WO2007062078A2 - Composes modulant l'activite thrombopoietine et procedes correspondants - Google Patents

Composes modulant l'activite thrombopoietine et procedes correspondants Download PDF

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WO2007062078A2
WO2007062078A2 PCT/US2006/045129 US2006045129W WO2007062078A2 WO 2007062078 A2 WO2007062078 A2 WO 2007062078A2 US 2006045129 W US2006045129 W US 2006045129W WO 2007062078 A2 WO2007062078 A2 WO 2007062078A2
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compound
oxo
optionally substituted
dihydro
hydroxy
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PCT/US2006/045129
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WO2007062078A3 (fr
Inventor
Lin Zhi
Dean P. Phillips
Jackline E. Dalgard
Richard J. Penuliar
Matthew H. Mcneill
Jyun-Hung Chen
Catalina Cuervo
Robert Higuchi
Yongkai Li
Oliver Long
Cornelis Arjan Van Oeveren
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Ligand Pharmaceuticals Inc.
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Priority to EP06838225A priority Critical patent/EP1951667A2/fr
Priority to JP2008558985A priority patent/JP2009519352A/ja
Priority to CA002630234A priority patent/CA2630234A1/fr
Priority to AU2006318527A priority patent/AU2006318527A1/en
Priority to BRPI0620532-1A priority patent/BRPI0620532A2/pt
Publication of WO2007062078A2 publication Critical patent/WO2007062078A2/fr
Publication of WO2007062078A3 publication Critical patent/WO2007062078A3/fr

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    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
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    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present invention relates to compounds and methods in the fields of chemistry and medicine. More specifically, the present invention relates to compounds that modulate one or more thrombopoietin activity and/or bind to thrombopoietin receptors, and to methods for making and using such compound.
  • Thrombopoietin also referred to as c-Mpl ligand, rnpl ligand, megapoietin, and megakaryocyte growth and development factor
  • TPO Thrombopoietin
  • c-Mpl ligand also referred to as c-Mpl ligand, rnpl ligand, megapoietin, and megakaryocyte growth and development factor
  • TPO has been cloned and its amino acid sequence and the cDNA sequence encoding it have been described. See e.g., U.S. 5,766,581 ; Kuter, D.J. et al., Proc. Natl. Acad. Sci., 91 :11104-11 108 (1994); de Sauvage F.V., et al., Nature, 369: 533-538 (1994); Lok, S. et al., Nature 369:565-568 (1994); Wending, F. et al., Nature, 369: 571-574 (1994), all of which are incorporated herein by reference in their entirety.
  • TPO activity results from binding of TPO to the TPO receptor (also called MPL).
  • TPO receptor also called MPL.
  • the TPO receptor has been cloned and its amino acid sequence has been described. See e.g., Vigon et al., Proc. Natl. Acad. Sci., 89:5640-5644 (1992), which is incorporated herein by reference in its entirety.
  • TPO modulators may be useful in treating a variety of hematopoietic conditions, including, but not limited to, thrombocytopenia. See e.g., Baser et al. Blood 89:3118-3128 (1997); Fanucchi et al. New Engl. J. Med. 336:404- 409 (1997), both of which are incorporated herein by reference in their entirety.
  • patients undergoing certain chemotherapies including but not limited to chemotherapy and/or radiation therapy for the treatment of cancer, may have reduced platelet levels.
  • treating such patients with a selective TPO modulator increases platelet levels.
  • selective TPO modulators stimulate production of glial cells, which may result in repair of damaged nerve cells.
  • the present invention provides a compound of Formula I, II, III, IV, V 3 or VI:
  • R 1 is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR 14 R 15 , an optionally substituted C]-C 6 alkyl, an optionally substituted Ci-C ⁇ haloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 3 and R 4 are independently selected from hydrogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 5 is selected from hydrogen, halogen, OR 14 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 8 and each R 9 is independently selected from hydrogen, OR 16 , NR 16 R 17 , an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, (CH 2 ) m R 18 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -Cg ring;
  • R 10 is selected from hydrogen, halogen, oxo, OR 16 , NR 16 R 17 , SR 16 , an optionally substituted Ci-C 6 alkyl, an optionally substituted C]-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 1 1 is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , and SR 14 ; or R 11 and R 4 are linked to form a optionally substituted heterocycle;
  • R 12 is selected from hydrogen, halogen, Ci-C 6 alkyl, Cj-C 6 haloalkyl, Cj- C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 13 is selected from hydrogen, halogen, CN, NO 2 , CO 2 R 14 , S(O)JR. 14 , Ci- C 4 alkyl, C 1 -C 4 haloalkyl, Ci-C 4 heteroalkyl, and Ci-C 4 haloheteroalkyl;
  • R 14 is selected from hydrogen, Ci-C ⁇ alkyl, CpC 6 haloalkyl, C]-C 6 heteroalkyl, and Cj-C 6 heterohaloalkyl;
  • R 15 is selected from hydrogen, SO 2 R 19 , Cj-C 6 alkyl, C 1 -C 5 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl;
  • R 16 and R 17 are each independently selected from hydrogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Cj-C 6 haloalkyl, an optionally substituted Cj-C 6 heteroalkyl, and (CH 2 )HiR 18 ; or one of R 16 and R 17 is an optionally substituted C 2 -C 6 alkyl and the other of R 16 and R 17 is null; or R 16 and R 17 are linked to form an optionally substituted C 3 -Cs ring;
  • R 18 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R 18 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system;
  • R 19 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and an optionally substituted aryl;
  • D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • L is NH or null
  • Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • U is selected from O, NR 4 , CR 3 R 4 , CO, and null;
  • W is selected from O, NR 4 , CR 3 R 4 , CO, and null;
  • X is N or CR 5 ;
  • Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted Cj-C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl;
  • Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -CiO aryl and an optionally substituted C 1 -C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 heteroalkyl, and an optionally substituted Ci-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -CiO aryl; m is 0, 1, 2, or 3; and n is 0 or 1 ; each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy,
  • D is not naphthyl if X is N and W is NH
  • D is not phenyl if X is CH, W is NH, Z is phenyl, and R 10 or R 11 is -(CH 2 ) O-6 OH,
  • R i i — D-R 10 (iii) I is not pyrazolyl or optionally substituted 5- hydroxypyrazolyl, and
  • U is not NH; provided further that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compounds of Formulas III or VI, then R 6 , R !0 , and R l ! do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
  • the present invention provides a compound of Formula I, II, or III as described above:
  • R 1 is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR 14 R 15 , an optionally substituted Ci-Cg alkyl, an optionally substituted Cj-Ce haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , S ⁇ 2NR 14 R !5 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , an optionally substituted Cj-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 3 and R 4 are independently selected from hydrogen, an optionally substituted Cj-C 6 alkyl, an optionally substituted Cj-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 5 is selected from hydrogen, halogen, OR 14 , Ci-C 6 alkyl, C]-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Cj-C 6 haloheteroalkyl;
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 8 and each R 9 is independently selected from hydrogen, OR 16 , NR 16 R 17 , an optionally substituted Cj-C 6 alkyl, an optionally substituted Cj-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, (CH 2 ) m R 18 > and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -C 8 ring;
  • R 10 is selected from hydrogen, halogen, oxo, OR 16 , NR 16 R 17 , SR 16 , an optionally substituted C]-C 6 alkyl, an optionally substituted Cj-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R" is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , and SR 14 ; or R ⁇ and R 4 are linked to form a optionally substituted heterocycle;
  • R 12 is selected from hydrogen, halogen, Cj-C 6 alkyl, Cj-C 6 haloalkyl, Cj- C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 14 is selected from hydrogen, CpC 6 alkyl, Ci-Ce haloalkyl, CpC 6 heteroalkyl, and Ci-C 6 heterohaloalkyl;
  • R 15 is selected from hydrogen, SO 2 R 19 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, Cj-C 6 heteroalkyl, and Cj-C 6 heterohaloalkyl;
  • R 16 and R 17 are each independently selected from hydrogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, and (CH 2 )JR.
  • R 16 and R 17 is an optionally substituted C 2 -C 6 alkyl and the other of R 16 and R 17 is null; or R 16 and R are linked to form an optionally substituted C 3 -C 8 ring;
  • R 18 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R 18 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system;
  • R 19 is selected from hydrogen, C1-C 3 alkyl, C 1 -C 3 haloalkyl, and an optionally substituted aryl;
  • D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • L is NH or null
  • Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • U is selected from O, NR 4 , CR 3 R 4 , CO, and null;
  • W is selected from O, NR 4 , CR 3 R 4 , CO, and null;
  • X is N or CR 5 ;
  • Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-Ce alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl;
  • Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -Ci 0 aryl and an optionally substituted Ci-C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Cj-C 6 alkyl, an optionally substituted Ci-C 6 heteroalkyl, and an optionally substituted Ci-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -Ci 0 aryU m is 0, 1, 2, or 3; and n is 0 or 1; each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, ary
  • D is not naphthyl if X is N and W is NH 5
  • D is not phenyl if X is CH, W is NH, Z is phenyl, and R 10 or R u is -(CH 2 ) O-6 OH 5
  • R 11 — D— R 10 (iii) I is not pyrazolyl or optionally substituted 5- hydroxypyrazolyl, and
  • U is not NH; provided further that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compound of Formula III, then R 6 , R 10 , and R 11 do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
  • the present invention provides a compound of Formula I 5 II, or III as described above; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
  • R 1 is selected from a halogen, OR 14 , NO 2 , CN, NR 14 R 15 , C 1 -C 4 alkyl, Ci- C 4 haloalkyl, an optionally substituted C r C 4 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere selected from tetrazole,
  • A, B 5 and C are each independently selected from O, S, and NR 20 ; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, Ci-C 4 heteroalkyl, and C 1 -C 4 heterohaloalkyl;
  • R 3 and R 4 are independently selected from hydrogen, Ci-C 4 alkyl, C]-C 4 haloalkyl, and an optionally substituted Ci -C 4 heteroalkyl;
  • R 5 is selected from hydrogen, OR 14 , Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 heteroalkyl, and Ci-C 4 haloheteroalkyl;
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 R 19 , OC(S)NR 14 R 15 , SC(O)NR 14 R 15 , and
  • A, B, and C are each independently selected from O, S, and N; each R 8 and each R 9 is independently selected from hydrogen, OR , NR 16 R 17 , Ci-C 4 alkyl, Cj-C 4 haloalkyl, an optionally substituted C r C 4 heteroalkyl, (CH 2 ) m R 18 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -C 8 ring;
  • R 10 is selected from hydrogen, halogen, oxo, Ci-C 4 alkyl, Cj -C 4 haloalkyl, and an optionally substituted Ci-C 4 heteroalkyl;
  • R" is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , and SR 14 ; or R 11 and R 4 are linked to form a optionally substituted heterocycle;
  • R 12 is selected from hydrogen, halogen, C]-C 4 alkyl, Ci-C 4 haloalkyl, Ci- C 4 heteroalkyl, and Ci -C 4 haloheteroalkyl;
  • R 13 is selected from hydrogen, halogen, CN 3 NO 2 , CO 2 R 14 , S(O) m R 14 , Cr C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 heteroalkyl, and Ci-C 4 haloheteroalkyl;
  • R 14 is selected from hydrogen, C 1 -C4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 heteroalkyl, and Ci-C 4 heterohaloalkyl;
  • R 15 is selected from hydrogen, SO 2 R 19 , Ci-C 4 alkyl, Ci-C 4 haloalkyl, and C 1 -C4 heteroalkyl;
  • R 16 and R 17 are each independently selected from hydrogen, Ci-C 4 alkyl, C J -C 4 haloalkyl, an optionally substituted C)-C 4 heteroalkyl, and (CH 2 ) m R 18 ; or one of R 16 and R 17 is C 2 -C 6 alkyl and the other of R 16 and R 17 is null; or R 16 and R 17 are linked to form an optionally substituted C 4 -C 7 ring;
  • R 19 is selected from hydrogen, C1-C 3 alkyl, Ci-C 3 haloalkyl, and aryl;
  • D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • G is selected from O, S, and NR 14 ;
  • J is selected from O, S, NR 14 , and CR 14 R 15 ;
  • K is O or S
  • Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • U is selected from O, NR 4 , CR 3 R 4 , CO, and null;
  • W is selected from O, NR 4 , CR 3 R 4 , CO, and null;
  • X is N or CR 5 ;
  • Y is selected from:
  • Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -CiO aryl and an optionally substituted Ci-Cs heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted Cj-C 6 heteroalkyl, and an optionally substituted Cj-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -C 1O aryl; m is 0, I 5 2, or 3; and n is 0 or 1; provided that if Y is R oriented in compounds of Formulas I or II to form a dihydropyrazolylene, then:
  • D is not naphthyl if X is N and W is NH 3
  • D is not phenyl if X is CH 5 W is NH, Z is phenyl, and R 10 or R 11 is -(CH 2 ) O-6 OH,
  • R 11 — D-R 10 (iii) I is not pyrazolyl or optionally substituted 5- hydroxypyrazolyl ?
  • U is not NH; provided further that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compound of Formula III, then R 6 , R 10 , and R 11 do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
  • the present invention provides a compound of Formula IV, V, or VI as described above:
  • R 1 is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR 14 R 15 , an optionally substituted Ci-Ce alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl; R 3 and R 4 are independently selected from hydrogen, an optionally substituted Cj-C 6 alkyl, an optionally substituted Cj-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 5 is selected from hydrogen, halogen, OR 14 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 8 and each R 9 is independently selected from hydrogen, OR 16 , NR 16 R 17 , an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted CpCe heteroalkyl, (CH 2 ) m R 18 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -Cs ring;
  • R 10 is selected from hydrogen, halogen, oxo, OR 16 , NR 16 R 17 , SR 16 , an optionally substituted Ci-C 6 alkyl, an optionally substituted C t -C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R n is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , and SR 14 ; or R ⁇ and R 4 are linked to form a optionally substituted heterocycle;
  • R 12 is selected from hydrogen, halogen, Ci-C 6 alkyl, Cj-C 6 haloalkyl, Ci- C 6 heteroalkyl, and C 1 -C 6 haloheteroalkyl;
  • R 13 is selected from hydrogen, halogen, CN, NO 2 , CO 2 R 14 , S(O) m R 14 , C 1 - C 4 alkyl. C 1 -C 4 haloalkyl, Cj -C 4 heteroalkyl, and C 1 -C 4 haloheteroalkyl;
  • R 14 is selected from hydrogen, C]-C 6 alkyl, Ci-C 6 haloalkyl, Cj-C 6 heteroalkyl, and C]-C 6 heterohaloalkyl;
  • R 15 is selected from hydrogen, SO 2 R 19 , C r C 6 alkyl, Cj-C 6 haloalkyl, C]-C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl;
  • R 16 and R 17 are each independently selected from hydrogen, an optionally substituted Cj-C 6 alkyl, an optionally substituted Ci-Ce haloalkyl, an optionally substituted Cj-C 6 heteroalkyl, and (CH 2 ) m R 18 ; or one of R 16 and R 17 is an optionally substituted C 2 -C 6 alkyl and the other of R 16 and R 17 is null; or R 16 and R 1 are linked to form an optionally substituted C 3 -C 8 ring; R is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R 18 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system;
  • R 19 is selected from hydrogen, C 1 -C 3 alkyl, Cj-C 3 haloalkyl, and an optionally substituted aryl;
  • D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • L is NH or null
  • Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • U is selected from O, NR 4 , CR 3 R 4 , CO, and null;
  • W is selected from O, NR 4 , CR 3 R 4 , CO, and null;
  • X is N or CR 5 ;
  • Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C ⁇ -Cio aryl and an optionally substituted Ci-Ce heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 heteroalkyl, and an optionally substituted Ci-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -Ci 0 aryl; m is 0, 1, 2, or 3; and n is 0 or 1; each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy
  • the present invention provides a compound of Formula IV, V, or VI or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
  • R 1 is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR 14 R 15 , an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 R 19 ,
  • A, B, and C are each independently selected from O, S, and N;
  • R 2 is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , an optionally substituted Ci-C ⁇ alkyl, an optionally substituted Ci-Ce haloalkyl, and an optionally substituted Ci-Cg heteroalkyl;
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 R 19 , OC(S)NR 14 R 15 , SC(O)NR 14 R 15 , and
  • the present invention provides a compound of Formula I, II, III, IV, V, or VI: or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
  • R 1 is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR 14 R 15 , an optionally substituted Cj-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , an optionally substituted C]-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 3 and R 4 are independently selected from hydrogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Cj-C 6 haloalkyl, and an optionally substituted Cj-C 6 heteroalkyl;
  • R 5 is selected from hydrogen, halogen, OR 14 , C]-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 10 is selected from hydrogen, halogen, oxo, OR 16 , NR 16 R 17 , SR 16 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci -C O heteroalkyl;
  • R 11 is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , and SR 14 ; or R 1 1 and R 4 are linked to form a optionally substituted heterocycle;
  • R 12 is selected from hydrogen, halogen, CpC 6 alkyl, Ci-C 6 haloalkyl, Q- C 6 heteroalkyl, and C]-C 6 haloheteroalkyl;
  • R 13 is selected from hydrogen, halogen, CN, NO 2 , CO 2 R 14 , S(O) m R 14 , C,- C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 heteroalkyl, and Ci-C 4 haloheteroalkyl;
  • R 14 is selected from hydrogen, C]-C 6 alkyl, C r C 6 haloalkyl, Ci-C 6 heteroalkyl, and C]-C 6 heterohaloalkyl;
  • R 15 is selected from hydrogen, SO 2 R 19 , CpC 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl;
  • R 16 and R 17 are each independently selected from hydrogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, and (CH 2 ) m R 18 ; or one of R 16 and R 17 is an optionally substituted C 2 -C 6 alkyl and the other of R 16 and R 17 is null; or R 16 and R 17 are linked to form an optionally substituted C 3 -Cs ring;
  • R 18 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R 18 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system;
  • R 19 is selected from hydrogen, Cj-C 3 alkyl, Ci-C 3 haloalkyl, and an optionally substituted aryl;
  • D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • L is NH or null
  • Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • U is selected from O, NR 4 , CR 3 R 4 , CO, and null;
  • W is selected from O 3 NR 4 , CR 3 R 4 , CO 3 and null;
  • X is N or CR 5 ;
  • Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted C I -C O alkyl, an optionally substituted Ci-C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl;
  • R 20 is selected from hydrogen, a substituted alkyl, a substituted aryl, and a substituted heteroaryl;
  • R 21 and R 22 are each independently selected from hydrogen, alkyl, and aryl; or R 21 and R 22 taken together with the nitrogen to which they are attached represent a 5 or 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;
  • the invention provides a compound selected from:
  • the invention provides a compound selected from:
  • a compound of Formula I, II, III, IV, V, or VI is a selective TPO modulator.
  • a compound Formula I 5 II, III, IV, V 5 or VI is a TPO mimic.
  • the invention provides methods for modulating a TPO activity. Certain such methods comprise contacting a cell with one or more compounds of the present invention. Such methods include, but are not limited to, contacting TPO and/or a TPO receptor with one or more compounds of the present invention.
  • the invention provides a method for identifying a compound that is capable of modulating TPO activity comprising: a) contacting a cell capable of a TPO activity with a compound of the present invention; and b) monitoring an effect on the cell.
  • the cell expresses a TPO receptor.
  • the invention provides methods of treating a patient comprising administering to the patient a compound of the present invention.
  • a patient suffers from thrombocytopenia.
  • one or more compounds of the present invention are administered to a patient before, during or after chemotherapy, bone marrow transplantation, and/or radiation therapy.
  • one or more compounds of the invention are administered to a patient suffering from aplastic anemia, bone marrow failure, and/or idiopathic thrombocytopenia.
  • one or more compounds of the present invention are administered to a patient suffering from a disease of the nervous system.
  • one or more compounds of the present invention are administered to a patient suffering from amyotrophic lateral sclerosis, multiple sclerosis, or multiple dystrophy. In certain embodiments, one or more compounds of the present invention are administered to a patient with a nerve injury, including, but not limited to, a spinal cord injury.
  • the invention provides pharmaceutical compositions comprising: i) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof; and ii) one or more compounds of the present invention.
  • the invention provides a selective TPO modulator. In certain embodiments, the invention provides a selective TPO receptor agonist. In certain embodiments, the invention provides a selective TPO receptor antagonist. In certain embodiments, the invention provides a selective TPO partial agonist. In certain embodiments, the invention provides a selective TPO receptor binding compound. In certain embodiments, the invention provides a TPO mimic.
  • Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen” and "H” are understood to have identical meaning.
  • Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, Hpofection).
  • Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. (1989)), which is incorporated herein by reference in its entirety for any purpose.
  • selective binding compound refers to a compound that selectively binds to any portion of one or more target.
  • selective TPO receptor binding compound refers to a compound that selectively binds to any portion of a TPO receptor.
  • selective binding refers to the ability of a selective binding compound to bind to a target receptor with greater affinity than it binds to a non-target receptor.
  • selective binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, or 1000 times greater than the affinity for a non-target.
  • target receptor refers to a receptor or a portion of a receptor capable of being bound by a selective binding compound.
  • a target receptor is a TPO receptor.
  • modulator refers to a compound that alters an activity.
  • a modulator may cause an increase or decrease in the magnitude of a certain activity compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities.
  • an inhibitor completely prevents one or more biological activities.
  • a modulator is an activator, which increases the magnitude of at least one activity.
  • the presence of a modulator results in a activity that does not occur in the absence of the modulator.
  • selective modulator refers to a compound that selectively modulates a target activity.
  • selective TPO modulator refers to a compound that selectively modulates at least one TPO activity.
  • selective TPO modulator includes, but is not limited to "TPO mimic” which refers to a compound, the presence of which results in at least one TPO activity. TPO mimics are described in WO 03/103686A1 and WO 01/21 180, both of which are incorporated herein by reference in their entirety.
  • selective modulates refers to the ability of a selective modulator to modulate a target activity to a greater extent than it modulates a non-target activity.
  • target activity refers to a biological activity capable of being modulated by a selective modulator.
  • Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, the proliferation and/or differentiation of progenitor cells, generation of platelets, and alleviation of symptoms of a disease or condition.
  • TPO activity refers to a biological activity that results, either directly or indirectly from the presence of TPO.
  • Exemplary TPO activities include, but are not limited to, proliferation and or differentiation of progenitor cells to produce platelets; hematopoiesis; growth and/or development of glial cells; repair of nerve cells; and alleviation of thrombocytopenia.
  • thrombocytopenia refers to a condition wherein the concentration of platelets in the blood of a patient is below what is considered normal for a healthy patient.
  • thrombocytopenia is a platelet count less than 450,000, 400,000, 350,000, 300,000, 250,000, 200,000, 150,000, 140,000, 130,000, 120,000, 110,000, 100,000, 75,000, or 50,000 platelets per microliter of blood.
  • receptor mediated activity refers to any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor.
  • agonist refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor.
  • partial agonist refers to a compound, the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude.
  • alkyl refers to an aliphatic hydrocarbon group.
  • An alkyl may be a "saturated alkyl,” which means that it does not contain any alkene or alkyne groups.
  • An alkyl group may be an "unsaturated alkyl,” which means that it comprises at least one alkene or alkyne group.
  • An alkyl, whether saturated or unsaturated, may be branched or straight chain.
  • Alkyls may be cyclic or non-cyclic.
  • Cyclic alkyls may include multicyclic systemd including fused alkyl rings.
  • Alkyls may be substituted or unsubstituted.
  • Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, each of which may be optionally substituted.
  • an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc.. up to and including 20 carbon atoms, although the term "alkyl” also includes instances where no numerical range of carbon atoms is designated).
  • lower alkyl refers to an alkyl comprising 1 to 5 carbon atoms.
  • intermediate alkyl refers to an alkyl comprising 5 to 10 carbon atoms.
  • An alkyl may be designated as "Cj-C 4 alkyl” or similar designations.
  • C 1 -C 4 alkyl indicates an alkyl having one, two, three, or four carbon atoms, e.g., the alkyl is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t- butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl.
  • alkenyl refers to an alkyl group comprising at least one carbon-carbon double bond.
  • alkynyl refers to an alkyl group comprising at least one carbon-carbon triple bond.
  • haloalkyl refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom. In certain of the embodiments in which two or more hydrogen atom are replaced with halogen atoms, the halogen atoms are all the same as one another. In certain of such embodiments, the halogen atoms are not all the same as one another.
  • straight-chain alkoxy refers to a group comprising the formula: -CCH 2 ) P O- wherein p is any integer.
  • Straight-chain alkoxy does not include substituted or branched alkoxy groups.
  • non-straight-chain-alkoxy-heteroalkyl refers to any heteroalkyl that is not a straight-chain alkoxy heteroalkyl.
  • non- straight-chain-alkoxy heteroalkyls include, but are not limited to: 2,2-isopropyloxy; 1,2- propyloxy; 1,1-ethyloxy; methylamino; ethylamino; propylamino; methylpyrrolidino; and methylpiperidino.
  • heterohaloalkyl refers to a heteroalkyl in which at least one hydrogen atom is replaced with a halogen atom.
  • Carbocycle refers to a group comprising a covalently closed ring, wherein each of the atoms forming the ring is a carbon atom.
  • Carbocylic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms.
  • Carbocycles may be optionally substituted.
  • heterocycle refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a heteroatom.
  • Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms). In heterocyclic rings comprising two or more heteroatoms, those two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted.
  • Binding to a heterocycle can be at a heteroatom or via a carbon atom.
  • binding for benzo-fused derivatives may be via a carbon of the benzenoid ring.
  • heterocycles include, but are not limited to the following:
  • D, E, F, and G independently represent a heteroatom.
  • Each of D, E, F, and G may be the same or different from one another.
  • heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same as one another, or some or all of the two or more heteroatoms may each be different from the others.
  • aromatic refers to a group comprising a covalently closed ring having a delocalized ⁇ -electron system.
  • Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms.
  • Aromatics may be optionally substituted. Examples of aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.
  • aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a Ci -6 alkoxy, a Ci ⁇ alkyl, a Ci -6 hydroxyalkyl, a Ci- 6 aminoalkyl, a Ci_ 6 alkylamino, an alkylsulfenyl, an alkylsulf ⁇ nyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl.
  • an aromatic group is substituted at one or more of the para, meta, and/or ortho positions.
  • aromatic groups comprising substitutions include, but are not limited to, phenyl, 3-halophenyl, 4- halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3- methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4- trifluoromethoxypheny], 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4- morpholin-4-ylphenyl, 4-pyrrolidin-l-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin- 1 -yl)pheny
  • aryl refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom.
  • Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
  • Aryl groups may be optionally substituted.
  • heteroaryl refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C 3 -8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms.
  • heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci- 6 -alkoxy, Ci-6-alkyl, Ci-6- hydroxyalkyl, Ci ⁇ -aminoalkyl, Ci -6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl.
  • substituents independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci- 6 -alkoxy, Ci-6-alkyl, Ci-6- hydroxyalkyl, Ci ⁇ -aminoalkyl, Ci -6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamo
  • heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1 ,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthal
  • non-aromatic ring refers to a group comprising a covalently closed ring that does not have a delocalized ⁇ -electron system.
  • cycloalkyl refers to a group comprising a non-aromatic ring wherein each of the atoms forming the ring is a carbon atom. Cycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Cycloalkyls may include multicyclic systems (e.g., fused ring systems). Cycloalkyls may be optionally substituted. In certain embodiments, a cycloalkyl comprises one or more unsaturated bonds.
  • cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, and cycloheptene.
  • non-aromatic heterocycle refers to a group comprising a non-aromatic ring wherein one or more atoms forming the ring is a heteroatom.
  • Non- aromatic heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms.
  • Non-aromatic heterocycles may be optionally substituted.
  • non-aromatic heterocycles comprise one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
  • non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4/f-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1 ,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1 ,3-oxathiane, 1,4-oxathiin, 1 ,4-oxathiane, tetrahydro-l,4-thiazine, 2/f-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, cycl
  • arylalkyl refers to a group comprising an aryl group bound to an alkyl group.
  • Carbocycloalkyl refers to a group comprising a carbocyclic cycloalkyl ring. Carbocycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycloalkyl groups may be optionally substituted.
  • Ring refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings may be optionally substituted. Rings may form part of a ring system. [0061] The term “ring system” refers to a either a single ring or two or more rings, wherein, if two or more rings are present, the two or more of the rings are fused. The term “fused” refers to structures in which two or more rings share one or more bonds.
  • carboxylic acid bioisostere refers to a group that is biologically equivalent to a carboxylic acid.
  • carboxylic acid bioisosteres include, but are not limited to, tetrazole, NHSO 2 R 15 , OC(S)NR 10 R 11 , SC(O)NR 10 R 11 , thiazolidinedione, oxazolidinedione, and l-oxa-2,4-d ⁇ azolidine-3 5 5-dione.
  • a carboxylic acid bioisoster comprises the following structure:
  • A, B, and C are each independently selected from O, S, and N.
  • spacer refers to an atom or group of atoms that separate two or more groups from one another by a desired number of atoms. For example, in certain embodiments, it may be desirable to separate two or more groups by one, two, three, four, five, six, or more than six atoms. In such embodiments, any atom or group of atoms may be used to separate those groups by the desired number of atoms. Spacers are optionally substituted. In certain embodiments, a spacer comprises saturated or unsaturated alkyls, heteroalkyls and/or haloalkyls. In certain embodiments, a spacer comprises atoms that are part of a ring.
  • spacers are provided.
  • 1 atom spacers include, but are not limited to, the following:
  • a and B represent groups which are separated by the desired number of atoms.
  • 2 atom spacers include, but are not limited to, the following:
  • a and B represent groups which are separated by the desired number of atoms.
  • Examples of 3 atom spacers include, but arc not limited to, the following: where A and B represent groups which are separated by the desired number of atoms. As is evident from the above examples, the atoms that create the desired separation may themselves be part of a group. That group may be, for example, an alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, or substituted alkyl all of which are optionally substituted.
  • the term "1- 5 atom spacer" refers to a spacer that separates two groups by 1, 2, 3, 4, or 5 atoms and does not indicate the total size of the group that constitutes the spacer.
  • the term "linked to form a ring” refers to instances where two atoms that are bound either to a single atom or to atoms that are themselves ultimately bound, are each bound to a linking group, such that the resulting structure forms a ring. That resulting ring comprises the two atoms that are linked to form a ring, the atom (or atoms) that previously linked those atoms, and the linker. For example, if A and B below are "linked to form a ring"
  • the resulting ring includes A, B, C, and a linking group. Unless otherwise indicated, that linking group may be of any length and may be optionally substituted.
  • resulting structures include, but are not limited to:
  • the two substituents that together form a ring are not immediately bound to the same atom.
  • the resulting ring comprises A, B, the two atoms that already link A and B and a linking group.
  • Examples of resulting structures include, but are not limited to:
  • the atoms that together form a ring are separated by three or more atoms. For example, if A and B, below, are linked to form a ring:
  • the resulting ring comprises A, B, the 3 atoms that already link A and B, and a linking group.
  • Examples of resulting structures include, but are not limited to:
  • nuclear refers to a group being absent from a structure.
  • R V R" example, in the structure ⁇ ⁇ , where in certain instances X is N, if X is N, one of R* or R" is null, meaning that only three groups are bound to the N.
  • R refers to a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).
  • C-carboxy refers to a group of formula -C(O)OR.
  • cyano refers to a group of formula -CN.
  • isocyanato refers to a group of formula -NCO.
  • thiocyanato refers to a group of formula -CNS.
  • isothiocyanato refers to a group of formula -NCS.
  • trimethanesulfonamido refers to a group of formula
  • dihydropyrazolylene refers to a di-radical of an optionally substituted dihydropyrazole ring, wherein the dihydropyrazole ring has the structure:
  • pyrazolyl refers to a radical of a pyrzole ring, wherein the pyrzole ring has the structure:
  • esters refers to a chemical moiety with formula -(R) n -COOR', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon), where n is 0 or 1.
  • amide refers to a chemical moiety with formula -(R) n -C(O)NHR' or -(R) n -NHC(O)R', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1.
  • R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1.
  • an amide may be an amino acid or a peptide.
  • amine include such groups that have been esterified or amidified. Procedures and specific groups used to achieve esterification and amidification are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.
  • the term "optionally substituted,” refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from: alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non- aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,
  • carrier refers to a compound that facilitates the incorporation of another compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • pharmaceutical agent refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a patient.
  • a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect.
  • a pharmaceutical agent comprises a prodrug.
  • a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like.
  • terapéuticaally effective amount refers to an amount of a pharmaceutical agent sufficient to achieve a desired therapeutic effect.
  • prodrug refers to an pharmaceutical agent that is converted from a less active form into a corresponding more active form in vivo.
  • pharmaceutically acceptable refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient.
  • co-administer refers to administering more than one pharmaceutical agent to a patient.
  • co-administered pharmaceutical agents are administered together in a single dosage unit.
  • co-administered pharmaceutical agents are administered separately.
  • co-administered pharmaceutical agents are administered at the same time.
  • co-administered pharmaceutical agents are administered at different times.
  • patient includes human and animal subjects.
  • substantially pure means an object species ( . e.g., compound) is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition).
  • a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all species present.
  • a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all species present in the composition.
  • the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single species.
  • tissue-selective refers to the ability of a compound to modulate a biological activity in one tissue to a greater or lesser degree than it modulates a biological activity in another tissue.
  • the biological activities in the different tissues may be the same or they may be different.
  • the biological activities in the different tissues may be mediated by the same type of target receptor.
  • a tissue-selective compound may modulate receptor mediated biological activity in one tissue and fail to modulate, or modulate to a lesser degree, receptor mediated biological activity in another tissue type.
  • the term "monitoring” refers to observing an effect or absence of any effect. In certain embodiments, one monitors cells after contacting those cells with a compound of the present invention. Examples of effects that may be monitored include, but are not limited to, changes in cell phenotype, cell proliferation, receptor activity, or the interaction between a receptor and a compound known to bind to the receptor.
  • cell phenotype refers to physical or biological characteristics. Examples of characteristics that constitute phenotype included, but are not limited to, cell size, cell proliferation, cell differentiation, cell survival, apoptosis (cell death), or the utilization of a metabolic nutrient (e.g., glucose uptake). Certain changes or the absence of changes in cell phenotype are readily monitored using techniques known in the art.
  • cell proliferation refers to the rate at which cells divide.
  • cells are in situ in an organism.
  • cell are grown in vitro in a vessel.
  • the number of cells growing in a vessel can be quantified by a person skilled in the art (e.g., by counting cells in a defined area using a microscope or by using laboratory apparatus that measure the density of cells in an appropriate medium).
  • One skilled in that art can calculate cell proliferation by determining the number of cells at two or more times.
  • contacting refers to bringing two or more materials into close enough proximity that they may interact. In certain embodiments, contacting can be accomplished in a vessel such as a test tube, a petri dish, or the like. In certain embodiments, contacting may be performed in the presence of additional materials. In certain embodiments, contacting may be performed in the presence of cells. In certain of such embodiments, one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact. Certain compounds [0111] Certain compounds that modulate one or more TPO activity and/or bind to TPO receptors play a role in health. In certain embodiments, compounds of the present invention are useful for treating any of a variety of diseases or conditions.
  • the present invention provides selective TPO modulators.
  • the invention provides selective TPO receptor binding agents.
  • the invention provides methods of making and methods of using selective TPO modulators and/or selective TPO receptor binding agents.
  • selective TPO modulators are agonists, partial agonists, and/or antagonists for the TPO receptor.
  • the present invention relates to compounds of Formula I, IL III, IV, V, or VI:
  • R 1 is selected from hydrogen, halogen, OR 14 ,
  • carboxylic acid bioisostere is selected from tetrazole, NHSO 2 R 19 , OC(S)NR 14 R 15 , SC(O)NR 14 R 15 , and wherein A, B, and C are each independently selected from O, S, and N.
  • each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , an optionally substituted C]-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl.
  • R 3 and R 4 are independently selected from hydrogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl.
  • R 5 is selected from a group of hydrogen, halogen, OR 14 , Cj-C 6 alkyl, Ci-C 6 haloalkyl, C 1 -C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl.
  • R 6 is selected from an optionally substituted Ci-Cio alkyl, an optionally substituted C]-Ci 0 haloalkyl, or an optionally substituted Q- CiQ heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R 6 is (CH 2 ) rn R 18 or C(O)NHR 18 .
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere.
  • the carboxylic bioisostere is selected from tetrazole, NHSO 2 R 19 , OC(S)NR 14 R 15 , SC(O)NR 14 R 15 , and
  • each R 8 and each R 9 is independently selected from hydrogen, OR 16 , NR 16 R 17 , an optionally substituted Ci-C 6 alky], an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Cj-C 6 heteroalkyl, (CH 2 ) m R l s , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -C 8 ring.
  • R 10 is selected from hydrogen, halogen, oxo, OR 16 , NR 16 R 17 , SR 16 , an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci- C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl.
  • R 1 ' is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , and SR 14 .
  • R 1 1 and R 4 are linked to form a optionally substituted heterocycle.
  • R 12 is selected from hydrogen, halogen, C r C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and C 1 -C 6 haloheteroalkyl.
  • R 13 is selected from hydrogen, halogen, CN, NO 2 , CO 2 R 14 , S(O) 1n R 14 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 heteroalkyl, and C 1 -C 4 haloheteroalkyl.
  • R 14 is selected from hydrogen, CpC 6 alkyl, C]-Ce haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl.
  • R 15 is selected from hydrogen, SO 2 R 19 , C 1 -C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and C 1 -C 6 heterohaloalkyl.
  • R 16 and R 17 are each independently selected from hydrogen, an optionally substituted Cj-C 6 alkyl, an optionally substituted C]-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, and (CH 2 ) m R 18 .
  • one of R 16 and R 17 is an optionally substituted C 2 -C 6 alkyl and the other of R 16 and R 17 is null.
  • R 16 and R 17 are linked to form an optionally substituted C 3 -C 8 ring.
  • R 18 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R ]8 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system.
  • R 19 is selected from hydrogen, C1-C 3 alkyl, C 1 -C 3 haloalkyl, and an optionally substituted aryl.
  • D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle.
  • E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle.
  • L is NH or null.
  • Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle.
  • U is selected from O 5 NR 4 , CR 3 R 4 , CO, and null.
  • W is selected from O, NR 4 , CR 3 R 4 , CO, and null.
  • X is N or CR 5 .
  • Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-Ce alkyl, an optionally substituted Ci -Ce heteroalkyl, an optionally substituted phenyl, and an optionally substituted
  • I is not pyrazolyl or optionally substituted 5-hydroxypyrazolyl, and (iv) U is not NH. In certain embodiments, if X is N and W is NH, then D is not phenyl.
  • Z is selected from null, a 2-5 atom spacer selected from an optionally substituted C 6 -C I O aryl and an optionally substituted Ci-C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycie or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Ci-Qs alkyl, an optionally substituted CrC 6 heteroalkyl, and an optionally substituted Cj-C 6 haloalkyl, each optionally fused with an optionally substituted Ce-C io aryl.
  • n is 0, 1, or 2. In certain embodiments, m is 0, 1 , 2, or 3.
  • n is 0 or 1.
  • R 6 , R 10 , and R 11 do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
  • the identities of those two or more particular groups are selected independently and, thus, may be the same or different from one another.
  • certain compounds of the invention comprise two or more R 14 groups.
  • the identities of those two or more R 14 groups are each selected independently.
  • those R 14 groups are all the same as one another; in certain embodiments, those R 14 groups are all different from one another; and in certain embodiments, some of those R 14 groups are the same as one another and some are different from one another. This independent selection applies to any group that is present in a compound more than once.
  • a compound of Formula I, II, III, IV, V, or VI is a selective TPO modulator.
  • a compound of Formula I, II, III, IV, V, or VI is a selective TPO receptor agonist. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective TPO receptor antagonist. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective TPO receptor partial agonist. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a tissue-specific selective TPO modulator. In certain embodiments, a compound of Formula I, II, HI, IV, V, or VI is a selective TPO receptor binding compound. In certain embodiments, a compound Formula I, II, III, IV, V, or VI is a TPO mimic.
  • the invention provides compounds selected from:
  • Certain compounds of the present inventions may exist as stereoisomers including optical isomers.
  • the present disclosure is intended to include all stereoisomers and both the racem ⁇ c mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are known in the art or that may be excluded by synthesis schemes known in the art designed to yield predominantly one enantiomer relative to another.
  • Scheme IH is a multi-step synthetic sequence that commences with the copper catalyzed cross-coupling of an oxindole such as structure 7 and an aryl or alkyl bromide to provide an N-substituted oxindole of structure 8. This is then converted into the structure 10 via reaction with either dimethylformamide dimethylacetal (or equivalent) or triethylorthoformate. This is then reacted with an amine to give the structure 11.
  • U R" may be present 0, 1, 2, or 3 times and each R is independently selected from the groups in the "optionally substituted" definition provided above.
  • Scheme VIII is a multi-step synthetic sequence that commences with enamine or enol ether formation of an iV-substituted oxindole of structure 25 or its analogs. This is then converted into the structure 27 via reaction with an amine partner.
  • R may be present 0, 1 , 2, or 3 times and each R is independently selected from the groups in the "optionally substituted" definition provided above.
  • the invention provides a salt corresponding to a selective TPO modulator.
  • the invention provides a salt corresponding to a selective TPO receptor binding agent.
  • a salt is obtained by reacting a compound with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • a salt is obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as choline, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)rnethylarnine, 4-(2- hydroxyethyl)-morpholine, l-(2-hydroxyethyl)-pyrrolidine, ethanolamine and salts with amino acids such as arginine, lysine, and the like.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as choline, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)
  • a salt is obtained by reacting a free acid form of a selective TPO modulator or selective TPO binding agent with multiple molar equivalents of a base, such as b ⁇ s-sodium, bis- ethanolamine, and the like.
  • a salt corresponding to a compound of the present invention is selected from acetate, ammonium, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, cholinate., clavulanate, citrate, dihydrochloride, diphosphate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabanine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mucate, napsylate, nitrate, N-methylglucamine, oxalate
  • one or more carbon atoms of a compound of the present invention are replaced with silicon. See e.g., WO 03/037905 Al; Tacke and Zilch, Endeavour, New Series, 10, 191-197 (1986); Bains and Tacke, Curr. Opin. Drug Discov Devel. Jul:6(4):526-43(2003), all of which are incorporated herein by reference in their entirety.
  • compounds of the present invention comprising one or more silicon atoms possess certain desired properties, including, but not limited to, greater stability and/or longer half-life in a patient, when compared to the same compound in which none of the carbon atoms have been replaced with a silicon atom.
  • assays may be used to determine the level of TPO modulating activity of the compounds of the present invention.
  • the potency of the compounds of the present invention as selective TPO modulators may be determined in a luciferase assay, such as those described in Lamb, et al., Nucleic Acids Research, 23: 3283-3289(1995) and/or Seidel et al., Proc. Nat. Acad. Sci. USA; 92: 3041- 3045 (1995), both of which are incorporated herein by reference in their entirety.
  • Techniques for formulation and administration of compounds of the present invention may be found for example, in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990, which is incorporated herein by reference in its entirety.
  • a pharmaceutical agent comprising one or more compounds of the present invention is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • a pharmaceutical agent comprising one or more compounds of the present invention is a liquid (e.g., a suspension, elixir and/or solution).
  • a liquid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • a pharmaceutical agent comprising one or more compounds of the present invention is a solid (e.g., a powder, tablet, and/or capsule).
  • a solid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a depot preparation.
  • Certain such depot preparations are typically longer acting than non-depot preparations.
  • such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises a delivery system.
  • delivery systems include, but are not limited to, liposomes and emulsions.
  • Certain delivery systems are useful for preparing certain pharmaceutical agents including those comprising hydrophobic compounds.
  • certain organic solvents such as dimethyl sulfoxide are used.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises one or more tissue-specific delivery molecules designed to deliver the pharmaceutical agent to specific tissues or cell types.
  • pharmaceutical agents include liposomes coated with a tissue-specific antibody.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises a co-solvent system.
  • co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water- miscible organic polymer, and an aqueous phase.
  • co- solvent systems are used for hydrophobic compounds.
  • VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM , and 65% w/v polyethylene glycol 300.
  • co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
  • identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises a sustained-release system.
  • a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers.
  • sustained-release systems may, depending on their chemical nature, release compounds over a period of hours, days, weeks or months.
  • Certain compounds used in pharmaceutical agent of the present invention may be provided as pharmaceutically acceptable salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises an active ingredient in a therapeutically effective amount.
  • the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
  • a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a prodrug.
  • prodrugs are useful because they are easier to administer than the corresponding active form.
  • a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form.
  • a prodrug may have improved solubility compared to the corresponding active form.
  • a prodrug is an ester.
  • such prodrugs are less water soluble than the corresponding active form.
  • such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility.
  • the ester in such prodrugs is metabolically hydrolyzed to carboxylic acid.
  • the carboxylic acid containing compound is the corresponding active form.
  • a prodrug comprises a short peptide (polyaminoacid) bound to an acid group.
  • the peptide is metabolized to form the corresponding active form.
  • a pharmaceutical agent comprising one or more compounds of the present invention is useful for treating a conditions or disorder in a mammalian, and particularly in a human patient.
  • Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous).
  • pharmaceutical intrathecals are administered to achieve local rather than systemic exposures.
  • pharmaceutical agents may be injected directly in the area of desired effect (e.g., in the renal or cardiac area).
  • a pharmaceutical agent comprising one or more compounds of the present invention is administered in the form of a dosage unit (e.g., tablet, capsule, bolus, etc.).
  • dosage units comprise a selective TPO modulator in a dose from about 1 ⁇ g/kg of body weight to about 50 mg/kg of body weight.
  • dosage units comprise a selective TPO modulator in a dose from about 2 ⁇ g/kg of body weight to about 25 mg/kg of body weight.
  • such dosage units comprise a selective TPO modulator in a dose from about 10 ⁇ g/kg of body weight to about 5 mg/kg of body weight.
  • pharmaceutical agents are administered as needed, once per day, twice per day, three times per day, or four or more times per day. It is recognized by those skilled in the art that the particular dose, frequency, and duration of administration depends on a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the pharmaceutical agent.
  • a pharmaceutical agent comprising a compound of the present invention is prepared for oral administration.
  • a pharmaceutical agent is formulated by combining one or more compounds of the present invention with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers enable compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
  • pharmaceutical agents for oral use are obtained by mixing one or more compounds of the present invention and one or more solid excipient.
  • Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl -cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • such a mixture is optionally ground and auxiliaries are optionally added.
  • pharmaceutical agents are formed to obtain tablets or dragee cores.
  • disintegrating agents ⁇ e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate) are added.
  • dragee cores are provided with coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to tablets or dragee coatings.
  • pharmaceutical agents for oral administration are push-fit capsules made of gelatin.
  • Such push-fit capsules comprise one or more compounds of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • pharmaceutical agents for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • one or more compounds of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • pharmaceutical agents are prepared for buccal administration. Certain of such pharmaceutical agents are tablets or lozenges formulated in conventional manner.
  • a pharmaceutical agent is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • a pharmaceutical agent comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical agents for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers.
  • Certain pharmaceutical agents for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Certain solvents suitable for use in pharmaceutical agents for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • such suspensions may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • a pharmaceutical agent is prepared for transmucosal administration.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • a pharmaceutical agent is prepared for administration by inhalation.
  • Certain of such pharmaceutical agents for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer.
  • Certain of such pharmaceutical agents comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined with a valve that delivers a metered amount.
  • capsules and cartridges for use in an inhaler or insufflator may be formulated.
  • Certain of such formulations comprise a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.
  • a pharmaceutical agent is prepared for rectal administration, such as a suppositories or retention enema.
  • Certain of such pharmaceutical agents comprise known ingredients, such as cocoa butter and/or other glycerides.
  • a pharmaceutical agent is prepared for topical administration.
  • Certain of such pharmaceutical agents comprise bland moisturizing bases, such as ointments or creams.
  • ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as EucerinTM, available from Beiersdorf (Cincinnati, Ohio).
  • Exemplary suitable cream bases include, but are not limited to, NiveaTM Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose CreamTM, available from Johnson & Johnson (New Brunswick, New Jersey), hydrophilic ointment (USP) and LubridermTM, available from Pfizer (Morris Plains, New Jersey).
  • the formulation, route of administration and dosage for a pharmaceutical agent of the present invention can be chosen in view of a particular patient's condition. (See e.g., Fingl et at 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1 , which is incorporated herein by reference in its entirety).
  • a pharmaceutical agent is administered as a single dose.
  • a pharmaceutical agent is administered as a series of two or more doses administered over one or more days.
  • a pharmaceutical agent of the present invention is administered to a patient between about 0.1% and 500%, 5% and 200%, 10% and 100%, 15% and 85%, 25% and 75%, or 40% and 60% of an established human dosage.
  • a suitable human dosage may be inferred from ED 5 O or ID50 values, or other appropriate values derived from in vitro or in vivo studies.
  • a daily dosage regimen for a patient comprises an oral dose of between 0.1 mg and 2000 mg, 5 mg and 1500 mg, 10 mg and 1000 mg, 20 mg and 500 mg, 30 mg and 200 mg, or 40 mg and 100 mg of a compound of the present invention.
  • a daily dosage regimen is administered as a single daily dose.
  • a daily dosage regimen is administered as two, three, four, or more than four doses.
  • a pharmaceutical agent of the present invention is administered by continuous intravenous infusion. In certain of such embodiments, from 0.1 mg to 500 mg of a composition of the present invention is administered per day.
  • a pharmaceutical agent of the invention is administered for a period of continuous therapy.
  • a pharmaceutical agent of the present invention may be administered over a period of days, weeks, months, or years.
  • Dosage amount, interval between doses, and duration of treatment may be adjusted to achieve a desired effect.
  • dosage amount and interval between doses are adjusted to maintain a desired concentration on compound in a patient.
  • dosage amount and interval between doses are adjusted to provide plasma concentration of a compound of the present invention at an amount sufficient to achieve a desired effect.
  • the plasma concentration is maintained above the minimal effective concentration (MEC).
  • pharmaceutical agents of the present invention are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the lime, between 30-90% of the time, or between 50-90% of the time.
  • the dosage regimen is adjusted to achieve a desired local concentration of a compound of the present invention.
  • a pharmaceutical agent may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • a pharmaceutical agent is in powder form for constitution with a suitable vehicle, e.g. , sterile pyrogen-free water, before use.
  • one or more pharmaceutical agents of the present invention are co-administered with one or more other pharmaceutical agents.
  • such one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical agents of the present invention.
  • such one or more other pharmaceutical agents are designed to treat a different disease or condition as the one or more pharmaceutical agents of the present invention.
  • such one or more other pharmaceutical agents are designed to treat an undesired effect of one or more pharmaceutical agents of the present invention.
  • one or more pharmaceutical agents of the present invention are co-administered with another pharmaceutical agent to treat an undesired effect of that other pharmaceutical agent.
  • one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the different times. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared together in a single formulation. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared separately.
  • Examples of pharmaceutical agents that may be co-administered with a pharmaceutical agent of the present invention include, but are not limited to, anti-cancer treatments, including, but not limited to, chemotherapy and radiation treatment; corticosteroids, including but not limited to prednisone; immunoglobulins, including, but not limited to intravenous immunoglobulin (IVIg); analgesics (e.g., acetaminophen); antiinflammatory agents, including, but not limited to non-steroidal anti-inflammatory drugs (e.g., ibuprofen, COX-I inhibitors, and COX-2, inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (e.g., biguanides, glucosidase inhibitors, insulins, sulfonylureas, and thiazolidenediones); adrenergic modifiers; diuretics; hormones (e.g., anabolic steroids, androg
  • the invention provides methods of treating a patient comprising administering one or more compounds of the present invention.
  • thrombocytopenia results from chemotherapy and/or radiation treatment.
  • thrombocytopenia results bone marrow failure resulting from bone marrow transplantation and/or aplastic anemia.
  • thrombocytopenia is idiopathic.
  • one or more compounds of the present invention are administered to a patient to in conjunction with harvesting peripheral blood progenitor cells and/or in conjunction with platelet apheresis. Such administration may be done before, during, and/or after such harvesting.
  • one or more compounds of the present invention are administered to a patient who suffers from a condition affecting the nervous system, including, but are not limited to, diseases affecting the nervous system and injuries to the nervous system. Such diseases, include, but not limited to, amyotrophic lateral sclerosis, multiple sclerosis, and multiple dystrophy.
  • Damage to the nervous system include, but are not limited to spinal cord injury or peripheral nerve damage, including, but not limited to, injury resulting from trauma or from stroke.
  • one or more compounds of the present invention are used to promote growth and/or development of glial cells. Such glial cells may repair nerve cells.
  • compounds of the present invention are used to treat psychological disorders, including, but not limited to, cognitive disorders.

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Abstract

La présente invention concerne des composés hétérocycliques contenant des amides, des compositions pharmaceutiques comprenant ces composés, des procédés permettant de moduler l'activité d'un récepteur thrombopoïétinique au moyen de ces composés, des procédés permettant d'identifier des composés tels que les modulateurs des récepteurs thrombopoïétiniques, et des procédés permettant de traiter une affection par administration de ces composés à un patient justifiant d'un tel traitement.
PCT/US2006/045129 2005-11-23 2006-11-21 Composes modulant l'activite thrombopoietine et procedes correspondants WO2007062078A2 (fr)

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EP06838225A EP1951667A2 (fr) 2005-11-23 2006-11-21 Composes modulant l'activite thrombopoietine et procedes correspondants
JP2008558985A JP2009519352A (ja) 2005-11-23 2006-11-21 トロンボポエチン活性調節化合物および方法
CA002630234A CA2630234A1 (fr) 2005-11-23 2006-11-21 Composes modulant l'activite thrombopoietine et procedes correspondants
AU2006318527A AU2006318527A1 (en) 2005-11-23 2006-11-21 Thrombopoietin activity modulating compounds and methods
BRPI0620532-1A BRPI0620532A2 (pt) 2005-11-23 2006-11-21 compostos e métodos para modular a atividade de trombopoietina

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US8530508B2 (en) 2007-10-09 2013-09-10 Glaxosmithkline Llc Thrombopoietin receptor agonist (TpoRA) kills acute human myeloid leukemia cells
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AU2006318527A1 (en) 2007-05-31
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EP1951667A2 (fr) 2008-08-06
KR20080080305A (ko) 2008-09-03
JP2009519352A (ja) 2009-05-14
WO2007062078A3 (fr) 2007-12-21
BRPI0620532A2 (pt) 2011-11-16

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