US20110112127A1 - Compounds and methods for kinase modulation, and indications therefor - Google Patents

Compounds and methods for kinase modulation, and indications therefor Download PDF

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US20110112127A1
US20110112127A1 US12/939,998 US93999810A US2011112127A1 US 20110112127 A1 US20110112127 A1 US 20110112127A1 US 93999810 A US93999810 A US 93999810A US 2011112127 A1 US2011112127 A1 US 2011112127A1
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pyridin
ylmethyl
fluoro
pyrrolo
lower alkyl
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Jiazhong Zhang
Prabha N. Ibrahim
Ryan Bremer
Wayne Spevak
Hanna Cho
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Plexxikon Inc
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Plexxikon Inc
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Priority to US12/939,998 priority Critical patent/US20110112127A1/en
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Priority to US14/033,291 priority patent/US9096593B2/en
Assigned to PLEXXIKON INC. reassignment PLEXXIKON INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BREMER, RYAN, CHO, HANNA, IBRAHIM, PRABHA N., ZHANG, JIAZHONG, SPEVAK, WAYNE
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Definitions

  • disclosed compounds are Fms kinase inhibitors. In certain embodiments disclosed compounds are both Fms and Kit kinase inhibitors. In certain embodiments disclosed compounds are both Fms and Flt-3 kinase inhibitors.
  • compounds are provided, as well as various salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof.
  • compounds are of Formula I′, Formula I, Formula II′, Formula II, Formula IIa, Formula III′ or Formula III as described below.
  • the compounds inhibit Fms protein kinase selectively relative to other protein kinases, including Kit and Flt-3 protein kinases.
  • the compounds inhibit both Fms protein kinase and Kit protein kinase.
  • the compounds inhibit both Fms protein kinase and Flt-3 protein kinase.
  • the compounds inhibit each of Fms protein kinase, Kit protein kinase and Flt-3 protein kinase.
  • Also contemplated in accordance with the present invention are methods for the use of the compounds in treating diseases and conditions associated with regulation of the activity of any of Fms protein kinase, Kit protein kinase, and Flt-3 protein kinase, including any mutations of these kinases.
  • the use of compounds for therapeutic methods involving modulation of protein kinases are provided.
  • the compounds are used for therapeutic methods involving modulation of Fms kinase, Fms and Kit kinases, Fms and Flt-3 kinases, or Fms, Kit and Flt-3 kinases including treatment of a variety of indications, including, but not limited to, rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, atherosclerosis, systemic lupus erythematosis, myelopreparation for autologous transplantation, transplant rejection, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy
  • Ar is selected from the group consisting of:
  • R 1 , R 3 and R 4 are each independently selected from the group consisting of —H, lower alkoxy, halogen, halogen substituted lower alkyl, alkoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 40 , —S(O) 2 —R 41 , —S(O) 2 —N(H)—R 42 , —N(H)—R 42 , —N(R 42 ) 2 , and —N(H)—S(O) 2 —R 43 , provided that at least two of R 1 , R 2 , R 3 and R 4 are —H and R 2 is —F, —Cl or —Br; or R 1 , R 2 and R 3 are —H and R 4 is —CF 3 ; or R 1 and R 4 are —H, R 2 is —O—CH 3 , and R 3 is —F; or R 2 and R 4 are —H, R 2 and
  • Ar 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-N-phenyl
  • R 7 is as defined herein.
  • Ar 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-N-phenyl
  • R 8 is as defined herein.
  • Ar 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-N-phenyl
  • Ar 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-N-phenyl
  • R 9 is as defined herein.
  • R 1 , R 3 and R 4 are H and R 2 is halogen. In other embodiments, R 1 , R 2 and R 3 are —H and R 4 is halo substituted lower alkyl. In other embodiments, R 1 and R 4 are —H and R 2 is lower alkoxy. In some embodiments, R 3 is halogen. In yet other embodiments, R 2 and R 4 are —H, R 1 is lower alkoxy and R 3 is halogen.
  • R 1 , R 2 and R 3 are —H and R 4 is CF 3 ; or ii) R 1 and R 4 are —H and R 2 is —OCH 3 ; or iii) R 3 is F; or iv) R 2 and R 4 are —H, R 1 is OCH 3 and R 3 is F.
  • the variables R 5 , R 6 and Ar are as defined herein.
  • R 5 is —H, —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 10 , —C(O)—N(H)—R 11 , —C(O)—O—R 11 , —S(O) 2 —R 12 , —S(O) 2 —N(H)—R 11 , —N(H)—C(O)—R 12 , and —N(H)—S(O) 2 —R 12 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl.
  • R 5 is H. All the other variables are as defined herein.
  • R 5 is —H.
  • R 5 is —H and R 6 is —H, —F, —Cl, —CH 3 , —CF 3 , —CN, —O—CH 3 , —S(O) 2 —CH 3 , —C(O)—NH—CH 3 , —C(O)—O—CH 3 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , or cyclopropyl. All the other variables are as defined herein.
  • R 6 is selected from the group consisting of H, halo, lower alkyl, lower alkoxy, fluoro substituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 13 , —C(O)—N(H)—R 14 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 , —N(H)—C(O)—R 15 , and —N(H)—S(O) 2 —R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl.
  • R 6 is halo, lower alkyl or fluoro substituted lower alkyl. All the other variables are as defined herein.
  • R 6 is —H.
  • R 6 is —H and R 5 is —H, —Cl, —CN, —C ⁇ CH, —O—CH 3 , or phenyl.
  • R 6 is halo, lower alkyl lower alkoxy, or fluoro substituted lower alkyl.
  • R 6 is halogen, methyl, methoxy, trifluoromethyl, or CN. All the other variables are as defined herein.
  • R 7 is H, halogen or lower alkyl. In other embodiments, R 7 is H, —F, —Cl, Br or —CH 3 . All the other variables are as defined herein.
  • R 8 is H, halogen or lower alkoxy. In other embodiments, R 8 is H, —F, —Cl, Br or —OCH 3 . All the other variables are as defined herein.
  • R 9 is H or halogen. In other embodiments, R 9 is —H or —Cl. All the other variables are as defined herein.
  • R 1 , R 3 and R 4 are —H; R 2 is —F, —Cl or —Br; and R 5 is —H.
  • R 1 , R 3 and R 4 are —H; R 2 is —F, —Cl or —Br; R 5 is —H; and R 6 is —H, —F, —Cl, —CH 3 , —CF 3 , —CN, —O—CH 3 , —S(O) 2 —CH 3 , —C(O)—NH—CH 3 , —C(O)—O—CH 3 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , or cyclopropyl. All the other variables are as defined herein.
  • R 1 , R 3 and R 4 are —H; R 2 is —F, —Cl or —Br; and R 6 is —H.
  • R 1 , R 3 and R 4 are —H; R 2 is —F, —Cl or —Br; R 6 is —H; and R 5 is —H, —Cl, —CN, —C ⁇ CH, —O—CH 3 , or phenyl. All the other variables are as defined herein.
  • R 1 , R 2 and R 3 are —H; and R 4 is —CF 3 ; and R 5 is —H.
  • R 1 , R 2 and R 3 are —H; and R 4 is —CF 3 ;
  • R 5 is —H; and
  • R 6 is —H, —F, —Cl, —CH 3 , —CF 3 , —CN, —O—CH 3 , —S(O) 2 —CH 3 , —C(O)—NH—CH 3 , —C(O)—O—CH 3 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , or cyclopropyl. All the other variables are as defined herein.
  • R 1 , R 2 and R 3 are —H; and R 4 is —CF 3 ; and R 6 is —H.
  • R 1 , R 2 and R 3 are —H; and R 4 is —CF 3 ;
  • R 6 is —H; and
  • R 5 is —H, —Cl, —CN, —C ⁇ CH, —O—CH 3 , or phenyl. All the other variables are as defined herein.
  • R 1 and R 4 are —H; R 2 is —O—CH 3 ; R 3 is —F; and R 5 is —H.
  • R 1 and R 4 are —H; R 2 is —O—CH 3 ; R 3 is —F; R 5 is —H; and R 6 is —H, —F, —Cl, —CH 3 , —CF 3 , —CN, —O—CH 3 , —S(O) 2 —CH 3 , —C(O)—NH—CH 3 , —C(O)—O—CH 3 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , or cyclopropyl. All the other variables are as defined herein.
  • R 1 and R 4 are —H; R 2 is —O—CH 3 ; R 3 is —F; and R 6 is —H.
  • R 1 and R 4 are —H; R 2 is —O—CH 3 ; R 3 is —F; R 6 is —H; and R 5 is —H, —Cl, —CN, —C ⁇ CH, —O—CH 3 , or phenyl. All the other variables are as defined herein.
  • R 2 and R 4 are —H; R 1 is —O—CH 3 ; R 3 is —F; and R 5 is —H.
  • R 2 and R 4 are —H; R 1 is —O—CH 3 ; R 3 is —F; R 5 is —H; and R 6 is —H, —F, —Cl, —CH 3 , —CF 3 , —CN, —O—CH 3 , —S(O) 2 —CH 3 , —C(O)—NH—CH 3 , —C(O)—O—CH 3 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , or cyclopropyl. All the other variables are as defined herein.
  • R 2 and R 4 are —H; R 1 is —O—CH 3 ; R 3 is —F; and R 6 is —H.
  • R 2 and R 4 are —H; R 1 is —O—CH 3 ; R 3 is —F; R 6 is —H; and R 5 is —H, —Cl, —CN, —C ⁇ CH, —O—CH 3 , or phenyl. All the other variables are as defined herein.
  • Ar is selected from the group consisting of:
  • R 5 is —H.
  • R 5 is —H and R 6 is —H, —F, —Cl, —CH 3 , —CF 3 , —CN, —O—CH 3 , —S(O) 2 —CH 3 , —C(O)—NH—CH 3 , —C(O)—O—CH 3 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , or cyclopropyl.
  • R 6 is —H. In some embodiments, R 6 is —H and R 5 is —H, —Cl, —CN, —C ⁇ CH, —O—CH 3 , or phenyl.
  • R 1 , R 3 and R 4 are —H; R 2 is —F, —Cl or —Br; and R 5 is —H.
  • R 1 , R 3 and R 4 are —H; R 2 is —F, —Cl or —Br; R 5 is —H; and R 6 is —H, —F, —Cl, —CH 3 , —CF 3 , —CN, —O—CH 3 , —S(O) 2 —CH 3 , —C(O)—NH—CH 3 , —C(O)—O—CH 3 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , or cyclopropyl.
  • R 1 , R 3 and R 4 are —H; R 2 is —F, —Cl or —Br; and R 6 is —H.
  • R 1 , R 3 and R 4 are —H; R 2 is —F, —Cl or —Br; R 6 is —H; and R 5 is —H, —Cl, —CN, —C ⁇ CH, —O—CH 3 , or phenyl.
  • R 1 , R 2 and R 3 are —H; and R 4 is —CF 3 ; and R 5 is —H.
  • R 1 , R 2 and R 3 are —H; and R 4 is —CF 3 ;
  • R 5 is —H; and
  • R 6 is —H, —F, —Cl, —CH 3 , —CF 3 , —CN, —O—CH 3 , —S(O) 2 —CH 3 , —C(O)—NH—CH 3 , —C(O)—O—CH 3 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , or cyclopropyl.
  • R 1 , R 2 and R 3 are —H; and R 4 is —CF 3 ; and R 6 is —H.
  • R 1 , R 2 and R 3 are —H; and R 4 is —CF 3 ;
  • R 6 is —H; and
  • R 5 is —H, —Cl, —CN, —C ⁇ CH, —O—CH 3 , or phenyl.
  • R 1 and R 4 are —H; R 2 is —O—CH 3 ; R 3 is —F; and R 5 is —H.
  • R 1 and R 4 are —H; R 2 is —O—CH 3 ; R 3 is —F; R 5 is —H; and R 6 is —H, —F, —Cl, —CH 3 , —CF 3 , —CN, —O—CH 3 , —S(O) 2 —CH 3 , —C(O)—NH—CH 3 , —C(O)—O—CH 3 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , or cyclopropyl.
  • R 1 and R 4 are —H; R 2 is —O—CH 3 ; R 3 is —F; and R 6 is —H.
  • R 1 and R 4 are —H; R 2 is —O—CH 3 ; R 3 is —F; R 6 is —H; and R 5 is —H, —Cl, —CN, —C ⁇ CH, —O—CH 3 , or phenyl.
  • R 2 and R 4 are —H; R 1 is —O—CH 3 ; R 3 is —F; and R 5 is —H.
  • R 2 and R 4 are —H; R 1 is —O—CH 3 ; R 3 is —F; R 5 is —H; and R 6 is —H, —F, —Cl, —CH 3 , —CF 3 , —CN, —O—CH 3 , —S(O) 2 —CH 3 , —C(O)—NH—CH 3 , —C(O)—O—CH 3 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , or cyclopropyl.
  • R 2 and R 4 are —H; R 1 is —O—CH 3 ; R 3 is —F; and R 6 is —H.
  • R 2 and R 4 are —H; R 1 is —O—CH 3 ; R 3 is —F; R 6 is —H; and R 5 is —H, —Cl, —CN, —C ⁇ CH, —O—CH 3 , or phenyl.
  • the compound is selected from the group consisting of:
  • R 7 is other than hydrogen. All the other variables are as defined herein.
  • R 6 and R 7 are not simulataneously H. All the other variables are as defined herein.
  • R 7 when R 7 is halogen, R 6 is other than H, halogen, heteroaryl, CN or lower alkyl. In certain instances, when R 7 is Cl, R 6 is other than H, Cl, pyrrazolyl, CN or CH 3 . All the other variables are as defined herein.
  • R 7 when R 7 is halogen, R 6 is other than halo substituted lower alkyl. In certain instances, when R 7 is Cl, R 6 is other than CF 3 . All the other variables are as defined herein.
  • R 7 when R 7 is halogen, R 2 is other than halogen substituted lower alkyl or lower alkoxy. In certain instances, when R 7 is F, R 2 is other than CF 3 or —OCH 3 . All the other variables are as defined herein.
  • R 6 is other than halogen, lower alkoxy, hydrogen or CN. In certain instances, when R 7 is —F, R 6 is other than Cl, OCH 3 , hydrogen or CN. In other instances, when R 7 is —F, R 3 is other than F. All the other variables are as defined herein.
  • R 7 when R 7 is hydrogen, R 6 is other than halogen, hydrogen, lower alkyl, CN, or lower alkoxy. In certain instances, when R 7 is hydrogen, R 6 is other than H, Cl, F, CH 3 , CN, —OCH 3 . All the other variables are as defined herein.
  • R 6 is other than H or halogen. In certain instances, when R 9 is Cl, R 6 is other than H or Cl. All the other variables are as defined herein.
  • R 6 is other than hydrogen. All the other variables are as defined herein.
  • R 1 , R 2 , R 3 and R 4 are not simultaneously hydrogen. All the other variables are as defined herein.
  • R 2 is other than halo substituted lower alkyl, for example, in one embodiment, R 2 is other than CF 3 . All the other variables are as defined herein.
  • R 18 and R 19 are each independently selected from the group consisting of H, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, alkoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —S(O) 2 —N(H)—R 22 , —N(H)—R 22 , —N(R 22 ) 2 , and —N(H)—S(O) 2 —R 23 , provided that at least two of R 16 , R 17 , R 18 and R 19 are —H;
  • R 6 is selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 13 , —C(O)—N(H)—R 14 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 , —N(H)—C(O)—R 15 , and —N(H)—S(O) 2 —R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl.
  • R 6 is F, Cl, Br, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, —CN, —C(O)—N(H)—R 14 , —N(H)—C(O)—R 15 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 or —N(H)—S(O) 2 —R 15 .
  • R 6 is methyl, ethyl, propyl, butyl, pentyl or hexyl. All other variables are as defined herein.
  • R 16 , R 17 , R 18 and R 19 are each independently selected from the group consisting of —H, —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —S(O) 2 —N(H)—R 22 , —N(H)—R 22 , —N(R 22 ) 2 , and —N(H)—S(O) 2 —R 23 , provided that at least two of R 16 , R 17 , R 18 and R 19 are —H.
  • R 17 and R 19 are H, halogen or lower alkyl. All other variables are as defined herein.
  • R 16 , R 17 , R 18 and R 19 are each independently selected from H, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, —OR 20 , or alkoxy substituted lower alkyl, provided that at least two of R 16 , R 17 , R 18 and R 19 are —H. All other variables are as defined herein.
  • R 16 , R 17 , and R 18 are H and R 19 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 16 , R 17 , and R 18 are H and R 19 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)R 22 , or —N(R 22 ) 2 .
  • R 16 , R 17 , and R 18 are H and R 19 is fluoro substituted lower alkyl or —O—R 20 .
  • R 16 , R 17 , and R 18 are H and R 19 is —CF 3 or —O—CH 3 . All other variables are as defined herein.
  • R 16 , R 17 , and R 19 are H and R 18 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 16 , R 17 , and R 19 are H and R 18 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 16 , R 17 , and R 19 are H and R 18 is —F, —Cl, or —O—R 20 .
  • R 16 , R 17 , and R 19 are H and R 18 is —F, —Cl, or —O—CH 3 . All other variables are as defined herein.
  • R 16 , R 18 , and R 19 are H and R 17 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 16 , R 18 , and R 19 are H and R 17 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 16 , R 18 , and R 19 are H and R 17 is —Cl, fluoro substituted lower alkyl, cycloalkylamino, or —O—R 20 .
  • R 16 , R 18 , and R 19 are H and R 17 is —Cl, —CF 3 , —O—CH 3 , or morpholin-4-yl. All other variables are as defined herein.
  • R 17 , R 18 , and R 19 are H and R 16 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 17 , R 18 , and R 19 are H and R 16 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 17 , R 18 , and R 19 are H and R 16 is —F, —CF 3 , morpholin-4-yl, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —O—CH 2 CF 3 , —O-cyclopentyl, —O-cyclohexyl, or —N(H)—CH 3 .
  • R 17 , R 18 , and R 19 are H and R 16 is —F, —CF 3 , or —O—CH 3 . All other variables are as defined herein.
  • R 16 and R 17 are H; and R 18 and R 19 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 16 and R 17 are H; and R 18 and R 19 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , or —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 16 and R 17 are H; and R 18 and R 19 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 . All other variables are as defined herein.
  • R 16 and R 18 are H; and R 17 and R 19 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 —S(O) 2 —R 21 —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 16 and R 18 are H; and R 17 and R 19 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 16 and R 18 are H; and R 17 and R 19 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 .
  • R 16 and R 18 are H; and R 17 and R 19 are independently —CF 3 or —O—CH 3 . All other variables are as defined herein.
  • R 16 and R 19 are H; and R 17 and R 18 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 16 and R 19 are H; and R 17 and R 18 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 . In some embodiments R 16 and R 19 are H; and R 17 and R 18 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 . In some embodiments R 16 and R 19 are H; and R 17 and R 18 are independently —F or —O—CH 3 . All other variables are as defined herein.
  • R 17 and R 18 are H; and R 16 and R 19 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 17 and R 18 are H; and R 16 and R 19 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 17 and R 18 are H; and R 16 and R 19 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 . All other variables are as defined herein.
  • R 17 and R 19 are H; and R 16 and R 18 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 17 and R 19 are H; and R 16 and R 18 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 17 and R 19 are H; and R 16 and R 18 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 .
  • R 17 and R 19 are H; and R 16 and R 18 are independently —F, —Cl, or —O—CH 3 . All other variables are as defined herein.
  • R 18 and R 19 are H; and R 16 and R 17 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 18 and R 19 are H; and R 16 and R 17 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 18 and R 19 are H; and R 16 and R 17 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 .
  • R 18 and R 19 are H; and R 16 and R 17 are independently —CF 3 , —O—CH 3 , or —N(CH 3 ) 2 . All other variables are as defined herein.
  • R 16 , R 17 , R 18 and R 19 are each independently from the group consisting of —H, —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —S(O) 2 —N(H)—R 22 , —N(H)—R 22 , —N(R 22 ) 2 , and —N(H)—S(O) 2 —R 23 , provided that at least two of R 16 , R 17 , R 18 and R 19 are —H.
  • R 17 and R 19 are H, halogen or lower alkyl. All other variables are as defined herein.
  • R 16 , R 17 , R 18 and R 19 are each independently selected from H, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, —OR 20 , or alkoxy substituted lower alkyl, provided that at least two of R 16 , R 17 , R 18 and R 19 are —H. All other variables are as defined herein.
  • R 16 , R 17 , and R 18 are H and R 19 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 16 , R 17 , and R 18 are H and R 19 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 16 , R 17 , and R 18 are H and R 19 is fluoro substituted lower alkyl or —O—R 20 .
  • R 16 , R 17 , and R 18 are H and R 19 is —CF 3 or —O—CH 3 . All other variables are as defined herein.
  • R 16 , R 17 , and R 19 are H and R 18 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 16 , R 17 , and R 19 are H and R 18 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 16 , R 17 , and R 19 are H and R 18 is —F, —Cl, or —O—R 20 .
  • R 16 , R 17 , and R 19 are H and R 18 is —F, —Cl, or —O—CH 3 . All other variables are as defined herein.
  • R 16 , R 18 , and R 19 are H and R 17 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 16 , R 18 , and R 19 are H and R 17 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 16 , R 18 , and R 19 are H and R 17 is —Cl, fluoro substituted lower alkyl, cycloalkylamino, or —O—R 20 .
  • R 16 , R 18 , and R 19 are H and R 17 is —Cl, —CF 3 , —O—CH 3 , or morpholin-4-yl. All other variables are as defined herein.
  • R 17 , R 18 , and R 19 are H and R 16 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 17 , R 18 , and R 19 are H and R 16 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 17 , R 18 , and R 19 are H and R 16 is —F, —CF 3 , morpholin-4-yl, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —O—CH 2 CF 3 , —O-cyclopentyl, —O-cyclohexyl, or —N(H)—CH 3 .
  • R 17 , R 18 , and R 19 are H and R 16 is —F, —CF 3 , or —O—CH 3 . All other variables are as defined herein.
  • R 16 and R 17 are H; and R 18 and R 19 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—S(O) 2 —R 23 .
  • R 16 and R 17 are H; and R 18 and R 19 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 16 and R 17 are H; and R 18 and R 19 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 . All other variables are as defined herein.
  • R 16 and R 18 are H; and R 17 and R 19 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 16 and R 18 are H; and R 17 and R 19 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 16 and R 18 are H; and R 17 and R 19 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 .
  • R 16 and R 18 are H; and R 17 and R 19 are independently —CF 3 or —O—CH 3 . All other variables are as defined herein.
  • R 16 and R 19 are H; and R 17 and R 18 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 16 and R 19 are H; and R 17 and R 18 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 . In some embodiments R 16 and R 19 are H; and R 17 and R 18 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 . In some embodiments R 16 and R 19 are H; and R 17 and R 18 are independently —F or —O—CH 3 . All other variables are as defined herein.
  • R 17 and R 18 are H; and R 16 and R 19 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 17 and R 18 are H; and R 16 and R 19 are independently —F, —Cl, lower alkyl, fluoro, substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 17 and R 18 are H; and R 16 and R 19 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 . All the other variables are as defined herein.
  • R 17 and R 19 are H; and R 16 and R 18 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 17 and R 19 are H; and R 16 and R 18 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 17 and R 19 are H; and R 16 and R 18 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 .
  • R 17 and R 19 are H; and R 16 and R 18 are independently —F, —Cl, or —O—CH 3 . All the other variables are as defined herein.
  • R 18 and R 19 are H; and R 16 and R 17 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —N(H)—R 22 , —N(R 22 ) 2 , or —N(H)—S(O) 2 —R 23 .
  • R 18 and R 19 are H; and R 16 and R 17 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 20 , —N(H)—R 22 , or —N(R 22 ) 2 .
  • R 18 and R 19 are H; and R 16 and R 17 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 .
  • R 18 and R 19 are H; and R 16 and R 17 are independently —CF 3 , —O—CH 3 , or —N(CH 3 ) 2 . All the other variables are as defined herein.
  • the compound is selected from the group consisting of:
  • the invention provides compounds having Formula III′:
  • R 6 is selected from the group consisting of halogen, lower alkyl, lower alkoxy, fluoro substituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 13 , —C(O)—N(H)—R 14 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 , —N(H)—C(O)—R 15 , and —N(H)—S(O) 2 —R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl.
  • R 6 is F, Cl, Br, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, —CN, —C(O)—N(H)—R 14 , —N(H)—C(O)—R 15 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 or —N(H)—S(O) 2 —R 15 .
  • R 6 is methyl, ethyl, propyl, butyl, pentyl or hexyl. All other variables are as defined herein.
  • R 24 , R 25 , R 26 and R 27 are each independently selected from the group consisting of —H, —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —S(O) 2 —N(H)—R 22 , —N(H)—R 22 , —N(R 22 ) 2 , and —N(H)—S(O) 2 —R 23 , provided that at least two of R 24 , R 25 , R 26 and R 27 are —H.
  • R 24 , R 25 , R 26 and R 27 are each independently selected from H, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, —OR 20 , or alkoxy substituted lower alkyl. All other variables are as defined herein.
  • R 24 , R 25 , and R 26 are H and R 27 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 28 , —S(O) 2 —R 29 , —N(H)—R 30 , —N(R 30 ) 2 , or —N(H)—S(O) 2 —R 31 .
  • R 24 , R 25 , and R 26 are H and R 27 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 28 , —N(H)—R 30 , or —N(R 30 ) 2 .
  • R 24 , R 25 , and R 26 are H and R 27 is fluoro substituted lower alkyl or —O—R 28 .
  • R 24 , R 25 , and R 26 are H and R 27 is —CF 3 or —O—CH 3 . All other variables are as defined herein.
  • R 24 , R 25 , and R 27 are H and R 26 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 28 , —S(O) 2 —R 29 , —N(H)—R 30 , —N(R 30 ) 2 , or —N(H)—S(O) 2 —R 31 .
  • R 24 , R 25 , and R 27 are H and R 26 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 28 , —N(H)—R 30 , or —N(R 30 ) 2 .
  • R 24 , R 25 , and R 27 are H and R 26 is —F, —Cl, or —O—R 28 .
  • R 24 , R 25 , and R 27 are H and R 26 is —F, —Cl, or —O—CH 3 . All other variables are as defined herein.
  • R 24 , R 26 , and R 27 are H and R 25 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 28 , —S(O) 2 —R 29 , —N(H)—R 30 , —N(R 30 ) 2 , or —N(H)—S(O) 2 —R 31 .
  • R 24 , R 26 , and R 27 are H and R 25 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 28 , —N(H)—R 30 , or —N(R 30 ) 2 .
  • R 24 , R 26 , and R 27 are H and R 25 is —Cl, fluoro substituted lower alkyl, cycloalkylamino, or —O—R 28 .
  • R 24 , R 26 , and R 27 are H and R 25 is —Cl, —CF 3 , —O—CH 3 , or 4-methyl-piperazin-1-yl. All other variables are as defined herein.
  • R 25 , R 26 , and R 27 are H and R 24 is —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 28 , —S(O) 2 —R 29 , —N(H)—R 30 , —N(R 30 ) 2 , or —N(H)—S(O) 2 —R 31 .
  • R 25 , R 26 , and R 27 are H and R 24 is —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 28 , —N(H)—R 30 , or —N(R 30 ) 2 .
  • R 25 , R 26 , and R 27 are H and R 24 is —F, —CF 3 , morpholin-4-yl, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —O—CH 2 CF 3 , —O-cyclopentyl, —O-cyclohexyl, or —N(H)—CH 3 .
  • R 25 . R 26 , and R 27 are H and R 24 is —F, —CF 3 , —O—CH 3 , —O—CH 2 CH 3 , or —O-cyclopentyl. All other variables are as defined herein.
  • R 24 and R 25 are H; and R 26 and R 27 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 28 , —S(O) 2 —R 29 , —N(H)—R 30 , —N(R 30 ) 2 , or —N(H)—S(O) 2 —R 31 .
  • R 24 and R 25 are H; and R 26 and R 27 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 28 , —N(H)—R 30 , or —N(R 30 ) 2 .
  • R 24 and R 25 are H; and R 26 and R 27 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 . All other variables are as defined herein.
  • R 24 and R 26 are H; and R 25 and R 27 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 28 , —S(O) 2 —R 29 , —N(H)—R 30 , —N(R 30 ) 2 , or —N(H)—S(O) 2 —R 31 .
  • R 24 and R 26 are H; and R 25 and R 27 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 28 , —N(H)—R 30 , or —N(R 30 ) 2 .
  • R 24 and R 26 are H; and R 25 and R 27 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 .
  • R 24 and R 26 are H; and R 25 and R 27 are independently —CF 3 or —O—CH 3 . All other variables are as defined herein.
  • R 24 and R 27 are H; and R 25 and R 26 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 28 , —S(O) 2 —R 29 , —N(H)—R 30 , —N(R 30 ) 2 , or —N(H)—S(O) 2 —R 31 .
  • R 24 and R 27 are H; and R 25 and R 26 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 28 , —N(H)—R 30 , or —N(R 30 ) 2 .
  • R 24 and R 27 are H; and R 25 and R 26 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 .
  • R 24 and R 27 are H; and R 25 and R 26 are independently —F or —O—CH 3 . All other variables are as defined herein.
  • R 25 and R 26 are H; and R 24 and R 27 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 28 , —S(O) 2 —R 29 , —N(H)—R 30 , —N(R 30 ) 2 , or —N(H)—S(O) 2 —R 31 .
  • R 25 and R 26 are H; and R 24 and R 27 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 28 , —N(H)—R 30 , or —N(R 30 ) 2 .
  • R 25 and R 26 are H; and R 24 and R 27 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 . All other variables are as defined herein.
  • R 25 and R 27 are H; and R 24 and R 26 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 28 , —S(O) 2 —R 29 , —N(H)—R 30 , —N(R 30 ) 2 , or —N(H)—S(O) 2 —R 31 .
  • R 25 and R 27 are H; and R 24 and R 26 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 28 , —N(H)—R 30 , or —N(R 30 ) 2 .
  • R 25 and R 27 are H; and R 24 and R 26 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 .
  • R 25 and R 27 are H; and R 24 and R 26 are independently —F or —O—CH 3 . All other variables are as defined herein.
  • R 26 and R 27 are H; and R 24 and R 25 are independently —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 28 , —S(O) 2 —R 29 , —N(H)—R 30 , —N(R 30 ) 2 , or —N(H)—S(O) 2 —R 31 .
  • R 26 and R 27 are H; and R 24 and R 25 are independently —F, —Cl, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, —O—R 28 , —N(H)—R 30 , or —N(R 30 ) 2 .
  • R 26 and R 27 are H; and R 24 and R 25 are independently —F, —Cl, CF 3 , —O—CH 3 , or —N(CH 3 ) 2 .
  • R 26 and R 27 are H; and R 24 and R 25 are independently —CF 3 , —O—CH 3 , or —N(CH 3 ) 2 . All other variables are as defined herein.
  • the compound is selected from the group consisting of:
  • compounds are provided, wherein the compound is selected from the group consisting of:
  • specification of a compound or group of compounds includes salts of such compound(s) (including pharmaceutically acceptable salts), formulations of such compound(s) (including pharmaceutically acceptable formulations), conjugates thereof, derivatives thereof, forms thereof, prodrugs thereof, and all stereoisomers thereof.
  • salts of such compound(s) including pharmaceutically acceptable salts
  • formulations of such compound(s) including pharmaceutically acceptable formulations
  • conjugates thereof derivatives thereof, forms thereof, prodrugs thereof, and all stereoisomers thereof.
  • a compound as described herein includes compounds of Formulae I and I′ including all sub-embodiments thereof, compounds of Formulae II, II′ and IIa, including all sub-embodiments thereof, compounds of Formulae III and III′ including all sub-embodiments thereof, and compounds as listed in the fourth aspect above.
  • methods for treating any of a Fms and/or Kit and/or Flt-3 protein kinase mediated disease or condition in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more compound(s) as described herein. In certain embodiments, the method involves administering to the subject an effective amount of a compound as described herein in combination with one or more other therapies for the disease or condition.
  • the invention provides methods for treating a Fms protein kinase mediated disease or condition in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more compound(s) as described herein. In one embodiment, the method involves administering to the subject an effective amount of a compound as described herein in combination with one or more other therapies for the disease or condition.
  • the invention provides methods for treating a Kit protein kinase mediated disease or condition in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more compound(s) as described herein.
  • the method involves administering to the subject an effective amount of a compound described herein in combination with one or more other therapies for the disease or condition.
  • a compound as described herein will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay.
  • the compound is selective relative to other protein kinases, such that the ratio of IC 50 for another kinase assessed comparably, divided by the IC 50 for Fms kinase is >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100, wherein the other protein kinase includes, but is not limited to CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.
  • a compound as described herein will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Kit kinase activity assay.
  • the compound is selective relative to other protein kinases, such that the ratio of IC 50 for another kinase assessed comparably divided by the IC 50 for Kit kinase is >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100, wherein the other protein kinase includes, but is not limited to CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.
  • a compound as described herein is a dual Fms/Kit inhibitor, i.e. will be approximately equipotent with respect to inhibition of Fms kinase and Kit kinase.
  • the compound will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay and will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a comparable generally accepted Kit kinase activity assay, wherein the ratio of IC 50 for Kit kinase divided by the IC 50 for Fms kinase is in the range of 20 to 0.05, also
  • the compound is selective relative to protein kinases other than Kit, such that the ratio of IC 50 for another kinase assessed comparably, divided by the IC 50 for Fms kinase is >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100, wherein the other protein kinase includes, but is not limited to CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.
  • the dual Fms/Kit inhibitor is a compound selected from the group consisting of:
  • a compound as described herein is a Fms selective inhibitor, i.e. will selectively inhibit Fms kinase relative to Kit kinase.
  • the compound will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay and when determined in a comparable generally accepted Kit kinase activity assay will have a ratio of IC 50 for Kit kinase divided by the IC 50 for Fms kinase of >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100.
  • the compound is also selective relative to protein kinases other than Kit, such that the ratio of IC 50 for another kinase assessed comparably, divided by the IC 50 for Fms kinase is >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100, wherein the other protein kinase includes, but is not limited to Flt-3, CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.
  • the Fms selective inhibitor is a compound selected from the group consisting of:
  • a compound as described herein is a dual Fms/Flt-3 inhibitor, i.e. will be approximately equipotent with respect to inhibition of Fms kinase and Flt-3 kinase.
  • the compound will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay and will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a comparable generally accepted Flt-3 kinase activity assay, wherein the ratio of IC 50 for Flt-3 kinase divided by the IC 50 for Fms kinase is in the range of 20 to 0.05, also 10 to 0.1, also 5 to 0.2.
  • the compound is selective relative to protein kinases other than Flt-3, such that the ratio of IC 50 for another kinase assessed comparably, divided by the IC 50 for Fms kinase is >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100, wherein the other protein kinase includes, but is not limited to CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.
  • the dual Fms/Flt-3 inhibitor also inhibits Kit.
  • the dual Fms/Flt-3 inhibitor is a compound selected from the group consisting of:
  • the dual Fms/Flt-3 inhibitor is a compound selected from the group consisting of:
  • a compound as described herein also inhibits the effects of a mutation of the kinase (e.g. Fms mutant, Kit mutant, Flt-3 mutant), including, but not limited to, a mutation that is related to a disease state, such as a cancer.
  • a mutation of the kinase e.g. Fms mutant, Kit mutant, Flt-3 mutant
  • compositions include a therapeutically effective amount of any one or more compound(s) as described herein and at least one pharmaceutically acceptable carrier, excipient, and/or diluent, including combinations of any two or more compounds as described herein.
  • the composition can further include a plurality of different pharmacologically active compounds, which can include a plurality of compounds as described herein.
  • the composition can include any one or more compound(s) as described herein along with one or more compounds that are therapeutically effective for the same disease indication.
  • the composition includes any one or more compound(s) as described herein along with one or more compounds that are therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect on the disease indication.
  • the composition includes any one or more compound(s) as described herein effective in treating a cancer and one or more other compounds that are effective in treating the same cancer, further wherein the compounds are synergistically effective in treating the cancer.
  • methods are provided for modulating the activity of a Fms and/or Kit and/or Flt-3 protein kinase, including any mutations thereof, by contacting the protein kinase with an effective amount of any one or more compound(s) as described herein.
  • the invention provides methods for treating a disease or condition mediated by Fms and/or Kit and/or Flt-3, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein.
  • the invention provides methods for treating a disease or condition mediated by Fms and/or Kit, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein in combination with one or more other suitable therapies for treating the disease.
  • the invention provides methods for treating a disease or condition mediated by Fms, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein.
  • the invention provides methods for treating a disease or condition mediated by Fms, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein in combination with one or more other suitable therapies for treating the disease.
  • the invention provides methods for treating a disease or condition mediated by Kit, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein.
  • the invention provides methods for treating a disease or condition mediated by Kit, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein in combination with one or more other suitable therapies for treating the disease.
  • the invention provides methods for treating a disease or condition mediated by Flt-3, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein.
  • the invention provides methods for treating a disease or condition mediated by Flt-3, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein in combination with one or more other suitable therapies for treating the disease.
  • the invention provides methods for treating a disease or condition mediated by Fms and Flt-3, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein.
  • the invention provides methods for treating a disease or condition mediated by Fms and Flt-3, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein in combination with one or more other suitable therapies for treating the disease.
  • the invention provides methods for treating a disease or condition mediated by Fms and Kit, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein.
  • the invention provides methods for treating a disease or condition mediated by Fms and Kit, including any mutations thereof, in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein in combination with one or more other suitable therapies for treating the disease.
  • the invention provides a method of treating a cancer in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein, in combination with one or more other therapies or medical procedures effective in treating the cancer.
  • Other therapies or medical procedures include suitable anticancer therapy (e.g. drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e.g. surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant).
  • the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapeutic agent (e.g. chemotherapeutic drug), radiation treatment (e.g.
  • x-ray, ⁇ -ray, or electron, proton, neutron, or a particle beam hyperthermia heating (e.g. microwave, ultrasound, radiofrequency ablation),
  • Vaccine therapy e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vector vaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine, dendritic cell peptide vaccines
  • gene therapy e.g. Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha
  • photodynamic therapy e.g. aminolevulinic acid, motexafin lutetium
  • the invention provides a method of treating a cancer in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein, in combination with one or more suitable chemotherapeutic agents.
  • the one or more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not limited to, adozelesin, altretamine, bendamustine, bizelesin, busulfan, carboplatin, carboquone, carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucid, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine, satraplatin, semustine, streptozocin, temozolomide, thiotepa, tre
  • PI3K inhibitors e.g. BEZ235, GDC-0941, XL147, XL765
  • Cdk4 inhibitors e.g. PD-332991
  • Akt inhibitors e.g. Akt inhibitors
  • Hsp90 inhibitors e.g. tanespimycin
  • farnesyltransferase inhibitors e.g. tipifarnib
  • the method of treating a cancer involves administering to the subject an effective amount of a composition including any one or more compound(s) of Formulae I or I′ in combination with a chemotherapeutic agent selected from capecitabine, 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, interferon- ⁇ , interleukin-2, or erlotinib.
  • a chemotherapeutic agent selected from capecitabine, 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, interferon- ⁇ , interleukin-2, or erlotinib.
  • the invention provides a method of treating a disease or condition in a subject in need thereof, by administering to the subject a therapeutically effective amount of any one or more compound(s) as described herein, a prodrug of such compound, a pharmaceutically acceptable salt of such compound or prodrug, or a pharmaceutically acceptable formulation of such compound or prodrug.
  • the compound can be alone or can be part of a composition.
  • the invention provides a method of treating a disease or condition in a subject in need thereof, by administering to the subject a therapeutically effective amount of any one or more compound(s) as described herein, a prodrug of such compound, a pharmaceutically acceptable salt of such compound or prodrug, or a pharmaceutically acceptable formulation of such compound or prodrug in combination with one or more other suitable therapies for the disease or condition.
  • kits that include a compound or composition thereof as described herein.
  • the compound or composition is packaged, e.g., in a vial, bottle, flask, which may be further packaged, e.g., within a box, envelope, or bag; the compound or composition is approved by the U.S.
  • the compound or composition is approved for administration to a mammal, e.g., a human, for a Fms and/or Kit protein kinase mediated disease or condition;
  • the invention kit includes written instructions for use and/or other indication that the compound or composition is suitable or approved for administration to a mammal, e.g., a human, for a Fms and/or Kit protein kinase-mediated disease or condition; and the compound or composition is packaged in unit dose or single dose form, e.g., single dose pills, capsules, or the like.
  • the invention provides methods for treating a Kit-mediated disease or condition in a subject in need thereof (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal Kit activity (e.g. kinase activity).
  • a subject in need thereof e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats
  • Kit activity e.g. kinase activity
  • invention methods may involve administering to the subject suffering from or at risk of a c-kit-mediated disease or condition an effective amount of one or more compound(s) as described herein.
  • the Kit mediated disease is selected from the group consisting of malignancies, including, but not limited to, mast cell tumors, small cell lung cancer, non-small cell lung cancer (NSCLC), testicular cancer, pancreatic cancer, breast cancer, merkel cell carcinoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, gastrointestinal stromal tumors (GISTs), tumor angiogenesis, glioblastoma, astrocytoma, neuroblastoma, neurofibromatosis (including Schwann cell neoplasia associated with neurofibromatosis), acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, mastocytosis, melanoma, and canine mast cell tumors; cardiovascular disease, including but not limited to atherosclerosis, cardiomyopathy, heart failure, pulmonary arterial hypertension and pulmonary fibrosis; inflammatory and autoimmune indications
  • the invention provides methods for treating a Fms-mediated disease or condition in a subject in need thereof (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal Fms activity (e.g. kinase activity).
  • a subject in need thereof e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats
  • invention methods may involve administering to the subject suffering from or at risk of a Fms-mediated disease or condition an effective amount of one or more compound(s) as described herein.
  • the Fms mediated disease is selected from the group consisting of inflammatory and autoimmune indications, including, but not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, psoriasis, dermatitis, ankylosing spondylitis, polymyositis, dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis, polymyalgia rheumatica, Sjogren's disease, Langerhan's cell histiocytosis (LCH), Still's disease, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), immune thrombocytopenic purpura (ITP), myelopreparation for autologous transplantation, transplant rejection, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macro
  • kidney and genitourinary diseases including, but not limited to, endometriosis, nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-associated renal complications (e.g. diabetic nephropathy), and renal hypertrophy; disorders of the nervous system, including, but not limited to, demyelinating disorders (e.g.
  • multiple sclerosis Charcot Marie Tooth syndrome
  • amyotrophic lateral sclerosis ALS
  • myasthenia gravis chronic demyelinating polyneuropathy, other demyelinating disorders, stroke, Alzheimer's disease and Parkinson's disease
  • pain including, but not limited to, chronic pain, acute pain, inflammatory pain, neuropathic pain, bone pain
  • malignancies including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lung cancer, pancreatic cancer, prostate cancer, breast cancer, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma, giant cell tumors, (e.g.
  • VNS pigmented villonodular synovitis
  • tumor angiogenesis melanoma
  • glioblastoma multiforme glioma
  • other tumors of the central nervous system metastasis of tumors to other tissues, osteolytic bone metastases, and other chronic myeloproliferative diseases such as myelofibrosis
  • vasculitis including but not limited to collagen vascular disease, polyarteritis nodosa, Behcet's disease, sarcoidosis, familiar Mediterranean fever, Churg-Strauss vasculitis, temporal arteritis, giant cell arteritis, Takayasu's arteritis
  • ophthalmic indications including but not limited to uveitis, scleritis, retinitis, age related macular degeneration, choroidal neovascularization, diabetic retinopathy; inherited disorders, including
  • the invention provides methods for treating a disease or condition mediated by Fms and Kit in a subject in need thereof (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal Fms activity and Kit activity (e.g. kinase activity).
  • a disease or condition characterized by abnormal Fms activity and Kit activity e.g. kinase activity
  • invention methods may involve administering to the subject suffering from or at risk of a disease or condition mediated by Fms and Kit an effective amount of one or more compound(s) as described herein.
  • the condition mediated by Fms and Kit is selected from the group consisting of rheumatoid arthritis, osteoarthritis, psoriatic arthritis, psoriasis, dermatitis, allergy, anaphylaxis, asthma, allergic rhinitis, ankylosing spondylitis, polymyositis, dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis, polymyalgia rheumatica, Sjogren's disease, Langerhan's cell histiocytosis, Still's disease, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis, immune thrombocytopenic purpura, myelopreparation for autologous transplantation, transplant rejection, chronic obstructive pulmonary disease, emphysema, Kawasaki's Disease, hemophagocytic syndrome, multicentric reticulohisti
  • the invention provides methods for treating a disease or condition mediated by Fms and Flt-3 in a subject in need thereof (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal Fms activity and flt-3 activity (e.g. kinase activity).
  • invention methods may involve administering to the subject suffering from or at risk of a disease or condition mediated by Fms and Flt-3 an effective amount of one or more compound(s) as described herein.
  • the condition mediated by Fms and Flt-3 is acute myeloid leukemia.
  • invention methods may involve administering an effective amount of one or more compound(s) as described herein to a subject in need thereof suffering from or at risk of a disease or condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, atherosclerosis, systemic lupus erythematosis, myelopreparation for autologous transplantation, transplant rejection, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy, type I
  • invention methods may involve administering an effective amount of one or more compound(s) as described herein to a subject in need thereof suffering from or at risk of a disease or condition selected from the group consisting of rheumatoid arthritis, gastrointestinal stromal tumors, melanoma, and neurofibromatosis, wherein the compound is an inhibitor of Kit, i.e. has an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Kit kinase activity assay.
  • invention methods may involve administering an effective amount of one or more compound(s) as described herein to a subject in need thereof suffering from or at risk of a disease or condition selected from the group consisting of multiple sclerosis, glioblastoma, Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, osteoarthritis, atherosclerosis, systemic lupus erythematosus, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, and renal hypertrophy, wherein the compound is a Fms selective inhibitor, i.e.
  • the compound is also selective relative to protein kinases other than Kit, such that the ratio of IC 50 for another kinase assessed comparably, divided by the IC 50 for Fms kinase is >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100, wherein the other protein
  • invention methods may involve administering an effective amount of one or more compound(s) as described herein to a subject in need thereof suffering from or at risk of a disease or condition selected from the group consisting of multiple sclerosis, glioblastoma, Alzheimer's disease, and Parkinson's disease, wherein the compound is a Fms selective inhibitor, i.e.
  • the compound has an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay and when determined in a comparable generally accepted Kit kinase activity assay will have a ratio of IC 50 for Kit kinase divided by the IC 50 for Fms kinase of >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100, and wherein the compound effectively crosses the blood brain barrier; in some embodiments, the compound is also selective relative to protein kinase other than Kit, such that the ratio of IC 50 for another kinase assessed comparably divided by the IC 50 for Fms kinase is >20, also >30, also >40, also >50, also >60, also >70, also >80
  • invention methods may involve administering an effective amount of one or more compound(s) as described herein to a subject in need thereof suffering from or at risk of a disease or condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, atherosclerosis, systemic lupus erythematosus, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, and renal hypertrophy, wherein the compound is a Fms selective inhibitor, i.e.
  • the compound has an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay and when determined in a comparable generally accepted Kit kinase activity assay will have a ratio of IC 50 for Kit kinase divided by the IC 50 for Fms kinase of >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100, and wherein the compound does not effectively cross the blood brain barrier; in some embodiments, the compound is also selective relative to protein kinase other than Kit, such that the ratio of IC 50 for another kinase assessed comparably divided by the IC 50 for Fms kinase is >20, also >30, also >40, also >50, also >60, also >70, also
  • invention methods may involve administering an effective amount of one or more compound(s) as described herein to a subject in need thereof suffering from or at risk of a disease or condition selected from the group consisting of metastatic breast cancer, prostate cancer, multiple myeloma, melanoma, brain metastases, neurofibromatosis, gastrointestinal stromal tumors, rheumatoid arthritis, and multiple sclerosis, wherein the compound is a dual Fms/Kit inhibitor, i.e.
  • the compound has an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay and will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a comparable generally accepted Kit kinase activity assay, wherein the ratio of IC 50 for Kit kinase divided by the IC 50 for Fms kinase is in the range of 20 to 0.05, also 10 to 0.1, also 5 to 0.2; in some embodiments, the compound is also selective relative to protein kinase other than Kit, such that the ratio of IC 50 for another kinase assessed comparably divided by the IC 50 for Fms kin
  • invention methods may involve administering an effective amount of one or more compound(s) as described herein to a subject in need thereof suffering from or at risk of acute myeloid leukemia, wherein the compound is a dual Fms/Flt-3 inhibitor, i.e.
  • the compound has an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay and will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a comparable generally accepted Flt-3 kinase activity assay, wherein the ratio of IC 50 for Flt-3 kinase divided by the IC 50 for Fms kinase is in the range of 20 to 0.05, also 10 to 0.1, also 5 to 0.2; in some embodiments, the compound is also selective relative to protein kinase other than Flt-3, such that the ratio of IC 50 for another kinase assessed comparably divided by the IC 50
  • one or more compounds or compositions as described herein can be used in the preparation of a medicament for the treatment of a Kit-mediated disease or condition selected from the group consisting of malignancies, including, but not limited to, mast cell tumors, small cell lung cancer, non-small cell lung cancer, testicular cancer, pancreatic cancer, breast cancer, merkel cell carcinoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, gastrointestinal stromal tumors, tumor angiogenesis, glioblastoma, astrocytoma, neuroblastoma, neurofibromatosis (including Schwann cell neoplasia associated with neurofibromatosis), acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, mastocytosis, melanoma, and canine mast cell tumors; cardiovascular disease, including but not limited to atherosclerosis, cardiomy
  • one or more compounds as described herein can be used in the preparation of a medicament for the treatment of a Fms-mediated disease or condition selected from the group consisting of inflammatory and autoimmune indications, including, but not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, psoriasis, dermatitis, ankylosing spondylitis, polymyositis, dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis, polymyalgia rheumatica, Sjogren's disease, Langerhan's cell histiocytosis (LCH), Still's disease, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), immune thrombocytopenic purpura (ITP), myelopreparation for autologous transplantation, transplant rejection, chronic obstructive pulmonary disease (
  • kidney and genitourinary diseases including, but not limited to, endometriosis, nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-associated renal complications (e.g. diabetic nephropathy), and renal hypertrophy; disorders of the nervous system, including, but not limited to, demyelinating disorders (e.g.
  • multiple sclerosis Charcot Marie Tooth syndrome
  • amyotrophic lateral sclerosis ALS
  • myasthenia gravis chronic demyelinating polyneuropathy, other demyelinating disorders, stroke, Alzheimer's disease and Parkinson's disease
  • pain including, but not limited to, chronic pain, acute pain, inflammatory pain, neuropathic pain, bone pain
  • malignancies including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lung cancer, pancreatic cancer, prostate cancer, breast cancer, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma, giant cell tumors, (e.g.
  • VNS pigmented villonodular synovitis
  • tumor angiogenesis melanoma
  • glioblastoma multiforme glioma
  • other tumors of the central nervous system metastasis of tumors to other tissues, osteolytic bone metastases, and other chronic myeloproliferative diseases such as myelofibrosis
  • vasculitis including but not limited to collagen vascular disease, polyarteritis nodosa, Behcet's disease, sarcoidosis, familiar Mediterranean fever, Churg-Strauss vasculitis, temporal arteritis, giant cell arteritis, Takayasu's arteritis
  • ophthalmic indications including but not limited to uveitis, scleritis, retinitis, age related macular degeneration, choroidal neovascularization, diabetic retinopathy; inherited disorders, including
  • the invention further provides one or more compounds or compositions as described herein for use in treating a Fms-mediated disease or condition as described herein.
  • one or more compounds as described herein can be used in the preparation of a medicament for the treatment of a Fms-mediated and Kit-mediated disease or condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, psoriatic arthritis, psoriasis, dermatitis, allergy, anaphylaxis, asthma, allergic rhinitis, ankylosing spondylitis, polymyositis, dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis, polymyalgia rheumatica, Sjogren's disease, Langerhan's cell histiocytosis, Still's disease, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis, immune thrombocytopenic purpura, myelopreparation for autologous transplantation, transplant rejection, chronic obstructive pulmonary disease, e
  • one or more compounds as described herein can be used in the preparation of a medicament for the treatment of a disease or condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, myelopreparation for autologous transplantation, transplant rejection, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy, type I diabetes, acute pain, inflammatory pain, neuropathic pain, acute myeloid leukemia, melanoma, multiple myeloma, metastatic breast cancer, prostate cancer, pan
  • one or more compounds as described herein that are Kit inhibitors can be used in the preparation of a medicament for the treatment of rheumatoid arthritis, gastrointestinal stromal tumors, melanoma or neurofibromatosis.
  • one or more compounds as described herein that are Fms selective inhibitors can be used in the preparation of a medicament for the treatment of multiple sclerosis, glioblastoma, Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, osteoarthritis, atherosclerosis, systemic lupus erythematosus, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, or renal hypertrophy.
  • one or more compounds as described herein that are Fms selective inhibitors that effectively cross the blood brain barrier can be used in the preparation of a medicament for the treatment of multiple sclerosis, glioblastoma, Alzheimer's disease, or Parkinson's disease.
  • one or more compounds as described herein that are Fms selective inhibitors that do not effectively cross the blood brain barrier can be used in the preparation of a medicament for the treatment of rheumatoid arthritis, osteoarthritis, atherosclerosis, systemic lupus erythematosus, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, or renal hypertrophy.
  • one or more compounds as described herein that are dual Fms/Kit inhibitors can be used in the preparation of a medicament for the treatment of metastatic breast cancer, prostate cancer, multiple myeloma, melanoma, acute myeloid leukemia, brain metastases, neurofibromatosis, gastrointestinal stromal tumors, rheumatoid arthritis, or multiple sclerosis.
  • one or more compounds as described herein that are dual Fms/Flt-3 inhibitors can be used in the preparation of a medicament for the treatment of acute myeloid leukemia.
  • the invention provides an intermediate compound of Formula V:
  • P 2 is an amino protecting group
  • Ar is selected from the group consisting of:
  • the invention provides a method for preparing a compound of Formula I′:
  • the method includes contacting a compound of Formula IV:
  • P 1 and P 2 are each independently an amino protecting group
  • X is H or a halogen
  • Ar is selected from the group consisting of:
  • the invention provides a method of preparing a compound of Formula II′:
  • the method includes contacting a compound of Formula VI:
  • P 1 and P 2 are each independently an amino protecting group;
  • X is H or a halogen;
  • R 6 is selected from the group consisting of H, halogen, lower alkyl, halogen substituted alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 13 , —C(O)—N(H)—R 14 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 , —N(H)—C(O)—R 15 , and —N(H)—S(O) 2 —R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl.
  • R 16 , R 17 , R 18 and R 19 are each independently selected from H, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, —OR 20 , or alkoxy substituted lower alkyl.
  • R 6 is lower alkyl.
  • R 6 is CH 3 or CN.
  • R 6 is methyl, ethyl or propyl.
  • P 1 and P 2 are amino protecting groups as described herein.
  • P 2 is t-butoxycarbonyl.
  • P 1 is phenylsulfonyl.
  • the contacting is performed by reacting the compounds of Formula VI with the compounds of Formula VII in the presence of a strong base, such as alkali metal hydroxide.
  • a strong base such as alkali metal hydroxide.
  • alkali metal hydroxide include NaOH, KOH and LiOH.
  • the contacting includes forming a Grignard reagent of compounds of Formula VI and further reacting the Grignard reagent of compounds of Formula VI with the compounds of Formula VII.
  • the invention provides a method of preparing a compound of Formula III′:
  • the method includes contacting a compound of Formula VI:
  • P 1 and P 2 are each independently an amino protecting group;
  • X is H or a halogen;
  • R 6 is selected from the group consisting of H, halogen, lower alkyl, halogen substituted alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 13 , —C(O)—N(H)—R 14 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 , —N(H)—C(O)—R 15 , and —N(H)—S(O) 2 —R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl.
  • R 16 , R 17 , R 18 and R 19 are each independently selected from H, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, —OR 20 , or alkoxy substituted lower alkyl.
  • R 6 is lower alkyl.
  • R 6 is CH 3 or CN.
  • R 6 is methyl, ethyl or propyl.
  • P 1 and P 2 are amino protecting groups as described herein.
  • P 2 is t-butoxycarbonyl.
  • P 1 is phenylsulfonyl.
  • the contacting is performed by reacting the compounds of Formula VI with the compounds of Formula VIII in the presence of a strong base, such as alkali metal hydroxide.
  • a strong base such as alkali metal hydroxide.
  • alkali metal hydroxide include NaOH, KOH and LiOH.
  • the contacting includes forming a Grignard reagent of compounds of Formula VI and further reacting the Grignard reagent of compounds of Formula VI with the compounds of Formula VII.
  • hydrogen includes for example 1 H, 2 H, 3 H; carbon includes for example 11 C, 12 C, 13 C, 14 C; oxygen includes for example 16 O, 17 O, 18 O; nitrogen includes for example 13 N, 14 N, 15 N; sulfur includes for example 32 S, 33 S, 34 S, 35 S, 36 S, 37 S, 38 S; fluoro includes for example 17 F, 18 F, 19 F; chloro includes for example 35 Cl, 36 Cl, 37 Cl, 38 Cl, 39 Cl; and the like.
  • Halogen or “Halo” refers to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).
  • Lower alkyl alone or in combination means an alkane-derived radical containing from 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl.
  • a lower alkyl is a straight or branched alkyl group containing from 1-6, 1-4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like.
  • a lower alkyl may be independently substituted as described herein, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, wherein the substituents are as indicated.
  • halo substituted lower alkyl denotes a lower alkyl group substituted with one or more halogen atoms, where preferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 halogen atoms, also 1, 2, or 3 halogen atoms.
  • possible substitutions are attached at any available atom to produce a stable compound.
  • fluoro substituted lower alkyl denotes a lower alkyl group substituted with one or more fluoro atoms, such as perfluoroalkyl, where preferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms.
  • exemplary fluoro substituted lower alkyl includes, but is not limited to, CF 3 , CF 2 CF 3 , CH 2 CF 3 , and the like. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • “Lower alkoxy” refers to those lower alkyl groups as defined herein attached to the remainder of the molecule via an oxygen atom.
  • Representative alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, n-pentoxy, n-heptoxy, and the like, as well as isomers thereof.
  • “Lower alkenyl” alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) and at least one, preferably 1-3, more preferably 1-2, most preferably one, carbon to carbon double bond. Carbon to carbon double bonds may be either contained within a straight chain or branched portion.
  • the straight chain or branched lower alkenyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like.
  • “Lower alkynyl” alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) containing at least one, preferably one, carbon to carbon triple bond.
  • the straight chain or branched lower alkynyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like.
  • Cycloalkyl refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
  • Heterocycloalkyl refers to a saturated or unsaturated non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally fused with benzo or heteroaryl of 5-6 ring members. Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. Heterocycloalkyl is also intended to include compounds in which a ring carbon may be oxo substituted, i.e.
  • the ring carbon is a carbonyl group, such as lactones and lactams.
  • the point of attachment of the heterocycloalkyl ring is at a carbon or nitrogen atom such that a stable ring is retained.
  • heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl.
  • “Cycloalkylamino” denotes the group —NR a R b , where R a and R b combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocycloalkyl may contain an additional heteroatom within the ring, such as O, N, or S, and may also be further substituted with lower alkyl.
  • Examples of 5-7 membered heterocycloalkyl include, but are not limited to, piperidine, piperazine, 4-methylpiperazine, morpholine, and thiomorpholine. It is understood that when cycloalkylamino is a substituent on other moieties, these are chemically feasible and attached at any available atom to provide a stable compound.
  • Protecting group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T. W. Greene and P. G. Wuts, P ROTECTIVE G ROUPS IN O RGANIC C HEMISTRY , (Wiley, 4th ed. 2006), Beaucage and Iyer, Tetrahedron 48:2223-2311 (1992), and Harrison and Harrison et al., C OMPENDIUM OF S YNTHETIC O RGANIC M ETHODS , Vols. 1-8 (John Wiley and Sons. 1971-1996).
  • Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), tri-isopropylsilyl (TIPS), phenylsulphonyl and the like (see also, Boyle, A. L. (Editor), C URRENT P ROTOCOLS IN N UCLEIC A CID C HEMISTRY , John Wiley and Sons, New York, Volume 1, 2000).
  • leaving group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or a group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the like.
  • halo such as chloro, bromo, and iodo
  • alkanesulfonyloxy arenesulfonyloxy
  • alkylcarbonyloxy e.g., acetoxy
  • arylcarbonyloxy mesyloxy, tosyloxy,
  • the terms “treat”, “treating”, “therapy”, “therapies”, and like terms refer to the administration of material, e.g., any one or more compound(s) as described herein in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., indication, and/or to prolong the survival of the subject being treated.
  • Fms and/or Kit protein kinase mediated disease or condition refers to a disease or condition in which the biological function of a Fms protein kinase, including any mutation thereof, a Kit protein kinase, including any mutation thereof, or both a Fms and Kit protein kinase, including any mutations thereof, affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of the Fms and/or Kit protein kinase alters the development, course, and/or symptoms of the disease or condition.
  • a Fms and/or Kit protein kinase mediated disease or condition includes a disease or condition for which modulation provides a therapeutic benefit, e.g. wherein treatment with Fms and/or Kit protein kinase inhibitor(s), including one or more compound(s) described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
  • Fms protein kinase mediated disease or condition refers to a disease or condition in which the biological function of a Fms protein kinase, including any mutations thereof, affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of the Fms protein kinase alters the development, course, and/or symptoms of the disease or condition.
  • the Fms protein kinase mediated disease or condition includes a disease or condition for which Fms inhibition provides a therapeutic benefit, e.g. wherein treatment with Fms inhibitor(s), including one or more compound(s) described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
  • Kit protein kinase mediated disease or condition refers to a disease or condition in which the biological function of a Kit protein kinase, including any mutations thereof, affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of the Kit protein kinase alters the development, course, and/or symptoms of the disease or condition.
  • the Kit protein kinase mediated disease or condition includes a disease or condition for which Kit inhibition provides a therapeutic benefit, e.g. wherein treatment with Kit inhibitor(s), including one or more compound(s) described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
  • the term “dual Fms/Kit inhibitor” refers to a compound that inhibits both Fms and Kit protein kinases, i.e. a compound having an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay and having an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a comparable generally accepted Kit kinase activity assay, wherein the activity is approximately equipotent on each.
  • Compounds are considered approximately equipotent if the ratio of IC 50 for Kit kinase activity divided by the IC 50 for Fms kinase activity is in the range of 20 to 0.05, also 10 to 0.1, also 5 to 0.2. Such compounds are effective in treating a disease or condition that is either or both of a Fms protein kinase mediated and Kit protein kinase mediated disease or condition. Such compounds are preferably, but not necessarily, selective with respect to other protein kinases, i.e.
  • the IC 50 for the other kinase divided by the IC 50 for Fms kinase is >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100.
  • the compounds are selective relative to other protein kinases including, but not limited to, CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.
  • a dual Fms/Kit inhibitor may be used to treat any Fms protein kinase mediated disease or condition
  • the dual inhibition of Fms and Kit provides beneficial effects in treating certain diseases or conditions, including, but not limited to, metastatic breast cancer, prostate cancer, multiple myeloma, melanoma, acute myeloid leukemia, brain metastases, neurofibromatosis, gastrointestinal stromal tumors, rheumatoid arthritis, or multiple sclerosis.
  • the term “dual Fms/Flt-3 inhibitor” refers to a compound that inhibits both Fms and Flt-3 protein kinases, i.e. a compound having an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay and having an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a comparable generally accepted Flt-3 kinase activity assay, wherein the activity is approximately equipotent on each.
  • Compounds are considered approximately equipotent if the ratio of IC 50 for Flt-3 kinase activity divided by the IC 50 for Fms kinase activity is in the range of 20 to 0.05, also 10 to 0.1, also 5 to 0.2. Such compounds are effective in treating a disease or condition that is either or both of a Fms protein kinase mediated and Flt-3 protein kinase mediated disease or condition. Such compounds are preferably, but not necessarily, selective with respect to other protein kinases, i.e.
  • the IC 50 for the other kinase divided by the IC 50 for Fms kinase is >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100.
  • the compounds are selective relative to other protein kinases including, but not limited to, CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.
  • a dual Fms/Flt-3 inhibitor may be used to treat any Fms protein kinase mediated disease or condition
  • the dual inhibition of Fms and Flt-3 provides beneficial effects in treating certain diseases or conditions, including, but not limited to, acute myeloid leukemia.
  • Fms selective inhibitor refers to a compound that selectively inhibits Fms kinase relative to Kit kinase, i.e. a compound having an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay and when determined in a comparable generally accepted Kit kinase activity assay will have a ratio of IC 50 for Kit kinase divided by the IC 50 for Fms kinase of >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100.
  • Such compounds are effective in treating a disease or condition that is Fms protein kinase mediated, without effecting Kit protein kinase.
  • Such compounds are preferably, but not necessarily, selective with respect to other protein kinases, i.e. when compared to another protein kinase, the IC 50 for the other kinase divided by the IC 50 for Fms kinase is >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100.
  • the compounds are selective relative to other protein kinases including, but not limited to, CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.
  • a Fms selective inhibitor may be used to treat any Fms protein kinase mediated disease or condition
  • the Fms selectivity provides beneficial effects in treating certain diseases or conditions, including, but not limited to, rheumatoid arthritis, Alzheimer's disease, Parkinson's disease, osteoarthritis, nephritis, diabetic nephropathy, or renal hypertrophy.
  • blood brain barrier refers to the physical barrier in the circulation system that prevents many substances, including certain small molecule drugs, from entering into the central nervous system (CNS). Drugs which are intended to interact with molecular targets in the CNS must cross the blood brain barrier to reach their intended targets. Conversely, peripherally acting agents should not cross the blood brain barrier so as to avoid any CNS related side effects.
  • the ability of a compound to penetrate the blood brain barrier is expressed as the blood brain barrier permeability or the ratio of the steady-state concentrations of the compound in the brain and in the blood.
  • the experimental blood brain barrier permeability can be measured by in vivo methods.
  • Various methods can be employed for measuring the fraction of compound transported from the blood to brain tissue, including brain blood partitioning, brain perfusion, brain uptake index, and intracerebral microdialysis.
  • these in vivo methods are laborious and low-throughput in nature.
  • in silico computational methods are often used to predict the blood brain barrier permeability prior to in vivo confirmation.
  • Most of the blood brain barrier models that have been built so far are based on the assumption that the majority of the compounds are transported across the blood brain barrier by passive diffusion.
  • polar surface area (PSA) shows the best correlation with the blood brain barrier permeability for passively diffused compounds.
  • Empirical evidence suggests that compounds having a polar surface area of 100 or greater typically have a low probability of crossing the blood brain barrier. Polar surface area is readily calculated from the compound structure using a published algorithm (Ertl et al., J. Med. Chem. 2000, 43:3714-3717).
  • a Fms selective inhibitor may be used to treat any Fms protein kinase mediated disease or condition
  • compounds that effectively cross the blood brain barrier provide beneficial effects in treating certain diseases or conditions, including, but not limited to, multiple sclerosis, glioblastoma, Alzheimer's disease, and Parkinson's disease
  • compounds that do not effectively cross the blood brain barrier provide beneficial effects in treating certain diseases or conditions, including, but not limited to, rheumatoid arthritis, osteoarthritis, atherosclerosis, systemic lupus erythematosus, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, or renal hypertrophy.
  • solid form refers to a solid preparation (i.e. a preparation that is neither gas nor liquid) of a pharmaceutically active compound that is suitable for administration to an intended animal subject for therapeutic purposes.
  • the solid form includes any complex, such as a salt, co-crystal or an amorphous complex, as well as any polymorph of the compound.
  • the solid form may be substantially crystalline, semi-crystalline or substantially amorphous.
  • the solid form may be administered directly or used in the preparation of a suitable composition having improved pharmaceutical properties.
  • the solid form may be used in a formulation comprising at least one pharmaceutically acceptable carrier or excipient.
  • substantially crystalline material embraces material which has greater than about 90% crystallinity; and “crystalline” material embraces material which has greater than about 98% crystallinity.
  • substantially amorphous material embraces material which has no more than about 10% crystallinity; and “amorphous” material embraces material which has no more than about 2% crystallinity.
  • the term “semi-crystalline” material embraces material which is greater than 10% crystallinity, but no greater than 90% crystallinity; preferably “semi-crystalline” material embraces material which is greater than 20% crystallinity, but no greater than 80% crystallinity.
  • a mixture of solid forms of a compound may be prepared, for example, a mixture of amorphous and crystalline solid forms, e.g. to provide a “semi-crystalline” solid form.
  • Such a “semi-crystalline” solid form may be prepared by methods known in the art, for example by mixing an amorphous solid form with a crystalline solid form in the desired ratio.
  • a compound mixed with acid or base forms an amorphous complex
  • a semi-crystalline solid can be prepared employing an amount of compound component in excess of the stoichiometry of the compound and acid or base in the amorphous complex, thereby resulting in an amount of the amorphous complex that is based on the stoichiometry thereof, with excess compound in a crystalline form.
  • the amount of excess compound used in the preparation of the complex can be adjusted to provide the desired ratio of amorphous complex to crystalline compound in the resulting mixture of solid forms.
  • preparing said complex with a 2:1 mole ratio of compound to acid or base will result in a solid form of 50% amorphous complex and 50% crystalline compound.
  • Such a mixture of solid forms may be beneficial as a drug product, for example, by providing an amorphous component having improved biopharmaceutical properties along with the crystalline component.
  • the amorphous component would be more readily bioavailable while the crystalline component would have a delayed bioavailability.
  • Such a mixture may provide both rapid and extended exposure to the active compound.
  • the term “complex” refers to a combination of a pharmaceutically active compound and an additional molecular species that forms or produces a new chemical species in a solid form.
  • the complex may be a salt, i.e. where the additional molecular species provides an acid/base counter ion to an acid/base group of the compound resulting in an acid:base interaction that forms a typical salt. While such salt forms are typically substantially crystalline, they can also be partially crystalline, substantially amorphous, or amorphous forms.
  • the additional molecular species, in combination with the pharmaceutically active compound forms a non-salt co-crystal, i.e.
  • the compound and molecular species do not interact by way of a typical acid:base interaction, but still form a substantially crystalline structure.
  • Co-crystals may also be formed from a salt of the compound and an additional molecular species.
  • the complex is a substantially amorphous complex, which may contain salt-like acid:base interactions that do not form typical salt crystals, but instead form a substantially amorphous solid, i.e. a solid whose X-ray powder diffraction pattern exhibits no sharp peaks (e.g. exhibits an amorphous halo).
  • the term “stoichiometry” refers to the molar ratio of two or more reactants that combine to form a complex, for example, the molar ratio of acid or base to compound that form an amorphous complex.
  • a 1:1 mixture of acid or base with compound i.e. 1 mole acid or base per mole of compound
  • amorphous solid form has a 1:1 stoichiometry.
  • composition refers to a pharmaceutical preparation suitable for administration to an intended subject for therapeutic purposes that contains at least one pharmaceutically active compound, including any solid form thereof.
  • the composition may include at least one pharmaceutically acceptable component to provide an improved formulation of the compound, such as a suitable carrier or excipient.
  • the term “subject” refers to a living organism that is treated with compounds as described herein, including, but not limited to, any mammal, such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats.
  • biopharmaceutical properties refers to the pharmacokinetic action of a compound or complex of the present invention, including the dissolution, absorption and distribution of the compound on administration to a subject.
  • certain solid forms of compounds of the invention such as amorphous complexes of compounds of the invention, are intended to provide improved dissolution and absorption of the active compound, which is typically reflected in improved C max (i.e. the maximum achieved concentration in the plasma after administration of the drug) and improved AUC (i.e. area under the curve of drug plasma concentration vs. time after administration of the drug).
  • pharmaceutically acceptable indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • “Hydrate” refers to a complex formed by combination of water molecules with molecules or ions of the solute.
  • Solvate refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
  • the solvent can be an organic compound, an inorganic compound, or a mixture of both. Solvate is meant to include hydrate.
  • Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.
  • 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.
  • the term “therapeutically effective” or “effective amount” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated.
  • the terms “synergistically effective” or “synergistic effect” indicate that two or more compounds that are therapeutically effective, when used in combination, provide improved therapeutic effects greater than the additive effect that would be expected based on the effect of each compound used by itself.
  • enzymes can be assayed based on their ability to act upon a detectable substrate.
  • a compound can be assayed based on its ability to bind to a particular target molecule or molecules.
  • the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as a protein kinase.
  • a biological activity associated with a particular biomolecule such as a protein kinase.
  • an inhibitor of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme, by decreasing the activity of the biomolecule, such as an enzyme.
  • Such activity is typically indicated in terms of an inhibitory concentration (IC 50 ) of the compound for an inhibitor with respect to, for example, an enzyme.
  • the term “contacting” means that the compound(s) are caused to be in sufficient proximity to a particular molecule, complex, cell, tissue, organism, or other specified material that potential binding interactions and/or chemical reaction between the compound and other specified material can occur.
  • “Pain” or a “pain condition” can be acute and/or chronic pain, including, without limitation, arachnoiditis; arthritis (e.g. osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout); back pain (e.g. sciatica, ruptured disc, spondylolisthesis, radiculopathy); burn pain; cancer pain; dysmenorrhea; headaches (e.g. migraine, cluster headaches, tension headaches); head and facial pain (e.g. cranial neuralgia, trigeminal neuralgia); hyperalgesia; hyperpathia; inflammatory pain (e.g.
  • irritable bowel syndrome pain associated with irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, cystitis, pain from bacterial, fungal or viral infection); keloid or scar tissue formation; labor or delivery pain; muscle pain (e.g. as a result of polymyositis, dermatomyositis, inclusion body myositis, repetitive stress injury (e.g. writer's cramp, carpal tunnel syndrome, tendonitis, tenosynovitis)); myofascial pain syndromes (e.g. fibromyalgia); neuropathic pain (e.g.
  • diabetic neuropathy causalgia, entrapment neuropathy, brachial plexus avulsion, occipital neuralgia, gout, reflex sympathetic dystrophy syndrome, phantom limb or post-amputation pain, postherpetic neuralgia, central pain syndrome, or nerve pain resulting from trauma (e.g. nerve injury), disease (e.g. diabetes, multiple sclerosis, Guillan-Barre Syndrome, myasthenia gravis, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, or cancer treatment); pain associated with skin disorders (e.g. shingles, herpes simplex, skin tumors, cysts, neurofibromatosis); sports injuries (e.g.
  • vascular disease or injury e.g. vasculitis, coronary artery disease, reperfusion injury (e.g. following ischemia, stroke, or myocardial infarcts)
  • other specific organ or tissue pain e.g. ocular pain, corneal pain, bone pain, heart pain, visceral pain (e.g. kidney, gall bladder, gastrointestinal), joint pain, dental pain, pelvic hypersensitivity, pelvic pain, renal colic, urinary incontinence
  • other disease associated pain e.g.
  • sickle cell anemia AIDS, herpes zoster, psoriasis, endometriosis, asthma, chronic obstructive pulmonary disease (COPD), silicosis, pulmonary sarcoidosis, esophagitis, heart burn, gastroesophageal reflux disorder, stomach and duodenal ulcers, functional dyspepsia, bone resorption disease, osteoporosis, cerebral malaria, bacterial meningitis); or pain due to graft v. host rejection or allograft rejections.
  • COPD chronic obstructive pulmonary disease
  • Protein kinases play key roles in propagating biochemical signals in diverse biological pathways. More than 500 kinases have been described, and specific kinases have been implicated in a wide range of diseases or conditions (i.e., indications), including for example without limitation, cancer, cardiovascular disease, inflammatory disease, neurological disease, and other diseases. As such, kinases represent important control points for small molecule therapeutic intervention.
  • Specific target protein kinases i.e. Fms kinase and Kit kinase, contemplated by the present invention are described in the art, including, without limitation, as described in U.S. patent application Ser. No. 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference with respect to such kinase targets, as well as the following:
  • Target kinase Fms i.e., feline McDonough sarcoma
  • Fms is a member of the family of genes originally isolated from the Susan McDonough strain of feline sarcoma viruses.
  • Fms is a transmembrane tyrosine kinase of 108.0 kDa coded by chromosome 5q33.2-q33.3 (symbol: CSF1R).
  • the structure of the transmembrane receptor Fms comprises two Ig-like domains, a IgC2-like domain, two additional Ig-like domains, a TM domain, and the TK domain.
  • Fms is the receptor for the macrophage colony-stimulating factor (M-CSF), and is crucial for the growth and differentiation of the monocyte-macrophage lineage. Upon binding of M-CSF to the extracellular domain of Fms, the receptor dimerizes and trans-autophosphorylates cytoplasmic tyrosine residues.
  • M-CSF macrophage colony-stimulating factor
  • M-CSF is a cytokine that controls the production, differentiation, and function of macrophages.
  • M-CSF stimulates differentiation of progenitor cells to mature monocytes, and prolongs the survival of monocytes. Furthermore, M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemotaxis, and secondary cytokine production of additional factors in monocytes and macrophages. Examples of such additional factors include granulocyte colony stimulating factor (G-CSF), interleukin-6 (IL-6), and interleukin-8 (IL-8).
  • G-CSF granulocyte colony stimulating factor
  • IL-6 interleukin-6
  • IL-8 interleukin-8
  • M-CSF stimulates hematopoiesis, promotes differentiation and proliferation of osteoclast progenitor cells, and has profound effects on lipid metabolism. Furthermore, M-CSF is important in pregnancy. Physiologically, large amounts of M-CSF are produced in the placenta, and M-CSF is believed to play an essential role in trophoblast differentiation (Motoyoshi, Int J Hematol. 1998, 67:109-22). The elevated serum M-CSF levels of early pregnancy may participate in the immunologic mechanisms responsible for the maintenance of the pregnancy (Flanagan & Lader, Curr Opin Hematol. 1998, 5:181-5).
  • Fms mutations Aberrant expression and/or activation of Fms has been implicated in acute myeloid leukemia, AML (Ridge et al, Proc. Nat. Acad. Sci., 1990, 87:1377-1380). Mutations at codon 301 are believed to lead to neoplastic transformation by ligand independence and constitutive tyrosine kinase activity of the receptor. The tyrosine residue at codon 969 has been shown to be involved in a negative regulatory activity, which is disrupted by amino acid substitutions. Accordingly, Fms mutations are most prevalent (20%) in chronic myelomonocytic leukemia and AML type M4 (23%), both of which are characterized by monocytic differentiation.
  • CML chronic myeloid leukemia
  • BC myeloid blast crisis
  • cytogenetic changes have been reported to precede the clinical signs of CML-BC by several months to years suggesting that other biological events may participate in the multistep process of acute transformation of CML.
  • the autocrine production of growth factors has been shown to occur in several hematological malignancies and particularly in AML. Specchia et al [Br J Haematol.
  • IL-1 beta gene is expressed in almost all cases of CML in myeloid blast crisis, and that a high proportion of cases showed constitutive expression of the M-CSF gene.
  • PMA phorbol myristate acetate
  • release of M-CSF protein was documented in three of five patients studied; however, no significant interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF), was detected in these patients.
  • IL-3 interleukin-3
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • G-CSF granulocyte colony-stimulating factor
  • COPD the major macrophage growth factor
  • airflow limitation that is not fully reversible.
  • the airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.
  • the chronic inflammation of COPD is observed through the airways, parenchyma, and pulmonary vasculature.
  • the inflammatory cell population consists of neutrophils, macrophages, and T lymphocytes, along with eosinophils in some patients.
  • Macrophages are postulated to play an orchestrating role in COPD inflammation by releasing mediators such as TNF-a, IL-8 and LTB4, which are capable of damaging lung structures and/or sustaining neutrophilic inflammation.
  • M-CSF/fms signaling is critical to osteoclast formation and survival of osteoclast precursors.
  • estrogen loss in menopause results in increased M-CSF and thus increased osteoclast number and bone resorption which leads to increased risk of fracture and osteoporosis.
  • blockage of this signal is a target for the inhibition of bone resorption (Teitelbaum, Science. 2000; 289:1504; Rohan, Science. 2000; 289:1508).
  • Atherosclerosis an inflammatory disease of the vessel walls, is associated with significant morbidity and mortality.
  • a effect for Fms inhibition in the treatment and prevention of atherosclerosis depends on several observations (Libby, Nature. 2002; 420:868-874).
  • monocytes resident in the arterial intima increase expression of scavenger receptors and internalize modified lipoproteins.
  • the resulting lipid-laden macrophages develop into foam cells characteristic of the atherosclerotic lesion.
  • Macrophages in atheroma secrete cytokines and growth factors involved in lesion progression. Additionally, macrophages replicate within the intima.
  • M-CSF activates the transition from monocyte to lipid-laden macrophage and augments expression of scavenger receptor A.
  • atherosclerotic plaques over-express M-CSF which is critical for atherosclerotic progression.
  • Mice deficient in M-CSF have been found to experience less severe atherosclerosis than mice with normal M-CSF (Rajavashisth, et. al., J. Clin. Invest. 1998; 101:2702-2710; Qiao, et. al., Am. J. Path. 1997; 150:1687-1699).
  • inhibitors of Fms disrupt M-CSF signaling, compromising monocyte to macrophage foam cell progression, macrophage survival and replication, and cytokine signaling that participates in lesion progression.
  • M-CSF alveolar macrophages
  • Fms emphysema
  • M-CSF has a role in the modulation of the accumulation and function of alveolar macrophages (AMs) in vivo (Shibata et al, Blood 2001, 98: pp. 2845-2852).
  • AMs alveolar macrophages
  • Osteopetrotic (Op/Op) mice have no detectable M-CSF and show variable tissue-specific reductions in macrophage numbers. Accordingly, it was hypothesized that AMs would be decreased in number and have altered function in Op/Op mice because of the absence of M-CSF.
  • Metastatic cancer cells cause bone destruction, with associated fracture, pain, deformation, and hypercalcaemia, due to production of osteoclasticogenic factors including M-CSF by tumor cells (Clohisy et al, Clin. Orthop. 2000, 373: 104-14). Binding of M-CSF to the Fms product stimulates formation of osteoclasts and osteolytic activity (Kodama et al, J. Exp. Med. 1991, 173: 269-72; Feng et al, Endocrinology 2002, 143: 4868-74). Accordingly, inhibition of osteoclast activity at the level of Fms offers a compelling target for amelioration of bone metastasis.
  • Fms is also a target for amelioration of metastatic breast cancer (Lawicki et al., Clin Chim Acta. 2006, September, 371(1-2):112-6; Wyckoff et al., Cancer Res. 2007, Mar. 15, 67(6):2649-56).
  • Nephritis is inflammation of the kidneys. It may be caused for example by a bacterial infection of the kidneys or exposure to a toxin. However, nephritis more commonly develops from an abnormal immune reaction, which can occur, for example, when an antibody attacks either the kidney itself or an antigen attached to kidney cells, or when an antigen-antibody complex formed elsewhere in the body attaches to cells in the kidney. Some types of nephritis involve infiltration of kidney tissues by white blood cells and deposits of antibodies. In other types of nephritis, inflammation may consist of tissue swelling or scarring without white blood cells or antibodies. Furthermore, nephritis can occur anywhere in the kidneys.
  • glomeruli progressive damage to glomeruli causes urine production to fall and metabolic waste products to build up in the blood.
  • damage to glomeruli is severe, inflammatory cells and injured glomerular cells accumulate, compressing the capillaries within the glomerulus and interfering with filtration. Scarring may develop, impairing kidney function and reducing urine production. In some cases, microthrombi may form in the small blood vessels, further decreasing kidney function.
  • nephritis involves the tubulointerstitial tissues; such inflammation is called tubulointerstitial nephritis.
  • kidneys When inflammation damages the tubules and the tubulointerstitial tissues, the kidneys may become unable to concentrate urine, eliminate (excrete) metabolic waste products from the body, or balance the excretion of sodium and other electrolytes, such as potassium. When the tubules and tubulointerstitial tissues are damaged, kidney failure often develops. Accordingly, inhibition of Fms offers a target for therapeutic intervention in nephritis due to the modulation of the inflammatory response comprising the etiology of the disease.
  • Lupus nephritis i.e., renal involvement in systemic lupus erythematosus (SLE) is a common disease manifestation with a poor prognosis.
  • SLE systemic lupus erythematosus
  • At least three potentially overlapping, immuno-pathogenic mechanisms for lupus nephritis are supported by experimental data.
  • Second, in situ formation of antigen and antibody complexes may similarly lead to complement activation and leucocyte mediated injury.
  • Third, antibodies against specific cellular targets may produce renal injury. An additional mechanism is observed in SLE patients with the antiphospholipid antibody syndrome.
  • Glomerular thrombosis can result from the hypercoagulability that accompanies antibodies directed against negatively charged phospholipid-protein complexes (e.g. biologic false positive VDRL, anticardiolipin antibodies, and lupus anticoagulant).
  • Mesangial lupus nephritis is accompanied by normal diagnostic findings or with a mild degree of proteinuria but typically absence of hypertension or abnormal urinary sediment.
  • Focal and diffuse proliferative lupus glomerulonephritis are often associated with the worst prognosis for renal survival and can be accompanied by nephrotic syndrome, significant hypertension and abnormal urine sediment.
  • Membranous lupus nephritis often presents with proteinuria, moderate to high grade, but usually normal urinary sediment in the absence of hypertension.
  • Mesangial lupus nephropathy is generally associated with an excellent prognosis, whereas proliferative lupus nephropathy, especially diffuse variant, is often characterized by hypertension, red cell casts and significant deterioration of renal function.
  • Nephrotic syndrome in the absence of hypertension, active urinary sediment or significant hypocomplementemia suggest the membranous variant of lupus nephropathy.
  • Membranous nephropathy generally is associated with a good prognosis and relative preservation of renal function.
  • membranous lupus nephropathy can, in fact, lead to loss of renal function and end stage renal disease (ESRD). Accordingly, inhibition of Fms offers a target for therapeutic intervention in lupus due to the modulation of the inflammatory response comprising the etiology of the disease.
  • Macrophage accumulation is a prominent feature in many forms of glomerulonephritis.
  • Local proliferation of macrophages within the kidney has been described in human and experimental glomerulonephritis and may have an important role in augmenting the inflammatory response.
  • Isbel et al (Nephrol Dial Transplant 2001, 16: 1638-1647) examined the relationship between local macrophage proliferation and renal expression of M-CSF. Glomerular and tubulointerstitial M-CSF expression was found to be up-regulated in human glomerulonephritis, being most prominent in proliferative forms of disease.
  • Insulin resistance and obesity are hallmark of type II diabetes and there is a strong correlation between insulin resistance and abdominal visceral fact accumulation (Bjorntrop, Diabetes Metab. Res. Rev., 1999, 15: 427-441).
  • Current evidence indicates that macrophages accumulating in adipose tissue release TNF-a and other factors that cause adipocyte changes (hypertrophy, lipolysis, reduced insulin sensitivity) and also promote insulin resistance in surrounding tissues. Therefore, macrophage accumulation in type 2 diabetes is important for disease progression. Accordingly, inhibition of Fms has potential in preventing the development of insulin resistance and hyperglycemia.
  • M-CSF the major macrophage growth factor
  • diseases such as for example inflammatory diseases. More particularly, because elevated levels of M-CSF are found in the disease state, modulation of the activity of Fms can ameliorate disease associated with increased levels of M-C SF.
  • a Fms inhibitor may be useful in treating inflammatory and autoimmune indications, including, but not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, psoriasis, dermatitis, ankylosing spondylitis, polymyositis, dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis, polymyalgia rheumatica, Sjogren's disease, Langerhan's cell histiocytosis (LCH), Still's disease, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), transplant rejection, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis; metabolic disorders, including, but not limited to
  • kidney and genitourinary diseases including, but not limited to, endometriosis, nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-associated renal complications (e.g.
  • disorders of the central nervous system including, but not limited to, multiple sclerosis, amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic demyelinating polyneuropathy, other demyelinating disorders, stroke, Alzheimer's disease and Parkinson's disease; inflammatory and chronic pain, including, but not limited to, bone pain; malignancies, including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lung cancer, pancreatic cancer, prostate cancer, breast cancer, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma, giant cell tumor of bone, giant cell tumor of tendon sheath (TGCT), pigmented villonodular synovitis (PVNS), tumor angiogenesis, melanoma, glioblastoma multiforme, glioma, other tumors of the central nervous system, metasta
  • Kit Target kinase Kit (i.e., feline Hardy-Zuckerman 4 sarcoma viral oncogene) is a 109.9 kDa transmembrane tyrosine kinase encoded by chromosome 4q12 (symbol: KIT).
  • Receptor protein tyrosine kinases RPTKs
  • the Stem Cell Factor (SCF) receptor Kit is a type III transmembrane RPTK that includes five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment. Kit plays an important role in the development of melanocytes, mast, germ, and hematopoietic cells.
  • SCF Stem Cell Factor
  • Kit Kit ligand
  • MEF mast cell growth factor
  • SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 Dalton, depending on alternative splicing of the mRNA to encode exon 6.
  • the larger protein can be proteolytically cleaved to form a soluble, glycosylated protein which noncovalently dimerizes.
  • Both the soluble and membrane-bound forms of SCF can bind to and activate Kit.
  • Kit For example, in the skin, SCF is predominantly expressed by fibroblasts, keratinocytes, and endothelial cells, which modulate the activity of melanocytes and mast cells expressing Kit.
  • marrow stromal cells express SCF and regulate hematopoiesis of Kit expressing stem cells.
  • intestinal epithelial cells express SCF and affect the interstitial cells of Cajal and intraepithelial lymphocytes.
  • sertoli cells and granulosa cells express SCF which regulates spermatogenesis by interaction with Kit on germ cells.
  • Kit Aberrant expression and/or activation of Kit has been implicated in a variety of pathologic states.
  • evidence for a contribution of Kit to neoplastic pathology includes its association with leukemias and mast cell tumors, small cell lung cancer, testicular cancer, and some cancers of the gastrointestinal tract and central nervous system.
  • Kit has been implicated in playing a role in carcinogenesis of the female genital tract sarcomas of neuroectodermal origin, and Schwann cell neoplasia associated with neurofibromatosis. It was found that mast cells are involved in modifying the tumor microenvironment and enhancing tumor growth (Yang et al., J Clin Invest.
  • Kit inihibitors can also be used to target melanoma (Smalley et al., Histol Histopathol. 2009, May, 24(5):643-50), gastrointestinal stromal tumors (Demetri, G D, Semin Oncol. 2001, October, 28(5 Suppl 17):19-26), neurofibromatosis (Yang et al., Cell, 2008, Oct. 31, 135(3):437-48), and multiple sclerosis (Secor et al., J Exp Med. 2000, Mar. 6, 191(5):813-22).
  • a Kit inhibitor may be useful in treating malignancies, including, but not limited to, mast cell tumors, small cell lung cancer, non-small cell lung cancer (NSCLC), testicular cancer, pancreatic cancer, breast cancer, merkel cell carcinoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, gastrointestinal stromal tumors (GISTs), tumor angiogenesis, glioblastoma, astrocytoma, neuroblastoma, neurofibromatosis (including Schwann cell neoplasia associated with neurofibromatosis), acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors; cardiovascular disease, including but not limited to atherosclerosis, cardiomyopathy, heart failure, pulmonary arterial hypertension, and pulmonary fibrosis; inflammatory and autoimmune indications, including,
  • Flt3 Target kinase
  • Fms-like tyrosine kinase 3 is a transmembrane tyrosine kinase of 112.8 kDa encoded by chromosome 13q12 (symbol: FLT3).
  • FLT3 chromosome 13q12
  • Lymphohematopoietic stem cells serve as a reservoir for virtually all blood cells but make up only approximately 0.01% of human or murine marrow cells. The ability to isolate and expand this population has clinical applications in bone marrow transplantations for cancer and genetic diseases.
  • Small et al. Proc. Nat. Acad. Sci. 1994, 91: 459-463 cloned the cDNA for stem cell tyrosine kinase 1, the human homolog of murine Flk2/Flt3, from a CD34+ hematopoietic stem cell-enriched library.
  • STK1 which is identical to FLT3, is a member of the type III receptor tyrosine kinase family that includes KIT, FMS, and platelet-derived growth factor receptor.
  • STK1 expression in human blood and marrow is restricted to CD34+ cells, a population greatly enriched by stem/progenitor cells.
  • Antisense oligonucleotides directed against STK1 sequences inhibited hematopoietic colony formation, most strongly in long-term bone marrow cultures.
  • An Flt3 inhibitor may be useful in treating acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia.
  • a number of different assays for kinase activity can be utilized for assaying for active modulators and/or determining specificity of a modulator for a particular kinase or group of kinases.
  • assays mentioned in the Examples below one of ordinary skill in the art can readily identify other assays that can be utilized and can modify an assay for a particular application. For example, numerous papers concerning kinases describe assays that can be used.
  • Additional alternative assays can employ binding determinations.
  • this sort of assay can be formatted either in a fluorescence resonance energy transfer (FRET) format, or using an AlphaScreen (amplified luminescent proximity homogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidin or the phosphor-specific antibody.
  • FRET fluorescence resonance energy transfer
  • AlphaScreen amplified luminescent proximity homogeneous assay
  • invention compounds may exist in a number of different forms or derivatives, all within the scope of the present invention.
  • Alternative forms or derivatives include, for example, (a) prodrugs, and active metabolites (b) tautomers, isomers (including stereoisomers and regioisomers), and racemic mixtures (c) pharmaceutically acceptable salts and (d) solid forms, including different crystal forms, polymorphic or amorphous solids, including hydrates and solvates thereof, and other forms.
  • Prodrugs are compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound.
  • Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties.
  • some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug.
  • Esters include, for example, esters of a carboxylic acid group, or S-acyl or O-acyl derivatives of thiol, alcohol, or phenol groups.
  • Prodrugs may also include variants wherein an —NH group of the compound has undergone acylation, such as the 7-position of the pyrrolo[2,3-d]pyrimidine ring or the 1-position of the 1H-pyrrolo[2,3-b]pyridine ring of compounds as described herein, where cleavage of the acyl group provides the free —NH group of the active drug.
  • Some prodrugs are activated enzymatically to yield the active compound, or a compound may undergo further chemical reaction to yield the active compound.
  • Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive.
  • bioprecursor prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs.
  • bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
  • the formation of active drug compound involves a metabolic process or reaction that is one of the following types:
  • Oxidative reactions are exemplified without limitation by reactions such as oxidation of alcohol, carbonyl, and acid functionalities, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O- and S-dealkylation, oxidative deamination, as well as other oxidative reactions.
  • Reductive reactions are exemplified without limitation by reactions such as reduction of carbonyl functionalitites, reduction of alcohol functionalities and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.
  • Reactions without change in the state of oxidation are exemplified without limitation to reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, new atomic linkages resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecule, and other such reactions.
  • Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improves uptake and/or localized delivery to a site(s) of action.
  • a transport moiety e.g., that improves uptake and/or localized delivery to a site(s) of action.
  • the linkage between the drug moiety and the transport moiety is a covalent bond
  • the prodrug is inactive or less active than the drug compound
  • the prodrug and any release transport moiety are acceptably non-toxic.
  • the transport moiety is intended to enhance uptake
  • the release of the transport moiety should be rapid.
  • it is desirable to utilize a moiety that provides slow release e.g., certain polymers or other moieties, such as cyclodextrins.
  • carrier prodrugs are often advantageous for orally administered drugs.
  • the transport moiety provides targeted delivery of the drug, for example the drug may be conjugated to an antibody or antibody fragment.
  • Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property).
  • lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids, or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols. Wermuth, supra.
  • Metabolites e.g., active metabolites
  • prodrugs as described above, e.g., bioprecursor prodrugs.
  • metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic processes in the body of a subject.
  • active metabolites are such pharmacologically active derivative compounds.
  • the prodrug compound is generally inactive or of lower activity than the metabolic product.
  • the parent compound may be either an active compound or may be an inactive prodrug.
  • one or more alkoxy groups can be metabolized to hydroxyl groups while retaining pharmacologic activity and/or carboxyl groups can be esterified, e.g., glucuronidation.
  • carboxyl groups can be esterified, e.g., glucuronidation.
  • there can be more than one metabolite where an intermediate metabolite(s) is further metabolized to provide an active metabolite.
  • a derivative compound resulting from metabolic glucuronidation may be inactive or of low activity, and can be further metabolized to provide an active metabolite.
  • Metabolites of a compound may be identified using routine techniques known in the art, and their activities determined using tests such as those described herein. See, e.g., Bertolini et al., 1997, J. Med. Chem., 40:2011-2016; Shan et al., 1997 , J Pharm Sci 86(7):756-757; Bagshawe, 1995 , Drug Dev. Res., 34:220-230; Wermuth, supra.
  • some of the compounds according to the present invention may exist as stereoisomers, i.e. having the same atomic connectivity of covalently bonded atoms yet differing in the spatial orientation of the atoms.
  • compounds may be optical stereoisomers, which contain one or more chiral centers, and therefore, may exist in two or more stereoisomeric forms (e.g. enantiomers or diastereomers).
  • stereoisomers i.e., essentially free of other stereoisomers
  • racemates i.e., essentially free of other stereoisomers
  • stereoisomers include geometric isomers, such as cis- or trans-orientation of substituents on adjacent carbons of a double bond. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Unless specified to the contrary, all such steroisomeric forms are included within the formulae provided herein.
  • a chiral compound of the present invention is in a form that contains at least 80% of a single isomer (60% enantiomeric excess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99% (98% e.e. or d.e.).
  • 60% enantiomeric excess (“e.e.”) or diastereomeric excess (“d.e.”) or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99% (98% e.e. or d.e
  • an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compound is present in optically pure form, such optically pure form being prepared and/or isolated by methods known in the art (e.g. by recrystallization techniques, chiral synthetic techniques (including synthesis from optically pure starting materials), and chromatographic separation using a chiral column.
  • a compound herein includes pharmaceutically acceptable salts of such compound.
  • compounds described herein can be in the form of pharmaceutically acceptable salts, or can be formulated as pharmaceutically acceptable salts.
  • Contemplated pharmaceutically acceptable salt forms include, without limitation, mono, bis, tris, tetrakis, and so on.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly can react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing chloride, bromide, iodide, hydrochloride, acetate, phenylacetate, acrylate, ascorbate, aspartate, benzoate, 2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4 dioate, hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate, glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate, isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate, malate, maleate, hydroxymaleate, methyl
  • pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, ethanolamine, diethanolamine, triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylenediamine, meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine, procaine, aluminum, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, ammonium, and mono-, di-, or tri-alkylamines (e.g.
  • diethylamine or salts derived from amino acids such as L-histidine, L-glycine, L-lysine, and L-arginine.
  • L-histidine amino acids
  • L-glycine amino acids
  • L-lysine amino acids
  • L-arginine amino acids
  • salts can be prepared by standard techniques.
  • the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • a salt can be prepared by reacting the free base and acid in an organic solvent. If the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an appropriate inorganic or organic base.
  • the compounds and salts may exist in different crystal or polymorphic forms, or may be formulated as co-crystals, or may be in an amorphous form, or may be any combination thereof (e.g. partially crystalline, partially amorphous, or mixtures of polymorphs) all of which are intended to be within the scope of the present invention and specified formulae.
  • salts are formed by acid/base addition, i.e.
  • co-crystals are a new chemical species that is formed between neutral compounds, resulting in the compound and an additional molecular species in the same crystal structure.
  • compounds of the invention are complexed with an acid or a base, including base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine, meglumine; acid addition salts, such as acetate, acetylsalicylate, besylate, camsylate, citrate, formate, fumarate, glutarate, hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate and tosylate; and amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, t
  • an amorphous complex is preferably formed rather than a crystalline material such as a typical salt or co-crystal.
  • the amorphous form of the complex is facilitated by additional processing, such as by spray-drying, mechanochemical methods such as roller compaction, or microwave irradiation of the parent compound mixed with the acid or base.
  • additional processing such as by spray-drying, mechanochemical methods such as roller compaction, or microwave irradiation of the parent compound mixed with the acid or base.
  • Such methods may also include addition of ionic and/or non-ionic polymer systems, including, but not limited to, hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and methacrylic acid copolymer (e.g. Eudragit® L100-55), that further stabilize the amorphous nature of the complex.
  • HPMCAS hydroxypropyl methyl cellulose acetate succinate
  • methacrylic acid copolymer e.g. Eudragit® L100-
  • amorphous complexes provide several advantages. For example, lowering of the melting temperature relative to the free base facilitiates additional processing, such as hot melt extrusion, to further improve the biopharmaceutical properties of the compound. Also, the amorphous complex is readily friable, which provides improved compression for loading of the solid into capsule or tablet form.
  • the formulae are intended to cover hydrated or solvated as well as unhydrated or unsolvated forms of the identified structures.
  • the indicated compounds include both hydrated and non-hydrated forms.
  • Other examples of solvates include the structures in combination with a suitable solvent, such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine
  • the methods and compounds will typically be used in therapy for human subjects. However, they may also be used to treat similar or identical indications in other animal subjects.
  • Compounds described herein can be administered by different routes, including injection (i.e. parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular), oral, transdermal, transmucosal, rectal, or inhalant. Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (hereby incorporated by reference herein).
  • compositions will comprise pharmaceutically acceptable carriers or excipients, such as fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers, and surfactants, which may be chosen to facilitate administration of the compound by a particular route.
  • carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like.
  • Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solution, dextrose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like.
  • WFI water for injection
  • Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethyl cellulose, cross-linked sodium carboxymethylcellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seed oil mineral oil, polyethylene glycol (e.g.
  • PEG 4000-8000 polyoxyethylene glycol
  • poloxamers povidone
  • crospovidone croscarmellose sodium
  • alginic acid casein
  • methacrylic acid divinylbenzene copolymer sodium docusate
  • cyclodextrins e.g. 2-hydroxypropyl-.delta.-cyclodextrin
  • polysorbates e.g.
  • polysorbate 80 cetrimide
  • TPGS d-alpha-tocopheryl polyethylene glycol 1000 succinate
  • magnesium lauryl sulfate sodium lauryl sulfate
  • polyethylene glycol ethers di-fatty acid ester of polyethylene glycols
  • a polyoxyalkylene sorbitan fatty acid ester e.g., polyoxyethylene sorbitan ester Tween®
  • polyoxyethylene sorbitan fatty acid esters sorbitan fatty acid ester, e.g.
  • a fatty acid such as oleic, stearic or palmitic acid
  • mannitol xylitol
  • sorbitol maltose
  • lactose
  • oral administration may be used.
  • Pharmaceutical preparations for oral use can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.
  • Compounds described herein may be combined with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g. aqueous, alcoholic, or oily solutions) and the like.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone); oily excipients, including vegetable and animal oils, such as sunflower oil, olive oil, or codliver oil.
  • fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol
  • cellulose preparations for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povid
  • the oral dosage formulations may also contain disintegrating agents, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate; a lubricant, such as talc or magnesium stearate; a plasticizer, such as glycerol or sorbitol; a sweetening such as sucrose, fructose, lactose, or aspartame; a natural or artificial flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring; or dye-stuffs or pigments, which may be used for identification or characterization of different doses or combinations. Also provided are dragee cores with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • compositions that can be used orally include push-fit capsules made of gelatin (“gelcaps”), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • injection parenteral administration
  • Compounds described herein for injection may be formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • Dispersions may also be prepared in non-aqueous solutions, such as glycerol, propylene glycol, ethanol, liquid polyethylene glycols, triacetin, and vegetable oils. Solutions may also contain a preservative, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • the compounds may be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use.
  • transmucosal, topical or transdermal administration may be used.
  • penetrants appropriate to the barrier to be permeated are used.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays or suppositories (rectal or vaginal).
  • Compositions of compounds described herein for topical administration may be formulated as oils, creams, lotions, ointments, and the like by choice of appropriate carriers known in the art.
  • Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C 12 ). In some embodiments, carriers are selected such that the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Creams for topical application are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of solvent (e.g., an oil), is admixed.
  • solvent e.g., an oil
  • administration by transdermal means may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art.
  • a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art.
  • the dosage administration will be continuous rather than intermittent throughout the dosage regimen.
  • compounds are administered as inhalants.
  • Compounds described herein may be formulated as dry powder or a suitable solution, suspension, or aerosol.
  • Powders and solutions may be formulated with suitable additives known in the art.
  • powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts.
  • Such solutions or suspensions may be administered by inhaling via spray, pump, atomizer, or nebulizer, and the like.
  • corticosteroids such as fluticasone proprionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate
  • beta agonists such as albuterol, salmeterol, and formoterol
  • anticholinergic agents such as ipratroprium bromide or tiotropium
  • vasodilators such as treprostinal and iloprost
  • enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies
  • an oligonucleotide such as single or double stranded DNA or RNA, siRNA
  • antibiotics such as tobramycin
  • muscarinic receptor antagonists leukotriene antagonists
  • cytokine antagonists protease inhibitors
  • cromolyn sodium nedocril sodium
  • sodium cromoglycate for example corticosteroids such as fluticasone proprionate, beclomethasone dipropionat
  • the amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound activity (in vitro, e.g. the compound IC 50 vs. target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g. biological half-life or bioavailability), the age, size, and weight of the subject, and the disorder associated with the subject. The importance of these and other factors are well known to those of ordinary skill in the art. Generally, a dose will be in the range of about 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject being treated. Multiple doses may be used.
  • the compounds described herein may also be used in combination with other therapies for treating the same disease.
  • Such combination use includes administration of the compounds and one or more other therapeutics at different times, or co-administration of the compound and one or more other therapies.
  • dosage may be modified for one or more of the compounds of the invention or other therapeutics used in combination, e.g., reduction in the amount dosed relative to a compound or therapy used alone, by methods well known to those of ordinary skill in the art.
  • use in combination includes use with other therapies, drugs, medical procedures etc., where the other therapy or procedure may be administered at different times (e.g. within a short time, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within a longer time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than a compound described herein, or at the same time as a compound described herein.
  • Use in combination also includes use with a therapy or medical procedure that is administered once or infrequently, such as surgery, along with a compound described herein administered within a short time or longer time before or after the other therapy or procedure.
  • the present invention provides for delivery of a compound described herein and one or more other drug therapeutics delivered by a different route of administration or by the same route of administration.
  • the use in combination for any route of administration includes delivery of a compound described herein and one or more other drug therapeutics delivered by the same route of administration together in any formulation, including formulations where the two compounds are chemically linked in such a way that they maintain their therapeutic activity when administered.
  • the other drug therapy may be co-administered with a compound described herein.
  • Use in combination by co-administration includes administration of co-formulations or formulations of chemically joined compounds, or administration of two or more compounds in separate formulations within a short time of each other (e.g.
  • Co-administration of separate formulations includes co-administration by delivery via one device, for example the same inhalant device, the same syringe, etc., or administration from separate devices within a short time of each other.
  • Co-formulations of a compound described herein and one or more additional drug therapies delivered by the same route includes preparation of the materials together such that they can be administered by one device, including the separate compounds combined in one formulation, or compounds that are modified such that they are chemically joined, yet still maintain their biological activity.
  • Such chemically joined compounds may have a linkage that is substantially maintained in vivo, or the linkage may break down in vivo, separating the two active components.
  • the mass spectrometry result indicated for a compound may have more than one value due to the isotope distribution of an atom in the molecule, such as a compound having a bromo or chloro substituent.
  • Compounds in the following examples are characterized by 1 H and 13 C NMR spectroscopy as well as mass spectrometry.
  • 5-Chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 2 was prepared in one step from 5-chloro-1H-pyrrolo[2,3-b]pyridine 1 as shown in Scheme 1.
  • 5-fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine is prepared similarly from 5-fluoro-1H-pyrrolo[2,3-b]pyridine.
  • 5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 4 was prepared in one step from 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 2 as shown in Scheme 2.
  • 3-Iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine 10 was prepared in one step from 5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8 as shown in Scheme 4.
  • 5-Iodo-4-methyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine 20 was prepared in two steps from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 17 as shown in Scheme 7.
  • 5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine 23 was prepared in one step from 5-iodo-1H-pyrrolo[2,3-b]pyridine 21 as shown in Scheme 8.
  • Aldehyde reagents that are used in making compounds are prepared according to the following protocols.
  • 5-Fluoro-1-methyl-2-oxo-1,2-dihydro-pyridine-3-carbaldehyde 33 was prepared in two steps from 5-fluoro-3-iodo-pyridin-2-ol 31 as shown in Scheme 10a.
  • the resulting material was purified by silica gel column chromatography, eluting with 100% ethyl acetate. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (33, 35 g, 226 mmol, 47.4%).
  • 5-Fluoro-2-methoxy-pyridine-3-carbaldehyde 37 was prepared in three steps from 3-bromo-5-fluoro-2-methoxy-pyridine 34 as shown in Scheme 10b.
  • the reaction was concentrated under vacuum, the residue dissolved in dichloromethane, and passed through a plug of silica, eluting with ethyl acetate to provide the desired compound as a white solid (35, 10 g, 54.0 mmol, 79%).
  • (2-Fluoro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 42 was prepared in three steps from 5-bromo-pyridin-2-ylamine 38 and 2-fluoro-benzaldehyde 39 as shown in Scheme 10c.
  • the resulting material was purified by silica gel column chromatography eluting with 20-60% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (40, 5.0 g).
  • N,N-dimethylformamide (2.6 mL, 34 mmol) was added and the mixture was stirred for 70 minutes at ⁇ 78° C., then allowed to warm up to room temperature for 1 hour.
  • the reaction was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was dried with sodium sulfate, filtered and filtrate concentrated under vacuum to provide the desired compound (41, 3.0 g), which was used in the next step without further purification.
  • the resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to give the desired compound (41, 3.50 g).
  • step 2 the first addition of t-butyllitium is replaced with n-butyllithium in pentane or by isopropylmagnesium chloride in tetrahydrofuran; for step 3, triethylamine is replaced with N,N-diisopropylethylamine, or dichloromethane is used as solvent.
  • step 3 the first addition of t-butyllitium is replaced with n-butyllithium in pentane or by isopropylmagnesium chloride in tetrahydrofuran; for step 3, triethylamine is replaced with N,N-diisopropylethylamine, or dichloromethane is used as solvent.
  • Compounds in the following table were characterized by 1 H and 13 C NMR spectroscopy as well as mass spectrometry.
  • step 1a no N,N-diisopropylethylamine is used; for step 3, the addition of isopropylmagnesium chloride is replaced with n-butyllithium in hexane; for step 4, triethylamine is included in the reaction and dichloromethane is used as solvent.
  • step 1a no N,N-diisopropylethylamine is used; for step 3, the addition of isopropylmagnesium chloride is replaced with n-butyllithium in hexane; for step 4, triethylamine is included in the reaction and dichloromethane is used as solvent.
  • Compounds in the following table were characterized by 1 H and 13 C NMR spectroscopy as well as mass spectrometry.
  • the resulting material was purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as white solid (58, 3.21 g).
  • Step 3 Preparation of (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (60)
  • Step 4 Preparation of (6-fluoro-5-formyl-pyridin-2-yl)-(5-fluoro-6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (61)
  • the reaction was allowed to warm to room temperature over 2 hours, then poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (61, 1.80 g).
  • Step 1 is prepared similarly to the protocol of Scheme 10e, as shown in the following table, where Step 1, Step 2, Step 3 and Step 4 reactants are provided in columns 1, 2, 3, and 4, respectively, with the resulting Boc protected aldehyde provided in column 5
  • the desired compound is the Boc protected bromo compound isolated after step 3 for use in subsequent reactions.
  • Reaction conditions are similar to those described for Scheme 10e, and may vary slightly for each step, for example, any of the solvents, reagents, reaction times, temperatures, work up conditions, or other reaction parameters may be varied employing alternate solvents, reagents, reaction times, temperatures, work up conditions, and the like, as are readily available to one skilled in the art.
  • step 2 is performed under nitrogen; step 3 includes N,N-diisopropylethylamine.
  • Compounds in the following table were characterized by 1 H and 13 C NMR spectroscopy as well as mass spectrometry.
  • Step 3 was prepared from 2,6-difluoro-pyridine 49 and (S)-1-(4-fluoro-phenyl)-ethylamine similarly to the protocol of step 1a of Scheme 10d, then steps 2-4 of Scheme 10e.
  • Step 3 also included N,N-diisopropylethylamine, as well as a subsequent addition of di-tert-butyldicarbonate and N,N-diisopropylethylamine.
  • Vinamidinium salt (68, 158 g, 413 mmol) and guanidine hydrochloride (69, 63.3 g, 455 mmol) were dissolved in 527 mL of acetonitrile and cooled on an ice/water bath.
  • Sodium hydroxide (66.1 mL, 50% w/w, 827 mmol) was added dropwise, keeping the temperature below 25° C. The reaction was allowed to warm to 25° C. and stirred for 4 hours, then diluted with water and filtered, stripped from ethanol/heptane, then triturated with heptane. The resulting solid was dried under vacuum to provide the desired compound (70, 37 g, 301 mmol, 72.7% yield).
  • Step 2 Preparation of (4-chloro-5-formyl-thiazol-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (76)
  • reaction mixture was poured into ice water, extracted with dichloromethane, washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum.
  • the resulting material was purified by silica gel column chromatography, eluting with ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (76, 1.5 g, 95%).
  • N-bromosuccinimide 116 g, 650 mmol was added in portions. After reacting for 2 hours, the solvent was removed under vacuum and the residue taken up in ethyl acetate, then poured into aqueous sodium thiosulfate. The organic layer was washed with warm water, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was crystallized from heptane to provide the desired compound (79, 172 g, 553 mmol, 85% yield).
  • the resulting material was dissolved in dichloromethane and passed through a plug of silica gel, eluting with ethyl acetate. The solvent was removed under vacuum to provide the desired compound as a peach colored solid (80, 70 g, 241 mmol, 88% yield).
  • 6-amino-nicotinic acid methyl ester (90, 0.678 g, 4.46 mmol) was combined with 5-fluoro-2-methoxy-pyridine-3-carbaldehyde (37, 0.532 g, 3.43 mmol), 10.6 mL of acetonitrile, trifluoroacetic acid (1.32 mL, 17.1 mmol) and triethylsilane (3.29 mL, 20.6 mol).
  • the reaction was heated to reflux for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum.
  • Step 2 Preparation of ⁇ 6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]pyridin-3-yl ⁇ -methanol (92)
  • Step 4 Preparation of (5-fluoro-2-methoxy-pyridin-3-ylmethyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (94)
  • Step 3 Preparation of (1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(2,2,5,5-tetramethyl-[1,2,5]azadisilolidin-1-yl)-pyridin-3-yl]-methanol (118) and (6-amino-pyridin-3-yl)-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (119)
  • n-butyllithium 7.10 mL, 2.50 M in hexane, 17.8 mmol
  • the reaction was stirred for 30 minutes at ⁇ 78° C. and allowed to warm to room temperature over an hour.
  • the reaction was cooled to ⁇ 78° C. and additional n-butyllithium (7.50 mL, 2.50 M in hexane, 18.8 mmol) was added slowly.
  • the reaction was concentrated under vacuum, combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane to provide the desired compound (120, 0.70 g).
  • Step 5 Preparation of (6-bromo-pyridin-3-ylmethyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2002)
  • Step 1 Preparation of [5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-dimethoxy-pyridin-3-ylmethyl)-amine (122)
  • Step 2 Preparation of [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-dimethoxy-pyridin-3-ylmethyl)-amine (P-1496)
  • Step 1 Preparation of ⁇ 5-[(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyrimidin-2-yl ⁇ -(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (124)
  • Step 2 Preparation of [5-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amine (125)
  • Step 3 Preparation of (5-fluoro-2-methoxy-pyridin-3-ylmethyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-1599)
  • Step 1 Preparation of ⁇ 5-[hydroxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-3-methoxy-pyridin-2-yl ⁇ -(4-methoxy-benzyl)-carbamic acid tert-butyl ester (127)
  • Step 3 Preparation of (5-fluoro-2-methoxy-pyridin-3-ylmethyl)-[3-methoxy-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-1547)
  • Additional compounds are prepared following the protocol of Scheme 14, where conditions may vary, for example, any of the solvents, reaction times, reagents, temperatures, work up conditions, or other reaction parameters may be varied employing alternate solvents, reagents, reaction times, temperatures, work up conditions, and the like, as are readily available to one skilled in the art.
  • Compounds are prepared using a suitable aldehyde in place 5-fluoro-2-methoxy-pyridine-3-carbaldehyde 37 in step 3. The following compounds are made using this procedure.
  • Compounds in the following table were characterized by 1 H and 13 C NMR spectroscopy as well as mass spectrometry.
  • Step 1 Preparation of (1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfanyl-pyrimidin-5-yl)-methanol (130)
  • the resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (131, 2.90 g).
  • Step 4 Preparation of [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[(S)-1-(4-fluorophenyl)-ethyl]-amine (P-2005)
  • the reaction was neutralized with the addition of 120 ⁇ L of acetic acid, solvents were removed under vacuum, and the resulting material was dissolved in 400 ⁇ L of dimethyl sulfoxide for purification by HPLC.
  • the desired compound was purified on Phenomenex C18 column (50 mm ⁇ 10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound.
  • MS (ESI) [M+H + ] + 381.9.
  • Step 1 Preparation of ⁇ 6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl ⁇ -(4-methoxy-benzyl)-carbamic acid tert-butyl ester (136)
  • Step 3 Preparation of (5- ⁇ [6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]methyl ⁇ -pyrimidin-2-yl)-methyl-amine (P-2095)
  • 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine 137, 9.72 mg, 0.04 mmol
  • 2-methylamino-pyrimidine-5-carbaldehyde 138, 11.0 mg, 0.08 mmol
  • silica supported cyanoborohydride 50 mg, 1 mmol/g, 0.05 mmol
  • step 3a was prepared similarly to the protocol of Scheme 16, where step 3 was replaced by the following step 3a:
  • Step 3a Preparation of 5-fluoro-3- ⁇ [6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]methyl ⁇ -1-methyl-1H-pyridin-2-one (P-2156)
  • step 3b similarly to the protocol of Scheme 16, where step 3 was replaced by the following step 3b:
  • Step 3b Preparation of N-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-C-phenyl-methanesulfonamide (P-2181)
  • 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 157 mg, 0.614 mmol) was mixed with 4 mL of dichloromethane and pyridine (149 ⁇ L, 1.84 mmol) and cooled to 0° C. in an ice water bath.
  • Phenyl-methanesulfonyl chloride 139, 0.234 g, 1.23 mmol was added and the reaction stirred at 0° C. for 1 hour, then warmed to room temperature and stirred overnight.
  • Aqueous saturated sodium bicarbonate was added and extracted with ethyl acetate.
  • step 3a may be substituted for step 3
  • conditions may vary, for example, any of the solvents, reaction times, reagents, temperatures, work up conditions, or other reaction parameters may be varied employing alternate solvents, reagents, reaction times, temperatures, work up conditions, and the like, as are readily available to one skilled in the art.
  • Step 2 Preparation of 5-chloro-3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (141)
  • Step 4 Preparation of 3- ⁇ 6-[tert-butoxycarbonyl-(5-fluoro-pyridin-3-ylmethyl)-amino]-2-fluoro-pyridin-3-ylmethyl ⁇ -5-chloro-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (144):
  • Step 5 Preparation of [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (P-2001)
  • Step 1 Preparation of [5-(3-chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-(5-fluoro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (147)
  • Step 2 Preparation of (3-chloro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-amine (P-2006)
  • Step 1 Preparation of (5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[5-(4-fluoro-benzylamino)-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-methanol (148)
  • Step 2 Preparation of [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-(4-methoxy-benzyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine (149)
  • 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 100 mg, 0.3902 mmol) was combined with 5-fluoro-2-methoxy-nicotinoyl chloride (151, 81.37 mg, 0.4292 mmol), 3.00 mL of tetrahydrofuran, and pyridine (0.06312 mL, 0.7804 mmol).
  • the reaction was stirred at room temperature overnight, then poured into aqueous 1N hydrochloric acid and extracted with ethyl acetate.
  • Step 1 Preparation ⁇ 5-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methoxy-methyl]-pyridin-2-yl ⁇ -(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (154)
  • Step 2 Preparation of [5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-2017)
  • Step 1a Preparation of [6-fluoro-5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-1622)
  • Step 3 Preparation of 5-fluoro-2-methoxy-pyridin-3-ylmethyl)-[5-(4-phenyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2171)
  • the mixture is diluted with ethyl acetate and water and the aqueous layer is separated and extracted with ethyl acetate.
  • the organic layers are combined and washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum.
  • the resulting material is purified by silica gel column chromatography eluting with methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound.
  • Step 1 Preparation of ⁇ 5-[(4-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl ⁇ -di-carbamic acid tert-butyl ester (163)
  • Step 3 Preparation of [5-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-1717)
  • Additional compounds are prepared following the protocol of Scheme 22, where conditions may vary, for example, any of the solvents, reaction times, reagents, temperatures, work up conditions, or other reaction parameters may be varied employing alternate solvents, reagents, reaction times, temperatures, work up conditions, and the like, as are readily available to one skilled in the art.
  • Compounds are prepared optionally replacing 6-trifluoromethyl-pyridine-3-carbaldehyde 160 with a suitable aldehyde in step 3. The following compounds are made using this procedure.
  • Compounds in the following table were characterized by 1 H and 13 C NMR spectroscopy as well as mass spectrometry.
  • Step 1 Preparation of ⁇ 5-[(1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl ⁇ -(4-methoxy-benzyl)-carbamic acid tert-butyl ester (166)
  • Step 4 Preparation of 4-[4-(1-benzenesulfonyl-3- ⁇ 2-fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl ⁇ -1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (170) and 4-[4-(3- ⁇ 2-fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl ⁇ -1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (P-1702):
  • Step 5 Preparation of (5-fluoro-2-methoxy-pyridin-3-ylmethyl)- ⁇ 6-fluoro-5-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl ⁇ -amine (P-1703)
  • Additional compounds are prepared following the protocol of Scheme 23, where conditions may vary, for example, any of the solvents, reaction times, reagents, temperatures, work up conditions, or other reaction parameters may be varied employing alternate solvents, reagents, reaction times, temperatures, work up conditions, and the like, as are readily available to one skilled in the art.
  • Compounds are prepared optionally replacing 5-fluoro-2-methoxy-pyridine-3-carbaldehyde 37, with a suitable aldehyde in step 3. The following compounds are made using this procedure.
  • Compounds in the following table were characterized by 1 H and 13 C NMR spectroscopy as well as mass spectrometry.
  • P-1669 is prepared in four steps from 5-bromo-3-iodo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester 171 and (6-fluoro-5-formyl-pyridin-2-yl)-(4-methoxy-benzyl)-carbamic acid tert-butyl ester 83 as shown in Scheme 24.
  • Step 1 Preparation of 5-bromo-3-( ⁇ 6-[tert-butoxycarbonyl-(4-methoxy-benzyl)-amino]-2-fluoro-pyridin-3-yl ⁇ -hydroxy-methyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (172)
  • the resulting material is taken up in 250 mL of dichloromethane and 250 mL of trifluoroacetic acid is added, then stirred at reflux for several hours.
  • the reaction is concentrated under vacuum and the resulting material is taken up in ethyl acetate and extraction with the addition of aqueous saturated potassium carbonate.
  • the organic layer is concentrated under vacuum and the resulting material is purified by silica gel column chromatography, eluting with 0-5% methanol in dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound.
  • Step 3 Preparation of [5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amine (P-1497)
  • Step 4 Preparation of N-(3- ⁇ 2-fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl ⁇ -1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide (P-1669)
  • the organic layer is concentrated under vacuum and the resulting material dissolved in dichloromethane and purified by silica gel column chromatography, eluting with 0-10% methanol in dichloromethane. Appropriate fractions are concentrated, and the material dissolved in tetrahydrofuran for further purification on a C18 reverse phase column, eluting with 0-100% methanol (with 10% tetrahydrofuran)/water. Appropriated fractions are combined and concentrated under vacuum. The resulting material is triturated with methyl tert-butyl ether and filtered, washing with methyl tert-butyl ether, then heptane. The solid is dried under vacuum to provide the desired compound.
  • Additional compounds are prepared following the protocol of Scheme 24, where conditions may vary, for example, any of the solvents, reaction times, reagents, temperatures, work up conditions, or other reaction parameters may be varied employing alternate solvents, reagents, reaction times, temperatures, work up conditions, and the like, as are readily available to one skilled in the art.
  • Compounds are prepared optionally replacing 5-fluoro-2-methoxy-pyridine-3-carbaldehyde 37, with a suitable aldehyde in step 3 and optionally replacing acetamide 174 with methanesulfonamide in step 4. The following compounds are made using this procedure.
  • Compounds in the following table were characterized by 1 H and 13 C NMR spectroscopy as well as mass spectrometry.
  • Step 4a Preparation of [6-fluoro-5-(5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amine (P-1688)
  • Step 4b Preparation of 3- ⁇ 2-fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl ⁇ -1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (P-1693)
  • reaction mixture is concentrated under vacuum, taken up in ethyl acetate and washed with water.
  • organic layer is concentrated under vacuum, the residue dissolved in dichloromethane and purified by silica gel column chromatography, eluting with 0-10% methanol in dichloromethane. Appropriated fractions are combined and concentrated under vacuum to provide the desired compound.
  • the reaction is concentrated under vacuum, the residue dissolved in tetrahydrofuran for purification on a C18 reverse phase column, eluting with 0-100% methanol (with 10% tetrahydrofuran)/water. Appropriated fractions are combined and concentrated under vacuum. The resulting material is triturated with ethyl acetate/heptane and filtered, washing with heptane. The solid is dried under vacuum to provide the desired compound.
  • Additional compounds are prepared following the protocol of Scheme 24, using steps 4a or steps 4b and step 5, where conditions may vary, for example, any of the solvents, reaction times, reagents, temperatures, work up conditions, or other reaction parameters may be varied employing alternate solvents, reagents, reaction times, temperatures, work up conditions, and the like, as are readily available to one skilled in the art.
  • Compounds are prepared optionally replacing 5-fluoro-2-methoxy-pyridine-3-carbaldehyde 37, with a suitable aldehyde in step 3. The following compounds are made using this procedure.
  • Compounds in the following table were characterized by 1 H and 13 C NMR spectroscopy as well as mass spectrometry.
  • Step 1 Preparation of (2-chloro-benzyl)- ⁇ 6-fluoro-5-[hydroxy-(5-methoxy-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl ⁇ -carbamic acid tert-butyl ester (176)
  • Step 2 Preparation of (2-chloro-benzyl)-[6-fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2034)
  • the compounds disclosed herein can be prepared in additional forms, such as polymorphs, salt forms and complexes. Such solid forms can further improve the biopharmaceutical properties, and can be further formulated to enhance biopharmaceutical properties.
  • compounds of the invention form acid addition salts such as hydrochloride or tosylate salts or form a complex with polyprotic acids, such as citric acid, preferably wherein the complex is substantially amorphous.
  • Such an amorphous complex can also be processed with addition of a polymer, such as HPMCAS, that further stabilizes the amorphous form.
  • the process can also include spray drying of the material.
  • Compound is dissolved in 400-500 mL of acetone and added with stirring and heat to 1 equivalent of citric acid dissolved in ethanol.
  • the solution is spray dried to provide the dried complex.
  • Additional material is formulated with addition of the compound/citrate complex to polymer in the same ratio of acetone/ethanol, for example using either HPMCAS or a mixture of Eudragit® L100-55 and Poloxamer 407.
  • components are combined in the weight ratios of 40-50% compound, 15-25% citric acid, 25-35% Eudragit® L100-55 and 1-10% Poloxamer 407.
  • components are combined in the weight ratios of 40-50% compound, 15-25% citric acid, and 30-40% HPMCAS.
  • the amorphous nature of the resulting complex or formulation of the complex can be determined by X-Ray Powder Diffraction (XRPD), infra-red spectrometry, and differential scanning calorimetry.
  • XRPD X-Ray Powder Diffraction
  • infra-red spectrometry X-Ray Powder Diffraction
  • differential scanning calorimetry For example using a ShimadzuXRD-6000 X-ray powder diffractometer using Cu K ⁇ radiation. The tube voltage and amperage are set to 40 kV and 40 mA, respectively. The divergence and scattering slits are set at 1° and the receiving slit was set at 0.15 mm Diffracted radiation is detected by a NaI scintillation detector. A ⁇ -2 ⁇ continuous scan at 3°/min (0.4 sec/0.02° step) from 2.5° to 40° 2 ⁇ is used.
  • a silicon standard is analyzed to check the instrument alignment. Data are collected and analyzed using XRD-6100/7000 v.5.0. Sample is prepared for analysis by placing it in an aluminum holder with silicon insert. The DSC is used to demonstrate that the complexes lack a characteristic transition and have completely melted before any free base crystalline transition, further supporting that these complexes are amorphous.
  • Fms selectivity relative to Kit and other kinases provides preferred activity for treating certain diseases, such as rheumatoid arthritis, Alzheimer's disease, Parkinson's disease, osteoarthritis, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, or renal hypertrophy.

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