WO2008010061A2 - 3-azabicyclo[3.1.0]hexanes ligands du récepteur vanilloïde, compositions pharmaceutiques les contenant et leurs procédés de préparation - Google Patents

3-azabicyclo[3.1.0]hexanes ligands du récepteur vanilloïde, compositions pharmaceutiques les contenant et leurs procédés de préparation Download PDF

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WO2008010061A2
WO2008010061A2 PCT/IB2007/002002 IB2007002002W WO2008010061A2 WO 2008010061 A2 WO2008010061 A2 WO 2008010061A2 IB 2007002002 W IB2007002002 W IB 2007002002W WO 2008010061 A2 WO2008010061 A2 WO 2008010061A2
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azabicyclo
isoquinolylaminocarboxamido
substituted
hexane
unsubstituted
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PCT/IB2007/002002
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WO2008010061A3 (fr
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Laxmikant Atmaram Gharat
Neelima Khairatkar Joshi
Jitendra Maganbhai Gajera
Pravin Sabhajit Yadav
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Glenmark Pharmaceuticals S.A.
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Publication of WO2008010061A2 publication Critical patent/WO2008010061A2/fr
Publication of WO2008010061A3 publication Critical patent/WO2008010061A3/fr

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    • 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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to substituted 3-azabicyclo [3.1.0] hexane derivatives, which are useful as vanilloid receptor ligands, methods of treating diseases, conditions and/or disorders modulated by vanilloid receptors with them, and processes for preparing them.
  • Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be either acute or chronic. While acute pain is usually self-limiting, chronic pain persists for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C. Bennett and F. Plum eds., 20th ed., 1996).
  • the sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to these harmful stimuli are known as "nociceptors". Nociceptors are primary sensory afferent (C and A ⁇ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH ⁇ 6) modalities.
  • Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis.
  • Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing.
  • VRl vanilloid receptors
  • Capsaicin (8-methyl-N-vanillyl-6-nonenamides; CAP) is known to stimulate pain pathways through the release of a variety of sensory afferent neurotransmitters via a specific cell surface capsaicin receptor, cloned as the first vanilloid receptor (VRl now known as TRPVl) (Caterina MJ, et.al, Science , Apr 14; 288 (5464): 306-13, 2000).
  • Capsaicin is the main pungent component in hot pepper. Hot pepper has been used historically not only as a spice, but also as a traditional medicine in the treatment of gastric disorders orally, and applied locally for the relief of pain and inflammation.
  • CAP has a wide spectrum of biological actions and not only exhibits effects on the cardiovascular and respiratory systems, but also induces pain and irritancy upon local application. However, after induction of pain, CAP induces desensitization to both CAP itself and also to other noxious stimuli, thereby stopping the pain.
  • the intradermal administration of CAP is characterized by an initial burning or hot sensation followed by a prolonged period of analgesia.
  • the analgesic component of VRl receptor activation is thought to be mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal.
  • CAP and its analogues such as olvanil, nuvanil, DA-5018, SDZ-249482, and resiniferatoxin are or have been used or under development as analgesic agents or therapeutic agents for urinary incontinence or skin disorders (Wrigglesworth and Walpole, Drugs of the Future, 23: pp 531-538, 1998).
  • VRl is widely expressed in non-neuronal tissues in various organ systems, and the functional roles of VRl in these systems are not properly understood at this time.
  • An increasing number of animal studies have revealed the possible involvement of VRl receptors in a number of pathologies.
  • VRl is a molecular target for various indications such as migraine, arthralgia, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, cardiac pain arising from an ischemic myocardium, Huntington's disease, memory deficits, restricted brain function, amyotrophic lateral sclerosis (ALS), dementia, urinary bladder hypersensitiveness, urinary incontinence, vulvodynia, pruritic conditions such as uremic pruritus, irritable bowel syndrome (IBS) including gastro-esophageal reflux disease (GERD), enteritis,ileitis, stomach-duodenal ulcer, inflammatory bowel disease including Crohn's disease, celiac disease, and inflammatory diseases such as pancreatitis, and
  • VRl antagonists are useful in multiple sub-types of pain such as acute, chronic, neuropathic pain or post-operative pain, as well as in pain due to neuralgia (e.g., post herpetic neuralgia, and trigeminal neuralgia), and in pain due to diabetic neuropathy, dental pain as well as cancer pain. Additionally, VRl antagonists will also prove useful in the treatment of inflammatory pain conditions such as arthritisor osteoarthritis. VRl antagonists hold potential benefit in diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis and anxiety disorders.
  • neuralgia e.g., post herpetic neuralgia, and trigeminal neuralgia
  • VRl antagonists will also prove useful in the treatment of inflammatory pain conditions such as arthritisor osteoarthritis.
  • VRl antagonists hold potential benefit in diabetes, obesity, urticaria, actinic
  • VRl vanilloid Receptor
  • Vanilloid agonists and antagonists have been developed for the treatment of pain.
  • the agonists work by desensitizing the receptor, while antagonists block its stimulation by (patho) physiological ligands.
  • the first antagonist, Capsazepine was developed by Novartis.
  • VRl antagonists are currently in preclinical evaluation, for example, Amore Pacific's PAC-20030, Neurogen's BCTC, Abbott's A-425619 and Amgen's AMG-9810.
  • PCT Publication Nos. WO 00/59510 (corresponding to U.S. Patent No. 6,414,149), WO 02/32411, WO 02/43762, and WO 2005/037284, disclose aminopyrimidines as sorbitol dehydrogenase inhibitors and their combination with a statin, a GABA agonist, or a hypertensive agent.
  • PCT Publication No. WO 02/34761 (U.S. Publication No. 2002/0094989) discloses pyrrolidine modulators of CCR5 chemokine receptors.
  • U.S. Publication No. 2004/0002504 describes substituted sulfonamides as NK-3 receptor antagonists.
  • PCT Publication No. WO 2005/051304 discloses certain AKT protein kinase inhibitors.
  • Vanilloid receptor modulating compounds are disclosed in U.S. Patent Nos. 6,933,311, 6,939,891, and 7,037,927, U.S. Publication No. 2006/0100460, and PCT Publication Nos. WO 02/08221, 02/16317, 02/16318, 02/16319, 2004/103281, 2004/108133, 2004/1 11009, 2006/044527 and 2006/045498.
  • the present invention relates to VRl receptor ligands of general formula (1):
  • X is O or S
  • R 1 is selected from
  • R 1 is linked to the main structure through any carbon atom in the ring and is optionally substituted with one or more R groups; each occurrence of R and R 6 is independently selected from hydrogen, nitro, cyano, formyl, acetyl, halogen, -OR 7 , -SR 7 , oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroary
  • R and R when both are directly bound to the same nitrogen atom, are joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which optionally includes one or more heteroatoms selected from O, NR a and S; each occurrence of R a and R b is independently selected from hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R C , -C(O)O-R 0 , -C(0)NR c R d , -S(O) m -R c , -S(O) m -NR c R d , -NR c R d , -OR C , -SR d , a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
  • R 2 and R 3 are independently selected from hydrogen, hydroxy and Ci -6 alkyl; and each occurrence of R 4 and R 5 is independently selected from hydrogen, halogen, and alkyl, or when R 4 and R 5 are bound to the same carbon atom, R 4 and R 5 together form oxo or thio.
  • the compound of formula (I) meets one, two, or all of the following criteria:
  • R 6 is not substituted or unsubstituted pyrimidine
  • R is not a substituted or unsubstituted pyrrolidinealkyl
  • R 1 is not a substituted or unsubstituted amino group.
  • Another preferred embodiment is a compound of formula (I) where X is O.
  • R 1 is an unsubstituted quinoline, quinolone, isoquinoline, or isoquinolone.
  • R 1 is a substituted or unsubstituted quinoline or isoquinoline attached to the nitrogen at position 5, 6, 7, or 8.
  • each R and R 6 is independently hydrogen, nitro, cyano, formyl, acetyl, halogen, or a substituted or unsubstituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group, or heterocyclylalkyl.
  • R 6 is a substituted or unsubstituted group selected from cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group, and heterocyclylalkyl, wherein the optional substitution(s) are selected from alkyl, hydroxy, nitro, cyano, formyl, acetyl, halogen, or trihalo alkyl.
  • each R is independently hydrogen, nitro, cyano, formyl, acetyl, halogen, or a substituted or unsubstituted alkyl
  • R 6 is a substituted or unsubstituted group selected from cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group, and heterocyclylalkyl, wherein the optional substitution(s) are selected from alkyl, hydroxy, nitro, cyano, formyl, acetyl, halogen, or trihalo alkyl.
  • R 6 is substituted or unsubstituted heteroaryl.
  • the VRl receptor ligand has the general formula
  • X is O or -S-;
  • R 2 , R 3 , R 4 and R 5 are hydrogen
  • R 6 is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, C(O)R 7 , S(O) 2 R 7 Or COOR 7 ; and R 7 is substituted or unsubstituted aryl.
  • FIG. 1 is a compound of formula (Ia), wherein R 6 is substituted with methyl, isopropyl, t-butyl, trifluoromethyl, bromo, chloro, fluoro, iodo, nitro, methoxy, cyclopropylmethoxy, difluoromethoxy, trifluoromethoxy, acetylamino, trifiuoroacetylamino or methanesulfonylamino.
  • R 6 is substituted with methyl, isopropyl, t-butyl, trifluoromethyl, bromo, chloro, fluoro, iodo, nitro, methoxy, cyclopropylmethoxy, difluoromethoxy, trifluoromethoxy, acetylamino, trifiuoroacetylamino or methanesulfonylamino.
  • R 6 is selected from phenyl, 2- fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,6- difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5- trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2-methoxyphenyl, A- methoxyphenyl, 2-isopropylphenyl, 4-isopropylphenyl, 4-t-butyl phenyl, 2,4-dimethylphenyl, 2- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2- trifluoromethoxyphenyl, 2-
  • R 6 is selected from benzyl, A- chlorobenzyl and 4-trifluoromethylbenzyl.
  • R 6 is selected from A- chlorophenylsulfonyl, 4-trifluoromethylphenylsulfonyl, 4-fluorophenylsulfonyl, 2,6- dichlorophenylsulfonyl, 2,6-difluorophenylsulfonyl, 2,4-dibromophenylsulfonyl, 2,4- dichlorophenylsulfonyl, 2-trifluoromethyl phenylsulfonyl, 2-fluorophenylsulfonyl, 2- chlorophenylsulfonyl, 2-bromophenylsulfonyl, phenylsulfonyl, 4-bromophenylsulfonyl, A- iodophenylsulfonyl or 4-methylphenylsulfonyl.
  • R 6 is selected from A- bromobenzoyl, 4-chlorobenzoyl, 3-fluorobenzoyl, 2-bromobenzoyl, 2-fluorobenzoyl, 2- chlorobenzoyl, 4-methyl benzoyl, 2-trifluoromethylbenzoyl, 4-trifluoromethyl benzoyl, 4-bromo benzoyl or 4-benzyl benzoyl.
  • R 6 is selected from A- bromobenzoyl, 4-chlorobenzoyl, 3-fluorobenzoyl, 2-bromobenzoyl, 2-fluorobenzoyl, 2- chlorobenzoyl, 4-methyl benzoyl, 2-trifluoromethylbenzoyl, 4-trifluoromethyl benzoyl, 4-bromo benzoyl or 4-benzyl benzoyl.
  • R 6 is selected from 3-(acetyl amino)pyridin-2-yl, 3-(trifluoroacetyl amino)pyridin-2-yl, 3-(methanesulphonyl amino) pyrid-2- yl, 3,5-dichloropyridin-2-yl, 3-bromopyridin-2-yl or 5-nitro-pyridin-2-yl.
  • Representative compounds of the present invention include those specified below and prodrugs thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, esters thereof, solvates thereof, tautomers thereof, stereoisomers thereof and polymorphs thereof.
  • the present invention should not be construed to be limited to the following examples. l ⁇ , 5 ⁇ , 6 ⁇ -[6-(5-isoquinolylaminocarboxamido)-3-(3-acetylaminopyrid-2-yl)]-3- azabicyclo [3.1.0]hexane (Compound No. 1),
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound of the present invention.
  • the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions of the present invention are useful in the treatment of diseases, conditions and/or disorders modulated by vanilloid receptor antagonists.
  • the present invention further provides a method of treating a disease, condition and/or disorder modulated by a vanilloid VRl receptor antagonist in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • the present invention further provides a method of treating a disease, condition and/or disorder modulated by a vanilloid VRl receptor antagonist in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of formula I, where R 6 is a substituted pyrimidine, a substituted or unsubstituted aminoalkyl or a substituted pyrrolidinemethyl group, or a pharmaceutical composition comprising at least one such compo ⁇ nd of formula I and a pharmaceutically acceptable excipient.
  • a method for preventing, ameliorating or treating diseases, disorders or syndromes mediated by a vanilloid receptor comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula I or Ia.
  • the disease, disorder or syndrome is pain or an inflammatory disease, disorder or syndrome mediated by VRl .
  • the disease, disorder or syndrome is selected from pain, acute pain, chronic pain, nociceptive pain, neuropathic pain, post-operative pain, dental pain, cancer pain, cardiac pain arising from an ischemic myocardium, pain due to migraine, arthalgia, neuropathies, neuralgia, trigeminal neuralgia, nerve injury, diabetic neuropathy, neurodegeneration, retinopathy, neurotic skin disorder, stroke, urinary bladder hypersensitiveness, urinary incontinence, vulvodynia, gastrointestinal disorders such as irritable bowel syndrome (IBS), gastro-esophageal reflux disease (GERD), enteritis, ileitis, stomach- duodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease, an inflammatory disease such as pancreatitis, respiratory disorder such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, dermatitis, pr
  • the disease, disorder or syndrome is neuropathic pain.
  • the disease, disorder or syndrome is urinary incontinence.
  • the disease, disorder or syndrome is overactive bladder or benign prostate hyperplasia.
  • the disease, disorder or syndrome is ulcerative colitis.
  • the disease, disorder or syndrome is asthma.
  • the disease, disorder or syndrome is inflammation.
  • the invention further provides intermediates useful in the preparation of the compounds of the present invention having the formula 26:
  • R 4 and R 5 are hydrogen
  • R 6 is selected from phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluor ⁇ phenyl, 2,4,6-trifluorophenyl, 3,4,5- trifluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-isopropylphenyl, 4-isopropylphenyl, 4- /-butyl phenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2- difluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 2-fluoroph
  • the invention further provides intermediates useful in the preparation of the compounds of the present invention having the formula 6a:
  • R 4 , R 3 , and R° are as defined above for formula 26 and PG is an N-protecting group as defined hereinafter (also referred to as an amino-protecting group).
  • the invention further provides intermediates useful in the preparation of the compounds of the present invention having the formula 7:
  • R 4 , R 5 , and R 6 are as defined above for formula 26.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl), n-butyl, n-pentyl, and 1,1 -dimethyl ethyl (t-butyl).
  • Ci -6 alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • aminoalkyl refers to an amino group directly bonded to an alkyl group as defined above.
  • the amino group is substituted or unsubstituted.
  • the aminoalkyl group may be attached to the main structure at any carbon atom in the alkyl group.
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, and 2-butenyl.
  • alkynyl refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH 3 and -OC 2 Hs.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 5 C 6 H 5 .
  • heterocyclic ring refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidiny
  • heterocyclyl refers to a heterocyclic ring radical as defined above.
  • the heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted.
  • the substituent on “substituted alkyl” is "substituted aryl”
  • the substituent on “substituted aryl” cannot be “substituted alkenyl”.
  • protecting group refers to a substituent that is employed to block or protect a particular functionality while other functional groups on the compound may remain reactive.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy- protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include, but are not limited to, acetyl, benzyl, tetrahydropyranyl and silyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Suitable carboxy-protecting groups include, but are not limited to, -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, and nitroethyl.
  • protecting groups and their use see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • prodrug means a compound that is transformed in vivo to yield a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • treating or “treatment” of a disease, state, disorder or condition includes:
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a disease, state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease, state, disorder or condition and its severity, as well as the age, weight, physical condition and responsiveness of the subject to be treated.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine), salts of chiral bases (such as alkylphenylamine, glycinol, and phenyl glycinol), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine), salts of non-natural amino acids (such as D-
  • salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • acid addition salts such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • the pharmaceutically acceptable salts of the present invention may be prepared by any of the conventional techniques known to a person of ordinary skill in the art, e.g., as described in Handbook of Pharmaceutical Salts-Properties, Selection and Use", P. Heinrich Stahl, Camille G. Wermuth [Eds.], VHCA and WILEY-VCH (2002).
  • solvates includes hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.
  • Certain compounds of present invention are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof, including racemates.
  • the different stereoisomeric forms may be separated one from the other by known methods, or any given isomer may be obtained by stereospecif ⁇ c or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof. For example, both tautomeric forms of the following moieties are contemplated:
  • the pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention.
  • the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is preferred.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di- Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders modulated by vanilloid VRl receptor antagonists.
  • the present invention further provides a method of treating a disease, condition and/or disorder modulated by vanilloid receptor antagonists in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • the method is particularly useful for treating diseases, conditions and/or disorders modulated by VRl receptor antagonists.
  • Diseases, conditions, and/or disorders that are modulated by vanilloid receptor antagonists which may be treated by the compounds and compositions of the present invention include, but are not limited to, migraine, arthralgia, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, cardiac pain arising from an ischemic myocardium, Huntington's disease, memory deficits, restricted brain function, amyotrophic lateral sclerosis (ALS), dementia, urinary bladder hypersensitiveness, urinary incontinence, vulvodynia, pruritic conditions such as uremic pruritus, irritable bowel syndrome (IBS) including gastro-esophageal reflux disease (GERD), enteritis, ileitis, stomach-duodenal ulcer, inflammatory bowel disease including Crohn's disease, celiac disease and inflammatory diseases such as pancreatitis, respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane
  • Non-limiting examples of types of pain modulated by vanilloid receptor antagonists include acute pain, chronic pain, neuropathic pain, post-operative pain, pain due to neuralgia (e.g., postherpetic neuralgia or trigeminal neuralgia), pain due to diabetic neuropathy, dental pain and cancer pain.
  • Other diseases, conditions, and/or disorders that are modulated by vanilloid receptor antagonists include, but are not limited to, inflammatory pain conditions (e.g. arthritis and osteoarthritis), diabetes, obesity, urticaria, actinic keratosis, keratoacanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis and anxiety disorders.
  • Another embodiment is a method of treating or preventing a disease or disorder mediated by or associated with the activity of the vanilloid receptor in a subject in need thereof (e.g., a mammal or human) by administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of the present invention.
  • Such diseases and disorders include, but are not limited to, disorders such as pain, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroesophageal reflux disorder (GERD), irritable bowel syndrome (IBS), inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, emesis, stomach duodenal ulcer and pruritus.
  • disorders such as pain, chronic pain, neuropathic pain, postoperative pain, rheumatoid
  • Yet another embodiment is a method of treating or preventing pain in a subject in need thereof by administering a therapeutically effective amount of the compound or pharmaceutical composition of the present invention.
  • the invention provides for the use of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder mediated or associated with the activity of vanilloid receptor.
  • the compounds of the present invention have potent analgesic and anti-inflammatory activity, and the pharmaceutical compositions of the present invention thus may be employed to alleviate or relieve acute, chronic or inflammatory pain, suppress inflammation, or treat urgent urinary incontinence.
  • the compounds of the present invention may be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.
  • the compounds and the pharmaceutical compositions of the present invention may be used alone or in combination with other pharmaceutically active compounds in the manufacture of a medicament for the therapeutic applications described herein.
  • R 3 is H
  • X is O
  • R 1 , R 2 , R 4 , R 5 , and R 6 are as defined in the general description
  • R 4 and R 5 are H or, when R 4 and R 5 are bound to the same carbon atom, together form an oxo or thio group.
  • a compound of formula 7 is reacted with a compound of formula 8a (where L is a leaving group, such as a halogen, aryloxy, alkoxy, imidazolyl, imidazolyl, benzimidazolyl, tetrazolyl, benzotetrazolyl, succinimidyloxy), preferably in the presence of a base (such as triethylamine or pyridine) to obtain a compound of formula (I).
  • L is a leaving group, such as a halogen, aryloxy, alkoxy, imidazolyl, imidazolyl, benzimidazolyl, tetrazolyl, benzotetrazolyl, succinimidyloxy
  • a base such as triethylamine or pyridine
  • the group R 3 in the compound of formula (I) formed by scheme Ia can be converted to a different R 3 group, such as alkyl, or aryl benzoyl, by methods known in the art.
  • a compound of formula 7 is reacted with a compound of formula 8b, preferably in the presence of a base (such as triethylamine or pyridine) to obtain the compound of formula (I).
  • a base such as triethylamine or pyridine
  • R 1 is selected from
  • R 1 is selected from formulas A and D.
  • a compound of formula 2 is converted into intermediate 2a, for example, by reacting a compound of formula 2 with bromoriitromethane, preferably in the presence of a base such as potassium carbonate, sodium carbonate or a quaternary ammonium salt and a solvent such as dimethyl formamide.
  • the compound of formula 2a is reduced to form a compound of formula 3, such as by reaction with a reducing agent such as lithium aluminum hydride, boranes, sodium borohydride, BF 3 (e.g., BF 3 ⁇ OEt 2 ), or a mixture thereof.
  • a reducing agent such as lithium aluminum hydride, boranes, sodium borohydride, BF 3 (e.g., BF 3 ⁇ OEt 2 ), or a mixture thereof.
  • the compound of formula 3 is reduced, for example, using reductive conditions such as hydrogenation in the presence of palladium (e.g., Pd/C), Raney nickel, iron/hydrochloric acid, or Raney nickel/hydrazine, to obtain a compound of formula 4.
  • the amine in the compound of formula 4 is then protected with a protecting group, such as t-butyloxy carbonyl (BOC), preferably in the presence of a base (such as triethyl amine, sodium carbonate, potassium carbonate or sodium hydroxide), in a suitable solvent (such as methanol, dichloromethane, chloroform or ethyl acetate) to give a compound of formula 5.
  • a protecting group such as t-butyloxy carbonyl (BOC)
  • BOC t-butyloxy carbonyl
  • a base such as triethyl amine, sodium carbonate, potassium carbonate or sodium hydroxide
  • a suitable solvent such as methanol, dichlorome
  • the compound of formula 5 is deprotected (i.e., the protecting group PGi is selectively removed), for example, under acidic conditions, such as with dry hydrochloric acid or trifluoroacetic acid in a suitable solvent, such as ethyl acetate, methanol, or dichloromethane, to provide a compound of formula 6 (as a free base or acid addition salt thereof).
  • a suitable solvent such as ethyl acetate, methanol, or dichloromethane
  • a compound of formula 6 with an appropriately substituted aryl/heteroaryl, aralkyl/heteroaralkyl halide (based on the desired R 6 substituent), preferably in the presence of a base such as triethylamine or potassium carbonate, or under metal catalyzed conditions such as in presence of copper or palladium provides a compound of formula 6a.
  • the compound of formula 6a is deprotected (i.e., the protecting group PG is removed), for example, under acidic conditions, such as dry hydrochloric acid or trifluoroacetic acid in a suitable solvent such as ethyl acetate, methanol or dichloromethane to provide a compound of formula 7.
  • the compound of formula 4 is reacted with an appropriately substituted aryl/heteroaryl, aralkyl/heteroaralkyl halide, preferably in the presence of a base such as triethylamine or potassium carbonate, or under metal catalyzed conditions such as in the presence of copper or palladium to provide a compound of formula 7 directly, without the use of protecting group chemistry.
  • a base such as triethylamine or potassium carbonate
  • metal catalyzed conditions such as in the presence of copper or palladium
  • the compound of formula 9 is reacted with an appropriately substituted compound of formula 10, for example, in the presence or absence of acid (such as acetic acid), to form intermediate 11.
  • Intermediate 11 is cyclized, for example, with a dehydrating agent,such as acetic anhydride or dicyclohexylcarbodiimide (DCC), to afford a compound of formula 12.
  • a dehydrating agent such as acetic anhydride or dicyclohexylcarbodiimide (DCC)
  • DCC dicyclohexylcarbodiimide
  • the compound of formula 12 is converted to a compound of formula 13, for example, by reaction with bromo nitro methane, preferably in the presence of a base such as potassium carbonate, sodium carbonate, or a quaternary ammonium salt.
  • the compound of formula 13 is reduced, for example, using reductive conditions such as hydrogenation in the presence of palladium, Raney nickel, iron/hydrochloric acid, or Raney nickel/hydrazine to obtain a compound of formula 7.
  • reductive conditions such as hydrogenation in the presence of palladium, Raney nickel, iron/hydrochloric acid, or Raney nickel/hydrazine
  • the compound of formula 13 is reduced, for example, with a reducing agent such as lithium aluminium hydride, boranes, or sodium borohydride, BF 3 (e.g., BF 3 OEt 2 ), or a mixture thereof to give a compound of formula 14.
  • a reducing agent such as lithium aluminium hydride, boranes, or sodium borohydride, BF 3 (e.g., BF 3 OEt 2 ), or a mixture thereof to give a compound of formula 14.
  • the compound of formula 14 is then reduced, for example, using reductive conditions such as hydrogenation in the presence of pal
  • the compound of formula 7 is synthesized as shown in scheme Hc.
  • the compound of formula 7, wherein R 4 and R 5 are hydrogen or together form an oxo group can be prepared as shown in scheme Hc above, using the reaction conditions provided by Tamin et al., or similar conditions. (Tamim F. Braish et. Al., Synlett: September 1996, 1100- 1102 and Catherine E. Brighty et al., Synlett: September 1996, 1097-1099).
  • the compound of formula 21 is obtained by the reaction of a N-benzylpyrroline compound of formula 19 with N,N-dibenzylformamide, for example, in the presence of Ti(OPr') 4 , MeMgCl, and/or cyclohexylmagnesium bromide in a suitable solvent such as tetrahydrofuran, dimethoxyethane, or dioxane.
  • a suitable solvent such as tetrahydrofuran, dimethoxyethane, or dioxane.
  • N-benzyl maleimide is reacted with an ylide of formula 22, for example, in a suitable solvent such as benzene, toluene, dichloromethane, or acetone under refluxing solvent conditions, to provide a mixture of endo (15a) and exo (15) isomers of a compound of formula 23.
  • a suitable solvent such as benzene, toluene, dichloromethane, or acetone under refluxing solvent conditions
  • the endo and exo isomers are separated, for example, by column chromatography.
  • the compounds of formula 15 and 15a are then converted to a compound of formula 7 and 7a, respectively, using for example the procedure described in Scheme Hc.
  • An amine compound of formula 7 is formed by reducing a nitro compound of formula 13, for example, using reductive conditions, such as hydrogenation in the presence of palladium or Raney nickel, iron/hydrochloric acid, or Raney nickel/hydrazine.
  • reductive conditions such as hydrogenation in the presence of palladium or Raney nickel, iron/hydrochloric acid, or Raney nickel/hydrazine.
  • Scheme Hg Yet another method of preparing a compound of formula 7, wherein R 4 and R 5 represent H and R 6 is as defined in the general description, is shown in scheme Hg below.
  • the compound of formula 25 is synthesized by reacting a compound of formula 24 wherein L is a leaving group such as halogen, a toluenesulphonylate (tosylate) or methanesulphonylate (mesylate) group, with an amine of the formula R 6 -NH 2 in the absence or presence of a base such as triethylamine or potassium carbonate.
  • L is a leaving group such as halogen, a toluenesulphonylate (tosylate) or methanesulphonylate (mesylate) group
  • the compound of formula 25 is reacted with N,N-dibenzylformamide, preferably in the presence of titanium isopropoxide, methyl magnesium chloride, methyl magnesium bromide, cyclohexylmagnesium bromide, or cyclohexylmagnesium chloride, in a solvent such as tetrahydrofuran, dimethoxyethane or dioxane, to obtain a compound of formula 26.
  • the exhaustive debenzylation of a compound of formula 26 for example using reductive conditions such as hydrogenation in the presence of palladium, platinum or Raney nickel, provides a compound of formula 7 (Chem. Eur. J. 8(16), 3789-3801, 2002).
  • a compound of formula 37 can be prepared using the procedure outlined in scheme III above.
  • a compound of formula 33, where PG is an N-protecting group include, but are not limited to, tert-butoxy carbonyl, benzyl carbamates (e.g., benzyl chloro formate), 9- fiuorenenylmethyl carbamate (e.g., 9-fluorenenylmethyl chloroformate), and vinyl carbamate (e.g., vinyl chloroformate)]
  • a compound of formula 34 wherein L is as defined above
  • the reaction is preferably performed in the presence one or more bases, for example, triethylamine, pyridine, sodium carbonate, potassium carbonate or lithium carbonate, and in one or more solvents, for example, an aprotic polar solvent (e.g., dimethylsulfoxide, dimethyl formamide, acetonitrile), a chlorinated solvent (e.g., dichloromethane, dichloroethane, chloroform), or a mixture thereof.
  • bases for example, triethylamine, pyridine, sodium carbonate, potassium carbonate or lithium carbonate
  • solvents for example, an aprotic polar solvent (e.g., dimethylsulfoxide, dimethyl formamide, acetonitrile), a chlorinated solvent (e.g., dichloromethane, dichloroethane, chloroform), or a mixture thereof.
  • bases for example, triethylamine, pyridine, sodium carbonate, potassium carbonate or lithium carbonate
  • solvents
  • the compound of formula 35 is deprotected, for example, by reacting it with a deprotecting agent such as para toluene sulphonic acid, methanesulphonic acid, piperidine, dichloroacetic acid or trifluoracetic acid, to form a compound of formula 36.
  • a deprotecting agent such as para toluene sulphonic acid, methanesulphonic acid, piperidine, dichloroacetic acid or trifluoracetic acid, to form a compound of formula 36.
  • the compound of formula 35 is deprotected in the presence of one or more bases, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate in one or more solvent aprotic polar solvent such as tetrahydrofuran, diethylether or a mixture thereof.
  • the compound of formula 36 is reacted with an arylsulfonyl halide, an aryl carbonyl halide, or an arylalkyl halide in presence of one or more bases such as triethylamine, pyridine, sodium carbonate, potassium carbonate or lithium carbonate, and in one or more aprotic polar solvents such as tetrahydrofuran, diethylether or a mixture thereof, to form a compound of formula 37.
  • bases such as triethylamine, pyridine, sodium carbonate, potassium carbonate or lithium carbonate
  • aprotic polar solvents such as tetrahydrofuran, diethylether or a mixture thereof
  • Compounds of formula 43 and 44 can be prepared by the reaction scheme shown above.
  • a compound of formula 4 is reacted with a compound of formula 38 in the presence of a base such as triethylamine or pyridine, in a polar aprotic solvent such as dimethylsulfoxide or dimethylformamide, to form a compound of formula 39.
  • the compound of formula 39 is reacted with a protecting agent (wherein PG is as defined above) to form a compound of formula 40.
  • a compound of formula 43 can be prepared as follows: A compound of formula 40 (when R' is NO 2 and R" is H) is reduced, for example, in the presence of a catalytic reducing agent (e.g., 10% palladium on carbon or platinum on carbon and hydrogen gas) or metal reducing agent (e.g., zinc/acetic acid or Fe/HCl), in the presence of a polar protic solvent such as methanol, ethanol, isopropanol or water to provide an amine compound of formula 41.
  • a catalytic reducing agent e.g., 10% palladium on carbon or platinum on carbon and hydrogen gas
  • metal reducing agent e.g., zinc/acetic acid or Fe/HCl
  • a polar protic solvent such as methanol, ethanol, isopropanol or water
  • the amine of the compound of formula 41 is reacted with methane sulfonyl chloride or trifluoroaceticanhydride or acetic anhydride to form a compound of formula 42 (wherein W is CO or SO 2 and R"' is CH 3 or CF 3 and PG is as defined earlier).
  • the compound of formula 42 is deprotected, for example, by reaction with a deprotecting agent (e.g., para toluene sulphonic acid, methanesulphonic acid, piperidine, dichloroacetic acid or trifluoracetic acid) to form a compound of formula 42a.
  • a deprotecting agent e.g., para toluene sulphonic acid, methanesulphonic acid, piperidine, dichloroacetic acid or trifluoracetic acid
  • the compound of formula 42a is reacted with phenyl isoquinolin-5-yl carbamate, for example, in the presence of a base such as triethylamine, in a polar aprotic solvent such as dimethyl sulfoxide or dimethyl formamide, to form a compound of formula 43.
  • a base such as triethylamine
  • a polar aprotic solvent such as dimethyl sulfoxide or dimethyl formamide
  • a compound of formula 44 can be prepared as follows: A compound of formula 40 (where R' is chloro or bromo and R" is chloro or nitro) is deprotected, for example, by reacting it with a deprotecting agent, (e.g., para toluene sulphonic acid, methanesulphonic acid, piperidine, dichloroacetic acid or trifluoracetic acid), to form a compound of formula 40a.
  • a deprotecting agent e.g., para toluene sulphonic acid, methanesulphonic acid, piperidine, dichloroacetic acid or trifluoracetic acid
  • the compound of formula 40a and 42a are reacted with phenyl isoquinolin-5-yl carbamate in the presence of a base such as triethylamine, in a polar aprotic solvent, such as dimethyl sulfoxide or dimethyl formamide, to form a compound of formula 44.
  • a base such as triethylamine
  • a polar aprotic solvent such as dimethyl sulfoxide or dimethyl formamide
  • Step 1 preparation of 2-Benzyl-4-nitrohexahydrocyclopropa[c] azole-1 ,3-dione
  • N-benzyl maleimide 5.0 g, 26.7 mmol
  • bromonitromethane 7.48 g, 52.4 mmol
  • celite 5.0 g
  • 4A molecular sieves 5.0 g
  • dimethyl formamide 50.0 mL
  • anhydrous potassium carbonate 7.4 g, 53.4 mmol
  • Step 2 preparation of Ia, 5a, 6a-(6-amino-3-benzyl)-3-azabicyclo [3.1.0] hexane
  • Step 5 Ia, 5a, 6a-6-amino-3-azabicyclo [3.1.0] hexane hydrochloride
  • Step 1 tert-butyl 6- ⁇ [(isoquinolin-5-ylamino)carbonyl] amino ⁇ -3-azabicyclo [3.1.0] hexane-3- carboxylate
  • Example 1 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -r6-(5-isoquinolylaminocarboxamido)-3-(3-(acetyl amino)pyrid-2-ylY
  • Step 1 Preparation of i -(acetyl amino) pyridin-2-yl] -3 -azabicyclo [3.1.0] hex-6-ylcarbamate
  • Step 2 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(3-(acetyl amino)pyrid-2-yl)] -3-azabicyclo [3.1.0] hexane
  • Step 1 Preparation ofTert-butyl 3- ⁇ 3-[(trifluoroacetyl) amino] pyridin-2-yl ⁇ -3-azabicyclo [3.1.0] hex-6-ylcarbamate
  • Step 2 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(3-(trifluoroacetyl amino) pyrid -2-yl)] -3-azabicyclo [3.1. OJhexane
  • Example 3 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -[6-(5-isoquinolylaminocarboxamido)-3-(3- (methanesulphonylamino) pyrid -2-yl)1-3-azabicyclo [3.1.01 hexane (Compound No. 3) Step 1: Preparation ofTert-butyl 3- ⁇ 3-[(methanesulphonyl) amino] pyridin-2-yl ⁇ -3-azabicyclo [3.1.0] hex-6-ylcarbamate
  • Step 2 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(3-(methanesulphonyll amino) pyrid -2-yl)] -3-azabicyclo [3.1. OJhexane
  • Step 1 Preparation of3-(3, 5-dichloropyridin-2-yl)-3-azabicyclo [3.1.0] hexan-6-amine
  • Step 2 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(3-(3,5-dichloro) pyrid -2-yl)] -3-azabicyclo [3.1. OJhexane
  • Step 1 Preparation of3-(3-bromopyridin-2-yl)-3-azabicyclo [3.1.0] hexan-6-amine
  • Step 2 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(3-(3-bromo) pyrid -2- y I)] -3-azabicyclo [3.1.0] hexane
  • a solution of l ⁇ , 5 ⁇ , 6 ⁇ -[6-amino-3-(3-bromo pyrid-2-yl)]-3-azabicyclo[3.1.0] hexane 100 mg, 0.40 mmol
  • phenyl isoquinolin-5-ylcarbamate 127 mg, 0.5116 mmol
  • dimethyl sulfoxide 5.0 mL
  • reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3 x 25mL). The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The residue obtained after removal of solvent was purified through silica gel column 2.0 % methanol in chloroform as an eluent to get 50 mg of product as off white solid.
  • Step 1 Preparation of3-(5-NItropyridin-2-yl)-3-azabicyclo [3.1.0] hexan-6-amine
  • Step 2 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(3-(5-nitro) pyrid -2- yl)] -3-azabicyclo [3.1.0] hexane
  • Step 1 Preparation of l-(2-fluorophenyl)-2,5-dihydro-lH-pyrrole
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(2-fluorophenyl)-3-azabicyclo[3.1.0] hexan-6- amine
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl [3-(2-fluorophenyl)-3-azabicyclo[3.1.OJhex-6- yl] carbamate
  • a suspension l ⁇ , 5 ⁇ , 6a-N,N-dibenzyl-3-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6- amine in methanol (20ml) and 10 % Pd/C (50% WAV) was hydrogenated in a parr hydrogenation apparatus for 2-12 hrs at room temperature. Progress of reaction was monitored by TLC. Reaction mixture was filtered through celite bed. To the filtrate BoC 2 O (20 mmol) was added and stirred at room temperature for 2 hrs. Reaction mixture was purified through silica gel column using mixture of pet ether and ethyl acetate as eluent to get pure product as white solid.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2-fluorophenyl)]-3- azabicyclo [3.1.0]hexane
  • Example 8 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -r6-(5-isoquinolylaminocarboxamido)-3-(4-fluorophenyl)l- 3-azabicvclo [3.1.01hexane (Compound No. 8)
  • Step 1 Preparation of l-(4-fluorophenyl)-2,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 4-fluoroaniline.
  • This compound was prepared by the same method as described in step 2 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -l-(4-fluorophenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl [3-(4-fluorophenyl)-3-azabicyclo[3.1.0] hex-6-yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from ⁇ N-dibenzyl-3-(4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(4-fluorophenyl)]-3- azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl [3-(4-fluorophenyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate and phenyl 7V-(isoquinolin-5-yl)carbamate.
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 4-isopropylaniline.
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(4-isopropylphenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzylformamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl [3-(4-isopropylphenyl)-3-azabicyclo[3.1.OJhex-6- yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -iV,N-dibenzyl-3-(4-isopropylphenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(4-isopropylphenyl)]- 3-azabicyclo [3.1.0] hexane
  • This compound was prepared by the same method as described in step 4 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ - [3-(4-isopropylphenyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate and phenyl 7V-(isoquinolin-5-yl)carbamate.
  • Step 1 Preparation of l-(2-methoxy phenyl)-2,5-dihydro-l H-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2-methoxyaniline.
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(2-methoxyphenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl [3-(2-methoxyphenyl)-3-azabicyclo[3.1.0] hex-6- yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from Ia, 5 ⁇ , 6 ⁇ -N,N-dibenzyl-3-(2-methoxyphenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2-methoxyphenyl)]-3- azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of the example 7 from tert-butyl [3-(2-methoxyphenyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate and phenyl TV- (isoquinolin-5-yl)carbamate.
  • Step 1 Preparation of l-(4-t-butylphenyl)-2,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 4-t-butyl aniline.
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(4-£-butylphenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzylformamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl [3-(4-t-butylphenyl)-3-azabicyclo [3.1.0] hex-6- yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example I from N,N-dibenzyl-3-(4-t-butylphenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(4-t-butylphenyl)]-3- azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of the example I froml ⁇ , 5 ⁇ , 6 ⁇ - [3-(4-t-butylphenyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate and phenyl ⁇ /-(isoquinolin-5-yl)carbamate.
  • Step 1 Preparation of l-(2,4-dimethylphenyl)-2,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2,4-dimethylaniline.
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-[(2,4-dimethyl)phenyl]-2,5-dihydro-lH-pyrrole and N,N-dibenzylformamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl [3-(2,4-dimethyl)phenyl] -3-azabicyclo[3.1.0] hex-6- yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from N,N-dibenzyl-3-[2,4-dimethylphenyl]-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2,4-dimethylphenyl)]- 3-azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -fert-butyl [3-(2,4-dimethyl)phenyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate and phenyl 7V-(isoquinolin-5-yl)carbamate.
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 4-(trifluoromethyl)aniline.
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-[(4-trifluoromethyl)phenyl]-2,5-dihydro-l //-pyrrole and N,N-dibenzyl formamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl [3-(4-trifluoromethyl)phenyl] -3- azabicyclo[3.1. OJhex-6-ylJ carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from N,N-dibenzyl-3-[(4-trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(4- trifluoromethyl)phenyl]-3-azabicyclo [3.1. OJhexane
  • This compound was prepared by the same method as described in step 4 of the example 7 from l ⁇ , 5 ⁇ , 6a-tert-buty ⁇ [3-(4-trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate and phenyl jV-(isoquinolin-5-yl)carbamate.
  • Step 1 Preparation of l-(4-methoxyphenyl)-2,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 4-methoxyaniline.
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(4-methoxy)phenyl-2,5-dihydro-lH-pyrrole and N,N-dibenzylformamide.
  • IR (JCBr) 3043, 2944, 2911, 2841, 2875, 1514, 1483, 1358, 1244, 1161, 1037, 962, 815 cm "1 .
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl [3-(4-methoxy)phenyl]-3-azabicyclo[3.1.0]hex-6-yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from N,N-dibenzyl-3-[(4-methoxy)phenyl]-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-((4-methoxy)phenyl]- 3-azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl [3-(4-methoxy)phenyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate and phenyl ⁇ /-(isoquinolin-5-yl)carbamate.
  • Step 1 Preparation of l-(3,4,5-trifluorophenyl)-2,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 3,4,5-trifluoroaniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(3,4,5-trifluorophenyl)-3- azabicyclo[3.1.0] hexan-6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(3,4,5-trifluorophenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl-3-(3,4,5-trifluorophenyl)-3-azabicyclo [3.1.0] hex-6- ylj carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6a-7V,N-dibenzyl-3-(3,4,5-trifluorophenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(3,4,5- trifluoro)phenyl] -3-azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl-3-(3,4,5-trifluorophenyl)-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of 1 -(2-difluoromethoxyphenyl)-2 ,5-dihydro-l H-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2-difluoromethoxyaniline.
  • Step 2 Preparation of 1 a, 5a, 6a-N,N-dibenzyl-3-(2-difluoromethoxyphenyl)-3-azabicyclo[3.1.0] hexan-6-amine
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl [3-(2-difluoromethoxy)phenyl]-3-azabicyclo 13.1.0] hex-6-yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -N,N-dibenzyl-3-(2-difluoromethoxyphenyl)-3-azabicyclo[3.1.0] hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2-difluoromethoxy) phenyl] -3 -azabicyclo [3. l.OJhexane
  • This compound was prepared by the same method as described in step 4 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl [3-(2-difluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hex-6- yljcarbamate and phenyl 7V-(isoquinolin-5-yl)carbamate.
  • Step 1 Preparation of 1 -(3 ,4-difluorophenyl)-2 ,5-dihydro-l H-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 3,4difluoro aniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(3,4-difluorophenyl)-3- azabicyclo[3.1.0] hexan-6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from 1 -(3 ,4,-difluoro)phenyl-2,5-dihydro-l H-pyrrole and N,N-dibenzyl formamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl [3-(3,4-difluoro)phenyl] -3-azabicyclo [3.1.0] hex-6- yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , ⁇ - ⁇ fN-dibenzyl-S-O ⁇ -difluorophenyl ⁇ -azabicyclop.l.OJhexan- ⁇ -amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(3 ,4-difluoro)phenyl] - 3-azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -te ⁇ t-butyl [3-(3,4-difluoro)phenyl]-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2-fluoro-5-methyl aniline.
  • Step 2 Preparation of Ia, 5a, 6a- N,N-dibenzyl-3-(2-fluoro-5-methylphenyl)-3-azabicyclo[3.1.0] hexan-6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(2-fluoro-5-methylphenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • IR (KBr) 3055, 2890, 2850, 1589, 1527, 1460, 1344, 1336, 1269, 1154, 1 114, 1092, 1000, 905, 815 cm 1 .
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl [3-(2-fluoro-5-methyl)phenyl] -3-azabicyclo [3.1.0] hex-6-yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 froml ⁇ , 5 ⁇ , 6 ⁇ - N,N-dibenzyl-3-(2-fluoro-5-methylphenyl)-3-azabicyclo[3.1.0] hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2-fluoro-5- methyl)phenyl] -3-azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl [3-(2-fluoro-5-methyl)phenyl]-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of 1 -(3 -fluorophenyl)-!, 5 -dihydro-1 H-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 3-fluoro aniline.
  • Step 2 Preparation of Ia, 5a, 6a- N,N-dibenzyl-3-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6- amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(3-fluorophenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzylformamide.
  • This compound was prepared by the same method as described in step 3 of the example 7 froml ⁇ , 5 ⁇ , 6a- N,7V-dibenzyl-3-(3-fluorophenyl)-3-azabicyclo[3.1.0] hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(3-fluoro)phenyl]-3- azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ - tert-butyl [3-(3-fluoro)phenyl]-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of l-[2-(cyclopropylmethoxy) phenyl] -2 ,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2-(cyclopropylmethoxy) aniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-[2-(cyclopropylmethoxy)phenyl] -3-azabicyclo [3.1.0] hexan-6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-[2-(cyclopropylmethoxy) phenyl]-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -N, ⁇ r -dibenzyl-3-[2-(cyclopropylmethoxy)phenyl]-3-azabicyclo [3.1.0]hexan-6- amine
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(3-fluoro)phenyl]-3- azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl-3-[2-(cyclopropylmethoxy)phenyl]-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 1 and 2,4-difluoro aniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(2,4-difluorophenyl)-3- azabicyclo[3.1.0] hexan-6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(2,4-difluorophenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl-3-[2,4-difluorophenyl]-3-azabicyclo [3.1.0] hex-6- yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -iV,N-dibenzyl-3-(2,4-difluorophenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2 ,4-difluoro)phenyl] - 3-azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl-3-[2,4-difluorophenyl]-3-azabicyclo [3.1.0] hex-6-yl] carbamateand phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of 1 -(2,6-di ⁇ uorophenyl)-2,5-dihydro-l H-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2,6-difluoroaniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(2,6-difluorophenyl)-3- azabicyclo[3.1.0] hexan-6-amine
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl-3-[2,6-difluorophenyl]-3-azabicyclo [3.1.0] hex-6- ylj carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ - ⁇ N-dibenzyl-3-(2,6-difluorophenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2,6-difluoro)phenyl]- 3-azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl-3-[2,6-difluorophenyl]-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of 1 -(2-fluoro-3-trifluoromethylphenyl)-2 ,5-dihydro-l H-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2-fluoro-3-(trifluoromethyl) aniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(2-fluoro-3-trifluoromethylphenyl)-3- azabicyclo[3.1.0] hexan-6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(2-fluoro-3-trifluoromethylphenyl)-2,5-dihydro-lH-pyrrole and N,N- dibenzylformamide.
  • Step 3 Preparation of Ia, 5a, 6a- tert-butyl-3-[2-fluoro-3-trifluoromethyl phenyl] -3-azabicyclo [3.1.0] hex-6-yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -N,N-dibenzyl-3-(2-fluoro-3-trifluoromethylphenyl)-3-azabicyclo [3.1.0] hexan- 6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2-fluoro-3-trifluoro methyl) phenyl ] -3-azabicyclo [3.1. OJhexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ - tert-butyl-3-[2-fluoro-3-trifluoromethyl phenyl]-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of 1 -(2-trifluoromethoxyphenyl)-2,5-dihydro-l H-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2-(trifluoromethoxy)aniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(2-trifluoromethoxyphenyl)-3- azabicyclo[3.1.0] hexan-6-amine
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl-3-[2- trifluoromethoxyphenyl]-3-azabicyclo [3.1.0] hex-6-yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6a-N,N-dibenzyl-3-(2-trifluoromethoxyphenyl)-3-azabicyclo[3.1.0] hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2-trifluoromethoxy) phenyl] -3-azabicyclo [3.1. OJhexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl-3-[2- trifluoromethoxy phenyl] -3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of l-(2-trifluoromethylphenyl)-2,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2-(trifluoromethyl) aniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(2-trifluoromethylphenyl)-3-azabicyclo [3.1.0] hexan-6-amine
  • Step 3 Preparation of Ia, 5a, 6a- tert-butyl-3-[2- trifluoromethy Iphenyl] -3 -azabicyclo [3.1.0] hex-6-yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from Ia, 5 ⁇ , 6 ⁇ -N,N-dibenzyl-3-(2-trifluoromethylphenyl)-3-azabicyclo [3.1.0] hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2- trifluoromethyl)phenyl] -3 -azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ - te ⁇ t-butyl-3-[2- trifluoromethylphenyl]-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of l-[2-fluoro-(5-trifluoromethyl) phenyl] -2, 5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2-fluoro-5-(trifluoromethyl) aniline.
  • Step2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-[2-fluoro-(5-trifluoromethyl)phenyl]-3- azabicyclo [3.1.0]hexan -6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-[2-fluoro-(5-trifluoromethyl) phenyl]-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl-3-[2-fluoro-(5-trifluoromethyl)phenyl]-3-azabicyclo [3.1.0] hex-6-yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -N,N-dibenzyl-3-[2-fluoro-(5-trifluoromethyl)phenyl]-3-azabicyclo [3.1.0]hexan -6-amine.
  • Step 4 Preparation of Ia, 5a, 6a- ⁇ 6-(5-isoquinolylaminocarboxamido)-3-[2-fluoro-(5-trifluoro methyl) phenyl] ⁇ -3-azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -ter?-butyl-3-[2-fluoro-(5-trifluoromethyl)phenyl]-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of l-(2-fluoro-4-difluoromethoxyphenyl)-2,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2-fluoro-4-(difiuoromethoxy) aniline.
  • Step2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-[2-fluoro-4-(difluoromethoxy)phenyl]-3- azabicyclo[3.1.0] hex-an- 6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(2-fluoro-4-difluoromethoxyphenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl-3-[2-fluoro-4-(difluoromethoxy)phenyl]-3- azabicyclo [3.1.0] hex-6-yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -N,7V-dibenzyl-3-[2-fluoro-4-(difluoromethoxy)phenyl]-3-azabicyclo[3.1.0] hex- an- 6-amine.
  • Step 4 Preparation of Ia, 5a, 6a- ⁇ 6-(5-isoquinolylaminocarboxamido)-3-[2-fluoro-(4-difluoro methoxy) phenyl] ⁇ -3 -azabicyclo [3.1. OJhexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl-3-[2-fluoro-4-(difluoromethoxy)phenyl] -3 -azabicyclo [3.1.0] hex-6- yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of 1 -(2 ,3 ,4-trifluorophenyl)-2 ,5-dihydro-l H-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2,3,4-trifluoroaniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(2 ,3 ,4-trifluorophenyl)-3- azabicyclo[3.1.0] hexan-6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(2,3,4-trifluorophenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -N,N-dibenzyl-3-(2,3,4-trifluorophenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2,3,4-trifluoro)phenyl J-3-azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -/ert-butyl-3-(2,3,4-trifluorophenyl)-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of l-(2,4,6-trifluorophenyl)-2,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2,4,6-trifluoro aniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(2,4,6-trifluorophenyl)-3- azabicyclo[3.1. OJ hexan-6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(2,4,6-trifluorophenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • Step 3 Preparation of Ja, 5a, 6a-tert-butyl-3-(2,4,6-trifluorophenyl)-3-azabicyclo [3.1.0] hex-6- yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ - ⁇ /;N-dibenzyl-3-(2,3,4-trifluorophenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2,4,6- tri ⁇ uoro)phenyl] -3-azabicyclo [3. l.OJhexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -fer/-butyl-3-(2,4,6-trifluorophenyl)-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of l-(2,3-difluorophenyl)-2,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2,3-difluoroaniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(2,3-difluorophenyl)-3- azabicyclo[3.1.0] hexan-6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(2,3-difluorophenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzylformamide.
  • Step 3 Preparation of Ia, 5a, 6a- tert-butyl-3-(2,3-difluorophenyl)-3-azabicyclo [3.1.0] hex-6- yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ - ⁇ /,7V-dibenzyl-3-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2,3-difluoro)phenyl]- 3-azabicyclo [3.1.0]hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ - tert-butyl-3-(2,3-difluorophenyl)-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of l-(2-fluoro-4-methylphenyl)-2,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2-fluoro-4-methyl aniline.
  • Step 2 Preparation of Ia, 5a, 6a- N,N-dibenzyl-3-(2-fluoro-4-methylphenyl)-3- azabicyclo[3.1.0] hexan-6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(2-fluoro-4-methylphenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl-3-(2-fluoro-4-methylphenyl)-3 -azabicyclo [3.1.0] hex-6-yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ - ⁇ /, ⁇ /-dibenzyl-3-(2-fluoro-4-methylphenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2-fluoro-4- methylphenyl) phenyl] -3-azabicyclo [3.1. OJhexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl-3-(2-fluoro-4-methylphenyl)-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of l-(2-isopropyl)-2 ,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2-isopropylaniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(2-isopropylphenyl)-3-azabicyclo[3.1.0]hexan- 6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(2-isopropyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzylformamide.
  • Step 3 Preparation of Ia, 5a, 6a- tert-butyl-3-(2-isopropylphenyl)-3-azabicyclo [3.1.0] hex-6- yl] carbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -MN-dibenzyl-3-(2-isopropylphenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2-isopropyl)phenyl]- 3-azabicyclo [3.1.0] hexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ - ter£-butyl-3-(2-isopropylphenyl)-3-azabicyclo [3.1.0] hex-6-yl] carbamate and phenyl isoquinolin-5-yl carbamate
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 3,5-difluoro aniline.
  • Step 2 Preparation of Ia, 5a, 6a-N,N-dibenzyl-3-(3,5-difluorophenyl)-3- azabicyclo[3.1. OJhexan-6-amine
  • This compound was prepared by the same method as described in step 2 of the example 7 from l-(3,5-difluorophenyl)-2,5-dihydro-lH-pyrrole and N,N-dibenzyl formamide.
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl 3-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hex-6- ylcarbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 froml ⁇ , 5 ⁇ , 6 ⁇ -7V, ⁇ /-dibenzyl-3-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylamiriocarboxamido)-3-(3,5-difluorophenyl]- 3-azabicyclo [3.1. OJhexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6 ⁇ -tert-butyl 3-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hex-6-ylcarbamate and phenyl isoquinolin-5-yl carbamate.
  • Step 1 Preparation of l-(2,4,5-trifluorophenyl)-2,5-dihydro-lH-pyrrole
  • This compound was prepared by the same method as described in step 1 of the example 7 from intermediate 5 and 2,4,5-trifiuoro aniline.
  • Step 2 Preparation of Ia, 5a, 6a- ⁇ ⁇ N-dibenzyl-3-(2 ,4 ' ,5-trifluorophenyl)-3- azabicyclo[3.1.0] hexan-6-amine
  • Step 3 Preparation of Ia, 5a, 6a-tert-butyl 3-(2,4,5-trifluorophenyl)-3-azabicyclo[3.1.0]hex-6- ylcarbamate
  • This compound was prepared by the same method as described in step 3 of the example 7 from l ⁇ , 5 ⁇ , 6 ⁇ - N, ⁇ /-dibenzyl-3-(2,4,5-trifluorophenyl)-3-azabicyclo[3.1.0]hexan-6-amine.
  • Step 4 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-(2,4,5- tri fluorophenyl] -3 -azabicyclo [3.1. OJhexane
  • This compound was prepared by the same method as described in step 4 of example 7 from l ⁇ , 5 ⁇ , 6a-tert-butyl 3-(2,4,5-trifluorophenyl)-3-azabicyclo[3.1.0]hex-6-ylcarbamate and phenyl isoquinolin-5-yl carbamate
  • Example 36 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -r6-(5-isoquinolylaminocarboxamido)-3-(2,4- difluoro)phenyl1-3-azabicvclo [3.1.01hexane triflate salt (Compound No. 36)
  • Example 37 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -r6-(5-isoquinolylaminocarboxamido)-3-(2,4- difluoro)phenyll-3-azabicyclo [3.1.01hexane hydrochloride salt (Compound No.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-(trifluoromethyl)benzene sulfonyl chloride.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-fluoro benzenesulfonyl chloride.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2,6-dichlorobenzene sulfonyl chloride,
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2,6-difluoro benzenesulfonyl chloride.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2,4-dibromo benzenesulfonyl chloride.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2,4-dichloro benzene sulfonyl chloride.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2-trifluoromethyl benzene sulfonyl chloride.
  • Example 47 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -[6-(5-isoquinolylaminocarboxamido)-3-((2- fluorophenyl)sulfonyll-3-azabicyclo F3.1.01hexane (Compound No. 47) This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2-fluoro benzene sulfonyl chloride.
  • Example 48 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -[6-(5-isoquinolylaminocarboxamido)-3-(2- chlorophenyl)sulfonyl1-3-azabicvclo [3.1.0]hexane (Compound No. 48)
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2-chloro benzene sulfonyl chloride.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2-bromo benzene sulfonyl chloride.
  • Example 50 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -r6-(5-isoquinolylaminocarboxamido)-3-( phenylsulfonyl)sulfonyn-3-azabicyclo r3.1.0]hexane (Compound No. 50)
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and benzene sulfonyl chloride.
  • Example 51 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -r6-(5-isoquinolylaminocarboxamido)-3-(4-bromophenyl) sulfonvH-3-azabicvclo [3.1.01hexane (Compound No. 51) This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-bromo benzene sulfonyl chloride,
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-iodo benzene sulfonyl chloride,
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-methyl benzene sulfonyl chloride.
  • Example 54 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -[6-(5-isoquinolylaminocarboxamido)-3-(4- bromobenzoyl)1-3-azabicyclo f3.1.0]hexane (Compound No. 54)
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-bromo benzoylchloride.
  • Example 55 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -[6-(5-isoquinolylaminocarboxamido)-3-(4- chlorobenzoyl)l-3-azabicyclo D.l .Oihexane (Compound No. 55)
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-chloro benzoyl chloride as off-white solid.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 3-fluoro benzoyl chloride as off-white solid.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2-bromo benzoyl chloride as a pale yellow solid.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2-fluorobenzoyl chloride as an off-white solid.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2-chloro benzoyl chloride as an pale yellow solid.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-methyl benzoyl chloride as a pale yellow solid.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 2-(trifluoromethyl) benzoyl chloride a white solid.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-(trifluoromethyl) benzoyl chloride.
  • This compound was prepared by the same method as described in the example 39 from N- 3-azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-bromo benzoyl chloride,
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and benzyl bromide.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-chloro benzyl bromide.
  • This compound was prepared by the same method as described in example 39 from N-3- azabicyclo[3.1.0]hex-6-yl-N'-isoquinolin-5-ylurea and 4-(trifluoromethyl) benzyl bromide.
  • Step 1 Preparation of 1 -phenyl-1 H-pyrrole-2 ,5-dione
  • Step 4 Preparation of Ia, 5a, ⁇ a-f ⁇ -ftertJ-butyloxycarbamoylJS-phenylS-azabicyclo [3.1.0] hexane
  • Step 5 Preparation of Ia, 5a, 6a-[6-(5-isoquinolylaminocarboxamido)-3-phenyl]-3-azabicyclo [3.1.0] hexane
  • Example 68 Preparation of N-P-O-trifluoromethylpyridin ⁇ -vQl-S-azabicyclop.l .O ' l-hex- ⁇ -yl- N-isoquinolin-5-yl urea (Compound No. 68) To a stirred solution of l-isoquinolin-7-yl-3- ⁇ 3-[3-(trifluoromethyl)pyridin-2-yl]-3- azabicyclo[3.1.0]hex-6-yl ⁇ thiourea (1.0 equi), triethylamine in dry THF at O 0 C was added 1,1- thicarbony diimidazole and stirred for 30-40 minutes.
  • Example 70 Preparation of l ⁇ , 5 ⁇ , 6 ⁇ -[6-(5-isoquinolylaminocarboxamido)-3-(5- trifluorornethylpyrid-2-yl)1-3-azabicyclo [3.1.0] hexane (Compound No. 70)
  • Step 1 Preparation of Ia, 5a, 6a-[6-(t-butyloxy carbonyl)-3-(4-t-butylbenzoyl)]-3-azabicyclo [3.1.0] hexane
  • Reaction mixture was then stirred at room temperature for 5-6 hours, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water and dried over anhydrous sodium sulfate, the residue obtained after removal of solvent was purified through silica gel column using 1% methanol in chloroform as an eluent to get 100 mg of product as off-white solid.
  • Example 75 Preparation of l-[3-(2,4-Difluorophenyl)-3-azabicvclo[3.1.0]hex-6-yl1-3-(2-methyl- l-oxo-l,2-dihvdro isoquinolin-S-ylVurea (Compound No. 75)
  • Step 4 Preparation of l-[3-(2,4-Difluorophenyl)-3-azabicyclo[3.1.0]hex-6-yl]-3-(2-methyl-l- oxo-1, 2-dihydro isoquinolin-5-yl)-urea
  • Example 76 Screening for TRPVl antagonist using 45 Calcium uptake assay:
  • a stock solution of capsaicin was made in ethanol and test compounds were prepared in 100% DMSO. Stock solutions were diluted to appropriate final concentrations in assay buffer keeping the final DMSO concentration between 0.1% and 0.55%. 45 Ca was used at a final concentration of 2.5 ⁇ Ci/ml ( 45 Ca, ICN).Assay buffer was composed of F-12 DMEM medium supplemented with 1.8 mM CaCl 2 (final cone.) and 0.1% Bovine serum albumin.(BSA from SIGMA) The wash buffer was Tyrodes solution supplemented with 0.1% BSA and 1.8 mM calcium.
  • Lysis buffer contained 50 mM Tris-HCl, pH7.5, 150 mM NaCl, 1% Triton X-100, 0.5% deoxycholate and 0.1% Sodium dodecyl sulphate (SDS 5 SIGMA ).
  • the assay was carried out with some modifications of the procedure as described by Toth et.al. ⁇ See Toth A et. al, Life Sciences 73 p 487-498, 2003).
  • Human TRPVl expressing CHO cells were grown in F-12 DMEM (Dulbecco's modified Eagle's medium -GIBCO) medium with 10% FBS (fetal bovine serum Hyclone), 1% penicillin-streptomycin solution, and 400 ⁇ g / ml of G- 418. Cells were seeded 48 h prior to the assay in 96 well plates to obtain ⁇ 50,000 cells per well on the day of experiment. Plates were incubated at 37 0 C in the presence of 5 % CO 2 .
  • Radioactivity in samples was measured as counts per minute (cpm) using Packard Biosciences Top Count.
  • the drug / vehicle / capsaicin treated 45 Ca uptake values were normalized over basal 45 Ca value. Data was expressed as % inhibition of 45 Ca uptake by test compound with respect to maximum 45 Ca uptake induced by capsaicin alone.
  • IC 50 value was calculated from dose response curve by nonlinear regression analysis using GraphPadPRISM software. The results summarized in the Table 2 and 3 below.

Abstract

La présente invention concerne des dérivés substitués de 3-azabicyclo[3.1.0]hexane utilisables en tant que ligands du récepteur vanilloïde, ainsi que des procédés qui les utilisent pour traiter des maladies, des affections et/ou des troubles induits par les récepteurs vanilloïdes et des procédés permettant de les préparer.
PCT/IB2007/002002 2006-07-17 2007-07-16 3-azabicyclo[3.1.0]hexanes ligands du récepteur vanilloïde, compositions pharmaceutiques les contenant et leurs procédés de préparation WO2008010061A2 (fr)

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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2009034433A2 (fr) * 2007-09-10 2009-03-19 Glenmark Pharmaceuticals, S.A. Dérivés de 3-azabicyclo [3.1.0] hexane utilisés comme ligands des récepteurs vanilloïdes
WO2009090548A2 (fr) * 2008-01-17 2009-07-23 Glenmark Pharmaceuticals, S.A. Dérivés de 3-azabicyclo[3.1.0]hexane utilisés comme ligands des récepteurs vanilloïdes
WO2012022487A1 (fr) * 2010-08-20 2012-02-23 Grünenthal GmbH Dérivés de carboxamide et d'urée cycliques substitués en tant que ligands du récepteur vanilloïde
US8795533B2 (en) 2007-07-17 2014-08-05 Hoffmann-La Roche Inc. Chromatographic methods
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WO2021235983A1 (fr) 2020-05-20 2021-11-25 Федеральное государственное бюджетное учреждение науки Тихоокеанский институт биоорганической химии им. Г.Б.Елякова Дальневосточного отделения Российской академии наук (ТИБОХ ДВО РАН) Moyen de prolongation d'une action analgésique
US11274082B2 (en) 2019-05-31 2022-03-15 Ikena Oncology, Inc. Tead inhibitors and uses thereof
CN114502540A (zh) * 2019-05-31 2022-05-13 医肯纳肿瘤学公司 Tead抑制剂和其用途
US11884647B2 (en) 2019-10-18 2024-01-30 The Regents Of The University Of California Compounds and methods for targeting pathogenic blood vessels

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WO2012022487A1 (fr) * 2010-08-20 2012-02-23 Grünenthal GmbH Dérivés de carboxamide et d'urée cycliques substitués en tant que ligands du récepteur vanilloïde
CN106470973A (zh) * 2014-06-12 2017-03-01 阿罗赛特制药公司 小分子lfa‑1抑制剂
CN106470973B (zh) * 2014-06-12 2020-08-04 阿罗赛特制药公司 小分子lfa-1抑制剂
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CN114502540A (zh) * 2019-05-31 2022-05-13 医肯纳肿瘤学公司 Tead抑制剂和其用途
US11458149B1 (en) 2019-05-31 2022-10-04 Ikena Oncology, Inc. TEAD inhibitors and uses thereof
US11760728B2 (en) 2019-05-31 2023-09-19 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11925651B2 (en) 2019-05-31 2024-03-12 Ikena Oncology, Inc. TEAD inhibitors and uses thereof
US11884647B2 (en) 2019-10-18 2024-01-30 The Regents Of The University Of California Compounds and methods for targeting pathogenic blood vessels
WO2021235983A1 (fr) 2020-05-20 2021-11-25 Федеральное государственное бюджетное учреждение науки Тихоокеанский институт биоорганической химии им. Г.Б.Елякова Дальневосточного отделения Российской академии наук (ТИБОХ ДВО РАН) Moyen de prolongation d'une action analgésique

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