Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to 4-azaindole derivatives and the pharmaceutical use thereof. More particularly, the present invention relates to 4-azaindole derivatives which are modulators of muscarinic acetylcholine receptor (mAChR) M1 (mAChR M1) and may be effective for the prevention or disease modifying or symptomatic treatment of cognitive deficits associated with neurological disorders such as Alzheimer-type dementia (AD) or dementia with Lewy bodies (DLB), and to a pharmaceutical composition comprising a 4-azaindole derivative as an active ingredient.
• mAChR muscarinic acetylcholine receptor
• AD Alzheimer-type dementia
• DLB dementia with Lewy bodies
• cholinergic hypofunction contributes to the cognitive deficits associated with Alzheimer's disease (Science, 1982, 215, 1237-1239) and acetylcholinesterase inhibitors, which inhibit acetylcholine hydrolysis, are used clinically for the treatment of cognitive impairment in Alzheimer's disease.
• Cholinergic deficits are also prominent in dementia with Lewy bodies (DLB) and when administered to patients with DLB the cholinesterase inhibitor donepezil has been reported to give significant improvements in behavioural measures (Ann. Neurol., 2012, 72(1), 41-52). Therefore, activation of central cholinergic neurotransmission via enhanced signalling of muscarinic receptors may be effective for the symptomatic treatment of cognitive deficits associated with neurological disorders such as AD or DLB.
• Muscarinic acetylcholine receptors are G-protein coupled receptors that mediate the actions of the neurotransmitter acetylcholine.
• Five distinct mammalian mAChR subtypes (M1-M5) have been identified in mammals.
• mAChR M1 which is predominantly expressed in the cortex, hippocampus and striatum, has been found to have an important role in cognitive processing (Psychopharmacology, 1987, 93, 470-476; Behav. Brain Res. 1988, 27, 9-20; Nature Neuroscience, 2002, 6, 51-58) and, more recently, has also been implicated as having a potential role in modifying Alzheimer's disease progression (Proc. Natl. Acad. Sci. USA, 1992, 89, 10075-10078).
• mAChR M2 is expressed in cardiac tissue and in smooth muscle whilst mAChR M3 is expressed in sweat and salivary glands (Pharmacology and Therapeutics, 2008, 117, 232).
• mAChR M2 is expressed in cardiac tissue and in smooth muscle whilst mAChR M3 is expressed in sweat and salivary glands (Pharmacology and Therapeutics, 2008, 117, 232).
• muscarinic activation by non-selective agonists has resulted in dose-limiting peripheral cholinergic side-effects which may be attributed to their relative lack of selectivity.
• Selective mAChR M1 activation may therefore prove useful in the treatment of cognitive impairment, including diseases such as Alzheimer's disease and DLB, as well as for the treatment of cognitive disorders associated with psychotic disorders such as schizophrenia, but without the peripheral cholinergic side-effects mediated predominantly through mAChR M2 and mAChR M3.
• mAChR M1 is known to contain one or more such allosteric sites, which may alter the affinity with which muscarinic ligands bind to the primary binding or orthosteric sites or affect downstream signalling (Molecular Pharmacology, 2000, 58, 194-207; Molecular Pharmacology, 2002, 62, 1492-1505).
• Positive Allosteric Modulators (PAM) of mAChR M1 are thus expected to be useful in enhancing muscarinic receptor function in a selective fashion, avoiding many of the potential side effects associated with activation of other muscarinic subtypes (Trends in Pharmacological Sciences, 2009, 30, 148-155).
• mAChR M1PAM compounds have been investigated as potential therapies for cognitive impairment associated with neurological disorders such as dementia (for example dementia associated with Alzheimer's disease), mild cognitive impairment and age related cognitive decline and also for psychiatric disorders such as schizophrenia, for example as described in WO2009094279, WO2011075371, WO2012158473, WO2013063549 and WO2013091773.
• dementia for example dementia associated with Alzheimer's disease
• psychiatric disorders such as schizophrenia, for example as described in WO2009094279, WO2011075371, WO2012158473, WO2013063549 and WO2013091773.
• Examples of other diseases that might be treatable or preventable with a compound which acts as a modulator of mAChR M1 are: Huntington's disease, amyotrophic lateral sclerosis (ALS), post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, Down's syndrome, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), cognitive disorders related to drug abuse including cocaine abuse, cognitive disorders related to nicotine withdrawal, autism, dementia, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, fragile-X syndrome, autism-spectrum disorders,
• An object of the present invention is to provide compounds that are modulators of mAChR M1 which may be useful as prophylactic or therapeutic agents for a neurological disorder such as Alzheimer-type dementia (AD) or dementia with Lewy bodies (DLB).
• an object of the present invention is to provide compounds that are positive allosteric modulators of mAChR M1.
• the present invention relates to a series of 4-azaindole derivatives which may act as positive allosteric modulators of mAChR M1. Specific aspects according to the present invention are:—
• R 1 is hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy
• R 2 is hydrogen
• R 4a is hydrogen or halogen
• R 4b is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy;
• R 4c is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 haloalkyl
• R 4d is hydrogen or halogen
• R 4a , R 4b , R 4c and R 4d is other than hydrogen and no more than two of R 4a , R 4b , R 4c and R 4d are hydrogen.
• a compound according to [2] or a pharmaceutically acceptable salt thereof which is 1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.
• a compound according to [2] or a pharmaceutically acceptable salt thereof which is 1-(4-fluoro-3-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.
• a compound according to [2] or a pharmaceutically acceptable salt thereof which is 1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.
• a compound according to [2] or a pharmaceutically acceptable salt thereof which is 1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.
• a compound according to [2] or a pharmaceutically acceptable salt thereof which is 1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.
• a compound according to [2] or a pharmaceutically acceptable salt thereof which is N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxybenzyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.
• a compound according to [2] or a pharmaceutically acceptable salt thereof which is 1-(3-fluoro-4-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.
• AD Alzheimer-type dementia
• a method for symptomatic treatment of cognitive impairment in Alzheimer-type dementia involving administering to a human subject in need thereof a therapeutically effective amount of a compound according to [1] or [2] or a pharmaceutically acceptable salt thereof.
• a method for symptomatic treatment of cognitive impairment in dementia with Lewy bodies (DLB) involving administering to a human subject in need thereof a therapeutically effective amount of a compound according to [1] or [2] or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition comprising a compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, as an active ingredient in association with a pharmaceutically acceptable carrier.
• the compounds of the present invention belong to a group of compounds of general formula (I), or a pharmaceutically acceptable salt thereof,
• Ring A is a non-aromatic C 5-8 carbocyclic group or a non-aromatic 5 to 8-membered heterocyclic group, wherein Ring A may be optionally substituted with one or more substituents independently selected from Substituent Group ⁇ ;
• R 1 is hydrogen, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy;
• R 2 is hydrogen, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy;
• Ring B is phenyl or a 5 to 6-membered heteroaryl group; n is 0 or 1;
• R 3 is phenyl or a 5 to 6-membered heteroaryl group, which phenyl or heteroaryl group may be optionally substituted with one or more substituents independently selected from Substituent Group ⁇ ;
• p 0, 1, 2, 3 or 4;
• each R 4 independently is a group selected from Substituent Group ⁇ ;
• each substituent selected from Substituent Group ⁇ is independently halogen, hydroxyl, cyano, nitro, —NR 5 R 5 , C(O)NR 5 R 5 , —C(O)OR 5 , —C(O)R 5 , —S(O) 2 R 5 , —NR 5 S(O) 2 R 5 , S(O) 2 NR 5 R 5 , —NR 5 C(O)R 5 , C 1-6 alkyl and C 1-6 alkoxy, which C 1-6 alkyl and C 1-6 alkoxy are each optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-6 alkyl) and —N(C 1-6 alkyl) 2 ; and
• each R 5 independently is hydrogen or C 1-6 alkyl.
• Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the present description encompasses all geometric and structural isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the description.
• Certain compounds of formula (I) may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present description encompasses all such solvated forms of compounds of formula (I).
• Ring A is a C 5-7 cycloalkyl group or a 6-membered heterocycloalkyl group, wherein Ring A is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1-4 alkyl and C 1-4 hydroxyalkyl.
• Ring A is a C 5-7 cycloalkyl group optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1-4 alkyl and C 1-4 hydroxyalkyl.
• Ring A is selected from:—
• Ring A is a piperidin-4-yl or piperidin-3-yl group, optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1-4 alkyl and C 1-4 hydroxyalkyl.
• Ring A is selected from:—
• Ring A is a tetrahydropyran-4-yl or tetrahydropyran-3-yl group optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1-4 alkyl and C 1-4 hydroxyalkyl. In an embodiment of formula (I), Ring A is selected from:—
• Ring A is a group of formula (II), wherein R a is hydroxyl, methyl or hydroxymethyl; and Z is CH 2 , CF 2 or O
• Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• R 1 is hydrogen, halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy.
• R 1 is hydrogen, chloro, cyano, methyl or methoxy.
• R 1 is hydrogen, chloro, cyano or methyl.
• R 2 is hydrogen, halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy.
• R 2 is hydrogen, cyano, methyl or methoxy.
• R 2 is hydrogen, cyano or methyl.
• n 0.
• p is 1 or 2 and each R 4 is independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy.
• Ring B is a phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl or pyrazol-4-yl group, wherein Ring B is optionally substituted with one or two substituents independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy.
• Ring B is a phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl or pyrazol-4-yl group, wherein Ring B is optionally substituted with one or two substituents independently selected from fluoro, chloro, cyano, methyl, trifluoromethyl, methoxy and trifluoromethoxy.
• Ring B is a phenyl group optionally substituted with one or two substituents independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy.
• Ring B is a phenyl group optionally substituted with one or two substituents independently selected from fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl and trifluoromethoxy.
• Ring B is selected from:—
• Ring B is a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl group, wherein Ring B is optionally substituted with one or two substituents independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy.
• Ring B is a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl group, wherein Ring B is optionally substituted with one or two substituents independently selected from fluoro, chloro, cyano, methyl and methoxy.
• Ring B is selected from:—
• Ring B is a thiazol-2-yl, a thiazol-4-yl or a pyrazol-4-yl group, any of which may be optionally substituted with one or two substituents independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy.
• Ring B is selected from:—
• n 1
• Ring B is a group of formula (III),
• R 3 is a phenyl, pyridin-2-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-4-yl, imidazol-2-yl or imidazol-4-yl group, wherein R 3 is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy; p is 0 or 1; and R 4 is halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy.
• Ring B is a group of formula (III) wherein R 3 is a phenyl group optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy; p is 0 or 1; and R 4 is halogen hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy.
• R 3 is a phenyl group optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N
• Ring B is:
• Ring B is a group of formula (III) wherein R 3 is a pyridin-4-yl or pyridin-2-yl group optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy; p is 0 or 1; and R 4 is halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy.
• R 3 is a pyridin-4-yl or pyridin-2-yl group optionally substituted with one or more substituents independently selected from halogen
• Ring B is selected from:—
• Ring B is a group of formula (III) wherein R 3 is a pyrazol-1-yl or pyrazol-4-yl group optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy; p is 0 or 1; and R 4 is halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy.
• R 3 is a pyrazol-1-yl or pyrazol-4-yl group optionally substituted with one or more substituents independently selected from halogen
• Ring B is selected from:—
• Ring B is a group of formula (III) wherein R 3 is an imidazol-2-yl or imidazol-4-yl group optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy; p is 0 or 1; and R 4 is halogen, hydroxyl, cyano, —NH 2 , —NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy.
• R 3 is an imidazol-2-yl or imidazol-4-yl group optionally substituted with one or more substituents independently selected from halogen,
• Ring B is selected from:—
• the present invention provides a compound or pharmaceutically acceptable salt which is
• An embodiment of formula (I) provides a compound of formula (IA), or a pharmaceutically acceptable salt thereof,
• R 1 is hydrogen, halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy;
• R 2 is hydrogen
• each R 4 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy.
• One embodiment of formula (IA) provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, chloro, methyl or methoxy; R 2 is hydrogen; p is 1 or 2 and each R 4 is independently selected from fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl and trifluoromethoxy.
• the present invention provides a compound of formula (IB), or a pharmaceutically acceptable salt thereof,
• R 1 is hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy
• R 2 is hydrogen
• R 4a is hydrogen or halogen
• R 4b is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy;
• R 4c is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 haloalkyl
• R 4d is hydrogen or halogen
• R 4a , R 4a , R 4c and R 4d is other than hydrogen and no more than two of R 4a , R 4b , R 4c and R 4d are hydrogen.
• the present invention provides a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, chloro, methyl or methoxy; R 2 is hydrogen; R 4a is hydrogen or fluoro; R 4b is hydrogen, fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl or trifluoromethoxy; R 4c is hydrogen, fluoro, methyl, methoxy or trifluoromethyl; and R 4d is hydrogen or fluoro; wherein at least one of R 4a , R 4b , R 4c and R 4d is other than hydrogen and no more than two of R 4a , R 4b , R 4c and R 4d are hydrogen.
• R 1 is hydrogen, chloro, methyl or methoxy
• R 2 is hydrogen
• R 4a is hydrogen or fluoro
• R 4b is hydrogen, fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl or trifluoromethoxy
• R 4c
• the present invention provides a compound of formula (IB) or a pharmaceutically acceptable salt thereof, which is
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, which is
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, which is
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, which is
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, which is
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, which is
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, which is
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, which is
• An embodiment of formula (I) provides a compound of formula (IC), or a pharmaceutically acceptable salt thereof,
• R 1 is hydrogen, halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy;
• R 2 is hydrogen
• each R 4 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy.
• the compound or pharmaceutically acceptable salt thereof is N-((1S,2S)-4,4-difluoro-2-hydroxycyclohexyl)-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.
• the compound or pharmaceutically acceptable salt thereof is N-((1R,2R)-4,4-difluoro-2-hydroxycyclohexyl)-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.
• non-aromatic C 5-8 carbocyclic group denotes a non-aromatic ring system having 5 to 8 ring carbon atoms, including cycloalkyl rings, partially saturated rings and bridged rings.
• cycloalkyl denotes saturated carbocyclic rings. Examples of “cycloalkyl” rings include cyclopentyl, cyclohexyl and cycloheptyl.
• non-aromatic 5-8-membered heterocyclic group denotes a non-aromatic ring system having 5 to 8 ring atoms wherein at least one ring atom is selected from nitrogen, oxygen and sulphur, including heterocycloalkyl rings and partially saturated rings.
• heterocycloalkyl denotes saturated heterocyclic rings.
• heteroaryl denotes aromatic rings having 5 to 6 ring atoms wherein at least one ring atom is selected from nitrogen, oxygen and sulphur.
• heteroaryl groups include furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl groups.
• C 1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms.
• Examples of the group include linear and branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl and 3-methylpentyl.
• C 1-6 haloalkyl denotes a C 1-6 alkyl group substituted with one or more halogen atoms wherein each halogen is independently selected from fluorine, chlorine, bromine and iodine.
• Examples of C 1-6 haloalkyl groups include CF 3 (trifluoromethyl), CHF 2 (difluoromethyl), CH 2 F (monofluoromethyl), CH 2 CF 3 , CH 2 CHF 2 and CH 2 CH 2 F.
• C 1-6 alkoxy refers to a group containing an alkyl group bonded to an oxygen atom.
• the group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, isopentoxy, sec-pentoxy, t-pentoxy, n-hexyloxy, isohexyloxy, 1,2-dimethylpropoxy, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 2-ethylbutoxy, 1,3-dimethylbutoxy, 2-methylpentoxy, 3-methylpentoxy and hexyloxy.
• Examples of a “C 1-6 haloalkoxy” group include —OCHF 2 (difluoromethoxy)
• C 1-4 hydroxyalkyl denotes a C 1-4 alkyl group substituted with one to three hydroxyl groups.
• Examples of C 1-4 hydroxyalkyl groups include —CH 2 OH (hydroxymethyl).
• a group is optionally substituted with one or more substituents
• the group may be substituted or unsubstituted.
• substituted the group may for example be substituted with 1, 2 or 3 substituents.
• crystal polymorphs of a compound of formula (I) may be present, the compound is similarly not limited thereto and may be present as a single crystal form or a mixture of single crystal forms.
• the compound may be an anhydride or a hydrate. Any of these forms are included in the scope of formula (I) and the present invention.
• the present description also includes isotopically-labelled compounds, which are identical to the compounds of formula (I), except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the description include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, phosphorous, chlorine, technetium and iodine, such as 2 H, 3 H, 11 C, 14 C, 13 N, 15 O, 18 F 32 P, 99m Tc, 123 I and 131 I.
• isotopically labeled compounds of formula (I) of this description can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
• the 4-azaindole derivative of formula (I) may be a pharmaceutically acceptable salt.
• Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
• Specific examples of the pharmaceutically acceptable salt include inorganic acid salts (such as sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrofluorides, hydrochlorides, hydrobromides and hydroiodides), organic carboxylates (such as acetates, oxalates, maleates, tartrates, fumarates, citrates, malonates and lactates), organic sulfonates (such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates and camphorsulfonates), amino acid salts (such as aspartates and
• the compound of formula (I) according to the present description can be converted to a pharmaceutically acceptable salt by a conventional method where necessary.
• the salt can be prepared by a method in which methods typically used in the field of organic synthetic chemistry and the like are appropriately combined. Specific examples of the method include neutralization titration of a free solution of the compound of the present description with an acid solution.
• the present description provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
• the present description provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in positive allosteric modulation of mAChR M1.
• the present description provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, which has potential use for treating or preventing a neurodegenerative disease.
• the present description provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, which has potential use for treating or preventing Alzheimer-type dementia (AD).
• AD Alzheimer-type dementia
• the present description provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a cognitive impairment improving agent in Alzheimer-type dementia (AD).
• AD Alzheimer-type dementia
• the present description provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament which has potential use for the treatment or prevention of Alzheimer-type dementia (AD).
• AD Alzheimer-type dementia
• the present description provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as a cognitive impairment improving agent in Alzheimer-type dementia (AD).
• AD Alzheimer-type dementia
• the description provides a method that has potential for use in treating or preventing Alzheimer-type dementia (AD) involving administering to a human subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• AD Alzheimer-type dementia
• the description provides a method for symptomatic treatment of cognitive impairment in Alzheimer-type dementia (AD) involving administering to a human subject in need thereof a therapeutically amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• AD Alzheimer-type dementia
• the present description provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, which has potential use for treating or preventing dementia with Lewy bodies (DLB).
• DLB dementia with Lewy bodies
• the present description provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a cognitive impairment improving agent in dementia with Lewy bodies (DLB).
• DLB dementia with Lewy bodies
• the present description provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament which has potential use for the treatment or prevention of dementia with Lewy bodies (DLB).
• a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament which has potential use for the treatment or prevention of dementia with Lewy bodies (DLB).
• DLB dementia with Lewy bodies
• the present description provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as a cognitive impairment improving agent in dementia with Lewy bodies (DLB).
• a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as a cognitive impairment improving agent in dementia with Lewy bodies (DLB).
• DLB dementia with Lewy bodies
• the present description provides a method that has potential for use in treating or preventing dementia with Lewy bodies (DLB) involving administering to a human subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• DLB dementia with Lewy bodies
• the present description provides a method for symptomatic treatment of cognitive impairment in dementia with Lewy bodies (DLB) involving administering to a human subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof
• the present description provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, which has potential for use in treating or preventing schizophrenia, including the cognitive deficits associated with schizophrenia.
• the present description provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament which has potential use for the treatment or prevention of schizophrenia, including the cognitive deficits associated with schizophrenia.
• the present description provides a method that has potential use for treating or preventing schizophrenia, including the cognitive deficits associated with schizophrenia, involving administering to a human subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• an amount means an amount sufficient to cause a benefit to the subject or at least to cause a change in the subject's condition.
• a further aspect of the description provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, as active ingredient in association with a pharmaceutically acceptable carrier.
• the composition may be in any suitable form, depending on the intended method of administration. It may for example be in the form of a tablet, capsule or liquid for oral administration, or of a solution or suspension for administration parenterally.
• the 4-azaindole derivative or pharmaceutically acceptable salt thereof according to the present description may be formulated by a conventional method.
• the dosage form include tablets, coated tablets such as film tablets and sugar-coated tablets, fine granules, granules, powders, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye drops, nasal drops, ear drops, cataplasms and lotions.
• These solid preparations such as tablets, capsules, granules and powders can contain generally 0.01 to 100 wt %, and preferably 0.1 to 100 wt % of the 4-azaindole derivative or pharmaceutically acceptable salt thereof according to the present description as an active ingredient.
• the active ingredient is formulated by blending ingredients generally used as materials for a pharmaceutical preparation and adding an excipient, a disintegrant, a binder, a lubricant, a colorant and a corrective typically used, and adding a stabilizer, an emulsifier, an absorbefacient, a surfactant, a pH adjuster, a preservative and an antioxidant where necessary, for example, using a conventional method.
• ingredients include animal and vegetable oils such as soybean oil, beef tallow and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; a silicone resin; silicone oil; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil and a polyoxyethylene-polyoxypropylene block copolymer; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, a carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerol, propylene
• excipient used examples include lactose, corn starch, saccharose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide.
• binder used include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a polypropylene glycol-polyoxyethylene block copolymer and meglumine
• disintegrant used include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and carboxymethylcellulose calcium.
• Examples of the lubricant used include magnesium stearate, talc, polyethylene glycol, silica and hydrogenated vegetable oil.
• Examples of the colorant used include those permitted to be added to pharmaceuticals.
• Examples of the corrective used include cocoa powder, menthol, empasm, mentha oil, borneol and cinnamon powder. Obviously, the ingredients are not limited to the above additive ingredients.
• an oral preparation is prepared by adding the 4-azaindole derivative or pharmaceutically acceptable salt thereof according to the present description as an active ingredient, an excipient and, where necessary, a binder, a disintegrant, a lubricant, a colorant, a corrective and the like, and then forming the mixture into powder, fine granules, granules, tablets, coated tablets, capsules or the like by a conventional method.
• tablets or granules may be appropriately coated, for example, sugar coated, where necessary.
• a syrup or an injection preparation is prepared by adding a pH adjuster, a solubilizer, an isotonizing agent and the like, and a solubilizing agent, a stabilizer and the like where necessary by a conventional method.
• the injection may be a previously prepared solution, or may be powder itself or powder containing a suitable additive, which is dissolved before use.
• the injection can contain usually 0.01 to 100 wt %, and preferably 0.1 to 100 wt % of the active ingredient.
• a liquid preparation for oral administration such as a suspension or a syrup can contain usually 0.01 to 100 wt %, and preferably 0.1 to 100 wt % of the active ingredient.
• an external preparation can be prepared by any conventional method without specific limitations.
• a base material any of various materials usually used for a pharmaceutical, a quasi drug, a cosmetic or the like can be used.
• the base material include materials such as animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals and purified water.
• a pH adjuster, an antioxidant, a chelator, a preservative and fungicide, a colorant, a flavor or the like can be added where necessary.
• ingredients such as an ingredient having a differentiation inducing effect, a blood flow enhancer, a bactericide, an antiphlogistic, a cell activator, vitamin, amino acid, a humectant and a keratolytic agent can be blended where necessary.
• the dose of the 4-azaindole derivative or pharmaceutically acceptable salt thereof according to the present description varies according to the degree of symptoms, age, sex, body weight, mode of administration, type of salt and specific type of disease, for example.
• the active ingredient is orally administered to an adult at about 30 ⁇ g to 10 g, preferably 100 ⁇ g to 5 g, and more preferably 100 ⁇ g to 1 g per day, or is administered to an adult by injection at about 30 ⁇ g to 1 g, preferably 100 ⁇ g to 500 mg, and more preferably 100 ⁇ g to 300 mg per day, in one or several doses, respectively.
• Compounds of formula (I) may be used in combination with other therapeutic agents, for example medicaments claimed to be useful as either disease modifying or symptomatic treatments of a neurological disorder such as Alzheimer-type dementia (AD) or schizophrenia.
• a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further active ingredient useful in treating a neurological disorder such as Alzheimer-type dementia (AD) or schizophrenia.
• the neurodegenerative neurological disorder is Alzheimer-type dementia (AD).
• Suitable examples of such further active ingredients may be symptomatic agents, for example M4 agonists or positive allosteric modulators (PAMs), acetylcholinesterase inhibitors (such as tetrahydroaminoacridine, donepezil hydrochloride and rivastigmine), NMDA receptor antagonists, nicotinic receptor agonists or allosteric modulators (such as ⁇ 7 agonists or allosteric modulators or ⁇ 4 ⁇ 2 agonists or allosteric modulators), PPAR agonists (such as PPAR ⁇ agonists), beta-site amyloid- ⁇ precursor protein cleavage enzyme 1 (hereinafter referred to as BACE1 or beta-secretase) inhibitors 5-HT4 receptor agonists or partial agonists, histamine H3 antagonists, 5-HT6 receptor antagonists or 5HT1A receptor ligands and, 5-HT2A antagonists, 5-HT7 antagonists, D1 agonists or PAMs, D2
• Such other therapeutic agents may be calcium channel blockers, HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) and lipid lowering agents, NGF (nerve growth factor) mimics, antioxidants, GPR3 ligands, plasmin activators, neprilysin (NEP) activators, IDE (insulin degrading enzyme) activators, melatonin MT1 and/or MT2 agonists, TLX/NR2E1 (tailless X receptor) ligands, GluR1 ligands, RAGE (receptor for advanced glycation end-products) antagonists, EGFR (epidermal growth factor receptor) inhibitors, FPRL-1 (formyl peptide-like receptor-1) ligands, GABA antagonists, and MICAL (molecule interacting with casL) inhibitors, e.g.
• HMG-CoA 3-hydroxy-3-methyl-glutaryl-CoA reducta
• oxoreductase inhibitors CB1 antagonists/inverse agonists, non-steroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory agents (for example agents that could be used to treat neuroinflammation either by enhancing or reducing neuroinflammation), amyloid precursor protein (APP) ligands, anti-amyloid vaccines and/or antibodies, agents that promote or enhance amyloid efflux and/or clearance, histone deacetylase (HDAC) inhibitors, EP2 antagonists, 11-beta HSD1 (hydroxysteroid dehydrogenase) inhibitors, liver X receptor (LXR) agonists or PAMs, lipoprotein receptor-related protein (LRP) mimics and/or ligands and/or enhancers and/or inhibitors, butyryl cholinesterase inhibitors, kynurinic acid antagonists and/or inhibitors of kynurenine aminotransferease (KAT), orphanin FQ/nociceptin (NOP)/opioid-
• the present description provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further active ingredient useful in treating Alzheimer-type dementia selected from:
• the present description provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further active ingredient useful in treating schizophrenia selected from:—
• the pharmaceutical product may, for example be a pharmaceutical composition comprising the first and further active ingredients in admixture.
• the pharmaceutical product may for example comprise the first and further active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate administration to a patient in need thereof.
• compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the description.
• each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
• an additional aspect of the description provides a method of preparation of a pharmaceutical composition, involving admixing at least one compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable adjuvants, diluents or carriers and/or with one or more other therapeutically or prophylactically active agents.
• solvent used in the steps described in the general preparation methods may vary according to the specific reagents used. Unless otherwise stated the choice of solvent is not particularly limited insofar as it does not inhibit the reaction, allows the reagents to be dissolved therein to a certain extent, and is inert during the reaction.
• General Preparation Method A is a method for preparing a compound of formula (I) according to the present description from a compound A-(1) as a raw material through multiple steps of Step A-(i) to Step A-(v), as depicted in scheme 1.
• RingA, RingB, R 1 , R 2 , R 3 R 4 , n and p are as defined above in respect of compounds of formula (I).
• PG is a suitable protecting group for nitrogen, such as Boc, CBz or phenylsulfone for example.
• LG is a suitable halogen leaving group, such as F, Cl, Br, I.
• Compounds of formula A-(1) are either commercially available, may be prepared by literature methods or may be prepared by methods known to those skilled in the art.
• the halogen introduced is not particularly limited, insofar as it permits the desired reactivity in the derivatives produced.
• bromine or iodine may be introduced. Methods of introducing bromine include those described in US20080009514A1 and WO201033980A2, and methods of introducing iodine include those described in WO2011/78984 A1, Bioorg. Med. Chem. Lett. 2009, 24, 6935-6938, and Org. Bio. Chem. 2011, 14, 5129-5136.
• the reaction may be performed with iodine in the presence of a suitable base.
• the solvent used in this step varies according to starting material and the reagent used.
• solvents include organic solvents, such as N-,N-dimethylformamide or N-,N-dimethylacetamide
• bases include inorganic bases, for example potassium hydroxide or sodium hydroxide.
• the reaction time is not particularly limited and is usually 0.5 to 72 hours, typically 0.5 to 5 hours.
• the reaction temperature varies according to the starting material, the reagent used and the like, and is typically in the range of from 20° C. to 100° C.
• the protection and deprotection of functional groups is, for example, described in references 1 and 2.
• the protecting group used in this step can be varied according to starting material, and is not particularly limited insofar as the protecting group does not interfere with reactions to which compound A-(3) and any future protected derivatives will be subjected.
• the reaction can be carried out using di-tert butyl dicarbonate and a suitable base.
• the solvent used in this step varies according to starting material and the reagent used.
• solvents include organic solvents, such as dichloromethane or tetrahydrofuran.
• bases include organic bases, such as triethylamine or DIPEA, or inorganic salts, for example sodium bicarbonate or potassium carbonate.
• the reaction time is not particularly limited and is usually 0.5 to 72 hours, typically 0.5 to 5 hours.
• the reaction temperature varies according to the starting material, the reagent used and the like, and is typically in the range of from 20° C. to 100° C.
• This step is a step of obtaining compound A-(4) by the reaction of compound A-(3) and an amine compound a-(iii) (RingA-NH 2 ) utilizing a transition metal-mediated coupling reaction in the presence of carbon monoxide and a suitable base.
• compound A-(3) can be transformed to A-(4) using a transition metal catalyst, for example a palladium catalyst such as palladium (II) acetate and XantphosTM in a 1:2 ratio.
• a transition metal catalyst for example a palladium catalyst such as palladium (II) acetate and XantphosTM in a 1:2 ratio.
• a wide variety of other related transition metal catalysts may also be suitable for this transformation, for example tetrakis(triphenylphosphine)palladium (0), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride, bis(triphenylphosphino) palladium (II) dichloride.
• the amount of the organometallic catalyst used is about 0.001 to 0.5 equivalent with respect to the raw material.
• Those skilled in the art will understand that many such catalysts are known and that many of such catalysts are capable of effecting this transformation and that the substrate A-(3) or the coupling partner may dictate which catalyst can or cannot be used.
• the aforementioned transition metal mediated coupling reactions require an amine compound a-(iii) to act as the coupling partner.
• Such amines are not particularly limited.
• the amount of the coupling partner used is not particularly limited and is usually 1 to 5 equivalents with respect to the compound A-(3)
• Amine compounds a-(iii) are either commercially available, may be prepared by literature methods or may be prepared by methods known to those skilled in the art.
• transition-metal mediated reactions require a solvent and often a base or salt is required to be present.
• the solvent used in this reaction is not particularly limited insofar as it does not inhibit the reaction.
• examples of the solvent include benzene, toluene, N,N-dimethylformamide, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, and the like and mixtures thereof.
• a base or salt is not particularly limited.
• base or salt examples include bases or salts such as sodium carbonate, potassium carbonate, barium hydroxide, cesium carbonate, potassium phosphate, cesium fluoride, potassium fluoride and solutions thereof, and organic bases, such as triethylamine, N,N-diisopropylethylamine
• the reaction can be carried out in an atmosphere of carbon monoxide with pressure typically ranging from 20 to 100 p.s.i.
• the reaction may be conducted at various temperatures, for example from room temperature to solvent reflux temperature.
• the reaction time is not particularly limited and is usually 0.5 to 48 hours, typically 0.5 to 24 hours.
• Suitable conditions to convert A-(4) to A-(5) include those described in references 1 and 2.
• A-(4) may be converted to A-(5) by treating with an acid e.g. TFA or HCl in ether or dioxane
• X may for example be Cl or Br.
• reaction in this step can be performed under many conditions known to those skilled in the art, such as those reported in WO2004/31188 A1, WO2010/80474 A1, WO2012/88469 A1 or WO2009/32125 A1, for example.
• Alkyl halides of formula a-(v) are either commercially available, may be prepared by literature methods or may be prepared by methods known to those skilled in the art.
• the solvent used in this step varies according to starting material and the reagent used.
• solvents include organic solvents, such as tetrahydrofuran mixed with water or N-,N-dimethylformamide in the absence of water.
• the base used is not particularly limited insofar as it does not react with the alkyl halide.
• bases include inorganic bases, for example cesium carbonate or potassium hydroxide.
• the reaction time is not particularly limited and is usually 0.5 to 72 hours, typically 0.5 to 5 hours.
• the reaction temperature varies according to the starting material, the reagent used and the like, and is typically in the range of from 20° C. to 100° C.
• Pd(PPh 3 ) 4 Palladium-tetrakis(triphenylphosphine)
• XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
• DMSO dimethylsulfoxide
• AIBN 2,2′-Azobis(2-methylpropionitrile)
• HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
• DMAP 4-dimethylamino pyridine
• CDCl 3 deutero-chloroform prep.—preparatory CD 3
• OD deutero-methanol
• the reaction was cooled to rt and poured onto EtOAc, the remaining solid in the reaction flask was sonicated with a small amount of THF and the slurry added to the EtOAc organic phases.
• the combined organic phases were washed with water (2 ⁇ ) then brine and the combined aqueous phases extracted with EtOAc (1 ⁇ ).
• the combined organic extracts were dried (MgSO 4 ), filtered and evaporated under vacuum to give the desired compound (8.72 g), which was taken on crude.
• the MeOH fractions were combined and reduced in vacuo, dissolved in MeOH and loaded onto a fresh 20 g SCX-2 cartridge, washing with 5CV MeOH, then eluted with 5CV 2M NH 3 /MeOH.
• the ammonia-containing fractions were combined with those from the first SCX-2 cartridge and reduced in vacuo to yield the desired compound (5.756 g).
• the reaction mixture was allowed to cool to rt and then diluted with EtOAc and transferred to a separatory funnel.
• the remaining solid in the microwave tube was dissolved in THF by sonication and added to the EtOAc layer.
• the organic layer was washed with water (2 ⁇ ) and brine.
• the combined aqueous layers were extracted with EtOAc and the combined organic layers dried over MgSO 4 , filtered and evaporated under vacuum to give a solid (8.48 g) which was taken on crude without further purification.
• reaction mixture was diluted with EtOAc and transferred to a separatory funnel Remaining solid in the microwave tube was dissolved in THF by sonication and added to the separatory funnel.
• the combined organic layers were washed with water (2 ⁇ ) then brine.
• the combined aqueous layers were extracted with EtOAc (2 ⁇ ) and the combined organic extracts dried over MgSO 4 , filtered and evaporated in vacuo to the crude desired compound which was taken on as such without further purification.
• trans-2-azido-5,5-difluorocyclohexanol (Intermediate 32), (4.35 g) in methanol (50 mL), was added 10% wet palladium on carbon (500 mg) and stirred under an atmosphere of hydrogen overnight.
• the residue was filtered through a pad of celite, washed with methanol and evaporated.
• the residue was dissolved in methanol and filtered through another pad of celite, a PTFE filter, then evaporated and purified by SCX-2 cartridge to afford the title compound (3.37 g).
• reaction mixture was cooled, poured onto EtOAc and the remaining solid in the reaction flask was added to the EtOAc organic phases by dissolving in water and the organic phases washed with water (2 ⁇ ) then brine.
• the combined organic extracts were dried (MgSO 4 ), filter and evaporate under vacuum to give the crude desired compound (989 mg), which was used crude.
• reaction mixture was cooled and poured onto EtOAc and the remaining solid in the reaction flask was added to the EtOAc organic phases by dissolving in water and the organic phases washed with water (2 ⁇ ) then brine and the combined organic extracts dried (MgSO 4 ), filtered and evaporated under vacuum.
• the crude desired compound was taken on as such.
• the suspension was cooled in an ice-bath and the ice-cold suspension was filtered and the solid washed with ice-cold methanol to give the desired compound (1.12 g).
• the mother liquor was evaporated and the residue purified by column chromatography (normal phase, 28 g amino silica, Biotage SNAP cartridge KP-Sil, gradient 0% to 100% EtOAc in n-hexane) to give more of the desired compound (600 mg).
• reaction mixture was diluted with EtOAc and the remaining solid in the reaction flask was dissolved/suspended in a small amount of THF ( ⁇ 2 mL) by sonication then added to the EtOAc organic phases then the combined organic phases washed with water (2 ⁇ ) then brine, dried (MgSO 4 ), filtered and evaporated under vacuum to give the crude product, which was used as such for Boc removal.
• N-Bromosuccinimide (2 g) was added to a solution of 4-fluoro-4′-methyl-1,1′-biphenyl (Intermediate 70), (1.8 g) in CHCl 3 (90 mL) followed by the addition of AIBN (300 mg). The reaction mixture was heated under reflux overnight. Once cooled, water was added and the crude product extracted with CHCl 3 . The organic phase was dried, filtered and evaporated under vacuum. The crude product was purified by column chromatography (silica), eluting with 1:99 EtOAc/hexanes to afford the title compound (850 mg).
• the reaction was cooled to rt and poured onto EtOAc, the remaining solid in the reaction flask was sonicated with a small amount of THF and the slurry added to the EtOAc organic phases.
• the combined organic phases were washed with water (2 ⁇ ) then brine and the combined aqueous phases extracted with EtOAc (1 ⁇ ).
• the combined organic extracts were dried (MgSO 4 ), filtered and evaporated under vacuum to give the desired compound (786 mg), which was taken on crude.
• the filtrate was reduced in vacuo.
• the residue was dissolved in MeOH (5 mL) and loaded onto an SCX-2 cartridge, washing with 5 CV MeOH, then eluting with 5 CV 2M NH3/MeOH.
• the basic fractions were combined and reduced in vacuo.
• the residue was purified by column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexane followed by 0% to 10% MeOH in EtOAc) to yield the desired compound (5 mg).

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