WO2016138533A2 - Small molecules that enable cartilage rejuvanation - Google Patents

Small molecules that enable cartilage rejuvanation Download PDF

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Publication number
WO2016138533A2
WO2016138533A2 PCT/US2016/020126 US2016020126W WO2016138533A2 WO 2016138533 A2 WO2016138533 A2 WO 2016138533A2 US 2016020126 W US2016020126 W US 2016020126W WO 2016138533 A2 WO2016138533 A2 WO 2016138533A2
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substituted
unsubstituted
nhc
nhnr
heterocycloalkyl
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English (en)
French (fr)
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WO2016138533A3 (en
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Denis EVSEENKO
Benjamin J. VAN HANDEL
Varghese John
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University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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Priority to EP16756554.8A priority Critical patent/EP3262040A4/en
Priority to KR1020177027191A priority patent/KR20170122788A/ko
Priority to AU2016224975A priority patent/AU2016224975B2/en
Priority to CA2977401A priority patent/CA2977401A1/en
Priority to JP2017545300A priority patent/JP2018508513A/ja
Priority to US15/553,353 priority patent/US11072592B2/en
Application filed by University of California Berkeley, University of California San Diego UCSD filed Critical University of California Berkeley
Priority to CN201680024174.9A priority patent/CN107531687A/zh
Publication of WO2016138533A2 publication Critical patent/WO2016138533A2/en
Publication of WO2016138533A3 publication Critical patent/WO2016138533A3/en
Anticipated expiration legal-status Critical
Priority to US16/213,958 priority patent/US11247974B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Articular cartilage is a highly specialized tissue formed from chondrocytes that protects the bones of diarthrodial joints from forces associated with load bearing and impact and allows nearly frictionless motion between articular surfaces.
  • Cartilage injury and minimal regeneration often lead to osteoarthritis, characterized by degradation of joints, including both articular cartilage and subchondral bone.
  • Osteoarthritis (OA) currently affects more than 25 million people in the United States alone, making joint surface restoration a major priority in modern medicine.
  • Regeneration of tissues is a complex process that can occur via multiple mechanisms. In some tissues with high turnover, such as blood or skin, replacement of dying cells is achieved by constant output from stem cells.
  • A is CR 14 or N.
  • B is CR 16 or N.
  • X is O, NR 19 or S.
  • L 1 is a bond or substituted or unsubstituted C1-C3 alkylene.
  • R 8 is hydrogen, halogen, -CX 8 1 3, -CHX 8 1 2 , -CH2X 8'1 , -CN, -SO n iR 8A , -SOviNR 8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(0)NHNR 8B R 8C , -NHC(0)NR 8B R 8C , -N(0) m i, -NR 8B R 8C , -C(0)R 8D , -C(0)OR 8D , -C(0)NR 8B R 8C , -OR 8A , -NR 8B S0 2 R 8A , -NR 8B C(0)R 8D ,
  • R 9 is hydrogen, halogen, -CX 9 1 3, - CHX 9 -CH 2 X 9 -CN, -SO nl R 9A , -SO vl NR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C ,
  • R 10 is hydrogen, halogen, - CX i i 3 , -CHX i i 2 , -CH 2 X i i , -CN, -SO n iR 10A , -SO v iNR 10B R 10C , -NHNR 10B R 10C ,
  • R 11 is hydrogen, halogen, -CX 1 L1 3 , -CHX 1 L1 2 , -CH 2 X 1 L1 , -CN, -SO n iR 11A , - SOviNR 11B R llc , -NHNR 11B R 11C , -ONR 11B R llc , -NHC(0)NHNR 11B R 11C , -NHC(0)NR 11B R 11C , -N(0) m i, -NR 11B R 11C , -C(0)R 11D , -C(0)OR 11D , -C(0)NR 11B R 11C , -OR 11A , -NR 11B S0 2 R 11A , - NR 11B C(0)R 11D , -NR 11B C(0)OR 11D , -NR 11B OR 11D , -OCX 11 , -OCHX 1L1 2 , substituted or unsubstituted alkyl,
  • R 13 is hydrogen, halogen, - CX 13 -CHX 13 -CH 2 X 13 - 1 , -CN, -SO n iR 13A , -SO v iNR 13B R 13C , -NHNR 13B R 13C ,
  • R 14 is hydrogen, halogen,
  • R 15 is hydrogen, halogen, -CX m 3 , -CHX 15 1 2 , -CH 2 X 15 1 , -CN, -SO n iR 15A , -SOviNR 15B R 15C , -NHNR 15B R 15C , -ONR 15B R 15C , -NHC(0)NHNR 15B R 15C , -NHC(0)NR 15B R 15C , -N(0) m i, -NR 15B R 15C , -C(0)R 15D , -C(0)OR 15D , -C(0)NR 15B R 15C , - OR 15A , -NR 15B S0 2 R 15A , -NR 15B C(0)R 15D , -NR 15B C(0)OR 15D , -NR 15B OR 15D , -OCX 15 - OCHX 15 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted
  • R 16 is hydrogen, halogen, - CX 16 1 3, -CHX 16 1 2, -CH 2 X 16 1 , -CN, -SO n iR 16A , -SO v iNR 16B R 16C , -NHNR 16B R 16C ,
  • R 18 is hydrogen, halogen, -CX lf 3 , -CHX 18 1 2 , -CH 2 X 18 1 , -CN, -SO n iR 18A , -SOviNR 18B R 18C , -NHNR 18B R 18C , -ONR 18B R 18C , -NHC(0)NHNR 18B R 18C , -NHC(0)NR 18B R 18C , -N(0) m i, -NR 18B R 18C , -C(0)R 18D , -C(0)OR 18D , -C(0)NR 18B R 18C , - OR 18A , -NR 18B S0 2 R 18A , -NR 18B C(0)R 18D , -NR 18B C(0)OR 18D , -NR 18B OR 18D , -OCX 18 - OCHX 18 1 2 , substituted or unsubstituted alkyl, substituted or unsubstitute
  • R is hydrogen, -COR C(0)NHNR 19B R 19C , -C(0)OR 19D , -S0 2 R 19A , C(0)NR 19B R 19C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • R 18D are independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -OH, -NH 2 , -COOH, - CONH 2 , -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH 2 ,
  • R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • X 1 1 , X 2 1 , X 3 ⁇ 1 , X 4 ⁇ 1 , X 5 ⁇ 1 , X 6 ⁇ 1 , X 7 ⁇ 1 , X 8 ⁇ 1 , X 9 ⁇ 1 , X 10 ⁇ 1 , X 11 ⁇ 1 , X 12 ⁇ 1 , X 13 ⁇ 1 , X 14 ⁇ 1 , X 15 ⁇ 1 , X 16 ⁇ 1 , X 17 ⁇ 1 and X 18'1 are independently -CI, -Br, -I or -F.
  • the symbol nl is 0, 1, 2, 3 or 4.
  • the symbols ml and vl are independently 1 or 2.
  • R 10 when A is CR 14 , then R 10 is not bromine. In embodiments, when B is CR 16 , then R 10 is not bromine. In embodiments, when L 1 is bond, then R 10 is not bromine. In embodiments, when one of R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 is hydrogen, then R 10 is not bromine. In embodiments, when R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are hydrogen, then R 10 is not bromine.
  • ⁇ R 1 i 9 y are hyd,rogen, , t ⁇ h TM en r R.1 1 0 U . is not bromine. In embodiments, R 10 is not bromine.
  • R 8 is hydrogen, halogen, -CX 8 1 3 , -CHX 8 1 2 , -CH 2 X 8 1 , -CN, -SO n iR 8A , -SOviNR 8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(0)NHNR 8B R 8C ,
  • R 9 is hydrogen, halogen, -CX 9 1 3, -CHX 9 1 2 , -CH 2 X 9 1 , - CN, -SO n iR 9A , -SOviNR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(0)NHNR 9B R 9C ,
  • R 10 is hydrogen, fluorine, chlorine or iodine, -CX 10 1 3, - CHX 10 1 2 , -CH 2 X 10 1 , -CN, -SO nl R 10A , -SO vl NR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(0) m i, -NR 10B R 10C , -C(O)R 10D , -C(O)OR 10D , -C(O)NR 10B R 10C , -OR 10A , -NR 10B SO 2 R 10A , -NR 10B C(O)R 10D , -NR 10B C(O)OR 10D , -NR 10B OR 10D , -OCX 10 1 3, -OCHX 10 1 2
  • R 11 is hydrogen, halogen, -CX 1L1 3 , -CHX 1 L1 2 , -CH 2 X 1 L1 , -CN, -SO n iR 11A , -SO v iNR 11B R l lc , -NHNR 11B R 11C , -ONR 11B R llc , -NHC(0)NHNR 11B R 11C , -NHC(0)NR 11B R 11C , -N(0) m i, - NR i iB R i ic _ C (o)R 11D , _c(0)OR 11D , -C(0)NR 11B R 11C , -OR 11A , -NR 11B S0 2 R 11A , - NR 11B C(0)R 11D , -NR 11B C(0)OR 11D ,
  • R is hydrogen, ha -CX ' 3, -CHX ' 2 , -CH 2 X ' , -CN, -SO n iR 12A , -SOviNR 12B R 12C , -NHNR 12B R 12C , -ONR 12B R 12C , -NHC(0)NHNR 12B R 12C , -NHC(0)NR 12B R 12C , -N(0) m i , -NR 12B R 12C , -C(0)R 12D , -C(0)OR 12D , -C(0)NR 12B R 12C , - OR 12A , -NR 12B S0 2 R 12A , -NR 12B C(0)R 12D , -NR 12B C(0)OR 12D , -NR 12B OR 12D , -OCX 12 - OCHX 12 1 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted
  • R 13 is hydrogen, halogen, - CX 13 -CHX 13 -CH2X 13 ' 1 , -CN, -SO n iR 13A , -SO v iNR 13B R 13C , -NHNR 13B R 13C ,
  • -ONR 13B R 13C -NHC(0)NHNR 13B R 13C , -NHC(0)NR 13B R 13C , -N(0) m i , -NR 13B R 13C , - C(0)R 13D , -C(0)OR 13D , -C(0)NR 13B R 13C , -OR 13A , -NR 13B S0 2 R 13A , -NR 13B C(0)R 13D , - NR 13B C(0)OR 13D , -NR 13B OR 13D , -OCX 13 , -OCHX 13 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 14 is hydrogen, halogen, -CX 14 1 3 , -CHX 14 1 2 , -CH 2 X 14 1 , -CN, -SO n iR 14A , - SOviNR 14B R 14C , -NHNR 14B R 14C , -ONR 14B R 14C , -NHC(0)NHNR 14B R 14C , -NHC(0)NR 14B R 14C , -N(0) m i , -NR 14B R 14C , -C(0)R 14D , -C(0)OR 14D , -C(0)NR 14B R 14C , -OR 14A , -NR 14B S0 2 R 14A , - NR 14B C(0)R 14D , -NR 14B C(0)OR 14D , -NR 14B OR 14D , -OCX 14 , -OCHX 14 1 2 , substituted or unsubstituted alkyl, substituted or unsub
  • R 15 is hydrogen, halogen, -CX 15 1 3, -CHX 15 1 2 , -CH 2 X 15 1 , -CN, -SOniR 15A , -SOviNR 15B R 15C , -NHNR 15B R 15C , -ONR 15B R 15C , -NHC(0)NHNR 15B R 15C , -NHC(0)NR 15B R 15C , -N(0) m i , -NR 15B R 15C , -C(0)R 15D , -C(0)OR 15D , -C(0)NR 15B R 15C , - OR 15A , -NR 15B S0 2 R 15A , -NR 15B C(0)R 15D , -NR 15B C(0)OR 15D , -NR 15B OR 15D , -OCX 15 - OCHX 15 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalky
  • R 16 is hydrogen, halogen, - CX 16 1 3, -CHX 16 1 2, -CH 2 X 16 1 , -CN, -SO n iR 16A , -SO v iNR 16B R 16C , -NHNR 16B R 16C ,
  • -ONR 16B R 16C -NHC(0)NHNR 16B R 16C , -NHC(0)NR 16B R 16C , -N(0) m i , -NR 16B R 16C , - C(0)R 16D , -C(0)OR 16D , -C(0)NR 16B R 16C , -OR 16A , -NR 16B S0 2 R 16A , -NR 16B C(0)R 16D , - NR 16B C(0)OR 16D , -NR 16B OR 16D , -OCX 16 1 3 , -OCHX 16 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 17 is hydrogen, halogen, -CX m 3 , -CHX 17 1 2 , -CH 2 X m , -CN, -SO n iR 17A , - SO v iNR 17B R 17C , -NHNR 17B R 17C , -ONR 17B R 17C , -NHC(0)NHNR 17B R 17C , -NHC(0)NR 17B R 17C , -N(0) m i, -NR 17B R 17C , -C(0)R 17D , -C(0)OR 17D , -C(0)NR 17B R 17C , -OR 17A , -NR 17B S0 2 R 17A , - NR 17B C(0)R 17D , -NR 17B C(0)OR 17D , -NR 17B OR 17D , -OCX 17 , -OCHX 17 1 2 , substituted or unsubstituted alkyl, substituted or
  • R is hydrogen, halogen, -CX ' 3 , -CHX ' 2 , -CH 2 X ' , -CN, -SO n iR 18A , -SO v iNR 18B R 18C , -NHNR 18B R 18C , -ONR 18B R 18C , -NHC(0)NHNR 18B R 18C , -NHC(0)NR 18B R 18C , -N(0) m i, -NR 18B R 18C , -C(0)R 18D , -C(0)OR 18D , -C(0)NR 18B R 18C , - OR 18A , -NR 18B S0 2 R 18A , -NR 18B C(0)R 18D , -NR 18B C(0)OR 18D , -NR 18B OR 18D , -OCX 18 - OCHX 18 1 2 , substituted or unsubstituted alkyl, substituted or unsubstit
  • R 19 is hydrogen, -COR 19D , - C(0)NHNR 19B R 19C , -C(0)OR 19D -S0 2 R 19A , C(0)NR 19B R 19C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • R 18D are independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , -CI 3 , -OH, -NH 2 , -COOH, - CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 ,
  • R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • X 1 1 , X 2 1 , X 3 ⁇ 1 , X 4 ⁇ 1 , X 5 ⁇ 1 , X 6 ⁇ 1 , X 7 ⁇ 1 , X 8 ⁇ 1 , X 9 ⁇ 1 , X 10 ⁇ 1 , X 11 ⁇ 1 , X 12 ⁇ 1 , X 13 ⁇ 1 , X 14 ⁇ 1 , X 15 ⁇ 1 , X 16 ⁇ 1 , X 17 ⁇ 1 and X 18'1 are independently -CI, -Br, -I or -F.
  • the symbol nl is 0, 1, 2, 3 or 4.
  • the symbols ml and vl are independently 1 or 2.
  • R 8 is hydrogen, halogen, -CX 8 1 3 , -CHX 8 1 2 , -CH 2 X 8 1 , -CN, -SO n iR 8A , -SOviNR 8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(0)NHNR 8B R 8C ,
  • R 9 is hydrogen, halogen, -CX 9' ⁇ , -CHX 9 1 2 , -CH 2 X 9 1 , - CN, -SO n iR 9A , -SOviNR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(0)NHNR 9B R 9C ,
  • R 10 is hydrogen, halogen, -CX 10 1 3 , -CHX 10 1 2 , -CH 2 X 10 1 , -CN, -SO n iR 10A , -SOviNR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(0) m i, -NR 10B R 10C , -C(O)R 10D , -C(O)OR 10D , -C(O)NR 10B R 10C , -
  • OCHX 10 1 2 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 11 is hydrogen, halogen, -
  • R 12 is hydrogen, halogen, -CX 12 1 3 , -CHX 12 1 2 , -CH 2 X 12 1 , -CN, -SO n iR 12A ,
  • R 15 is hydrogen, halogen, - CX 15 -CHX 15 -CH 2 X 15 - 1 , -CN, -SO n iR 15A , -SO v iNR 15B R 15C , -NHNR 15B R 15C ,
  • R 18 is hydrogen, halogen, - -CH2X 1 8' 1 , -CN, -SO n iR 18A , -SO v iNR 18B R 18C , -NHNR 18B R 18C ,
  • -ONR 18B R 18C -NHC(0)NHNR 18B R 18C , -NHC(0)NR 18B R 18C , -N(0) m i, -NR 18B R 18C , - C(0)R 18D , -C(0)OR 18D , -C(0)NR 18B R 18C , -OR 18A , -NR 18B S0 2 R 18A , -NR 18B C(0)R 18D , - NR 18B C(0)OR 18D , -NR 18B OR 18D , -OCX 18 1 3 , -OCHX 18 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 19 is hydrogen, -COR 19D , -C(0)NHNR 19B R 19C , -C(0)OR 19D -S0 2 R 19A , - C(0)NR 19B R 19C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • R 16C , R 16D , R 17A ⁇ R 17B , R 17C , R 17D , R 18A* R 18B , R 18C and R 18D are independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , -CI 3 , -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO4H, - S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, - NHC(0)-OH, -NHOH, -OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , - OCHI 2
  • R 13C , R 14B , R 14C , R 15B , R 15C , R 16B , R 16C , R 17B , R 17C , R 18B and R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • X 1 1 , X 2 1 , X 3 1 , X 4 1 , X 5 1 , X 6 1 , X 7 1 , X 8 1 , X 9 1 , X 10 1 , X 11 1 , X 12 1 , X 13 1 , X 14 1 , X 15 1 , X 16 1 , X 17 1 and X 18 1 are independently -CI, -Br, -I or -F.
  • the symbol nl is 0, 1, 2, 3 or 4.
  • the symbols ml and vl are independently 1 or 2.
  • R 8 is hydrogen, halogen, -CX 8 1 3 , -CHX 8 1 2 , -CH 2 X 8 1 , -CN, -SO n iR 8A , -SOviNR 8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(0)NHNR 8B R 8C ,
  • R 9 is hydrogen, halogen, -CX 9 1 3, -CHX 9 1 2 , -CH 2 X 9 1 , - CN, -SO n iR 9A , -SO v iNR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(0)NHNR 9B R 9C ,
  • R 10 is hydrogen, halogen, -CX 10 1 3, -CHX 10 1 2 , -CH 2 X 10 1 , -CN, -SO n iR 10A , -SOviNR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(0) m i, -NR 10B R 10C , -C(O)R 10D , -C(O)OR 10D , -C(O)NR 10B R 10C , -
  • OCHX 10 1 2 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 11 is hydrogen, halogen, -
  • R 12 is hydrogen, halogen, -CX 12 1 3 , -CHX 12 1 2 , -CH 2 X 12 1 , -CN, -SO n iR 12A ,
  • R is hydrogen, halogen, -CX ' 3, -CHX ' 2 , -CH 2 X ' , -CN, -SO n iR 13A , -SO v iNR 13B R 13C , -NHNR 13B R 13C , -ONR 13B R 13C , -NHC(0)NHNR 13B R 13C , -NHC(0)NR 13B R 13C , -N(0) m i, -NR 13B R 13C , -C(0)R 13D , -C(0)OR 13D , -C(0)NR 13B R 13C , - OR 13A , -NR 13B S0 2 R 13A , -NR 13B C(0)R 13D , -NR 13B C(0)OR 13D , -NR 13B OR 13D , -OCX 13 - OCHX 13 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted
  • R 15 is hydrogen, halogen, - CX 15 -CHX 15 -CH 2 X 15 - 1 , -CN, -SO n iR 15A , -SO v iNR 15B R 15C , -NHNR 15B R 15C ,
  • R 18 is hydrogen, halogen, -CX 18 1 3 , -CHX 18 1 2 , -CH 2 X 18 1 , -CN, -SO n iR 18A , -SO v iNR 18B R 18C , -NHNR 18B R 18C , -ONR 18B R 18C , -NHC(0)NHNR 18B R 18C , -NHC(0)NR 18B R 18C , -N(0) m i, -NR 18B R 18C , -C(0)R 18D , -C(0)OR 18D , -C(0)NR 18B R 18C , - OR 18A , -NR 18B S0 2 R 18A , -NR 18B C(0)R 18D , -NR 18B C(0)OR 18D , -NR 18B OR 18D , -OCX 18 - OCHX 18 1 2 , substituted or unsubstituted alkyl, substituted or unsubsti
  • R is hydrogen, -COR C(0)NHNR 19B R 19C , -C(0)OR 19D , -S0 2 R 19A , C(0)NR 19B R 19C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • R 18D are independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -OH, -NH 2 , -COOH, - CONH 2 , -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH 2 ,
  • R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • X 1 1 , X 2 1 , X 3 ⁇ 1 , X 4 ⁇ 1 , X 5 ⁇ 1 , X 6 ⁇ 1 , X 7 ⁇ 1 , X 8 ⁇ 1 , X 9 ⁇ 1 , X 10 ⁇ 1 , X 11 ⁇ 1 , X 12 ⁇ 1 , X 13 ⁇ 1 , X 14 ⁇ 1 , X 15 ⁇ 1 , X 16 ⁇ 1 , X 17 ⁇ 1 and X 18'1 are independently -CI, -Br, -I or -F.
  • the symbol nl is 0, 1, 2, 3 or 4.
  • the symbols ml and vl are independently 1 or 2.
  • compositions are also provided herein.
  • a pharmaceutical composition in one aspect is a
  • composition that includes a compound described herein and a pharmaceutically acceptable excipient.
  • a method of increasing MYC expression in a cell includes contacting the cell with a binding site 1 gpl30 receptor agonist.
  • a method of increasing pSTAT3 expression in a cell including contacting the cell with a binding site 1 gpl30 receptor agonist.
  • a method of regulating chondrocyte activation, maturation and/or differentiation comprising contacting a chondrocyte with a binding site 1 gpl30 receptor agonist.
  • a method of regenerating or repairing tissue in a subject in need thereof includes administering to the subject a therapeutically effective amount of a binding site 1 gpl30 receptor agonist.
  • a method of repairing a joint surface injury in a subject comprising administering to the subject a therapeutically effective amount of a binding site 1 gpl30 receptor agonist.
  • a method of treating a cartilage degenerative disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a binding site 1 gpl30 receptor agonist.
  • a method of increasing secretion of cartilaginous matrix in cartilage comprises contacting a gpl30 receptor with a binding site 1 gpl30 receptor agonist.
  • a method of modulating the activity of a gpl30 receptor in a cell comprising contacting the cell with a binding site 1 gpl30 receptor agonist.
  • a method of transforming a mature adult cell into a progenitor cell including contacting the cell with a binding site 1 gpl30 receptor agonist.
  • the binding site 1 gpl30 receptor agonist of the methods provided herein is a compound of Formula (III):
  • A is CR or N.
  • B is CR or N.
  • X is O, NR 19 or S.
  • L 1 is a bond or substituted or unsubstituted C 1-C3 alkylene.
  • R 8 is hydrogen, halogen, -CX 8 1 3 , -CHX 8 1 2 , -CH 2 X 8 1 , -CN, -SO n iR 8A , -SO v iNR 8B R 8C , -NHNR 8B R 8C ,
  • -ONR 8B R 8C -NHC(0)NHNR 8B R 8C , -NHC(0)NR 8B R 8C , -N(0) m i, -NR 8B R 8C , -C(0)R 8D , - C(0)OR 8D , -C(0)NR 8B R 8C , -OR 8A , -NR 8B S0 2 R 8A , -NR 8B C(0)R 8D , -NR 8B C(0)OR 8D , - NR 8B OR 8D , -OCX 8 , -OCHX 8 1 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • R 9 is hydrogen, halogen, -CX 9 1 3 , -CHX 9 1 2 , -CH 2 X 9 1 , -CN, -SO n iR 9A , -SO v iNR 9B R 9C ,
  • R 10 is hydrogen, halogen, -CX 10 1 3 , -CHX 10 1 2 , -CH 2 X 10 1 , -CN, -SO n iR 10A , -SO v iNR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(0) m i, - NR IOB R IOC _ C(0)R IOD _ c(O )OR 10D , -C(O)NR 10B R 10C , -OR 10A , -NR 10B SO 2 R 10A , - NR 10B C(O)R 10D , -NR 10B C(O)OR 10D , -NR 10B OR 10D , -OCX 10 1 3 , -OCHX 10 1 2 , substituted or un
  • R 11 is hydrogen, halogen, -CX 1 L 1 3, -CHX 1 L1 2 , -CH 2 X 1L1 , -CN, -SO n iR 11A , -SOviNR 11B R llc , -NHNR 11B R 11C , -ONR 11B R llc , -NHC(0)NHNR 11B R llc , -NHC(0)NR 11B R 11C , -N(0) m i, -NR 11B R 11C , -C(0)R 11D , -C(0)OR 11D , -C(0)NR 11B R 11C , - OR 11A , -NR 11B S0 2 R 11A , -NR 11B C(0)R 11D , -NR 11B C(0)OR 11D , -NR 11B OR 11D , -OCX 11 - OCHX 1 L1 2 , substituted or unsubstituted alkyl, substituted or un
  • -ONR 12B R 12C -NHC(0)NHNR 12B R 12C , -NHC(0)NR 12B R 12C , -N(0) m i, -NR 12B R 12C , - C(0)R 12D , -C(0)OR 12D , -C(0)NR 12B R 12C , -OR 12A , -NR 12B S0 2 R 12A , -NR 12B C(0)R 12D , - NR 12B C(0)OR 12D , -NR 12B OR 12D , -OCX 12 , -OCHX 12 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 13 is hydrogen, halogen, -CX 13 1 3 , -CHX 13 1 2 , -CH 2 X 13 1 , -CN, -SO n iR 13A , - SOviNR 13B R 13C , -NHNR 13B R 13C , -ONR 13B R 13C , -NHC(0)NHNR 13B R 13C , -NHC(0)NR 13B R 13C , -N(0) m i , -NR 13B R 13C , -C(0)R 13D , -C(0)OR 13D , -C(0)NR 13B R 13C , -OR 13A , -NR 13B S0 2 R 13A , - NR 13B C(0)R 13D , -NR 13B C(0)OR 13D , -NR 13B OR 13D , -OCX 13 , -OCHX 13 1 2 , substituted or unsubstituted alkyl, substituted or unsub
  • R 15 is hydrogen, halogen, - CX 15 -CHX 15 -CH2X 15' 1 , -CN, -SOniR 15A , -SO v iNR 15B R 15C , -NHNR 15B R 15C ,
  • -ONR 15B R 15C -NHC(0)NHNR 15B R 15C , -NHC(0)NR 15B R 15C , -N(0) m i , -NR 15B R 15C , - C(0)R 15D , -C(0)OR 15D , -C(0)NR 15B R 15C , -OR 15A , -NR 15B S0 2 R 15A , -NR 15B C(0)R 15D , - NR 15B C(0)OR 15D , -NR 15B OR 15D , -OCX 15 , -OCHX 15 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 16 is hydrogen, halogen, -CX 16 1 3 , -CHX 16 1 2 , -CH 2 X 16 1 , -CN, -SO n iR 16A , - SOviNR 16B R 16C , -NHNR 16B R 16C , -ONR 16B R 16C , -NHC(0)NHNR 16B R 16C , -NHC(0)NR 16B R 16C , -N(0) m i , -NR 16B R 16C , -C(0)R 16D , -C(0)OR 16D , -C(0)NR 16B R 16C , -OR 16A , -NR 16B S0 2 R 16A , - NR 16B C(0)R 16D , -NR 16B C(0)OR 16D , -NR 16B OR 16D , -OCX 16 1 3 , -OCHX 16 1 2 , substituted or unsubstituted alkyl, substituted or
  • R is hydrogen, ha -CX ' 3, -CHX ' 2 , -CH 2 X ' , -CN, -SO n iR 17A , -SOviNR 17B R 17C , -NHNR 17B R 17C , -ONR 17B R 17C , -NHC(0)NHNR 17B R 17C , -NHC(0)NR 17B R 17C , -N(0) m i , -NR 17B R 17C , -C(0)R 17D , -C(0)OR 17D , -C(0)NR 17B R 17C , - OR 17A , -NR 17B S0 2 R 17A , -NR 17B C(0)R 17D , -NR 17B C(0)OR 17D , -NR 17B OR 17D , -OCX 17 - OCHX 17 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
  • R 18 is hydrogen, halogen, - CX 1 3, -CHX 18 - ⁇ , -CH2X 18 - 1 , -CN, -SO n iR 18A , -SO v iNR 18B R 18C , -NHNR 18B R 18C , -ONR 18B R 18C , -NHC(0)NHNR 18B R 18C , -NHC(0)NR 18B R 18C , -N(0) m i, -NR 18B R 18C , - C(0)R 18D , -C(0)OR 18D , -C(0)NR 18B R 18C , -OR 18A , -NR 18B S0 2 R 18A , -NR 18B C(0)R 18D , - NR 18B C(0)OR 18D , -NR 18B OR 18D , -OCX 18 1 3 , -OCHX 18 1 2 , substituted or unsubstituted alkyl, substituted or
  • C(0)NR 19B R 19C substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • R 16C , R 16D , R 17A ⁇ R 17B , R 17C , R 17D , R 18A* R 18B , R 18C and R 18D are independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , -CI 3 , -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO4H, - S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, - NHC(0)-OH, -NHOH, -OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -0CHC1 2 , -OCHBr 2 , - OCHI 2
  • R 13C , R 14B , R 14C , R 15B , R 15C , R 16B , R 16C , R 17B , R 17C , R 18B and R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • X 1 1 , X 2 1 , X 3 1 , X 4 1 , X 5 1 , X 6 1 , X 7 1 , X 8 1 , X 9 1 , X 10 1 , X 11 1 , X 12 1 , X 13 1 , X 14 1 , X 15 1 , X 16 1 , X 17 1 and X 18 1 are independently -CI, -Br, -I or -F.
  • the symbol nl is 0, 1, 2, 3 or 4.
  • the symbols ml and vl are independently 1 or 2.
  • composition comprising a gpl30 receptor bound to a binding site 1 gpl30 receptor agonist.
  • the binding site 1 gpl30 receptor agonist is bound to the binding site 1 of the gp 130 receptor.
  • the binding site 1 gpl30 receptor agonist of the compositions provided herein is a compound of Formula (III):
  • A is CR 14 orN.
  • B is CR 16 or N.
  • X is O, NR 19 or S.
  • L 1 is a bond or substituted or unsubstituted C1-C3 alkylene.
  • R 8 is hydrogen, halogen, -CX 81 3 , -CHX 81 2 , -CH 2 X 81 , -CN, -SO n iR 8A , -SO v iNR 8B R 8C , -NHNR 8B R 8C ,
  • -ONR 8B R 8C -NHC(0)NHNR 8B R 8C , -NHC(0)NR 8B R 8C , -N(0) m i, -NR 8B R 8C , -C(0)R 8D , - C(0)OR 8D , -C(0)NR 8B R 8C , -OR 8A , -NR 8B S0 2 R 8A , -NR 8B C(0)R 8D , -NR 8B C(0)OR 8D , - NR 8B OR 8D , -OCX 8 , -OCHX 8 1 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • R 9 is hydrogen, halogen, -CX 91 3 , -CHX 9 1 2 , -CH 2 X 91 , -CN, -SO n iR 9A , -SO v iNR 9B R 9C ,
  • R 11 is hydrogen, halogen, -CX 1L1 3, -CHX 1L1 2 , -CH 2 X 1L1 , -CN, -SOniR 11A , -SOviNR 11B R llc , -NHNR 11B R 11C , -ONR 11B R llc , -NHC(0)NHNR 11B R llc , -NHC(0)NR 11B R 11C , -N(0) m i, -NR 11B R 11C , -C(0)R 11D , -C(0)OR 11D , -C(0)NR 11B R 11C , - OR 11A , -NR 11B S0 2 R 11A , -NR 11B C(0)R 11D , -NR 11B C(0)OR 11D , -NR 11B OR 11D , -OCX 11 - OCHX 1 L1 2 , substituted or unsubstituted alkyl, substituted or unsubsti
  • R 12 is hydrogen, halogen, - CX 12 - ⁇ , -CHX 12 - ⁇ , -CH 2 X 12'1 , -CN, -SO n iR 12A , -SO v iNR 12B R 12C , -NHNR 12B R 12C ,
  • -ONR 12B R 12C -NHC(0)NHNR 12B R 12C , -NHC(0)NR 12B R 12C , -N(0) m i, -NR 12B R 12C , - C(0)R 12D , -C(0)OR 12D , -C(0)NR 12B R 12C , -OR 12A , -NR 12B S0 2 R 12A , -NR 12B C(0)R 12D , - NR 12B C(0)OR 12D , -NR 12B OR 12D , -OCX 12 , -OCHX 12 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 13 is hydrogen, halogen, -CX 13 1 3 , -CHX 13 1 2 , -CH 2 X 13 1 , -CN, -SO n iR 13A , - SO v iNR 13B R 13C , -NHNR 13B R 13C , -ONR 13B R 13C , -NHC(0)NHNR 13B R 13C , -NHC(0)NR 13B R 13C , -N(0) m i, -NR 13B R 13C , -C(0)R 13D , -C(0)OR 13D , -C(0)NR 13B R 13C , -OR 13A , -NR 13B S0 2 R 13A , - NR 13B C(0)R 13D , -NR 13B C(0)OR 13D , -NR 13B OR 13D , -OCX 13 , -OCHX 13 1 2 , substituted or unsubstituted alkyl, substituted or
  • R 14 is hydrogen, halogen, -CX 14 1 3 , -CHX 14 1 2 , -CH 2 X 14 1 , -CN, -SO nl R 14A , -SO vl NR 14B R 14C , -NHNR 14B R 14C , -ONR 14B R 14C , -NHC(0)NHNR 14B R 14C , -NHC(0)NR 14B R 14C , -N(0) ml , -NR 14B R 14C , -C(0)R 14D , -C(0)OR 14D , -C(0)NR 14B R 14C , - OR 14A , -NR 14B S0 2 R 14A , -NR 14B C(0)R 14D , -NR 14B C(0)OR 14D , -NR 14B OR 14D , -OCX 14 - OCHX 14 1 2 , substituted or unsubstituted alkyl, substituted or unsubstit
  • R 15 is hydrogen, halogen, - CX 15 -CHX 15 -CH 2 X 15 - 1 , -CN, -SO n iR 15A , -SO v iNR 15B R 15C , -NHNR 15B R 15C ,
  • -ONR 15B R 15C -NHC(0)NHNR 15B R 15C , -NHC(0)NR 15B R 15C , -N(0) m i, -NR 15B R 15C , - C(0)R 15D , -C(0)OR 15D , -C(0)NR 15B R 15C , -OR 15A , -NR 15B S0 2 R 15A , -NR 15B C(0)R 15D , - NR 15B C(0)OR 15D , -NR 15B OR 15D , -OCX 15 , -OCHX 15 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 16 is hydrogen, halogen, -CX 16 1 3 , -CHX 16 1 2 , -CH 2 X 16 1 , -CN, -SO n iR 16A , - SO v iNR 16B R 16C , -NHNR 16B R 16C , -ONR 16B R 16C , -NHC(0)NHNR 16B R 16C , -NHC(0)NR 16B R 16C , -N(0) m i, -NR 16B R 16C , -C(0)R 16D , -C(0)OR 16D , -C(0)NR 16B R 16C , -OR 16A , -NR 16B S0 2 R 16A , - NR 16B C(0)R 16D , -NR 16B C(0)OR 16D , -NR 16B OR 16D , -OCX 16 1 3 , -OCHX 16 1 2 , substituted or unsubstituted alkyl, substitute
  • R 18 is hydrogen, halogen, - CX 1 3, -CHX 18 ⁇ , -CH2X 1 8' 1 , -CN, -SO n iR 18A , -SO v iNR 18B R 18C , -NHNR 18B R 18C ,
  • -ONR 18B R 18C -NHC(0)NHNR 18B R 18C , -NHC(0)NR 18B R 18C , -N(0) m i, -NR 18B R 18C , - C(0)R 18D , -C(0)OR 18D , -C(0)NR 18B R 18C , -OR 18A , -NR 18B S0 2 R 18A , -NR 18B C(0)R 18D , - NR 18B C(0)OR 18D , -NR 18B OR 18D , -OCX 18 1 3 , -OCHX 18 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 19 is hydrogen, -
  • C(0)NR 19B R 19C substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • R 16C , R 16D , R 17A ⁇ R 17B , R 17C , R 17D , R 18A* R 18B , R 18C and R 18D are independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , -CI 3 , -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, - S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, - NHC(0)-OH, -NHOH, -OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , - OCHI 2
  • R 13C , R 14B , R 14C , R 15B , R 15C , R 16B , R 16C , R 17B , R 17C , R 18B and R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • X 1 1 , X 2 1 , X 3 1 , X 4 1 , X 5 1 , X 6 1 , X 7 1 , X 8 1 , X 9 1 , X 10 1 , X 11 1 , X 12 1 , X 13 1 , X 14 1 , X 15 1 , X 16 1 , X 17 1 and X 18 1 are independently -CI, -Br, -I or -F.
  • the symbol nl is 0, 1, 2, 3 or 4.
  • the symbols ml and vl are independently 1 or 2.
  • FIGS. 1A-1D Pre-chondrocytes represent a transcriptionally distinct population in developing limbs.
  • Fig. IB Unsupervised gene cluster analysis of significantly differentially expressed genes in laser capture microdissected pre-chondrocytes (PC) from a 5-6 week specimen versus total limb cells (TLC) from the same specimen.
  • FIG. 1C Cartoon demonstrating principal component analysis.
  • FIG. ID Genes enriched in chondrocyte condensations (pre-chondrocytes) are tabulated.
  • FIGS. 2A-2D Definitive resting (immature) chondrocytes at 17 weeks are enriched for components of the LIF signaling pathway.
  • FIG. 2A Resting chondrocytes were isolated by dissecting a -200 mm thick layer of cells from the femoral epiphysis as indicated by the dotted line.
  • FIG. 2B Unsupervised clustering of 1222 genes differentially expressed between pre- chondrocytes (PC, 6 independent specimens) and definitive 17 week fetal resting chondrocytes (RC, 3 independent specimens).
  • FIG. 2C Principal component analysis performed on all probe sets demonstrated the reproducibility of data between biological replicates.
  • FIG. 2D Genes enriched in 17 week fetal resting chondrocytes.
  • FIGS. 3A-3G BMPR1B and LIFR delineate resting chondrocytes after de novo chondrogenesis.
  • FIG. 3A Developmental dynamics of BMPR1B expression in human chondrocytes. BMPR1B is highly expressed in resting chondrocytes at 8, 12 and 17 weeks of development, but is clearly absent in hypertrophic chondrocytes after 12 weeks. Positive signal is shown in brown color (3, 3'-diaminobenzidine), nuclei counterstained with hematoxylin.
  • LIFR is expressed by resting chondrocytes and not by hypertrophic chondrocytes, while LIF is expressed by both resting chondrocytes and neighboring synovial cells.
  • FIG. 3C In post-natal articular cartilage, resting chondrocytes in the superficial zone (negative for Safranin O and Fast
  • FIG. 3D Reserve chondrocytes in the growth plate region at the same stage also express BMPR1B and LIFR; hypertrophic chondrocytes are negative.
  • FIG. 3E At later adult stages, a subset of BMPR1B+ and LIFR+ cells (arrows) remain in the surface layer of normal articular cartilage from the knee joint, while LIF (FIG. 3F) is minimally secreted by synovial cells.
  • FIG. 4 RNA-seq analysis of early limb bud, pluripotency and JAK-STAT pathway genes in human embryonic (5-6 weeks), fetal (17 weeks) and adult articular chondrocytes.
  • FIGS. 5A-5D Molecular and functional comparison of adult and fetal human articular cartilage.
  • FIG. 5A Western blot showing p-STAT3 and c-MYC levels; Histone 3 is a housekeeping gene.
  • FIG. 5B Proliferating, EDU + cells in cartilage explants.
  • FIG. 5C
  • FIG. 6 Proliferation of chondrocytes (arrows) and expression of the stem cell marker ALDH1A1 and LIFR in adult articular cartilage explants treated with LIF (50 ng/mL for 3 days).
  • FIGS. 8A-8B depicts photomicrograph of articular cartilage in 60-year old subject showing BMPR1B+ cells. Boxed section is enlarged in FIG. 8B.
  • FIGS. 9A-9C BMPR1B+ cells in fetus are proliferative and produce elevated levels of matrix components compared with adult.
  • FIGS. lOA-lOC Photomicrographs of fetal synovium and cartilage in isotype, LIFR and LIF specimens.
  • FIG. 10B Photomicrographs of adult synovium and cartilage in isotype, LIFR and LIF specimens, as indicated.
  • FIG. 11 Analysis of effect of soluble LIFR on levels of pSTAT3, c-Myc and H3. Reagent conditions are as indicated in the figure. It is observed that soluble LIF receptor reduces levels of p-STAT3 and c-MYC in fetal chondrocytes.
  • FIGS. 12A-12B Inhibition of p-STAT and c-Myc markedly reduced fetal chondrocyte survival and clonal potential.
  • FIG. 12A Cell sorting results for control (left), p-STAT3 inhibitor (middle) and c-MYC inhibitor (right), y-axis: FSC (forward scatter), x-axis: increasing concentration of Annexin V-FITC.
  • FIG. 12B Histogram depicting % clonogenic cells (fetal BMPR1B+ chondrocytes) under: control, p-STAT3 and c-MYC inhibitor conditons.
  • FIG. 13 LIF increases levels of pSTAT and c-Myc and stimulated proliferation of BMPR1B+ chondrocytes in adult cartilage explants.
  • Figure depict photomicrographs of control (left) and LIF (right) for BMPR1B, EDU and Dapi.
  • FIG. 14 Figures depict results spectrum of screening from 170,000 compounds to identify 469 compounds.
  • FIG. 15. Figure depicts % positive z-scores for 469 compounds selected for least mCherry expression. % positive as defined as the percentage of live nuclei that overlapped with mCherry signal, which is a multi-wavelength cell scoring function used to select for greatest loss of mCherry signal.
  • FIG. 16 Figure depicts results of further screening of 75 compounds having lowest positive scores in mCherry procedure. 469 compounds were re-tested to confirm first round results. Compounds with the 75 lowest % positive scores were selected for further studies, all of which showed at least 50% decrease compared to mean negative control scores. Mean (75) 33.78%; Min: 12.32%; Max: 45.69%. Mean (469) 79.89%. (-) Control mean: 96.83%.
  • FIG. 17 Figure depicts results of further screening to arrive at seven compounds. Assayed protein and reagent conditions are set forth in the figure.
  • FIG. 18 Figure depicts expression of p-STAT, c-Myc and Histone (H3) for compound CRM-423 (Cmpd 423).
  • FIGS. 19A-19C Figures depict result of cell sorting experiment showing that LIF and Cmpd 423 increase chondrocytes survival in adult explants.
  • FIG. 19A control
  • FIGG 19B LIF (50 ng/mL)
  • FIG. 19C CRM-423 (10 uM).
  • FIG. 20A-20B Figures depict histogram results showing that LIF and compounds disclosed herein increase percentage of BMPR1B+ immature chondrocytes in culture.
  • FIG. 20A % positive for (left to right): control, BMP4, LIF, CRM-423 1 uM; and CRM-423 10 uM.
  • FIG. 20B Clonogenic potential (%) for (left to right): control, LIF, and CRM-A.
  • FIGS. 21A-21B Figures depict that BMPR1B+ adult chondrocytes demonstrate significantly higher collagen production potential BMPR1B+ cells.
  • FIG. 21A cell sorting results for isotype (left), BMPR18 ne (middle), and BMPR18+ cells (right).
  • FIG. 21B CRM- 423 (right panel) stimulates collagen 2 product by adult chondrocytes compared with control (DMSO, left panel).
  • FIG. 22 Figure provides photomicrographs showing expansion of chondrocytes in the apical region of cultured cartilage explants, increasing autologous cartilage tissue.
  • FIG. 23 Figure provides expression levels for compounds disclosed herein and indicated in the figure.
  • FIGS. 24A-24D Compounds disclosed herein were assayed for modulatory effects on P-STAT3 and c-MYC.
  • FIG. 24A Stat+/Myc+.
  • FIG. 24B Stat-/Myc-.
  • FIG. 24C Stat- /Myc+.
  • FIG. 24D Stat+/Myc-.
  • FIGS. 25A-25H BMPR1B + articular cartilage cells have distinct molecular and functional signatures at different ontogenetic stages.
  • FIG. 25A Sorting strategy to isolate BMPR1B + cells from human fetal and adult articular cartilage.
  • FIG. 25B Hierarchical clustering of RNA-Seq data over all genes; blue indicates stronger positive correlation, while red represents weaker concordance.
  • FIG. 25C Selected Gene Ontology (GO) categories derived from differentially expressed genes enriched in fetal cells (p ⁇ 0.05, >2-fold higher).
  • FIG. 25D Heat map depicting average relative gene expression of chondrogenic and mitogenic genes.
  • FIG. 25E Selected gene sets enriched in fetal cells as determined by GSEA, with Normalized Enrichment Scores (NES), p values and False Discovery Rates (FDR) shown.
  • FIG. 25F Comparison of metabolic activity (Extracellular acidification rate and oxygen consumption rate; ECAR and OCR, respectively) of fetal and adult human articular cartilage cells. ECAR is a measure of glycolytic activity, while OCR is a readout for oxidative phosphorylation.
  • FIG. 25G Evaluation of the ability of human fetal and adult articular cartilage cells to transit Millicell membranes.
  • FIG. 25H Colony- forming ability of single human fetal and adult articular cartilage cells when plated at low density in Matrigel. Data are represented at mean ⁇ SD. See also tables of FIGS. 32A-32B.
  • FIGS. 26A-26J LIF/STAT3/MYC signaling is prominent in fetal articular chondrocytes and can activate a fetal-like phenotype in adult cells.
  • FIG. 26A Levels of phospho-STAT3 (pSTAT3) and MYC protein were quantitated in human fetal and adult articular chondrocytes relative to histone H3.
  • FIG. 26B Effects of soluble LIF receptor (sLIFR) on MYC and pSTAT3 protein levels on fetal articular chondrocytes after 72 hours.
  • sLIFR soluble LIF receptor
  • FIG. 26C Detection of apoptotic cells using TUNEL staining and flow cytometry analysis of fetal articular cartilage explants cultured in the absence (control) or presence of a MYC (10058-F4) or STAT3 (STATTIC) inhibitor for 24 hours.
  • FIG. 26D Quantification of proliferating cells via EdU incorporation in fetal articular cartilage explants and also by flow cytometry analysis for BrdU. Scale bars represent 100 ⁇ .
  • FIG. 26E Assessment of metabolic activity of human fetal articular chondrocytes cultured in the presence or absence of MYC or STAT3 inhibitors.
  • FIG. 26F Migration capacity of fetal articular chondrocytes was assessed using a Transwell® assay in the absence or presence of MYC and STAT3 inhibitors.
  • FIG. 26G Protein levels of MYC and pSTAT3 were measured in adult human articular chondrocytes with and without incubation with LIF. Data are shown normalized to histone H3.
  • FIG. 26H Migratory capacity of adult human articular chondrocytes in a Transwell® assay measured in the presence or absence of LIF.
  • FIG. 261 Single adult human articular chondrocytes were cultured with or without LIF for 5 weeks to allow detection of colony- forming cells.
  • FIG. 26J Explants of adult pig articular cartilage were incubated with EdU in the presence or absence of LIF to detect proliferating cells. Scale bars represent 25 ⁇ .
  • FIGS. 27A-27B Small molecule screen to identify regulators of cartilage
  • FIG. 27 A Schematic representation of the high throughput screen performed to identify putative small molecules regulators of chondrocyte differentiation state.
  • Limb mesenchymal cells were isolated from mouse embryos carrying a CollOal-mCherry transgene. Compounds were considered positive hits if they reduced mCherry signal after induction with pro-differentiation factors.
  • 2701 Overnight fresh limb digest
  • 2702 COLlOALmCherry primary limb mesenchyme
  • 2703 Culture medium (phenyl red free
  • %-positive cell scoring programs computes % viable cells expressing mCherry by DAPI and Cy3 signal overlap; 2704: increase in mCherry signal; 2705: negative control; 2706: decrease in mCherry signal.
  • FIG. 27B Quantitation of top 75 positive hits.
  • FIG. 27C Quantification of alkaline phosphatase levels in human fetal articular chondrocytes treated with BMP -4 in absence
  • FIGS. 28A-28I Small molecule-mediated activation of a fetal-like molecular and functional phenotype in adult articular cartilage.
  • FIG. 28A Adult human articular chondrocytes were incubated with or without RCGD 423 and levels of MYC and pSTAT3 were quantified relative to histone H3.
  • FIG. 28B Levels of MYC and pSTAT3 protein were measured in pig adult articular chondrocytes to determine the effects of RCGD 423 in a dose- and time-dependent manner; histone H3 was used as a loading control.
  • FIG. 28C Migration of adult human articular chondrocytes in a Transwell® assay was assessed in the presence and absence of RCGD 423.
  • FIG. 28D Adult human articular chondrocytes were incubated with or without RCGD 423 in hydrogel for 24 hours and then apoptotic cells were quantitated via flow cytometry for Annexin V.
  • FIG. 28E Single human adult articular chondrocytes were cultured for 5 weeks with or without stimulation with RCGD 423.
  • FIG. 28F Proliferation in explants of adult pig articular cartilage in the absence or presence of RCGD 423 as shown by EdU incorporation.
  • FIG. 28G Metabolic activity of human adult articular chondrocytes (ECAR and OCR) was assessed in the presence or absence of RCGD 423; the response in these parameters to stimulation with LIF is shown for comparison.
  • FIG. 28H Seven samples of human adult articular chondrocytes were cultured with or without RCGD 423 and then subjected to RNA-Seq. Genes that were significantly enriched in 4/7 drug- treated samples (annotated with "D") when compared to their untreated controls were analyzed using GO. Selected categories and their respective p values are shown.
  • FIG. 281) Heat map depicting the 31 genes in the "M phase" GO category. Relative expression for all 14 matched samples are shown.
  • FIGS. 29A-29C RCGD 423 acts through a mechanism similar to LIF.
  • FIG. 29A Levels of MYC and pSTAT3 protein were measured in adult pig articular chondrocytes in the presence or absence of LIF and JAK or gpl30 inhibitors. Histone H3 was used as a loading control.
  • FIG. 29B Adult pig articular chondrocytes were cultured in the presence of the indicated combinations of RCGD 423, JAK and/or gpl30 inhibitors and the levels of MYC and pSTAT3 proteins were quantitated relative to histone H3.
  • FIGS. 30A-30B RCGD 423 does not promote catabolism.
  • FIG. 30A Adult pig articular chondrocytes were cultured for 24 hours with the indicated cytokines or RCGD 423 and the levels of pSTAT3 and MYC were measured with respect to histone H3. Representative data for other proteins in the MAPK (p38 and MEK1/2), AKT (phospho-AKT; pAKT) or NF-KB (NF-KB p65) are also shown.
  • FIGS. 31A-31D RCGD 423 promotes cartilage repair in a living tissue context.
  • FIG. 31 A Experiments were conducted to test the tissue reparative function of compounds disclosed herein.
  • FIG. 31A depicts histograms of amounts of glycosaminoglycans (GAGs) and collagen 2 observed under control conditions and after administration of RCGD 423.
  • FIG. 3 IB The duration of the effects elicited by RCGD 423 was determined by applying the drug for 24 hours and then washing it out. Protein levels of pSTAT3 and MYC were determined at the indicated time points after wash out; histone H3 was used as a loading control.
  • FIG. 31 A Experiments were conducted to test the tissue reparative function of compounds disclosed herein.
  • FIG. 31A depicts histograms of amounts of glycosaminoglycans (GAGs) and collagen 2 observed under control conditions and after administration of RCGD 423.
  • FIG. 3 IB The duration of the effects elicite
  • FIGS. 32A-32B Adult Human BMPR1B+ Articular Chondrocytes Evidence a Heightened Inflammatory Response Coupled with Reduced Proliferation and Migration.
  • Gene Ontology GO; FIG. 32A
  • GSEA Gene Set Enrichment Analysis
  • FIG. 33 BMPR1B, LIFR and gpl30 Identify Largely Overlapping Populations of Articular Chondrocytes Throughout Development. Immunohistochemistry for LIFR and its co- receptor gpl30 demonstrated that their expression mostly overlaps in both adolescent (left three columns) and adult (rightmost panel) articular chondrocytes in the superficial zone; a similar population of chondrocytes expressed BMPR1B. All three proteins were absent from chondrocytes present in the adolescent growth plate. Positive signal is indicatged. Scale bars represent 25 ⁇ .
  • FIGS. 34A-34B BMPR1B LIFR + Cells are Enriched for Anabolic Gene Expression.
  • FIG. 34A Sorting of adult human articular cartilage yields multiple populations, including BMPR1B LIFR + chondrocytes that are negative for CD34.
  • FIG. 34B Compared to other cartilage populations, these cells express significantly increased levels of the cartilage matrix proteins aggrecan (ACAN) and collagen II (COL2A1).
  • FIG. 35 RCGD 423 Preserves BMPR1B+ Chondrocytes in Culture.
  • Adult pig chondrocytes were cultured in the presence of various cytokines or RCGD 423 and the number of cells expressing BMPR1B were quantitated using flow cytometry.
  • Know mitogens for cartilage, including PDGF-BB and FGF2 promoted dramatic loss of BMPR1B + cells.
  • RCGD 423 and LIF acted to maintain cells with the BMPR1B+ phenotype.
  • FIG. 36 PCR Validation of Selected Genes Following Treatment with RCGD 423.
  • RNA was isolated from adult human chondrocytes after treatment with RCGD 423. Genes were chosen for validation based on their upregulation in 4 or more adult human cartilage specimens.
  • FIG. 37 Exposure to TNF-a Abrogates the Effects of RCGD 423.
  • Adult pig chondrocytes were cultured in the presence of various cytokines and/or RCGD 423.
  • both the inflammatory cytokines TNF-a and IL-l inhibit accumulation of pSTAT3 and MYC proteins, only TNF-a prevents the increases in these proteins in the presence of RCGD 423, suggesting that TNF-a represents a major barrier to improved functional properties in cartilage.
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C1 0 means one to ten carbons).
  • Alkyl is not cyclized.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl,
  • an unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-).
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, S, Se and Si, and wherein the nitrogen, selenium, and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heteroalkyl is not cyclized.
  • the heteroatom(s) O, N, P, S, Se, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH 2 -CH 2 -0-CH 3 , -CH 2 -CH 2 -NH-CH 3 ,
  • heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy,
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R, -C(0)NR, -NR'R", -OR, -SeR', -SR, and/or -S0 2 R.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.
  • cycloalkyl and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl,
  • heterocycloalkyl examples include, but are not limited to, l-(l ,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl,
  • a "cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(0)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (e.g. 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms (e.g. N, O, or S), wherein sulfur heteroatoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1- pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- is
  • arylene and heteroarylene are selected from the group of acceptable substituents described below.
  • a fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl.
  • a fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl.
  • heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.
  • heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl.
  • Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein.
  • Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different.
  • Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings).
  • Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene).
  • heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • alkylsulfonyl means a moiety having the formula -S(0 2 )-R', where R' is an alkyl group as defined above. R' may have a specified number of carbons (e.g., "Ci-C 4 alkylsulfonyl").
  • oxy refers to— O— .
  • aryloxy refers to a substituted or unsubstitued aryl group attached to the parent molecular moiety through an oxy i.e. an ether group.
  • An example of an unsubstituted aryl ether group is phenoxy (i.e. C 6 H 5 O-).
  • heteroaryloxy refers to a substituted or unsubstitued heteroaryl group attached to the parent molecular moiety through an oxy i.e. a heteroaryl ether group.
  • An example of an unsubstituted heteroaryl ether group is thiophenyl (i.e.C 4 H 3 SO-).
  • alkyl and heteroalkyl radicals including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,
  • R, R", R'", and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R, R", R", and R"" group when more than one of these groups is present.
  • R and R" When R and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5- , 6-, or 7-membered ring.
  • -NR'R includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl
  • substituents for the aryl and heteroaryl groups are varied and are selected from, for
  • Substituents for rings may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
  • the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
  • the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
  • a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
  • the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
  • a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
  • the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring- forming substituents are attached to non-adjacent members of the base structure.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR') q -U-, wherein T and U are independently -NR-, -0-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(O) -, -S(0)2-, -S(0) 2 NR'-, or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') S -X'- (C"R"') d -, where s and d are independently integers of from 0 to 3, and X' is -0-, -NR-, -S-, -S(O)-, -S(0) 2 -, or -S(0) 2 NR'-.
  • R, R, R", and R' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heteroatom or "ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • a “substituent group,” as used herein, means a group selected from the following moieties:
  • a “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 2 o alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or
  • a "lower substituent” or " lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.
  • each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C2 0 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C2 0 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-C 8 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute
  • stereochemistry as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention.
  • the compounds of the present invention do not include those which are known in art to be too unstable to synthesize and/or isolate.
  • the present invention is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefmic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • isomers refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • the symbol denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
  • a or “an,” as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C1-C2 0 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group.
  • each R 13 substituent may be distinguished for example as R 13A , R 13B , R 13C , R 13D , etc., wherein each of R 13A , R 13B , R 13C , R 13D , etc. is defined within the scope of the definition of R 13 and optionally differently.
  • salt refers to acid or base salts of the compounds used in the methods of the present invention.
  • acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
  • a "nitrile” refers to a organic compound having a -CN group.
  • a “protected secondary amine” refers to the covalent attachment of a monovalent chemical moiety to an amine nitrogen atom that functions to prevent the amine moiety from reacting with reagents used in the chemical synthetic methods described herein (commonly referred to as “protecting” the amine group) and may be removed under conditions that do not substantially degrade the molecule of which the amine moiety forms a part (commonly referred to as “deprotecting" the amine group) thereby yielding a free amine.
  • An amine protecting group can be acid labile, base labile, or labile in the presence of other reagents.
  • Amine protecting groups include but are not limited to: -carbamates (such as -carbobenzyloxy (Cbz), -t- butoxycarbonyl (t-Boc), -fluorenylmethyloxycarbonyl (Fmoc), and -allyl carbamates), -benzyl, - 4-methoxyphenyl, or -2,4-dimethoxyphenyl.
  • -carbamates such as -carbobenzyloxy (Cbz), -t- butoxycarbonyl (t-Boc), -fluorenylmethyloxycarbonyl (Fmoc), and -allyl carbamates
  • -benzyl - 4-methoxyphenyl, or -2,4-dimethoxyphenyl.
  • the compound is a chemical species set forth in the Examples section or figures.
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.
  • species e.g. chemical compounds including biomolecules or cells
  • contacting and “reacting” are used synonymously and may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme.
  • contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.
  • a "binding site 1 gpl30 receptor agonist,” as used herein is a compound (e.g. a biomolecule or synthetic chemical molecule (e.g. a small molecule)) capable of binding to the binding site 1 of the gp 130 receptor and increasing gp 130 activity or function.
  • the binding site 1 gpl30 receptor agonist is specifically designed to fit within the binding site 1 of the gpl30 receptor and make contact with amino acids residing on the suface of the binding site 1 of the gpl30 receptor.
  • the compound is a synthetic chemical molecule designed, according to the disclosure provided herein, to bind to the binding site 1 gpl30 receptor.
  • the synthetic chemical molecule is a small molecule (a low molecular weight ( ⁇ 900 daltons) organic compound).
  • the binding site 1 gpl30 receptor agonist is a biomolecule.
  • the biomolecule is an antibody or functional fragment thereof designed, according to the disclosure provided herein, to bind to the binding site 1 of the gp 130 receptor.
  • binding site 1 of the gpl30 receptor is a binding pocket within the gp 130 receptor.
  • the sequence for the gpl30 receptor is set forth in SEQ ID NO: l .
  • the sequence for the binding site 1 of the gpl30 receptor is set forth in SEQ ID NO:2 and SEQ ID NO:3 and includes amino acids corresponding to positions 173, 174, 175 and 176 in gpl30 or amino acid residues KAKR as set forth in SEQ ID NO:4.
  • amino acid residue in a protein or receptor "corresponds" to a given residue when it occupies the same essential structural position within the protein or receptor as the given residue, for example, in homologous proteins that may have a different numbering convention.
  • the binding site 1 of the gpl30 receptor is shown in FIG. 29C.
  • amino acid residues and fragments of gpl30 disclosed herein are referred to as corresponding to the entire (918 amino acid) length of gpl30 and/or gpl30 without the signaling fragment that is 22 amino acid residues in length (e.g, KAKR as set forth in SEQ ID NO:4 is referred to herein as corresponding to positions 173, 174, 175 and 176 and/or positions 151, 152, 153 and 154 in gpl30).
  • biomolecule is used in its customary sense and refers to a molecule that is present in living organisms and synthetic derivatives thereof, including macromolecules such as proteins, carbohydrates, lipids, and nucleic acids, as well as small molecules such as primary metabolites, secondary metabolites, and natural products.
  • a biomolecule includes but is not limited to nucleic acids (e.g. DNA and RNA), peptide nucleic acids, sugars, peptides, proteins, antibodies, lipids, small molecule affinity ligands e.g. inhibitors, biotin and haptens.
  • gpl30 receptor Assays for the gpl30 receptor, gpl30, gpl30 protein, IL6ST receptor, IL6ST or “IL6ST protein” are here used interchangeably and according to their common, ordinary meaning (e.g., transmembrane protein "glycoprotein 130") and refer to proteins of the same or similar names and functional fragments and homologs thereof.
  • the term includes any recombinant or naturally occurring form of, or variants thereof that maintain gpl30 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to gpl30).
  • the gp 130 receptor has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1 or a functional fragment thereof (e.g. 700 contiguous amino acids of SEQ ID NO: 1, 750 contiguous amino acids of SEQ ID NO: 1, 800 contiguous amino acids of SEQ ID NO: 1, 850 contiguous amino acids of SEQ ID NO: 1 870 contiguous amino acids of SEQ ID NO: 1, 880 contiguous amino acids of SEQ ID NO: 1, 890 contiguous amino acids of SEQ ID NO: 1, 900 contiguous amino acids of SEQ ID NO: lor 910 contiguous amino acids of SEQ ID NO: 1).
  • a functional fragment thereof e.g. 700 contiguous amino acids of SEQ ID NO: 1, 750 contiguous amino acids of SEQ ID NO: 1, 800 contiguous amino acids of SEQ ID NO: 1, 850 contiguous amino acids of SEQ ID NO: 1 870 contiguous amino acids of S
  • salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
  • the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids.
  • the present invention includes such salts.
  • examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid.
  • These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the present invention provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein include those compounds that readily undergo chemical or enzymatic changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • salt refers to acid or base salts of the compounds used in the methods of the present invention.
  • acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
  • treating refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a patient's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination,
  • an "effective amount” is an amount sufficient to accomplish a stated purpose (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce one or more symptoms of a disease or condition).
  • An example of an "effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • the exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g. , Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • the therapeutically effective amount can be initially determined from cell culture assays.
  • Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
  • therapeutically effective amounts for use in humans can also be determined from animal models.
  • a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.
  • the dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
  • Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
  • an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient.
  • This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.
  • Control or "control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).
  • activation means positively affecting (e.g. increasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the activator.
  • Activation may refer to reduction of a disease or symptoms of disease.
  • Activation may refer to an increase in the activity of a particular protein or nucleic acid target.
  • the protein may be gpl30.
  • activation includes, at least in part, partially or totally increasing stimulation, increasing, promoting, or expediting activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein.
  • modulator refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule.
  • modulate is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, a modulator of a target protein changes by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. A modulator of a disease decreases a symptom, cause, or characteristic of the targeted disease.
  • “Selective” or “selectivity” or the like of a compound refers to the compound's ability to discriminate between molecular targets. "Specific”, “specifically”, “specificity”, or the like of a compound refers to the compound's ability to cause a particular action, such as inhibition, to a particular molecular target with minimal or no action to other proteins in the cell.
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • preparation is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • administering means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
  • a slow-release device e.g., a mini-osmotic pump
  • Parenteral administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • compositions disclosed herein can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • the compositions of the present invention may additionally include components to provide sustained release and/or comfort.
  • Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,91 1,920; 5,403,841 ; 5,212, 162; and 4,861,760.
  • compositions disclosed herein can also be delivered as microspheres for slow release in the body.
  • microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci.
  • the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis.
  • liposomes particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g. , Al- Muhammed, J. Microencapsul.
  • compositions can also be delivered as nanoparticles.
  • compositions may include compositions wherein the active ingredient (e.g. compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e. , in an amount effective to achieve its intended purpose.
  • a therapeutically effective amount i.e. , in an amount effective to achieve its intended purpose.
  • the actual amount effective for a particular application will depend, inter alia, on the condition being treated.
  • compositions When administered in methods to treat a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule, and/or reducing, eliminating, or slowing the progression of disease symptoms.
  • the dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated, kind of concurrent treatment, complications from the disease being treated or other health-related problems.
  • Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of Applicants' invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art.
  • the compounds described herein can be used in combination with one another, with other active drugs known to be useful in treating a disease (e.g. joint surface injury, arthritis or cartilage degenerative disease) or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
  • a disease e.g. joint surface injury, arthritis or cartilage degenerative disease
  • adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
  • the compounds described herein may be coadministered with one another or with other active drugs known to be useful in treating a disease.
  • co-administer it is meant that a compound described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example, an anti-cartilage degenerative agent as described herein.
  • the compounds described herein can be administered alone or can be co-administered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent).
  • the preparations can also be combined, when desired, with other active substances (e.g. anti-cartilage degenerative or anti-arthritic agents).
  • Co-administration includes administering one active agent (e.g.
  • coadministration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent.
  • coadministration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order.
  • Co-administration can be accomplished by co- formulation, i.e., preparing a single pharmaceutical composition including both active agents.
  • the active agents can be formulated separately.
  • the active and/or adjunctive agents may be linked or conjugated to one another.
  • the compounds described herein may be combined with treatments for cartilage degenerative disorders.
  • association in the context of a substance or substance activity or function associated with a disease means that the disease is caused by (in whole or in part), a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function, or a side-effect of the compound (e.g. toxicity) is caused by (in whole or in part) the substance or substance activity or function.
  • Patient refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein.
  • Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
  • a patient is human.
  • Disease or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.
  • Disease as used herein may refer to cartilage degenerative disease, joint surface injury or arthritis.
  • linker as described herein is a divalent chemical group that covalently joins one chemical moiety to another. Specific examples of linkers are described herein. Linkers may be polyethylene (PEG) linkers or bioconjugate linkers.
  • a cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring.
  • Cells may include prokaryotic and eukaroytic cells.
  • Prokaryotic cells include but are not limited to bacteria.
  • Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
  • Nucleic acid refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form, and complements thereof.
  • polynucleotide refers to a linear sequence of nucleotides.
  • nucleotide typically refers to a single unit of a polynucleotide, i.e. , a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof.
  • nucleic acid as used herein also refers nucleic acids that have the same basic chemical structure as naturally occurring nucleic acids. Such analogues have modified sugars and/or modified ring substituents, but retain the same basic chemical structure as the naturally occurring nucleic acid.
  • a nucleic acid mimetic refers to chemical compounds that have a structure that is different the general chemical structure of a nucleic acid, but functions in a manner similar to a naturally occurring nucleic acid.
  • analogues include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, and peptide- nucleic acids (PNAs).
  • proliferative program refers to the ability of a cell to proliferate.
  • cell proliferation requires production of collagen.
  • activating compound refer to compounds disclosed herein having the ability to increase expression of p-STAT3 and c-Myc in a competent adult chondrocyte.
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted hetero
  • the compound of Formula (I) has the structure following:
  • n is an integer in the range 0 to 5, and R 6 at each occurrence is independently halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 2 C1,
  • R 6 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 6 is substituted alkyl, substituted cycloalkyl, substituted heteroalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl. In embodiments, R 6 is unsubstituted phenyl.
  • R 6 is phenyl substituted with substituted or unsubstituted alkyl, substituted or unsubstituted lower alkyl, -NH 2 , halogen, -COOH,, or substituted or unsubstituted heteroaryl.
  • the activating compound has the structure of Formula (I) following:
  • R 4 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and, R 5 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 7 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 7 is substituted alkyl, substituted cycloalkyl, substituted heteroalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl.
  • A is CR 14 or N.
  • B is CR 16 or N.
  • X is O, NR 19 or S.
  • L 1 is a bond or substituted or unsubstituted C1-C3 alkylene.
  • R 8 is hydrogen, halogen, -CX 8 1 3 , -CHX 8 1 2 , -CH 2 X 8 1 , -CN, -SO n iR 8A , S0viNR ⁇ ⁇ 8
  • -NUNR R ONR R , -NHC(0)NFINR R ,— NHC(0)NR R , -N(0) m i, -M R ,
  • R 9 is hydrogen, halogen, -CX 9 1 3 , -CHX 9 1 2 , -CH 2 X 9 1 , -CN, -SO n iR 9A , -SO v iNR 9B R 9C ,
  • R 10 is hydrogen, halogen, -CX 10 1 3 , -CHX 10 1 2 , -CH 2 X 10 1 , -CN, -SO n iR 10A , - SO v iNR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(0) ml , -NR 10B R 10C , -C(O)R 10D , -C(O)OR 10D , -C(O)NR 10B R 10C , -OR 10A , -NR 10B SO 2 R 10A , - NR 10B C(O)R 10D , -NR 10B C(O)OR 10D , -NR 10B OR 10D , -OCX 10 1 3 , -OCHX 10 1 2
  • R 11 is hydrogen, halogen, -CX 1 L1 3 , -CHX 1 L1 2 , -CH 2 X 1 L1 , -CN, -SO n iR 11A , - SO v iNR 11B R l lc , -NHNR 11B R 11C , -ONR 11B R l lc , -NHC(0)NHNR 11B R 11C , -NHC(0)NR 11B R 11C , -N(0) m i, -NR 11B R 11C , -C(0)R 11D , -C(0)OR 11D , -C(0)NR 11B R 11C , -OR 11A , -NR 11B S0 2 R 11A , - NR 11B C(0)R 11D , -NR 11B C(0)OR 11D , -NR 11B OR 11D , -OCX 11 , -OCHX 1 L1 2 , substituted or
  • R 12 is hydrogen, halogen, -CX 12 1 3 , -CHX 12 1 2 , -CH 2 X 12 1 , -CN, -SO n iR 12A , - SO v iNR 12B R 12C , -NHNR 12B R 12C , -ONR 12B R 12C , -NHC(0)NHNR 12B R 12C , -NHC(0)NR 12B R 12C , -N(0) m i, -NR 12B R 12C , -C(0)R 12D , -C(0)OR 12D , -C(0)NR 12B R 12C , -OR 12A , -NR 12B S0 2 R 12A , - NR 12B C(0)R 12D , -NR 12B C(0)OR 12D , -NR 12B OR 12D , -OCX 12 , -OCHX 12 1 2 , substituted or unsubstituted alkyl,
  • R 13 is hydrogen, halogen, -CX 13 1 3 , -CHX 13 1 2 , -CH 2 X 13 1 , -CN, -SO n iR 13A , - SO v iNR 13B R 13C , -NHNR 13B R 13C , -ONR 13B R 13C , -NHC(0)NHNR 13B R 13C , -NHC(0)NR 13B R 13C , -N(0) m i, -NR 13B R 13C , -C(0)R 13D , -C(0)OR 13D , -C(0)NR 13B R 13C , -OR 13A , -NR 13B S0 2 R 13A , - NR 13B C(0)R 13D , -NR 13B C(0)OR 13D , -NR 13B OR 13D , -OCX 13 , -OCHX 13 1 2 , substituted or unsubstituted alkyl,
  • R 14 is hydrogen, halogen, -CX 14 1 3 , -CHX 14 1 2 , -CH 2 X 14 1 , -CN, -SO n iR 14A , - SO vl NR 14B R 14C , -NHNR 14B R 14C , -ONR 14B R 14C , -NHC(0)NHNR 14B R 14C , -NHC(0)NR 14B R 14C , -N(0) ml , -NR 14B R 14C , -C(0)R 14D , -C(0)OR 14D , -C(0)NR 14B R 14C , -OR 14A , -NR 14B S0 2 R 14A , - NR 14B C(0)R 14D , -NR 14B C(0)OR 14D , -NR 14B OR 14D , -OCX 14 , -OCHX 14 1 2 , substituted or unsubstituted alkyl,
  • R 15 is hydrogen, halogen, -CX 15 1 3 , -CHX 15 1 2 , -CH 2 X 15 1 , -CN, -SO n iR 15A , - SO v iNR 15B R 15C , -NHNR 15B R 15C , -ONR 15B R 15C , -NHC(0)NHNR 15B R 15C , -NHC(0)NR 15B R 15C , -N(0) m i, -NR 15B R 15C , -C(0)R 15D , -C(0)OR 15D , -C(0)NR 15B R 15C , -OR 15A , -NR 15B S0 2 R 15A , - NR 15B C(0)R 15D , -NR 15B C(0)OR 15D , -NR 15B OR 15D , -OCX 15 , -OCHX 15 1 2 , substituted or unsubstituted alkyl,
  • R 16 is hydrogen, halogen, -CX 16 1 3 , -CHX 16 1 2 , -CH 2 X 16 1 , -CN, -SO n iR 16A , - SO v iNR 16B R 16C , -NHNR 16B R 16C , -ONR 16B R 16C , -NHC(0)NHNR 16B R 16C , -NHC(0)NR 16B R 16C , -N(0) m i, -NR 16B R 16C , -C(0)R 16D , -C(0)OR 16D , -C(0)NR 16B R 16C , -OR 16A , -NR 16B S0 2 R 16A , - NR 16B C(0)R 16D , -NR 16B C(0)OR 16D , -NR 16B OR 16D , -OCX 16 1 3 , -OCHX 16 1 2 , substituted or unsubstituted alky
  • R 17 is hydrogen, halogen, -CX m 3 , -CHX m 2 , -CH 2 X m , -CN, -SO n iR 17A , - SO v iNR 17B R 17C , -NHNR 17B R 17C , -ONR 17B R 17C , -NHC(0)NHNR 17B R 17C , -NHC(0)NR 17B R 17C , -N(0) m i, -NR 17B R 17C , -C(0)R 17D , -C(0)OR 17D , -C(0)NR 17B R 17C , -OR 17A , -NR 17B S0 2 R 17A , - NR 17B C(0)R 17D , -NR 17B C(0)OR 17D , -NR 17B OR 17D , -OCX 17 , -OCHX 17 1 2 , substituted or unsubstituted alkyl,
  • R 18 is hydrogen, halogen, -CX 18 1 3 , -CHX 18 1 2 , -CH 2 X 18 1 , -CN, -SO n iR 18A , - SO v iNR 18B R 18C , -NHNR 18B R 18C , -ONR 18B R 18C , -NHC(0)NHNR 18B R 18C , -NHC(0)NR 18B R 18C , -N(0) m i, -NR 18B R 18C , -C(0)R 18D , -C(0)OR 18D , -C(0)NR 18B R 18C , -OR 18A , -NR 18B S0 2 R 18A , - NR 18B C(0)R 18D , -NR 18B C(0)OR 18D , -NR 18B OR 18D , -OCX 18 1 3 , -OCHX 18 1 2 , substituted or unsubstituted alky
  • R 19 is hydrogen, -COR 19D , -C(0)NHNR 19B R 19C , -C(0)OR 19D -S0 2 R 19A ,
  • C(0)NR 19B R 19C substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • R 18D are independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -OH, -NH 2 , -COOH, - CONH 2 , -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH 2 ,
  • R 16C , R 17B , R 17C , R 18B and R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • X 1 ⁇ 1 , X 2 ⁇ 1 , X 3 ⁇ 1 , X 4 ⁇ 1 , X 5 ⁇ 1 , X 6 ⁇ 1 , X 7 ⁇ 1 , X 8 ⁇ 1 , X 9'1 , X 10'1 , X 1 L1 , X 12'1 , X 13'1 , X 14'1 , X 15'1 , X 16'1 , X 17 1 and X 18 1 are independently -CI, -Br, -I or -F.
  • the symbol nl is 0, 1, 2, 3 or 4.
  • the symbols ml and vl are independently 1 or 2.
  • R 10 when A is CR 14 ; B is CR 16 ; L 1 is bond; and R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are independently hydrogen, then R 10 is not bromine.
  • L 1 is a bond.
  • X is NH.
  • A is CR 14 .
  • A is N.
  • B is CR 16 .
  • B is N.
  • the compound has Formula (Ilia):
  • nl, ml, vl, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 1V are as described herein.
  • R 14 is hydrogen.
  • R 10 is hydrogen.
  • the compound has Formula (Illb):
  • nl , ml, vl, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , R 18 and R 19 are as described herein.
  • the compound has Formula (IIIc):
  • nl, ml, vl, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 , R 17 , R 18 and R 19 are as described herein.
  • R , R and R are independently hydrogen.
  • R n and R 12 are independently hydrogen.
  • R 18 is hydrogen.
  • R is fluorine, chlorine or iodine, -CX ial 3 , -CHX 1U 1 2 , -CH2X 1 -CN, -SO n iR 10A , -SO v iNR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(0) m i, -NR 10B R 10C , -C(O)R 10D , -C(O)OR 10D , -C(O)NR 10B R 10C , - OR 10A , -NR 10B SO 2 R 10A , -NR 10B C(O)R 10D , -NR 10B C(O)OR 10D , -NR 10B OR 10D , -OCX 10 1
  • R 10 is fluorine, chlorine, bromine or iodine. In embodiments, R 10 is fluorine, chlorine or iodine. In embodiments, R 10 is fluorine. In embodiments, R 8 , R 9 , R 11 , R 12 , R 13 , R 15 , R 17 , R 18 and R 19 are independently hydrogen.
  • R 8 is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO3H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 8E -substituted or unsubstituted alkyl, R 8E -substituted or unsubstituted alkyl, R 8
  • R 8 is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, - SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, - NHC(0)H, -NHC(0)OH, -NHOH, -OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , - OCHBr 2 , -OCHI 2 , R 8E -substituted or unsubstituted C1-C6 alkyl, R 8E -substituted or
  • R 8E is independently oxo, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 8E is independently oxo, halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO3H, - SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, - NHC(0)OH, -NHOH, -OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , - OCHI 2 , R -substituted or unsubstituted Ci-C 6 alkyl, R -substituted or unsubstituted 2 to
  • R 9 is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO3H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 9E -substituted or unsubstituted alkyl, R 9E -substituted
  • R 9 is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, - SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, - NHC(0)H, -NHC(0)OH, -NHOH, -OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , - OCHBr 2 , -OCHI 2 , R 9E -substituted or unsubstituted C1-C6 alkyl, R 9E -substituted or unsubstituted C1-
  • R 9E is independently oxo, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 9E is independently oxo, halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO3H, - SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, - NHC(0)OH, -NHOH, -OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , - OCHI 2 , R 9F -substituted or unsubstituted C1-C6 alkyl, R 9F -substituted or unsubstituted
  • R is independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 10E -substituted or unsubstituted alkyl, R 10E -substituted
  • R 10E is independently oxo, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 10F -substituted or unsubstituted alkyl, R 10F -substituted or unsubstituted alky
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 11 is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 11E is independently oxo, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 12 is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , -
  • R 12 is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 12E is independently oxo, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 12E is independently oxo, halogen, -CF 3 , -CCI 3 , -CBr 3 , -
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 13 is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 13E -substituted or unsubstituted alkyl, R 13E -substituted or unsubstituted alkyl, R 13
  • R 13E is independently oxo, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 14 is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 14E -substituted or unsubstituted alkyl, R 14E -substituted or unsubstituted alkyl, R 14
  • R 14 is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO3H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCB1-3, -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 14E -substituted or unsubstituted C1-C6 alkyl, R 14E -substituted or unsubstituted C1-
  • R 14E is independently oxo, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 14E is independently oxo, halogen, -CF 3 , -CCI 3 , -CBr 3 , -
  • R 15 is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 15E -substituted or unsubstituted alkyl, R 15E -substituted or unsubstituted alkyl, R 15
  • R 15E is independently oxo, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 16 is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 16E -substituted or unsubstituted alkyl, R 16E -substituted or unsubstituted alkyl, R 16
  • R 16E is independently oxo, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 17 is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 17E -substituted or unsubstituted alkyl, R 17E -substituted or unsubstituted alkyl, R 17
  • R 17E is independently oxo, halogen, -CF 3 , -CC1 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCl 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 17F -substituted or
  • R 17E is independently oxo, halogen, -CF 3 , -CC1 3 , -CBr 3 , -
  • R 18 is independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCl 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 18E -substituted or
  • R 18 is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 1SE is independently oxo, halogen, -CF 3 , -CC1 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCB1-3, -OCI3, -OCHF 2 , -OCHCl 2 ,
  • R is independently oxo, halogen, -CF 3 , -CCI 3 , -CBr 3 , -
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 19 is independently hydrogen, -COH, -C(0)NHNH 2 , -C(0)OH - S0 2 H, -C(0)NH 2 , R 19E -substituted or unsubstituted alkyl, R 19E -substituted or unsubstituted heteroalkyl, R 19E -substituted or unsubstituted cycloalkyl, R 19E -substituted or unsubstituted heterocycloalkyl, R 19E -substituted or unsubstituted aryl, or R 19E -substituted or unsubstituted heteroaryl.
  • R 19E is independently oxo, halogen, -CF 3 , -CCI3, -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 19F -substituted or
  • R 19E is independently oxo, halogen, -CF 3 , -CCI 3 , -CBr 3 , -
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 8A is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO3H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 8AF -substituted or unsubstituted alkyl, R 8AF -substituted or unsubstituted alkyl, R
  • R is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 8B is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 8BF -substituted or
  • R is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • 8BF 8BF unsubstituted C1-C6 alkyl, R -substituted or unsubstituted 2 to 6 membered heteroalkyl, R substituted or unsubstituted C3-C6 cycloalkyl, R 8BF -substituted or unsubstituted 3 to 6 membered 8BF 8BF
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 8C is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 8CF -substituted or
  • R 8C is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 8B and R 8C bonded to the same nitrogen atom may optionally be joined to form a R 8CF -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 8CF - substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 8D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 8DF -substituted or
  • R is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 9A is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCl 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 9AF -substituted or unsubstituted alkyl, R 9AF -substituted alkyl
  • R 9B is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCl 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 9BF -substituted or unsubstituted alkyl, R 9BF -substituted or unsub
  • R is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 9CF -substituted or
  • R 9C is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 9B and R 9C bonded to the same nitrogen atom may optionally be
  • R 9D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 9DF -substituted or unsubstituted alkyl, R 9DF -substituted or unsubstituted alkyl, R
  • R 10A is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 10AF -substituted or unsubstituted alkyl, R 10AF -substit
  • R 10B is independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 10BF -substituted or unsubstituted alkyl, R 10BF -substituted or unsubstituted alkyl, R
  • R 10C is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , -
  • R 10B and R 10C bonded to the same nitrogen atom may optionally be joined to form a R 10CF -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 10CF - substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 10D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 10DF -substituted or unsubstituted alkyl, R 10DF -substituted or unsubstituted alkyl, R
  • R 11A is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH2, -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCB1-3, -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 11AF -substituted or unsubstituted alkyl, R 11AF -substituted or unsubstituted alkyl
  • R 11B is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 11BF -substituted or unsubstituted alkyl, R 11BF -substituted or unsubstituted alkyl, R
  • R 11C is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , -
  • R 11C is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 11B and R 11C bonded to the same nitrogen atom may optionally be joined to form a R 11CF -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 11CF - substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 11D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 11DF -substituted or unsubstituted alkyl, R 11DF -substituted or unsubstituted alkyl,
  • R 12A is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 12A is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 12B is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 12BF -substituted or unsubstituted alkyl, R 12BF -substituted alkyl, R 12
  • R 12C is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 12CF -substituted or
  • R 12C is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R and R bonded to the same nitrogen atom may optionally be
  • R 12D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 12DF -substituted or unsubstituted alkyl, R 12DF -substituted or unsubstitute
  • R 13A is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 13AF -substituted or unsubstituted alkyl, R 13AF -substituted or unsubstituted alkyl, R
  • R 13B is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 13BF -substituted or unsubstituted alkyl, R 13BF -substituted or unsubstituted alkyl, R
  • R 13C is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 13CF -substituted or
  • R 13C is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO3H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCB1-3, -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 13CF -substituted or
  • R and R bonded to the same nitrogen atom may optionally be
  • R 13D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 13DF -substituted or unsubstituted alkyl, R 13DF -substituted or unsubstituted alkyl, R
  • R 14A is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 14AF -substituted or unsubstituted alkyl, R 14AF -substituted or unsubstituted alkyl, R
  • R 14A is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO3H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCB1-3, -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 14AF -substituted or unsubstituted C1-C6 alkyl, R 14AF -substituted or unsubstituted 2
  • R 14B is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 14BF -substituted or unsubstituted alkyl, R 14BF -substituted or unsubstituted alkyl, R
  • R 14C is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 14CF -substituted or unsubstituted alkyl, R 14CF -substituted or unsubstituted alkyl, R
  • R 14B and R 14C bonded to the same nitrogen atom may optionally be joined to form a R 14CF -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 14CF - substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 14D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO3H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 14DF -substituted or unsubstituted alkyl, R 14DF -substituted or unsubstituted alkyl, R
  • R 15A is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 15AF -substituted or unsubstituted alkyl, R 15AF -substituted or unsubstituted alkyl, R
  • R 15B is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO3H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 15BF -substituted or unsubstituted alkyl, R 15BF -substituted or unsubstituted alkyl, R
  • R 15C is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 15CF -substituted or
  • R 15C is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 15B and R 15C bonded to the same nitrogen atom may optionally be joined to form a R 15CF -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 15CF - substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 15D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 15DF -substituted or unsubstituted alkyl, R 15DF -substituted or unsubstituted alkyl, R
  • R 16A is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 16AF -substituted or unsubstituted alkyl, R 16AF -substituted or unsubstituted alkyl, R
  • R 16B is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO3H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 16BF -substituted or unsubstituted alkyl, R 16BF -substituted or unsubstituted alkyl, R
  • R 16C is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 16CF -substituted or unsubstituted alkyl, R 16CF -substituted or unsubstituted alkyl, R
  • R 16B and R 16C bonded to the same nitrogen atom may optionally be joined to form a R 16CF -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 16CF - substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 16D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 16DF -substituted or unsubstituted alkyl, R 16DF -substituted alkyl,
  • R 17A is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 17AF -substituted or unsubstituted alkyl, R 17AF -substituted or unsubstituted alkyl,
  • R 17B is independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCl 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 17BF -substituted or unsubstituted alkyl, R 17BF -substituted or unsub
  • R 17C is independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCl 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 17CF -substituted or
  • R 17C is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R and R bonded to the same nitrogen atom may optionally be 17CF 17CF joined to form a R -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 17D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 17DF -substituted or unsubstituted alkyl, R 17DF -substituted or unsubsti
  • R 18A is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 18AF -substituted or
  • R is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R is independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -OCHF 2
  • R is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • heterocycloalkyl R -substituted or unsubstituted phenyl, or R -substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 18C is independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 18CF -substituted or unsubstituted alkyl, R 18CF -substituted or unsubstituted alkyl, R
  • R is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R and R bonded to the same nitrogen atom may optionally be
  • R 18D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCBr 3 , -OCI 3 , -
  • R is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -
  • R 19A is independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 19AF -substituted or unsubstituted alkyl, R 19AF -substituted or unsubstituted alkyl, R
  • R 19B is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , -
  • R 19C is independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 19CF -substituted or unsubstituted alkyl, R 19CF -substituted or unsubstituted alkyl, R
  • R 19B and R 19C bonded to the same nitrogen atom may optionally be joined to form a R 19CF -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 19CF - substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 19D is independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF 3 , -OCCI 3 , -OCB1-3, -OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 19DF -substituted or unsubstituted alkyl, R 19DF -substituted or
  • L 1 is independently a bond, O, N(R 20 ), S or R 20E -substituted or unsubstituted C1-C3 alkylene.
  • R 20 is independently hydrogen, -COH, -C(0)NHNH 2 , -C(0)OH -S0 2 H, -C(0)NH 2 , R 20E -substituted or unsubstituted alkyl, R 20E -substituted or unsubstituted heteroalkyl, R 20E - substituted or unsubstituted cycloalkyl, R 20E -substituted or unsubstituted heterocycloalkyl, R 20E - substituted or unsubstituted aryl, or R 20E -substituted or unsubstituted heteroaryl.
  • R 20E is independently oxo, halogen, -CF 3 , -CCI 3 , -CBr 3 , - CI 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, - OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , R 20F -substituted or
  • R 20E is independently oxo, halogen, -CF 3 , -CCI 3 , -CBr 3 , -
  • a compound as described herein may include multiple instances of ml, nl, vl, and/or other variables.
  • each variable may optional be different and be appropriately labeled to distinguish each group for greater clarity. For example, where each
  • nl, vl is different, they may be referred to, for example, as
  • R is assumed by R , R , R , R 84 , R 85 , R 86
  • R 9 is assumed by R 9'1 , R 92 , R 93 , R 94 , R 95 , R 9'6
  • R 10 is assumed by R 101 , R 10'2 , R 10'3 , R 10'4 , R 10'5 , R 10'6
  • R 11 is assumed by R 111 , R 11 - 2 , R 11 - 3 , R 11 - 4 , R 11 - 5 , R 1L6 , R 11 - 7
  • R 12 is assumed by R 121 , R 122 , R 123 , R 124 , R 125 , R 12'6 , R 12 - 7 , the definition of
  • the definition of ml is assumed by ml 1 , ml 2 , ml 3 , ml 4 , ml 5 , ml 6
  • the definition of nl is assumed by nl 1 , nl 2 , nl 3 , nl 4 , nl 5 , nl 6
  • the definition of vl is assumed by vl 1 , vl 2 , vl 3 , vl 4 , vl 5 ,vl 6 .
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(MPA-2/RCGD 423N). [0258] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0258] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0258] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0258] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0258] In embodiments, N-(MPA-2/RCGD 423N). [0258] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0258] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0258] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0258] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0258] In embodiments, the compound is N-(MPA-2/RCGD 423N).
  • the compound is a compound described herein (e.g., in an aspect, embodiment, example, table, figure, scheme, appendix, or claim).
  • compositions comprising a gpl30 receptor bound to a binding site 1 gpl30 receptor agonist.
  • the binding site 1 gpl30 receptor agonist is bound to the binding site one of the gpl30 receptor.
  • the binding site 1 gpl30 receptor agonist is non-covalently bound to gpl30 receptor.
  • binding site 1 comprises amino acid residues lysine, alanine, arginine and lysine corresponding to positions 173, 174, 175 and 176 (SEQ ID NO:3) within the binding site 1 of the gpl30 receptor as set forth in SEQ ID NO:2.
  • the binding site 1 gpl30 receptor agonist is a small molecule, an antibody or a polypeptide.
  • a pharmaceutical composition that includes a compound described herein and a pharmaceutically acceptable excipient.
  • the binding site 1 gpl30 receptor agonist is a compound described herein.
  • compositions in one aspect is a
  • composition that includes a compound described herein and a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable salt thereof is included in a therapeutically effective amount.
  • compositions may be prepared and administered in a wide variety of dosage formulations.
  • Compounds described may be administered orally, rectally, or by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally).
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier may be a finely divided solid in a mixture with the finely divided active component.
  • the active component may be mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to 70% of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition.
  • Such co-solvents include:
  • co-solvents are typically employed at a level between about 0.01 % and about 2% by weight. Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation.
  • Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing.
  • Such agents are typically employed at a level between about 0.01% and about 2% by weight.
  • the pharmaceutical compositions may additionally include components to provide sustained release and/or comfort.
  • Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841;
  • the pharmaceutical composition may be intended for intravenous use.
  • the pharmaceutical composition may be intended for intravenous use.
  • pharmaceutically acceptable excipient can include buffers to adjust the pH to a desirable range for intravenous use.
  • buffers including salts of inorganic acids such as phosphate, borate, and sulfate are known.
  • the pharmaceutical composition may include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose.
  • a therapeutically effective amount i.e., in an amount effective to achieve its intended purpose.
  • the actual amount effective for a particular application will depend, inter alia, on the condition being treated.
  • the dosage and frequency (single or multiple doses) of compounds administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated; presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen.
  • Other therapeutic regimens or agents can be used in conjunction with the methods and compounds disclosed herein.
  • Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring response of the constipation or dry eye to the treatment and adjusting the dosage upwards or downwards, as described above.
  • Dosages may be varied depending upon the requirements of the subject and the compound being employed.
  • the dose administered to a subject in the context of the
  • compositions presented herein should be sufficient to effect a beneficial therapeutic response in the subject over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. [0281] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compounds effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
  • an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient.
  • This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.
  • the ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD5 0 (the amount of compound lethal in 50% of the population) and ED5 0 (the amount of compound effective in 50% of the population).
  • Compounds that exhibit high therapeutic indices are preferred.
  • Therapeutic index data obtained from cell culture assays and/or animal studies can be used in formulating a range of dosages for use in humans.
  • the dosage of such compounds preferably lies within a range of plasma concentrations that include the ED5 0 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. See, e.g.
  • particularly suitable admixtures for the compounds included in the pharmaceutical composition may be injectable, sterile solutions, oily or aqueous solutions, as well as suspensions, emulsions, or implants, including
  • carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene -block polymers, and the like. Ampoules are convenient unit dosages.
  • compositions presented herein may include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
  • the method includes contacting the cell with a binding site 1 gpl30 receptor agonist or with an effective amount of a compound described herein thereby increasing MYC expression.
  • Also provided herein is a method of increasing pSTAT3 expression in a cell including contacting the cell with a binding site 1 gpl30 receptor agonist or with an effective amount of a compound described herein thereby increasing pSTAT3 expression.
  • the contacting may be performed in vitro.
  • the contacting may be performed in vivo.
  • the method includes contacting a chondrocyte with a binding site 1 gpl30 receptor agonist or with an effective amount of a compound described herein.
  • the chondrocyte activation includes an increase in proliferation, migration, metabolism or any combination thereof.
  • kits for regenerating or repairing tissue in a subject in need thereof including administering to the subject a therapeutically effective amount of a binding site 1 gpl30 receptor agonist or with an effective amount of a compound described herein.
  • the tissue is cartilage.
  • a method of repairing a joint surface injury in a subject comprising administering to the subject a therapeutically effective amount of a binding site 1 gpl30 receptor agonist or with an effective amount of a compound described herein.
  • Also provided herein is a method of treating a cartilage degenerative disease in a subject in need thereof.
  • the method includes administering to the subject a therapeutically effective amount of a binding site 1 gpl30 receptor agonist or with an effective amount of a compound described herein.
  • the disorder is arthritis.
  • the disorder is osteoarthritis.
  • the disorder is rheumatoid arthritis.
  • methods of increasing secretion of cartilaginous matrix in cartilage including contacting a gpl30 receptor with a binding site 1 gpl30 receptor agonist or with an effective amount of a compound described herein.
  • the cartilaginous matrix is in articular cartilage.
  • the cartilaginous matrix includes collagens and proteoglycans.
  • the method includes contacting the cell with a binding site 1 gpl30 receptor agonist or with an effective amount of a compound described herein.
  • the activity of the gpl30 receptor is increased. In embodiments, the activity of the gpl30 receptor is decreased or inhibited. In embodiments, the activity is heterodimerization.
  • Also provided herein is a method of transforming a mature adult cell to a progenitor cell, comprising contacting the cell with a binding site 1 gpl30 receptor agonist or with an effective amount of a compound described herein.
  • the cell is a human cell.
  • the cell is a chondrocyte.
  • the chondrocyte is an adult chondrocyte.
  • the binding site 1 gpl30 receptor agonist is a compound described herein (e.g., a compound of Formula (III) as described herein, Formula (Ilia) as described herein, Formula (Illb) as described herein, Formula (IIIc) as described herein, in an aspect, embodiment, example, table, figure, scheme, appendix or claim).
  • the compound is N-(0300] in embodiments, N-(0300] in embodiments, N-(0300] in embodiments, N-(0300] in embodiments, N-(0300] in embodiments, N-(0300] in embodiments, N-(0300] in embodiments, N-(0300] in embodiments, N-(0300] in embodiments, N-(0300] in embodiments, N-(0300] in embodiments, the compound is N-[0300]
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(MPA-2/RCGD 423N). [0302] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0302] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0302] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0302] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0302] In embodiments, N-(MPA-2/RCGD 423N). [0302] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0302] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0302] In embodiments, N-(MPA-2/RCGD 423N). [0302] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0302] In embodiments, the compound is N-(MPA-2/RCGD 423N). [0302]
  • the compound is N-(0303] in embodiments, N-(0303] in embodiments, N-(0303] in embodiments, N-(0303] in embodiments, N-(0303] in embodiments, N-(0303] in embodiments, N-(0303] in embodiments, N-(0303] in embodiments, N-(0303] in embodiments, N-(0303] in embodiments, N-(0303] in embodiments, the compound is N-[0303]
  • a method for activating a proliferative program in competent adult chondrocytes includes contacting a competent adult chondrocyte with an activating compound.
  • the activating compound is capable of increasing expression of p- STAT3 and c-Myc in the competent adult chondrocyte.
  • Embodiments disclosed herein include embodiments PI to P5 following.
  • Embodiment PI A method for activating a proliferative program in competent adult chondrocytes, said method comprising contacting a competent adult chondrocyte with an activating compound, said activating compound capable of increasing expression of p-STAT3 and c-Myc in said competent adult chondrocyte.
  • Embodiment P2 The method accordin to embodiment PI, wherein said activating
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
  • R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • Embodiment P3 The method according to embodiment P2, wherein said activating
  • n is an integer from 0 to 5; and R 6 at each occurrence is independently
  • Embodiment P4 The method according to embodiment P3, wherein R 6 is phenyl substituted with substituted or unsubstituted alkyl, substituted or unsubstituted lower alkyl, - NH 2 , halogen, -COOH, or substituted or unsubstituted heteroaryl.
  • Embodiment P5. The method according to embodiment P2, wherein said activating
  • Embodiment 1 A compound of structural Formula (III):
  • R 9 is hydrogen, halogen, -CX 9 1 3, -CHX 9 1 2 , -CH 2 X 9 1 , -CN, -SO n iR 9A , -SOviNR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(0)NHNR 9B R 9C ,
  • R 10 is hydrogen, halogen, -CX 10 1 3, -CHX 10 1 2 , -CH 2 X 10 1
  • R 12 is hydrogen, halogen, -CX 12 1 3 , -CHX 12 1 2 , -CH 2 X 12 1 , -CN, -SO n iR 12A ,
  • R 15 is hydrogen, halogen, -CX 15 1 3 , -CHX 15 1 2 , -CH 2 X 15 1 , -CN, -SO n iR 15A ,
  • R 16 is hydrogen, halogen, -CX 16 1 3, -CHX 16 1 2 , -CH 2 X 16 1 ,
  • R 17 is hydrogen, halogen,
  • R 18 is hydrogen, halogen, -CX 18 1 3 , -CHX 18 1 2 , -CH 2 X 18 1 , -CN, -SO n iR 18A , -
  • R 19 is hydrogen, -COR 19D , -C(0)NHNR 19B R 19C , -C(0)OR 19D -S0 2 R 19A , C(0)NR 19B R 19C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 19 is hydrogen, -COR 19D , -C(0)NHNR 19B R 19C , -C(0)OR 19D -S0 2 R 19A , C(0)NR 19B R 19C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substitute
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X 1'1 , X 2 ⁇ 1 , X 3 ⁇ 1 , X 4 ⁇ 1 , X 5 ⁇ 1 , X 6 ⁇ 1 , X 7 ⁇ 1 , X 8 ⁇ 1 , X 9 ⁇ 1 , X 10 ⁇ 1 , X 1 , X 12 ⁇ 1 , X 13 ⁇ 1 , X 14 ⁇ 1 , X 15 ⁇ 1 , X 16 ⁇ 1 , X 17 ⁇ 1 and X 18'1 are independently -CI, -Br, -I or -F, with the proviso that when A is CR 14 ; B is CR 16 ; L 1 is bond; and R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17
  • Embodiment 2 The compound of embodiment 1, wherein L 1 is a bond and X is NH.
  • Embodiment 3 The compound of embodiment 2, wherein R 13 , R 15 , R 17 and R 18 are independently hydrogen.
  • Embodiment 4 The compound of embodiment 3, wherein R 8 , R 9 , R 11 and R 12 are independently hydrogen.
  • Embodiment s The compound of embodiment 4, wherein: A is CR 14 ; and B is CR 16 .
  • Embodiment 6 The compound of embodiment 5, wherein: R 10 is hydrogen, fluorine, chlorine, iodine, -CX 10 1 3 , -CHX 10 1 2 , -CH 2 X 10 1 , -CN, -SO n iR 10A , -SO v iNR 10B R 10C ,
  • Embodiment 7 The compound of embodiment 6, wherein R 10 is fluorine, chlorine or iodine.
  • Embodiment 8 The compound of embodiment 2, wherein R 8 , R 9 , R 11 , R 12 , R 13 , R 15 , R 17 and R 18 are independently hydrogen.
  • Embodiment 9 The compound of embodiment 8, wherein: A is N; B is CR 16 ; and R 16 is hydrogen.
  • Embodiment 10 The compound of embodiment 9, wherein R 10 is fluorine, chlorine, bromine or iodine.
  • Embodiment 1 The compound of embodiment 8, wherein A and B are independently N; and R 10 is fluorine, chlorine, bromine or iodine.
  • Embodiment 12 A compound of structural Formula (Ilia):
  • nl is an integer from 0 to 4; ml and vl are independently 1 or 2; R 8 is hydrogen, halogen, -CX 8 1 3 , -CHX 8 1 2 , -CH 2 X 8 1 , -CN, -SO n iR 8A , -SO v iNR 8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(0)NHNR 8B R 8C , -NHC(0)NR 8B R 8C , -N(0) m i, -NR 8B R 8C , - C(0)R 8D , -C(0)OR 8D , -C(0)NR 8B R 8C , -OR 8A , -NR 8B S0 2 R 8A , -NR 8B C(0)R 8D , -NR 8B C(0)OR 8D , —OR 8A , -NR 8B S0 2 R 8A
  • R 9 is hydrogen, halogen, -CX 9 1 3 , -CHX 9 1 2 , -CH 2 X 9 1 , -CN, -SO n iR 9A , -SO v iNR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(0)NHNR 9B R 9C , -NHC(0)NR 9B R 9C , -N(0) m i, -NR 9B R 9C , - C(0)R 9D , -C(0)OR 9D , -C(0)NR 9B R 9C , -OR 9A , -NR 9B S0 2 R 9A , -NR 9B S0 2 R 9A ,
  • R 10 is hydrogen, fluorine, chlorine or iodine, -CX 10 1 3 , -CHX 10 1 2 , -CH 2 X 10 1 , -CN, -SO n iR 10A , - SOviNR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(0) ml , -NR 10B R 10C , -C(O)R 10D , -C(O)OR 10D , -C(O)NR 10B R 10C , -OR 10D , -C(O)NR 10B R 10C , -OR 10D , -C(O)NR 10B R 10C , -OR 10D , -C(O)NR 10B R 10C , -OR 10D , -C
  • -ONR 12B R 12C -NHC(0)NHNR 12B R 12C , -NHC(0)NR 12B R 12C , -N(0) m i, -NR 12B R 12C , - C(0)R 12D , -C(0)OR 12D , -C(0)NR 12B R 12C , -OR 12A , -NR 12B S0 2 R 12A , -NR 12B C(0)R 12D , - NR 12B C(0)OR 12D , -NR 12B OR 12D , -OCX 12 , -OCHX 12 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 13 is hydrogen, halogen,
  • -ONR 15B R 15C -NHC(0)NHNR 15B R 15C , -NHC(0)NR 15B R 15C , -N(0) m i, -NR 15B R 15C , - C(0)R 15D , -C(0)OR 15D , -C(0)NR 15B R 15C , -OR 15A , -NR 15B S0 2 R 15A , -NR 15B C(0)R 15D , - NR 15B C(0)OR 15D , -NR 15B OR 15D , -OCX 15 , -OCHX 15 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 16 is hydrogen, halogen,
  • R is hydrogen, halogen, -CX ' 3, -CHX 17 ' 1 2 , -CH 2 X 17 ' 1 s ,
  • R 18 is hydrogen, halogen, - -CH2X 18'1 , -CN, -SO n iR 18A , -SO v iNR 18B R 18C , -NHNR 18B R 18C ,
  • R 19 is hydrogen, -COR 19D , -C(0)NHNR 19B R 19C , -C(0)OR 19D -S0 2 R 19A ,
  • R 19C substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R 1A ' R 1B , R 1C , R 1D , R 2A ' R 2B , R 2C , j ⁇ 2D R 3A R 3B R 3C R 3D R 4A R 4B R 4C R 4D R 5A - R 5B R 5C R 5D R 6A - R 6B R 6C R 6D R 7A ' R 7B R 7C p7D p8A, p8B p8C p 8D R 9A - R 9B R 9C R 9D RIOA, lA, - ⁇ ⁇ p UC p UD
  • R 16C , R 16D , R 17A ⁇ R 17B , R 17C , R 17D , R 18A ⁇ R 18B , R 18C and R 18D are independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , -CI 3 , -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -SO 3 H, -SO 4 H, - SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, - NHC(0)-OH, -NHOH, -OCF3, -OCCI3, -OCBr 3 , -OCI3, -OCHF 2 , -0CHC1 2 , -OCHBr 2 , - OCHI 2 , substituted or unsub
  • R 13C , R 14B , R 14C , R 15B , R 15C , R 16B , R 16C , R 17B , R 17C , R 18B and R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X 1 1 , X 2 1 , X 3 1 , X 4 1 , X 5 1 , X 6 1 , X 7 1 , X 8 1 , X 9 1 , X 10 1 ,
  • X 11 1 , X r 1 l Z 2 . 1 l, X v 1 1 J 3. 1 1, X ⁇ 14 4 ⁇ 1 , X ⁇ 13 5 ⁇ ⁇ 1 , X ⁇ 10 6 ⁇ 1 , X ⁇ 1 1'- ⁇ 1 and X 1 1 8 8 ' . 1 1 are independently -CI, -Br, -I or -F. 0324] Embodiment 13.
  • nl is an integer from 0 to 4; ml and vl are independently 1 or
  • R 8 is hydrogen, halogen, -CX 8 1 3 , -CHX 8 1 2 , -CH 2 X 8 1 , CN, -SO n iR , -SO v iNR ⁇ R 1
  • R 9 is hydrogen, halogen, -9.1 9.1 > 9A > 9B , 9C
  • R 10 is hydrogen, halogen, -CX 10 1 3 , -CHX 10 1 2 , -CH 2 X 10 1 , -CN, -SO n iR 10A , -SO v iNR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(0) m i, - NR IOB R IOC _ C(0)R IOD _ C (0)0R IOD _ C(0 ) N R 10 V oc , _ O R 10A , -NR 10B SO
  • R 11 is hydrogen, halogen, -CX 1 L1 3 , -CHX 1 L1 2 , -CH 2 X 1 L1 , -CN, -SO n iR 11A , -SOviNR 11B R llc , -NHNR 11B R 11C , -ONR 11B R llc , -NHC(0)NHNR 11B R llc , -NHC(0)NR
  • -ONR 12B R 12C -NHC(0)NHNR 12B R 12C , -NHC(0)NR 12B R 12C , -N(0) m i, -NR 12B R 12C , - C(0)R 12D , -C(0)OR 12D , -C(0)NR 12B R 12C , -OR 12A , -NR 12B S0 2 R 12A , -NR 12B C(0)R 12D , - NR 12B C(0)OR 12D , -NR 12B OR 12D , -OCX 12 , -OCHX 12 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 13 is hydrogen, halogen,
  • -ONR 16B R 16C -NHC(0)NHNR 16B R 16C , -NHC(0)NR 16B R 16C , -N(0) m i, -NR 16B R 16C , - C(0)R 16D , -C(0)OR 16D , -C(0)NR 16B R 16C , -OR 16A , -NR 16B S0 2 R 16A , -NR 16B C(0)R 16D , - NR 16B C(0)OR 16D , -NR 16B OR 16D , -OCX 16 1 3 , -OCHX 16 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 17 is hydrogen, halogen
  • R 18D are independently hydrogen, halogen, -CF 3 , -CCI 3 , -CBr 3 , -CI 3 , -OH, -NH 2 , -COOH, -
  • nl is an integer from 0 to 4; ml and vl are independently 1 or
  • R s is hydrogen, halogen, -CX 8 1 3 , -CHX 8 ' 2 , -CH 2 X S 1 , -CN, -SO n iR SA , -SO v iNR s 3 ⁇ 4 ;
  • -CX 10 is hydrogen, halogen, -CX 10. -CHX iai 2 , CH 2 X 10 - 1 , -CN, -SO n iR 1UA , -SO v iNR 1UB R -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(0) m i, - NR IOB R IOC _ C(0)R IOD _ c(O )OR 10D , -C(O)NR 10B R 10C , -OR 10A , -NR 10B SO 2 R 10A , - NR 10B C(O)R 10D , -NR 10B C(O)OR 10D , -NR 10B OR 10D , -OCX 10 1 3 , -OCHX 10 1 2 , substituted or unsubstit
  • -ONR 12B R 12C -NHC(0)NHNR 12B R 12C , -NHC(0)NR 12B R 12C , -N(0) m i, -NR 12B R 12C , - C(0)R 12D , -C(0)OR 12D , -C(0)NR 12B R 12C , -OR 12A , -NR 12B S0 2 R 12A , -NR 12B C(0)R 12D , - NR 12B C(0)OR 12D , -NR 12B OR 12D , -OCX 12 , -OCHX 12 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 13 is hydrogen, halogen,
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X 1'1 , ⁇ X 22 ⁇ 1 ,, ⁇ X 33 ⁇ 1 ,, ⁇ X 44 ⁇ 1 ,, ⁇ X 55 ⁇ 1 ,, ⁇ X 66 ⁇ 1 ,, ⁇ X ⁇ 7 ⁇ 1 ,, ⁇ X 88 ⁇ 1 ,, ⁇ X 9 ⁇ 1 , X 10 ⁇ 1 , X 1 , X 12 ⁇ 1 , X 13 ⁇ 1 , X 14 ⁇ 1 , X 15 ⁇ 1 , X 16 ⁇ 1 , X 17 ⁇ 1 and X are independently -CI, -Br, -I or -F.
  • Embodiment 16 The method of embodiment 15, wherein the cell is a chondrocyte.
  • Embodiment 17 A method of increasing pSTAT3 expression in a cell, comprising contacting the cell with a binding site 1 gpl30 receptor agonist.
  • Embodiment 18 The method of embodiment 17, wherein the cell is a chondrocyte.
  • Embodiment 19 A method of regulating chondrocyte activation, maturation and/or differentiation, comprising contacting a chondrocyte with a binding site 1 gpl30 receptor agonist.
  • Embodiment 20 The method of embodiment 19, wherein the chondrocyte activation comprises an increase in proliferation, migration, metabolism or any combination thereof.
  • Embodiment 21 The method of embodiment 19, wherein the chondrocyte is an adult chondrocyte.
  • Embodiment 22 A method of regenerating or repairing tissue in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a binding site 1 gpl30 receptor agonist.
  • Embodiment 23 The method of embodiment 22, wherein the tissue is cartilage.
  • Embodiment 24 A method of repairing a joint surface injury in a subject, comprising administering to the subject a therapeutically effective amount of a binding site 1 gpl30 receptor agonist.
  • Embodiment 25 A method of treating a cartilage degenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a binding site 1 gpl30 receptor agonist.
  • Embodiment 26 A method of increasing secretion of cartilaginous matrix in cartilage, comprising contacting a gpl30 receptor with a binding site 1 gpl30 receptor agonist.
  • Embodiment 27 The method of embodiment 26, wherein the cartilaginous matrix is in articular cartilage.
  • Embodiment 28 The method of embodiment 26, wherein the cartilaginous matrix comprises collagens and proteoglycans.
  • Embodiment 29 A method of modulating the activity of a gpl30 receptor in a cell, comprising contacting the cell with a binding site 1 gpl30 receptor agonist.
  • Embodiment 30 The method of embodiment 29, wherein the activity of the gpl30 receptor is increased.
  • Embodiment 31 The method of embodiment 29, wherein the activity of the gp 130 receptor is decreased or inhibited.
  • Embodiment 32 The method of embodiment 30, wherein the activity is
  • Embodiment 33 The method of embodiment 29, wherein the cell is a chondrocyte.
  • Embodiment 34 A method of transforming a mature adult cell to a progenitor cell, comprising contacting the cell with a binding site 1 gpl30 receptor agonist.
  • Embodiment 35 The method of embodiment 34, wherein the cell is a human cell.
  • Embodiment 36 The method of embodiment 34, wherein the cell is a chondrocyte.
  • Embodiment 37 The method of any one of embodiments 15 to 36, wherein the binding site 1 gpl30 receptor agonist is a compound of Formula (III):
  • A is CR 14 or N; B is CR 16 or N; X is O, NR 19 or S; L 1 is a bond or substituted or unsubstituted C 1-C3 alkylene; nl is an integer from 0 to 4; ml and vl are independently 1 or 2; R 8 is hydrogen, halogen, -CX 8 1 3 , -CHX 8 1 2 , -CH 2 X 8 1 , -CN, -SO n iR 8A , - SOviNR 8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(0)NHNR 8B R 8C , -NHC(0)NR 8B R 8C , - N(0) m i, -NR 8B R 8C , -C(0)R 8D , -C(0)OR 8D , -C(0)NR 8B R 8C ,
  • R 9 is hydrogen, halogen, -CX 9'1 ⁇ -CHX 9 1 2 , -CH 2 X 9 1 , - CN, -SO n iR 9A , -SOviNR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(0)NHNR 9B R 9C ,
  • R 10 is hydrogen, halogen, -CX 10 1 3 , -CHX 10 1 2 , -CH 2 X 10 1
  • -ONR 11B R l lc -NHC(0)NHNR 11B R 11C , -NHC(0)NR 11B R 11C , -N(0) m i, -NR 11B R 11C , - C(0)R 11D , -C(0)OR 11D , -C(0)NR 11B R 11C , -OR 11A , -NR 11B S0 2 R 11A , -NR 11B C(0)R 11D , - NR 11B C(0)OR 11D , -NR 11B OR 11D , -OCX 11 , -OCHX 1 L1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 12 is hydrogen,
  • -ONR 14B R 14C -NHC(0)NHNR 14B R 14C , -NHC(0)NR 14B R 14C , -N(0) m i , -NR 14B R 14C , - C(0)R 14D , -C(0)OR 14D , -C(0)NR 14B R 14C , -OR 14A , -NR 14B S0 2 R 14A , -NR 14B C(0)R 14D , - NR 14B C(0)OR 14D , -NR 14B OR 14D , -OCX 14 , -OCHX 14 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 15 is hydrogen, halogen,
  • -ONR 17B R 17C -NHC(0)NHNR 17B R 17C , -NHC(0)NR 17B R 17C , -N(0) m i , -NR 17B R 17C , - C(0)R 17D , -C(0)OR 17D , -C(0)NR 17B R 17C , -OR 17A , -NR 17B S0 2 R 17A , -NR 17B C(0)R 17D , - NR 17B C(0)OR 17D , -NR 17B OR 17D , -OCX 17 , -OCHX 17 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 18 is hydrogen, halogen,
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 3 ⁇ 4 n( j
  • Embodiment 38 The method of embodiment 37, wherein L 1 is a bond and X is NH.
  • Embodiment 39. The method of embodiment 38, wherein R 13 , R 15 , R 17 and R 18 are independently hydrogen.
  • Embodiment 40. The method of embodiment 39, wherein R 8 , R 9 , R 11 and R 12 are independently hydrogen.
  • Embodiment 41. The method of embodiment 40, wherein: A is CR 14 ; and B is CR 16 .
  • Embodiment 42 The method of embodiment 41, wherein: R is fluorine, bromine, chlorine, or iodine; and R 14 and R 16 are independently hydrogen.
  • Embodiment 43 The method of embodiment 38, wherein R 8 , R 9 , R 11 , R 12 , R 13 , R 15 , R 17 and R 18 are independently hydrogen.
  • Embodiment 44 The method of embodiment 43, wherein: A is N; B is CR 16 ; and R 16 is hydrogen.
  • Embodiment 45 The method of embodiment 44, wherein R 10 is fluorine, chlorine, bromine or iodine.
  • Embodiment 46 The method of embodiment 43, wherein: A and B are independently N; and R 10 is fluorine, chlorine, bromine or iodine.
  • Embodiment 47 A composition comprising a gpl30 receptor bound to a binding site 1 gpl30 receptor agonist, wherein the binding site 1 gpl30 receptor agonist is bound to the binding site one of the gp 130 receptor.
  • Embodiment 48 The composition of embodiment 47, wherein the binding site 1 gpl30 receptor agonist is non-covalently bound to gpl30 receptor.
  • Embodiment 49 The composition of embodiment 47, wherein binding site 1 comprises amino acid residues lysine, alanine, arginine and lysine corresponding to positions 173, 174, 175 and 176 of the gpl30 receptor.
  • Embodiment 50 The composition of embodiment 47, wherein the binding site 1 gpl30 receptor agonist is a small molecule, an antibody, protein or a polypeptide.
  • Embodiment 51 The composition of embodiment any one of embodiments 47 to 50, wherein the binding site 1 gpl30 receptor agonist is a compound of structural Formula (III):
  • A is CR 14 or N; B is CR 16 or N; X is O, NR 19 or S; L 1 is a bond or substituted or unsubstituted C 1-C3 alkylene; nl is an integer from 0 to 4; ml and vl are independently 1 or 2; R B is hydrogen, halogen, -CX 8 1 3 , -CHX - B 8. 1 1 2 , -CH 2 X - B 8.
  • R 9 is hydrogen, halogen, -CX 9 1 3, -CHX 9 1 2 , -CH 2 X 9 1 , - CN, -SO n iR 9A , -SOviNR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(0)NHNR 9B R 9C ,
  • R 10 is hydrogen, halogen, -CX 10 1 3 , -CHX 10 1 2 , -CH 2 X 10 1
  • OCHX 10 1 2 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 11 is hydrogen, halogen, -
  • R is hydrogen, halogen, -CX ' 3, -CHX ' 2 , -CH 2 X ' ,
  • OCHX 13 1 2 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 14 is hydrogen, halogen, -
  • R 15 is hydrogen, halogen, -CX 15 1 3 , -CHX 15 1 2 , -CH 2 X 15 1 , -CN, -SO n iR 15A , -
  • R 16 is hydrogen, halogen, -CX 16 1 3 , -CHX 16 1 2 , -CH 2 X 16 1 ,
  • R 16A is hydrogen, halogen, - CX 17 - ⁇ , -CHX 17 ⁇ , -CH 2 X 17'1 , -CN, -SO n iR 17A , -SO v iNR 17B R 17C , -NHNR 17B R 17C ,
  • -ONR 17B R 17C -NHC(0)NHNR 17B R 17C , -NHC(0)NR 17B R 17C , -N(0) m i, -NR 17B R 17C , - C(0)R 17D , -C(0)OR 17D , -C(0)NR 17B R 17C , -OR 17A , -NR 17B S0 2 R 17A , -NR 17B C(0)R 17D , - NR 17B C(0)OR 17D , -NR 17B OR 17D , -OCX 17 , -OCHX 17 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 18 is hydrogen, halogen, hal
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X 1'1 , X 2 ⁇ 1 , X 3 ⁇ 1 , X 4 ⁇ 1 , X 5 ⁇ 1 , X 6 ⁇ 1 , X 7 ⁇ 1 , X 8 ⁇ 1 , X 9 ⁇ 1 , X 10 ⁇ 1 , X 1 , X 12 ⁇ 1 , X 13 ⁇ 1 , X 14 ⁇ 1 , X 15 ⁇ 1 , X 16 ⁇ 1 , X 17 ⁇ 1 and X 18'1 are independently -CI, -Br, -I or -F.
  • Embodiment 52 A pharmaceutical composition, comprising a compound of Formula (III) and a pharmaceutically acceptable excipient:
  • A is CR 14 or N; B is CR 16 or N; X is O, NR 19 or S; L 1 is a bond or substituted or unsubstituted C 1-C3 alkylene; nl is an integer from 0 to 4; ml and vl are independently -8.1 -8.1 , 8A
  • R B is hydrogen, halogen, -CX 8 1 3 , -CHX B 1 2 , -CH 2 X B 1 , -CN, -SO n iR SO v iNR 8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(0)NHNR 8B R 8C , -NHC(0)NR 8B R 8C , - N(0) m i, -NR 8B R 8C , -C(0)R 8D , -C(0)OR 8D , -C(0)NR 8B R 8C , -OR 8A , -NR 8B S0 2 R 8A , - NR 8B C(0)R 8D , -NR 8B C(0)OR 8D ,— NR 8B OR 8D , -OCX 8 , -OCHX 8 1 2 , substituted or
  • R 9 is hydrogen, halogen, -CX 9 1 3, -CHX 9 1 2 , -CH 2 X 9 1 , - CN, -SO n iR 9A , -SO v iNR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(0)NHNR 9B R 9C ,
  • R 10 is hydrogen, halogen, -CX 10 1 3 , -CHX 10 1 2 , -CH 2 X 10 1
  • R 11 is hydrogen, halogen, - CX 1 L 1 3, -CHX 1 L 1 2, -CH 2 X 1 L1 , -CN, -SO n iR 11A , -SO v iNR 11B R llc , -NHNR 11B R 11C ,
  • -ONR 11B R l lc -NHC(0)NHNR 11B R 11C , -NHC(0)NR 11B R 11C , -N(0) m i, -NR 11B R 11C , - C(0)R 11D , -C(0)OR 11D , -C(0)NR 11B R 11C , -OR 11A , -NR 11B S0 2 R 11A , -NR 11B C(0)R 11D , - NR 11B C(0)OR 11D , -NR 11B OR 11D , -OCX 11 , -OCHX 1 L1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 12 is hydrogen,
  • OCHX 13 1 2 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 14 is hydrogen, halogen, -
  • R 15 is hydrogen, halogen, -CX 15 1 3 , -CHX 15 1 2 , -CH 2 X 15 1 , -CN, -SO n iR 15A , -
  • R 16 is hydrogen, halogen, -CX 16 1 3, -CHX 16 1 2 , -CH 2 X 16 1 , -CN, -SO n iR 16A , -SO v iNR 16B R 16C , -NHNR 16B R 16C , -ONR 16B R 16C , -NHC(0)NHNR 16B R 16C , -NHC(0)NR 16B R 16C , -N(0)
  • -ONR 17B R 17C -NHC(0)NHNR 17B R 17C , -NHC(0)NR 17B R 17C , -N(0) m i, -NR 17B R 17C , - C(0)R 17D , -C(0)OR 17D , -C(0)NR 17B R 17C , -OR 17A , -NR 17B S0 2 R 17A , -NR 17B C(0)R 17D , - NR 17B C(0)OR 17D , -NR 17B OR 17D , -OCX 17 , -OCHX 17 1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 18 is hydrogen, halogen, hal
  • OCHCl 2 , -OCHBr 2 , -OCHI 2 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • R 18C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X 1'1 , X 2 ⁇ 1 , X 3 ⁇ 1 , X 4 ⁇ 1 , X 5 ⁇ 1 , X 6 ⁇ 1 , X 7 ⁇ 1 , X 8 ⁇ 1 , X 9 ⁇ 1 , X 10 ⁇ 1 , X 1 , X 12 ⁇ 1 , X 13 ⁇ 1 , X 14 ⁇ 1 , X 15 ⁇ 1 , X 16 ⁇ 1 , X 17 ⁇ 1 and X 18'1 are independently -CI, -Br, -I or -F.
  • the current disclosure bridges the fields of orthopedic surgery, stem cell research and developmental biology to develop a novel, clinically-relevant approach for cartilage

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WO2019169135A1 (en) 2018-02-28 2019-09-06 University Of Southern California Compositions and methods for modulating inflammatory and degenerative disorder
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CN112877283A (zh) * 2021-02-10 2021-06-01 安徽农业大学 一种鸡原代软骨细胞分离培养及鉴定的方法
CN114276999A (zh) * 2022-03-03 2022-04-05 中日友好医院(中日友好临床医学研究所) 黑素瘤细胞株及其制备方法
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