EP2344463A2 - Nouveaux composés en tant que ligands des récepteurs cannabinoïdes - Google Patents

Nouveaux composés en tant que ligands des récepteurs cannabinoïdes

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Publication number
EP2344463A2
EP2344463A2 EP09752053A EP09752053A EP2344463A2 EP 2344463 A2 EP2344463 A2 EP 2344463A2 EP 09752053 A EP09752053 A EP 09752053A EP 09752053 A EP09752053 A EP 09752053A EP 2344463 A2 EP2344463 A2 EP 2344463A2
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EP
European Patent Office
Prior art keywords
tert
butyl
ylidene
butylisothiazol
methoxybenzamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09752053A
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German (de)
English (en)
Inventor
William A. Carroll
Teodozyj Kolasa
Tongmei Li
Derek W. Nelson
Meena V. Patel
Sridhar Peddi
Arturo Perez-Medrano
Xuequing Wang
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Abbott Laboratories
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Abbott Laboratories
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Publication date
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Publication of EP2344463A2 publication Critical patent/EP2344463A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • 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
    • A61P35/00—Antineoplastic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the present application relates to isothiazolylidene containing compounds, compositions comprising such compounds, and methods for treating conditions and disorders using such compounds and compositions.
  • CBi receptors are highly expressed in the central nervous system and to a lesser degree in the periphery in a variety of tissues of the cardiovascular and gastrointestinal systems.
  • CB 2 receptors are most abundantly expressed in multiple lymphoid organs and cells of the immune system, including spleen, thymus, tonsils, bone marrow, pancreas and mast cells.
  • CBi receptors The psychotropic effects caused by ⁇ 9 -THC and other nonselective CB agonists are mediated by CBi receptors. These CBi receptor-mediated effects, such as euphoria, sedation, hypothermia, catalepsy, and anxiety, have limited the development and clinical utility of nonselective CB agonists.
  • CB 2 modulators are analgesic in pre-clinical models of nociceptive and neuropathic pain without causing the adverse side effects associated with CBi receptor activation. Therefore, compounds that selectively target CB 2 receptors are an attractive approach for the development of novel analgesics. Pain is the most common symptom of disease and the most frequent complaint with which patients present to physicians.
  • Pain is commonly segmented by duration (acute vs. chronic), intensity (mild, moderate, and severe), and type (nociceptive vs. neuropathic).
  • Nociceptive pain is the most well known type of pain, and is caused by tissue injury detected by nociceptors at the site of injury. After the injury, the site becomes a source of ongoing pain and tenderness. This pain and tenderness are considered “acute” nociceptive pain. This pain and tenderness gradually diminish as healing progresses and disappear when healing is complete. Examples of acute nociceptive pain include surgical procedures (post-operative pain) and bone fractures. Even though there may be no permanent nerve damage, "chronic" nociceptive pain results from some conditions when pain extends beyond six months. Examples of chronic nociceptive pain include osteoarthritis, rheumatoid arthritis, musculoskeletal conditions (e.g., back pain), cancer pain, etc.
  • Neuropathic pain is defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system" by the International Association for the Study of Pain. Neuropathic pain is not associated with nociceptive stimulation, although the passage of nerve impulses that is ultimately perceived as pain by the brain is the same in both nociceptive and neuropathic pain.
  • the term neuropathic pain encompasses a wide range of pain syndromes of diverse etiologies. The three most commonly diagnosed pain types of neuropathic nature are diabetic neuropathy, cancer neuropathy, and HIV pain.
  • neuropathic pain is diagnosed in patients with a wide range of other disorders, including trigeminal neuralgia, post-herpetic neuralgia, traumatic neuralgia, fibromyalgia, phantom limb, as well as a number of other disorders of ill-defined or unknown origin.
  • the compounds of the present invention are novel CB 2 receptor modulators that have utility in treating pain, including nociceptive and neuropathic pain.
  • CB 2 receptors The location of CB 2 receptors on the surface of immune cells suggests a role for these receptors in immunomodulation and inflammation. Recent studies have demonstrated that CB 2 receptor ligands have immunomodulatory and anti-inflammatory properties. Therefore, compounds that interact with CB 2 receptors offer a unique pharmacotherapy for the treatment of immune and inflammatory disorders.
  • R 1 is alkyl, alkenyl, alkynyl, -(CR a R b ) m -OH, -(CR a R b ) m -O(alkyl), -(CR a R b ) m -CN, haloalkyl, G 1 , -NR Z1 R Z5 , or -OR Z5 ;
  • R Z5 is alkyl, haloalkyl, G la , -(CR a R b ) m -G la , -(CR a R b ) n -OR zl , -(CR a R b ) n -N(R zl )(R zl ), -(CR a R b ) m -C(O)O(R zl ), -(CR a R b ) m -C(O)R zl , -(CR a R b ) m -C(O)N(R zl )(R zl ), -(CR a R b ) m -S(O) 2 R zl , -(CR a R b ) m -S(O) 2 N(R zl )(R zl ), or -(CR a R b ) m -CN;
  • R 3 is hydrogen, alkyl, halogen, -CN, -G 2 , haloalkyl, or -(CR a R b ) m -G 2 ;
  • R 4 is alkyl, alkenyl, alkynyl, -(CR a R b ) n -CN, -(CR a R b ) n -OH, -(CR a R b ) n -0 (alkyl), haloalkyl, G 2 , or -(CR a R b ) m -G 2 ; or
  • R 2 and R 3 , or R 3 and R 4 together with the atoms to which they are attached, form a five-, six-, or seven-membered monocyclic ring containing zero or one additional double bond, zero or one additional heteroatom selected from O, S, N, and N(H), each said monocyclic ring is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents (R 21 ) selected from the group consisting of oxo, alkyl, alkenyl, alkynyl, halogen, -CN, -O(R la ), -C(O)OH, -C(O)O(alkyl), -C(O)(R la ), -N(R Z3 )(R 3a ), -N(R 3a )C(0)R la , -N(R 3a )C(0)0(R la ), -N(R 3a )C(O)N(R Z3 )(R 3a ),
  • R Za at each occurrence, is independently hydrogen, alkyl, haloalkyl, -(CR c R d ) p -O(alkyl), Q 1 , -(CR c R d ) q -CN, or -(CR 0 R ⁇ q -G 1 ;
  • R zb at each occurrence, is independently hydrogen, alkyl, haloalkyl, G 1 , or
  • R Z1 at each occurrence, is independently hydrogen, alkyl, or haloalkyl
  • R Z2a is independently hydrogen, alkyl, haloalkyl, G 1 , or R Z2b , at each occurrence, is independently hydrogen, alkyl, haloalkyl, G 1 , -C(O)R Zc ,
  • R Zc is independently hydrogen, alkyl, haloalkyl, G 1 , or
  • R zd is independently alkyl, haloalkyl, G 1 , or -(CR 6 R ⁇ t -G 1 ;
  • a 1 is R la , -(CR lg R lh ) u -A 2 , -N(R Z3 )C(O)R la , -N(R Z3 )C(O)OR 2a , -N(R Z3 )(R la ), or
  • R Z6 is alkoxyalkyl, hydroxyalkyl, cyanoalkyl, haloalkoxyalkyl, G 2 , or -(CR k R x ) v -G 2 ;
  • L 1 and L 2 are each independently O or N(R Z3 );
  • R la and R 3a at each occurrence, are each independently hydrogen, alkyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, cyanoalkyl, haloalkoxyalkyl, G 2 , or -(CR k R x ) v -G 2 ;
  • R 2a at each occurrence, is independently alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, cyanoalkyl, haloalkoxyalkyl, G 2 , or -(CR k R x ) v -G 2 ;
  • G 2 is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, wherein each G 2 is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of -G 3 , -(CR 2g R 2h ) w -G 3 , alkyl, alkenyl, alkynyl, halogen, -CN, oxo, -NO 2 , -OR lb , -OC(O)R lb , -OC(O)N(R Z4 )(R 3b ), -SR lb , -S(O) 2 R 2b , -S(O) 2 N(R Z4 )(R 3b ), -C(O)R lb , -C(O)OR lb , -C(O)N(R Z4 )(R 3b ), -N(R Z4 )(
  • G 3 at each occurrence, is independently monocyclic heterocycle, monocyclic heteroaryl, or monocyclic cycloalkyl; wherein each occurrence of G 3 is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -N(R Z4 )(R 3b ), alkyl, haloalkyl, alkoxy, haloalkoxy, halo, oxo, CN, and OH; m, q, t, u, v, and w, at each occurrence, are each independently 1, 2, 3, 4, or 5; n and p, at each occurrence, are each independently 2, 3, 4, or 5;
  • R lb and R 3b are each independently hydrogen, alkyl, haloalkyl, monocyclic cycloalkyl, or -(CR 2g R 2h ) w -monocyclic cycloalkyl;
  • R 2b at each occurrence, is independently alkyl, haloalkyl, monocyclic cycloalkyl, or
  • R a , R c , R d , R e , R f , R lg , R 2g , R 2h , R k , and R x are each independently hydrogen, halogen, alkyl, or haloalkyl;
  • R lh is independently hydrogen, halogen, alkyl, haloalkyl, -OR lb , -N(R Z4 )(R 3b ), -N(R Z4 )C(O)R lb , -N(R Z4 )C(O)O(R lb ), or -N(R Z4 )S(O) 2 R lb ; each occurrence of R b is independently hydrogen, halogen, alkyl, haloalky, or OH;
  • R Z3 and R Z4 are each independently hydrogen, alkyl, or haloalkyl; and the monocyclic cycloalkyl, as a substituent or as part of a substituent as represented by R lb , R 2b , and R 3b , is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, oxo, and alkoxy; with the proviso that the compound is other than 4-methyl-N-[(3Z)-l -phenyl- 1,4,5, 6-tetrahydro-3H-cyclopenta[c]isothiazol-3- ylidene]benzenesulfonamide;
  • compositions comprising therapeutically effective amount of one or more compound(s) described herein or pharmaceutically acceptable salts, solvates, or salts of solvates thereof, in combination with one or more pharmaceutically acceptable carrier(s).
  • Such compositions can be administered in accordance with methods described herein, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders related to cannabinoid (CB) receptor subtype CB 2 .
  • CBD cannabinoid
  • the methods are useful for treating conditions related to pain such as, but not limited to, chronic pain, neuropathic pain, nociceptive pain, osteoarthritric pain, inflammatory pain, cancer pain, lower back pain, post operative pain, and eye pain; inflammatory disorders, immune disorders, neurological disorders, cancers of the immune system, respiratory disorders, obesity, diabetes, cardiovascular disorders, or for providing neuroprotection.
  • solvates in the manufacture of medicaments for the treatment of the disease or conditions described above, alone or in combination with one or more pharmaceutically acceptable carrier(s), particularly for the treatment of pain such as, but not limited to, chronic pain, neuropathic pain, nociceptive pain, osteoarthritric pain, inflammatory pain, cancer pain, lower back pain, post operative pain, and eye pain, or combinations thereof.
  • pain such as, but not limited to, chronic pain, neuropathic pain, nociceptive pain, osteoarthritric pain, inflammatory pain, cancer pain, lower back pain, post operative pain, and eye pain, or combinations thereof.
  • the present compounds may have one or more variable that occurs more than one time in any substituent or in the compounds or any other formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated from a reaction mixture. a. Definition of Terms
  • alkenyl means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl (allyl), 2-methyl-2-propenyl, 3-butenyl, but-1-enyl, 4- pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkyl means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
  • alkyl as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 10 carbon atoms.
  • lower alkyl or "Ci_ 6 alkyl” means a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms.
  • Ci_ 3 alkyl means a straight or branched chain hydrocarbon containing 1 to 3 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl (1-methylpropyl), iso-butyl, tert-butyl, n-pentyl, 1,1- dimethylpropyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylene denotes a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms.
  • Representative examples of alkylene include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH(CH 3 )CH 2 -.
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl (ethynyl), 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • aryl as used herein, means phenyl or a bicyclic aryl.
  • the bicyclic aryl is naphthyl (including naphth-1-yl), or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl.
  • Representative examples of the aryl groups include, but are not limited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl.
  • the bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the bicyclic ring system.
  • the aryl groups can be unsubstituted or substituted.
  • cyano refers to a -CN group.
  • cyanoalkyl refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, and 3-cyanopropyl.
  • cycloalkyl or "cycloalkane” as used herein, means a monocyclic, a bicyclic, or a tricyclic, or a spirocyclic cycloalkyl.
  • the monocyclic cycloalkyl is a carbocyclic ring system containing three to eight carbon atoms, zero heteroatoms and zero double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • C 3-6 cycloalkyl means a monocyclic cycloalkyl containing three to six carbon atoms, zero heteroatoms and zero double bonds. Examples of C 3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the bicyclic cycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkyl ring, or a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge containing one, two, three, or four carbon atoms.
  • bicyclic cycloalkyls include, but are not limited to, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl (including bicyclo[2.2.2]oct-l-yl), bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, and bicyclo[4.2.1]nonyl.
  • Tricyclic cycloalkyls are exemplified by a bicyclic cycloalkyl fused to a monocyclic cycloalkyl, or a bicyclic cycloalkyl in which two non-adjacent carbon atoms of the ring systems are linked by an alkylene bridge of between one and four carbon atoms of the bicyclic cycloalkyl ring.
  • Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0 3 ' 7 ]nonane (octahydro- 2,5-methanopentalene or noradamantane), and tricyclo[3.3.1.1 3 ' 7 ]decane (adamantane).
  • Spirocyclic cycloalkyl is exemplified by a monocyclic cycloalkyl ring wherein two of the substituents on the same carbon atom of the ring, together with said carbon atom, form a 4-, 5-, or 6-membered monocyclic cycloalkyl.
  • An example of a spirocyclic cycloalkyl is spiro[2.5]octane.
  • the monocyclic, bicyclic, tricyclic, and spirocyclic cycloalkyls can be unsubstituted or substituted, and are attached to the parent molecular moiety through any substitutable atom contained within the ring system.
  • cycloalkenyl or "cycloalkene” as used herein, means a monocyclic or a bicyclic hydrocarbon ring system.
  • the monocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms and zero heteroatoms.
  • the four-membered ring systems have one double bond, the five-or six-membered ring systems have one or two double bonds, and the seven- or eight-membered ring systems have one, two or three double bonds.
  • monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • the bicyclic cycloalkenyl is a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group.
  • the monocyclic or bicyclic cycloalkenyl ring may contain one or two alkylene bridges, each consisting of one, two or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system.
  • bicyclic cycloalkenyl groups include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl and 1,6-dihydro-pentalene.
  • the monocyclic and bicyclic cycloalkenyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring systems, and can be unsubstituted or substituted.
  • halo or halogen as used herein, means Cl, Br, I, or F.
  • haloalkoxy means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkoxyalkyl as used herein, means a haloalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkoxyalkyl include, but are not limited to, chloromethoxymethyl and trifluoromethoxymethyl.
  • haloalkyl as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen.
  • Ci_6 haloalkyl as used herein, means a Ci_6 alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen.
  • haloalkyl include, but are not limited to, chloromethyl, fluoromethyl, 2- fluoroethyl, 1,1-difluoroethyl, 2,2-difiuoroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro- 1 , 1 -dimethylethyl, 2-fluoro- 1 , 1 -dimethylethyl, trifluoromethyl, difluoromethyl, 4-fluoro-4-methylpentyl, 4,4-difluoropentyl, 4-fluorobutyl, 3-fluoro-3- methylbutyl, 4,4,4-trifluorobutyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • heterocycle or “heterocyclic” as used herein, means a monocyclic, a bicyclic, a tricyclic, or a spirocyclic ring system, containing at least one heteroatom.
  • the monocyclic heterocycle is a three-, four-, five-, six-, or seven-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
  • the three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S.
  • the f ⁇ ve-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • the seven-membered ring contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl (including azetidin-1-yl), azepanyl, aziridinyl, diazepanyl, dihydro-oxazolyl (e.g.
  • 4,5-dihydro-l,3-oxazol-2-yl 1,3-dioxanyl (including l,3-dioxan-2-yl), 1,3-dioxolanyl, dihydropyranyl (including 3,4-dihydro-2H- pyran-6-yl), 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl (including morpholin-4-yl), 4,5- dihydroisoxazolyl (including 4,5-dihydroisoxazol-5-yl), dihydro-oxazinyl (e.g.
  • the bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a bridged monocyclic heterocycle ring system in which two non adjacent atoms of the ring are linked by an alkylene bridge containing one, two, three, or four carbon atoms.
  • bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, oxabicyclo[2.2.1]heptyl (including oxabicyclo[2.2.1]hept-2-yl), and 2,3-dihydro-lH-indolyl.
  • Spirocyclic heterocycle means a monocyclic heterocycle wherein two of the substituents on the same carbon atom form a A-, 5-, or 6-membered monocyclic cycloalkyl, wherein the cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 alkyl groups.
  • Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non adjacent atoms of the bicyclic ring are linked by an alkylene bridge consisting of one, two, three, or four carbon atoms.
  • tricyclic heterocycles include, but are not limited to, octahydro-2,5- epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[ ⁇ ]furan, hexahydro-lH-1,4- methanocyclopenta[c]furan, aza-admantane such as l-azatricyclo[3.3.1.1 3 ' 7 ]decane, and oxa- adamantane such as 2-oxatricyclo[3.3.1.1 3 ' 7 ]decane.
  • the monocyclic, bicyclic, tricyclic, and spirocyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.
  • the nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized and the nitrogen atoms may optionally be quarternized.
  • heteroaryl as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl.
  • the monocyclic heteroaryl is a five- or six-membered ring.
  • the f ⁇ ve-membered ring contains two double bonds.
  • the five membered ring may contain one heteroatom selected from O or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or sulfur atom.
  • the six-membered ring contains three double bonds and one, two, three or four nitrogen atoms.
  • monocyclic heteroaryl include, but are not limited to, furanyl (including furan-2-yl), imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl (including l,3-thiazol-4-yl, l,3-thiazol-2-yl), thienyl (including thien-2-yl), triazolyl, and triazinyl.
  • the bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle.
  • bicyclic heteroaryl groups include, but not limited to, benzo furanyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, 6,7-dihydro-l,3-benzothiazolyl, imidazo[l,2- ⁇ ]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl (including quinolin-8-yl), thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and 5,6,7,8-tetrahydroquinolin-5-yl.
  • the monocyclic and bicyclic heteroaryl groups can be substituted or unsubstituted and are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring systems.
  • the nitrogen and sulfur heteroatoms of the heteroaryl rings may optionally be oxidized, and are contemplated within the scope of the invention.
  • heteroatom means a nitrogen, oxygen, or sulfur atom.
  • hydroxyalkyl as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, 2- hydroxy-2-methylpropyl, 1 -hydroxy- 1-methylethyl, and 2-ethyl-4-hydroxyheptyl.
  • hydroxy as used herein, means an -OH group.
  • R 2 is alkyl (e.g., methyl, ethyl, n-propyl, isobutyl, n-butyl, n-pentyl, and the like), alkenyl (for example, allyl, vinyl, but-1- enyl, and the like), alkynyl, -(CR a R b ) m -CN, haloalkyl (e.g., 4-fluoro-4-methylpentyl, 4,4- difluoropentyl, 3 -fluoro-3 -methylbutyl, 4,4,4-trifluorobutyl, 4-fluorobutyl), -(CR a R b ) m -O(R Za ), or -(CR a R b )
  • alkyl e.g., methyl, ethyl, n-propyl, isobutyl, n-butyl, n-pentyl, and the
  • R 2 is alkyl (e.g., methyl, ethyl, n-propyl, isobutyl, n-butyl, n-pentyl, and the like), alkenyl (for example, allyl, vinyl, but-1- enyl, and the like), alkynyl, or Ci_ 6 haloalkyl (e.g., 4-fluoro-4-methylpentyl, 4,4- difluoropentyl, 3 -fluoro-3 -methylbutyl, 4,4,4-trifluorobutyl, 4-fluorobutyl).
  • alkyl e.g., methyl, ethyl, n-propyl, isobutyl, n-butyl, n-pentyl, and the like
  • alkenyl for example, allyl, vinyl, but-1- enyl, and the like
  • alkynyl or Ci_ 6 haloalkyl (e
  • R 2 is G 1 wherein G 1 is as described in the Summary.
  • G 1 include, but are not limited to, cycloalkyl (e.g. monocyclic cycloalkyl such as, but not limited to, cyclopropyl) and heterocycle (e.g. monocyclic heterocycle such as, but not limited to, tetrahydropyranyl), each of which is optionally substituted as described generally in the Summary section.
  • the optional substituents when present, include, but are not limited to, alkyl (e.g. methyl, ethyl), oxo, and haloalkyl.
  • R 2 is -(CR a R b ) m -G 1 wherein m, G 1 , R a , m, and R b are as described in the Summary.
  • G 1 include, but are not limited to, aryl (e.g. phenyl), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), heterocycle (e.g. 4,5- dihydroisoxazolyl, morpholinyl, 1,3-dioxanyl, 1,3-dioxolanyl, tetrahydrofuranyl), heteroaryl (e.g.
  • furanyl, 1,3-thiazolyl, thienyl each of which is optionally substituted as described generally in the Summary section.
  • the optional substituents when present, include, but are not limited to, alkyl (e.g. methyl, ethyl), haloalkyl, and oxo.
  • R a and R b are as described generally in the Summary section. Examples of R a include, but are not limited to, hydrogen and Ci_6 alkyl (e.g. methyl, ethyl, isopropyl). Examples of R b include, but are not limited to, hydrogen, Ci_ 6 alkyl (e.g. methyl, ethyl, isopropyl), and OH.
  • Ci_ 6 alkyl e.g. methyl,
  • R 2 is -O(R Za ) or -N(R zl )(R Z2b ) wherein R Za , R Z1 , and R Z2b are as set forth in the Summary.
  • R Za include, but are not limited to, hydrogen, alkyl (e.g. Ci_6 alkyl such as, but not limited to, methyl, ethyl, 1-methylpropyl, isopropyl), haloalkyl (e.g., 4-fluorobutyl), -(CR c R d ) q -CN and wherein R c , R d , q, G 1 are as set forth in the Summary.
  • alkyl e.g. Ci_6 alkyl such as, but not limited to, methyl, ethyl, 1-methylpropyl, isopropyl
  • haloalkyl e.g., 4-fluorobutyl
  • R c , R d , q, G 1
  • G 1 is optionally substituted phenyl or optionally substituted pyrrolidinyl.
  • R c and R d are each independently hydrogen or Ci_6 alkyl (e.g. methyl, ethyl, isopropyl).
  • q is 1 or 2.
  • R Z1 for example, is hydrogen or Ci_3 alkyl (e.g. methyl).
  • R Z2b for example, is -C(O)O(R Zc ) wherein R Zc is as described in the Summary.
  • R Zc for example, is Ci_ 6 alkyl (e.g. tert-butyl).
  • R 2 is -(CR a R b ) m -O(R Za )or -(CR a R b ) m -N(R zl )(R Z2b ) wherein m, R a , R , R a , R , and R are as described in the Summary and in embodiments herein.
  • R Za is hydrogen, alkyl (e.g. Ci_6 alkyl such as, but not limited to, methyl, ethyl, 1-methylpropyl, isopropyl), haloalkyl (e.g.
  • Ci_ 6 haloalkyl such as, but not limited to, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl), or -(CR c R d ) q -G 1 wherein q, R c , R d , and G 1 are as described in the Summary and in embodiments herein.
  • G 1 is optionally substituted heterocycle (e.g. monocyclic heterocycle such as, but not limited to, tetrahydrofuran) or optionally substituted phenyl.
  • each occurrence of R a , R c , and R d are, for example, independently, hydrogen or Ci_6 alkyl (e.g. methyl, ethyl, isopropyl).
  • R b at each occurrence is, for example, independently, hydrogen, Ci_6 alkyl (e.g. methyl, ethyl, isopropyl), or OH.
  • q is 1 or 2. In certain embodiments, q is 1.
  • R Z1 and R Z2b are, for example, independently hydrogen or Ci_6 alkyl (e.g. methyl, ethyl, isopropyl).
  • R 3 is hydrogen, alkyl, halogen, -CN, -G 2 , haloalkyl, or -(CR a R b ) m -G 2 .
  • R 3 is hydrogen, Ci_6 alkyl (e.g. methyl), haloalkyl, or an optionally substituted cycloalkyl (e.g. optionally substituted monocyclic cycloalkyl such as, but not limited to, cyclopropyl optionally substituted with one or two Ci_ 3 alkyl groups).
  • R 3 is hydrogen or Ci_ 6 alkyl (e.g. methyl).
  • R 4 is alkyl, alkenyl, alkynyl, -(CR a R b ) n -CN, -(CR a R b ) n -OH, -(CR a R b ) n -O(alkyl), haloalkyl, G 2 , or -(CR a R b ) m -G 2 .
  • R 4 is alkyl (e.g. Ci_6 alkyl such as, but not limited to, methyl, tert-butyl, 1,1-dimethylpropyl), haloalkyl (e.g.
  • G 2 e.g. optionally substituted C 3-6 cycloalkyl such as, but not limited to, optionally substituted cyclopropyl or optionally substituted cyclobutyl, or optionally substituted monocyclic heterocycle such as, but not limited to, optionally substituted oxetanyl or optionally substituted tetrahydrofuranyl).
  • G 2 is cyclopropyl or cyclobutyl, each of which is optionally substituted with one or two Ci_ 3 alkyl (e.g. methyl).
  • m if present, is as described in the Summary.
  • m is 1, 2, 3, or 4.
  • m is 1, 2, or 3.
  • m is 1 or 2.
  • R 1 is alkyl, alkenyl, alkynyl, -(CR a R b ) m -0H, -(CR a R b ) m -O(alkyl), -(CR a R b ) m -CN, haloalkyl, G 1 , -NR Z1 R Z5 , or -OR Z5 .
  • R 1 is G 1 , -NR Z1 R Z5 , or -OR Z5 wherein G 1 , R Z1 , and R Z5 are as set forth in the Summary and in embodiments herein.
  • R 1 is -OR Z5 wherein R Z5 is as disclosed in the Summary.
  • R Z5 is alkyl (e.g. neopentyl), haloalkyl (e.g. 2,2,2-trichloroethyl), or G la
  • G la is as set forth in the Summary.
  • G la is optionally substituted cycloalkyl such as, but not limited to, optionally substituted adamantyl.
  • R 1 is -NR Z1 R Z5 wherein R Z1 and R Z5 are as set forth in the Summary.
  • R Z5 is G la or -(CR a R b ) m -C(O)N(R zl )(R zl ) wherein G la , R a , R b , m, and R Z1 are as set forth in the Summary.
  • each occurrence of R a and R b are each independently hydrogen or alkyl (e.g. methyl, ethyl, tert-butyl).
  • R Z1 at each occurrence, is independently hydrogen or alkyl (e.g. methyl, ethyl, tert-butyl).
  • G la for example, is 1 or 2.
  • G la is optionally substituted cycloalkyl such as, but not limited to, optionally substituted cyclohexyl.
  • Non limiting examples of the optional substituents of G la are alkyl, haloalkyl, and oxo.
  • R 1 is G 1 wherein G 1 is as described generally in the Summary.
  • G 1 is aryl (e.g., phenyl, naphthyl), heteroaryl (e.g. quinolin-8-yl), heterocycle (e.g.
  • R 1 is G 1 , wherein G 1 is phenyl or naphthyl, each of which is optionally substituted as described generally in the Summary and embodiments herein below.
  • R 1 is G 1 , wherein G 1 is heteroaryl, optionally substituted as described in the Summary and embodiments herein below. In certain embodiments, R 1 is optionally substituted quinolin-8-yl. In certain embodiments, R 1 is G 1 , wherein G 1 is cycloalkyl (e.g., e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl), each of which is optionally substituted as described in the Summary and embodiments herein below.
  • cycloalkyl e.g., e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl
  • R 1 is G 1 , wherein G 1 is heterocycle, optionally substituted as described in the Summary.
  • R 1 is pyrrolidinyl, dihydropyranyl, oxa- adamantyl, or oxabicyclo[2.2.1]heptyl, each of which is optionally substituted as described in the Summary and in embodiments herein below.
  • examples of the optional susbtituents of G 1 when R 1 is G 1 include, but are not limited to:
  • alkyl e.g. methyl, ethyl, isopropyl
  • alkynyl e.g. ethynyl
  • halogen e.g. F, Cl, I
  • R la is as disclosed in the Summary.
  • each occurrence of R la is independently hydrogen or Ci_6 alkyl (e.g. methyl);
  • L 1 and A 1 are as disclosed in the Summary.
  • L 1 is O and A 1 is R la , N(R Z3 )(R la ), or -(CR lg R lh ) u -A 2 , wherein R la , R Z3 , R lg , R lh , u, and A 2 are as disclosed in the Summary and embodiments herein.
  • R Z3 is hydrogen and R la is alkyl (e.g. tert-butyl, isopropyl).
  • R la is hydrogen, alkyl (e.g. Ci_ 6 alkyl such as, but not limited to, methyl, ethyl), haloalkyl (e.g. 2,2,2-trifluoroethyl, 2-fluoroethyl, trifluoromethyl), hydroxyalkyl (e.g. 2- hydroxy-2-methylpropyl), or -(CR k R x ) v -G 2 ; wherein R k , R x , v, and G 2 are as disclosed in the Summary.
  • R k , R x are, for example, are each independently hydrogen or Ci_ 3 alkyl (e.g.
  • G 2 for example, is optionally substituted heterocycle (e.g. optionally substituted monocyclic heterocycle such as, but not limited to, pyrrolidinyl, oxazolidinyl, piperidinyl), or optionally substituted heteroaryl (e.g. optionally substituted monocyclic heteroaryl such as, but not limited to, pyridinyl, pyrazinyl).
  • optional substituents of G 2 include, but are not limited to, Ci_ 6 alkyl (e.g. methyl), oxo, halogen, and haloalkyl.
  • a 2 for example, is CON(R Z3 )(R 3a ) or CN, wherein R Z3 and R 3a are as disclosed in the Summary.
  • R lg and R lh are, for example, hydrogen, u, for example, is 1.
  • R Z3 and R 3a for CON(R Z3 )(R 3a ) include, but are not limited to, hydrogen and Ci_6 alkyl (e.g., methyl).
  • Other examples of compounds include, but are not limited to, those wherein the substituent of R 1 is iZ-A 1 wherein L 1 is N(R Z3 ), and A 1 is as disclosed in the Summary.
  • R Z3 and R la are each independently hydrogen or Ci_ 6 alkyl (e.g., methyl);
  • R 2a is Ci_6 alkyl (e.g., methyl),
  • R la is as disclosed in theSummary.
  • R la is hydrogen, Ci_ 6 alkyl (e.g. methyl, ethyl), or G 2 wherein G 2 is as disclosed in the Summary.
  • G 2 is optionally substituted phenyl or optionally substituted heterocycle (e.g. optionally substituted azetidinyl, pyrrolidinyl).
  • the optional substituents of G 2 include, but are not limited to, alkyl (e.g. methyl), halogen (e.g. F, Cl), -OR lb (e.g. R lb is hydrogen or Ci_ 3 alkyl), and haloalkyl (e.g.
  • R la is hydrogen or Ci_ 6 alkyl (e.g. methyl, ethyl, tert-butyl),
  • R is hydrogen or Ci_ 6 alkyl (e.g., methyl).
  • R a for example, is hydrogen, C 1- , alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), alkynyl (e.g. prop-2-ynyl), alkoxy (e.g. methoxy), haloalkyl (e.g. 2,2,2-trifluoroethyl), hydroxyalkyl (e.g.
  • R k , R x are, for example, are each independently hydrogen or Ci_3 alkyl (e.g. methyl), v, for example, is 1.
  • G 2 for example, is phenyl, heteroaryl (e.g. monocyclic heteroaryl such as, but not limited to, pyridinyl), cycloalkyl (e.g.
  • monocyclic cycloalkyl such as, but not limited to, cyclopropyl, cyclobutyl) or heterocycle (e.g. monocyclic heterocycle such as, but not limited to, tetrahydrofuranyl, pyrrolidinyl); each of which is optionally substituted as described in the Summary, for example, optionally substituted with substituents independently selected from the group consisting of alkyl, halogen, and haloalkyl;
  • R 3a is hydrogen or Ci_6 alkyl (e.g., methyl)
  • R la is hydrogen, Ci_6 alkyl (e.g., methyl)
  • G 2 is phenyl or heterocycle (e.g. monocyclic heterocycle such as, but not limited to, azetidinyl, pyrrolidinyl, morpholinyl), each of which is optionally substituted as described in the Summary and herein.
  • the optional substituent of G 2 include, but are not limited to, alkyl, halogen, haloalkyl, and OH;
  • haloalkyl e.g. difluoromethyl, 1,1-difluoroethyl, fluoromethyl, trifluoromethyl
  • n N(R 3a )C(O)O(R la ) wherein R 3a and R la are as disclosed in the Summary.
  • R 3a is hydrogen
  • R la is Ci_ 6 alkyl (e.g., methyl, ethyl, tert-butyl);
  • R Z3 is hydrogen or Ci_6 alkyl (e.g., methyl)
  • R 3a is hydrogen, Ci_6 alkyl (e.g., methyl), hydroxyalkyl (e.g. 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl), or G 2 wherein G 2 is as disclosed in the Summary, for example, G 2 is optionally substituted phenyl; and
  • G 2 wherein G 2 is as disclosed in the Summary.
  • G 2 is phenyl, heterocycle (e.g. dihydro-l,3-oxazolyl, dihydro-l,3-oxazinyl), or heteroaryl (e.g. pyridinyl), each of which is optionally substituted as described in the Summary.
  • the optional substituents of G 2 include, but are not limited to, Ci_6 alkyl (e.g. methyl), halogen (e.g. F, Cl), haloalkyl (e.g. trifluoromethyl), and CN.
  • n is 1, 2, 3, or 4. In other embodiments, m is 1, 2, or 3. In yet other embodiments, m is 1 or 2.
  • R 3 is hydrogen or Ci_6 alkyl (e.g. methyl).
  • R 3 is hydrogen, Ci_ 6 alkyl (e.g. methyl), haloalkyl, or an optionally substituted cycloalkyl (e.g. optionally substituted monocyclic cycloalkyl such as, but not limited to, cyclopropyl optionally substituted with one or two Ci_3 alkyl groups); and R 2 is alkyl (e.g., methyl, ethyl, n-propyl, isobutyl, n-butyl, n-pentyl, and the like), alkenyl (for example, allyl, vinyl, but-1- enyl, and the like), alkynyl, -(CR a R b ) m -CN, haloalkyl (e.g., 4-fluoro-4-methylpentyl, 4,4- difluoropentyl, 3-fluoro-3-methylbutyl, 4,4,4
  • R 3 is hydrogen or Ci_ 6 alkyl (e.g. methyl). Another aspect is directed to a group of compounds of Formula (I) wherein R 3 is hydrogen, Ci_ 6 alkyl (e.g.
  • R 2 is alkyl (e.g., methyl, ethyl, isobutyl, n-butyl, n-pentyl, and the like), alkenyl (for example, allyl, vinyl, but-1-enyl, and the like) or Ci_ 6 haloalkyl (e.g., 4-fluoro-4-methylpentyl, 4,4-difluoropentyl, 3-fluoro-3- methylbutyl, 4,4,4-trifluorobutyl, 4-fluorobutyl).
  • R 3 is hydrogen or Ci_6 alkyl (e.g. methyl).
  • Yet another aspect is directed to a group of compounds of Formula (I) wherein R 3 is hydrogen, Ci_ 6 alkyl (e.g. methyl), haloalkyl, or an optionally substituted cycloalkyl (e.g. optionally substituted monocyclic cycloalkyl such as, but not limited to, cyclopropyl optionally substituted with one or two Ci_3 alkyl groups); and R 2 is G 1 wherein G 1 is as described in the Summary and the Detailed Description sections. Examples of G 1 include, but are not limited to, cycloalkyl (e.g. monocyclic cycloalkyl such as, but not limited to, cyclopropyl) and heterocycle (e.g.
  • R 3 is hydrogen, Ci_ 6 alkyl (e.g. methyl), haloalkyl, or an optionally substituted cycloalkyl (e.g. optionally substituted monocyclic cycloalkyl such as, but not limited to, cyclopropyl
  • R is hydrogen or Ci_6 alkyl (e.g. methyl).
  • R 3 is hydrogen, Ci_ 6 alkyl (e.g. methyl), haloalkyl, or an optionally substituted cycloalkyl (e.g.
  • G 1 optionally substituted monocyclic cycloalkyl such as, but not limited to, cyclopropyl optionally substituted with one or two Ci_3 alkyl groups
  • R 2 is wherein G 1 , R a , m, and R b are as described in the Summary and the Detailed Description sections.
  • G 1 include, but are not limited to, aryl (e.g. phenyl), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), heterocycle (e.g.
  • R b examples include, but are not limited to, hydrogen, Ci_6 alkyl (e.g. methyl, ethyl, isopropyl), and OH.
  • R 3 is hydrogen or Ci_ 6 alkyl (e.g. methyl).
  • m is 1 or 2.
  • a further aspect is directed to a group of compounds of Formula (I) wherein R is hydrogen, Ci_ 6 alkyl (e.g. methyl), haloalkyl, or an optionally substituted cycloalkyl (e.g.
  • R zb , R a , R b , and R Z1 are, for example, independently, hydrogen or Ci_6 alkyl (e.g. methyl, ethyl, isopropyl).
  • R 3 is hydrogen or Ci_ 6 alkyl (e.g. methyl).
  • a still further aspect is directed to a group of compounds of Formula (I) wherein R is hydrogen, Ci_ 6 alkyl (e.g. methyl), haloalkyl, or an optionally substituted cycloalkyl (e.g.
  • R Za optionally substituted monocyclic cycloalkyl such as, but not limited to, cyclopropyl optionally substituted with one or two Ci_ 3 alkyl groups
  • R 2 is -O(R Za ) or -N(R zl )(R Z2b ) wherein R Za , R Z1 , and R Z2b are as set forth in the Summary and the Detailed Description section.
  • R Za include, but are not limited to, hydrogen, alkyl (e.g.
  • Ci_6 alkyl such as, but not limited to, methyl, ethyl, 1-methylpropyl, isopropyl), haloalkyl (e.g., A- fluorobutyl), -(CR c R d ) q -CN, and -(CR 0 R ⁇ -G 1 wherein R c , R d , q, and G 1 are as set forth in the Summary and the Detailed Description sections.
  • G 1 for example, is optionally substituted phenyl or optionally substituted pyrrolidinyl.
  • Each occurrence of R c and R d are each independently hydrogen or Ci_ 6 alkyl (e.g. methyl, ethyl, isopropyl).
  • R Z1 is hydrogen or Ci_ 3 alkyl (e.g. methyl).
  • R Z2b for example, is -C(O)O(R Zc ) wherein R Zc is as described in the Summary.
  • R Zc for example, is Ci_6 alkyl (e.g. tert-butyl).
  • R 3 is hydrogen or Ci_6 alkyl (e.g. methyl).
  • Still yet another aspect is directed to a group of compounds of Formula (I) wherein R 3 is hydrogen, Ci_ 6 alkyl (e.g. methyl), haloalkyl, or an optionally substituted cycloalkyl (e.g.
  • R Za is hydrogen, alkyl (e.g.
  • Ci_ 6 alkyl such as, but not limited to, methyl, ethyl, 1-methylpropyl, isopropyl), haloalkyl (e.g. Ci_ 6 haloalkyl such as, but not limited to, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2,2- difluoroethyl), or -(CR c R d ) q -G 1 wherein q, R c , R d , and G 1 are as described in the Summary and in the Detailed Description sections.
  • G 1 is optionally substituted heterocycle (e.g.
  • each occurrence of R a , R c , and R d are, for example, independently, hydrogen or Ci_6 alkyl (e.g. methyl, ethyl, isopropyl).
  • R b at each occurrence is, for example, independently, hydrogen, Ci_ 6 alkyl (e.g. methyl, ethyl, isopropyl), or OH.
  • q is 1 or 2. In certain embodiments, q is 1.
  • R Z1 and R Z2b are, for example, independently hydrogen or Ci_ 6 alkyl (e.g. methyl, ethyl, isopropyl).
  • R 3 is hydrogen or Ci_6 alkyl (e.g. methyl).
  • m is 1, 2, 3, or 4.
  • Still another group of compounds of Formula (I) include, but are not limited to, those wherein R 2 and R 3 , together with the atoms to which they are attached, form a five-, six-, or seven-membered monocyclic ring containing zero or one additional double bond, zero or one additional heteroatom selected from O, S, N, and N(H), each said monocyclic ring is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents (R 21 ) selected from the group consisting of oxo, alkyl, alkenyl, alkynyl, halogen, -CN, -O(R la ), -C(O)OH, -C(O)O(alkyl), -C(O)(R la ), -N(R Z3 )(R 3a ), -N(R 3a )C(0)R la , -N(R 3a )C(0)0(R la ), -N(R 3a )C(O
  • two adjacent or non-adjacent atoms of each said monocyclic ring are optionally linked by an alkylene bridge of one, two, three, or four carbon atoms; and two substituents (R 21 ) on the same carbon atom, together with said carbon atom, optionally form a 3-6 membered monocyclic ring containing 0, 1, or 2 heteroatoms selected from O, S, and N(H).
  • R 2 and R 3 together with the atoms to which they are attached, form a six-membered monocyclic ring containing zero additional double bond, zero or one N(H) in the ring, each said ring is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents (R 21 ) selected from the group consisting of oxo, alkyl, alkenyl, alkynyl, halogen, -CN, -O(R la ), -C(O)OH, -C(O)O(alkyl), -C(O)(R la ), -N(R Z3 )(R 3a ), -N(R 3a )C(O)R la , -N(R 3a )C(O)O(R la ), -N(R 3a )C(O)O(R la ), -N(R 3a )C(O)O(R la ), -N(R 3a )C(O
  • G 3 is absent, CH 2 , N(H), O, or S;
  • R 21 is an optional substituent on any substitutable atoms of the ring containing G 3 , and has values as described herein above, r is 0, 1, 2, 3, 4, or 5, and R 1 , R 4 , and L are as described generally the Summary and in embodiments above and herein.
  • G 3 is N(H).
  • G 3 is CH 2 .
  • R 21 include, but are not limited to, alkyl (e.g. Ci_6 alkyl such as, but not limited to, methyl, ethyl, isopropyl, n-butyl, n-propyl), haloalkyl (e.g.
  • Ci_6 haloalkyl such as, but not limited to, trifluoromethyl), -C(O)O(Ci_ 6 alkyl), -C(O)OH, and oxo; and two R 21 on the same carbon atoms, together with said carbon atom, optionally form a 3-6 membered monocyclic ring, optionally containing heteroatom(s) as described generally in the Summary.
  • r is 0, 1, 2, or 3. In other embodiments, r is 0, 1, or 2.
  • R 1 , R 4 , L, and the optional substituents, when present, are as described generally in the Summary section and in embodiments described above and herein.
  • examples of a subgroup include those wherein R 1 is G 1 , -NR Z1 R Z5 , or -OR Z5 wherein G 1 , R Z1 and R Z5 are as set forth in the Summary and the Detailed Description sections.
  • Examples of another subgroup of compounds of Formula (I) or (II) include, but are not limited to, those wherein R 1 is -OR Z5 and R Z5 is as disclosed in the Summary and the Detailed Description sections.
  • R Z5 is alkyl (e.g. neopentyl), haloalkyl (e.g. 2,2,2-trichloroethyl), or G la
  • G la is as set forth in the Summary and the Detailed Description sections.
  • G la is optionally substituted cycloalkyl such as, but not limited to, optionally substituted adamantyl.
  • R 1 is -NR Z1 R Z5
  • R Z1 and R Z5 are as set forth in the Summary and the Detailed Description sections.
  • R Z5 is G la or
  • R a and R b are each independently hydrogen or alkyl (e.g. methyl, ethyl, isopropyl, tert-butyl).
  • R Z1 at each occurrence, is independently hydrogen or alkyl (e.g. methyl, ethyl, tert-butyl).
  • m for example, is 1 or 2.
  • G la is optionally substituted cycloalkyl such as, but not limited to, optionally substituted cyclohexyl, as described in the Summary and the Detailed Description sections.
  • examples of a subgroup include those wherein R 1 is G 1 , and G 1 is as described in the Summary and the Detailed Description sections.
  • G 1 is aryl (e.g., phenyl, naphthyl), heteroaryl (e.g. quinolin-8-yl), heterocycle (e.g.
  • pyrrolidinyl oxabicyclo[2.2.1]heptyl, dihydropyranyl
  • cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl
  • cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl
  • a subgroup of compounds of Formula (I) or (II) include, but are not limited to, those wherein R 1 is heteroaryl (e.g. quinolin-8-yl), optionally substituted as described generally in the Summary and and the Detailed Description sections.
  • R 1 is heterocycle (e.g. pyrrolidinyl, oxabicyclo[2.2.1]heptyl, oxa-adamantyl, dihydropyranyl), optionally substituted as described generally in the Summary and and the Detailed Description sections.
  • a subgroup of compounds of Formula (I) or (II) include, but are not limited to, those wherein R 1 is cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl), optionally substituted as described generally in the Summary and and the Detailed Description sections.
  • R 1 is cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, adamantyl, noradamantyl), optionally substituted as described generally in the Summary and and the Detailed Description sections.
  • L and R 4 are as described generally in the Summary section and in embodiments described above and herein.
  • R 4 is alkyl (e.g. Ci_6 alkyl such as, but not limited to, methyl, tert-butyl, 1,1-dimethylpropyl), haloalkyl (e.g. 2-fluoro-l,l-dimethylethyl, 2,2,2-trifluoro-l,l- dimethylethyl), or G 2 , wherein G 2 is as described in the Summary.
  • G 2 is optionally substituted C 3 _ 6 cycloalkyl (e.g. optionally substituted cyclopropyl or optionally substituted cyclobutyl) or optionally substituted monocyclic heterocycle (e.g.
  • G 2 is cyclopropyl or cyclobutyl, each of which is optionally substituted with one or two Ci_ 3 alkyl (e.g. methyl).
  • Ci_ 3 alkyl e.g. methyl
  • R 3 is hydrogen or Ci_6 alkyl
  • R 4 is alkyl, haloalkyl, or G 2
  • G 2 is as described in the Summary and the Detailed Description sections.
  • R 3 is hydrogen, Ci_ 6 alkyl, haloalkyl, or an optionally substituted cycloalkyl
  • L is C 1-6 alkyl), haloalkyl, or G 2 ;
  • G 1 , R zb , R za , R Z1 , R Z2b , R a , R b , m, R Z5 , and G 2 are as described in the Summary and the Detailed Description sections, and any combination of L as described above.
  • L is S(O) 2 .
  • R is hydrogen, Ci_6 alkyl, haloalkyl, or an optionally substituted cycloalkyl
  • R 1 is G 1 ;
  • R 4 is alkyl (e.g. C 1-6 alkyl), haloalkyl, or G 2 ; and G 1 , R zb , R Za , R Z1 , R Z2b , R a , R b , m, and G 2 are as described in the Summary and the Detailed Description sections, and any combination of L as described above.
  • L is S(O) 2 .
  • R 3 is hydrogen or Ci_6 alkyl
  • R 2 is alkyl, alkenyl, alkynyl, -(CR a R b ) m -CN, haloalkyl, -(CR a R b ) m -0(R Za ) or R 4 is alkyl (e.g. Ci_6 alkyl), haloalkyl, or G 2
  • R 1 is optionally substituted phenyl or optionally substituted naphthyl
  • R a , R b , m, R Za , G 1 , and G 2 are as described in the Summary and the Detailed Description sections, and any combination of L as described above.
  • L is S(O) 2 .
  • R 3 is hydrogen or C 1-6 alkyl
  • R 2 is alkyl, alkenyl, alkynyl, -(CR a R b ) m -CN, haloalkyl, -(CR a R b ) m -0(R Za ) or -(CR 11 R 1 VG 1
  • R 4 is alkyl (e.g. Ci_ 6 alkyl), haloalkyl, or G 2
  • R 1 is optionally substituted cycloalkyl
  • R a , R b , m, R Za , G 1 , and G 2 are as described in the Summary and the Detailed Description sections, and any combination of L as described above.
  • L is S(O) 2 .
  • R 1 is G 1 , -NR Z1 R Z5 , -OR Z5 ; and R 4 is alkyl (e.g. Ci_ 6 alkyl), haloalkyl, or G 2 ; R Z5 , R Z1 , G 1 , and G 2 are as described in the Summary and the Detailed Description sections, and any combination of L as described above.
  • L is S(O) 2 .
  • Still other compounds that are intended include those wherein R 2 and R 3 , together with the carbon atoms to which they are attached, form a monocyclic ring as generally described in the Summary and in embodiments herein above, R 1 is G 1 ; and R 4 is alkyl (e.g. Ci_6 alkyl), haloalkyl, or G 2 ; G 1 and G 2 are as described in the Summary and the Detailed Description sections, and any combination of L as described above.
  • L is S(O) 2 .
  • Still other compounds that are intended include those wherein R 2 and R 3 , together with the carbon atoms to which they are attached form a monocyclic ring as generally described in the Summary and in embodiments herein above, R 1 is optionally substituted phenyl or optionally substituted naphthyl; and R 4 is alkyl (e.g. Ci_ 6 alkyl), haloalkyl, or G 2 ; G 2 is as described in the Summary and the Detailed Description sections, and any combination of L as described above.
  • L is S(O) 2 .
  • R 1 is optionally substituted cycloalkyl
  • R 4 is alkyl (e.g. Ci_6 alkyl), haloalkyl, or G 2 (e.g. C3-6 cycloalkyl); G 2 is as described in the Summary and the Detailed Description sections, and any combination of L as described above.
  • L is S(O) 2 .
  • Exemplary compounds include, but are not limited to,
  • N 3 [(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidene]-4-methoxyisophthalamide; N-[(5Z)-2-tert-butyl-4-(4-hydroxy-4-methylpentyl)isothiazol-5(2H)-ylidene]-2- fluoro-3-(trifluoromethyl)benzamide;
  • Stereoisomers of the present application may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom.
  • R and S used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the present application may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution which is well known to those of ordinary skill in the art.
  • Geometric isomers may exist in the present compounds. Geometric isomers and mixtures thereof resulting from the disposition of substituents around a carbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkyl group, or a heterocycle group are contemplated. Substituents around a carbon-carbon double bond or a carbon-nitrogen bond are designated as being of Z or E configuration and substituents around a cycloalkyl or a heterocycle are designated as being of cis or trans configuration. Compounds disclosed herein may exhibit the phenomenon of tautomerism.
  • Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 32 P, 35 S, 18 F, 36 Cl, and 125 I.
  • Compounds that contain other isotopes of these and/or other atoms are within the scope of this application.
  • the isotope-labeled compounds contain deuterium ( 2 H), tritium ( 3 H) or 14 C isotopes.
  • Isotope-labeled compounds can be prepared by the general methods well known to persons having ordinary skill in the art. Such isotope-labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples and Schemes sections by substituting a readily available isotope-labeled reagent for a non-labeled reagent.
  • compounds may be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuteric acid such as D 2 SO 4 ZD 2 O.
  • the isotope-labeled compounds may be used as standards to determine the effectiveness of CB2 ligands in binding assays.
  • Isotope containing compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)).
  • non-radio active isotope containing drugs such as deuterated drugs called “heavy drugs”
  • Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment.
  • Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %.
  • Stable isotope labeling of a drug may alter its physico-chemical properties such as pKa and lipid solubility. These effects and alterations may affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Accordingly, the incorporation of an isotope at a site of metabolism or enzymatic transformation will slow said reactions potentially altering the pharmcokinetic profile or efficacy relative to the non-istopic compound.
  • the compounds may be prepared by a variety of processes well known for the preparation of compounds of this class.
  • the compounds wherein the groups L, L 1 , A 1 , m, q, r, u, G 1 , G 2 , R a , R b , R c , R d , R Z1 , R Z3 , R Z5 , R Z2b , R Za , R 21 , R 1 , R la , R lg , R lh , R 2 , R 2a , R 3 , R 3a , and R 4 have the meanings as set forth in the summary section and in embodiments herein above unless otherwise noted, can be synthesized as shown in Schemes 1-14.
  • KOtBu potassium tert-butoxide
  • MeCN for acetonitrile
  • MeOH for methanol
  • NMP for N- methyl morpholine
  • PdCl 2 (PPh 3 ) 2 for bis(triphenylphosphine)palladium(II) dichloride
  • PdCl 2 (dppf) for [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
  • rt room temperature
  • TBAF for is tetrabutyl ammonium fluoride
  • TMSI for iodotrimethylsilane
  • TFA trifluoroacetic acid
  • THF for tetrahydrofuran.
  • Isothiazolylidene compounds of structure (3) can be prepared by reacting a substituted imine of structure (1) with an isothiocyanate of structure (2) in a solvent such as but not limited to tetrahydrofuran, diethylether, acetonitrile, dichloromethane or chloroform, at a temperature from about 0 0 C to about room temperature, for a period between about 1 and about 24 hours, followed by treatment with iodine or bromine, in a mixture of pyridine and methanol or ethanol, and subsequent treatment with sodium bicarbonate upon workup.
  • a solvent such as but not limited to tetrahydrofuran, diethylether, acetonitrile, dichloromethane or chloroform
  • Isothiocyanates of structure (2) can be synthesized by treating acid halides of formula R 1 C(O)X 1 wherein X 1 is halogen, with potassium thiocyanate in a solvent such as tetrahydrofuran, acetone, or mixture thereof, at ambient temperature.
  • the acid halides can be obtained from the corresponding acids using general procedures known to one skilled in the art, for example, by treating with thionyl chloride in a suitable solvent such as toluene, at a temperature from about room temperature to about the reflux temperature of the solvent used.
  • Imines of structure (1) can be obtained from treatment of aldehydes of formula R 2 CH 2 CHO with amines of formula R 4 NH 2 , optionally in the presence of an acid such as acetic acid, and optionally in the presence of a dehydrating agent such as magnesium sulfate, in a solvent such as dichloromethane.
  • the reaction can be conducted at about room temperature to about 60 0 C.
  • Aminoisothiazoles of structure (6) can be brominated with bromine in solvents such as benzene and/or acetic acid to provide compounds of formula (7).
  • Acylation of compounds of structure (7) with acid halides of formula R 1 COX 1 , in the presence of a base such as triethylamine and in solvents such as tetrahydrofuran or dichloro methane afford compounds of structure (8).
  • the transformation can be accomplished by treating compounds of structure (7) with acids of formula R 1 COOH in the presence of a coupling agent, a base and optionally a coupling auxiliary.
  • Examples of coupling reagents include, but are not limited to, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), 1,3- dicyclohexylcarbodiimide (DCC), polymer supported 1,3-dicyclohexylcarbodiimide (PS- DCC), O-(7-azabenzotriazol- 1 -yl)-N,N,N ' ,N ' -tetramethyluronium hexafluorophosphate (HATU), and O-benzotriazol- l-yl-N,N,N', N' -tetramethyluronium tetrafluoroborate (TBTU).
  • BOPCl bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • DCC 1,3- dicyclohexylcarbodiimide
  • PS- DCC polymer supported 1,3-dicyclohexylcarbodiimide
  • Examples of coupling auxiliarys include but are not limited to l-hydroxy-7-azabenzotriazole (HOAT) and 1-hydroxybenzotriazole hydrate (HOBT).
  • suitable bases include, but are not limited to, an organic base such as N-methyl morpholine or diisopropylethylamine, or an inorganic base such as sodium bicarbonate.
  • the coupling reaction can be carried out in a solvent such as chloroform, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, or mixtures thereof, at a temperature from about 0 0 C to about 50 0 C.
  • the conversion can be performed in a solvent such as dimethylacetamide with heating at a temperature from about 50 0 C to about 120 0 C.
  • Compounds of structure (11) can be obtained from compounds of structure (10) by (a) treatment with Lawesson's reagent, in a solvent such as toluene, at a temperature of about room temperature to about 80 0 C, and (b) treatment of the product from step (a) with mercury (II) acetate and cyanamide.
  • Compounds of formula (15) can be converted to compounds of formula (16) using the conditions described above for the conversion of compounds (7) to compounds (8).
  • Compounds of formula (15) can be converted to compounds of formula (17) by reaction with a reagent R 1 SO 2 Cl in the presence of a base such as, but not limited to, triethylamine or diethylisopropylamine and in a solvent such as, but not limited to, dichloromethane, tetrahydrofuran or dimethylformamide at room temperature to about 50 0 C.
  • a base such as, but not limited to, triethylamine or diethylisopropylamine
  • a solvent such as, but not limited to, dichloromethane, tetrahydrofuran or dimethylformamide at room temperature to about 50 0 C.
  • Compounds of formula (15) can be transformed to compounds of formula ( 19) by reaction with compounds of formula (18) in the presence of a base such as, but not limited to, triethylamine in solvents such as, but not limited to, ethanol, acetonitrile, tetrahydrofuran or toluene at temperatures from room temperature to about 100 0 C.
  • a base such as, but not limited to, triethylamine
  • solvents such as, but not limited to, ethanol, acetonitrile, tetrahydrofuran or toluene at temperatures from room temperature to about 100 0 C.
  • compounds of formula (15) can be transformed to compounds of formula (19) through the intermediate compounds (20).
  • Compounds of formula (15) can be converted to compounds of formula
  • the intermediate (20) can be treated with a boronic acid (HO) 2 B-R 1 in the presence of copper carboxylates (like commercially available copper acetate or copper 2- thiophenecarboxylate), a trialkylphosphite (e.g., triethylphosphite) and tris(dibenzylideneacetone)dipalladium(0) or other selected Pd(O) catalysts in dimethoxyethane (or other aprotic solvents) at 80-100 0 C for 12-24 hours to give compounds of formula (19).
  • copper carboxylates like commercially available copper acetate or copper 2- thiophenecarboxylate
  • a trialkylphosphite e.g., triethylphosphite
  • Compounds of formula (21) can be converted to compounds of formula (22) by reaction with an acid such as trifluoroacetic acid in a solvent such as dichloromethane or by reaction with hydrochloric acid.
  • the compounds of formula (22) can be converted to compounds of formula (23) wherein R 21 is alkyl, alkenyl, alkynyl, -C(O)(R la ), -SO 2 (R 2a ), -C(O)N(R Z3 )(R 3a ), -S(O) 2 N(R Z3 )(R 3a ), -(CR lg R lh ) u -G 2 , -(CR lg R lh ) u -CN, -(CR lg R lh ) u -O(R la ), and haloalkyl by a variety of transformations well known to those skilled in the art.
  • the substituent R 21 may be appended via the well-known reductive amination method by reaction with an appropriate aldehyde or ketone reagent in the presence of a reducing agent such as sodium cyanoborohydride.
  • a reducing agent such as sodium cyanoborohydride.
  • Another well-known method to transform (22) to (23) is by alkylation with a suitable halide, tosylate, mesylate or triflate reagent.
  • R 21 groups that can be appended in this manner are alkyl, alkenyl, alkynyl, -(CR lg R lh ) u -G 2 , -(CR lg R lh ) u -CN, -(CR lg R lh ) u -O(R la ), and haloalkyl.
  • R 21 groups such as -C(O)(R la ), -SO 2 (R 2a ), -C(O)N(R Z3 )(R 3a ) and -S(O) 2 N(R Z3 )(R 3a ) can be appended by reaction with appropriate acyl halides, sulfonyl halides, carbamoyl halides or isocyanates using conditions well-known to those skilled in the art.
  • Compounds of formula (24) can be converted to compounds of formula (25) by Standard synthetic transformations well known to those skilled in the art.
  • (24) can be converted to amines of formula (25) wherein R Z2b is hydrogen, alkyl, haloalkyl, G 1 or -(CR c R d )q-G 1 by displacement of the corresponding halide, mesylate or tosylate derived from (24) with an appropriate amine R zl R Z2b NH.
  • Compounds (24) can be converted to primary amine compounds (25) (R Z1 and R Z2b are each hydrogen) through displacement of the corresponding halide, mesylate or tosylate with an azide reagent and then reduction of the latter using methods well-known to those skilled in the art.
  • Compounds (25) wherein R Z1 and R Z2b are each hydrogen can be converted to compounds (25) wherein R Z1 or R Z2b are other than hydrogen by standard synthetic transformations involving reaction with carbonyl compounds (ie, reductive amination), alkyl halides, acyl halides, sulfonyl halides, isocyanates and the like.
  • Compounds of formula (24) can be converted to compounds of formula (26) by standard etherif ⁇ cation methods well-known to those skilled in the art.
  • compounds (26) can be prepared by displacement of the corresponding halide, mesylate or tosylate derived from (24) with an appropriate alcohol R Za -0H.
  • Reaction of compounds of formula (15) with isocyanates in a solvent such as, but not limited to, dichloromethane, toluene, dioxane, or dimethylformamide, at a temperature from about 25 0 C to about 150 0 C can provide compounds of formula (27) wherein R Z1 is hydrogen.
  • treatment of compounds of formula (15) with carbamylchlorides of formula ClCONR 21 R 25 in a solvent such as, but not limited to, dichloromethane, toluene, dioxane, or dimethylformamide, at a temperature from about 25 0 C to about 150 0 C can provide compounds of formula (27) wherein R 21 is other than hydrogen.
  • Reaction of compounds of formula (15) with chloro formates or fluoro formates in a solvent such as, but not limited to, dichloromethane, tetrahydrofuran, or dimethylformamide, in the presence of a base such as, but not limited to, triethylamine, at a temperature from about 25 0 C to about 50 0 C can provide compounds of formula (28) wherein R 25 is as defined in formula (I).
  • Reaction of compounds of formula (15) with 4-nitrophenylcarbonochloridate in a solvent such as, but not limited to, tetrahydrofuran or dichloromethane in the presence of a base such as, but not limited to, diisopropylethylamine or triethylamine, at about room temperature provides the intermediate (29).
  • the intermediate (29) can be converted to (27) by reaction with amines of formula HNR 21 R 25 in a solvent such as, but not limited to, tetrahydrofuran, acetonitrile, or dimethylformamide, at temperatures from about 25 0 C to about 150 0 C. This reaction may be facilitated with microwave irradiation.
  • Camphoric acid ((lR,3S)-l,2,2-trimethyl-l,3-cyclopentanedicarboxylic acid) can be reacted with phosphorus pentachloride in a solvent such as, but not limited to, hexane at a temperature from about room temperature to about 80 0 C to provide an intermediate bis acid chloride, that can be reacted sequentially with compound (15), followed by an alcohol HOR la , in a solvent such as tetrahydrofuran, in the presence of a base such as triethylamine, to provide a mixture of (30) and (31).
  • the mixture of (30) and (31) can be separated by silica gel chromatography.
  • the foregoing sequence can also be conducted starting from (-) camphoric acid using the same conditions to provide analogous products with the opposite stereochemistries.
  • Compounds of formula (30), wherein R , 1a a is alkyl, can be reacted with an alkali metal hydroxide (e.g., potassium hydroxide) in aqueous alcohol solvent (e.g., water-ethanol) at temperatures from about room temperature to about 80 0 C to provide the carboxylic acid compounds (32).
  • an alkali metal hydroxide e.g., potassium hydroxide
  • aqueous alcohol solvent e.g., water-ethanol
  • Compounds of formula (32) can be transformed to compounds of formula (33) by reaction with an amine HNR Z3 R 3a (or salt thereof) in a solvent such as, but not limited to, tetrahydrofuran or dimethylformamide in the presence of a coupling reagent such as N-(3- dimethylaminopropyl)-n'-ethylcarbodiimide hydrochloride (EDC), l,l '-carbonyldiimidazole (CDI), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), 1,3-dicyclohexylcarbodiimide (DCC), polymer supported 1,3-dicyclohexylcarbodiimide (PS-DCC), O-(7-azabenzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), or O-benzotriazol
  • the reaction is generally conducted in the presence or absence of a base such as, but not limited to, N-methyl morpholine, triethylamine, or diisopropylethylamine.
  • a base such as, but not limited to, N-methyl morpholine, triethylamine, or diisopropylethylamine.
  • Compounds of formula (33) wherein R 3a is hydroxyalkyl can be converted to the corresponding oxazolines by reaction with para-toluenesulfonyl chloride, N,N-dimethylaminopyridine and triethylamine.
  • Compounds of formula (32) can be reacted under Curtius-type rearrangement conditions, well known to those skilled in the art, to provide the corresponding amines, carbamates, ureas, or amides according to the choice of reaction conditions.
  • Compounds of formula (35), wherein L, L 1 , R 2 , R 3 and R 4 are as defined in formula (I); A 10 is A 1 or a chemical derivative or precursor thereof, R G1 represents the optional substituents of G 1 as defined in formula (I), and z is 0, 1, 2, 3, or 4, can be prepared from compounds of formula (34) by reaction with either an alcohol HO-A 10 or an amine HN(R Z3 )(A 10 ) in the presence or absence of a base such as, but not limited to, potassium tert- butoxide, sodium tert-butoxide, or triethylamine in a solvent such as, but not limited to, tetrahydrofuran or dimethylformamide at temperatures between about 0 0 C and 150 0 C.
  • the reaction with HN(R Z3 )(A 10 ) may be facilitated with microwave irradition.
  • reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Reactions may be worked up in the convention manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.
  • Starting materials may be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.
  • an optically active form of a compound When an optically active form of a compound is required, it may be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
  • a pure geometric isomer of a compound when required, it may be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.
  • Example 1C 5 -chloro-2-methoxvbenzoyl isothiocyanate The product of Example IB ( ⁇ 60 mmol) and KSCN (5.83 g, 60 mmol) were mixed in anhydrous tetrahydrofuran (25 mL) and anhydrous acetone (40 mL) and stirred at room temperature for 2 hrs. The reaction was diluted with diethyl ether (100 mL), filtered through celite and solvents evaporated in vacuo to provide the title compound.
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ 3.95 (s, 3H), 6.95 (d, IH), 7.52 (dd, IH), 7.84 (d, IH).
  • Example IA ⁇ /-[(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidenel-5-chloro-2-methoxybenzamide
  • tetrahydrofuran 10 mL
  • N2 tetrahydrofuran
  • the crude was flash chromatographed, eluting with diethyl ether:CH2Cl2:hexane (7:3:3) to provide 2.68 g of the desired product with impurities running above and below.
  • This material was dissolved in a minimum of CH2CI2, hexane added until slightly cloudy and allowed to sit for 4 hours.
  • a white crystalline solid was collected and washed with cold 1 :1 C ⁇ C ⁇ hexane to provide 962.78 mg of the title compound.
  • the mother liquor was recrystallized from methanol to provide 555 mg additional title compound.
  • Example 4A hexahydro-2,5-methanopentalene-3a(lH)-carbonyl chloride 3-Noradamantane carboxylic acid (4.99 g, 30.1 mmol) and SOCl 2 (5 mL, 69 mmol) in toluene (5 mL) were heated to 65 0 C until vigorous evolution of gas commenced. The heating bath was removed for 5-10 minutes until gas evolution had moderated. Heating the reaction again at 65 0 C was resumed for 2 hours. The reaction was cooled to room temperature, the volatiles removed in vacuo and toluene added and evaporated (2x) to remove excess SOCl 2 . The crude acid chloride was used without further purification.
  • Example 4B The product of Example 4B (1.29 g, 3.79 mmol), K 2 CO 3 (0.85 g) and iodomethane (1.2 mL, 5 equiv.) in a mixture of acetonitrile (10 mL), tetrahydrofuran (10 mL) and CH 2 Cl 2 (3 mL) were stirred overnight at room temperature, treated with additional iodomethane (1.2 mL), heated to 65 0 C for 3 h then stirred overnight at room temperature. The reaction was evaporated in vacuo, partitioned between H 2 O/CH 2 C1 2 and the aqueous extracted again (2x) with CH 2 Cl 2 . The organics were dried (MgSO 4 ), filtered and solvent evaporated.
  • the reaction was stirred under N 2 for 1 h, filtered through a 0.45 ⁇ m PFTE filter, washed with 0.5 ml dry CH 2 Cl 2 , diluted with 2 mL tetrahydrofuran, and treated with Example 1C (703 mg, 3.09 mmol) with continued stirring.
  • the reaction was treated with I 2 (750 mg), methanol (5 mL) and pyridine (1 mL) and continued stirring at room temperature for Ih.
  • the reaction was partitioned between saturated NaHCOs/diethyl ether and stirred overnight. The layers were separated and the aqueous was extracted again with diethyl ether. The combined organic extracts were dried (MgSO 4 ), filtered and solvent evaporated.
  • the crude was flash chromatographed on silica gel, eluting with diethyl ether:CH 2 Cl 2 :hexane (7:1 :3) to provide 88.9 mg of the desired product with slight impurity.
  • the product was chromatographed a second time using an Analogix® IT280TM instrument using an SF15-12g column, gradient eluting with ethyl acetate:hexane (0:100 to 50:50) over 20 minutes to provide 75 mg of the title compound.
  • Example 6A ⁇ /-[(5Z)-4-allyl-2-tert-butylisothiazol-5(2H)-ylidenel-5-chloro-2-methoxybenzamide
  • the title compound was prepared using the procedure as described in Example ID, substituting Example 6A for Example IA.
  • the product was purified by chromatography using an Analogix® IT280TM over a SF40-115 g column, gradient eluting with ethyl acetate :hexane (0:100 to 50:50 over 20 minutes, then 10 minutes at 50:50) to provide 1.1 g of material that contained some small impurities.
  • Example HC N-r(5Z)-2-tert-butyl-4-(2-(rtert-butyl( ' dimethv ⁇ silylloxylethv ⁇ isothiazol-5( ' 2H)-ylidenel-5- chloro-2-methoxybenzamide
  • the title compound was prepared using the procedure as described in Example ID substituting Example 1 IB for IA.
  • Example 16A N-r(5Z)-4-(2-aminoethv ⁇ -2-tert-butylisothiazol-5(2H)-ylidene1-5-chloro-2- methoxybenzamide
  • EtOH 10 mL
  • Example 16 A The product from Example 16 A (60 mg, 0.16 mmol) in CH 2 Cl 2 (10 mL) was treated with paraformaldehyde (60 mg) and sodium boroneacetate (44 mg, 0.16 mmol). The mixture was stirred at rt for 12 hrs. Diluted with H 2 O, the mixture was extracted with CH 2 Cl 2 (Ix). The organics were combined, dried (MgSO ), filtered and solvent evaporated.
  • the residue was purified by reverse phase preparative HPLC on a Waters Symmetry C 8 column (25 mm x 100 mm, 7 ⁇ m particle size) using a gradient of 10 % to 100 % acetonitrile:0.1 % aqueous trifluoroacetic acid over 8 minutes (10 minutes run time) at a flow rate of 40 niL/minutes to afford 13 mg (20 %) of the title compound.
  • the residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm x 100 mm, 7 ⁇ m particle size) using a gradient of 10 % to 100 % acetonitrile:0.1 % aqueous trifluoroacetic acid over 8 minutes (10 minutes run time) at a flow rate of 40 mL/minutes to afford 29 mg (22 %) of the title compound.
  • Example 15A The product from Example 15A (50 mg, 0.13 mmol) in NMP (1 mL) was treated with hydroxylamine hydrochloride (18 mg, 0.26 mmol). The mixture was heated at 100 0 C in a microwave reactor (300W, CEM Explorer®) for 15 min. The crude mixture was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm x 100 mm, 7 ⁇ m particle size) using a gradient of 10 % to 100 % acetonitrile:0.1 % aqueous trifluoroacetic acid over 8 minutes (10 minutes run time) at a flow rate of 40 niL/minute to afford the title compound.
  • Example 20 N-r(5Z)-2-tert-butyl-4-(2.3-dihvdroxypropy ⁇ isothiazol-5(2H)-ylidene1-5-chloro-2- methoxybenzamide
  • the product from Example 6B 160 mg, 0.44 mmol) in acetone (3 mL) and water (0.5 mL) was treated with 4-methymorpholine N-oxide (154 mg, 1.32 mmol) and osmium tetroxide (6 mg, 0.02 mmol). The mixture was stirred at rt for 12 hrs, quenched with saturated aqueous Na 2 S 2 O 3 and extracted twice with isopropanol/ CH 2 Cl 2 (1 :3).
  • Example 6B The product from Example 6B (200 mg, 0.55 mmol) in acetone (6 mL) and water (3 mL) was treated with osmium tetroxide (5 mg, 0.02 mmol). The mixture was stirred at rt for 10 min, then to the mixture was added sodium periodate (258 mg, 1.2 mmol) in portions. The reaction was stirred at rt for 12 hrs, quenched with saturated aqueous Na 2 S 2 O 3 and extracted twice with isopropanol/ CH 2 Cl 2 (1 :3). The organics were combined, dried (MgSO ), filtered and solvent evaporated.
  • osmium tetroxide 5 mg, 0.02 mmol
  • Example 2 N- IY5ZV2-tert-butyl-4- r(methoxyimino)methyl1isothiazol-5 (2HV ylidenei -5 -chloro-2- methoxybenzamide The title compound was prepared using the procedure as described in Example 15B substituting Example 21 A for Example 15 A.
  • Example 21 A The product from Example 21 A (50 mg, 0.14 mmol) in THF (5 mL) was cooled to - 40 0 C. To the solution was dropwise added isopropylmagnesium bromide (3 M) (94 ⁇ L, 0.28 mmol). The reaction was kept at -40 0 C for 30 min, quenched with saturated aqueous NH 4 Cl, and the mixture was extracted with EtOAc (2x). The organics were combined, dried (MgSO 4 ), filtered and solvent evaporated.
  • 3 M isopropylmagnesium bromide
  • the residue was purified by reverse phase preparative HPLC on a Waters Symmetry C 8 column (25 mm x 100 mm, 7 ⁇ m particle size) using a gradient of 10 % to 100 % acetonitrile:0.1 % aqueous trifluoroacetic acid over 8 minutes (10 minutes run time) at a flow rate of 40 mL/minute to afford 7.8 mg (14 %) of the title compound.
  • Example 25B A solution of Example 25B (200 mg, 0.53 mmol) was added to the reaction mixture, which was allowed to warm to room temperature and stir overnight. The reaction was quenched with NH 4 Cl then acetone and extracted with EtOAc (2X). The organics were combined, dried (MgSO 4 ), filtered and solvent evaporated. The residue was purified by column chromatography using an Analogix® Intelliflash280 TM (SiO 2 , 0-50% Hexane in ethyl acetate) to afford 159 mg (77 %) of the title compound.
  • Example 21 The title compound was prepared using the procedure as described in Example 21 A substituting hept-6-enenitrile for Example 6B.
  • Example 35 ⁇ /-r(5Z)-4-benzyl-2-tert-butylisothiazol-5(2H)-ylidenel-5-chloro-2-methoxybenzamide
  • TFA 0.5 mL
  • triethylsilane 54 mg, 0.5 mmol
  • Example 36 A O- ⁇ 1 - ⁇ (5Z)-2-tert-buty ⁇ -5- ⁇ r(5-chloro-2-methoxyphenyl)carbonvHimino
  • the product from Example 33 (32 mg, 0.07 mmol) in CH 2 Cl 2 (5 mL) containing pyridine (17 mg, 0.2 mmol) was treated dropwise with O-phenyl carbonochloridothioate (18 mg, 0.11 mmol).
  • Example 36 A The product from Example 36 A (32 mg, 0.06 mmol) was immediately treated with 2mL (0.03 mmol) of a stock solution of AIBN (12 mg (0.073 mmol in 5 mL of anhydrous toluene)) and tributylstannane (33.3 mg, 0.114 mmol), and the resulting mixture was heated to 85-90 0 C. After 30 min, additional tributylstannane (33.3 mg, 0.114 mmol) and AIBN stock solution (1 mL) were added.
  • AIBN (12 mg (0.073 mmol in 5 mL of anhydrous toluene)
  • tributylstannane 33.3 mg, 0.114 mmol
  • Example 37 A O- ⁇ 1 - ⁇ (5Z)-2-tert-buty ⁇ -5- ⁇ [(5-chloro-2-methoxyphenyl)carbonyllimino
  • the title compound was prepared using the procedure as described in Example 36A substituting Example 23 for Example 33.
  • Example 37B N-r(5Z)-2-tert-butyl-4-isobutylisothiazol-5(2H)-ylidenel-5-chloro-2-methoxybenzamide The title compound was prepared using the procedure as described in Example 36B substituting Example 37A for Example 36A.
  • Example 38 A Q- ⁇ [(5Z)-2-tert-butyl-5- ⁇ [(5-chloro-2-methoxyphenyl)carbonyllimino
  • the title compound was prepared using the procedure as described in Example 36A substituting Example 34 for Example 33.
  • Example 38B N-r(5Z)-2-tert-butyl-4-(cvclobutylmethv ⁇ isothiazol-5(2H)-ylidene1-5-chloro-2- methoxybenzamide The title compound was prepared using the procedure as described in Example 36B substituting Example 38A for Example 36A.
  • N-r(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidenel-2,5-dimethoxybenzamide A mixture of the product from Example HOB (400 mg), 2,5-dimethoxybenzoic acid (86 mg, 0.47 mmol), EDCI (181 mg, 0.94 mmol), HOBt (145 mg, 0.94 mmol) and DMAP (12 mg, 0.1 mmol) in pyridine (1OmL) was stirred at rt for 1 hr. The solvent was removed in vacuo, the mixture diluted with water, and extracted with EtOAc. The organic extract was dried (Na 2 SO 4 ), filtered and concentrated.
  • Example 42 N-[(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidenel-5-fluoro-2-methoxybenzamide The title compound was prepared using the procedure as described in Example 41 substituting 5-fluoro-2-methoxybenzoic acid for 2,5-dimethoxybenzoic acid.
  • Example 47A ⁇ /-r(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidenel-5-chloro-2-fluorobenzamide
  • the residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm x 100 mm, 7 ⁇ m particle size) using a gradient of 10 % to 100 % acetonitrile:0.1 % aqueous trifluoroacetic acid over 8 minutes (10 minutes run time) at a flow rate of 40 niL/minute to afford 34 mg (28 %) of the title compound.
  • Example 5OD ethyl [(5Z)-2-tert-butyl-4-(furan-2-ylmethyl)isothiazol-5(2H)-ylidenelcarbamate The title compound was prepared using the procedure as described in Example ID substituting Example 5OC for Example IA and o-ethyl carbonisothiocyanatidate for Example 1C.
  • Example 52A Q- ⁇ r(5Z)-2-tert-butyl-5- ⁇ r(5-chloro-2-methoxyphenyl)carbonyllimino
  • Example 53 A 3-(thiophen-2-yl)propan- 1 -ol The title compound was prepared using the procedure as described in Example 5OA substituting 3-(thiophen-2-yl)propanoic acid for 3-(furan-2-yl)propanoic acid. MS (DCI/NH 4 + ) m/z 143 (M + H) + .
  • Example 53D ethyl r(5Z)-2-fert-butyl-4-(thiophen-2-ylmethyl)isothiazol-5 (2H)-ylidenel carbamate
  • the title compound was prepared using the procedure as described in Example ID substituting Example 53C for Example IA and o-ethyl carbonisothiocyanatidate for Example ICMS (DCI/N ⁇ 4 + ) m/z 325 (M + H) + .
  • Example 54 N-r(5Z)-2-tert-butyl-4-(thien-2-ylmethv ⁇ isothiazol-5(2H)-ylidene1-5-chloro-2- methoxybenzamide
  • the title compound was prepared using the procedure as described in Example 41 substituting Example 53E for Example HOB and 5-chloro-2-methoxybenzoic acid for 2,5- dimethoxybenzoic acid.
  • Example HOB The title compound was prepared from Example HOB using the procedure as described in Example 41 substituting 5-(tert-butoxycarbonylamino)-2-methoxybenzoic acid for 2,5-dimethoxybenzoic acid.
  • Example 55 A The product from Example 55 A (71mg, 0.15 mmol) was treated with TFA (1 mL) at rt for 10 min, solvent removed and the mixture treated with saturated aqueous NaHCO 3 , and extracted with EtOAc (2X). The organic layer was dried over MgSO 4 , filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intellifiash280 TM (SiO 2 , 0-50% Hexane in ethyl acetate) to afford 51 mg (92 %) of the title compound.
  • Example 56A A mixture of Example 56A (350 mg, 0.97 mmol) and cesium carbonate (375 mg, 1.94 mmol) in DMF (20 mL) was treated with iodomethane (165 mg, 1.17 mmol). The mixture was stirred at rt for 2 hrs, diluted with H 2 O and extracted with EtOAc (2X). The organic layer was dried over MgSO 4 , filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280 TM (SiO 2 , 0-50% Hexane in ethyl acetate) to afford 246 mg (68 %) of the title compound.
  • Aqueous sodium hydroxide (6M) (85 ⁇ L) was added dropwise to a stirred solution of urea hydrogen peroxide (223 mg, 2.4 mmol) and Example 56B (100 mg, 0.267 mmol) in
  • Example 61 N-r(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidenel-5-iodo-2-methoxvbenzamide
  • the title compound was prepared from Example HOB using the procedure as described in Example 41 substituting 5-iodo-2-methoxybenzoic acid for 2,5- dimethoxybenzoic acid.
  • Example 62B N-r(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidenel-5-ethvnyl-2-methoxybenzamide
  • THF 10 mL
  • Example HOB The title compound was prepared from Example HOB using the procedure as described in Example 41 substituting 5-acetyl-2-hydroxybenzoic acid for 2,5- dimethoxybenzoic acid. MS (DCI/N ⁇ 4 + ) m/z 375 (M + H) + .
  • Example 56B The title compound was prepared using the procedure as described in Example 56B substituting Example 64A for Example 56A.
  • Example 56B The product from Example 56B (140 mg, 0.37 mmol) was dissolved in CH 2 Cl 2 (4 mL), treated with DAST (121 mg, 0.75 mmol) and a drop of MeOH to catalyze the reaction. The mixture was stirred at rt for 12 hrs, quenched with saturated aqueous NaHCO 3 and extracted with CH 2 Cl 2 (2X). The combined organic layers were dried over MgSO 4 , filtered and concentrated.
  • the residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm x 100 mm, 7 ⁇ m particle size) using a gradient of 10 % to 100 % acetonitrile:0.1 % aqueous trifluoroacetic acid over 8 minutes (10 minutes run time) at a flow rate of 40 niL/minute to afford the title compound.
  • Example 75A 6-oxoheptanal The title compound was prepared using the procedure as described in Example 21 A substituting 1-methylcyclohex-l-ene for Example 6B.
  • Example 75 C ethyl [(5Z)-2-ferf-butyl-4-(4-oxopentyl)isothiazol-5(2H)-ylidene] carbamate
  • the title compound was prepared using the procedure as described in Example ID substituting Example 75B for Example IA and o-ethyl carbonisothiocyanatidate for Example 1C.
  • Example 75E N-r(5Z)-2-tert-butyl-4-(4-oxopentv ⁇ isothiazol-5(2H)-ylidene1-5-chloro-2- methoxybenzamide The title compound was prepared using the procedure as described in Example 41 substituting Example 75D for Example HOB.
  • Example 26E The product from Example 26E (110 mg, 0.3 mmol) was treated with concentrated sulfuric acid (ImL). The mixture was heated at 40 0 C for 1 hr, diluted with H 2 O, neutralized with saturated Na 2 CO 3 , and extracted with EtOAc (2X). The combined organic layers were dried over MgSO 4 , filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280 TM (SiO 2 , 0-50% Hexane in ethyl acetate) to afford 107 mg (93 %) of the title compound.
  • Example 80 The product from Example 80 (50 mg, 0.12 mmol) in CH 2 Cl 2 (4 mL) was treated with DAST (38 mg, 0.24 mmol) at -78 0 C. The mixture was stirred at -78 0 C for 1.5 hrs, quenched with saturated aqueous NaHCO 3 and extracted with CH 2 Cl 2 (2X). The combined organic layers were dried over MgSO 4 , filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280 TM (SiO 2 , 0-50% Hexane in ethyl acetate) to afford 29 mg (58 %) of the title compound.
  • DAST 38 mg, 0.24 mmol
  • Example 84A 5-oxohexanal The title compound was prepared using the procedure as described in Example 21 A substituting 1-methylcyclopent-l-ene for Example 6B.
  • Example 84B for Example IA and o-ethyl carbonisothiocyanatidate for Example 1C.
  • Example 28A The product from Example 28A (300 mg, 0.85 mmol) in CH 2 Cl 2 (10 mL) containing triethylamine (257 mg, 2.54 mmol) was treated with methanesulfonyl chloride (145 mg, 1.27 mmol) at 0 0 C. The mixture was stirred for 30 min at 0 0 C, diluted with water and extracted with CH 2 Cl 2 (2X). The combined organic layers were dried over MgSO 4 , filtered and concentrated to afford the title compound.
  • Example 86 N-r(5Z)-2-tert-butyl-4-(4.4-difluoropentv ⁇ isothiazol-5(2H)-ylidene1-5-chloro-2- methoxybenzamide The title compound was prepared using the procedure as described in Example 69 substituting Example 75E for Example 64B.
  • Example 87A The title compound was prepared using the procedure as described in Example 83 substituting Example 87A for Example 80.
  • Example 85A The title compounds was obtained from Example 85A using the procedure as described in Example 85B substituting (R)-(tetrahydrofuran-2-yl)methanol for 2,2,2- trifiuoroethanol.
  • Example 85A The title compounds was obtained from Example 85A using the procedure as described in Example 85B substituting 2-fluoroethanol for 2,2,2-trifluoroethanol.
  • Example 85A The title compounds was obtained from Example 85A using the procedure as described in Example 85B substituting 2,2-difluoroethanol for 2,2,2-trifluoroethanol.
  • Example 92A ethyl r(5Z)-4-butyl-2-ferf-butylisothiazol-5 (2H)-ylidenel carbamate
  • hexanal Aldrich, 20.0 g, 200 mmol
  • acetonitrile 20 mL
  • t-butylamine Aldrich, 16.1 g, 220 mmol
  • the mixture was stirred at room temperature overnight.
  • the solids were removed by vacuum filtration through a glass frit and the liquor was concentrated by rotary evaporator to give the crude imine as a pale yellow oil.
  • the crude imine was dissolved in anhydrous tetrahydrofuran (200 mL) containing pyridine (Aldrich, 15.8 g, 200 mmol) and 0-ethyl carbonisothiocyanatidate (Aldrich, 15.7 g, 120 mmol) was added dropwise. The resulting yellow mixture was stirred at room temperature for 1 hour. Anhydrous methanol (100 mL) and iodine (Aldrich, 30.5 g, 120 mmol) were added to form a brown slurry. The mixture was stirred at room temperature for 2 hours. The excess iodine was quenched by addition of solid sodium metabisulfite until the mixture changed to yellow.
  • Example 92 A To a 250-mL, round-bottomed flask containing a magnetic stir bar were added the product from Example 92 A (7.11 g, 25.0 mmol) and chloroform (100 mL). Neat iodotrimethylsilane (Aldrich, 6.25 g, 31.1 mmol) was added. A reflux condenser with nitrogen inlet was attached and a heating mantle was applied. The yellow reaction mixture was heated to 60 0 C and stirred overnight. After cooling to room temperature, saturated aqueous sodium bicarbonate solution was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 50 mL).
  • Neat triethylamine (Aldrich, 1.09 g, 10.8 mmOl) was added via syringe to form a tan solution.
  • the reaction flask was heated to 60 0 C in a shaker block and mixed for 2 hours. The volatiles were removed by rotary evaporator to give a brown oil.
  • the product was purified by flash chromatography (silica gel: 2-20% ethyl acetate in hexanes) to afford the title compound.
  • Example 92B The product from Example 92B and racemic 3-(methoxycarbonyl)-2,2,3- trimethylcyclopentanecarboxylic (Maybridge) were processed using the method described in Example 92C to afford the title compound.
  • 1 H NMR (DMSO-J 6 ) ⁇ ppm 0.53 (s, 3H), 0.90 (t, J 7.3 Hz, 3H), 1.20 (s, 3H), 1.23 (s, 3H), 1.23-1.40 (m, 2H), 1.41-1.50 (m, IH), 1.57 (s, 9H), 1.57-1.67 (m, 2H), 1.71-1.84 (m, IH), 2.24-2.36 (m, IH), 2.41-2.48 (m, IH), 2.61-2.67 (m, 2H), 3.00-3.06 (m, IH), 3.59 (s, 3H), 8.51 (s, IH).
  • Example 92B The product from Example 92B and 1-phenylcyclohexanecarboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound.
  • 1 H NMR (DMSO-J 6 ) ⁇ ppm 0.90 (t, J 7.3 Hz, 3H), 1.20-1.77 (m, 21H), 2.61-2.69 (m, 4H), 7.10-7.15 (m, IH), 7.21-7.27 (m, 2H), 7.35-7.39 (m, 2H), 8.51 (s, IH).
  • MS (ESI+) m/z 399 (M+H) + Anal, calcd. for C 24 H 34 N 2 OS: C, 72.32; H, 8.60; N, 7.03. Found: C, 72.24; H, 8.59; N, 7.10.
  • Example 92B The product from Example 92B and (2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid (Acros) were processed using the method described in Example 92C to afford the title compound.
  • Example 92B The product from Example 92B and 3-oxocyclopentanecarboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound.
  • 1 H NMR (DMSO-J 6 ) ⁇ ppm 0.91 (t, J 7.5 Hz, 3H), 1.25-1.36 (m, 2H), 1.57 (s, 9H), 1.55-1.84 (m, 2H), 1.98-2.06 (m, IH), 2.13-2.28 (m, 3H), 2.39-2.42 (m, 2H), 2.61-2.66 (m, 2H), 3.27- 3.34 (m, IH), 8.55 (s, IH).
  • Example 96 and 3,3-difluoroazetidine hydrochloride were processed using the method described in Example 99 to afford the title compound.
  • 1 H NMR (DMSO-J 6 ) ⁇ ppm 0.51 (s, 3H), 0.90 (t, J 7.3 Hz, 3H), 1.22 (s, 3H), 1.25 (s, 3H), 1.26-1.36 (m, 2H), 1.39-1.48 (m, 1H),1.57 (s, 9H), 1.57-1.78 (m, 3H), 1.93-2.07 (m, IH), 2.62-2.67 (m, 2H), 2.72-2.83 (m, IH), 2.88-2.94 (m, IH), 4.14-4.37 (m, 2H), 4.41-4.52 (m, IH), 4.73-4.86 (m, IH), 8.50 (s, IH).
  • Example 104A tert-butyl 3- ⁇ r(5Z)-4-butyl-2-fert-butylisothiazol-5(2H)-ylidenelcarbamovUpyrrolidine-l- carboxylate
  • the product from Example 92B and l-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound.
  • MS (ESI+) m/z 410 (M+ ⁇ ) + MS (ESI+) m/z 410 (M+ ⁇ ) + .
  • Example 104C ethyl 3 -( ⁇
  • the product from Example 104B and ethylchloro formate (Aldrich) were processed using the method described in Example 102 to afford the title compound.
  • Example 105 3-((r(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidene1aminolcarbonyl)-1.2.2- trimethylcyclopentanecarboxylic acid
  • the product from Example 93 was processed using the method described in Example
  • Example 92B The product from Example 92B and l-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound.
  • 1 H NMR (DMSO-J 6 ) ⁇ 0.91 (t, J 7.3 Hz, 3H), 1.27-1.35 (m, 2H), 1.39 (s, 9H),
  • Example 108 methyl 4-((r(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)- ylidenelaminol carbonyl)bicvclor2.2.21octane- 1 -carboxylate
  • the product from Example 92B and 4-(methoxycarbonyl)bicyclo[2.2.2]octane-l- carboxylic acid (Oakwood) were processed using the method described in Example 92C to afford the title compound.
  • Example 109 N-r(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidenel-5-oxo-l-phenylpyrrolidine-3- carboxamide The product from Example 92B and 5-oxo-l-phenylpyrrolidine-3-carboxylic acid
  • Example HOA ethyl r(5Z)-4-butyl-2-ferf-butylisothiazol-5 (2H)-ylidenel carbamate To a solution of Example IA (4.2 g, 27 mmol) in THF (100 niL) at room temperature under N 2 was added O-ethyl carbonisothiocyanatidate (3.55 g, 27 mmol). The reaction mixture was stirred for 1 hour and iodine (6.8 g, 27 mmol), MeOH (100 mL) and pyridine (10 mL) were added. The reaction mixture was stirred for 2 hours. The reaction mixture was poured into saturated NaHCOsZEt 2 O and stirred for 30 minutes.
  • Example HOA A solution of Example HOA (3.95 g, 13.89 mmol) in chloroform (35 mL) was treated with TMSI (2.65 mL, 19.5 mmol). The reaction mixture was stirred at 65 0 C for 8 hours, cooled to room temperature, quenched with water and extracted between CH 2 Cl 2 and saturated NaHCO 3 , dried (MgSO 4 ) and concentrated to give the title compound (2.45g , 83% yield).
  • Example HOB A mixture of Example HOB (2.06g, 9.71 mmol) and dimethyl cyanocarbonimidodithioate (1.36 g, 9.3 mmol) in THF (35 mL) was treated with Et 3 N (0.98 g, 9.71 mmol) and stirred at 45 0 C for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by chromatography (hexane-EtOAc 1 : 1) to afford 1.65g, (55% yield) of the title compound.
  • Example HOC To a mixture of Example HOC (0.67 g, 2.15 mol), 2-methoxy-5-chlorophenylboronic acid (1.046 g, 5.6 mmol), copper(I)acetate (0.794 g, 6.47 mmol) in dimethoxyethane (35 mL) were added tris(dibenzylideneacetone)dipalladium(0) 0.289 g, 0.315 mmol) and triethyl phosphite (0.170 mg, 1.0 mmol) and the mixture was refluxed for 16 h. The mixture was then concentrated under reduced pressure and the residue was chromatographed (hexane-EtOAc 1 : 1) to afford 550 mg (62% yield) of the title compound.
  • Example ID (380mg, 1 mmol) in toluene (25mL) was added P 2 S 5 (220mg, 1 mmol) and the reaction mixture was heated at 82 0 C for 75 minutes, concentrated under reduced pressure and purified via column chromatography (SiO 2 , 0-25% EtOAc in hexanes) to provide the title compound (0.14 g, 34% yield).

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Abstract

La présente invention porte sur des composés contenant de l'isothiazolylidène de formule (I) dans laquelle R1, R2, R3, R4, et L sont tels que définis dans la description, sur des compositions comprenant de tels composés et sur des méthodes permettant de traiter des pathologies et des troubles à l'aide de tels composés et de telles compositions.
EP09752053A 2008-11-04 2009-11-04 Nouveaux composés en tant que ligands des récepteurs cannabinoïdes Withdrawn EP2344463A2 (fr)

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CA2647598A1 (fr) 2006-05-31 2007-12-06 Abbott Laboratories Nouveaux composes constituant des ligands de recepteurs cannabinoides et utilisations de ces composes
US8841334B2 (en) 2006-05-31 2014-09-23 Abbvie Inc. Compounds as cannabinoid receptor ligands and uses thereof
CA2681586A1 (fr) 2007-03-28 2008-10-09 Abbott Laboratories Nouveaux composes en tant que ligands de recepteurs cannabinoides
US7872033B2 (en) 2007-04-17 2011-01-18 Abbott Laboratories Compounds as cannabinoid receptor ligands
US8501794B2 (en) * 2007-04-17 2013-08-06 Abbvie Inc. Compounds as cannabinoid receptor ligands
CN101711253A (zh) 2007-05-18 2010-05-19 雅培制药有限公司 用作大麻素受体配体的新化合物
US9193713B2 (en) 2007-10-12 2015-11-24 Abbvie Inc. Compounds as cannabinoid receptor ligands
US8846730B2 (en) 2008-09-08 2014-09-30 Abbvie Inc. Compounds as cannabinoid receptor ligands
EP2428507B1 (fr) 2008-09-16 2015-10-21 AbbVie Bahamas Ltd. Ligands du récepteur cannabinoïde
PA8854001A1 (es) 2008-12-16 2010-07-27 Abbott Lab Compuestos novedosos como ligandos de receptores de canabinoides
PT3619196T (pt) 2017-05-04 2022-07-06 Bayer Cropscience Ag Derivados de 2-{[2-(feniloximetil)piridin-5-il]oxi}-etanamina e compostos relacionados como agentes de controlo de pragas e.g. para a proteção de plantas
KR20210091690A (ko) * 2018-08-20 2021-07-22 베서, 파마 엘엘씨 신규 칸나비노이드 및 칸나비노이드 산 및 이의 유도체

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