WO2014028669A1 - Novel compounds for modulation of ror-gamma activity - Google Patents

Novel compounds for modulation of ror-gamma activity Download PDF

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WO2014028669A1
WO2014028669A1 PCT/US2013/055017 US2013055017W WO2014028669A1 WO 2014028669 A1 WO2014028669 A1 WO 2014028669A1 US 2013055017 W US2013055017 W US 2013055017W WO 2014028669 A1 WO2014028669 A1 WO 2014028669A1
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optionally substituted
alkyl
compound
pharmaceutically acceptable
acceptable salt
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PCT/US2013/055017
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French (fr)
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Richard H. Hutchings
John Howard Jones
Jianhua Chao
Istvan J. Enyedy
Douglas MARCOTTE
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Biogen Idec Ma Inc.
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
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    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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    • C07C317/30—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07C2601/00—Systems containing only non-condensed rings
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    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/18—All rings being cycloaliphatic the ring system containing six carbon atoms
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    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
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    • C07C2602/50—Spiro compounds

Definitions

  • the present invention relates to aryl sulfones and related compounds that are modulators of ROR-gamma activity.
  • the invention also provides pharmaceutical compositions comprising these modulators. Also provided are methods of using these modulators to treat ROR-gamma mediated diseases.
  • Autoimmune diseases occur when the immune system attacks and destroys healthy body tissue.
  • Other inflammatory diseases such as asthma, do not necessarily result from a direct attack on healthy tissue but rather from improper or uncontrolled immune responses.
  • Agents that modulate the development and function of cells of the immune system can be useful as therapies for such diseases.
  • Nuclear receptors are a superfamily of ligand- regulated DNA-binding transcription factors that are expressed by many cell types and control a broad spectrum of physiological processes. Drugs that target nuclear receptors are used in the treatment of numerous human diseases. Pharmaceutical nuclear receptor agonists or antagonists, such as tamoxifen for oestrogen receptors (targeted in breast cancer), thiazolidinediones for peroxisome proliferator-activated receptor- ⁇ (PPARy) (targeted in type II diabetes), or dexamethasone for the glucocorticoid receptor (targeted in inflammatory diseases), are among the most commonly used drugs.
  • the nuclear receptor, RAR-related orphan receptor C (RORC, ROR-gamma, ROR-gamma-t, and RORy), is expressed in cells of the immune system and plays an important role in immune system function.
  • RORC nuclear receptor
  • ROR-gamma The nuclear receptor, ROR-related orphan receptor C
  • RORy The nuclear receptor, ROR-gamma, ROR-gamma-t, and RORy
  • RORC nuclear receptor, ROR-gamma, ROR-gamma-t, and RORy
  • the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula I:
  • a 1 , A 2 , A 3 , and A 4 are each independently C or N;
  • R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
  • R 2 and R 3 are each independently H, optionally substituted alkyl, optionally substituted C3-S cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R 2 and R 3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4a , R 4b , R 4c , and R 4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl;
  • R a and R are each independently H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl;
  • R 6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, R 6a and R 6b are each independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or R 6a and R 61 together form an optionally substituted heterocycloalkyl ring; or
  • R 40 and R 6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
  • the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula la:
  • X is SO or S0 2 ;
  • a 1 , A 2 , A 3 , and A 4 are each independently C or N;
  • R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
  • R 2 and R 3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R 2 and R 3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4a , R 4b , R 4c , and R 4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl;
  • R 6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or R 40 and R 6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
  • R 40 and R 6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring, as shown in Formula la 1 :
  • W 1 is CR 7a R 7b , NR 7c , or O;
  • W 2 and W 3 are each independently CR 7a R 7b , NR 7c , O, or a bond;
  • R 7a , R 7b , and R 7c are each independently H or C 1-4 alkyl.
  • the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula lb:
  • X is SO or S0 2 ;
  • a 1 , A 2 , A 3 , and A 4 are each independently C or N;
  • R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl
  • R 2 and R 3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R 2 and R 3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4a , R 4b , R 4c , and R 4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
  • R 6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or
  • R 40 and R 6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
  • the compounds of Formula I, Formula la, Formula la 1 , and Formula lb can include one or more of the following embodiments.
  • R 2 and R 3 together form cycloalkyl, cycloalkenyl,
  • cycloketonyl heterocyclyl, spirocyclyl, or bicyclyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, carboxyl, and acetyl.
  • R 2 and R 3 are each independently H, optionally substituted Ci-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted OCi_6 alkyl, CN, OH.
  • R 4c is H, optionally substituted Ci_6 alkyl, optionally substituted OCi_6 alkyl, optionally substituted carbocycle, halogen, CN, OH, or absent; and R 6 is optionally substituted alkyl, optionally substituted C2-6 alkenyl, optionally substituted carbocycle, or optionally substituted heterocycle.
  • R 40 is H, optionally substituted Ci_6 alkyl, optionally substituted OCi_6 alkyl, optionally substituted carbocycle, halogen, CN, OH, or absent; and R 6 is optionally substituted alkyl, optionally substituted C2-6 alkenyl, optionally substituted carbocycle, or optionally substituted heterocycle; and R 2 and R 3 together form cycloalkyl, cycloalkenyl, cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, carboxyl, and acetyl.
  • R 40 is H, optionally substituted Ci_6 alkyl, optionally substituted OCi_6 alkyl, optionally substituted carbocycle, halogen, CN, OH, or absent; and R 6 is optionally substituted alkyl, optionally substituted C 2 -6 alkenyl, optionally substituted carbocycle, or optionally substituted heterocycle; and R 2 and R 3 are each independently H, optionally substituted Ci_6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted Od_ 6 alkyl, CN, OH.
  • the invention includes a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a
  • the invention includes a method of modulating the activity of an ROR-gamma receptor with a modulator of ROR-gamma, comprising contacting the receptor with a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I modulates the activity of an ROR-gamma receptor in vitro. In another embodiment, the compound of Formula I modulates the activity of an ROR-gamma receptor in vivo. In one embodiment, the compound of Formula I is a modulator of the ROR-gamma receptor.
  • the invention includes a method of treating or reducing the severity of an ROR-gamma receptor mediated disease in a patient comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • an ROR-gamma receptor mediated disease can include an automimmune disease.
  • an autoimmune disease is selected from the group consisting of Ankylosing spondylitis, Asthma, Behcet's disease, Chronic obstructive pulmonary disease, Crohn's disease, Diabetes Mellitus Type 1, Multiple Sclerosis, Neuromyelitis optica, Polymyalgia Rheumatica, Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren's syndrome, Systemic Lupus Erythematosus, Systemic sclerosis, Transplant rejection, Inflammatory Bowel Disease, Ulcerative Colitis and Uveitis. DETAILED DESCRIPTION OF THE INVENTION
  • aliphatic encompasses the terms alkyl, alkenyl, alkynyl. Unless otherwise stated, aliphatic can include both substituted alkyl, alkenyl, and alkynyl and unsubstituted alkyl, alkenyl, and alkynyl.
  • an "alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6, 1-4, or 1, 2, 3, 4, 5, 6, 7, or 8) carbon atoms.
  • C 1-n alkyl refers to an alkyl group containing 1-n carbon atoms.
  • Ci-5 alkyl refers to an alkyl group containing 1, 2, 3, 4, or 5 carbon atoms.
  • An alkyl group can be straight or branched.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2- ethylhexyl.
  • an "alkenyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
  • an "alkynyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one triple bond. Like an alkyl group, an alkynyl group can be straight or branched.
  • an “amino” group refers to -NR X R Y wherein each of R x and R Y is independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl,
  • heterocycloalkyl alkyl, heteroaryl, or carbonyl each of which are defined herein.
  • amino groups include alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino,
  • sulfonylamino alkylamino, carbonylamino, carboxy, oxo, hydroxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylalkylcarbonyl, heteroarylcarbonyl, or heteroaralkylcarbonyl.
  • a "carbonyl” group when used alone or as part of another structure refers to -(CO)R x , where R x is defined above.
  • R x is defined above.
  • carbonyl is not the terminal group (e.g., arylaminoalkylcarbonyl) it is represented by -C(0)R x .
  • carbonyl groups can include optionally substituted aminocarbonyl, alkoxyalkoxycarbonyl, alkylaminocarbonyl, arylcarbonyl (e.g., haloarylcarbonyl), heterocycloalkylcarbonyl, heterocycloalkenylcarbonyl, arylaminocarbonyl (e.g., haloarylaminocarbonyl),
  • alkoxy arylcarbonyl e.g., haloalkoxyarylcarbonyl
  • alkylheterocyclo alkenylcarbonyl, heteroarylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl (e.g.,
  • haloalkoxycarbonyl alkylarylcarbonyl, cycloalkylcarbonyl, alkylheteroarylcarbonyl, arylsulfonylcarbonyl, aminocarbonyl, sulfonylcarbonyl, alkylcarbonyl,
  • R x and R Y include sulfonylaminocarbonyl, alkylcarbonyl, carbonylamino, carboxy, oxo, hydroxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylalkylcarbonyl, heteroarylcarbonyl, or
  • an "aryl” group used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to an aromatic monocyclic ring ((e.g., phenyl); an aromatic Cs-Cio bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl,
  • tetrahydroindenyl an aromatic C 10 -C 14 tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, anthracenyl, or tetrahydroanthracenyl); or a C 8 -C 14 benzofused group having 2-3 carbocyclic rings in which one or more of the rings are aromatic.
  • a benzofused group includes phenyl fused with two or more C 4 _8 carbocyclic moieties.
  • an "aralkyl” group refers to an alkyl group (e.g., a C 1-4 alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” are defined herein. An example of an aralkyl group is benzyl.
  • heteroaryl refers to an alkyl group that is substituted with a heteroaryl. Both “alkyl” and “heteroaryl” are defined herein.
  • cycloaliphatic means a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon ring that has a single point of attachment to the rest of the molecule. Cycloaliphatic rings are 3-8 membered monocyclic rings (e.g., 3-6 membered rings). Cycloaliphatic rings also include 8-12 membered bicyclic hydrocarbon rings, (e.g., 10 membered bicyclic hydrocarbon rings).
  • a cycloaliphatic group encompasses a "cycloalkyl” group and a "cycloalkenyl” group.
  • a "cycloalkyl” group refers to a saturated carbocyclic mono-, bi-, tri-, or multicyclic (fused or bridged) ring of 3-10 (e.g., 4-6, 5-10, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.
  • bicyclic cycloalkyl groups include octahydro-indenyl, decahydro- naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, bicycle[2.2.1]heptanyl, bicycle[3.1.1]heptanyl, or the like.
  • multicyclic groups include adamantyl, cubyl, norbornyl, or the like.
  • a "cycloalkenyl” group refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds.
  • Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl.
  • spiro refers to two rings joined by a single carbon atom common to both, wherein the spirocyclyl ring system has 3-14 (e.g., 4-6, 5-10, 6-12, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14) carbon atoms.
  • spirocyclyl groups include spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[2.5]octanyl, spiro[2.6]nonanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[3.6]decanyl, spiro[4.4]nonanyl, spiro[4.5]decanyl, spiro[4.6]undecanyl,
  • Carbocycle indicates a fully saturated, partially saturated, or unsaturated C 3-10 monocyclic or bicyclic ring having only carbon ring atoms.
  • Bicyclic carbocycles may be fused or spirocyclic ring systems.
  • C 3-10 carbocyclic groups include fully saturated cycloalkyl rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl rings); partially saturated carbocyclic groups (e.g., cyclopropene, cyclobutene, cyclopentene and cyclohexene rings); bicyclic moieties (e.g., indene, 2,3-dihydro-indene, and 1,2,3,4-tetrahydronaphthalene groups);
  • bridged moieties e.g., bicyclo[3.1.0]hexane, bicyclo[3.2.1]octane, and bicyclo[3.1 .ljheptane groups
  • spirocyclic carbocycles e.g., spiro[2.3]hexane, spiro[2.4]hexane
  • Unsaturated carbocyclic moieties include phenyl and naphthyl groups.
  • heterocycles includes each possible atomic orientation for the groups listed.
  • oxadiazole includes 1,2,3-oxadiazole, 1,3,4-oxadiazole and 1,2,4-oxadiazole
  • thiadiazole includes 1,2,3- thiadiazole, 1,3,4-thiadiazole and 1,2,4-thiadiazole.
  • heterocycle or “heterocyclic,” or “heterocyclyl” as used herein indicates a fully saturated, partially saturated, or unsaturated 3- to 12-membered monocyclic or bicyclic ring having from 1 to 5 ring heteroatoms selected from O, S or N.
  • the bicyclic heterocycles may be fused or spirocyclic ring systems.
  • Monocyclic or bicyclic heterocycles alone, and together with fused or spirocyclic groups, include aziridines, oxirane, azetidine, azirine, thirene, oxetane, oxazetidine, tetrazole, oxadiazole, thiadiazole, triazole, isoxazole oxazole, oxathiazole, oxadiazolone, isothiazole, thiazole, imidazole, pyrazole, isopyrazole, diazine, oxazine, dioxazine, oxadiazine, thiadiazine, oxathiazole, triazine, thiazine, dithiazine, tetrazine, pentazine, pyrazolidine, pyrrole, pyrrolidine, furan, thiophene, isothiophene, tetrazine, tria
  • spirocyclic heterocycles include oxaspiro[2.3]hexaneI l-oxaspiro[3.4]octane, 1- oxaspiro[2.5]octaneI 2-oxaspiro[4.5]decane, 2,6-diazaspiro[3.2]heptane, azaspiro[2.5]octane, 6-aza-spiro[2.5]octane, l,6-diazaspiro[2.5]octane, 7-aza-spiro[3.5]nonane, 3-aza- spiro[5.5]undecane, 8-azaspiro[4.5]decane, l,3-diazaspiro[4.5]decane, 2,8- diazaspiro[5.5]hendecaneI 3,9- diazaspir0[5.5]hendecane, and l-ox-6-azaspiro[2.5]octane
  • heterocycles includes each possible atomic orientation for the groups listed.
  • oxadiazole includes 1 ,2,3-oxadiazole, 1,3,4-oxadiazole and 1,2,4-oxadiazole; the term thiadiazole.
  • a heterocycloalkyl group refers to a 3-10 membered mono or bicyclic (fused or bridged) (e.g., 4-6, 5-10, 3, 4, 5, 6, 7, 8, 9, or 10-membered mono or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof).
  • heterocycloalkyl group examples include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1 ,4-dioxolanyl, 1 ,4-dithianyl, 1,3- dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[ ⁇ ]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza- bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octanyl
  • a monocyclic heterocycloalkyl group may be fused with a phenyl moiety such as tetrahydroisoquinoline.
  • Heterocycloalkyl ring structures can be optionally substituted at any chemically viable position on the ring or rings.
  • a "heterocycloalkenyl” group refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S).
  • heterocycloalkenyls examples include 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, or 2-pyrazolyl.
  • Monocyclic heteroaliphatics are numbered according to standard chemical nomenclature. For instance:
  • a “heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring structure having 4 to 15 (e.g., 5-9, 6-13, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof), and wherein one or more rings of the bicyclic or tricyclic ring structure is aromatic.
  • a heteroaryl group includes a benzofused ring system having 2 to 3 rings.
  • a benzofused group includes benzo fused with one or two C 4 _8 heterocyclic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[ ⁇ ]furyl, benzoyl thiophenyl, quinolinyl, or isoquinolinyl).
  • C 4 _8 heterocyclic moieties e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[ ⁇ ]furyl, benzoyl thiophenyl, quinolinyl, or isoquinolinyl.
  • heteroaryl examples include azetidinyl, pyridyl, 1H- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo[Z?]furyl, benzo[Z?]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-l,2,5-thiadiazol
  • monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.
  • Monocyclic heteroaryls are numbered according to standard chemical nomenclature. For instance:
  • bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo[ ⁇ ]furyl, benzo[ ⁇ ]thiophenyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolizyl, isoindolyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, indolizinyl, imidazopyridinyl, tetrahydrobenzoazepinyl, tetrahydrobenzooxazepinyl, be
  • Bicyclic heteroaryls are numbered according to standard chemical nomenclature. For instance:
  • heteroaryl group refers to an alkyl group (e.g., a C 1-4 alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” have been defined above.
  • cyclic moiety includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined previously.
  • cycloketonyl refers to a cycloaliphatic moiety where at least one carbon atom of the ring forms a double bond to oxygen.
  • examples of cycloketonyl compounds include cyclobutonyl, cyclopentonyl, cyclohexonyl, and cycloheptonyl.
  • a "carbamoyl” group refers to a group having the structure -O-CO- NR x R y or -NR x -CO-0-R z wherein R x and R y have been defined above and R z can be alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl.
  • a "carboxy” (or “carboxyl”) and a “sulfo" group refer to -COOH or -COOR x and -S0 3 H or -S0 3 R x , respectively.
  • a "hydroxy" or “hydroxyl” group refers to -OH.
  • an "alkoxy” or “alkoxyl” group refers to an alkyl-O- group where "alkyl” has been defined previously. Moreover an alkoxy group includes structures comprising two alkoxy groups on the same atom or adjacent atoms that form a ring together with the atom(s) to which they are bound.
  • a "sulfoxy” group refers to -0-SO-R x or -SO-0-R x , where R x has been defined above.
  • a "mercapto” group refers to -SH.
  • a "sulfonyl” group refers to -S(0) 2 -R x , wherein R x has been defined above.
  • sulfonyls include optionally substituted alkylsulfonyl, arylsulfonyl (e.g., haloarylsulfonyl), heteroarylsulfonyl (e.g., alkylheteroarylsulfonyl), or the like.
  • sulfinyl refers to -S(0)-R x , wherein R x has been defined above.
  • examples of sulfinyls include alkylsulfinyl.
  • sulfanyl refers to -S-R x , wherein R x has been defined above.
  • examples of sulfanyls include alkylsulfanyl.
  • halogen or halo group refers to fluorine, chlorine, bromine or iodine.
  • haloaliphatic refers to an aliphatic group substituted with 1 -3 halogen atoms on each carbon atom.
  • haloalkyl includes the group - CF 3 .
  • a "sulfamoyl” group refers to the structure -S(0) 2 -NR x R y or -NR X - S(0) 2 -R z wherein R x , R y , and R z have been defined above.
  • a "sulfamide” group refers to the structure -NR X -S(0) 2 -NR Y R z wherein R x , R Y , and R z have been defined above.
  • a "carbonylamino" group used alone or in connection with another group refers to an amido group such as Rx-C(0)-NR x -.
  • an alkylcarbonylamino includes alkyl-C(0)-NR x -, wherein R x has been defined above.
  • aminocarbonyl used alone or in connection with another group refers to an amido group such as N(Rx) 2 -C(0)-.
  • an "alkoxycarbonyl” used alone or in connection with another group refers to a carbonyl group such as alkyl-O-C(O)-.
  • alkoxyalkyl refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.
  • aminoalkoxyalkyl refers to an alkyl group such as N(R X ) 2 - alkyl-O-alkyl-, wherein R x and alkyl have been defined above.
  • alkoxyalkylaminoalkyl refers to an alkyl group such as alkyl-O- alkyl-N(R x ) 2 -alkyl-, wherein alkoxy, R x and alkyl have been defined above.
  • an “aminocarbonyl” refers to an amido group such as -NR -C(O)-, wherein R x has been defined above.
  • an “aminosulfonyl” refers to the structure -N(R X )2-S(0)2-, wherein R x has been defined above.
  • aminoalkyl refers to the structure N(R x )2-alkyl-.
  • cyanoalkyl refers to the structure (CN)-alkyl-.
  • alkylsulfonyl' group refers to the structure alkyl-S(0)2-.
  • a "sulfonylamino" group refers to the structure Rx-S(0)2-N(R X )2-, wherein R x has been defined above.
  • urea refers to the structure -NR x -CO-NR Y R z and a "thiourea” group refers to the structure -NR X -CS-NR Y R Z .
  • R x , R Y , and R z have been defined above.
  • pictured substituents drawn with a single, unattached wavy line drawn perpendicular to a bond of the substituent is meant to show the attachment point of the substituent.
  • the pyrrole substituent is ached to the main core structure by the ring nitrogen, while the pyrro le substitue is shown as attached to the main core structure by the carbon atom adjacent to the ring nitrogen.
  • pictured ring structures drawn with a substituent' s bond overlayed on one of the ring bonds shows that the substituent can be at any substitutable atom of the entire ring structure, whether the ring structure is monocyclic or multicyclic.
  • pictured structures having methyl substituents are drawn to show those methyl substituents as an external bond. Specifically, the structure, is identical
  • divalent substituents such as an amide, shown as -C(0)N(Rx)-, are meant to include the substituent in both directions.
  • the generic structure
  • Some examples of generic divalent substituents include, but are not limited to -CO-, -CS-, -CONQ 2 -, -C0 2 -, -OCO-, -NQ 2 -, -NQ 2 C0 2 -, -0-, -NQ 2 CONQ 2 -, -OCONQz-, -NQ 2 CO-, -S-, -SO-, -S0 2 -, -S0 2 NQ 2 -, -NQ 2 S0 2 -, and -NQ 2 S0 2 NQ 2 -.
  • substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • substituents are described above in the definitions and below in the description of compounds and examples thereof.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • the substituents can be bound to the same atom (carbon, nitrogen, oxygen) or two or more different atoms.
  • a ring substituent such as a
  • heterocycloalkyl may be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom.
  • substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
  • Substituents can include, but are not limited to, alkyl, cycloalkyl, alkenyl, amino, carbonyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroaralkyl, acyl, carbamoyl, carboxy, hydroxyl, alkoxy, sulfoxy, mercapto, sulfonyl, sulfinyl, sulfanyl, halogen, haloaliphatic, haloalkoxy, cyano, sulfamoyl, sulfamide, carbonylamino, aminocarbonyl, alkoxycarbonyl, alkoxyalkyl, aminocarbonyl, aminosulfonyl, oxo, aminoalkyl, aminoalkoxyalkyl, alkoxyalkylaminoalkyl, cyanoal
  • stable or chemically feasible refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • an effective amount is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient.
  • the interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep. , 50: 219 (1966).
  • Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970).
  • patient refers to a mammal, including a human.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers
  • stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
  • all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula I:
  • X is SO or S0 2 ;
  • a 1 , A 2 , A 3 , and A 4 are each independently C or N;
  • R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
  • R 2 and R 3 are each independently H, optionally substituted alkyl, optionally substituted C3-S cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R 2 and R 3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4a , R 4b , R 4c , and R 4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl;
  • R 5a and R 5b are each independently H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl;
  • R 6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl,
  • R 6a and R 6b are each independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or R 6a and R' together form an optionally substituted heterocycloalkyl ring; or
  • R 40 and R 6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
  • the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of the Formula la:
  • X is SO or S0 2 ;
  • a 1 , A 2 , A 3 , and A 4 are each independently C or N;
  • R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
  • R 2 and R 3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R 2 and R 3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4a , R 4b , R 4c , and R 4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl;
  • R 6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or R 40 and R 6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
  • the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula lb:
  • X is SO or S0 2 ;
  • a 1 , A 2 , A 3 , and A 4 are each independently C or N;
  • R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
  • R 2 and R 3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R 2 and R 3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4a , R 4b , R 4c , and R 4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
  • R 6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or
  • R 40 and R 6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
  • the compounds of Formula I and Formula la can include one or more of the following embodiments.
  • a 1 , A 2 , A 3 , and A 4 are each C; A 1 , A 2 , and A 4 are each C, and A 3 is N;
  • a 1 , A 3 , and A 4 are each C, and A 2 is N;
  • a 1 and A 4 are each C and A 2 and A 3 are each N; or
  • a 3 and A 4 are each C and A 1 and A 2 are each N.
  • a 1 , A 2 , and A 4 are each C;
  • R 4a , R 4b , and R 4d are each H, optionally substituted C1-4 alkyl, optionally substituted OC1-4 alkyl, halogen, or OH.
  • R 4a , R 4b , and R 4d are each independently Ci_ 3 alkyl, OCi_ 3 alkyl, F, CI, Br, or OH; wherein the C1-3 alkyl and OC1-3 alkyl are each optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 4a , R 4b , and R 4d are each independently H, C3 ⁇ 4, C 2 H 5 , OCH 3 , OC2H5, CH 3 , CF 3 , OCF 3 , F, CI, or OH. In other embodiments, R 4a , R 4b , and R 4c are each H.
  • a 1 and A 2 are each C, and A 4 is N;
  • R 4a and R 4b are each independently H, optionally substituted Ci ⁇ alkyl, optionally substituted OCi-4 alkyl, halogen, or OH;
  • R 4d is absent.
  • R 4a and R 4b are each independently H, CH 3 , C 2 H 5 , OCF 3 , OCH 3 , OC2H5, F, CI, or OH.
  • a 1 and A 4 are each C, and A 2 is N;
  • R 4a and R 4d are each independently H, optionally substituted Ci ⁇ alkyl, optionally substituted OCi-4 alkyl, halogen, or OH;
  • R 4b is absent.
  • R 4a and R 4d are each independently H, CH 3 , C 2 H 5 , OCF 3 , OCH 3 , OC 2 H 5 , F, CI, or OH.
  • a 2 and A 4 are each C, and A 1 is N;
  • R and R are each independently H, optionally substituted C 1-4 alkyl, optionally substituted OCi- 4 alkyl, halogen, or OH;
  • R 4a is absent.
  • R 4b and R 4d are each independently H, CH 3 , C 2 H 5 , OCF 3 , OCH 3 , OC 2 H 5 , F, CI, or OH.
  • a 1 and A 2 are each N, and A 4 is C;
  • R 4a and R 4b are each absent;
  • R 4d is H, optionally substituted C 1-4 alkyl, optionally substituted OCi_ 4 alkyl, halogen, or OH.
  • R 4d is H, CH 3 , C 2 H 5 , OCF 3 , OCH 3 , OC 2 H 5 , F, CI, or OH.
  • a 1 and A 4 are each N, and A 2 is C;
  • R 4a and R 4d are each absent;
  • R 4b is H, optionally substituted C 1-4 alkyl, optionally substituted OCi_ 4 alkyl, halogen, or OH.
  • R 4b is H, CH 3 , C 2 H 5 , OCF 3 , OCH 3 , OC 2 H 5 , F, CI, or OH.
  • a 2 and A 4 are each N, and A 1 is C;
  • R 4b and R 4d are each absent;
  • R 4a is H, optionally substituted C alkyl, optionally substituted OC ⁇ alkyl, halogen, or OH.
  • R 4a is H, CH 3 , C 2 H 5 , OCF 3 , OCH 3 , OC 2 H 5 , F, CI, or OH.
  • a 1 , A 2 , and A 4 are each N;
  • R 4a , R 4b , and R 4d are each absent.
  • R 40 and R 6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring as shown in Formula la 1 .
  • W 1 is CR 7a , R 7b , NR 7c , or O;
  • W 2 and W 3 are each independently CR 7a R 7b , NR 7c , O, or a bond;
  • R 7a , R 7b , and R 7c are each independently H or C M alkyl.
  • a 1 , A 2 , and A 4 are each C.
  • W 1 is CR 7a R 7b
  • W 2 and W 3 are each CR 7a R 7b or a bond
  • W 1 is O, and W 2 and W 3 are each CR 7a R 7b or a bond;
  • W 2 is O, and W 1 and W 3 are each CR 7a R 7b or a bond;
  • W 3 is O, and W 1 and W 2 are each CR 7a R 7b or a bond; or
  • R 7a and R 7b are each independently H or Ci_ 3 alkyl.
  • W 1 and W 2 are each CR 7a R 7b ;
  • W 3 is O
  • R 7a and R 7b are each independently H or CH 3 .
  • W 1 is C(CH 3 )(CH 3 ) and W 2 is CH 2 .
  • the compounds of Formula I, Formula la, Formula lb, and Fomula la 1 can include one or more of the following embodiments.
  • R 2 and R 3 together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
  • R 1 is optionally substituted carbocyclyl
  • R 5 is an optionally substituted alkyl, or optionally substituted carbocyclyl.
  • one of R 4a , R 4b , and R 4d is H and the remaining are each independently C 1-3 alkyl, OCi_ 3 alkyl, F, CI, Br, or OH; wherein the C 1-3 alkyl and OCi_ 3 alkyl are each optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 4a , R 4b , and R 4d are each independently H, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , CH 3 , CF 3 , OCF 3 , F, CI, or OH. In other embodiments, R 4a , R 4b , and R 4d are each H.
  • R 4a , R 4b , and R 4d are H, halogen, optionally substituted alkyl or absent.
  • R 4a , R 4b , R 4c , and R 4d are each independently H, C 1-4 alkyl, Ci-4 haloalkyl, OC1-4 alkyl, halogen, CN, OH, or absent.
  • R 4a is H, Ci_ 3 alkyl, OCi_ 3 alkyl, or absent;
  • R 4b is H, Ci_ 3 alkyl, OCi_ 3 alkyl, F, CI, Br, haloalkyl, or absent;
  • R 40 is H, C 1-3 alkyl, OCi_ 3 alkyl, or absent;
  • R 4d is H, Ci_3 alkyl, OCi_ 3 alkyl.
  • R 4a is H, C 1-3 alkyl, or absent
  • R is H, Ci_ 3 alkyl, CI, CF 3 , or absent;
  • R 40 is H, C 1-3 alkyl, or absent
  • R 4d is H or Ci_ 3 alkyl.
  • R 2 and R 3 together form cycloalkyl, cycloalkenyl, cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, carboxyl, and acetyl.
  • R 2 and R 3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_ 4 alkyl, OCi_ 4 alkyl, OH, F, CI, Br, amino, or carboxyl.
  • R 2 and R 3 together form cycloalkyl, cycloalkenyl, cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, oxo, amino, carboxyl, acetyl, alkyl-OH, haloalkyl, and -(alkyl-Q) n -alkyl, wherein each Q is independently O, NH, or N(C 1-4 alkyl), and each n is independently 1 or 2.
  • R 2 and R 3 together form cycloalkyl optionally substituted with aminoalkoxyalkyl, alkoxyalkylaminoalkyl or (C 1-4 alkoxy) 2 .
  • R 2 and R 3 together form cycloalkyl optionally substituted with -(alkyl-Q) n -alkyl, wherein each Q is independently O, NH, or N(C 1-4 alkyl), and n is 1 or 2.
  • R 2 and R 3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl, each independently is optionally substituted with aminoalkoxyalkyl, alkoxyalkylamino alkyl or (C 1-4 alkoxy) 2 .
  • R 2 and R 3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl, each independently is optionally substituted with -(alkyl-Q) n -alkyl, wherein each Q is independently O, NH, or N(C 1-4 alkyl), and n is 1 or 2.
  • R 2 and R 3 together form cyclopropyl optionally substituted with aminoalkoxyalkyl, alkoxyalkylamino alkyl or (C 1-4 alkoxy) 2
  • R 2 and R 3 together form cyclopropyl optionally substituted with -(alkyl-Q) n -alkyl, wherein each Q is independently O, NH, or N(C 1-4 alkyl), and n is 1 or 2.
  • R 2 and R 3 together form cyclopropyl optionally substituted with ethanol, propan-2-ol, methoxypropane, difluoroethane, 2-ethoxy-N,N- dimethylethanamine, 1 -ethoxy-2-methoxyethane, N-ethyl-2-methoxyethanamine, or N-ethyl- 2-methoxy-N-methylethanamine.
  • R ⁇ is H, optionally substituted Ci_6 alkyl, optionally substituted OCi_6 alkyl, optionally substituted carbocycle, halogen, CN, OH, or absent; and R 6 is optionally substituted alkyl, optionally substituted C 2 _ 6 alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl.
  • R 2 and R 3 together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring. In some of these
  • X is S0 2 .
  • R 1 is optionally substituted carbocycle.
  • R 5 , and R 6 are each independently H, optionally substituted alkyl or optionally substituted carbocycle.
  • R 4a , R , R , R are each independently H, halo, optionally substituted alkyl or absent.
  • R 1 is optionally substituted phenyl. In some embodiments, the phenyl is unsubstituted. In other embodiments, the phenyl is substituted with a halogen.
  • R 2 and R 3 together form cycloalkyl, cycloalkenyl, cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, carboxyl, and acetyl.
  • R 2 and R 3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_ 4 alkyl, OCi_ 4 alkyl, OH, F, CI, Br, amino, or carboxyl.
  • R 2 and R 3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, carboxyl, acetyl, alkyl-OH, haloalkyl, and -(alkyl-Q) n -alkyl, wherein each Q is independently O, NH, or N(C 1-4 alkyl), and n is 1 or 2.
  • R 2 and R 3 together form a ring selected from any of the following formulas:
  • R 2 and R 3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH 3 , C 2 H 5 , C 3 H7, OCH 3 , OC 2 H 5 , OC 3 H7, OH, F, CI, and Br.
  • R 2 and R 3 together form oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, N-C 1-2 alkyl azetidine, N-C 1-2 alkyl pyrrolidine, N-C 1-2 alkyl piperidine, N-acetylazetidine, N-acetylpyrrolidine, or N- acetylpiperidine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C 1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
  • R 2 and R 3 together form tetrahydrofuran
  • tetrahydropyran pyrrolidine, piperidine, N-C 1-2 alkyl pyrrolidine, N-C 1-2 alkyl piperidine, N- acetylpyrrolidine, or N- acetylpiperidine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH 3 , OCH 3 , OH, F, and CI.
  • R 2 and R 3 together form cyclobutanone, cyclopentanone, cyclohexanone, or cycloheptanone; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
  • R 2 and R 3 together form cyclobutanone, cyclopentanone, or cyclohexanone; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH 3 , C 2 H 5 , C 3 H7, OCH 3 , OC 2 H 5 , OC 3 H7, OH, F, CI, and Br.
  • R 2 and R 3 together form spiro[2.3]hexanyl
  • R 2 and R 3 together form spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[2.5]octanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl,
  • each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C3 ⁇ 4, C 2 3 ⁇ 4, C 3 H7, OCH 3 , OC 2 3 ⁇ 4, OC 3 H7, OH, F, CI, and Br.
  • R 2 and R 3 together form bicyclo[1.1.0]butyl
  • bicyclo[2.1.0]pentyl bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[5.1.0]octyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[5.2.0]nonyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[5.3.0]decyl, bicyclo[4.4.0]decyl, bicyclo[5.4.0]undecyl, or bicyclo[5.5.0]dodecyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C 1-4 alkyl, OCi ⁇ alkyl, OH, F, CI, Br, amino, and carboxyl.
  • R 2 and R 3 together form bicyclo[l. l.OJbutyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, or bicyclo[4.4.0]decyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH 3 , C 2 3 ⁇ 4, C 3 H7, OCH 3 , OC2H5, OC3H7, OH, F, CI, and Br.
  • R 2 and R 3 together form:
  • R 2 and R 3 together form:
  • R 2 and R 3 together form:
  • R 2 and R 3 together form:
  • R 2 and R 3 are each independently H, optionally substituted Ci-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted OCi_6 alkyl, CN, OH.
  • R 2 and R 3 are each independently H, C 1-4 alkyl, C3-6 cycloalkyl, OCi ⁇ alkyl, CN, or OH; wherein each of the Ci_ 4 alkyl, C 3 _ 6 cycloalkyl, and OCi_ 4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C 1-2 alkyl, OC 1-2 alkyl, OH, halogen, amino, and carboxyl.
  • R 2 and R 3 are each independently H, C 1-2 alkyl, OCi-3 alkyl, or OH; wherein each of the C 1-2 alkyl and OC 1-2 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH 3 , OCH 3 , F, CI, and Br.
  • R 2 and R 3 are each CH 3 .
  • R 1 is optionally substituted aryl. In a further embodiment, R 1 is optionally substituted alkyl. In a further embodiment, R 1 is C 1-5 alkyl; wherein the C 1-5 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 1 is C2-6 alkenyl; wherein the C2-6 alkenyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 1 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 1 is cyclopentyl or cyclohexyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C 1-4 alkyl, fluoroalkyl hydroxyl, OC1-4 alkyl, carboxyl, amino, and halogen.
  • R 1 is optionally substituted heterocyclyl.
  • R 1 is aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl
  • R 1 is optionally substituted aryl or optionally substituted heteroaryl.
  • R 1 is pyrrole, furan, thiophene, isothiophene, phenyl, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl, pyridine, pyrimidine, or pyrazine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, haloalkoxyl, carboxyl, amino, and halogen.
  • R 1 is pyrrole, furan, thiophene, isothiophene, phenyl, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl, pyridine, pyrimidine, or pyrazine; wherein each of the foregoing moieties is optionally substituted with halogen.
  • R 1 is phenyl substituted with halogen.
  • R 1 is phenyl substituted with CI, Br or F.
  • R 1 is phenyl substituted with CI.
  • R 1 is phenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_ 4 alkyl, OCi_ 4 alkyl, CF 3 , OCF 3 , F, CI, and CN.
  • R 1 can include:
  • R 1 is
  • a 1 , A 2 , and A 4 are each C;
  • R 4a , R 4b , and R 4d are each H, optionally substituted C 1-4 alkyl, optionally substituted OC 1 -4 alkyl, halogen, or OH.
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl.
  • R 5 is optionally substituted alkyl.
  • R 5 is Ci_s alkyl; wherein the Ci_s alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 5 is C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of F, OCi_3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxetane.
  • R 5 is C 2 -6 alkenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 5 is optionally substituted alkylaryl.
  • R 5 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl.
  • R 5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl,
  • R 5 is optionally substituted heterocyclyl.
  • R 5 is aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 5 is optionally substituted aralkyl, optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 5 is benzyl optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 5 is benzyl optionally substituted with halogen, for example CI, F, or Br.
  • R 5 is benzyl optionally substituted with F.
  • R 5 is optionally substituted heteroaralkyl optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In some of these embodiments, R 5 is optionally substituted
  • R 5 is optionally substituted
  • R 5 is
  • R 5 is methylpyrazole, optionally substituted with methyl. [00168] In some of these embodiments, R 5 is
  • R 5 can include:
  • X is SO
  • X is S0 2 .
  • the compound of Formula I includes a structure selected from the group below:
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl. In some of these embodiments, R 5 is optionally substituted alkyl. In some of these embodiments, R 5 is C 1-5 alkyl; wherein the Ci_s alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl,
  • R 5 is Ci_ 4 alkyl; wherein the Ci_ 4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of F, OC1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxetane.
  • R 5 is C2-6 alkenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 5 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl.
  • R 5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl,
  • cyclopentenyl or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 5 is optionally substituted heterocyclyl.
  • R 5 can include aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkyl, haloalkyl, cyclo
  • R can include:
  • R 5 can included
  • R 6 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted alkoxyl.
  • R 6 is optionally substituted alkyl.
  • R 6 is C 1-5 alkyl; wherein the C 1-5 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 6 is C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of F, OCi-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxetane.
  • R 6 is C 2 -6 alkenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl,
  • R 6 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl.
  • R 6 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or a C 6 -io bicyclic cycloalkyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 6 is optionally substituted heterocyclyl.
  • R 6 can include aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxy
  • R 6 is optionally substituted aryl or optionally substituted heteroaryl.
  • R 6 is pyrrole, furan, thiophene, isothiophene, phenyl, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl, pyridine, pyrimidine, pyrazole, or pyrazine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
  • R 6 is phenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_ 4 alkyl, OCi_ 4 alkyl, CF 3 , OCF 3 , F, CI, and CN.
  • R 6 is pyridine that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of d_ 4 alkyl, Od_ 4 alkyl, CF 3 , OCF 3 , F, CI, and CN.
  • R 6 can include tert-butyl, cyclobutane, cyclopentane, or cyclohexane.
  • R 6 is H.
  • R 6 is alkoxyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci ⁇ alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, OCi_ 4 alkyl, carboxyl, amino, and halogen.
  • R 6 is Ci_ 4 alkoxyl selected from the group consisting of methoxy, methoxymethylpropane, methoxypropane, ethoxy, propyloxy and butoxy, each independently optionally substituted with one or more unsubstituted substituents selected from the group consisting of C 1-4 alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, OC1-4 alkyl, carboxyl, amino, and halogen.
  • R 6 is:
  • X is SO.
  • X is S0 2 .
  • the invention is directed to a compound of Formula I or pharmaceutically acceptable salts thereof, wherein:
  • X is S0 2 ;
  • a 1 and A 4 are each C;
  • a 2 and A 3 are each independently C or N;
  • R 1 is phenyl, optionally substituted with a group selected from halogen and Ci-4alkyl wherein the alkyl is optionally substituted with halogen;
  • R 2 and R 3 together form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl
  • R 4a , R 4b , R 4c , and R 4d are each independently H, optionally substituted Ci_6alkyl, halogen, or absent when the ring atom to which they are attached is N;
  • R 5 is optionally substituted Ci_6alkyl or optionally substituted carbocyclyl
  • R 6 is optionally substituted Ci_6alkyl, or optionally substituted carbocyclyl, or
  • R 40 and R 6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
  • the invention is directed to a compound of Formula I,
  • a 1 and A 4 are each C;
  • a 2 and A 3 are each independently C or N;
  • R 1 is phenyl optionally substituted with a group selected from halogen, CH 3 and CF 3 ;
  • R 2 and R 3 together form a 6 membered heterocyclyl or a 6 membered carbocyclyl;
  • R 4a , R 4b , R 40 , and R 4d are each independently H, Ci_ 4 alkyl, halogen, or absent;
  • R 5 is optionally substituted Ci_ 6 alkyl or optionally substituted carbocyclyl
  • R 6 is optionally substituted Ci_ 4 alkyl, or Ci_ 7 carbocyclyl.
  • the invention is directed to a compound of Formula I, Formula la, or pharmaceutically acceptable salts thereof, wherein:
  • X is S0 2 ;
  • a 1 and A 4 are each C;
  • a 2 and A 3 are each independently C or N;
  • R 1 is phenyl optionally substituted with a group selected from halogen, CH 3 and CF 3 ;
  • R 2 and R 3 together form a pyranyl or a 6 membered bicyclic carbocyclyl
  • R 4a , R 4b , R 40 , and R 4d are each independently H, Ci_ 4 alkyl, halogen, or absent;
  • R 5 is optionally substituted Ci_ 6 alkyl or optionally substituted carbocyclyl
  • R 6 is optionally substituted Ci_ 4 alkyl, or Ci_ 7 carbocyclyl.
  • the invention is directed to a compound of Formula I or pharmaceutically acceptable salts thereof, wherein:
  • X is S0 2 ;
  • a 1 and A 4 are each C;
  • a 2 and A 3 are each independently C or N;
  • R 1 is phenyl optionally substituted with a group selected from halogen, CH 3 and CF 3 ;
  • R 2 and R 3 together form a pyranyl or a 6 membered bicyclic carbocyclyl; [00210] R , R , R , and R 4d are each independently H, halogen or absent;
  • R 5 is optionally substituted Ci_ 6 alkyl or optionally substituted carbocyclyl
  • R 6 is optionally substituted Ci- 4 alkyl, or Ci_ 7 carbocyclyl.
  • R 2 and R 3 together form an optionally substituted monocyclic carbocyclyl or a monocyclic heterocyclyl; and X is S, SO or S0 2 ; and A 1 , A 2 , A 3 , A 4 , R 1 ' R 4a , R 4b , R 4c , R 4d , R 5 , and R 6 are defined as in Formula I.
  • one of A 1 and A 4 is nitrogen and A 2 , A 3 , R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 5 , and R 6 are defined as in Formula I.
  • one of A 1 and A 2 is nitrogen and A 2 , A 3 , R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 5 , and R 6 are defined as in Formula I.
  • R 4a is H and A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4b , R 40 , R 4d , R 5 , and R 6 are defined as in Formula I.
  • R 4d is H and A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4b , R 4c , R 4a , R 5 , and R 6 are defined as in Formula I.
  • R 6 is a C 2 -C 5 alkyl and A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4a , R 4b , R 40 , R 4d , and R 5 are defined as in Formula I.
  • R 6 is amino, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted heterocyclyl, and A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , and R 5 are defined as in Formula I.
  • the invention is directed to a compound of Formula I or pharmaceutically acceptable salts thereof, wherein:
  • X is S0 2 ;
  • a 1 and A 4 are each independently C or N;
  • a 2 and A 3 are each independently C or N;
  • R 1 is phenyl, optionally substituted with a group selected from halogen and Ci_ 4 alkyl wherein the Ci-4 alkyl is optionally substituted with halogen;
  • R 2 and R 3 together form a cycloaliphatic or heterocycloalkyl each of which is independently unsubstituted or substituted with one or more of Ci_ 6 alkyl, Ci_ 6 alkoxyl, halogen, oxo, hydroxyl, carboxyl, acetyl, Ci_ 6 alkyl-OH, Ci_ 6 haloaliphatic, amino, and -(alkyl-Q) n -alkyl, wherein each Q is independently O, NH, or N(Ci_ 4 alkyl), and n is 1 or 2.
  • R a , R , R °, and R are each independently H, optionally substituted Ci_6 alkyl, halogen, or absent when the ring atom to which they are attached is N;
  • R 5 is optionally substituted Ci_6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted cycloalkyl;
  • R 6 is optionally substituted Ci_ 6 alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted Ci_6 alkoxyl;
  • the invention is directed to a compound of Formula la or pharmaceutically acceptable salts thereof, wherein the compound of Formula la has the structure:
  • R is F or CI
  • R is H, F, CI, or methoxy
  • R 6 is , O ' R wherein R Z1 is alkyl , or , wherein X 2 is CR Z2 or N, and R Z2 is an alkyl, H or F.
  • X 2 is CR' mbodiments of the above formula, the compound can be:
  • the invention is directed to a compound of Formula la or pharmaceutically acceptable salts thereof, wherein the compound of Formula la has the structure:
  • a 3 is C or N
  • R 4b is F or CI
  • R 5 is optionally substituted C 3 -6 cycloalkyl, optionally substituted 3 to 7 membered heterocycloalkyl, optionally substituted C7-16 aralkyl, optionally substituted 6 to 10 membered heteroaralkyl, or Ci_6 alkyl optionally substituted with one to four of Ci_6 cycloalkyl, C 6 -s aryl, or 3 to 7 membered heterocycloalkyl, each of the foregoing substituents may be independently unsubstituted or substituted with one or more of Ci ⁇ alkyl or halogen; and
  • R 6 is Ci-6 alkyl, C 3 -10 cycloalkyl, 4 to 7 membered heteroaryl, C 6 -i 4 aryl, or Ci_6 alkoxyl, wherein each of the foregoing moieties is independently unsubstituted or substituted with one or more of Ci_ 4 alkyl or halogen.
  • the invention is directed to a compound of Formula la or pharmaceutically acceptable salts thereof, wherein the compound of Formula la has the structure:
  • a 3 is C or N
  • R 4b is F or CI
  • R 5 is optionally substituted C 3 -6 cycloalkyl, optionally substituted 3 to 7 membered heterocycloalkyl, or Ci_ 6 alkyl optionally substituted with one to four of Ci_ 6 cycloalkyl, C 6 -i4 aryl, or 3 to 7 membered heterocycloalkyl, each of the foregoing substituents may be independently unsubstituted or substituted with one or more of Ci ⁇ alkyl or halogen; and R 6 is Ci-6 alkyl, C 3 - 1 0 cycloalkyl, 4 to 7 membered heteroaryl, C 6 -i4 aryl, or Ci_6 alkoxyl, wherein each of the foregoing moieties is independently unsubstituted or substituted with one
  • the compound of Formula I can be a compound as shown in Table 1 or a pharmaceutically acceptable salt thereof.
  • the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula lb:
  • X is SO or S0 2 ;
  • a 1 , A 2 , A 3 , and A 4 are each independently C or N;
  • R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
  • R 2 and R 3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R 2 and R 3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4a , R 4b , R 4c , and R 4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
  • R 6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or
  • R 40 and R 6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
  • the compound of Formula lb can be a compound as shown in Table 2. Table 2. Exemplary Embodiments of the Compounds of Formula lb.
  • the invention includes a pharmaceutical composition comprising a compound of Formula I, Formula la, Formula la 1 , or Formula lb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
  • the invention includes pharmaceutically acceptable salts of the compounds of Tables 1 and 2.
  • the present invention includes within its scope pharmaceutically acceptable prodrugs of the compounds of the present invention.
  • a "pharmaceutically acceptable prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof.
  • the prodrugs increase the rate of a compound of this invention or an active metabolite or residue thereof.
  • compositions of this invention refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxyprop
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their
  • Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N + (Ci_4 alkyl) 4 salts.
  • alkali metal e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium
  • ammonium and N + (Ci_4 alkyl) 4 salts e.g., sodium and potassium
  • alkali metal e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium
  • ammonium e.g., sodium and sodium and sodium and potassium
  • N + (Ci_4 alkyl) 4 salts e.g., sodium and potassium
  • ammonium e.g., sodium and potassium
  • N + (Ci_4 alkyl) 4 salts e.g., sodium and potassium
  • ammonium e.g., sodium and potassium
  • N + (Ci_4 alkyl) 4 salts
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally- acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
  • the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,
  • the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this invention are formulated for oral administration.
  • compositions should be formulated so that a dosage of between about 0.01 to about 100 mg/kg body weight/day of the modulator can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • additional therapeutic agents which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention.
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as "appropriate for the disease, or condition, being treated.”
  • the compound of Formula I, Formula la, Formula la 1 , or Formula lb, or a pharmaceutically acceptable salt thereof can inhibit the activity of an ROR-gamma receptor.
  • the compound of Formula I, Formula la, Formula la 1 , or Formula lb, or a pharmaceutically acceptable salt thereof can inhibit the activity of an ROR-gamma receptor in vitro.
  • the compound of Formula I, Formula la, Formula la 1 , or Formula lb, or a pharmaceutically acceptable salt thereof can also inhibit the activity of an ROR-gamma receptor in vivo.
  • the invention includes a method of inhibiting the activity of an ROR-gamma receptor, comprising contacting the receptor with a compound of Formula I, Formula la, Formula la 1 , or Formula lb, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I, Formula la, Formula la 1 , or Formula lb, or a pharmaceutically acceptable salt thereof inhibits the activity of an ROR-gamma receptor in vitro.
  • the compound of Formula I, Formula la, Formula la 1 , or Formula lb, or a pharmaceutically acceptable salt thereof inhibits the activity of an ROR-gamma receptor in vivo.
  • the compound of Formula I is a modulator of ROR-gamma activity.
  • the compound of Formula la is a modulator of ROR-gamma activity.
  • the compound of Formula la 1 is a modulator of ROR-gamma activity.
  • the compound of Formula lb is a modulator of ROR-gamma activity.
  • the invention includes a method of treating or reducing the severity of an ROR-gamma receptor mediated disease in a patient comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • an ROR-gamma receptor mediated disease can include an automimmune disease.
  • an autoimmune disease is selected from the group consisting of Ankylosing, spondylitis, Asthma, Behcet's disease, Chronic obstructive pulmonary disease, Crohn's disease, Diabetes Mellitus Type 1, Multiple Sclerosis, Neuromyelitis optica, Polymyalgia Rheumatica, Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren's syndrome, Systemic Lupus Erythematosus, Systemic sclerosis, Transplant rejection, Inflammatory Bowel Disease, Ulcerative Colitis and Uveitis.
  • the invention includes a method of modulating the activity of an ROR-gamma receptor with a modulator of ROR-gamma, comprising contacting the receptor with a compound of Formula I, Formula la, Formula la 1 , or Formula lb, or a
  • the compound of Formula I, Formula la, Formula la 1 , or Formula lb, or a pharmaceutically acceptable salt thereof modulates the activity of an ROR-gamma receptor in vitro.
  • the compound of Formula I, Formula la, Formula la 1 , or Formula lb, or a pharmaceutically acceptable salt thereof modulates the activity of an ROR-gamma receptor in vivo.
  • the compound of Formula I is a modulator of the ROR-gamma receptor.
  • the compound of Formula la is a modulator of the ROR-gamma receptor.
  • the compound of Formula la 1 is a modulator of the ROR-gamma receptor
  • the compound of Formula lb is a modulator of the ROR-gamma receptor.
  • the compounds of Formula I, Formula la, Formula la 1 , or Formula lb, or a pharmaceutically acceptable salt thereof may be readily synthesized from commercially available starting materials using methods known in the art. Exemplary synthetic routes to produce compounds of Formula I, Formula la, Formula la 1 , or Formula lb, or a
  • Step 1 n-BuLi (12 mL, 30.6 mmol) was added to a solution of compound 1-1 (3.0 g, 27.8 mmol) in THF (60 mL) at -78 °C. The mixture was stirred for 0.5h at 0 °C. Then, CH 3 I (4.3 g, 30.6 mmol) was added. The reaction mixture was stirred for another 2 hours at room temperature. Water (60 mL) was added. The mixture was extracted with EtOAc (50 mL x 3).
  • Step 4 Sodium 4-(trifluoromethyl)benzenesulfinate (0.34 g, 1.46 mmol), compound
  • Example #37 NaH (8 mg, 1.15 mmol) was added to a solution of compound 1-5 (100 mg, 0.23 mmol) in THF (10 mL). Then l-bromo-2-(2-bromoethoxy)ethane (107 mg, 0.46 mmol) was added and stirred overnight at 50 °C. The mixture was cooled to room temperature. Water (10 mL) was added. The mixture was extracted with DCM (15 mL x 3). Combined organic layer was washed with brine, dried over anhydrous Na 2 S0 4 , concentrated, and purified by pre-TLC and pre-HPLC to give the desired product as white solid.
  • Step 1 Cyclohexanecarbonyl chloride (5.4 g, 37 mmol) was added to a solution of
  • Step 2 n-BuLi (9.1 mL, 22.8 mmol) was added dropwise to a solution of compound 2-2 (3.0 g, 9.1 mmol) in THF (50 mL) at 0 °C. The mixture was stirred for lh at 0 °C.
  • Step 3 The same procedure with the step 3 of Scheme 1 was applied to the preparation of compound 2-4.
  • LC-MS: m/z 325.1 [M+H] + .
  • Step 4 The same procedure with the step 4 of Scheme 1 was applied to the preparation of compound 2-5.
  • LC-MS: m/z 455.1 [M+H] + .
  • Step 1 4-chlorobenzenethiol (1.339 g, 9.3 mmol), compound 3-1 (1 g, 6.17 mmol), K2CO 3 (2.567 g, 18.6 mmol) in dioxane (20 mL) was stirred for 1.5 hrs at 30 °C. After filtered, the filtrate was concentrated. Water (20 mL) was added to the resulting residue. The mixture was extracted with EtOAc (20 mL x 3). Combined organic layer was washed with brine, dried over anhydrous Na 2 S0 4 , concentrated, and purified by flash column
  • Step 4 A mixture of compound 3-4 (0.21 g, 0.65 mmol), TEA (0.263 g, 2.6 mmol), pivaloyl chloride (0.234 g, 1.94 mmol) in THF (15 mL) was refluxed for 24 hrs. After being washed with brine (100 mL), the mixture was dried over anhydrous Na 2 S0 4 , and
  • Step 1 sodium 4-chlorobenzenesulfinate (1 g, 6.17 mmol), compound 4-1 (1.56 g, 7.4 mmol), Bu 4 NI (1.37 g, 3.7 mmol), KI (0.615 g, 3.7 mmol) in DMF (30 mL) was stirred at 30 °C for 1 hrs. After being filtered, the filtrate was concentrated. Water (100 mL) was added to the resulting residue. The mixture was extracted with EtOAc (50 mL x 2).
  • Step 2 To a solution of compound 4-2 (6.6 g, 21.8 mmol) in THF (120 mL) was added NaH (70 w/w 1.5 g, 43.7 mmol) in portions. After the mixture stirred at room temperature for 10 min, 1 -bromo-2-(2-bromoethoxy)ethane (10 g, 43.7 mmol) was added and the resulting mixture was refluxed for 4 hrs. Brine (100 mL) was added. The mixture was extracted with EtOAc (50 mL x 2).
  • Example #25 A mixture of compound 4-6 (0.08 g, 0.2 mmol), TEA (0.082 g, 0.82 mmol), pivaloyl chloride (0.074 g, 0.61 mmol) in THF (15 mL) was refluxed overnight. After being washed with brine (20 mL), the mixture was dried over anhydrous Na 2 S0 4 , and concentrated. The residue was purified by prep-TLC to give target compound as a white solid.
  • Example #14 was prepared following the procedure for Example #11, but using ethaneamine in step 4 and cyclobutanecarbonyl chloride in step 6: J H NMR (300 MHz,
  • Example #111 was prepared following the procedure for Example #23, but using propan-2-amine in step 4: *H NMR (300 MHz, CDC1 3 ) ⁇ 8.20 (s, 1H), 7.85 - 7.75 (m, 3H),
  • Example #17 was prepared following the procedure for Example #11,
  • Step 4 The same procedure with the step 4 of Scheme 1 was applied to the preparation of compound 4a-5.
  • LC-MS: m/z 375 [M+H] + .
  • Step 5 The same procedure with the step 4 of Scheme 3 was applied to the preparation of compound 4a-6.
  • LC-MS: m/z 459 [M+H] + .
  • Step 1 n-BuLi (4.8 mL, 12 mmol) was added dropwise to a solution of 5-bromo-2- chloro-3-methylpyridine (2.1 g, 10.0 mmol) in THF (40 mL) at -78 °C. Then DMF (1.5 g, 20 mmol) was added, and stirred for another 2 hours at -78 °C. Methanol (12 mL) was added to quench the reaction. NaBH 4 (1.1 g, 30 mmol) was added, and stirred for 0.5h. Ice water (40 mL) was added. The mixture was extracted with DCM (30 mL x 3).
  • LC-MS: m/z 220.0 [M+H] + .
  • Step 3 The same procedure with the step 4 of Scheme 1 was applied to the preparation of compound 5-4.
  • LC-MS: m/z 316.0 [M+H] + .
  • Step 4 The same procedure with the step 5 of Scheme 1 was applied to the preparation of compound 5-5.
  • LC-MS: m/z 385.9 [M+H] +
  • Step 5 Compound 5-5 (0.37 g, 0.96 mmol), Et 3 N (0.48 g, 4.8 mmol) and EtNH 2 (70% in water, 0.22 g, 4.8 mmol) in NMP (10 mL) was sealed in tube, and stirred for 6 hours at 150 °C. The solvent was removed by reduced pressure. Water (20 mL) was added. The mixture was extracted with EA (10 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na 2 S0 4 , concentrated, and purified by flash column
  • Example #35 Pivaloyl chloride (0.38 g, 3.15 mmol) was added to a solution of compound 5-6 (0.25 g, 0.63 mmol) and Et 3 N (0.32 mmol, 3.15 mmol) in THF (20 mL). The mixture was stirred at 80 °C overnight. The mixture was cooled to room temperature. Water (20 mL) was added. The mixture was extracted with DCM (15 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na 2 S0 4 , concentrated and purified by pre-TLC and pre-HPLC to give the product as white solid.
  • Example #113 was prepared as described in Scheme 5, except using
  • LC-MS: m/z 493.1 [M+H] + .
  • Step 1 A mixture of compound 6-1 (4 g, 20.8 mmol) in DCM (100 mL) was added oxalyl chloride (10.5 g, 83.2 mmol) dropwise. The resulting mixture was stirred at room temperature for 12 hours. Then methanol (6.7 g, 208 mmol) was added into the above solution at 0 °C. After being stirred at room temperature for another 0.5 hours, the mixture was washed with H 2 0 (100 mL), extracted with DCM (100 mL x 2), the organic phase was dried over anhydrous Na 2 S0 4 and concentrated, purified by flash column chromatography to give product 6-2 as white solid.
  • Step 3 To a mixture of compound 6-3 (1.7 g, 8 mmol) in THF (80 mL) was added LAH (0.6 g, 16 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours. Then the reaction was quenched with H 2 0 (2 mL) and filtered. The filtrate was concentrated to give crude product 6-4 as yellow oil.
  • LC-MS: m/z 187.1 [M+H] + .
  • Example #32 To a mixture of compound 6-6 (0.22 g, 0.51 mmol) and NaH (40 mg, 1.02 mmol) in THF (20 mL) was added 1 -(2-bromoethoxy)-2-bromoethane (176 mg, 0.76 mmol) at rt. The resulting mixture was stirred for 6 hours at 75°C, then quenched with H 2 0 (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na 2 S0 4 , concentrated and purified by preparative TLC to give the as white solid.
  • Step 4 To a solution of compound 7-4 (0.415 g, 2.29 mmol), CBr 4 (0.913 g, 2.75 mmol) in DCM (50 mL) was added PPI1 3 (0.78 g, 2.977 mmol) in portions at r.t. The resulting mixture was stirred at r.t. for 0.5 hrs. Then the reaction solution was used directly in step 5 of Scheme 7.
  • LC-MS: m/z 244.0 [M+H] + .
  • Step 1 Under nitrogen atmosphere, to a solution of compound 8-1 (1.0 g, 5 mmol) in dry THF (30 mL) was added ri-But.yllithium, 2.5 M solution in THF (3 mL, 7.5 mmol) dropwise under minus 78 degree. The solution was stirred at -78 degree for 10 min, followed by addition of dry DMF (0.73 g, 10 mmol). The mixture was stirred for 30 min at this temperature and then quenched with H 2 0 (30 mL), extracted with EA (30 mL x 2). The combined organic layer was dried over anhydrous Na 2 S0 4 and concentrated to give product 8-2 as yellow oil.
  • LC-MS: m/z 156.1 [M+H] + .
  • Example #31 To compound 8-7 (15 mg, 0.038 mmol) was added pivaloyl chloride (5 mL), the mixture was stirred for 12 hours at 100 °C. After removed of most of pivaloyl chloride, water (10 mL) was added. The mixture was extracted with EtOAc (10 mL x 2). Combined organic layers was dried over anhydrous Na 2 S0 4 , concentrated and purified by pre-TLC to give the product as white solid.
  • *H NMR 300 MHz, CDC13) ⁇ 7.52 - 7.07 (m, 6H), 4.04 - 3.24 (m, 6H), 2.60 - 2.49 (m, 7H), 1.10 - 1.04 (m, 12H).
  • LC-MS: m/z 479.0 [M+H] + .
  • LC-MS: m/z 215.0 [M+H] + .
  • Step 3 Under nitrogen atmosphere, to a solution of Compound 9-3 (0.5 g, 1.68 mmol) in dry THF (20 mL) was added n-Buiyiluhium, 2.5 M solution in THF (1.0 mL, 2.52 mmol) dropwise under minus 80 degree. The solution was stirred at -80 degree for 5 min, followed by addition of dry DMF (0.24 g, 3.36 mmol). The mixture was stirred for another 10 min at this temperature and then quenched with H 2 0 (20 mL), extracted with EtOAc (20 mL X 3). The combined organic layer was washed with brine (20 mL), dried over Na 2 S0 4 and concentrated to give crude product 9-4 as yellow oil.
  • LC-MS: m/z 249.2 [M+H] + .
  • Example #33 A mixture of compound 9-8 (180 mg, 0.32 mmol) and NaH (15 mg, 0.64 mmol) in THF (10 mL) was added l-(2-bromoethoxy)-2-bromoethane (340 mg, 1.47 mmol) at rt. The resulting mixture was stirred for 3h at 70°C, then quenched with H 2 0 (10 mL), extracted three times with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 S0 4 , and concentrated. The residue was purified by preparative TLC to give target compound Example 33 as yellow oil.
  • Step 3 Under nitrogen atmosphere, to a solution of Compound 10-3 (1.48 g, 4.73 mmol) in dry THF (20 mL) was added n-Butyllithiuni, 2.5 M solution in THF (2.8 mL, 7.09 mmol) dropwise under minus 80 degree. The solution was stirred at -80 degree for 5 min, followed by addition of dry DMF (0.69 g, 9.46 mmol). The mixture was stirred for another 10 min at this temperature and then quenched with H 2 0 (20 mL), extracted with EtOAc (20 mL X 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na 2 S0 4 and concentrated to give crude product 10-4 as a yellow oil.
  • LC-MS: m/z 264.2 [M+H] +
  • Step 5 A mixture of compound 10-5 (0.45 g, 1.70 mmol), 4-chlorobenzenethiol (0.29 g, 2.04 mmol), K 2 C0 3 (0.70 g, 5.09 mmol), methanesulfonyl chloride (0.23 g, 2.04 mmol), KI (0.42 g, 2.55 mmol) and 18-C-6 (45 mg, 0.17 mmol) in THF ( 20 mL) was stirred for 3 days at rt, then diluted with EtOAc (50 mL), washed with H 2 0 (20 mL), brine (20 mL), dried over anhydrous Na 2 S0 4 , and concentrated.
  • Example #110 To a solution of compound 10-6 (35 mg, 0.09 mmol) in DCM (5 mL) was added m-CPBA (46 mg, 0.27 mmol) at rt. The reaction mixture was stirred at rt for 2 hr, then diluted with EtOAc (10 mL), washed with 4N NaOH (5 mL), brine (5 mL), dried over anhydrous Na 2 S0 4 , and concentrated.
  • Step 3 Under nitrogen atmosphere, to a solution of compound 11-3 (0.8 g, 2.64 mmol) in dry THF (30 mL) was added ri-Butyllithiuir!, 2.5 M solution in THF (2.1 ml,, 5.28 mmol) dropwise under minus 78 degree. The solution was stirred at -78 degree for 10 min, followed by addition of dry DMF (0.73 g, 10 mmol). The mixture was stirred for 30 min at this temperature and then quenched with H 2 0 (30 mL), extracted with EA (30 mL x 2). The combined organic layer was dried over Na 2 S0 4 , concentrated and purified by flash column chromatography to give product 11-4 as a yellow oil.
  • LC-MS: m/z 253.1 [M+H] + .
  • Example #7 To a mixture of compound 11-7 (75 mg, 0.18 mmol) and NaH (15 mg, 0.36 mmol) in THF (10 mL) was added 1 -(2-bromoethoxy)-2-bromoethane (63 mg, 0.27 mmol) at rt. The resulting mixture was stirred for 12 hours at 75°C, then quenched with H 2 0 (15 mL), extracted with EA (15 mL x 2). The combined organic layers were dried over Na 2 S0 4 , concentrated and purified by preparative TLC to give product as a yellow solid.
  • Example #230 was prepared as described in Scheme 11, using (R)- ⁇ - cyclohexylethanamine in step 1.
  • LC-MS: m/z 206.9 [M+H] + .
  • Step 2 The same procedure with step 6 of Scheme 11 was applied to the preparation of compound 12-3 as yellow oil.
  • LC-MS: m/z 302.9 [M+H] + .
  • Step 3 The same procedure with step 1 of Scheme 9 was applied to the preparation of compound 12-4 as yellow oil.
  • LC-MS: m/z 311.9 [M+H] + .
  • Step 4 The same procedure with step 2 of Scheme 11 was applied to the preparation of compound 12-5 as yellow oil.
  • LC-MS: m/z 396.1 [M+H] + .
  • Step 1 The same procedure with step 1 of Scheme 6 was applied to the preparation of compound 13-2.
  • LC-MS: m/z 206.0 [M+H] + .
  • Step 2 The same procedure with step 3 of Scheme 6 was applied to the preparation of compound 13-3.
  • LC-MS: m/z 178.0 [M+H] + .
  • Step 3 The same procedure with step 4 of Scheme 7was applied to the preparation of compound 13-4.
  • LC-MS: m/z 239.9 [M+H] + .
  • Step 4 The same procedure with step 5 of Scheme 7 was applied to the preparation of compound 13-5.
  • LC-MS: m/z 336.0 [M+H] + .
  • Step 5 Compound 13-5 (0.8 g, 2.4 mmol) and m-CPBA (0.85 g, 4.8 mmol) was added into 1 ,2-dichloroethane (30 mL), the mixture was stirred for 12 hours at 100 °C, after removed of most of 1,2-dichloroethane, the residue was purified by flash column
  • Step 8 Compound of 13-8 (80 mg, 0.22 mmol) was added pivaloyl chloride (5 mL), the mixture was stirred for 12 hours at 100 °C. After removed of most of pivaloyl chloride, water (10 mL) was added. The mixture was extracted with EtOAc (10 mL x 3). Combined organic layers were dried over anhydrous Na 2 S0 4 , concentrated to give the product 13-9 as yellow solid.
  • LC-MS: m/z 454.9 [M+H] + .
  • Example #15 To a mixture of compound 13-9 (60 mg, 0.13 mmol) and NaH (11 mg, 0.26 mmol) in THF (10 mL) was added 1 -(2-bromoethoxy)-2-bromoethane (46 mg, 0.2 mmol) at rt. The resulting mixture was stirred for 12 hours at 75°C, then quenched with H 2 0 (15 mL), extracted with EA (15 mL x 2). The combined organic layers were dried over Na 2 S0 4 , concentrated and purified by preparative TLC to give Example #15 as a yellow solid.
  • Step 1 To a mixture of compound 14-1 (1 g, 3 mmol) and NaH (240 mg, 6 mmol) in THF (40 mL) was added l-(2-bromoethoxy)-2-bromoethane (1.05 g, 4.5 mmol) at rt. The resulting mixture was stirred for 4 hours at 75°C, then quenched with H 2 0 (50 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na 2 S0 4 , concentrated and purified by flash column chromatography to give product 14-2 as a yellow solid.
  • LC-MS: m/z 405.9 [M+H] + .
  • Example #29 Compound of 14-3 (70 mg, 0.168 mmol) was added
  • Step 1 Under a nitrogen atmosphere, to a solution of compound 15-1 (6 g, 20.2 mmol) in dry THF (50 mL) was added n-Butyllithiiim, 2.5 M solution in THF (12 ml ,, 30.3 mmol) dropwise under minus 80 degree. The solution was stirred at -80 degree for 1 hr, followed by addition of dry DMF (2.9 g, 40.4 mmol). The mixture was stirred for another 1 hr at this temperature and then quenched with H 2 0 (20 mL), extracted with EA (20 mL X 3). The combined organic layer was washed with brine (20 mL), dried over Na 2 S0 4 and concentrated to give crude product The crude product was purified by column
  • Step 6 A mixture of compound 7 (120 mg, 0.32 mmol), 1,3-dibromopropane 8 (195 mg, 0.97 mmol), NaH (39 mg, 60%, 1.61 mmol) in THF (20 mL) was stirred at 80 degree overnight. Then the mixture was diluted with H 2 0 (10 mL), extracted with EA (20 mL X 3). The combined organic layer was washed brine (30 mL), dried over Na 2 S0 4 and concentrated. The residue was purified by preparative TLC to give Example #95 as a white solid.
  • LC-MS: m/z 428.2 [M+H] + .
  • LC-MS: m/z 402.1 [M+H] + .
  • LC-MS: m/z 482.1 [M+H] + .
  • Example #97 was prepared using 4-(trifluoromethyl)benzenethiol in step 4 and
  • LC-MS: m/z 496.1 [M+H] + .
  • Example #81 was prepared using 3,5-dimethylbenzenethiol in step 4 and 1,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CDC1 3 ) ⁇ 7.05 - 6.91 (m, 6H),
  • Example #84 was prepared using 4-ethylbenzenethiol in step 4 and 1,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CDC1 3 ) ⁇ 7.28 - 7.11 (m, 6H), 6.83 (s, 1H), 4.09 (s, 2H), 3.91 - 3.84 (m, 2H), 2.83 - 2.64 (m, 4H), 2.26 (brs, 2H), 2.03 (brs, 2H), 1.66 (brs, 2H), 1.25 - 1.18 (m, 4H), 1.05 (s, 6H).
  • LC-MS: m/z 456.2 [M+H] + .
  • Example #87 was prepared using 4-isopropylbenzenethiol in step 4 and 1,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CD 3 OD) ⁇ 7.31 - 7.04 (m, 6H),
  • LC-MS: m/z 512.2 [M+H] + .
  • Example #79 was prepared using 3,4-dimethoxybenzenethiol in step 4 and 1,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CDC1 3 ) ⁇ 7.06 - 6.71 (m, 6H),
  • Example #80 was prepared using 4-(ieri-butyl)benzenethiol in step 4 and 1 ,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CDC1 3 ) ⁇ 7.31 - 7.25 (m, 4H),
  • LC-MS: m/z 402.1 [M+H] + .
  • Step 1 Under nitrogen atmosphere, to a solution of compound 1 (4 g, 13.5 mmol) in dry THF (20 mL) was added n-Butyllithium, 2.5 M solution (in TilF 8.1 mL, 20.2 mmol) dropwise under minus 80 degrees. The solution was stirred at -80 degree for 1 hr, followed by addition of cyclopentanone (2.3 g, 26.9 mmol). The mixture was stirred for another 1 hr at this temperature and then quenched with H 2 0 (5 mL), extracted with EA (20 mL X 3).
  • Step 2 To a mixture of compound 16-10 (80 mg, 0.26 mmol) and Znl 2 (42 mg, 0.13 mmol) in dry DCM (5 mL) was added 4-niethoxybenzenethiol (44 mg, 0.32 mmol) at r.t. The resulting mixture was stirred at r.t for 0.5 hr, then quenched with H 2 0 (5 mL), extracted with EA (10 mL X 3). The combined organic layer was washed with brine (10 mL), dried over Na 2 S0 4 and concentrated to give product.
  • LC-MS: m/z 426.2 [M+H] + .
  • Example #75 A mixture of compound 16-11 (83 mg, 0.2 mmol) and m-CPBA (101 mg, 0.59 mmol) in DCM (5 mL) was stirred at r.t for 2 hrs. Then it was diluted with EA (20 mL), and washed with brine (10 mL), dried over anhydrous Na 2 S0 4 and concentrated to give product, which was purified by preparative TLC or HPLC to give target compound as white solid.
  • Example #70 was prepared using 3-(trifluoromethyl)benzenethiol in step 2: J H NMR (300 MHz, CD 3 OD) ⁇ 7.98 - 7.96 (m, 1H), 7.70 - 7.62 (m, 2H), 7.49 (s, 1H), 4.17 (s, 2H), 3.89 - 3.87 (m, 2H), 2.80 - 2.77 (m, 2H), 2.39 - 2.37 (m, 2H), 2.07 - 2.05 (m, 2H), 1.73 -
  • Example #67 was prepared using 3,4-dimethylbenzenethiol in step 2: J H NMR
  • LC- MS: m/z 580.1 [M+H] + .
  • Example #69 was prepared using 3- fluoro-4-methoxybenzenethiol in step 2: 1 H
  • Example #72 was prepared using 3-isopropoxybenzenethiol in step 2: 1 H NMR
  • Example #68 was prepared using 3,5-difluorobenzenethiol in step 2: 1 H NMR
  • LC-MS: m/z 434.2 [M+H] + .
  • Step 1 Compound 17-2 was prepared from compound 17-1 using the procedure described in Scheme 16, Step 1 using dihydro-2H-pyran-3(4H)-one instead of
  • Step 2 Compound 17-3 was prepared from compound 17-2 using the procedure described in Scheme 16, Step 2 using 4-chlorobenzenethiol in place of 4- methoxybenzenethiol.
  • LC-MS: m/z 446.1 [M+H] + .
  • Step 1 Under nitrogen atmosphere, to a solution of compound 1 (1.68 g, 5.66 mmol) in dry THF (30 mL) was added n-Butyllithiura, 2.5 M solution (in THF 3.4 mL, 8.48 mmol) dropwise under -78 degrees. The solution was stirred at -78 degree for 1 hr, followed by addition of tert-butyl 3-oxopyrrolidine-l-carboxylate (2.1 g, 11.3 mmol). The mixture was stirred for another 1 hr at this temperature and then quenched with H 2 0 (5 mL), extracted with EA (30 mL X 3).
  • Step 2 To a mixture of compound 18-17 (1.2 g, 2.97 mmol) in MsOH (10 mL) and
  • Step 5 To a mixture of compound 18-20 (0.14 g, 0.25 mmol) in EA (5 mL) was added a sat.
  • Example #54 A mixture of compound 18-21 (140 mg, 0.3 mmol), (HCHO) n (91 mg, 3.03 mmol) and a drop of HCOOH in DCM (10 mL) was stirred at r.t for 4 hrs, followed by the addition of NaBH(OAc)3 (0.19 g, 0.9 mmol). After being stirred overnight, the mixture was diluted with DCM (20 mL). Then it was washed with brine (10 mL), dried over Na 2 S0 4 and concentrated to give product, which was purified by preparative TLC and HPLC to give target compound as white solid.
  • Step 1 To a mixture of compound 18b-22, prepared on route to Example #56, (0.3 g, 0.68 mmol) and TEA (0.2 g, 2.03 mmol) in DCM (20 mL) was added acetyl chloride (0.08 g, 1.01 mmol) dropwise at 0 degree. After being stirred at r.t for 3 hrs, the mixture was washed with brine (10 mL), dried over Na 2 S0 4 and concentrated. The residue was purified by preparative TLC to give target compound as colorless oil.
  • Example #89 To a solution of Example #91 (30 mg, 0.063 mmol) in MeOH (10 mL) was added 10%Pd/C (10 mg). The mixture was charged with hydrogen balloon and stirred at room temperature for 2 hrs. After filtration, the filtrate was concentrated to give the product as a white solid.
  • Step 1 To a solution of compound 20-24 (0.5 g, 3.4 mmol) in THF (20 mL) was added LAH (0.39 g, 10.2 mmol) at 0 degree. The mixture was stirred at r.t for 4 hrs and then quenched with ice water (1 mL). The mixture was filtered and concentrated to give product as a yellow oil.
  • Example #63 To a solution of compound 15-7c (70 mg, 0.16 mmol) and NaH (24 mg, 60% purity, 0.48 mmol) in THF (5 mL) was added compound 26 (110 mg, 0.45 mmol) at r.t. The mixture was stirred at 70 degree for 12 hrs and then poured into ice water (10 mL). The mixture was extracted with EA (10 mL X2). The combined organic layer was washed with brine (20 mL), dried over Na 2 S0 4 and concentrated to give crude product which was purified by preparative TLC to give target compound as a white solid.
  • Example #62 A solution of compound 21-30 (0.4 g, 0.82 mmol) and Grubbs Catalyst 2 nd Generation (70 mg, 0.082 mmol) in DCM (10 mL) was stirred at r.t overnight. Then it was concentrated and the residue was purified by preparative TLC to give the product Example # 62 as a yellow solid.
  • Example #49 To a solution of Example #62 (100 mg, 0.22 mmol), Cu (0.5 g, 7.8 mmol), I 2 (50 mg, 0.2 mmol) in Toluene (10 mL) was added diiodomethane (0.64 mL, 7.8 mmol) at r.t. The mixture was stirred at 97 degree for 48 hrs and then filtered. The filtrate was concentrated to give crude product which was purified by preparative TLC to give target compound as a white solid.
  • Example #61 A solution of Example #62 (0.1 g, 0.22 mmol) in H 2 0 2 (2 mL) and HCOOH (4 mL) was stirred at 40 degree for 3 hrs and then concentrated. The residue was purified by preparative TLC to give target compound as a white solid.
  • Step 1 To a solution of compound 15-7b (2.4 g, 5.9 mmol) in THF (60 mL) was added NaH (0.7 g, 29.5 mmol) in portions at r.t. After being stirred at r.t for 0.5 hrs, the mixture was added 3-bromoprop-l-ene (1.4 g, 11.8 mmol) and stirred overnight at 30 degree. Then it was poured into ice water (50 mL). The mixture was extracted with EA (60 mL X 3). The combined organic layer was washed with brine (100 mL), dried over Na 2 S0 4 and concentrated to give the desired product as a yellow oil.
  • LC-MS: m/z 448.1 [M+H] + .
  • Step 2 To a solution of compound 22-31 (1.2 g, 2.68 mmol) in DCM (40 mL) was added m-CPBA (2.3 g, 13.4 mmol) at r.t. The mixture was stirred at r.t overnight and then washed with Na 2 S0 3 (40 mL), brine (40 mL), dried over Na 2 S0 4 and concentrated to give the product as a yellow solid.
  • LC-MS: m/z 464.1 [M+H] + .
  • Example #51 To a solution of Example #57 (0.25 g, 0.54 mmol) in DCM (10 mL) was added PCC (0.1 g, 1.2 mmol) at r.t. The mixture was stirred at 30 degree for 5 hrs and then filtered. The filtrate was concentrated to give the product as a yellow solid.
  • LC-MS: m/z 462.1 [M+H] + .
  • Example #47 To a solution of Example #51 (60 mg, 0.13 mmol) in DCM (10 mL) was added DAST (200 mg, 1.24 mmol) at r.t. After stirred at r.t for 48 hrs, the mixture was concentrated to give crude product which was purified by preparative TLC to give the target compound as a white solid.
  • H NMR 300 MHz, CD 3 OD
  • ⁇ 7.50 - 7.13 (m, 6H), 6.85 (s, 1H), 4.12 (s, 2H), 3.89 - 3.28 (m, 4H), 3.26 - 3.24 (m, 2H), 1.14 (t, / 6.9 Hz, 3H), 1.01 (s, 6H).
  • Example #52 To a solution of Example #51 (0.01 g, 0.02 mmol) in Et 2 0 (10 mL) was added Methylmagnesiumbromide (3M in THF, 0.2 mL, 0.6 mmol) at minus 70 degree. The mixture was allowed to warm to r.t and stirred overnight. Then it was concentrated to give crude product. The crude product was purified by preparative TLC to give target compound as a white solid.
  • Methylmagnesiumbromide 3M in THF, 0.2 mL, 0.6 mmol
  • LC-MS: m/z 492.1 [M+H] + .
  • Step 3 Compound 23-35 was prepared using the procedure described in Scheme 15, Step 2.
  • LC-MS: m/z 280.2 [M+H] + .
  • Step 5 Compound 23-37 was prepared using the procedure described in Scheme
  • LC-MS: m/z 504.1 [M+H] + .
  • Example #48 was prepared as described in Scheme 23 except
  • Example #58 was prepared following the procedure for Example #48, but using 1- bromo-2-(2-bromoethoxy)ethane in step 7: *H NMR (300 MHz, CD 3 OD) ⁇ 7.47 - 7.03 (m,
  • Example #55 Prepared from compound 24-88 following the same procedure described for Example #95. *H NMR (300 MHz, CD 3 OD) ⁇ 7.89 - 7.83 (m, 4H), 7.24 - 6.97 (m, 3H), 4.54 - 4.52 (m, 1H), 4.22 - 4.18 (m, 1H), 4.07 - 4.02 (m, 1H), 3.90 - 3.88 (m, 2H), 2.98 - 2.29 (m, 4H), 1.72 - 1.63 (m, 1H), 1.45 - 1.42 (m, 1H), 1.16 - 1.12 (m, 3H), 0.99 - 0.94 (m, 6H).
  • Step 3 n-BuLi (0.7 mL, 1.65 mmol) was added to a solution of compound 25-3 (0.5 g, 1.5 mmol) in THF (20 mL) at -78 °C. The mixture was stirred for 0.5h at -78 °C. Then DMF (0.2 g, 3.0 mmol) was added. The reaction was stirred for another 0.5h at -78 °C.
  • Step 5 The solution of compound 25-5 (0.06 g, 0.17 mmol), sodium 4- chlorobenzenesulfinate (0.037 g, 0.187 mmol), TBAI (0.031 g, 0.085 mmol) and KI (0.028 g, 0.17 mmol) in DMF (10 mL) was stirred for overnight at rt. Water (10 mL) was added. The mixture was extracted with EA (20 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na 2 S0 4 , concentrated, and purified by flash column
  • Example #4 The solution of compound 25-6 (100 mg, 0.23 mmol) in THF (10 mL) was NaH (140 mg, 9.7 mmol, 60 w/w) at rt. Then 1 -bromo-2-(2-bromoethoxy)ethane (70 mg, 0.3 mmol) was added and stirred overnight at 50 °C. The mixture was cooled to room temperature. Water (10 mL) was added. The mixture was extracted with DCM (15 mL x 3). Combined organic layer was washed with brine, dried over anhydrous Na 2 S0 4 , concentrated, and purified by pre-TLC and pre-HPLC to give the desired product as a white solid.
  • Example # 101 was prepared following the procedure for Example #4, except 4- bromo-3-chloroaniline was used as starting material in step 1:
  • LC-MS: m/z 511.9 [M+H] + .
  • Example #122 was prepared according to the procedures described in Scheme 25, except using sodium-3-fluorobenzenesulfinate in step 5.
  • LC-MS: m/z 496.1 [M+H] + .
  • Example #123 was prepared as described in Scheme 25, except using sodium-4- trifluoromethoxybenzenesulfinate in step 5.
  • Example #124 was prepared as described in Scheme 25, except using sodium-3,4- dichloromethoxybenzenesulfinate in step 5.
  • LC-MS: m/z 546.0 [M+H]+.
  • Example #129 was prepared as described in Scheme 25, except using sodium-3- chloro-4-methoxybenzenesulfinate in step 5.
  • Example #131 was prepared as described in Scheme 25, except using sodium-3- trifluoromethoxybenzenesulfinate in step 5. !
  • Example #135 was prepared as described in Scheme 25, except using 4-bromo-2- chloroaniline in step 1 and cyclobutanecarbonyl chloride in step 2.
  • J H NMR 300 MHz, CDCI 3 ) ⁇ 7.35 - 7.31 (m, 4H), 7.11 - 7.04 (m, 3H), 5.01 - 4.92 (m, 1H), 4.04 - 4.01 (m, 2H), 3.36 - 3.29 (m, 2H), 2.70 - 2.63 (m, 3H), 2.39 - 2.25 (m, 4H), 1.81 - 1.66 (m, 4H), 1.1 1 - 0.99 (m, 6H).
  • Example #136 was prepared as described in Scheme 25, except using 4-bromo-2- chloroaniline in step 1 and cyclobutanecarbonyl chloride in step 2.
  • 1 H NMR 300 MHz, CDCI 3 ) ⁇ 7.63 - 7.43 (m, 4H), 7.03 - 6.91 (m, 3H), 4.98 - 4.89 (m, 1H), 4.33 (s, 2H), 2.76 - 2.68 (m, 2H), 2.34 - 2.23 (m, 2H), 1.74 - 1.52 (m, 4H), 1.08 - 0.96 (m, 6H).
  • LC-MS: m/z 424.1 [M+H] + .
  • Example #137 was prepared as described in Scheme 25, except using 4-bromo-2- methylaniline in step 1 and cyclobutanecarbonyl chloride in step 2.
  • Example #138 was prepared as described in Scheme 25, except using 4-bromo-2- chloroaniline in step 1 and l , l-bis(iodomethyl)cyclopropane in step 6.
  • 1 H NMR 300 MHz, CDCI 3 ) ⁇ 7.35 - 7.25 (m, 4H), 6.94 - 6.80 (m, 3H), 4.57 - 4.48 (m, 1H), 3.35 - 3.29 (m, 2H), 2.77 - 2.69 (m, 2H), 2.16 (s, 3H), 1.25 - 0.94 (m,15H), 0.72 - 0.66 (m, 2H), 0.51- 0.45 (m, 2H).
  • Step 3 The same procedure with the step 3 of Scheme 1 was applied to the preparation of compound 26-4.
  • LC-MS: m/z 270.1 [M+H] + .
  • Step 4 The same procedure with the step 4 of Scheme 1 was applied to the preparation of compound 26-5.
  • LC-MS: m/z 332.0 [M+H] + .
  • Step 5 The same procedure with the step 5 of Scheme 1 was applied to the preparation of compound 26-6.
  • LC-MS: m/z 462.0 [M+H] + .
  • LC-MS: m/z 531.9 [M+H] + .
  • Example #38 was prepared following the procedure for Example #18, except 4- bromo-2-(trifluoromethyl)aniline was used as starting material in step 1:
  • 1 H NMR 300 MHz, CDC1 3 ) ⁇ 7.63 - 7.51 (m, 1H), 7.39 - 7.26 (m, 6H), 4.37 - 4.16 (m, 2H), 4.08 - 3.94 (m, 2H), 3.36 - 3.12 (m, 2H), 2.75 - 2.54 (m, 2H), 2.49 - 2.33 (m, 2H), 1.28 - 0.99 (m, 12H).
  • LC-MS: m/z 532.2 [M+H] + .
  • Step 1 The same procedure with the step 1 of Scheme 1 was applied to the preparation of compound 27-2.
  • LC-MS: m/z 228.0 [M+H] + .
  • Step 2 The same procedure with the step 2 of Scheme 1 was applied to the preparation of compound 27-3.
  • LC-MS: m/z 312.1 [M+H] + .
  • Step 3 The same procedure with the step 3 of Scheme 1 was applied to the preparation of compound 27-4.
  • LC-MS: m/z 264.1 [M+H] + .
  • Step 5 The same procedure with the step 5 of Scheme 1 was applied to the preparation of compound 27-6.
  • LC-MS: m/z 422.1 [M+H] + .
  • Step 2 To a 0°C solution of compound 28-2 (0.6 g, 2.66 mmol) in THF (40 mL) was added L1AIH 4 (0.202 g, 5.32 mmol). The reaction was stirred for 2 hrs. then quenched with water and 10% NaOH aqueous solution. The resulting mixture was filtered and the filtrate evaporated to give crude 28-3 as a colorless oil.
  • LC-MS: m/z 198.1 [M+H] + .
  • Step 3 To a 0°C solution of compound 28-3 (0.456 g, 2.3 mmol) in CH 2 C1 2 (10 mL) was added PBr 3 (0.623g, 2.3 mmol). The reaction was stirred for 1 nr. and poured into a mixture of sodium 4-chlorobenzenesulfinate (0.548 g, 2.76 mmol), TBAI (0.17 g, 0.46 mmol) and KI (0.458 g, 2.76 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 3 hrs. The reaction was quenched with water and extracted with EA (20 mL x 3).
  • Example #116 was prepared as described in Scheme 28, except using
  • Example #117 was prepared as described in Scheme 28, except using
  • Example #118 was prepared as described in Scheme 28, except using
  • Example #119 was prepared as described in Scheme 28, except using 4-bromo-2- methylaniline and cyclopropylmethanamine in step 1.
  • J H NMR 300 MHz, CDCI 3 ) ⁇ 7.37 - 7.31 (m, 4H), 7.20 - 7.12 (m, 2H), 6.99 - 6.96 (m, 2H), 4.14 - 4.08 (m, 1H), 4.01 - 3.97 (m, 2H), 3.34 - 3.25 (m, 2H), 2.66 - 2.62 (m, 2H), 2.42 - 2.38 (m, 2H), 2.20 (s, 3H), 1.26 - 1.00 (m, 10H), 0.44 - 0.41 (m, 2H), 0.16 - 0.10 (m, 1H), -0.03 - -0.09 (m, 1H).
  • Step 1 To a mixture of compound 29-1 (prepared as outlined in Scheme 6, using sodium 3-(trifluoromethyl)benzenesulfinate in Step 4) (0.2 g, 0.43 mmol) in THF (10 mL) was added NaH (21 mg, 0.87 mmol), then followed by 2-(3-bromopropoxy)-tetrahydro-2H- pyran (0.14g, 0.65 mmol) at r.t. The resulting mixture was stirred overnight at 70 °C, quenched with H 2 0 (10 mL) and extracted with EA (10 mL x 3).
  • Step 2 A mixture of compound 29-2 (0.91 g, 1.37 mmol), PPTS (35 mg, 0.14 mmol) in EtOH (20 mL) was stirred at 80 °C for 1 hr. and concentrated in vacuo.
  • Step 3 To a 0 °C mixture of compound 29-3 (0.75 g, 1.44 mmol) and CBr 4 (0.5 g, 1.51 mmol) in DCM (15 mL) was added ⁇ 13 ⁇ 4 (0.4 g, 1.51 mmol). The reaction miture was stirred at r.t. for 20 min. the concentrated. The residue was purified by column
  • Step 4 To a 0 °C mixture of compound 1-4 (0.2 g, 0.34 mmol) and NaH (41 mg, 1.72 mmol) in THF (15 mL) was added (HCHO) n (0.27 g, 3.43 mmol). The reaction was stirred for 2 hrs. then warmed to rt and stirred for another 2 hrs. The reaction was quenched with H 2 0 (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine (lOmL), dried over Na 2 S0 4 and concentrated. The residue was purified by prep. TLC to give Example #139 as a white solid.
  • Step 2 A mixture of compound 30-2 (0.3 g, 1.2 mmol), sodium 4- chlorobenzenesulfinate (0.29 g, 1.44 mmol), KI (28 mg, 0.24 mmol), TBAI (88 mg, 0.24 mmol) in DMF (50 Ml) was stirred at room temperature for lh. The crude 30-3 was used directly in next step without purification.
  • Example #143 was prepared as described in Scheme 30, except using
  • Example #144 was prepared as described in Scheme 30, except the ethyl substituent was inserted in Step 5 using sodium hydride and ethyl iodide as outlined in

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Abstract

The present invention relates to aryl sulfones and related compounds that are modulators of ROR-gamma receptors. The invention also provides pharmaceutical compositions comprising these modulators, and methods of modulating ROR-gamma receptors using them. Also provided are methods of using aryl sulfones and related compounds as modulators of ROR-gamma to treat ROR-gamma mediated diseases.

Description

NOVEL COMPOUNDS FOR MODULATION OF ROR-samma ACTIVITY
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of United States Provisional Patent Application Serial Nos. 61/683,651, filed August 15, 2012 and 61/786,278, filed March 14, 2013, the disclosures of which are incorporated herein by reference in their entireties.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to aryl sulfones and related compounds that are modulators of ROR-gamma activity. The invention also provides pharmaceutical compositions comprising these modulators. Also provided are methods of using these modulators to treat ROR-gamma mediated diseases.
BACKGROUND OF THE INVENTION
[0003] Dysregulation of the immune system is a common cause of human disease.
Autoimmune diseases occur when the immune system attacks and destroys healthy body tissue. Other inflammatory diseases, such as asthma, do not necessarily result from a direct attack on healthy tissue but rather from improper or uncontrolled immune responses. Agents that modulate the development and function of cells of the immune system can be useful as therapies for such diseases.
[0004] One method of achieving such modulation is by targeting the function of nuclear receptors expressed in the immune system. Nuclear receptors are a superfamily of ligand- regulated DNA-binding transcription factors that are expressed by many cell types and control a broad spectrum of physiological processes. Drugs that target nuclear receptors are used in the treatment of numerous human diseases. Pharmaceutical nuclear receptor agonists or antagonists, such as tamoxifen for oestrogen receptors (targeted in breast cancer), thiazolidinediones for peroxisome proliferator-activated receptor-γ (PPARy) (targeted in type II diabetes), or dexamethasone for the glucocorticoid receptor (targeted in inflammatory diseases), are among the most commonly used drugs. The nuclear receptor, RAR-related orphan receptor C (RORC, ROR-gamma, ROR-gamma-t, and RORy), is expressed in cells of the immune system and plays an important role in immune system function. Disclosed herein are aryl sulfones and related compounds that are useful as modulators of ROR-gamma activity. SUMMARY OF THE INVENTION
[0005] In one aspect, the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula I:
Figure imgf000003_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000003_0002
is SO or SO
A1, A2, A3, and A4 are each independently C or N;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R2 and R3 are each independently H, optionally substituted alkyl, optionally substituted C3-S cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R2 and R3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
R4a, R4b, R4c, and R4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl; R a and R are each independently H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl;
R6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, R6a and R6b are each independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or R6a and R61 together form an optionally substituted heterocycloalkyl ring; or
R40 and R6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
[0006] In another aspect, the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula la:
Figure imgf000004_0001
Formula la
or pharmaceutically acceptable salts thereof, wherein:
X is SO or S02;
A1, A2, A3, and A4 are each independently C or N;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R2 and R3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R2 and R3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
R4a, R4b, R4c, and R4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl; R6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or R40 and R6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
[0007] In some embodiments of Formula I, and la, R40 and R6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring, as shown in Formula la1 :
Figure imgf000005_0001
Formula la1
or a pharmaceutically acceptable salt thereof,
wherein:
W1 is CR7aR7b, NR7c, or O;
W2 and W3 are each independently CR7aR7b, NR7c, O, or a bond; and
R7a , R7b, and R7c are each independently H or C1-4 alkyl.
[0008] In another aspect, the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula lb:
Figure imgf000005_0002
Formula lb
or pharmaceutically acceptable salts thereof, wherein:
X is SO or S02;
A1, A2, A3, and A4 are each independently C or N;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; R2 and R3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R2 and R3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
R4a, R4b, R4c, and R4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or
R40 and R6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
[0009] The compounds of Formula I, Formula la, Formula la1, and Formula lb can include one or more of the following embodiments.
[0010] In one embodiment, R2 and R3 together form cycloalkyl, cycloalkenyl,
cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, carboxyl, and acetyl.
[0011] In another embodiment, R2 and R3 are each independently H, optionally substituted Ci-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted OCi_6 alkyl, CN, OH.
[0012] In still another embodiment, R4c is H, optionally substituted Ci_6 alkyl, optionally substituted OCi_6 alkyl, optionally substituted carbocycle, halogen, CN, OH, or absent; and R6 is optionally substituted alkyl, optionally substituted C2-6 alkenyl, optionally substituted carbocycle, or optionally substituted heterocycle.
[0013] In yet another embodiment, R40 is H, optionally substituted Ci_6 alkyl, optionally substituted OCi_6 alkyl, optionally substituted carbocycle, halogen, CN, OH, or absent; and R6 is optionally substituted alkyl, optionally substituted C2-6 alkenyl, optionally substituted carbocycle, or optionally substituted heterocycle; and R2 and R3 together form cycloalkyl, cycloalkenyl, cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, carboxyl, and acetyl.
[0014] In a further embodiment, R40 is H, optionally substituted Ci_6 alkyl, optionally substituted OCi_6 alkyl, optionally substituted carbocycle, halogen, CN, OH, or absent; and R6 is optionally substituted alkyl, optionally substituted C2-6 alkenyl, optionally substituted carbocycle, or optionally substituted heterocycle; and R2 and R3 are each independently H, optionally substituted Ci_6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted Od_6 alkyl, CN, OH.
[0015] In several embodiments, R4c and R6 taken together form an optionally substituted heterocyclic ring.
[0016] In another aspect, the invention includes a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier or adjuvant.
[0017] In another aspect, the invention includes a method of modulating the activity of an ROR-gamma receptor with a modulator of ROR-gamma, comprising contacting the receptor with a compound of Formula I, or a pharmaceutically acceptable salt thereof.
[0018] In one embodiment of this aspect, the compound of Formula I modulates the activity of an ROR-gamma receptor in vitro. In another embodiment, the compound of Formula I modulates the activity of an ROR-gamma receptor in vivo. In one embodiment, the compound of Formula I is a modulator of the ROR-gamma receptor.
[0019] In yet another aspect, the invention includes a method of treating or reducing the severity of an ROR-gamma receptor mediated disease in a patient comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
[0020] In one embodiment of this aspect, an ROR-gamma receptor mediated disease can include an automimmune disease. In some embodiments, an autoimmune disease is selected from the group consisting of Ankylosing spondylitis, Asthma, Behcet's disease, Chronic obstructive pulmonary disease, Crohn's disease, Diabetes Mellitus Type 1, Multiple Sclerosis, Neuromyelitis optica, Polymyalgia Rheumatica, Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren's syndrome, Systemic Lupus Erythematosus, Systemic sclerosis, Transplant rejection, Inflammatory Bowel Disease, Ulcerative Colitis and Uveitis. DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0021] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed. : Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0022] As used herein the term "aliphatic' encompasses the terms alkyl, alkenyl, alkynyl. Unless otherwise stated, aliphatic can include both substituted alkyl, alkenyl, and alkynyl and unsubstituted alkyl, alkenyl, and alkynyl.
[0023] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6, 1-4, or 1, 2, 3, 4, 5, 6, 7, or 8) carbon atoms. As used herein, the terminology C1-n alkyl refers to an alkyl group containing 1-n carbon atoms. For example, Ci-5 alkyl refers to an alkyl group containing 1, 2, 3, 4, or 5 carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2- ethylhexyl.
[0024] As used herein, an "alkenyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
[0025] As used herein, an "alkynyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one triple bond. Like an alkyl group, an alkynyl group can be straight or branched.
[0026] As used herein, an "amino" group refers to -NRXRY wherein each of Rx and RY is independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl,
(heterocycloalkyl)alkyl, heteroaryl, or carbonyl each of which are defined herein. Examples of amino groups include alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino,
(azacycloalkylcarbonyl)amino, heteroaralkylcarbonylamino, heteroarylcarbonylamino, carbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, cycloalkylcarbonylamino. When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NRX-. Rx has the same meaning as defined above. A nonexhaustive list of possible Rx and RY includes
sulfonylamino, alkylamino, carbonylamino, carboxy, oxo, hydroxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylalkylcarbonyl, heteroarylcarbonyl, or heteroaralkylcarbonyl.
[0027] As used herein, a "carbonyl" group, when used alone or as part of another structure refers to -(CO)Rx, where Rx is defined above. When the term "carbonyl" is not the terminal group (e.g., arylaminoalkylcarbonyl) it is represented by -C(0)Rx. Without limitation, carbonyl groups can include optionally substituted aminocarbonyl, alkoxyalkoxycarbonyl, alkylaminocarbonyl, arylcarbonyl (e.g., haloarylcarbonyl), heterocycloalkylcarbonyl, heterocycloalkenylcarbonyl, arylaminocarbonyl (e.g., haloarylaminocarbonyl),
cyanoalkylarylcarbonyl, heterocycloalkoxycarbonyl, alkynyloxycarbonyl,
cycloalkoxycarbonyl, heterobicycloarylcarbonyl, alkylheteroarylaminocarbonyl,
alkoxy arylcarbonyl (e.g., haloalkoxyarylcarbonyl), (alkylheterocyclo)alkenylcarbonyl, heteroarylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl (e.g.,
haloalkoxycarbonyl), alkylarylcarbonyl, cycloalkylcarbonyl, alkylheteroarylcarbonyl, arylsulfonylcarbonyl, aminocarbonyl, sulfonylcarbonyl, alkylcarbonyl,
alkylsulfonylcarbonyl, alkylcarbonyl, arylaminocarbonyl, or the like. A nonexhaustive list of possible Rx and RY includes sulfonylaminocarbonyl, alkylcarbonyl, carbonylamino, carboxy, oxo, hydroxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylalkylcarbonyl, heteroarylcarbonyl, or
heteroaralkylcarbonyl.
[0028] As used herein, an "aryl" group used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to an aromatic monocyclic ring ((e.g., phenyl); an aromatic Cs-Cio bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl,
tetrahydroindenyl); an aromatic C10-C14 tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, anthracenyl, or tetrahydroanthracenyl); or a C8-C14 benzofused group having 2-3 carbocyclic rings in which one or more of the rings are aromatic. For example, a benzofused group includes phenyl fused with two or more C4_8 carbocyclic moieties.
[0029] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a C1-4 alkyl group) that is substituted with an aryl group. Both "alkyl" and "aryl" are defined herein. An example of an aralkyl group is benzyl.
[0030] A "heteroaralkyl" group refers to an alkyl group that is substituted with a heteroaryl. Both "alkyl" and "heteroaryl" are defined herein.
[0031] The term "cycloaliphatic" means a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon ring that has a single point of attachment to the rest of the molecule. Cycloaliphatic rings are 3-8 membered monocyclic rings (e.g., 3-6 membered rings). Cycloaliphatic rings also include 8-12 membered bicyclic hydrocarbon rings, (e.g., 10 membered bicyclic hydrocarbon rings). A cycloaliphatic group encompasses a "cycloalkyl" group and a "cycloalkenyl" group.
[0032] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic mono-, bi-, tri-, or multicyclic (fused or bridged) ring of 3-10 (e.g., 4-6, 5-10, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms. Without limitation, examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like. Without limitation, examples of bicyclic cycloalkyl groups include octahydro-indenyl, decahydro- naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, bicycle[2.2.1]heptanyl, bicycle[3.1.1]heptanyl, or the like. Without limitation, multicyclic groups include adamantyl, cubyl, norbornyl, or the like.
[0033] A "cycloalkenyl" group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl.
[0034] The terms "spiro," "spirocycle," or "spirocyclic," or "spirocyclyl" as used herein, refer to two rings joined by a single carbon atom common to both, wherein the spirocyclyl ring system has 3-14 (e.g., 4-6, 5-10, 6-12, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14) carbon atoms. Examples of spirocyclyl groups include spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[2.5]octanyl, spiro[2.6]nonanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[3.6]decanyl, spiro[4.4]nonanyl, spiro[4.5]decanyl, spiro[4.6]undecanyl,
spiro[5.5]undecanyl, spiro[5.6]dodecanyl, or spiro[6.6.]tridecanyl.
[0035] The terms "carbocycle," "carbocyclic" or "carbocyclyl" as used herein indicates a fully saturated, partially saturated, or unsaturated C3-10 monocyclic or bicyclic ring having only carbon ring atoms. Bicyclic carbocycles may be fused or spirocyclic ring systems. C3-10 carbocyclic groups include fully saturated cycloalkyl rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl rings); partially saturated carbocyclic groups (e.g., cyclopropene, cyclobutene, cyclopentene and cyclohexene rings); bicyclic moieties (e.g., indene, 2,3-dihydro-indene, and 1,2,3,4-tetrahydronaphthalene groups);
bridged moieties (e.g., bicyclo[3.1.0]hexane, bicyclo[3.2.1]octane, and bicyclo[3.1 .ljheptane groups); and spirocyclic carbocycles (e.g., spiro[2.3]hexane, spiro[2.4]hexane,
spiro[3.3]heptane, spiro[3.4]octane, spiro[2.5]octane, spiro[4.5]decane and
spiro[5.5]hendecane). Unsaturated carbocyclic moieties include phenyl and naphthyl groups.
[0036] It will be understood that the terms listed above for heterocycles includes each possible atomic orientation for the groups listed. For instance, the term oxadiazole includes 1,2,3-oxadiazole, 1,3,4-oxadiazole and 1,2,4-oxadiazole; the term thiadiazole includes 1,2,3- thiadiazole, 1,3,4-thiadiazole and 1,2,4-thiadiazole.
[0037] The terms "heterocycle" or "heterocyclic," or "heterocyclyl" as used herein indicates a fully saturated, partially saturated, or unsaturated 3- to 12-membered monocyclic or bicyclic ring having from 1 to 5 ring heteroatoms selected from O, S or N. The bicyclic heterocycles may be fused or spirocyclic ring systems. Monocyclic or bicyclic heterocycles, alone, and together with fused or spirocyclic groups, include aziridines, oxirane, azetidine, azirine, thirene, oxetane, oxazetidine, tetrazole, oxadiazole, thiadiazole, triazole, isoxazole oxazole, oxathiazole, oxadiazolone, isothiazole, thiazole, imidazole, pyrazole, isopyrazole, diazine, oxazine, dioxazine, oxadiazine, thiadiazine, oxathiazole, triazine, thiazine, dithiazine, tetrazine, pentazine, pyrazolidine, pyrrole, pyrrolidine, furan, thiophene, isothiophene, tetrazine, triazine, morpholine, thiazine, piperazine, pyrazine, pyridazine, pyrimidine, piperidine, pyridine, pyran, thiopyran, azepine, diazepine, triazepine, azepane, 3-aza- bicylco[3.2.1]octane, 2-lo aza-bicylco[2.2.1]heptane, octahydrocyclopentapyrrole, aza- bicyclo-nonane, indole, indoline, isoindoline, indolizine, octahydro-isoindole, 2- azaspiro[4.5]decane, 6-azaspiro[2.5]octane, 7-azaspiro[3.5]nonane, 8-azaspiro[4.5]decane, 3- asaspiro[5.5]undecane, l-oxa-7-azaspiro[4.4]nonane, l-oxa-8-azaspiro[4.5]decane, purine, benzothiazole, benzoxazole, indazole, benzofuran, and isobenzofuran. Examples of spirocyclic heterocycles include oxaspiro[2.3]hexaneI l-oxaspiro[3.4]octane, 1- oxaspiro[2.5]octaneI 2-oxaspiro[4.5]decane, 2,6-diazaspiro[3.2]heptane, azaspiro[2.5]octane, 6-aza-spiro[2.5]octane, l,6-diazaspiro[2.5]octane, 7-aza-spiro[3.5]nonane, 3-aza- spiro[5.5]undecane, 8-azaspiro[4.5]decane, l,3-diazaspiro[4.5]decane, 2,8- diazaspiro[5.5]hendecaneI 3,9- diazaspir0[5.5]hendecane, and l-ox-6-azaspiro[2.5]octane. It will be understood that the terms listed above for heterocycles includes each possible atomic orientation for the groups listed. For instance, the term oxadiazole includes 1 ,2,3-oxadiazole, 1,3,4-oxadiazole and 1,2,4-oxadiazole; the term thiadiazole.
[0038] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono or bicyclic (fused or bridged) (e.g., 4-6, 5-10, 3, 4, 5, 6, 7, 8, 9, or 10-membered mono or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1 ,4-dioxolanyl, 1 ,4-dithianyl, 1,3- dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[^]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza- bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octanyl, 2,6-dioxa-tricyclo[3.3.1.03'7]nonyl, tropane. A monocyclic heterocycloalkyl group may be fused with a phenyl moiety such as tetrahydroisoquinoline. Heterocycloalkyl ring structures can be optionally substituted at any chemically viable position on the ring or rings.
[0039] A "heterocycloalkenyl" group, as used herein, refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S).
Examples of heterocycloalkenyls include 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, or 2-pyrazolyl. Monocyclic heteroaliphatics are numbered according to standard chemical nomenclature. For instance:
Figure imgf000012_0001
2-Pyrazoline
[0040] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring structure having 4 to 15 (e.g., 5-9, 6-13, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof), and wherein one or more rings of the bicyclic or tricyclic ring structure is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes benzo fused with one or two C4_8 heterocyclic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[^]furyl, benzoyl thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, 1H- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo[Z?]furyl, benzo[Z?]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-l,2,5-thiadiazolyl, or 1,8-naphthyridyl.
[0041] Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature. For instance:
Figure imgf000013_0001
Furan Thiazole Pyrimidine
[0042] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo[^]furyl, benzo[^]thiophenyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolizyl, isoindolyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, indolizinyl, imidazopyridinyl, tetrahydrobenzoazepinyl, tetrahydrobenzooxazepinyl, benzo[ 1 ,4]oxazinyl, benzodihydro[ 1 ,4]oxazinyl,
benzo[l,3]oxazinyl, benzodihydro[l,3]oxazinyl, fused pyrido[l,4]oxazinyl, fused
pyrido[l,3]oxazinyl, fused pyrido[l,4]dihydrooxazinyl, fused pyrido[l,3]dihydrooxazinyl, fused pyrimido[l,4]oxazinyl, fused pyrimido[l,3]oxazinyl, fused
pyrimido[l,4]dihydrooxazinyl, fused pyrimido[l,3]dihydrooxazinyl, fused
pyrizo[l,4]oxazinyl, fused pyrizo[l,3]oxazinyl, fused pyrizo[l,4]dihydrooxazinyl or fused pyrizo[l,3]dihydrooxazinyl or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature. For instance:
Figure imgf000014_0001
Figure imgf000014_0002
Quinoxaline
[0043] A "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a C1-4 alkyl group) that is substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" have been defined above.
[0044] As used herein, "cyclic moiety" includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined previously.
[0045] As used herein, "cycloketonyl" refers to a cycloaliphatic moiety where at least one carbon atom of the ring forms a double bond to oxygen. Examples of cycloketonyl compounds include cyclobutonyl, cyclopentonyl, cyclohexonyl, and cycloheptonyl.
[0046] As used herein, an "acyl" group refers to a formyl group or alkyl-C(=0)- (also referred to as "alkylcarbonyl") where "alkyl" has been defined previously. Acetyl and pivaloyl are examples of acyl groups.
[0047] As used herein, a "carbamoyl" group refers to a group having the structure -O-CO- NRxRy or -NRx-CO-0-Rz wherein Rx and Ry have been defined above and Rz can be alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl.
[0048] As used herein, a "carboxy" (or "carboxyl") and a "sulfo" group refer to -COOH or -COORx and -S03H or -S03Rx, respectively.
[0049] As used herein, a "hydroxy" or "hydroxyl" group refers to -OH.
[0050] As used herein, an "alkoxy" or "alkoxyl" group refers to an alkyl-O- group where "alkyl" has been defined previously. Moreover an alkoxy group includes structures comprising two alkoxy groups on the same atom or adjacent atoms that form a ring together with the atom(s) to which they are bound.
[0051] As used herein, a "sulfoxy" group refers to -0-SO-Rx or -SO-0-Rx, where Rx has been defined above. [0052] As used herein, a "mercapto" group refers to -SH.
[0053] As used herein, a "sulfonyl" group refers to -S(0)2-Rx, wherein Rx has been defined above. Examples of sulfonyls include optionally substituted alkylsulfonyl, arylsulfonyl (e.g., haloarylsulfonyl), heteroarylsulfonyl (e.g., alkylheteroarylsulfonyl), or the like.
[0054] As used herein a "sulfinyl" group refers to -S(0)-Rx, wherein Rx has been defined above. Examples of sulfinyls include alkylsulfinyl.
[0055] As used herein a "sulfanyl" group refers to -S-Rx, wherein Rx has been defined above. Examples of sulfanyls include alkylsulfanyl.
[0056] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.
[0057] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1 -3 halogen atoms on each carbon atom. For instance, the term haloalkyl includes the group - CF3.
[0058] As used herein, a "sulfamoyl" group refers to the structure -S(0)2-NRxRy or -NRX - S(0)2-Rz wherein Rx, Ry, and Rz have been defined above.
[0059] As used herein, a "sulfamide" group refers to the structure -NRX -S(0)2-NRYRz wherein Rx, RY, and Rz have been defined above.
[0060] As used herein, a "carbonylamino" group used alone or in connection with another group refers to an amido group such as Rx-C(0)-NRx-. For instance an alkylcarbonylamino includes alkyl-C(0)-NRx-, wherein Rx has been defined above.
[0061] As used herein, a "aminocarbonyl" group used alone or in connection with another group refers to an amido group such as N(Rx)2-C(0)-.
[0062] As used herein, an "alkoxycarbonyl" used alone or in connection with another group refers to a carbonyl group such as alkyl-O-C(O)-.
[0063] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.
[0064] As used herein, an "aminoalkoxyalkyl" refers to an alkyl group such as N(RX)2- alkyl-O-alkyl-, wherein Rx and alkyl have been defined above.
[0065] As used herein, "alkoxyalkylaminoalkyl" refers to an alkyl group such as alkyl-O- alkyl-N(Rx)2-alkyl-, wherein alkoxy, Rx and alkyl have been defined above. [0066] As used herein, an "aminocarbonyl" refers to an amido group such as -NR -C(O)-, wherein Rx has been defined above.
[0067] As used herein, an "aminosulfonyl" refers to the structure -N(RX)2-S(0)2-, wherein Rx has been defined above.
[0068] As used herein, an "oxo" refers to =0.
[0069] As used herein, an "aminoalkyl" refers to the structure N(Rx)2-alkyl-.
[0070] As used herein, a "cyanoalkyl" refers to the structure (CN)-alkyl-.
[0071] As used herein, an "alkylsulfonyl' group refers to the structure alkyl-S(0)2-.
[0072] As used herein, a "sulfonylamino" group refers to the structure Rx-S(0)2-N(RX)2-, wherein Rx has been defined above.
[0073] As used herein, a "urea" group refers to the structure -NRx-CO-NRYRz and a "thiourea" group refers to the structure -NRX-CS-NRYRZ. Rx, RY, and Rz have been defined above.
[0074] As used herein, pictured substituents drawn with a single, unattached wavy line drawn perpendicular to a bond of the substituent is meant to show the attachment point of the substituent. For example, the pyrrole substituent, , is ached to the main core structure by the ring nitrogen, while the pyrro
Figure imgf000016_0001
le substitue is shown as attached to the main core structure by the carbon atom adjacent to the ring nitrogen.
[0075] As used herein, pictured ring structures drawn with a substituent' s bond overlayed on one of the ring bonds shows that the substituent can be at any substitutable atom of the entire ring structure, whether the ring structure is monocyclic or multicyclic. For example,
the R substituent on the structure,
Figure imgf000016_0002
, can be substituted on any atom of the piperidine
ring, and the R substituent on the structure,
Figure imgf000016_0003
, can be substituted on any atom of the benzene ring or piperidine ring.
[0076] As used herein, pictured structures having methyl substituents are drawn to show those methyl substituents as an external bond. Specifically, the structure,
Figure imgf000017_0001
is identical
to the structure
Figure imgf000017_0002
.
[0077] As depicted herein, divalent substituents, such as an amide, shown as -C(0)N(Rx)-, are meant to include the substituent in both directions. For example, the generic structure
Figure imgf000017_0003
. Some examples of generic divalent substituents include, but are not limited to -CO-, -CS-, -CONQ2-, -C02-, -OCO-, -NQ2-, -NQ2C02-, -0-, -NQ2CONQ2-, -OCONQz-, -NQ2CO-, -S-, -SO-, -S02-, -S02NQ2-, -NQ2S02-, and -NQ2S02NQ2-.
[0078] In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. The substituents can be bound to the same atom (carbon, nitrogen, oxygen) or two or more different atoms. A ring substituent, such as a
heterocycloalkyl, may be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
[0079] Substituents can include, but are not limited to, alkyl, cycloalkyl, alkenyl, amino, carbonyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroaralkyl, acyl, carbamoyl, carboxy, hydroxyl, alkoxy, sulfoxy, mercapto, sulfonyl, sulfinyl, sulfanyl, halogen, haloaliphatic, haloalkoxy, cyano, sulfamoyl, sulfamide, carbonylamino, aminocarbonyl, alkoxycarbonyl, alkoxyalkyl, aminocarbonyl, aminosulfonyl, oxo, aminoalkyl, aminoalkoxyalkyl, alkoxyalkylaminoalkyl, cyanoalkyl, alkylsulfonyl, and sulfonylamino.
[0080] In general, the term "unsubstituted" refers to a chemical moiety that includes no substituents.
[0081] The phrase "stable or chemically feasible," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
[0082] As used herein, an effective amount is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep. , 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.
[0083] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single
stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
Modulators of ROR-gamma activity
[0084] In one aspect, the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula I:
Figure imgf000019_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000019_0002
X is SO or S02;
A1, A2, A3, and A4 are each independently C or N;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R2 and R3 are each independently H, optionally substituted alkyl, optionally substituted C3-S cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R2 and R3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
R4a, R4b, R4c, and R4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl;
R5a and R5b are each independently H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl; R6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, R6a and R6b are each independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or R6a and R' together form an optionally substituted heterocycloalkyl ring; or
R40 and R6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
[0085] In another aspect, the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of the Formula la:
Figure imgf000020_0001
Formula la
or pharmaceutically acceptable salts thereof, wherein:
X is SO or S02;
A1, A2, A3, and A4 are each independently C or N;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R2 and R3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R2 and R3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
R4a, R4b, R4c, and R4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl;
R6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or R40 and R6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
[0086] In another aspect, the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula lb:
Figure imgf000021_0001
Formula lb
or pharmaceutically acceptable salts thereof, wherein:
X is SO or S02;
A1, A2, A3, and A4 are each independently C or N;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R2 and R3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R2 and R3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
R4a, R4b, R4c, and R4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or
R40 and R6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
[0087] The compounds of Formula I and Formula la can include one or more of the following embodiments.
[0088] In some embodiments:
A1, A2, A3, and A4 are each C; A1, A2, and A4 are each C, and A3 is N;
A1, A3, and A4 are each C, and A2 is N;
A1 and A4 are each C and A2 and A3 are each N; or
A3 and A4 are each C and A1 and A2 are each N.
[0089] In one embodiment:
A1, A2, and A4 are each C; and
R4a, R4b, and R4d are each H, optionally substituted C1-4 alkyl, optionally substituted OC1-4 alkyl, halogen, or OH.
[0090] In a further embodiment, R4a, R4b, and R4d are each independently Ci_3 alkyl, OCi_3 alkyl, F, CI, Br, or OH; wherein the C1-3 alkyl and OC1-3 alkyl are each optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In some of these embodiments, R4a, R4b, and R4d are each independently H, C¾, C2H5, OCH3, OC2H5, CH3, CF3, OCF3, F, CI, or OH. In other embodiments, R4a, R4b, and R4c are each H.
[0091] In one embodiment:
A1 and A2 are each C, and A4 is N;
R4a and R4b are each independently H, optionally substituted Ci^ alkyl, optionally substituted OCi-4 alkyl, halogen, or OH; and
R4d is absent.
[0092] In a further embodiment, R4a and R4b are each independently H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
[0093] In one embodiment:
A1 and A4 are each C, and A2 is N;
R4a and R4d are each independently H, optionally substituted Ci^ alkyl, optionally substituted OCi-4 alkyl, halogen, or OH; and
R4b is absent.
[0094] In a further embodiment, R4a and R4d are each independently H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
[0095] In one embodiment:
A2 and A4 are each C, and A1 is N; R and R are each independently H, optionally substituted C1-4 alkyl, optionally substituted OCi-4 alkyl, halogen, or OH; and
R4a is absent.
[0096] In a further embodiment, R4b and R4d are each independently H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
[0097] In one embodiment:
A1 and A2 are each N, and A4 is C;
R4a and R4b are each absent; and
R4d is H, optionally substituted C1-4 alkyl, optionally substituted OCi_4 alkyl, halogen, or OH.
[0098] In a further embodiment, R4d is H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
[0099] In one embodiment:
A1 and A4 are each N, and A2 is C;
R4a and R4d are each absent; and
R4b is H, optionally substituted C1-4 alkyl, optionally substituted OCi_4 alkyl, halogen, or OH.
[00100] In a further embodiment, R4b is H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
[00101] In one embodiment:
A2 and A4 are each N, and A1 is C;
R4b and R4d are each absent; and
R4a is H, optionally substituted C alkyl, optionally substituted OC^ alkyl, halogen, or OH.
[00102] In a further embodiment, R4a is H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
[00103] In one embodiment:
A1, A2, and A4 are each N; and
R4a, R4b, and R4d are each absent.
[00104] In some embodiments of Formula I and la, R40 and R6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring as shown in Formula la1.
[00105] In some embodiments of Formula I and la, R40 and R6 taken together form an optionally substituted heterocyclic ring as shown in Formula la1:
Figure imgf000024_0001
Formula la1
or a pharmaceutically acceptable salt thereof,
wherein:
W1 is CR7a, R7b, NR7c, or O;
W2 and W3 are each independently CR7a R7b, NR7c, O, or a bond; and
R7a, R7b, and R7c are each independently H or C M alkyl.
[00106] In some of embodiments of Formula la1 :
A1, A2, and A4 are each C.
[00107] In some embodiments of the compounds of Formula la1 include the following:
W1 is CR7aR7b, and W2 and W3 are each CR7aR7b or a bond;
W1 is O, and W2 and W3 are each CR7aR7b or a bond;
W2 is O, and W1 and W3 are each CR7aR7b or a bond;
W3 is O, and W1 and W2 are each CR7aR7b or a bond; or
R7a and R7b are each independently H or Ci_3 alkyl.
[00108] In some embodiments of the compounds of Formula la1 include the following:
W1 and W2 are each CR7aR7b;
W3 is O; and
R7a and R7b are each independently H or CH3.
[00109] For example, W1 is C(CH3)(CH3) and W2 is CH2.
[00110] The compounds of Formula I, Formula la, Formula lb, and Fomula la1 can include one or more of the following embodiments.
[00111] In one embodiment, R2 and R3 together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
[00112] In another embodiment, R1 is optionally substituted carbocyclyl , and R5 is an optionally substituted alkyl, or optionally substituted carbocyclyl.
[00113] In a further embodiment, one of R4a, R4b, and R4d is H and the remaining are each independently C1-3 alkyl, OCi_3 alkyl, F, CI, Br, or OH; wherein the C1-3 alkyl and OCi_3 alkyl are each optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In some of these embodiments, R4a, R4b, and R4d are each independently H, CH3, C2H5, OCH3, OC2H5, CH3, CF3, OCF3, F, CI, or OH. In other embodiments, R4a, R4b, and R4d are each H.
[00114] In still other embodiments, R4a, R4b, and R4d are H, halogen, optionally substituted alkyl or absent.
[00115] In some embodiments, R4a, R4b, R4c, and R4d are each independently H, C1-4 alkyl, Ci-4 haloalkyl, OC1-4 alkyl, halogen, CN, OH, or absent.
[00116] In some exemplary embodiments:
R4a is H, Ci_3 alkyl, OCi_3 alkyl, or absent;
R4b is H, Ci_3 alkyl, OCi_3 alkyl, F, CI, Br, haloalkyl, or absent;
R40 is H, C1-3 alkyl, OCi_3 alkyl, or absent; and
R4d is H, Ci_3 alkyl, OCi_3 alkyl.
[00117] In other exemplary embodiments:
R4a is H, C1-3 alkyl, or absent;
,4b
R is H, Ci_3 alkyl, CI, CF3, or absent;
R40 is H, C1-3 alkyl, or absent; and
R4d is H or Ci_3 alkyl.
[00118] In some embodiments, R2 and R3 together form cycloalkyl, cycloalkenyl, cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, carboxyl, and acetyl. In some of these embodiments, R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_4 alkyl, OCi_4 alkyl, OH, F, CI, Br, amino, or carboxyl.
[00119] In some embodiments, R2 and R3 together form cycloalkyl, cycloalkenyl, cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, oxo, amino, carboxyl, acetyl, alkyl-OH, haloalkyl, and -(alkyl-Q)n-alkyl, wherein each Q is independently O, NH, or N(C1-4 alkyl), and each n is independently 1 or 2.
[00120] In some embodiments, R2 and R3 together form cycloalkyl optionally substituted with aminoalkoxyalkyl, alkoxyalkylaminoalkyl or (C1-4 alkoxy)2.
[00121] In some embodiments, R2 and R3 together form cycloalkyl optionally substituted with -(alkyl-Q)n-alkyl, wherein each Q is independently O, NH, or N(C1-4 alkyl), and n is 1 or 2.
[00122] In some embodiments, R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl, each independently is optionally substituted with aminoalkoxyalkyl, alkoxyalkylamino alkyl or (C1-4 alkoxy)2.
[00123] In some embodiments, R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl, each independently is optionally substituted with -(alkyl-Q)n-alkyl, wherein each Q is independently O, NH, or N(C1-4 alkyl), and n is 1 or 2.
[00124] In some embodiments, R2 and R3 together form cyclopropyl optionally substituted with aminoalkoxyalkyl, alkoxyalkylamino alkyl or (C1-4 alkoxy)2
[00125] In some embodiments, R2 and R3 together form cyclopropyl optionally substituted with -(alkyl-Q)n-alkyl, wherein each Q is independently O, NH, or N(C1-4 alkyl), and n is 1 or 2.
[00126] In some embodiments, R2 and R3 together form cyclopropyl optionally substituted with ethanol, propan-2-ol, methoxypropane, difluoroethane, 2-ethoxy-N,N- dimethylethanamine, 1 -ethoxy-2-methoxyethane, N-ethyl-2-methoxyethanamine, or N-ethyl- 2-methoxy-N-methylethanamine.
[00127] In some embodiments, R^ is H, optionally substituted Ci_6 alkyl, optionally substituted OCi_6 alkyl, optionally substituted carbocycle, halogen, CN, OH, or absent; and R6 is optionally substituted alkyl, optionally substituted C2_6 alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl.
[00128] In several embodiments, R2 and R3 together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring. In some of these
embodiments, X is S02 . In some of these embodiments, R1 is optionally substituted carbocycle. In some of these embodiments, R5, and R6 are each independently H, optionally substituted alkyl or optionally substituted carbocycle. In some of these embodiments, R4a, R , R , R are each independently H, halo, optionally substituted alkyl or absent. In some of these embodiments, R1 is optionally substituted phenyl. In some embodiments, the phenyl is unsubstituted. In other embodiments, the phenyl is substituted with a halogen.
[00129] In some embodiments, R2 and R3 together form cycloalkyl, cycloalkenyl, cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, carboxyl, and acetyl. In some exemplary embodiments, R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_4 alkyl, OCi_4 alkyl, OH, F, CI, Br, amino, or carboxyl.
[00130] In some exemplary embodiments, R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, carboxyl, acetyl, alkyl-OH, haloalkyl, and -(alkyl-Q)n-alkyl, wherein each Q is independently O, NH, or N(C1-4 alkyl), and n is 1 or 2.
[00131] For example, R2 and R3 together form a ring selected from any of the following formulas:
Figure imgf000027_0001
Figure imgf000028_0001
[00133] In further embodiments, R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, C2H5, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and Br.
[00134] In other embodiments, R2 and R3 together form oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, N-C1-2 alkyl azetidine, N-C1-2 alkyl pyrrolidine, N-C1-2 alkyl piperidine, N-acetylazetidine, N-acetylpyrrolidine, or N- acetylpiperidine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
[00135] In still other embodiments, R2 and R3 together form tetrahydrofuran,
tetrahydropyran, pyrrolidine, piperidine, N-C1-2 alkyl pyrrolidine, N-C1-2 alkyl piperidine, N- acetylpyrrolidine, or N- acetylpiperidine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, OCH3, OH, F, and CI. [00136] In yet other embodiments, R2 and R3 together form cyclobutanone, cyclopentanone, cyclohexanone, or cycloheptanone; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl. In some of these embodiments, R2 and R3 together form cyclobutanone, cyclopentanone, or cyclohexanone; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, C2H5, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and Br.
[00137] In still other embodiments, R2 and R3 together form spiro[2.3]hexanyl,
spiro[2.4]heptanyl, spiro[2.5]octanyl, spiro[2.6]nonanyl, spiro[3.3]heptanyl,
spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[3.6]decanyl, spiro[4.4]nonanyl, spiro[4.5]decanyl, spiro[4.6]undecanyl, spiro[5.5]undecanyl, spiro[5.6]dodecanyl, or spiro[6.6.]tridecanyl; wherein each of the foregoing moieties is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of Ci_4 alkyl, OCi_4 alkyl, OH, F, CI, Br, amino, and carboxyl.
[00138] In some exemplary embodiments, R2 and R3 together form spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[2.5]octanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl,
spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C¾, C2¾, C3H7, OCH3, OC2¾, OC3H7, OH, F, CI, and Br.
[00139] In yet other embodiments, R2 and R3 together form bicyclo[1.1.0]butyl,
bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[5.1.0]octyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[5.2.0]nonyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[5.3.0]decyl, bicyclo[4.4.0]decyl, bicyclo[5.4.0]undecyl, or bicyclo[5.5.0]dodecyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OCi^ alkyl, OH, F, CI, Br, amino, and carboxyl.
[00140] In some of these embodiments, R2 and R3 together form bicyclo[l. l.OJbutyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, or bicyclo[4.4.0]decyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, C2¾, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and Br.
[00141] In some exemplary embodiments, R2 and R3 together form:
Figure imgf000030_0001
[00142] In other exemplary embodiments, R2 and R3 together form:
Figure imgf000030_0002
[00143] For example, R2 and R3 together form:
Figure imgf000031_0001
[00144] For example, R2 and R3 together form:
Figure imgf000031_0002
[00145] In some embodiments, R2 and R3 are each independently H, optionally substituted Ci-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted OCi_6 alkyl, CN, OH.
[00146] In some of these embodiments, R2 and R3 are each independently H, C1-4 alkyl, C3-6 cycloalkyl, OCi^ alkyl, CN, or OH; wherein each of the Ci_4 alkyl, C3_6 cycloalkyl, and OCi_ 4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-2 alkyl, OC1-2 alkyl, OH, halogen, amino, and carboxyl.
[00147] In some exemplary embodiments, R2 and R3 are each independently H, C1-2 alkyl, OCi-3 alkyl, or OH; wherein each of the C1-2 alkyl and OC1-2 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, OCH3, F, CI, and Br. For example, R2 and R3 are each CH3.
[00148] In one embodiment, R1 is optionally substituted aryl. In a further embodiment, R1 is optionally substituted alkyl. In a further embodiment, R1 is C1-5 alkyl; wherein the C1-5 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
[00149] In one embodiment, R1 is C2-6 alkenyl; wherein the C2-6 alkenyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
[00150] In one embodiment, R1 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl. In some of these embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. [00151] In a further embodiment, R1 is cyclopentyl or cyclohexyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, fluoroalkyl hydroxyl, OC1-4 alkyl, carboxyl, amino, and halogen.
[00152] In one embodiment, R1 is optionally substituted heterocyclyl. In a further embodiment, R1 is aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
[00153] In one embodiment, R1 is optionally substituted aryl or optionally substituted heteroaryl. In some of these embodiments, R1 is pyrrole, furan, thiophene, isothiophene, phenyl, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl, pyridine, pyrimidine, or pyrazine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, haloalkoxyl, carboxyl, amino, and halogen. In some embodiments, R1 is pyrrole, furan, thiophene, isothiophene, phenyl, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl, pyridine, pyrimidine, or pyrazine; wherein each of the foregoing moieties is optionally substituted with halogen. In some embodiments, R1 is phenyl substituted with halogen. In some embodiments, R1 is phenyl substituted with CI, Br or F. In some embodiments, R1 is phenyl substituted with CI.
[00154] In an exemplary embodiment, R1 is phenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_4 alkyl, OCi_4 alkyl, CF3, OCF3, F, CI, and CN. In some exemplary embodiments, R1 can include:
Figure imgf000032_0001
Figure imgf000033_0001
32 [00157] In another embodiment, R1 is
Figure imgf000034_0001
[00158] In one embodiment:
A1, A2, and A4 are each C; and
R4a, R4b, and R4d are each H, optionally substituted C1-4 alkyl, optionally substituted OC1-4 alkyl, halogen, or OH.
[00159] In some embodiments, R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl.
[00160] In some embodiments, R5 is optionally substituted alkyl. In some of these embodiments, R5 is Ci_s alkyl; wherein the Ci_s alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
[00161] In some further embodiments, R5 is C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of F, OCi_3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxetane.
[00162] In some embodiments, R5 is C2-6 alkenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
[00163] In some embodiments, R5 is optionally substituted alkylaryl.
[00164] In some embodiments, R5 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl. In some of these embodiments, R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl,
cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. [00165] In some embodiments, R5 is optionally substituted heterocyclyl. In some of these embodiments, R5 is aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
[00166] In some embodiments, R5 is optionally substituted aralkyl, optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In some of these embodiments, R5 is benzyl optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In some of these embodiments, R5 is benzyl optionally substituted with halogen, for example CI, F, or Br. In some of these embodiments, R5 is benzyl optionally substituted with F.
[00167] In some embodiments, R5 is optionally substituted heteroaralkyl optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In some of these embodiments, R5 is optionally substituted
methylpyrazole, methylthiophene, methylpyrrole, methylfuran, methylindene,
methylnaphthalene, methylpyridine, methylpyrimidine, or methylpyrazine, each
independently optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. R5 is optionally substituted
methylpyrazole, methylthiophene, methylpyrrole, methylfuran, methylindene,
methylnaphthalene, methylpyridine, methylpyrimidine, or methylpyrazine, each
independently optionally substituted with C1-4 alkyl. In some embodiments, R5 is
methylpyrazole, optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_4 alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In some embodiments, R5 is methylpyrazole, optionally substituted with methyl. [00168] In some of these embodiments, R5 is
Figure imgf000036_0001
[00169] In some embodiments, R5 can include:
Figure imgf000036_0002
[00170] In some embodiments, X is SO.
[00171] In other embodiments, X is S02.
[00172] In some embodiments, the compound of Formula I includes a structure selected from the group below:
Figure imgf000036_0003
Figure imgf000037_0001
[00173] In each of the foregoing structures, R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl. In some of these embodiments, R5 is optionally substituted alkyl. In some of these embodiments, R5 is C1-5 alkyl; wherein the Ci_s alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl,
heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In some further embodiments, R5 is Ci_4 alkyl; wherein the Ci_4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of F, OC1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxetane.
[00174] In one embodiment, R5 is C2-6 alkenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In some embodiments, R5 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl. In some of these embodiments, R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl,
cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
[00175] In some embodiments, R5 is optionally substituted heterocyclyl. In some of these embodiments, R5 can include aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In some exemplary embodiments,
R can include:
Figure imgf000038_0001
In some embodiments, R5 can includ
Figure imgf000038_0002
[00176] In each of the foregoing structures, R6 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted alkoxyl.
[00177] In each of the foregoing structures, R6 is optionally substituted alkyl. In some of these embodiments, R6 is C1-5 alkyl; wherein the C1-5 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In other embodiments, R6 is C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of F, OCi-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxetane. In one embodiment, R6 is C2-6 alkenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl,
heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In one embodiment, R6 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl.
[00178] In some of these embodiments, R6 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or a C6-io bicyclic cycloalkyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
[00179] In some embodiments, R6 is optionally substituted heterocyclyl. In these embodiments, R6 can include aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
[00180] In some embodiments, R6 is optionally substituted aryl or optionally substituted heteroaryl. In some of these embodiments, R6 is pyrrole, furan, thiophene, isothiophene, phenyl, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl, pyridine, pyrimidine, pyrazole, or pyrazine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen. In some exemplary embodiments, R6 is phenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_4 alkyl, OCi_4 alkyl, CF3, OCF3, F, CI, and CN. In some embodiments, R6 is pyridine that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of d_4 alkyl, Od_4 alkyl, CF3, OCF3, F, CI, and CN. For example R6 can include tert-butyl, cyclobutane, cyclopentane, or cyclohexane. In some embodiments, R6 is H.
[00181] In some of these embodiments, R6 is alkoxyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci^ alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, OCi_4 alkyl, carboxyl, amino, and halogen. In some exemplary embodiments, R6 is Ci_4 alkoxyl selected from the group consisting of methoxy, methoxymethylpropane, methoxypropane, ethoxy, propyloxy and butoxy, each independently optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, OC1-4 alkyl, carboxyl, amino, and halogen.
[00182] In each of the foregoing structures, R6 is:
Figure imgf000040_0001
[00183] In each of the foregoing structures, X is SO.
[00184] In each of the foregoing structures, X is S02.
[00185] In a further embodiment, the invention is directed to a compound of Formula I or pharmaceutically acceptable salts thereof, wherein:
X is S02;
A1 and A4 are each C;
A2 and A3 are each independently C or N;
R1 is phenyl, optionally substituted with a group selected from halogen and Ci-4alkyl wherein the alkyl is optionally substituted with halogen;
R2 and R3 together form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;
R4a, R4b, R4c, and R4d are each independently H, optionally substituted Ci_6alkyl, halogen, or absent when the ring atom to which they are attached is N;
R5 is optionally substituted Ci_6alkyl or optionally substituted carbocyclyl;
R6 is optionally substituted Ci_6alkyl, or optionally substituted carbocyclyl, or
R40 and R6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
[00186] In another embodiment, the invention is directed to a compound of Formula I,
Formula la, Formula lb, or pharmaceutically acceptable salts thereof, wherein: [00187] X is S02;
[00188] A1 and A4 are each C;
[00189] A2 and A3 are each independently C or N;
[00190] R1 is phenyl optionally substituted with a group selected from halogen, CH3 and CF3;
[00191] R2 and R3 together form a 6 membered heterocyclyl or a 6 membered carbocyclyl;
[00192] R4a, R4b, R40, and R4d are each independently H, Ci_4alkyl, halogen, or absent;
[00193] R5 is optionally substituted Ci_6alkyl or optionally substituted carbocyclyl;
[00194] R6 is optionally substituted Ci_4alkyl, or Ci_7carbocyclyl.
[00195] In another embodiment, the invention is directed to a compound of Formula I, Formula la, or pharmaceutically acceptable salts thereof, wherein:
[00196] X is S02;
[00197] A1 and A4 are each C;
[00198] A2 and A3 are each independently C or N;
[00199] R1 is phenyl optionally substituted with a group selected from halogen, CH3 and CF3;
[00200] R2 and R3 together form a pyranyl or a 6 membered bicyclic carbocyclyl;
[00201] R4a, R4b, R40, and R4d are each independently H, Ci_4alkyl, halogen, or absent;
[00202] R5 is optionally substituted Ci_6alkyl or optionally substituted carbocyclyl;
[00203] R6 is optionally substituted Ci_4alkyl, or Ci_7carbocyclyl.
[00204] In another embodiment, the invention is directed to a compound of Formula I or pharmaceutically acceptable salts thereof, wherein:
[00205] X is S02;
[00206] A1 and A4 are each C;
[00207] A2 and A3 are each independently C or N;
[00208] R1 is phenyl optionally substituted with a group selected from halogen, CH3 and CF3;
[00209] R2 and R3 together form a pyranyl or a 6 membered bicyclic carbocyclyl; [00210] R , R , R , and R4d are each independently H, halogen or absent;
[00211] R5 is optionally substituted Ci_6alkyl or optionally substituted carbocyclyl;
[00212] R6 is optionally substituted Ci-4alkyl, or Ci_7carbocyclyl.
[00213] In some embodiments, R2 and R3 together form an optionally substituted monocyclic carbocyclyl or a monocyclic heterocyclyl; and X is S, SO or S02; and A1, A2, A3, A4, R1' R4a, R4b, R4c, R4d, R5, and R6 are defined as in Formula I. In still further embodiments, one of A1 and A4 is nitrogen and A2, A3, R1, R2, R3, R4a, R4b, R4c, R4d, R5, and R6 are defined as in Formula I.
[00214] In still further embodiments, one of A1 and A2 is nitrogen and A2, A3, R1, R2, R3, R4a, R4b, R4c, R4d, R5, and R6 are defined as in Formula I.
[00215] In some embodiments, R4a is H and A1, A2, A3, A4, R1, R2, R3, R4b, R40, R4d, R5, and R6 are defined as in Formula I.
[00216] In some embodiments, R4d is H and A1, A2, A3, A4, R1, R2, R3, R4b, R4c, R4a, R5, and R6 are defined as in Formula I.
[00217] In some embodiments, R6 is a C2-C5 alkyl and A1, A2, A3, A4, R1, R2, R3, R4a, R4b, R40, R4d, and R5 are defined as in Formula I.
[00218] In some embodiments, R6 is amino, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted heterocyclyl, and A1, A2, A3, A4, R1, R2, R3, R4a, R4b, R4c, R4d, and R5 are defined as in Formula I.
[00219] In a further embodiment, the invention is directed to a compound of Formula I or pharmaceutically acceptable salts thereof, wherein:
X is S02;
A1 and A4 are each independently C or N;
A2 and A3 are each independently C or N;
R1 is phenyl, optionally substituted with a group selected from halogen and Ci_4 alkyl wherein the Ci-4 alkyl is optionally substituted with halogen;
R2 and R3 together form a cycloaliphatic or heterocycloalkyl each of which is independently unsubstituted or substituted with one or more of Ci_6 alkyl, Ci_6 alkoxyl, halogen, oxo, hydroxyl, carboxyl, acetyl, Ci_6 alkyl-OH, Ci_6 haloaliphatic, amino, and -(alkyl-Q)n-alkyl, wherein each Q is independently O, NH, or N(Ci_4 alkyl), and n is 1 or 2. R a, R , R °, and R are each independently H, optionally substituted Ci_6 alkyl, halogen, or absent when the ring atom to which they are attached is N;
R5 is optionally substituted Ci_6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted cycloalkyl;
R6 is optionally substituted Ci_6 alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted Ci_6 alkoxyl;
[00220] In one embodiment, the invention is directed to a compound of Formula la or pharmaceutically acceptable salts thereof, wherein the compound of Formula la has the structure:
Figure imgf000043_0001
wherein:
R is F or CI;
R is H, F, CI, or methoxy;
Figure imgf000043_0002
Figure imgf000043_0003
, wherein Xi is CH2, or O; and
R6 is
Figure imgf000043_0004
, O' R wherein RZ1 is alkyl , or , wherein X2 is CRZ2 or N, and RZ2 is an alkyl, H or F. In one embodiment, X2 is CR' mbodiments of the above formula, the compound can be:
Figure imgf000044_0001
Figure imgf000045_0001
or a pharmaceutically acceptable salt thereof.
[00222] In one embodiment, the invention is directed to a compound of Formula la or pharmaceutically acceptable salts thereof, wherein the compound of Formula la has the structure:
Figure imgf000045_0002
or a pharmaceutically acceptable salt thereof,
wherein:
A3 is C or N;
R4b is F or CI;
is H, F, CI, methoxy or absent when A3 is N;
R5 is optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 7 membered heterocycloalkyl, optionally substituted C7-16 aralkyl, optionally substituted 6 to 10 membered heteroaralkyl, or Ci_6 alkyl optionally substituted with one to four of Ci_6 cycloalkyl, C6-s aryl, or 3 to 7 membered heterocycloalkyl, each of the foregoing substituents may be independently unsubstituted or substituted with one or more of Ci^ alkyl or halogen; and
R6 is Ci-6 alkyl, C3-10 cycloalkyl, 4 to 7 membered heteroaryl, C6-i4 aryl, or Ci_6 alkoxyl, wherein each of the foregoing moieties is independently unsubstituted or substituted with one or more of Ci_4 alkyl or halogen. [00223] In one embodiment, the invention is directed to a compound of Formula la or pharmaceutically acceptable salts thereof, wherein the compound of Formula la has the structure:
Figure imgf000046_0001
or a pharmaceutically acceptable salt thereof,
wherein:
A3 is C or N;
R4b is F or CI;
is H, F, CI, methoxy or absent when A3 is N;
R5 is optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 7 membered heterocycloalkyl, or Ci_6 alkyl optionally substituted with one to four of Ci_6 cycloalkyl, C6-i4 aryl, or 3 to 7 membered heterocycloalkyl, each of the foregoing substituents may be independently unsubstituted or substituted with one or more of Ci^ alkyl or halogen; and R6 is Ci-6 alkyl, C3-10 cycloalkyl, 4 to 7 membered heteroaryl, C6-i4 aryl, or Ci_6 alkoxyl, wherein each of the foregoing moieties is independently unsubstituted or substituted with one
Figure imgf000046_0002
Figure imgf000047_0001

Figure imgf000048_0001

Figure imgf000049_0001

Figure imgf000050_0001

Figure imgf000051_0001
methyl (4-(4-((4-chlorophenyl)sulfonyl)tetrahydro-2H-pyran- 4-yl)-2-fluorophenyl)(isopropyl)carbamate
pyran-4-
Figure imgf000051_0002
isopropyl (4-(4-((4-chlorophenyl)sulfonyl)tetrahydro-2H- pyran-4-yl)-2-fluorophenyl)(isopropyl)carbamate
or a pharmaceutically acceptable salt thereof.
[00227] For example, the compound of Formula I can be a compound as shown in Table 1 or a pharmaceutically acceptable salt thereof. Exemplary Embodiments of the Compound of Formula I.
Table 1. Exemplary Embodiments of the Compound of Formula I
Figure imgf000051_0003
Figure imgf000052_0001
Figure imgf000053_0001
2-y|)-A/-ethylpivalamide
Figure imgf000054_0001
ethylcyclobutanecarboxamide
Figure imgf000055_0001
/V-ethylpivalamide
Figure imgf000056_0001
yl)pyridin-2-yl)cyclobutanecarboxamide
Figure imgf000057_0001
Figure imgf000058_0001
-N-et ypvaam e
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Ex # Structure
69
5-ethyl-8-(l-((3-fluoro-4-methoxyphenyl)sulfonyl)cyclopentyl)-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
70
5-ethyl-3,3-dimethyl-8-(l-((3-(trifluoromethyl)phenyl)sulfonyl)cyclopentyl)-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
71
5-ethyl-8-(l-((4-fluoro-3-methylphenyl)sulfonyl)cyclopentyl)-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
72
5-ethyl-8-(l-((3-isopropoxyphenyl)sulfonyl)cyclopentyl)-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
73
5-ethyl-3,3-dimethyl-8-(l-tosylcyclopentyl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)- one
74
8-(l-((3-chloro-4-fluorophenyl)sulfonyl)cyclopentyl)-5-ethyl-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Ex # Structure
91
8-(l-((4-chlorophenyl)sulfonyl)cyclohexyl)-5-ethyl-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
92
F
5 -ethyl- 3 , 3 -dimethy 1-8 -( 1 - ((4- (trifluoromethyl)phenyl)sulf onyl)cyclohexyl) -2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
93
8-(l-((4-chlorophenyl)sulfonyl)cyclobutyl)-5-ethyl-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
94
F
5-ethyl-3,3-dimethyl-8-(l-((4-(trifluoromethyl)phenyl)sulfonyl)cyclobutyl)-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
95
5 -ethyl- 3 , 3 -dimethyl- 8- ( 1 -(phenylsulf onyl)cyclobuty l)-2 , 3 - dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
96
5 -ethyl- 3 , 3 -dimethy 1-8 -( 1 - (phenylsulf onyl)cyclopentyl) -2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Ex # Structure
162
A/-(4-(4-((4-chlorophenyl)sulfonyl)tetrahydro-2/-/- pyran-4-yl)-2-fluorophenyl)-A/-cyclobutyl-3- fluorobenzamide
163
A/-(4-(4-((4-chlorophenyl)sulfonyl)tetrahydro-2H-pyran-4- yl)-2-fluorophenyl)-/V- cyclobutylcyclopentanecarboxamide
164
A/-(4-(4-((4-chlorophenyl)sulfonyl)tetrahydro-2/-/-pyran-4- yl)-2-fluorophenyl)-/V-cyclobutylacetamide
165
A/-(4-(4-((4-chlorophenyl)sulfonyl)tetrahydro- 2/-/-pyran-4-yl)-2-fluorophenyl)-A/- cyclobutylcyclopropanecarboxamide
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
, or p larmaceutically acceptable salts thereof.
[00228] In another aspect, the invention provides aryl sulfones and related compounds that are modulators of ROR-gamma activity, wherein the modulators are compounds of Formula lb:
Figure imgf000102_0001
Formula lb
or pharmaceutically acceptable salts thereof, wherein:
X is SO or S02;
A1, A2, A3, and A4 are each independently C or N;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R2 and R3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R2 and R3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
R4a, R4b, R4c, and R4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or
R40 and R6 taken together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
[00229] For example, the compound of Formula lb can be a compound as shown in Table 2. Table 2. Exemplary Embodiments of the Compounds of Formula lb.
Figure imgf000103_0001
Ex # Structure
147
A/-(5-(4-((4-chlorophenyl)sulfonyl)tetrahydro-2/-/- pyran-4-yl)-2-fluorophenyl)-/V-ethylpivalamide
186
A/-(6-(4-((4-chlorophenyl)sulfonyl)tetrahydro-2H- pyran-4-yl)-3-fluoropyridin-2-yl)-/V-ethylpivalamide
or a pharmaceutically acceptable salt thereof.
Formulations, Administrations, and Uses
[00230] In another aspect, the invention includes a pharmaceutical composition comprising a compound of Formula I, Formula la, Formula la1, or Formula lb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant. In some embodiments of this aspect, the invention includes pharmaceutically acceptable salts of the compounds of Tables 1 and 2.
[00231] The present invention includes within its scope pharmaceutically acceptable prodrugs of the compounds of the present invention. A "pharmaceutically acceptable prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof. In some embodiments, the prodrugs increase the
bioavailability of the compounds of this invention when such compounds are administered to a mammal or which enhance delivery of the parent compound to a biological compartment relative to the parent species.
[00232] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[00233] Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their
pharmaceutically acceptable acid addition salts.
[00234] Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N+(Ci_4 alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
[00235] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
[00236] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
[00237] The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
[00238] Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[00239] The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
[00240] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
[00241] For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,
2-octyldodecanol, benzyl alcohol and water.
[00242] For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
[00243] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
[00244] In some exemplary embodiments, the pharmaceutically acceptable compositions of this invention are formulated for oral administration.
[00245] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration. In some embodiments, the compositions should be formulated so that a dosage of between about 0.01 to about 100 mg/kg body weight/day of the modulator can be administered to a patient receiving these compositions.
[00246] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
[00247] Depending upon the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."
Methods
[00248] The compound of Formula I, Formula la, Formula la1, or Formula lb, or a pharmaceutically acceptable salt thereof, can inhibit the activity of an ROR-gamma receptor. For example, the compound of Formula I, Formula la, Formula la1, or Formula lb, or a pharmaceutically acceptable salt thereof, can inhibit the activity of an ROR-gamma receptor in vitro. The compound of Formula I, Formula la, Formula la1, or Formula lb, or a pharmaceutically acceptable salt thereof, can also inhibit the activity of an ROR-gamma receptor in vivo.
[00249] In one aspect, thus, the invention includes a method of inhibiting the activity of an ROR-gamma receptor, comprising contacting the receptor with a compound of Formula I, Formula la, Formula la1, or Formula lb, or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the compound of Formula I, Formula la, Formula la1, or Formula lb, or a pharmaceutically acceptable salt thereof, inhibits the activity of an ROR-gamma receptor in vitro. In another embodiment, the compound of Formula I, Formula la, Formula la1, or Formula lb, or a pharmaceutically acceptable salt thereof, inhibits the activity of an ROR-gamma receptor in vivo. In some embodiments, the compound of Formula I is a modulator of ROR-gamma activity. In some embodiments, the compound of Formula la is a modulator of ROR-gamma activity. In some embodiments, the compound of Formula la1 is a modulator of ROR-gamma activity. In some embodiments, the compound of Formula lb is a modulator of ROR-gamma activity.
[00250] In another aspect, the invention includes a method of treating or reducing the severity of an ROR-gamma receptor mediated disease in a patient comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. [00251] In some embodiments of this aspect, an ROR-gamma receptor mediated disease can include an automimmune disease. In some embodiments, an autoimmune disease is selected from the group consisting of Ankylosing, spondylitis, Asthma, Behcet's disease, Chronic obstructive pulmonary disease, Crohn's disease, Diabetes Mellitus Type 1, Multiple Sclerosis, Neuromyelitis optica, Polymyalgia Rheumatica, Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren's syndrome, Systemic Lupus Erythematosus, Systemic sclerosis, Transplant rejection, Inflammatory Bowel Disease, Ulcerative Colitis and Uveitis.
[00252] In another aspect, the invention includes a method of modulating the activity of an ROR-gamma receptor with a modulator of ROR-gamma, comprising contacting the receptor with a compound of Formula I, Formula la, Formula la1, or Formula lb, or a
pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the compound of Formula I, Formula la, Formula la1, or Formula lb, or a pharmaceutically acceptable salt thereof, modulates the activity of an ROR-gamma receptor in vitro. In another embodiment, the compound of Formula I, Formula la, Formula la1, or Formula lb, or a pharmaceutically acceptable salt thereof, modulates the activity of an ROR-gamma receptor in vivo. In one embodiment, the compound of Formula I is a modulator of the ROR-gamma receptor. In one embodiment, the compound of Formula la is a modulator of the ROR-gamma receptor. In one embodiment, the compound of Formula la1 is a modulator of the ROR-gamma receptor In one embodiment, the compound of Formula lb is a modulator of the ROR-gamma receptor.
Synthetic Procedures
[00253] The compounds of Formula I, Formula la, Formula la1, or Formula lb, or a pharmaceutically acceptable salt thereof, may be readily synthesized from commercially available starting materials using methods known in the art. Exemplary synthetic routes to produce compounds of Formula I, Formula la, Formula la1, or Formula lb, or a
pharmaceutically acceptable salt thereof, are provided in the general schemes and examples below. The examples below are given to provide a better understanding of the synthetic procedures of the invention and are not meant to be limiting in any way. [00254] Scheme 1. Synthesis of Example #37
Figure imgf000110_0001
[00255] Step 1: n-BuLi (12 mL, 30.6 mmol) was added to a solution of compound 1-1 (3.0 g, 27.8 mmol) in THF (60 mL) at -78 °C. The mixture was stirred for 0.5h at 0 °C. Then, CH3I (4.3 g, 30.6 mmol) was added. The reaction mixture was stirred for another 2 hours at room temperature. Water (60 mL) was added. The mixture was extracted with EtOAc (50 mL x 3). Combined organic layer was washed with brine, dried over anhydrous Na2S04, concentrated and purified by flash column chromatography (PE/EA=2/1) to give the desired product 1-1 as yellow oil. LC-MS: m/z = 123.2 [M+H]+.
[00256] Step 2: Cyclohexanecarbonyl chloride (1.5 g, 10.1 mmol) was added to a solution of compound 1-2 (0.5 g, 4.6 mmol) and Et3N (1.4 g, 13.8 mmol) in DCM (20 mL). The mixture was stirred for 0.5 hour at room temperature. Water (20 mL) was added. The mixture was extracted with DCM (15 mL x 3). Combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated to give the desired product 1-3 as yellow solid. LC- MS: m/z = 233.2 [M+H]+.
[00257] Step 3: Compound 1-3 (2.7 g, 11.6 mmol), NBS (4.1 g, 23.2 mmol) and AIBN (1.9 g, 11.6 mmol) in CC14 (50 mL) was stirred for overnight at 70 °C. The mixture was filtered, and the filtrate was added to water (60 mL). The mixture was extracted with DCM (40 mL x 3). Combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated to give the crude product 1-4 as yellow oil. LC-MS: m/z = 311.1 [M+H]+.
[00258] Step 4: Sodium 4-(trifluoromethyl)benzenesulfinate (0.34 g, 1.46 mmol), compound
1-4 (0.3 g, 0.97 mmol), TBAI (0.36 g, 0.97 mmol) and KI (0.24 g, 1.46 mmol) in DMF (50 mL) was stirred for overnight at 30 °C. Water (20 mL) was added. The mixture was extracted with EtOAc (20 mL x 3). Combined organic layer was washed with brine, dried over anhydrous Na2S04, concentrated, and purified by flash column chromatography (PE/EA=2/1) to give the product 1-5 as white solid. LC-MS: m/z = 441.1 [M+H]+. *H NMR (300 MHz, CDC13) δ 8.19 - 7.31 (m, 7H), 4.32 (s, 2H), 3.42 - 3.16 (s, 3H), 2.49 - 2.45 (m, 1H), 1.85 - 0.97 (m, 10H).
[00259] Example #37:. NaH (8 mg, 1.15 mmol) was added to a solution of compound 1-5 (100 mg, 0.23 mmol) in THF (10 mL). Then l-bromo-2-(2-bromoethoxy)ethane (107 mg, 0.46 mmol) was added and stirred overnight at 50 °C. The mixture was cooled to room temperature. Water (10 mL) was added. The mixture was extracted with DCM (15 mL x 3). Combined organic layer was washed with brine, dried over anhydrous Na2S04, concentrated, and purified by pre-TLC and pre-HPLC to give the desired product as white solid. JH NMR (300 MHz, CDCI3) δ 8.16 (s, 1H), 7.68 - 7.58 (m, 6H), 4.02 - 3.99 (m, 2H), 3.46 (s, 3H), 3.33 - 3.31 (m, 2H), 2.60 - 2.41 (m, 5H), 1.82 - 1.62 (m, 8H), 1.25 - 1.23 (m, 2H); HPLC = 99.5% (214 nm), 100% (254 nm), tR = 4.72 min. LC-MS: m/z = 511.1 [M+H]+, tR = 1.64 min.
[00260] Scheme 2. Synthesis of Example #36
Figure imgf000111_0001
[00261] Step 1: Cyclohexanecarbonyl chloride (5.4 g, 37 mmol) was added to a solution of
5-methylpyridin-2-amine 2-1 (2.0 g, 18.5 mmol) and Et3N (5.6 g, 55.5 mmol) in DCM (40 mL). The mixture was stirred for 3 hours at room temperature. Water (50 mL) was added.
The mixture was extracted with DCM (40 mL x 2). Combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated to give the product 2-2 as yellow solid. LC-MS: m/z = 329.3 [M+H]+.
[00262] Step 2: n-BuLi (9.1 mL, 22.8 mmol) was added dropwise to a solution of compound 2-2 (3.0 g, 9.1 mmol) in THF (50 mL) at 0 °C. The mixture was stirred for lh at 0 °C.
CH3CH2I (1.7 g, 10.9 mmol) was added. The reaction mixture was stirred for another 2 hours at room temperature. Then the mixture was stirred overnight at 70 °C. The solvent was removed by reduced pressure. The residue was purified by silica-gel column chromatography (PE/EA=2/1) to give the desired product 2-3 as yellow oil. LC-MS: m/z = 247.2 [M+H]+.
[00263] Step 3: The same procedure with the step 3 of Scheme 1 was applied to the preparation of compound 2-4. LC-MS: m/z = 325.1 [M+H]+.
[00264] Step 4: The same procedure with the step 4 of Scheme 1 was applied to the preparation of compound 2-5. LC-MS: m/z = 455.1 [M+H]+.
[00265] Example #36: The same procedure with the step 5 of Scheme 1 was applied to the preparation of Example #36. *H NMR (300 MHz, CDC13) δ 8.16 (s, 1H), 7.68 - 7.58 (m, 6H), 4.02 - 3.88 (m, 4H), 3.35 - 3.28 (m, 2H), 2.65 - 2.39 (m, 5H), 194 - 1.50 (m, 7H), 1.24 - 1.10 (m, 6H). HPLC = 99.8% (214 nm), 100% (254 nm), tR = 4.84 min. LC-MS: m/z = 525.2 [M+H]+, tR = 1.68 min.
[00266] Scheme 3. Synthesis of Examples #21 and 34
Figure imgf000112_0001
[00267] Step 1: 4-chlorobenzenethiol (1.339 g, 9.3 mmol), compound 3-1 (1 g, 6.17 mmol), K2CO3 (2.567 g, 18.6 mmol) in dioxane (20 mL) was stirred for 1.5 hrs at 30 °C. After filtered, the filtrate was concentrated. Water (20 mL) was added to the resulting residue. The mixture was extracted with EtOAc (20 mL x 3). Combined organic layer was washed with brine, dried over anhydrous Na2S04, concentrated, and purified by flash column
chromatography (PE/EA=20/1) to give the product 3-2 as white solid. LC-MS: m/z = 269.9 [M+H]+.
[00268] Step 2: To a solution of compound 3-2 (7.6 g, 25 mmol) in 1,2-dichloroethane (100 mL) was added m-CPBA (13 g, 75 mmol) at rt. The reaction mixture was refluxed overnight, then diluted with EtOAc (10 mL), washed with saturated Na2S203 (100 mL), 4N NaOH (100 mL), brine(100 mL), dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography eluting with PE/EA = 1/1 to give target compound 3-3 as yellow solid. LC-MS: m/z = 317.9 [M+H]+.
[00269] Step 3: A mixture of compound 3-3 (0.7 g, 2.2 mmol), TEA (0.667 g, 6.6 mmol), propan-2-amine (0.39 g, 6.6 mmol) in NMP (5 mL) was stirred at 150 °C for 15 hrs. After concentrated, the crude product was purified by column chromatography eluting with DCM/MeOH = 20/1 to give target compound 3-4 as yellow oil. LC-MS: m/z = 325.0
[M+H]+.
[00270] Step 4: A mixture of compound 3-4 (0.21 g, 0.65 mmol), TEA (0.263 g, 2.6 mmol), pivaloyl chloride (0.234 g, 1.94 mmol) in THF (15 mL) was refluxed for 24 hrs. After being washed with brine (100 mL), the mixture was dried over anhydrous Na2S04, and
concentrated to the residue. The residue was purified by column chromatography eluting with PE/EA = 3/1 to give target compound 3-5 as yellow solid. LC-MS: m/z = 409.1 [M+H]+.
[00271] Example #34: The same procedure with the step 5 of Scheme 1 was applied to the preparation of compound Example #34. *H NMR (300 MHz, CDC13) δ 8.14 (s, 1H), 7.78 - 7.75 (m, 1H), 7.37 - 7.29 (m, 4H), 7.20 - 7.17 (m, 1H), 5.00 - 4.75 (m, 1H), 4.02 (d, / = 11.1 Hz, 2H), 3.26 (t, / = 11.4 Hz, 2H), 2.66 (t, / = 10.8 Hz, 2H), 2.40 (d, / = 14.1 Hz, 2H), 1.45 - 0.84 (m, 15H). HPLC = 98.7% (214 nm), 100% (254 nm), tR = 4.39 min. LC-MS: m/z = 479.0 [M+H]+.
[00272] Example #21: was prepared following the procedure for Example 34, but 2- methylpropane-2-amine in step 3 and cyclobutanecarbonyl chloride in step 4: 1H NMR (300 MHz, CDCI3) δ 8.18 (s, 1H), 7.91 - 7.65 (m, 1H), 7.39 - 7.31 (m, 4H), 7.13 (d, / = 8.1 Hz, 1H), 4.05 (d, / = 10.2 Hz, 2H), 3.28 (t, / = 11.4 Hz, 2H), 2.79 - 2.56 (m, 3H), 2.51 - 2.22 (m, 4H), 1.77 - 1.56 (m, 4H), 1.32 (s, 9H). HPLC = 100% (214 nm), 100% (254 nm), tR = 4.45 min. LC-MS: m/z = 491.0 [M+H]+. [00273] Scheme 4. Synthesis of Examples #5, 10, 11, 12, 13, 14, 17, 19, 22, 23, 25, 26, 27, 30, 102, and 111.
Figure imgf000114_0001
[00274] Step 1: sodium 4-chlorobenzenesulfinate (1 g, 6.17 mmol), compound 4-1 (1.56 g, 7.4 mmol), Bu4NI (1.37 g, 3.7 mmol), KI (0.615 g, 3.7 mmol) in DMF (30 mL) was stirred at 30 °C for 1 hrs. After being filtered, the filtrate was concentrated. Water (100 mL) was added to the resulting residue. The mixture was extracted with EtOAc (50 mL x 2). Combined organic layer was washed with brine, dried over anhydrous Na2S04, concentrated, and purified by flash column chromatography (PE/EA=10/1) to give the product 4-2 as yellow solid. LC-MS: m/z = 301.9 [M+H]+.
[00275] Step 2: To a solution of compound 4-2 (6.6 g, 21.8 mmol) in THF (120 mL) was added NaH (70 w/w 1.5 g, 43.7 mmol) in portions. After the mixture stirred at room temperature for 10 min, 1 -bromo-2-(2-bromoethoxy)ethane (10 g, 43.7 mmol) was added and the resulting mixture was refluxed for 4 hrs. Brine (100 mL) was added. The mixture was extracted with EtOAc (50 mL x 2). Combined organic layer was washed with brine, dried over anhydrous Na2S04, concentrated, and purified by flash column chromatography (DCM/MeOH = 30/1) to give the product 4-3 as yellow solid. LC-MS: m/z = 371.9 [M+H]+.
[00276] Step 3: To a solution of compound 4-3 (2 g, 5.38 mmol) in 1,2-dichloroethane (50 mL) was added m-CPBA (2.79 g, 16.1 mmol) at rt. The reaction mixture was refluxed overnight, then diluted with EtOAc (10 mL), washed with saturated Na2S2C>3 (50 mL), 4N NaOH (50 mL), brine (50 mL), dried over anhydrous Na2S04, and concentrated. The residue was purified by preparative column chromatography eluting with DCM/MeOH = 20/1 to give target compound 4-4 as white solid. LC-MS: m/z = 387.9 [M+H]+.
[00277] Step 4: A mixture of compound 4-4 (0.2 g, 0.52 mmol), cyclopropanamine (0.088 g, 1.55 mmol) in NMP (5 mL) was stirred at 100 °C for 48 hrs. After being concentrated to give the crude product, the crude product was purified by column chromatography eluting with DCM/MeOH = 25/1 to give target compound 4-5 as yellow oil, 0.107 g. LC-MS: m/z = 409.1 [M+H]+.
[00278] Step 5: A mixture of compound 4-5 (0.107 g, 0.26 mmol), Iron powder (0.147 g, 2.62 mmol) in AcOH (20 mL) was stirred at r.t overnight. After being filtered, the filtrate was diluted with EA (60 mL) and 1 N NaOH (60 mL). The organic layer was washed with brine (60 mL), dried over anhydrous Na2S04, and concentrated to the crude product. The crude product was purified by column chromatography eluting with DCM/MeOH = 25/1 to give target compound 4-6 as white solid.
[00279] Example #25: A mixture of compound 4-6 (0.08 g, 0.2 mmol), TEA (0.082 g, 0.82 mmol), pivaloyl chloride (0.074 g, 0.61 mmol) in THF (15 mL) was refluxed overnight. After being washed with brine (20 mL), the mixture was dried over anhydrous Na2S04, and concentrated. The residue was purified by prep-TLC to give target compound as a white solid. *H NMR (300 MHz, CDC13) δ 8.05 (d, / = 2.7 Hz, 1H), 7.74 (dd, / = 8.4, 2.7 Hz, 1H), 7.38 - 7.30 (m, 4H), 7.21 (d, 7 = 8.4 Hz, 1H), 4.01 (d, / = 11.4 Hz, 2H), 3.29 (t, / = 11.1 Hz, 2H), 3.03 - 2.92 (m, 1H), 2.79 - 2.59 (m, 2H), 2.39 (d, / = 13.2 Hz, 2H), 1.28 - 1.01 (m, 9H), 0.93 - 0.82 (m, 2H), 0.64 - 0.51 (m, 2H). HPLC = 98.5% (214 nm), 97.3% (254 nm), tR = 4.25 min. LC-MS: m/z = 477.0 [M+H]+.
[00280] Example #26: was prepared following the procedure for Example 25, but using cyclobutaneamine in step 4: *H NMR (300 MHz, CDC13) δ 8.16 (d, / = 2.4 Hz, 1H), 7.80 (dd, / = 8.4, 2.7 Hz, 1H), 7.43 - 7.29 (m, 4H), 7.18 - 7.15 (m, 1H), 4.83 - 4.70 (m, 1H), 4.03 (d, / = 12.3 Hz, 2H), 3.28 (t, / = 11.4 Hz, 2H), 2.77 - 2.58 (m, 2H), 2.44 - 2.40 (m, 2H), 2.20 - 2.12 (m, 2H), 1.79 - 1.55 (m, 4H), 1.03 (s, 9H). HPLC = 97.1% (214 nm), 95.3% (254 nm), tR = 4.48 min. LC-MS: m/z = 491.0 [M+H]+.
[00281] Example #30: was prepared following the procedure for Example 25, but using 2- methoxyethaneamine in step 4: *H NMR (300 MHz, CDC13) δ 8.09 (s, 1H), 7.76 - 7.72 (m, 1H), 7.47 - 7.27 (m, 5H), 4.02 - 3.88 (m, 4H), 3.57 (t, / = 5.4 Hz, 2H), 3.31 - 3.25 (m, 5H), 2.66 - 2.60 (m, 2H), 2.45 - 2.37 (m, 2H), 1.11 (s, 9H). HPLC = 99.4% (214 nm), 99.5% (254 nm), tR = 4.20 min. LC-MS: m/z = 494.9 [M+H]+.
[00282] Example #27: was prepared following the procedure for Example 25, but using ethaneamine in step 4: *H NMR (300 MHz, CDC13) δ 8.15 (s, 1H), 7.80 - 7.77 (m,lH), 7.41 - 7.23 (m, 5H), 4.04 - 4.00 (m, 2H), 3.86 - 3.84 (m, 2H), 3.30 (t, J = 12.0 Hz, 2H), 2.77 - 2.52 (m, 2H), 2.43 - 2.39 (m,2H), 1.45 - 0.70 (m, 12H). HPLC = 99.7% (214 nm), 99.8% (254 nm), tR = 4.23 min. LC-MS: m/z = 465.2 [M+H]+.
[00283] Example #19: was prepared following the procedure for Example 25, but using cyclopropanemethaneamine in step 4: !H NMR (300 MHz, CDC13) δ 8.14 (d, J = 2.4 Hz, 1H), 7.76 (dd, / = 8.7, 2.7 Hz, 1H), 7.41 - 7.35 (m, 4H), 7.29 (d, / = 6.9 Hz, 1H), 4.03 (d, / = 11.4 Hz, 2H), 3.66 (d, / = 6.9 Hz, 2H), 3.28 (t, / = 11.4 Hz, 2H), 2.80 - 2.59 (m, 2H), 2.42 (d, / = 12.9 Hz, 2H), 1.10 (s, 9H), 1.02 (s, 1H), 0.46 - 0.39 (m, 2H), 0.06 - 0.03 (m, 2H). HPLC = 98.8% (214 nm), 99.2% (254 nm), tR = 4.57 min. LC-MS: m/z = 491.1 [M+H]+.
[00284] Example #11: was prepared following the procedure for Example 25, but using oxybis(ethane-2,l)dimethanesulfonate in step 2 and ethaneamine in step 4: JH NMR (300 MHz, CDC13) δ 7.96 (d, / = 2.4 Hz, 1H), 7.60 (dd, / = 8.1, 2.7 Hz, 1H), 7.51 - 7.30 (m, 4H), 7.15 (d, / = 8.4 Hz, 1H), 3.77 (q, / = 7.2 Hz, 2H), 3.37 (d, / = 13.8 Hz, 2H), 2.73 (d, / = 13.8 Hz, 2H), 1.29 - 0.95 (m, 12H), 0.69 - 0.64 (m, 2H), 0.52 - 0.47 (m, 2H). HPLC = 95.2% (214 nm), 96.1% (254 nm), tR = 5.03 min. LC-MS: m/z = 461.0 [M+H]+.
[00285] Example #10: was prepared following the procedure for Example 11 , but using propan-2-amine in step 4: *H NMR (300 MHz, CDC13) δ 8.01 (s, 1H), 7.68 - 7.66 (m, 1H), 7.45 - 7.28 (m, 4H), 7.14 (d, 7 = 8.1 Hz, 1H), 4.93 - 4.78 (m, 1H), 3.38 (d, / = 13.2 Hz, 2H), 2.75 (d, / = 13.2 Hz, 2H), 1.34 - 0.81 (m, 15H), 0.75 - 0.63 (m, 2H), 0.58 - 0.44 (m, 2H). HPLC = 94.1% (214 nm), 96.7% (254 nm), tR = 5.15 min. LC-MS: m/z = 475.0 [M+H]+.
[00286] Example #12: was prepared following the procedure for Example #11, but using ethanamine in step 4 and cyclopentanecarbonyl chloride in step 6: JH NMR (300 MHz, CDCI3) δ 8.02 (d, J = 2.4 Hz, 1H), 7.61 (d, / = 8.1 Hz, 1H), 7.45 - 7.33 (m, 4H), 7.26 - 7.22 (m, 1H), 3.92 (dd, / = 14.1, 7.2 Hz, 2H), 3.35 (d, / = 13.5 Hz, 2H), 2.79 - 2.72 (m, 3H), 1.91 - 1.68 (m, 6H), 1.59 - 1.48 (m, 2H), 1.15 (t, / = 6.0 Hz, 3H), 0.78 - 0.38 (m, 4H). HPLC = 96.1% (214 nm), 99.0% (254 nm), tR = 5.14 min. LC-MS: m/z = 473.1 [M+H]+.
[00287] Example #14: was prepared following the procedure for Example #11, but using ethaneamine in step 4 and cyclobutanecarbonyl chloride in step 6: JH NMR (300 MHz,
CD3OD) δ 8.26 - 8.06 (m, 1H), 7.86 - 7.66 (m, 1H), 7.63 - 7.41 (m, 4H), 7.30 - 7.24 (m, 1H),
3.87 - 3.75 (m, 2H), 3.37 (d, J = 9.6 Hz, 1H), 3.23 - 3.00 (m, 1H), 2.82 (d, 7 = 13.8 Hz, 1H), 2.26 - 2.14 (m, 3H), 1.93 - 1.70 (m, 5H), 1.17 - 0.99 (m, 3H), 0.72 - 0.17 (m, 4H). HPLC = 95.7% (214 nm), 99.1 % (254 nm), tR = 4.88 min. LC-MS: m/z = 459.0 [M+H]+.
[00288] Example #23: was prepared following the procedure for Example #25, but using sodium 3-trifluoromethylbenzenesulfinate in step 1 and ethaneamine in step 4: 1H NMR (300 MHz, CD3OD) δ 8.35 (s, 1H), 8.06 - 8.03 (m, 1H), 7.76 - 7.36 (m, 5H), 3.99 - 3.96 (m, 2H), 3.78 - 3.76 (m, 2H), 3.31 - 3.30 (m, 2H), 2.58 - 2.56 (m, 4H), 1.18 - 1.03 (m, 12H). HPLC = 98.2% (214 nm), 95.9% (254 nm), tR = 4.49 min. LC-MS: m/z = 499.0 [M+H]+.
[00289] Example #22: was prepared following the procedure for Example #23, but using cyclobutanecarbonyl chloride in step 6: *H NMR (300 MHz, CD3OD) δ 8.30 (s, 1H), 8.03 - 8.01 (m, 1H), 7.89 - 7.35 (m, 5H), 4.00 - 3.96 (m, 2H), 3.89 - 3.84 (m, 2H), 3.32 - 3.30 (m, 3H), 2.52 - 250 (m, 4H), 2.26 - 2.23 (m, 2H), 1.90 - 1.86 (m, 4H), 1.15 (t, J = 6.9 Hz, 3H). HPLC = 96.7% (214 nm), 97.6% (254 nm), tR = 4.36 min. LC-MS: m/z = 497.0 [M+H]+.
[00290] Example #13: was prepared following the procedure for Example #25, but replacing step 4 with steps 1 and 2 of Scheme 21: *H NMR (300 MHz, CD3OD) δ 8.37 (d, J = 2.1 Hz, 1H), 7.91 (d, / = 8.4 Hz, 1H), 7.64 - 7.52 (m, 4H), 7.38 (d, / = 8.4 Hz, 1H), 5.59 (s, 2H), 3.76 - 3.62 (m, 4H), 3.31 - 3.13 (m, 2H), 1.15 - 1.05 (m, 12H). HPLC = 99.6% (214 nm), 99.7% (254 nm), tR = 4.69 min. LC-MS: m/z = 447.1 [M+H]+.
[00291] Example #5: was prepared following the procedure for Example #25, but using sodium 3-trifluoromethylbenzenesulfinate in step 1: !H NMR (300 MHz, CDC13) δ 8.15 - 7.55 (m, 6H), 7.20 (d, / = 8.4Hz, 6H), 4.05 - 3.95 (m, 2H), 3.34 - 3.26 (m, 2H), 3.12 - 2.95 (m, 1H), 2.75 - 2.654 (m, 2H), 2.42 - 2.35 (m, 2H), 1.09 (s, 9H), 0.98 - 0.78 (m, 2H), 0.61 - 0.57 (m, 2H). HPLC = 100% (214 nm), 100% (254 nm), tR = 4.49 min. LC-MS: m/z = 511.0 [M+H]+.
[00292] Example #102: was prepared following the procedure for Example #25, but using n-butyl lithium/ dihydro-2H-pyran-3(4H)-one in step 2 and ethaneamine in step 4: JH NMR (300 MHz, CDCI3) δ 8.23 (d, / = 2.5 Hz, 1H), 7.73 (dd, / = 8.5, 2.5 Hz, 1H), 7.39 - 7.36 (m, 2H), 7.28 (d, / = 8.5 Hz, 1H), 7.23 - 7.20 (m, 2H), 4.51 - 4.47 (m, 1H), 4.16 - 4.12 (m, 1H), 3.89 - 3.84 (m, 1H), 3.65 (q, J = 7.0 Hz, 2H), 3.56 - 3.47 (m, 1H), 2.70 - 2.54 (m, 2H), 1.68 - 1.58 (m, 2H), 1.08 - 1.01 (m, 12H). HPLC = 96.2% (214 nm), 97.8% (254 nm), tR = 4.53 min. LC-MS: m/z = 465.0 [M+H]+.
[00293] Example #111: was prepared following the procedure for Example #23, but using propan-2-amine in step 4: *H NMR (300 MHz, CDC13) δ 8.20 (s, 1H), 7.85 - 7.75 (m, 3H),
7.68 - 7.50 (m, 2H), 7.25 - 7.19 (m, 1H), 4.85 - 4.80 (m, 1H), 4.05 - 3.99 (m, 2H), 3.25 (t, / = 11.1 Hz, 2H), 2.70 - 2.57 (m, 2H), 2.44 - 2.38 (m, 2H), 1.15 - 1.01 (m, 15H). HPLC = 100% (214 nm), 99.3% (254 nm), tR = 4.62 min. LC-MS: m/z = 513.0 [M+H]+.
[00294] Example #17: was prepared following the procedure for Example #11,
cyclopropylmethylamine in step 4: *H NMR (300 MHz, CDC13) δ 7.98 (d, J = 2.7 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.41 - 7.32 (m, 4H), 7.19 (d, / = 8.4 Hz, 1H), 3.60 (d, / = 3.9 Hz, 2H), 3.38 (d, / = 10.5 Hz, 2H), 2.70 (d, / = 13.8 Hz, 2H), 1.09 - 0.98 (m, 10H), 0.66 - 0.65 (m, 2H), 0.42 - 0.38 (m, 4H), 0.03 - 0.01 (m, 2H). HPLC = 100% (214 nm), 100% (254 nm), tR = 5.32 min. LC-MS: m/z = 487.0 [M+H]+.
[00295] Scheme 4a: synthesis of Example #100
Figure imgf000118_0001
Ex.100
[00296] Step 1: To a solution of compound 4a-l (5 g, 26 mmol) in DMSO (20 mL) was 2- methoxyethylamine (7ml, 80mmol). The mixture was stirred overnight at 80°C, Subsequently the reaction solution was concentrated to the residue. The residue was purified by silica-gel column chromatography, eluting with PE/EA=10/1, to give the desired product 2. LC-MS: m/z = 244 [M+H]+.
[00297] Step 2: Compound 4a-2 (5 g, 20 mmol) was dissolved in THF (20 ml) and cooled to 0°C. 1.0M lithium tetrahydroaluminate in THF was added and the reaction stirred for 2 hrs. The reaction was quenched at 0°C by adding 0.5 ml water, followed by addition of 1.0 ml of 10% NaOH and 1.5 ml water. The solution was filtered and solvent removed in vacuo. LC- MS: m/z = 216 [M+H]+.
[00298] Step 3: PPh3 (1.8 g, 7.0 mmol) and CBr4 (2.3 g, 7.0 mmol) was added to a solution of compound 4a-3 (1.0 g, 6.4 mmol) in DCM (50 mL). The mixture was stirred for 0.5h at room temperature. Water (50 mL) was added. The mixture was extracted with DCM (50 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na2S04, concentrated, and purified by flash column chromatography (PE/EA=101) to give the product 4a-4. LC-MS: m/z = 279 [M+H]+.
[00299] Step 4: The same procedure with the step 4 of Scheme 1 was applied to the preparation of compound 4a-5. LC-MS: m/z = 375 [M+H]+.
[00300] Step 5: The same procedure with the step 4 of Scheme 3 was applied to the preparation of compound 4a-6. LC-MS: m/z = 459 [M+H]+.
[00301] Example #100: The same procedure with the step 5 of Scheme 1 was applied to the preparation of compound Example #100. *H NMR (300 MHz, CDC13) δ 7.37 - 7.27 (m, 6H), 7.25 - 7.11 (m, 1H), 4.38 - 4.35 (m, 1H), 4.05 - 3.98 (m, 2H), 3.52 - 3.48 (m, 2H), 3.42 - 3.38 (m, 5H), 3.07 - 3.05 (m, 1H), 2.66 - 2.63 (m, 2H), 2.38 - 2.32 (m, 2H), 1.08 (s, 9H). HPLC = 99.5% (214 nm), 100% (254 nm), tR = 4.77 min. LC-MS: m/z = 527.8 [M+H]+.
[00302] Example #105: was prepared following the procedure for Example #100, except cyclopropylmethanamine was used in step 1: !H NMR (300 MHz, CDC13) δ 7.38 - 7.28 (m, 6H), 7.14 - 7.10 (m, 1H), 4.22 - 4.15 (m, 1H), 4.02 - 3.98 (m, 2H), 3.27 (t, / = 11.8 Hz, 2H), 2.84 - 2.60 (m, 3H), 2.38 - 2.33 (m, 2H), 1.33 - 1.04 (m, 9H), 0.98 - 0.88 (m, 1H), 0.47 - 0.36 (m, 2H), 0.16 - 0.09 (m, 1H), -0.06 - -0.14 (m, 1H). HPLC = 99.4% (214 nm), 99.0% (254 nm), tR = 5.24 min. LC-MS: m/z = 523.9 [M+H]+.
[00303] Scheme 5. Synthesis of Example #35
Figure imgf000119_0001
[00304] Step 1: n-BuLi (4.8 mL, 12 mmol) was added dropwise to a solution of 5-bromo-2- chloro-3-methylpyridine (2.1 g, 10.0 mmol) in THF (40 mL) at -78 °C. Then DMF (1.5 g, 20 mmol) was added, and stirred for another 2 hours at -78 °C. Methanol (12 mL) was added to quench the reaction. NaBH4 (1.1 g, 30 mmol) was added, and stirred for 0.5h. Ice water (40 mL) was added. The mixture was extracted with DCM (30 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na2S04, concentrated and purified by flash column chromatography (PE/EA=2/1) to give the product 5-2 as yellow oil. LC-MS: m/z = 158.1 [M+H]+.
[00305] Step 2: PPh3 (0.18 g, 0.70 mmol) and CBr4 (0.23 g, 0.70 mmol) was added to a solution of compound 5-2 (0.1 g, 0.64 mmol) in DCM (10 mL). The mixture was stirred for 0.5h at room temperature. Water (15 mL) was added. The mixture was extracted with DCM (15 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na2S04, concentrated, and purified by flash column chromatography (PE/EA=101) to give the product 5-3 as white solid. LC-MS: m/z = 220.0 [M+H]+.
[00306] Step 3: The same procedure with the step 4 of Scheme 1 was applied to the preparation of compound 5-4. LC-MS: m/z = 316.0 [M+H]+.
[00307] Step 4: The same procedure with the step 5 of Scheme 1 was applied to the preparation of compound 5-5. LC-MS: m/z = 385.9 [M+H]+
[00308] Step 5: Compound 5-5 (0.37 g, 0.96 mmol), Et3N (0.48 g, 4.8 mmol) and EtNH2 (70% in water, 0.22 g, 4.8 mmol) in NMP (10 mL) was sealed in tube, and stirred for 6 hours at 150 °C. The solvent was removed by reduced pressure. Water (20 mL) was added. The mixture was extracted with EA (10 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na2S04, concentrated, and purified by flash column
chromatography (PE/EA=2/1) to give the product 5-6 as yellow oil. LC-MS: m/z = 395.1 [M+H]+.
[00309] Example #35: Pivaloyl chloride (0.38 g, 3.15 mmol) was added to a solution of compound 5-6 (0.25 g, 0.63 mmol) and Et3N (0.32 mmol, 3.15 mmol) in THF (20 mL). The mixture was stirred at 80 °C overnight. The mixture was cooled to room temperature. Water (20 mL) was added. The mixture was extracted with DCM (15 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na2S04, concentrated and purified by pre-TLC and pre-HPLC to give the product as white solid. *H NMR (300 MHz, CDC13) δ 8.05 (s, 1H), 7.58 (s, 1H), 7.41 - 7.39 (m, 2H), 7.25 - 7.22 (m, 4H), 4.02 - 3.98 (m, 2H), 3.67 - 3.65 (m, 2H), 3.32 - 3.24 (m, 2H), 2.51 - 2.37 (m, 7H), 1.09 - 0.96 (m, 12H). HPLC = 98.5% (214 nm), 98.7% (254 nm), tR = 4.31 min. LC-MS: m/z = 479.2 [M+H]+.
[00310] Example #113: was prepared as described in Scheme 5, except using
cyclobutylamine in step 1. 1H NMR (300 MHz, CDC13) δ 7.97 (d, J = 2.1 Hz, 1H), 7.65 (s, 1H), 7.34 (q, J = 8.4 Hz, 4H), 4.76 (s, 1H), 4.03 (d, J = 10.8 Hz, 2H), 3.234 - 3.26 (m, 2H), 2.75 - 2.60 (m, 2H), 2.44 - 2.39 (m, 2H), 2.22 (s, 3H), 2.01 (bs, 2H), 1.71 - 1.56 (m, 4H), 1.06 (s, 9H). LC-MS: m/z = 505.0 [M+H]+.
[00311] Example #114: was prepared as described in Scheme 5, except using propane-2- amine in step 1. *H NMR (300 MHz, CDC13) δ 7.92 (d, J = 2.4 Hz, 1H), 7.61 (s, 1H), 7.33 (q, J = 8.7 Hz, 4H), 4.37 (bs, 1H), 4.00 (d, J = 11.7 Hz, 2H), 3.27 (t, J = 11.7 Hz, 2H), 2.71 - 2.56 (m, 2H), 2.46 - 2.23 (m, 5H), 1.37 - 0.88 (m, 15H). LC-MS: m/z = 493.1 [M+H]+.
[00312] Scheme 6. Synthesis of Example #32
Figure imgf000121_0001
Figure imgf000121_0002
[00313] Step 1: A mixture of compound 6-1 (4 g, 20.8 mmol) in DCM (100 mL) was added oxalyl chloride (10.5 g, 83.2 mmol) dropwise. The resulting mixture was stirred at room temperature for 12 hours. Then methanol (6.7 g, 208 mmol) was added into the above solution at 0 °C. After being stirred at room temperature for another 0.5 hours, the mixture was washed with H20 (100 mL), extracted with DCM (100 mL x 2), the organic phase was dried over anhydrous Na2S04 and concentrated, purified by flash column chromatography to give product 6-2 as white solid.
[00314] Step 2: Compound 6-2 (3.2 g, 15.5 mmol), Et3N (7.8 g, 77.5 mmol) and EtNH2 (70% in water, 3.5 g, 77.5 mmol) was added into NMP (50 mL). The mixture was stirred for 6 hours at 100 °C. The solvent was removed by reduced pressure. Water (80 mL) was added. The mixture was extracted with EtOAc (80 mL x 3). Combined organic layers was dried over anhydrous Na2S04, concentrated and purified by flash column chromatography to give the product 6-3 as white solid. LC-MS: m/z = 215.0 [M+H]+.
[00315] Step 3: To a mixture of compound 6-3 (1.7 g, 8 mmol) in THF (80 mL) was added LAH (0.6 g, 16 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours. Then the reaction was quenched with H20 (2 mL) and filtered. The filtrate was concentrated to give crude product 6-4 as yellow oil. LC-MS: m/z = 187.1 [M+H]+.
[00316] Step 4: To a mixture of compound of 6-4 (0.6 g, 3.2 mmol), sodium 4- chlorobenzenesulfinate (0.76 g, 3.8 mmol) and TEA (0.65 g, 6.4 mmol) in DCM (40 mL) was added methanesulfonyl chloride (0.43 g, 3.8 mmol). Then the mixture was stirred for 2 hours at room temperature. Water (40 mL) was added. The mixture was extracted with EtOAc (40 mL x 2). Combined organic layers was dried over anhydrous Na2S04, concentrated, and purified by flash column chromatography to give the product 6-5 as white solid. LC-MS: m/z = 345.0 [M+H]+.
[00317] Step 5: To compound of 6-5 (0.2 g, 0.58 mmol) was added pivaloyl chloride (5 mL), the mixture was stirred for 12 hours at 100 °C. After removed of most of pivaloyl chloride, water (10 mL) was added. The mixture was extracted with EtOAc (10 mL x 3). Combined organic layers were dried over anhydrous Na2S04, concentrated to give the product 6-6 as yellow solid. LC-MS: m/z = 429.0 [M+H]+.
[00318] Example #32: To a mixture of compound 6-6 (0.22 g, 0.51 mmol) and NaH (40 mg, 1.02 mmol) in THF (20 mL) was added 1 -(2-bromoethoxy)-2-bromoethane (176 mg, 0.76 mmol) at rt. The resulting mixture was stirred for 6 hours at 75°C, then quenched with H20 (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2S04, concentrated and purified by preparative TLC to give the as white solid. *H NMR (300 MHz, CDC13) δ 8.04 - 7.37 (m, 6H), 4.04 - 3.25 (m, 6H), 2.62 - 2.35 (m, 4H), 1.13 - 1.10 (m, 12H); HPLC = 100% (214 nm), 100% (254 nm), tR = 4.77 min. LC-MS: m/z = 498.9 [M+H]+. [00319] Scheme 7. Synthesis of Example #20
Figure imgf000123_0001
[00320] Step 1: To a mixture of compound 7-1 (4.14 g, 26.1 mmol) in DCM (100 mL) was added oxalyl chloride (3.98 g, 31.3 mmol) dropwise. DMF (0.05 mL) was added and the resulting mixture was stirred at room temperature until the compound 7-1 was dissolved. Then MeOH (2 mL) was added dropwise and stirred for another 0.5 hr. After being washed with brine (100 mL), the mixture was dried over anhydrous Na2SC>4 and concentrated to give crude product. The crude product was purified by silica-gel column chromatography (eluting with PE/EA = 4/1) to yield the desired product 7-2 as white solid. LC-MS: m/z = 173.1
[M+H]+.
[00321] Step 2: A mixture of compound 7-2 (1.73 g, 10 mmol), oxetan-3 -amine (0.88 g, 12 mmol) and TEA (4.04 g, 40 mmol) in NMP (20 mL) was stirred overnight at 100°C. The mixture was concentrated to give the residue. The residue was purified by silica-gel column chromatography (eluting with PE/EA = 10/1) to yield the desired product 7-3 as yellow solid. LC-MS: m/z = 210.1 [M+H]+.
[00322] Step 3: To a mixture of compound 7-3 (3.3 g, 15.7 mmol) in THF (50 mL) was added LAH (1.194 g, 31.4 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 2 hrs. Then the reaction was quenched with H20 (2 mL) and filtered. The filtrate was concentrated to give crude product. The crude product was purified by silica-gel column chromatography (eluting with MeOH/EA = 1/10) to yield the desired product 7-4 as white solid. LC-MS: m/z = 182.0 [M+H]+.
[00323] Step 4: To a solution of compound 7-4 (0.415 g, 2.29 mmol), CBr4 (0.913 g, 2.75 mmol) in DCM (50 mL) was added PPI13 (0.78 g, 2.977 mmol) in portions at r.t. The resulting mixture was stirred at r.t. for 0.5 hrs. Then the reaction solution was used directly in step 5 of Scheme 7. LC-MS: m/z =244.0 [M+H]+.
[00324] Step 5: The solution of compound 7-5 prepared from last step was added to a mixture of sodium 4-chlorobenzenesulfinate (0.578 g, 2.75 mmol), Bu4NI (0.339 g, 0.92 mmol), KI (0.42 g, 3.53 mmol) in DMF (50 mL). The resulting mixture was stirred at r.t. for 1 hr. Then it was washed with brine (100 mL x 2), the mixture was dried over anhydrous Na2S04 and concentrated to give crude product. The crude product was purified by flash column chromatography (eluting with DCM/MeOH = 20/1) to yield the desired product 7-6 as white solid. LC-MS: m/z = 339.9 [M+H]+.
[00325] Step 6: To a solution of compound 7-6 (355 mg, 1.04 mmol), TEA (315 mg, 3.12 mmol) in DCM (20 mL) was added pivaloyl chloride (151 mg, 1.25 mmol) dropwise at r.t. After being stirred at r.t. for 1 hr, the solution was washed with brine (20 mL), dried over Na2S04 and concentrated to give crude product. The crude product was purified by flash column chromatography (eluting with DCM/MeOH = 20/1) to yield the desired product 7-7 as white solid. LC-MS: m/z = 424.0 [M+H]+.
[00326] Example #20: A mixture of compound 7-7 (100 mg, 0.24 mmol), NaH (30 mg, 70 w/w, 0.88 mmol), l-bromo-2-(2-bromoethoxy)ethane (170 mg, 0.72 mmol) in THF (50 mL) was stirred at 72 °C for 4 hr. Then it was washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated to give crude product. The crude product was purified by prep TLC and flash column chromatography (eluting with DCM/MeOH = 20/1) to yield the desired product as a white solid. *H NMR (300 MHz, CDC13) δ 8.11 (d, J = 8.7 Hz, 1H), 7.51 (d, / = 9.0 Hz, 1H), 7.36 (d, / = 8.7 Hz, 2H), 7.27 - 7.24 (m, 2H), 5.38 - 5.29 (m, 1H), 4.79 (t, / = 7.2 Hz, 2H), 4.43 (t, / = 6.9 Hz, 2H), 4.04 (d, / = 12.0 Hz, 2H), 3.29 - 3.12 (m, 2H), 2.69 (d, J = 3.6 Hz, 4H), 1.04 (s, 9H). HPLC = 92.9% (214 nm), 87% (254 nm), tR = 3.99 min. LC-MS: m/z = 494.0 [M+H]+. [00327] Scheme 8. Synthesis of Example #31
Figure imgf000125_0001
[00328] Step 1: Under nitrogen atmosphere, to a solution of compound 8-1 (1.0 g, 5 mmol) in dry THF (30 mL) was added ri-But.yllithium, 2.5 M solution in THF (3 mL, 7.5 mmol) dropwise under minus 78 degree. The solution was stirred at -78 degree for 10 min, followed by addition of dry DMF (0.73 g, 10 mmol). The mixture was stirred for 30 min at this temperature and then quenched with H20 (30 mL), extracted with EA (30 mL x 2). The combined organic layer was dried over anhydrous Na2S04 and concentrated to give product 8-2 as yellow oil. LC-MS: m/z = 156.1 [M+H]+.
[00329] Step 2: A mixture of compound 8-2 (0.55 g, 3.5 mmol), NaBH4 (0.4 g, 10.5 mmol) in dry THF (40 mL) was stirred at rt for 6 hours. After quenched with H20 (30 mL), the mixture was extracted with EtOAc (30 mL x 2). The combined organic layer was dried over Na2S04 and concentrated. The resulting residue was purified by column chromatography to give product 8-3 as yellow oil. LC-MS: m/z = 158.0 [M+H]+.
[00330] Step 3: PPh3 (0.333 g, 1.27 mmol) and CBr4 (0.423 g, 1.27 mmol) was added to the solution of 8-3 (0.2 g, 1.27 mmol) in DCM (20 mL). The mixture was stirred for 0.5h at room temperature. Concentrated and purified by flash column chromatography to give the product 8-4 as yellow solid. LC-MS: m/z = 219.9 [M+H]+.
[00331] Step 4: Compound 8-4 (0.18 g, 0.83 mmol), sodium 4-chlorobenzenesulfinate (0.486 g, 2.45 mmol), TBAI (0.136 g, 0.37 mmol) and KI (0.06 g, 0.37 mmol) in DMF (20 mL) was stirred for 1 hour at rt. After removed of most of DMF, water (20 mL) was added. The mixture was extracted with EtOAc (20 mL x 2). Combined organic layers was dried over anhydrous Na2S04, concentrated and purified by flash column chromatography to give product 8-5 as white solid. LC-MS: m/z = 315.9 [M+H]+.
[00332] Step 5: To a mixture of compound 8-5 (200 mg, 0.63 mmol) and NaH (55 mg, 1.26 mmol) in THF (12 mL) was added l-(2-bromoethoxy)-2-bromoethane (220 mg, 0.95 mmol) at rt. The resulting mixture was stirred for 12 hours at 75°C, then quenched with H20 (15 mL), extracted with EtOAc (15 mL x 2). The combined organic layers were dried over anhydrous Na2S04, concentrated and purified by preparative TLC to give product 8-6 as yellow solid. LC-MS: m/z = 386.1 [M+H]+.
[00333] Step 6: Compound 8-6 (60 mg, 0.155 mmol), Et3N (80 mg, 0.78 mmol) and EtNH2 (70% in water, 35 mg, 0.78 mmol) was added into NMP (5 mL). The mixture was stirred for 12 hours at 150 °C. The solvent was removed by reduced pressure. Water (10 mL) was added. The mixture was extracted with EtOAc (10 mL x 2). Combined organic layers was dried over Na2S04, concentrated and purified by pre-TLC to give the product 8-7 as white solid. LC-MS: m/z = 395.1 [M+H]+.
[00334] Example #31: To compound 8-7 (15 mg, 0.038 mmol) was added pivaloyl chloride (5 mL), the mixture was stirred for 12 hours at 100 °C. After removed of most of pivaloyl chloride, water (10 mL) was added. The mixture was extracted with EtOAc (10 mL x 2). Combined organic layers was dried over anhydrous Na2S04, concentrated and purified by pre-TLC to give the product as white solid. *H NMR (300 MHz, CDC13) δ 7.52 - 7.07 (m, 6H), 4.04 - 3.24 (m, 6H), 2.60 - 2.49 (m, 7H), 1.10 - 1.04 (m, 12H). HPLC = 94.2% (214 nm), 96.7% (254 nm), tR = 4.35 min. LC-MS: m/z = 479.0 [M+H]+.
[00335] Scheme 9. Synthesis of Example #33
Figure imgf000126_0001
[00336] Step 1: A mixture of compound 9-1 and aqueous EtNH2 (10 mL) in NMP (5 mL) was stirred for 3 days at 80°C in a sealed tube, then concentrated. The residue was diluted with EtOAc (50 mL), washed with H20 (10 mL), brine (10 mL), dried over anhydrous Na2S04, concentrated, and purified by column chromatography, eluting with PE/EA = 4/1 to give target compound 9-2 as yellow oil. LC-MS: m/z = 215.0 [M+H]+.
[00337] Step 2: To a mixture of compound 9-2 (1.89 g, 8.22 mmol) and NEt3 (2.49 g, 24.7 mmol) in THF (20 mL) was added pivaloyl chloride (1.98 g, 16.4 mmol) at rt. The resulting mixture was stirred for lh at rt, then diluted with EtOAc (50 mL), washed with H20 (10 mL), brine (10 mL), dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography, eluting with PE/EA = 4/1 to give target compound 9-3 as yellow oil. LC-MS: m/z = 299.0 [M+H]+.
[00338] Step 3: Under nitrogen atmosphere, to a solution of Compound 9-3 (0.5 g, 1.68 mmol) in dry THF (20 mL) was added n-Buiyiluhium, 2.5 M solution in THF (1.0 mL, 2.52 mmol) dropwise under minus 80 degree. The solution was stirred at -80 degree for 5 min, followed by addition of dry DMF (0.24 g, 3.36 mmol). The mixture was stirred for another 10 min at this temperature and then quenched with H20 (20 mL), extracted with EtOAc (20 mL X 3). The combined organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated to give crude product 9-4 as yellow oil. LC-MS: m/z = 249.2 [M+H]+.
[00339] Step 4: A mixture of Compound 9-4 (0.47 g, 1.91 mmol), NaBH4 (0.22 g, 5.72 mmol) in dry THF (20 mL) was stirred at r.t for 2h. After quenched with H20 (20 mL), the mixture was extracted with EtOAc (20 mL X 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated. The resulting residue was purified by column chromatography, eluting with PE/EA = 2/1 to give target compound 9-5 as yellow oil, LC-MS: m/z = 251.1 [M+H]+.
[00340] Step 5: To a mixture of compound 9-5 (160 mg, 0.64 mmol) and NEt3 (0.19 g, 1.92 mmol) in CH2C12 (10 mL) was added methanesulfonyl chloride (147 mg, 1.28 mmol) at rt. The resulting mixture was stirred for lh at rt, then concentrated. The residue was purified by column chromatography, eluting with PE/EA = 4/1 to give target compound 9-6 as colorless oil. LC-MS: m/z = 269.1 [M+H]+.
[00341] Step 6: A mixture of compound 9-6 (170 mg, 0.63 mmol), sodium 4- chlorobenzenesulfinate (189 mg, 0.96 mmol), KI (53 mg, 0.32 mmol) and tetrabutyl ammonium iodide (117 mg, 0.32 mmol) in DMF (10 mL) was stirred for 2h at rt. After being diluted with EtOAc (50 mL), the reaction mixture was washed with H20 (10 mL X 3), brine (10 mL), dried over anhydrous Na2S04, and concentrated. The residue was purified by preparative column chromatography eluting with PE/EA = 4/1 to give target compound 9-7 as yellow oil. LC-MS: m/z = 409.0 [M+H]+.
[00342] Step 7: To a mixture of compound 9-7 (200 mg, 0.49 mmol) and NaH (59 mg, 2.45 mmol) in THF (10 mL) was added l-(2-bromoethoxy)-2-bromoethane (340 mg, 1.47 mmol) at rt. The resulting mixture was stirred for 5h at 70°C, then quenched with H20 (10 mL), extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04, and concentrated. The residue was purified by preparative TLC to give target compound 9-8 as yellow oil. LC-MS: m/z = 559.0 [M+H]+.
[00343] Example #33: A mixture of compound 9-8 (180 mg, 0.32 mmol) and NaH (15 mg, 0.64 mmol) in THF (10 mL) was added l-(2-bromoethoxy)-2-bromoethane (340 mg, 1.47 mmol) at rt. The resulting mixture was stirred for 3h at 70°C, then quenched with H20 (10 mL), extracted three times with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2S04, and concentrated. The residue was purified by preparative TLC to give target compound Example 33 as yellow oil. JH NMR (300 MHz, CDC13) δ 7.86 (s, 1H), 7.48 - 7.35 (m, 4H), 7.05 (s, 1H), 4.05 - 4.00 (m, 2H), 3.79 (q, / = 6.9 Hz, 2H), 3.38 - 3.26 (m, 2H), 3.00 - 2.52 (m, 7H), 1.23 - 1.00 (m, 12H). HPLC = 96.5% (214 nm), 96.7% (254 nm), tR = 4.39 min. LC-MS: m/z = 479.0 [M+H]+.
[00344] Scheme 10. Synthesis of Example #110
Figure imgf000128_0001
[00345] Step 1: A mixture of compound 10-1 (2 g, 9.9 mmol), iodoethane (2 g, 12.9 mmol) and NaH (0.48 g, 19.8 mmol) in DMF (20 mL) was stirred for 2h at 60°C. After being diluted with EtOAc (100 mL), the reaction mixture was washed with H20 (20 mL X 3), brine (50 mL), dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography, eluting with PE/EA = 10/1 to give target compound 10-2 as yellow oil. LC- MS: m/z = 230.0 [M+H]+.
[00346] Step 2: A mixture of compound 10-2 (1.41 g, 8.22 mmol), NEt3 (1.86 g, 18.4 mmol) and pivaloyl chloride (1.98 g, 16.4 mmol) in THF (20 mL) was added pivaloyl chloride (1.48 g, 12.3 mmol) was stirred for 3 days at 60°C, then diluted with EtOAc (50 mL), washed with H20 (10 mL), brine (10 mL), dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography, eluting with PE/EA = 4/1 to give target compound 10-3 as yellow oil. LC-MS: m/z = 314.0 [M+H]+.
[00347] Step 3: Under nitrogen atmosphere, to a solution of Compound 10-3 (1.48 g, 4.73 mmol) in dry THF (20 mL) was added n-Butyllithiuni, 2.5 M solution in THF (2.8 mL, 7.09 mmol) dropwise under minus 80 degree. The solution was stirred at -80 degree for 5 min, followed by addition of dry DMF (0.69 g, 9.46 mmol). The mixture was stirred for another 10 min at this temperature and then quenched with H20 (20 mL), extracted with EtOAc (20 mL X 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated to give crude product 10-4 as a yellow oil. LC-MS: m/z = 264.2 [M+H]+
[00348] Step 4: A mixture of compound 10-4 (1.1 g, 4.18 mmol), NaBH4 (0.48 g, 12.5 mmol) in dry THF (10 mL) was stirred at r.t for 2h. After quenched with H20 (20 mL), the mixture was extracted with EtOAc (20 mL X 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated. The resulting residue was purified by column chromatography, eluting with PE/EA = 2/1 to give target compound 10-5 as yellow oil. LC-MS: m/z = 266.1 [M+H]+.
[00349] Step 5: A mixture of compound 10-5 (0.45 g, 1.70 mmol), 4-chlorobenzenethiol (0.29 g, 2.04 mmol), K2C03 (0.70 g, 5.09 mmol), methanesulfonyl chloride (0.23 g, 2.04 mmol), KI (0.42 g, 2.55 mmol) and 18-C-6 (45 mg, 0.17 mmol) in THF ( 20 mL) was stirred for 3 days at rt, then diluted with EtOAc (50 mL), washed with H20 (20 mL), brine (20 mL), dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography, eluting with PE/EA = 4/1 to give target compound 10-6 as colorless oil. LC-MS: m/z = 392.0 [M+H]+. [00350] Example #110: To a solution of compound 10-6 (35 mg, 0.09 mmol) in DCM (5 mL) was added m-CPBA (46 mg, 0.27 mmol) at rt. The reaction mixture was stirred at rt for 2 hr, then diluted with EtOAc (10 mL), washed with 4N NaOH (5 mL), brine (5 mL), dried over anhydrous Na2S04, and concentrated. The residue was purified by preparative column chromatography eluting with PE/EA = 2/1 to give target compound Example #110 as yellow oil. *H NMR (300 MHz, CDC13) δ 7.72 - 7.51 (m, 4H), 4.44 (s, 2H), 3.91 (q, / = 7.1 Hz, 2H), 2.34 (s, 6H), 1.32 - 1.01 (m, 12H). HPLC = 99.2% (214 nm), 99.4% (254 nm), tR = 4.78 min. LC-MS: m/z = 423.9 [M+H]+.
[00351] Scheme 11. Synthesis of Example #7
Figure imgf000130_0001
[00352] Step 1: Compound 11-1 (2 g, 10 mmol), Et3N (2 g, 20 mmol) and EtNH2 (70% in water, 0.68 g, 15 mmol) was added into THF (30 mL), the mixture was stirred for 6 hours at rt. The solvent was removed by reduced pressure. Water (30 mL) was added. The mixture was extracted with EtOAc (30 mL x 3). Combined organic layers were dried over Na2S04, concentrated and purified by flash column chromatography to give the product 11-2 as a yellow oil. LC-MS: m/z = 218.9 [M+H]+.
[00353] Step 2: To a compound of 11-2 (1.35 g, 6.2 mmol) was added pivaloyl chloride (5 mL), the mixture was stirred for 12 hours at 100 °C. After cooling to room temperature, water (10 mL) was added. The mixture was extracted with EA (10 mL x 2). Combined organic layers was dried over Na2S04, concentrated and purified by flash column chromatography to give product 11-3 as a white solid. LC-MS: m/z = 302.9 [M+H]+.
[00354] Step 3: Under nitrogen atmosphere, to a solution of compound 11-3 (0.8 g, 2.64 mmol) in dry THF (30 mL) was added ri-Butyllithiuir!, 2.5 M solution in THF (2.1 ml,, 5.28 mmol) dropwise under minus 78 degree. The solution was stirred at -78 degree for 10 min, followed by addition of dry DMF (0.73 g, 10 mmol). The mixture was stirred for 30 min at this temperature and then quenched with H20 (30 mL), extracted with EA (30 mL x 2). The combined organic layer was dried over Na2S04, concentrated and purified by flash column chromatography to give product 11-4 as a yellow oil. LC-MS: m/z = 253.1 [M+H]+.
[00355] Step 4: A mixture of compound 11-4 (0.44 g, 1.74 mmol), NaBH4 (0.132 g, 3.48 mmol) in dry THF (20 mL) was stirred at rt for 6 hours. After quenched with H20 (30 mL), the mixture was extracted with EA (30 mL x 2). The combined organic layer was dried over Na2S04 and concentrated. The resulting residue was purified by column chromatography to give product 11-5 as a yellow oil. LC-MS: m/z = 255.1 [M+H]+.
[00356] Step 5: PPh3 (0.215 g, 0.82 mmol) and CBr4 (0.27 g, 0.82 mmol) was added to a solution of compound 11-5 (0.2 g, 0.82 mmol) in DCM (20 mL). The mixture was stirred for 0.5h at room temperature. Concentrated and purified by flash column chromatography to give the product 11-6 as a yellow solid. LC-MS: m/z = 317.0 [M+H]+.
[00357] Step 6: Compound 11-6 (0.12 g, 0.31 mmol), sodium 4-chlorobenzenesulfinate (67 mg, 0.34 mmol), TBAI (37 mg, 0.1 mmol) and KI (17 mg, 0.1 mmol) in DMF (10 mL) was stirred for 1 hour at rt. After removed of most of DMF, water (20 mL) was added. The mixture was extracted with EA (20 mL x 2). Combined organic layers was dried over Na2S04, concentrated and purified by flash column chromatography to give product 11-7 as a white solid. LC-MS: m/z = 412.9 [M+H]+.
[00358] Example #7: To a mixture of compound 11-7 (75 mg, 0.18 mmol) and NaH (15 mg, 0.36 mmol) in THF (10 mL) was added 1 -(2-bromoethoxy)-2-bromoethane (63 mg, 0.27 mmol) at rt. The resulting mixture was stirred for 12 hours at 75°C, then quenched with H20 (15 mL), extracted with EA (15 mL x 2). The combined organic layers were dried over Na2S04, concentrated and purified by preparative TLC to give product as a yellow solid. 1H NMR (300 MHz, CDC13) δ 7.93 - 7.37 (m, 6H), 4.04 - 4.01 (m, 2H), 3.80 - 3.78 (m, 2H), 3.33 - 3.29 (m, 2H), 2.63 - 2.59 (m, 2H), 2.38 - 2.34 (m, 2H) 1.18 - 1.10 (s, 12H). HPLC = 97.3% (214 nm), 98.4% (254 nm), tR = 4.61 min. LC-MS: m/z = 483.1 [M+H]+.
[00359] Example #230: was prepared as described in Scheme 11, using (R)- \- cyclohexylethanamine in step 1. 'HNMR: (400 MHz, MeOD) δ: 8.13 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 11.2, 2.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.29-4.27 (m, 1H), 3.99-3.95 (m, 2H), 3.26-3.19 (m, 2H), 2.56-2.52 (m, 4H), 2.15-2.12 (m, 1H), 1.76- 1.66 (m, 5H), 1.22-0.91 (m, 17H). LCMS (ESI): (M+H: 565). [00360] Example #231: was prepared as described in Scheme 11, using phenylethylamine in step 1. *HNMR: (400 MHz, MeOD) δ: 8.11 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.24-7.13 (m, 6H), 5.78-5.73 (m, 1H), 3.96-3.88 (m, 2H), 3.16-3.13 (m, 1H), 3.04-3.01 (m, 1H), 2.50-2.44 (m, 4H), 1.53 (d, J = 4.2 Hz, 3H), 1.02 (s, 9H). LCMS (ESI): (M+H: 581).
[00361] Scheme 12. Synthesis of Examples #2 and #9
Figure imgf000132_0001
[00362] Step 1: A mixture of compound 12-1 (1.18 g, 9.18 mmol), NBS (1.96 g, 11.0 mmol) and benzoyl peroxide (0.11 g, 0.46 mmol) in CC14 (30 mL) was stirred overnight at 90°C. After concentration, the resulting mixture was purified by column chromatography, eluting with PE/EA = 10/1 to give target compound 12-2 as yellow oil. *H NMR (300 MHz, CDC13) δ 8.65 (s, 2H), 4.41 (s, 2H). LC-MS: m/z = 206.9 [M+H]+.
[00363] Step 2: The same procedure with step 6 of Scheme 11 was applied to the preparation of compound 12-3 as yellow oil. LC-MS: m/z = 302.9 [M+H]+.
[00364] Step 3: The same procedure with step 1 of Scheme 9 was applied to the preparation of compound 12-4 as yellow oil. LC-MS: m/z = 311.9 [M+H]+.
[00365] Step 4: The same procedure with step 2 of Scheme 11 was applied to the preparation of compound 12-5 as yellow oil. LC-MS: m/z = 396.1 [M+H]+.
[00366] Example #9: The same procedure with step 7 of Scheme 11 was applied to the preparation of Example #9 as white solid. *H NMR (300 MHz, CDC13) δ 8.34 (s, 2H), 7.47 - 7.35 (m, 4H), 4.03 - 3.91 (m, 4H), 3.29 (t, / = 11.5 Hz, 2H), 2.63 - 2.34 (m, 4H), 1.28 - 1.16 (m, 12H). HPLC = 99.9% (214 nm), 99.8% (254 nm), tR = 4.77 min. LC-MS: m/z = 466.0 [M+H]+.
[00367] Example #2: was prepared following the procedure for Example #9, but oxybis(ethane-2, l-diyl)dimethanesulfonate was used in step 5: *H NMR (300 MHz, CDC13) δ 8.24 (s, 2H), 7.45 - 7.37 (m, 4H), 3.96 - 3.88 (m, 2H), 3.39 - 3.34 (m, 2H), 2.68 - 2.63 (m, 2H), 1.25 - 1.12 (m, 12H), 0.65 - 0.51 (m, 4H). HPLC = 98.7% (214 nm), 97.1% (254 nm), tR = 5.42 min. LC-MS: m/z = 461.9 [M+H]+.
[00368] Scheme 13. Synthesis of Examples #6, 8, 15, and 16.
Figure imgf000133_0001
[00369] Step 1: The same procedure with step 1 of Scheme 6 was applied to the preparation of compound 13-2. LC-MS: m/z = 206.0 [M+H]+.
[00370] Step 2: The same procedure with step 3 of Scheme 6 was applied to the preparation of compound 13-3. LC-MS: m/z = 178.0 [M+H]+.
[00371] Step 3: The same procedure with step 4 of Scheme 7was applied to the preparation of compound 13-4. LC-MS: m/z = 239.9 [M+H]+.
[00372] Step 4: The same procedure with step 5 of Scheme 7 was applied to the preparation of compound 13-5. LC-MS: m/z = 336.0 [M+H]+. [00373] Step 5: Compound 13-5 (0.8 g, 2.4 mmol) and m-CPBA (0.85 g, 4.8 mmol) was added into 1 ,2-dichloroethane (30 mL), the mixture was stirred for 12 hours at 100 °C, after removed of most of 1,2-dichloroethane, the residue was purified by flash column
chromatography to give product 13-6 as a white solid. LC-MS: m/z = 351.9 [M+H]+.
[00374] Step 6: A solution of cyclopropylmethanamine (150 mg, 1.55 mmol) and compound 13-6 (150 mg, 0.42 mmol) in NMP (10 mL) was stirred at 100 °C for 12 hours. After being concentrated, the crude product was purified by flash column chromatography to give product 13-7 as white solid. LC-MS: m/z = 387.0 [M+H]+.
[00375] Step 7: A solution of compound 13-7 (110 mg, 0.28 mmol), iron power (56 mg, 0.84 mmol) in CH3COOH (5 mL) was stirred at rt for 12 hours. After being concentrated, the crude product was purified by flash column chromatography to give product 13-8 as yellow solid. LC-MS: m/z = 370.9 [M+H]+.
[00376] Step 8: Compound of 13-8 (80 mg, 0.22 mmol) was added pivaloyl chloride (5 mL), the mixture was stirred for 12 hours at 100 °C. After removed of most of pivaloyl chloride, water (10 mL) was added. The mixture was extracted with EtOAc (10 mL x 3). Combined organic layers were dried over anhydrous Na2S04, concentrated to give the product 13-9 as yellow solid. LC-MS: m/z = 454.9 [M+H]+.
[00377] Example #15: To a mixture of compound 13-9 (60 mg, 0.13 mmol) and NaH (11 mg, 0.26 mmol) in THF (10 mL) was added 1 -(2-bromoethoxy)-2-bromoethane (46 mg, 0.2 mmol) at rt. The resulting mixture was stirred for 12 hours at 75°C, then quenched with H20 (15 mL), extracted with EA (15 mL x 2). The combined organic layers were dried over Na2S04, concentrated and purified by preparative TLC to give Example #15 as a yellow solid. *H NMR (300 MHz, CDC13) δ 8.05 - 7.40 (m, 6H), 4.04 - 3.22 (m, 6H), 2.64 - 2.34 (m, 4H), 1.13 - 1.03 (m, 10H), 0.37 - 0.01 (m, 4H). HPLC = 95.2% (214 nm), 95.8% (254 nm), tR = 5.09 min. LC-MS: m/z = 524.9 [M+H]+.
[00378] Example #8: was prepared following the procedure for Example #15, except cyclopropaneamine was used in step 6: *H NMR (300 MHz, CDC13) δ 8.01 - 7.32 (m, 6H), 4.05 - 4.01 (m, 2H), 3.32 - 3.22 (m, 3H), 2.65 - 2.61 (m, 2H), 2.38 - 2.34 (m, 2H), 1.16 (s, 9H), 0.84 - 0.53 (m, 4H). HPLC = 98.3% (214 nm), 99.2% (254 nm), tR = 4.67 min. LC-MS: m/z = 510.9 [M+H]+.
[00379] Example #6: was prepared following the procedure for Example #15, except sodium 4-(trifluoromethyl)benzenesulfonate was used in step 4: *H NMR (300 MHz, CDC13) δ 8.13 - 7.57 (m, 6H), 4.04 - 3.22 (m, 6H), 2.62 - 2.36 (m, 4H), 1.13 - 1.03 (m, 10H), 0.38 - 0.01 (m, 4H). HPLC = 95.1% (214 nm), 96.9% (254 nm), tR = 5.20 min. LC-MS: m/z = 558.9 [M+H]+.
[00380] Example #16: was prepared following the procedure for Example #15, except 2- methoxyethaneamine was used in step 6: *H NMR (300 MHz, CDC13) δ 8.02 - 7.35 (m, 6H), 4.18 - 3.21 (m, 11H), 2.74 - 2.28 (m, 4H), 1.12 (s, 9H). HPLC = 99.4% (214 nm), 99.4% (254 nm), tR = 4.66 min. LC-MS: m/z = 528.9 [M+H]+.
[00381] Scheme 14. Synthesis of Example #28 and #29
Figure imgf000135_0001
[00382] Step 1: To a mixture of compound 14-1 (1 g, 3 mmol) and NaH (240 mg, 6 mmol) in THF (40 mL) was added l-(2-bromoethoxy)-2-bromoethane (1.05 g, 4.5 mmol) at rt. The resulting mixture was stirred for 4 hours at 75°C, then quenched with H20 (50 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na2S04, concentrated and purified by flash column chromatography to give product 14-2 as a yellow solid. LC-MS: m/z = 405.9 [M+H]+.
[00383] Step 2: A solution of EtNH2 (110 mg, 2.45 mmol) and compound 14-3 (200 mg, 0.49 mmol) in NMP (15 mL) was stirred at 100 °C for 12 hours. After being concentrated, the crude product was purified by pre-TLC to give product 14-3 as a white solid. LC-MS: m/z = 415.0 [M+H]+.
[00384] Example #29: Compound of 14-3 (70 mg, 0.168 mmol) was added
cyclobutanecarbonyl chloride (2 mL), the mixture was stirred for 6 hours at 100 °C. After removed of most of cyclobutanecarbonyl chloride, water (10 mL) was added. The mixture was extracted with EtOAc (15 mL x 2). Combined organic layers were dried over anhydrous
Na2S04, concentrated to the residue. The residue was purified by pre-HPLC to give the
Example #29 as a yellow solid. *H NMR (300 MHz, CDC13) δ 8.11 (d, / = 2.4 Hz, 1H), 7.80
(s, 1H), 7.47 - 7.39 (m, 4H), 4.03 (d, / = 12 Hz, 2H), 3.79 (br, 2H), 3.33 - 3.31 (m, 2H), 2.94 (br, 2H), 2.61 - 2.59 (m, 2H), 2.43 - 2.41 (m, 4H), 1.82 (br, 4H), 1.14 (t, / = 7.2 Hz, 3H). HPLC = 100% (214 nm), 100% (254 nm), tR = 4.46 min. LC-MS: m/z = 496.9 [M+H]+.
[00385] Example #28: was prepared following the procedure for Example #29, except cyclopentanecarbonyl chloride was used in step 3: !H NMR (300 MHz, CDC13) δ 8.10 (d, / = 2.4 Hz, 1H), 7.81 (s, 1H), 7.40 - 7.32 (m, 4H), 4.03 (d, / = 11.4 Hz, 2H), 3.85 (br, 2H), 3.37 - 3.32 (m, 2H), 2.62 - 2.58 (m, 2H), 2.41 - 2.37 (m, 2H), 1.95 - 1.41 (m, 9H), 1.15 (t, / = 6.9 Hz, 3H). HPLC = 98.2% (214 nm), 99.8% (254 nm), tR = 4.69 min. LC-MS: m/z = 510.9 [M+H]+.
[00386] Scheme 15. Synthesis of Example #95.
Figure imgf000136_0001
[00387] Step 1: Under a nitrogen atmosphere, to a solution of compound 15-1 (6 g, 20.2 mmol) in dry THF (50 mL) was added n-Butyllithiiim, 2.5 M solution in THF (12 ml ,, 30.3 mmol) dropwise under minus 80 degree. The solution was stirred at -80 degree for 1 hr, followed by addition of dry DMF (2.9 g, 40.4 mmol). The mixture was stirred for another 1 hr at this temperature and then quenched with H20 (20 mL), extracted with EA (20 mL X 3). The combined organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated to give crude product The crude product was purified by column
chromatography, eluting with PE/EA = 4/1 to give compound 15-2 as a yellow oil. LC-MS: m/z = 248.2 [M+H]+.
[00388] Step 2: A mixture of compound 15-2 (3.7 g, 15 mmol), NaBH4 (1.7 g, 44.9 mmol) in dry THF (50 mL) was stirred at r.t overnight. After quenched with H20 (20 mL), the mixture was extracted with EA (50 mL X 3). The combined organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated. The resulting residue was purified by column chromatography, eluting with PE/EA = 2/1, to give compound 15-3 as white solid. LC-MS: m/z = 250.2 [M+H]+.
[00389] Step 3: To a solution of compound 15-3 (2.7 g, 10.8 mmol) in DCM (100 mL) was added PBr3 (5.9 g, 21.7 mmol) at 0 degree. The mixture was stirred at 0 degree for 2 hrs and then poured into ice water (100 mL). The mixture was basified with 1 N NaOH to pH = 7, extracted with DCM (100 mL X 3). The combined organic layer was washed brine (30 mL), dried over Na2S04 and concentrated. The residue was purified by column chromatography, eluting with PE/EA = 4/1, to give compound 15-4 as yellow oil. LC-MS: m/z = 312.0
[M+H]+.
[00390] Step 4: To a solution of compound 15-4 (0.8 g, 2.56 mmol) and K2C03 (0.424 g, 3.07 mmol) in 1,4-dioxane (20 mL) was added sodium benzenethiolate (0.373 g, 2.82 mmol) at room temperature. The mixture was stirred at room temperature overnight. Then the mixture was poured into water (10 mL), extracted with DCM (20 mL X 3). The combined organic layer was washed brine (30 mL), dried over Na2S04 and concentrated to give compound 15-6a as colorless oil. LC-MS: m/z = 342.1 [M+H]+.
[00391] Step 5: To a solution of compound 15-6 (0.85 g, 2.49 mmol) in acetic acid (10 mL) was added 30% H202 (10 mL, 14.9 mmol) at room temperature. The mixture was stirred at room temperature for 2 hrs and then poured into ice water (100 mL). The mixture was extracted with DCM (20 mL X 3). The combined organic layer was washed brine (30 mL), dried over Na2S04 and concentrated. The residue was purified by column chromatography, eluting with PE/EA = 2/1, to give compound 15-7. LC-MS: m/z = 374.2 [M+H]+.
[00392] Step 6: A mixture of compound 7 (120 mg, 0.32 mmol), 1,3-dibromopropane 8 (195 mg, 0.97 mmol), NaH (39 mg, 60%, 1.61 mmol) in THF (20 mL) was stirred at 80 degree overnight. Then the mixture was diluted with H20 (10 mL), extracted with EA (20 mL X 3). The combined organic layer was washed brine (30 mL), dried over Na2S04 and concentrated. The residue was purified by preparative TLC to give Example #95 as a white solid.1H NMR (300 MHz, CDC13) δ 7.63 - 7.58 (m, 1H), 7.48 - 7.46 (m, 2H), 7.41 - 7.36 (m, 2H), 7.10 - 7.07 (m, 1H), 6.96 - 6.93 (m, 1H), 6.68 (d, / = 2.1 Hz, 1H), 4.12 (s, 2H), 3.92 (q, / = 7.2 Hz, 2H), 3.36 - 3.26 (m, 2H), 2.68 - 2.58 (m, 2H), 2.46 - 2.32 (m, 1H), 2.10 - 1.98 (m, 1H), 1.22 (t, / = 7.2 Hz, 2H), 1.09 (s, 6H). LC-MS: m/z = 414.1 [M+H]+.
[00393] The following Examples (79, 80, 81, 82, 83, 84, 87, 88, 90, 91, 92, 93, 94, 96, 97,
98, and 99) were all prepared following the same general procedure as outlined in Scheme 15. The procedures only differ by which aryl thiol was used in step 4 and/or which dibromide was used in step 6.
[00394] Example #96: was prepared using 1 ,4-dibromobutane in step 6: JH NMR (300 MHz, CD3OD) δ 7.65 - 7.60 (m, 1H), 7.45 - 7.38 (m, 4H), 7.19 - 7.08 (m, 2H), 6.92 (d, / = 2.1 Hz, 1H), 4.12 (s, 2H), 3.88 (q, / = 6.9 Hz, 2H), 2.83 - 2.75 (m, 2H), 2.38 - 2.30 (m, 2H), 2.07 - 1.95 (m, 2H), 1.72 - 1.68 (m, 2H), 1.14 (t, J = 6.9 Hz, 3H), 1.03 (s, 6H). HPLC = 98.5% (214 nm), 99.1 % (254 nm), tR = 4.72 min. LC-MS: m/z = 428.2 [M+H]+.
[00395] Example #93: was prepared using 4-chlorobenzenethiol in step 4: white solid; 1H NMR (300 MHz, CDC13) δ 7.36 - 7.28 (m, 4H), 7.07 - 7.04 (m, 1H), 6.90 - 6.86 (m, 1H), 6.68 (d, 7 = 2.1 Hz, 1H), 4.09 (s, 2H), 3.87 (q, 7 = 7.2 Hz, 2H), 3.27 - 3.17 (m, 2H), 2.63 - 2.53 (m, 2H), 2.41 - 2.26 (m, 1H), 2.02 - 1.93 (m, 1H), 1.17 (t, 7 = 7.2 Hz, 3H), 1.04 (s, 6H). HPLC = 99.3% (214 nm), 100% (254 nm), tR = 4.91 min. LC-MS: m/z = 448.1 [M+H]+.
[00396] Example #98: was prepared using 4-chlorobenzenethiol in step 4 and 1,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CD3OD) δ 7.50 - 7.36 (m, 4H), 7.26 - 7.19 (m, 1H), 7.16 - 7.09 (m, 1H), 7.00 (d, 7 = 3.6 Hz, 1H), 4.15 (s, 2H), 3.90 (q, 7 = 6.9 Hz, 2H), 2.86 - 2.74 (m, 2H), 2.43 - 2.32 (m, 2H), 2.08 - 2.00 (m, 2H), 1.77 - 1.67 (m, 2H), 1.16 (t, 7 = 7.0 Hz, 3H), 1.04 (s, 6H). HPLC = 98.5% (214 nm), 99.3% (254 nm), tR = 8.14 min. LC-MS: m/z = 402.1 [M+H]+.
[00397] Example #91: was prepared using 4-chlorobenzenethiol in step 4 and 1,5- dibromopentane in step 6:white solid, *H NMR (300 MHz, CD3OD) δ 7.47 - 7.35 (m, 4H), 7.28 - 7.25 (m, 1H), 7.16 - 7.12 (m, 1H), 7.02 (d, J = 2.4 Hz, 1H), 4.16 (s, 2H), 3.91 (q, 7 = 6.9 Hz, 2H), 2.62 - 2.58 (m, 2H), 2.24 - 2.14 (m, 2H), 1.79 - 1.75 (m, 2H), 1.64 - 1.60 (m, 1H), 1.38 - 1.15 (m, 6H), 1.04 (s, 6H). HPLC = 96.2% (214 nm), 97.3% (254 nm), tR = 5.61 min.. LC-MS: m/z = 496.1 [M+H]+.
[00398] Example #90: was prepared using 4-chlorobenzenethiol in step 4 and 1 -bromo-2- ((2-bromothoxy)ethane in step 6: *H NMR (300 MHz, CDC13) δ 7.36 - 7.30 (m, 4H), 7.14 - 7.12 (m, 1H), 7.05 - 7.02 (m, 1H), 6.91 (d, 7 = 2.1 Hz, 1H), 4.14 (s, 2H), 3.98 - 3.86 (m, 4H), 3.30 (t, 7 = 11.4 Hz, 2H), 2.67 - 2.57 (m, 2H), 2.37 - 2.32 (m, 2H), 1.21 (t, 7 = 6.9 Hz, 3H), 1.06 (s, 6H). HPLC = 98.9% (214 nm), 100% (254 nm), tR = 4.64 min. LC-MS: m/z = 478.1 [M+H]+.
[00399] Example #94: was prepared using 4-(trifluoromethyl)benzenethiol in step 4: white solid, *H NMR (300 MHz, CDC13) δ 7.62 - 7.55 (m, 4H), 7.07 - 7.04 (m, 1H), 6.92 - 6.89 (m, 1H), 6.65 (s, 1H), 4.05 (s, 2H), 3.87 (q, 7 = 6.9 Hz, 2H), 3.32 - 3.23 (m, 2H), 2.66 - 2.57 (m, 2H), 2.44 - 2.32 (m, 1H), 2.06 - 1.96 (m, 1H), 1.17 (t, 7 = 7.2 Hz, 3H), 1.03 (s, 6H). HPLC = 99.1% (214 nm), 99.8% (254 nm), tR = 5.37 min. LC-MS: m/z = 482.1 [M+H]+.
[00400] Example #97: was prepared using 4-(trifluoromethyl)benzenethiol in step 4 and
1,4-dibromobutane in step 6: white solid, *H NMR (300 MHz, CD3OD) δ 7.75 - 7.61 (m,
4H), 7.21 - 7.11 (m, 2H), 6.96 (d, 7 = 2.4 Hz, 1H), 4.10 (s, 1H), 3.88 (q, 7 = 6.9 Hz, 2H), 2.87 - 2.78 (m, 2H), 2.43 - 2.34 (m, 2H), 2.06 - 2.01 (m, 2H), 1.78 - 1.69 (m, 2H), 1.14 (t, 7 = 7.2 Hz, 3H), 1.01 (s, 6H). HPLC = 96.2% (214 nm), 97.3% (254 nm), tR = 5.61 min.. LC- MS: m/z = 496.1 [M+H]+.
[00401] Example #92: was prepared using 4-(trifluoromethyl)benzenethiol in step 4 and 1,5-dibromopentane in step 6: white solid, *H NMR (300 MHz, CD3OD) δ 7.77 - 7.74 (m, 2H), 7.62 - 7.59 (m, 2H), 7.27 - 7.25 (m, 1H), 7.18 - 7.14 (m, 1H), 7.01 (d, 7 = 2.1 Hz, 1H),
4.12 (s, 2H), 3.90 (q, 7 = 6.9 Hz, 2H), 2.65 - 2.61 (m, 2H), 2.27 - 2.17 (m, 2H), 1.81 - 1.75 (m, 2H), 1.67 - 1.60 (m, 1H), 1.40 - 1.15 (m, 6H), 1.03 (s, 6H). HPLC = 100% (214 nm), 100% (254 nm), tR = 5.78 min. LC-MS: m/z = 510.1 [M+H]+.
[00402] Example #88: was prepared using 3,4-dichlorobenzenethiol in step 4 and 1,4- dibromobutane in step 6:white solid, *H NMR (300 MHz, CDC13) δ 7.42 - 7.36 (m, 2H), 7.25 - 7.22 (m, 1H), 7.07 - 6.97 (m, 3H), 4.15 (s, 2H), 3.87 (q, 7 = 6.9 Hz, 2H), 2.80 - 2.72 (m, 2H), 2.32 - 2.23 (m, 2H), 2.09 - 1.98 (m, 2H), 1.73 - 1.68 (m, 2H), 1.18 (t, 7 = 7.2 Hz, 3H), 1.04 (s, 6H). HPLC = 100% (214 nm), 100% (254 nm), tR = 5.79 min. LC-MS: m/z = 496.1 [M+H]+.
[00403] Example #81: was prepared using 3,5-dimethylbenzenethiol in step 4 and 1,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CDC13) δ 7.05 - 6.91 (m, 6H),
4.13 (s, 2H), 3.89 - 3.85 (m, 2H), 2.81 - 2.77 (m, 2H), 2.28 - 2.19 (m, 10H), 1.65 (brs, 2H), 1.18 (t, 7 = 7.2 Hz, 3H), 1.04 (s, 6H). HPLC = 98.6% (214 nm), 99.3% (254 nm), tR = 5.21 min.. LC-MS: m/z = 456.2 [M+H]+.
[00404] Example #82: was prepared using 3,5-dichlorobenzenethiol in step 4 and 1,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CDC13) δ 7.51 (s, 1H), 7.25 - 7.22 (m, 2H), 7.08 - 6.96 (m, 3H), 4.18 (s, 2H), 3.90 - 3.85 (m, 2H), 2.76 (brs, 2H), 2.30 (brs, 2H), 2.06 (brs, 2H), 1.71 (brs, 2H), 1.20 (t, 7 = 7.2, 3H), 1.05 (s, 6H). HPLC = 95.2% (214 nm), 95.9% (254 nm), tR = 5.27 min. LC-MS: m/z = 496.1 [M+H]+.
[00405] Example #84: was prepared using 4-ethylbenzenethiol in step 4 and 1,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CDC13) δ 7.28 - 7.11 (m, 6H), 6.83 (s, 1H), 4.09 (s, 2H), 3.91 - 3.84 (m, 2H), 2.83 - 2.64 (m, 4H), 2.26 (brs, 2H), 2.03 (brs, 2H), 1.66 (brs, 2H), 1.25 - 1.18 (m, 4H), 1.05 (s, 6H). HPLC = 97.5% (214 nm), 97.3% (254 nm), tR = 5.53 min. LC-MS: m/z = 456.2 [M+H]+.
[00406] Example #87: was prepared using 4-isopropylbenzenethiol in step 4 and 1,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CD3OD) δ 7.31 - 7.04 (m, 6H),
6.78 (s, 1H), 4.07 (s, 2H), 3.88 - 3.83 (m, 2H), 2.92 - 2.78 (m, 3H), 2.27 (brs, 2H), 2.02 (brs, 2H), 1.65 (brs, 2H), 1.23 - 1.14 (m, 9H), 1.04 (s, 6H). HPLC = 100% (214 nm), 100% (254 nm), tR = 5.56 min. LC-MS: m/z = 470.2 [M+H]+.
[00407] Example #83: was prepared using 3-(trifluoromethoxy)benzenethiol in step 4 and 1,4-dibromobutane in step 6: white solid, *H NMR (300 MHz, CDC13) δ 7.38 - 7.37 (m, 3H), 7.05 - 6.92 (s, 4H), 4.14 (s, 2H), 3.91 - 3.86 (m, 2H), 2.79 - 2.76 (m, 3H), 2.28 (brs, 2H), 2.05 (brs, 2H), 1.68 (brs, 2H), 1.18 (t, / = 7.2 Hz, 3H), 1.04 (s, 6H). HPLC = 98.6% (214 nm), 98.7% (254 nm), tR = 5.68 min. LC-MS: m/z = 512.2 [M+H]+.
[00408] Example #79: was prepared using 3,4-dimethoxybenzenethiol in step 4 and 1,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CDC13) δ 7.06 - 6.71 (m, 6H),
4.11 (s, 2H), 3.88 - 3.71 (m, 8H), 2.77 - 2.75 (m, 3H), 2.26 (brs, 2H), 2.01 (brs, 2H), 1.64 (brs, 2H), 1.20 (t, / = 7.2 Hz, 3H), 1.05 (s, 6H). HPLC = 100% (214 nm), 100% (254 nm), tR = 4.59 min. LC-MS: m/z = 488.1 [M+H]+.
[00409] Example #80: was prepared using 4-(ieri-butyl)benzenethiol in step 4 and 1 ,4- dibromobutane in step 6: white solid, *H NMR (300 MHz, CDC13) δ 7.31 - 7.25 (m, 4H),
7.12 - 6.76 (m, 3H), 4.06 (s, 2H), 3.88 - 3.83 (m, 8H), 2.87 - 2.85 (m, 3H), 2.27 (brs, 2H), 2.03 (brs, 2H), 1.57 (brs, 2H), 1.29 (s, 9H), 1.17 (t, / = 7.2 Hz, 3H), 1.05 (s, 6H).. HPLC = 98.8% (214 nm), 98.8% (254 nm), tR = 5.78 min. LC-MS: m/z = 484.1 [M+H]+.
[00410] Example #99: was prepared using 2 equivelents of iodomethane in step 6: white solid, *H NMR (300 MHz, CDC13) δ 7.55 (t, J = 7.2 Hz, IH), 7.47 - 7.40 (m, 2H), 7.37 - 7.28 (m, 2H), 7.24 - 7.17 (m, IH), 7.12 - 7.05 (m, IH), 7.00 - 6.96 (m, IH), 4.12 (s, 2H), 3.88 (q, J = 7.0 Hz, 2H), 1.80 (s, 6H), 1.17 (t, / = 7.0 Hz, 3H), 1.04 (s, 6H). HPLC = 98.5% (214 nm), 99.3% (254 nm), tR = 8.14 min. LC-MS: m/z = 402.1 [M+H]+.
[00411] Scheme 16. Synthesis of Example #75.
Figure imgf000140_0001
Step 1 10 11
Figure imgf000140_0002
[00412] Step 1: Under nitrogen atmosphere, to a solution of compound 1 (4 g, 13.5 mmol) in dry THF (20 mL) was added n-Butyllithium, 2.5 M solution (in TilF 8.1 mL, 20.2 mmol) dropwise under minus 80 degrees. The solution was stirred at -80 degree for 1 hr, followed by addition of cyclopentanone (2.3 g, 26.9 mmol). The mixture was stirred for another 1 hr at this temperature and then quenched with H20 (5 mL), extracted with EA (20 mL X 3). The combined organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated to give crude product The crude product was purified by column chromatography, eluting with PE/EA = 2/1 2.29 g, yellow oil. *H NMR (300 MHz, CDC13) δ 7.31 - 7.27 (m, 1H), 7.23 - 7.21 (m, 1H), 7.15 - 7.11 (m, 1H), 4.20 (s, 2H), 3.88 (q, 7 = 7.1 Hz, 2H), 2.01 - 1.92 (s, 6H), 1.89 - 1.81 (m, 2H), 1.19 (t, 7 = 7.1 Hz, 3H), 1.00 (d, 7 = 6.9 Hz, 6H). LC-MS: m/z = 304.2 [M+H]+.
[00413] Step 2: To a mixture of compound 16-10 (80 mg, 0.26 mmol) and Znl2 (42 mg, 0.13 mmol) in dry DCM (5 mL) was added 4-niethoxybenzenethiol (44 mg, 0.32 mmol) at r.t. The resulting mixture was stirred at r.t for 0.5 hr, then quenched with H20 (5 mL), extracted with EA (10 mL X 3). The combined organic layer was washed with brine (10 mL), dried over Na2S04 and concentrated to give product. LC-MS: m/z = 426.2 [M+H]+.
[00414] Example #75: A mixture of compound 16-11 (83 mg, 0.2 mmol) and m-CPBA (101 mg, 0.59 mmol) in DCM (5 mL) was stirred at r.t for 2 hrs. Then it was diluted with EA (20 mL), and washed with brine (10 mL), dried over anhydrous Na2S04 and concentrated to give product, which was purified by preparative TLC or HPLC to give target compound as white solid. *H NMR (300 MHz, CD3OD) δ 7.34 - 7.30 (m, 2H), 7.21 - 7.19 (m, 1H), 7.12 - 7.09 (m, 1H), 6.96 - 6.90 (m, 3H), 4.15 (s, 2H), 3.93 - 3.85 (m, 5H), 2.80 - 2.72 (m, 2H), 2.38 - 2.30 (m, 2H), 2.06 - 1.95 (m, 2H), 1.76 - 1.62 (m, 2H), 1.16 (t, 7 = 7.2 Hz, 3H), 1.04 (s, 6H). HPLC = 100% (214 nm), 100% (254 nm), tR = 7.88 min. LC-MS: m/z = 458.2 [M+H]+.
[00415] The following Examples (64. 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 77, 78, and 86) where all prepared following the same general procedure as outlined in Scheme 16. The procedures only differ by which thiol was used in step 2.
[00416] Example #74: was prepared using 3-chloro-4-fluorobenzenethiol in step 2: 1H NMR (300 MHz, CD3OD) δ 7.54 - 7.48 (m, 1H), 7.40 - 7.31 (m, 2H), 7.24 - 7.21 (m, 1H), 7.09 - 7.06 (m, 2H), 4.19 (s, 2H), 3.90 (q, 7 = 6.9 Hz, 2H), 2.83 - 2.73 (m, 2H), 2.42 - 2.33(m, 2H), 2.11 - 1.98 (m, 2H), 1.74 - 1.65 (m, 2H), 1.17 (t, 7 = 7.2 Hz, 3H), 1.03 (s, 6H). HPLC = 97.3% (214 nm), 100% (254 nm), tR = 8.71 min. LC-MS: m/z = 480.0 [M+H]+. [00417] Example #70: was prepared using 3-(trifluoromethyl)benzenethiol in step 2: JH NMR (300 MHz, CD3OD) δ 7.98 - 7.96 (m, 1H), 7.70 - 7.62 (m, 2H), 7.49 (s, 1H), 4.17 (s, 2H), 3.89 - 3.87 (m, 2H), 2.80 - 2.77 (m, 2H), 2.39 - 2.37 (m, 2H), 2.07 - 2.05 (m, 2H), 1.73 -
1.71 (m, 2H), 1.20 - 1.15 (m, 3H), 1.01 (s, 6H). HPLC = 99.4% (214 nm), 99.5% (254 nm), tR = 5.56 min. LC-MS: m/z = 496.3 [M+H]+.
[00418] Example #73: was prepared using 4-methylbenzenethiol in step 2:: H NMR (300 MHz, CD3OD) δ 7.30 - 7.18 (m, 5H), 7.11 - 7.08 (m, 1H), 6.94 (d, / = 2.4 Hz, 1H), 4.14 (s, 2H), 3.89 (q, / = 6.9 Hz, 2H), 2.83 - 2.73 (m, 2H), 2.40 - 2.29 (m, 5H), 2.04 - 1.99 (m, 2H),
1.72 - 1.67 (m, 2H), 1.15 (t, / = 7.2 Hz, 1H), 1.04 (s, 6H). HPLC = 99.0% (214 nm), 98.7% (254 nm), tR = 8.32 min. LC-MS: m/z = 442.1 [M+H]+.
[00419] Example #67: was prepared using 3,4-dimethylbenzenethiol in step 2: JH NMR
(300 MHz, CD3OD) δ 7.20 - 6.97 (m, 6H), 4.16 (s, 2H), 3.97 - 3.88 (m, 2H), 2.79 - 2.72 (m, 2H), 2.32 - 2.23 (m, 8H), 2.01 (brs, 2H), 1.69 (brs, 2H), 1.16 (t, / = 7.2 Hz, 3H), 1.03 (s, 6H). HPLC = 99.8% (214 nm), 99.8% (254 nm), tR = 5.22 min. LC-MS: m/z = 456.2 [M+H]+.
[00420] Example #66: was prepared using 4-cyanobenzenethiol in step 2: JH NMR (300 MHz, CD3OD) δ 7.81 - 7.59 (m, 4H), 7.23 - 7.05 (m, 3H), 4.15 (s, 2H), 3.90 - 3.88 (m, 2H), 2.81 (brs, 2H), 2.39 (brs, 2H), 2.04 (brs, 2H), 1.71 (brs, 2H), 1.13 (t, / = 7.2 Hz, 3H), 0.97 (s, 6H). HPLC = 97.6% (214 nm), 98.6% (254 nm), tR = 7.65 min. LC-MS: m/z = 453.1
[M+H]+.
[00421] Example #78: was prepared using 4-(trifluoromethoxy)benzenethiol in step 2: JH NMR (300 MHz, CDC13) δ 7.46 - 7.43 (m, 2H), 7.25 - 6.86 (m, 5H), 4.10 (s, 2H), 3.88 - 3.83 (m, 2H), 2.80 (brs, 2H), 2.28 (brs, 2H), 2.05 (brs, 2H), 1.68 (brs, 2H), 1.17 (t, / = 7.2 Hz, 3H), 1.04 (s, 6H). HPLC = 100% (214 nm), 100% (254 nm), tR = 5.46 min. LC-MS: m/z = 512.0 [M+H]+.
[00422] Example #65: was prepared using 3-(trifluoromethoxy)-4-chlorobenzenethiol in step 2: *H NMR (300 MHz, CDC13) δ 7.77 (s, 2H), 7.48 (s, 1H), 7.26 - 7.05 (m, 3H), 4.17 (s, 2H), 3.89 - 3.87 (m, 2H), 2.78 (brs, 2H), 2.38 (brs, 2H), 2.05 (brs, 2H), 1.73 (brs, 2H), 1.18 (t, J = 1.2 Hz, 3H), 1.00 (s, 6H). HPLC = 96.4% (214 nm), 96.4% (254 nm), tR = 5.89 min. LC- MS: m/z = 580.1 [M+H]+.
[00423] Example #69: was prepared using 3- fluoro-4-methoxybenzenethiol in step 2: 1H
NMR (300 MHz, CD3OD) δ 7.32 - 6.89 (m, 6H), 4.16 (s, 2H), 3.94 - 3.91 (m, 5H), 2.75 (brs,
2H), 2.35 (brs, 2H), 2.02 (brs, 2H), 1.89 (brs, 2H), 1.15 (t, J = 6.9 Hz, 3H), 1.03 (s, 6H).
HPLC = 99.2% (214 nm), 99.6% (254 nm), tR = 5.11 min. LC-MS: m/z = 476.1 [M+H]+. [00424] Example #86: was prepared using 3-chloro-5-fluorobenzenethiol in step 2: JH NMR (300 MHz, CDC13) δ 7.29 - 7.26 (m, 1H), 7.19 (s, 1H), 7.09 - 6.96 (m, 4H), 4.16 (s, 2H), 3.90 - 3.85 (m, 2H), 2.78 - 2.75 (m, 2H), 2.33 - 2.30 (m, 2H), 2.08 - 2.04 (m, 2H), 1.72 - 1.70 (m, 2H), 1.21 - 1.17 (m, 3H), 1.06 (s, 6H). HPLC = 100% (214 nm), 100% (254 nm), tR = 5.36 min. LC-MS: m/z = 480.1 [M+H]+.
[00425] Example #72: was prepared using 3-isopropoxybenzenethiol in step 2: 1H NMR
(300 MHz, CD3OD) δ 7.34 - 7.31 (m, 1H), 7.22 - 7.13 (m, 3H), 6.81 - 6.80 (m, 1H), 4.54 - 4.52 (m, 1H), 4.15 (s, 1H), 3.90 - 3.88 (m, 2H), 2.78 - 2.77 (m, 2H), 2.38 - 2.36 (m, 2H), 2.02 - 1.99 (m, 2H), 1.70 - 1.68 (m, 2H), 1.29 - 1.27 (m, 6H), 1.19 - 1.15 (m, 3H), 1.03 (s, 6H). HPLC = 95.6% (214 nm), 97.7% (254 nm), tR = 5.39 min. LC-MS: m/z = 486.2 [M+H]+.
[00426] Example #68: was prepared using 3,5-difluorobenzenethiol in step 2: 1H NMR
(300 MHz, CD3OD) δ 7.33 - 7.01 (m, 6H), 4.17 (s, 2H), 3.91 - 3.88 (m, 2H), 2.80 (brs, 2H), 2.41 (brs, 2H), 2.09 (brs, 2H), 1.73 (brs, 2H), 1.14 (t, / = 7.2 Hz, 3H), 1.02 (s, 6H). HPLC = 96.2% (214 nm), 98.6% (254 nm), tR = 5.35 min. LC-MS: m/z = 464.1 [M+H]+.
[00427] Example #71: was prepared using 4-fluoro-3-methylbenzenethiol in step 2: 1H NMR (300 MHz, CD3OD) δ 7.27 - 7.19 (m, 3H), 7.12 - 7.01 (m, 3H), 4.17 (s, 2H), 3.91 - 3.89 (m, 2H), 2.77 - 2.75 (m, 2H), 2.36 - 2.33 (m, 2H), 2.22 - 2.21 (m, 2H), 2.03 - 2.01 (m, 2H), 1.71 - 1.69 (m, 2H), 1.19 - 1.14 (m, 3H), 1.03 (s, 6H). HPLC = 95.1 % (214 nm), 98.2% (254 nm), tR = 5.37 min. LC-MS: m/z = 460.2 [M+H]+.
[00428] Example #77: was prepared using cyclohexanethiol in step 2: !H NMR (300 MHz, CD3OD) δ 7.59 - 7.37 (m, 3H), 4.25 (s, 2H), 3.94 - 3.90 (m, 2H), 2.84 - 2.48 (m, 6H), 1.94 (brs, 2H), 1.78 - 1.34 (m, 7H), 1.30 - 1.03 (m, 14H). HPLC = 98.4% (214 nm), 98.6% (254 nm), tR = 6.78 min. LC-MS: m/z = 434.2 [M+H]+.
[00429] Example #64: was prepared using cyclopentanethiol in step 2: !H NMR (300 MHz, CD3OD) δ 7.55 - 7.35 (m, 3H), 4.42 (s, 2H), 3.95 - 3.91 (m, 2H), 3.31 - 3.29 (m, 1H), 2.65 (brs, 2H), 2.47 (brs, 2H), 1.94 (brs, 2H), 1.70 - 1.49 (m, 10H), 1.16 (t, / = 7.2 Hz, 3H), 1.01 (s, 6H). HPLC = 96.6% (214 nm), 97.8% (254 nm), tR = 6.24 min. LC-MS: m/z = 420.2 [M+H]+. [00430] Scheme 17. Synthesis of Examples #43 and #76.
Figure imgf000144_0001
[00431] Step 1: Compound 17-2 was prepared from compound 17-1 using the procedure described in Scheme 16, Step 1 using dihydro-2H-pyran-3(4H)-one instead of
cyclopentanone. LC-MS: m/z = 320.2 [M+H]+.
[00432] Step 2: Compound 17-3 was prepared from compound 17-2 using the procedure described in Scheme 16, Step 2 using 4-chlorobenzenethiol in place of 4- methoxybenzenethiol. LC-MS: m/z = 446.1 [M+H]+.
[00433] Example #43: Example # 43 was prepared from compound 17-3 using the procedure described in Scheme 16, step-3 using m-CPBA. !H NMR (300 MHz, CDC13) δ 7.37 - 7.29 (m, 4H), 7.17 - 7.09 (m, 2H), 7.07 (d, 7 = 1.8 Hz, 1H), 4.48 - 4.44 (m, 1H), 4.17 - 4.11 (m, 3H), 3.92 - 3.82 (m, 1H), 3.55 - 3.47 (m, 1H), 2.67 - 2.51 (m, 2H), 1.72 - 1.64 (m, 2H), 1.19 (t, 7 = 7.2 Hz, 3H), 1.05 (s, 6H). HPLC = 99.9% (214 nm), 99.9% (254 nm), tR = 4.72 min. LC-MS: m/z = 478.1 [M+H]+.
[00434] Example #76: was prepared following Scheme 17 except dihydrofuran-3(2H)-one was used in step 1 and 4-(trifluoromethyl)benzenethiol was used in step 2: *H NMR (300 MHz, CD3OD) δ 7.80 - 7.70 (m, 4H), 7.25 - 7.22 (m, 1H), 7.06 - 7.03 (m, 1H), 6.90 (d, 7 = 2.1 Hz, 1H), 4.97 - 4.94 (m, 1H), 4.21 - 4.03 (m, 4H), 3.94 - 3.84 (m, 3H), 3.19 - 3.10 (m, 1H), 2.69 - 2.59 (m, 1H), 1.14 (t, 7 = 7.2 Hz, 3H), 1.01 (d, 7 = 2.4 Hz, 6H). HPLC = 98.4% (214 nm), 98.9% (254 nm), tR = 7.40 min. LC-MS: m/z = 498.1 [M+H]+. [00435] Scheme 18. Synthesis of Examples #54 and #56.
Figure imgf000145_0001
[00436] Step 1: Under nitrogen atmosphere, to a solution of compound 1 (1.68 g, 5.66 mmol) in dry THF (30 mL) was added n-Butyllithiura, 2.5 M solution (in THF 3.4 mL, 8.48 mmol) dropwise under -78 degrees. The solution was stirred at -78 degree for 1 hr, followed by addition of tert-butyl 3-oxopyrrolidine-l-carboxylate (2.1 g, 11.3 mmol). The mixture was stirred for another 1 hr at this temperature and then quenched with H20 (5 mL), extracted with EA (30 mL X 3). The combined organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated to give crude product. The crude product was purified by column chromatography, eluting with PE/EA = 2/1, to give the product 16-17 as colorless oil. LC-MS: m/z = 405.1 [M+H]+.
[00437] Step 2: To a mixture of compound 18-17 (1.2 g, 2.97 mmol) in MsOH (10 mL) and
DCM (2 mL) was added 4-chlorobenzenethiol (1.3 g, 8.91 mmol) at r.t arid followed by addition of I O (1 mL). The resulting mixture was stirred at r.t for 48 hrs. Then the mixture was diluted with H20 (15 mL), extracted with EA (10 mL X 3). The combined organic layer was washed with brine (10 mL), dried over Na2S04 and concentrated to give crude product as a yellow oil. LC-MS: m/z = 431.0 [M+H]+.
[00438] Step 3: To a mixture of compound 18-18 (0.65 g, 1.51 mmol) and TEA (0.46 g, 4.53 mmol) in DCM (20 mL) was added Boc20 (0.49 g, 2.27 mmol). After being stirred at r.t for 2 hrs, the mixture was washed with brine (10 mL), dried over Na2S04 and concentrated. The residue was purified by column chromatography, eluting with PE/EA = 3/1, to give the product 18-19 as yellow oil. LC-MS: m/z = 531.0 [M+H]+.
[00439] Step 4: To a mixture of compound 18-19 (0.3 g, 0.56 mmol) in DCM (20 mL) was added m-CPBA (0.48 g, 2.82 mmol). After being stirred at r.t for 2 hrs, the mixture was washed with brine (10 mL), dried over Na2S04 and concentrated. The residue was purified by column chromatography, eluting with PE/EA = 3/1, to give the product 18-20 as yellow oil. LC-MS: m/z = 585.1 [M+Na]+. [00440] Step 5: To a mixture of compound 18-20 (0.14 g, 0.25 mmol) in EA (5 mL) was added a sat. solution of HCl (g) in EA (5 mL) at 0 degree. After being stirred at 0 degree for 1 h, the mixture was concentrated and the residue was diluted with 0.5 N hydrochloric acid (10 mL). The solution was washed with EA (10 mL). Then it was basified with sat. NaHCC>3 solution to pH = 8-9 and extracted with EA (10 mL X 3). The combined organic layer was washed with brine (10 mL), dried over Na2S04 and concentrated to give product. 18-21 as yellow oil. LC-MS: m/z = 463.1 [M+H]+.
[00441] Example #54: A mixture of compound 18-21 (140 mg, 0.3 mmol), (HCHO)n (91 mg, 3.03 mmol) and a drop of HCOOH in DCM (10 mL) was stirred at r.t for 4 hrs, followed by the addition of NaBH(OAc)3 (0.19 g, 0.9 mmol). After being stirred overnight, the mixture was diluted with DCM (20 mL). Then it was washed with brine (10 mL), dried over Na2S04 and concentrated to give product, which was purified by preparative TLC and HPLC to give target compound as white solid. *H NMR (300 MHz, CD3OD) δ 7.48 - 7.40 (m, 4H), 7.24 - 7.21 (m, 1H), 7.10 - 7.06 (m, 1H), 6.96 (d, J = 2.4 Hz, 1H), 4.15 (s, 2H), 3.89 (q, 7 = 7.2 Hz, 2H), 3.63 - 3.59 (m, 1H), 3.47 - 3.43 (m, 1H), 3.06 - 2.98 (m, 1H), 2.85 - 2.81 (m, 2H), 2.61 - 2.52 (m, 1H), 2.41 (s, 3H), 1.14 (t, / = 7.2 Hz, 3H), 1.03 (s, 6H). HPLC = 97.2% (214 nm), 100% (254 nm), tR = 3.14 min. LC-MS: m/z = 477.2 [M+H]+.
[00442] Example # 56: was prepared as described in Scheme 18, except ieri-butyl 4- oxopiperidine-l-carboxylate was used in step 1 instead of ieri-butyl-3-oxopyrrolidine-l- carboxylate: *H NMR (300 MHz, CD3OD) δ 7.50 - 7.40 (m, 4H), 7.30 - 7.28 (m, 1H), 7.18 - 7.14 (m, 1H), 7.06 (d, / = 2.1 Hz, 1H), 4.17 (s, 2H), 3.92 (q, / = 6.9 Hz, 2H), 2.93 - 2.89 (m, 2H), 2.65 - 2.51 (m, 4H), 2.17 (s, 3H), 1.99 - 1.91 (m, 2H), 1.19 (t, / = 6.9 Hz, 3H), 1.05 (s, 6H). HPLC = 98.8% (214 nm), 99.4% (254 nm), tR = 3.39 min. LC-MS: m/z = 491.1
[M+H]+.
[00443] Scheme 18b. Synthesis of Examples #59 and #60.
Figure imgf000146_0001
[00444] Step 1: To a mixture of compound 18b-22, prepared on route to Example #56, (0.3 g, 0.68 mmol) and TEA (0.2 g, 2.03 mmol) in DCM (20 mL) was added acetyl chloride (0.08 g, 1.01 mmol) dropwise at 0 degree. After being stirred at r.t for 3 hrs, the mixture was washed with brine (10 mL), dried over Na2S04 and concentrated. The residue was purified by preparative TLC to give target compound as colorless oil. 1H NMR (300 MHz, CDCI3) δ 7.13 - 7.06 (m, 3H), 7.03 - 6.97 (m, 1H), 6.96 - 6.88 (m, 3H), 4.18 - 4.07 (m, 2H), 4.00 - 3.70 (m, 4H), 2.22 - 2.06 (m, 7H), 2.04 (s, 1H), 1.26 (t, 7 = 7.1 Hz, 1H), 1.19 (t, 7 = 7.0 Hz, 3H), 1.04 (s, 6H). LC-MS: m/z = 508.9 [M+H]+.
[00445] Example #60: was prepared from compound 18b-23 following the same procedure described for compound 18-20. *H NMR (300 MHz, CD3OD) δ 7.49 - 7.37 (m, 4H), 7.32 - 7.29 (m, 1H), 7.20 - 7.16 (m, 1H), 7.08 (d, 7 = 2.4 Hz, 1H), 4.59 - 4.54 (m, 1H), 4.16 (s, 2H), 4.02 - 3.87 (m, 3H), 3.03 - 2.95 (m, 1H), 2.70 - 2.25 (m, 5H), 2.10 (s, 3H), 1.17 (t, 7 = 7.2 Hz, 3H), 1.05 (s, 6H). HPLC = 96.5% (214 nm), 99.1% (254 nm), tR = 4.04 min. LC-MS: m/z = 518.9 [M+H]+.
[00446] Example #59: was prepared as described in Scheme 18b: JH NMR (300 MHz, CD3OD) δ 7.51 - 7.44 (m, 4H), 7.26 - 7.23 (m, 1H), 7.07 - 6.89 (m, 2H), 4.81 - 4.75 (m, 1H), 4.15 (s, 2H), 3.94 - 3.54 (m, 5H), 3.26 - 3.08 (m, 1H), 2.77 - 2.56 (m, 1H), 2.19 (s, 1H), 2.05 (s, 2H), 1.15 (t, 7 = 7.2 Hz, 3H), 1.03 (s, 6H). HPLC = 95.1% (214 nm), 95.9% (254 nm), tR = 4.02 min. LC-MS: m/z = 504.9 [M+H]+.
[00447] Scheme 19. Synthesis of Example #89.
Figure imgf000147_0001
[00448] Example #89: To a solution of Example #91 (30 mg, 0.063 mmol) in MeOH (10 mL) was added 10%Pd/C (10 mg). The mixture was charged with hydrogen balloon and stirred at room temperature for 2 hrs. After filtration, the filtrate was concentrated to give the product as a white solid. *H NMR (300 MHz, CD3OD) δ 7.64 - 7.58 (m, 1H), 7.42 - 7.33 (m, 4H), 7.21 - 7.19 (m, 1H), 7.10 - 7.06 (m, 1H), 6.92 (d, 7 = 2.1 Hz, 1H), 4.10 (s, 2H), 3.86 (q, 7 = 6.9 Hz, 2H), 2.58 - 2.53 (m, 2H), 2.20 - 2.11 (m, 2H), 1.76 - 1.69 (m, 2H), 1.61 - 1.55 (m, 1H), 1.34 - 1.11 (m, 6H), 1.01 (s, 6H). HPLC = 98.1% (214 nm), 97.9% (254 nm), tR = 4.95 min. LC-MS: m/z = 442.2 [M+H]+. [00449] Scheme 20. Synthesis of Example #63.
Figure imgf000148_0001
Step 3 ^ J
Ex. 63
[00450] Step 1: To a solution of compound 20-24 (0.5 g, 3.4 mmol) in THF (20 mL) was added LAH (0.39 g, 10.2 mmol) at 0 degree. The mixture was stirred at r.t for 4 hrs and then quenched with ice water (1 mL). The mixture was filtered and concentrated to give product as a yellow oil.
[00451] Step 2: To a solution of compound 20-25 (0.25 g, 2.2 mmol) and TEA (1.1 g, 11 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.75 g, 6.6 mmol) at 0 degree. The mixture was stirred at r.t for 3 hrs and then poured into ice water (10 mL). The mixture was extracted with DCM (10 mL X2). The combined organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated to give product as a yellow oil. LC-MS: m/z = 274.7 [M+H]+
[00452] Example #63: To a solution of compound 15-7c (70 mg, 0.16 mmol) and NaH (24 mg, 60% purity, 0.48 mmol) in THF (5 mL) was added compound 26 (110 mg, 0.45 mmol) at r.t. The mixture was stirred at 70 degree for 12 hrs and then poured into ice water (10 mL). The mixture was extracted with EA (10 mL X2). The combined organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated to give crude product which was purified by preparative TLC to give target compound as a white solid. *H NMR (300 MHz, CD3OD) δ 7.75 - 7.72 (m, 2H), 7.61 - 7.58 (m, 2H), 7.20 - 7.16 (m, 2H), 7.97 - 7.96 (m, 1H), 4.12 - 4.10 (m, 2H), 3.89 - 3.87 (m, 2H), 2.92 - 2.90 (m, 1H), 2.73 - 2.71 (m, 1H), 2.55 - 2.50 (m, 1H), 2.42 - 2.39 (m, 1H), 1.93 - 1.91 (m, 1H), 1.54 - 1.51 (m, 1H), 1.24 (s, 3H), 1.17 - 1.12 (m, 3H), 1.02 - 1.01 (m, 6H), 0.83 (s, 3H). HPLC = 100% (214 nm), 100% (254 nm), tR = 6.04 min. LC-MS: m/z = 524.0 [M+H]+. [00453] Scheme 20b. Synthesis of Example #85.
Figure imgf000149_0001
[00454] Compound 28: Was prepared from compound 20b-27 following the same procedure described for compound 20-26. LC-MS: m/z = 258.7 [M+H]+.
[00455] Example #85: Was prepared from compound 20b-28 following the same procedure described for Example #63. *H NMR (300 MHz, CD3OD) δ 7.81 - 7.73 (m, 4H), 7.24 - 7.22 (m, 1H), 7.05 - 7.02 (m, 1H), 6.82 (d, / = 2.1 Hz, 1H), 4.09 (s, 2H), 3.89 (q, / = 7.2 Hz, 2H), 3.40 - 3.36 (m, 2H), 2.80 - 2.75 (m, 2H), 1.15 (t, / = 7.2 Hz, 3H), 1.02 (s, 6H), 0.63 - 0.58 (m, 2H), 0.51 - 0.46 (m, 2H). HPLC = 96.9% (214 nm), 98.5% (254 nm), tR = 5.42 min. LC-MS: m/z = 508.1 [M+H]+.
[00456] Scheme 21. Synthesis of Examples #49, 61 and 62.
Figure imgf000149_0002
[00457] Step 1: To a solution of compound 15-7b (2.4 g, 5.9 mmol) in THF (60 mL) was added NaH (0.7 g, 29.5 mmol) in portions at r.t. After being stirred at r.t for 0.5 hrs, the mixture was added 3-bromoprop-l-ene (1.4 g, 11.8 mmol) and stirred overnight at 30 degree. Then it was poured into ice water (50 mL). The mixture was extracted with EA (60 mL X3). The combined organic layer was washed with brine (100 mL), dried over Na2SO"4 and concentrated to give product 30 as a yellow oil. LC-MS: m/z = 488.1 [M+H]+.
[00458] Example #62: A solution of compound 21-30 (0.4 g, 0.82 mmol) and Grubbs Catalyst 2nd Generation (70 mg, 0.082 mmol) in DCM (10 mL) was stirred at r.t overnight. Then it was concentrated and the residue was purified by preparative TLC to give the product Example # 62 as a yellow solid. *H NMR (300 MHz, CD3OD) δ 7.56 - 7.46 (m, 4H), 7.25 - 7.05 (m, 3H), 5.62 (s, 2H), 4.18 (s, 2H), 4.03 - 3.91 (m, 2H), 3.65 - 3.58 (m, 2H), 3.13 - 3.05 (m, 2H), 1.16 (t, J = 6.9 Hz, 3H), 1.03 (s, 6H). HPLC = 99.8% (214 nm), 99.8% (254 nm), tR = 5.34 min. LC-MS: m/z = 460.1 [M+H]+.
[00459] Example #49: To a solution of Example #62 (100 mg, 0.22 mmol), Cu (0.5 g, 7.8 mmol), I2 (50 mg, 0.2 mmol) in Toluene (10 mL) was added diiodomethane (0.64 mL, 7.8 mmol) at r.t. The mixture was stirred at 97 degree for 48 hrs and then filtered. The filtrate was concentrated to give crude product which was purified by preparative TLC to give target compound as a white solid. *H NMR (300 MHz, CD3OD) δ 7.50 - 6.98 (m, 7H), 4.17 (s, 2H), 3.93 - 3.91 (m, 2H), 3.36 - 3.34 (m, 1.5H), 2.77 - 2.75 (m, 0.5H), 2.61 - 2.53 (m, 2H), 1.55 - 1.52 (m, 1.5H), 1.18 (t, / = 7.2 Hz, 3H), 1.05 (s, 6H), 0.98 (brs, 0.5H), 0.44 (brs, 0.5H), 0.13 (brs, 0.5H). HPLC = 99.7% (214 nm), 99.8% (254 nm), tR = 5.26 min. LC-MS: m/z = 474.1 [M+H]+.
[00460] Example #61: A solution of Example #62 (0.1 g, 0.22 mmol) in H202 (2 mL) and HCOOH (4 mL) was stirred at 40 degree for 3 hrs and then concentrated. The residue was purified by preparative TLC to give target compound as a white solid. *H NMR (300 MHz, CD3OD) δ 7.45 - 6.95 (m, 7H), 4.27 - 4.24 (m, 1H), 4.14 (s, 2H), 3.90 - 3.87 (m, 3H), 3.08 (brs, 2H), 2.77 - 2.73 (m, 2H), 2.27 - 2.19 (m, 1H), 1.15 (t, / = 6.9 Hz, 3H), 1.01 (s, 6H). HPLC = 100% (214 nm), 100% (254 nm), tR = 3.69 min. LC-MS: m/z = 493.9 [M+H]+.
[00461] Scheme 22. Synthesis of Examples #47, 51 and 57.
Figure imgf000150_0001
[00462] Step 1: To a solution of compound 15-7b (2.4 g, 5.9 mmol) in THF (60 mL) was added NaH (0.7 g, 29.5 mmol) in portions at r.t. After being stirred at r.t for 0.5 hrs, the mixture was added 3-bromoprop-l-ene (1.4 g, 11.8 mmol) and stirred overnight at 30 degree. Then it was poured into ice water (50 mL). The mixture was extracted with EA (60 mL X 3). The combined organic layer was washed with brine (100 mL), dried over Na2S04 and concentrated to give the desired product as a yellow oil. LC-MS: m/z = 448.1 [M+H]+.
[00463] Step 2: To a solution of compound 22-31 (1.2 g, 2.68 mmol) in DCM (40 mL) was added m-CPBA (2.3 g, 13.4 mmol) at r.t. The mixture was stirred at r.t overnight and then washed with Na2S03 (40 mL), brine (40 mL), dried over Na2S04 and concentrated to give the product as a yellow solid. LC-MS: m/z = 464.1 [M+H]+.
[00464] Example #57: To a solution of compound 22-32 (0.4 g, 0.86 mmol) in THF (20 mL) was added Methylniagnesiumbromide (3M in THF, 0.6 mL, 1.8 mmol) at minus 70 degree. The mixture was allowed to warm to r.t during 0.5 hrs. Then it was quenched with H20 (30 mL) and extracted with EA (20 mL X 3). The combined organic layer was washed with brine (40 mL), dried over Na2S04 and concentrated to give crude product. The crude product was purified by column chromatography, eluting with PE/EA = 3/1, to give pure product as a yellow solid. *H NMR (300 MHz, CD3OD) δ 7.48 - 7.37 (m, 4H), 7.23 - 7.07 (m, 2H), 6.86 (s, 1H), 4.11 (s, 2H), 4.10 - 3.84 (s, 3H), 3.08 - 3.05 (m, 2H), 2.96 - 2.93 (m, 2H), 1.13 (t, / = 6.9 Hz, 3H), 1.00 (s, 6H). HPLC = 97.5% (214 nm), 98.8% (254 nm), tR = 4.02 min. LC-MS: m/z = 464.2 [M+H]+.
[00465] Example #51: To a solution of Example #57 (0.25 g, 0.54 mmol) in DCM (10 mL) was added PCC (0.1 g, 1.2 mmol) at r.t. The mixture was stirred at 30 degree for 5 hrs and then filtered. The filtrate was concentrated to give the product as a yellow solid. JH NMR (300 MHz, CD3OD) δ 7.49 - 7.46 (m, 4H), 7.26 - 7.01 (m, 2H), 6.86 (s, 1H), 4.18 - 4.11 (s, 4H), 3.91 - 3.88 (m, 4H), 1.14 (t, / = 7.2 Hz, 3H), 1.01 (s, 6H). HPLC = 98.4% (214 nm), 99.2% (254 nm), tR = 4.51 min. LC-MS: m/z = 462.1 [M+H]+.
[00466] Example #47: To a solution of Example #51 (60 mg, 0.13 mmol) in DCM (10 mL) was added DAST (200 mg, 1.24 mmol) at r.t. After stirred at r.t for 48 hrs, the mixture was concentrated to give crude product which was purified by preparative TLC to give the target compound as a white solid. *H NMR (300 MHz, CD3OD) δ 7.50 - 7.13 (m, 6H), 6.85 (s, 1H), 4.12 (s, 2H), 3.89 - 3.28 (m, 4H), 3.26 - 3.24 (m, 2H), 1.14 (t, / = 6.9 Hz, 3H), 1.01 (s, 6H). HPLC = 98.1 % (214 nm), 97.4% (254 nm), tR = 4.98 min. LC-MS: m/z = 484.1 [M+H]+. [00467] Scheme 22b. Synthesis of Examples #50 and #52.
Figure imgf000152_0001
[00468] Example #52: To a solution of Example #51 (0.01 g, 0.02 mmol) in Et20 (10 mL) was added Methylmagnesiumbromide (3M in THF, 0.2 mL, 0.6 mmol) at minus 70 degree. The mixture was allowed to warm to r.t and stirred overnight. Then it was concentrated to give crude product. The crude product was purified by preparative TLC to give target compound as a white solid. *H NMR (300 MHz, CD3OD) δ 7.48 - 7.45 (m, 2H), 7.39 - 7.36 (m, 2H), 7.24 - 7.21 (m, 1H), 7.03 - 7.01 (m, 1H), 6.83 (s, 1H), 4.11 (s, 2H), 3.89 - 3.84 (s, 2H), 3.33 - 3.31 (m, 2H), 2.72 - 2.68 (m, 2H), 1.13 (t, J = 6.9 Hz, 3H), 1.04 (s, 3H), 1.00 (s, 6H). HPLC = 95.3%, (214 nm), 95.7% (254 nm), tR = 4.26 min. LC-MS: m/z = 478.1
[M+H]+.
[00469] Example #50: Prepared from Example #51 following the procedure described for Example #88. *H NMR (300 MHz, CD3OD) δ 7.48 - 7.37 (m, 4H), 7.25 - 7.23 (m, 1H), 7.05 - 7.03 (m, 1H), 6.85 (s, 1H), 4.11 (s, 2H), 3.89 - 3.87 (s, 2H), 3.32 - 3.29 (m, 5H), 2.62 - 2.58 (m, 2H), 1.14 (t, / = 6.9 Hz, 3H), 1.04 (s, 3H), 1.00 (s, 6H). HPLC = 99.8% (214 nm), 100% (254 nm), tR = 4.79 min. LC-MS: m/z = 492.1 [M+H]+.
[00470] Scheme 23. Synthesis of Examples #44, 45 46, 48, 53 and 58.
Figure imgf000152_0002
[00471] Step 1: To a mixture of compound 23-32 (2 g, 7.43 mmol) in THF (30 mL) was added NaH (0.54 g, 60%, 22.3 mmol) at r.t, followed by the addition of l-bromo-2- methoxyethane (1.6 g, 11.2 mmol) and KI (3.7 g, 22.3 mmol). The resulting mixture was stirred at 40 degree overnight. Then the mixture was diluted with H20 (10 mL), extracted with EA (30 mL X 3). The combined organic layer was washed brine (30 mL), dried over Na2S04 and concentrated. The residue was purified by column chromatography, eluting with PE/EA = 4/1, to give product 23-33 as yellow oil. LC-MS: m/z = 328.0 [M+H]+.
[00472] Step 2: Compound 23-34 was prepared using the procedure described in Scheme 15, Step 1. LC-MS: m/z = 278.1 [M+H]+.
Step 3: Compound 23-35 was prepared using the procedure described in Scheme 15, Step 2. LC-MS: m/z = 280.2 [M+H]+.
[00473] Step 4: Compound 23-36 was prepared using the procedure described in Scheme 15, Step 3. LC-MS: m/z = 342.1 [M+H]+.
[00474] Step 5: Compound 23-37 was prepared using the procedure described in Scheme
15, Step 4. LC-MS: m/z = 406.1 [M+H]+.
[00475] Step 6: Compound 23-38 was prepared using the procedure described in Scheme
16, Step 3. LC-MS: m/z = 438.1 [M+H]+.
[00476] Example #45: *H NMR (300 MHz, CDC13) δ 7.41 - 7.31 (m, 5H), 6.94 - 6.90 (m, 1H), 6.73 (d, / = 2.1 Hz, 1H), 4.12 (s, 2H), 3.94 (t, J = 5.4 Hz, 2H), 3.62 (t, / = 5.4 Hz, 2H), 3.35 - 3.29 (m, 5H), 2.70 - 2.66 (m, 2H), 1.06 (s, 6H), 0.67 - 0.62 (m, 2H), 0.48 - 0.43 (m, 2H). HPLC = 100% (214 nm), 100% (254 nm), tR = 5.17 min. LC-MS: m/z = 504.1 [M+H]+.
[00477] Example #46: was prepared following the procedure for Example #45, but using l-bromo-2-(2-bromoethoxy)ethane in step 7 : *H NMR (300 MHz, CDC13) δ 7.45 - 7.34 (m, 5H), 7.06 - 7.03 (m, 1H), 6.91 (d, / = 2.1 Hz, 1H), 4.16 (s, 2H), 3.99 - 3.95 (m, 4H), 3.64 (t, J = 5.4 Hz, 2H), 3.36 - 3.26 (m, 5H), 2.67 - 2.57 (m, 2H), 2.37 - 2.33 (m, 2H), 1.08 (s, 6H). HPLC = 100% (214 nm), 100% (254 nm), tR = 4.36 min. LC-MS: m/z = 508.1 [M+H]+.
[00478] Example #48: was prepared as described in Scheme 23 except
(bromomethyl)cyclopropane was used in step 1 instead of l-bromo-2-methoxyethane: 1H NMR (300 MHz, CD3OD) δ 7.47 - 7.46 (m, 4H), 7.23 - 7.22 (m, 1H), 7.03 - 7.02 (m, 1H), 6.83 (s, 1H), 4.14 (s, 2H), 3.78 - 3.76 (s, 2H), 3.31 - 3.30 (m, 5H), 2.76 - 2.72 (m, 2H), 1.02 - 0.97 (m, 7H), 0.52 - 0.44 (s, 6H), 0.18 - 0.16 (s, 2H),. HPLC = 98.6% (214 nm), 98.9% (254 nm), tR = 5.59 min. LC-MS: m/z = 500.1 [M+H]+.
[00479] Example #58: was prepared following the procedure for Example #48, but using 1- bromo-2-(2-bromoethoxy)ethane in step 7: *H NMR (300 MHz, CD3OD) δ 7.47 - 7.03 (m,
7H), 4.17 (s, 2H), 3.80 - 3.77 (s, 2H), 3.77 - 3.75 (m, 2H), 2.31 - 3.29 (m, 2H), 2.55 - 2.50
(m, 4H), 1.29 - 0.98 (s, 7H), 0.45 - 0.43 (s,2H), 0.20 - 0.18 (s,2H). HPLC = 95.4% (214 nm),
95.3% (254 nm), tR = 4.93 min. LC-MS: m/z = 504.1 [M+H]+. [00480] Example #44: was prepared as described in Scheme 23 except 2,2,2-trifluoroethyl trifluoromethanesulfonate was used in step 1 instead of l-bromo-2-methoxyethane: 1H NMR (300 MHz, CDC13) δ 7.38 - 7.32 (m, 4H), 7.13 - 7.10 (m, 1H), 6.71 - 6.62 (m, 2H), 4.59 (q, J = 8.7 Hz, 2H), 3.82 (s, 2H), 3.30 - 3.26 (m, 2H), 2.69 - 2.64 (m, 2H), 1.33 (s, 6H), 0.64 - 0.58 (m, 2H), 0.46 - 0.40 (m, 2H). HPLC = 96.7% (214 nm), 97.8% (254 nm), tR = 6.64 min. LC- MS: m/z = 528.0 [M+H]+.
[00481] Example #53: was prepared as described for Example #44 except 1 -bromo-2-(2- bromoethoxy)ethane was used in step 7 instead of cyclopropane-l,l-diylbis(methylene) dimethanesulfonate: *H NMR (300 MHz, CDC13) δ 7.38 - 7.26 (m, 4H), 7.21 - 7.12 (m, 1H), 6.90 - 6.71 (m, 2H), 4.68 - 4.54 (m, 2H), 3.94 (d, / = 9.7 Hz, 2H), 3.83 (s, 2H), 3.40 - 3.25 (m, 2H), 2.62 - 2.48 (m, 2H), 2.42 - 2.27 (m, 2H), 1.34 (s, 6H). HPLC = 96.4% (214 nm), 96.5% (254 nm), tR = 5.88 min. LC-MS: m/z = 532.1 [M+H]+.
[00482] Scheme 24. Synthesis of Example #55.
Figure imgf000154_0001
[00483] Step 1: To a mixture of compound 24-87 (1 g, 4.3 mmol), TEA (0.87 g, 8.6 mmol) in DCM (30 mL) was added 1 ,4-dibromobutan-2-ol (0.88 g, 5.16 mmol) and the mixture was stirred at r.t for 3 hrs. The mixture was washed with brine (20 mL), dried over Na2S04 and concentrated. The resulting residue was purified by column chromatography, eluting with PE/EA = 20/1, to give the product 24-88 as a colorless oil.
[00484] Example #55: Prepared from compound 24-88 following the same procedure described for Example #95. *H NMR (300 MHz, CD3OD) δ 7.89 - 7.83 (m, 4H), 7.24 - 6.97 (m, 3H), 4.54 - 4.52 (m, 1H), 4.22 - 4.18 (m, 1H), 4.07 - 4.02 (m, 1H), 3.90 - 3.88 (m, 2H), 2.98 - 2.29 (m, 4H), 1.72 - 1.63 (m, 1H), 1.45 - 1.42 (m, 1H), 1.16 - 1.12 (m, 3H), 0.99 - 0.94 (m, 6H). HPLC = 97.7% (214 nm), 97.3% (254 nm), tR = 4.89 min. LC-MS: m/z = 512.1 [M+H]+. [00485] Scheme 25. Synthesis of Example #4, 101, 103, 104, 106, 107, 108, and 109.
Figure imgf000155_0001
25-1 25-2 Step 2 25-3
Figure imgf000155_0002
Figure imgf000155_0003
[00486] Step 1: 4-bromo-2-chlorobenzenamine 25-1 (0.5 g, 2.4 mmol), Et3SiH (0.56 g, 4.8 mmol), acetone (0.28 g, 4.8 mmol) and Ιη(¾ (0.16 g, 0.72 mmol) were dissolved in methanol (20 mL). The mixture was stirred at room temperature overnight. The solvent was removed by reduced pressure, and the residue was purified by flash column chromatography (PE/EA = 10/1) to give the product 25-2 as yellow oil. LC-MS: m/z = 247.9 [M+H]+.
[00487] Step 2: Compound 25-2 (5.0 g, 20 mmol) and pivaloyl chloride (3.6 g, 30 mmol) were stirred in sealed tube at 120 °C overnight. Water (80 mL) was added, and the mixture was extracted by DCM (60 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na2S04, concentrated and purified by silica-gel column chromatography (PE/EA = 10/1) to give the product 25-3 as yellow solid. LC-MS: m/z = 332.0 [M+H]+.
[00488] Step 3: n-BuLi (0.7 mL, 1.65 mmol) was added to a solution of compound 25-3 (0.5 g, 1.5 mmol) in THF (20 mL) at -78 °C. The mixture was stirred for 0.5h at -78 °C. Then DMF (0.2 g, 3.0 mmol) was added. The reaction was stirred for another 0.5h at -78 °C.
Methanol (3 mL) was added, then NaBH4 (0.11 g, 3.0 mmol) was added at 0 °C. The reaction mixture was further stirred for 0.5h. The mixture was extracted with EA (30 mL x 3).
Combined organic layers was washed with brine (20 mL x 2), dried over anhydrous Na2S04, concentrated and purified by silica-gel column chromatography (PE/EA = 5/1) to give the product 25-4 as white solid. LC-MS: m/z = 284.2 [M+H]+.
[00489] Step 4: The solution of compound 25-4 (0.1 g, 0.35 mmol) and PPh3 (0.093 g, 0.35 mmol) in DCM (10 mL) was added CBr4 (0.11 g, 0.35 mmol) at rt. The mixture was stirred at rt for 0.5h. Water (15 mL) was added. The mixture was extracted with DCM (10 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na2S04, concentrated and purified by silica-gel column chromatography (PE/EA = 10/1) to give the product 25-5 as yellow oil. LC-MS: m/z = 345.9 [M+H]+.
[00490] Step 5: The solution of compound 25-5 (0.06 g, 0.17 mmol), sodium 4- chlorobenzenesulfinate (0.037 g, 0.187 mmol), TBAI (0.031 g, 0.085 mmol) and KI (0.028 g, 0.17 mmol) in DMF (10 mL) was stirred for overnight at rt. Water (10 mL) was added. The mixture was extracted with EA (20 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na2S04, concentrated, and purified by flash column
chromatography (PE/EA = 2/1) to give the product 25-6 as white solid. LC-MS: m/z = 441.9 [M+H]+.
[00491] Example #4: The solution of compound 25-6 (100 mg, 0.23 mmol) in THF (10 mL) was NaH (140 mg, 9.7 mmol, 60 w/w) at rt. Then 1 -bromo-2-(2-bromoethoxy)ethane (70 mg, 0.3 mmol) was added and stirred overnight at 50 °C. The mixture was cooled to room temperature. Water (10 mL) was added. The mixture was extracted with DCM (15 mL x 3). Combined organic layer was washed with brine, dried over anhydrous Na2S04, concentrated, and purified by pre-TLC and pre-HPLC to give the desired product as a white solid. JH NMR (300 MHz, CDC13) δ 7.36 - 7.15 (m, 7H), 4.62 (brs, 1H), 4.02 - 3.98 (m, 2H), 3.28 (t, / = 11.4 Hz, 2H), 2.66 - 2.64 (m, 2H), 2.38 - 2.36 (m, 2H), 1.51 (s, 3H), 1.25 - 1.05 (m, 12H). HPLC = 99.2% (214 nm), 99.6% (254 nm), tR = 5.14 min. LC-MS: m/z = 511.9 [M+H]+.
[00492] Example # 101: was prepared following the procedure for Example #4, except 4- bromo-3-chloroaniline was used as starting material in step 1: 1H NMR (300 MHz, CDCI3) δ 7.60 (d, / = 8.7 Hz, 1H), 7.35 (s, 4H), 7.13 - 7.04 (m, 2H), 4.95 - 4.87 (m, 1H), 4.08 - 4.01 (m, 2H), 3.55 - 3.29 (m, 3H), 2.74 - 2.54 (m, 3H), 1.07 - 1.02 (m, 15H). HPLC = 99.4% (214 nm), 99.5% (254 nm), tR = 5.13 min. LC-MS: m/z = 511.9 [M+H]+.
[00493] Example #103: was prepared following the procedure for Example #4, except sodium 3-chloro-4-methylbenzenesulfinate was used in step 5: *H NMR (300 MHz, CDC13) δ 7.38 - 7.12 (m, 6H), 4.62 - 4.58 (m, 1H), 4.01 - 3.97 (m, 2H), 3.30 - 3.23 (m, 2H), 2.64 - 2.63 (m, 2H), 2.42 - 2.33 (m, 5H), 1.26 - 1.05 (m, 15H). HPLC = 100% (214 nm), 100% (254 nm), tR = 5.38 min. LC-MS: m/z = 525.9 [M+H]+.
[00494] Example #104: was prepared following the procedure for Example #4, except step 6 was replaced with steps 1 and 2 of Scheme 21: *H NMR (300 MHz, CDC13) δ 7.33 - 7.07 (m, 7H), 4.61 - 4.57 (m, 1H), 2.72 - 2.60 (m, 3H), 1.42 - 1.40 (m, 2H), 1.29 - 1.02 (m, 15H) , 1.02 - 1.00 (m, 1H). HPLC = 99.4% (214 nm), 99.3% (254 nm), tR = 5.94 min. LC-MS: m/z = 507.9 [M+H]+.
[00495] Example #106: was prepared following the procedure for Example #4, except sodium 3-chloro-4-fluorobenzenesulfinate was used in step 5: *H NMR (300 MHz, CDC13) δ 7.48 - 7.13 (m, 6H), 4.65 (s, 1H), 4.04 - 4.00 (m, 2H), 3.32 - 3.25 (m, 2H), 2.65 - 2.61 (m, 2H), 2.38 - 2.33 (m, 2H), 1.27 - 1.06 (m, 15H). HPLC = 99.5% (214 nm), 99.9% (254 nm), tR = 5.22 min. LC-MS: m/z = 529.9 [M+H]+.
[00496] Example #107: was prepared following the procedure for Example #4, except oxybis(ethane-2- 1 diyl)dimethylsulfonate was used in step 6: *H NMR (300 MHz, CD3OD) δ 7.51 - 7.12 (m, 7H), 3.37 - 3.35 (m, 3H), 2.79 - 2.75 (m, 2H), 1.29 - 1.01 (m, 15H), 0.63 - 0.46 (m, 4H). HPLC = 96.2% (214 nm), 95.4% (254 nm), tR = 5.92 min. LC-MS: m/z = 508.0 [M+H]+.
[00497] Example #108: was prepared following the procedure for Example #4, except sodium 3-fluorobenzenesulfinate was used in step 5: !H NMR (300 MHz, CDC13) δ 7.87 - 7.77 (m, 2H), 7.59 - 7.52 (m, 2H), 7.31 - 7.15 (m, 3H), 4.59 - 4.57 (m, 1H), 4.02 - 3.98 (m, 2H), 3.30 - 3.23 (m, 2H), 2.67 - 2.63 (m, 2H), 2.37 - 2.32 (m, 2H), 1.26 - 1.22 (m, 3H), 1.08 - 1.05 (m, 12H). HPLC = 99.6% (214 nm), 99.5% (254 nm), tR = 5.28 min. LC-MS: m/z = 546.0 [M+H]+.
[00498] Example #109: was prepared following the procedure for Example #4, except n- butyl lithium and dihydro-2H-pyran-3(4H)-one were used in step 6: JH NMR (300 MHz, CD3OD) δ 7.53 - 7.29 (m, 7H), 4.65 - 4.52 (m, 2H), 4.17 - 4.13 (m, 1H), 4.85 - 4.79 (m, 1H), 3.57 - 3.49 (m, 1H), 2.76 - 2.69 (m, 1H), 2.62 - 2.52 (m, 1H), 1.77 - 1.67 (m, 1H), 1.51 - 1.39 (m, 1H), 1.29 - 1.01 (m, 15H). HPLC = 100% (214 nm), 100% (254 nm), tR = 5.38 min. LC- MS: m/z = 511.9 [M+H]+.
[00499] Example #122: was prepared according to the procedures described in Scheme 25, except using sodium-3-fluorobenzenesulfinate in step 5. JH NMR (300 MHz, CDCI3) δ 7.58 - 7.05 (m, 7H), 4.63 (s, 1H), 4.01 (d, / = 11.4 Hz, 2H), 3.29 (t, / = 11.6 Hz, 2H), 2.68 - 2.62 (m, 2H), 2.38 (d, / = 13.8 Hz, 2H), 1.13 - 1.03 (m, 15H). LC-MS: m/z = 496.1 [M+H]+.
[00500] Example #123: was prepared as described in Scheme 25, except using sodium-4- trifluoromethoxybenzenesulfinate in step 5. *H NMR (300 MHz, CDC13) δ 7.43 (d, / = 8.8 Hz, 2H), 7.21 - 7.19 (m, 5H), 4.63 (s, 1H), 4.02 (d, / = 11.1 Hz, 1H), 3.29 (t, / = 11.8 Hz, 2H), 2.69 - 2.66 (m, 7 = 17.8, 7.9 Hz, 2H), 2.38 (d, / = 13.3 Hz, 2H), 1.13 - 1.08 (m, 15H). LC-MS: m/z = 562.1 [M+H]+. [00501] Example #124: was prepared as described in Scheme 25, except using sodium-3,4- dichloromethoxybenzenesulfinate in step 5. *H NMR (300 MHz, CDC13) δ 7.49 - 7.13 (m, 6H), 4.61 (s, 1H), 4.01 (d, / = 9.8 Hz, 2H), 3.29 (t, / = 11.5 Hz, 2H), 2.67 - 2.63 (m, 2H), 2.35 (d, / = 13.8 Hz, 2H), 1.15 - 1.06 (m, 15H). LC-MS: m/z = 546.0 [M+H]+.
[00502] Example #125: was prepared as described in Scheme 25, except sodium-3-fluoro- 4-methoxybenzenesulfinate was used in step 5. !H NMR (300 MHz, CDC13) δ 7.25 - 6.88 (m, 6H), 4.63 (s, 1H), 3.99 - 3.95 (m, 5H), 3.28 (t, / = 11.3 Hz, 2H), 2.65 - 2.61 (m, 2H), 2.36 (d, / = 14.0 Hz, 2H), 1.13 - 1.05 (m, 15H). LC-MS: m/z = 526.1 [M+H]+.
[00503] Example #126: was prepared as described in Scheme 25, except using sodium-3- cyanobenzenesulfinate in step 5. *H NMR (300 MHz, CDC13) δ 7.50 - 7.18 (m, 7H), 4.63 (s, 1H), 4.02 (d, / = 12.0 Hz, 2H), 3.29 (t, / = 11.1 Hz, 2H), 2.68 - 2.62 (m, 2H), 2.36 (d, / =
15.5 Hz, 2H), 1.16 - 1.06 (m, 15H). LC-MS: m/z = 503.0 [M+H]+.
[00504] Example #127: was prepared as described in Scheme 25, except using sodium-3- methoxybenzenesulfinate in step 5. *H NMR (300 MHz, CDC13) δ 7.28 - 6.87 (m, 7H), 4.60 (s, 1H), 4.00 (d, / = 11.6 Hz, 2H), 3.80 (s, 3H), 3.27 (t, / = 11.7 Hz, 2H), 2.68 - 2.63 (m, 2H), 2.41 (s, 2H), 1.13 (m, 15H). LC-MS: m/z = 508.2 [M+H]+.
[00505] Example #128: was prepared as described in Scheme 25, except using sodium-4- methoxybenzenesulfinate in step 5. *H NMR (300 MHz, CDC13) δ 7.22 - 7.19 (m, 5H), 6.81 (d, / = 8.8 Hz, 2H), 4.63 (s, 1H), 3.99 (d, / = 11.2 Hz, 2H), 3.84 (s, 3H), 3.28 (t, / = 11.6 Hz, 2H), 2.65 - 2.63 (m, 2H), 2.35 (d, / = 11.8 Hz, 2H), 1.13 - 1.08 (m, 15H). LC-MS: m/z = 508.2 [M+H]+.
[00506] Example #129: was prepared as described in Scheme 25, except using sodium-3- chloro-4-methoxybenzenesulfinate in step 5. *H NMR (300 MHz, CDC13) δ 7.24 - 7.13 (m, 5H), 6.86 (d, / = 8.6 Hz, 1H), 4.61 (s, 1H), 3.98 (d, / = 18.4 Hz, 5H), 3.27 (t, / = 11.1 Hz, 2H), 2.64 (t, / = 10.6 Hz, 2H), 2.35 (d, / = 13.8 Hz, 2H), 1.17 - 1.06 (m, 15H). LC-MS: m/z = 542.1 [M+H]+.
[00507] Example #130: was prepared as described in Scheme 25, except using sodium-4- cyanobenzenesulfinate in step 5. *H NMR (300 MHz, CDC13) δ 7.67 (d, J = 8.3 Hz, 2H), 7.50 (d, / = 8.3 Hz, 2H), 7.21 - 7.19 (m, 3H), 4.65 (s, 1H), 4.02 (d, / = 11.1 Hz, 2H), 3.30 (t, / =
11.6 Hz, 2H), 2.67 (t, 7 = 10.4 Hz, 2H), 2.36 (d, / = 13.0 Hz, 2H), 1.15 - 1.10 (m, 15H). LC- MS: m/z = 503.1 [M+H]+. [00508] Example #131: was prepared as described in Scheme 25, except using sodium-3- trifluoromethoxybenzenesulfinate in step 5. !H NMR (300 MHz, CDC13) δ 7.27 (m, 7H), 4.60 (s, 1H), 4.01 - 3.94 (m, 2H), 3.28 - 3.21 (m, 2H), 2.66 - 2.61 (m, 2H), 2.36 (d, / = 13.7 Hz, 2H), 1.13 - 1.05 (m, 15H). LC-MS: m/z = 562.1 [M+H]+.
[00509] Example #132: was prepared as described in Scheme 25. !H NMR (400 MHz, MeOD) δ 7.66 (d, / = 8.87Hz, 2H), 7.55 (d, / = 8.87 Hz, 2H) 7.33 (d, / = 1.7 Hz, 1H) 7.27 (d, / = 8.03 HZ, 1H) 7.18 (dd, / = 8.03, 1.7 Hz, 1H) 4.62 (s, 2H), 4.54 (br.s, 1H) 1.02 (d, / = 6.63 Hz, 3H), 0.97 (d, / = 6.78 Hz, 3H).LC-MS: m/z = 441.9 [M+H]+.
[00510] Example #133: was prepared as described in Scheme 25, except using 4-bromo-2- chloroaniline in step 1. *H NMR (300 MHz, CDC13) δ 7.36 - 7.33 (m, 4H), 7.14 - 6.98 (m, 3H), 4.945 - 4.85 (m, 1H), 4.03 - 3.99 (m, 2H), 3.29 (t, / = 1 1.7 Hz, 2H), 2.72 - 2.62 (m, 2H), 2.37 - 2.62 (m, 2H), 1.07 - 1.04 (m, 15H). LC-MS: m/z = 495.9 [M+H]+.
[00511] Example #134: was prepared as described in Scheme 25, except using 4-bromo-2- chloroaniline in step 1. *H NMR (300 MHz, CDC13) δ 7.58 - 7.40 (m, 4H), 7.08 - 6.87 (m, 3H), 4.90 - 4.85 (m, 1H), 4.33 (s, 2H), 1.01 - 0.88 (m, 15H). LC-MS: m/z = 425.9 [M+H]+.
[00512] Example #135: was prepared as described in Scheme 25, except using 4-bromo-2- chloroaniline in step 1 and cyclobutanecarbonyl chloride in step 2. JH NMR (300 MHz, CDCI3) δ 7.35 - 7.31 (m, 4H), 7.11 - 7.04 (m, 3H), 5.01 - 4.92 (m, 1H), 4.04 - 4.01 (m, 2H), 3.36 - 3.29 (m, 2H), 2.70 - 2.63 (m, 3H), 2.39 - 2.25 (m, 4H), 1.81 - 1.66 (m, 4H), 1.1 1 - 0.99 (m, 6H). LC-MS: m/z = 493.9 [M+H]+.
[00513] Example #136: was prepared as described in Scheme 25, except using 4-bromo-2- chloroaniline in step 1 and cyclobutanecarbonyl chloride in step 2. 1H NMR (300 MHz, CDCI3) δ 7.63 - 7.43 (m, 4H), 7.03 - 6.91 (m, 3H), 4.98 - 4.89 (m, 1H), 4.33 (s, 2H), 2.76 - 2.68 (m, 2H), 2.34 - 2.23 (m, 2H), 1.74 - 1.52 (m, 4H), 1.08 - 0.96 (m, 6H). LC-MS: m/z = 424.1 [M+H]+.
[00514] Example #137: was prepared as described in Scheme 25, except using 4-bromo-2- methylaniline in step 1 and cyclobutanecarbonyl chloride in step 2. 1H NMR (300 MHz, CDCI3) δ 7.34 - 7.27 (m, 4H), 7.14 - 6.91 (m, 3H), 4.86 - 4.77 (m, 1H), 4.05 - 3.97 (m, 2H), 3.40 - 3.28 (m, 2H), 2.71 - 2.39 (m, 6H), 2.22 - 2.07 (m, 4H), 1.83 - 1.59 (m, 4H), 1.21 (d, J = 6.8 Hz, 3H), 0.94 (d, / = 6.8 Hz, 3H). LC-MS: m/z = 490.0 [M+H]+
[00515] Example #138: was prepared as described in Scheme 25, except using 4-bromo-2- chloroaniline in step 1 and l , l-bis(iodomethyl)cyclopropane in step 6. 1H NMR (300 MHz, CDCI3) δ 7.35 - 7.25 (m, 4H), 6.94 - 6.80 (m, 3H), 4.57 - 4.48 (m, 1H), 3.35 - 3.29 (m, 2H), 2.77 - 2.69 (m, 2H), 2.16 (s, 3H), 1.25 - 0.94 (m,15H), 0.72 - 0.66 (m, 2H), 0.51- 0.45 (m, 2H). LC-MS: m/z = 488.0 [M+H]+.
[00516] Scheme 26. Synthesis of Examples #3, 18, 24, 38, 39, 40, 41, and 42.
Figure imgf000160_0001
26-1 Step 1 26-2 Step 2 Step 3
Figure imgf000160_0002
[00517] Step 1: Pivaloyl chloride (0.7 g, 5.76 mmol) was added to a solution of compound 26-1 (1.0 g, 4.8 mmol) and Et3N (1.0 g, 9.6 mmol) in DCM (40 mL). The mixture was stirred at room temperature overnight. Water (50 mL) was added. The mixture was extracted with DCM (40 mL x 2). Combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated to give the product 26-2 as colorless oil. LC-MS: m/z = 289.9 [M+H]+.
[00518] Step 2: The solution of compound 26-2 (7.6 g, 26 mmol) in THF (100 mL) was added NaH (3.1 g, 78 mmol). The mixture was stirred at rt for 0.5h. Then Etl (8.2 g, 52 mmol) was added, and stirred at 70 °C overnight. The mixture was cooled to rt. Water (120 mL) was added. The mixture was extracted with EA (80 mL x 3). Combined organic layers was washed with brine, dried over anhydrous Na2S04, concentrated and purified by silica-gel column chromatography (PE/EA = 10/1) to give the product 26-3 as yellow oil. LC-MS: m/z = 317.9 [M+H]+.
[00519] Step 3: The same procedure with the step 3 of Scheme 1 was applied to the preparation of compound 26-4. LC-MS: m/z = 270.1 [M+H]+.
[00520] Step 4: The same procedure with the step 4 of Scheme 1 was applied to the preparation of compound 26-5. LC-MS: m/z = 332.0 [M+H]+. [00521] Step 5: The same procedure with the step 5 of Scheme 1 was applied to the preparation of compound 26-6. LC-MS: m/z = 462.0 [M+H]+.
[00522] Example #3: *H NMR (300 MHz, CDC13) δ 7.66 - 7.53 (m, 4H), 7.23 - 6.98 (m, 3H), 4.18 (brs, 1H), 4.02 - 3.98 (m, 2H), 3.31 (t, / = 11.8 Hz, 2H), 3.19 - 3.02 (m, 1H), 2.65 - 2.61 (m, 2H), 2.40 - 2.36 (m, 2H), 1.55 (s, 3H), 1.25 - 1.04 (m, 9H). HPLC = 99.3.% (214 nm), 99.7% (254 nm), tR = 5.12 min. LC-MS: m/z = 531.9 [M+H]+.
[00523] Example #18: was prepared following the procedure for Example #3, except sodium 4-chlorobenzenesulfinate was used in step 5: *H NMR (METHANOL-d4) δ: 7.38 - 7.49 (m, 2H), 7.25 - 7.34 (m, 2H), 6.87 - 6.96 (m, 2H), 6.60 (d, J = 8.3 Hz, OH), 4.03 (q, J = 7.2 Hz, 2H), 3.85 - 3.98 (m, 2H), 2.35 - 2.55 (m, 3H), 2.01 (s, 3H), 1.28 (t, J = 7.0 Hz, 4H), 1.13 (s, 9H). LC-MS: m/z = 478.0 [M+H]+.
[00524] Example #38: was prepared following the procedure for Example #18, except 4- bromo-2-(trifluoromethyl)aniline was used as starting material in step 1: 1H NMR (300 MHz, CDC13) δ 7.63 - 7.51 (m, 1H), 7.39 - 7.26 (m, 6H), 4.37 - 4.16 (m, 2H), 4.08 - 3.94 (m, 2H), 3.36 - 3.12 (m, 2H), 2.75 - 2.54 (m, 2H), 2.49 - 2.33 (m, 2H), 1.28 - 0.99 (m, 12H). HPLC = 98.0% (214 nm), 97.5% (254 nm), tR = 5.10 min. LC-MS: m/z = 532.2 [M+H]+.
[00525] Example #39: was prepared following the procedure for Example #38, except 4- bromo-2-(trifluoromethyl)aniline was used as starting material in step 1 and oxybis(ethane- 2,l-diyl)dimethylsulfonate was used in step 6: *H NMR (300 MHz, CDC13) δ 7.65 - 7.54 (m, 4H), 7.43 - 7.40 (m, 1H), 7.20 - 7.07 (m, 2H), 4.29 - 4.22 (m, 1H), 3.41 - 3.35 (m, 2H), 3.15 - 2.73 (m, 3H), 1.15 - 1.11 (m, 12H), 0.70 - 0.65 (m, 2H), 0.53 - 0.47 (m, 2H). HPLC = 100% (214 nm), 100% (254 nm), tR = 5.96 min. LC-MS: m/z = 562.2 [M+H]+.
[00526] Example #42: was prepared following the procedure for Example #3, except 4- bromoaniline was used as starting material in step 1 and sodium 3 (trifluoromethyl) benzenesulfinate was used in step 5: *H NMR (300 MHz, CDC13) δ 7.83 - 7.82 (m, 1H), 7.59 - 7.52 (m, 3H), 7.25 - 7.15 (m, 4H), 4.02 - 3.98 (m, 2H), 3.72 - 3.70 (m, 2H), 3.29 - 3.25 (m, 2H), 2.67 - 2.64 (m, 2H), 2.42 - 2.37 (m, 2H), 1.12 - 1.10 (m, 3H), 1.04 (s, 9H). HPLC = 100% (214 nm), 100% (254 nm), tR = 4.84 min. LC-MS: m/z = 498.2 [M+H]+.
[00527] Example #40: was prepared following the procedure for Example #42, except sodium 4- (trifluoromethyl) benzenesulfinate was used in step 5: LC-MS: m/z = 494 [M+H]+.
[00528] Example #41: was prepared following the procedure for Example #42, except oxybis(ethane-2-l-diyl)dimethanesulfonate was used in step 6: LC-MS: m/z = 498 [M+H]+. [00529] Example #24: was prepared following the procedure for Example #18, except 4- bromo-2-methylaniline was used as starting material instep 1: LC-MS: m/z = 479 [M+H]+.
[00530] Scheme 27. Synthesis of Example #1
Figure imgf000162_0001
[00531] Step 1: The same procedure with the step 1 of Scheme 1 was applied to the preparation of compound 27-2. LC-MS: m/z = 228.0 [M+H]+.
[00532] Step 2: The same procedure with the step 2 of Scheme 1 was applied to the preparation of compound 27-3. LC-MS: m/z = 312.1 [M+H]+.
[00533] Step 3: The same procedure with the step 3 of Scheme 1 was applied to the preparation of compound 27-4. LC-MS: m/z = 264.1 [M+H]+.
[00534] Step 4: To a solution of Compound 3a-4 (0.31 g, 1.18 mmol) in DCM (10 mL) was added PBr3 (0.32 g, 1.18 mmol) at 0 degree. The mixture was stirred at 0 degree for 2 hrs and then poured into ice water (10 mL). The mixture was extracted with DCM (10 mL X 3). The combined organic layer was washed brine (10 mL), dried over Na2S04 and concentrated give crude compound 27-5 as yellow oil. LC-MS: m/z = 326.0 [M+H]+.
[00535] Step 5: The same procedure with the step 5 of Scheme 1 was applied to the preparation of compound 27-6. LC-MS: m/z = 422.1 [M+H]+.
[00536] Step 6: The same procedure with the step 6 of Scheme 1 was applied to the preparation of Example #1. *H NMR (300 MHz, CDC13) δ 7.32 - 7.25 (m, 4H), 7.02 - 6.99 (m, 3H), 4.58 (brs, 1H), 3.31 (d, / = 9.3 Hz, 2H), 3.29 (t, / = 11.5 Hz, 2H), 2.65 - 2.60 (m, 2H), 2.40 - 2.36 (m, 2H), 2.19 (s, 3H), 1.22 (d, / = 6.6 Hz, 3H), 1.04 - 0.95 (m, 12H). HPLC = 99.7.% (214 nm), 98.4% (254 nm), tR = 5.01 min. LC-MS: m/z = 492.0 [M+H]+.
[00537] Example #112: was prepared following the procedure described in Example #23, except using l,l-bis(iodomethyl)cyclopropane in step 2. !H NMR (301 MHz, CDC13) δ 8.04 (d, J = 2.4 Hz, 1H), 7.89 - 7.54 (m, 5H), 7.18 (d, / = 8.4 Hz, 1H), 3.79 (q, J = 7.2 Hz, 2H), 3.38 (d, / = 13.8 Hz, 2H), 2.76 (d, / = 13.8 Hz, 2H), 1.23 - 1.03 (m, 12H), 0.71 - 0.59 (m, 2H), 0.56 - 0.42 (m, 2H). . LC-MS: m/z = 495.0 [M+H]+.
[00538] PREPARATIVE EXAMPLE #115
[00539] Scheme 28.
Figure imgf000163_0001
[00540] Step 1: A mixture of compound 28-1 (1.5 g, 7.9.5 mmol), cyclopropanamine (1.36 g, 23.9 mmol) in DMSO (5 mL) was stirred at 80°C for 8 h. The reaction was quenched with water and extracted with EA (10 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 5/1) to give 28-2 as a yellow oil. LC-MS: m/z = 226.0 [M+H]+.
[00541] Step 2: To a 0°C solution of compound 28-2 (0.6 g, 2.66 mmol) in THF (40 mL) was added L1AIH4 (0.202 g, 5.32 mmol). The reaction was stirred for 2 hrs. then quenched with water and 10% NaOH aqueous solution. The resulting mixture was filtered and the filtrate evaporated to give crude 28-3 as a colorless oil. LC-MS: m/z = 198.1 [M+H]+.
[00542] Step 3: To a 0°C solution of compound 28-3 (0.456 g, 2.3 mmol) in CH2C12 (10 mL) was added PBr3 (0.623g, 2.3 mmol). The reaction was stirred for 1 nr. and poured into a mixture of sodium 4-chlorobenzenesulfinate (0.548 g, 2.76 mmol), TBAI (0.17 g, 0.46 mmol) and KI (0.458 g, 2.76 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 3 hrs. The reaction was quenched with water and extracted with EA (20 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 2/1) to give 28-4 as a white solid. LC-MS: m/z = 323.9 [M+H]+.
[00543] Step 4: The reaction mixture of compound 28-4 (200 mg, 0.56 mmol) and pivaloyl chloride (5 mL) was stirred at 100°C overnight. Then the solvent was evaporated and the residue was purified by prep-TLC (eluent: PE/EA = 2/1) to give 28-5 as a colorless oil. LC- MS: m/z = 439.9 [M+H]+.
[00544] Step 5: To a solution of compound 28-5 (53 mg, 0.12 mmol) in dry DMF (5 mL) was added NaH (15 mg, 0.6 mmol) and 2,2'-dibromodiethyl ether (84 mg, 0.36 mmol) at r.t and then stirred overnight. Water was added and the resulting mixture was extracted with EA (20 mL x 3). The combined organic layers were dried over Na2S04 and evaporated. The residue was purified by prep-TLC (eluent: PE/EA = 2/1) to give Example #115 as a white solid. *H NMR (300 MHz, CDC13) δ 7.37 - 7.28 (m, 4H), 7.25 - 7.24 (m, 1H), 7.13 - 7.03 (m, 2H), 4.03 - 3.96 (m, 2H), 3.33 - 3.19 (m, 3H), 2.70 - 2.60 (m, 2H), 2.38 - 2.30(m, 2H), 1.16 (s, 9H), 0.87 - 0.79 (m, 2H), 0.50 - 0.43 (m, 2H). LC-MS: m/z = 509.9 [M+H]+.
[00545] Example #116: was prepared as described in Scheme 28, except using
cyclobutylamine in step 1. *H NMR (300 MHz, CDC13) δ 7.25 - 7.07 (m, 7H), 4.97 - 4.95 (m, 1H), 4.04 (d, / = 10.9 Hz, 2H), 3.34 (t, / = 11.8 Hz, 2H), 2.72 - 2.15 (m, 9H), 1.76 - 1.58 (m, 8H). LC-MS: m/z = 522.0 [M+H]+.
[00546] Example #117: was prepared as described in Scheme 28, except using
cyclobutylamine in step 1 and cyclobutanecarbonyl chloride in step 4. 1H NMR (300 MHz, CDCI3) δ 7.26 - 7.07 (m, 7H), 4.97 (s, 1H), 4.04 (d, J = 10.9 Hz, 2H), 3.34 (t, 7" = 11.8 Hz, 2H), 2.67 - 1.58 (m, 17H). LC-MS: m/z = 522.0 [M+l].
[00547] Example #118: was prepared as described in Scheme 28, except using
cyclopentylamine in step 1. *H NMR (300 MHz, CDC13)5 7.22 - 7.11 (m, 7H), 4.52 (s, 1H), 4.02 - 3.97 (m, 2H), 3.29 (t, / = 12.2 Hz, 2H), 2.70 - 2.65 (m, 2H), 2.38 - 2.35 (m, 2H), 2.05 - 2.87 (m, 2H), 1.52 - 1.38(s, 6H), 1.09 (s, 9H). LC-MS: m/z = 537.9 [M+H]+.
[00548] Example #119: was prepared as described in Scheme 28, except using 4-bromo-2- methylaniline and cyclopropylmethanamine in step 1. JH NMR (300 MHz, CDCI3) δ 7.37 - 7.31 (m, 4H), 7.20 - 7.12 (m, 2H), 6.99 - 6.96 (m, 2H), 4.14 - 4.08 (m, 1H), 4.01 - 3.97 (m, 2H), 3.34 - 3.25 (m, 2H), 2.66 - 2.62 (m, 2H), 2.42 - 2.38 (m, 2H), 2.20 (s, 3H), 1.26 - 1.00 (m, 10H), 0.44 - 0.41 (m, 2H), 0.16 - 0.10 (m, 1H), -0.03 - -0.09 (m, 1H). LC-MS: m/z = 504.1 [M+H]+.
[00549] Example #120: was prepared as described in Scheme 28, except using 4-bromo-2- methylaniline and cyclopentylamine in step 1. !H NMR (300 MHz, CDC13) δ 7.34 - 7.26 (m, 4H), 7.10 - 6.95 (m, 3H), 4.53 - 4.39 (m, 1H), 4.04 - 4.94 (m, 2H), 3.36 - 3.25 (m, 2H), 2.70 - 2.60 (m, 2H), 2.41 - 2.37 (m, 2H), 2.18 (s, 3H), 2.11 - 2.01 (m, 1H), 1.80 - 1.44 (m, 7H), 1.04 (s, 9H). ). LC-MS: m/z = 518.0 [M+H]+.
[00550] Example #121: was prepared as described in Scheme 28, except using 4-bromo-2- methylaniline and cyclopropylamine in step 1. !H NMR (300 MHz, CDC13) δ 7.36 - 7.27 (m, 4H), 7.13 - 7.00 (m, 3H), 4.85 - 4.74 (m, 1H), 4.02 - 3.95 (m, 2H), 3.31 (t, / = 11.7 Hz, 2H), 2.72 - 2.62 (m, 2H), 2.42 - 2.34 (m, 2H), 2.11 (s, 3H), 2.01 - 1.92 (m, 1H), 1.83- 1.41 (m, 5H), 1.06 (s, 9H). LC-MS: m/z = 504.0 [M+H]+.
[00551] PREPARATIVE EXAMPLE #139
Figure imgf000165_0001
[00553] Step 1: To a mixture of compound 29-1 (prepared as outlined in Scheme 6, using sodium 3-(trifluoromethyl)benzenesulfinate in Step 4) (0.2 g, 0.43 mmol) in THF (10 mL) was added NaH (21 mg, 0.87 mmol), then followed by 2-(3-bromopropoxy)-tetrahydro-2H- pyran (0.14g, 0.65 mmol) at r.t. The resulting mixture was stirred overnight at 70 °C, quenched with H20 (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2S04, and concentrated to the crude product. The crude product was purified by column chromatography eluting with PE/EA = 3/1 to give target compound 29-2 as a colorless oil, 0.08 g. LC-MS: m/z = 626.9 [M+Na]+. [00554] Step 2: A mixture of compound 29-2 (0.91 g, 1.37 mmol), PPTS (35 mg, 0.14 mmol) in EtOH (20 mL) was stirred at 80 °C for 1 hr. and concentrated in vacuo. The residue was diluted with EA (30 mL), washed with brine (10 mL), dried over anhydrous Na2S04, and concentrated to give target compound 29-3 as a colorless oil. LC-MS: m/z = 521.1 [M+H]+.
[00555] Step 3: To a 0 °C mixture of compound 29-3 (0.75 g, 1.44 mmol) and CBr4 (0.5 g, 1.51 mmol) in DCM (15 mL) was added ΡΡ1¾ (0.4 g, 1.51 mmol). The reaction miture was stirred at r.t. for 20 min. the concentrated. The residue was purified by column
chromatography eluting with PE/EA = 4/1 to give target compound 29-4 as a colorless oil. LC-MS: m/z = 584.8 [M+H]+.
[00556] Step 4: To a 0 °C mixture of compound 1-4 (0.2 g, 0.34 mmol) and NaH (41 mg, 1.72 mmol) in THF (15 mL) was added (HCHO)n (0.27 g, 3.43 mmol). The reaction was stirred for 2 hrs. then warmed to rt and stirred for another 2 hrs. The reaction was quenched with H20 (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine (lOmL), dried over Na2S04 and concentrated. The residue was purified by prep. TLC to give Example #139 as a white solid. *H NMR (300 MHz, CDC13) δ 8.24 (s, 1H), 7.90 - 7.73 (m, 3H), 7.63 - 7.53 (m, 2H), 4.47 (d, J = 12.3 Hz, 1H), 4.15 (d, / = 12.0 Hz, 1H), 3.90 (dd, / = 11.4, 3.6 Hz, 1H), 3.70 (bs, 2H), 3.53 (t, / = 10.5 Hz, 1H), 2.64 (d, / = 5.4 Hz, 2H), 1.73 (d, / = 14.1 Hz, 2H), 1.15 - 1.06 (m, 12H). LC-MS: m/z = 532.9 [M+H]+.
[00557] Examples #140 and #141 were prepared as described in Scheme 29, starting with Compound 6-6.
[00558] After cyclisation of the THP ring the two enantiomers were separated by chiral HPLC (Diacel chiralpak OJ-H 250 x 20 mm, 5 urn column. Mobile phase MeOH:C02 (15:85). Flow rate 40 mL/min.). Enantiomer 1 (first off the column) was labeled Example #141: *H NMR (300 MHz, CDC13) 5 8.18 (d, 7 = 2.1 Hz, 1H), 7.87 (d, / = 2.4 Hz, 1H), 7.35 (q, / = 8.5 Hz, 4H), 4.52 (d, / = 12.3 Hz, 1H), 4.12 (d, / = 12.0 Hz, 1H), 4.00 - 3.42 (m, 4H), 2.63 - 2.55 (m, 2H), 1.73 - 1.50 (m, 2H), 1.19 - 1.02 (m, 12H). LC-MS: m/z = 499.1
[M+H]+.
[00559] Enantiomer 2 (second off the column) was labeled Example #141: !H NMR (300 MHz, CDCI3) δ 8.18 (d, / = 2.1 Hz, 1H), 7.87 (d, / = 2.1 Hz, 1H), 7.35 (q, / = 8.7 Hz, 4H), 4.50 (d, J = 12.5 Hz, 1H), 4.12 (d, / = 12.0 Hz, 1H), 3.98 - 3.38 (m, 4H), 2.68 - 2.58 (m, 2H), 1.76 - 1.56 (m, 2H), 1.27 - 0.89 (m, 12H). LC-MS: m/z = 499.0 [M+H]+.
[00560] PREPARATIVE EXAMPLE #142. [00561] Scheme 30.
Figure imgf000167_0001
[00562] Step 1: To a 0°C solution of compound 30-1 (0.5 g, 2.67 mmol) in DCM (30 mL) was added PBr3 (0.87 g, 3.20 mmol) drop wise. The reaction was stirred at 0°C for 1 nr. then quenched with water (10 m L) and extracted with DCM (30 mL x 3). The combined organic layer was washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 10/1) to give 30-2 as a colorless oil. NMR (300 MHz, CDC13) δ 7.90 (s, 1H), 7.60 - 7.51 (m, 2H), 4.47 (s, 2H).
[00563] Step 2: A mixture of compound 30-2 (0.3 g, 1.2 mmol), sodium 4- chlorobenzenesulfinate (0.29 g, 1.44 mmol), KI (28 mg, 0.24 mmol), TBAI (88 mg, 0.24 mmol) in DMF (50 Ml) was stirred at room temperature for lh. The crude 30-3 was used directly in next step without purification.
[00564] Step 3: To the crude 30-3 was added NaH (0.14 g, 5.99 mmol) and l-bromo-2-(2- bromoethoxy)ethane (0.83 g, 3.59 mmol). The mixture was stirred at room temperature for 1 hr. The reaction was quenched with water (10 m L), and extracted with EA (50 mL x 3). The combined organic layer was washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 2/1) to give 30-4 as a colorless oil. LC-MS: m/z = 437.9 [M+Na]+.
[00565] Step 4: A mixture of compound 30-4 (0.29 g, 0.7 mmol) and iron powder (0.2 g, 3.49 mmol) in AcOH (30 mL) was stirred at room temperature overnight. The solvent was evaporated and the residue was diluted with water (30 m L) and basified with NaHCC>3 to pH = 7. The mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated to give 30-5 as a yellow oil. *H NMR (300 MHz, CDC13) δ 7.37 - 7.28 (m, 4H), 7.13 - 7.10 (m, 1H), 7.74 - 7.73 (m, 1H), 6.37 - 6.34 (m, 1H), 3.96 - 3.92 (m, 2H), 3.36 - 3.28 (m, 2H), 2.60 - 2.50 (m, 2H), 2.31 - 2.26 (m, 2H). LC-MS: m/z = 407.7 [M+Na]+.
[00566] Step 5: A mixture of 30-5 (100 mg, 0.26 mmol), Et3SiH (60 mg, 0.52 mmol), InCl3 (17 mg, 0.08 mmol) and propan-2-one (30 mg, 0.52 mmol) in MeOH (10 mL) was stirred at room temperature overnight. The mixture was evaporated and the residue was purified by column chromatography (eluent: PE/EA = 1/1) to give 30-6 as a colorless oil. LC-MS: m/z = 427.9 [M+H]+.
[00567] Step 6: A mixture of compound 30-6 (70 mg, 0.16 mmol) and pivaloyl chloride (10 mL) was stirred at 120°C overnight. The solvent was evaporated and the residue purified by column chromatography (eluent: PE/EA = 1/1) to give Example #142 as a white solid. JH NMR (300 MHz, CDC13) δ 7.43 - 7.39 (m, 5H), 7.20 - 7.09 (m, 2H), 4.63 - 4.59 (m, 1H), 4.03 - 3.94 (m, 2H), 4.34 - 3.23 (m, 2H), 2.65 - 2.54 (m, 2H), 2.40 - 2.32 (m, 2H), 1.15 - 0.82 (m, 15H). LC-MS: m/z = 512.0 [M+H]+.
[00568] Example #143: was prepared as described in Scheme 30, except using
cyclobutanone in step 5.
[00569] *H NMR (300 MHz, CDC13) δ 7.41 - 7.39 (m, 6H), 7.10 - 7.05 (m, 1H), 4.84 - 4.74 (m, 1H), 4.01 - 3.96 (m, 2H), 3.35 - 3.29 (m, 2H), 2.67 - 2.55 (m, 2H), 2.44 - 2.32 (m, 2H), 2.28 - 2.02 (m, 2H), 1.77 - 1.51 (m, 4H), 1.08 (s, 9H). LC-MS: m/z = 524.1 [M+H]+.
[00570] Example #144: was prepared as described in Scheme 30, except the ethyl substituent was inserted in Step 5 using sodium hydride and ethyl iodide as outlined in
Scheme 10 Step 1:
[00571] *H NMR (400 MHz, CDC13) δ 7.50 - 7.39 (m, 5H), 7.22 - 7.20 (m, 2H), 4.19 - 4.09 (m, 2H), 4.01 (t, / = 11.2 Hz, 2H), 3.31 (q, / = 12.1 Hz, 2H), 3.08 - 2.99 (m, 1H), 2.64 - 2.57 (m, 2H), 2.45 - 2.34 (m, 2H), 1.09 - 1.04 (m, 12H). LC-MS: m/z = 498.1 [M+H]+.
[00572] PREPARATIVE EXAMPLE #145. [00573] Scheme 31.
Figure imgf000169_0001
[00574] Step 1: To a solution of compound 31-1 (2 g, 11.7 mmol) in DCM (30 mL) was added PBr3 (3.8 g, 14 mmol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hr. The mixture was quenched with water (50 m L) and extracted with DCM (50 mL x 3). The combined organic layer was washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 10/1) to give 31-2 as a colorless oil. 'Pi NMR (300 MHz, CDC13) 58.11 - 8.07 (m, 1H), 7.69 - 7.64 (m, 1H), 7.31 - 7.25 (m, 1H), 4.48 (s, 2H).
[00575] Step 2: A mixture of 31-2 (0.5 g, 1.5 mmol), sodium 4-chlorobenzenesulfinate (0.36 g, 1.80 mmol), KI (49 mg, 0.3 mmol), and TBAI (110 mg, 0.3 mmol) in DMF (20 mL) was stirred at room temperature for lh. The mixture was evaporated and the residue purified by column chromatography (eluent: PE/EA = 2/1) to give 31-3 as a yellow oil. LC-MS: m/z = 351.9 [M+Na]+.
[00576] Step 3: A mixture of 31-3 (0.64 g, 1.49 mmol) and iron powder (0.84 g, 14.9 mmol) in AcOH (30 mL) was stirred at room temperature overnight. The solvent was evaporated and the residue diluted with water (30 m L), basified with NaHCC>3 to pH = 7. The mixture was extracted with EA (20 mL x 3). The combined organic layer was washed with water and brine, dried over Na2S04 and evaporated to give 31-4 as a yellow oil. LC-MS: m/z = 300.0 [M+H]+. [00577] Step 4: A mixture of compound 31-4 (300 mg, 1 mmol), Et3SiH (230 mg, 2 mmol), Ιη(¾ (67 mg, 0.3 mmol) and propan-2-one (120 mg, 2 mmol) in MeOH (100 mL) was stirred at room temperature overnight. The mixture was evaporated and the residue was purified by column chromatography (eluent: PE/EA = 2/1) to give 31-5 as a yellow oil. LC-MS: m/z = 341.9 [M+H]+.
[00578] Step 5: A mixture of compound 31-5 (200 mg, 0.59 mmol) and pivaloyl chloride (20 mL) was stirred at 110°C overnight. The solvent was evaporated and the residue purified by column chromatography (eluent: PE/EA = 1/1) to give 31-6 as a yellow oil. LC-MS: m/z = 425.9 [M+H]+.
[00579] Step 6: To the mixture of 31-6 (120 mg, 0.28 mmol) in DMF (10 mL) was added NaH (34 mg, 1.41 mmol) and l-bromo-2-(2-bromoethoxy)ethane (200 mg, 0.85 mmol). The mixture was stirred at room temperature for 1 hr, then quenched with water (10 m L), and extracted with EA (20 mL x 3). The combined organic layer was washed with water and brine, dried over Na2S04, filtered and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 1/1) to give Example #145 as a white solid. *H NMR (300 MHz, CDC13) δ 7.43 - 7.36 (m, 4H), 7.19 - 7.07 (m, 3H), 4.95 - 4.85 (m, 1H), 4.04 - 3.93 (m, 2H), 3.30 (t, / = 11.6 Hz, 2H), 2.64 - 2.57 (m, 2H), 2.43 - 2.31 (m, 2H), 1.11 - 0.97 (m, 15H). LC-MS: m/z = 496.1 [M+H]+.
[00580] Example #146: was prepared as described in Scheme 31, except using
cyclobutanone in step 4:
[00581] *H NMR (300 MHz, CDC13) δ 7.47 - 7.34 (m, 4H), 7.24 - 7.08 (m, 3H), 4.87 - 4.76 (m, 1H), 4.01 - 3.97 (m, 2H), 3.34 - 3.26 (m, 2H), 2.65 - 2.55 (m, 2H) 2.40 - 2.31 (m, 2H), 2.10 - 2.05 (m, 2H), 1.65 - 1.53 (m, 4H), 1.07 (s, 9H). LC-MS: m/z = 508.1 [M+H]+.
[00582] Example #147: was prepared as described in Scheme 31, except the ethyl substituent was inserted in step 5 using sodium hydride and ethyl iodide as outlined in
Scheme 10 step 1
[00583] *H NMR (300 MHz, CDC13) δ 7.40 - 7.33 (m, 4H), 7.23 - 7.11 (m, 3H), 4.03 - 3.94 (m, 2H), 3.57 - 3.47 (m, 2H), 3.29 (t, / = 11.6 Hz, 2H), 2.65 - 2.55 (m, 2H), 2.41 - 2.32 (m, 2H), 1.09 - 0.98 (m, 12H). LC-MS: m/z = 482.1 [M+H]+. [00584] PREPARATIVE EXAMPLE #148.
[00585] Scheme 32.
Figure imgf000171_0001
[00586] Step 1: A mixture of 3-fluoro-2-nitropyridine (3 g, 21.1 mmol) and K2CO3 (5.8 g, mmol) in MeOH (30 mL) was refluxed for lh and then cooled to room temperature. The mixture was filtered and the filtrate evaporated to give crude 32-2 as a yellow oil. LC-MS: m/z = 155.1 [M+H]+.
[00587] Step 2: A mixture of compound 32-2 (3.2 g, 20.6 mmol), Fe (5.8 g, 130.2 mmol) and AcOH (30 mL) was stirred at room temperature for lh. The mixture was filtered and to the filtrate was added Py HBr Br2. The reaction stirred at room temperature overnight. Solvent was evaporated and the residue diluted with CH3OH. The mixture was basified to pH 7 with NaHCC>3 and evaporated. The residue was purified by column chromatography (eluent:
PE/EA = 2/1) to give 32-3 as a yellow oil. LC-MS: m/z = 203.0 [M+H]+.
[00588] Step 3: To a solution of 32-3 (1 g, 4.95 mmol) and TEA (1.5 g, 14.9 mmol) in dry THF (50 mL) acetyl chloride (0.78 g, 19.9 mmol) was slowly added at room temperature. The mixture was stirred overnight then washed with water and brine. The residue was dried over Na2S04, filtered and evaporated to give 32-4 as a yellow oil. LC-MS: m/z = 286.9
[M+H]+.
[00589] Step 4: LiAlH4 (470 mg, 12.2 mmol) was added at room temperature to a solution of 1-4 (1.4 mg, 4.9 mmol) in THF (30 mL) and the solution stirred for 2h. The reaction was quenched with water and 10% NaOH aqueous solution. The resulting mixture was filtered and the filtrate evaporated to give 32-5 as a colorless oil. LC-MS: m/z = 230.9 [M+H]+. [00590] Step 5: A mixture of Compound 32-5 (0.48 g, 2.09 mmol) and pivaloyl chloride (20 mL) was stirred at 100°C overnight. The solvent was evaporated and the residue purified by column chromatography (eluent: PE/EA = 8/1) to give 32-6 as a yellow oil. LC-MS: m/z = 315.1 [M+H]+.
[00591] Step 6: To a solution of compound 32-6 (0.23 g, 0.73 mmol) in THF (20 mL) nBuLi was added (0.5 mL, 1.1 mmol) at -78°C and the reaction stirred for 5 mins. DMF (0.11 g, 1.46 mmol) was added and stirred for 10 min. The reaction was quenched with water and the resulting mixture was filtered and the filtrate evaporated to give crude 32-7 as a yellow oil. LC-MS: m/z = 265.1 [M+H]+.
[00592] Step 7: A mixture of crude 32-7 (0.18 g, 0.68 mmol) and NaBH4 (0.078 g, 2.05 mmol) in MeOH (10 mL) was stirred at room temperature for 1 h. The solvent was evaporated and the residue purified by column chromatography (eluent: PE/EA = 1/1) to give 32-8 as a colorless oil. LC-MS: m/z = 267.1 [M+H]+.
[00593] Step 8: To a solution of compound 32-8 (80 mg, 0.3 mmol) and CBr4 (105 mg, 0.32 mmol) in CH2CI2 (5 mL), PPI13 (83 mg, 0.32 mmol) was added at room temperature and stirred for 10 min. The reaction was evaporated and the residue purified by column chromatography (eluent: PE/EA = 3/1) to give 32-9 as a colorless oil. LC-MS: m/z = 328.9 [M+H]+.
[00594] Step 9: A mixture of compound 32-9 (160 mg, 0.49 mmol), sodium 4- chlorobenzenesulfinate (0.15 g, 0.73 mmol), TBAI (36 mg, 0.1 mmol) and KI (11 mg, 0.1 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. NaH (59 mg, 2.44 mmol) and l-bromo-2-(2-bromoethoxy)ethane (0.34 g, 1.46 mmol) were added. The resulting reaction was stirred at room temperature for another 3 h. The reaction was quenched with water and extracted with EA (20 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 1/1) to give Example #148 as a white solid. *H NMR (300 MHz, CDCI3) δ 7.61 - 7.60 (m, 1H), 7.39 - 7.29 (m, 5H), 4.05 - 4.01 (m, 2H), 3.85 - 3.50 (m, 5H), 3.33 (t, / = 11.7 Hz, 2H), 2.72 - 2.62 (m, 2H), 2.40 - 2.36 (m, 2H), 1.12 - 1.05 (m, 12H). LC-MS: m/z = 495.2 [M+H]+. [00595] PREPARATIVE EXAMPLE #149.
[00596] Scheme 32B.
Figure imgf000173_0001
32B-1 step 1 32B-2 step 2 32B-3
Figure imgf000173_0002
step 4 32B-5 32B-6 step 6
Figure imgf000173_0003
[00597] Step 1: The reaction mixture of 3-fluoro-2-nitropyridine (5 g, 35.2 mmol), K2CO3 (9.72 g, mmol) and C2H5OH (50 mL) was refluxed for 2h and then the mixture was cooled to room temperature. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (eluent: PE/EA = 5/1) to give 32B-2 as a yellow oil. JH NMR (300 MHz, CDC13) δ 8.06-8.04 (m, 1H), 7.53-7.46 (m, 2H), 4.20 (q, / = 7.0 Hz, 2H), 1.47 (t, / = 7.0 Hz, 3H). LC-MS: m/z = 169.1 [M+H]+.
[00598] Step 2: The reaction mixture of 32B-2 (5.5 g, 32.7 mmol), Fe (9.2 g, 163.7 mmol) and AcOH (200 Ml) was stirred at room temperature for lh. Then the mixture was filtered and to the filtrate was added Py HBr Br2. The mixture was stirred at room temperature overnight. The mixture was evaporated and the residue was dissolved in CH3OH. The mixture was basified with ammonia water and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 7/1 to 5/1) to give 32B-3 as a yellow solid. JH NMR (300 MHz, CDC13) δ 7.66 (d, / = 1.9 Hz, 1H), 6.97 (d, / = 1.9 Hz, 1H), 4.85 (s, 2H), 4.03 (q, J = 7.0 Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H). LC-MS: m/z = 216.9, 218.9 [M+H]+.
[00599] Step 3: nBuLi (18 mL, 45.9 mmol) was added to a -78°C solution of compound 32B-3 (1.66 g, 7.64 mmol) and THF (50 mL) under N2 and the reaction stirred for 30 mins. DMF (1.12 g, 15.3 mmol) was added and stirred for 2h. After completion, the reaction was quenched with water. The resulting mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (eluent: PE/EA = 5/1 to 3/1) to give 32B-4 as a yellow solid. LC-MS: m/z = 167.0 [M+H]+. [00600] Step 4: To the solution of 32B-4 (810 mg, 4.87 mmol), DIPEA (3.14 g, 24.4 mmol) and CH2CI2 (20 mL) was added acetyl chloride (1.15 g, 14.61 mmol) slowly at 0°C and stirred for 2h. The mixture was washed with water and brine, dried over Na2S04, filtered and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 5/1 to 3/1) to give 32B-5 as a yellow solid. LC-MS: m/z = 251.0 [M+H]+.
[00601] Step 5: L1AIH4 (461 mg, 12.15 mmol) was added to a 0°C solution of 32B-5 (0.76 mg, 3.04 mmol) and THF (30 mL) under N2 and stirred for 3h. The reaction was quenched with water and 10% NaOH aqueous solution. The resulting mixture was filtered and the filtrate evaporated. The residue was purified by column chromatography (eluent:
CH2C12/CH30H = 50/1) to give 32B-6 as a colorless oil. LC-MS: m/z = 197.2 [M+H]+.
[00602] Step 6: The reaction of 32B-6 (150 mg, 0.76 mmol), sodium 4- chlorobenzenesulfinate (152 mg, 0.76 mmol), Et3N (230 g, 2.28 mmol), methylsulfonyl chloride (104 mg, 0.91 mmol) and DMF (5 mL) was stirred at room temperature overnight. Water was added and the mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 3/1) to give 32B-7 as a yellow gum. LC-MS: m/z = 354.9 [M+H]+.
[00603] Step 7: The mixture of 32B-7 (46 mg, 0.13 mmol) and pivaloyl chloride (5 mL) was stirred at 130°C for 2h. The solvent was evaporated and the residue purified by prep-TLC (eluent: PE/EA = 2/1) to give 32B-8 as a colorless gum. LC-MS: m/z = 438.9 [M+H]+.
[00604] Step 8: To the solution of compound 32B-8 (30+48 mg, 0.068+0.11 mmol) in dry DMF (5 mL) was added NaH (14+22 mg, 0.34+0.55 mmol) and 2,2'-dibromodiethyl ether (48+76 mg, 0.21+0.33 mmol) at 0°C and then stirred at the same temperature for lh. Water was added and the resulting mixture was extracted with EA (20 mL x 3). The combined organic layers were dried over Na2S04, filtered and evaporated. The residue was purified by prep-TLC (eluent: CH2C12/CH30H = 250/4) to give Example #149 as a colorless gum. *H NMR (300 MHz, CDC13) δ 7.55 (s, 1H), 7.37-7.26 (m, 5H), 4.07-3.99 (m, 4H), 3.65 (s, 2H), 3.35-3.27 (m, 2H), 2.64-2.59 (m, 2H), 2.35 (d, / = 13.8 Hz, 2H), 1.43 (t, J = 6.9 Hz, 3H), 1.11-1.04 (m, 12H). LC-MS: m/z = 509.1 [M+H]+. [00605] PREPARATIVE EXAMPLE #150.
[00606] Scheme 32C.
Figure imgf000175_0001
[00607] Step 1: mixture of compound 32-9 (0.44 g, 1.34 mmol), sodium 4- chlorobenzenesulfinate (0.4 g, 2.01 mmol), TBAI (0.1 g, 0.27 mmol) and KI (31 mg, 0.27 mmol) in DMF (20 mL) was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with EA (20 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 1/1) to give the 32C-1 as a yellow oil. LC-MS: m/z = 424.9 [M+H]+.
[00608] Step 2: A mixture of compound 32C-1 (0.2 g, 0.47 mmol), BBr3 (0.59 g, 2.36 mmol) and DCM (20 mL) was stirred at 40°C overnight. The reaction was quenched with water, basified with NaHCC>3, and extracted with EA (20 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated to give 32C-2 as a colorless oil. LC-MS: m/z = 411.0 [M+H]+.
[00609] Step 3: A mixture of 32C-2 (0.15 g, 0.37 mmol), 2-bromopropane (0.067 g, 0.55 mmol) and K2CO3 (0.1 g, 0.73 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction was quenched with water and extracted with EA (20 mL). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated to give crude 32C-3 as a yellow oil. LC-MS: m/z = 453.0 [M+H]+.
[00610] Step 4: To a solution of 32C-3 (140 mg, 0.31 mmol) in dry DMF (10 mL) was added NaH (23 mg, 0.93 mmol) and 2,2'-dibromodiethyl ether (150 mg, 0.62 mmol) at room temperature and then stirred for 3h. Water was added and the resulting mixture was extracted with EA (20 mL x 3). The combined organic layers were dried over Na2S04 and evaporated. The residue was purified by prep-TLC (eluent: PE/EA = 1/1) to give Example # 150 as a white solid. *H NMR (300 MHz, CDC13) δ 7.55 (s, 1H), 7.38 - 7.30 (m, 5H), 4.61 - 4.53 (m, 1H), 4.05 - 3.99 (m, 2H), 4.73 - 3.60 (m, 2H), 3.33 (t, " = 11.7 Hz, 2H), 2.71 - 2.62 (m, 2H), 2.39 - 2.31 (m, 2H), 1.36 (d, / = 6.0 Hz, 6H), 1.16 - 1.03 (m, 12H). LC-MS: m/z = 523.2 [M+H]+.
[00611] Example #151: was prepared as described in Scheme 32C, using
(bromomethyl)cyclopropane in step 3. *H NMR (300 MHz, CDC13) 57.60 (s, 1H), 7.38 - 7.30 (m, 5H), 4.04 - 3.98 (m, 2H), 3.83 - 3.64 (m, 4H), 3.32 (t, / = 11.5 Hz, 2H), 2.71 - 2.60 (m, 2H), 2.39 - 2.31 (m, 2H), 1.32 - 0.96 (m, 13H), 0.71 - 0.65 (m, 2H), 0.40 - 0.36 (m, 2H). LC-MS: m/z = 535.2 [M+H]+.
[00612] PREPARATIVE EXAMPLE #152
[00613] Scheme 33.
Figure imgf000176_0001
[00614] Step 1: A mixture of 33-1 (Ri, R2 = H) (2.4 g, 14 mmol) and cyclobutanamine (2 g, 28 mmol) in DMSO (30 mL) was stirred at 60 °C for 12 hrs. The reaction was poured into ice water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL) and dried over Na2S04. After being concentrated, the crude product was purified by flash column chromatography eluting with PE/EA = 10/1 to give 33- 2 as a white solid, *H NMR (300 MHz, CDC13) δ 7.72 - 7.68 (m, 1H), 7.63 - 7.58 (m, 1H), 6.60 - 6.54 (m, 1H), 4.01 - 3.96 (m, 1H), 3.85 (s, 3H), 2.48 - 2.42 (m, 2H), 1.97 - 1.83 (m, 4H). LC-MS: m/z = 224.1 [M+H]+.
[00615] Step 2: LAH (0.72 g, 18.8 mmol) was added to a mixture of 33-2 (2.1 g, 9.4 mmol) in THF (120 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H20 (3 mL) and filtered. The filtrate was concentrated to give crude 33-3 as a yellow oil. LC-MS: m/z = 196.1 [M+H]+. [00616] Step 3: To a mixture of 33-3 (1.2 g, 6.1 mmol), sodium 4-chlorobenzenesulfinate (1.33 g, 6.7 mmol) and TEA (1.85 g, 18.3 mmol) in DMF (50 mL) was added
methanesulfonyl chloride (1.05 g, 9.2 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours. Water (40 mL) was added and the mixture extracted with EtOAc (40 mL x 2). Combined organic layers were dried over anhydrous Na2S04, concentrated, and purified by flash column chromatography to give the product 33-4 as a yellow solid. LC-MS: m/z = 353.9 [M+H]+.
[00617] Step 4: A mixture of compound of 33-4 (0.3 g, 0.85 mmol) and pivaloyl chloride (10 mL) was stirred at 110 °C for 4 hours. After removed of most of pivaloyl chloride, water (20 mL) was added. The mixture was extracted with EtOAc (20 mL x 2). The combined organic layer was dried over anhydrous Na2S04, concentrated to give 33-5 as a yellow solid. LC-MS: m/z = 438.1 [M+H]+.
[00618] Step 5: To a mixture of compound 33-5 (0.25 g, 0.58 mmol) and NaH (47 mg, 1.16 mmol) in THF (20 mL) was added l-(2-bromoethoxy)-2-bromoethane (202 mg, 0.87 mmol) at rt. The resulting mixture was stirred at 75°C for 6 hours, then quenched with H20 (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2S04, concentrated and purified by preparative TLC to give Example #152 as a white solid. *H NMR (300 MHz, CDC13) δ 7.33 (s, 4H), 7.12 - 7.01 (m, 3H), 4.84 - 4.77 (m, 1H), 4.02 (d, / = 10.8 Hz, 2H), 3.30 (t, / = 11.4 Hz, 2H), 2.78 - 2.57 (m, 2H), 2.35 (d, / = 13.2 Hz, 2H), 2.13 (d, / = 6.3 Hz, 2H), 1.67 - 1.56 (m, 4H), 1.07 (s, 9H). LC-MS: m/z = 508.1
[M+H]+.
[00619] Example #153: was prepared as described in Scheme 33, using cyclobutylamine in step 1. *H NMR (300 MHz, CDC13) δ 7.24 - 7.13 (m, 5H), 6.86 (d, / = 8.6 Hz, 1H), 4.61 (s, 1H), 3.98 (d, / = 18.4 Hz, 5H), 3.27 (t, / = 11.1 Hz, 2H), 2.64 (t, / = 10.6 Hz, 2H), 2.35 (d, J = 13.8 Hz, 2H), 1.17 - 1.06 (m, 15H). LC-MS: m/z = 542.1 [M+H]+.
[00620] Example #154: was prepared as described in Scheme 33, using ethylamine in step 1. *H NMR (300 MHz, CDC13) δ 7.33 (s, 4H), 7.19-7.13 (m, 1H), 7.08-6.98 (m, 2H), 4.01- 3.96 (m, 2H), 3.61 (br, 2H), 3.29-3.28 (m, 2H), 2.63-2.62 (m, 2H), 2.36-2.32 (m, 2H) 1.08 (br, 12H). LC-MS: m/z = 482.0 [M+H]+.
[00621] Example #155: was prepared as described in Scheme 33, using tert-butylamine in step 1. *H NMR (300 MHz, CDC13) δ 7.34 - 7.32 (m, 3H), 7.15-6.96 (m, 4H), 4.03-3.99 (m, 2H), 3.29-3.22 (m, 2H), 2.67-2.64 (m, 2H), 2.35-2.33 (m, 2H), 1.34 (s, 9H), 0.97 (s, 9H). LC- MS: m/z = 510.2 [M+H]+.
[00622] Example #156: was prepared as described in Scheme 33, using 2- methoxyethanamine in step 1. *H NMR (300 MHz, CDC13) δ 7.36-7.26 (m, 5H), 7.06 (dd, J = 11.4, 2.2 Hz, 1H), 6.96 (dd, / = 8.4, 2.1 Hz, 1H), 4.00 (d, / = 11.6 Hz, 2H), 3.75 (s, 2H), 3.54 (t, / = 5.2 Hz, 2H), 3.34-3.22 (m, 5H), 2.70-2.60 (m, 2H), 2.34 (d, / = 13.8 Hz, 2H), 1.08 (s, 9H). LC-MS: m/z = 511.9 [M+H]+.
[00623] Example #157: was prepared as described in Scheme 33, using
dimethylethane-l,2-diamine in step 1. *H NMR (300 MHz, CDC13) δ 7.39-7.27 (m, 5H), 7.08 (d, / = 11.4 Hz, 1H), 6.99 (d, / = 8.4 Hz, 1H), 4.00 (d, / = 10.2 Hz, 2H), 3.70 (s, 2H), 3.29 (t, / = 11.6 Hz, 2H), 2.65 (td, / = 13.5, 4.2 Hz, 2H), 2.49 (t, / = 7.3 Hz, 2H), 2.34 (d, / = 14.0 Hz, 2H), 2.26 (s, 6H), 1.08 (s, 9H). LC-MS: m/z = 525.1 [M+H]+.
[00624] Example #158: was prepared as described in Scheme 33, using 1-methoxypropan- 2-amine in step 1. *H NMR (400 MHz, MeOD) δ 7.51 (d, / = 8.6 Hz, 2H), 7.42 (d, / = 8.5 Hz, 2H), 7.35 (s, 1H), 7.31-7.27 (m, 1H), 7.18 (s, 1H), 5.04 (s, 1H), 3.99 (d, / = 11.4 Hz, 2H), 3.33-3.25 (m, 7H), 2.59-2.56 (m, 4H), 1.07 (s, 9H), 0.98 (s, 3H). ). LC-MS: m/z = 525.9 [M+H]+.
[00625] Example #159: was prepared as described in Scheme 33, using
dimethylpropane-l,2-diamine in step 1. *H NMR (300 MHz, CDC13) δ 7.43-7.30 (s, 5H), 7.07 (d, / = 11.3 Hz, 1H), 6.95 (d, / = 8.0 Hz, 1H), 5.09 (s, 1H), 4.01 (d, / = 11.4 Hz, 2H), 3.28 (t, / = 11.7 Hz, 2H), 2.67 (t, / = 12.2 Hz, 2H), 2.38-2.02 (m, 10H), 1.04 (s, 9H), 0.96 (s, 3H). LC-MS: m/z = 539.2 [M+H]+.
[00626] Example #160: was prepared as described in Scheme 33, using cyclobutylamine in step 1 and cyclobutanecarbonyl chloride in step 4. !H NMR (300 MHz, CDC13) δ 7.34 (s, 4H), 7.06-7.04 (m, 3H), 4.99 (s, 1H), 4.03-4.00 (m, 2H), 3.37-3.29 (m, 2H), 2.77-2.66 (m, 3H), 2.35-2.13 (m, 6H), 1.75-1.56 (m, 8H). LC-MS: m/z = 506.0 [M+H]+.
[00627] Example #161: was prepared as described in Scheme 33, using cyclobutylamine in step 1 and cyclohexanecarbonyl chloride in step 4. !H NMR (300 MHz, CDC13) δ 7.37 - 7.34 (m, 4H), 7.13 - 7.07 (m, 3H), 5.01 - 4.98 (m, 1H), 4.05 - 4.02 (m, 2H), 3.33 - 3.27 (m, 2H), 2.71 - 2.64 (m, 3H), 2.34 - 2.16 (m, 4H), 1.86 - 0.94 (m, 15H). LC-MS: m/z = 534.1 [M+H]+.
[00628] Example #162: was prepared as described in Scheme 33, using cyclobutylamine in step 1 and 3-fluorobenzoyl chloride in step 4. *H NMR (300 MHz, CDC13) δ 7.28 - 6.90 (m, 11H), 5.01 - 4.92 (m, 1H), 3.96 - 3.93 (m, 2H), 3.16 - 3.10 (m, 2H), 2.58 - 2.55 (m, 3H), 2.23 - 2.15 (m, 4H), 1.66 - 1.60 (m, 4H). LC-MS: m/z = 546.1 [M+H]+. [00629] Example #163: was prepared as described in Scheme 33, using cyclobutylamine in step 1 and cyclopentanecarbonyl chloride in step 4. !H NMR (300 MHz, CDC13) δ 7.35 - 7.28 (m, 4H), 7.13 - 7.04 (m, 3H), 5.05 - 4.98 (m, 1H), 4.05 - 4.01 (m, 2H), 3.35 (t, / = 11.3 Hz, 2H), 2.72 - 2.65 (m, 2H), 2.35 - 2.13 (m, 5H), 2.84 - 1.42 (m, 12H). LC-MS: m/z = 520.1 [M+H]+.
[00630] Example #164: was prepared as described in Scheme 33, using cyclobutylamine in step 1 and acetyl chloride in step 4. *H NMR (300 MHz, CDC13) δ 7.35 - 7.29 (m, 4H), 7.15 - 7.04 (m, 3H), 5.08 - 4.99 (m, 1H), 4.04 - 4.00 (m, 2H), 3.34 (t, / = 11.5 Hz, 2H), 2.71 - 2.61 (m, 2H), 2.39 - 2.04 (m, 5H), 1.80 - 1.58 (m, 7H). LC-MS: m/z = 466.1 [M+H]+.
[00631] Example #165: was prepared as described in Scheme 33, using cyclobutylamine in step 1 and cyclopropanecarbonyl chloride in step 4. !H NMR (300 MHz, CDC13) δ 7.34 - 7.27 (m, 4H), 7.20 - 7.08 (m, 3H), 5.05 - 4.96 (m, 1H), 4.04 - 4.01 (m, 2H), 3.36 (t, 7" = 11.5 Hz, 2H), 2.69 - 2.62 (m, 2H), 2.41 - 2.36 (m, 2H), 2.26 - 2.14 (m, 2H), 1.79 - 1.55 (m, 4H), 1.03 (s, 3H), 0.73 - 0.57 (m, 2H). LC-MS: m/z = 492.1 [M+H]+.
[00632] Example #166: was prepared as described in Scheme 33, with R2 being Fluoro and using ethylamine in step 1. *H NMR (300 MHz, CDC13) δ 7.38 (s, 4H), 6.89-6.86 (m, 2H), 4.02-3.99 (m, 2H), 3.63 (br, 2H), 3.33-3.25 (m, 2H), 2.63-2.61 (m, 2H), 2.31-2.27 (m, 2H) 1.12 - 1.10 (m, 12H). LC-MS: m/z = 500.1 [M+H]+.
[00633] Example #167: was prepared as described in Scheme 33, with R2 being Fluoro and using cyclopropylamine in step 1. *H NMR (300 MHz, CDC13) δ 7.38 - 7.37 (m, 4H), 6.87- 6.85 (m, 2H), 4.03 - 3.97 (m, 2H), 3.34-3.26 (m, 2H), 3.16 (s, 1H), 2.67-2.64 (m, 2H), 2.33- 2.27 (m, 2H), 1.26 (br, 9H), 0.83 (br, 2H), 0.56 (br, 2H). LC-MS: m/z = 512.2 [M+H]+.
[00634] Example #168: was prepared as described in Scheme 33, with R2 being Fluoro and using cyclobutylamine in step 1. *H NMR (300 MHz, CDC13) δ 7.38 (s, 4H), 6.91-6.88 (m, 2H), 4.79 (s, 1H), 4.05-4.01 (m, 2H), 3.34-3.24 (m, 2H), 2.67-2.64 (m, 2H), 2.33-2.31 (m, 2H), 2.28 (br, 2H), 1.61 (br, 4H), 1.07 (br, 9H). LC-MS: m/z = 526.1 [M+H]+.
[00635] Example #169: was prepared as described in Scheme 33, with R2 being Fluoro and using tert-butylamine in step 1. *H NMR (300 MHz, CDC13) δ 7.37 (s, 4H), 6.86 - 6.83 (m, 2H), 4.03 - 3.99 (m, 2H), 3.28 - 3.21 (m, 2H), 2.66 - 2.62 (m, 2H), 2.30 - 2.26 (m, 2H), 1.36 (s, 9H), 0.99 (s, 9H). LC-MS: m/z = 528.2 [M+H]+.
[00636] Example #170: was prepared as described in Scheme 33, with R2 being Fluoro and using l-methoxypropan-2-amine in step 1. !H NMR (400 MHz, CDC13) δ 7.42-7.37 (m, 4H), 6.93 (d, J = 10.6 Hz, 1H), 6.84 (d, J = 10.4 Hz, 1H), 4.74 (d, J = 5.6 Hz, 1H), 4.04 (d, J = 11.8 Hz, 2H), 3.53 (dd, / = 9.4, 4.6 Hz, 1H), 3.37-3.27 (m, 6H), 2.71-2.64 (m, 2H), 2.30 (t, J = 15.2 Hz, 2H), 1.14-1.08 (m, 12H). LC-MS: m/z = 543.9 [M+H]+.
[00637] Example #171: was prepared as described in Scheme 33, with R2 being Fluoro and using cyclopropylmethanamine in step 1. *H NMR (300 MHz, CDC13) δ 7.40 (s, 4H), 6.88 (d, / = 8.9 Hz, 2H), 4.01 (d, / = 10.1 Hz, 2H), 3.49 (s, 2H), 3.26 (t, / = 11.7 Hz, 2H), 2.64 (td, / = 13.7, 4.1 Hz, 2H), 2.29 (d, / = 13.5 Hz, 2H), 1.11 (s, 9H), 0.96-0.90 (m, 1H), 0.38 (d, / = 7.6 Hz, 2H), -0.05 (d, / = 4.8 Hz, 2H). LC-MS: m/z = 526.1 [M+H]+.
[00638] Example # 172: was prepared as described in Scheme 33, with R2 being Fluoro and using propan-2-amine in step 1. *H NMR (300 MHz, CDC13) δ 7.36 (s, 4H), 6.87-6.848 (m, 2H), 4.83 (br, 1H), 4.02-3.99 (m, 2H), 3.31-3.23 (m, 2H), 2.65-2.63 (m, 2H), 2.31-2.26 (m, 2H) 1.04 (br, 15H). LC-MS: m/z = 514.1 [M+H]+.
[00639] Example # 173: was prepared as described in Scheme 33, with Ri being Fluoro and using cyclobutylamine in step 1. *H NMR (300 MHz, CDC13) δ 7.43-7.35 (m, 4H), 7.24-7.18 (m, 1H), 6.75 (dd, / = 12.5, 6.5 Hz, 1H), 4.81-4.73 (m, 1H), 4.09-4.03 (m, 2H), 3.31 (t, / = 12.5 Hz, 2H), 2.56 (s, 4H), 2.16-2.14 (m, 2H), 1.63-1.60 (m, 4H), 1.11 (s, 9H). LC-MS: m/z = 526.1 [M+H]+.
[00640] Example # 174: was prepared as described in Scheme 33, with Ri being Fluoro and using propan-2-amine in step 1. *H NMR (400 MHz, CDC13) δ 7.43 (q, J = 8.8 Hz, 4H), 7.23 (dd, / = 10.9, 7.1 Hz, 1H), 6.77 (dd, / = 12.7, 6.5 Hz, 1H), 4.90 (dt, / = 13.4, 6.7 Hz, 1H), 4.08 (dt, / = 11.8, 3.1 Hz, 2H), 3.33 (t, / = 12.6 Hz, 2H), 2.60-2.58 (m, 4H), 1.14 (s, 9H), 1.08 (d, / = 6.6 Hz, 6H). LC-MS: m/z = 513.9 [M+H]+.
[00641] Example #175: was prepared as described in Scheme 33, with Ri being Fluoro and using cyclopropylamine in step 1. *H NMR (300 MHz, CDC13) δ 7.39 (s, 4H), 7.18 (dd, J = 10.7, 7.0 Hz, 1H), 6.71 (dd, J = 12.5, 6.5 Hz, 1H), 4.04 (d, J = 12.0 Hz, 2H), 3.32 (t, J = 12.3 Hz, 2H), 3.10-3.08 (m, 1H), 2.56 (s, 4H), 1.18 (s, 9H), 0.86-0.84 (m, 2H), 0.53 (s, 2H). LC- MS: m z = 583.2 [M+H]+.
[00642] Example #176: was prepared as described in Scheme 33, with Ri being Fluoro and using tert-butylamine in step 1. *H NMR (300 MHz, CDC13) δ 7.45-7.37 (m, 4H), 7.18 (dd, J = 10.8, 7.2 Hz, 1H), 6.77 (dd, / = 12.6, 6.6 Hz, 1H), 4.05 (d, J = 11.8 Hz, 2H), 3.27 (t, / = 10.8 Hz, 2H), 2.55 (s, 4H), 1.34 (s, 9H), 0.99 (s, 9H). LC-MS: m/z = 472.1 [M+H]+. [00643] PREPARATIVE EXAMPLE #177
[00644] Scheme 34.
Figure imgf000181_0001
[00645] Step 1: A reaction mixture of 34-1 (3.5 g, 18.2 mmol) and SOCl2 (2.17 g, 18.2 mmol) in CH3OH (50 mL) was stirred at 50°C for 3 hrs. The solvent was evaporated and the resulting residue was purified by column chromatography (eluent: PE/EA = 10/1) to give 34- 2 as a colorless oil. LC-MS: m/z = 207.5 [M+H]+.
[00646] Step 2: A reaction mixture of 34-2 (1.1 g, 5.32 mmol) and cyclopropanamine (608 mg, 10.65 mmol) in DMSO (10 mL) was stirred at 70°C overnight. Water was added and the resulting mixture was extracted with EA (30 mL x 3). The combined organic layer was washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE to PE/EA = 10/1) to give 34-3 as a colorless oil. JH NMR (300 MHz, CDCI3) «Π.73 (dd, 7 = 1.9, 1.3 Hz, 1H), 7.58 (dd, 7 = 13.1, 1.9 Hz, 1H), 4.68 (s, 1H), 3.86 (s, 3H), 3.02-2.94 (m, 1H), 0.82-0.76 (m, 2H), 0.62-0.59 (m, 2H). LC-MS: m/z = 244.1 [M+H]+.
[00647] Step 3: L1AIH4 (393 mg, 10.34 mmol) was added to a 0°C solution of 34-3 (1.26 g, 5.17 mmol) in THF (30 mL) under N2 and stirred for 2h. The reaction was quenched with water and 10% NaOH aqueous solution. The resulting mixture was filtered and the filtrate evaporated. The residue was purified by column chromatography (eluent: CH2C12/CH30H = 10/1 to 6/1) to give 34-4 as a colorless oil. *H NMR (300 MHz, CDC13) δ 7.05-7.04 (m, 1H), 6.94 (dd, 7 = 12.6, 1.9 Hz, 1H), 4.52 (s, 2H), 2.92-2.84 (m, 1H), 0.75-0.69 (m, 2H), 0.59-0.53 (m, 2H). LC-MS: m/z = 216.1 [M+H]+.
[00648] Step 4: A mixture of 34-4 (960 mg, 4.45 mmol), sodium 4-chlorobenzenesulfinate (1.06 g, 5.34 mmol) and Et3N (1.35 g, 13.35 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water was added and the mixture extracted with EA (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE.EA = 25/1 to 12/1) to give 34-5 as a brown gum. *H NMR (300 MHz, CDC13) δ 7.62 (d, / = 8.6 Hz, 2H), 7.47 (d, / = 8.6 Hz, 2H), 6.77-6.71 (m, 2H), 4.30 (s, 1H), 4.13 (s, 2H), 2.89 (td, / = 6.7, 3.5 Hz, 1H), 0.75 (q, / = 6.6 Hz, 2H), 0.57 (s, 2H). LC-MS: m/z = 374.0 [M+H]+.
[00649] Step 5: A mixture of 34-5 (310 mg, 0.83 mmol) and pivaloyl chloride (10 mL) was stirred at 100°C for 6h. Then the solvent was evaporated and the residue purified by column chromatography (eluent: PE/EA = 6/1 to 2/1) to give 34-6 as a colorless gum. 1H NMR (301 MHz, CDCI3) δ 7.61 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.00 (s, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.27 (s, 2H), 3.13 (s, 1H), 1.43-0.37 (m, 13H). LC-MS: m/z = 458.0 [M+H]+.
[00650] Step 6: NaH (94 mg, 2.36 mmol) and 2,2'-dibromodiethyl ether (273 mg, 1.18 mmol) were added to a 0°C solution of 34-6 (270 mg, 0.59 mmol) in dry DMF (10 mL) and stirred for lh. Water was added and the resulting mixture extracted with EA (30 mL x 3). The combined organic layers were dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 8/1 to 1/1) to give Example #177 as a white solid. *H NMR (300 MHz, CDC13) δ 7.42-7.32 (m, 4H), 7.03-6.95 (m, 2H), 4.00 (d, / = 10.9 Hz, 2H), 3.34-3.16 (m, 3H), 2.67-2.58 (m, 2H), 2.29 (d, / = 13.6 Hz, 2H), 1.47-0.65 (m, 13H). LC-MS: m/z = 528.1 [M+H]+.
[00651] Example #178: was prepared as described in Scheme 34, but using ethylamine in step 2.^ NMR (300 MHz, CDC13) δ 7.38 (s, 4H), 7.09 - 6.98 (m, 2H), 4.02 - 3.99 (m, 3H), 3.33 - 3.14 (m, 3H), 2.61 - 2.59 (m, 2H), 2.33 - 2.29 (m, 2H), 1.41 (br, 1H), 0.87 - 0.85 (m, 9H), 0.65 - 0.58 (m, 2H). LC-MS: m/z = 515.9 [M+H]+.
[00652] Example #179: was prepared as described in Scheme 34, but using
cyclobutylamine in step 2.1H NMR (300 MHz, CDC13) δ 7.37-7.34 (m, 4H), 7.03 - 6.97 (m, 2H), 4.67 (br, 1H), 4.01 - 3.97 (m, 2H), 3.28 - 3.21 (m, 2H), 2.62 - 2.59 (m, 2H), 2.35 - 2.28 (m, 2H), 2.15 (br, 1H), 1.57 (br, 4H), 1.39 (br, 2H),1.01 (br, 7H). LC-MS: m/z = 542.1
[M+H]+.
[00653] Example #180: was prepared as described in Scheme 34, but using
cyclopropylmethanamine in step 2. *H NMR (400 MHz, CDC13) δ 7.42 (s, 4H), 7.12 (s, 1H), 7.01 (d, / = 10.2 Hz, 1H), 4.04 (d, / = 10.0 Hz, 3H), 3.29 (s, 2H), 2.92 (s, 1H), 2.66 (s, 2H), 2.33 (d, / = 13.4 Hz, 2H), 1.51 (d, / = 42.3 Hz, 2H), 1.05 (d, / = 52.1 Hz, 8H), 0.40 (s, 2H), 0.09 (s, 1H), -0.14 (s, 1H). LC-MS: m/z = 542.1 [M+H]+.
[00654] Example #181: was prepared as described in Scheme 34, but using (R)-l- cyclopropylethanamine in step 2. *H NMR (400 MHz, CDC13) δ 7.41 (s, 4H), 7.10 (s, 1H), 7.00 (d, / = 10.5 Hz, 1H), 4.03 (d, " = 11.4 Hz, 2H), 3.62 (d, / = 57.0 Hz, 1H), 3.27 (t, / = 10.6 Hz, 2H), 2.66 (t, / = 11.1 Hz, 2H), 2.32 (d, / = 13.8 Hz, 2H), 1.37 (d, 7 = 6.2 Hz, 3H),
1.08 (s, 9H), 0.78 (dd, / = 25.2, 21.5 Hz, 1H), 0.49-0.10 (m, 4H). LC-MS: m/z = 555.7
[M+H]+.
[00655] Example #182: was prepared as described in Scheme 34, but using (S)-l- cyclopropylethanamine in step 2. *H NMR (400 MHz, CDC13) δ 7.41 (s, 4H), 7.10 (s, 1H), 7.00 (d, / = 10.6 Hz, 1H), 4.04 (d, / = 11.1 Hz, 2H), 3.62 (d, / = 55.1 Hz, 1H), 3.27 (t, / = 10.4 Hz, 2H), 2.66 (t, / = 10.8 Hz, 2H), 2.32 (d, / = 13.6 Hz, 2H), 1.37 (d, / = 6.1 Hz, 3H),
1.09 (s, 9H), 0.81-0.70 (m, 1H), 0.49-0.12 (m, 4H). LC-MS: m/z = 555.7 [M+H]+.
[00656] Example #183: was prepared as described in Scheme 34, but using propan-2-amine in step 2. *H NMR (300 MHz, CDC13) δ 7.39-7.37 (m, 4H), 7.05 - 6.97 (m, 2H), 4.47 (br, 1H), 4.12 - 3.99 (m, 2H), 3.30 - 3.22 (m, 2H), 2.64 - 2.59 (m, 2H), 2.29 - 2.23 (m, 2H), 1.21 - 0.88 (m, 15H). LC-MS: m/z = 530.0 [M+H]+.
[00657] PREPARATIVE EXAMPLE #184
[00658] Scheme 34B.
Figure imgf000183_0001
[00659] Step 1: A mixture of 34-2 (1.5 g, 7.26 mmol), l -methoxypropan-2-amine (1.29 g, 14.5 mmol) and DMSO (10 mL) was stirred at 70°C overnight. Water was added and the resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (eluent: PE to PE/EA = 100/1) to give 34B-1 as a colorless oil. JH NMR (301 MHz, CDC13) δ 7.75-7.74 (m, 1H), 7.54 (dd, / = 13.6, 1.9 Hz, 1H), 4.59 (s, 1H), 4.13-4.08 (m, 1H), 3.84 (s, 3H), 3.45-3.35 (m, 5H), 1.23 (d, / = 6.5 Hz, 3H). LC-MS: m/z = 276.0 [M+H]+.
[00660] Step 2: L1AIH4 (431 mg, 11.33 mmol) was added to a 0°C solution of 34B-1 (1.25 g, 4.53 mmol) and THF (40 mL) and stirred for 2h. The reaction was quenched with water and 10% NaOH aqueous solution. The resulting mixture was filtered and the filtrate evaporated. The residue was purified by column chromatography (eluent: PE/EA = 8/1 to 4/1) to give 34B-2 as a colorless gum. *H NMR (301 MHz, CDC13) δ 7.06 (d, J = 0.5 Hz, 1H), 6.90 (dd, / = 12.7, 1.9 Hz, 1H), 4.52 (s, 2H), 3.90-3.84 (m, 1H), 3.37 (d, / = 4.1 Hz, 2H), 3.34 (s, 3H), 1.18 (dd, / = 6.5, 0.5 Hz, 3H). LC-MS: m/z = 248.0 [M+H]+.
[00661] Step 3: A mixture of 34B-2 (800 mg, 3.23 mmol), sodium 4-chlorobenzenesulfinate (769 mg, 3.88 mmol), Et3N (979 mg, 9.69 mmol), methylsulfonyl chloride (444 mg, 3.88 mmol) and DMF (10 mL) was stirred at room temperature overnight. Water was added and the mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 10/1 to 8/1) to give 34B-3 as a colorless gum. 1H NMR (301 MHz, CD3OD) δ 7.67 (d, / = 8.6 Hz, 2H), 7.58 (d, / = 8.5 Hz, 2H), 6.89 (s, 1H), 6.82 (d, / = 13.2 Hz, 1H), 4.42 (s, 2H), 3.91 (s, 1H), 3.40 (d, / = 4.4 Hz, 2H), 3.34 (s, 3H), 1.18 (d, J = 6.6 Hz, 3H). LC-MS: m/z = 405.9 [M+H]+.
[00662] Step 4: A mixture of 34B-3 (600 mg, 1.48 mmol) and pivaloyl chloride (10 mL) was stirred at 100°C overnight. The solvent was evaporated and the residue purified by column chromatography (eluent: PE/EA = 8/1 to 3/1) to give 34B-4 as a colorless gum. LC- MS: m/z = 490.0 [M+H]+.
[00663] Step 5: NaH (126 mg, 3.15 mmol) and 2,2' -dibromodiethyl ether (293 mg, 1.26 mmol) were added to a 0°C solution of compound 34B-4 (310 mg, 0.63 mmol) in dry DMF (5 mL) under N2 and stirred for 30 min. Water was added and the resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 5/1 to 3/1) to give 34B-5 as a white solid *H NMR (400 MHz, CDC13) δ 7.43-7.38 (m, 4H), 7.10- 6.96 (m, 2H), 4.33-4.31 (m, 1H), 4.04 (d, / = 11.4 Hz, 2H), 3.71-3.54 (m, 2H), 3.35-3.29 (m, 5H), 2.70-2.62 (m, 2H), 2.34-2.29 (m, 2H), 1.45-1.17 (m, 4H), 1.7 (s, 8H). LC-MS: m z = 560.1 [M+H]+.
[00664] Step 6: BBr3 (0.02 mL) was added to a solution of compound 34B-5 (60 mg, 0.11 mmol) and CH2CI2 (5 mL) and stirred at room temperature for lh. The mixture was washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by prep- TLC(eluent: CH2C12/CH30H = 50/1) to give 34B-6 as a colorless gum. LC-MS: m/z = 527.7 [M+H]+.
[00665] Step 7: 9-BBN was added to a solution of 34B-6 (15 mg, 0.028 mmol) in THF (5 mL) at 0°C and the mixture was stirred overnight. 3N NaOH (0.2 mL) and 30% H202 (0.2 mL) were added slowly to the reaction mixture at 0°C and then the mixture was stirred for 6h at room temperature. After being extracted with EA (10 mL x2), the organic layers were washed with brine, dried over Na2S04 and concentrated. The residue was purified by prep- TLC (eluent: CH2CI2/CH3OH = 50/1) to give the impure product which was purified by prep- HPLC to give Example #184 as a white solid. *H NMR (400 MHz, CDC13) δ 7.43 (s, 4H), 7.15-7.01 (m, 2H), 4.03 (d, J = 10.4 Hz, 2H), 3.94-3.83 (m, 3H), 3.30 (t, J = 11.8 Hz, 2H), 2.63 (t, J = 11.0 Hz, 2H), 2.33 (d, J = 13.4 Hz, 2H), 1.40 (d, J = 6.2 Hz, 1H), 1.28 (d, J = 6.7 Hz, 2H), 1.09 (s, 9H). LC-MS: m/z = 546.1 [M+H]+.
[00666] PREPARATIVE EXAMPLE #185
[00667] Scheme 35.
Figure imgf000185_0001
[00668] Step 1: A mixture of 35-1 (6.1 g, 40 mmol), NBS (10.7 g, 60 mmol) and AIBN (1.3 g, 8 mmol) in CC14 (200 mL) was stirred overnight at 80°C. After concentration, the resulting mixture was purified by column chromatography, eluting with PE/EA = 20/1 to 35- 2 as a yellow oil. LC-MS: m/z = 230.9 [M+H]+
[00669] Step 2: A solution of Sodium 4-chlorobenzenesulfinate (2.16 g, 10.92 mmol), 35-2 (2.1 g, 9.1 mmol), Bu4NI (0.67 g, 1.82 mmol) and KI (0.3 g, 1.82 mmol) in DMF (60 mL) was stirred at 30 °C for 2 hrs. After filtration, the filtrate was concentrated. Water (100 mL) was added and the mixture extracted with EtOAc (60 mL x 2). Combined organic layers were washed with brine, dried over anhydrous Na2S04, concentrated, and purified by flash column chromatography (PE/EA=3/1) to give 35-3 as a white solid. LC-MS: m/z = 326.8 [M+H]+.
[00670] Step 3: : A mixture of 35-3 (1.6 g, 4.9 mmol) and iron powder (1.37 g, 24.5 mmol) in AcOH (80 mL) was stirred at r.t for 4 hrs. After filtration the filtrate was diluted with EA (100 mL x 2) and 1 N NaOH (60 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2S04, and concentrated to the crude product. The crude 35-4 was purified by column chromatography (PE/EA=1/1) to give 35-4 as a yellow solid. LC-MS: m/z = 296.9 [M+H]+.
[00671] Step 4: Acetyl chloride (0.59 g, 0.75 mmol) was added slowly to a 0 °C solution of 35-4 (0.9 g, 0.31 mmol) and TEA (1.5 g, 14.9 mmol) in dry DCM (30 mL). After stirring at room temperature for 2 hrs, the mixture was washed with water and brine, dried over Na2S04 and evaporated to give crude 35-5. The crude product was purified by column
chromatography (PE/EA=3/1) to give 35-5 as a yellow solid. LC-MS: m/z = 338.9 [M+H]+.
[00672] Step 5: A mixture of 35-5 (0.334 g, 1 mmol), I2 (0.758 g, 3 mmol) and NaBH4 (0.114 g, 3 mmol) in THE (30 mL) was stirred at room temperature for 12 hrs. The reaction was quenched with H20 (30 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated. The crude product was purified by column chromatography (PE/EA=2/1) to give 35-6 as a yellow solid. LC-MS: m/z = 324.9 [M+H]+.
[00673] Step 6: A mixture of 35-6 (0.24 g, 0.75 mmol) and pivaloyl chloride (8 mL) was stirred at 110°C for 4 hrs. Solvent was evaporated and the residue purified by column chromatography (eluent: PE/EA = 2/1) to give 35-7 as a yellow solid. LC-MS: m/z = 408.9 [M+H]+.
[00674] Step 7: NaH (0.052 g, 1.28 mmol) and 2,2'-dibromodiethyl ether (0.22 g, 0.96 mmol) were added to a solution of 35-7 (0.26 g, 0.64 mmol) in dry THF (20 mL). The resulting solution was stirred at 75°C for 4 hrs. Water was added and the mixture extracted with EA (20 mL x 3). The combined organic layers were dried over Na2S04 and evaporated. The residue was purified by prep-TLC (eluent: PE/EA = 1/1) to give Example #185 as a white solid. *H NMR (300 MHz, CDC13) δ 7.56 - 7.54 (m, 1H), 7.46 - 7.43 (m, 1H), 7.32 - 7.24 (m, 4H), 4.17- 4.15 (m, 1H), 3.98 - 3.94 (m, 2H), 3.19 - 3.15 (m, 2H), 3.01 (br, 1H), 2.62 - 2.52 (m, 4H), 2.14 (s, 3H), 1.13 - 1.08 (m, 12H). LC-MS: m/z =479.1 [M+H]+.
[00675] PREPARATIVE EXAMPLE #186
[00676] Scheme 36.
Figure imgf000187_0001
[00677] Step 1: PBr3 (3.8 g, 14 mmol) was added dropwise to a 0°C solution of 36-1 (2 g, 11.7 mmol) in DCM (30 mL). The reaction was stirred at 0°C for 1 hr. The reaction was quenched with water (50 m L) and extracted with DCM (50 mL x 3). The combined organic layer was washed with water, brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 10/1) to give 36-2 as a colorless oil. 1H NMR (300 MHz, CDC13) 58.11 - 8.07 (m, 1H), 7.69 - 7.64 (m, 1H), 7.31 - 7.25 (m, 1H), 4.48 (s, 2H).
[00678] Step 2: A mixture of 36-2 (0.5 g, 1.5 mmol), sodium 4-chlorobenzenesulfinate (0.36 g, 1.80 mmol), KI (49 mg, 0.3 mmol) and TBAI (110 mg, 0.3 mmol) in DMF (20 mL) was stirred at room temperature for lh. Solvent was evaporated and the residue purified by column chromatography (eluent: PE/EA = 2/1) to give 36-3 as a yellow oil. LC-MS: m/z = 351.9 [M+Na]+. [00679] Step 3: A mixture of 36-3 (0.64 g, 1.49 mmol) and iron powder (0.84 g, 14.9 mmol) in AcOH (30 mL) was stirred at room temperature overnight. Solvent was evaporated and the residue diluted with water (30 m L) and basified with NaHCC>3 to pH = 7. The mixture was extracted with EA (20 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated to give 36-4 as a yellow oil. LC-MS: m/z = 300.0 [M+H]+.
[00680] Step 4: A mixture of 36-4 (300 mg, 1 mmol), Et3SiH (230 mg, 2 mmol), InCl3 (67 mg, 0.3 mmol) and propan-2-one (120 mg, 2 mmol) in MeOH (100 mL) was stirred at room temperature overnight. The mixture was evaporated and the residue purified by column chromatography (eluent: PE/EA = 2/1) to give 36-5 as a yellow oil. LC-MS: m/z = 341.9 [M+H]+.
[00681] Step 5: A mixture of 36-5 (200 mg, 0.59 mmol) and pivaloyl chloride (20 mL) was stirred at 110°C overnight. Solvent was evaporated and the residue purified by column chromatography (eluent: PE/EA = 1/1) to give 36-6 as a yellow oil. LC-MS: m/z = 425.9 [M+H]+.
[00682] Step 6: NaH (34 mg, 1.41 mmol) and l-bromo-2-(2-bromoethoxy)ethane (200 mg, 0.85 mmol) were added to a mixture of 36-6 (120 mg, 0.28 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 1 hr. The reaction was quenched with water (10 m L) and extracted with EA (20 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 1/1) to give Example #186 as a white solid. *H NMR (300 MHz, CDC13) δ 7.43 - 7.36 (m, 4H), 7.19 - 7.07 (m, 3H), 4.95 - 4.85 (m, 1H), 4.04 - 3.93 (m, 2H), 3.30 (t, / = 11.6 Hz, 2H), 2.64 - 2.57 (m, 2H), 2.43 - 2.31 (m, 2H), 1.11 - 0.97 (m, 15H). LC-MS: m/z = 496.1 [M+H]+.
[00683] PREPARATIVE EXAMPLE #187, 188 and 189
[00684] Scheme 37.
Figure imgf000189_0001
[00685] Step 1: NaH (0.28 g, 7.1 mmol) and 3-bromoprop-l-ene (0.78 g, 6.5 mmol) were added to a 0°C solution of 25-6 (2.6 g, 5.9 mmol) in dry DMF (50 mL). The resulting mixture was stirred at 0°C for 3 hrs. Water was added and the solution extracted with EA (30 mL x 3). The combined organic layers were dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE/EA = 5/1) to give 37-1 as a yellow oil. LC- MS: m/z = 481.9 [M+H]+.
[00686] Step 2: m-CPBA (2.1 g, 10.4 mmol) was added at r.tto a solution of 37-1 (2.5 g, 5.2 mmol) in 1 ,2-dichloroethane (40 mL). The reaction was refluxed overnight, then diluted with DCM (30 mL), washed with saturated Na2S203 (50 mL), 4N NaOH (50 mL), brine (50 mL), dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography eluting with PE/EA = 2/1 to give 37-2 as a colorless oil. LC-MS: m/z = 497.9 [M+H]+.
[00687] Step 3: NaH (60 w/w 0.08 g, 2 mmol) was added in portions to a solution of compound 37-2 (0.5 g, 1 mmol) in THF (10 mL). The mixture was stirred at room
temperature overnight and then water (10 mL) was added. The mixture was extracted with EtOAc (20 mL x 2). Combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by prep. TLC to give the racemic 37-3 as a yellow oil. LC-MS: m/z = 497.9 [M+H]+.
[00688] The two isomers were seperated by chiral HPLC (IC 250 x 20 mm column. Mobile phase hexanes:ethanol 80:20 (0.1% TFA). Flow rate 20 mL/min.) with Example #187 eluting first and Example #188 eluting second.
[00689] Step 4: PCC (0.15 g, 0.72 mmol) was added in portions.to a solution of 37-3 (0.12 g, 0.24 mmol) in DCM (10 mL). The mixture was stirred at room temperature overnight. Water (15 mL) was added and the mixture extracted with DCM (10 mL x 2). Combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by prep. TLC to give 37-4 as a yellow oil. LC-MS: m/z = 495.9 [M+H]+.
[00690] Step 5: MeMgBr (3M in THF, 0.2 mL, 0.6 mmol) was added to a -45°C solution of 37-4 (0.2 g, 0.4 mmol) in THF (5 mL). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by prep. TLC to give Example 189 as a white solid. *H NMR (300 MHz, CDC13) δ 7.44 - 7.06 (m, 7H), 4.56 (s, 1H), 2.94 - 2.91 (m, 1H), 2.43 - 2.38 (m, 1H), 2.05 2.02 (m, 1H), 1.16 (m, 19H). LC-MS: 512.1 [M+l].
[00691] Example # 190: NaH (60%w/w 12 mg, 0.3 mmol) was added in portions to a solution of compound 37-5 (75 mg, 0.15 mmol) in THF (5 mL) followed by iodomethane (43 mg, 0.3 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by prep. TLC to give Example #190 as a white solid. !H NMR (300 MHz, CDCI3) δ 7.24 - 7.16 (m, 7H), 4.61 (s, 1H), 3.08 (s, 3H), 2.42 - 2.31 (m, 2H), 2.06 - 2.01 (m, 1H), 1.73 - 1.68 (m, 1H), 1.12 - 1.07 (m, 18H). LC-MS: m/z = 525.9 [M+H]+.
[00692] PREPARATIVE EXAMPLE #191
[00693] Scheme 37B.
Figure imgf000190_0001
[00694] Step 1: DAST (97 mg, 0.6 mmol) was added to a solution of 37-4 (100 mg, 0.2 mmol) in DCM (10 mL). The mixture was stirred at room temperature overnight and then quenched with H20 (15 mL). The mixture was extracted with DCM (10 mL X 3). The combined organic layer was washed with brine (30 mL), dried over Na2S04 and concentrated. The resulting residue was purified by prep. TLC to give Example #191 as a yellow oil. *H NMR (300 MHz, CDC13) δ 7.39 - 7.21 (m, 7H), 5.47 - 5.41 (m, 1H), 4.53 (s, 1H), 2.81 (s, 1H), 2.20 (s, 1H), 1.85 (s, 1H), 1.11 - 1.00 (m, 15H). LC-MS: m/z = 517.9 [M+H]+.
[00695] PREPARATIVE EXAMPLE #192
[00696] Scheme 37C.
Figure imgf000191_0001
[00697] Step 1: A mixture of 37-3 (80 mg, 0.16 mmol), NaH (19 mg, 0.48 mmol) and 1- bromo-2-methoxyethane (44 mg, 0.32 mmol) was stirred at 50°C overnight. The reaction was quenched with water and extracted with EA (15 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by prep. TLC (eluent: PE/EA = 2/1) to Example #192 as a yellow oil. *H NMR (300 MHz, CDCI3) δ 7.31 - 7.03 (m, 7H), 4.56 (s, 1H), 3.41 - 3.30 (m, 8H), 2.95 - 2.91 (m, 1H), 2.65 (t, J = 15.0 Hz, 1H), 2.05 - 2.02 (m, 1H), 1.09 - 0.94 (m, 16H). LC-MS: m/z = 556.1 [M+H]+.
[00698] Example #193: was prepared as described in Scheme 38, using 2-bromo-N,N- dimethylethaneamine in step 1. *H NMR (400 MHz, CDC13) δ 7.43 - 7.02 (m, 7H), 4.63 (s, 1H), 3.64 - 2.02 (m, 15H), 1.40 - 1.09 (m, 15H). LC-MS: m/z = 569.1 [M+H]+.
[00699] PREPARATIVE EXAMPLE #194
[00700] Scheme 37D.
Figure imgf000191_0002
[00701] Step 1: A mixture of 37-4 (100 mg, 0.2 mmol), Et3SiH (58 mg, 0.5 mmol), InCl3 (22 mg, 0.1 mmol) and 2-methoxyethanamine (23 mg, 0.3 mmol) in MeOH (10 mL) was adjusted to pH = 6 with hydrogen chloride in EtOH. The mixture was stirred at room temperature overnight. The mixture was evaporated and the residue purified by prep. TLC (eluent: PE/EA = 2/1) to give Example #194 as a colorless oil. *H NMR (400 MHz, CDC13) δ 7.41 - 7.06 (m, 7H), 4.57 (s, 1H), 3.49 - 3.46 (m, 2H), 3.30 (s, 13H), 2.78 - 2.74 (m, 4H), 2.10 - 2.05 (m, 2H), 1.01 - 0.94 (m, 16H). LC-MS: m/z = 555.1 [M+H]+.
[00702] PREPARATIVE EXAMPLE #195
[00703] Scheme 37E.
Figure imgf000192_0001
[00704] Step 1: A reaction mixture of Example #194 (120 mg, 0.21 mmol), Et3SiH (73 mg, 0.63 mmol), In(¾ (24 mg, 0.11 mmol) and formaldehyde (63 mg, 2.1 mmol) in MeOH (10 mL) was stirred at room temperature overnight. The mixture was evaporated and the residue purified by prep. TLC (eluent: PE/EA = 2/1) to give Example #195 as a colorless oil. 1H NMR (300 MHz, CDC13) δ 7.31 - 7.07 (m, 7H), 4.58 (s, 1H), 3.37 - 3.28 (m, 5H), 2.26 - 1.93 (m, 10H), 1.10 - 0.95 (m, 15H). LC-MS: m/z = 568.9 [M+H]+.
[00705] Example #209: was prepared as described in Scheme 33, using 2- morpholinoethaneamine in step 1. *H NMR (400 MHz, CDC13) δ 13.15 (br, 1H), 7.47-7.36 (m, 5H), 7.19 (d, J = 11.2 Hz, 1H),7.04 (d, J = 7.6 Hz, 1H), 4.28 (t, J = 12.0 Hz, 2H), 4.10 (s, 2H), 3.99 (s, 4H), 3.96 (br, 2H), 3.37 (d, J = 11.6 Hz, 2H), 3.20 (s, 2H), 3.00 (d, J = 11.2 Hz, 2H), 2.64 (t, J = 11.2Hz, 2H), 2.35 (d, J = 5.6 Hz, 2H), 1.07 (s, 9H). LC-MS: m/z = 567
[M+H]+.
[00706] Example #210: was prepared as described in Scheme 33, using 2- cyclopropylethaneamine in step 1. *H NMR (400 MHz, CDC13) δ 7.37-7.32 (m, 4H), 7.18 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 11.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.02 (d, J = 10.4 Hz, 2H), 3.68-3.57 (m, 2H), 3.33 (t, J = 11.6 Hz, 2H), 2.68-2.61 (m, 2H), 2.36 (d, J = 13.6 Hz, 2H), 1.45 (q, J = 7.2 Hz, 2H) 1.09 (s, 9H), 0.60-0.58 (m, 1H), 0.46-0.43 (m, 2H), 0.08-0.04 (m, 2H). LC-MS: m/z = 522 [M+H]+.
[00707] Example #211: was prepared as described in Scheme 33, using (S)-l- cyclohexylethaneamine in step 1. *H NMR (400 MHz, CDC13) δ: 7.34 (s, 4H), 7.14 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 11.6 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 4.62 (br, 1H), 4.03 (d, J = 11.2 Hz, 2H), 3.30 (t, J = 11.2 Hz, 2H), 2.67 (t, J = 10.4 Hz, 2H), 2.37 (d, J = 10.4 Hz, 2H), 1.99 (m, 1H), 1.77-1.67 (m, 4H), 1.25-0.82 (m, 18H). LC-MS: m/z = 564 [M+H]+.
[00708] Example #212: was prepared as described in Scheme 33, using (R)-3,3- dimethylbutan-2-amine in step 1. *H NMR (400 MHz, CDC13) δ: 7.44-7.33 (m, 5H), 7.04 (d, J = 10.8 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 5.13 (br, 1H), 4.02 (d, J = 10.8Hz, 2H), 3.30 (q, J = 11.2 Hz, 2H), 2.70 (t, J = 10.4 Hz, 2H), 2.36 (d, J = 12.8 Hz, 2H), 1.01-0.87 (m, 21H). LC- MS: m/z = 538 [M+H]+.
[00709] Example #213: was prepared as described in Scheme 33, using (S)-3,3- dimethylbutan-2-amine in step 1. *H NMR (400 MHz, CDC13) δ: 7.44-7.33 (m, 5H), 7.04 (d, J = 10.8 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 5.13 (br, 1H), 4.02 (d, J = 10.8Hz, 2H), 3.30 (q, J = 11.2 Hz, 2H), 2.70 (t, J = 10.4 Hz, 2H), 2.36 (d, J = 12.8 Hz, 2H), 1.01-0.87 (m, 21H). LC- MS: m/z = 538 [M+H]+.
[00710] Example #214: was prepared as described in Scheme 33, using 2- cyclohexylethaneamine in step 1. *H NMR (400 MHz, CDC13) δ: 7.37-7.32 (m, 4H), 7.17 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 11.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.00 (d, J = 10.4 Hz, 2H), 3.59 (br, 1H), 3.31 (t, J = 10.4 Hz, 2H), 2.65 (t, J = 13.6 Hz, 2H), 2.35 (d, J = 13.6 Hz, 2H),
I.70-1.57 (m, 6H), 1.42-1.37 (m, 2H), 1.24-1.14 (m, 4H), 1.08 (s, 9H), 0.96-0.86 (m, 2H). LC-MS: m/z = 564 [M+H]+.
[00711] Example #215: was prepared as described in Scheme 33, using (1-methyl-lH- pyrazol-4-yl)methaneamine in step 1. *H NMR (400 MHz, CDC13) δ: 7.39-7.30 (m, 5H), 7.15-7.02 (m, 2H), 6.92-6.87 (m, 2H), 3.99 (d, J = 12.0 Hz, 2H), 3.85 (s, 3H), 3.26 (t, J =
I I.6Hz, 2H), 2.66-2.59 (m, 2H), 2.31 (d, J = 13.2 Hz, 2H), 1.07 (s, 9H). LC-MS: m/z = 548 [M+H]+.
[00712] Example #216: was prepared as described in Scheme 33, using (S)-l- cyclopropylethanamine in step 1. *H NMR (400 MHz, CDC13) δ: 7.36-7.31 (m, 5H), 7.07- 6.99 (m, 2H), 4.10 (br, 1H), 4.01 (d, J = 12.0 Hz, 2H), 3.24-3.30 (m, 2H), 2.71-2.64 (m, 2H), 2.36 (d, J = 14.0 Hz, 2H), 1.14-1.13 (m, 3H), 1.05 (s, 9H), 0.42-0.39 (m, 5H). LC-MS: m/z = 522 [M+H]+.
[00713] Example #217: was prepared as described in Scheme 33, using (R)-l- cyclopropylethanamine in step 1. *H NMR (400 MHz, CDC13) δ: 7.36-7.31 (m, 5H), 7.07-
6.99 (m, 2H), 4.10 (br, 1H), 4.01 (d, J = 12.0 Hz, 2H), 3.24-3.30 (m, 2H), 2.71-2.64 (m, 2H),
2.36 (d, J = 14.0 Hz, 2H), 1.14-1.13 (m, 3H), 1.05 (s, 9H), 0.42-0.39 (m, 5H). LC-MS: m/z = 522 [M+H]+.
[00714] Example #218: was prepared as described in Scheme 33, using (4- fluorophenyl)methanamine in step 1. *H NMR (400 MHz, CDC13) δ: 7.39-7.30 (m, 4H), 7.14-7.07 (m, 2H), 6.92-6.87 (m, 2H), 6.82-6.80 (m, 2H), 3.99 (d, J = 10.0 Hz, 2H), 3.21 (t, J = 7.4 Hz, 2H), 2.66-2.59 (m, 2H), 2.28 (d, J = 13.2 Hz, 2H), 1.07 (s, 9H). LC-MS: m/z = 562 [M+H]+.
[00715] Example #219: was prepared as described in Scheme 33, using (R)-l- cyclopropylpropan-2-amine in step 1. *H NMR (400 MHz, CDC13) δ: 7.39-7.34 (m, 4H), 7.16 (t, J = 8.0 Hz, IH), 7.07-7.01 (m, 2H), 4.68 (br, IH), 4.05 (d, J = 10.0Hz, 2H), 3.46 (t, J = 11.6 Hz, 2H), 2.73 (t, J = 3.2 Hz, 2H), 2.38 (d, J = 13.6 Hz 2H), 1.57-1.53 (m, IH) 1.11- 1.07 (m, 13H), 0.70-0.68 (m, IH), 0.52-0.48 (m, 2H), 0.18-0.97 (m, 2H). LC-MS: m/z = 536 [M+H]+.
[00716] Example #220: was prepared as described in Scheme 33, using (S)-l- cyclopropylpropan-2-amine in step 1. *H NMR (400 MHz, CDC13) δ: 7.39-7.34 (m, 4H), 7.16 (t, J = 8.0 Hz, IH), 7.07-7.01 (m, 2H), 4.68 (br, IH), 4.05 (d, J = 10.0Hz, 2H), 3.46 (t, J = 11.6 Hz, 2H), 2.73 (t, J = 3.2 Hz, 2H), 2.38 (d, J = 13.6 Hz 2H), 1.57-1.53 (m, IH) 1.11- 1.07 (m, 13H), 0.70-0.68 (m, IH), 0.52-0.48 (m, 2H), 0.18-0.97 (m, 2H). LC-MS: m/z = 536 [M+H]+.
[00717] Example #221: was prepared as described in Scheme 33, using (R)-l- cyclobutylethanamine in step 1. *H NMR (400 MHz, CDC13) δ: 7.37 (s, 4H), 7.07-7.00 (m, 3H), 4.01 (d, J = 12.0 Hz, 2H), 3.34 (t, J = 11.6 Hz, 2H), 2.73-2.66 (m, 2H), 2.39 (d, J = 14.0 Hz, 2H), 1.07 (s, 9H), 0.89 (s, 3H). LC-MS: m/z = 536 [M+H]+.
[00718] PREPARATIVE EXAMPLE #222:
[00719] SCHEME 38.
Figure imgf000195_0001
38-7 Ex. 222
[00720] Step 1: To a solution compound 38-1 (8.0 g, 44 mmol, 1.0 eq.) in dry MeOH (80 mL) were added cyclobutanone (6.2 g, 88 mmol, 2.0 eq.) and InCi3 (4.9 g, 22 mmol, 0.5 eq.), and then the mixture was stirred at 35 °C for 2.5 h. TLC (PE/EA = 6/1) showed that the reaction was complete. Then the mixture was concentrated under reduced pressure. The residue was partitioned between EA (100 mL) and water (150 mL) and the aqueous layer was extracted with EA (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SC>4, filtered, and concentrated in vacuum. The residue was purified by column chromatography, eluted with PE/EA (50/1 ~ 30/1) to give compound 38-2 as a white solid. 'HNMR: (400 MHz, CDC13) δ: 7.62 (dd, J = 8.4, 1.6 Ηζ,ΙΗ), 7.40 (d, J = 1.6 Hz, 1H), 6.45 (d, / = 8.4 Hz, 1H), 4.83 (br, 1H), 3.98-3.95 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 2.48- 2.45 (m, 2H), 1.91-1.82 (m, 4H).
[00721] Step 2: A mixture of compound 38-2 (4.0 g, 17 mmol, 1.0 eq.) and NCS (3.0 g, 22.1 mmol, 1.3 eq.) in MeCN (50 mL) was stirred at 60 °C for 3 h. TLC (PE/EA = 8/1) showed that the reaction was complete. Then the mixture was concentrated under reduced pressure. To the residue was added EA (100 mL), NaOH aq (22 mL, 1 mol/L) and water (150 mL) with stirring. The aqueous layer was separated and extracted with EA (100 mL x 3). The combined organic layers were washed with water (150 mL) and brine (150 mL), dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by column chromatography, eluted with PE/EA (40/1 ~ 20/1) to give compound 38-3 as an oil. 'HNMR: (400 MHz, CDC13) δ: 7.6 (d, / = 1.6 Ηζ,ΙΗ), 7.35 (d, / = 1.6 Hz, 1H), 4.58 (br, 1H), 4.47- 4.43 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.37-2.32 (m, 2H), 1.89-1.83 (m, 2H), 1.74-1.63 (2H).
[00722] Step 3: A mixture of compound 38-3 (2.2 g, 8.1 mmol, 1.0 eq.) in pivaloyl chloride (20 mL) was stirred at 75 °C for 1.5 h. LCMS showed that the reaction was complete. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography, eluted with PE/EA (40/1 ~ 20/1) to give compound 38-4 as a colorless oil.
'HNMR: (400 MHz, CDC13) δ: 7.76 (s, 1H), 7.50 (s, 1H), 4.66-4.62 (m, 1H) 3.95 (s, 3H), 3.90 (s, 3H), 2.10-2.08 (m, 2H), 1.73-1.54 (m, 4H), 0.98 (s, 9H).
[00723] Step 4: To a solution of compound 38-4 (2.3 g, 6.5 mmol, 1.0 eq.) in dry THF (50 mL) was added in portions LAH (0.62 g, 16.3 mmol, 2.5 eq.) at -30 °C, and then the mixture was stirred at -30 °C for 20 min. TLC (PE/EA = 3/1) showed that the reaction was complete. To the mixture was added dropwise water (0.6 mL) at -40 ~ -20 °C followed by 15% aq. NaOH (0.6 mL) and water (1.5 mL). Na2S04 (ca. 10 g) was added and the mixture was stirred at room temperature for 15 min. The mixture was filtered, and the filter cake was washed with EA (20 mL x 3). The combined filtrates were concentrated in vacuum. The residue was purified by re-crystallization from PE/EA (30 mL/3 mL) to give compound 38-5 as a white solid. 'HNMR: (400 MHz, CDC13) δ: 7.07 (s, 1H), 6.91 (s, 1H), 4.73-4.72 (d, / = 4.8 Hz, 2H), 4.68-4.62 (m, 1H), 3.83 (s, 3H), 2.11-2.06 (m, 3H), 1.75-1.72 (m, 2H), 1.58-1.53 (m, 2H), 0.98 (s, 9H).
[00724] Step 5: To a solution of compound 38-5 (1.0 g, 3.1 mmol, 1.0 eq) in dry DCM (20 mL) were added PPh3 (1.2 g, 4.7 mmol, 1.5 eq) and CBr4 (1.56 g, 4.7 mmol, 1.5 eq) at 0-5 °C under nitrogen, and then the mixture was stirred at room temperature for 1 h. TLC (PE/EA = 3/1) showed that most of compound 38-5 was consumed. The mixture was concentrated in vacuum and the residue was purified by column chromatography, eluted with PE/EA (12/1 ~ 10/1) to give compound 38-6 as a white solid. 'HNMR: (400 MHz, DMSO) δ: 7.30 (s, 1H), 7.25 (s, 1H), 4.72 (s, 2H), 4.56-4.52 (m, 1H), 3.83 (s, 3H), 1.99-1.96 (m, 2H), 1.67-1.52 (m, 4H), 0.89 (s, 9H).
[00725] Step 6: To a solution of sodium 4-chlorobenzenesulfinate (230 mg, 1.16 mmol, 1.05 eq) in DMSO (6 mL) was added compound 38-6 (428 mg, 1.1 mmol, 1.0 eq) in portions at 60 °C, and then the mixture was stirred at 60 °C for 1 h. TLC (PE/EA = 3/1) showed that the reaction was complete. The mixture was cooled to room temperature, and poured into water (50 mL) with stirring. The formed solid was collected by filtration, washed with water (10 mL x 2), then dissolved in EA (30 mL). The obtained organic solution was washed with brine (20 mL), dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by re-crystallization from PE/EA (12 mL/3 mL) to give compound 38-7 as a white solid. 'HNMR: (400 MHz, CDC13) δ: 7.59 (d, / = 8.8 Hz, 2H), 7.4 (d, / = 8.8 Hz, 2H), 6.69 (s, 1H), 6.61 (s, 1H), 4.62-4.60 (m, 1H), 4.29 (s, 2H), 3.73 (s, 3H), 2.08-2.06 (m, 2H), 1.61- 1.40 (m, 4H), 0.96 (s, 9H).
[00726] Step 7: To a solution of 38-7 (242 mg, 0.5 mmol, 1.0 eq) in THF (6 mL) were added NaH (120 mg, 3 mmol, 6.0 eq, 60% dispensed in mineral oil) and bis(2-bromoethyl) ether (255 mg, 1.1 mmol, 2.2 eq), and then the mixture was stirred at 75 °C for 6 h. LCMS showed that the reaction was complete. The mixture was cooled to room temperature, and poured into water (30 mL). The mixture was extracted with EA (20 mL x2) and the combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by preparative HPLC (Mobile phase A: water with 0.05% HC1, Mobile phase B: acetonitrile; Column: Synergi 150*30mm; Detection wavelength: 220nm) to give Example #222 as a white solid. 'HNMR: (400 MHz, DMSO) δ: 7.55 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 4.65-4.55 (m, 1H), 3.96-3.92 (m, 2H), 3.68 (s, 3H), 3.22 (t, / = 11.2 Hz, 2H), 2.52- 2.43 (m, 4H), 2.12-2.01 (m, 2H), 1.70-1.56 (m, 4H), 0.99 (s, 9H). LCMS(ESI): (M+Na: 576).
[00727] PREPARATIVE EXAMPLE #223:
[00728] SCHEME 38b.
Figure imgf000198_0001
[00729] Stepl: To a mixture of compound 38b-l (25.5 g, 153 mmol, 1.0 eq.) in dry MeOH (250 mL) was added dropwise SOCl2 (50 mL) under ice-water bath, and then the mixture was stirred at reflux overnight. TLC (PE/EA = 2/1) showed that the reaction was complete. Then the mixture was concentrated under reduced pressure. The mixture was diluted with water (500 mL), basified to pH = 9 with 1 N aq. NaOH, and extracted with EA (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2S04, filtered, and concentrated to give target compound 38b-2. 'HNMR: (400 MHz, DMSO) δ: 7.40 (dd, J = 8.4, 1.6 Ηζ,ΙΗ), 7.29 (d, / = 1.6 Hz, 1H), 6.64 (d, / = 8.4 Hz, 1H), 5.65 (br, 2H), 3.81 (s, 3H), 3.76 (s, 3H).
[00730] Step 2: A mixture of compound 38b-2 (12.0 g, 66 mmol, 1.0 eq.) in MeCN (150 mL) and NCS (13 g, 99 mmol, 1.5 eq.) was stirred at 90 °C for 5 h. TLC (PE/EA = 3/1) showed that most of compound 38b-2 was converted into target compound. Then the mixture was concentrated under reduced pressure. The residue was dissolved in saturated aqueous K2CO3 solution (500 mL) and EA (200 mL). The aqueous layer was extracted with EA (300 mL x 3). The combined organic layer were washed with brine (300 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography, eluted with PE/EA (25/1 ~ 15/1) to give compound 38b-3. 'HNMR: (400 MHz, DMSO) δ: 7.48 (s, 1H), 7.27 (s, 1H), 5.81 (br, 2H), 3.86 (s, 3H), 3.79 (s, 3H). [00731] Step 3: A mixture of compound 38b-3 (5.0 g, 23 mmole, 1.0 eq.), cyclopropylboronic acid (4.0 g, 46 mmol, 2.0 eq.), Cu(OAc)2 (5.1 g, 28 mmol, 1.2 eq.), Bipy (4.4 g, 28 mmol, 1.2 eq.) and Na2C03 (4.9 g, 46 mmol, 2.0 eq.) in DCE (60 mL) was stirred at 70 oC for 3.5 h. The mixture was then cooled to room temperature and filtered, and the filter cake was washed with DCM (20 mL x 3). The combined filtrates were concentrated in vacuum and the residue was purified by column chromatography, eluted with PE/EA (30/1) to give 38b-4. 'HNMR: (400 MHz, CDC13) δ: 7.64 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 1.2 Hz, 1H), 4.68 (br, 1H), 3.87 (s, 6H), 3.10-3.07 (m, 1H), 0.76-0.69 (m, 2H), 0.58-0.51 (m, 2H).
[00732] Step 4: A mixture of 38b-4 (2.0 g, 7.8 mmol, 1.0 eq.) in pivaloyl chloride (20 mL) was stirred at 75 °C for 2 h. TLC (PE/EA = 2/1) showed that the reaction was complete. The mixture was slowly poured into water (150 mL) and then basified to 12- 13 by slow addition of solid NaOH. The mixture was extracted with EA (60 mL x 3) and the combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by column chromatography, eluted with PE/EA (20/1 ~ 15/1) to give compound 38b-5. 'HNMR: (400 MHz, CDC13) δ: 7.74 (s, 1H), 7.46 (s, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.15-3.13 (m, 1H), 0.98 (s, 9H), 0.65-0.63 (m, 2H), 0.57-0.4 (m, 2H). LCMS(ESI): (M+l : 339.9).
[00733] Step 5 To a solution of 38b-5 (1.6 g, 4.7 mmol, 1.0 eq.) in anhydrous THF (20 mL) was added in portions LAH (0.39 g, 10.3 mmol, 2.2 eq.) at -30 °C, and then the mixture was stirred at -30 °C for 20 min. TLC (PE/EA = 1/1) showed that the reaction was complete. To the mixture was added dropwise water (0.4 mL) at -30 °C followed by 15% aq. NaOH (0.4 mL) and water (1 mL). Anhydrous Na2S04 (ca. 10 g) was added and the mixture was slowly warmed to 0 °C. After stirring for 30 min, the mixture was filtered and the filter cake was washed with EA (10 mL x 2). The combined filtrates were concentrated in vacuum to give compound 38b-6 which was directly used in the next step without further purification.
'HNMR: (400 MHz, CDC13) δ: 7.04 (s, 1H), 6.87 (s, 1H), 4.71 (s, 2H), 3.81 (s, 3H), 3.15- 3.12 (m, 1H), 2.30 (br, 1H), 0.99 (s, 9H), 0.63-0.41 (m, 4H). LCMS(ESI): (M+l : 311.8).
[00734] Step 6: To a solution of 38b-6 (400 mg, 1.6 mmol, 1.0 eq.) in dry DCM (12 mL) was added dropwise TEA (323 mg, 3.2 mmol, 2.0 eq.) and MsCl (274 mg, 2.4 mmol, 1.5 eq.) under ice-water bath, and then the mixture was stirred at room temperature for 15 min.
LCMS showed that the reaction was complete. The mixture was diluted with DCM (20 mL), washed with water (40 mL) and brine (15 mL), dried over Na2S04, filtered, and concentrated to give crude compound 38b-7 which was directly used in the next step without further purification. 'HNMR: (400 MHz, CDC13) δ: 7.10 (s, 1H), 6.86 (s, 1H), 5.17 (s, 2H), 3.84 (s, 3H), 3.36-3.12 (m, 1H), 3.06 (s, 3H), 0.99 (s, 9H), 0.65-0.41 (m, 4H).
[00735] Step 7: To a solution of sodium 4-chlorobenzenesulfinate (400 mg, 2.0 mmol, 1.2 eq.) in DMSO (5 mL) was added a solution of 38b-7 (660 mg, 1.7 mmol, 1.0 eq.) in DMSO (10 mL) drop wise at 60 °C, and then the mixture was stirred at 60 °C for 2 h. TLC (PE/EA = 2/1) showed that the reaction was complete. The mixture was cooled to room temperature, and poured into water (80 mL) under stirring. The solid was collected by filtration, washed with water (10 mL x 2), and then dissolved in EA (80 mL). The obtained organic solution washed with brine (50 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by re-crystallization from PE/EA (10 mL/3 mL) to give product 38b-8. 'HNMR: (400 MHz, CDCI3) δ: 7.60 (d, / = 8.4 Hz, 2H), 7.46 (d, / = 8.4 Hz, 2H), 6.69 (s, 1H), 6.60 (s, 1H), 4.28 (s, 2H), 3.81 (s, 3H), 3.12-3.10 (m, 1H), 0.98 (s, 9H), 0.64-0.35 (m, 4H).
[00736] Step 8: To a solution of 38b-8 (300 mg, 0.64 mmol, 1.0 eq.) in THF (8 mL) were added NaH (152 mg, 3.8 mmol, 6.0 eq., 60% in mineral oil) and bis(2-bromoethyl) ether (327 mg, 1.4 mmol, 2.2 eq.), and then the mixture was stirred at 75 °C overnight. LCMS showed that the reaction was complete. The mixture was cooled to room temperature, and slowly poured into water (20 mL). The aqueous mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by preparative HPLC (Mobile phase A: water with 0.05% HCl, Mobile phase B: acetonitrile; Column: YMC 150*30mm; Detection wavelength: 220nm) to give Example # 223. *HNMR: (400 MHz, DMSO) δ: 7.57(d, J = 8.4 Hz, 2H), 7.39 (d, / = 8.8 Hz, 2H), 6.97 (d, / = 1.6 Hz 1H), 6.76 (d, / = 1.6 Hz, 1H), 3.94 (d, 7" = 11.6 Hz, 2H), 3.64 (s, 3H), 3.21-3.10 (m, 3H), 2.55-2.50 (m, 2H), 2.43-2.35 (m, 2H), 1.05 (s, 9H), 0.69-0.35 (m, 4H). LCMS(ESI): (M+Na: 562).
[00737] PREPARATIVE EXAMPLE #224:
[00738] SCHEME 38c.
Figure imgf000201_0001
Ex.224
[00739] Stepl: To a solution of compound 38c-2 (3.5 g, 14.3 mmol, 1.0 eq.) in DME (30 mL) were added l-cyclopropylpropan-2-amine (1.7 g, 17.2 mmol, 1.2 eq.), i-BuONa (3.0 g, 31.5 mmol, 2.2 eq.) and pre-Pd-brettphos (0.46 g, 0.572 mmol, 0.04 eq.) under N2, and then the mixture was stirred at 95 °C under N2 overnight. TLC (PE/EA = 15/1) showed that the reaction was complete. The reaction mixture was concentrated in vacuum. The residue was portioned between EA (150 mL) and water (300 mL). The aqueous layer was separated and extracted with EA (150 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography, eluted by PE/EA (50/1 ~ 35/1) to give compound 38c-3 as an oil. 'HNMR: (400 MHz, CDC13) δ: 7.65 (dd, / = 8.4, 1.2 Hz, IH), 7.42 (d, / = 1.2 Hz, IH), 6.58 (d, / = 8.4 Hz, IH), 4.69 (br, IH), 3.91 (s, 3H), 3.88 (s, 3H), 3.70-3.51 (m, IH), 1.62-1.56 (m, IH), 1.42- 1.38 (m, IH), 1.49 (d, / = 6.0 Hz, 3H), 0.77-0.75 (m, IH), 0.52-0.49 (m, 2H), 0.13-0.09 (m, 2H).
[00740] Step 2: To a solution of compound 38c-3 (1.05 g, 4.0 mmol, 1.0 eq.) in MeCN (16 mL) was added NCS (0.56 g, 4.2 mmol, 1.05 eq.) at 70 °C for 3 h. TLC (PE/EA = 5/1) showed that the reaction was complete. The reaction mixture was concentrated and the residue was purified by column chromatography, eluted by PE/EA (60/1 ~ 50/1) to give compound 38c-4. 'HNMR: (400 MHz, CDC13) δ: 7.68 (s, IH), 7.39 (s, IH), 4.41 (br, IH), 4.30-4.26 (m, IH), 3.91 (s, 3H), 3.90 (s, 3H), 1.52-1.48 (m, IH), 1.32-1.27 (m, IH), 1.22 (d, / = 6.4 Hz, 3H), 0.73-0.71 (m, IH), 0.48-0.45 (m, 2H), 0.07-0.06 (m, 2H).
[00741] Step 3: A mixture of compound 38c-4 (1.0 g, 3.4 mmol, 1.0 eq.) in pivaloyl chloride (12 mL) was stirred at 115 °C for 6 h. TLC (PE/EA = 8/1) showed that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography, eluted by PE/EA (45/1 ~ 35/1) to give compound 38c-5. 'HNMR: (400 MHz, CDC13) δ: 7.76 (s, IH), 7.50 (s, 0.5H), 7.49 (s, 0.5H), 4.05-4.02 (m, IH), 3.99 (s, 3H), 3.90 (s, 3H), 1.66-1.62 (m, 2H), 1.21 (d, 7 = 6.8 Hz, 1.5H), 1.18 (d, / = 6.8 Hz, 1.5H), 0.98 (s, 9H), 0.75-0.60 (m, IH), 0.45-0.37 (m, 2H), 0.10-0.07 (m, 2H).
[00742] Step 4: To a solution of compound 38c-5 (0.85 g, 2.2 mmol, 1.0 eq.) in anhydrous THF (30 mL) was added LAH (0.21 g, 5.5 mmol, 2.5 eq.) in portions at -35 ~ -25 °C, and then the mixture was stirred at -30 °C for 30 min. TLC (PE/EA = 3/1) showed that the reaction was complete. The reaction was quenched by slow addition of water (0.2 mL), followed by 15% aq. NaOH (0.2 mL) and water (0.6 mL) at -35 ~ -20 °C. To the mixture was added Na2S04 (ca. 25 g) and the mixture was stirred at room temperature for 20 min. The mixture was filtered, and the filter pad was washed with EA (20 mL x 3). The combined filtrates were concentrated in vacuum and the residue was purified by column
chromatography, eluted by PE/EA (6/1 ~ 3/1) to give target compound 38c-6 as a colorless oil. 'HNMR: (400 MHz, CDC13) δ: 7.05 (s, IH), 6.88 (s, 0.5H), 6.86 (s, 0.5H), 4.74 (d, / = 6.4 Hz, 2H), 4.12-4.07 (m, IH), 3.85 (s, 1.5H), 3.84 (s, 1.5H), 1.94 (t, / = 6.4 Hz, IH), 1.65- 1.58 (m, 2H), 1.19 (d, / = 7.2 Hz, 1.5H), 1.17 (d, / = 7.2 Hz, 1.5H), 0.98 (s, 9H), 0.70-0.60 (m, IH), 0.45-0.38 (m, 2H), 0.10-0.08 (m, 2H).
[00743] Step 5: To a solution of compound 38c-6 (0.78 g, 2.2 mmol, 1.0 eq.) in anhydrous DCM (25 mL) were added PPh3 (0.86 g, 3.3 mmol, 1.5 eq.) and CBr4 (1.1 g, 3.3 mmol, 1.5 eq) under ice-water bath, and then the mixture was stirred at room temperature for 1 h. TLC (PE/EA = 3/1) showed that the reaction was complete. The mixture was concentrated in vacuum and the residue was purified by column chromatography, eluted by PE/EA (50/1 ~ 40/1) to give compound 38c-7 as a colorless oil. 'HNMR: (400 MHz, CDC13, rotamer) δ: 7.10 (s, IH), 6.85 (s, 0.5H), 6.84 (s, 0.5H), 4.45 (s, 2H), 4.15-4.00 (m, IH), 3.86 (s, 1.5H), 3.85 (s, 1.5H), 1.66-1.061 (m, 2H), 1.20 (d, 7 = 6.8 Hz, 1.5H), 1.18 (d, / = 6.8 Hz, 1.5H), 0.98 (s, 9H), 0.70-0.60 (m, IH), 0.45-0.37 (m, 2H), 0.02-0.08 (m, 2H). [00744] Step 6: To a solution of sodium 4-chlorobenzenesulfinate (0.42 g, 2.1 mmol, 1.1 eq.) in DMSO (10 mL) was added compound 38c-7 (0.8 g, 1.9 mmol, 1.0 eq.) portion wise at 60 °C, and then the mixture was stirred at 60 °C for 1 h. TLC (PE/EA = 3/1) showed that the reaction was complete. The mixture was cooled to room temperature, poured into ice-water (50 mL) under stirring. The formed solid was collected by filtration, washed with water (5 mL x 2), and then dissolved in EA (30 mL). The obtained solution was dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography, eluted by PE/EA (6/1 ~ 5/1) to give compound 38c-8 as a white solid. *HNMR: (400 MHz, CDC13) δ: 7.60 (dd, / = 8.4, 1.6 Hz, 2H), 7.46 (d, / = 8.4 Hz, 2H), 6.71 (s, 0.5H), 6.69 (s, 0.5H), 6.61 (s, 0.5H), 6.58 (s, 0.5H), 4.29 (s, 2H), 4.08-4.04 (m, 1H), 3.75 (s, 1.5H), 3.73 (s, 1.5H), 1.58- 1.52 (m, 2H), 1.13 (d, / = 7.2 Hz, 1.5H), 1.10 (d, / = 7.2 Hz, 1.5H), 0.96 (s, 9H), 0.70-0.60 (m, 1H), 0.46-0.39 (m, 2H), 0.09-0.07 (m, 2H).
[00745] Step 7: To a solution of compound 38c-8 (300 mg, 0.59 mmol, 1.0 eq.) in anhydrous THF (8 mL) were added NaH (142 mg, 3.54 mmol, 6.0 eq., 60% dispensed in mineral oil) and bis(2-bromoethyl) ether (302 mg, 1.3 mmol, 2.2 eq), and then the mixture was stirred at 85 °C for 4.5 h. TLC (PE/EA = 3/1) showed that the reaction was complete. The mixture was cooled to room temperature, poured into ice-water (50 mL) under stirring, and then extracted with EA (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by preparative HPLC (Mobile phase A: water with 0.05% HC1, Mobile phase B: acetonitrile; Column: Synergi 150 x 30 mm; Detection wavelength: 220 nm) to afford Example # 224 as a white solid. *HNMR: (400 MHz, DMSO) δ: 7.54 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.03 (s, 0.5H), 7.02 (s, 0.5H), 6.70 (s, 0.5H), 6.67 (s, 0.5 H), 3.92-3.88 (m, 3H), 3.61 (s, 1.5H), 3.60 (s, 1.5H), 3.10-3.04 (m, 2H), 2.58-2.51 (m, 2H), 2.36-2.30 (m, 2H), 1.51-1.40 (m, 2H), 1.06 (d, / = 7.6 Hz, 1.5H), 1.03 (d, / = 7.6 Hz, 1.5H), 0.87 (s, 9H), 0.70-0.60 (m, 1H), 0.46-0.39 (m, 2H), 0.06-0.02 (m , 2H). LCMS(ESI): (M+Na: 604).
[00746] Example #225: was prepared as described in Scheme 38c, using (R)
cyclohexylethanamine in step 1. *HNMR: (400 MHz, DMSO) δ: 7.56 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.04 (s, 0.5H), 7.02 (s, 0.5H), 6.69 (s, 0.5H), 6.65 (s, 0.5H), 3.91 (d, J = 10.0 Hz, 2H), 3.82-3.79 (m, 1H), 3.61 (s, 1.5H), 3.59 (s, 1.5H), 3.11-3.05 (m, 2H), 2.60- 2.51 (m, 2H), 2.36-2.30 (m, 2H), 1.85-1.60 (m, 6H), 1.10-0.88 (m, 17H). LCMS(ESI):
(M+Na: 632).
[00747] Example #226: was prepared as described in Scheme 38c, using (S)-l- cyclohexylethanamine and cyclopropanecarbonyl chloride in step 3. 'HNMR: (400 MHz, DMSO) δ: 7.54 (d, J = 8.4 Hz, 2H), 7.44-7.37 (m, 4H), 4.40-4.36 (m, 0.6H), 4.18-4.13 (m, 0.4H), 3.89 (d, J = 11.6 Hz, 2H), 3.18 (t, J = 12.4 Hz, 2H), 2.52 (d, J = 1.6 Hz, 2H), 2.50-2.31 (m, 2H), 1.77-1.41 (m, 6H), 1.09-0.68 (m, 14H). LCMS(ESI): (M+Na: 616).
[00748] PREPARATIVE EXAMPLE #232:
[00749] SCHEME 38d.
Figure imgf000204_0001
38d-8 Ex. 232
[00750] Step 1: To a solution of compound 38d-l (14.0 g, 77.0 mmol, 1.0 eq.) and Me2S (5.7 g, 92.4 mmol, 1.2 eq) in anhydrous DCM (200 mL) was added in portions NCS (12.3 g, 92.4 mmol, 1.2 eq) at 80 °C, and then the mixture was stirred at room temperature for 40 min. To the mixture was added TEA (11.7 g, 115.5 mmol, 1.5 eq), and then the mixture was stirred at 65 °C for 3 h. TLC (PE/EA = 3/1) showed that most of compound 38d-l was converted into 38d-2. The mixture was washed with 10% aq. NaOH (40 mL x 2) and brine (100 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography, eluted with PE/EA (9/1 ~ 7/1) to give crude 38d-2 which was purified further by re-crystallization from PE/EA (3/1, 50 mL) to give pure compound 38d-2 as a white solid. 'HNMR: (400 MHz, CDC13) δ: 7.44 (s, 1H), 7.42 (s, 1H), 4.69 (br, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.72 (s, 2H), 1.97 (s, 3H). [00751] Step 2: A mixture of compound 38d-2 (6.3 g, 26 mmol, 1.0 eq.) and Raney Ni (63 g) in EtOH (150 mL) was stirred at 30 °C under 50 psi of hydrogen pressure for 2.5 h. TLC (PE/EA = 3/1) showed that the reaction was complete. The mixture was filtered, and the filter cake was washed with EtOH (100 mL x 4). The combined filtrates were concentrated to give crude compound 33d-3 as a colorless oil. 'HNMR: (400 MHz, CDC13) δ: 7.48 (s, 1H) 7.36 (s, 1H), 4.18 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 2.19 (s, 3H).
[00752] Example #232: was prepared as described in Scheme 38, using compound 38d-3 as starting material in step 1. 'HNMR: (400 MHz, DMSO) δ: 7.51 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 6.77 (s, 1H), 6.63 (s, 1H), 4.52-4.47 (m, 1H), 3.95-3.92 (m, 2H), 3.62 (s, 3H), 3.23-3.18 (m, 2H), 2.51-2.40 (m, 4H), 2.17-2.05 (m, 5H), 1.73-1.57 (m, 4H), 0.95 (s, 9H). LCMS(ESI): (M+Na: 556).
[00753] Example #233: was prepared as described in Scheme 38b, using compound 38d-3 as starting material in step 3. 'HNMR: (400 MHz, DMSO) δ: 7.53 (d, J = 8.8 Hz, 2H), 7.36 (d, / = 8.8 Hz, 2H), 6.73 (s, 1H), 6.60 (s, 1H), 3.94 (d, / = 11.6 Hz, 2H), 3.58 (s, 3H), 3.21- 3.19 (m, 3H), 2.51-2.42 (m, 4H), 2.06 (s, 3H), 1.06 (s, 9H), 0.67-0.64 (m, 2H), 0.39-0.26 (m , 2H). LCMS(ESI): (M+Na: 542).
[00754] PREPARATIVE EXAMPLE #234:
[00755] SCHEME 38e.
Figure imgf000205_0001
Ex. 234
[00756] Step 1: To a solution compound 38e-l (1.41 g, 10 mmol, 1.0 eq.) in CH3CN (50 mL) was added NBS (1.96 g, 11 mmol, 1.1 eq.) in portions at room temperature. The mixture was stirred at room temperature for 2 h, at which time TLC (PE/EA = 5/1) showed the reaction was complete. The mixture was concentrated in vacuum. The residue was dissolved in EA (50 mL), washed with water (50 mL x 2), saturated aqueous NaHCC>3 (50 mL x 2) and brine (50 mL), dried over Na2S04 and concentrated in vacuum to give crude product 38e-2 as a black oil, which was directly used in the next step without further purification. 'HNMR: (400 MHz, CDC13) δ: 6.95 (d, / = 10.0 Hz, 1H), 6.85 (s, 1H), 4.82 (br, 2H), 3.80 (s, 3H).
[00757] Step 2: To a solution compound 38e-2 (6.6 g, 30 mmol, 1.0 eq.) and Et3SiH (8.7 g, 75 mmol, 2.5 eq.) in dry MeOH (60 mL) were added cyclobutanone (3.2 g, 45 mmol, 1.5 eq.) and Ιη(¾ (0.99 g, 4.5 mmol, 0.15 eq.), and then the mixture was stirred at 35 °C overnight. TLC (PE/EA = 6/1) showed that the reaction was complete. Then the mixture was concentrated under reduced pressure. The residue was partitioned between EA (100 mL) and water (150 mL) and the aqueous layer was extracted with EA (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2S04, filtered, and
concentrated in vacuum. The residue was purified by column chromatography, eluted by PE/EA (50/1 ~ 30/1) to give crude product, which further purified by preparative HPLC to give compound 38e-3 as a white solid. 'HNMR: (400 MHz, CDC13) δ: 6.83 (d, J = 10.8 Hz, 1H), 6.71 (s, 1H), 4.13-4.08 (m, 1H), 3.84 (s, 3H), 3.82 (br, 1H), 2.34-2.30 (m, 2H), 1.84- 1.66 (m, 4H).
[00758] Step 3: A mixture of compound 38e-3 (750 mg, 2.73 mmol, 1.0 eq.) in pivaloyl chloride (20 mL) was stirred at 75 °C for 1.5 h. LCMS showed that the reaction was complete. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography, eluted by PE/EA (40/1 ~ 20/1) to give compound 38e-4 (as a white solid. 'HNMR: (400 MHz, CDC13) δ: 6.98 (d, J = 8.0 Hz, 2H), 6.87 (s, 1H), 4.71-4.68 (m, 1H), 3.81 (s, 3H), 2.17-2.14 (m, 1H), 1.99-1.91 (m, 1H), 1.68-1.62 (m, 1H), 1.56-1.49 (m, 3H), 0.98 (s, 9H).
[00759] Step 4: To a mixture of compound 38e-4 (440 mg, 1.22 mmol, 1.0 eq.), HCOOLi (283 mg, 4.88 mmol, 4.0 eq), TEA (493 mg, 4.88 mmol, 4.0 eq.) in DMF (40 mL) was added Pd(OAc)2 (24 mg, 0.12 mmol, 0.1 eq.) and Xantphos (72 mg, 0.24 mmol 0.2 eq) under N2. Ac20 (493 mg, 4.88 mmol, 4.0 eq) was then added into the mixture under N2. The resulting mixture was stirred at 90 °C for 2 h. TLC (PE:EA = 3:1) showed the reaction was complete. The mixture was poured into water (50 mL), basified to pH = 12, and washed with EtOAc (20 mL x 2). The aqueous phase was collected, acidified to pH = 3, and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over anhydrous Na2S04, concentrated to give the crude product 38e-5 as yellow oil which was directly used in the next step without further purification.
[00760] Step 5: To a mixture of crude compound 38e-5 (394 mg, 1.22 mmol, 1.0 eq.) and K2C03 (842 mg, 6.1 mmol, 5.0 eq.) in DMF (10 mL) was added CH3I (2.0 g, 14 mmol, 11 eq.). The mixture was stirred at 30 °C for 4 h. TLC (PE/EA = 5/1) showed the reaction was complete. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed by brine (20 mL x 2) and concentrated in vacuum and the residue was purified by flash column chromatography (eluent: PE/EA = 10/1) to give the product 38e-6 as a yellow oil. 'HNMR: (400 MHz, CDC13) δ: 7.49 (d, / = 8.8 Hz, 1H), 7.44 (s, 1H), 4.76-4.72 (m, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 2.22-2.17 (m, 1H), 1.99-1.98 (m, 1H), 1.70-1.68 (m, 2H), 1.60-1.52 (m, 2H), 1.00 (s, 9H).
[00761] Example #234: was prepared as described in Scheme 38, using compound 38e-6 as starting material in step 4. 'HNMR: (400 MHz, DMSO) δ: 7.35 (s, 4H), 6.61 (s, 1H), 6.55 (d, J = 10.4 Hz, 1H), 4.71-4.69 (m, 1H), 4.02 (d, / = 11.2 Hz, 2H), 3.70 (s, 3H), 3.31 (t, / = 11.2 Hz, 2H), 2.69 (t, / = 11.2 Hz, 2H), 2.31 (d, / = 11.2 Hz, 2H), 2.19-2.16 (m, 1H), 1.99-1.95 (m, 1H), 1.62-1.54 (m, 4H), 1.00 (s, 9H). LCMS(ESI): (M+H: 538).
[00762] PREPARATIVE EXAMPLE #227:
[00763] SCHEME 39.
Figure imgf000207_0001
[00764] Step 1: A mixture of compound 39-1 (11.4 g, 66 mmol, 1.0 eq.), DIEA (17.1 g, 132 mmol, 3.0 eq.), (/?)-l-cyclohexylethanamine (10 g, 80 mmol, 1.2 eq.) in DMSO (150 mL) was stirred at 120 °C for 12 h. TLC (PE:EA = 30:1) showed the reaction was complete. Then the mixture was poured into ice-water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated in vacuum. The crude product was purified by flash column
chromatography (eluent: PE/EA = 100/1) to give target compound 39-2 as a white solid. 'HNMR: (400 MHz, CDC13) δ: 7.70 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 12.4 Hz , J = 2.0 Hz, 1H), 6.61 (t, / = 8.4 Hz, 1H), 4.24 (br, 1H), 3.85 (s, 3H), 3.43-3.37 (m, 1H), 2.18-1.69 (m, 5H), 1.28-1.24 (m, 1H), 1.23-1.04 (m, 8H).
[00765] Step 2: To a mixture of compound 39-2 (8.4 g, 30 mmol, 1.0 eq.) in CH3CN (20 mL) was added NCS (6.3 g, 45 mmol, 1.5 eq.) and the mixture was stirred at 60 °C for 3 h. TLC (PE:EA = 30:1) showed the reaction was complete. The mixture was concentrated to give the crude product which was purified by column chromatography (eluent: PE/EA = 100/1) to give target compound 39-3 as a white solid. *HNMR: (400 MHz, CDC13) δ: 7.79 (s, 1H), 7.57 (dd, / = 13.6, 2.0 Hz, 1H), 4.33 (br, 1H), 3.88 (s, 3H), 3.87-3.82 (m, 1H), 1.86- 1.70 (m, 5H), 1.41-1.03 (m, 9H).
[00766] Step 3: To a mixture of compound 39-3 (5.0 g, 16 mmol, 1.0 eq.) in THF (50 mL) was added LAH (1.2 g, 32 mmol, 2.0 eq.) in portions at -30 °C. The resulting mixture was stirred at this temperature for 3 h. TLC (PE:EA = 3:1) showed the reaction was complete. Then the reaction was quenched with H20 (1.2 mL) at -30 °C, 15% aq. NaOH (1.2 mL) and H20 (3.6 mL) were added in turn, the resulting mixture was stirred at room temperature for 30 min and then filtered. The filtrate was concentrated to give the crude product which was purified by flash column chromatography (eluent: PE/EA = 10/1) to give target compound 39-4 as a white solid.
[00767] 'HNMR: (400 MHz, CDC13) δ: 7.09 (s, 1H), 6.94 (dd, / = 12.8, 2.0 Hz, 1H), 4.55 (d, / = 4.4 Hz, 2H), 3.78 (br, 1H), 3.66-3.64 (m, 1H), 1.81-1.64 (m, 6H), 1.25-1.20 (m, 1H), 1.18-1.09 (m, 8H).
[00768] Step 4: To a mixture of compound 39-4 (2.8 g, 10 mmol, 1.0 eq.), sodium 4- chlorobenzenesulfinate (2.4 g, 12 mmol, 1.2 eq.) and TEA (2.0g, 20 mmol, 2.0 eq.) in DMF (50 mL) was added methanesulfonyl chloride (1.7 g, 15 mmol, 1.5 eq.) at ice-bath. The mixture was stirred at room temperature for 2 h. TLC (PE:EA = 3:1) showed most of compound 39-4 was consumed. Subsequently the reaction mixture was concentrated. The residue was diluted with water (40 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were dried over anhydrous Na2S04, concentrated and further purified by flash column chromatography (eluent: PE/EA = 5/1) to give the product 39-5 as a white solid. *HNMR: (400 MHz, CDC13) δ: 7.61 (d, J = 8.4 Hz, 2H),7.49 (m, J = 8.4 Hz, 2H), 6.81 (s, 1H), 6.73 (dd, / = 13.2, 2 Hz, 1H), 4.16 (s, 2H), 3.91 (br, 1H), 3.71-3.67 (m, 1H), 1.81-1.64 (m, 5H), 1.12-1.04 (m, 9H).
[00769] Step 5: A mixture of compound 39-5 (600 mg, 1.45 mmol, 1.0 eq.) in pivaloyl chloride (10 mL) was stirred at 110 °C for 12 h. LC-MS showed the reaction was complete. Then the mixture was concentrated in vacuum. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over anhydrous Na2S04> concentrated to give the crude product, which was purified by flash column chromatography (eluent: PE/EA =3/1) to give the product 39-6 as a white solid. *HNMR: (400 MHz, CDC13) δ: 7.63 (d, / = 8.4 Hz, 2H),7.48 (d, / = 8.4 Hz, 2H), 7.05 (s, 0.4H), 7.03 (s, 0.6H), 6.93 (d, / = 12.8 Hz, 0.6H), 6.90 (d, J = 12.8 Hz, 0.4H), 4.27 (s, 2H), 4.15-4.13 (m, 1H), 1.89-1.62 (m, 6H), 1.30-0.88 (m, 17H).
[00770] Step 6: To a mixture of compound 39-6 (500 mg, 0.95 mmol, 1.0 eq.) and NaH (151 mg, 3.79 mmol, 4.0 eq., 60% dispensed in mineral oil) in THF (20 mL) was added 1- bromo-2-(2-bromoethoxy)ethane (551 mg, 2.37 mmol, 2.5 eq.) at room temperature. The resulting mixture was stirred at 75 °C for 12 h. LC-MS showed the reaction was complete. The reaction was then quenched with H20 (20 mL) and extracted with EtOAc (20 mL x 3). Then combined organic layers were dried over anhydrous Na2S04, concentrated and purified by preparative HPLC (Mobile phase A: water with 0.05% HCl, Mobile phase B: acetonitrile; Column: Agella Venusil ASB C18 150 x 21.2 mm x 5um; Detection wavelength: 220 nm) to give Example # 227 as a white solid. *HNMR: (400 MHz, CDC13) δ: 7.39-7.30 (m, 4H), 7.09 (s, 0.4H), 7.06 (s, 0.6H), 7.01 (d, / = 11.2 Hz, 0.6H), 6.98 (d, / = 11.2 Hz, 0.4H), 4.11-4.05 (m, 0.6H), 4.04 (d, / = 12.0 Hz, 2H), 3.85-3.78 (m, 0.4H), 3.29 (t, / = 11.2 Hz, 2H), 2.66- 2.59 (m, 2H), 2.30 (d, / = 13.2 Hz, 2H), 1.92-1.75 (m, 6H), 1.19-0.99 (m, 17H). LCMS (ESI): (M+H: 598).
[00771] Example #228: was prepared as described in Scheme 39, using
cyclopropanecarbonyl chloride in step 5.
*HNMR: (400 MHz, CDC13) δ: 7.54 (d, J = 8.4 Hz, 2H), 7.44-7.37 (m, 4H), 4.40-4.36 (m, 0.6H), 4.18-4.13 (m, 0.4H), 3.89 (d, J = 11.6 Hz, 2H), 3.18 (t, J = 12.4 Hz, 2H), 2.52 (d, J = 1.6 Hz, 2H), 2.50-2.31 (m, 2H), 1.77-1.41 (m, 6H), 1.09-0.68 (m, 14H). LCMS (ESI):
(M+H: 582).
[00772] Example #229: was prepared as described in Scheme 39, using (S)- \- cyclohexylethanamine in step 1.
'HNMR: (400 MHz, CDC13) δ: 7.39-7.30 (m, 4H), 7.09 (s, 0.4H), 7.06 (s, 0.6H), 7.01 (d, J = 1 1.2 Hz, 0.6H), 6.98 (d, J = 11.2 Hz, 0.4H), 4.11-4.05 (m, 0.6H), 4.04 (d, J = 12.0 Hz, 2H), 3.85-3.78 (m, 0.4H), 3.29 (t, J = 1 1.2 Hz, 2H), 2.66-2.59 (m, 2H), 2.30 (d, J = 13.2 Hz, 2H), 1.92-1.75 (m, 6H), 1.19-0.99 (m, 17H). LCMS (ESI): (M+H: 598).
[00773] PREPARATIVE EXAMPLE #235:
[00774] SCHEME 40.
Figure imgf000210_0001
40-7 Ex. 235
[00775] Step 1: A solution compound 40-1 (6.0 g, 32 mmol, 1.0 eq.) and cyclopropanamine (5.5 g, 96 mmol, 3.0 eq.) in DMSO (30 mL) was heated at 130 °C overnight. TLC (PE/EA = 10/1) showed that most of compound 40-1 was consumed. The mixture was cooled to room temperature, poured into water (120 mL) and then extracted with PE/EA (4/1 , 50 mL x 2). The combined organic layers were washed with brine (60 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography, eluted with PE/EA (30/1 ~ 10/1) to give compound 40-2 as an oil. 'HNMR: (400 MHz, DMSO) δ: 7.99 (s, IH), 7.41 (s, IH), 6.27 (s, IH), 2.71 -2.65 (m, IH), 2.25 (s, 3H), 0.67-0.64 (m, 2H), 0.48-0.46 (m, 2H).
[00776] Step 2: A mixture of compound 40-2 (1.2 g, 5.3 mmol, 1.0 eq.) in pivaloyl chloride
(12 mL) was stirred at 180 °C for 10 h. The reaction was performed in two batches. TLC
(PE/EA = 6/1) showed that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography, eluted with PE/EA (25/1 ~ 15/1) to give compound 40-3 as a yellow oil. 'HNMR: (400 MHz, CDC13) δ: 8.43 (s, 1H), 8.08 (s, 1H), 3.12-3.08 (m, 1H), 2.21 (s, 3H), 0.98 (s, 9H), 0.71-0.68 (m, 2H), 0.27-0.24 (m, 2H).
[00777] Step 3: To a solution of compound 40-3 (2.4 g, 7.7 mmole, 1.0 eq.) in dry THF (40 mL) was added dropwise n-BuLi (7.7 mL, 19.3 mmol, 2.5 eq. 2.5 M in n-hexane) at -65 ~ -60 °C under N2, and then the mixture was stirred at -65 °C for 20 min. To the mixture was added dropwise dry DMF (2 mL), and then the mixture was stirred -65 °C for 1 h. TLC (PE/EA = 2/1) showed that the reaction was complete. The mixture was quenched with water (5 mL) at -60 -40 °C under stirring. Then the mixture was allowed to warm to room temperature, diluted with water (50 mL) and extracted with EA (30 mL x3). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography, eluted with PE/EA (5/1) to give compound 40-4 as a yellow oil.
[00778] 'HNMR: (400 MHz, CDC13) δ: 10.10 (s, 1H), 8.77 (s, 1H), 8.06 (s, 1H), 3.18-3.16 (t, 1H), 2.34 (s, 3H), 1.24 (s, 9H), 0.80-0.79 (m, 2H), 0.43-0.42 (m, 2H).
[00779] Step 4: To a solution of compound 40-4 (0.91 g, 3.5 mmol, 1.0 eq.) in dry THF (8 mL) was added in portions NaBH4 (0.29 g, 7.7 mmol, 2.2 eq.) under ice-water bath, and then the mixture was stirred at room temperature for 1 h. TLC (PE/EA = 1/1) showed that the reaction was complete. The mixture was quenched with water (20 mL) under ice- water bath and then extracted with EA (15 mL x 3). The combined extracts were washed with brine (30 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography, eluted with PE/EA (1/1 ~ 1/5) to give compound 40-5 as a white solid. 'HNMR: (400 MHz, CDC13) δ: 8.24 (s, 1H), 7.63 (s, 1H), 4.73 (s, 2H), 3.16-3.14 (m, 1H), 2.27 (s, 3H), 1.01 (s, 9H), 0.78-0.72 (m, 2H), 0.47-0.43 (m, 2H).
[00780] Step 5: To a solution of compound 40-5 (0.42 g, 1.6 mmol, 1.0 eq.) in dry DCM (10 mL) were added PPI13 ((0.63 g, 2.4 mmol, 1.5 eq.) and CBr4 (0.80 g, 2.4 mmol, 1.5 eq) under ice- water bath, and then the mixture was stirred at room temperature for 1.5 h under N2. TLC (PE/EA = 1/1) showed that the reaction was complete. The mixture was concentrated in vacuum and the residue was purified by column chromatography, eluted with PE/EA (6/1) to give compound 40-6 as a white solid. 'HNMR: (400 MHz, CDC13) δ: 8.31 (d, J = 2.4 Hz, 1H), 7.64 (d, / = 2.4 Hz, 1H), 4.46 (s, 2H), 3.17-3.13 (m, 1H), 2.28 (s, 3H), 1.06 (s, 9H), 0.78-0.73 (m, 2H), 0.45-0.42 (m, 2H). [00781] Step 6: A mixture of compound 40-6 (0.41 g, 1.3 mmol, 1.0 eq.) and sodium 4- chlorobenzenesulfinate (0.28 g, 1.4 mmol, 1.1 eq.) in DMSO (6 mL) was stirred at 60 °C for 1 h. TLC (PE/EA = 2/1) showed that the reaction was complete. The mixture was cooled to room temperature, poured into ice-water (40 mL) under stirring. The solid formed was filtered, washed with water (5 mL x 2), and then dissolved in EA (40 mL). The solution obtained was dried over Na2S04, filtered, and concentrated. The residue was purified by re- crystallization from PE/EA (12 mL/3 mL) to give 40-7 as a white solid. 'HNMR: (400 MHz, CDC13) δ: 7.76 (s, 1H), 7.58 (d, / = 8.8 Hz, 2H), 7.56 (s, 1H), 7.46 (d, / = 8.8 Hz, 2H), 4.30 (s, 2H), 3.15-3.11 (m, 1H), 2.26 (s, 3H), 1.04 (s, 9H), 0.77-0.73 (m, 2H), 0.37-0.32 (m, 2H).
[00782] Step 7: To a solution of compound 40-7 (0.25 g, 0.6 mmol, 1.0 eq.) in dry DMF (8 mL) were added CS2CO3 (0.59 g, 1.8 mmol, 3.0 eq.) and bis(2-bromoethyl) ether (0.42 g, 1.8 mmol, 3.0 eq.), and then the mixture was stirred at 90 °C for 2 days. LCMS showed that all compound 7 was converted into target product. The mixture was cooled to room
temperature, diluted with water (30 mL) and extracted with EA (20 mL x 3), washed with brine. The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography, eluted with PE/EA (3/1 ~ 1/1) to give the crude product, which was further purified by preparative HPLC (Mobile phase A: water with 0.05% HC1, Mobile phase B: acetonitrile; Column: Synergi 150 x 30 mm; Detection wavelength: 220 nm) to afford Example # 235 as a white solid. 'HNMR: (400 MHz, CDC13) δ: 8.25 (s, 1H), 8.14 (s, 1H), 7.51 (d, / = 8.0 Hz, 2H), 7.39 (d, / = 8.0 Hz, 2H), 4.05-3.97 (m, 2H), 3.87-3.82 (m, 1H), 3.25 (s, 2H), 2.57-2.38 (m, 4H), 2.30 (s, 3H), 1.51 (s, 9H), 1.13-1.12 (m, 2H), 0.73-0.70 (m, 2H). LCMS(ESI): (M+Na: 513).
[00783] PREPARATIVE EXAMPLE #196:
[00784] SCHEME 42.
Figure imgf000212_0001
Ex. 196 [00785] Step 1: To a mixture of compound 42-1 (10 g, 58 mmol, 1.0 eq.) in DMSO (20 mL) was added DIEA (15 g, 116 mmol, 2.0 eq.) and isopropylamine (3.4 g, 69 mmol, 1.2 eq.). The mixture was stirred at 70°C for 3 days. TLC (PE:EA = 30:1) showed the starting material was consumed completely. Then the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated in vacuum. The crude product was purified by flash column chromatography (eluent: PE/EA = 30:1) to give target compound 42-2 as a white solid.
[00786] 'HNMR: (400 MHz, CDC13) δ = 7.72 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 6.63 (t, / = 8.4 Hz, 1H), 4.35 (br, 1H), 3.88 (s, 3H), 3.76-3.65 (m, 1H), 1.26 (d, / = 6.4 Hz, 6H).
[00787] Step 2: To a mixture of compound 42-2 (2.10 g, 0.01 mol, 1.0 eq.) in THF (150 mL) was added LAH (0.76 g, 0.02 mol, 2.0 eq.) in portions at -30°C. The resulting mixture was stirred at 0 °C for 2 h. TLC (PE:EA = 3:1) showed the starting material was consumed completely. Then the reaction was quenched by careful addition of H20 (0.7 mL) followed by 15% aq. NaOH (0.7 mL) and H20 (2.1 mL). The resulting mixture was stirred at 0°C for 20 min and then filtered. The filtrate was concentrated in vacuum and the crude product was further purified by flash column chromatography (eluent: PE/EA = 3/1) to give target compound 42-3 as a colorless oil.
[00788] 'HNMR: (400 MHz, CDC13) δ = 7.01-6.97 (m, 2H), 6.64-6.68 (m, 1H), 4.53 (d, / = 5.2 Hz, 2H), 3.72-3.59 (m, 2H), 1.23 (d, / = 6.8 Hz, 6H).
[00789] Step 3: To a mixture of compound 42-3 (552 mg, 3.0 mmol, 1.0 eq.), sodium 4- chlorobenzenesulfinate (653 mg, 3.3 mmol, 1.0 eq.) and TEA (606 mg, 6.0 mmol, 2.0 eq.) in DMF (10 mL) was added methanesulfonyl chloride (513 mg, 4.5 mmol, 1.5 eq.) at 0°C. Then the mixture was stirred at room temperature for 12 h. TLC (PE:EA = 3:1) showed the starting material was consumed completely. The reaction mixture was concentrated in vacuo. The residue was diluted with water (40 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were dried over anhydrous Na2S04, concentrated in vacuum and purified by flash column chromatography (eluent: PE/EA = 10/1) to give the product as a yellow solid.
[00790] *HNMR: (400 MHz, CDC13) δ = 7.59 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.77-6.72 (m, 3H), 4.19 (s, 2H), 3.67-3.60 (m, 1H), 1.26 (d, / = 6.4 Hz, 6H). [00791] Step 4: To a mixture of compound 42-4 (400 mg, 1.17 mmol, 1.0 eq.) in DCM (10 mL) was added DIEA (296 mg, 2.3 mmol, 2.0 eq.) and acetyl chloride (358 mg, 4.68 mmol, 4.0 eq.). The mixture was refluxed for 12 h. LCMS showed the starting material was consumed completely. The reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were dried over anhydrous Na2S04, concentrated to give the crude product, which was purified by flash column chromatography (eluent: PE/EA = 10/1) to give the product as a yellow solid. LCMS(ESI): 17642-37-3b (M+H: 384).
[00792] Step 5: To a mixture of compound 42-5 (0.24 g, 0.63 mmol, 1.0 eq.) and NaH (100 mg, 2.52 mmol, 4.0 eq., 60% dispensed in mineral oil) in DMF (20 mL) was added l-(2- bromoethoxy)-2-bromoethane (291 mg, 1.26 mmol, 2.0 eq.) at room temperature. The resulting mixture was stirred at 70°C for 12 h. LCMS showed the starting material was consumed. Then the mixture was cooled to room temperature, poured into H20 (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2S04, concentrated in vacuum and purified by preparative HPLC (Mobile phase A: water with 0.05% HC1, Mobile phase B: acetonitrile; Column: Synergi 150*30mm; Detection wavelength: 220 nm) to give the desired pure compound Example# 196 as white solid. *HNMR: (400 MHz, CDC13) δ = 7.35-7.29 (m, 4H), 7.13-7.08 (m, 3H), 5.03-5.00 (m, 1H), 4.03 (d, / = 11.2 Hz, 2H), 3.33 (t, / = 11.2 Hz, 2H), 2.70-2.62 (m, 2H), 2.37 (d, / = 13.6 Hz, 2H), 1.80 (s, 3H), 1.14 (d, / = 6.0 Hz, 3H), 1.01 (d, / = 5.6 Hz, 3H). LCMS(ESI): 17642-40- 2B (M+H: 454).
[00793] Example # 197 was prepared as described in Scheme 42, except using 4 isobutyryl chloride in step 4. *H NMR (400 MHz, CDC13) δ = 7.34-7.29 (m, 4H), 7.11-7.07 (m, 3H), 5.02-4.99 (m, 1H), 4.03 (d, J = 11.2 Hz, 2H), 3.35 (t, / = 11.2 Hz, 2H), 2.68 (t, / = 11.2 Hz, 2H), 2.37 (d, / = 13.6 Hz, 2H), 2.13 (m, 1H), 1.12-1.08 (m, 6H), 1.02-0.99 (m, 6H). LC-MS: M/Z = 482 [M+H]+.
[00794] Example 198: was prepared as described in Scheme 42, except using
cyclopropanecarbonyl chloride in step 4. *H NMR (400 MHz, DMSO) δ = 7.50 (d, J = 7.2 Hz, 2H), 7.34-7.24 (m, 3H), 7.23 (d, J = 7.6 Hz, 1H), 4.82-4.74 (m, 1H), 3.91-3.88 (m, 2H), 3.18-3.12 (m, 2H), 2.62-2.53 (m, 2H), 2.38-2.32 (m, 2H),), 1.17-0.86 (m, 7H), 0.84-0.55 (m, 4H). LC-MS: M/Z = 480 [M+H]+.
[00795] Example #199: was prepared as described in Scheme 42, except using 1- methylcyclopropanecarbonyl chloride in step 4. !H NMR (400 MHz, CDCL3) δ = 7.36-7.30 (m, 4H), 7.16-7.07 (m, 2H), 7.04-7.02 (m, IH), 4.91-4.85 (m, IH), 4.05-3.95 (m, 2H), 3.34- 3.28 (m, 2H), 2.70-2.63 (m, 2H), 2.342.17 (m, 2H), 1.15-0.93 (m, 11H), 0.42-0.35 (m, 2H). LC-MS: M/Z = 494 [M+H]+.
[00796] Example #200: was prepared as described in Scheme 42, except using 3,3- difluorocyclobutanecarbonyl chloride in step 4. *H NMR (400 MHz, CDCL3) δ = 7.39 (d, J = 7.2 Hz, 2H), 7.34 (d, J = 7.2 Hz, 2H), 7.15-7.08 (m, 3H), 5.01-4.94 (m, IH), 4.04 (d, J = 11.6 Hz, 2H), 3.32 (t, J = 11.6 Hz, 2H), 2.92-2.89 (m, 2H), 2.68-2.65 (m, 2H), 2.51-2.50 (m, IH), 2.39-2.35 (m, 4H), 1.12 (d, J = 7.2 Hz, 3H), 1.02 (d, J=7.2 Hz, 3H). LC-MS: M/Z = 552 [M+H]+.
[00797] Example #201: was prepared as described in Scheme 42, except using 3,3- dimethylbutanoyl chloride in step 4. *H NMR (400 MHz, CDCL3) δ: 7.36-7.30 (m, 4H), 7.11-7.02 (m, 3H), 5.04-5.00 (m, IH), 4.03 (d, J = 11.8 Hz, 2H), 3.35 (t, J = 11.8 Hz, 2H), 2.68 (t, J = 11.8 Hz, 2H), 2.35 (d, J = 14.0 Hz, 2H), 1.91-1.82 (m, 2H), 1.12 (d, J = 6.8 Hz, 3H), 0.98 (m, 12H). LC-MS: M/Z = 510 [M+H]+.
[00798] Example #202: was prepared as described in Scheme 42, except using 1-methyl- lH-pyrazole-4-carbonyl chloride in step 4. *H NMR (400 MHz, CDCL3) δ: 7.47-7.39 (m, 4H), 7.31-7.26 (m, 2H), 7.14-7.12 (m, 2H), 6.77 (br. IH), 5.12-5.09 (m, IH), 4.01 (d, J = 9.6 Hz, 2H), 3.79 (s, 3H), 3.31 (t, J = 11.2 Hz, 2H), 2.57 (t, J = 11.2 Hz, 2H), 2.37 (d, J = 13.6 Hz, 2H) 1.22-1.12 (m, 6H). LC-MS: M/Z = 520 [M+H]+.
[00799] Example #203: was prepared as described in Scheme 42, except using nicotinoyl chloride in step 4. *H NMR (400 MHz, CD3OH) δ: 8.88 (s, IH), 8.80 (s, IH), 8.40 (s, IH), 7.90 (s, IH), 7.53-7.51 (m, 3H), 7.35 (d, J = 8.0 Hz, 2H), 7.17 (m, 2H), 5.12-5.01 (m, IH), 3.93-3.90 (m, 2H), 3.12-3.01 (m, 2H), 2.46-2.41 (m, 4H), 1.39 (d, J = 6.0 Hz, 3H), 1.22 (d, J = 6.0 Hz, 3H). LC-MS: M/Z = 517 [M+H]+.
[00800] Example #204: was prepared as described in Scheme 42, except using picolinoyl chloride in step 4. *H NMR (400 MHz, CD3OH) δ: 8.31 (s, IH), 7.80 (s, IH), 7.53-7.23 (m, 7H), 7.02-6.98 (m, 2H), 5.03-4.99 (m, IH), 3.89-3.78 (m, 2H), 3.31-3.30 (m, 2H), 2.44-2.33 (m, 4H), 1.33 (d, J = 6.4 Hz, 3H), 1.20 (s J = 6.4 Hz, 3H). LC-MS: M/Z = 517 [M+H]+.
[00801] Example #205: was prepared as described in Scheme 42, except using
isonicotinoyl chloride in step 4. *H NMR (400 MHz, CD3OH) δ: 8.75 (d, J = 4.0 Hz, 2H),
7.87 (d, J = 4.0 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.47-7.45 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H),
7.18-7.15 (m, 2H), 5.07-5.03 (m, IH), 3.91-3.85 (m, 2H), 3.12-3.01 (m, 2H), 2.46-2.41 (m,
4H), 1.39 (d, J = 6.4 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H). LC-MS: M/Z = 517 [M+H]+. [00802] Example #206: was prepared as described in Scheme 42, except using 6- methylpicolinoyl chloride in step 4. *H NMR (400 MHz, CDC13) δ: 7.59-7.54 (m, IH), 7.49- 7.48 (m, IH), 7.25-7.20 (m, 5H), 7.04-7.03 (m, IH), 6.91-6.84 (m, 2H), 5.14-5.11 (m, IH), 3.97-3.95 (m, 2H), 3.21-3.15 (m, 2H), 2.56 (m, 2H), 2.31-2.24 (m, 5H), 1.31 (d, J = 6.4 Hz, IH), 1.22 (d, J = 6.4 Hz, IH). LC-MS: M/Z = 531 [M+H]+.
[00803] Example #207: was prepared as described in Scheme 42, except using (1S,2S,4R)- bicyclo[2.2.1]heptane-2-carbonyl chloride in step 4. *H NMR (400 MHz, DMSO) δ: 7.55- 7.51 (m, 2H), 7.41-7.38 (m, 2H), 7.36-7.18 (m, 3H), 4.79-4.71 (m, IH), 3.94-3.91 (m, 2H), 3.21-3.13 (m, 2H), 2.50 (m, IH), 2.44-2.38 (m, 4H), 2.19-2-16 (m, IH), 1.91-1.04 (m, 16H). LC-MS: M/Z = 534 [M+H]+.
[00804] Example #208: was prepared as described in Scheme 42, except using Boc- chloride in step 4. *H NMR (400 MHz, CDC13) δ: 7.33 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.08-7.04 (m, 2H), 6.89 (d, J = 8.0 Hz, IH), 4.57-4.53 (m, IH), 3.98 (d, J = 11.8 Hz 2H), 3.30 (t, J = 11.8 Hz, 2H), 2.65 (t, J = 11.8 Hz, 2H), 2.32 (d, J = 13.6 Hz, 2H), 1.40 (s, 9H), 1.19-1.09 (m, 6H). LC-MS: M/Z = 534 [M+Na]+.
[00805] Example #238: was prepared as described in Scheme 42, except using methyl chloroformate in step 4. *H NMR (400 MHz, CDC13) δ: 7.33 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.08-7.04 (m, 2H), 6.89 (d, J = 8.0 Hz, IH), 4.57-4.53 (m, IH), 3.98 (d, J = 11.8 Hz 2H), 3.70 (s, 3H), 3.30 (t, J = 11.8 Hz, 2H), 2.65 (t, J = 11.8 Hz, 2H), 2.32 (d, J = 13.6 Hz, 2H), 1.19-1.09 (m, 6H). LC-MS: M/Z = 469 [M+Na]+.
[00806] Example #239: was prepared as described in Scheme 42, except using ethyl chloroformate in step 4. *H NMR (400 MHz, CDC13) δ: 7.33 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.08-7.04 (m, 2H), 6.89 (d, J = 8.0 Hz, IH), 4.57-4.53 (m, IH), 4.05 (m, 2H), 3.98 (d, J = 11.8 Hz 2H), 3.70 (s, 3H), 3.30 (t, J = 11.8 Hz, 2H), 2.65 (t, J = 11.8 Hz, 2H), 2.32 (d, J = 13.6 Hz, 2H), 1.30-1.05 (m, 9H). LC-MS: M/Z = 506 [M+Na]+.
[00807] Example #240: was prepared as described in Scheme 42, except using isopropyl chloroformate in step 4. *H NMR (400 MHz, CDC13) δ: 7.33 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.08-7.04 (m, 2H), 6.89 (d, J = 8.0 Hz, IH), 5.05-4.95 (m, IH), 4.57-4.53 (m, IH), 4.05 (m, 2H), 3.98 (d, J = 11.8 Hz 2H), 3.70 (s, 3H), 3.30 (t, J = 11.8 Hz, 2H), 2.65 (t, J = 11.8 Hz, 2H), 2.32 (d, J = 13.6 Hz, 2H), 1.30-1.05 (m, 12H). LC-MS: M/Z = 520 [M+Na]+.
[00808] PREPARATIVE EXAMPLE #236:
[00809] SCHEME 43.
Figure imgf000217_0001
Ex. 236
Step 1: To a mixture of 43-1 (22 g, 160 mmol, 1.0 eq.) in SOCl2 (300 mL) was added DMF (1 mL). The mixture was heated to reflux overnight and then concentrated in vacuum to give the crude product 43-2 which was directly used in the next step without further purification.
Step 2: To a mixture of CuBr.SMe2 (22.6 g, 110 mmol, 1.1 eq.) in THF (800 mL) was added dropwise i-BuLi (1.3 M in hexane, 90 mL, 110 mmol, 1.1 eq.) at -78 °C under N2, and the mixture was stirred at -78 °C for 30 min. Then, a solution of crude 43-2 (25 g, 100 mmol, 1.0 eq.) in THF (200 mL) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 2 h, and then quenched with saturated aqueous NH4C1 (1 L) and extracted with MTBE (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2S04 and concentrated in vacuum to give the crude product which was purified by flash column chromatography (eluent: PE) to give 43-3 as colorless oil. 'HNMR: (400 MHz, CDC13) δ = 7.35-7.30 (m, 2H), 7.11 (t, 7 = 7.2 Hz, 1H), 1.26 (s, 9H).
[00810] Step 3: To a mixture of methyl triphenylphonium bromide (41.3 g, 0.116 mol, 2.0 eq.) in THF (200 mL) at -78 °C was added dropwise n-BuLi (2.5 M in hexane, 46 mL, 0.116 mol, 2.0 eq.) under nitrogen. The mixture was allowed to stir at 0 °C for 30 min, and then re- cooled to -78 °C. To the reaction mixture was added dropwise a solution of compound 43-3 (15 g, 0.058 mol, 1.0 eq.) in THF (50 mL). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Saturated aqueous NH4C1 (300 mL) was added to quench the reaction and the mixture was extracted with MTBE (200 mL x 2). The combined organic layers were washed with brine (200 mL) and dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by flash column chromatography (eluent: PE) to give the product 43-4 as a colorless oil. *HNMR: (400 MHz, CDC13) δ = 7.23-7.21 (m, 2H), 6.96 (t, 7 = 8.0 Hz, 1H), 5.31 (s, 1H), 4.83 (s, 1H), 1.10 (s, 9H).
[00811] Step 4: To a mixture of compound 43-4 (7.0 g, 27 mmol, 1.0 eq.) in THF (200 mL) at 0 °C BH3 (1.0 M in THF, 270 mL, 270 mmol, 10.0 eq.) was added dropwise. The reaction mixture was allowed to warm to room temperature, and stirred for 1 h. 1 M aq. NaOH solution (67 mL) and H202 (30% wt. in H20, 9.18 g, 270 mmol, 10.0 eq.) was slowly added. The reaction mixture was stirred at room temperature for 1 h, and then partitioned between MTBE (300 mL) and H20 (300 mL). The aqueous layer was extracted with MTBE (100 mL x 2). The combined organic layers were washed with brine (300 mL), dried over Na2S04, filtered, and concentrated to give crude product 43-5, which was directly used in the next step without purification. *HNMR: (400 MHz, CDC13) δ: 7.29-7.23 (m, 2H), 7.17-7.15 (m, 1H), 4.08-3.94 (m, 2H), 3.65 (t, / = 6.8 Hz, 1H), 3.12 (br, 1H), 0.93 (s, 9H).
[00812] Step 5: To a mixture of 43-5 (7.0 g, 0.025 mol, 1.0 eq.) in DMF (500 mL) at room temperature was added PDC (47.9 g, 0.127 mol, 5.0 eq.) in portions. The mixture was stirred at this temperature for 16 h, and then diluted with EtOAc (300 mL), filtered through a celite pad. The filtrate was washed with H20 (200 mL x 2) and brine (200 mL), dried with Na2S04, filtered and concentrated to give the crude product which was purified by flash column chromatography (eluent: PE:EA = 10:1) to give 43-6 (2.0 g, 27%) as a white solid. !HNMR: (400 MHz, CDCI3) δ: 7.59 (t, / = 8.0 Hz, 1H), 7.27-7.24 (m, 2H), 3.93 (s, 1H), 1.02 (s, 9H).
[00813] Step 6: To a mixture of 43-6 (1.0 g, 3.47 mmol, 1.0 eq.) in DMF (10 mL) at room temperature was added dimethylamine hydrochloride (0.34 g, 4.14 mmol, 1.2 eq.), DIEA (1.34 g, 10.47 mmol, 3.0 eq.) and HATU (1.9 g, 5.2 mmol, 1.5 eq.). The resulting mixture was stirred at room temperature overnight. TLC (PE:EA = 4:1) showed the reaction was complete. The mixture was poured into H20 (50 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and concentrated to give 43-7. *HNMR: (400 MHz, CDC13) δ: 7.63 (t, / = 8.4 Hz, 1H), 7.28-7.24 (m, 2H), 4.10 (s, 1H), 2.98 (s, 3H), 2.90 (s, 3H), 1.04 (s, 9H).
[00814] Step 7: To a mixture of 43-7 (1.0 g, 3.16 mmol, 1.0 eq.), HCOOLi (733 mg, 12.64 mmol, 4.0 eq), TEA (1.27 g, 12.64 mmol, 4.0 eq.) in DMF (40 mL) was added Pd(OAc)2 (63 mg, 0.32 mmol, 0.1 eq.) and Xantphos (189 mg, 0.63 mmol 0.2 eq.) under N2. Ac20 (1.27 g, 12.64 mmol, 4.0 eq.) was then added into the mixture under N2. The resulting mixture was stirred at 90 °C overnight. TLC (PE:EA = 3:1) showed the reaction was complete. The mixture was poured into water (50 mL), basified to pH = 12 by solid NaOH, and washed with EtOAc (20 mL x 2). The aqueous phase was acidified to pH = 3 by 3M aq. HC1, and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over anhydrous Na2S04, concentrated to give the crude 43-8 as a yellow oil which was directly used in the next step without further purification.
[00815] *HNMR: (400 MHz, CDC13) δ: 7.84-7.83 (m, 2H), 7.77-7.75 (m, 1H), 4.21(s, 1H), 4.01 (d, / = 12.0 Hz, 2H), 3.00 (s, 3H), 2.93 (s, 3H), 1.04 (s, 9H).
[00816] Step 8: To a mixture of crude compound 43-8 (660 mg) in MeOH (10 mL) was added dropwise SOCl2 (1 mL). The resulting mixture was stirred at reflux overnight. TLC (PE:EA = 2:1) showed the reaction was complete, After evaporation to remove the solvent, the residue was dissolved in EA (10 mL), washed with saturated aqueous NaHCC>3 (10 mL) and brine (10 mL), dried over anhydrous Na2S04 and concentrated in vacuum to give the crude product which was purified by column chromatography (eluent: PE/EA = 10/1) to give the product 43-9 as an oil.
[00817] *HNMR: (400 MHz, CDC13) δ: 7.82-7.71 (m, 3H), 4.20 (s, 1H), 3.93 (s, 3H), 2.99 (s, 3H), 2.93 (s, 3H), 1.06 (s, 9H).
[00818] Step 9: To a mixture of 43-9 (240 mg, 0.88 mmol, 1.0 eq.) in THF (10 mL) was added LAH (67 mg, 1.76 mmol, 2.0 eq.) in portions at -30 °C. The resulting mixture was stirred at this temperature for 3 h. TLC (PE:EA = 30:1) showed the reaction was complete. Then the reaction was quenched by slow addition of H20 (0.1 mL) at -30 °C, 15% aq. NaOH (0.1 mL) and H20 (0.3 mL) were added in turn, the resulting mixture was stirred at room temperature for 30 min and then filtered. The filtrate was concentrated to give the crude product 43-10 as a white solid, which was directly used in the next step without further purification. *HNMR: (400 MHz, CDC13) δ: 7.66 (t, / = 8.0 Hz, 1H), 7.12-7.09 (m, 2H), 4.70(s, 2H), 4.12 (s, 1H), 3.76-3.60 (m, 1H), 2.98 (s, 3H), 2.91 (s, 3H), 1.05 (s, 9H).
[00819] Step 10: To a mixture of compound 43-10 (220 mg, 0.786 mmol, 1.0 eq.) in DCM (20 mL) was added PPh3 (309 mg, 1.180 mmol, 1.5 eq.) and CBr4 (394 mg, 1.18 mmol, 1.5 eq.) under N2. The mixture was stirred at room temperature for 4 h. TLC (PE:EA = 3:1) showed the reaction was complete. Then the mixture was concentrated to give the residue. The residue was purified by column chromatography (eluent: PE/EA = 10/1) to give 43- 11 as an oil.
[00820] *HNMR: (400 MHz, CDC13) δ: 7.70 (t, / = 8.0 Hz, 1H), 7.15-7.10 (m, 2H), 4.47 (s, 2H), 4.14 (s, 1H), 3.00 (s, 3H), 2.92 (s, 3H), 1.05 (s, 9H).
[00821] Step 11: To a mixture of 43-11 (65 mg, 0.20 mmol, 1.0 eq.) in DMF (5 mL) was added sodium 4-chlorobenzenesulfinate (47 mg, 0.24 mmol, 1.2 eq.). The mixture was stirred at room temperature for 3 h. TLC (PE:EA = 3:1) showed the reaction was complete. The mixture was diluted with H20 (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated to give 43-12 (60 mg) as a white solid.
[00822] LCMS (ESI): (M+H: 426).
[00823] Step 12: To a mixture of 43-12 (60 mg, 0.14 mmol, 1.0 eq.) and NaH (22 mg, 0.56 mmol, 4.0 eq., 60% dispensed in mineral oil) in THF (10 mL) was added l-bromo-2-(2- bromoethoxy)ethane (82 mg, 0.35 mmol, 2.5 eq.) at room temperature. The resulting mixture was stirred at 75 °C for 12 h. TLC (PE:EA = 3:1) showed the reaction was complete. The reaction was then quenched with H20 (10 mL) and extracted with EtOAc (10 mL x 3). Then combined organic layers were dried over anhydrous Na2S04i concentrated and purified by preparative HPLC (Mobile phase A: water with 0.05% HC1, Mobile phase B: acetonitrile; Column: synergi Max-RP 150 x 30 mm x 4 um; Detection wavelength: 220 nm) to give
Example #236 as a white solid. *HNMR: (400 MHz, CDC13) δ: 7.66 (t, 7 = 8.0 Hz, 1H), 7.29-7.22 (m, 4H), 7.04 (dd, 7 = 10.0 Hz, 1.6 Hz, 1H), 6.85 (d, 7 = 8.0 Hz, 1H), 4.16 (s, 1H), 3.99-3.96 (m, 2H), 3.36 (t, 7 = 11.6 Hz, 1H), 3.03 (s, 3H), 2.94 (s, 3H), 2.59 (t, 7 = 4.0 Hz, 2H), 2.37-2.32 (m, 2H), 1.05 (s, 9H). LCMS(ESI): (M+H: 496).
[00824] Example #237: was prepared as described in Scheme 43, except using pyrrolidine in step 6. *HNMR: (400 MHz, CDC13) δ: 7.82 (t, 7 = 8.0 Hz, 2H), 7.31-7.25 (m, 4H), 7.05 (d, 7 = 10.4 Hz, 1H), 6.88 (d, 7 = 8.0 Hz, 1H), 4.03-3.98 (m, 3H), 3.61-3.53 (m, 2H), 3.42-3.32 (m, 4H), 2.64 (t, 7 =11.6 Hz, 2H), 2.39 (t, 7 =10.0 Hz, 2H), 2.09-1.84 (m, 4H), 1.07 (s, 9H).
LCMS(ESI): (M+H: 522).
[00825] Assay 1: Biochemical GST-RORy TR-FRET assay
[00826] Assay 1 is a method that measures the disruption or activation of co-activator peptide/RORy binding by quantifying the ability of molecules to inhibit or enhance the activity of RORy.
[00827] RORy TR-FRET Assay Reagents Name Units/Amount Source Catalog Number Storage
Biotin-TRAP220 (500 μΜ) Anaspec Custom -80 °C
Biotin-
PVS SM AGNTKNHPML MNLLKDNPAQ
GST-RORy (14.74μΜ) Biogen Idee. In-house -80 °C (LBD)
DMSO 100% Fisher D128-500 RT
Streptavidin 13.7uM SA Prozyme PJ25S 4 °C, in the
Allophycocyanin (2.15 mg/ml) dark
(SA-APC)
Lance Eu- 473μg/ml Perkin Elmer AD0254 4 °C W1024 Anti (2.96μΜ)
GST
[00828] RORy TR-FRET Assay Buffer Components
Figure imgf000221_0001
Figure imgf000221_0002
[00830] Final conditions for RORy FRET Assay: (20 μL· of compound + 5 μί of detection mix = 25 μΕ total assay volume): 20 mM Tris-HCl pH 7.0, 60 mM NaCl, 5 mM MgCl2, ImM DTT, 0.1%BSA; 10 nM GST-RORy (LBD); 400nM Biotin-TRAP220; 50nM SA-APC; 1.5nM Eu-Anti GST IgG; 1.0% DMSO.
[00831] Assay Protocol:
[00832] Compound dilutions were prepared (125x final test concentrations) by making a 6.25 mM dilution from a 10 mM stock using 100% DMSO. Three-fold dilutions of the compounds were then prepared for nine points beyond the 6.25 mM starting concentration (6.25, 2.083, 0.6944, 0.2315, 0.0772, 0.0257, 0.00857, 0.00286, 0.00095, and 0.00032 mM). For example, 15 μί of 10 mM of the compound was added into 9 μL· of DMSO, and 10 μL· of the resulting solution was titrated into 20 μL· of DMSO. A 5x detection mix was prepared to the required volume (5 μυτ&Άθύο well + overage) by adding 5x the final concentrations of GST-ROR-gamma, Eu-Anti GST antibody, Biotin-TRAP220, and SA-APC in assay buffer containing 1% DMSO. Five μΕ per well of the 5x detection mix was added to a black 384 well assay plate. Then, 1 μΕ of 125x of the test compound in 100% DMSO was added into 99 μΕ of assay buffer in the compound buffer dilution greiner plate to result in a final DMSO concentration of 1%. Assay controls (0% inhibition and 100% inhibition controls) were added into columns 1,12, 13, and 24 of the 384 well dilution greiner plate. For the 0% inhibition control, 1 μΕ of 100% DMSO was added into 99 μΕ of assay buffer. For the 100% inhibition control, 1 μΕ of 3.125 mM T0901317 (125x 25 μΜ final concentration) was added. The compound was mixed and 20 μΕ of the compound was transferred to the assay plate containing 5 μΕ of 5x detection mix. The plate was shaken for one minute, centrifuged at 1000 rpm for 10 seconds, incubated at room temperature for 60 minutes, and read on a plate reader. The LJL Analyst settings were as follows: Ratio: acceptor/donor; Acceptor:
HRTF(Packard); Excitation: Europium FRET 330nm; Emission: FRET acceptor 665nm; Donor: HRTF(Packard); Excitation: Europium FRET 330nm; Emission: FRET chelate donor; Flashes/well: 100; Intergration time: 400 μ8; Interval between: 1x10 ms flashes; Delay after flash: 50 μ8.
[00833] Data analysis:
[00834] The RORy FRET assay is an end point assay with a readout (emission ratio) of acceptor/donor* 1000. The assay dose response testing is performed in duplicate points per concentration, with ten dilution concentrations per compound curve. The conversion of raw data to % Activity is performed using assay controls, where 100% Activity is represented by the average DMSO controls. Zero percent Activity is the average of the 25 μΜ, T0901317 compound controls. IC curve fitting is performed using graphpad prism, and fitting to the sigmoidal dose-response (variable slope) equation as follows:
Y=Bottom + (Top-Bottom)/(l+10A((LogEc5o-X)*HillSlope)); where X is the logarithm of concentration and Y is the response (Y begins at the Bottom and goes to Top with a sigmoid shape, which is identical to the "four parameter logistic equation")
[00835] In the final assay plate setup, there were sixteen compounds per 384 well plate. The DMSO controls (0% Inhibition) were in columns 1 and 13. The 25 μΜ T0901317 controls (100% Inhibition) were in columns 12 and 24. The compound titrations were in columns 2- 11 , 14-23. Ten-point IC50 curves were generated with n=2 per concentration.
[00836] Assay 2: Protocol of the ROR Gal4 cellular reporter assay 293T cells
[00837] Cell Cultivation.
Figure imgf000223_0001
[00838] Cells were used for transactivation assays following 2 to 3 passages after thawing from liquid nitrogen. The freeze medium was culture medium supplemented with DMSO to 10%. The routine culture includes two weekly passages. The cells were discarded after 4-6 weeks in assay production. For transactivation assay purposes, the cells were grown to subconfluence (80-90%).
[00839] Subcultivation of 293T cells. Cells were seeded in a T75 cm2 flask in 20 mL of culture medium by adding 50 mL of FBS, 5 mL of Glutamax, 5 mL of NEAA, 5 mL of Sodium Pyruvate, and 5 mL of Pen/Strep to a 500 mL MEM bottle (with phenol red). The cells were grown at 37 °C in the presence of 5% C02 until they reached subconfluence (80-90%), at which point the culture medium was discarded. PBS (about 5 mL per flask) was added to the flask at room temperature, and the cells were detached by tapping the flask. The viable cells were counted, the desired number of cells was transferred into a new flask, and the volume of the new flask was completed with new culture medium (final volume: 20 mL in a T75 cm2 flask). The flasks were incubated at 37°C under 5% of C02.
[00840] Performance of the ROR Gal4 cellular reporter assays. On Day 1, cells were seeded in 96 well plates in plating medium (MEM w/o phenol red, 10% CCDS). On Day 2, the plating medium was removed and the cells were transfected. About 4-6 hours after transfection, assay medium (MEM without phenol red and serum) was added, and then the compounds were added. On Day 3, the cells were lysed, lucif erase buffers were added, and luminescence was measured in a dual-flash procedure.
[00841] Seeding cells. For each assay point, 50,000 293T cells per well of a 96 well white walled, clear bottom assay plate were used. Cells were plated in plating medium by adding 50 mL of CCDS, 5 mL of Glutamax, 5 mL of NEAA, 5 mL of Sodium Pyruvate, and 5 mL Pen/Strep to a 500 mL MEM bottle (without phenol red). Trypsinate cells were used for plating to ensure reproducibility of the process. After one washing step with about 10 mL of PBS, 1.5 mL of Trypsin-EDTA solution (Sigma-Aldrich; T3924) was added. After 2 to 3 minutes, the flask was tapped and 8 mL of culture medium was added. The cells were spun down for 2 minutes at 200xg, the supernatant was discarded, and the cells were resuspended in a small volume by pipetting the suspension up and down more than 10 times. As cells tend to form clumps, special care must be taken to separate cells from each other. Cells were then counted and plated with 50,000 cells per well in 100 μL· plating medium. The 96 well assay plates were incubated overnight at 37 °C with 5% C02 in a humidified atmosphere.
[00842] Transfection. The transfection was carried out using a PEI solution generated at Phenex, with 71 ng total DNA per well (50 ng of nuclear receptor expressing plasmid plus 20 ng of pFR-Luc reporter and 0.5 ng of pRL-CMV reporter for each well). The DNA:PEI- solution ratio is 1 :5 ^g^L), with a PEI concentration of 0.45 μg/μL, and a DNA:PEI ratio of 1 :2.25 (μ8/μ8).
[00843] The DNA solution was prepared by diluting the DNA in OptiMEM and gently vortexing. Enough solution should be prepared for \5μL· of DNA mix per well. For the experiments described herein, a 16% excess was used. For example, for one assay plate, 2.24 μg of Firefly Luciferase reporter plasmid (pFR-Luc), 5.6 μg of NR expression vector (pCMV-BD-nuclear receptor), and 56 ng of Renilla Luciferase reporter plasmid was used. These DNA amounts were diluted in 1680 μΐ, OptiMEM.
[00844] The PEI-solution was prepared by diluting the PEI in the same volume of
OptiMEM. The amount of PEI-solution was calculated using the following formula: μg of DNA x 5. For the experiments described herein, a 16% excess was used. For example, for one assay plate, 39.8 μL· of PEI-solution was diluted in 1640 μL· of OptiMEM.
[00845] The transfection mix was generated by immediately adding the PEI-solution to the plasmid solution (the plasmid solution was not added to the PEI-solution), vortexing gently, and incubating the resulting solution for a minimum of 20 minutes at room temperature. [00846] The plating medium is removed from the cells by dumping the plate and tapping dry on paper towels.
[00847] The transfection mix (PEI + DNA) was added to the adherent cells. The 96 well assay plates were incubated for 4-6 hrs at 37 °C with 5% C02 in a humidified atmosphere.
[00848] Compound treatment and enzyme activity measurement. The master DMSO compound plate was made by diluting the compounds from the 10 mM stock in column 11, and then diluting in a ratio of 1 :3 across the plate to column 4. Column 3 contained DMSO only (high control), and column 3 contained 2.5 mM Tularik control (low). The compounds were at 1000X.
[00849] To a new 96- well plate, 132 μL· of plating media (with CCDS) was added to every well. Then, 1 μL· was transferred from each well of the DMSO compound plate to the corresponding well of the new dilution plate. The DMSO concentration was 7.5% and the compounds were 7.5X. The plate was covered and mixed on a plate shaker. About 4-6 hours after adding the transfection solution, 100 μL· of assay medium was added to the cells. The assay medium was prepared by adding 5mL of Glutamax, 5 mL of NEAA, 5 mL Sodium Pyruvate, and 5 mL Pen/Strep to a 500ml MEM bottle (w/o phenol red). Exactly 20 μΕ of the compounds from the new dilution plate were added to the cells in triplicate. Although all of the wells on the edge of plate were excluded from analysis due to edge effects, they should all contain the same final volume of media: 150μΕ (1.3% CCDS, 0.1% DMSO and IX compound). The cells were incubated at 37 °C with 5% C02 in a humidified atmosphere for 16 to 20 hours. After the incubation, the medium was completely removed by dumping and tapping the plate dry on paper towels. Exactly 20 μΕ of lx Passive Lysis Buffer (Promega) was added and the plates were incubated at room temperature on a plate shaker for 10-15 min.
[00850] The measurement was performed using a BMG LUMIstar OPTIMA luminescence plate reader. First, 75 μL· per well of Firefly lucif erase buffer was injected. Exactly 1.1 seconds after the start of the Firefly buffer injection, 75 μL· per well of Renilla lucif erase buffer was injected. The complete measurement time was 2 seconds per well. For the direct firefly measurements, the average of the values 7-11 (0.6 to 1 sec) was used. For the direct renilla measurements, the average of the values 16-20 (1.5 to 1.9 sec) was used.
[00851] Materials and equipment used for ROR Gal4 cellular reporter assays. All plasmids used for the transfection of 293T cells were prepared with QIAGEN Maxi, Giga or Mega Kits and were eluted and diluted with MilliQ water. [00852] Firefly Luciferase Buffer
Figure imgf000226_0001
[00853] Renilla Luciferase Buffer
Figure imgf000226_0002
[00854] Materials.
Name Company Cat.No
293T cells DSMZ ACC635
MEM (with Phenol Red) Sigma Aldrich M2279
MEM (without Phenol Red) Fisher Scientific (Ivtg) VX51200087
OptiMEM Fisher Scientific (Ivtg) VX31985054
FBS Sigma Aldrich F7542
CCDS Perbio (HyClone) SH30068.03
Glutamax Invitrogen 35050038
Pen/Strep Sigma Aldrich P4333
Sodium Pyruvate Sigma Aldrich S8636
Non Essential Amino Acids (NEAA) Sigma Aldrich M7145
PBS Sigma Aldrich D8537
PEI Sigma Aldrich 408727
DMSO Sigma Aldrich 41648
Passive Lysis Buffer (5x) Promega E1941
D-Luciferine PJK 260150
Coelentrazine PJK 260350 EGTA Sigma Aldrich E3889
ATP Sigma Aldrich A26209
AMP Sigma Aldrich 01930
BSA (fraction V) Serva 11930.04
T75 Flasks NUNC 353136
U-bottom 96 well plates Greiner 650101
96 well assay plates Corning 3903
[00855] Equipment.
Name Company Type
LUMIstar OPTIMA BMG (with two Reagent Injectors)
Pipetting Robot BioTek Precision XS
[00856] ROR-gamma has been implicated in the development and function of lymphoid tissue inducer cells, thymocytes, γδ T cells, natural killer cells, and both cytotoxic and helper αβ T cells. These cell types and soluble factors produced by these cells, including the cytokines IL-17, IL-17F and IL-26, have been demonstrated to contribute to autoimmune pathology in numerous animal models of disease and have been implicated in the
pathogenesis of human immune-mediated diseases. Modulators of ROR-gamma block the development of these pathogenic cell types and the proinflamatory cytokines they produce. Such action provides therapeutic benefit to the immune mediated diseases in which these cells act.
[00857] The compounds are modulators of ROR-gamma activity against the nuclear receptor. Most of the compounds of the invention have IC50 values of less than 1 μΜ, and others have IC50 values as low as 0.100 μΜ, still others have IC50 values as low as 0.010 μΜ, as determined by the Biochemical GST-RORy TR-FRET assay. Additional information is provided in the Table below.
Ex # Fret IC50 Ex # Fret IC50 Ex # Fret IC50 Ex # Fret IC50 (2.5nM (2.5nM (2.5nM (2.5nM 1 XKD) 1 XKD) 1 XKD) 1 XKD) (μΜ) (μΜ) (μΜ) (μΜ)
1 E 45 E 89 E 133 E
2 C 46 E 90 E 134 C
3 D 47 E 91 E 135 E
4 E 48 D 92 E 136 D
5 D 49 F 93 F 137 E
6 E 50 E 94 E 138 D
7 C 51 C 95 D 139 E
8 E 52 E 96 D 140 E
9 D 53 C 97 F 141 D
10 C 54 D 98 F 142 C
11 B 55 E 99 C 143 D
12 C 56 B 100 E 144 C
13 D 57 E 101 E 145 D
14 C 58 E 102 A 146 D
15 D 59 D 103 E 147 C
16 D 60 D 104 E 148 C
17 C 61 D 105 E 149 c
18 D 62 F 106 D 150 c
19 D 63 D 107 D 151 c
20 A 64 D 108 D 152 E
21 D 65 F 109 E 153 E
22 D 66 D 110 C 154 D
23 C 67 F 111 C 155 E
24 E 68 F 112 C 156 E
25 D 69 E 113 E 157 C
26 D 70 F 114 D 158 E
27 C 71 F 115 E 159 C
28 E 72 E 116 E 160 E
29 E 73 F 117 F 161 E
30 C 74 F 118 E 162 F
31 A 75 E 119 E 163 F
32 D 76 E 120 E 164 D
33 A 77 E 121 E 165 E
34 D 78 F 122 D 166 E
35 A 79 D 123 E 167 E
36 C 80 D 124 E 168 E
37 A 81 F 125 D 169 F
38 C 82 D 126 D 170 E
39 A 83 F 127 D 171 E
40 C 84 F 128 D 172 E
41 D 85 D 129 C 173 E
42 D 86 E 130 D 174 E
43 E 87 E 131 D 175 D
44 A 88 F 132 C 176 E
227
13041377.4 Ex # Fret IC50 Ex # Fret IC50 (2.5nM (2.5nM 1 XKD) 1 XKD) (μΜ) (μΜ)
177 F 221 E
178 E 222 E
179 F 223 E
180 E 224 E
181 E 225 D
182 E 226 D
183 E 227 E
184 D 228 E
185 C 229 E
186 D 230 D
187 D 231 D
188 D 232 E
189 C 233 E
190 C 234 E
191 D 235 D
192 D 236 D
193 A 237 D
194 C 238 E
195 D 239 E
196 D 240 F
197 E
198 E
199 E
200 D
201 F
202 C
203 D
204 E
205 C
206 D
207 E
208 F
209 D
210 E
211 E
212 E
213 F
214 E
215 C
216 E
217 E
218 D
219 D
220 E [00858] In the foregoing Table, IC50 data is represented as follows: greater than or equal to 20 microMolar is designated at A; less than 20 microMolar but greater than or equal to 10 microMolar is designated as B; less than 10 microMolar but greater than or equal to 1 microMolar is designated at C; less than 1 microMolar but greater or equal to 100 nanoMolar is designated as D; less than 100 nanoMolar but greater or equal to 10 nanoMolar is designated as E; and less than 10 nanoMolar is designated as F.
[00859] Assay 3: RORy Splenocyte IL-17
[00860] Reagents and buffer used in RORy Splenocyte IL-17 assay
Figure imgf000230_0001
Figure imgf000230_0002
[00861] Equipment and Materials.
Figure imgf000230_0003
229
13041377.4 96 well plate for ELISA Costar, # 3590
Mouse IL-17 DuoSet ELISA Development R & D systems, # Dy421
kit
Microplate Spectrophotometer SpectraMax® Plus 384
70 μιη Nylon Cell Strainer BD Falcon, # REF 352350
Centrifuge Eppendorf, # Centrifuge 5702R
Swing-bucket rotor for Centrifuge 5702 Eppendorf, # A-4-38
[00862] Assay Protocol.
[00863] Day -1. The round-bottom 96 well plate (Corning, # 3799) was coated with 10 μg per mL of anti-mCD3e in PBS (50 μΕ per well) and stored at 4 °C overnight.
[00864] Day 0. The primary compound dilutions (lOOOx final test concentrations) were prepared in a 96 well polypropylene plate (Greiner Bio-one, # 651201) by making a 5 mM dilution from a 10 mM stock using 100% DMSO. Three-fold dilutions of the compounds were then prepared for seven points beyond the 5 mM starting concentration (5, 1.667, 0.556, 0.185, 0.062, 0.021, 0.007, and 0.002 mM). For example, 10 μΕ of 10 mM compound was added into 10 μΕ of DMSO, of which 8 μΕ was titrated into 16 μΕ of DMSO. The plate was covered and stored in a hood at room temperature.
[00865] The splenocytes were then prepared. Spleens from 3 wild type C57BL/6 mice were harvested, and then dissociated using a syringe plunger with a 70 μιη cell strainer (BD Falcon, # REF 352350) on a 50 mL tube. The cells were rinsed through the strainer using about 20 mL RPMI, and then centrifuged for 5 minutes at 0.3 rcf (1300 rpm, Eppendorf, # Centrifuge 5702R, # rotor A-4-38). The supernatant was discarded. The pellet was dispersed and properly resuspended by tapping the tube and adding to the pellet 1 mL of lysis buffer per spleen. After incubation at room temperature for 5 minutes, the cells were centrifuged for 5 min at 0.3 rcf and the supernatant was discarded. The cells were resuspended in 5 mL RPMI and counted. The cell concentration was then adjusted to 5xl06 cells per mL. Anti- mCD3e were aspirated from the wells, and 100 μL· per well of the cells were coated in a 96 well plate (Corning, #3799).
[00866] A mixture of cytokines and antibody in RPMI (5% excess) was prepared: 1 ng/mL TGF-b, 10 ng/mL IL-6, 0.625 ng/mL IL-23, 5 μ^πιΐ anti-mCD28. To each well was added 90 μΐ of the cytokines antibody mixture, to result in a total volume of 190 μΐ per well.
[00867] Exactly 5 μΐ, of the diluted compound was added to the 245 μΐ, RPMI, the solution was mixed, and \0 μL was transferred to each well. The final volume for each well was 200 UL, resulting in a final concentration of 5, 1.667, 0.556, 0.185, 0.062, 0.021, 0.007, 0.002 μΜ for each compound. Control wells were prepared by adding 7 μΐ 100% DMSO into 343 μΐ RPMI for the DMSO high controls, and 2.5 μΜ T0901317 for the low controls (prepared by adding 4 of 5 mM T0901317 stock to 4 μΐ. DMSO, mixing the solution, and then add 7 μΐ. into 343 μΐ RPMI). The cells were incubated at 37 °C in C02 incubator for 2 days.
[00868] Day 2. The supernatant was collected at stored at -20 °C. The IL- 17 cytokine level from the supernatant was then determined using the Mouse IL-17 DuoSet ELISA
Development kit. Assay dose response testing was performed in triplicate points per concentration using eight dilution concentrations per compound curve. The conversion of raw data to % Activity was performed using assay controls, where 100% Activity was represented by the average DMSO controls, and 0% Activity was the average of the 2.5 μΜ T0901317 compound controls. EC50 curve fitting was performed using graphpad prism and fitting to the sigmoidal dose-response (variable slope) equation as follows: Y = Bottom + (Top-Bottom)/(l+10A((LogEC50-X)*HillSlope)), with all of the variables as previously described.

Claims

What is claimed is:
1. A compound of Formula I:
Figure imgf000233_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000233_0002
X is SO or S02;
A1, A2, A3, and A4 are each independently C or N;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R2 and R3 are each independently H, optionally substituted alkyl, optionally substituted C3_s cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R2 and R3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
R4a, R4b, R4c, and R4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N; R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl;
R5a and R5b are each independently H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl;
R6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl; R6a and R6b are each independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or R6a and R' together form an optionally substituted heterocycloalkyl ring; or
R40 and R6 taken together form an optionally substituted heterocyclic ring.
2. The compound of claim 1 , wherein the compound of Formula I is Formula la:
Figure imgf000234_0001
Formula la
or pharmaceutically acceptable salts thereof, wherein:
X is SO or S02;
A1, A2, A3, and A4 are each independently C or N;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R2 and R3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R2 and R3 together form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;
R4a, R4b, R4c, and R4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N; R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl;
R6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or R^ and R6 taken together form an optionally substituted heterocyclic ring.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R^ and R6 taken together form an optionally substituted heterocyclic ring.
4. The compound of claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula la is Formula la1:
Figure imgf000235_0001
Formula la1
or a pharmaceutically acceptable salt thereof,
wherein:
W1 is CR7a, R7b, NR7c, or O;
W2 and W3 are each independently CR7aR7b, NR7c, O, or a bond; and
R7a , R7b, and R7c are each independently H or Ci_4 alkyl.
5. The com ound of claim 1, wherein the com ound of Formula I is Formula lb:
Figure imgf000235_0002
Formula lb
or pharmaceutically acceptable salts thereof, wherein: X is SO or S02;
A1, A2, A3, and A4 are each independently C or N;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R2 and R3 are each independently H, optionally substituted alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted alkoxyl, amino, CN, OH, or R2 and R3 together form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
R4a, R4b, R4c, and R4d are each independently H, optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, halogen, amino, CN, OH, or absent when the ring atom to which they are bound is N;
R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R6 is H, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or
R40 and R6 taken together form an optionally substituted heterocyclic ring.
6. The compound of claim 2 or 4, or 5, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein A1, A2, and A4 are each C;
A1 and A2 are each C, and A4 is N;
A1 and A4 are each C, and A2 is N; or
A2 and A4 are each C, and A1 is N.
8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein X is S02.
9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted carbocyclyl, and R5 is optionally substituted alkyl, optionally substituted heterocyclyl, or optionally substituted carbocyclyl.
10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R4a, R4b, and R4d are each independently H, halogen, optionally substituted alkyl or absent.
11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl.
12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl, unsubstituted or substituted with halogen.
13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein: R2 and R3 together form optionally substituted cycloalkyl, optionally substituted
cycloalkenyl, optionally substituted cycloketonyl, optionally substituted heterocyclyl, optionally substituted spirocyclyl, or optionally substituted bicyclyl;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, oxo, carboxyl, acetyl, alkyl-OH, haloalkyl, and -(alkyl-Q)n-alkyl, wherein each Q is independently O, NH, or N(C1-4 alkyl), and n is 1 or 2.
14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein, R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, or carboxyl.
15. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R40 is H, optionally substituted Ci_6 alkyl, optionally substituted OCi_6 alkyl, optionally substituted carbocycle, halogen, CN, OH, or absent; and
R6 is optionally substituted alkyl, optionally substituted C2-6 alkenyl, optionally substituted alkoxyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl.
16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.
17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, and A4 are each C;
A1, A2, and A4 are each C, and A3 is N;
A1, A3, and A4 are each C, and A2 is N;
A1 and A4 are each C and A2 and A3 are each N; or A3 and A4 are each C and A1 and A2 are each N.
18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein X is S02.
19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R1, are each independently optionally substituted alkyl, optionally substituted carbocycle, or optionally substituted heterocyclyl.
20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R4a, R4b, R40, R4d are each independently H, halo, optionally substituted alkyl or absent.
21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted phenyl.
22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl, unsubstituted or substituted with halogen.
23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form cycloalkyl, cycloalkenyl, cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl;
wherein each of the foregoing moieties is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, oxo, amino, carboxyl, acetyl, alkyl-OH, haloalkyl, and -(alkyl-Q)n-alkyl, wherein each Q is independently O, NH, or N(C1-4 alkyl), and n is 1 or 2.
24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein, R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, or carboxyl.
25. The compound of claims 1-13 or 15-23, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form a ring selected from any of the following formulas:
Figure imgf000239_0001
26. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein:
R2 and R3 together form cycloalkyl, cycloalkenyl, cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, oxo, amino, carboxyl, acetyl, alkyl-OH, haloalkyl, and -(alkyl-Q)n-alkyl, wherein each Q is independently O, NH, or N(Ci^ alkyl), and n is 1 or 2.
27. The compound of claim 6 or 26, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_4 alkyl, OCi_4 alkyl, OH, F, CI, Br, amino, and carboxyl.
28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, C2H5, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and Br.
29. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more substituents selected from the group consisting of CH3, C2H5, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and -(alkyl-Q)n-alkyl, wherein each Q is independently O, NH, or N(Ci_4 alkyl), and n is 1 or 2.
30. The compound of claim 6 or 26, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, N-C1-2 alkyl azetidine, N-C1-2 alkyl pyrrolidine, N-C1-2 alkyl piperidine, N-acetylazetidine, N-acetylpyrrolidine, or N-acetylpiperidine;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, N-C1-2 alkyl pyrrolidine, N-C1-2 alkyl piperidine, N-acetylpyrrolidine, or N-acetylpiperidine;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, OCH3, OH, F, and CI.
32. The compound of claim 6 or 26, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form cyclobutanone, cyclopentanone, cyclohexanone, or cycloheptanone; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form cyclobutanone, cyclopentanone, or cyclohexanone; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, C2H5, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and Br.
34. The compound of claim 6 or 26, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[2.5]octanyl, spiro[2.6]nonanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl,
spiro[3.6]decanyl, spiro[4.4]nonanyl, spiro[4.5]decanyl, spiro[4.6]undecanyl,
spiro[5.5]undecanyl, spiro[5.6]dodecanyl, or spiro[6.6.]tridecanyl;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[2.5]octanyl,
spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl,
spiro[4.5]decanyl, or spiro[5.5]undecanyl;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C¾, C2H5, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and Br.
36. The compound of claim 6 or 26, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl,
bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[5.1.0]octyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[5.2.0]nonyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[5.3.0]decyl, bicyclo[4.4.0]decyl, bicyclo[5.4.0]undecyl, or bicyclo[5.5.0]dodecyl;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, or bicyclo[4.4.0]decyl;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, C2H5, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and Br. The compound of claim 6 or 26, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form:
Figure imgf000242_0001
39. The compound of any one of claims 6, 26 or 38, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form:
Figure imgf000242_0002
40. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently H, optionally substituted Ci_6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted OCi_6 alkyl, CN, or OH.
41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently H, C1-4 alkyl, C3-6 cycloalkyl, OC1-4 alkyl, CN, or OH;
wherein each of the C1-4 alkyl, C3-6 cycloalkyl, and OC1-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-2 alkyl, OC1-2 alkyl, OH, halogen, amino, and carboxyl.
42. The compound of claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently H, C1-2 alkyl, OCi_3 alkyl, or OH;
wherein each of the C1-2 alkyl and OC1-2 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, OCH3, F, CI, and Br.
43. The compound of any one of claims 40-42, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each CH3.
44. The compound of any one of claims 1-10 or 26-43, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted alkyl.
45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R1 is Ci-5 alkyl;
wherein the C1-5 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
46. The compound of any one of claims 1-10 or 26-43, or a pharmaceutically acceptable salt thereof, wherein R1 is C2-6 alkenyl;
wherein the C2_6 alkenyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
47. The compound of any one of claims 1-10 or 26-43, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl.
48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
49. The compound of claim 47 or 48, or a pharmaceutically acceptable salt thereof, wherein R1 is cyclopentyl or cyclohexyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_4 alkyl, fluoroalkyl hydroxyl, OCi_4 alkyl, carboxyl, amino, and halogen.
50. The compound of any one of claims 1-10 or 26-43, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted heterocyclyl.
51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein R1 is aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide,
tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine;
wherein each of the foregoing moieties is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
52. The compound of any one of claims 1-10 or 26-43, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted aryl or optionally substituted heteroaryl.
53. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein R1 is pyrrole, furan, thiophene, isothiophene, phenyl, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl, pyridine, pyrimidine, or pyrazine;
wherein each of the foregoing moieties is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, cyano, alkoxyl, haloalkoxyl, carboxyl, amino, and halogen.
54. The compound of claim 52 or 53, or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OCi_4 alkyl, CF3, OCF3, F, CI, and CN.
55. The compound of any one of claims 1-10 or 26-43, or a pharmaceutically acceptable salt thereof, wherein R1 is:
Figure imgf000245_0001
56. The compound of any one of claims 1-10, 26-43 or 55, or a pharmaceutically acceptable salt thereof, wherein R1 is:
Figure imgf000245_0002
57. The compound of any one of claims 4-6 or 26-56, or a pharmaceutically acceptable salt thereof, wherein:
A1, A2, and A4 are each C; and
R4a, R4b, and R4d are each H, optionally substituted C1-4 alkyl, optionally
substituted OCi^ alkyl, halogen, or OH.
58. The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein R4a, R4b, and R4d are each independently Ci_3 alkyl, OCi_3 alkyl, F, CI, Br, or OH; wherein the Ci-3 alkyl and OC1-3 alkyl are each optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
59. The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein R4a, R4b, and R4d are each independently H, CH3, C2H5, OCH3, OC2H5, CH3, CF3, OCF3, F, CI, or OH.
60. The compound of claim 57 or 58, or a pharmaceutically acceptable salt thereof, wherein R4a, R4b, and R4d are each H.
61. The compound of any one of claims 1-6 or 26-56, or a pharmaceutically acceptable salt thereof, wherein:
A1 and A2 are each C, and A4 is N;
R4a and R4b are each independently H, optionally substituted Ci^ alkyl, optionally substituted OCi-4 alkyl, halogen, or OH; and
R4d is absent.
62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R 4a and R4b are each independently H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
63. The compound of any one of claims 1-6 or 26-56, or a pharmaceutically acceptable salt thereof, wherein:
A1 and A4 are each C, and A2 is N;
R4a and R4d are each independently H, optionally substituted Ci^ alkyl, optionally substituted OCi-4 alkyl, halogen, or OH; and
R4b is absent.
64. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein R4a and R4d are each independently H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
65. The compound of any one of claims 1-6 or 26-56, or a pharmaceutically acceptable salt thereof, wherein:
A2 and A4 are each C, and A1 is N;
R4b and R4d are each independently H, optionally substituted C1-4 alkyl, optionally substituted OCi-4 alkyl, halogen, or OH; and
R4a is absent.
66. The compound of claim 65, or a pharmaceutically acceptable salt thereof, wherein R4b and R4d are each independently H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
67. The compound of any one of claims 1-6 or 26-54, or a pharmaceutically acceptable salt thereof, wherein:
A1 and A2 are each N, and A4 is C;
R4a and R4b are each absent; and
R4d is H, optionally substituted C1-4 alkyl, optionally substituted OC1-4 alkyl, halogen, or OH.
68. The compound of claim 67, or a pharmaceutically acceptable salt thereof, wherein R4d is H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
69. The compound of any one of claims 1-6 or 26-56, or a pharmaceutically acceptable salt thereof, wherein:
A1 and A4 are each N, and A2 is C;
R4a and R4d are each absent; and
R4b is H, optionally substituted C1-4 alkyl, optionally substituted OC1-4 alkyl, halogen, or OH.
70. The compound of claim 69, or a pharmaceutically acceptable salt thereof, wherein R4b is H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
71. The compound of any one of claims 1-6 or 26-56, or a pharmaceutically acceptable salt thereof, wherein:
A2 and A4 are each N, and A1 is C;
R4b and R4d are each absent; and
R4a is H, optionally substituted C1-4 alkyl, optionally substituted OC1-4 alkyl, halogen, or OH.
72. The compound of claim 71, or a pharmaceutically acceptable salt thereof, wherein R4a is H, CH3, C2H5, OCF3, OCH3, OC2H5, F, CI, or OH.
73. The compound of any one of claims 1-6 or 26-56, or a pharmaceutically acceptable salt thereof, wherein:
A1, A2, and A4 are each N; and
R4a, R4b, and R4d are each absent.
74. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl.
75. The compound of claim 74, or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted alkyl.
76. The compound of claim 75, or a pharmaceutically acceptable salt thereof, wherein R is Ci-5 alkyl; wherein the C1-5 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl,
heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
77. The compound of claim 75 or 76, or a pharmaceutically acceptable salt thereof, wherein R5 is C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of F, OC1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxetane.
78. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt thereof, wherein R5 is C2-6 alkenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
79. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted cycloalkyl or optionally substituted cycloalkenj
80. The compound of claim 79, or a pharmaceutically acceptable salt thereof, wherein R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
81. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted heterocyclyl.
82. The compound of claim 81, or a pharmaceutically acceptable salt thereof, wherein R is aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine;
wherein each of the foregoing moieties is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
83. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted aryl or optionally substituted heteroaryl.
84. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted aralkyl or optionally substituted heteroaralkyl.
85. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt
Figure imgf000249_0001
86. The compound of any one of claims 4-85, or a pharmaceutically acceptable salt thereof, wherein:
W1 is CR7aR7b, and W2 and W3 are each CR7aR7b or a bond;
W1 is O, and W2 and W3 are each CR7aR7b or a bond;
W2 is O, and W1 and W3 are each CR7aR7b or a bond; W3 is O, and W1 and W2 are each CR7aR7b or a bond; or
R7a and R7b are each independently H or Ci_3 alkyl.
87. The compound of claim 86, or a pharmaceutically acceptable salt thereof, wherein: W1 and W2 are each CR7aR7b;
W3 is O; and
R7a and R7b are each independently H or CH3.
88. The compound of claim 86, or a pharmaceutically acceptable salt thereof, wherein W1 is C(CH3)(CH3) and W2 is CH2.
89. The compound of any one of claims 1-86, or a pharmaceutically acceptable salt thereof, wherein X is SO.
90. The compound of any one of claims 1-86, or a pharmaceutically acceptable salt thereof, wherein X is S02.
91. The compound of any one of claims 1-2 or claim 5, or a pharmaceutically acceptable salt thereof, wherein:
R^ is H, optionally substituted Ci_6 alkyl, optionally substituted OCi_6 alkyl, optionally substituted carbocycle, halogen, CN, OH, or absent; and
R6 is optionally substituted alkyl, optionally substituted C2_6 alkenyl, optionally substituted alkoxyl, optionally substituted carbocycle, or optionally substituted heterocycle.
92. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form an optionally substituted carbocyclic ring, or an optionally substituted heterocyclic ring.
93. The compound of claim 92, or a pharmaceutically acceptable salt thereof, wherein: R2 and R3 together form cycloalkyl, cycloalkenyl, cycloketonyl, heterocyclyl, spirocyclyl, or bicyclyl;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, alkoxyl, OH, halogen, amino, oxo, carboxyl, acetyl, alkyl-OH, haloalkyl, and -(alkyl-Q)n-alkyl, wherein each Q is independently O, NH, or N(C1-4 alkyl), and n is 1 or 2.
94. The compound of claim 92 or 93, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
95. The compound of claim 94 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, C2H5, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and Br.
96. The compound of claim 92 or 93, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, N-C1-2 alkyl azetidine, N-C1-2 alkyl pyrrolidine, N-C1-2 alkyl piperidine, N-acetylazetidine, N-acetylpyrrolidine, or N-acetylpiperidine;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
97. The compound of claim 96 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, N-C1-2 alkyl pyrrolidine, N-C1-2 alkyl piperidine, N-acetylpyrrolidine, or N-acetylpiperidine; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, OCH3, OH, F, and CI.
98. The compound of claim 92 or 93, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form cyclobutanone, cyclopentanone, cyclohexanone, or cycloheptanone; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
99. The compound of claim 98 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form cyclobutanone, cyclopentanone, or cyclohexanone; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, C2H5, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and Br.
100. The compound of claim 92 or 93, or a pharmaceutically acceptable salt thereof, wherein:
R2 and R3 together form spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[2.5]octanyl, spiro[2.6]nonanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl,
spiro[3.6]decanyl, spiro[4.4]nonanyl, spiro[4.5]decanyl, spiro[4.6]undecanyl,
spiro[5.5]undecanyl, spiro[5.6]dodecanyl, or spiro[6.6.]tridecanyl;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
101. The compound of claim 100 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[2.5]octanyl,
spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl,
spiro[4.5]decanyl, or spiro[5.5]undecanyl;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C¾, C2H5, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and Br.
102. The compound of claim 92 or 93, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl,
bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[5.1.0]octyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[5.2.0]nonyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[5.3.0]decyl, bicyclo[4.4.0]decyl, bicyclo[5.4.0]undecyl, or bicyclo[5.5.0]dodecyl;
wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, OH, F, CI, Br, amino, and carboxyl.
103. The compound of claim 102 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, or bicyclo[4.4.0]decyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH3, C2H5, C3H7, OCH3, OC2H5, OC3H7, OH, F, CI, and Br.
104. The compound of claim 92 or 93, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form:
Figure imgf000253_0001
105. The compound of any one of claims 92-93 or 104, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 to ether form
Figure imgf000253_0002
106. The compound of claim 89 or 90, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently H, optionally substituted Ci_6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted OCi_6 alkyl, halogen, CN, OH.
107. The compound of claim 106 or a pharmaceutically acceptable salt thereof, wherein R 2 and R3 are each independently H, C1-4 alkyl, C3-6 cycloalkyl, OC1-4 alkyl, halogen, CN, or OH; wherein each of the C1-4 alkyl, C3-6 cycloalkyl, and OC1-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci_2 alkyl, OCi_2 alkyl, OH, halogen, amino, and carboxyl.
108. The compound of claim 106 or 107, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently H, C1-2 alkyl, OC1-2 alkyl, F, CI, Br, or OH;
wherein each of the C1-2 alkyl and OC1-2 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C¾, OCH3, F, CI, and Br.
109. The compound of any one of claims 106-108 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each CH3.
110. The compound of any one of claims 89-109 or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted alkyl.
111. The compound of claim 110 or a pharmaceutically acceptable salt thereof, wherein R1 is Ci_5 alkyl
optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
112. The compound of any one of claims 89-109 or a pharmaceutically acceptable salt thereof, wherein R1 is C2_6 alkenyl
optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
113. The compound of any one of claims 89-109 or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl.
114. The compound of claim 113 or a pharmaceutically acceptable salt thereof, wherein R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
115. The compound of claim 113 or 114, or a pharmaceutically acceptable salt thereof, wherein R1 is cyclopentyl or cyclohexyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of Ci-4 alkyl, haloalkyl, hydroxyl, OC1-4 alkyl, carboxyl, amino, and halogen.
116. The compound of any one of claims 89-109 or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted heterocyclyl.
117. The compound of claim 116 or a pharmaceutically acceptable salt thereof, wherein R1 is aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide,
tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine;
wherein each of the foregoing moieties is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
118. The compound of any one of claims 89-109 or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted aryl or optionally substituted heteroaryl.
119. The compound of claim 118 or a pharmaceutically acceptable salt thereof, wherein R1 is pyrrolyl, furanyl, thiophenyl, isothiophenyl, phenyl, indenyl, naphthalenyl,
tetrahydronaphthyl, tetrahydroindenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
wherein each of the foregoing moieties is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
120. The compound of claim 118 or 119, or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, CF3, OCF3, F, CI, and CN.
121. The compound of any one of claims 89-109 or a pharmaceutically acceptable salt thereof, wherein R1 is:
Figure imgf000256_0001
122. The compound of any one of claims 89-109 or 121, or a pharmaceutically acceptable salt thereof, wherein R1 is:
Figure imgf000256_0002
123. The compound of any one of claims 89-122 or a pharmaceutically acceptable salt thereof, wherein:
A1, A2, A3, and A4 are each C;
A1, A2, and A3 are each C, and A4 is N;
A1, A2, and A4 are each C, and A3 is N;
A1, A3, and A4 are each C, and A2 is N;
A2, A3, and A4 are each C, and A1 is N;
A1 and A2 are each C and A3 and A4 are each N;
A1 and A3 are each C and A2 and A4 are each N;
A1 and A4 are each C and A2 and A3 are each N; A2 and A3 are each C and A1 and A4 are each N;
A2 and A4 are each C and A1 and A3 are each N; or
A3 and A4 are each C and A1 and A2 are each N;
wherein:
when A1 is N, then R4a is absent;
when A2 is N, then R4b is absent;
when A3 is N, then R40 is absent; and
when A4 is N, then R4d is absent.
124. The compound of claim 123 or a pharmaceutically acceptable salt thereof, wherein: A1, A2, A3, and A4 are each C;
A1, A2, and A4 are each C, and A3 is N;
A1, A3, and A4 are each C, and A2 is N;
A1 and A4 are each C and A2 and A3 are each N; or
A3 and A4 are each C and A1 and A2 are each N.
125. The compound of any one of claims 89-124 or a pharmaceutically acceptable salt thereof, wherein R4a, R4b, R40, and R4d are each independently H, Ci_4 alkyl, Ci_4 haloalkyl, OCi_4 alkyl, halogen, CN, OH, or absent.
126. The compound of claim 125 or a pharmaceutically acceptable salt thereof, wherein: R4a is H, Ci_3 alkyl, OCi_3 alkyl, or absent;
R4b is H, Ci_3 alkyl, OCi_3 alkyl, F, CI, Br, haloalkyl, or absent;
R40 is H, Ci-3 alkyl, OC1-3 alkyl, or absent; and
R4d is H, Ci_3 alkyl, OCi_3 alkyl.
127. The compound of claim 126 or a pharmaceutically acceptable salt thereof, wherein: R4a is H, Ci-3 alkyl, or absent;
R4b is H, Ci_3 alkyl, CI, CF3, or absent;
R40 is H, Ci-3 alkyl, or absent; and
R4d is H or Ci_3 alkyl.
128. The compound of any one of claims 89-127 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I comprises:
Figure imgf000258_0001
129. The compound of any one of claims 89-128 or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl or optionally substituted aralkyl.
130. The compound of claim 129 or a pharmaceutically acceptable salt thereof, wherein R5 is Ci-5 alkyl; wherein the C1-5 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl,
heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
131. The compound of claim 129 or 130, or a pharmaceutically acceptable salt thereof, wherein R5 is C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of F, OC1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxetane.
132. The compound of any one of claims 89-128 or a pharmaceutically acceptable salt thereof, wherein R5 is C2-6 alkenyl that is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
133. The compound of any one of claims 89-128 or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted cycloalkyl or optionally substituted cycloalkenyl.
134. The compound of claim 133 or a pharmaceutically acceptable salt thereof, wherein R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
135. The compound of any one of claims 89-128 or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted heterocyclyl.
136. The compound of claim 135 or a pharmaceutically acceptable salt thereof, wherein R5 is aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide,
tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine;
wherein each of the foregoing moieties is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
137. The compound of any one of claims 89-128 or a pharmaceutically acceptable salt
Figure imgf000259_0001
Figure imgf000260_0001
138. The compound of any one of claims 89-128, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted aralkyl or optionally substituted heteroaralkyl.
139. The compound of claim 138, or a pharmaceutically acceptable salt thereof, wherein R5 is aralkyl or heteroaralkyl optionally substituted with one or more unsubstituted substituents selected from the group consisting of halogen and C1-4 alkyl.
140. The compound of claim 89-139 or a pharmaceutically acceptable salt thereof, wherein R6 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted alkoxyl.
141. The compound of claim 89-140 or a pharmaceutically acceptable salt thereof, wherein R6 is optionally substituted alkyl.
142. The compound of claim 141 or a pharmaceutically acceptable salt thereof, wherein R6 is Ci-5 alkyl; wherein the C1-5 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl,
heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
143. The compound of claim 141 or a pharmaceutically acceptable salt thereof, wherein R6 is Ci-4 alkyl; wherein the C1-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of F, OC1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxetane.
144. The compound of any one of claims 89-140 or a pharmaceutically acceptable salt thereof, wherein R6 is C2-6 alkenyl that is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
145. The compound of any one of claims 89-140 or a pharmaceutically acceptable salt thereof, wherein R6 is optionally substituted cycloalkyl, or optionally substituted
cycloalkenyl.
146. The compound of claim 145 or a pharmaceutically acceptable salt thereof, wherein R6 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl; wherein each of the foregoing moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
147. The compound of any one of claims 89-140 or a pharmaceutically acceptable salt thereof, wherein R6 is optionally substituted heterocyclyl.
148. The compound of claim 147 or a pharmaceutically acceptable salt thereof, wherein R6 is aziridine, oxirane, azetidine, azirine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, pyrrolidone, tetrahydrothiophene, thietane dioxide,
tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, piperidine, piperidinone, piperazine, pyran, thiopyran, azepane, or azepine;
wherein each of the foregoing moieties is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
149. The compound of any one of claims 89-140 or a pharmaceutically acceptable salt thereof, wherein R6 is optionally substituted aryl or optionally substituted heteroaryl.
150. The compound of claim 149 or a pharmaceutically acceptable salt thereof, wherein R6 is pyrrole, furan, thiophene, isothiophene, phenyl, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl, pyrazole, pyridine, pyrimidine, or pyrazine;
wherein each of the foregoing moieties is optionally substituted with one or more
unsubstituted substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.
151. The compound of claim 150 or a pharmaceutically acceptable salt thereof, wherein R6 is phenyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, OC1-4 alkyl, CF3, OCF3, F, CI, and CN.
152. The compound of any one of claims 89-140 or a pharmaceutically acceptable salt thereof, wherein R6 is tert-butyl, cyclobutane, cyclopentane, or cyclohexane.
153. The compound of any one of claims 89-140 or a pharmaceutically acceptable salt thereof, wherein R6 is alkoxyl that is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-4 alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, OC1-4 alkyl, carboxyl, amino, and halogen.
154. The compound of any one of claims 89-152, or a pharmaceutically acceptable salt thereof, wherein R6 is:
Figure imgf000262_0001
The compound of claim 1 , wherein the compound of Formula I
Figure imgf000262_0002
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
y - -et ypvaam e
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Ex # Structure
68
F
8-(l-((3,5-difluorophenyl)sulfonyl)cyclopentyl)-5-ethyl-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
69
5-ethyl-8-(l-((3-fluoro-4-methoxyphenyl)sulfonyl)cyclopentyl)-3,3-dimethyl- 2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one
70
5-ethyl-3,3-dimethyl-8-(l-((3-(trifluoromethyl)phenyl)sulfonyl)cyclopentyl)- 2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one
71
5-ethyl-8-(l-((4-fluoro-3-methylphenyl)sulfonyl)cyclopentyl)-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
72
5-ethyl-8-(l-((3-isopropoxyphenyl)sulfonyl)cyclopentyl)-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
73
5-ethyl-3,3-dimetnyl-8-(l-tosylcyclopentyl)-2,3-dihydrobenzo[b][l,4]oxazepin-
4(5H)-one
Figure imgf000277_0001
Figure imgf000278_0001
Ex # Structure
84
5-ethyl-8-(l-((4-ethylphenyl)sulfonyl)cyclopentyl)-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
85
5-ethyl-3,3-dimethyl-8-(5-((4-(trifluoromethyl)phenyl)sulfonyl)spiro[2.3]hexan- 5-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one
86
F
8-(l-((3-chloro-5-fluorophenyl)sulfonyl)cyclopentyl)-5-ethyl-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
87
5-ethyl-8-(l-((4-isopropylphenyl)sulfonyl)cyclopentyl)-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
88
8-(l-((3,4-dichlorophenyl)sulfonyl)cyclopentyl)-5-ethyl-3,3-dimethyl-2,3- dihydrobenzo[b] [ 1 ,4]oxazepin-4(5H)-one
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Ex # Structure
175
A/-(4-(4-((4-chlorophenyl)sulfonyl)tetrahydro- 2/-/-pyran-4-yl)-2,5-difluorophenyl)-/V- cyclopropylpivalamide
176
A/-(terf-butyl)-A/-(4-(4-((4- chlorophenyl)sulfonyl)tetrahydro-2/-/-pyran- 4-yl)-2,5-difluorophenyl)pivalamide
177
A/-(2-chloro-4-(4-((4- chlorophenyl)sulfonyl)tetrahydro-2H-pyran-4-yl)-6- fluorophenyl)-A/-cyclopropylpivalamide
178
A/-(2-chloro-4-(4-((4- chlorophenyl)sulfonyl)tetrahydro-2H-pyran-4-yl)-6- fluorophenyl)-A/-ethylpivalamide
Figure imgf000299_0001
fluorophenyl)-/V-(1 -cyclopropylethyl)pivalamide
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
pyran-4-yl)-2-fluorophenyl)(isopropyl)carbamate or a pharmaceutically acceptable salt thereof.
156. The compound of claim 5, wherein the compound of Formula lb is:
Figure imgf000313_0002
Figure imgf000314_0001
or a pharmaceutically acceptable salt thereof.
157. A pharmaceutical composition comprising the compound of any one of claims 1-156 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
158. A method of modulating the activity of an ROR-gamma receptor in vitro comprising contacting the receptor with the compound of any one of claims 1-156 or a pharmaceutically acceptable salt thereof.
159. A method of modulating the activity of an ROR-gamma receptor in vivo comprising contacting the receptor with the compound of any one of claims 1-156 or a pharmaceutically acceptable salt thereof.
160. The method of claim 158 or 159, wherein the compound of any one of claims 1-156 or a pharmaceutically acceptable salt thereof is a modulator of the ROR-gamma receptor.
161. A method of treating or reducing the severity of an ROR-gamma receptor mediated disease in a patient comprising administering the compound of any one of claims 1-156 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
162. The method of claim 161, wherein the disease is selected from the group consisting of Ankylosing, spondylitis, Asthma, Behcet's disease, Chronic obstructive pulmonary disease, Crohn's disease, Diabetes Mellitus Type 1, Multiple Sclerosis, Neuromyelitis optica, Polymyalgia Rheumatica, Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren's syndrome, Systemic Lupus Erythematosus, Systemic sclerosis, Transplant rejection, Inflammatory Bowel Disease, Ulcerative Colitis and Uveitis.
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