WO2014008214A1 - Composés contenant biaryle comme agonistes inverses de récepteurs ror-gamma - Google Patents

Composés contenant biaryle comme agonistes inverses de récepteurs ror-gamma Download PDF

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WO2014008214A1
WO2014008214A1 PCT/US2013/048992 US2013048992W WO2014008214A1 WO 2014008214 A1 WO2014008214 A1 WO 2014008214A1 US 2013048992 W US2013048992 W US 2013048992W WO 2014008214 A1 WO2014008214 A1 WO 2014008214A1
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alkyl
compound
optionally substituted
independently
formula
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PCT/US2013/048992
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Jianhua Chao
Istvan J. Enyedy
Kevin Guertin
Richard H. Hutchings
John Howard Jones
Noel Powell
Kurt D. VANVLOTEN
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Biogen Idec Ma Inc.
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Publication of WO2014008214A1 publication Critical patent/WO2014008214A1/fr

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    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
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Definitions

  • the present invention relates to biaryl-containing inverse agonists of ROR-gamma receptors.
  • the invention also provides pharmaceutical compositions comprising these inverse agonists. Also provided are methods of using these inverse agonists 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.
  • the nuclear receptor, RAR-related orphan receptor C (RORC, ROR-gamma, ROR-gamma-t, RORy), is expressed in cells of the immune system and plays an important role in immune system function.
  • RORC nuclear receptor, ROR-related orphan receptor C
  • biaryl-containing compounds that are useful as inverse agonists of ROR-gamma.
  • the invention provides biaryl-containing inverse agonists
  • gamma receptors wherein the inverse agonists are compounds of Formula I:
  • R la and R lb are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl,
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, Ci_ 4 alkyl, OCi_ 4 alkyl, or CF 3 ;
  • R 3 is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR 4 , halogen, SR 4 ,
  • R 4 , R 5 , and R 6 are each independently optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
  • R 7 is Ci_ 4 alkyl, or
  • R 3 and R 7 may be taken together to form an optionally substituted 4- to 7-membered
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_ 4 alkyl, OR 4 , NR 5 R 6 , CF 3 , or CN, or any 2 adjacent substituents of R 8a , R 8b , R 8c , R 8d , and R 8e may be taken together to form an optionally substituted 4- to 7-membered cycloaliphatic or optionally substituted 4- to 7-membered heterocyclic ring;
  • X is CH or N
  • J is a bond or C 1-4 alkylene.
  • the compound of Formula I is a compound of Formula I-a:
  • W is CR 7c R 7d , O, or NR 7a ;
  • R 7a and R 7b are each independently H or Ci_ 4 alkyl
  • R 7c and R 7d are each independently H, C 1-4 alkyl, or halogen;
  • n 1, 2, or 3.
  • R 3 is H, alkyl, substituted alkyl, halogen, NR 5 R 6 , or an optionally substituted heterocycloalkyl; and R 7 is alkyl.
  • R 3 is OR 4 .
  • R 3 is SR 4 , or S(0) 2 R 4 .
  • R 8a , R 8b , R 8c , R 8d , and R 8e may be taken together to form an optionally substituted 4- to 7-membered cycloaliphatic or optionally substituted 4- to 7-membered heterocyclic ring.
  • the compound is a compound of Formula I-b:
  • R la and R lb are each independently H, optionally substituted alkyl, optionally
  • substituted cycloalkyl optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl,
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, Ci_ 4 alkyl, OCi_ 3 alkyl , or CF 3 ;
  • R 3 is H, optionally substituted alkyl, OR 4 , halogen, SR 4 , S(0) 2 R 4 , NR 5 R 6 , or an
  • R 4 , R 5 , and R 6 are each independently optionally substituted alkyl, optionally
  • R 7 is Ci_ 4 alkyl, or
  • R 3 and R 7 may be taken together to form an optionally substituted 4- to 7- membered heterocyclic ring
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_ 4 alkyl, OR 4 , NR 5 R 6 ,
  • X is CH or N
  • the invention includes a compound of Formula II:
  • J is a bond or C 1-4 alkylene
  • X 1 is CH or N
  • X 2 is C-R 2a or N
  • X 3 is C-R 2b or N
  • X 4 is C-R 2d or N
  • X 5 is S, or O
  • Z 1 and Z 2 are each independently H or optionally substituted alkyl
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, Ci_ 4 alkyl, OC ]-4 alkyl, or
  • R is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR , halogen, SR 4 , S(0) 2 R 4 , NR 5 R 6 , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl; each R 4 is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted
  • R 5 and R 6 are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
  • R 7 is Ci_ 4 alkyl, or
  • R 3 and R 7 may be taken together to form an optionally substituted 5- to 7- membered heterocyclic ring
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_ 4 alkyl, OR 4 , NR 5 R 6 , CF 3 , or CN;
  • R 9 is a bond, optionally substituted alkylene, or optionally substituted cycloalkylene;
  • R 10 is NR la R lb , hydroxyl, or optionally substituted alkyl
  • R 12a and R 12b are each independently optionally substituted alkyl
  • R 12a and R 12b may be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring
  • R la and R lb taken together form an optionally substituted 4- to 7-membered heterocyclic ring.
  • the invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-ki or Formula II- k 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
  • the invention includes a method of modulating the activity of an ROR-gamma receptor with an inverse agonist, comprising contacting the receptor with a compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-ki or Formula II- k 2 , or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-ki or Formula II-k 2 or a pharmaceutically acceptable salt thereof modulates the activity of an ROR-gamma receptor in vitro.
  • the compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-ki or Formula II- k 2 , or a pharmaceutically acceptable salt thereof modulates the activity of an ROR-gamma receptor in vivo.
  • the compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-ki, Formula II-k 2 , or a pharmaceutically acceptable salt thereof is an inverse agonist 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, Formula I-a, Formula I-b, Formula II, Formula II-ki, Formula II-k 2 , 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.
  • aliphatic encompasses the terms alkyl, alkenyl, alkynyl. Unless otherwise stated, aliphatic can include both substituted 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.
  • alkylene refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond.
  • the alkylene group can be linear or branched.
  • Non-limiting examples of alkylene groups include -CH 2 - -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH 3 )CH 2 CH 2 - and - CH 2 CH(CH 3 )CH2-.
  • cycloalkylene refers to a cycloalkyl substituent having a hydrogen replaced with a bond at the same carbon atom or a different carbon atom, for example, 3 ⁇ 4 or v .
  • a heterocycloalkylene is a heterocycloalkyl substituent having a hydrogen replaced with a bond, etc.
  • 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, (azacycloalkylcarbonyl)amino, heteroaralkylcarbonylamino, heteroarylcarbonylamino, carbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino,
  • 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 (e.g., phenyl); an aromatic bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); an aromoatic tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, anthracenyl, or
  • a 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, spiro, 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.
  • 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.
  • heterocycloaliphatic and “heterocyclic” encompasses a heterocycloalkyl group and a heterocycloalkenyl group.
  • a "heterocycloalkyl” group refers to a 3-10 membered mono or bicyclic (fused, spriro, 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[ ⁇ ]furyl, benzo[ ⁇ ]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-l ,2,5-thiadiazolyl
  • 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[Z?]furyl, benzo[Z?]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
  • 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.
  • 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 "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.
  • 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.
  • an "alkoxycarbonyl” used alone or in connection with another group refers to a carbonyl group such as alkyl-O-C(O)-.
  • a "carboxyalkoxy” group used alone or in connection with another group refers to a carboxy (COOH-) bonded to an alkoxy group -C-0-( C 2 _ 4 alkyl), for example, -CO(C 2 - 4 alkyl)COOH
  • alkoxyalkyl refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.
  • an “aminocarbonyl” refers to an amido group such as -NR x -C(0)-, 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(RX)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(RX)2-, wherein Rx has been defined above.
  • urea 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.
  • 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, ⁇ 5 */ is shown as attached to the main core structure by the ring nitrogen
  • the pyrrole substituent, , 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.
  • divalent substituents such as an amide, shown as -C(0)N(Rx)-, are meant to include the substituent in both directions.
  • X is an unsubstituted amide can be or .
  • Some examples of generic divalent substituents include, but are not limited to -CO-, -CS-, -CONQ2-, -C02-, -OCO-, -NQ2-, -NQ2C02-, -0-, -NQ2CONQ2- , -OCONQ2-, -NQ2CO-, -S-, -SO-, -S02-, -S02NQ2-, -NQ2S02-, and -NQ2S02NQ2-.
  • substituted includes, but is not limited to, the replacement of radicals (for example, hydrogen radicals) in a given structure with the radical of a specified substituent or addition of the specified radical substituent to an atom (for example, sulfur or phosphorous).
  • radicals for example, hydrogen radicals
  • an atom for example, sulfur or phosphorous
  • sulfur can be optionally substituted with one or more oxo substituents.
  • 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 (C, S, N, or O) 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, sulfo, sulfonyl, sulfinyl, sulfanyl, halogen, haloaliphatic, sulfamoyl, sulfamide,
  • 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.
  • 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
  • the compounds disclosed herein also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass most prevalent in nature.
  • isotopes suitable for inclusion in the disclosed compounds include, without limitation
  • isotopes of hydrogen such as H and H
  • isotopes of carbon such as C and C
  • isotopes of carbon such as C and C
  • isotopes of nitrogen such as N
  • isotopes of oxygen such as O and O
  • isotopes of phosphorus such as 31 P and 32 P
  • isotopes of sulfur such as 35 S
  • isotopes of fluorine such as 18 F
  • isotopes of chlorine such as 36 C1.
  • Certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, 3 H, or 14 C), which may be useful in drug and/or substrate tissue distribution studies.
  • isotopically labeled structures included in the invention are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the isotopically labeled structures; 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 of isotopically labeled structures as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the isotopically labeled structures are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the isotopically labeled structures of the invention are within the scope of the invention.
  • the invention provides biaryl-containing inverse agonists of ROR- gamma receptors, wherein the inverse agonists are compounds of Formula I:
  • R la and R lb are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl,
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, Ci_ 4 alkyl, OCi_ 4 alkyl, or CF 3 ;
  • R 3 is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR 4 , halogen, SR 4 ,
  • R 4 , R 5 , and R 6 are each independently optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
  • R 7 is Ci_ 4 alkyl, or
  • R 3 and R 7 may be taken together to form an optionally substituted 4- to 7-membered
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_ 4 alkyl, OR 4 , NR 5 R 6 , CF 3 , or CN, or any 2 adjacent substituents of R 8a , R 8b , R 8c , R 8d , and R 8e may be taken together to form an optionally substituted 4- to 7-membered cycloaliphatic or optionally substituted 4- to 7-membered heterocyclic ring;
  • X is CH or N
  • J is a bond or C 1-4 alkylene.
  • the invention includes a compound of Formula I, wherein:
  • R la and R lb are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl- alkyl, optionally substituted cycloalkyl-alkyl,
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, Ci_ 4 alkyl, OCi_ 3 alkyl , or
  • R 3 is H, optionally substituted alkyl, OR 4 , halogen, SR 4 , S(0) 2 R 4 , NR 5 R 6 , or an optionally substituted heterocycloalkyl;
  • R 4 , R 5 , and R 6 are each independently optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
  • R 7 is Ci_ 4 alkyl, or
  • R 3 and R 7 may be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_ 4 alkyl, OR 4 , NR 5 R 6 , CF 3 , or CN;
  • X is CH or N
  • J is a bond or C 1-4 alkylene.
  • the compound of Formula I is a compound of Formula I-a:
  • R 7a and R 7b are each independently H or C1-4 alkyl
  • R 7c and R 7d are each independently H, C1-4 alkyl, or halogen;
  • n 1, 2, or 3.
  • R 3 is H, alkyl, substituted alkyl, halogen, NR 5 R 6 , or an optionally substituted heterocycloalkyl; and R 7 is alkyl.
  • R 3 is OR 4 .
  • the invention includes a compound of Formula I-b:
  • R la and R lb are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl,
  • R 3 is H, optionally substituted alkyl, OR 4 , halogen, SR 4 , S(0) 2 R 4 , NR 5 R 6 , or an
  • R 4 , R 5 , and R 6 are each independently optionally substituted alkyl, optionally
  • R 7 is Ci_ 4 alkyl, or
  • R 3 and R 7 may be taken together to form an optionally substituted 4- to 7- membered heterocyclic ring
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_ 4 alkyl, OR 4 , NR 5 R 6 ,
  • X is CH or N
  • the invention includes a compound of Formula II
  • J is a bond or Ci_ 4 alkylene
  • X 1 is CH or N
  • X 2 is C-R 2a or N
  • X 3 is C-R 2b or N
  • X 4 is C-R 2d or N
  • X 5 is S, or O
  • Z 1 and Z 2 are each independently H or optionally substituted alkyl
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, Ci_ 4 alkyl, OCi_ 4 alkyl , or
  • R 3 is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR 4 , halogen, SR 4 , S(0) 2 R 4 , NR 5 R 6 , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl; each R 4 is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R 5 and R 6 are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
  • R 7 is Ci_ 4 alkyl, or
  • R 3 and R 7 may be taken together to form an optionally substituted 5- to 7- membered heterocyclic ring
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_ 4 alkyl, OR 4 , NR 5 R 6 , CF 3 , or CN;
  • R 9 is a bond, optionally substituted alkylene, or optionally substituted cycloalkylene;
  • R 10 is NR la R lb , hydroxyl, or optionally substituted alkyl;
  • R a and R are each independently optionally substituted alkyl, or
  • R 12a and R 12b may be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring;
  • R la and R lb are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl- alkyl,
  • J is a bond or C 1-4 alkylene
  • X 1 is CH or N
  • X 2 is C-R 2a or N
  • X 3 is C-R 2b or N
  • X 4 is C-R 2d or N;
  • X 5 is S, or O;
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, Ci_ 4 alkyl, OCi_ 4 alkyl , or CF 3 ;
  • R 3 is H, optionally substituted alkyl, OR 4 , halogen, SR 4 , S(0) 2 R 4 , NR 5 R 6 , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;
  • each R 4 is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl
  • R 5 , and R 6 are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
  • R 7 is Ci_ 4 alkyl, or
  • R 3 and R 7 may be taken together to form an optionally substituted 5- to 7-membered heterocyclic ring
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_ 4 alkyl, OR 4 , NR 5 R 6 , CF 3 , or CN;
  • R 9 is a bond, optionally substituted alkylene, or optionally substituted cycloalkylene;
  • R 10 is NR la R lb , or hydroxyl;
  • R la and R lb are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl- alkyl, optionally substituted cycloalkyl-alkyl,
  • R la and R lb taken together form an optionally substituted 4- to 7-membered heterocyclic ring.
  • the invention includes a compound of Formula II-k 2 :
  • X 1 is CH or N
  • X 2 is C-R 2a or N
  • X 3 is C-R 2b or N
  • X 4 is C-R 2d or N
  • X 5 is S, or O
  • Z 1 and Z 2 are each independently H or optionally substituted alkyl
  • R 3 is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR 4 , halogen, SR 4 , S(0) 2 R 4 , NR 5 R 6 , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl; each R 4 is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R 5 and R 6 are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
  • R 7 is Ci_ 4 alkyl, or
  • R 3 and R 7 may be taken together to form an optionally substituted 5- to 7- membered heterocyclic ring
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_ 4 alkyl, OR 4 , NR 5 R 6 , CF 3 , or CN;
  • R 9 is a bond, optionally substituted alkylene, or optionally substituted cycloalkylene;
  • R 10 is NR la R lb , hydroxyl, or optionally substituted alkyl
  • R 12a and R 12b are each independently optionally substituted alkyl
  • R 12a and R 12b may be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring
  • R la and R lb are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl- alkyl,
  • R la and R lb taken together form an optionally substituted 4- to 7-membered heterocyclic ring.
  • R 5 and R 6 are each independently optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • a representative compound of Formula I is Formula I-a:
  • W is CR 7c R 7d , O, or NR 7a ;
  • R 7a and R 7b are each independently H or C 1 -4 alkyl
  • R 7c and R 7d are each independently H, C 1 -4 alkyl, or halogen; and, n is 1, 2, or 3.
  • R la , R lb , R 2a , R 2b , R 20 , R 2d , R 4 , R 5 , R 6 , R 8a , R 8b , R 8c , R 8d , and R 8e , and X can be applicable to the compounds of Formula I, Formula II, Formula II-ki, Formula II-k 2 and Formula I-a, as provided herein before and herein after.
  • R 3 , and R 7 can be applicable to the compounds of Formula I or Formula II, Formula II-ki, and Formula II-k 2 , as provided herein before and herein after.
  • R 7a , R 7b , R 7c , R 7d and W can be applicable to the compounds of Formula I-a, as provided herein before and herein after.
  • R la and R lb are each independently: H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl, or R la and R lb taken together form an optionally substituted 4- to 7- membered heterocyclic ring.
  • R la and R lb are each independently: H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted
  • heterocycloalkyl-alkyl optionally substituted cycloalkyl-alkyl,
  • R la and R lb taken together form an optionally substituted 4- to 7- membered heterocyclic ring.
  • R la and R lb are each independently an optionally substituted alkyl, wherein the alkyl may be optionally substituted with one to three of hydroxyl, carboxy, amino, sulfonyl, sulfo, alkoxy, C 2 _ 4 carboxyalkoxy, C 2 _ 4 alkoxycarbonyl, aminocarbonyl, Ci_ 4 alkyl, and heteroaryl.
  • the amino substituted Ci_ 4 alkyl is Ci_ 4 alkyl substituted with an alkylcarbonylamino, N(CH 3 ) 2 , or NH 2 .
  • the 4- to 7- membered heterocyclic ring optionally substituted with an alkyl is a 4- to 7- membered heterocyclic ring substituted with an alkyl, wherein the alkyl is further substituted with hydroxyl.
  • the 4- to 7- membered heterocyclic ring is optionally substituted with Ci_ 4 alkyl further substituted with hydroxyl.
  • the 4- to 7- membered heterocyclic ring optionally substituted with an amino is a 4- to 7- membered heterocyclic ring substituted with NH 2 , alkylsulfonylamino, or alkylcarbonylamino.
  • the 4- to 7- membered heterocyclic ring optionally substituted with an alkoxy is a 4- to 7- membered heterocyclic ring substituted with alkoxy, wherein the alkoxy is further substituted with hydroxyl.
  • R la and R lb are each independently: H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted
  • heterocycloalkyl-alkyl optionally substituted cycloalkyl-alkyl,
  • R la and R lb taken together form an optionally substituted 4- to 7- membered heterocyclic ring, wherein the 4- to 7- membered heterocyclic ring is substituted by one or
  • R la and R lb are each independently:
  • Ci_6 alkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone,
  • Ci_6 aralkyl furyl-Ci-6 alkyl, thiophenyl-Ci-6 alkyl, 2H-pyrrolyl-Ci_6 alkyl, pyrrolyl-Ci-6 alkyl, oxazolyl-Ci-6 alkyl, thazolyl-Ci-6 alkyl, imidazolyl-Ci_6 alkyl, pyrazolyl-Ci_ 6 alkyl, isoxazolyl-Ci_6 alkyl, isothiazolyl-Ci_6 alkyl,
  • R taken together form azetidine, pyrrolidine, piperidine, pyrrolidone, piperidinone, morpholine, diazetidine, or piperazine;
  • each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl,
  • R la and R lb are each independently:
  • Ci-6 alkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetane,
  • each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl,
  • R la and R lb are each independently:
  • Ci-6 alkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone,
  • Ci_6 aralkyl furyl-Ci-6 alkyl, thiophenyl-Ci-6 alkyl, 2H-pyrrolyl-Ci_6 alkyl, pyrrolyl-Ci-6 alkyl, oxazolyl-Ci-6 alkyl, thazolyl-Ci-6 alkyl, imidazolyl-Ci-6 alkyl, pyrazolyl-Ci-6 alkyl, isoxazolyl-Ci-6 alkyl, isothiazolyl-Ci-6 alkyl,
  • azetidine, pyrrolidine, piperidine, pyrrolidone, piperidinone, morpholine, diazetidine, or piperazine is optionally substituted with one or more of:
  • R la and R lb may be taken to form a 4- to 7- membered heterocyclic ring optionally substituted with one or more of OH, OR lc , NR lc R ld and optionally substituted alkyl, wherein R lc and R ld are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • R la and R lb are each independently:
  • Ci-4 alkyl cyclobutyl, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, tetrahydrothiopene dioxide, C 1-4 aralkyl, pyrrolyl- Ci-4 alkyl, imidazolyl-Ci-4 alkyl, pyrazolyl-Ci-4 alkyl, pyridyl-Ci-4 alkyl,
  • each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C 1-4 alkyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone, piperidinone, diazetidine, piperazine, morpholine, thietane, tetrahydrothiophene, tetrahydrothiopyran, thietane dioxide, tetrahydrothiophene dioxide,
  • R la and R lb are each independently:
  • each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH 3 , C2H5, OH, OCH 3 , OC2H5, CH2COOH, C2H4COOH, C 3 H 6 COOH, N(Me)(Me), N(Me)(Et),
  • At least one of R la and R lb is an unsubstituted, non-H moiety; or, R la and R lb taken together form an unsubstituted hetercyclic ring.
  • At least one of R la and R lb is a substituted non-H moiety; or, R la and R lb taken together form a substituted hetercyclic ring.
  • R la and R lb are each independently selected from the group consisting of H, CH 3 , C2H5, C 3 H7, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, phenyl, 2-pyridyl, 3 -pyridyl, 4- pyridyl,
  • R la and R lb are H. In another embodiment, R la and R lb are each independently H, CH 3 , C2H5, or C 3 H7.
  • one of R la and R lb is H, and the other of R la and R lb is
  • one of R la and R lb is CH 3 , and the other of R la and R HO'
  • HO HO HO- is HO ⁇ " ⁇ " ⁇ >V OH
  • one of R la and R lb is H, and the other of R la and R lb is
  • one of R la and R lb is H, and the other of R la and R lb is
  • one of R la and R lb is H, and the other of R la and R lb is [00122] In another embodiment, one of R la and R lb is H, and the other of R la and R lb is
  • one of R la and R lb is H, and the other of R la and R lb is oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, or
  • R la and R is H, and the other of R la and R is phenyl,
  • one of R la and R lb is H, and the other of R la and R lb is 2- pyridyl, 3-pyridyl, 4-pyridyl.
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, C 1-4 alkyl, OC M alkyl , or CF 3 . In other embodiments, R 2a , R 2b , R 20 , and R 2d are each
  • R 2a , R 2b , R 2c , and R 2d are each independently H, F, CI, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , OC 3 H 7 , or CF 3 .
  • R 2a , R 2b , R 20 , and R 2d are each independently H, F, CI, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , or CF 3 .
  • R 2a , R 20 , and R 2d are each independently H or F; and, R 2b is H, F, CI, CH 3 , C 2 H 5 , OCH 3 , or OC 2 H5.
  • R 2b is H, F, CI, CH 3 , C 2 H 5 , OCH 3 , or OC 2 H5.
  • R 2a , R 2b , R 2c , and R 2d are each H;
  • R 2a , R 20 , and R 2d are each H, and R 2b is F;
  • R 2a , R 2b , and R 3 ⁇ 4 are each H, and R 2d is F;
  • R 2a , R 20 , and R 2d are each H, and R 2b is OCH 3 ;
  • R 2a , R 20 , and R 2d are each H, and R 2b is CH 3 ;
  • R 2a , R 20 , and R 2d are each H, and R 2b is CI;
  • R 2a , R 2b , and R 2d are each H, and R 3 ⁇ 4 is F;
  • R 2a and R 2b are each F, and R 3 ⁇ 4 and R 2d are each H; or,
  • R 2a and R 2c are each H, R 2c is CI, and R 2d is F.
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, F, CI, Ci_4 alkyl, OCi_ 4 alkyl, NR 5 R 6 , CF 3 , or CN.
  • R 8a , R 8b , R 8c , R 8d , and R* are each independently F, CI, CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , or CF 3 .
  • R 8a and R 8e are each independently H, F, CI, or CH 3 ;
  • R 8b and R 8d are each independently H, CI, F, CH 3 , OCH 3 , or CF 3 ;
  • R 8c is H, CI, CH 3 , or OCH 3 .
  • R 8c , R 8d , and R 8e are each H;
  • R 8d , and R 8e are each H, and R 8c is CI;
  • R 8d , and R 8e are each H, and R 8c is CH 3 ;
  • R 8d , and R 8e are each H, and R 8c is OCH 3 ;
  • R 8d , and R 8e are each H, and R 8b is CI;
  • R 8d , and R 8e are each H, and R 8b is CF 3 ;
  • R 8d , and R 8e are each H, and R 8b is CH 3 ;
  • R 8d , and R 8e are each H, and R 8b is OCH 3 ;
  • R 8d , and R 8e are each H and R 8b is F;
  • R 8d , and R 8e are each H, and R 8a is CI;
  • R 8d , and R 8e are each H, and R 8a is CH 3 ;
  • R 8d are each H, R 8a is F, and R 8e is CI;
  • R 8e are each H, and R 8b and R 8c are each CI;
  • R 8e are each H, and R 8a and R 8c are each CI; or,
  • R 8d are each H, and R 8a and R 8e are each F.
  • X is N. In other embodiments, X is CH.
  • R 7a and R 7b are each independently H or Ci_ 3 alkyl. In one embodiment, R 7a and R 7b are each independently H or CH 3 , or CH 2 CH 3 . In another embodiment, R 7a and R 7b are each independently H or CH 3 .
  • W is CR °R . In some of these
  • R 7c and R 7d are each independently H, Ci_ 3 alkyl, or F. In other of these embodiments, R 7c and R 7d are each independently H, CH 3 , or F. For example, R 7c and R 7d are both H, both CH , or both F.
  • W is O. In other embodiments, W is NR 7a ; and, R 7a is Ci_ 3 alkyl, such as CH 3
  • n is 1. In other embodiments, n is 2. In still other embodiments, n is 3. [00134] In some embodiments:
  • R la and R lb are each independently:
  • Ci-6 alkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetane,
  • Ci_6 aralkyl furyl-Ci-6 alkyl, thiophenyl- Ci-6 alkyl, 2H-pyrrolyl-Ci_6 alkyl, pyrrolyl-Ci_6 alkyl, oxazolyl-Ci_6 alkyl, thazolyl-Ci-6 alkyl, imidazolyl-Ci-6 alkyl, pyrazolyl-Ci_6 alkyl, isoxazolyl-Ci-6 alkyl, isothiazolyl-Ci_6 alkyl, l,3,4-thiadiazolyl-Ci_6 alkyl, 2H-pyranyl-Ci_6 alkyl, 4-H-pranyl-Ci_6 alkyl, pyridyl
  • pyrimidyl-Ci-6 alkyl pyrazyl-Ci-6 alkyl, l,3,5-triazyl-Ci_6 alkyl; or,
  • substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen;
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, Ci_ 4 alkyl, OCi_ 4 alkyl , or CF 3 ; and, R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, F, CI, Ci_ 4 alkyl, OC ⁇ alkyl, NR 5 R 6 , CF 3 , or CN.
  • R la and R lb are each independently:
  • piperidine pyrrolidone, piperidinone, diazetidine, piperazine, morpholine, thietane, tetrahydrothiophene, tetrahydrothiopyran, thietane dioxide, tetrahydrothiophene
  • R 2a , R 2b , R 2c , and R 2d are each independently H, F, CI, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , or CF 3 ;
  • R 7a and R 7b are each independently H or C 1-3 alkyl
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently F, CI, CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , or CF 3.
  • each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH 3 , C 2 H 5 , OH, OCH 3 , OC 2 H 5 , CH 2 COOH, C 2 H 4 COOH, C 3 H 6 COOH,
  • R 2b is H, F, CI, CH 3 , C 2 H 5 , OCH 3 , or OC 2 H 5 ;
  • R 7a and R 7b are each independently H or CH 3 , or CH 2 CH 3 ;
  • R 7c and R 7d are each independently H, CH 3 , or F;
  • R 8a and R 8e are each independently H, F, CI, or CH 3 ;
  • R 8b and R 8d are each independently H, CI, F, CH 3 , OCH 3 , or CF 3 ;
  • R 8c is H, CI, CH 3 , or OCH 3 ;
  • X is CH.
  • R la and R lb are each independently selected from the group consisting of H, CH 3 , C 2 Hs,
  • R 2a , R 2b , R 2c , and R 2d are each selected from the group consisting of H, F, CI, CH 3 , and OCH3; wherein:
  • R 2a , R 2b , R 2c , and R 2d are each H;
  • R a , and R 2d are each H, and R ZD is F;
  • R 2a , R 2b , and R 3 ⁇ 4 are each H, and R 2d is F;
  • R 2a , R 2 ", and R a are each H, and R ZD is OCH 3 ;
  • R 2a , R 2 ", and R fl are each H, and R D is CH 3 ;
  • R za , and R 2d are each H, and R ZD is CI;
  • R 2a , R 2b , and R 2d are each H, and R 2 " is F;
  • R ia and R Zb are each F, and R and R ,2 a d a . re each H; or,
  • R 2a and R 2c are each H, R c is CI, and R 2d is F;
  • R 7a and R 7b are each independently H or CH 3 ;
  • R 7c and R 7d are each independently H, CH 3 , or F; wherein:
  • R 7c and R 7d are both H
  • R 7c and R 7d are both CH 3 ;
  • R 7c and R 7d are both F;
  • R 8a , R 8b , R 8c , R 8d and R 8e are each selected from the group consisting of H, F, CI, CH 3 , OCH 3 , and CF 3 , wherein:
  • R 8a , R 8b , R 8c , R 8 , and R 8e are each H;
  • R 8a , R 8b , R 8d , and R 8e are each H, and R 8c is CI;
  • R 8a , R 8b , R 8d , and R ee are each H, and R a is CH 3 ;
  • R , R , R , and R 5e are each H, and R 5C is OCH 3 ;
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is CI;
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is CF 3 ;
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is CH 3 ;
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is OCH 3 ;
  • R 8a , R 8c , R 8d , and R 8e are each H and R 8b is F;
  • R 8b , R 8c , R 8d , and R 8e are each H, and R 8a is CI;
  • R 8b , R 8c , R 8d , and R 8e are each H, and R 8a is CH 3 ;
  • R 8b , R 8c , and R 8d are each H, R 8a is F, and R 8e is CI;
  • R 8a , R 8d , and R 8e are each H, and R 8b and R 8c are each CI;
  • R 8b , R 8d , and R 8e are each H, and R 8a and R 8c are each CI; or,
  • R 8b , R 8c , and R 8d are each H, and R 8a and R 8e are each F.
  • R la and R lb are each H. In another embodiment, R la and R lb are each independently H, CH 3 , C2H5, or C 3 H7.
  • one of R la and R lb is H, and the other of R la and R lb is
  • one of R la and R lb is H, and the other of R la and R lb is
  • one of R la and R lb is H, and the other of R la and R lb is
  • one of R la and R lb is H, and the other of R la and R lb is oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, or
  • one of R la and R lb is H, and the other of R la and R lb is phenyl,
  • one of R la and R lb is H, and the other of R la and R lb is 2-pyridyl, 3-pyridyl, 4-pyridyl.
  • R la and R lb are each independently H or CH 3 ;
  • R 2a , R 20 , and R 2d are each H;
  • R 2b is CI
  • R 7a and R 7b are each H;
  • W is CR 7c R 7d ;
  • R 7c and R 7d are each H;
  • R 8a , R 8b , R 8c , R 8d and R 8e are each selected from the group consisting of H, F, CI, CH 3 , OCH 3 , and CF 3 ;
  • X is CH
  • n 2.
  • the compound is a compound of Formula I-b, wherein:
  • R la and R lb are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl;
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, C M alkyl, OC M alkyl, or CF 3 ;
  • R 3 are each independently H, or optionally substituted alkyl;
  • R 7 are each independently H, F, or optionally substituted alkyl
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, F, CI, optionally substituted alkyl, or
  • R 4 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;
  • X is CH.
  • the compound is a compound of Formula I-b, wherein:
  • R la and R lb are each independently H;
  • R 2a , R 2b , R 2c , and R 2d are each independently H, or halogen;
  • R 3 are each independently H, or optionally substituted alkyl
  • R 7 are each independently H, F, or optionally substituted alkyl
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, F, CI, optionally substituted alkyl, or OCi-4 alkyl optionally substituted with halogen;
  • R 8a , R 8b and R 8c together form a 4 to 7 membered optionally substituted cycloalkyl ring or a 4 to 7 membered optionally substituted heterocycloalkyl ring;
  • X is CH.
  • the compound of Formula I-a can be a compound as shown in Table 1 or a pharmaceutically acceptable salt thereof.
  • IC 50 data is represented as follows: greater than or equal to 10 microMolar is designated at A; less than 10 microMolar but greater than or equal to 1 microMolar is designated as B; less than 1 microMolar but greater than or equal to 500 nanoMolar is designated at C; less than 500 nanoMolar but greater or equal to 100 nanoMolar is designated as D; less than 100 nanoMolar is designated at E.
  • Methods for the determination of the IC 50 data of Table 1 are provided in the description of Assay 1 below.
  • the compound of Formula I-a can include:
  • R 3 is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR 4 , halogen, SR 4 , S(0) 2 R 4 , NR 5 R 6 , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl.
  • R 3 is H, optionally substituted alkyl, OR 4 , halogen, SR 4 , S(0) 2 R 4 , NR 5 R 6 , or an optionally substituted heterocycloalkyl.
  • R 3 is H, optionally substituted alkyl, OR 4 , halogen, or NR 5 R 6 , SR 4 , S(0) 2 R 4 , or an optionally substituted heterocycloalkyl; and, R 7 is alkyl.
  • R 3 is H, optionally substituted alkyl, OR 4 , halogen, NR 5 R 6 , SR 4 , S(0) 2 R 4 or an optionally substituted heterocycloalkyl; and, R 7 is alkyl.
  • R 3 is H, optionally substituted alkyl, halogen, NR 5 R 6 , SR 4 , S(0) 2 R 4 or an optionally substituted heterocycloalkyl.
  • R 3 is H, optionally substituted alkyl, halogen, or NR 5 R 6 .
  • R 3 is H, optionally substituted alkyl, optionally substituted heteroaryl, OR 4 , halogen, NR 5 R 6 , SR 4 , S(0) 2 R 4 , or an optionally substituted
  • R 7 is alkyl
  • R 4 is an optionally substituted alkyl or an optionally substituted cycloalkyl.
  • R 4 is alkyl, which is optionally substutued with halogen, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
  • R 4 is cycloalkyl which is optionally substituted with halogen, alkyl, halogen, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
  • R 4 is selected from the group consisting of ⁇ ,
  • R 3 is optionally substituted alkyl, optionally substituted heteroaryl, NR 5 R 6 , or an optionally substituted heterocycloalkyl.
  • R 3 is an optionally substituted alkyl.
  • R 3 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, or pentyl.
  • R 3 is -CD 3 .
  • R 3 is NR 5 R 6 , and wherein R 5 and R 6 are each independently optionally substituted alkyl.
  • R 3 is NR 5 R 6 , wherein R 5 and R 6 are each independently methyl, ethyl, propyl, isopropyl, butyl, t-butyl, or pentyl, each of which is optionally substituted with halogen.
  • R 3 is an optionally substituted heterocycloalkyl.
  • R 3 is an optionally substituted monocyclic
  • heterocycloalkyl selected from the group consisting of azetidyl, pyrollidyl, piperidyl, morpholyl, piperazyl, tetrahydrofuranyl, each of which is optionally substituted with halogen, cyano, oxo, -CF 3 , alkyl, and cycloalkyl.
  • R 3 is selected from the group consisting of
  • R 3 is an optionally substituted bicyclic heterocycloalkyl.
  • R 3 is an optionally substituted heteroaryl.
  • R 3 is an optionally substutued pyrollyl, pyrazolyl, immidazolyl, pyridyl, pyrazyl, furanyl, thiophenyl, and thiazolyl.
  • the pyrollyl, pyrazolyl, immidazolyl, pyridyl, pyrazyl, furanyl, thiophenyl, and thiazolyl is optionally substituted with halogen.
  • R 3 is
  • R la and R lb are each independently H, Ci_6 alkyl, C1-7 cycloalkyl, or Ci_6 aralkyl; wherein each of the foregoing non-H moieties is 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 la and R lb are each independently H or Ci ⁇ alkyl; wherein the Ci-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-3 alkyl, hydroxyl, and OC1-3 alkyl.
  • R la and R lb are each independently H or unsubstituted Ci-3 alkyl. In other embodiments, R la and R lb are each H.
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, C1-4 alkyl, OC ⁇ alkyl , or CF 3 .
  • R 2a , R 2b , R 20 , and R 2d are each
  • R 2a , R 2c , and R are each independently H; and, R is H, F, or CI.
  • R 2a , R 20 , and R 2d are each H; and, R 2b is CI.
  • R 3 is H, C1-4 alkyl, or halogen; wherein the C1-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-3 alkyl, halogen, hydroxyl, alkoxyl, carboxyl, and amino.
  • R 3 is C1-3 alkyl, F, CI, or Br; wherein the C1-3 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-2 alkyl, halogen, hydroxyl, OC1-3 alkyl, carboxyl, and amino.
  • R 3 is CH 3 , C 2 H 5 , CF 3 , F, CI or Br; wherein the CH 3 and C2H5 are each optionally substituted with one or more halogen.
  • R 3 is CH 3 , C2H5 , CF 3 , F, CI, or Br.
  • R 7 is Ci_6 alkyl. In other embodiments, R 7 is C1-4 alkyl. In still other embodiments, R 7 is C1-3 alkyl. In some exemplary embodiments, R 7 is CH 3 or
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_4 alkyl, OCi_ 4 alkyl, NR 5 R 6 , CF 3 , or CN.
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, F, CI, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , or CN.
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, F, CI, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , or CN.
  • R 8a and R 8e are each independently H, F, or CI;
  • R 8b and R 8d are each independently H, F, OCH 3 , or CN; and
  • R 8c is H, F, or CI.
  • R 8a and R 8e are each independently H, F, or CI;
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is CN;
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is OCH 3 ;
  • R 8b , R 8c , and R 8d are each H, and R 8a and R 8e are each F or CI;
  • R 8b , R 8d , and R 8e are each H, R 8a is CI, and R 8c is F; or
  • R 8b and R 8e are each H, R 8a and R 8d are each F, and R 8c is CI.
  • J is a bond or CH2.
  • R la and R lb are each independently H, Ci_6 alkyl, C1-7 cycloalkyl, or Ci_6 aralkyl; wherein each of the foregoing non-H moieties is 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 2a , R 2b , R 2c , and R 2d are each independently H, halogen, Ci_ 4 alkyl, OCi_ 4 alkyl , or CF 3 ;
  • R 3 is H, CM alkyl, halogen, or NR 5 R 6 ;
  • R 7 is Ci-6 alkyl
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_ 4 alkyl, OC M alkyl, NR 5 R 6 , CF 3 , or CN.
  • R la and R lb are each independently H or C 1-4 alkyl
  • R 2a , R 2b , R 2c , and R 2d are each independently F, CI, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , or CF 3 ;
  • R 3 is C 1-3 alkyl, F, CI, or Br;
  • R 7 is Ci_ 4 alkyl
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, F, CI, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , or CN; and,
  • J is a bond or CH 2 .
  • R la and R lb are each independently H or unsubstituted C 1-3 alkyl
  • R 2a , R 20 , and R 2d are each independently H;
  • R 2b is H, F, or CI
  • R 3 is CH 3 , C 2 H 5 , CF 3 , F, CI or Br; wherein the CH 3 and C2H5 are each optionally substituted with one or more halogen;
  • R 7 is Ci_3 alkyl
  • R 8a and R 8e are each independently H, F, or CI;
  • R 8b and R 8d are each independently H, F, OCH 3 , or CN; and,
  • R 8c is H, F, or CI.
  • R la and R lb are each H
  • R 2a , R 3 ⁇ 4 , and R 2d are each H;
  • R 2b is CI
  • R 3 is CH 3 , C 2 H 5, CF 3 , F, CI, or Br;
  • R 7 is CH 3 or C 2 H 5 ;
  • R 8a , R 8b , R 8c , R 8d and R 8e are each selected from the group consisting of H, CN, OCH 3 , F, and CI wherein:
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is CN;
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is OCH 3 ;
  • R 8b , R 8c , and R 8d are each H, and R 8a and R 8e are each F or CI;
  • R 8b , R 8d , and R 8e are each H, R 8a is CI, and R 8c is F; or
  • R 8b and R 8e are each H, R 8a and R 8d are each F, and R 8c is CI.
  • R 3 is OR 4 .
  • R la and R lb are each independently H, Ci_6 alkyl, C1-7 cycloalkyl, or Ci_6 aralkyl; wherein each of the foregoing non-H moieties is 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 la and R lb are each independently H or Ci ⁇ alkyl; wherein the Ci-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-3 alkyl, hydroxyl, and OC1-3 alkyl.
  • R la and R lb are each independently H or unsubstituted Ci-3 alkyl. In yet other embodiments, R la and R lb are each H.
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, C1-4 alkyl, OCi_ 3 alkyl , or CF 3 . In other embodiments, R 2a , R 2b , R 20 , and R 2d are each
  • R 2a , R 2c , and R are each independently H; and, R is H, F, or CI.
  • R 2a , R 20 , and R 2d are each H; and, R 2b is CI.
  • R 4 is C1-5 alkyl; wherein the C1-5 alkyl is optionally substituted with: one or more unsubstituted substituents selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, cycloalkyl, and heterocycloalkyl; or substituted heterocycloalkyl.
  • R 4 is C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted with: one or more unsubstituted substituents selected from the group consisting of CI, F, Ci-2 alkyl, C1-2 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, and tetrahydrofuran; substituted oxetane; or substituted tetrahydrofuran.
  • R 4 is C1-4 alkyl; wherein the Ci ⁇ alkyl is optionally substituted with: one or more unsubstituted substituents selected from the group consisting of F, CH 3 , OCH 3 , cyclopropyl, cyclobutyl, and oxetane; or substituted oxetane.
  • R 4 is CH 3 , C2H5,
  • R 7 is Ci_6 alkyl. In other embodiments, R 7 is C1-4 alkyl. In still other embodiments, R 7 is C1-3 alkyl. In some exemplary embodiments, R 7 is CH 3 or
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_4 alkyl, OCi_ 4 alkyl, NR 5 R 6 , CF 3 , or CN.
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, F, CI, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , or CN.
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, F, CI, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , or CN.
  • R 8a and R 8e are each independently H, F, or CI;
  • R 8b and R 8d are each independently H, F, OCH 3 , or CN; and
  • R 8c is H, F, or CI.
  • R 8a and R 8e are each independently H, F, or CI;
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is CN;
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is OCH 3 ;
  • R 8b , R 8c , and R 8d are each H, and R 8a and R 8e are each F or CI;
  • R 8b , R 8d , and R 8e are each H, R 8a is CI, and R 8c is F; or R and R 5e are each H, R and R are each F, and c is CI.
  • J is a bond. In other embodiments, J is a Ci_ 4 alkylene.
  • R la and R lb are each independently H, Ci_6 alkyl, C1-7 cycloalkyl, or Ci_6 aralkyl;
  • substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen;
  • R 2a , R 2b , R 2c , and R 2d are each independently H, halogen, Ci_ 4 alkyl, OCi_ 3 alkyl , or CF 3 ;
  • R 4 is Ci_5 alkyl;
  • C1-5 alkyl is optionally substituted with: one or more unsubstituted
  • R 7 is Ci_6 alkyl
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, Ci_ 4 alkyl, OC M alkyl, NR 5 R 6 , CF 3 , or CN; and,
  • R la and R lb are each independently H or Ci_ 4 alkyl
  • Ci_ 4 alkyl is optionally substituted with one or more unsubstituted
  • R 2a , R 2b , R 2c , and R 2d are each independently F, CI, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , or CF 3 ;
  • R 4 is Ci_ 4 alkyl
  • Ci_ 4 alkyl is optionally substituted with: one or more unsubstituted
  • R 7 is Ci_ 4 alkyl
  • R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, F, CI, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , or CN. [00206] In still other embodiments:
  • R la and R lb are each independently H or unsubstituted C 1-3 alkyl
  • R 2a , R 20 , and R 2d are each independently H;
  • R 2b is H, F, or CI
  • R 4 is Ci_4 alkyl
  • C 1-4 alkyl is optionally substituted with: one or more unsubstituted
  • substituents selected from the group consisting of F, CH 3 , OCH 3 , cyclopropyl, cyclobutyl, and oxetane; or substituted oxetane;
  • R 7 is Ci_3 alkyl
  • R 8a and R 8e are each independently H, F, or CI;
  • R 8b and R 8d are each independently H, F, OCH 3 , or CN; and,
  • R & is H, F, or CI.
  • R la and R lb are each H
  • R 2a , R 20 , and R 2d are each H;
  • R 7 is CH 3 or C 2 H 5 ;
  • R 8a , R 8b , R 8c , R 8d and R 8e are each selected from the group consisting of H, CN, OCH 3 , F, or CI wherein:
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is CN;
  • R 8a , R 8c , R 8d , and R 8e are each H, and R 8b is OCH 3 ;
  • R 8b , R 8c , and R 8d are each H, and R 8a and R 8e are each F or CI;
  • R 8b , R 8d , and R 8e are each H, R 8a is CI, and R 8c is F; or
  • R 8b and R 8e are each H, R 8a and R 8d are each F, and R 8c is CI.
  • the compound of Fonnula I is a compound as shown in Table 2 or a pharmaceutically acceptable salt thereof
  • the compound of Formula I-b is a compound as shown in Table 3 or a pharmaceutically acceptable salt thereof
  • the compound of Formula II is a compound shown in Tables 4 and 5 or a pharmaceutically acceptable salt thereof.
  • IC 50 data is represented as follows: greater than or equal to 10 microMolar is designated at A; less than 10 microMolar but greater than or equal to 1 microMolar is designated as B; less than 1 microMolar but greater than or equal to 500 nanoMolar is designated at C; less than 500 nanoMolar but greater or equal to 100 nanoMolar is designated as D; less than 100 nanoMolar is designated at E.
  • Methods for the determination of the IC 50 data of Tables 2-5 are provided in the description of Assay 1 below.
  • the compound of Formula I or Formula II can include:
  • one or both of the R 3 or R 7 substituents contain at least one deuterium.
  • both the R 3 and R 7 substituents each contain at least one deuterium.
  • the R 7 substituent is alkyl, and wherein the alkyl contains at least one deuterium.
  • the R 7 substituent is methyl, and wherein the methyl contains at least one deuterium.
  • the R 7 substituent is - CD 3 .
  • the R 3 substituent is optionally substituted alkoxy or optionally substituted heterocycloalkyl, and wherein the R substituent contains at least one deuterium.
  • the R 3 substituent is 2- methylpropoxy, 2,2-dimethylpropoxy, cyclopropylmethoxy, cyclobutylmethoxy, pyrollidinyl, or piperidinyl, and wherein the R substituent contains at least one deuterium.
  • R 3 substituent is selected from:
  • the compound of Formula II is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound has the Formula Ila:
  • the compound has the Formula Ila ⁇
  • the compound is Compound 240:
  • the compound has the Formula lib:
  • the compound has the Formula Hb ⁇
  • the compound is Compound 241:
  • the compound has the Formula lie:
  • Formula lie or a pharmaceutically acceptable salt thereof.
  • the compound is Compound 242:
  • the compound has the Formula lid:
  • the compound has the Formula Ildi:
  • the compound has the Formula He:
  • R 7e is CH 3 or CD 3 .
  • the compound has the Formula Ilf:

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Abstract

La présente invention concerne des agonistes inverses, contenant biaryle, de récepteurs ROR-gamma. L'invention concerne également des compositions pharmaceutiques comprenant ces agonistes inverses contenant biaryle et des procédés de modulation de récepteurs ROR-gamma au moyen de ces agonistes inverses. Des procédés d'utilisation d'agonistes inverses contenant biaryle pour traiter des maladies médiées par ROR-gamma sont également décrits.
PCT/US2013/048992 2012-07-02 2013-07-02 Composés contenant biaryle comme agonistes inverses de récepteurs ror-gamma WO2014008214A1 (fr)

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US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
CN112341435B (zh) * 2019-08-09 2021-10-22 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341435A (zh) * 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN113912622A (zh) * 2020-07-10 2022-01-11 上海纽思克生物科技有限公司 三环嘧啶酮类化合物、其制备方法、其组合物和用途
CN113912622B (zh) * 2020-07-10 2023-12-01 上海纽思克生物科技有限公司 三环嘧啶酮类化合物、其制备方法、其组合物和用途

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