WO2007004038A1 - Dérivés d'aminothiazole servant d'agonistes du récepteur de la thrombopoïétine - Google Patents

Dérivés d'aminothiazole servant d'agonistes du récepteur de la thrombopoïétine Download PDF

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WO2007004038A1
WO2007004038A1 PCT/IB2006/001836 IB2006001836W WO2007004038A1 WO 2007004038 A1 WO2007004038 A1 WO 2007004038A1 IB 2006001836 W IB2006001836 W IB 2006001836W WO 2007004038 A1 WO2007004038 A1 WO 2007004038A1
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thiazol
fluoro
phenyl
trifluoromethyl
ylcarbamoyl
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PCT/IB2006/001836
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English (en)
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Laura Cook Blumberg
Matthew Frank Brown
Michael John Munchhof
Lawrence Alan Reiter
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Pfizer Products Inc.
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Publication of WO2007004038A1 publication Critical patent/WO2007004038A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This disclosure relates to aminothiazole derivatives. More particularly, this disclosure relates to 2-acylaminothiazole derivatives and processes for the preparation of, intermediates used in the preparation of, compositions containing them and the uses of such derivatives.
  • the presently disclosed compounds are agonists of the thrombopoietin (TPO) receptor.
  • TPO mimetics have a number of therapeutic applications, particularly in their use as promoters of thrombopoiesis and megakaryocytopoiesis.
  • Megakaryocytes are bone marrow-derived cells, which are responsible for producing circulating blood platelets. Although comprising ⁇ 0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells. See Kuter et al., Proc. Natl. Acad. Aci. USA, 91: 11104-11108 (1994).
  • Megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polyploid cells.
  • the endomitotic rate increases, higher ploidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold. See Harker, J. Clin. Invest.. 47: 458-465 (1968).
  • the endomitotic rate decreases, lower ploidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%.
  • TPO thrombopoietin
  • TPO has been shown in several studies to increase platelet counts and increase platelet size. Specifically, TPO is thought to affect megakaryocytopoiesis in several ways: (1) it produces increases in megakaryocyte size and number; (2) it produces an increase in DNA content, in the form of polyploidy, in megakaryocytes; (3) it increases megakaryocyte endomitosis; (4) it produces increased maturation of megakaryocytes; and (5) it produces an increase in the percentage of precursor cells, in the form of small acetylcholinesterase-positive cells, in the bone marrow.
  • TPO has potential useful application in both the diagnosis and the treatment of various hematological disorders, for example, diseases primarily due to platelet defects (See Harker et al., Blood, 91 : 4427-4433 (1998)). Ongoing clinical trials with TPO have indicated that TPO can be administered safely to patients (See Basser et al., Blood. 89: 3118-3128 (1997); Fanucchi et al., New Engl. S. Med., 336: 404-409 (1997)).
  • TPO has been cloned and characterized. See Kuter et al., Proc. Natl. Acad. ScL USA. 91 : 11104-11108 (1994): Barley et al.. Cell, 72:1117-1124 (1994): Kaushansky et al., Nature, 369:568-571 (1994); Wendling et al., Nature, 369: 571-574 (1994); and Sauvage et al., Nature, 369: 533-538 (1994).
  • Thrombopoietin is a glycoprotein having at least two forms with apparent molecular masses of 251 kDa and 31 kDa, with a common N-terminal amino acid sequence. See Baatout, Haemostasis, 27: 1-8 (1997); Kaushansky, New Engl. J. Med.. 339: 746-754
  • Thrombopoietin appears to have two distinct regions separated by a potential Arg- Arg cleavage site.
  • the amino-terminal region is highly conserved in man and mouse, and has some homology with erythropoietin and interferon-a and interferon-b.
  • the carboxy- terminal region shows wide species divergence.
  • TPO-R also known as c-mpl
  • TPO-R is a member of the haematopoietin growth factor receptor family, a family characterized by a common structural design of the extracellular domain, including for conserved C residues in the N-terminal portion and a WSXWS motif close to the transmembrane region.
  • TPO-R as a key regulator of megakaryopoiesis is the fact that exposure of CD34 + cells to synthetic oligonucleotides antisense to TPO-R RNA significantly inhibits the appearance of megakaryocyte colonies without affecting erythroid or myeloid colony formation.
  • EP 1 207 155 A1 refers to pharmaceutical compositions exhibiting thrombopoietin receptor agonism containing as an active ingredient compounds of the following formula
  • EP 1 207 155 A1 teaches in part X 1 being an optionally substituted thiazole, Y 1 being - NHCO-, and Z 1 being an optionally substituted arylene. EP 1 207 155 A1, however, does not teach or suggest the presently disclosed substituted pyridyl moiety of presently disclosed Formula I.
  • WO 2005/007651A1 refers to a 2-acylaminothiazole derivative useful in treating thrombopenia of the following formula
  • WO 2005/007651 A1 teaches in part R 1 being preferably cyclic aminos or other secondary amines, A being preferably methylene, R 2 being preferably 4-chlorothiophen-2-yl or 4- methylthiophen-2-yl, and R 3 being preferably pyridine-3-yl substituted at the fifth position by chloro or fluoro and substituted at the sixth position with substituted lower alkyls, optionally substituted piperidin-1-yl or optionally substituted piperazin-1-yl.
  • WO 2005/007651 A1 does not teach or suggest the presently disclosed 5-H substituted aminothiazoles being useful as potent TPO agonists. To the contrary, WO 2005/007651A1 claims the oral activity of its compounds is attributed to the introduction of a lower alkylene having an amino group as the thiazole fifth position substituent.
  • the presently disclosed aminothiazoles are effective as agonists of the TPO receptor.
  • the presently disclosed 5-H substituted aminothiazoles achieve desirable pharmacological properties in addition to being potent TPO agonists.
  • d is 0 or 1 ;
  • X is -O- or R 9 N-, wherein R 9 is H or (C r C 6 )alkyl;
  • R 1 is (CrC 6 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, or (C 2 -C 9 )heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl moieties of (C r C 6 )alkyl, (C 3 - Cio)cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl, or R 9 are independently optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, R 4 (CrC 6 )alkyl, R 4 (CrC 6 )alkoxy, R 4 (C r C 6 )alkoxycarbonyl, R 4 (C r C 6
  • R 5 and R 6 are each (C r C 6 )alkyl optionally independently substituted by (d-CeJalkoxy, hydroxy, carboxy, amino, (C r C 6 )alkylamino, [(CrC6)alkyl] 2 N-, (d-CeJalkylthio, (C 1 - C 6 )alkylsulfinyl, (CrC 6 )alkylsulfonyl or aminocarbonyl; or R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 4 to 8 membered ring wherein the 6 to 8 membered rings optionally contain one to three members selected from the group consisting of O, S, S(O), S(O) 2 , NH and ((C r C 6 )alkyl)-N-; and the ring so formed is optionally substituted by (C 1 -C 6 JaIkOXy, hydroxy, carboxy, amino, (C 1 - C 6 )
  • R 2 is R 7 (C 6 -C 10 )aryl or R 7 (C 2 -C 9 )heteroaryl; wherein R 7 is one to three groups selected from hydrogen, halo, cyano, nitro, carboxy, hydroxy, amino, aminocarbonyl, R 8 (C 1 -C 6 )alkyl, R 8 (C 3 -C 10 )cycloalkyl, R 8 (CrC 6 )alkoxy, R 8 (C 1 -C 6 )alkoxycarbonyl, R 8 (C 1 -C 6 )alkylthio, R 8 (C r C 6 )alkylsulfinyl, R 8 (C r C 6 )alkylsulfonyl, R 8 (C r C 6 )alkylaminosulfonyl, R 8 (C r C 6 )alkylsulfonylamino, R 8 (C r C 6 )alkylamino, R 8 (C
  • R 1 is (C r C 6 )a ⁇ Wy ⁇ optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, R 4 (C 1 -C 6 )alkyl, R 4 (CrC 6 )alkoxy, R 4 (C r C 6 )alkoxycarbonyl, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (C r C 6 )alkylaminosulfonyl, R 4 (C r C 6 )alkylsulfonylamino, R 4 (C r C 6 )alkylamino, R 4 (C r C 6 )alkylamino, R 4 (C r C 6 )alkylcarbox
  • R 5 and R 6 are each (CrQ ⁇ alkyl optionally independently substituted by (CrC 6 )alkoxy, hydroxy, carboxy, amino, (CrCeJalkylamino, [(Ci-C 6 )alkyl] 2 N-, (CrC 6 )alkyIthio, (C 1 - C 6 )alkylsulfinyl, (Ci-C 6 )alkylsulfonyl or aminocarbonyl; or R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 4 to 8 membered ring wherein the 6 to 8 membered rings optionally contain one to three members selected from the group consisting of O, S, S(O), S(O) 2 , NH and ((CrC 6 )alkyl)-N-; and the ring so formed is optionally substituted by (CrC 6 )alkoxy, hydroxy, carboxy, amino, (C 1 - C 6 )alkyla
  • d is 0 and R 1 is (C 3 - C 10 )cycloalkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, R 4 (C r C 6 )alkyl, R 4 (C r C ⁇ )alkoxy, R 4 (C,-C 6 )alkoxycarbonyl, R 4 (C r C 6 )alkylthio, R 4 (CrC 6 )aIkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (C r C 6 )aIkylsulfonylamino, R 4 (C r C 6 )alkylamino, R 4 (CrC 6 )a!kylcarboxy, R 4 (CrC 6 )alkylaminocarbony
  • R 1 is (C 2 - Cg)heterocycloalkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, R 4 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C r C 6 )alkoxycarbonyl, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (C r C 6 )alkylaminosulfonyl, R 4 (C r C 6 )alkylsulfonylamino, R 4 (C r C 6 )alkylamino, R 4 (Cr C 6 )alkylamino, R 4 (CrC 6 )alkylalky
  • R 5 and R 6 are each (CrCeJalkyl optionally independently substituted by (CrC 6 )alkoxy, hydroxy, carboxy, amino, (CrCeJalkylamino, [(C r C 6 )alkyl] 2 N-, (Ci-C 6 )alkylthio, (C 1 - C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl or aminocarbonyl; or R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 4 to 8 membered ring wherein the 6 to 8 membered rings optionally contain one to three members selected from the group consisting of O, S, S(O), S(O) 2 , NH and ((C r C 6 )alkyl)-N-; and the ring so formed is optionally substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino, (C 1 - C B
  • C 9 heteroaryl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, R 4 (Ci-C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C r C 6 )alkoxycarbonyl, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (C r C 6 )alkylaminosulfonyl, R 4 (CrC 6 )alkylsulfonylamino, R 4 (C r C 6 )alkylamino, R 4 (C r C 6 )alkylamino, R 4 (C r C 6 )alkylcarboxy, R 4 (Ci-C 6
  • R 5 and R 6 are each (C r C 6 )alkyl optionally independently substituted by (C 1 -C 6 JaIkOXy, hydroxy, carboxy, amino, (CrCeJalkylamino, [(CrC 6 )alkyl] 2 N-, (CrCeJalkylthio, (C-,- C 6 )alkylsulfinyl, (C r C 6 )alkylsulfonyl or aminocarbonyl; or R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 4 to 8 membered ring wherein the 6 to 8 membered rings optionally contain one to three members selected from the group consisting of O, S, S(O), S(O) 2 , NH and ((CrC 6 )alkyl)-N-; and the ring so formed is optionally substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino, (C 1 - C 6
  • d is 1
  • X is -O-
  • R 1 is (C 1 - C 6 )alkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, R 4 (C 1 -C 6 )alkyl, R 4 (C r C 6 )alkoxy, R ⁇ d-Cejalkoxycarbonyl, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (CrC 6 )alkylaminosulfonyl, R 4 (C 1 -C 6 )alkylsulfonylamino, R 4 (C r C 6 )alkylamino, R 4 (Cr C 6 )alkylamino, R 4 (Cr
  • d is 1
  • X is R 9 N- wherein R 9 is H -
  • R 1 is (CrC 6 )alkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, R 4 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (d-C ⁇ )alkylsulfinyl.
  • R 5 and R 6 are each (C r C 6 )alkyl optionally independently substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino, (CrC 6 )alkylamino, [(Ci-C 6 )alkyl] 2 N-, (C 1 -C 6 )alkylthio, (C 1 - C 6 )alkylsulfinyl, (CrC 6 )alkylsulfonyl or aminocarbonyl; or R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 4 to 8 membered ring wherein the 6 to 8 membered rings optionally contain one to three members selected from the group consisting of O, S, S(O), S(O) 2 , NH and ((C 1 -C 6 )alkyl)-N-; and the ring so formed is optionally substituted by (C 1 -C 6 JaIkOXy, hydroxy, carboxy, amino, (
  • R 1 is (C r C 6 )alkyl, wherein the alkyl moiety of (CrC 6 )alkyl or R 9 is independently optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, R 4 (C 1 -C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C r C 6 )alkoxycarbonyl, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (CrC 6 )alkylaminosulfonyl, R 4 (C r C 6 )alkylsulfonylamino, R 1 ⁇ (C 1 -
  • R 5 and R 6 are each (CrCeJalkyl optionally independently substituted by (CrC 6 )alkoxy, hydroxy, carboxy, amino, (CrCeOaikylamino, [(C 1 -C 6 )alkyl] 2 N-, (C 1 -C 6 )alkylthio, (C 1 - C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl or aminocarbonyl; or R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 4 to 8 membered ring wherein the 6 to 8 membered rings optionally contain one to three members selected from the group consisting of O, S, S(O), S(O) 2 , NH and ((CrC 6 )alkyl)-N-; and the ring so formed is optionally substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino, (C 1 -
  • d is 1
  • X is -0-
  • R 1 is (C 3 - C 10 )cycloalkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, R 4 (d-C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C 1 -C 6 )alkoxycarbonyl, R 4 (C r C 6 )alkylthio, R 4 (C 1 -C 6 )alkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (C 1 -C 6 )alkylaminosulfonyl, R 4 (CrC 6 )alkylsulfonylamino, R 4 (C r C 6 )alkylamino, R 4 (C r C 6 )alkylamino,
  • R 1 is (C 3 -C 10 )cycloalkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, R 4 (d- C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (d-C 6 )alkoxycarbonyl, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (C 1 -C 6 )alkylaminosulfonyl, R 4 (C 1 -C 6 )alkylsulfonylamino, R 4 (C r C 6 )alkylamino, R 4 (d-C 6 )alkylcarboxy, R 4 (C 1 -C 6 )
  • R 5 and R 6 are each (d-C 6 )alkyl optionally independently substituted by (CrC 6 )alkoxy, hydroxy, carboxy, amino, (d-dOalkylamino, [(CrC 6 )alkyl] 2 N-, (CrC 6 )alkylthio, (C 1 - C 6 )alkylsulfinyl, (C r C 6 )alkylsulfonyl or aminocarbonyl; or R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 4 to 8 membered ring wherein the 6 to 8 membered rings optionally contain one to three members selected from the group consisting of O, S, S(O), S(O) 2 , NH and ((C r C 6 )alkyl)-N-; and the ring so formed is optionally substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino, (C 1 - C 6 )al
  • d is 1
  • X is R 9 N- wherein R 9 is (C r C 6 )alkyl
  • R 1 is (C 3 -C 10 )cycloalkyl
  • the alkyl or cycloalkyl moieties of (C 3 - C 10 )cycloalkyl or R 9 are independently optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, R 4 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C r C 6 )alkoxycarbonyl, R 4 (C r C 6 )alkylthio, R 4 (CrC6)alkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (C r C 6 )alkylami
  • R 5 and R 6 are each (CrC 6 )alkyl optionally independently substituted by (CrC ⁇ alkoxy, hydroxy, carboxy, amino, (CrQOalkylamino, [(C r C 6 )alkyl] 2 N-, (C r C 6 )alkylthio, (C 1 - C 6 )alkylsulfinyl, (C r C 6 )alkylsulfonyl or aminocarbonyl; or R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 4 to 8 membered ring wherein the 6 to 8 membered rings optionally contain one to three members selected from the group consisting of O, S, S(O), S(O) 2 , NH and ((C r C 6 )alkyl)-N-; and the ring so formed is optionally substituted by (C 1 -C 6 )BIkOXy, hydroxy, carboxy, amino, (C 1 - C 6
  • C 6 )alkyl aminocarbonyl-O-, aminotCrC ⁇ alkoxycarbonyl, R 4 (C 1 -C 6 )alkylaminocarbonyl-O-, R 4 (C 1 -C 6 )alkylamino(C 1 -C 6 )alkoxycarbonyl, R 4 (CrC 6 )alkoxycarbonylamino, R 4 (C r
  • R 5 and R 6 are each (C 1 -C 6 JaIk ⁇ optionally independently substituted by (Ci-C 6 )alkoxy, hydroxy, carboxy, amino, (CrCeJalkylamino, [(CrC 6 )alkyl] 2 N-, (CrC 6 )alkylthio, (C 1 -
  • R 3 is halo, cyano, nitro, carboxy, hydroxy, amino, aminocarbonyl, trifluoromethoxy, HF 2 C-O-, (C 3 -C 10 )cycloalkyl, R 4 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy,
  • R 4 (CrC 6 )alkylamino, trifluoromethyl, wherein R 4 is one to three groups selected from hydrogen, (C r C 6 )alkoxy, hydroxy, carboxy, HO 3 S-, amino, (C 1 -C 6 )alkylamino, R 5 R 6 N-, (CrC 6 )alkylthio, (CrCeJalkylsulfinyl, (C 1 - C 6 )alkylsulfonyl or aminocarbonyl;
  • R 5 and R 6 are each (C r C 6 )alkyl optionally independently substituted by (C 1 -C 6 JaIkOXy, hydroxy, carboxy, amino, (CrCeJalkylamino, [(CrC 6 )alkyl] 2 N-, (Ci-C 6 )alkylthio, (C 1 -
  • variable R 1 is directly bonded to the main structure, notably a pyridyl ring carbon atom. That is, when d is 0, R 1 is not linked to the pyridyl ring by an atom, node, or linkage point other than a pyridyl ring carbon atom, but rather is directly bonded to the pyridyl ring. As such, when d is 0, compounds of Formula I will have the following general structure:
  • R 9 N- wherein R 9 is (C r C 6 )alkyl
  • the alkyl moiety of R 9 can be substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO 3 S-, amino, aminocarbonyl, aminosulfonyl, R 4 (C 1 -C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (CrC ⁇ )alk ⁇ xyca ⁇ tonyl, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (CrC 6 )alkylaminosulfonyl, R 4 (CrC 6 )alkylcarbonyl
  • R 1 is (C 2 -C 9 )heterocycloalkyl optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO 3 S-, aminosulfonyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 4 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylamino and R 4 (C 1 -C 6 )alkoxy(C 1 -C 6 )alkylamino, wherein R 4 is as defined above.
  • R 2 is R 7 -phenyl or R 7 -pyridinyl, wherein R 7 is as defined above.
  • R 1 is (C 2 -C 9 )heterocycloalkyl optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO 3 S-, aminosulfonyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 4 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C 1 -C 6 )alkylthio, R 4 (C r C 6 )alkylamino and R 4 (C 1 -C 6 )alkoxy(C 1 -C 6 )alkylamino; and R 2 is R 7 -phenyl or R 7 -pyridinyl, wherein R 4 and R 7 are as defined above.
  • R 1 is pyrrolidinyl, piperidinyl or piperazinyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO 3 S-, aminosulfonyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 4 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylamino and C 6 )alkylamino, wherein R 4 is as defined above.
  • R 1 is pyrrolidinyl, piperidinyl or piperazinyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO 3 S-, aminosulfonyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 4 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylamino and R 4 (C 1 -C 6 )alkoxy(C 1 - C 6 )alkylamino; and R 2 is R 7 -phenyl or R 7 -pyridinyl, wherein R 4 and R 7 are as defined above.
  • R 1 is pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, piperidinyl, piperazinyl, or 1 ,4-dioxanyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO 3 S-, aminosulfonyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 4 (C r C 6 )alkyl, R 4 (C r
  • R 4 is as defined above; and R 2 is R 7 -phenyl or R 7 -pyridinyl, and wherein R 7 is as defined above.
  • R 2 is R 7 -phenyl or R 7 -pyridinyl, wherein R 7 is selected from the group consisting of: cyano, halo, hydroxy, amino, R 8 (C r C 6 )alkyl, R 8 (C r C 6 )alkoxy, R 8 (C r C 6 )alkylthio, R 8 (C 3 -C 10 )cycloalkyl, trifluoromethyl and trifluoromethoxy, and wherein R 8 is as defined above.
  • R 3 is hydrogen, halo, cyano, nitro, hydroxy, trifluoromethoxy, HF 2 C-O- or trifluoromethyl.
  • R 1 is pyrrolidinyl, piperidinyl or piperazinyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO 3 S-, aminosulfonyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 4 CC 1 - C 6 )alkyl, R 4 (C 1 -C 6 )alkoxy, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylamino and R 4 (C r C 6 )alkoxy(Cr C 6 )alkylamino; and R 3 is hydrogen, halo, cyano, nitro, hydroxy, trifluoromethoxy, HF 2 CO- or trifluoromethyl, wherein R 4 is as defined above.
  • R 2 is R 7 -phenyl or R 7 -pyridinyl; and R 3 is hydrogen, halo, cyano, nitro, hydroxy, trifluoromethoxy, H F 2 CO- or trifluoromethyl, wherein R 7 is as defined above.
  • R 1 is pyrrolidinyl, piperidinyl or piperazinyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO 3 S-, aminosulfonyl, (C 6 -C 10 )BIyI, (C 2 -C 9 )heteroaryl, R 4 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (CrC 6 )alkylthio, R 4 (C r C 6 )alkylamino and R 4 (C 1 -C 6 )alkoxy(C 1 - C 6 )alkylamino;
  • R 2 is R 7 -phenyl or R 7 -pyridinyl, wherein R 7 is selected from the group consisting of: cyano, halo, hydroxy, amino, R 8 (C r C 6 )alkyl, R 8 (C r C 6 )alkyl,
  • the presently disclosed compounds of Formula I, or a pharmaceutically acceptable salt or prodrug thereof are selected from the group consisting of:
  • R group(s) is hydrogen
  • the moiety to which the R group is attached is effectively unsubstituted by a group other than hydrogen.
  • R groups when such terms are substituted by a certain number of R groups and the R groups are hydrogen, other hydrogen atoms that may already be present on the moiety to which the R groups are attached continue to be present.
  • R 4 (CrC 6 )alkyl where R 4 is three groups selected from hydrogen and (CrC 6 )alkyl is a n-butyl radical
  • the resulting group is n-butyl having the chemical formula C 4 H 9 .
  • R 7 (C 6 -C 10 )aryl wherein R 7 is two groups selected from hydrogen and (C 6 -Ci 0 )aryl is a phenyl radical
  • the resulting group is phenyl radical having the chemical formula C 6 H 5 .
  • a group shown not directly bonded to an atom on a ring indicates that the group can be bonded to any ring atom at any available position.
  • the R 3 group shown in Formula I can be bonded to any available position on the pyridyl ring, i.e., the carbon atoms at positions 3, 4, or 6.
  • the other unsubstituted ring atoms continue to be "substituted" by an appropriate number of hydrogen atoms.
  • R 3 is a hydrogen atom bonded to the 3 position of the pyridyl ring
  • those of skill in the art will appreciate that the carbon atoms at the 4 and 6 positions of the pyridyl ring will each continue to be substituted by a hydrogen atom.
  • R 3 is hydrogen
  • the hydrogen atoms present on pyridyl ring prior to substitution are unaffected by the R 3 substitution.
  • other variations will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • a pharmaceutical composition for (a) treating or preventing a disorder or condition selected from decreased megakary ⁇ poiesis and platelet numbers, decreased hematopoietic stem cells, decreased erythopoiesis and myelopoiesis; aiding bone marrow repopulation after bone marrow or cord blood transplant; expanding megakaryocyte and stem cell numbers in vitro prior to transplant; increasing platelet numbers in normal individuals prior to surgery, cytoreductive chemotherapy, or radiation treatment; increasing platelet numbers in normal individuals prior to platelet pheresis to harvest platelets for later transfusion; increasing platelet numbers in thrombocytopenic patients or (b) treating or preventing a disorder or condition that can be treated or prevented by agonizing the TPO receptor in a mammal, including a human, comprising an amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, effective in such disorders or conditions and a pharmaceutically acceptable carrier.
  • a method is disclosed for agonizing the TPO receptor in a mammal, including a human
  • a method for: treating or preventing a disorder or condition selected from decreased megakaryopoiesis and platelet numbers, decreased hematopoietic stem cells, decreased erythopoiesis and myelopoiesis; aiding bone marrow repopulation after bone marrow or cord blood transplant; expanding megakaryocyte and stem cell numbers in vitro prior to transplant; increasing platelet numbers in normal individuals prior to surgery, cytoreductive chemotherapy, or radiation treatment; increasing platelet numbers in normal individuals prior to platelet pheresis to harvest platelets for later transfusion; increasing platelet numbers in thrombocytopenic patients, in a mammal, including a human, comprising administering to said mammal an amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, effective in treating such a disorder or condition.
  • the method further comprises co-administering a therapeutically effective amount of an agent selected from the group consisting of: a colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonists, soluble receptors, receptor agonists or antagonist antibodies, or small molecules or peptides that act by the same mechanisms as one or more of said agents.
  • an agent selected from the group consisting of: G-CSF,
  • GM-CSF GM-CSF, TPO, M-CSF, EPO, Gro-beta, IL-11 , SCF, FLT3 ligand, LIF, 1L-3, IL-6, IL-I 1 Progenipoietin, NESP, SD-01 , IL-8, and IL-S or a biologically active derivative of any of said agents.
  • a method for enhancing platelet production obtained from a donor comprising administering to said donor a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof prior to platelet pheresis, blood donation or platelet donation.
  • a method for enhancing the number of peripheral blood stem cells obtained from a donor comprising administering to said donor a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof prior to leukapheresis.
  • the method further comprises co-administering a therapeutically effective amount of a hematopoietic-cell mobilizing agent selected from the group consisting of: a colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist, adhesion molecule antagonists and antibodies.
  • a hematopoietic-cell mobilizing agent selected from the group consisting of: a colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist, adhesion molecule antagonists and antibodies.
  • the mobilizing agent is selected from the group consisting of: G-CSF, GM-CSF, TPO, EPO, Gro-beta, 1L-8, Cytoxan, VLA-4 inhibitors, SCF, FLT3 ligand or a biologically active derivative of G-CSF, GM-CSF, TPO, EPO, Gro-beta and 1L-8.
  • the agent causes terminal differentiation in certain types of hematopoietic malignancies.
  • certain terms used herein to describe the presently disclosed methods, compositions, biological effects, etc. such as “decreased”, “increasing”, “normal”, as used in the phrases “decreased hematopoietic stem cells”, “increasing platelet numbers”, and “normal individuals”, respectively, it should be understood that such terms are used in a relative qualitative sense based on a quantitative departure from the norm.
  • the "norm” is indicative of a "normal individual” recognized by those of skill in the art and may vary amongst individuals depending on, e.g., the demographic group of which the individual is a member, size, weight, gender, etc.
  • pharmaceutically acceptable salt means either a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.
  • prodrug means a pharmacological derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug.
  • prodrugs are variations or derivatives of the compounds of Formula I that have groups cleavable under certain metabolic conditions, which when cleaved, become the compounds of Formula I. Such prodrugs then are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation.
  • Prodrug compounds herein may be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and the number of functionalities present in a precursor- type form.
  • Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (See, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif., 1992).
  • Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative, etc.
  • acid derivatives such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative, etc.
  • other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability.
  • Prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of the presently disclosed compounds.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.
  • (Ci-C 6 )alkyl means a saturated linear or branched free radical consisting essentially of 1 to 6 carbon atoms and a corresponding number of hydrogen atoms.
  • exemplary (CrC 6 )alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.
  • other (d-C 6 )alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • (C 3 -C 10 )cycloalkyl means a nonaromatic saturated free radical forming at least one ring consisting essentially of 3 to 10 carbon atoms and a corresponding number of hydrogen atoms.
  • (C 3 -Ci 0 )cycloalkyl groups can be monocyclic or multicyclic. Individual rings of such multicyclic cycloalkyl groups can have different connectivities, e.g., fused, bridged, spiro, etc. in addition to covalent bond substitution.
  • Exemplary (C 3 -C 10 )cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo[3.2.1]octanyl, octahydro-pentalenyl, spiro[4.5]decanyl, cyclopropyl substituted with cyclobutyl, cyclobutyl substituted with cyclopentyl, cyclohexyl substituted with cyclopropyl, etc.
  • other (C 3 -C 10 )cycloalkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • (C 2 -C 9 )heterocycloalkyl means a nonaromatic free radical having 3 to 10 atoms (i.e., ring atoms) that form at least one ring, wherein 2 to 9 of the ring atoms are carbon and the remaining ring atom(s) (i.e., hetero ring atom(s)) is selected from the group consisting of nitrogen, sulfur, and oxygen.
  • (C 2 -C 9 )heterocycloalkyl groups can be monocyclic or multicyclic. Individual rings of such multicyclic heterocycloalkyl groups can have different connectivities, e.g., fused, bridged, spiro, etc.
  • Exemplary (C 2 -C 9 )heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1 ,3-oxazolidin-3-yl, isothiazolidinyl, 1 ,3- thiazolidin-3-yl, 1 ,2-pyrazolidin-2-yl, 1 ,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2- tetrahydrothiazin-2-yl, 1 ,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,
  • the (C 2 -C 9 )heterocycloalkyl group typically is attached to the main structure via a carbon atom or a nitrogen atom.
  • the term "(C 2 -C 9 )heteroaryl” means an aromatic free radical having 5 to 10 atoms (i.e., ring atoms) that form at least one ring, wherein 2 to 9 of the ring atoms are carbon and the remaining ring atom(s) (i.e., hetero ring atom(s)) is selected from the group consisting of nitrogen, sulfur, and oxygen.
  • (C 2 -C 9 )heteroaryl groups can be monocyclic or multicyclic. Individual rings of such multicyclic heteroaryl groups can have different connectivities, e.g., fused, etc. in addition to covalent bond substitution.
  • Exemplary (C 2 -C 9 )heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1 ,3,5-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,3- oxadiazolyl, 1 ,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,4-triazinyl, 1 ,2,3-triazinyl, 1 ,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridiny
  • the (C 2 -C 9 )heteroaryl group typically is attached to the main structure via a carbon atom, however, those of skill in the art will realize when certain other atoms, e.g., hetero ring atoms, can be attached to the main structure.
  • other (C 2 -C 9 )heteroaryl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • the term "(C 6 -Ci 0 )aryl” means phenyl or naphthyl.
  • the term “halo” means fluorine, chlorine, bromine, or iodine.
  • the term "amino" means a free radical having a nitrogen atom and 1 to
  • amino generally refers to primary and secondary amines.
  • a tertiary amine is represented by the general formula RR 1 N-, wherein R and R' are carbon radicals that may or may not be identical.
  • amino generally may be used herein to describe a primary, secondary, or tertiary amine, and those of skill in the art will readily be able to ascertain the identification of which in view of the context in which this term is used in the present disclosure.
  • ACN refers to acetonitrile.
  • DMF refers to N,N-dimethylformamide.
  • DMSO dimethylsulfoxide
  • EtOAc refers to ethyl acetate
  • EtOH refers to ethanol.
  • Hunig's Base refers to diisopropylethyl amine (“DIPEA"). MeOH refers to methanol.
  • NaOH refers to sodium hydroxide.
  • THF refers to tetrahydrofuran.
  • TFA refers to trifluoroacetic acid.
  • reaction 1 of Preparation A a compound of formula A-1 is reacted with sulfuryl chloride and stirred preferably at 40-60 0 C for about 2 hours. The reaction is then concentrated to dryness. To the resulting residue is added a protic solvent, such as ethanol, and thiourea. The reaction is then refluxed for about 24 hours and subsequently worked-up in accordance with methods known in the art to give a product of formula A-2.
  • a protic solvent such as ethanol, and thiourea
  • reaction 2 of Preparation A a compound of formula A-2 is dissolved in a solvent, such as chloroform, in an inert environment. HCI is then added to the mixture and stirring occurs for about 2 hours.
  • the solvent is preferably replaced with toluene and the resulting mixture is cooled to about 0 0 C and trimethylaluminum is added dropwise.
  • the reaction mixture is stirred for about 12-18 hours at room temperature and subsequently worked-up in accordance with methods known in the art to give a product of formula A-3.
  • reaction 1 of Preparation B the compound of formula B-1 is reacted with trimethylsilyldiazomethane dropwise in the presence of one or more solvents selected from toluene, methanol, hexanes, etc. at about 0 0 C.
  • the reaction mixture is allowed to reach room temperature where it stirs for about 12-18 hours.
  • the reaction mixture is subsequently worked-up in accordance with methods known in the art to give a product of formula B-2.
  • reaction 1 of Preparation C the compound of formula C-1 is reacted with thionyl chloride dropwise in the presence of a solvent such as anhydrous toluene.
  • DMF is added to the reaction mixture.
  • the reaction mixture subsequently is stirred for about 2-4 hours at room temperature in an inert environment.
  • the reaction mixture is then worked-up in accordance with methods known in the art to give a product of formula C- 2.
  • reaction 1 of Preparation D the compound of formula D-1 is reacted with a compound of formula D-2 in the presence of Pd 0 under Suzuki coupling conditions known by those of skill in the art to form a compound of formula D-3.
  • the compound of formula D-1 is reacted with a compound of formula D-2 using Stille coupling conditions (i.e., using tributyltin) to form a compound of D-3.
  • a compound of formula D-1 is readily prepared using known methods in the art to make such triflated compounds. For example, a compound of formula I is prepared by reacting a ketone with a triflating agent.
  • reaction 2 of Scheme 1 the compound of formula 1-1 is reacted with a primary or secondary amine in a solvent such as DMSO, THF, ACN, etc. Hunig's base is also added to the reaction mixture where subsequent heating between 40 0 C and 60 0 C, preferably 50 0 C for about 1-3 days occurs.
  • the reaction mixture is subsequently worked-up in accordance with methods known in the art to give a product of formula I-2.
  • R 1 contains an ester moiety that can be subsequently saponified to afford the corresponding carboxylic acid.
  • the aforementioned primary and secondary amine need not be of the formula R 1 R 9 N-, but rather can be a cyclic amine, such as piperidine, piperazine, morpholine, etc.
  • reaction 1 of Scheme 2 the acid chloride compound of formula C-2 is reacted with the amine compound of A-2 in a solvent, such as anhydrous THF, in the presence of anhydrous pyridine.
  • a solvent such as anhydrous THF
  • the resulting reaction mixture is generally heated to about 60°C for about 12-18 hours in an inert environment.
  • the reaction mixture is subsequently worked-up in accordance with methods known in the art to give a product of formula 11-1.
  • reaction 2 of Scheme 2 the compound of formula 11-1 is reacted with a primary or secondary amine in accordance with methods presented above for reaction 2 of Scheme 1 to give a product of formula 11-2.
  • R 1 contains an ester moiety that can be subsequently saponified to afford the corresponding carboxylic acid.
  • the aforementioned primary and secondary amine need not be of the formula R 1 R 9 N-, but rather can be a cyclic amine, such as piperidine, piperazine, morpholine, etc.
  • reaction 1 of Scheme 3 the compound of formula 1-1/11-1 is reacted with a compound of formula R 1 -OM, where M is a metal such as, Na, K, Li, etc.
  • M is a metal such as, Na, K, Li, etc.
  • the reaction is conducted in the presence of an anhydrous solvent, such as THF, in an inert environment.
  • an anhydrous solvent such as THF
  • the product of formula 111-1 is isolated using methods known in the art.
  • R 1 contains an ester moiety that can be subsequently saponified to afford the corresponding carboxylic acid.
  • reaction 1 of Scheme 4 the compound of formula D-3 is reacted with a compound of formula A-2 in the presence of CO and Pd 0 .
  • the reaction is conducted in the presence of an anhydrous solvent, such as THF, in an inert environment.
  • an anhydrous solvent such as THF
  • the product of formula IV-1 is isolated using methods known in the art.
  • R 1 contains an ester moiety that can be subsequently saponified to afford the corresponding carboxylic acid.
  • All pharmaceutically acceptable salts, prodrugs, tautomers, hydrates and solvates of the compounds presently disclosed are also within the scope of the present disclosure.
  • Presently disclosed compounds that are basic in nature are generally capable of forming a wide variety of different salts with various inorganic and/or organic acids.
  • salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds can be readily prepared using conventional techniques, e.g., by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as, for example, methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
  • Acids which can be used to prepare the pharmaceutically acceptable acid addition salts of the base compounds are those which can form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1 ,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
  • non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate
  • Presently disclosed compounds that are acidic in nature are generally capable of forming a wide variety of different salts with various inorganic and/or organic bases.
  • such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a pharmaceutically acceptable base addition salt.
  • base addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields of the desired solid salt.
  • Bases which can be used to prepare the pharmaceutically acceptable base addition salts of the base compounds are those which can form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations, such as, alkali metal cations (e.g., potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine-(meglumine), lower alkanolammonium and other such bases of organic amines.
  • pharmacologically acceptable cations such as, alkali metal cations (e.g., potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine-(meglumine), lower alkanolammonium and other such bases of organic amines.
  • Isotopically-labeled compounds are also within the scope of the present disclosure.
  • an "isotopically-labeled compound” refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 O,
  • the compounds may be useful in drug and/or substrate tissue distribution assays. Tritiated ( 3 H) and carbon-14 ( 14 C) labeled compounds are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopically labeled compounds presently disclosed, including pharmaceutical salts and prodrugs thereof, can be prepared by any means known in the art.
  • Stereoisomers e.g., cis and trans isomers
  • optical isomers of a presently disclosed compound e.g., R and S enantiomers
  • racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.
  • the compounds, salts, prodrugs, hydrates, and solvates presently disclosed can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof.
  • Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, all tautomers are within the scope of the present disclosure.
  • Atropisomers are also within the scope of the present disclosure. Atropisomers refer to compounds that can be separated into rotationally restricted isomers.
  • compositions comprising at least one presently disclosed compound and at least one pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can be any such carrier known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro edit. 1985).
  • Pharmaceutical compositions of the compounds presently disclosed may be prepared by conventional means known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable carrier.
  • a presently disclosed compound can be formulated as a pharmaceutical composition for oral, buccal, parenteral (e.g., intravenous, intramuscular or subcutaneous), topical, rectal or intranasal administration or in a form suitable for administration by inhalation or insufflation.
  • parenteral e.g., intravenous, intramuscular or subcutaneous
  • topical e.g., rectal or intranasal administration or in a form suitable for administration by inhalation or insufflation.
  • the compounds presently disclosed may also be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in United States Patents 3,119,742, 3,492,397, 3,538,214, 4,060,598, and 4,173,626.
  • the pharmaceutical composition may take the form of, for example, a tablet or capsule prepared by conventional means with a pharmaceutically acceptable excipient(s) such as a binding agent (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filler (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricant (e.g., magnesium stearate, talc or silica); disintegrant (e.g., potato starch or sodium starch glycolate); and/or wetting agent (e.g., sodium lauryl sulphate).
  • a binding agent e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • filler e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricant e.g., magnesium stearate, talc or silica
  • disintegrant
  • Liquid preparations for oral administration may take the form of a, for example, solution, syrup or suspension, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with a pharmaceutically acceptable additive(s) such as a suspending agent (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicle (e.g., almond oil, oily esters or ethyl alcohol); and/or preservative (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • a suspending agent e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicle e.g., almond oil, oily esters or
  • the composition may take the form of tablets or lozenges formulated in a conventional manner.
  • Presently disclosed compounds may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain a formulating agent such as a suspending, stabilizing and/or dispersing agent recognized by those of skill in the art.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a presently disclosed compound may be formulated as an ointment or cream.
  • Presently disclosed compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • presently disclosed compounds may be conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the presently disclosed compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a presently disclosed compound and a suitable powder base such as lactose or starch.
  • a proposed dose of a presently disclosed compound for oral, parenteral or buccal administration to the average adult human for the treatment or prevention of a TPO-related disease state is about 0.1 mg to about 2000 mg. In certain embodiments, the proposed dose is from about 0.1 mg to about 200 mg of the active ingredient per unit dose. Irrespective of the amount of the proposed dose, administration of the compound can occur, for example, 1 to 4 times per day.
  • Aerosol formulations for the treatment or prevention of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains about 20 ⁇ g to about 10.OOO ⁇ g, preferably, about 20 ⁇ g to about 10OO ⁇ g of a presently disclosed compound.
  • the overall daily dose with an aerosol will be within the range from about 100 ⁇ g to about 100 mg. In certain embodiments, the overall daily dose with an aerosol generally will be within the range from about 100 ⁇ g to about 10 mg.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • Aerosol combination formulations for the treatment or prevention of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains from about 0.01 mg to about 1000 mg of a combination comprising a presently disclosed compound. In certain embodiments, each metered dose or "puff' of aerosol contains about 0.01 mg to about 100 mg of a combination comprising a presently disclosed compound. In certain embodiments, each metered dose or "puff' of aerosol contains about 1 mg to about 10 mg of a combination comprising a presently disclosed compound. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • compositions and methods of treatment or prevention comprising administering prodrugs of at least one presently disclosed compound are also within the scope of the present disclosure.
  • a murine hematopoietic IL3 dependent cell line BaF3 transfected with the human TPO receptor (TPOr) and the STAT1/3 responsive ⁇ -lactamase reporter was used to assess the agonist activity of the presently disclosed compounds against the TPO receptor in the present assay.
  • the present assay measures the induction of the ⁇ -lactamase enzymatic activity in response to TPOr stimulation.
  • CCF4/AM a membrane-permeant substrate ester derived from CCF4 and a fluorescent substrate for ⁇ -lactamases, was added to the cells to monitor the observed activity because it is known that as CCF4/AM is accumulated intracellular ⁇ in mammalian cells, CCF4/AM is converted to CCF4 by endogenous cytoplasmic esterases.
  • the substrate fluoresces green (530nm), and the product of its ⁇ -lactamase catalyzed hydrolysis fluoresces blue (460nm).
  • the transfected BaF3 IL-3 dependent cell line was maintained in RPMI (Gibco, #12376-018), 10% heat inactivated fetal bovine serum (Hyclone SH30070.03), 250ug/ml Zeocyn (Invitrogen, #204281), 0.5mg/ml Geneticin (Gibco, #10131-035), 10ng/ml hTpo (R&D Systems, 288-TP-025), and 1 % Penicillin-Streptomycin. The cells were split 1 :5 three times per week.
  • the cells were washed three times for about 10 minutes at about 500xg and the media was replaced with phenol red free RPMI (Gibco, #11835-030) with 10% FBS without hTPO for about 18 hours.
  • Drug dilutions were prepared in RPMI and 0.1% BSA ("assay media") and were subsequently delivered in triplicate 20 ⁇ L of compound into a 384-well Costar clear bottom, black plate (VWR, #29444-080) using a BioMek (Beckman-Coulter). Columns 1-18 were reserved for drug dilutions. Columns 19-22 were used as control columns.
  • the cells were washed three times for about 10 minutes (each wash) at 500xg in a solution of phenol red free RPMI and assay media. After the final wash, the cells were resuspended in about 1OmL of assay media and counted using Trypan Blue. 2OuL of cells were added to columns 1-20 of the 384-well plate using a Multi-drop (ThermoLabSystems) for a final cell concentration of 10,000 cells per well. The plate was spun at about 300xg for about 1 second.
  • the Stimulation Index was as follows: [(460/530 ratio drug samples/460/530 No Stimulation Ratio)] -1.
  • the reported EC 50 values were calculated by plotting SI ratio drug against SI ratio hTPO control.
  • Chromatography refers to column chromatography performed using 32-63 mm silica gel and executed under nitrogen pressure (flash chromatography) conditions. Room or ambient temperature refers to 20-25°C. All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields. Concentration or concentration at reduced pressure means that a rotary evaporator was used (in vacuo).
  • protecting groups may be required during synthesis. After the target molecule is made, the protecting group can be removed by methods well known to those of ordinary skill in the art, such as described in Greene and Wuts, Protective Groups in Organic Synthesis. (2 nd Ed, John Wiley & Sons 1991).
  • LCMS liquid chromatography on reverse phase with mass spectrometry detection
  • Gradient elution was applied with increase of concentration of acetonitrile in 0.01 % aqueous formic acid from 5% to 100% during 3.75 min period.
  • Mass spectrometer Micromass ZMD was used for molecular ion identification.
  • Reaction 1 5.6-Dichloro-N-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)pyridine-3- carboxamide
  • methyl 5,6- dichloropyridine-3-carboxylate 6.5mmol
  • Dry toluene 28mL
  • the resulting suspension was stirred for a few minutes and N- (chloro(methyl)alumino)-4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-amine (7.8mmol) was added in small portions.
  • Examples 2-24 were made in accordance with "General Procedure A” by replacing N 1 N- dimethylpiperidin-4-amine dihydrochloride with the appropriate amine. Certain other deviations from “General Procedure A” are indicated.
  • Examples 26-33 were made in accordance with "General Procedure B” by replacing 4- (pyrrolidin-i-yl)-piperidine with the amine identified. Certain other deviations from “General Procedure B” are indicated.
  • Reaction 1 5.6-Dichloro-N-r4-(2-fluoro-3-trifluoromethyl-prienv ⁇ -thiazol-2-yl1-nicotinamide
  • 5OmL 5Ommol
  • Dry toluene 28mL
  • the resulting suspension was stirred for a few minutes and N-(chloro(methyl)alumino)-4-(2-fluoro-3- (trifluoromethyl)phenyl)thiazol-2-amine (7.8mmol) was added in small portions.
  • Reaction 1 6-Chloro-N-r4-(2-fluoro-3-trifluoromethyl-phenvh-thiazol-2-vn-nicotinamide
  • 6-Chloro-nicotinic acid methyl ester 6.5mmol
  • Dry toluene 28mL
  • the resulting suspension was stirred for a few minutes and N-(chloro(methyl)alurnino)-4-(2-fluoro-3- (trifluoromethyl)phenyl)thiazol-2-amine (7.8mmol) was added in small portions. After addition was complete, the reaction was heated to 90 0 C and stirred for about 24 hours.
  • Example 38 was made in accordance with "General Procedure D” by replacing piperidine-4- carboxylic acid with the appropriate amine. Certain other deviations from “General Procedure D” are indicated.
  • Examples 40-42 were made in accordance with "General Procedure E” by replacing piperidine-4-carboxamide with the appropriate amine. Certain other deviations from “General Procedure E” are indicated.

Abstract

L'invention concerne un composé de la formule (I) dans laquelle R1, R2, R3, X, et d sont définis tels qu'indiqués ci-dessus. Les composés présentés dans cette invention sont des agonistes de la TPO utiles comme promoteurs de la thrombopoïèse et de la mégacaryocytopoïèse.
PCT/IB2006/001836 2005-07-05 2006-06-27 Dérivés d'aminothiazole servant d'agonistes du récepteur de la thrombopoïétine WO2007004038A1 (fr)

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WO2009017098A1 (fr) 2007-07-31 2009-02-05 Shionogi & Co., Ltd. Composition pharmaceutique contenant un composé actif sur le plan optique possédant une activité d'agoniste du récepteur de la thrombopoïétine et son intermédiaire
WO2011042797A1 (fr) * 2009-10-08 2011-04-14 Icozen Therapeutics Pvt. Ltd. Dérivés de pyrazole en tant que modulateurs du canal calcique activé par la libération du calcium
WO2011139765A3 (fr) * 2010-04-27 2012-03-08 Calcimedica, Inc. Composés qui modulent le calcium intracellulaire
EP2547676A2 (fr) * 2010-03-17 2013-01-23 Taivex Therapeutics Inc. Modulateurs de l'activité hec1 et procédés associés
WO2013074459A1 (fr) 2011-11-14 2013-05-23 Ligand Pharmaceuticals, Inc. Procédés et compositions associés au récepteur du facteur de stimulation des colonies de granulocytes
CN104395752A (zh) * 2011-11-21 2015-03-04 泰纬生命科技股份有限公司 对hec1活性调节剂具有反应的癌症的生物标记
US8993612B2 (en) 2009-10-08 2015-03-31 Rhizen Pharmaceuticals Sa Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
US8999983B2 (en) 2011-11-29 2015-04-07 Taivex Therapeutics Corporation Modulators of Hec1 activity and methods therefor
WO2018045907A1 (fr) 2016-09-08 2018-03-15 四川科伦博泰生物医药股份有限公司 Nouveau dérivé de 2-acylaminothiazole, son procédé de préparation et son utilisation
US9962370B2 (en) 2013-03-15 2018-05-08 Ligand Pharmaceuticals Incorporated Methods of treatment associated with the granulocyte colony-stimulating factor receptor
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EP1466912A1 (fr) * 2002-01-18 2004-10-13 Yamanouchi Pharmaceutical Co. Ltd. Derive de 2-acylaminothiazole et son sel
WO2005007651A1 (fr) * 2003-07-17 2005-01-27 Astellas Pharma Inc. Derive 2-acylaminothiazole ou sel de celui-ci

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US10174034B2 (en) 2009-10-08 2019-01-08 Rhizen Pharmaceuticals Sa Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
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