 4.59 (s, 1 H) 7.00 - 7.16 (m, 3 H) 7.28 - 7.35 (m, 1 H)
ES': 288 Intermediate 18: 3-oxo-2-[2-(pyrroIidin-l-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-l carboxylic acid
Figure imgf000045_0001
Prepared as described for 2-methyl-3-oxo-l, 2,3 ,4-tetrahydroisoquinoline-l -carboxylic acid (Intermediate 12) using ethyl 2-bromo-2-[2-(2-ethoxy-2-oxoethyl)pheayl]acetate (Intermediate 11, 10 g, 30.4 mmol) and 2-(pyrrolidin-l-yl)ethanamine (4.17 g, 36.S mmol) to afford the title compound.
ES": 287
Intermediate 19: fer/-butyl N-[(lS,2S)-2-[2-(cyclopropylmethyl)-3-oxo-l,2r3,4- tetrahydroisoquinoline-l-carboxamido]-2^3-dihydro-1H-inden-l-yl]carbamate
Figure imgf000045_0002
H
Figure imgf000045_0003
TEA (0.341 mL, 2.446 mmol) was added to a suspension of ter/-butyl ((lS,2S)-2-amino- 2,3-dihydro-1H-inden-l-yl)carbamate (0.223 g, 0.897 mmol), 2-(cyclopropylmethyl)-3- oxo- 1,2,3 ,4-tetrahydroisoquinoline-l -carboxylic acid (Intermediate 14, 0.2 g, 0.81S mmol), EDC.HC1 (0.234 g, 1.223 mmol) and HOAt (0.189 g, 1.223 mmol) in DCM (5 mL). The reaction was stirred at room temperature overnight. The mixture was diluted with DCM and washed with 5% citric acid, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 25-100% EtOAc/petroleum ether to afford the title compound.
MS ES+: 476
Intermediate 20: 2-benzyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid
Figure imgf000046_0001
Prepared as described for 2-methyl-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 12) using ethyl 2-bromo-2-[2-(2-ethoxy-2-oxoethyl)phenyl]acetate (Intermediate 11, 10.0 g, 30.4 mmol) and benzylamine (3.91 g, 36.5 mmol) to afford the title compound.
1H NMR (400 MHz, OMSO-d6) δ ppm 3.17 (s, 2 H) 3.65 - 3.92 (m, 2 H) 4.51 (s, 1 H) 5.22 - 5.46 (m, 1 H) 6.99 - 7.33 (m, 9 H)
ES_: 280
Intermediate 21; ferf-butyl N-[(lS,2S)-2-(2-benzyl-3-oxo-l,2,3,4- tetrahydroisoquinoline-l-carboxamido)-2,3-dihydro-1H-inden-l-yl]carbamate
Figure imgf000046_0002
Prepared as described for tert-butyl N-[(lS,2S)-2-[2-(cyclopropylmethyl)-3-oxo-l,2,3,4- tetrahydroisoquinoline- l-amido]-2,3-dihydro-1H-inden-l-yl]carbamate (Intermediate 19) using 2-benzyl-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 20, 0.170 g, 0.604 mmol) and tert-butyl ((lS,2S>2-amino-2,3-dihydro-1H-inden-l- yl)carbamate (0.150 g, 0.604 mmol) to afford the title compound.
MS ES+: 512
Intermediate 22: /erf-butyl ((lS,2S)-2-(3-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)- 1,2,3,4-tetrahydroisoqninoline-l-carboxamido)-2,3-dihydro-1H-inden-l-yl)carbamate
Figure imgf000047_0001
Prepared as described for tert-butyl N-[( lS,2S)-2-[2-(cyclopropylmethyl)-3-oxo- 1,2,3,4- tetrahydroisoquinoline- l-amido]-2,3-dihydro- 1H-inden- 1 -yljcarbamate (Example 19) using 2-[(oxan-4-yl)methyl]-3-oxo-l,2,3,4-tetrahydroisoqmnoline-l-carboxylic acid (Intermediate 17, 0.S00 g, 1.728 mmol) and tert-butyl ((lS,2S)-2-amino-2,3-dihydro-1H- inden-l-yl)carbamate (0.429 g, 1.728 mmol) to afford the title compound.
MS ES+: 520
Intermediate 23: methyl 2-oxo-2,4-dihydro-1H-3,l-benzoxazine-4-carboxylate
Figure imgf000047_0002
O O
Step (i): 2-hydroxy-2-(2-nitrophenyl)acetonitriIe
Sodium hydrogen sulphate (16.53 g, 158.8 mmol) was added to a suspension of 2- nitrobenzaldehyde (20 g, 132.3 mmol) in water (250 ml). The reaction was stirred at room temperature until all solid had dissolved. The solution was cooled to 0 °C under nitrogen. A solution of potassium cyanide (10.34 g, 158.8 mmol) in water (50 mL) was added drop wise to the cooled solution. The reaction was stirred at 0 °C for 30 min, then was allowed to warm to room temperature and stirred for 18 h. The resultant solid was filtered, washed with water and dried in vacuo to afford the title compound. 1H NMR (400 MHz, CDC13) δ ppm 3.76 (s, 1 H) 6.20 (s, 1 H) 7.59 - 7.72 (m, 1 H) 7.76 - 7.89 (m, 1 H) 7.98 (d, J=7.63 Hz, 1 H) 8.21 (d, J=8.17 Hz, 1 H)
Step (ii): 2-hydroxy-2-(2-nitrophenyl)acetic acid
A stirred solution of 2-hydroxy-2-(2-nitrophenyl)acetonitrile (15.26 g, 86.68 mmol) in concentrated hydrochloric acid (150 mL) was heated to reflux for 6 h. The mixture was allowed to cool to room temperature and then diluted with water. The mixture was continuously extracted with diethyl ether for 10 h. The organic phase was concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-_/6) δ ppm 5.64 (s, 1 H) 7.53 - 7.60 (m, 1 H) 7.71 - 7.79 (m, 1 H) 7.79 - 7.86 (m, 1 H) 7.95 - 8.03 (m, 1 H)
MS ES": 196
Step (Hi): methyl 2-hydroxy-2-(2-nitrophenyl)acetate
A solution o_f^hydrpxy:2-(2-ni¾ophenyl)acetic acid (15.85.g^80.40-nimol) in thionyl— chloride (100 mL, 1370 mmol) was heated to reflux for 1 hour. The reaction mixture was concentrated in vacuo. MeOH (100 mL) was added slowly to the residue. The resultant solution was heated to reflux overnight. The solution was allowed to cool and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 5-15% EtOAc/hexane to afford the title compound.
'H NMR (400 MHz, CDC13) δ ppm 3.70 (d, J=4.63 Hz, 1 H) 3.76 (s, 3 H) 5.83 (d, J=4.36 Hz, 1 H) 7.47 - 7.57 (m, 1 H) 7.61 - 7.73 (m, 2 H) 8.01 (d, J=8.17 Hz, 1 H)
MS ES+: 212
Step (iv): methyl 2-oxo-2,4-dihydro-1H-3,l-benzoxazine-4-carboxylate
A stirred suspension of methyl 2-hydroxy-2-(2-nitrophenyl)acetate (9.88 g, 46.8 mmol) and palladium on carbon (10% w/w, 1 g, 0.94 mmol) in EtOH (100 mL) was evacuated and backfilled with hydrogen. The reaction was stirred at room temperature for 2 days. The reaction mixture was filtered through a pad of diatomaceous earth, washing with further EtOH. The filtrate was concentrated in vacuo. A mixture of the residue, phosgene (20% w/v solution in toluene, 18.97 mL, 38.36 mmol) and TEA (7.64 mL, 54.80 mmol) in THF (150 mL) was stirred at room temperature overnight. TEA (25% v/v solution in MeOH, 40 mL) was added. The reaction was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc and water. The organics were dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 5-10% EtOAc/DCM to afford the title compound.
1H NMR (400 MHz, DMSO--/6) δ ppm 3.67 (s, 3 H) 6.14 (s, 1 H) 6.88 (d, J=7.90 Hz, 1 H) 7.00 - 7.10 (m, 1 H) 7.25 - 7.36 (m, 2 H) 10.34 (s, 1 H)
MS ES+: 208
Intermediate 24: lithio l-methyl-2-oxo-2,4-dihydro-1H-3,l-benzoxazine-4-carboxylate
Figure imgf000049_0001
Step (i): methyl l-methylr2-oxo-2,4rdihydro-1H-3,l-benzoxazine-4*carboxylate— " Sodium hydride (60 % dispersion in mineral oil, 0.6S1 g, 27.1 mmol) was added to a cooled (0 °C) solution of methyl 2-oxo-2,4-dihydro-1H-3,l-benzoxazine-4-carboxylate (Intermediate 23, 2.81 g, 13.6 mmol) in DMF (100 mL) under nitrogen. The reaction was stirred at 0 °C for 10 min. Methyl iodide (1.27 mL, 20.3 mmol) was added to the reaction mixture. The reaction was stirred at 0 °C for 30 min, then allowed to warm to room temperature and stirred for 18 h. The reaction was diluted with sat. aqueous NH4C1 and extracted with EtOAc. The phases were separated, the organic washed twice with 50% sat. aqueous NaCl, dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-100% EtO Ac/petroleum ether to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 3.27 (s, 3 H) 3.68 (s, 3 H) 6.15 (s, 1 H) 7.07 - 7.20
(m, 2 H) 7.34 - 7.47 (m, 2 H)
MS ES+: 222
Step (ii): lithio l-methyl-2-oxo-2,4-dihydro-1H-3,l-benzoxazine-4-carboxylate
Lithium hydroxide (0.022 g, 0.94 mmol) was added to a solution of methyl l-methyl-2- oxo-2,4-(hhydro-1H-3,l-benzoxazine-4-carboxylate (0.200 g, 0.90 mmol) in MeOH (4 mL) and water (1 mL). The reaction was stirred at room temperature overnight. Further lithium hydroxide (0.06 g, 0.2S mmol) was added to the reaction mixture. The reaction was stirred at room temperature for a further 2 h. The mixture was concentrated in vacuo to afford the title compound.
MS ES+: 208 (M-Li)
Intermediate 25: diethyl 4,5-dihydro-1H-pyrrolo[3,2,l-ij]quinoUne-6,6(2H)- dicarboxylate
Figure imgf000050_0001
Step (i): 2-chloro-l-(2,3-dihydro-1H-indol-l-yl)ethan-l-one
A solution of 2-chloroacetyl chloride (4.83 g, 42.8 mmol) in DCM (10 mL) was added drop wise over approximately 5 min to a solution of 2,3-dihydro-1H-indole (5 g, 42.0 mmol) and DIPEA (8.06 mL, 46.2 mmol) in DCM (SO mL) in an ice-water bath. The reaction was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was partitioned between water and DCM. The organic phase was sequentially passed through a pad of silica, activated charcoal and diatomaceous earth and the filtrate concentrated in vacuo to afford the title compound.
MS ES+: 196
Step (ii): diethyl 2-(2-(indolin-l-yI)-2-oxoethyl)malonate
Sodium hydride (60% dispersion in mineral oil, 0.80 g, 20.0 mmol) was added to a solution of 1,3-diethyl propanedioate (3.20 g, 20.0 mmol) in THF (50 mL). The mixture was stirred under nitrogen until effervescence ceased. A solution of 2-chloro-l-(2,3- (iihydro-1H-indol-l-yl)ethan-l-one (1.96 g, 10.0 mmol) in THF (10 mL) was added. The mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was partitioned between water and EtOAc. The organic phase was dried (MgSO-j) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 30-100% EtOAc/petroleum ether to afford the title compound.
MS ES+: 320
Step (iii): diethyl 4,5-dihydro-1H-pyrrolo[3,2,l-ij]quinoline-6,6(2H)-dicarboxylate Manganese(in) acetate dihydrate (1.104 g, 4.12 mmol) was added to a solution of diethyl 2-(2-(indolin-l-yl)-2-oxoethyl)malonate (0.263 g, 0.824 mmol) in acetic acid (20 mL). The mixture was heated at reflux in air for 3 h. The mixture was concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 30-100% EtOAc/petroleum ether to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 1.14 - 1.19 (m, 6 H) 3.05 (s, 2 H) 3.16 (t, J=8.57 Hz, 2 H) 3.92 (t, J=8.48 Hz, 2 H) 4.10 - 4.25 (m, 4 H) 6.97 - 7.04 (m, 1 H) 7.23 (d, J=8.07 Hz, 2 H)
MS ES+: 318
Intermediate 26: 8-fluoro-l-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid
Figure imgf000051_0001
Step (i): 1,3-diethyl 2-{[(2-fluorophenyl)(methyl)carbamoyl]methyl}propanedioate
A solution of 2-chloroacetyl chloride (4.79 g, 42.4 mmol) in DCM (10 mL) was added drop wise to a solution of 2-fluoro-N-methylaniline (5.2 g, 41.6 mmol) and DIPEA (7.98 mL, 45.7 mmol) in DCM (50 mL) in an ice-water bath over approximately 5 min. The reaction was stirred at room temperature for 5 min. The mixture was partitioned between water and DCM. The organic phase was dried and concentrated in vacuo. NaH (60% dispersion in mineral oil, 1.83 g, 45.8 mmol) was added portion wise to a cooled (ice-water bath) solution of 1,3-diethyl propanedioate (6.98 mL, 45.8 mmol) in THF (50 mL). The mixture was stirred under nitrogen until effervescence ceased. A solution of the previous residue in THF (10 mL) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 4h then allowed to stand for 18 h. The mixture was concentrated in vacuo and the residue partitioned between water and EtOAc. The aqueous phase was acidified to approximately pH 1 with HC1 (2N, aq), then extracted with EtOAc. The combined organic phases were dried (MgS04) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 10-30%
EtOAc/petroleum ether to afford the title compound.
MS ES+: 326
Step (ii): 8-fluoro-l-methyl-2-oxo-l,2,3,4-terrahydroquinoIine-4-carboxylic acid Manganese(in) acetate dihydrate (5.97 g, 22.3 mmol) was added to a solution of 1,3- diethyl 2-{[(2-fluorophenyl)(methyl)carbamoyl]methyl}propanedioate (3.62 g, 11.1 mmol) in acetic acid (30 mL). The mixture was heated at 100 °C in air for 30 rain, then at reflux for 1 hour. After cooling, the reaction mixture was filtered, washing with diethyl ether. The filtrate was concentrated in vacuo and dissolved in ethanol (30 mL). NaOH (2M aq, 30 mL, 60.0 mmol) was added to the mixture. The reaction was heated at 60 °C for 30 min. The mixture was concentrated in vacuo, diluted with water and extracted with DCM. The aqueous phase was filtered through activated charcoal and diatomaceous earth, washing with water. The filtrate was acidified to approximately pH 1 with HC1 (2N) and extracted with EtOAc. The combined organic phases were dried (MgS04) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-100% EtOAc/petroleum ether, and triturated with diethyl ether to afford the tide compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (d, J=4.49 Hz, 2 H) 3.26 (d, J=6.60 Hz, 3 H) 3.93 (t, J=4.63 Hz, 1 H) 7.06 - 7.25 (m, 3 H) 12.81 (br. s., 1 H)
MS ES+: 224
Intermediate 27: 5J-difluoro-l-methyl-2-oxo-l,2,3,4-tetrahydroqumoline-4- carboxylic acid 0
F. NH F. F.
VNY^CI
Step (i) ^ o Step (ii)
Figure imgf000053_0001
F
Figure imgf000053_0002
Figure imgf000053_0003
F
Step(iii)
N ;0
Figure imgf000053_0004
Step (i): 2-chloro-N-(3,5-difluorophenyl)-N-methyIacetainide
A solution of 3,5-difluoro-N-methylaniline (4.29 g, 30.0 mmol) and DIPEA (5.76 mL, 33.0 mmol) in DCM (10 mL) was added drop wise to an ice-water bath cooled solution of 2- chloroacetyl chloride (3.46 g, 30.6 mmol) in DCM (30 mL) over approximately 5 min. The mixture was allowed to warm to room temperature and stirred for a further 5 min. The mixture was partitioned between water and DCM. The organic phase was dried (MgS04) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 20-40% EtOAc/petroleum ether to afford the title compound.
•H NMR (300 MHz, DMSO-d6) δ ppm 3.23 (s, 3 H) 4.26 (br. s., 2 H) 7.16 - 7.39 (m, 3 H)
MS ES+: 220
Step (ii): 1,3-diethyl 2-{[(3,5- difluorophenyl)(methyl)carbamoyl]methyl}propanedioate
Sodium hydride (60% dispersion in mineral oil, 0.364 g, 9.11 mmol) was added portion wise to an ice-water bath cooled solution of 1,3-diethyl propanedioate (1.39 mL, 9.11 mmol) in THF (20 mL) under nitrogen. The mixture was stirred at room temperature until effervescence ceased. A solution of 2-chloro-N-(3,5-difluorophenyl)-N-methylacetamide (1.00 g, 4.55 mmol) in THF (5 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour then allowed to stand for a further 2 h. The mixture was partitioned between HC1 (2N) water and EtOAc. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organic phases were dried (MgS04) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 10-30% EtOAc/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSCwfc) δ ppm 1.16 (t, J=7.11 Hz, 6 H) 2.72 (br. s., 2 H) 3.18 (br. s., 3 H) 3.77 (t, J=7.34 Hz, 1 H) 4.04 - 4.17 (m, 4 H) 7.14 - 7.35 (m, 3 H)
MS ES+: 344
Step (iii): 5,7-difluoro-l-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid Manganese(III) acetate dihydrate (2.36 g, 8.80 mmol) was added to a solution of 1,3- diethyl 2-{[(3,5-difluorophenyl)(methyl)carbamoyl]methyl}propanedioate (1.51 g, 4.40 mmol) in acetic acid (15 mL). The mixture was heated at 120 °C in air for 30 min. After cooling, the reaction mixture was concentrated in vacuo. The residue was sequentially passed through a pad of silica, activated charcoal and diatomaceous earth, washing with EtOAc. The filtrate was concentrated in vacuo. The residue was dissolved in EtOH (5 mL) and NaOH (2M aq, 5 mL, 10.0 mmol) was added. The mixture was heated under microwave irradiation at 100 °C for 1 hour. Further sodium hydroxide (2M aq, 5 mL, 10.0 mmol) was added and the mixture heated under microwave irradiation at 100 °C for a further 30 min. The mixture was partitioned between water and DCM. The phases were separated and the aqueous phase was extracted with further DCM, acidified with HC1 (2M) and extracted with DCM and then DCM:THF (3:1). The combined organic phases were dried (MgS04) and concentrated in vacuo to afford the title compound.
lR NMR (400 MHz, DMSO-<&) δ ppm 1.91 (s, 1 H) 2.81 - 2.86 (m, 2 H) 3.21 (s, 3 H) 4.07 - 4.11 (m, 1 H) 6.89 - 6.94 (m, 1 H) 6.95 - 7.02 (m, 1 H)
MS ES+: 242
Intermediate 28; 2-chloro-N-cvcIoDropvl-N-phenvlacetamide
Figure imgf000054_0001
A mixture of bromobenzene (1.57 g, 10.0 mmol), BENAP (0.187 g, 0.300 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.092 g, 0.10 mmol) and sodium /er/-butoxide (1.44 g, 15.0 mmol) in toluene (15 mL) was degassed and a nitrogen atmosphere introduced. Cyclopropanamine (0.914 g, 16.0 mmol) was added. The resulting mixture was heated at 80 °C for 24 h. The mixture was partitioned between water and EtOAc. The organic phase was dried (MgS04) and concentrated in vacuo. The residue was dissolved in DCM (10 mL) and DIPEA (1.92 mL, 11.0 mmol) was added. The mixture was cooled in an ice-water bath and chloroacetyl chloride (0.801 mL, 10.00 mmol) in DCM (5 mL) was added drop wise. The reaction was stirred at 0 °C for 5 min. The mixture was partitioned between water and DCM. The organic phase was dried (MgS04) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 30-100% EtO Ac/petroleum ether to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 0.51 (br. s., 2 H) 0.81 (d, J=5.85 Hz, 2 H) 3.12 - 3.27 (m, 1 H) 4.41 (br. s., 2 H) 7.20 - 7.37 (m, 3 H) 7.38 - 7.47 (m, 2 H)
MS ES+: 210
Intermediate 29: l-cyclopropyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic add
Figure imgf000055_0001
Prepared as described for Intermediate 27, steps 2 and 3 using 2-chloro-N-cyclopropyl-N- phenylacetamide (Intermediate 28, 0.520 g, 2.48 mmol) to afford the title compound. 'H NMR (400 MHz, DMSCwfc) 8 ppm 0.10 - 0.22 (m, 1 H), 0.54 - 0.65 (m, 1 H), 0.88 - 0.99 (m, 1 H), 1.06 - 1.14 (m, 1 H), 2.67 - 2.76 (m, 3 H), 3.74 - 3.83 (m, 1 H), 6.95 - 7.08 (m, 1 H), 7.21 - 7.38 (m, 3 H), 12.26 - 12.87 (m, 1 H)
MS ES+: 232
Intermediate 30: methyl 2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate
Figure imgf000055_0002
Step (i): 1,3-dimethyl 2-diazopropanedioate
1,3-dimethyl propanedioate (2.72 g, 20.6 mmol) was added drop wise over 5 min to an ice- water bath cooled mixture of 4-acetamidobenzene-l-sulfonyl azide (5.0 g, 20.8 mmol) and TEA (3.07 mL, 22.0 mmol) in MeCN (30 mL). The reaction was stirred at 0 °C for 1 hour, then allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered, washing with a mixture of hexane and diethyl ether (1:1) and the filtrate concentrated in vacuo. The residue was stirred in a mixture of hexane and diethyl ether (1:1, 70 mL) for 5 min and then filtered. The filtrate was concentrated in vacuo to afford the title compound.
■H NMR (400 MHz, CDCI3) δ ppm 3.84 (s, 6 H)
Step (ii): methyl 2-methyl-3-oxo-l,2,3,4-tetrahydroisoquinoline-4-carboxylate A solution of 1,3-dimethyl 2-diazopropanedioate (0.130 g, 0.82 mmol) in MeOH (2 mL) was added drop wise to a mixture of benzyl(methyl)amine (0.100 g, 0.82 mmol), silver(I) oxide (0.021 g, 0.091 mmol) and pentamethylcyclopentadienylrhodium(III) chloride dimer (0.013 g, 0.021 mmol) in MeOH (4 mL) under nitrogen. The reaction was heated to 60 °C overnight. The reaction mixture was allowed to cool to room temperature, filtered through diatomaceous earth and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 30-40% EtOAc/hexane to afford the title compound. 1H NMR (400 MHz, CDCI3) δ ppm 3.17 (s, 3 H), 3.70 (s, 3 H), 4.27 - 4.35 (m, 1 H), 4.62 (s, 1 H), 4.84 - 4.91 (m, 1 H), 7.19 - 7.24 (m, 1 H), 7.27 - 7.35 (m, 3 H)
Intermediate 31: methyl 4-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylate
Figure imgf000056_0001
A solution of diisopropylamine (0.845 mL, 5.93 mmol) in THF (10 mL) was cooled in a dry ice/acetone bath. nBuLi (2.5M in hexanes) (2.372 mL, 5.93 mmol) was added, followed by methyl 2-methyl-3-oxo-l,2,3,4-tetrahydroisoquinoline-4-carboxylate
(Intermediate 30, 1.00 g, 4.56 mmol) in THF (15 mL) (over ca. 55 min). The mixture was stirred cold for 30 min then in an ice/water bath for 30 min and then cooled to ca. -70 °C again. A solution of NFS I (1.582 g, 5.02 mmol) in THF (10 mL) was added and the mixture stirred and allowed to warm to ca. 0 °C. Acetic acid (1.044 mL, 18.25 mmol) was added and the mixture partitioned between water and EtOAc. The organic phase was dried (MgSCU) and concentrated in vacuo. The residue was purified by column chromatography on silica, eluted with 20-50% EtOAc/petroleum ether to afford the title compound.
•H NMR (400 MHz, DMSO-d6) δ ppm 3.11 (s, 3 H), 3.69 (s, 3 H), 4.67 - 4.81 (m, 2 H), 7.38 - 7.48 (m, 3 H), 7.50 - 7.57 (m, 1 H)
MS ES+: 238
Intermediate 32: l-methyl-2-oxo-2,3,4,5-tetrabydro-1H-l-benzazepine-5-carboxylic acid
Figure imgf000057_0001
Step (i): 1,3-diethyl 2-{2-[methyl(phenyl)carbamoyl]ethyl}propanedioate
To a stirred solution of N-methylaniline (5.00 g, 46.6 mmol) and K2C03 (12.9 g, 93.3 mmol) in THF (100 mL) at 0 °C under N2 was added acryloyl chloride (4.65 g, 51.3 mmol) in a drop wise fashion. The resulting mixture was stirred at 0°C for 45 min. Diethyl malonate (37.4 g, 233 mmol) was added and the mixture was heated to reflux for 4h. EtOH(10 mL) was added and the reaction was heated to reflux for a further 48h. The reaction was cooled and partitioned between EtOAc and water. The organic phase was collected, washed three times with NaOH (1M) and brine, dried (Na2SC>4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica, eluted with 15-40% EtOAc/hexanes to afford the title compound.
'H NMR (400 MHz, CDClj) 8 ppm 1.08 - 1.27 (m, 6 H), 2.09 - 2.21 (m, 4 H), 3.20 - 3.32 (m, 3 H), 3.34 - 3.46 (m, 1 H), 4.04 - 4.18 (m, 4 H), 7.10 - 7.23 (m, 2 H), 7.30 - 7.46 (m, 3 H)
MS ES+: 322
Step (ii): 5,5-diethyl l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-l-benzazepine-5,5- dicarboxylate
Manganese(in) acetate dihydrate (7.90 g, 29.5 mmol) was added to a solution of 1,3- diethyl 2-{2-[methyl(phenyl)carbamoyl]ethyl}propanedioate (3.79 g, 11.79 mmol) in AcOH (30 mL). The mixture was heated at 100 °C in air for 1 hour. The mixture was allowed to cool and the solid material was filtered through a pad of silica (containing 1 cm, decolourising charcoal and diatomaceous earth). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica, eluted with 20-50%
EtOAc/petroleum ether. This material was further purified by column chromatography on silica, eluted with 15-40% EtO Ac/petroleum ether to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 1.09 - 1.24 (m, 6 H), 2.07 - 2.18 (m, 2 H), 2.55 - 2.96 (m, 2 H), 3.03 (s, 3 H), 3.97 - 4.34 (m, 4 H), 7.05 - 7.10 (m, 1 H), 7.25 - 7.31 (m, 1 H), 7.36 - 7.41 (m, 1 H), 7.42 - 7.48 (m, 1 H)
MS ES+: 320
Step (iii): l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-l-benzazepine-5-carboxylic acid LiOH (0.087 mg, 3.63 mmol) was added to a solution/suspension of 5,5-diethyl 1-methyl- 2-oxo-2,3,4,5-tetrahydro-1H-l-benzazepine-5,5-dicarboxylate (0.232 g, 0.726 mmol) in THF (6 mL). The mixture was stirred at room temperature for 48 h. The mixture was partitioned between HC1 (2N) and EtOAc. The organic phase was dried (MgS04) and concentrated in vacuo to afford the title compound.
MS ES+: 220
Intermediate 33: 2-cyclopropanecarbonyl-l,2^3,4-tetrahydroisoquinoIine-l-carboxylic acid (single enantiomer)
Figure imgf000058_0001
Step (i): methyl 2-cycIopropanecarbonyl-1,2,3,4-tetrahydroisoquinoline-l-carboxylate Cyclopropanecarbonyl chloride (0.50 mL, 5.51 mmol) was added to a solution of methyl 1,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (1.0 g, 4.39 mmol) and TEA (1.7 ml, 12.20 mmol) in DCM (40 mL) under nitrogen and stirred at room temperature for 1 h. The mixture was diluted with DCM and washed with saturated bicarb, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-75% EtOAc/petroleum ether to afford the title compound.
1H NMR (300 MHz, DMSO-t¼) 8 ppm 0.67 - 0.85 (m, 4 H), 2.00 - 2.16 (m, 1 H), 2.76 - 2.99 (m, 2 H), 3.57 - 3.70 (m, 3 H), 3.94 - 4.11 (m, 2 H), 5.65 - 6.23 (m, 1 H), 7.12 - 7.36 (m, 3 H), 7.39 - 7.55 (m, 1 H)
MS ES+: 260
Step (ii): 2-cyclopropanecarbonyl-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (single enantiomer)
LiOH (0.526 g, 21.98 mmol) was added to a solution of methyl 2-cyclopropanecarbonyl- 1,2,3,4-tetrahydroisoquinoline-l-carboxylate (1.14 g, 4.40 mmol) in MeCN (10 mL) and water (10 mL) and stirred for 18 h. The mixture was acidified to pH 1 with HC1 (2N) and extracted three times with EtOAc. The combined organics were washed with brine, dried (phase separator) and concentrated in vacuo. The residue was purified by chiral SFC (23% isocratic IP A + 0.3% FA, IC column) to afford the title compound as the first eluting peak.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.61 - 0.93 (m, 4 H), 0.95 - 1.11 (m, 2 H), 1.88 - 2.15 (m, 1 H), 2.70 - 3.05 (m, 2 H), 3.71 - 4.07 (m, 2 H), 7.16 - 7.31 (m, 3 H), 7.41 - 7.60 (m, 1 H)
Intermediate 34; tert-butyl N-[(lS,2S)-2-{6-fluoro-2-[(2-methyl-M-thiazol-4- yl)methyl]-l,2,3,4-tetrahydroisoquinoline-l-carboxamido}-2,3-dihydro-lH-inden-l- yl] carbamate
Figure imgf000060_0001
Step (i): ethyl 6-fluoro-2-[(2-raethyl-U-thiazol-4-yl)methyl]-1,2,3,4- tetrahydroisoquinoline-l-carboxylate
2-methylthiazole-4-carbaldehyde (0.049 g, 0.385 mmol) was added to a stirred solution of ethyl 6-fluoro-l,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (0.100 g, 0.385 mmol) and TEA (0.054 mL, 0.385 mmol) in DCM (5 mL) under nitrogen and stirred for 45 min. Sodium triacetoxyborohydride (0.163 g, 0.770 mmol) was added and stirring continued for 45 min. The reaction mixture was washed with water, dried (phase separator) and concentrated in vacuo. The residue was purified by column chromatography on silica, eluted with 0-100% EtO Ac/petroleum ether to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.20 (t, J = 7.08 Hz, 3 H), 2.62 (s, 3 H), 2.69 - 2.97 (m, 3 H), 3.32 - 3.42 (m, 1 H), 3.86 (s, 2 H), 4.12 (q, J = 7.08 Hz, 2 H), 4.52 (s, 1 H), 6.95 - 7.05 (m, 2 H), 7.18 - 7.26 (m, 1 H), 7.28 (s, 1 H)
Step (ii): 6-fluoro-2-[(2-methyl-l-3-thiazol-4-yl)methyl]-1,2,3,4- tetrahydroisoquinoline-l-carboxylic acid
LiOH (0.120 g, 5.02 mmol) was added to a stirred solution of ethyl 6-fluoro-2-[(2-methyl- l,3-miazol-4-yl)memyl]-l,2,3,4-tetrahy(koisoqumoline-l-carboxylate (0.112 g, 0.335 mmol) in dioxane (5 mL) and water (5 mL). After 4 h the reaction mixture was acidified to pH~l with HC1 (2N) and extracted with DCM and then EtOAc. The combined organics were dried (phase separator) and concentrated in vacuo to afford the title compound. lR NMR (300 MHz, DMSO-d6) δ ppm 2.61 - 2.66 (m, 3 H), 2.80 - 3.04 (m, 3 H), 3.35 - 3.46 (m, 1 H), 4.01 - 4.07 (m, 2 H), 4.60 - 4.75 (m, 1 H), 6.98 - 7.09 (m, 2 H), 7.28 - 7.38 (m, 1 H), 7.42 (s, 1 H), 11.90 - 12.12 (m, 1 H)
Step (Hi): /erf-butyl N-[(lS,2S)-2-{6-fluoro-2-[(2-methyl-M-thiazol-4-yl)niethyl]- 1,2,3,4-tetrahydroisoquinotine-l-carbox
T3P (50% in EtOAc) (0.272 mL, 0.457 mmol) was added to a stirred solution of TEA (0.093 mL, 0.685 mmol), 6-fluoro-2-[(2-methyl-l,3-thiazol-4-yl)methyl]-l,2,3,4- tetrahydroisoquinoline-1-carboxylic acid (0.070 g, 0.228 mmol) and tert-butyl ((lS,2S)-2- amino-2,3-dihydro-1H-inden-l-yl)carbamate (0.057 g, 0.228 mmol) in DCM (2 mL) and stirred for 30 min. The reaction mixture was washed with sodium bicarbonate solution, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0 - 70% EtOAc/petroleum ether to afford the title compound.
'H NMR (400 MHz, DMSO-tf*) δ ppm 1.29 - 1.49 (m, 9 H), 2.55 - 2.62 (m, 3 H), 2.63 - 2.95 (m, 4 H), 2.98 - 3.30 (m, 3 H), 3.74 - 3.89 (m, 2 H), 4.18 - 4.27 (m, 1 H), 4.36 - 4.47 (m, 1 H), 5.10 - 5.19 (m, 1 H), 6.87 - 7.03 (m, 2 H), 7.05 - 7.48 (m, 7 H)
Intermediate 35: /erf-butyl N-((lS,2S)-2-[2-(2,2-difluoroethyl)-1,2,3,4- tetrahydroisoquinoline-l-carboxamido]-2,3-dihydro-1H-inden-l-yl]carbamate
Figure imgf000061_0001
Step (i): ethyl 2-(2,3-difluoroethyl)-l^^,4-tetrahydroisoquinoline-l-carboxylate Three reactions were carried out and combined for purification. Reaction 1 : 2,2- difluoroethyl methanesulfonate (0.298 g, 1.862 mmol) was added to a stirred suspension of ethyl 1,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (0.300 g, 1.241 mmol) and K2CO3 (0.343 g, 2.482 mmol) in MeCN (10 mL) and heated to 60°C for 18h. DIPEA (0.434 mL, 2.482 mmol) and 2,2-difluoroethyl methanesulfonate (0.298 g, 1.862 mmol) were added and the reaction stirred at 60°C for 6 h. The reaction was heated to 80 °C and left overnight. The reaction mixture was heated in the microwave at 160 °C for lhr.
Reaction 2: 2,2-difluoroethyl methanesulfonate (0.331 g, 2.069 mmol) was added to a vial containing a solution of ethyl 1,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (0.100 g, 0.414 mmol) and DEPEA (0.361 mL, 2.069 mmol) in MeCN (2 mL). The reaction was heated in the microwave to 160°C for 30 min. The reaction was heated for a further 30 min at 160°C.
Reaction 3: l,l-difluoro-2-iodoethane (1.00 g, S.21 mmol) was added to a vial containing a suspension of ethyl 1,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (0.2S2 g, 1.042 mmol) and DIPEA (0.910 mL, S.21 mmol) in MeCN (S mL), and this was heated in the microwave to 160 °C for 30 min.
The reaction mixtures of the three reactions were combined and partitioned between DCM and water. The organic phase was dried (phase separator) and concentrated in vacuo prior to purification by column chromatography on silica, eluted with 0 - 50% EtOAc/petroleum ether to afford the title compound.
JH NMR (400 MHz, DMSO-d6) 8 ppm 1.17 - 1.22 (m, 3 H), 2.65 - 2.78 (m, 1 H), 2.82 - 2.97 (m, 2 H), 2.98 - 3.13 (m, 2 H), 3.39 - 3.52 (m, 1 H), 4.07 - 4.19 (m, 2 H), 4.64 (s, 1 H), 5.94 - 6.30 (m, 1 H), 7.11 - 7.28 (m, 4 H)
Step (ii): 2-(2,2-difluoroethyl)-l^i,3,4-tetrahydroisoquinoline-l-carboxylic acid
LiOH (0.222 g, 9.28 mmol) was added to a stirred solution of ethyl 2-(2,2-difluoroethyl)- 1,2,3,4-tetrahydroisoquinoline-l-carboxylate (0.250 g, 0.928 mmol) in dioxane (2 mL) and water (2mL) and stirred for 18h. The reaction mixture was acidified with HC1 (2N) to pH~l and extracted with EtOAc. Organics passed through a phase separator and concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-d6) 8 ppm 2.61 - 2.77 (m, 1 H), 2.81 - 2.95 (m, 2 H), 3.01 - 3.16 (m, 2 H), 3.37 - 3.54 (m, 1 H), 4.48 - 4.65 (m, 1 H), 5.95 - 6.32 (m, 1 H), 7.09 - 7.24 (m, 3 H), 7.26 - 7.36 (m, 1 H), 12.26 - 13.14 (m, 1 H)
Step (iii): tert-butyl N-[(lS^S)-2-[2-(2^difluoroethyl)-l^,4-tetrahydroisoquinoUne- l-carboxamido]-2,3-dihydro-lH-inden-l-yl]carbamate
TCP (50% in EtOAc) (0.987 ml, 1.658 mmol) was added to a stirred solution of 2-(2,2- difluoroethyl)-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (0.200 g, 0.829 mmol), TEA (0.336 mL, 2.487 mmol) and fer/-butyl ((lS,2S)-2-amino-2,3-dihydro-1H-inden-l- yl)carbamate (0.206 g, 0.829 mmol) in DCM. After stirring for 30 min the reaction was washed with saturated sodium bicarbonate solution and purified by column
chromatography on silica, eluted with 0 - 70% EtOAc/petrol to afford the title compound.
1H NMR (400 MHz, DMSO-d6) 8 ppm 1.30 - 1.50 (m, 9 H), 2.56 - 3.13 (m, 7 H), 3.37 - 3.52 (m, 1 H), 4.25 - 4.39 (m, 2 H), 5.01 - 5.22 (m, 1 H), 6.03 - 6.41 (m, 1 H), 7.03 - 7.37 (m, 9 H), 8.46 - 8.60 (m, 1 H)
Intermediate 36: fer/-butyl N-[(lS,2S)-2-{2-[(l-methyl-1H-pyrazol-5-yl)methyl]- l^,4-tetrahydroisoquinoIine-l-carboxamido}-2,3-dihydro-1H-inden-l-yl]carbamate
Figure imgf000063_0001
H
Figure imgf000063_0002
Prepared as described for /erf-butyl N-[(lS,2S)-2-{6-fluoro-2-[(2-methyl-l,3-thiazol-4- yl)methyl]- 1 ,2,3,4-tetrahydroisoquinoline-l -amido} -2,3-dihydro- 1H-inden- 1 -yl]carbamate (Intermediate 34) using l-methyl-1H-pyrazole-5-carbaldehyde (0.228 g, 2.069 mmol) and ethyl 1,2,3,4-tetrahydroisoquinoline-l-carboxylate hydrochloride (0.500 g, 2.069 mmol) to afford the title compound.
1H NMR (400 MHz, CD2C12) δ ppm 1.59 (s, 10 H), 2.09 - 2.19 (m, 2 H), 2.21 - 2.28 (m, 3 H), 2.44 - 2.56 (m, 1 H), 2.66 - 2.81 (m, 2 H), 3.29 - 3.56 (m, 2 H), 5.39 - 5.46 (m, 1 H), 5.85 - 6.11 (m, 2 H), 7.02 - 7.12 (m, 2 H), 7.15 - 7.24 (m, 2 H), 7.28 - 7.37 (m, 2 H), 7.38 - 7.50 (m, 2 H), 7.69 - 7.80 (m, 2 H), 8.19 - 8.37 (m, 2 H)
Intermediate 37: tert-butyl N-[(lS^S)-2-{2-[(pyrimidin-5-yl)methyl]-1,2,3,4- tetrahydroisoquinoline-l-carboxamido}-2,3-dihydro-1H-inden-l-yl]carbamate
Figure imgf000064_0001
Prepared as described for /er/-butyl N-[(lS,2S>2-{6-fluoro-2-[(2-methyl-l,3-thiazoI-4- yl)methyl]- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamido} -2,3-dihydro- 1 H-inden- 1 - yl]carbamate (Intermediate 34) using pyrimidine-5-carbaldehyde (0.224 g, 2.069 mmol) and ethyl 1,2,3 ,4-tetrahydroisoquinoline- 1-carboxylate hydrochloride (0.S00 g, 2.069 mmol) to afford the title compound.
'H NMR (300 MHz, OUSO-de) δ ppm 1.27 - 1.37 (m, 9 H), 2.68 - 3.27 (m, 6 H), 3.53 - 3.69 (m, 1 H), 3.82 - 3.96 (m, 1 H), 4.14 - 4.52 (m, 2 H), 5.06 - 5.28 (m, 1 H), 7.03 - 7.41 (m, 9 H), 8.45 - 8.64 (m, 1 H), 8.83 - 8.93 (m, 2 H), 9.09 - 9.17 (m, 1 H)
Intermediate 38: N-((trans)-l-methoyv-2,3-dihvdro-1H-inden-2-vn-1.23.4- tetrahydroisoquinoline-l-carboxamide hydrochloride
Figure imgf000064_0002
Step (i): /erf-butyl l-[((trans)-l-methozy-2,3-dihydro-1H-inden-2-yl)carbamoyI]- l,2,3,4-tetrahydroisoquinoline-2-carboxylate
T3P (50% in EtOAc) (3.22 mL, 5.41 mmol) was added to a solution of 2-(/eri- butoxycarbonyl)-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (1.00 g, 3.61 mmol),(trans)- l-methoxy-2,3-dihydro-1H-inden-2-amine (Intermediate 2, 0.647 g, 3.97 mmol) and TEA (0.754 mL, 5.41 mmol) in DCM (20 mL). The reaction was stirred at room temperature for 1.5 h. The mixture was partitioned between DCM and saturated NaHCCh, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-50% EtOAc/petroleum ether to afford the title compound. 'Η NMR (300 MHz, DMSO-4s) δ ppm 1.34 - 1.50 (m, 9 H), 2.66 - 2.83 (m, 2 H), 2.94 - 3.09 (m, 1 H), 3.13 - 3.28 (m, 3 H), 3.34 - 3.39 (m, 1 H), 3.45 - 3.66 (m, 1 H), 3.82 - 3.96 (m, 1 H), 4.20 - 4.37 (m, 1 H), 4.60 - 4.74 (m, 1 H), 5.17 - 5.41 (m, 1 H), 7.13 - 7.37 (m, 7 H), 7.40 - 7.59 (m, 1 H), 8.57 - 8.80 (m, 1 H)
MS ES+: 445 (M+Na)
Step (ii): N-((/ra/t5)-l-methoxy-2,3-dihydro-1H-inden-2-yl)-1,2,3,4- tetrahydroisoquinoline-l-carboxamide hydrochloride
HC1 (4N in dioxane) (3.64 mL, 14.56 mmol) was added to a suspension of /er/-butyl 1- [((transy 1 -methoxy-2,3-dihydro- 1 H-inden-2-yl)carbamoyl]- 1 ,2,3 ,4- tetrahydroisoquinoline-2-carboxylate (1.23 g, 2.91 mmol) in MeOH (20 mL). DCM (5 mL) was added to aid solubility. The reaction was stirred at room temperature for 18 h. A further 0.5 mL HC1 (4N in dioxane) was added and the reaction stirred for 1 hour. The solution was concentrated in vacuo and azeotroped with toluene to afford the title compound.
1H NMR (400 MHz, DMSO) δ 2.76 - 2.89 (m, 1 H), 2.92 - 3.01 (m, 1 H), 3.06 - 3.20 (m, 1 H), 3.34 - 3.44 (m, 3 H), 3.46 (s, 1 H), 3.62 - 3.76 (m, 1 H), 4.38 - 4.49 (m, 1 H), 4.73 - 4.83 (m, 1 H), 4.98 - 5.09 (m, 1 H), 7.10 - 7.45 (m, 7 H), 9.40 - 9.55 (m, 1 H)
MS ES+: 323
Intermediate 39; l-(cycIopropylmethyl)-2-oxo-2,4-dihydro-1H-3,l-benzoxazine-4- carboxylic acid
Figure imgf000065_0001
Step (i): methyl l-(cyclopropylmethyl)-2-oxo-2,4-dihydro-1H-3,l-benzoxazine-4- carboxylate
NaH (60% dispersion in mineral oil, 0.077 g, 1.931 mmol) was added to a solution of methyl 2-oxo-2,4-dihydro-1H-3,l-benzoxazine-4-carboxylate (Intermediate 23, 0.20 g, 0.96S mmol) in DMF (5 mL) under nitrogen at 0 °C. The reaction was stirred at 0 °C for 10 min, then (bromomethyl)cyclopropane (0.140 mL, 1.448 mmol) was added and the reaction stirred for 1 hour. The reaction was stirred for a further 6 h. The mixture was partitioned between EtOAc and water. The phases were separated and the aqueous extracted twice with EtOAc. The combined organics were washed with half saturated brine, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-50% EtOAc/petroleum ether to afford the title compound.
1H NMR (400 MHz, CD3OD) δ ppm 0.35 - 0.63 (m, 4 H), 1.23 - 1.29 (m, 1 H), 3.75 (s, 3 H), 3.86 - 3.93 (m, 2 H), 5.94 (s, 1 H), 7.13 - 7.21 (m, 1 H), 7.22 - 7.31 (m, 1 H), 7.37 - 7.49 (m, 2 H)
MS ES+: 262
Step (ii): l-(cyclopropyImethyl)-2-oxo-2,4-dihydro-1H-3,l-benzoxazine-4-carboxylic acid
LiOH (0.022 g, 0.919 mmol) was added to a solution of methyl l-(cyclopropylmethyl)-2- oxo-2,4-dihydro-1H-3,l-benzoxazine-4-carboxylate (0.048 g, 0.184 mmol) in MeCN (1 mL) and water (1 mL) and stirred for 18 h. The mixture was acidified to pH 1 with HC1 (2N) and extracted three times with EtOAc. The combined organics were washed with brine, dried (phase separator) and concentrated in vacuo, to afford the title compound. •H NMR (400 MHz, CD2C12) 8 ppm 0.21 - 0.57 (m, 4 H), 1.06 - 1.20 (m, 1 H), 3.71 - 3.86 (m, 2 H), 6.25 - 6.42 (m, 2 H), 7.03 - 7.18 (m, 2 H), 7.32 - 7.47 (m, 2 H)
MS ES+: 248
Intermediate 40: (cw)-2-azido-2,3-dihydro-1H-inden-l-ol
OH OH
Figure imgf000066_0001
Trans C1s
Step (i): (trans)-2-bromo-2,3-dihydro-1H-inden-l-ol
NBS (25.2 g, 141 mmol) was added portion wise to a solution of 1H-indene (15.0 mL, 129 mmol) in THF (150 mL) and water (150 mL). The reaction was stirred at room temperature over 4 days open to the air. The mixture concentrated in vacuo then partitioned between EtOAc and water. The phases were separated and the aqueous extracted twice with EtOAc. The combined organics were washed with saturated Na2S203, brine, dried (MgSC^) and concentrated in vacuo. The crude material was triturated with diethyl ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.04 - 3.16 (m, 1 H), 3.50 - 3.63 (m, 1 H), 4.27 - 4.36 (m, 1 H), 5.06 - 5.13 (m, 1 H), 5.94 - 6.00 (m, 1 H), 7.20 - 7.31 (m, 3 H), 7.32 - 7.40 (m, 1 H)
Step (u): (c/s)-2-azido-2,3-dihydro-1H-inden-l-ol
A suspension of (/ra«i)-2-bromo-2,3-dihydro-1H-inden-l-ol (10.0 g, 46.9 mmol) and sodium azide (3.36 g, 51.6 mmol) in DMSO (100 mL) was heated to 60 °C for 1.5 h. The mixture was partitioned between diethyl ether and water. The phases were separated and the aqueous extracted three times with diethyl ether. The combined organics were washed with water, half saturated brine, and brine, dried (MgS04) and concentrated in vacuo to afford a pale yellow solid. A suspension of the solid in DMSO (lOOmL) was treated with sodium azide (2.288 g, 35.2 mmol) and heated to 60 °C for 2 h. The reaction was cooled and partitioned between diethyl ether and water. The phases were separated and the aqueous extracted three times with diethyl ether. The combined organics were washed with water, half saturated brine, and brine, dried (MgS04) and concentrated in vacuo to afford the title compound.
•H NMR (300 MHz, CDC13) δ ppm 2.31 - 2.37 (m, 1 H), 3.08 - 3.29 (m, 2 H), 4.31 - 4.41 (m, 1 H), 5.12 - 5.23 (m, 1 H), 7.27 - 7.34 (m, 3 H), 7.40 - 7.52 (m, 1 H)
Intermediate 41: (cw)-2-amino-2,3-dihydro-1H-inden-l-ol
OH OH
Figure imgf000067_0001
Cis Cis
A suspension of (c/i)-2-azido-2,3-dihydro-1H-inden-l-ol (Intermediate 40, 0.400 g, 2.283 mmol) and palladium on carbon (10% w/w) (0.243 g, 0.228 mmol) in EtOH (10 mL) was evacuated and purged with nitrogen three times, then stirred under an atmosphere of hydrogen for 2 h. The suspension was filtered through diatomaceous earth and
concentrated in vacuo. The crude product was loaded onto a cation exchange cartridge, washed with methanol and eluted with 2M NH3/MeOH solution then concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-c¾) 6 ppm 1.40 - 2.10 (m, 2 H), 2.54 - 2.65 (m, 1 H), 2.86 - 3.04 (m, 1 H), 3.15 - 3.51 (m, 1 H), 4.48 - 4.69 (m, 1 H), 5.10 - 5.54 (m, 1 H), 7.09 - 7.21 (m, 3 H), 7.28 - 7.36 (m, 1 H)
Intermediate 43; (4S)-N-((c/s)-l-hydroxy-2,3-dihydro-1H-inden-2-yl)-l-niethyl-2-oxo- 1,2,3,4-tetrahydroquinoline-4-carboxamide
Figure imgf000068_0001
OH
cis
Figure imgf000068_0002
COlVfU (1.38 g, 3.22 mmol) was added to a stirred solution of (4S)-l-methyl-2-oxo- l,2,3,4-tetrahydroquinoline-4-carboxylic acid (Intermediate 1, 0.600 g, 2.92 mmol), (cis)- 2-amino-2,3-dihydro-1H-inden-l-ol (Intermediate 41, 0.436 g, 2.92 mmol) and 2,2,6,6- tetramethylpiperidine (0.413 g, 2.92 mmol) in DCM (15 mL) and stirred for 1 h. The reaction mixture was washed with water and purified by column chromatography on silica, eluted with 0-100% EtOAc/petroleum ether to afford the title compound.
MS ES_: 335
Intermediate 44: (4SVN-fflS.2SVl-amino-2,3-dihvdro-1H-inden-2-vI1-l-methvl-2- oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide
Step (i): tert-butyl N-[(lS,2S)-2-[(4S)-l-methyl-2-oxo-1,2,3,4-tetrahydroquinoUne-4- amido]-2,3-dihydro-1H-inden-l-yl]carbamate
Prepared as described for (4S)-N-((cw)-l-hydroxy-2,3-dihydro-1H-inden-2-yI)-l-methyl- 2-oxo-l, 2,3 ,4-tetrahydroquinoline-4-carboxamide Intermediate 43 using (4S)-l-methyl-2- oxo-1, 2,3 ,4-tetrahydroquinoline-4-carboxylic acid (Intermediate 1, 0.SOg, 2.44 mmol) to afford the title compound.
1H NMR (400 MHz, OMSO-d6) δ ppm 1.35 - 1.49 (m, 9 H), 2.61 - 2.73 (m, 3 H), 3.11 - 3.22 (m, 1 H), 3.23 (s, 3 H), 3.79 (s, 1 H), 4.24 - 4.39 (m, 1 H), 4.96 - 5.05 (m, 1 H), 6.90 - 7.03 (m, 1 H), 7.06 - 7.13 (m, 2 H), 7.15 - 7.25 (m, 3 H), 7.27 - 7.37 (m, 3 H), 8.57 - 8.68 (m, 1 H)
Step (ii): (4S)-N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-l-methyl-2-oxo-1,2,3,4- tetrahydroquinoline-4-carboxamide
HC1 (4N in dioxane) (5.04. mL, 20.15_mmol)_was added to a stirred solution of-tert-butyl- N-[(lS,2S)-2-[(4S)-l-meAyl-2-oxo-l,2,3,4-tetrahydroquinoline^-mido]-2,^
inden-l-yl]carbamate (1.07 g, 2.015 mmol) in DCM (10 mL) and stirred at room temperature for 18 h. The reaction was partitioned between DCM and sodium bicarbonate solution. The organics were collected, dried (phase separator) and concentrated in vacuo to afford the title compound.
'H NMR (400 MHz, DMSCwfc) 8 ppm 1.99 - 2.19 (m, 2 H), 2.57 - 2.67 (m, 1 H), 2.69 - 2.74 (m, 2 H), 3.15 - 3.26 (m, 4 H), 3.77 - 3.84 (m, 1 H), 3.89 - 3.99 (m, 1 H), 4.03 - 4.10 (m, 1 H), 7.01 - 7.07 (m, 1 H), 7.08 - 7.12 (m, 1 H), 7.16 - 7.24 (m, 3 H), 7.28 - 7.33 (m, 2 H), 7.37 - 7.42 (m, 1 H), 8.45 - 8.57 (m, 1 H)
Intermediate 45: l,3-dimethyl-2-oxo-l^,4-tetrahydroquinoline-4-carboxylic acid Step (iii) N .0
■JO
Figure imgf000070_0001
Figure imgf000070_0002
Step (iv)
N ;0
Figure imgf000070_0003
O^OH
Step (i): 2-bromo-N-methyl-N-phenylpropanamide
To a solution of N-methylaniline (6.25g, 58.3 mmol) in DCM (40 mL) at 0°C was added TEA^(-12;5 mL, 89rl-mmol) foUowed-by 2-bromopropanoyl chloride (i0.0 g, 58.3 mmol) in a drop wise fashion. The reaction was warmed to room temperature for 2 h. HC1 (2M, aq) was added and stirred for 5 min. The organic phase was separated, washed with brine, dried (Na2SC>4) and concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, CDC13) 5 ppm 1.68 - 1.80 (m, 3 H), 3.30 (s, 3 H), 4.21 - 4.33 (m, 1 H), 7.28 - 7.33 (m, 2 H), 7.38 - 7.50 (m, 3 H)
Step (ii): 1 ^-diethyl 2-{l-[methyl(phenyl)carbamoyl]ethyl}propanedioate
To a stirring solution of diethyl malonate (9.02 mL, S9.0 mmol) in THF (1000 mL) at room temperature was added potassium tert-butoxide (6.63g, S9.0 mmol). The reaction was stirred at room temperature for 10 min and 2-bromo-N-methyl-N-phenylpropanamide (13.0 g, S3.7 mmol) was added. The reaction was stirred at room temperature for 1 hour and then heated to reflux for 2 h. The reaction was partitioned between EtOAc and water. The organic phase was collected, dried (Na2S04) and concentrated in vacuo to afford the title compound.
•H NMR (400 MHz, CDC13) δ ppm 0.91 - 1.02 (m, 3 H), 1.23 - 1.33 (m, 6 H), 3.06 - 3.20 (m, 1 H), 3.26 (s, 3 H), 3.83 - 3.92 (m, 1 H), 4.11 - 4.27 (m, 4 H), 7.34 - 7.49 (m, 5 H) Step (iii): 4,4-diethyl l,3-dimethyl-2-oxo-l,2,3,4-tetrahydroquinoline-4,4- dicarboxylate
To a stirring solution of 1,3-diethyl 2-{l-[methyl(phenyl)carbamoyl]ethyl}propanedioate (5.0 g, 15.6 mmol) in AcOH (250 mL) was added Mn(OAc)3.2H20 (25g, 93.6 mmol) under N2 and the reaction was stirred at reflux for 4 h. The reaction was concentrated in vacuo and the resulting residue was partitioned between water and DCM. The aqueous phase was further extracted with DCM and the combined organics were dried (Na2S04) and concentrated in vacuo. The resulting residue was passed through a pad of silica, eluted with 0-5% MeOH in DCM to afford the title compound.
1H NMR (400 MHz, CDC13) 8 ppm 1.19 - 1.25 (m, 9 H), 3.35 (s, 3 H), 4.09 - 4.32 (m, 5 H), 6.96 - 7.04 (m, 1 H), 7.08 - 7.16 (m, 1 H), 7.31 - 7.40 (m, 1 H), 7.52 - 7.60 (m, 1 H)
Step (iv): 13-dimethyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxylic acid
To a solution of 4,4-diethyl !,3-dimelhyl-2-oxo__ 1 ,2,3 ,4-tetrahydroquinoline^4,4-— — dicarboxylate (2 g, 6.26 mmol) in EtOH (80 mL) at 0°C was added KOH (10%, aq) (15 mL). The reaction was warmed to room temperature and then heated to reflux for 2.5 h. The reaction was concentrated in vacuo and the resulting solution was acidified (25% cone. HC1, aq) and extracted twice with EtOAc. The organics were combined, dried (Na2S04) and concentrated in vacuo. The resulting residue was dried under vacuum and triturated with cold Et20 to afford the title compound. l¥L NMR (400 MHz, CDCI3) δ ppm 1.14 - 1.21 (m, 3 H), 3.06 - 3.18 (m, 1 H), 3.35 (s, 3 H), 3.55 - 3.61 (m, 1 H), 6.95 - 7.13 (m, 2 H), 7.27 - 7.38 (m, 2 H), 8.35 - 9.08 (m, 1 H)
Intermediate 46: l-cyclopropyl-7-fluoro-3-methyl-2-oxo-1,2,3,4-tetrahydroquinoline- 4-carboxylic acid (single diastereomer) Step(i) lV,VBr step (ii) F
Figure imgf000072_0001
Figure imgf000072_0002
Figure imgf000072_0003
Step (iv)
Figure imgf000072_0004
O^OH
Step (i): methyl 2-(2-bromo-4-fluorophenyl)acetate
To a stirred solution of 2-(2-bromo-4-fluorophenyl)acetic acid (5 g, 21.46 mmol) in MeOH (SO mL) was added cone. H2S04 (10 drops) and the reaction was stirred at room temperature for 18 h. A further 10 drops of cone. H2S04 were added and the reaction was stirred at room temperature for a further 24 h. The mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc and saturated NaHC03 solution. The organic phase was collected, dried (Na2S04) and concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, CDC13) δ ppm 3.72 (s, 3 H), 3.77 (s, 2 H), 6.97 - 7.06 (m, 1 H), 7.25 - 7.29 (m, 1 H), 7.30 - 7.35 (m, 1 H)
Step (ii): 1-tert-butyl 4-methyl 3-(2-bromo-4-fluorophenyl)-2-methyIbutanedioate
Sodium hydride (60% dispersion in mineral oil) (1.02 g, 25.43 mmol) was added to a solution of methyl 2-(2-bromo-4-fluorophenyl)acetate (5.24 g, 21.19 mmol) and 1,3- dimethyl-3,4,5,6-tetrahyaYo-2(lH)-pyrimidinone (2.56 mL, 21.19 mmol) in anhydrous THF (50 mL). The reaction mixture was stirred for 15 min. before a solution of tert-butyl- 2-bromopropionate (5.32 g, 25.43 mmol) in anhydrous THF (5 mL) was added to it. The reaction mixture was stirred at room temperature overnight. The reaction mixture was heated to 60°C for a further 24 h. After that time, the mixture was cooled to room temperature and poured onto water. The mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated in vacuo. The crude material was purified by column chromatography on silica, eluted with 10% EtOAc/hexane to afford the title compound.
•H NMR (400 MHz, CDCb) 8ppm 0.87 - 1.01 (m, 2 H), 1.19 (s, 4 H), 1.23 - 1.29 (m, 1 H), 1.46 (s, 5 H), 2.92 - 3.23 (m, 1 H), 3.55 - 3.72 (m, 3 H), 4.29 - 4.46 (m, 1 H), 6.94 - 7.07 (m, 1 H), 7.26 - 7.49 (m, 2 H)
Step (iii): 3-(2-bromo-4-fluorophenyl)-4-methoxy-2-methyl-4-oxobutanoic acid
HQ (4N in dioxane) (58.3 mL, 0.23 mol) was added to a stirred solution of 1-tert-butyl 4- methyl 3-(2-bromo-4-fluorophenyl)-2-methylbutanedioate (5.83 g, 15.54 mmol) in DCM (20 mL). The resulting mixture was stirred at 40°C over the weekend. The reaction was concentrated in vacuo. The crude material was purified by column chromatography on silica, eluted with 2-4% MeOH/DCM to afford the title compound.
1H NMR (400 MHz, CDC13) δ ppm 0.96 - 1.34 (m, 3 H), 3.11 - 3.24 (m, 1 H), 3.67 - 3.73 (m, 3 H), 4.39 - 4.58 (m, 1 H), 6.98 - 7.09 (m, 1 H), 7.19 - 7.43 (m, 2 H)
Step (iv): methyl 2-(2-bromo-4-fluorophenyl)-3-(cyclopropylcarbamoyl)-3- methylpropanoate
Cyclopropylamine (3.95 mL, 57.03 mmol) was added drop wise to a stirred solution of 3- (2-bromo-4-fluorophenyl)-4-methoxy-2-methyl-4-oxobutanoic acid (4.55 g, 14.26 mmol), EDC .HC1 (4.10 g, 21.39 mmol), 4-(dimethylamino)pyridine (1.74 g, 14.26 mmol) and TEA (4 mL, 28.52 mmol) in anhydrous DCM (200 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with DCM, washed with water, dried (Na2S04) and concentrated in vacuo. The crude material was purified by column chromatography on silica, eluted with 2-5% MeOH/DCM to afford the title compound.
'H NMR (400 MHz, CDC13) δ ppm 0.46 - 0.69 (m, 2 H), 0.74 - 0.84 (m, 2 H), 0.87 - 1.03 (m, 3 H), 2.66 - 2.90 (m, 2 H), 3.59 - 3.71 (m, 3 H), 4.34 - 4.59 (m, 1 H), 5.35 - 5.82 (m, 1 H), 6.94 - 7.09 (m, 1 H), 7.28 - 7.45 (m, 2 H)
Step (v): methyl l-cyclopropyl-7-fluoro-3-methyl-2-oxo-1,2,3,4-tetrahydroquinoline- 4-carboxylate
A mixture of methyl 2-(2-bromo-4-fluorophenyl)-3-(cyclopropylcarbamoyl)-3- methylpropanoate (2.74 g, 7.64 mol), K2C03 (3.17 g, 22.92 mmol), chloro(2- dicyclohexylphosphino-2',4^6'-1riisopropyl- 1 , 1 '-biphenyl)[2-(2 '-amino- 1 , Γ- biphenyl)]palladium(II) (1.20 g, 1.S3 mmol) and XPhos (1.46 g, 3.06 mmol) in toluene (200 mL) was heated to 110°C in a sealed tube for 26 h. The mixture was allowed to cool to room temperature and it was stirred for 72 h. The mixture was partitioned between DCM and water. The organic phase was dried (Na2S04) and concentrated in vacuo. The crude material was purified by column chromatography on silica, eluted with (0-1%
MeOH/DCM to afford the title compound.
MS ES+: 278
Step (vi): l-cyclopropyl-7-fluoro-3-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4- carboxylic acid (single diastereomer)
LiOH.H20 (0.96S g, 22.99 mmol) was added to a stirred solution of methyl 1-cyclopropyl- 7-fluoro-3-methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxylate (3.19 g) in THF:H20 (4:1) (SO mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between diethyl ether and water. The aqueous layer was acidified to pH 2 with HC1 (IN, aq). The aqueous layer was extracted twice with EtOAc. The organics were combined, washed with brine, dried (Na2SC>4) and concentrated in vacuo. The crude material was purified by column chromatography on silica, eluted with 0-5% MeOH/DCM. The resulting residue was further purified by reverse phase preparative HPLC to afford the title compound.
JH NMR (400 MHz, CDC13) δ ppm 0.36 - 0.51 (m, 1 H), 0.75 - 0.87 (m, 1 H), 0.92 - 1.08 (m, 1 H), 1.11 - 1.23 (m, 4 H), 2.64 - 2.80 (m, 1 H), 2.99 - 3.12 (m, 1 H), 3.39 - 3.50 (m, 1 H), 6.68 - 6.81 (m, 1 H), 6.98 - 7.09 (m, 1 H), 7.14 - 7.22 (m, 1 H)
Intermediate 47: 2-(cyclopropylmethyl)-N-((cw)-l-hydroxy-2,3-dihydro-1H-inden-2- yI)-3-oxo-1,2,3,4-tetrahydroisoquinoline-l-carboxamide
Figure imgf000074_0001
O' NH Prepared as described for (4S)-N-((cw)-l-hydroxy-2,3-ihydro-1H-inden-2-yl)-l-methyl- 2-oxo-l, 2,3 ,4-tetrahydroquinoline-4-carboxamide (Intermediate 43) using 2- (cyclopropylmethyl)-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid
(Intermediate 14, 0.426 g, 1.737 mmol) and (cw)-2-ammo-2,3-dihydro-1H-inden-l-ol (Intermediate 41, 0.28S g, 1.911 mmol) to afford the title compound.
'H NMR (400 MHz, DMSO-Ji) δ ppm 0.11 - 0.51 (m, 4 H), 0.89 - 1.05 (m, 1 H), 2.82 - 2.98 (m, 1 H), 2.99 - 3.10 (m, 2 H), 3.16 - 3.28 (m, 1 H), 3.36 - 3.60 (m, 2 H), 3.84 - 3.96 (m, 1 H), 4.17 - 4.34 (m, 1 H), 4.75 - 4.91 (m, 1 H), 5.34 - 5.50 (m, 2 H), 7.09 - 7.29 (m, 6 H), 7.32 - 7.60 (m, 1 H), 8.31 - 8.54 (m, 1 H)
Intermediate 48; /erf-butyl N-((/ra«5)-2-amino-7-fluoro-23-dihydro-1H-inden-l-yl)- N-methylcarbamate
Step (i) K Step (iv)
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000075_0003
Figure imgf000075_0005
-N NH2
Figure imgf000075_0006
Figure imgf000075_0004
Step (i): 7-fluoro-2,3-dihydro-1H-inden-l-ol
LiAlHU (1M in THF) (36.6 mL, 36.6 mmol) was added to an ice-water bath cooled solution of 7-fluoro-2,3-dihydro-1H-inden-l-one (5.0 g, 33.3 mmol) in diethyl ether (100 mL) under nitrogen. The reaction was stirred in the ice-water bath for 90 minutes. Water (5 mL) was added drop wise to the cold reaction mixture over 30 minutes. The mixture was filtered through diatomaceous earth, washing with further diethyl ether, then concentrated in vacuo to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 1.85 - 1.95 (m, 1 H), 2.20 - 2.33 (m, 1 H), 2.70 - 2.81 (m, 1 H), 2.99 - 3.11 (m, 1 H), 5.22 - 5.28 (m, 1 H), 6.88 - 6.99 (m, 1 H), 7.03 - 7.10 (m, 1 H), 7.23 - 7.31 (m, 1 H) MS ES": 151
Step (ii): 4-fluoro-1H-indene p-Toluenesulfonic acid monohydrate (0.520 g, 2.73 mmol) was added to a solution of 7- fluoro-2,3-dihydro-1H-inden-l-ol (4.16 g, 27.3 mmol) in Toluene (50 mL) under nitrogen. The reaction was heated to reflux with Dean-Stark apparatus for 4 hours. The reaction mixture was allowed to cool to room temperature and the contents of the Dean-Stark trap were returned to the reaction mixture. The reaction mixture was washed with NaHCC>3, dried (phase separator) and most of the toluene was removed by fractional distillation. The residue was purified by column chromatography on silica, eluted with 100% petrol to afford the title compound as a 41% mixture in toluene.
Figure imgf000076_0001
Freshly prepared ter/-butyl hypochlorite (0.778 mL, 6.88 mmol) was added to a mixture of 2-(trimethylsilyl)ethanesulfonamide (0.831 g, 4.58 mmol), 4-fluoro-1H-indene (~41 wt% in toluene) (1.5 g, 4.58 mmol) and sodium iodide (1.031 g, 6.88 mmol) in MeCN (45 mL) under nitrogen, in dim light. The reaction was stirred at room temperature for 2.5 hours. The reaction was quenched with sat aq. sodium thiosulfate and extracted with ethyl acetate. The organic extract was dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-20% ethyl acetate/petroleum ether to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 0.03 (s, 9 H), 0.92 - 1.02 (m, 2 H), 3.13 - 3.28 (m, 4 H), 3.87 - 3.93 (m, 1 H), 4.33 - 4.39 (m, 1 H), 7.03 - 7.17 (m, 2 H), 7.29 - 7.39 (m, 1 H) MS ES+: 314
Step (iv): N-[7-fluoro-l-(methylamino)-(trans)-2,3-dihydro-1H-inden-2-yl]-2- (trimethylsilyl)ethane-l-sulfonamide Lithium perchlorate (11 mg, 0.103 mmol) was added to a solution of 2-fluoro-l-[2-
Figure imgf000077_0001
mmol) and methanamine (2M solution in THF) (1.014 mL, 2.029 mmol) in Acetonitrile (2 mL) in a microwave vial. The vial was sealed and the reaction was heated to 35 °C from for 4.S hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organics were dried (phase separator) and concentrated in vacuo. The crude product was loaded onto a cation exchange cartridge, washed with methanol and eluted with 2M ammonia/methanol solution then concentrated in vacuo to afford the title compound.
'H NMR (400 MHz, CD2Cl2-d6) δ ppm 0.08 (s, 9 H), 0.98 - 1.10 (m, 2 H), 1.86 - 2.06 (m, 1 H), 2.47 (s, 3 H), 2.77 - 2.87 (m, 1 H), 3.00 - 3.16 (m, 2 H), 3.42 - 3.54 (m, 1 H), 3.98 - 4.10 (m, 1 H), 4.30 - 4.36 (m, 1 H), 4.51 - 4.74 (m, 1 H), 6.86 - 6.97 (m, 1 H), 7.01 - 7.08 (m, l H), 7.21 - 7.31 (m, 1 H)
MS ES+: 345
Step (v): ten-butyl N-{7-fluoro-2-[2-(trimethylsUyl)ethanesulfonamido]-(trans)-2yJ- dihydro-1H-inden-l-yl}-N-methylcarbamate
BOC-Anhydride (0.217 mL, 0.936 mmol) was added to a solution of N-[7-fluoro-l- (memylamino)-(trans)-2,3-dihydro-1H-m
(293 mg, 0.850 mmol) and DEPEA (0.163 mL, 0.936 mmol) in DCM (4 mL) under nitrogen. The reaction was stirred at room temperature for 1 hour. The mixture was partitioned between further DCM and water. The phases were separated and the aqueous extracted with DCM. The combined organics were concentrated in vacuo to afford the title compound.
MS ES+: 445.4
Step (vi): ferf-butyl N^2-amino-7-fluoro-(trans)-2,3-dihydro-1H-inden-l-yl)-N- methylcarbamate
Cesium fluoride (387 mg, 2.55 mmol) was added to a solution tert-butyl N-{7-fluoro-2-[2- (trimemylsilyl)ethanesulfonamido]-(trans)-2,3-dihydro- 1 H-inden- 1 -yl} -N- methylcarbamate (378 mg, 0.850 mmol) in DMF (4 ml) under nitrogen. The reaction was heated to 95 °C for 72 h. Further cesium fluoride (387 mg, 2.5S mmol) was added to the reaction mixture. The reaction was stirred at 95 °C for a further 24 h. The reaction mixture was allowed to cool to room temperature. The mixture was partitioned between ethyl acetate and saturated NaHCCh. The phases were separated and the aqueous extracted with ethyl acetate. The combined organics were dried (phase separator) and concentrated in vacuo. The crude product was loaded onto a cation exchange cartridge, washed with methanol and eluted with 2M ammonia/methanol solution then concentrated in vacuo to the title compound.
'H NMR (400 MHz, CD2Cl2-d6) δ ppm 1.35 - 1.57 (m, 9 H), 2.65 (d, J= 12.75 Hz, 4 H), 3.16 - 3.30 (m, 1 H), 3.58 - 3.75 (m, 1 H), 5.19 - 5.53 (m, 1 H), 6.80 - 6.92 (m, 1 H), 7.00 (d, J= 7.43 Hz, 1 H), 7.16 - 7.28 (m, 1 H)
MS ES+: 281
Intermediates 49 and SO: (lS)-l-[(4S)-4-benzyl-2-oxo-l^-oxazolidine-3-carbonyl]-2- (cyclopropylmethyl)-l^,3,4-tetrahydroisoquinoIin-3-one and (lR)-l-[(4S)-4-benzyl-2- oxo-l^-oxazolidme-3-carbonyl]-2-(cyclopropylmethyl>l^^,4-terrahydroisoqumolin- 3-one
Figure imgf000078_0001
A solution of 2-(cyclopropylmethyl)-3-oxo- 1 ,2,3,4-tetrahydroisoquinoline- 1 -carboxylic acid (Intermediate 14, 16.7g, 58.2 mmol) in THF (500 mL) at -10°C was treated with TEA (9.73 mL, 69.8 mmol) folowed by pivolyl chloride (7.53 mL, 61.1 mmol) in a dropwise fashion. The reaction was allowed to stir at -10°C for lh. In a separate flask a solution of (4S)-4-benzyl-l,3-oxazolidin-2-one (10.32 g, 58.2 mmol) in THF (100 mL) was cooled to -78°C and treated with nBuLi (2.5M in hexanes, 24.5 mL, 61.1 mmol) in a dropwise fashion. The reaction was stirred at -78°C for 20 min. The solution is canulated into the previously reacted solution of acid, TEA and pivolyl chloride at -78°C and the reaction was allowed to warm to rt over 18h. The reaction was quenched with NH4C1 solution and extarcted with EtOAc. The organic was collected, washed with 2M HC1, NaHC03 solution and brine, dried (Na2S04) and concentrated in vacuo. The resulting residue was purified by column chromatography on silica, eluted with 17-33%
EtOAc/hexanes to afford the title compounds
Intermediate 49 : first eluting diastereomer (lS)-l-[(4S)-4-benzyl-2-oxo-l,3- oxazolidine-3-carbonyl]-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-3-one
'H NMR (400 MHz, CDC13) δ ppm 0.22 - 0.41 (m, 2 H), 0.44 - 0.64 (m, 2 H), 0.93 - 1.07 (m, 1 H), 2.62 - 2.76 (m, 1 H), 2.95 - 3.05 (m, 1 H), 3.39 - 3.50 (m, 1 H), 3.64 (d, J= 19.30 Hz, 1 H), 3.89 - 4.00 (m, 1 H), 4.06 - 4.18 (m, 2 H), 4.19 - 4.28 (m, 1 H), 4.42 - 4.53 (m, 1 H), 6.85 (s, 1 H), 7.17 - 7.26 (m, 4 H), 7.28 - 7.37 (m, 4 H), 7.53 - 7.61 (m, 1 H)
MS ES+: 405
Intermediate 50: second eluting diastereomer (lR)-l-[(4S)-4-benzyl-2-oxo-l^- oxazolidine-3-carbonyI]-2-(cyclopropylmethyl)-l,2r3,4-tetrahydroisoquinolin-3-one •H NMR (400 MHz, CDCI3) δ ppm 0.15 - 0.32 (m, 2 H), 0.35 - 0.45 (m, 1 H), 0.48 - 0.59 (m, 1 H), 0.83 - 1.00 (m, 1 H), 2.59 - 2.70 (m, 1 H), 2.75 - 2.83 (m, 1 H), 2.89 - 3.02 (m, 1 H), 3.61 (d,J= 19.35 Hz, 1 H), 3.81 - 3.91 (m, 1 H), 4.05 (d,J= 19.62 Hz, 1 H), 4.18 - 4.25 (m, 1 H), 4.29 - 4.41 (m, 1 H), 4.69 - 4.81 (m, 1 H), 6.73 - 6.84 (m, 3 H), 7.05 - 7.23 (m, 4 H), 7.26 - 7.38 (m, 2 H), 7.66 - 7.76 (m, 1 H)
MS ES+: 405
Intermediate 51: (lS)-2-(cyclopropylmethyl)-N-((cw)-l-hydroxy-2,3-dihyd inden-2-yl)-3-oxo-l,2,3,4-tetrahydroisoquinoUne-l-carboxamide
Figure imgf000079_0001
Step (i): (lS)-2-(cyclopropylmethyl)-3-oxo-l^l^,4-tetrahydroisoquinoline-l- carboxylic acid
To a stirring solution of (lS)-l-[(4S)-4-benzyl-2-oxo-l,3-oxazolidine-3-carbonyl]-2- (cyclopropylmethyl)-l,2,3,4-tetrahydroisoquinolin-3-one (Intermediate 49, 5.00g, 12.37 mmol) in THF (90 mL) and water (30 mL) at 0°C was added LiOH.H20 (1.04g, 24.8 mmol) followed by ¾(½ (30% in H20, 11.22g, 100.0 mmol) in a portionwise fashion. The reaction was stirred at 0°C for 2 h and allowed to warm to room temperature over 18 h. Sodium thiosulfate solution was added carefully and the pH was adjusted to pH4-5. The aqueous was exatracted with EtOAc, dried (Na2S04) and concentrated in vacuo. The resulting residue was triturated with DCM to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 0.17 - 0.29 (m, 2 H), 0.33 - 0.50 (m, 2 H), 0.88 - 1.00 (m, 1 H), 3.15 - 3.25 (m, 2 H), 3.48 (d, J= 19.07 Hz, 1 H), 3.65 (d,7= 19.35 Hz, 1 H), 5.33 (s, 1 H), 7.20 - 7.35 (m, 3 H), 7.42 - 7.48 (m, 1 H)
MS ES+: 246
Step (ii): (lS)-2-(cyclopropylmethyl)-N-((cw)-l-hydroxy-2^3-dihydro-1H-inden-2-yl)- 3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxamide
COMU (0.818 g, 1.911 mmol) was added to a stirred solution of 2-(cyclopropyImethyl)-3- oxo-1, 2,3, 4-tetrahydroisoquinoline-l-carboxylic acid (0.426 g, 1.737 mmol), (cis)-2- amino-2,3-dihydro-1H-inden-l-ol (0.285 g, 1.911 mmol) and 2,2,6,6-tetramethylpiperidine (0.245 g, 1.737 mmol) in DCM (15 mL) and stirred for 1 h. The reaction mixture was washed with water and purified by column chromatography on silica, eluted with 0-100% ethyl acetate/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) 8 ppm 0.14 - 0.48 (m, 4 H), 0.90 - 1.07 (m, 1 H), 2.81 - 3.11 (m, 3 H), 3.13 - 3.28 (m, 1 H), 3.35 - 3.61 (m, 2 H), 3.82 - 3.95 (m, 1 H), 4.17 - 4.36 (m, 1 H), 4.73 - 4.91 (m, 1 H), 5.43 - 5.49 (m, 1 H), 7.09 - 7.44 (m, 7 H), 7.49 - 7.60 (m, 1 H), 8.32 - 8.59 (m, 1 H)
Intermediate 52: 2-(3-fluoropropyl)-3-oxo-1,2,3,4-tetrahydroisoquinoline-l- carboxylic acid
Figure imgf000080_0001
O' ΌΗ
Prepared as described 2-methyl-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 12) using ethyl 2-bromo-2-[2-(2-ethoxy-2-oxoethyl)phenyl]acetate (Intermediate 11, 13.6 g, 41.3 mmol) and 3-fluoropropan-l -amine hydrochloride (4.7g, 41.3 mmol) to afford the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 1.88 - 2.12 (m, 3 H), 3.26 - 3.30 (m, 1 H), 3.32 - 3.37 (m, 1 H), 3.41 - 3.52 (m, 1 H), 3.87 - 4.04 (m, 2 H), 4.32 - 4.58 (m, 2 H), 7.08 - 7.17 (m, 1 H), 7.19 - 7.29 (m, 2 H), 7.44 - 7.54 (m, 1 H)
MS ES+: 252
Intermediates 53 and 54: (lSH-[(4S)-4-benzvl-2-oxo-13-oxazoUdine-3-carbonv_l-2- (3-fluoropropyl)-l,2,3,4-tetrahydroisoquinolin-3-one and (lR)-l-[(4S)-4-benzyl-2- oxo-M-oxazolidine-3-carbonyl]-2-(3-fluoropropyl)-1,2,3,4-tetrahydroisoquinolin-3- one
Figure imgf000081_0001
A solution of 2-(3-fluoropropyl)-3-oxo- 1,2,3 ,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 52, 4.0 g, 13.6 mmol) in THF (10 mL) at -10°C was treated with TEA (7.27 mL, 16.3 mmol) in a dropwise fashion with stirring followed by pivolyl chloride (0.105 mL, 14.3 mmol). The reaction was stirred at -10°C for 30 min. A second flask containing (4S)-4-benzyl-l,3-oxazolidin-2-one (151 mg, 13.6 mmol) in THF (10 mL) at -78°C was treated with nBuLi (2.5M in hexanes, 5.72 mL, 14.3 mmol) in a dropwise fashion. The reaction was stirred at -78 °C for 20 min. The resulting solution was canulated to a cooled solution (-78 °C) of the mixed anhydride above. The reaction was stirred at -78 °C for 30 min and allowed to warm to room temperature for 4h. The reaction was quenched with NH4CI solution and extracted with EtOAc. The organic was collected, washed with IN HC1, bicarbonate and brine, dried (MgS04) and concentrated in vacuo. The resulting residue was purified by column chromatography on silica, eluted with 20-33% ethyl acetate/hexanes to afford the title compounds.
Intermediate 53: first eluting diatereomer, (lS)-l-[(4S)-4-benzyl-2-oxo-13- oxazolidine-3-carbonyl]-2-(3-fluoropropyl)-l,2r3,4-tetrahydroisoquinolin-3-one 1H NMR (400 MHz, CDC13) 6 ppm 1.93 - 2.15 (m, 2 H), 2.77 - 2.88 (m, 1 H), 3.31 - 3.50 (m, 2 H), 3.62 (d, J= 19.35 Hz, 1 H), 3.83 - 3.96 (m, 1 H), 4.11 (d, J= 19.35 Hz, 1 H), 4.15 - 4.30 (m, 2 H), 4.39 - 4.63 (m, 3 H), 6.77 (s, 1 H), 7.16 - 7.26 (m, 4 H), 7.28 - 7.39 (m, 4 H), 7.52 - 7.59 (m, 1 H)
MS ES+: 411
Intermediate 54; second eluting diastereomer, (lR)-l-[(4S)-4-benzyl-2-oxo-ly5- oxazoIidine-3-carbonyl]-2-(3-fluoropropyl>1,2,3,4-tetrahydroisoquinolin-3-one
1H NMR (400 MHz, CDC13) δ ppm 1.88 - 2.09 (m, 2 H), 2.60 - 2.70 (m, 1 H), 2.74 - 2.82 (m, 1 H), 3.29 - 3.39 (m, I H), 3.59 (d, J= 19.35 Hz, 1 H), 3.76 - 3.87 (m, 1 H), 4.03 (d, J = 19.07 Hz, 1 H), 4.16 - 4.24 (m, 1 H), 4.32 - 4.43 (m, 2 H), 4.46 - 4.56 (m, 1 H), 4.69 - 4.83 (m, 1 H), 6.71 - 6.84 (m, 3 H), 7.09 - 7.23 (m, 4 H), 7.24 - 7.41 (m, 2 H), 7.64 - 7.74 (m, l H)
MS ES+: 411
Intermediate 55; (lS)-2-(3-fluoropropyl)-3-oxo-l,2,3,4-tetrahydroisoquinoline-l- carboxylic acid
Figure imgf000082_0001
A solution of (lS)-l-[(4S)-4-beiizyl-2-oxo-l,3-oxazolidine-3-carbonyl]-2-(3-fluoropropyl)- l,2,3,4-tetrahydroisoquinolin-3-one (Intermediate 53, 1.72g, 4.19 mmol) in THF (55 mL) and water (18 mL) was at 0°C was was treated with LiOH.H20 (0.352 g, 8.38 mmol) followed by H2O2.H2O (3.47 mL, 33.52 mmol) in a dropwise fashion. The reaction was stirred at 0 °C for 2 h and warmed to room temperature for 18 h. The reaction was carefully quenched with sodium thiosulfate and the pH adjusted to pHl and extracted with EtOAc. The organic was collected, washed with brine, dried (Na2S04) and concentrated in vacuo. The aqueous was concentrated in vacuo and combined with the organic layer and purified by column chromatography on silica, eluted with 100% EtOAc with 1% AcOH to afford the title compound. 'Η NMR (400 MHz, CD3OD) δ ppm 1.87 - 2.10 (m, 2 H), 3.31 - 3.38 (m, 2 H), 3.52 (d, J= 19.07 Hz, 1 H), 3.82 (d, J= 19.07 Hz, 1 H), 3.88 - 3.96 (m, 1 H), 4.31 - 4.56 (m, 2 H), 5.20 (s, 1 H), 7.15 - 7.23 (m, 1 H), 7.25 - 7.35 (m, 2 H), 7.45 - 7.53 (m, 1 H)
MS ES+: 252
2. Examples
Example 1 : N-(2,3-dihydro-1H-inden-2-vl)-l-methvl-1.2.3.4-tetrahvdroauinoline-4- carboxamide
Figure imgf000083_0001
T3P (50% in EtOAc) (0.344 mL, 0.392 mmol) was added to a solution of 1 -methyl- 1,2,3,4- tetrahydroquinoline-4-carboxylic acid (0.05 g, 0.261 mmol), 2,3-dihydro-1H-inden-2- amine (0.037 mL, 0.288 mmol) and TEA (0.055 mL, 0.392 mmol) in DCM (2 mL) under nitrogen. The reaction was stirred at room temperature for 1.5 h. The mixture was diluted with DCM and washed with saturated bicarb, dried (phase separator) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 - 1.95 (m, 1 H) 1.96 - 2.08 (m, 1 H) 2.73 - 2.86 (m, 4 H) 3.03 - 3.13 (m, 1 H) 3.14 - 3.24 (m, 2 H) 3.36 - 3.42 (m, 2 H) 3.50 - 3.60 (m, 1 H) 4.41 - 4.54 (m, 1 H) 6.52 (t, J=7.34 Hz, 1 H) 6.60 (d, J=8.07 Hz, 1 H) 6.87 (d, J=7.34 Hz, 1 H) 6.95 - 7.05 (m, 1 H) 7.08 - 7.27 (m, 4 H) 8.34 (d, J=6.97 Hz, 1 H)
ES+: 307
Example 2; N-(2,3-dmvdro-1H-inden-2-vlH-methvl-2-oxo-1.2.3.4- tetrahydroquinoline-4-carboxamide N P
Figure imgf000084_0001
HATU (0.120 g, 0.315 mmol) was added to a solution of l-methyl-2-oxo-l,2,3,4- tetrahydroquiooline-4-carboxylic acid (0.062 g, 0.3 mmol) and DEPEA (0.0S8 mL, 0.330 mmol) in DMF (0.5 mL). The mixture was stirred for 5 min, then 2,3-dihydro-1H-inden-2- amine (0.040 g, 0.3 mmol) was added and stirring continued for 5 min. The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound.
1H NMR (400 MHz, DMSO-fd6) δ ppm 2.61 - 2.84 (m, 4 H) 3.10 - 3.27 (m, 5 H) 3.73 (t, J=5.81 Hz, 1 H) 4.35 - 4.49 (m, 1 H) 6.95 - 7.05 (m, 1 H) 7.08 (d, J=8.08 Hz, 1 H) 7.12 - 7.19 (m, 2 H) 7.19 - 7.36 (m, 4 H) 8.47 (d, J=7.07 Hz, 1 H)
MS ES+: 321
Example 3; N-f2.3-dihvdro-1H-inden-2-vlV-2-methvl-l-oxo-l.23.4- tetrahydroisoquinoline-4-carboxamide
O
Figure imgf000084_0002
Prepared as described for N-(2,3-dihydro-1H-inden-2-yl)-l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide (Example 2) from 2-methyl-l-oxo-l,2,3,4- tetrahydroisoquinoline-4-carboxylic acid (0.123 g, 0.6 mmol) and 2,3-dihydro-1H-inden-2- amine (0.080 g, 0.6 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.75 - 2.89 (m, 2 H) 3.01 (s, 3 H) 3.14 - 3.28 (m, 2 H) 3.60 - 3.79 (m, 2 H) 3.83 - 3.95 (m, 1 H) 4.43 - 4.60 (m, 1 H) 7.09 - 7.21 (m, 2 H) 7.21 - 7.31 (m, 3 H) 7.34 - 7.44 (m, 1 H) 7.44 - 7.58 (m, 1 H) 7.81 - 7.97 (m, 1 H) 8.56 (d, J=6.79 Hz, 1 H) MS ES+: 321
Examples 4 and 5: (4S)-N-(2 J-dihvdro-1H-inden-2-vlM-methvl-2-oxo-1.2.3.4- tetrahydroquinoline-4-carboxamide and (4R)-N-(2,3-dihydro-1H-inden-2-yl)-l methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxamide
Figure imgf000085_0001
N-(2,3-dihydro- 1 H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3 ,4-tetrahydroquinoline-4- carboxamide (Example 2) was purified by chiral SFC (40% isopropanol, ID column) to afford the title compounds. Absolute stereochemistry confirmed by X-ray crystallography. Example 4 - 1" eluting peak
1H NMR (400 MHz, DMSO-d6) δ ppm 2.61 - 2.84 (m, 4 H) 3.10 - 3.27 (m, 5 H) 3.73 (t, J=5.81 Hz, 1 H) 4.35 - 4.49 (m, 1 H) 6.95 - 7.05 (m, 1 H) 7.08 (d, J=8.08 Hz, 1 H) 7.12 - 7.19 (m, 2 H) 7.19 - 7.36 (m, 4 H) 8.47 (d, J=7.07 Hz, 1 H)
MS ES+: 321
Example 4 - 2nd eluting peak
lE NMR (400 MHz, DMSO-d6) δ ppm 2.61 - 2.84 (m, 4 H) 3.10 - 3.27 (m, 5 H) 3.73 (t, J=5.81 Hz, 1 H) 4.35 - 4.49 (m, 1 H) 6.95 - 7.05 (m, 1 H) 7.08 (d, J=8.08 Hz, 1 H) 7.12 - 7.19 (m, 2 H) 7.19 - 7.36 (m, 4 H) 8.47 (d, J=7.07 Hz, 1 H)
MS ES+: 321
Examples 6 and 7; (4S)-N-((trans)-l-methoxy-2,3-dihydro-1H-inden-2-yl)-l-methyl-2- oxo-l,2,3,4-tetrahydroquinoline-4-carboxamide (single stereoisomers) CCr°
Trans
Figure imgf000086_0001
2,2,6,6-Tetramethylpiperidine (0.131 g, 0.928 mmol) was added to a suspension of (4S)-1- methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxylic acid (0.200 g, 0.97S mmol)
(Intermediate 1), (/ra¾y)-l-methoxy-2,3-dihydro-1H-inden-2-amine (0.1S1 g, 0.928 mmol) (Intermediate 2) and COMU (0.437 g, 1.021 mmol) in DCM (4 mL) under nitrogen. The reaction was stirred at room temperature for 1 hour. The mixture was partitioned between DCM and water, passed through a phase separator and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0- 100% EtO Ac/petroleum ether, then by reverse phase chromatography on CI 8 silica eluted with 5-70% MeCN/water (with 0.05% NH3). The residue was further purified by chiral SFC (25% MeOH, Lux-Cl column) to afford the title compounds.
Example 6 - 1" eluting peak
1H NMR (400 MHz, DMSO-d6) δ ppm 2.64 - 2.74 (m, 3 H) 3.19 - 3.29 (m, 7 H) 3.72 - 3.78 (m, 1 H) 4.25 - 4.34 (m, 1 H) 4.56 - 4.61 (m, 1 H) 6.98 - 7.12 (m, 2 H) 7.19 - 7.34 (m, 6 H) 8.53 (d, J=8.07 Hz, 1 H)
MS ES+: 351
Example 7 - 2nd eluting peak
•H NMR (400 MHz, DMSO-d6) δ ppm 2.60 - 2.76 (m, 3 H) 3.17 - 3.26 (m, 4 H) 3.38 (s, 3 H) 3.70 - 3.76 (m, 1 H) 4.25 - 4.34 (m, 1 H) 4.62 - 4.67 (m, 1 H) 6.99 - 7.12 (m, 2 H) 7.20 - 7.39 (m, 6 H) 8.51 (d, J=7.70 Hz, 1 H)
MS ES+: 351
Example 8: (4S)-N-((fro/w>l-ethoxy-2,3-dihydro-1H-inden-2-yl)-l-methyl-2-oxo- 1,2,3,4-tetrahydroquinoline-4-carboxamide Trans
Figure imgf000087_0001
Prepared as described for (4S)-N-((/rawi)-l-methoxy-2,3-dihydro-1H-inden-2-yl)-l- methyl-2-oxo-l ,2,3,4-tetrahydroquinoline-4-carboxamide (single stereoisomers)
(Examples 6 and 7) from (S)-l-methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxylic acid (0.2 g, 0.975 mmol) (Intermediate 1) and (trans)-l-methoxy-2,3-dihydro-1H-inden- 2-amine (0.165 g, 0.928 mmol) (Intermediate 3) to afford the title compound after purification by reverse phase chromatography on CI 8 silica eluted with 5-70%
MeCN/water (with 0.05% NH3).
'H NMR (400 MHz, DMSO-ί/ί) δ ppm 0.96 - 1.16 (m, 3 H) 2.60 - 2.76 (m, 3 H) 3.14 - 3.27 (m, 4 H) 3.37 - 3.48 (m, 1 H) 3.54 - 3.78 (m, 2 H) 4.21 - 4.32 (m, 1 H) 4.65 - 4.77 (m, 1 H) 6.97 - 7.05 (m, 1 H) 7.05 - 7.12 (m, 1 H) 7.19 - 7.36 (m, 6 H) 8.46 - 8.56 (m, 1 H) MS ES+: 365
Example 9: fert-butvl N-raS.2SV2-(l-methvl-2-oxo-1.2.3.4-tetrahvdroQuinoline-4- amido)-2,3-dihydro-1H-inden-l-yl]carbamate
Figure imgf000087_0002
O' NH
H
Figure imgf000087_0003
/erf-Butyl ((lS,2S)-2-amino-2,3-dihydro-1H-inden-l-yl)carbamate (1.00 g, 4.03 mmol) was added to a solution of l-methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxylic acid (0.826 g, 4.03 mmol) in DCM (10 mL), then EDC.HC1 (1.160 g, 6.04 mmol), HOAT (0.997 g, 6.04 mmol) and TEA (1.401 mL, 12.08 mmol) were added under nitrogen. The reaction was stirred at room temperature for 18 h. The reaction was washed with sodium bicarbonate, HC1 and brine, dried (phase separator) and concentrated in vacuo. The residue was triturated with ether and the solid filtered off and dried in vacuo to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (d, J=1.00 Hz, 9 H) 2.56 - 2.77 (m, 3 H) 3.05 - 3.20 (m, 1 H) 3.23 (s, 3 H) 3.73 - 3.98 (m, 1 H) 4.25 - 4.37 (m, 1 H) 4.95 - 5.06 (m, 1 H) s 6.89 - 7.41 (m, 10 H)
MS ES+: 436
Example 10: N-raS,2S)-l-amino-2.3-dihvdro-1H-inden-2-vll-l-methvl-2-oxo-1.2.3.4- tetrahydroquinoline-4-carboxamide hydrochloride
10
Figure imgf000088_0001
te^Butyl N-[(lS,2S)-2-(l-metoyl-2-oxo-l,2^
dihydro-1H-inden-l-yl]carbamate (1.6 g, 3.67 mmol) (Example 9) was treated with HCI
(4N in dioxane) (5 mL) and stirred for 2 h. The reaction was concentrated in vacuo and the residue was triturated with ether and filtered to afford the title compound.
1H NMR (400 MHz, DMSCwfc) 8 ppm 2.64 - 3.00 (m, 3 H) 3.24 (s, 3 H) 3.26 - 3.35 (m, 1
H) 3.77 - 3.92 (m, 1 H) 4.30 - 4.48 (m, 1 H) 4.53 - 4.70 (m, 1 H) 6.95 - 7.15 (m, 2 H) 7.21
- 7.45 (m, 6 H) 7.54 - 7.71 (m, 1 H) 8.53 - 8.69 (m, 1 H) 8.94 - 9.08 (m, 1 H)
MS ES+: 336
Examples 11 and 12: N-raS.2SVl-amino-2,3-dihvdro-1H-inden-2-vll-l-methvl-2-oxo- l,2,3,4-tetrahydroquinoline-4-carboxamide (single diastereomers)
Figure imgf000088_0002
Figure imgf000088_0003
N-[( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]- 1 -methyl-2-oxo- 1 ,2,3 ,4- tetrahydroquinoline-4-carboxamide (Example 10) was purified by chiral SFC (26% EtOH+0.1% DEA, ID column) to afford the title compounds.
Example 11 - 1" eluting peak
■H NMR (400 MHz, DMSO-d6) δ ppm 2.53 - 2.60 (m, 1 H) 2.69 - 2.78 (m, 2 H) 3.07 - 3.16 (m, 1 H) 3.24 (s, 3 H) 3.75 - 3.85 (m, 1 H) 3.91 - 4.03 (m, 1 H) 4.03 - 4.12 (m, 1 H) 6.92 - 7.50 (m, 10 H) 8.50 (d, J=7.15 Hz, 1 H)
MS ES+: 336
Example 12 - 2nd eluting peak
'H NMR (400 MHz, DMSO-d6) 8 ppm 2.59 - 2.78 (m, 3 H) 3.09 - 3.27 (m, 4 H) 3.76 - 3.85 (m, 1 H) 3.86 - 3.97 (m, 1 H) 3.99 - 4.13 (m, 1 H) 6.94 - 7.48 (m, 10 H) 8.51 (d, J=6.97 Hz, 1 H)
MS ES+: 336
Example 13; l-methyl-2-oxo-N^[(lS,2S)-l-[(propan-2-yl)amino]-2v3-dihydro^1H-— inden-2-yl]-l^,4-tetrahydroqumoline-4-carboxamide
Figure imgf000089_0001
Propan-2-one (0.031 g, 0.538 mmol) was added to a stirred suspension of N-((1S,2S)-1- amino-2,3-dihydro- 1 H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3,4-tetrahydroquinoline-4- carboxamide hydrochloride (0.100 g, 0.269 mmol) (Example 10) and TEA (0.037 mL, 0.269 mmol) in THF (2 mL) and stirred for 45 min before addition of sodium
triacetoxyhydroborate (0.114 g, 0.538 mmol). The reaction was stirred for 30 min at room temperature and then quenched by the addition of water and extracted with DCM. The organic was collected, dried (phase separator) and purified by column chromatography on basic silica, eluted with 0-100% EtO Ac/petroleum ether to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.72 - 1.08 (m, 6 H) 2.57 - 2.85 (m, 3 H) 2.98 - 3.25 (m, 5 H) 3.65 - 3.80 (m, 1 H) 3.97 - 4.26 (m, 2 H) 6.97 - 7.22 (m, 5 H) 7.23 - 7.43 (m, 3 H) 8.35 - 8.52 (m, 1 H)
MS ES+: 378
Example 14: N-faS,2S)-l-[(cvdopropvlmethvnaminol-2,3-dihvdro-1H-inden-2-vll-l- methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide
Figure imgf000090_0001
Prepared as described for l-methyl-2-oxo-N-[(lS,2S)-l-[(propan-2-yl)amino]-2,3-dihydro- 1H-inden-2-yl]-l,2,3,4-tetrahyckoquinoline-4-carboxamide (Example 13) fromN- (( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3 ,4- tetrahydroquinoline-4-carboxamide hydrochloride (0.100 g, 0.269 mmol) (Example 10) and cyclopropanecarbaldehyde (0.019 g, 0.269 mmol) to afford the title compound.
1H NMR (400 MHz, CD2C12) δ 0.00 - 0.17 (m, 2 H), 0.34 - 0.51 (m, 2 H), 0.81 - 1.01 (m, 1 H), 2.38 - 2.65 (m, 3 H), 2.67 - 2.75 (m, 1 H), 3.01 - 3.12 (m, 1 H), 3.24 - 3.41 (m, 4 H), 3.61 - 3.67 (m, 1 H), 3.88 - 4.08 (m, 1 H), 4.29 - 4.46 (m, 1 H), 5.70 - 5.91 (m, 1 H), 6.98 - 7.09 (m, 2 H), 7.13 - 7.42 (m, 6 H)
MS ES+: 390
Example 15: l-methyl-N-[(lS,2S)-l-{[(oxan-4-yl)methyl]amino}-2,3-dihydro-1H- inden-2-yl]-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide
Figure imgf000090_0002
Prepared as described for l-methyl-2-oxo-N-[(lS,2S)-l-[(propan-2-yl)amino]-2,3-dihydro- 1H-inden-2-yl]-l,2,3,4-telxahydroquinoline^-carboxamide (Example 13) from N- (( 1 S ,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3 ,4- tetrahydroquinoline-4-carboxamide hydrochloride (0.100 g, 0.269 mmol) (Example 10) and tetrahydro-2H-pyran-4-carbaldehyde (0.061 g, 0.S38 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 - 1.27 (m, 3 H) 1.36 - 1.73 (m, 3 H) 2.00 (s, 1 H) 2.32 (d, J=6.33 Hz, 1 H) 2.55 - 2.79 (m, 3 H) 3.09 - 3.31 (m, 6 H) 3.67 - 3.88 (m, 3 H) 3.93 - 4.10 (m, 1 H) 4.13 - 4.32 (m, 1 H) 6.96 - 7.13 (m, 2 H) 7.16 - 7.22 (m, 3 H) 7.25 - 7.41 (m, 3 H) 8.36 - 8.56 (m, 1 H)
MS ES+: 434
Example 16: N-[(lS,2S)-l-cyclopropaneamido-2,3-dihydro-1H-inden-2-yl]-l-methyl- 2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide
Figure imgf000091_0001
N-^lS^SJ-l-amino^.S-dihydro-1H-inden^-ylJ-l-methyl^-oxo-l.^S^- tetrahydroquinoline-4-carboxamide hydrochloride (0.127 g, 0.342 mmol) (Example 10) was added to a solution of cyclopropanecarbonyl chloride (0.036 g, 0.342 mmol) in DCM (10 mL) then TEA (0.119 mL, 1.025 mmol) was added under nitrogen. The reaction was stirred at room temperature for 3 h. The reaction mixture was washed with HC1 and brine, dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography on silica eluted with EtO Ac/petroleum ether 0-100%, then EtOAc/MeOH 0-100%, to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.60 - 0.89 (m, 4 H) 1.50 - 1.70 (m, 1 H) 2.57 - 2.81 (m, 3 H) 3.05 - 3.21 (m, 1 H) 3.32 (s, 3 H) 3.68 - 3.83 (m, 1 H) 4.23 - 4.39 (m, 1 H) 5.24 - 5.46 (m, 1 H) 6.93 - 7.38 (m, 8 H) 8.44 - 8.76 (m, 2 H)
MS ES+: 404 Examples 17 and 18: N-f(lS,2SVl-(dimethvlaminoV2.3-dihvdro-1H-inden-2-vll-l- methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxamide (single stereoisomers)
Figure imgf000092_0001
NH
Figure imgf000092_0002
Paraformaldehyde (0.016 g, 0.538 mmol) was added to a stirred suspension of N-((1S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3 ,4-tetrahydroquinoline-4- carboxamide hydrochloride (0.100 g, 0.269 mmol) (Example 10) and TEA (0.037 mL, 0.269 mmol) in THF (2 mL) and stirred for 1 h before addition of sodium
triacetoxyhydroborate (0.114 g, 0.S38 mmol). Stirred overnight at room temperature, then temperature increased to 50°C for 1 h. More paraformaldehyde (0.016 g, 0.S38 mmol) and sodium triacetoxyhydroborate (0.114 g, 0.S38 mmol) were added and stirring continued for 3 h, then quenched by the addition of water and extracted with DCM. Organic phase purified by column chromatography on basic silica, eluted with 0-100% EtO Ac/petroleum ether to afford the title compounds
Example 17 - 1" eluting peak
lH NMR (400 MHz, DMSO-d6) δ ppm 2.01 (s, 6 H) 2.61 - 2.77 (m, 3 H) 3.03 - 3.25 (m, 4 H) 3.60 - 3.79 (m, 1 H) 4.09 (d, J=6.51 Hz, 1 H) 4.39 - 4.58 (m, 1 H) 6.91 - 7.11 (m, 2 H) 7.16 - 7.23 (m, 4 H) 7.24 - 7.37 (m, 2 H) 8.41 (d, J=1.00 Hz, 1 H)
MS ES+: 364
Example 18 - 2nd eluting peak
1H NMR (400 MHz, DMSO-t¼) δ ppm 2.20 (s, 6 H) 2.58 - 2.79 (m, 3 H) 3.02 - 3.26 (m, 4 H) 3.60 - 3.76 (m, 1 H) 4.16 (d, J=5.87 Hz, 1 H) 4.41 - 4.62 (m, 1 H) 6.89 - 7.12 (m, 2 H) 7.16 - 7.39 (m, 6 H) 8.42 - 8.57 (m, 1 H)
MS ES+: 364 Examples 19 and 20: N-f2.3-dihvdro-1H-inden-2-vn-l-ethvl-2-oxo-l.2,3.4- tetrahydroquinoline-4-carboxamide (single enantiomers)
Figure imgf000093_0001
2,3-Dihydro-1H-inden-2-amine (0.0S3 g, 0.397 mmol) was added to a stirred solution of 1- ethyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxylic acid (0.087 g, 0.397 mmol)
(Intermediate 4), HATU (0.166 g, 0.437 mmol) and DIPEA (0.142 mL, 0.794 mmol) in DMF (l.S mL) and stirred for 1 hour. The reaction mixture was diluted with MeOH and purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3). The resulting residue was further purified by chiral SFC (30% isocratic EtOH, AD column) to afford the title compounds.
Example 19 -1st eluting peak
'H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.02 Hz, 3 H) 2.59 - 2.86 (m, 4 H) 3.08 - 3.25 (m, 2 H) 3.63 - 3.73 (m, 1 H) 3.79 - 4.02 (m, 2 H) 4.30 - 4.51 (m, 1 H) 7.00 (t, J=6.97 Hz, 1 H) 7.06 - 7.36 (m, 7 H) 8.45 (d, J=6.97 Hz, 1 H)
MS ES+: 335
Example 20 - 2nd eluting peak
1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.02 Hz, 3 H) 2.59 - 2.86 (m, 4 H) 3.08 - 3.25 (m, 2 H) 3.63 - 3.73 (m, 1 H) 3.79 - 4.02 (m, 2 H) 4.30 - 4.51 (m, 1 H) 7.00 (t, J=6.97 Hz, 1 H) 7.06 - 7.36 (m, 7 H) 8.45 (d, J=6.97 Hz, 1 H)
MS ES+: 335
Example 21: ferf-butyl l-[(2,3-dihydro-1H-inden-2-yl)carbamoyl]-l,2,3,4- tetrahydroisoquinoline-2-carboxyIate
Figure imgf000094_0001
2,3-Dihydro-1H-inden-2-amine (0.240 g, 1.803 mmol) was added to a solution of 2-{tert- butoxycarbonyl)-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (0.S g, 1.803 mmol) in DCM (10 mL) then EDC.HC1 (0.519 g, 2.70 mmol), HOAT (0.446 g, 2.70 mmol) and TEA (0.627 mL, S.41 mmol) were added under nitrogen. The reaction was stirred at room temperature for 18 h. The reaction mixture was washed with water, IN HCI, and sat. NaHCCh, dried (MgS04) and concentrated in vacuo to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 1.28 - 1.51 (m, 9 H) 2.58 - 3.26 (m, 6 H) 3.46 - 3.63 (m, 1 H) 3.74 - 3.93 (m, 1 H) 4.28 - 4.47 (m, 1 H) 5.20 (s, 1 H) 7.05 - 7.30 (m, 7 H) 7.36 - 7.51 (m, l H) 8.57 (m, 1 H)
MS ES+: 293 (M-BOC)
Example 22: N-(2,3-dihydro-1H-inden-2-yl)-1,2,3,4-tetrahydroisoquinoline-l- carboxamide hydrochloride
NH HCI
Figure imgf000094_0002
HCI (4N in dioxane) (6 mL) was added to fer/-butyl l-[(2,3-dihydro-1H-inden-2- yl)carbamoyl]-l,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 21, 0.520 g, 1.325 mmol) under nitrogen. The reaction was stirred at room temperature for 3 h. The reaction was diluted with ether and the solid filtered off to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.81 - 3.00 (m, 2 H) 3.10 (d, J=6.97 Hz, 1 H) 3.21 - 3.42 (m, 4 H) 3.59 - 3.74 (m, 1 H) 4.48 - 4.62 (m, 1 H) 5.02 (s, 1 H) 7.09 - 7.41 (m, 10 H) 9.45 (d, J=6.97 Hz, 1 H)
MS ES+: 293 Example 23: N-(2.3-dihvdro-1H-inden-2-vn-2-f2-methoxvacetv»-1.23.4- tetrahydroisoquinoline-l-carboxamide
Figure imgf000095_0001
TEA (0.212 mL, 1.521 mmol), 2-methoxyacetyl chloride (0.040 g, 0.365 mmol), N-(2,3- dihydro- 1 H-inden-2-yl)- 1,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide hydrochloride (Example 22, 0.100 g, 0.304 mmol) and DCM (5 mL) were combined and stirred for 1 hour. The reaction mixture was washed with water and the organic phase was dried (phase separator) and purified by column chromatography on silica, eluted with 0-100%
EtOAc/petroleum ether to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 2.62 - 3.26 (m, 6 H) 3.31 (s, 3 H) 3.49 - 3.80 (m, 1 H) 3.88 - 4.27 (m, 3 H) 4.32 - 4.53 (m, 1 H) 5.62 (s, 1 H) 7.05 - 7.51 (m, 8 H) 8.68 (d, J=7.24 Hz, 1 H)
MS ES+: 365
Examples 24 and 25; N-f2,3-dihvdro-1H-inden-2-vl)-2-f2-methoxvacetvn-1.2.3.4- tetrahydroisoquinoline-l-carboxamide (single enantiomers)
Figure imgf000095_0002
N-(2,3-dihydro- 1 H-inden-2-yl)-2-(2-methoxyacetyl)- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 - carboxamide (Example 23) was purified by chiral SFC (40% isocratic IP A, IA column) to afford the title compounds.
Example 24 - 1" during peak 'Η NMR (400 MHz, DMSO-d6) δ ppm 2.62 - 3.26 (m, 6 H) 3.31 (s, 3 H) 3.49 - 3.80 (m, 1 H) 3.88 - 4.27 (m, 3 H) 4.32 - 4.53 (m, 1 H) 5.62 (s, 1 H) 7.05 - 7.51 (m, 8 H) 8.68 (d, J=7.24 Hz, 1 H)
MS ES+: 365
Example 25 - 2nd eluting peak
'H NMR (400 MHz, DMSO-d6) 8 ppm 2.62 - 3.26 (m, 6 H) 3.31 (s, 3 H) 3.49 - 3.80 (m, 1 H) 3.88 - 4.27 (m, 3 H) 4.32 - 4.53 (m, 1 H) 5.62 (s, 1 H) 7.05 - 7.51 (m, 8 H) 8.68 (d, J=7.24 Hz, 1 H)
MS ES+: 365
Example 26; 2-cyclopropanecarbonyl-N-(2,3-dihydro-1H4nden-2-yl)-l,2,3,4- tetrahydroisoquinoline-l-carboxamide
Figure imgf000096_0001
Prepared as described for N-(2>3-dihydro-1H-inden-2-yl)-2-(2-methoxyacetyl)-l,2,3,4- tetrahydroisoquinoline-l-carboxamide (Example 23) from N-(2,3-dihydro-1H-inden-2-yl)- 1,2,3,4-tetrahydroisoquinoline-l-carboxamide hydrochloride (Example 22, 0.370 g, 1.125 mmol) and cyclopropanecarbonyl chloride (0.118 g, 1.125 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO--/6) δ ppm 0.64 - 0.87 (m, 4 H) 1.81 - 2.10 (m, 1 H) 2.61 - 2.94 (m, 2 H) 3.04 - 3.26 (m, 4 H) 3.73 - 4.53 (m, 3 H) 5.50 - 5.84 (m, 1 H) 7.02 - 7.53 (m, 8 H) 8.60 (d, J=7.24 Hz, 1 H)
ES": 359
Example 27: N2-cvcloproDvI-Nl-(2,3-dihvdro-1H-inden-2-vlV1.2,3.4- tetrahydroisoquinoline-l,2-dicarboxamide
Figure imgf000097_0001
Isocyanatocyclopropane (0.038 g, 0.4S6 mmol) was added to a stirred solution of N-(2,3- dihydro- 1 H-inden-2-yl)- 1 ,2,3,4-tetrahydroisoquinoline- 1 -carboxamide hydrochloride (Example 22, 0.100 g, 0.304 mmol) and TEA (0.212 mL, 1.S21 mmol) in DCM (1 mL). After 1 hour, the reaction mixture was washed with water, dried (phase separator) and purified by column chromatography on silica, eluted with 0-100% EtO Ac/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.26 - 0.61 (m, 4 H) 2.54 - 2.60 (m, 1 H) 2.64 - 2.87 (m, 3 H) 2.89 - 3.03 (m, 1 H) 3.05 - 3.25 (m, 2 H) 3.44 - 3.60 (m, 1 H) 3.68 - 3.84 (m, 1 H) 4.28 - 4.48 (m, 1 H) 5.47 (s, 1 H) 6.55 (br. s., 1 H) 7.03 - 7.30 (m, 7 H) 7.40 (d, J=6.51 Hz, 1 H) 8.50 (d, J=7.06 Hz, 1 H)
MS ES+: 376
Example 28: 2-(cyclopropylmethyl)-N-(2r3-dihydro-1H-inden-2-yl)-l,2,3,4- tetrahydroisoquinoline-l-carboxamide
Figure imgf000097_0002
(Bromomethyl)cyclopropane (0.081 g, 0.602 mmol) was added to a stirred suspension of N-(2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide (Example 22, free base formed by cation exchange cartridge, 0.160 g, 0.547 mmol) and K2CO3 (0.151 g, 1.094 mmol) in DMF (5 mL) and left at room temperature for 18 h. More (bromomethyl)cyclopropane (0.040 g, 0.301 mmol) was added and stirring continued. After 4 h, the reaction mixture was partitioned between DCM and water. The organic phase was dried (phase separator) and purified by column chromatography on silica, eluted with 0-100% EtOAc/petroleum ether to afford impure product. Further product extracted from aqueous phase with EtOAc and the combined crude products were purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compound.
•H NMR (400 MHz, DMSO-_fc) δ ppm 0.00 - 0.17 (m, 2 H), 0.34 - 0.53 (m, 2 H), 0.81 - 0.95 (m, 1 H), 2.29 - 2.43 (m, 2 H), 2.52 - 2.60 (m, 1 H), 2.64 - 2.94 (m, 4 H), 3.05 - 3.18 (m, 2 H), 3.34 - 3.43 (m, 1 H), 4.12 (s, 1 H), 4.39 - 4.51 (m, 1 H), 7.06 - 7.23 (m, 7 H), 7.25 - 7.31 (m, 1 H), 8.03 - 8.12 (m, 1 H)
MS ES+: 347
Example 29: 2-(cyclopropanesulfonyl)-N-(2,3-dihydro-1H-inden-2-yl)-1,2,3,4- tetrahydroisoquinoline-l-carboxamide
Figure imgf000098_0001
TEA (0.318 mL, 2.281 mmol), cyclopropanesulfonyl chloride (0.077 g, 0.547 mmol), N- (2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide hydrochloride (Example 22, 0.150 g, 0.456 mmol) and DCM (5 mL) were combined and stirred for 1 h at room temperature. More cyclopropanesulfonyl chloride (0.077 g, 0.547 mmol) was added and stirring continued for a further 18 h. The reaction mixture was washed with water and the organic phase was dried (phase separator) and purified by column chromatography on silica, eluted with 0-100% EtO Ac/petroleum ether to afford the title compound.
1H NMR (400 MHz, OMSO-ek) δ ppm 0.75 - 1.06 (m, 4 H) 2.70 - 2.98 (m, 4 H) 3.07 - 3.28 (m, 2 H) 3.30 - 3.41 (m, 1 H) 3.67 - 3.79 (m, 1 H) 4.01 - 4.21 (m, 1 H) 4.31 - 4.53 (m, 1 H) 5.28 (s, 1 H) 7.09 - 7.38 (m, 8 H) 8.83 (d, J=7.24 Hz, 1 H)
MS ES+: 397
Example 30: N-faS,2S)-l-amino-2 J-dihvdro-1H-inden-2-vll-2- cyclopropanecarbonyl-1,2,3,4-tetrahydroisoquinoline-l-carboxamide
Figure imgf000099_0001
HC1 (4N in dioxane) (0.789 mL, 3. IS mmol) was added to a solution of /erf-butyl N- [(1 S,2S)-2-(2-cyclopropanecarbonyl- 1 ,2,3,4-tetrahydroisoquinoline- l-carboxamido)-2,3- dihydro-1H-inden-l-yl]carbamate (Intermediate 5, 0.1S0 g, 0.3 IS mmol) in DCM (2 mL) and stirred at room temperature for 18. h. More HC1 (4N in dioxane) (0.789 mL, 3. IS mmol) was added and stirring continued for a further S h. The reaction mixture was diluted with MeOH and loaded onto a cation exchange cartridge, washed with MeOH and eluted with 2M NH3/MeOH solution then concentrated in vacuo with the washings. The crude product was purified by reverse phase chromatography on CI 8 silica eluted with 5-95% MeCN/water (with 0.05% NH3) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.61 - 0.89 (m, 4 H) 2.03 - 2.16 (m, 1 H) 2.56 - 3.26 (m, 4 H) 3.71 - 4.33 (m, 4 H) 5.65 - 5.89 (m, 1 H) 7.01 - 7.38 (m, 7 H) 7.52 (d, J=17.61 Hz, 1 H) 8.47 - 8.86 (m, 1 H)
MS ES+: 376
Example 31; N-f(lS-2SVl-amiiio-23-dihydro-1H-inden-2-vll-2- cyclopropanecarbonyl-6-fluoro-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomer)
Figure imgf000099_0002
Prepared as described for N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-2- cyclopropanecarbonyl-l,2,3,4-tetrahydroisoquinoline-l-carboxamide (Example 30) from /er/-butyl ((1 S,2S)-2-(2-(cyclopropanecarbonyl)-6-fluoro-l ,2,3,4-tetrahydroisoquinoline- 1- carboxamido)-2,3-dihydro-1H-inden-l-yl)carbamate (Intermediate 6, single stereoisomer, 0.215 g, 0.436mmol) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 0.57 - 0.92 (m, 4 H) 1.80 - 2.15 (m, 3 H) 2.94 - 3.20 (m, 3 H) 3.74 - 4.30 (m, 5 H) 5.70 (s, 1 H) 6.93 - 7.36 (m, 6 H) 7.44 - 7.60 (m, 1 H) 8.42 - 8.84 (m, 1 H)
MS ES+: 394
Example 32; N-[(1S,2S)-l-amino-2.3-dihvdro-1H-inden-2-yll-2- cyclopropanecarbonyl-6-fluoro-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomer)
Figure imgf000100_0001
Figure imgf000100_0002
Prepared as described for N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-2- cyclopropanecarbonyl-l,2,3,4-tetrahydroisoquinoline-l-carboxamide (Example 30) from tert-butyl (( 1 S,2S)-2-(2-(cyclopropanecarbonyl)-6-fluoro- 1 ,2,3,4-tetrahydroisoquinoline- 1 - carboxamido)-2,3-dihydro-1H-inden-l-yl)carbamate (Intermediate 7, single stereoisomer) (0.215 g, 0.436 mmol) to afford the title compound.
•H NMR (300 MHz, DMSO-d6) δ ppm 0.57 - 0.88 (m, 4 H) 1.68 - 2.15 (m, 3 H) 2.56 - 3.21 (m, 4 H) 3.63 - 4.30 (m, 4 H) 5.64 - 5.83 (m, 1 H) 6.93 - 7.35 (m, 6 H) 7.44 - 7.62 (m, 1 H) 8.44 - 8.82 (m, 1 H)
MS ES+: 394
Example 33: N-[(1S,2S)-l-amino-2,3-dihvdro-1H-inden-2-vll-6-chloro-2- cyclopropanecarbonyl-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomer)
Figure imgf000101_0001
Prepared as described for N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-2- cyclopropanecarbonyl-l,2,3,4-tetrahydroisoquinoline-l-carboxamide (Example 30) from tert-butyl (( 1 S,2S)-2-(6-chloro-2-(cyclopropanecarbonyl)- 1 ,2,3,4-tetrahydroisoquinoline- l-carboxamido)-2,3-dihydro-1H-inden-l-yl)carbamate (Intermediate 8, single stereoisomer, 0.170 g, 0.333 mmol) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 0.61 - 0.92 (m, 4 H) 1.81 - 2.17 (m, 3 H) 2.56 - 3.20 (m, 4 H) 3.58 - 4.29 (m, 4 H) 5.62 - 5.89 (m, 1 H) 7.06 - 7.24 (m, 3 H) 7.26 - 7.38 (m, 3 H) 7.44 - 7.57 (m, 1 H) 8.50 - 8.84 (m, 1 H)
MS ES+: 410
Example 34; N-i(1S,2S)-l-amino-2,3-dihvdro-1H-inden-2-vll-6-chloro-2- cyclopropanecarbonyl-1,2,3,4-tetrahydroisoquinoIine-l-carboxamide (single stereoisomer)
Figure imgf000101_0002
Figure imgf000101_0003
Prepared as described for N-[( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]-2- cyclopropanecarbonyl-l,2,3,4-tetrahydroisoquinoline-l-carboxamide (Example 30) from tert -butyl ((lS,2S)-2-(6-cUoro-2-(cyclopropanecarbonyl)-l,2,3,4-tetrahydroisoquinoline- l-carboxamido)-2,3-dihydro-1H-inden-l-yl)carbamate (Intermediate 9, single stereoisomer, 0.180 g, 0.353 mmol) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 0.59 - 0.87 (m, 4 H) 1.78 - 2.16 (m, 3 H) 2.55 - 3.21 (m, 4 H) 3.66 - 4.28 (m, 4 H) 5.64 - 5.88 (m, 1 H) 7.07 - 7.63 (m, 7 H) 8.45 - 8.85 (m,
1 H) MS ES+: 410
Examples 35 and 36:
Figure imgf000102_0004
cyclopropanecarbonyl-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomer)
Figure imgf000102_0001
Figure imgf000102_0002
N-[( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]-2-cyclopropanecarbonyl- 1 ,2,3,4- tetrahydroisoquinoline-l-carboxamide (Example 30) was purified by chiral SFC (34% isocratic EtOH+0.5% DEA, Lux-C4 column) to afford the title compounds.
Example 35 - l(t eluted peak
1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 - 0.90 (m, 4 H) 1.90 - 2.16 (m, 1 H) 2.57 - 3.24 (m, 4 H) 3.61 - 4.27 (m, 3 H) 5.62 - 5.85 (m, 1 H) 7.06 - 7.58 (m, 8 H)
MS ES+: 376
Example 36 - 2nd eluted peak
1H NMR (400 MHz, DMSO-d6) δ ppm 0.60 - 0.89 (m, 4 H) 1.99 - 2.14 (m, 1 H) 2.55 - 3.22 (m, 4 H) 3.71 - 4.34 (m, 4 H) 5.56 - 5.90 (m, 1 H) 6.98 - 7.56 (m, 8 H) 8.50 - 8.85 (i 1 H)
MS ES+: 376
Example 37: 2-cyclopropanecarbonyl-N-(2,3-dihydro-1H-inden-2-yl)-1,2,3,4- tetrahydroisoquinoline-4-carboxamide
O
Figure imgf000102_0003
TEA (0.138 g, 1.3 mmol) was added to a solution of N-(2,3-dihydro-1H-inden-2-yl)- l,2,3,4-tetrahydroisoquinoline-4-carboxamide hydrochloride salt (Intermediate 10, 0.100 g, 0.3 mmol) in DCM (3 mL) and stirred for 20 min. Cyclopropyl carbonyl chloride (0.0S3 g, 0.S1 mmol) was added at 0 °C and stirred for 3 h at room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude compound was purified by column chromatography on silica, eluted at 0-80% EtOAc/hexane to afford the title compound.
■H NMR (400 MHz, DMSO-d6) δ ppm 0.55 - 0.89 (m, 4 H) 1.94 - 2.12 (m, 1 H) 2.69 - 2.91 (m, 2 H) 3.09 - 3.29 (m, 2 H) 3.55 - 4.16 (m, 3 H) 4.39 - 4.72 (m, 2 H) 4.77 - 5.09 (m, 1 H) 6.97 - 7.35 (m, 8 H) 8.47 - 8.72 (m, 1 H)
MS ES+: 361
Example 38: N-r2.3-dihvdro-1H-inden-2-vlV2-q-methoxvacetvn-l.2,3.4- tetrahydroisoquinoIine-4-carboxamide
O
Figure imgf000103_0001
Prepared as described for 2-cyclopropanecarbonyl-N-(2,3-dihydro-1H-inden-2-yl)-l,2,3,4- tetrahydroisoquinoline-4-carboxamide (Example 37) from N-(2,3-dihydro-1H-inden-2-yl)- l,2,3,4-tetrahydroisoquinoline-4-carboxamide hydrochloride salt (Intermediate 10 , 0.1 g, 0.3 mmol) and 2-methoxy acetyl chloride (0.055 g, 0.51 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) 8 ppm 2.73 - 2.91 (m, 2 H) 3.03 - 3.30 (m, 5 H) 3.54 - 4.31 (m, 5 H) 4.41 - 4.78 (m, 3 H) 6.94 - 7.42 (m, 8 H) 8.41 - 8.67 (m, 1 H)
MS ES+: 365
Examples 39 and 40: N-(23-dihvdro-1H-inden-2-vlV2-(2-methoxvacetvn-1.2 J.4- tetrahydroisoquinoline-4-carboxamide (single enantiomers)
Figure imgf000104_0001
N-(2,3-dihydro- 1 H-inden-2-yl)-2-(2-methoxyacetyl)- 1 ,2,3 ,4-tetrahydroisoquinoline-4- carboxamide (Example 38) was purified by chiral SFC (26% isocratic EtOH, Lux-C4 column) to afford the title compounds.
Example 39 - 1" eluting enantiomer
1H NMR (400 MHz, DMSO-d6) δ ppm 2.73 - 2.91 (m, 2 H) 3.03 - 3.30 (m, 5 H) 3.54 - 4.31 (m, 5 H) 4.41 - 4.78 (m, 3 H) 6.94 - 7.42 (m, 8 H) 8.41 - 8.67 (m, 1 H)
MS ES+: 365
Example 40 - 2nd eluting enantiomer
1H NMR (400 MHz, DMSO-d6) 6 ppm 2.73 - 2.91 (m, 2 H) 3.03 - 3.30 (m, 5 H) 3.54 - 4.31 (m, 5 H) 4.41 - 4.78 (m, 3 H) 6.94 - 7.42 (m, 8 H) 8.41 - 8.67 (m, 1 H)
MS ES+: 365
Example 41: 2-(2-cyclopropyiacetyI)-N-(2,3-dihydro-1H-inden-2-yl)-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000104_0002
N-(2,3-aUhycko-1H-inden-2-yl)-l,2,3,4-tetrahya^oisoqumolme-4-carboxamide
hydrochloride salt (Intermediate 10, 0.07 g, 0.21 mmol) and cyclopropyl acetic acid (0.025 g, 0.21 mmol) were dissolved in DMF (5 mL). EDC.HC1 (0.062 g, 0.32 mmol), HOBt (0.034 g, 0.25 mmol) andN-methyl morpholine (0.107 g, 1.0 mmol) were added sequentially and stirred for 15 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (sodium sulphate) and concentrated in vacuo prior to purification by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compound.
'H NMR (400 MHz, DMSCwfc) δ ppm 0.03 - 0.17 (m, 2 H) 0.34 - 0.55 (m, 2 H) 0.82 - 1.08 (m, 1 H) 2.18 - 2.41 (m, 2 H) 2.75 - 2.92 (m, 2 H) 3.14 - 3.28 (m, 2 H) 3.47 - 4.14 (m, 3 H) 4.38 - 4.81 (m, 3 H) 6.96 - 7.35 (m, 8 H) 8.40 - 8.65 (m, 1 H)
MS ES+: 375
Example 42: 2-(cyclopropanesulfonyl)-N-(2,3-dihydro-1H-inden-2-yl)-1,2,3,4- tetrahydroisoquinoline-4-carboxamide
O
Figure imgf000105_0001
TEA (0.138 g, 1.36 mmol) was added to a solution of N-(2,3-dihydro-1H-inden-2-yl)- l,2,3,4-tetrahydroisoquinoline-4-carboxamide hydrochloride salt (Intermediate 10 , 0.100 g, 0.3 mmol) in DCM (5 mL) at room temperature and stirred for 20 min. Cyclopropyl sulfonyl chloride (0.085 g, 0.65 mmol) was added at 0 °C and stirred for 3 h at room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried (sodium sulphate) and concentrated in vacuo. The crude compound was purified by column chromatography on silica, eluted with 0-70% EtOAc/hexane to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 0.76 - 1.08 (m, 4 H) 2.58 - 2.72 (m, 1 H) 2.79 - 2.93 (m, 2 H) 3.14 - 3.29 (m, 2 H) 3.42 - 3.55 (m, 1 H) 3.72 - 3.97 (m, 2 H) 4.28 - 4.64 (m, 3 H) 6.94 - 7.46 (m, 8 H) 8.68 (d, J=6.71 Hz, 1 H)
MS ES+: 397
Example 43; 2-(cvclopropvlmethyn-N-(23-dihvdro-1H-inden-2-ylV1.2,3.4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000106_0001
N-(2,3-dihydro-1H-inden-2-yl)-l,2)3,4-tetrahydroisoquinoline-4-carboxamide
hydrochloride salt (Intermediate 10, 0.1 g, 0.3 mmol) and cyclopropyl carboxaldehyde (0.085 g, 1.2 mmol) were dissolved in MeOH (10 mL). Acetic acid (0.073 g, 1.2 mmol) was added and the reaction was stirred for 3 h at room temperature. The reaction mixture was cooled to 0 °C and NaCNBH3 (0.073 g, 1.27 mmol) was added. The reaction was stirred for 15 h at room temperature. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compound.
1H NMR (400 MHz, CD3OD) 8 ppm 0.00 - 0.19 (m, 2 H) 0.39 - 0.73 (m, 2 H) 1.24 - 1.40 (m, 1 H) 2.15 - 2.49 (m, 2 H) 2.61 - 2.97 (m, 3 H) 3.11 - 3.31 (m, 3 H) 3.49 - 3.94 (m, 3 H) 4.44 - 4.62 (m, 1 H) 7.05 - 7.35 (m, 8 H)
MS ES+: 347
Example 44: N-(2,3-dihydro-1H-inden-2-yl)-2-methyl-3-oxo-l,2,3,4- tetrahydroisoquinoUne-l-carboxamide
Figure imgf000106_0002
T3P (50% in EtOAc) (0.37 mL, 0.614 mmol) and TEA (0.34 mL, 2.456 mmol) were added to a solution of 2-methyl-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid
(Intermediate 12, 0.063 g, 0.307 mmol) and 2,3-dihydro-1H-inden-2-amine (0.041 g, 0.307 mmol) in THF (3 mL). The reaction was stirred for 4 h before partitioning between EtOAc and NaHC03 solution. The organic phase was separated, dried (sodium sulfate), concentrated in vacuo and the residue purified by column chromatography on silica, eluted with 0-5% MeOH/DCM to afford the title compound.
'H NMR (400 MHz, CDC13) δ ppm 2.63 - 2.85 (m, 2 H) 3.07 (s, 3 H) 3.15 - 3.37 (m, 2 H) 3.45 - 3.82 (m, 2 H) 4.59 - 4.73 (m, 1 H) 4.83 (s, 1 H) 6.21 (d, J=7.36 Hz, 1 H) 7.04 - 7.46 5 (m, 8 H)
MS ES+: 321
Example 45: N-2,3 -dihvdro-1H-inden-2-vl)-2-(2-methoxyethvn-3-oxo-l,2,3,4- tetrahydroisoquinoline-l-carboxamide
10
Figure imgf000107_0001
Prepared as described for N-(2,3-dihydro-1H-inden-2-yl)-2-methyl-3-oxo-l,2,3,4- tetrahydroisoquinoline-l-carboxamide (Example 44) from 2-(2-methoxyethyl)-3-oxo- 1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 13, 0.200 g, 0.687 mmol) and 2,3-dihydro-1H-inden-2-amine (0.091 g, 0.687 mmol) to afford the title compound.
1H NMR (400 MHz, CDCI3) δ ppm 2.53 - 2.85 (m, 2 H) 3.10 - 3.36 (m, 5 H) 3.45 - 3.66 (m, 4 H) 3.72 - 3.91 (m, 2 H) 4.53 - 4.73 (m, 1 H) 4.98 (s, 1 H) 6.55 (d, J=7.08 Hz, 1 H) 7.04 - 7.42 (m, 8 H)
MS ES+: 365
Examples 46 and 47: N-f2,3-dihvdro-1H-inden-2-vl>-2-(2-methoxvethvl)-3-oxo-l^ J.4- tetrahydroisoquinoline-l-carboxamide (single enantiomers)
Figure imgf000107_0002
O' NH N-(2,3-dihydro- 1 H-inden-2-yl>2-(2-methoxyethyl)-3-oxo-l,2,3,4-tetrahydroisoquinoline- 1-carboxamide (Example 45) was purified by chiral SFC (26% isocratic EtOH, AD column) to afford the title compounds.
Example 46 - l(t eluted peak
1H NMR (400 MHz, DMSO-d6) 6 ppm 2.57 - 2.65 (m, 1 H) 2.78 - 2.86 (m, 1 H) 3.04 - 3.14 (m, 1 H) 3.16 - 3.25 (m, 5 H) 3.37 - 3.46 (m, 3 H) 3.69 - 3.77 (m, 1 H) 3.82 - 3.91 (m, 1 H) 4.31 - 4.41 (m, 1 H) 5.12 (s, 1 H) 7.12 - 7.30 (m, 7 H) 7.48 (d, J=6.79 Hz, 1 H) 8.77 (d, J=7.15 Hz, 1 H)
MS ES+: 365
Example 47 - 2nd eluted peak
'H NMR (400 MHz, DMSO-flfc) δ ppm 2.57 - 2.65 (m, 1 H) 2.78 - 2.86 (m, 1 H) 3.04 - 3.14 (m, 1 H) 3.16 - 3.25 (m, 5 H) 3.37 - 3.46 (m, 3 H) 3.69 - 3.77 (m, 1 H) 3.82 - 3.91 (m, 1 H) 4.31 - 4.41 (m, 1 H) 5.12 (s, 1 H) 7.12 - 7.30 (m, 7 H) 7.48 (d, J=6.79 Hz, 1 H) 8.77 (d, J=7.15 Hz, 1 H)
MS ES+: 365
Example 48: 2-(cyclopropylmethyl)-N-(2,3-dihydro-1H-inden-2-yl)-3-oxo-1,2,3,4- tetrahydroisoquinoline-l-carboxamide
Figure imgf000108_0001
Prepared as described for N-(2,3-dihydro-1H-inden-2-yl)-2-methyl-3-oxo-l,2,3,4- tetrahydroisoquinoline-l-carboxamide (Example 44) from 2-(cyclopropylmethyl)-3-oxo- 1,2,3,4-tetrahyaVoisoqumoline-l-carboxylic acid (Intermediate 14, 0.300 g, 1.043 mmol) and 2,3-dihydro-1H-inden-2-amine (0.139 g, 1.043 mmol) to afford the title compound. 'H NMR (400 MHz, CDC13) 6 ppm 0.15 - 0.34 (m, 2 H) 0.36 - 0.52 (m, 2 H) 0.82 - 0.99 (m, 1 H) 2.59 - 2.80 (m, 2 H) 3.18 - 3.39 (m, 3 H) 3.42 - 3.63 (m, 2 H) 3.71 - 3.82 (m, 1 H) 4.55 - 4.72 (m, 1 H) 5.00 (s, 1 H) 6.21 (br. s., 1 H) 7.09 - 7.22 (m, 4 H) 7.23 - 7.34 (m, 3 H) 7.34 - 7.45 (m, 1 H)
MS ES+: 361 Example 49: N-(2,3-dihydro-1H-inden-2-yl)-2-€thyl-3-oxo-1,2,3,4- tetrahydroisoquinoUne-l-carboxamide
;0
Figure imgf000109_0001
Prepared as described for N-(2,3-dihydro-1H-inden-2-yl)-2-methyl-3-oxo-l,2,3,4- tetrahydroisoquinoline-l-carboxamide (Example 44) from 2-ethyl-3-oxo-l,2,3,4- tetrahydroisoquinoline-l-carboxylic acid (Intermediate 15, 0.300 g, 1.15 mmol) and 2,3- dihydro-1H-inden-2-amine (0.1SS g, 1.15 mmol) to afford the title compound.
1H NMR (400 MHz, CDC13) 6 ppm 1.04 - 1.18 (m, 3 H) 2.59 - 2.80 (m, 2 H) 3.11 - 3.38 (m, 3 H) 3.40 - 3.60 (m, 1 H) 3.63 - 3.96 (m, 2 H) 4.55 - 4.76 (m, 1 H) 4.88 (s, 1 H) 6.32 (d, J=7.63 Hz, 1 H) 7.02 - 7.49 (m, 8 H)
MS ES+: 335
Example 50: N-(2.3-dihvdro-1H-inden-2-vn-3-oxo-2-rfDvridin-2-vnmethvll-1.2,3.4- tetrahydroisoquinoline-l-carboxamide
Figure imgf000109_0002
Prepared as described for N-(2,3-dihydro-1H-inden-2-yl)-2-methyl-3-oxo-l,2,3,4- tetrahydroisoquinoline-l-carboxamide (Example 44) from 3-oxo-2-[(pyridin-2-yl)methyl]- 1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 16, 0.400 g, 1.23 mmol) and 2,3-dihydro-1H-inden-2-amine (0.164 g, 1.23 mmol) to afford the title compound. 'H NMR (400 MHz, CDC13) δ ppm 2.59 - 2.88 (m, 2 H) 3.17 - 3.37 (m, 2 H) 3.49 - 3.63 (m, 1 H) 3.80 - 4.01 (m, 1 H) 4.47 - 4.70 (m, 2 H) 4.76 - 5.37 (m, 2 H) 6.95 - 7.44 (m, 10 H) 7.56 - 7.69 (m, 1 H) 8.07 (d, J=4.63 Hz, 1 H) 8.70 - 8.97 (m, 1 H) MS ES+: 398
Example 51 ; N-(2.3-dihvdro-1H-inden-2-vn-2-rf oxan-4-vl)methvll-3-oxo-1.2.3.4- tetrahydroisoquinoline-l-carboxamide
.0
Figure imgf000110_0001
Prepared as described for N-(2,3-dihydro-1H-inden-2-yl)-2-niethyl-3-oxo-l,2,3,4- tetrahydroisoquinoline-l-carboxamide (Example 44) from 2-[(oxan-4-yl)methyl]-3-oxo- 1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 17, 0.400 g, 1.21 mmol) and 2,3-dihydro-1H-inden-2-amine (0.161 g, 1.21 mmol) to afford the title compound. •H NMR (400 MHz, CDC13) δ ppm 1.22 - 1.57 (m, 4 H) 1.77 - 2.00 (m, 1 H) 2.57 - 2.91 (m, 3 H) 3.14 - 3.36 (m, 4 H) 3.47 - 3.61 (m, 1 H) 3.72 - 3.99 (m, 4 H) 4.56 - 4.71 (m, 1 H) 4.81 (s, 1 H) 6.13 (d, J=7.08 Hz, 1 H) 7.05 - 7.39 (m, 8 H)
MS ES+: 405
Example 52: N-(2,3-dihvdro-1H-inden-2-vl)-3-oxo-2-[2-(pvrroUdin-l-vnethvll-l,2,3,4- tetrahydroisoquinoline-l-carboxamide
Figure imgf000110_0002
Prepared as described for N-(2,3-dihydro- 1 H-inden-2-yl)-2-methyl-3-oxo- 1 ,2,3,4- tetrahydroisoquinoline-l-caiboxamide (Example 44) from 3-oxo-2-[2-(pyrroIidin-l- yl)ethyl]-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 18, 0.408 g, 1.31 mmol) and 2,3-dihydro-1H-inden-2-amine (0.175 g, 1.31 mmol) to afford the title compound. 1H NMR (400 MHz, CDC13) δ ppm 1.44 - 2.08 (m, 4 H) 2.30 - 2.95 (m, 3 H) 2.96 - 3.15 (m, 4 H) 3.17 - 3.35 (m, 3 H) 3.46 - 3.57 (m, 1 H) 3.60 - 3.75 (m, 1 H) 4.01 - 4.24 (m, 2 H) 4.48 - 4.65 (m, 1 H) 5.25 (s, 1 H) 7.03 - 7.40 (m, 8 H) 8.33 (d, J=7.36 Hz, 1 H)
MS ES+: 404
Examples 53 and 54: N-rflS.2S)-l-amino-2,3-dihvdro-1H-inden-2-vll-2- (cyclopropylmethyl)-3-oxo-1,2,3,4-tetrahydroisoquinoUne-l-carboxaniide (single stereoisomers)
Figure imgf000111_0001
HC1 (4N in dioxane) (0.815_mL,_3.26jnmpl) was added.to a solution of /erf-butyl N— [( 1 S,2S)-2-[2-(cyclopropylmethyl)-3-oxo- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamido]- 2,3-dihydro-1H-inden-l-yl]carbamate (Intermediate 19, 0.310 g, 0.652 mmol) in MeOH (10 mL). The reaction was stirred at room temperature for 18h. The solution was concentrated in vacuo and azeotroped with toluene. The crude product was loaded onto a cation exchange cartridge, washed with MeOH and eluted with 2M NHi/MeOH solution then concentrated in vacuo. The crude product was purified by column chromatography on basic silica, eluted with 0-5% MeOH/DCM to afford the product as a mixture of diastereomers. The mixture was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compounds.
Example 53 - lrt eluted peak
1H NMR (400 MHz, DMSO-d6) 8 ppm 0.18 - 0.30 (m, 2 H) 0.37 - 0.52 (m, 2 H) 0.86 - 1.02 (m, 1 H) 1.81 (br. s., 2 H) 2.58 - 2.70 (m, 1 H) 3.14 - 3.29 (m, 3 H) 3.37 - 3.48 (m, 1 H) 3.78 - 3.95 (m, 2 H) 4.03 (d, J=7.34 Hz, 1 H) 5.20 (s, 1 H) 7.14 - 7.23 (m, 4 H) 7.24 - 7.33 (m, 3 H) 7.52 - 7.60 (m, 1 H) 8.75 - 8.82 (m, 1 H)
MS ES+: 376
Example 54 - 2nd eluted peak 'Η NMR (400 MHz, DMSO-d6) δ ppm 0.17 - 0.31 (m, 2 H) 0.37 - 0.57 (m, 2 H) 0.89 - 1.03 (m, 1 H) 1.98 (br. s., 2 H) 2.42 - 2.48 (m, 1 H) 2.99 - 3.10 (m, 1 H) 3.14 - 3.24 (m, 1 H) 3.32 - 3.38 (m, 1 H) 3.39 - 3.48 (m, 1 H) 3.81 - 3.96 (m, 2 H) 4.05 - 4.16 (m, 1 H) 5.21 (s, 1 H) 7.07 - 7.38 (m, 7 H) 7.47 - 7.62 (m, 1 H) 8.70 - 8.87 (m, 1 H)
MS ES+: 376
Examples 55 and 56: N-[flS,2S)-l-amino-2,3-dihydro-1H-indeii-2-vll-2-benzvl-3-oxo- 1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomers)
Figure imgf000112_0001
Figure imgf000112_0002
Prepared as described for N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-2- (cyclopropylmethyl)-3-oxo- 1 ,2,3,4-tetrahydroisoquinoline- 1-carboxamide (Examples 53 and 54) from tert-butyl N-[(lS,2S)-2-(2-berizyW-oxo-l,2,3,4-tetrahydioisoquinoline-l- carboxamido)-2,3-dihydro-1H-inden-l-yl]carbamate (Intermediate 21, 0.196 g, 0.383 mmol) to afford the title compounds.
Example 55 - 1" eluted peak
'H NMR (300 MHz, CD3OD) δ ppm 2.50 - 2.68 (m, 1 H) 3.14 - 3.27 (m, 1 H) 3.58 - 3.73 (m, 1 H) 3.88 - 4.03 (m, 2 H) 4.11 - 4.27 (m, 1 H) 4.51 - 4.63 (m, 1 H) 4.89 - 5.06 (m, 2 H) 7.16 - 7.42 (m, 13 H)
MS ES+: 412
Example 56 - 2nd eluted peak
1H NMR (300 MHz, CD3OD) δ ppm 2.57 - 2.68 (m, 1 H) 3.13 - 3.25 (m, 1 H) 3.58 - 3.70 (m, 1 H) 3.87 - 4.04 (m, 2 H) 4.15 - 4.26 (m, 1 H) 4.65 - 4.74 (m, 1 H) 4.87 - 4.94 (m, 1 H) 5.04 (s, 1 H) 7.10 - 7.43 (m, 13 H)
MS ES+: 412
Examples 57 and 58; N-i(lS.2SVl-amino-2,3-dihydro-1H-inden-2-vlI-2-f(oxan-4- yl)methyl]-3-oxo-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomers)
Figure imgf000113_0001
Prepared as described for N-[(lS,2S)-l-amino-2,3-dmydro-1H-inden-2-yl]-2- (cyclopropylmethyl)-3-oxo- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide (Examples 53 and 54) from /er/-butyl ((lS,2S)-2-(3-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-l,2,3,4- tetrahydroisoquinoline- 1 -carboxamido)-2,3-dihydro- 1 H-inden- 1 -yl)carbamate
(Intermediate 22, 0.220 g, 0.423 mmol) to afford the title compounds.
Example 57 - 1" eluted peak
1H NMR (400 MHz, DMSO-d6) 8ppm 1.07 - 1.30 (m, 2 H) 1.37 - 1.59 (m, 2 H) 1.72 - 2.13 (m, 3 H) 2.58 - 2.69 (m, 1 H) 2.89 - 3.05 (m, 1 H) 3.12 - 3.26 (m, 3 H) 3.38 - 3.47 (m,
1 H) 3.50 - 3.61 (m, 1 _H) 3.73 - 3,86_(m, 3 H) 3.87-3.99 (m, 1 H)_4.00 - 4.10_(nv 1 H) -
5.11 (s, 1 H) 7.06 - 7.36 (m, 7 H) 7.48 - 7.58 (m, 1 H) 8.85 (d, J=7.15 Hz, 1 H)
MS ES+: 420
Example 58 - 2nd eluted peak
1H NMR (400 MHz, DMSO-d6) 8 ppm 1.03 - 1.30 (m, 2 H) 1.37 - 1.61 (m, 2 H) 1.71 - 1.91 (m, 1 H) 2.03 - 2.22 (m, 2 H) 2.36 - 2.48 (m, 1 H) 2.85 - 3.11 (m, 2 H) 3.16 - 3.28 (m,
2 H) 3.40 - 3.51 (m, 1 H) 3.56 - 3.68 (m, 1 H) 3.73 - 3.98 (m, 4 H) 4.07 - 4.17 (m, 1 H)
5.12 (s, 1 H) 7.08 - 7.37 (m, 7 H) 7.46 - 7.55 (m, 1 H) 8.83 (d, J=7.15 Hz, 1 H)
MS ES+: 420
Examples 59.60. and 61: N-(2,3-dihvdro-1H-inden-2-yl)-7-fluoro-2-oxo-1.2,3.4- tetrahydroquinoline-4-carboxamide, N-(2,3-dihydro-1H-inden-2-yl)-7-fluoro-l- methyl-2H)xo-1,2,3,4-tetrahydroquinolin-e 4-carboxamide and N-(2,3-dihydro-1H- inden-2-yl)-7-fluor(>-l,4-dimethyl-2-xo-1,2,3,4-tetrahydroqumoUne-4-carboxamide
Figure imgf000114_0001
Sodium hydride (60 % dispersion in mineral oil, 0.402 g, 10.04 mmol) was added to 7- fluoro-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxylic acid (1.0 g, 4.78 mmol) in DMF (5 mL). The mixture was stirred at room temperature under nitrogen. Methyl iodide (0.747 mL, 11.9S mmol) then DMF (S mL) was added. The reaction was stirred for 1 h. Further DMF (10 mL) was added and the mixture was stirred at room temperature for 18 h. The mixture was partitioned between water and EtOAc. The organic phase was washed with water, dried (MgS04) and concentrated in vacuo. The residue was taken up in MeOH (10 mL) and NaOH (2M aq, 7.17 mL, 14.34 mmol). The mixture was stirred at room temperature for 90 min. The mixture was acidified (2N HC1) and extracted with DCM. The combined organic phases were dried (MgS04) and concentrated in vacuo. HATU (1.218 g, 3.20 mmol) was added to a solution of the residue and DIPEA (0.S86 mL, 3.36 mmol) in DMF (3 mL). The mixture was stirred and allowed to stand for 5 min. 2,3-Dihydro-1H- inden-2-amine (0.406 g, 3. OS mmol) was added. The mixture was stirred and allowed to stand for 5 min. The mixture was diluted with EtOH and purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compounds.
Example 59: N-(2,3-dihydro-1H-inden-2-yl)-7-fluoro-2-oxo-1,2,3,4- tetrahydroquinoline-4-carboxamide
1H NMR (400 MHz, DMSO-c¾) δ ppm 2.53 - 2.57 (m, 1 H) 2.59 - 2.73 (m, 2 H) 2.74 - 2.85 (m, 1 H) 3.08 - 3.25 (m, 2 H) 3.73 (t, J=5.59 Hz, 1 H) 4.33 - 4.47 (m, 1 H) 6.58 - 6.67 (m, 1 H) 6.68 - 6.80 (m, 1 H) 7.08 - 7.31 (m, 5 H) 8.47 (d, J=6.97 Hz, 1 H) 10.06 (s, 1 H) MS ES+: 325
Example 60: N-(2,3-dihydro-1H-inden-2-yl)-7-fluoro-l-methyl-2-oxo-l,2-3,4- tetrahydroquinoIine-4-carboxamide
1H NMR (400 MHz, DMS(W6) δ ppm 2.60 - 2.82 (m, 4 H) 3.08 - 3.24 (m, 5 H) 3.71 (t, J=5.46 Hz, 1 H) 4.34 - 4.46 (m, 1 H) 6.80 - 6.88 (m, 1 H) 6.93 - 6.99 (m, 1 H) 7.10 - 7.25 (m, 4 H) 7.26 - 7.33 (m, 1 H) 8.47 (d, J=6.97 Hz, 1 H)
MS ES+: 339
Example 61 :
Figure imgf000115_0002
tetrahydroquinoline-4-carboxamide
1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 3 H) 2.45 (d, J=15.77 Hz, 1 H) 2.65 - 2.81 (m, 2 H) 3.02 - 3.18 (m, 3 H) 3.21 (s, 3 H) 4.41 - 4.54 (m, 1 H) 6.86 - 6.92 (m, 1 H) 6.96 - 7.02 (m, 1 H) 7.09 - 7.21 (m, 4 H) 7.27 - 7.33 (m, 1 H) 7.63 (d, J=7.34 Hz, 1 H)
MS ES+: 353
Examples 62 and 63: N-(2.3-dihvdro-1H-inden-2-yl)-7-fluoro-l-methvl-2-oxo-1.23.4- tetrahydroquinoline-4-carboxamide (single enantiomers)
Figure imgf000115_0001
N-(2,3-dihydro- 1 H-inden-2-yl)-7-fluoro- 1 -methyl-2-oxo- 1 ,2,3 ,4-tetrahydroquinoline-4- carboxamide (Example 60) was purified by chiral SFC (26% isocratic EtOH, ED column) to afford the title compounds.
Example 62: first eluting enantiomer:
lH NMR (400 MHz, CDC13) δ ppm 2.63 - 2.80 (m, 3 H) 3.10 - 3.19 (m, 1 H) 3.21 - 3.36 (m, 5 H) 3.58 (t, J=5.87 Hz, 1 H) 4.65 - 4.77 (m, 1 H) 5.66 (d, J=6.97 Hz, 1 H) 6.69 - 6.78 (m, 2 H) 7.08 - 7.14 (m, 1 H) 7.15 - 7.24 (m, 4 H)
MS ES+: 339
Example 63: second eluting enantiomer:
'H NMR (400 MHz, CDC13) δ ppm 2.63 - 2.80 (m, 3 H) 3.10 - 3.19 (m, 1 H) 3.21 - 3.36 (m, 5 H) 3.58 (t, J=5.87 Hz, 1 H) 4.65 - 4.77 (m, 1 H) 5.66 (d, J=6.97 Hz, 1 H) 6.69 - 6.78 (m, 2 H) 7.08 - 7.14 (m, 1 H) 7.15 - 7.24 (m, 4 H)
MS ES+: 339 Examples 64. 65 and 66: N-(2,3-dihvdro-1H-inden-2-vIV6-fluoro-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide, N-(2,3-dihydro-1H-inden-2-yl)-6-fluoro-l- methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxamide and N-(2r3-dihydro-1H- inden-2-yl)-6-fluoro-l,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide
F
Figure imgf000116_0001
Prepared as described for N-(2,3-dihydro-1H-inden-2-yl)-7-fluoro-2-oxo-l,2,3,4- te1rahydroquinoline-4-carboxamide, N-(2,3-&hy^
oxo- 1 ,2,3,4-tetrahydroquinoline-4-carboxamide and N-(2,3-dihydro- 1H-inden-2-yl)-7- fluoro-l,4-dimethyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxamide (Examples 59, 60, and 61) from 6-fluoro-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxylic acid (1.0 g, 4.78 mmol) to afford the title compounds.
Example 64: N-(2,3-dihydro-1H-inden-2-yl)-6-fluoro-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide
1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 - 2.86 (m, 4 H) 3.08 - 3.26 (m, 2 H) 3.66 - 3.80 (m, 1 H) 4.34 - 4.50 (m, 1 H) 6.80 - 6.90 (m, 1 H) 6.94 - 7.30 (m, 6 H) 8.47 (d, J=6.97 Hz, l H) 9.99 (s, 1 H)
MS ES+: 325
Example 65: N-(2,3-dihydro-1H-inden-2-yl)-6-fluoro-l-methyl-2-oxo-1,2,3,4- tetrahydroquinoline-4-carboxamide
'H NMR (400 MHz, DMSO- d6) δ ppm 2.58 - 2.87 (m, 4 H) 3.09 - 3.26 (m, 5 H) 3.69 - 3.78 (m, 1 H) 4.31 - 4.49 (m, 1 H) 7.02 - 7.31 (m, 7 H) 8.47 (d, J=7.15 Hz, 1 H)
MS ES+: 339
Example 66: N-(2,3-dihydro-1H-inden-2-yl)-6-fluoro-l,4-dimethyI-2-oxo-1,2,3,4- tetrahydroquinoline-4-carboxamide
1H NMR (400 MHz, DMSO- d6) δ ppm 1.47 (s, 3 H) 2.45 (d, J=15.77 Hz, 1 H) 2.63 - 2.84 (m, 2 H) 3.00 - 3.18 (m, 3 H) 3.22 (s, 3 H) 4.32 - 4.55 (m, 1 H) 7.01 - 7.24 (m, 7 H) 7.66 (d, J=7.34 Hz, 1 H)
MS ES+: 353
5 Example 67: N-(2,3-dihydro-1H-inden-2-yI)-4-methyl-3-oxo-l,2,3,4- tetrahydroquinoxaline-l-carboxamide
Figure imgf000117_0001
NH
Figure imgf000117_0002
Bis(trichloromethyl) carbonate (0.107 g, 0.360 mmol) was added to a solution of 1-methyl- l,2,3,4-tetrahydroquinoxalin-2-one (0.097 g, 0.6 mmol) and pyridine (0.051 mL, 0.630 mmol) in DCM (3 mL) under nitrogen. The mixture was stirred at room temperature and left to stand for 1 h. 2,3-Dihydro-1H-inden-2-amine (0.400 g, 3.00 mmol) was added. The mixture was stirred and allowed to stand for 30 min. The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compound.
1H NMR (400 MHz, DMSO-</tf) δ ppm 2.83 - 2.93 (m, 2 H) 3.10 - 3.22 (m, 2 H) 3.32 (s, 3 H) 4.26 (s, 2 H) 4.39 - 4.52 (m, 1 H) 7.03 - 7.10 (m, 1 H) 7.10 - 7.26 (m, 7 H) 7.42 (d, J=7.89 Hz, 1 H)
MS ES+: 322
Example 68: N-f2,3-dihvdro-1H-inden-2-vn-l-methvl-2-oxo-2.4-dihvdro-1H-3.1- benzoxazine-4-carboxamide
Figure imgf000117_0003
2,3-Dihydro-1H-inden-2-amine (0.266 g, 1.S7 mmol) was added to a mixture of lithio 1- methyl-2-oxo-2,4-dihydro-1H-3,l-benzoxazine-4-carboxylate (Intermediate 24, 0.223 g, 1.05 mmol), HATU (0.597 g, 1.57 mmol) and TEA (1.46 mL, 10.5 mmol) in DCM (20 mL) under N2. The reaction was stirred at room temperature for 72 h. DMF (4 mL) was added to the reaction mixture. The reaction was stirred at room temperature for a further 24 h. The mixture was partitioned between DCM and water. The organic phase was separated and the aqueous extracted with further DCM. The combined organics were dried (Na2S04) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% formic acid) to afford the title compound.
1H NMR (400 MHz, CDC13) δ ppm 2.70 - 2.99 (m, 2 H) 3.29 - 3.45 (m, 5 H) 4.68 - 4.91 (m, 1 H) 5.63 (s, 1 H) 6.78 (d, J=7.08 Hz, 1 H) 6.95 (d, J=8.17 Hz, 1 H) 7.06 - 7.29 (m, 5 H) 7.30 - 7.44 (m, 1 H) 7.55 (d, J=7.63 Hz, 1 H)
MS ES+: 323
Example 69: Nj-(2,3-djhydro-1H-indenr2-yl)-4-oxo-2,4,5,6^tetrahydro-1H - pyrrolo[3^4-U]quinoline-6-carboxamide
Figure imgf000118_0001
NaOH (2M aq, 1 mL, 2.0 mmol) was added to a solution of diethyl 4,5-dihydro-1H- pyrrolo[3,2,l-ij]quinoline-6,6(2H)-dicarboxylate (Intermediate 25, 0.055 g, 0.173 mmol) in EtOH (2 mL). The mixture was heated under microwave irradiation at 100 °C for 10 min. The mixture was acidified (2N HC1) and extracted with EtOAc. The organic phase was dried (MgS04) and concentrated in vacuo. HATU (0.032 g, 0.084 mmol) was added to a solution of half of the residue and DDPEA (0.015 mL, 0.088 mmol) in DMF (0.5 mL). The reaction was stirred at room temperature and allowed to stand for 5 min. 2,3-dihydro- 1H-inden-2-amine (0.011 g, 0.080 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 5 min. The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 2.57 - 2.86 (m, 4 H) 3.08 - 3.25 (m, 4 H) 3.75 - 3.97 (m, 3 H) 4.36 - 4.50 (m, 1 H) 6.81 - 6.95 (m, 1 H) 6.98 - 7.29 (m, 6 H) 8.53 (d, J=6.97 Hz, 1 H)
MS ES+: 332
Example 70: N-f2,3-dihvdro-1H-inden-2-vn-8-fluoro-l-methvl-2-oxo-l.2,3.4- tetrahydroquinoline-4-carboxamide
Figure imgf000119_0001
HATU (120 mg, 0.32 mmol) was added to a solution of 8-fluoro-l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxylic acid (Intermediate 26, 0.067 g, 0.30 mmol) and DEPEA (0.058 mL, 0.33 mmol) in DMF (0.5 mL). The reaction was stirred at room temperature and allowed to stand for 5 min. 2,3-Dihydro-1H-inden-2-amine (0.040 g, 0.30 mmol) was added. The mixture was stirred at room temperature and left to stand for 5 min. The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 2.57 - 2.86 (m, 4 H) 3.03 - 3.28 (m, 5 H) 3.66 - 3.84 (m, 1 H) 4.32 - 4.51 (m, 1 H) 6.97 - 7.32 (m, 7 H) 8.48 (d, J=7.01 Hz, 1 H)
MS ES+: 339
Examples 71 and 72: N-(2,3-dihvdro-1H-inden-2-yl)-5-fluoro-l-methvl-2-oxo-1.2,3.4- tetrahydroquinoline-4-carboxamide and 8-bromo-N-(2,3-dihydro-1H-inden-2-yl)-5- fluoro-l-methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxamide
Figure imgf000120_0001
\J \_J
A solution of 2-chloroacetyl chloride (1.20 g, 10.6 mmol) in DCM (5 mL) was added drop wise to an ice-water bath cooled solution of 2-bromo-S-fluoro-N-methylaniline hydrochloride (2.S0 g, 10.4 mmol) and DEPEA (2.0 mL, 11.4 mmol) in DCM (20 mL) over approximately S min. The reaction was stirred at 0 °C for 5 min. The mixture was partitioned between water and DCM. The organic phase was dried (MgS04) and concentrated in vacuo. Sodium hydride (60% dispersion in mineral oil, 0.831 g, 20.8 mmol) was added portion wise to an ice- water bath cooled solution of 1,3-diethyl propanedioate (3.17 mL, 20.8 mmol) in THF (30 mL) under nitrogen. The mixture was stirred at 0 °C until effervescence ceased. A solution of the previous residue in THF (10 mL) was added. The mixture was stirred at 0 °C and allowed to stand for 18 h. The mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSCu) and concentrated in vacuo. The material was purified by column chromatography on silica, eluted with 20-50%
EtOAc/petroleum ether. The crude material was dissolved in acetic acid (30 mL).
Manganese (ΙΠ) acetate dihydrate (5.57 g, 20.8 mmol) was added. The reaction was heated at reflux for 30 min. After cooling, the reaction mixture was concentrated in vacuo. The material was purified by column chromatography on silica, eluted with 30-100%
EtOAc/petroleum ether. NaOH (2M aq, 20 mL, 40.0 mmol) was added to a solution of the previous crude material in EtOH (40 mL). The mixture was heated at 60 °C for 30 min. The mixture was concentrated in vacuo and the residue diluted with water and extracted with DCM. The aqueous phase was acidified with HC1 (2N) and extracted with DCM. The combined organic phases were dried and concentrated in vacuo. HATU (0.200 g, 0.S2S mmol) was added to a solution of approximately one sixth of the residue in DMF (0.5 mL). The mixture was stirred at room temperature and allowed to stand for 5 min. 2,3-Dihydro- 1H-inden-2-amine (0.067 g, 0.50 mmol) was added. The mixture was stirred at room temperature for 1 h. The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% N¾) to afford the title compounds.
Example 71 : N-(2,3-dihydro-1H-inden-2-yl)-5-fluoro-l-methyI-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide
1H NMR (400 MHz, DMSO-d6) δ ppm 2.56 - 2.89 (m, 4 H) 3.08 - 3.26 (m, 5 H) 3.65 - 3.77 (m, 1 H) 4.26 - 4.47 (m, 1 H) 6.75 - 6.90 (m, 1 H) 6.91 - 7.03 (m, 1 H) 7.09 - 7.36 (m, 5 H) 8.47 (d, J=6.97 Hz, 1 H)
MS ES+: 339
Example 72: 8-bromo-N-(2r3-dihydro-1H-inden-2-yl)-5-flu0ro-l-methyl-2-oxo-1,2,3,4- tetrahydroquinoline-4-carboxamide
'H NMR (400 MHz, DMSO-d6) δ ppm 2.56 - 2.66 (m, 1 H) 2.66 - 2.84 (m, 2 H) 2.84 - 3.02 (m, 1 H) 3.06 - 3.21 (m, 2 H) 3.32 (s, 3 H) 3.92 (d, J=4.77 Hz, 1 H) 4.30 - 4.53 (m, 1 H) 6.94 - 7.04 (m, 1 H) 7.07 - 7.30 (m, 4 H) 7.54 - 7.77 (m, 1 H) 8.51 (d, J=7.15 Hz, 1 H) MS ES+: 417
Example 73: N-(2,3-dihydro-1H-inden-2-yl)-5,7-difluoro-l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide
Figure imgf000121_0001
HATU (0.120 g, 0.315 mmol) was added to a solution of 5,7-difluoro-l-methyl-2-oxo- l,2,3,4-tetrahydroquinoline-4-carboxylic acid (Intermediate 27, 0.072 g, 0.3 mmol) and DIPEA (0.058 mL, 0.330 mmol) in DMF (0.5 mL) at room temperature. The mixture was stirred at room temperature and allowed to stand for 5 min. 2,3-Dihydro-1H-inden-2-amine (0.040 g, 0.300 mmol) was added. The mixture was stirred at room temperature and allowed to stand for 1 hour. The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compound. 1H NMR (400 MHz, DMSO-c¾) δ ppm 2.56 - 2.83 (m, 3 H) 2.84 - 3.00 (m, 1 H) 3.08 - 3.27 (m, 5 H) 3.84 - 4.04 (m, 1 H) 4.27 - 4.47 (m, 1 H) 6.82 - 6.99 (m, 2 H) 7.08 - 7.32 (m, 5 H) 8.45 (d, J=7.15 Hz, 1 H)
MS ES+: 357
Example 74: l-cydopropyl-N-(2,3-dihydro-1H-inden-2-yl)-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide
Figure imgf000122_0001
-Prepared as deseribed-for N-(2,3-dihydro- 1 H-inden-2-yl)-5 ,7-difluoro- 1 -rnethyl-2-oxo- l,2,3,4-tetrahydroquinoline-4-carboxamide (Example 73) from l-cyclopropyl-2-oxo- l,2,3,4-tetrahydroquinoline-4-carboxylic acid (Intermediate 29, 0.116 g, 0.50 mmol), and 2,3-dihydro-1H-inden-2-amine (0.067 g, 0.50 mmol). The mixture was partitioned between EtOAc and water. The phases were separated and the organic washed with water, dried (MgSCU) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 20-100% EtOAc/petroleum ether to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 0.21 - 0.44 (m, 1 H) 0.52 - 0.74 (m, 1 H) 0.88 - 1.13 (m, 2 H) 2.56 - 2.86 (m, 5 H) 3.05 - 3.25 (m, 2 H) 3.51 - 3.70 (m, 1 H) 4.29 - 4.50 (m, 1 H) 6.92 - 7.05 (m, 1 H) 7.09 - 7.38 (m, 7 H) 8.35 (d, J=6.97 Hz, 1 H)
MS ES+: 347
Examples 75 and 76: N-[(lS.2SVl-amino-2,3-dihvdro-1H-inden-2-vll-l-cvclopropvl-2- oxo-1 ,2,3,4-tetrahydroquinoline-4-carboxamide hydrochloride (single stereoisomers) Y - o
Figure imgf000123_0001
H2N*.
HCI
Figure imgf000123_0002
HATU (0.200 g, 0.53 mmol) was added to a solution of l-cyclopropyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxylic acid (Intermediate 29, 116 mg, 0.S0 mmol) and DIPEA (0.096 mL, 0.SS mmol) in DMF (1 mL). The mixture was stirred at room temperature and allowed to stand for 5 min and /erf-Butyl N-[(lS,2S)-2-amino-2,3-dihydro-1H-inden-l- yl]carbamate (0.124 g, 0.S00 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between water and EtOAc. The organic phase was washed with water, dried (MgS04) and concentrated in vacuo. HCI (4N in dioxane) (0.62S mL, 2.50 mmol) was added to a solution of the residue in DCM (3 mL). The reaction was stirred at room temperature for 3 h. Further HCI (4N in dioxane) (0.625 mL, 2.500 mmol) was added and the reaction was stirred at room temperature for a further 1 hour. The mixture was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford two components. Each component was separately dissolved in DCM (3 mL) and THF (3 mL) and treated with hydrogen chloride (4 M in dioxane, 0.088 mL, 0.35 mmol). The reactions were each allowed to stand for 15 min and then concentrated in vacuo, co-evaporating with diethyl ether to afford the title compounds.
Example 75- first eluting stereoisomer:
'H NMR (400 MHz, DMSO-d6) δ ppm 0.26 - 0.44 (m, 1 H) 0.56 - 0.77 (m, 1 H) 0.89 - 1.18 (m, 2 H) 2.58 - 2.80 (m, 3 H) 2.81 - 2.97 (m, 1 H) 3.33 - 3.44 (m, 1 H) 3.66 - 3.82 (m, 1 H) 4.22 - 4.42 (m, 1 H) 4.47 - 4.65 (m, 1 H) 6.89 - 7.08 (m, 1 H) 7.20 - 7.46 (m, 6 H) 7.61 (d, J=7.34 Hz, 1 H) 8.58 (br. s., 3 H) 8.82 (d, J=6.05 Hz, 1 H)
MS ES+: 362
Example 76 - second eluting stereoisomer:
1H NMR (400 MHz, DMSO-d6) δ ppm 2.62 - 2.86 (m, 5 H) 3.19 - 3.42 (m, 2 H) 3.55 - 3.65 (m, 2 H) 3.66 - 3.78 (m, 1 H) 4.36 - 4.50 (m, 1 H) 4.52 - 4.66 (m, 1 H) 6.93 - 7.13 (m, 1 H) 7.27 - 7.45 (m, 6 H) 7.62 (d, J=7.15 Hz, 1 H) 8.63 (br. s., 3 H) 8.80 (d, J=6.97 Hz, 1 H)
MS ES+: 362
Examples 77 and 78: N-[(lS.2S>-l-amino-2,3-dihvdro-1H-inden-2-vll-8-fluoro-l- methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxainide hydrochloride,
stereoisomers 1 and 2
Figure imgf000124_0001
Prepared as described for N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-l-cyclopropyl- 2-oxo-l ,2,3 ,4-tetrahydroquinoline-4-carboxamide hydrochloride, (single stereoisomers) (Examples 75 and 76) from 8-fluoro-l-methyl-2-oxo- 1,2,3, 4-tetrahydroquinoline-4- carboxylic acid (Intermediate 26, 0.212 g, 0.95 mmol) to afford the title compounds.
Example 77 - first eluting stereoisomer:
'H NMR (400 MHz, DMSO-i/i) 8 ppm 2.65 - 2.74 (m, 1 H), 2.77 - 2.97 (m, 2 H), 3.28 (d, J= 6.24 Hz, 3 H), 3.35 - 3.47 (m, 1 H), 3.78 - 3.95 (m, 1 H), 4.24 - 4.44 (m, 1 H), 4.50 - 4.68 (m, 1 H), 7.02 - 7.14 (m, 1 H), 7.15 - 7.26 (m, 2 H), 7.27 - 7.44 (m, 3 H), 7.64 (d, J= 7.34 Hz, 1 H), 8.62 (br. s., 3 H), 9.01 (d, J= 6.24 Hz, 1 H)
MS ES+: 354
Example 78 - second eluting stereoisomer:
'H NMR (400 MHz, DMSO-d6) δ ppm 2.67 - 2.91 (m, 3 H), 3.14 - 3.42 (m, 4 H), 3.76 - 3.94 (m, 1 H), 4.32 - 4.51 (m, 1 H), 4.53 - 4.71 (m, 1 H), 7.04 - 7.39 (m, 6 H), 7.64 (d,J= 7.15 Hz, 1 H), 8.68 (br. s., 3 H), 9.06 (d,J= 6.97 Hz, 1 H)
MS ES+: 354 Example 79: N-(2.3-dihvdro-1H-inden-2-vn-2-methvl-3-oxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000125_0001
A solution of methyl 2-methyl-3-oxo-l,2,3,4-tetrahydroisoquinoline-4-carboxylate (Intermediate 30, 0.064 g, 0.292 mmol) and 2,3-dihydro-1H-inden-2-amine (0.194 g, 1.46 mmol) in EtOH (l.S mL) was heated under microwave irradiation at ISO °C for 1 hour. The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% N¾) to afford the title compound.
1H NMR (400 MHz, OMSO-d6) δ ppm 2.61 - 2.73 (m, 1 H) 2.73 - 2.88 (m, 1 H) 3.01 (s, 3 H) 3.07 - 3.26 (m, 2 H) 4.24 - 4.54 (m, 3 H) 4.71 - 5.00 (m, 1 H) 7.07 - 7.37 (m, 8 H) 8.75 (d, J=6.97 Hz, l H)
MS ES+: 321
Examples 80 and 81; N-(2.3-dihvdro-1H-inden-2-vn-8-fluoro-l-methvl-2-oxo-1.2,3.4- tetrahydroquinoIine-4-carboxamide (single enantiomers)
Figure imgf000125_0002
N-(2,3-dihydro- 1 H-inden-2-yl)- 8-fluoro- 1 -methyl-2-oxo- 1 ,2,3 ,4-tetrahydroquinoline-4- carboxamide (Example 70, 0.320 g, 0.946 mmol) was purified by chiral SFC (18% isocratic MeOH, IC column) to afford the title compounds.
Example 80: first eluting enantiomer 1H NMR (300 MHz, DMSO-.&) δ ppm 2.57 - 2.86 (m, 4 H) 3.03 - 3.28 (m, 5 H) 3.66 - 3.84 (m, 1 H) 4.32 - 4.51 (m, 1 H) 6.97 - 7.32 (m, 7 H) 8.48 (d, J=7.01 Hz, 1 H)
MS ES+: 339
Example 81: second eluting enantiomer
1H NMR (300 MHz, DMSO-d6) δ ppm 2.57 - 2.86 (m, 4 H) 3.03 - 3.28 (m, 5 H) 3.66 - 3.84 (m, 1 H) 4.32 - 4.51 (m, 1 H) 6.97 - 7.32 (m, 7 H) 8.48 (d, J=7.01 Hz, 1 H)
MS ES+: 339
Examples 82 and 83: l-cyclopropyl-N-(2,3-dihydro-1H-inden-2-yl)-2-oxo-1,2,3,4- tetrahydroquinoline-4-carboxamide (single enantiomers)
Figure imgf000126_0001
1 -cyclopropyl-N-(2,3-dihydro- 1 H-inden-2-yl)-2-oxo- 1 ,2,3 ,4-tetrahydroquinoline-4- carboxamide (Example 74, 0.102 g, 0.295 mmol) was purified by chiral SFC (32% isocratic EtOH, Lux-C4 column) to afford the title compounds.
Example 82: first eluting enantiomer
'H NMR (400 MHz, DMSO-d6) δ ppm 0.21 - 0.44 (m, 1 H) 0.52 - 0.74 (m, 1 H) 0.88 - 1.13 (m, 2 H) 2.56 - 2.86 (m, 5 H) 3.05 - 3.25 (m, 2 H) 3.51 - 3.70 (m, 1 H) 4.29 - 4.50 (m, 1 H) 6.92 - 7.05 (m, 1 H) 7.09 - 7.38 (m, 7 H) 8.35 (d, J=6.97 Hz, 1 H)
MS ES+: 347
Example 83: second eluting enantiomer
•H NMR (400 MHz, DMSO-d6) δ ppm 0.21 - 0.44 (m, 1 H) 0.52 - 0.74 (m, 1 H) 0.88 - 1.13 (m, 2 H) 2.56 - 2.86 (m, 5 H) 3.05 - 3.25 (m, 2 H) 3.51 - 3.70 (m, 1 H) 4.29 - 4.50 (m, 1 H) 6.92 - 7.05 (m, 1 H) 7.09 - 7.38 (m, 7 H) 8.35 (d,J=6.97Hz, 1 H)
MS ES+: 347 Example 84: N-(2.3-dihvdro-1H-inden-2-vn-4-fluoro-2-methvl-3-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000127_0001
A solution of methyl 4-fluoro-2-methyl-3-oxo- 1,2,3 ,4-tetrahydroisoquinoline-4- carboxylate (Intermediate 31, 0.474 g, 1.00 mmol) and 2,3-dihydro-1H-inden-2-amine (0.933 g, 4.00 mmol) in EtOH (3 mL) was heated at 120 °C for 10 h in the microwave. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica, eluted with 30-100% EtOAc/petroleum ether then 0-6%
MeOH/DCM. The resulting residue was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% N¾) to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 2.81 - 3.00 (m, 2 H) 3.00 - 3.20 (m, 5 H) 4.28 - 4.51 (m, 1 H) 4.51 - 4.62 (m, 1 H) 4.72 - 4.89 (m, 1 H) 7.03 - 7.28 (m, 4 H) 7.34 - 7.60 (m, 4 H) 8.99 (d, J=6.97 Hz, l H)
MS ES+: 339
Examples 85 and 86; N-(2,3-dihydro-1H-inden-2-yl)-4-fluoro-2-methyl-3-oxo-l,23.4- tetrahydro.soquinoline-4-carboxamide (single enantiomers)
Figure imgf000127_0002
N-(2,3-dihydro- 1 H-inden-2-yl)-4-fluoro-2-methyl-3-oxo- 1 ,2,3 ,4-tetrahydroisoquinoline-4- carboxamide (Example 84, 0.095 g, 0.281 mmol) was purified by chiral SFC (26% isocratic IP A, IC column) to afford the title compounds. Example 85: first eluting enantiomer
1H NMR (400 MHz, DMSO-d6) δ ppm 2.81 - 3.00 (m, 2 H) 3.00 - 3.20 (m, 5 H) 4.28 - 4.51 (m, 1 H) 4.51 - 4.62 (m, 1 H) 4.72 - 4.89 (m, 1 H) 7.03 - 7.28 (m, 4 H) 7.34 - 7.60 (m, 4 H) 8.99 (d, J=6.97 Hz, 1 H)
MS ES+: 339
Example 86: second eluting enantiomer
1H NMR (400 MHz, DMSO-d6) δ ppm 2.81 - 3.00 (m, 2 H) 3.00 - 3.20 (m, 5 H) 4.28 - 4.51 (m, 1 H) 4.51 - 4.62 (m, 1 H) 4.72 - 4.89 (m, 1 H) 7.03 - 7.28 (m, 4 H) 7.34 - 7.60 (m, 4 H) 8.99 (d, J=6.97 Hz, 1 H)
MS ES+: 339
Example 87: N-a.3-dihvdro-1H-inden-2-vn-l-methvl-2-oxo-2.3.4^-tetrahvdro-1H-1- benzazepine-S-carboxamide
Figure imgf000128_0001
Prepared as described for N-(2,3-dihydro-1H-inden-2-yl)-l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide (Example 2) using l-methyl-2-oxo-2,3,4,5-tetrahydro- 1H-l-benzazepine-5-carboxylic acid (Intermediate 32, 0.066 g, 0.3 mmol) and 2,3- dihydro-1H-inden-2-amine (0.040 g, 0.300 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.00 - 2.19 (m, 3 H) 2.27-2.38 (m, 1 H) 2.64 - 2.83 (m, 2 H) 3.14 - 3.28 (m, 5 H) 3.60 - 3.72 (m, 1 H) 4.47 - 4.64 (m, 1 H) 7.05 - 7.41 (m, 8 H), 8.30 (br s, 1 H)
MS ES+: 335
Example 88: 2-cyclopropanecarbonyl-N-((frfl/is)-l-methoxy-2,3-dihydro-1H-inden-2- yl)-1,2,3,4-tetrahydroisoquinoline-l-carboxamide
Figure imgf000129_0001
T3P (50% in EtOAc) (0.537 ml, 1.225 mmol) was added to a solution of 2- (cyclopropanecarbonyl)- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxylic acid (Intermediate 33, single enantiomer), 0.180 g, 0.735 mmol), DIPEA (0.268 mL, 1.532 mmol) and (/rawi)-l-methoxy-2,3-dihydro-1H-inden-2-amine (Intermediate 2, 0.100 g, 0.613 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 30 min. The reaction was diluted with DCM and saturated bicarbonate solution, dried (phase separator) and concentrated in vacuo. The crude material was purified by column chromatography on silica, eluted with 0-100% EtO Ac/petroleum ether then submitted for further purification by reverse phase preparative HPLC to afford the title compound.
•H NMR (400 MHz, DMSO-d6) δ ppm 0.62 - 0.88 (m, 4 H) 1.80 - 2.12 (m, 1 H) 2.61 - 2.92 (m, 2 H) 3.07 - 3.37 (m, 5 H) 3.76 - 4.38 (m, 3 H) 4.54 - 4.72 (m, 1 H) 5.57 - 5.81 (m, 1 H) 7.14 - 7.50 (m, 8 H) 8.59 - 8.93 (m, 1 H)
MS ES+: 391
Examples 89 and 90; N-iaS.2SVl-amino-2,3-dihvdro-1H-inden-2-vll-6-nuoro-2-ff2- methyl-l^-thiazol-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomers)
Figure imgf000129_0002
O' NH
Figure imgf000129_0003
HC1 (4N in dioxane) (0.401 mL, 1.603 mmol) was added to a stirred solution of /er/-butyl N-[(lS,2S)-2-{6-fluoro-2-[(2-methyl-l,3-thiazol-4-yl)methyl]-l,2,3,4- tetrahydroisoquinoline- 1 -carboxamido}-2,3-dihydro- 1H-inden- l-yl]carbamate
(Intermediate 34, 0.043 g, 0.080 mmol) in DCM (2 mL) and stirred at room temperature for 18 h. More HC1 (4N in dioxane) (0.401 mL, 1.603 mmol) was added and stirring continued for a further 3 h. The reaction mixture was partitioned between DCM/MeOH (9: 1) and saturated sodium bicarbonate solution and the organics were concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% N¾) to afford the title compounds.
Example 89: first eluting stereoisomer
1H NMR (300 MHz, OMSO-d6) δ ppm 1.65 - 2.18 (m, 2 H) 2.55 - 3.23 (m, 9 H) 3.70 - 4.28 (m, 5 H) 6.89 - 7.45 (m, 8 H) 8.38 (d, J=7.63 Hz, 1 H)
MS ES+: 437
Example 90: second eluting stereoisomer
'H NMR (300 MHz, DMSO-d6) δ ppm 1.78 - 2.15 (m, 2 H) 2.55 - 3.26 (m, 9 H) 3.65 - 4.31 (m, 5 H) 6.89 - 7.51 (m, 8 H) 8.35 (d, J=7.50 Hz, 1 H)
MS ES+: 437
Example 91 and 92: N-i(lS.2S)-l-amino-2 J-dihvdro-1H-inden-2-vll-2-f2.2- difluoroethyl)-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomers)
Figure imgf000130_0001
Figure imgf000130_0002
Prepared as described for N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-6-fluoro-2- [(2-methyl-l^-thiazoM-yl)methyl]-1,2,3,4-tetrahydroisoqumoline-l-carboxamide (single stereoisomers) (Examples 89 and 90) using fer/-butyl ((lS,2S>2-(2-(2,2- difluoroethyl)- 1,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamido)-2,3 -dihydro- 1 H-inden- 1 - yl)carbamate (Intermediate 35, 0.225 g, 0.477 mmol) to afford the title compounds.
Example 91: first eluting stereoisomer 1H NMR (400 MHz, DMSO-d6) δ ppm 1.90 (br. s., 2 H) 2.61 - 2.79 (m, 2 H) 2.89 - 3.18 (m, 2 H) 3.46 - 3.59 (m, 1 H) 3.91 - 4.04 (m, 1 H) 4.06 - 4.15 (m, 1 H) 4.35 (s, 1 H) 6.07 - 6.42 (m, 1 H) 7.06 - 7.22 (m, 6 H) 7.26 - 7.34 (m, 2 H) 8.38 (d, J=7.61 Hz, 4 H)
MS ES+: 372
Example 92: second eluting stereoisomer
1H NMR (400 MHz, DMSO-d6) δ ppm 1.82 - 2.06 (m, 2 H) 2.54 - 2.63 (m, 1 H) 2.72 - 2.87 (m, 3 H) 2.91 - 3.05 (m, 2 H) 3.06 - 3.17 (m, 1 H) 3.43 - 3.55 (m, 1 H) 3.88 - 4.05 (m, 1 H) 4.07 - 4.19 (m, 1 H) 4.35 (s, 1 H) 6.09 - 6.46 (m, 1 H) 7.02 - 7.23 (m, 6 H) 7.27 - 7.36 (m, 2 H) 8.36 (d, J=7.61 Hz, 1 H)
MS ES+: 372
Examples 93 and 94; N-(1S,.2SVl-amino-2,3-dihvdro-1H-inden-2-vll-2-[ri-methvl- 1H-pyrazol-S-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomers)
Figure imgf000131_0001
O' NH
Figure imgf000131_0002
Prepared as described for N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-6-fluoro-2- [(2-methyl-l^-thiazoM-yl)methyl]-l,2,3,4-tetrahydroisoquinoUne-l<arboxamide (single stereoisomers) (Examples 89 and 90) using tert-butyl ((lS,2S)-2-(2-((l-methyl- 1H-pyrazol-5-yl)methyl)-l,2,3,4-tetra^
inden-l-yl)carbamate (Intermediate 36, 0.280 g, 0.558 tnmol) to afford the title compounds.
Example 93: first eluting stereoisomer
'H NMR (300 MHz, DMSO-d6) δ ppm 2.29 - 2.50 (m, 1 H) 2.63 - 2.92 (m, 3 H) 3.03 - 3.20 (m, 1 H) 3.33 (br. s., 4 H) 3.75 (s, 1 H) 4.11 (s, 2 H) 4.20 - 4.26 (m, 1 H) 5.77 (s, 2 H) 6.22 - 6.32 (m, 1 H) 7.10 - 7.24 (m, 6 H) 7.26 - 7.40 (m, 3 H) 8.34 - 8.49 (m, 1 H) MS ES+: 402 Example 94: second eluting stereoisomer
1H NMR (300 MHz, DMSO-d6) δ ppm 2.28 (br. s., 2 H), 2.55 - 2.91 (m, 3 H), 3.09 - 3.19 (m, 1 H), 3.20 - 3.29 (m, 1 H), 3.34 (s, 2 H), 3.66 - 3.76 (m, 1 H), 3.97 - 4.09 (m, 1 H), 4.11 - 4.19 (m, 1 H), 4.23 (s, 1 H), 5.77 (s, 2 H), 6.27 (s, 1 H), 7.04 - 7.27 (m, 7 H), 7.29 - 7.37 (m, 3 H), 8.33 - 8.43 (m, 1 H)
MS ES+: 402
Examples 95 and 96: N-raS.2SH-amino-2 J-dihvdro-1H-inden-2-vll-2-irnvrimidin-S- yl)methyl]-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomers)
Figure imgf000132_0001
Prepared as described for N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-6-fluoro-2- [(2-methyl-l^-thiazoM-yl)methyl]-l,2,3,4-tetrahydroisoquinoline-l-carboxamide (single stereoisomers) (Examples 89 and 90) ½r/-butyl N-[(lS,2S)-2-{2-[(pyrimidin-5- yl)methyl]- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamido} -2,3-dihydro- 1 H-inden- 1 - yl]carbamate (Intermediate 37, 0.240 g, 0.480 tnmol) to afford the title compounds.
Example 95: first eluting stereoisomer
1H NMR (300 MHz, DMSO-d6) δ ppm 2.10 - 2.22 (m, 1 H), 2.62 - 2.97 (m, 3 H), 3.01 - 3.16 (m, 1 H), 3.22 - 3.40 (m, 2 H), 3.65 - 3.77 (m, 1 H), 3.83 - 3.94 (m, 1 H), 3.98 - 4.18 (m, 2 H), 4.24 (s, 1 H), 5.77 (s, 1 H), 7.10 - 7.24 (m, 6 H), 7.27 - 7.37 (m, 2 H), 8.36 - 8.47 (m, 1 H), 8.88 (s, 2 H), 9.13 (s, 1 H)
MS ES+: 400
Example 96: second eluting stereoisomer
lH NMR (300 MHz, DMSO-d6) δ ppm 2.02 (br. s., 2 H), 2.53 - 2.66 (m, 2 H), 2.69 - 2.82 (m, 1 H), 2.85 - 2.99 (m, 1 H), 3.01 - 3.13 (m, 1 H), 3.14 - 3.25 (m, 1 H), 3.58 - 3.73 (m, 1 H), 3.88 - 4.19 (m, 3 H), 4.24 (s, 1 H), 7.08 - 7.25 (m, 6 H), 7.27 - 7.39 (m, 2 H), 8.33 - 8.42 (m, 1 H), 8.90 (s, 2 H), 9.13 (s, 1 H)
MS ES+: 400
Examples 97.98.99 and 100: 2-(3-cyanopropanoyl)-N-((//-fl«s)-l-niethoxy-2,3- dihydro-1H-inden-2-yl)-l,23,4-tetrahydroisoquinoliiie-l-carboxaiiiide (single stereoisomers)
Figure imgf000133_0001
T3P (50% in EtOAc) (0.622 mL, 1.045 mmol) was added to a solution of N-((/ra;w)-l- methoxy-2,3-dihydro- 1H-inden-2-yl)- 1 ,2,3,4-tefrahydroisoquinoliner 1 -carboxamide - hydrochloride (Intermediate 38, 0.25 g, 0.697 mmol), 3-cyanopropanoic acid (0.076 g, 0.766 mmol) and TEA (0.291 ml, 2.090 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour. The mixture was partitioned between DCM and saturated NaHCC>3, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-100% EtO Ac/petroleum ether to afford the product as a mixture of 4 diastereomers. The residue was purified by chiral SFC (34% isocratic EtOH, IC column) to afford three peaks. Peaks 1 and 2 were single stereoisomers and peak 3 was further purified by chiral SFC (40% isocratic IPA, AD column) to afford the other two stereoisomers. Each peak was further purified where required by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compounds.
Example 97: first eluting stereoisomer
1H NMR (400 MHz, CD2C12) δ ppm 2.44 - 2.54 (m, 2 H), 2.65 - 2.81 (m, 3 H), 2.84 - 2.94 (m, 1 H), 3.08 - 3.18 (m, 1 H), 3.35 - 3.47 (m, 4 H), 3.56 - 3.70 (m, 1 H), 3.83 - 3.95 (m, 1 H), 4.45 - 4.57 (m, 2 H), 5.80 (s, 1 H), 6.92 - 7.03 (m, 1 H), 7.15 - 7.40 (m, 8 H)
ES-: 402 Example 98: second eluting stereoisomer
'H NMR (400 MHz, DMSO- d6) δ ppm 2.62 - 3.00 (m, 7 H), 3.02 - 3.13 (m, 1 H), 3.18 - 3.27 (m, 3 H), 3.55 - 3.65 (m, 1 H), 3.97 - 4.07 (m, 1 H), 4.21 - 4.38 (m, 1 H), 4.58 - 4.69 (m, 1 H), 5.65 (s, 1 H), 7.14 - 7.40 (m, 7 H), 7.42 - 7.50 (m, 1 H), 8.65 - 8.82 (m, 1 H) ES": 402
Example 99: first eluting peak from third eluting peak stereoisomer
1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 - 2.71 (m, 3 H), 2.74 - 3.00 (m, 3 H), 3.04 - 3.25 (m, 2 H), 3.34 - 3.38 (m, 3 H), 3.53 - 3.66 (m, 1 H), 3.95 - 4.05 (m, 1 H), 4.19 - 4.32 (m, 1 H), 4.63 - 4.71 (m, 1 H), 5.64 (s, 1 H), 7.16 - 7.41 (m, 7 H), 7.45 - 7.54 (m, 1 H), 8.66 - 8.78 (m, 1 H)
ES": 402
Example 100: second eluting peak from third eluting peak stereoisomer
1H NMR (400 MHz, DMSO-d6) δ ppm 2.61 - 2.70 (m, 3 H), 2.76 - 3.29 (m, 4 H), 3.32 (s, 3 H), 3.37 (s, 1 H), 3.54 - 3.64 (m, 1 H), 3.87 - 4.07 (m, 1 H), 4.18 - 4.30 (m, 1 H), 4.63 - 4.78 (m, 1 H), 5.64 (s, 1 H), 7.20 - 7.36 (m, 7 H), 7.41 - 7.55 (m, 1 H), 8.63 - 8.89 (m, 1 H) ES": 402
Examples 101. 102. 103 and 104: N-q/raii5)-l-methoxv-2,3-dihvdro-1H-inden-2-vn-2- [(oxan-4-yl)methyl]-3-oxo-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single steroisomers)
Figure imgf000134_0001
TEA (0.361 mL, 2.59 mmol) was added to a suspension of
2-[(oxan-4-yl)methyl]-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid
(Intermediate 17, 0.25 g, 0.864 mmol), (trans)-l-methoxy-2,3-dihydro-1H-inden-2- amine (0.148 g, 0.907 mmol), EDC (0.248 g, 1.296 mmol) and HOAt (0.200 g, 1.296 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 18 h. The mixture was diluted with DCM and washed with 5% citric acid, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 25-100% EtOAc/petroleum ether. The crude material was purified by chiral SFC (30% isocratic IP A, Lux-C4 column) to afford three peaks, peak one as a mixture of two stereoisomers and peaks two and three as single stereoisomers. Peak one was further purified by chiral SFC (18% isocratic EtOH, AD column) to afford the two further single stereoisomers.
Example 101: Second eluting peak single stereoisomer
'H NMR (400 MHz, DMSO-d6) δ ppm 1.07 - 1.29 (m, 3 H), 1.34 - 1.43 (m, 1 H), 1.49 - 1.57 (m, 1 H), 1.70 - 1.81 (m, 1 H), 2.58 - 2.65 (m, 1 H), 2.93 - 3.01 (m, 1 H), 3.12 - 3.25 (m, 3 H), 3.38 (s, 3 H), 3.40 - 3.47 (m, 1 H), 3.48 - 3.56 (m, 1 H), 3.78 - 3.87 (m, 2 H), 3.89 - 3.97 (m, 1 H), 4.21 - 4.29 (m, 1 H), 4.63 - 4.67 (m, 1 H), 7.18 - 7.36 (m, 6 H), 7.38 - 7.49 (m, 2 H), 8.83 - 8.88 (m, 1 H)
MS ES+: 435
Example 102: third eluting peak single stereoisomer
lH NMR (400 MHz, DMSO-d6) δ ppm 1.09 - 1.18 (m, 1 H), 1.19 - 1.28 (m, 1 H), 1.36 - 1.45 (m, 1 H), 1.49 - 1.57 (m, 1 H), 1.73 - 1.86 (m, 1 H), 2.69 - 2.78 (m, 1 H), 2.89 - 2.98 (m, 1 H), 3.15 (s, 3 H), 3.16 - 3.24 (m, 2 H), 3.25 - 3.31 (m, 1 H), 3.41 - 3.48 (m, 1 H),
3.56 - 3.63 (m, 1 H), 3.78 - 3.87 (m, 2 H), 3.88 - 3.95 (m, 1 H), 4.19 - 4.28 (m, 1 H), 4.53 -
4.57 (m, 1 H), 5.08 (s, 1 H), 7.18 - 7.35 (m, 7 H), 7.41 - 7.46 (m, 1 H), 8.91 - 8.96 (m, 1 H) MS ES+: 435
Example 103: First eluting peak from first eluting peak single stereoisomer
'H NMR (300 MHz, DMSO-c¾) δ ppm 1.11 - 1.30 (m, 2 H), 1.33 - 1.60 (m, 2 H), 1.67 -
1.87 (m, 1 H), 2.56 - 2.69 (m, 1 H), 2.91 - 3.04 (m, 1 H), 3.14 - 3.26 (m, 3 H), 3.38 (s, 3
H), 3.44 - 3.59 (m, 2 H), 3.76 - 4.01 (m, 3 H), 4.20 - 4.32 (m, 1 H), 4.60 - 4.70 (m, 1 H),
5.07 (s, 1 H), 7.16 - 7.52 (m, 8 H), 8.81 - 8.92 (m, 1 H)
MS ES+: 435
Example 104: Second eluting peak from first eluting peak single stereoisomer 1H NMR (300 MHz, DMSCwfc) δ ppm 1.12 - 1.27 (m, 2 H), 1.37 - 1.58 (m, 2 H), 1.75 - 1.86 (m, 1 H), 2.69 - 2.80 (m, 1 H), 2.90 - 2.99 (m, 1 H), 3.16 (s, 3 H), 3.19 - 3.30 (m, 3 H), 3.39 - 3.50 (m, 1 H), 3.53 - 3.65 (m, 1 H), 3.78 - 3.87 (m, 2 H), 3.88 - 4.01 (m, 1 H), 4.20 - 4.28 (m, 1 H), 4.56 (d, J = 4.26 Hz, 1 H), 5.09 (s, 1 H), 7.18 - 7.40 (m, 7 H), 7.41 - 7.47 (m, 1 H), 8.91 - 9.01 (m, 1 H)
MS ES+: 435
Examples 105. 106. 107 and 108: 2-(cyclopropylmethyI)-N-((/ra/i5>l-methoxy-2,3- dihydro-1H-inden-2-yl>-3-oxo-1,2,3,4-tetrahydroisoquinoline-l-carboxainide (single stereoisomers)
Figure imgf000136_0001
TEA (0.426 mL, 3.06 mmol) was added to a solution of 2-(cyclopropylmethyl)-3-oxo- 1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 14, 0.25 g, 1.019 mmol), (/raws)-l-methoxy-2,3-dihydro-1H-inden-2-amine (Intermediate 2, 0.175 g, 1.070 mmol), EDC (0.293 g, 1.529 mmol) and HOAt (0.236 g, 1.529 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 4 h. The mixture was diluted with DCM and washed with 5% citric acid, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 25-100%
EtOAc/petroleum ether. The crude material was purified by chiral SFC (40% isocratic EtOH, AD column) to afford the two pairs of diastereomers. Peak 1 was further purified by chiral SFC (40% isocratic IP A, IC column) and peak 2 was further purified by chiral SFC (20% isocratic EtOH, IC column) to afford the title compounds.
Example 105: first eluting peak from first eluting peak single stereoisomer
1H NMR (400 MHz, DMSO-d6) δ ppm 0.13 - 0.26 (m, 2 H), 0.35 - 0.50 (m, 2 H), 0.84 - 0.95 (m, 1 H), 2.57 - 2.65 (m, 1 H), 3.14 - 3.22 (m, 2 H), 3.22 - 3.30 (m, 1 H), 3.33 (s, 3 H), 3.38 - 3.47 (m, 1 H), 3.85 - 3.93 (m, 1 H), 4.20 - 4.27 (m, 1 H), 4.61 - 4.66 (m, 1 H), 5.15 (s, 1 H), 7.18 - 7.22 (m, 1 H), 7.22 - 7.33 (m, 5 H), 7.34 - 7.38 (m, 1 H), 7.45 - 7.55 (m, 1 H), 8.73 - 8.86 (m, 1 H)
MS ES+: 391
Example 106: second eluting peak from first eluting peak single stereoisomer
1H NMR (400 MHz, DMSO-d6) δ ppm 0.18 - 0.29 (m, 2 H), 0.37 - 0.52 (m, 2 H), 0.86 - 0.97 (m, 1 H), 2.69 - 2.77 (m, 1 H), 3.12 (s, 3 H), 3.19 - 3.32 (m, 4 H), 3.38 - 3.48 (m, 1 H), 3.86 - 3.94 (m, 1 H), 4.19 - 4.29 (m, 1 H), 4.50 - 4.57 (m, 1 H), 7.17 - 7.33 (m, 7 H), 7.44 - 7.53 (m, 1 H), 8.84 - 8.96 (m, 1 H)
MS ES+: 391
Example 107: first eluting peak from second eluting peak single stereoisomer 'H NMR (400 MHz, DMSO-d6) δ ppm 0.11 - 0.26 (m, 2 H), 0.34 - 0.49 (m, 2 H), 0.82 - 0.95 (m, 1 H), 2.56 - 2.65 (m, 1 H), 3.13 - 3.21 (m, 2 H), 3.22 - 3.30 (m, 1 H), 3.33 (s, 3 H), 3.39 - 3.46 (m, 1 H), 3.84 - 3.95 (m, 1 H), 4.16 - 4.29 (m, 1 H), 4.60 - 4.66 (m, 1 H), 5.14 (s, 1 H), 7.16 - 7.33 (m, 6 H), 7.34 (s, 1 H), 7.45 - 7.54 (m, 1 H), 8.73 - 8.85 (m, 1 H) MS ES+: 391
Example 108: second eluting peak from second eluting peak single stereoisomer
•H NMR (400 MHz, DMSO-d6) δ ppm 0.14 - 0.29 (m, 2 H), 0.34 - 0.53 (m, 2 H), 0.83 - 0.99 (m, 1 H), 2.64 - 2.77 (m, 1 H), 3.10 (s, 3 H), 3.18 - 3.29 (m, 3 H), 3.38 - 3.46 (m, 1 H), 3.82 - 3.94 (m, 1 H), 4.17 - 4.30 (m, 1 H), 4.49 - 4.56 (m, 1 H), 5.16 (s, 1 H), 7.14 - 7.32 (m, 7 H), 7.44 - 7.52 (m, 1 H), 8.84 - 8.94 (m, 1 H)
MS ES+: 391
Example 109: l-(cyclopropyImetliyl)-N-(2,3-dihydro-1H-inden-2-yl)-2-oxo-2,4- dihydro-1H-3,l-benzoxazine-4-carboxamide
Figure imgf000138_0001
Prepared as described for N-(2,3-dihydro-1H-inden-2-yl)-l-methyl-l,2,3,4- tetrahydroquinoline-4-carboxamide (Example 1) using l-(cyclopropylmethyl)-2-oxo-2,4- dihydro-1H-benzo[d][l,3]oxazine-4-carboxylic acid (Intermediate 39, 0.04S g, 0.182 mmol) and 2,3-dihydro-1H-inden-2-amine (0.026 ml, 0.200 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.31 - 0.49 (m, 4 H) 1.08 - 1.20 (m, 1 H) 2.64 - 2.73 (m, 1 H) 2.78 - 2.86 (m, 1 H) 3.08 - 3.25 (m, 2 H) 3.78 (d, J=6.60 Hz, 2 H) 4.36 - 4.46 (m, 1 H) 5.68 (s, 1 H) 7.04 - 7.39 (m, 8 H) 8.69 (d, J=7.15 Hz, 1 H)
MS ES+: 363
Example 110 and 111: (4S)-N-((cw)-l-hydroxy-2,3-dihydro-1H-inden-2-yl)-l-methyl- 2-oxo-l,2,3,4-tetrahydroquinolme-4-carboxamide (single stereoisomers)
Figure imgf000138_0002
OH
cis
Figure imgf000138_0003
COMU (1.38 g, 3.22 mmol) was added to a stirred solution of (4S>l-methyl-2-oxo- l,2,3,4-tetrahydroquinoline-4-carboxylic acid (Intermediate 1, 0.600 g, 2.92 mmol), (cis)- 2-arnino-2,3-dihydro-1H-inden-l-ol (Intermediate 41, 0.436 g, 2.92 mmol) and 2,2,6,6- tetramethylpiperidine (0.413 g, 2.92 mmol) in DCM (15 mL) and stirred for 1 hour. The reaction mixture was washed with water and purified by column chromatography on silica, eluted with 0-100% EtOAc/petroleum ether to afford the 2 separated diastereomers. The 2 diastereomers were further purified by column chromatography on silica eluted with 1 - 100% EtO Ac/petroleum ether and then further purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% N¾) to afford the title compounds.
Example 110: first eluting stereoisomer
1H NMR (300 MHz, DMSO-</tf) δ ppm 2.59 - 2.75 (m, 2 H) 2.77 - 3.12 (m, 2 H) 3.31 (s, 3 H) 3.86 - 4.02 (m, 1 H) 4.24 - 4.41 (m, 1 H) 4.80 - 4.93 (m, 1 H) 5.30 - 5.45 (m, 1 H) 6.93
- 7.12 (m, 2 H) 7.15 - 7.37 (m, 5 H) 7.43 (d, J=7.08 Hz, 1 H) 8.02 (d, J=7.70 Hz, 1 H) MS ES": 335
Example 111: second eluting stereoisomer
'H NMR (300 MHz, DMSO-d6) δ ppm 2.66 - 3.04 (m, 4 H) 3.22 (s, 3 H) 3.84 - 3.99 (m, 1 H) 4.20 - 4.43 (m, 1 H) 4.77 - 4.92 (m, 1 H) 5.25 - 5.39 (m, 1 H) 6.88 - 7.11 (m, 2 H) 7.16
- 7.42 (m, 6 H) 8.09 (d, J=7.98 Hz, 1 H)
MS ES": 335
Example 112: (4SVl-methvl-2-oxo-N-f(/raiis)-l-(pvrrolidin-l-vn-2.3-dihvdro-1H- inden-2-yl]-l,2y3,4-tetrahydroquinoline-4-carboxamide (single diastereomer)
Figure imgf000139_0001
Figure imgf000139_0002
Methanesulfonic anhydride (0.205 g, 1.177 mmol) as a solution in THF (2 mL) was added to an acetone / dry ice bath cooled solution of (4S)-N-((cw)-l-hydroxy-2,3-dihydro-1H- inden-2-yl)-l-memyl-2-oxo-l,2,3,4-te1rahydroquinoline-4-carboxamide (Intermediate 43, 0.198 g, 0.589 mmol) and TEA (0.179 g, 1.766 mmol) in THF (4 mL) under nitrogen. The reaction was warmed to 0 °C and stirred for 30 min. Pyrrolidine (0.209 g, 2.94 mmol) was added and the reaction left to warm to room temp for 18 h. The reaction mixture was partitioned between DCM and water and the organics were purified by column chromatography on basic silica, eluted with 0-100% EtO Ac/petroleum ether. The crude material was loaded onto a cation exchange cartridge, washed with MeOH and eluted with
2M NH3/MeOH solution then concentrated in vacuo to afford the title compound.
•H NMR (400 MHz, DMSO-i¾) δ ppm 1.44 - 1.71 (m, 4 H) 2.29 - 2.47 (m, 2 H) 2.54 -
2.77 (m, 5 H) 3.15 - 3.26 (m, 4 H) 3.64 - 3.75 (m, 1 H) 4.03 - 4.10 (m, 1 H) 4.36 - 4.57 (m,
1 H) 6.93 - 7.10 (m, 2 H) 7.15 - 7.34 (m, 6 H) 8.43 (d, J=7.61 Hz, 1 H)
MS ES+: 390
Example 113: (4S)-l-methyl-N-[(/'rfl/Js)-l-(morpholin-4-yl)-2,3-dihydro-1H-inden-2- yl]-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxamide (single stereoisomer)
Figure imgf000140_0001
Methanesulfonic anhydride (0.155 g, 0.892 mmol) as a solution in THF (2 mL) was added to an acetone/ dry ice bath cooled solution of (4S)-N-((cw)-l-hydroxy-2,3-dihydro-1H- inden-2-yl)- l-methyl-2-oxo-l, 2,3, 4-tetrahydroquinoline-4-carboxamide (Example 110, 0.150 g, 0.446 mmol) and TEA (0.181 mL, 1.338 mmol) in THF (4 mL) under nitrogen. The bath was switched to an ice/water bath and stirred for -30 min. Morpholine (0.194 g, 2.230 mmol) was added and the reaction left to warm to room temperature for 18 h. The reaction mixture was partitioned between DCM and water and the organics purified by column chromatography on basic silica, eluted with 0-100% EtO Ac/petroleum ether. The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.12 - 2.29 (m, 4 H) 2.62 - 2.79 (m, 3 H) 3.05 - 3.27 (m, 4 H) 3.34 - 3.50 (m, 4 H) 3.68 - 3.75 (m, 1 H) 4.01 - 4.13 (m, 1 H) 4.45 - 4.61 (m, 1 H) 6.98 - 7.04 (m, 1 H) 7.05 - 7.12 (m, 1 H) 7.17 - 7.23 (m, 4 H) 7.25 - 7.33 (m, 1 H) 7.34 - 7.41 (m, 1 H) 8.42 (d, J=8.62 Hz, 1 H)
MS ES+: 406 Example 114: (4S)-N-[(trans)-l-(4,4-difluoroDiperidin-l-vn-2 ,3-dihvdro-1H-inden-2- yl]-l-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide (single stereoisomer)
Figure imgf000141_0001
Prepared as described for (4S)-l-methyl-N-[(trans)-l-(morpholin-4-yl)-2,3-dihydro-1H- inden-2-yl]-2-oxo-l ,2,3,4-tetrahydroquinoline-4-carboxamide (single
stereoisomer)(Example 113) using (4S)-N-((cw)-l-hydroxy-2,3-dihydro-1H-inden-2-yl)-l- methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxamide (Example 111, 0.133 g, 0.395 mmol) and 4,4-diiluoropiperidine (0.239 g, 1.977 mmol) to afford the title compound. 'H NMR (400 MHz, DMSO-d6) δ ppm 1.82 - 2.03 (m, 4 H), 2.54 - 2.78 (m, 7 H), 3.06 - 3.18 (m, 1 H), 3.33 (s, 3 H), 3.68 - 3.76 (m, 1 H), 4.24 - 4.33 (m, 1 H), 4.38 - 4.51 (m, 1 H), 6.97 - 7.12 (m, 2 H), 7.17 - 7.36 (m, 6 H), 8.45 - 8.58 (m, 1 H)
MS ES+: 440
Example llS: (4S)-N-[(trans) -(4-cvanopiperidin-l-vlV2.3-dihvdro-1H-inden-2-yl]-l- methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxamide (single stereoisomer)
Figure imgf000141_0002
Prepared as described for (4S)-l-methyl-N-[(trans)-l-(morpholin-4-yl)-2,3-dihydro-1H- inden-2-yl]-2-oxo-l ,2,3,4-tetrahydroqumoline-4-carboxainide (single stereoisomer) (Example 113) using (4S)-N- (cis)4-hydroxy-2,3-dihydro-1H-inden-2-yl)-l-methyl-2- oxo-1, 2,3 ,4-tetrahydroquinoline-4-carboxamide (Example 111, 0.133 g, 0.395 mmol) and 4-cyanopiperidine (0.218 g, 1.977 mmol) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 - 1.75 (m, 2 H), 1.80 - 1.90 (m, 2 H), 2.29 - 2.40 (m, 1 H), 2.42 - 2.50 (m, 2 H), 2.60 - 2.74 (m, 4 H), 2.76 - 2.86 (m, 1 H), 3.08 - 3.16 (m, 1 H), 3.23 (s, 3 H), 3.69 - 3.75 (m, 1 H), 4.16 - 4.22 (m, 1 H), 4.40 - 4.52 (m, 1 H), 6.99 - 7.06 (m, 1 H), 7.07 - 7.12 (m, 1 H), 7.17 - 7.26 (m, 4 H), 7.27 - 7.35 (m, 2 H), 8.46 - 8.54 (m, 1 H)
MS ES+: 429
Example 116: (4SVN-[1S,2SVl-[(2,2-difluoroethvnaminol-2,3-dihvdro-1H-inden-2- yl]-l-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide
Figure imgf000142_0001
DIPEA (0.521 mL, 2.98 mmol), l,l-difluoro-2-iodoethane (0.572 g, 2.98 mmol), (4S)-N- ((lS,2S)4-amino-2,3-dihydro-1H-inden-2-yl)-l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide (Intermediate 44, 0.200 g, 0.596 mmol) and MeCN (5 mL) were combined in a vial and heated in the microwave at 160°C for 30 min. The reaction mixture was partitioned between DCM and water and the organic phase purified by column chromatography on silica, eluted with 0-100% EtOAc/petroleum ether. The residue was further purified by reverse phase chromatography on CI 8 silica eluted with 5- 95% MeCN/water (with 0.05% NH3) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 - 2.42 (m, 1 H) 2.60 - 2.90 (m, 5 H) 3.14 - 3.26 (m, 4 H) 3.70 - 3.81 (m, 1 H) 3.97 - 4.06 (m, 1 H) 4.14 - 4.26 (m, 1 H) 5.60 - 6.03 (m, 1 H) 6.96 - 7.04 (m, 1 H) 7.07 - 7.13 (m, 1 H) 7.16 - 7.24 (m, 3 H) 7.25 - 7.31 (m, 2 H) 7.33 - 7.39 (m, 1 H) 8.49 (d, J=8.07 Hz, 1 H)
MS ES+: 400
Example 117: (4S)-l-methyl-2-oxo-N-[(trans)-l-(propane-l-sulfonyl)-2,3-dihydro-1H- inden-2-yl]-l ,2,3,4-tetrahydroquinoIine-4-carboxamide (single stereoisomer)
Figure imgf000143_0001
Methanesulfonic anhydride (0.067 g, 0.386 mmol) as a solution in THF (0.S mL) was added to an acetone/dry ice bath cooled solution of (4S)-N-((c/-j)-l-hydroxy-2,3-dihydro- 1 H-inden-2-yl)- 1 -methyl-2-oxo- 1 ,2,3 ,4-tetrahydroquinoline-4-carboxamide (Example 111, 0.065 g, 0.193 mmol) and TEA (0.078 mL, 0.580 mmol) in THF (1 mL) under nitrogen. The bath was switched to an ice/water bath and stirred for 30 min. Sodium propane- 1-thiolate (0.019 g, 0.193 mmol) was added to the reaction and the reaction was allowed to warm to room temperature for 2 h. More sodium propane- 1-thiolate (0.080 g, 0.813 mmol) was added and the reaction stirred at room temperature for 18 h. The reaction mixture was partitioned between DCM and water and the organics were purified by column chromatography on silica, eluted with 0-70% EtOAc/petroleum ether. The crude material was taken up in DCM (1 mL) and m-CPBA (27.3 mg, 0.158 mmol) was added. After 90 min the reaction mixture was washed with water, concentrated in vacuo and purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 0.76 - 1.09 (m, 3 H) 1.77 (d, J=7.52 Hz, 2 H) 2.64 - 2.92 (m, 3 H) 2.97 - 3.28 (m, 5 H) 3.37 - 3.55 (m, 1 H) 3.64 - 3.77 (m, 1 H) 4.47 - 4.69 (m, 1 H) 4.74 - 4.93 (m, 1 H) 6.93 - 7.15 (m, 2 H) 7.22 - 7.35 (m, 3 H) 7.37 - 7.42 (m, 2 H) 7.50 (d, J=7.52 Hz, 1 H) 8.82 (d, J=7.61 Hz, 1 H)
MS ES+: 427
Example 118: N-f2,3-dihvdro-1H-inden-2-vlV-U-dimethvl-2-oxo-UJ.4- tetrahydroquinoline-4-carboxamide (Single diastereomer)
Figure imgf000144_0001
T3P (50% in EtOAc) (0.300 mL, 0.342 mmol) was added to a solution of 2,3-dihydro-1H- inden-2-amine (0.033 ml, 0.2S1 mmol), l,3-dimethyl-2-oxo- 1,2,3 ,4-tetrahydroquinoline-4- carboxylic acid (Intermediate 45, 0.0S g, 0.228 mmol) and TEA (0.048 mL, 0.342 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 1 hour. The mixture was diluted with DCM and washed with 10% citric acid solution, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 12-75% EtO Ac/petroleum ether to afford the title compound as a single diastereomer.
'HNMR (400 MHz, DMSCwfc) δ ppm 1.04 (d, J=6.97 Hz, 3 H) 2.70 - 2.86 (m, 3 H) 3.16 - 3.28 (m, 5 H) 3.47 (d, J=8.07 Hz, 1 H) 4.45 - 4.57 (m, 1 H) 6.98 - 7.11 (m, 2 H) 7.11 - 7.19 (m, 3 H) 7.21 - 7.33 (m, 3 H) 8.58 (d, J=6.97 Hz, 1 H)
MS ES+: 335
Example 119: N-(23-dihvdro-1H-inden-2-vlM3-dimethvl-2-oxo-1.23.4- tetrahydroquinoline-4-carboxamide (single stereoisomer)
Figure imgf000144_0002
N-(2,3-dihydro-1H-mden-2-yl>l,3-dimemyl-2-oxo-l,2,3,4-tetrahyo^
carboxamide (Example 118) was purified by chiral SFC (18% isocratic EtOH, AD column) as the first eluting peak to afford the title compound. 'Η NMR (400 MHz, DMSO-ί/ί) δ ppm 1.01 - 1.10 (m, 3 H), 2.70 - 2.84 (m, 3 H), 3.12 - 3.27 (m, 5 H), 3.43 - 3.52 (m, 1 H), 4.44 - 4.60 (m, 1 H), 6.97 - 7.20 (m, 5 H), 7.22 - 7.35 (m, 3 H), 8.54 - 8.63 (m, 1 H)
MS ES+: 335
Example 120: l-cyclopropyl-N-(2r3-dihydro-1H-inden-2-yl)-7-fluoro-3-methyl-2-oxo l,2,3,4-tetrahydroquinoline-4-carboxamide (single diastereomer)
Figure imgf000145_0001
Prepared as described for N-(2,3-dihydro-1H-iiiden-2-yl)-l-methyl-l,2,3,4- tetrahydroquinoline-4-carboxamide (Example 1) using l-cyclopropyl-7-fluoro-3-methyl- 2-oxo-l,2,3,4-tetrahydroquinoline-4-carboxylic acid (Intermediate 46, 0.05 g, 0.190 mmol) and 2,3-dihydro-1H-inden-2-amine (0.028 g, 0.209 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.41 - 0.58 (m, 2 H), 0.98 - 1.03 (m, 3 H), 1.04 - 1.09 (m, 2 H), 2.60 - 2.83 (m, 4 H), 3.11 - 3.26 (m, 2 H), 3.34 - 3.40 (m, 1 H), 4.38 - 4.54 (m, 1 H), 6.78 - 6.90 (m, 1 H), 7.07 - 7.28 (m, 6 H), 8.39 - 8.48 (m, 1 H)
MS ES+: 379
Example 121 and 122: 2-(cyclopropylmethyl)-N-((fra/is)-l-methanesulfonyl-2,3- dihydro-1H-inden-2-yl)-3-oxo-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (single diastereoisomers)
Figure imgf000146_0001
Prepared as described for -(4S)-l-methyl-2-oxo-N-[(/ran-r)-l -(propane- l-sulfonyl)-2,3- dihydro- 1 H-inden-2-yl] -1,2,3 ,4-tetrahydroquinoline-4-carboxamide (single stereoisomer) (Example 117) using 2-(cyclopropylmemyl)-N-((cw)-l-hydroxy-2,3-dihydro-1H-inden-2- yl)-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxamide (Intermediate 47, 0.300 g, 0.797 mmol) and sodium methanethiolate (0.279 g, 3.98 rnmol). The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compounds.
Example 121: first eluting diastereomer
1H NMR (400 MHz, CD3OD) δ ppm 0.26 - 0.35 (m, 2 H), 0.49 - 0.63 (m, 2 H), 0.97 - 1.09 (m, 1 H), 2.90 (s, 3 H), 2.94 - 3.04 (m, 1 H), 3.23 - 3.31 (m, 1 H), 3.47 - 3.68 (m, 3 H), 4.05 - 4.15 (m, 1 H), 4.33 - 4.38 (m, 1 H), 4.92 - 4.99 (m, 1 H), 5.15 (s, 1 H), 7.16 - 7.35 (m, 5 H), 7.39 - 7.45 (m, 2 H), 7.48 - 7.53 (m, 1 H)
MS ES+: 439
Example 122: second eluting diastereomer
lH NMR (400 MHz, CD3OD) δ ppm 0.15 - 0.29 (m, 2 H), 0.38 - 0.46 (m, 1 H), 0.48 - 0.57 (m, 1 H), 0.90 - 1.03 (m, 1 H), 2.78 - 2.85 (m, 1 H), 3.09 (s, 3 H), 3.24 - 3.30 (m, 1 H), 3.42 - 3.59 (m, 3 H), 4.05 - 4.12 (m, 1 H), 4.64 - 4.68 (m, 1 H), 4.81 - 4.85 (m, 1 H), 5.12 (s, 1 H), 7.20 - 7.24 (m, 1 H), 7.25 - 7.35 (m, 3 H), 7.36 - 7.44 (m, 3 H), 7.54 - 7.59 (m, 1 H)
MS ES+: 439
Example 123: (1 S)-2-(cyclopropylmethyl)-3-oxo-N-[(frc/is)-l-(propane-2-sulfonyl)- 2,3Hiihydro-1H-inden-2-yl]-1,2,3,4-tetrahydroisoquinoIine-l-carboxamide (single stereoisomer)
Figure imgf000147_0001
Methanesulfonic anhydride (0.093 g, 0.S31 mmol) as a solution in THF (1 mL) was added to an acetone/dry ice bath cooled solution of (lS)-2-(cyclopropylmethyl)-N-((c/i)-l- hydroxy-2,3-dihydro- 1 H-inden-2-yl)-3-oxo- 1 ,2,3,4-tetrahydroisoquinoline- 1 -carboxamide (Intermediate 52, 0.100 g, 0.266 mmol) and TEA (0.107 mL, 0.797 mmol) in THF (2 mL) under nitrogen. The bath was switched to an ice/water bath and stirred for 30 min. Sodium propane-2-thiolate (0.130 g, 1.328 mmol) and lS-crown-S (0.0S9 g, 0.266 mmol) were added to the mesylate and the reaction allowed to warm to room temperature. After 6h the reaction mixture was partitioned between EtOAc and water and the organics were
...concentrated zn.vacMO.-The resulting residue was dissolved-in DCM (2 mL) and mCPBA ~ (0.1 IS g, 0.66S mmol) was added. After lh the reaction mixture was washed with saturated sodium bicarbonate solution, dried (phase separator) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluted with MeCN / water (with 0.1% NH3) to afford the title compound as the first eluting peak, one single stereoisomer. The other stereoisomer was not isolated.
1H NMR (300 MHz, CD3OD) δ ppm 0.21 - 0.37 (m, 2 H), 0.46 - 0.65 (m, 2 H), 0.96 - 1.08 (m, 4 H), 1.19 - 1.28 (m, 3 H), 2.89 - 3.04 (m, 1 H), 3.15 - 3.25 (m, 1 H), 3.46 - 3.75 (m, 4 H), 4.03 - 4.14 (m, 1 H), 4.28 (s, 1 H), 4.93 - 5.04 (m, 1 H), 5.12 (s, 1 H), 7.15 - 7.50 (m, 8 H)
MS ES+: 467
Example 124; 2-(3-fluoropropanoyl)-N-((i,ro/»j{)-l-methoxy-23-dihydro-1H-inden-2- yl)-l^,4-tetrahydroisoquinotine-l-carboxamide (diastereomeric mixture)
Figure imgf000148_0001
Prepared as described for N-(2,3-dihydro-l H-inden-2-yl)-l -methyl- 1,2,3 ,4- tetrahydroquinoline-4-carboxamide (Example 1) using N-((/ra?w)-l-memoxy-2,3-dihydro- 1 H-inden-2-yl)- 1,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide hydrochloride
(Intermediate 38, 0.1 g, 0.279 tnmol) and 3-fiuoropropanoic acid (0.028 g, 0.307 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 - 3.14 (m, 5 H), 3.14 - 3.40 (m, 4 H), 3.59 - 3.86 (m, 1 H), 3.89 - 4.16 (m, 1 H), 4.20 - 4.39 (m, 1 H), 4.56 - 4.83 (m, 3 H), 5.48 - 5.68 (m, 1 H), 7.15 - 7.53 (m, 8 H), 8.67 - 8.93 (m, 1 H)
MS ES+: 397
Examples 125. 126. 127 and 128: 2-(3-fluoropropanoyl)-N-((trans)-l-methoxy-2,3- dihydro-lH-inden-2-yl)-l,23,4-tetrahydroisoquinoUne-l-carboxamide (single stereoisomers)
Figure imgf000148_0002
2-(3-fluoropropajQoyl)-N-(l-memoxy-2,3-dihydro-1H-inden-2-yl)-l,2,3,4- tetrahydroisoquinoline-1 -carboxamide (Example 124) was purified by chiral SFC (26% isocratic IPA, IC column) to afford the title compounds.
Example 125: first eluting stereoisomer 1H NMR (400 MHz, DMSO-d6) δ ppm 2.60 - 3.13 (m, 6 H), 3.27 (s, 3 H), 3.60 - 3.69 (m, 1 H), 3.94 - 4.07 (m, 1 H), 4.23 - 4.39 (m, 1 H), 4.57 - 4.70 (m, 2 H), 4.72 - 4.83 (m, 1 H), 5.67 (s, 1 H), 7.14 - 7.35 (m, 7 H), 7.42 - 7.50 (m, 1 H), 8.67 - 8.93 (m, 1 H)
MS ES+: 397
Example 126: second eluting stereoisomer
1H NMR (400 MHz, OUSO-d6) δ ppm 2.63 - 3.14 (m, 5 H), 3.17 - 3.29 (m, 4 H), 3.60 - 3.70 (m, 1 H), 3.95 - 4.12 (m, 1 H), 4.23 - 4.39 (m, 1 H), 4.57 - 4.70 (m, 2 H), 4.72 - 4.82 (m, 1 H), 5.67 (s, 1 H), 7.13 - 7.34 (m, 7 H), 7.42 - 7.50 (m, 1 H), 8.67 - 8.95 (m, 1 H) MS ES+: 397
Example 127: third eluting stereoisomer
1H NMR (400 MHz, DMSO-rfe) δ ppm 2.59 - 2.71 (m, 1 H), 2.79 - 3.03 (m, 3 H), 3.04 - 3.22 (m, 2 H), 3.34 - 3.37 (m, 3 H), 3.59 - 3.72 (m, 1 H), 3.95 - 4.09 (m, 1 H), 4.21 - 4.40 (m, 1 H), 4.60 - 4.81 (m, 3 H), 5.66 (s, 1 H), 7.18 - 7.37 (m, 7 H), 7.39 - 7.54 (m, 1 H), 8.67 - 8.91 (m, l H)
MS ES+: 397
Example 128: fourth eluting stereoisomer
1H NMR (400 MHz, OMSO-d6) δ ppm 2.57 - 2.72 (m, 1 H), 2.80 - 3.01 (m, 3 H), 3.03 - 3.28 (m, 2 H), 3.34 - 3.37 (m, 3 H), 3.59 - 3.85 (m, 1 H), 3.89 - 4.10 (m, 1 H), 4.21 - 4.38 (m, 1 H), 4.59 - 4.69 (m, 2 H), 4.70 - 4.80 (m, 1 H), 5.66 (s, 1 H), 7.18 - 7.38 (m, 7 H), 7.40 - 7.51 (m, 1 H), 8.67 - 8.89 (m, 1 H)
MS ES+: 397
Example 129: 2-(cvclopropylmethvn-N--[^rfl/i5>-7-fluoro-l-(methylamino)-2,3- dihydro-1H-inden-2-yl]-3-oxo-1,2,3,4-tetrahydroisoquinoline-l-carboxamide (diasteromeric mixture) P
trans
Figure imgf000150_0001
Prepared as described for (4S)-N-((/rani)-l-methoxy-2,3-dihydro-1H-inden-2-yl)-l- methyl-2-oxo-l)2,3,4-tetrahydroquinoline-4-carboxamide (single stereoisomers) (Example 6) using 2-(cyclopropylmethyl)-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 14, 68 mg, 0.277 mmol) and ter/-butyl N-(2-amino-7-fluoro-2,3-dihydro- 1H-inden-l-yl)-N-methyl carbamate (Intermediate 48, 70 mg, 0.2S0 mmol). The crude material was purified by column chromatography on silica, eluted with 0-100% ethyl acetate/petrol and then by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to afford the title compound.
'H NMR (400 MHz, DMSO-d6) δ ppm 0.05 - 0.25 (m, 2 H), 0.30 - 0.50 (m, 2 H), 0.76 - 0.93 (m, 1 H), 2.07 - 2.18 (m, 2 H), 2.30 (s, 2 H), 2.60 - 2.79 (m, 1 H), 3.09 - 3.26 (m, 2 H), 3.33 - 3.49 (m, 2 H), 3.85 - 4.09 (m, 2 H), 4.10 - 4.40 (m, 1 H), 5.04 - 5.15 (m, 1 H), 6.96 - 7.04 (m, 1 H), 7.07 - 7.13 (m, 1 H), 7.15 - 7.34 (m, 4 H), 7.37 - 7.47 (m, 1 H), 8.61 - 8.73 (m, 1 H)
MS ES+: 408
Example 130: N-(2,3-dihvdro-1H-inden-2-vI)-3-f4-fluorophenvn-2-methvl-l-oxo- l,2,3,4-tetrahydroisoquinoline-4-carboxamide (diasteromeric mixture)
O
Figure imgf000150_0002
Prepared as described for /<?r/-butyl l-[(2,3-dihydro-1H-inden-2-yl)carbamoyl]-l,2,3,4- tetrahydroisoquinoline-2-carboxylate (Example 21) using 3-(4-fluorophenyl)-2-methyl-l- oxo-1, 2,3 ,4-tetrahydroisoquinoline-4-carboxylic acid (prepared as described for close analogue in J. Het. Chem. 1993, 30, 1, 257, lg, 3.34 mmol) and_2,3-dihydro-1H-inden-2- amine (0.445 g, 3.34 mmol). The crude material was purified by trituration with diethyl ether to afford the title compound.
'H NMR (400 MHz, DMSO-i1H 8 ppm 2.64 - 2.94 (m, 4 H) 3.03 - 3.24 (m, 3 H) 4.40 (d, J=7.15 Hz, 1 H) 5.20 (s, 2 H) 7.09 - 7.31 (m, 11 H) 7.35 - 7.49 (m, 1 H) 8.50 - 8.68 (m, 1 H)
MS ES+: 415
Examples 131 and 132: flS)-2-(3-fluoroDroDvlVN-(trans) -l-methoxv-2.3-dihvdi inden-2-yl)-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxamide (single
stereoisomers)
Figure imgf000151_0001
Figure imgf000151_0002
Prepared as described for (4S)-N-((/ranj)-l-methoxy-2,3-dihydro-1H-inden-2-yl)-l- methyl-2-oxo- 1,2,3 ,4-tetrahydroquinoline-4-carboxamide (single stereoisomers)
(Examples 6 and 7) using (lS)-2-(3-fluoropropyl)0-oxo-l,2,3,4-tetrahydroisoquinoline-l- carboxylic acid (Intermediate 55, 50 mg, 0.199 mmol) and (trans)- l-methoxy-2,3- dihydro-1H-inden-2-amine (Intermediate 2, 33 mg, 0.199 mmol). The crude material was purified by chiral SFC (16% isocratic EtOH, IC column) to afford the title compounds.
Example 131: First eluting stereoisomer
1H NMR (400 MHz, DMSO-d6) δ ppm 1.73 - 1.97 (m, 2 H), 2.57 - 2.71 (m, 1 H), 3.16 - 3.29 (m, 2 H), 3.37 (s, 3 H), 3.45 (d, J= 19.35 Hz, 1 H), 3.56 - 3.68 (m, 1 H), 3.90 (d, J= 18.98 Hz, 1 H), 4.22 - 4.30 (m, 1 H), 4.32 - 4.43 (m, 1 H), 4.44 - 4.57 (m, 1 H), 4.64 (d, J= 3.85 Hz, 1 H), 5.08 (s, 1 H), 7.16 - 7.34 (m, 6 H), 7.35 - 7.39 (m, 1 H), 7.44 - 7.53 (m, 1 H), 8.88 - 8.94 (m, 1 H)
MS ES+: 397
Example 132: second eluting stereoisomer 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75 - 2.00 (m, 2 H), 2.65 - 2.78 (m, 1 H), 3.14 (s, 3 H), 3.21 - 3.30 (m, 2 H), 3.45 (d,J= 19.26 Hz, 1 H), 3.68 (s, 1 H), 3.88 (d, J= 19.17 Hz, 1 H), 4.20 - 4.30 (m, 1 H), 4.34 - 4.43 (m, 1 H), 4.45 - 4.58 (m, 2 H), 5.10 (s, 1 H), 7.16 - 7.34 (m, 7 H), 7.41 - 7.49 (m, 1 H), 8.97 (d, J= 7.98 Hz, 1 H)
MS ES+: 397
3. Biological efficacy of compounds of the invention
mGluR7 Assay
The ability of the test compounds to activate mGluR7 was determined by their ability to reduce forskolin stimulated cAMP production. Compounds were assessed in a CRE- directed luciferase reporter gene assay, using a stable CHO cell line expressing the CRE- luc reporter and human mGluR7 genes. In this cell line, production of cAMP stimulated the transcription of the luciferase gene and luciferase activity was then measured in a luminescent enzyme assay (Steady Glo assay; Promega E2550). Activation of mGluR7 decreased the forskolin stimulated luminescence-signal. — — - -■— — - —
The day prior to the assay, compounds were serially diluted in DMSO (lOOx final assay concentration (FAC)), in 384- well plates which were then stored in the dark at room temperature (RT) until use. Cells were seeded at 12.5 k/well in white, clear bottom 384- well plates (Coming 3707) and left for one hour at RT followed by an overnight incubation (37 °C). The following day, the DMSO compound plate was diluted 1:20 (5x FAC) in Opti-MEM I (Life Technologies 11058021). The growth media was removed from the cell plate and replaced with 15 μΐ Opti-MEM I, followed by a 5 μΐ addition from the 5x compound plate and a fifteen minute incubation (37 °C). Forskolin (Sigma F3917) was then added to the wells (5 μΐ of 2.5 μΜ) and the plate was incubated for five hours (37 °C). During this incubation, the Steady Glo Substrate reagent was warmed to 37 °C. Aliquots (1 lml; stored at -20 °C) of this reagent were prepared by dissolving the contents of 1 vial of lyophilised substrate in 100 ml Steady-Glo buffer. A 25 μΐ addition of the substrate was made to all wells and the plate was incubated for thirty minutes at RT, on a plate shaker (300 rpm; in the dark). Luminescence was then measured using the EnVision Multilabel Reader (Perkin Elmer). Compound activity was examined using a 10-point, half log concentration-response range and each concentration was tested in duplicate wells. Luminescence values were normalised to 'maximum' (forskolin alone) and 'minimum' (forskolin in the presence of tool mGluR7 agonist) controls. EC50 values were derived from this data using non-linear s regression and a four parameter curve fit. The EC50 values for the compounds of the Examples are shown in Table 1.
Results
Table 1
Figure imgf000153_0001
Figure imgf000154_0001
References s 1. O'Connor R.M., Finger B.C., Flor P.J. and Cryan J.F., 2010. Metabotropic
glutamate receptor 7: at the interface of cognition and emotion. Eur J Pharmacol., 639 (1- 3), 123-31. 2. Konieczny J. and Lenda T., 2013 Contribution of the mGluR7 receptor to antiparkinsonian-like effects in rats: a behavioral study with the selective agonist
AMN082. Pharmacol Rep., 65 (5), 1194-1203.
3. Greco B., Lopez S., van der Putten H. and Flor P.J., 2010. Amalric M.
M etabotropic glutamate 7 receptor subtype modulates motor symptoms in rodent models of Parkinson's disease. J Pharmacol Exp Ther., 332 (3), 1064-71.
4. Bradley S.R., Standaert D.G., Levey A.I. and Conn P.J., 1999. Distribution of group III mGluRs in rat basal ganglia with subtype-specific antibodies. Ann N Y Acad Sex., 868, 531-4.
5. Conn P.J. and Niswender CM., 2006. mGluR7's lucky number. Proceedings of the National Academy of Sciences of the United States of America, 103 (2), 251-2.
6. Hovelse N., Sotty F., Montezinho L., Pinheiro P., Herrik K. and Mark A.,2012. Therapeutic Potential of Metabotropic Glutamate Receptor Modulators. Curr
NeuropharmacoL, 10 (1), 12-48.
7. Kandaswamy R, McQuillin A,,_Curtis D. and Gurling H., 2014.. Allelic- Association, DNA Resequencing and Copy Number Variation at the Metabotropic Glutamate Receptor GRM7 Gene Locus in Bipolar Disorder. Am J Med Genet B
Neuropsychiatr Genet., 165 (4), 365-72.
8. Palucha-Poniewiera A., Szewczyk B. and Pile A, 2014.. Activation of the mTOR signaling pathway in the antidepressant-like activity of the mGlu5 antagonist MTEP and the mGlu7 agonist AMN082 in the FST in rats. Neuropharmacology, 82, 59-68.
9. Palucha A., Klak K., Branski P., van der Putten H., Flor P.J. and Pile A., 2007. Activation of the mGlu7 receptor elicits antidepressant-like effects in mice.
Psychopharmacology (Berl)., 194 (4), 555-62.
10. Kalinichev M., Rouillier M., Girard F., Royer-Urios I., Bournique B., Finn T. et al., 2013. ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: in vitro and in vivo characterization. J Pharmacol Exp Ther., 344 (3), 624-36.
11. Bolonna A.A., Kerwin R.W., Munro J., Arranz M.J., Makoff A.J., 2001.
Polymorphisms in the genes for mGluR types 7 and 8: association studies with
schizophrenia. Schizophr Res., 47 (1), 99-103.
12. Friedman, R. A., et al., 2009. GRM7 variants confer susceptibility to age-related hearing impairment. Hum Mol Genet 18(4), 785-796.

Claims

C L A I M S
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof
wherein
Figure imgf000156_0001
n is O or 1;
X, Y and Z have the following meanings:
(i) Z is >CH2, >CHCH3 or >0, Y is >CH2 or >C=O and X is >NR5
where R5 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or
5 4
C3-C6 cycloalkylmethyl or, alternatively, R and R may together form a C2-C3 alkylene chain, or
(ii) Z is >CHR6a, X is >C=O and Y is >NR6b where R6a represents hydrogen, (halo)C1-C6 alkyl, (halo)C3~C6 cycloalkyl or (halo)phenyl and
R^ represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkylmethyl, or
(iii) Z is >CH2, X is >CH2 and Y is >NR7, >NC(O)R7 or >NS02R7 where
7
R represents either a C3-C6 cycloalkyl group, or, a C1-C6 alkyl group optionally substituted by at least one substituent independently selected from C1-C6 alkoxy and C3-C6 cycloalkyl, or (iv) Z is >C=O, X is ><:¾ and Y is >NR , or
(v) X is >CH2, Y is >CH2 and Z is >NR8, >NC(O)R9, >NC(O)NHR9 or
9 8
>NS02R where R represents hydrogen or a C1-C6 alkyl group optionally substituted by at least one substituent independently selected from halogen, C3-C6 cycloalkyl and a S- to 6-membered saturated or unsaturated heterocycle, wherein the heterocycle is optionally substituted by at least one
9
C1-C3 alkyl substituent, and R represents a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, or a C1-C6 alkyl group optionally substituted by at least one substituent independently selected from halogen, cyano, C1-C6 alkoxy and C3-C6 cycloalkyl, or
(vi) X is >CH2, Y is >C=O and Z is >NR10 where R10 represents a C1-C6 alkyl group optionally substituted by. at least one-substituent -independently- — selected from halogen, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl or a S- to
6-membered saturated or unsaturated heterocycle;
1 2 3
R , R and R each independently represent hydrogen or halogen;
4 5
R represents hydrogen, halogen or is joined to R as defined above;
D represents >C(R* V or, when Z is >C¾, D may additionally represent a nitrogen atom;
R represents hydrogen, halogen or C1-C5 alkyl;
12
R represents hydrogen, hydroxyl, C1-C6 alkoxy, C1-C6 alkylsulphonyl or
NR13R,4 ;
13 14
R and R each independently represent hydrogen, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, C1-C6 alkoxycarbonyl, or C1-C½ alkyl optionally substituted by at least one substituent independently selected from halogen, C3-C6 cycloalkyl or a 5- to 6- membered saturated or unsaturated heterocycle, or R and R together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing a further ring heteroatom selected from nitrogen and oxygen, wherein the heterocyclic ring is optionally substituted by at least one substituent independently selected from halogen, cyano, C1-C5 alkyl and
C1-C6 alkoxy;
R15 represents hydrogen or halogen; and
R16 represents hydrogen or halogen.
1 2 3 4
2. A compound according to claim 1, wherein R , R , R and R each represent hydrogen.
3. A compound according to claim 1 or claim 2, wherein R5 represents hydrogen,
C1-C2 alkyl, cyclopropyl or cyclopropylmethyl.
6a
4. A compound according to any one of the preceding claims, wherein R represents hydrogen or halophenyl.
5. A compound according to any one of the preceding claims, wherein R6b represents hydrogen or methyl.
7
6. A compound according to any one of the preceding claims, wherein R represents either a cyclopropyl group, or, a C1-C2 alkyl group optionally substituted by at least one substituent independently selected from C1-C2 alkoxy and cyclopropyl. g
7. A compound according to any one of the preceding claims, wherein R represents hydrogen or a C1-C2 alkyl group optionally substituted by at least one substituent independently selected from fluorine, cyclopropyl and a 5- to 6-membered unsaturated heterocycle, wherein the heterocycle is optionally substituted by at least one methyl substituent.
9
8. A compound according to any one of the preceding claims, wherein R represents a
C1-C4 alkoxy group, a cyclopropyl group, or a C1-C2 alkyl group optionally substituted by at least one substituent independently selected from fluorine, cyano and methoxy.
9. A compound according to any one of the preceding claims, wherein R10 represents a C1-C3 alkyl group optionally substituted by at least one substituent independently selected from fluorine, methoxy, cyclopropyl, phenyl or a 5- to 6-membered saturated or unsaturated heterocycle.
10. A compound according to any one of the preceding claims, wherein D is CH.
11. A compound of formula (I) as defined in claim 1 selected from:
N-(2,3-dihydro- 1H-inden-2-yl)- 1 -methyl- 1 ,2,3,4-tetrahydroquinoline-4-carboxamide; N-(2,3-dihydro-1H-inden-2-yl)-l-methyl-2-oxo-l,2,3,4-tetrahydroquinoline-4- carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-2-methyl- 1 -oxo- 1 ,2,3,4- tetrahydroisoquinoline-4- carboxamide;
(4S)-N-(2,3-dihydro-1H-inden-2-yl)-l-metoy^
carboxamide;
(4R)-N-(2,3-dihydro-1H-mden-2-yl)-l-m^^
carboxamide;
(4S)-N-((/rani)-l-methoxy-2,3-mhydro-1H-inden-2-yl)-l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide;
(4S)-N-((/rawi>l-emoxy-2,3-mhydro-1H-inden-2-yl)-l-me%l-2-oxo-l,2,3 tetrahydroquinoline-4-carboxamide;
tert butyl N-[(lS,2S>2-(l-memyl-2-oxo-l,2,3,4-tetrahydroquinoUne-4-ami dihydro- 1 H-inden- 1 -yl]carbamate; N-[( 1 S,2S)- l-amino-2,3-dihydro- 1 H-inden-2-yl]-l -methyl-2-oxo- 1 ,2,3,4- tetrahydroquinoline-4-carboxamide;
l-memyl-2-oxo-N-[(lS,2S)-l-[(propan-2-yl)ami^
1 ,2,3 ,4-tetrahydroquinoline-4-carboxamide;
N-[(lS,2S)-l-[(cyclopropylmemyl)amino^
1 ,2,3 ,4-tetrahydroquinoline-4-carboxamide;
1- memyl-N-[(lS,2S)-l-{[(oxan-4-yl)memyl^
1 ,2,3 ,4-tetrahydroquinoline-4-carboxamide;
N-[(lS,2S)-l-cyclopropaneamido-2,3-dihydro-1H-inden-2-yl]-l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide;
N-[(lS,2S)-l-(dimemylamino>2,3-dihyd^
tetrahydroquinoline-4-carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-l-ethyl-2-oxo-l,2,3,4-tetrahydroquinoline-4- carboxamide
ter/-butyl l-[(2,3-(lihydro-l]^in^
carboxylate;
N-(2,3-dihydro- 1H-inden-2-yl)- 1 ,2,3,4-tetrahydroisoquinoline- 1 -carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-2-(2-methoxyacetyl)-l,2,3,4-te1rahydroisoquinolm carboxamide;
2- cyclopropanecarbonyl-N-(2,3-dihy(lro-1H-inden-2-yl)-l,2,3,4-tetrahy(koisoquinoline- 1 -carboxamide;
N2-cyclopropyl-N l-(2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3,4-tetrahydroisoquinolme- 1 ,2- dicarboxamide;
2-(cyclopropylmethyl)-N-(2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3,4-tetrahydroisoquinoline- 1 -carboxamide;
2-(cyclopropanesulfonyl)-N-(2,3-dihydro-1H-inden-2-yl>l,2,3,4- tetrahydroisoquinoline- 1 -carboxamide;
N-[( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]-2-cyclopropanecarbonyl- 1 ,2,3 ,4- tetrahydroisoquinoline- 1 -carboxamide;
N-[( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]-2-cyclopropanecarboayl-6-fluoro- 1 ,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamide;
N-[( 1 S,2S)- 1 -amino-2,3-dihydro- 1 H-inden-2-yl]-6-chloro-2-cyclopropanecarbonyl- 1,2,3,4-tetrahydroisoquinoline-l-carboxamide; 2-cyclopropanecarbonyl-N-(2,3-dihydro-1H-m
4-carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-2-(2-memoxyacety^^
carboxamide;
2-(2-cyclopropylacetyl)-N-(2,3-dihydro- 1 H-inden-2-yl)- 1 ,2,3 ,4-tetrahydroisoquinoline- 4-carboxamide;
2-(cyclopropanesulfonyl)-N-(2,3-dihydro-1H-inden-2-yl)-l,2,3,4- tetrahydroisoquinoline-4-carboxamide;
2-(cyclopropylmetJiyl)-N-(2,3-dihy<ko-1H-inden-2-yl)-l,2,3,4-tetrahydroisoquin^ 4-carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-2-methyl-3-oxo- 1 ,2,3,4-tetrahydroisoquinoline- 1- carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-2-(2-methoxyethyl)-3-oxo-l,2,3,4- tetrahydroisoquinoline- 1 -carboxamide;
2-(cyclopropyJmethyl)-N-(2> - — — - tetrahydroisoquinoline- 1 -carboxamide;
N-(2,3-dihydro- 1H-inden-2-yl)-2-ethyl-3-oxo- 1 ,2,3,4-tetrahydroisoquinoline-l- carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-3-oxo-2-[(pyridin-2-yl)methyl]-l,2,3,4- tetrahydroisoquinoline- 1 -carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-2-[(oxan-4-yl)methyl]-3-oxo-l,2,3,4- tetrahydroisoquinoline- 1 -carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-3-oxo-2-[2-(pyrrolidin-l-yl)ethyl]-l,2,3,4- tetrahydroisoquinoline- 1 -carboxamide;
N-[(lS,2S)-l-amino-2,3-dihydro-1H-inden-2-yl]-2-(cyclopropyteieAyl)-3-oxo-l,2,3,4^ tetrahydroisoquinoline- 1 -carboxamide;
N-[(lS,2S)-l-amino-2,3-dihydro-1H-iden-2-yl]-2-benzyl-3-oxo-l,2,3,4- tetrahydroisoquinoline- 1 -carboxamide;
N-[(lS,2S)-l-amino-2,3-flhydro-1H-ind^
tetrahydroisoquinoline- 1-carboxamide;
N-(2,3-(lihydro-1H-inden-2-yl)-7-fluoro-2-oxo-l,2,3,4-tetrahydroquinolm^
carboxamide; N-(2,3-dihydro- 1 H-inden-2-yl)-7-fluoro- 1 -methyl-2-oxo- 1 ,2,3 ,4-tetrahydroquinoline-4- carboxamide;
N-(2,3-dihydro-1H-inden-2-yl>7-fluoro-l,4-dimethyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide;
N-(2>3-dihydro-1H-inden-2-yl)-6-fluoro-2-oxo-l,2>3,4-tetrahydroquinoline-4- carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-6-fluoro- l-methyl-2-oxo- 1 ,2,3,4-tetrahydroquinoline-4- carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-6-fluoro- 1 ,4-dimethyl-2-oxo- 1 ,2,3 ,4- tetrahydroquinoline-4-carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-4-methyl-3-oxo- 1 ,2,3,4-tetrahydroquinoxaline- 1 - carboxamide;
N-(2,3-dihydro- 1H-inden-2-yl)- 1 -methyl-2-oxo-2,4-dihydro- 1 H-3 , 1 -benzoxazine-4- carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-4-oxo-2,4,5,6-tetrahydro- 1 H-pyrrolo[3,2,l-ij]quinoline- 6-carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yI)-8-fluoro- 1 -methyl-2-oxo- 1 ,2,3 ,4-tetrahydroquinoline-4- carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yI)-5-fluoro- 1 -methyl-2-oxo- 1 ,2,3 ,4-tetrahydroquinoline-4- carboxamide;
8-bromo-N-(2,3-dihy(liO-1H-inden-2-yl)-5-fluoro-l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide;
N-(2,3-dihydro-1H-inden-2-yl)-5,7-difluoro-l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-4-carboxamide;
l-cyclopropyI-N-(2,3-^hydro-1H-inden-2-yl)-2-oxo-l,2,3,4-tetrahydroquin^ carboxamide;
N-[( 1 S,2S> 1 -amino-2,3-dihydro- 1 H-inden-2-yl]- 1 -cyclopropyl-2-oxo- 1 ,2,3,4- tetrahydroquinoline-4-carboxamide;
N-[(l S,2S)- 1 -amino-2,3-dihydro- 1H-inden-2-yl]-8-fluoro- l-methyl-2-oxo- 1 ,2,3,4- tetrahydroquinoline-4-carboxamide;
N-(2,3-dihydro- 1 H-inden-2-yl)-2-methyl-3-oxo- 1 ,2,3 ,4-tetrahydroisoquinoline-4- carboxamide;
Figure imgf000163_0001
Figure imgf000164_0002
mixtures thereof; and pharmaceutically acceptable salts of any of the foregoing.
12. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 which comprises reacting a compound of formula (Π) or a salt thereof,
Figure imgf000164_0001
in which n, X, Y, Z, D, R , R , R and R are as defined in formula (I), with a compound of formula (III) or a salt thereof,
Figure imgf000165_0001
and optionally thereafter carrying out one or more of the following procedures:
• converting a compound of formula (I) into another compound of formula (I)
• removing any protecting groups
■ forming a pharmaceutically acceptable salt.
13. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents.
14. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, for use in therapy.
15. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, for use in treating alcohol, drug or nicotine addiction.
16. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, for use in treating hearing loss or tinnitus.
17. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, for use in treating schizophrenia.
PCT/JP2017/033368 2016-09-07 2017-09-07 Indane derivatives useful as modulators of mglur7 WO2018047983A1 (en)

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