WO2007036769A1 - Aminothiazole derivatives as agonists of the thrombopoietin receptor - Google Patents

Aminothiazole derivatives as agonists of the thrombopoietin receptor Download PDF

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WO2007036769A1
WO2007036769A1 PCT/IB2006/001830 IB2006001830W WO2007036769A1 WO 2007036769 A1 WO2007036769 A1 WO 2007036769A1 IB 2006001830 W IB2006001830 W IB 2006001830W WO 2007036769 A1 WO2007036769 A1 WO 2007036769A1
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alkyl
alkylamino
alkoxy
trifluoromethyl
hydroxy
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PCT/IB2006/001830
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French (fr)
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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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    • 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 a!., P roc. 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 The gene encoding TPO has been cloned and characterized. See Kuter et al., Proc. Natl. Acad. ScL USA. 91: 11104-11108 (1994); Barley et ai., CeN,_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.
  • 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 human TPO receptor
  • c-mpl human TPO receptor
  • CD34 + cells in humans See Methia et al., Blood, 82: 1395-1401 (1993)). Further evidence for 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. Some workers postulate that the receptor functions as a homodimer, similar to the situation with the receptors for G-CSF and erythropoietin. (See Alexander et al., EMBO J., 14: 5569- 5578 (1995)).
  • 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 2005/007651 A1 refers to a 2-acylarninothiazole 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-CI/5-F substituted aminothiazoles being useful as potent TPO agonists.
  • 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-CI/5-F substituted aminothiazoles achieve desirable pharmacological properties in addition to being potent TPO agonists.
  • X is -O- or R 9 N-, wherein R 9 is H or (C r C 6 )alkyl; Y is chloro orfluoro;
  • R 1 is (C r C 6 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, or (C 2 -C 8 )heteroaryl, wherein the alkyl, cycloalkyl, heterocycloaikyl, and heteroaryl moieties of (C r C 6 )alkyl, (C 3 - Cio)cycioalkyl, (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 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C r C 6 )alkoxycarbonyl, R 4
  • R 5 and R 6 are each (C r C 6 )alkyl optionally independently substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino, (C r C 6 )alkylarnino, [(C 1 -C 6 )BIkYl] 2 N-, (C r C 6 )alkylthio, (C 1 - C 6 )alkylsulfinyl, (C 1 -C 6 )BIkYlSuIfOnYl 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 B )alkyl)-N-; and the ring so formed is optionally substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino
  • R 3 is hydrogen, 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 (C r C 6 )alkylamino, trifluoromethyl, wherein R 4 is as defined above; with the proviso that when d is 1 , R 1 cannot be (C 2 -C 9 )heterocycloalkyl or (C 2 -
  • R 1 is (Ci-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 r C ⁇ )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 )alkylamino, R 4 (C
  • R 5 and R 6 are each (Ci-C 6 )alkyl optionally independently substituted by (C.
  • d is O 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 (Ci-C ⁇ )alkyl, R 4 (C r C 6 )alkoxy, R 4 (CrC 6 )alkoxycarbonyl, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alky!sulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (C 1 -C 6 )alkylaminosulfonyl, R 4 (C r C 6 )alkylsulfonylamino, R 4 (C r C 6 )alkylamino, R 4 (C r C 6 )alkylcar
  • d is O and 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 1 -C 6 )alkylthio, R 4 (CrC 6 )a!kylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (C r C 6 )alkylaminosulfonyl, R 4 (C 1 -C 6 )alkylsulfonylamino, R 4 (C r C 6 )alkylamino, R 4 (C r C 6 )alkylamino, R 4 (C r
  • R 5 and R 6 are each (Ci-C 6 )alkyl optionally independently substituted by (Ci-C 6 )alk
  • Cg)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 (C r C 6 )alkyl, R 4 (C r C ⁇ )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 1 -C 6 )alkylsulfonylamino, R 4 (C r C 6 )alkylamino, R 4 (CrC 6 )alkylcarboxy, R 4 (C r C 6 )alkylaminocarbonyl, aminocarbony
  • R 5 and R 6 are each (Ci-C 6 )alkyl optionally independently substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino, (Ci-C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 N-, (Ci-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 (CrC 6 )alkoxy, hydroxy, carboxy, amino, (C 1
  • 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 r C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C r C 6 )alkoxycarbonyl, R 4 (C r C ⁇ )alkylthio, R 4 (C r C 6 )alkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (C r C 6 )alkylaminosulfonyl, R 4 (Ci-C 6 )alkylsulfonylamino, R 4 (C r
  • R 5 and R 6 are each (C-i-C 6 )alkyl optionally independently substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino, (C r C 6 )alkylamino, [(C 1 -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 )aIkyl)-N-; and the ring so formed is optionally substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino,
  • d is 1
  • X is R 9 N- wherein R 9 is H -
  • R 1 is (Ci-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 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 1 -C 6 )alkylsulfonyl, R 4 (C r C 6 )alkylaminosulfonyl, R 4 (CrC 6 )alkylsulfonylamino, R 4 (C,- C 6 )alkylamino,
  • d is 1
  • X is R 9 N- wherein R 9 is (C r C 6 )alkyl
  • R 1 is (CrCe ⁇ lkyl, wherein the alkyl moiety of (C r C 6 )alkyi 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-,-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 1 -C 6 )alkylaminosulfonyl, R 4 (C (C
  • R 5 and R 6 are each (C r C 6 )alkyl optionally independently substituted by (C 1 -C 6 )BIkOXy, hydroxy, carboxy, amino, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 N-, (C r C 8 )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 1 S(O), S(O) 2 , NH and ((C r C 6 )alkyl)-N-; and the ring so formed is optionally substituted by (CrC 6 )alkoxy, hydroxy, carboxy, amino,
  • 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 (C 1 -C 6 )alkyl, R 4 (C 1 - 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 1 -C a )alkylaminosulfonyl, R 4 (C 1 -C 6 )alkylsulfonylamino, R 4 (C,- C 6 )alkylamino, R 4 (C,- C 6 )alky
  • R 5 and R 6 are each (C,-C 6 )alkyl optionally independently substituted by (Ci-C e )alkoxy, hydroxy, carboxy, amino, (C r C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 N-, (C r C 6 )alkylthio, (C r 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 1 -C 6 )alkyl)-N-; and the ring so formed is optionally substituted by (CrC 6 )alkoxy, hydroxy, carboxy, amino, (
  • d is 1
  • X is R 9 N- wherein R 9 is H -
  • R 1 is (C 3 -Ci 0 )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 ⁇ )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 )
  • R 5 and R 6 are each (C 1 -C 6 )BIk ⁇ optionally independently substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino, (C r C 6 )alkylamino, (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 (Ci-C 6 )alkoxy, hydroxy, carboxy, amino, (C 1 - C 6 )alkylamino, [(C r
  • X is R 9 N- wherein R 9 is (CrCe ⁇ lkyl, and R 1 is (C 3 -C 10 )cycloalkyl, wherein the alkyl or cycloalkyl moieties of (C 3 - Cio)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 (C r C 6 )alkylsulfinyl, R 4 (C r C 6 )alkylsulfonyl, R 4 (C r C 6 )alkylaminosul
  • d is O and R 1 is (C 2 - C 9 )heterocycloalkyl, [(C r C 6 )alkyl] 2 N-, [(CrC 6 )alkyl][(C 3 -C 10 )cycloalky!]N-, wherein the alkyl, cycloalkyl, and heterocycloalkyl, moieties of (C 2 -C 9 )heterocycloalkyl, [(Ci-C 6 )alkyl] 2 N-, [(C 1 - C 6 )alkyl][(C 3 -C 10 )cycIoalkyl]N- 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, aminosulfonyl, R 4 (C r C 6 )alkyl, R 4 (
  • R 5 and R 6 are-each (CrC 6 )alkyl optionally independently substituted by (Ci-C 6 )alkoxy, hydroxy, carboxy, amino, (C r C ⁇ )alkylamino, [(CrC 6 )alkyl] 2 N-, (C r C 6 )alkylthio, (C 1 -
  • R 3 is halo, cyano, nitro, carboxy, hydroxy, amino, aminocarbonyl, trifluoromethoxy, HF 2 C-O-, (C 3 -Ci 0 )cycloalkyl, R 4 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy,
  • R 4 (C r C 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 r C 6 )alkylamino, R 5 R 6 N-, (C r C 6 )alkylthio, (C 1 -C B )alkylsulfinyl, (C 1 -
  • R 5 and R 6 are each (C 1 -C B )alkyl optionally independently substituted by (C r C 6 )alkoxy, hydroxy, carboxy, amino, (C 1 -C 6 )alkylamino, [(Ci-C 6 )alkyl] 2 N-, (C 1 -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 O, 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 8 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 (CrC 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 1 -
  • R 5 and R 6 are each (Ci-C 6 )alkyl optionally independently substituted by (CrC ⁇ alkoxy, hydroxy, carboxy, amino, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 N-, (C r C 6 )alkylthio, (C 1 - C 6 )alkyisulfinyl, (CrCeJalkylsulfonyl 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 r C 6 )alkoxy, hydroxy, carboxy, amino, (C 1 - C
  • 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 ⁇ -Ci 0 )aryl, (C 2 -C 9 )heteroaryl 1 R 4 (C r C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C 1 -C ⁇ )alkylthio, R 4 (C r C 6 )alkylamino and R 4 (C r C 6 )alkoxy(CrC 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 -Ci 0 )aryl, (C 2 -C 9 )heteroaryl, R 4 (C r C 6 )alkyl, R 4 CC 1 - 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
  • 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 t - C ⁇ )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 r C 6 )alkoxy(C r 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,- C 6 )alkyl, R 4 (C r C 6 )alkoxy, R 4 (C r C 6 )alkylthio, R 4 (C r C B )alkylamino and R 4 CC 1 -C 6 )BIkOXy(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,
  • 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- ortrifluoromethyl.
  • 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 B )heteroaryl, R 4 (C r C 6 )alkyl, R 4 (CrC 6 )alkoxy, R 4 (C r C 6 )alkylthio, R 4 (C r C 6 )alkylamino and R 4 (C r C 6 )alkoxy(C r C ⁇ )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, HF 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 -Ci 0 )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 r C 6 )alkoxy(C r 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 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 (Ci-C 6 )alkyl where R 4 is three groups selected from hydrogen and (C r C 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 Hs.
  • 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.
  • a pharmaceutical composition for (a) 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 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 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: 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.
  • the agent is selected from the group consisting of: G-CSF, GM-CSF, TPO, M-CSF, EPO, Gro-beta, IL-11 , SCF, FLT3 ligand, LIF, 1L-3, IL-6, IL-I, 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, 1 L-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 )alky means a saturated linear or branched free radical consisting essentially of 1 to 6 carbon atoms and a corresponding number of hydrogen atoms.
  • exemplary (C r C 6 )alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.
  • other (C r C 6 )alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • (C 3 -Cio)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 -C 10 )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 -Ci 0 )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) thatform 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, isdxazolidinyl, 1 ,3-oxazoIidin-3-yI, 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 (C 2 - C 9 )heterocycloalkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • (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 )heteroaryi 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-triazinyI, 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 ⁇ -C 10 )aryr means phenyl or naphthyl.
  • the term "halo" means fluorine, chlorine, bromine, or iodine.
  • amino means a free radical having a nitrogen atom and 1 to 2 hydrogen atoms.
  • 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, Nevertheless, the term “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 refers to 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 1 of Preparation E the compound of formula E- 1 is reacted with a primary or secondary amine, e.g. of the formula R 1 R 9 N-, in the presence of a solvent such as anhydrous dioxane and potassium hydrogen phosphate.
  • a solvent such as anhydrous dioxane and potassium hydrogen phosphate.
  • reaction 2 of Preparation E the compound of formula E-2 is dissolved in a solvent such as dichloromethane at room temperature. Thionyl chloride is then added and the reaction mixture is subsequently heated with stirring to about 40-50 0 C for about 1-2 hours. The reaction mixture is then worked-up in accordance with methods known by those of skill in the art to afford the product E-3.
  • a solvent such as dichloromethane
  • reaction 1A of Preparation F 1 the compound of formula F-1 is reacted with sulfuryl chloride in accordance with the procedure presented above for reaction 1 of Preparation A to afford a compound of formula F-2.
  • reaction 2A of Preparation F 1 the compound of formula F-2 is reacted with
  • reaction 1B of Preparation F the compound of formula F-1 is dissolved in sulfuryl chloride and stirred at about 40-60°Cfor about 12-18 hours.
  • the reaction mixture is concentrated in vacuo to afford the compound of formula F-3, which is carried on without further work-up in the next reaction.
  • reaction 2B of Preparation F the compound of formula F-3 is reacted with thiourea in the presence of a polar solvent such as EtOH.
  • a polar solvent such as EtOH.
  • the reaction mixture is heated to about 40- 6O 0 C for about 12-18 hours and subsequently worked-up in accordance with methods known by those of skill in the art to afford a product of formula F-4.
  • reaction 1 of Scheme J the ester compound of formula B-2 is reacted with the alumino-chloro compound of formula A-3 in the presence of a solvent, such as toluene, in an inert environment.
  • the reaction mixture is heated to about 9O 0 C for about 24 hours.
  • the reaction mixture is subsequently worked-up in accordance with methods known in the art to give a product of formula 1-1.
  • 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 4O 0 C and 6O 0 C, preferably 5O 0 C for about 1-3 days occurs.
  • 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.
  • reaction mixture is generally heated to about 60 0 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. in 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.
  • the reaction is conducted in the presence of an anhydrous solvent, such as THF, in an inert environment.
  • 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.
  • reaction 1 of Scheme 5 the compound of formula E-3 is reacted with a compound of formula F-4 in the presence of a solvent such as anhydrous pyridine at about 9O 0 C for about
  • 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, lac
  • 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 1 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.
  • 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.
  • the present disclosure also provides pharmaceutical 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 10,000 ⁇ g, preferably, about 20 ⁇ g to about 1000 ⁇ 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 10O ⁇ 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.
  • TPO receptor TPOr
  • 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,
  • 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. In particular, column 19 contained cells and 300ng/mL Peprotech hTPO; column 20 contained cells and 100ng/mL mlL3; column 21 contained cells and assay media; and column 22 contained only assay media.
  • 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. Incubation occurred for about 5 hours at about 37°C under 5% CO 2 .
  • 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 0 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
  • Reaction 1 5-Chloro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-amine To a 50OmL reaction vessel was added 2-chloro-1-(4-fluoro-3- (trifluoromethyl)phenyl)ethanone (175mmol) and sulfuryl chloride (350mmol). The reaction mixture was stirred at 50 0 C for about 2 hours. The reaction mixture was then concentrated to dryness. EtOH (25OmL) and thiourea (180mmol) was added to the resulting residue. The reaction mixture was then refiuxed at 90°C for about 24 hours.
  • Reaction 1A 4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-amine
  • SELECTFLUOR ® (16.0 g, 44.5 mmol) was added to a stirred suspension of 4-(4-fluoro- 3-(trifluoromethyl)phenyl)thiazol-2-amine (10.49 g, 40.0 mmol) in anhydrous acetonitrile (200 mL) at O 0 C. The reaction mixture was allowed to warm to room temperature overnight. The solvent volume was reduced in vacuo and then subsequently diluted with dichloromethane (150 mL).

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Abstract

A compound of the formula (I) wherein R1, R2, R3, X, Y, and d are defined as above. The presently disclosed compounds are TPO agonists useful as promoters of thrombopoiesis and megakaryocytopoiesis.

Description

AMINOTHIAZOLE DERIVATIVES AS AGONISTS OF THE THROMBOPOIETIN RECEPTOR
TECHNICAL FIELD 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.
BACKGROUND
The presently disclosed compounds are agonists of the thrombopoietin (TPO) receptor. As such, the presently disclosed 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 a!., P roc. 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. In response to a decreased platelet count, 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). In contrast, In response to an elevated platelet count, the endomitotic rate decreases, lower ploidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%.
The exact physiological feedback mechanism by which the mass of circulating platelets regulate the endomitotic rate and number of bone marrow megakaryocytes is not known. The circulating thrombopoietic factor involved in mediating this feedback loop is now thought to be thrombopoietin (TPO). More specifically, TPO has been shown to be the main humoral regulator in situations involving thrombocytopenia. See, e.g., Metcalf,
Nature, 369:519-520 (1994). 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. Because platelets (thrombocytes) are necessary for blood clotting and when their numbers are very low a patient is at risk of death from catastrophic hemorrhage, 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)). In addition, recent studies have provided a basis for the projection of efficacy of TPO therapy in the treatment of thrombocytopenia, and particularly thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transplantation as treatment for cancer or lymphoma. (See Harker, Curr. Qpin HematoL 6: 127-134 (1999)).
The gene encoding TPO has been cloned and characterized. See Kuter et al., Proc. Natl. Acad. ScL USA. 91: 11104-11108 (1994); Barley et ai., CeN,_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 (1998). 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.
The DNA sequences and encoded peptide sequences for human TPO receptor (TPO-R; also known as c-mpl) have been described. (See Vigon et al., Proc. Natl. Acad. Sci. USA, 89: 5640-5644 (1992)). 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. (See Bazan, Proc. Natl. Acad. Sci. USA. 87: 6934- 6938 (1990)). Evidence that this receptor plays a functional role in hematopoiesis includes observations that its expression is restricted to spleen, bone marrow, or fetal liver in mice (see Souyri et al., GeJI, 63: 1137-1147 (1990)) and to megakaryocytes, platelets, and
CD34+ cells in humans (See Methia et al., Blood, 82: 1395-1401 (1993)). Further evidence for 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. Some workers postulate that the receptor functions as a homodimer, similar to the situation with the receptors for G-CSF and erythropoietin. (See Alexander et al., EMBO J., 14: 5569- 5578 (1995)).
The slow recovery of platelet levels in patients suffering from thrombocytopenia is a serious problem, and has lent urgency to the search for a blood growth factor agonist able to accelerate platelet regeneration (See Kuter, Seminars in Hematology, 37: Supp 4: 41-49 (2000)).
It would be desirable to provide compounds, which allow for the treatment of thrombocytopenia by acting as a TPO mimetic.
Previous attempts to provide drug-like TPO mimetics have not been entirely desirable with regard to certain pharmacological properties, e.g., oral bioavailability. For example, EP 1 207 155 A1 refers to pharmaceutical compositions exhibiting thrombopoietin receptor agonism containing as an active ingredient compounds of the following formula
Figure imgf000004_0001
EP 1 207 155 A1 teaches in part X1 being an optionally substituted thiazole, Y1 being - NHCO-, and Z1 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.
In another example, WO 2005/007651 A1 refers to a 2-acylarninothiazole derivative useful in treating thrombopenia of the following formula
Figure imgf000004_0002
WO 2005/007651 A1 teaches in part R1 being preferably cyclic aminos or other secondary amines, A being preferably methylene, R2 being preferably 4-chlorothiophen-2-yl or 4- methylthiophen-2-yl, and R3 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 , however, does not teach or suggest the presently disclosed 5-CI/5-F 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 As disclosed herein, it unexpectedly has been discovered that the presently disclosed aminothiazoles are effective as agonists of the TPO receptor. In particular, it unexpectedly has been discovered that the presently disclosed 5-CI/5-F substituted aminothiazoles achieve desirable pharmacological properties in addition to being potent TPO agonists.
SUMMARY
The disclosure therefore provides in accordance with one aspect, a compound of the Formula
Figure imgf000005_0001
or a pharmaceutically acceptable salt or prodrug thereof; wherein d is 0 or 1 ;
X is -O- or R9N-, wherein R9 is H or (CrC6)alkyl; Y is chloro orfluoro;
R1 is (CrC6)alkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, or (C2-C8)heteroaryl, wherein the alkyl, cycloalkyl, heterocycloaikyl, and heteroaryl moieties of (CrC6)alkyl, (C3- Cio)cycioalkyl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl, or R9 are independently optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(CrC6)alkyl, R4(CrC6)alkoxy, R4(Cr C6)alkoxycarbonyl, R4(C1-C6)alkylthio, R4(C1-C6)alkylsulfinyl, R4(CrC6)alkylsulfonyl, R4(Cr C6)alkylaminosulfonyl, R4(C1-C6)alkylsulfonylamino, R4(CrC6)alkylamino, R4(Cr Cβ)alkylcarboxy, R4(CrC6)alkylaminocarbonyl, aminocarbonylamino, R4(Cr C6)alkylaminocarbonylamino, aminocarbonyl(C1-C6)alkyl, R4(Ci-C6)alkylaminocarbonyl(C1- C6)alkyl, aminocarbonyl-O-, amino(CrC6)alkoxycarbonyl, R4(CrC6)alkylaminocarbonyl-O-, R4(C1-C6)alkylamino(Ci-C6)alkoxycarbonyl, R4(Ci-C6)alkoxycarbonylamino, R4(Cr C6)alkoxy(CrC6)alkylamino, trifluoromethyl, trifluoromethyl(C1-C6)alkyl, trifluoromethylcarbonylamino, (CrC6)alkylcarbonylamino, [(C1-C6)alkylcarbonyl][(C1-C6)alkyl]N- , (CrC6)alkylcarbonyl, (C6-Cio)aryl(CrC6)alkoxycarbonylamino, (C6-C10)aryl, (C2-C9)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(CrC6)alkyl]a-(CF2)b-[(C1-C6)alkyl]c- wherein a is 0 or 1 , b is 1, 2, 3 or 4, and c is 0 or 1 ; R5R6N-, R5R6N-carbonyl, R5R6N-carbonylamino, R5R6N- carbonyl(Ci-C6)alkyl and R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (Ci-C6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (C1- C6)alkylsulfonyl or aminocarbonyl;
R5 and R6 are each (CrC6)alkyl optionally independently substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (CrC6)alkylarnino, [(C1-C6)BIkYl]2N-, (CrC6)alkylthio, (C1- C6)alkylsulfinyl, (C1-C6)BIkYlSuIfOnYl or aminocarbonyl; or R5 and R6 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 ((CrCB)alkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(C1-C6)BIkYl]2N-, (C1-C6)alkylthio, (CrC6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl; R2 is R7(C6-C10)aryl or R7(C2-C8)heteroaryl; wherein R7 is one to three groups selected from hydrogen, halo, cyano, nitro, carboxy, hydroxy, amino, amihocarbonyl, R8(Ci-C6)alkyl, R8(C3-C10)cycloalkyl, R8(CrC6)alkoxy, R8(CrC6)alkoxycarbonyl, R8(CrC6)alkylthio, R8(Cr C6)alkylsulfinyl, R8(CrC6)alkylsulfonyl, R8(CrC6)alkyiaminosulfonyl, R8(Cr C6)alkylsulfonylamino, R8(CrC6)alkylamino, R8(CrC6)alkylcarboxy, R8(C1- C6)alkylaminocarbonyl, aminocarbonylamino, R8(CrC6)alkylaminocarbonylamino, aminocarbonyl(CrC6)alkyl, R8(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, aminocarbonyl-0-, amino(CrC6)alkoxycarbonyl, R8(Ci-C6)alkylaminocarbonyl-O-, R8(C1-C6)alkylamino(C1- C6)alkoxycarbonyl, R8(CrC6)alkoxycarbonylamino-, R8(C1-C6)alkoxy(C1-C6)alkylamino, trifluoromethyl, trifluoromethoxy, trifluoromethyl(CrC6)alkyl, R8(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b-[(C1-C6)alkyl]c-, wherein a is O or 1 , b is 1 , 2, 3 or 4, and c is O or 1 ; R5R6N-, R5R6N-carbonyl, R5R6N-carbonylamino-, R5R6N-carbonyl(CrC6)alkyl or R5R6N-carbonyl-O-, wherein R5 and R6 are as defined above; wherein R8 is one to three groups selected from hydrogen, (CrC6)a!kyl, (C3- C10)cycloalkyl, (C1-C6)BIkOXy, hydroxy, cyano, carboxy, amino, (CrC6)alkylannino, R5R6N-, (C1- C6)alkylthio, (CrC6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl, wherein R5 and R6 are as defined above;
R3 is hydrogen, halo, cyano, nitro, carboxy, hydroxy, amino, aminocarbonyl, trifluoromethoxy, HF2C-O-, (C3-C10)cycloalkyl, R4(CrC6)alkyl, R4(CrC6)alkoxy, R4(Cr C6)alkylamino, trifluoromethyl, wherein R4 is as defined above; with the proviso that when d is 1 , R1 cannot be (C2-C9)heterocycloalkyl or (C2-
C9)heteroaryl. In certain embodiments, in the compound of Formula I, d is 0 and R1 is (Ci-C6)alkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(CrCβ)alkyl, R4(CrC6)alkoxy, R4(CrC6)alkoxycarbonyl, R4(CrC6)alkylthio, R4(CrC6)alkylsulfinyl, R4(CrC6)alkylsulfonyl, R4(CrC6)alkylaminosulfonyl, R4(CrC6)alkylsulfonylamino, R4(CrC6)alkylamino, R4(Cr C6)alkylcarboxy, R4(C1-C6)alkylaminocarbonyl, aminocarbonylamino, R4(Cr C6)alkylaminocarbonylamino, aminocarbonyl(C1-C6)alkyl, R4(Ci-C6)alkylaminocarbonyl(C1- C6)alkyl, aminocarbonyl-O-, amino(CrC6)alkoxycarbonyl, R4(CrC6)alkylaminocarbonyl-O-, R4(CrC6)alkylamino(Ci-C6)alkoxycarbonyl, R4(C1-C6)alkoxycarbonylamino, R4(Cr C6)alkoxy(C1-C6)alkylamino, trifluoromethyl, trifluoromethyl(CrC6)alkyl, trifluoromethylcarbonylamino, (Ci-C6)alkylcarbonylamino, [(CrC6)alkylcarbonyl][(C1-C6)alkyl]N- , (CrC6)alkylcarbonyl, (C6-C10)aryl(C1-C6)alkoxycarbonylamino, (C6-C10)aryl, (C2-C8)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b-[(C1-C6)alkyl]c- wherein a is 0 or 1 , b is 1 , 2, 3 or 4, and c is 0 or 1; R5R6N-, R5R6N-carbonyl, R5R6N-carbonylamino, R5R6N- carbonyl(CrC6)alkyl and R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (C1-C6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (CrC6)alkylthio, (CrC6)alkylsulfinyI, (C1- C6)alkylsulfonyl or aminocarbonyl;
R5 and R6 are each (Ci-C6)alkyl optionally independently substituted by (C.|-C6)alkoxy, hydroxy, carboxy, amino, (CrC6)alkylamino, [(CrC6)alkyl]2N-, (CrC6)alkylthio, (C1- C6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl; or R5 and R6 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 ((CrC6)alkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(CrC6)alkyl]2N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl.
In certain embodiments, in the compound of Formula I, d is O and R1 is (C3- C10)cycloalkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(Ci-Cβ)alkyl, R4(Cr C6)alkoxy, R4(CrC6)alkoxycarbonyl, R4(CrC6)alkylthio, R4(CrC6)alky!sulfinyl, R4(Cr C6)alkylsulfonyl, R4(C1-C6)alkylaminosulfonyl, R4(CrC6)alkylsulfonylamino, R4(Cr C6)alkylamino, R4(CrC6)alkylcarboxy, R4(C1-C6)alkylaminocarbonyl, aminocarbonylamino, R4(CrC6)alkylaminocarbonylamino, aminocarbonyl(CrC6)alkyl, R4(Cr C6)alkylaminocarbonyl(C1-C6)alkyl, aminocarbonyl-O-, amino(CrC6)alkoxycarbonyl, R4(Cr C6)alkylaminocarbonyl-O-, R4(C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R4(Cr C6)alkoxycarbonylamino, R4(CrC6)alkoxy(CrC6)alkylamino, trifluoromethyl, trifluoromethyl(Cr C6)alkyl, trifluoromethylcarbonylamino, (C1-C6)alkylcarbonylamino, [(C1-C6)alkylcarbonyl][(C1- Cβ)alkyl]N-, (Ci-Cβ)alkylcarbonyl, (C6-C1o)aryl(C1-C6)alkoxycarbonylamino, (C6-C10)aryl, (C2- C9)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b-[(C1- C6)alkyl]c- wherein a is 0 or 1 , b is 1 , 2, 3 or 4, and c is 0 or 1 ; R5R6N-, R5R6N-carbonyl, R5R6N- carbonylamino, R5R6N-carbonyl(CrC6)alkyl and R5R6N-carbonyl-0-; wherein R4 is one to three groups selected from hydrogen, (CrC6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (C1-Cβ)alkytthio, (CrC6)alkylsulfinyl, (C1- C6)alkylsulfonyl or aminocarbonyl; R5 and R6 are each (CrC6)alkyl optionally independently substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (CrC6)alkylamino, [(Ci-C6)alkyl]2N-, (CrC6)alkylthio, (C1- Cβ)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl; or R5 and R6 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 ((CrC6)alkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(Ci-C6)alkyl]2N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl.
In certain embodiments, in the compound of Formula I, d is O and R1 is (C2- Cg)heterocycloalkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(Cr C6)alkyl, R4(CrC6)alkoxy, R4(CrC6)alkoxycarbonyl, R4(C1-C6)alkylthio, R4(CrC6)a!kylsulfinyl, R4(CrC6)alkylsulfonyl, R4(CrC6)alkylaminosulfonyl, R4(C1-C6)alkylsulfonylamino, R4(Cr C6)alkylamino, R4(CrC6)alkylcarboxy, R4(C1-C6)alkylaminocarbonyl, aminocarbonylamino, R4(CrC6)a!kylaminocarbonylamino, aminocarbonyl(CrC6)a!kyl, R4(Cr
C6)alkylaminocarbonyl(C1-C6)alkyl, aminocarbonyl-O-, amino(C1-C6)alkoxycarbonyl, R4(Cr C6)alkylaminocarbonyl-O-, R4(C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R4(C,- C6)alkoxycarbonylamino, R4(C1-C6)alkoxy(Ci-C6)alkylamino, trifluoromethyl, trifluoromethyl(Cr C6)alkyl, trifluoromethylcarbonylamino, (CrC^alkylcarbonylamino, [(C1-C6)aIkylcarbonyl][(C1- C6)alkyl]N-, (CrC6)alkyicarbonyl, (C6-C1o)aryl(C1-C6)alkoxycarbonylamino, (C6-C10)aryl, (C2- C9)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b-[(C.r C6)alkyl]c- wherein a is O or 1 , b is 1 , 2, 3 or 4, and c is O or 1 ; R5R6N-, R5R6N-carbonyl, R5R6N- carbonylamino, R5R6N-carbonyl(CrC6)alkyl and R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (CrC6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (C1- C6)alkylsulfonyl or aminocarbonyl; R5 and R6 are each (Ci-C6)alkyl optionally independently substituted by (Ci-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, [(CrCe)alkyl]2N-, (CrC6)alkylthio, (C1-
C6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl; or R5 and R6 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,-C6)alkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(CrC6)alkyl]2N-, (C1-C6)alkylthio, (CrC6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl. In certain embodiments, in the compound of Formula I, d is O and R1 is (C2-
Cg)heteroaryl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(CrC6)alkyl, R4(Cr Cβ)alkoxy, R4(CrC6)alkoxycarbonyl, R4(CrC6)alkylthio, R4(CrC6)alkylsulfinyl, R4(Cr C6)alkylsulfonyl, R4(CrC6)alkylaminosulfonyl, R4(C1-C6)alkylsulfonylamino, R4(Cr C6)alkylamino, R4(CrC6)alkylcarboxy, R4(CrC6)alkylaminocarbonyl, aminocarbonylamino, R4(CrC6)alkylaminocarbonylamino, aminocarbonyl(CrC6)alkyl, R4(Cr C6)alkylaminocarbonyl(C1-C6)alkyl, aminocarbonyl-O-, amino(Ci-C6)alkoxycarbonyi, R4(C1,- C6)alkylaminocarbonyl-0-, R4(Ci-C6)alkylamino(C1-C6)alkoxycarbonyl , R4(Cr C6)alkoxycarbonylamino, R4(C1-C6)alkoxy(C1-C6)alkylamino, trifluoromethyl, trifluoromethyl(Ci- C6)alkyl, trifluoromethylcarbonylamino, (C1-C6)alkylcarbonylamino, [(Ci-C6)alkylcarbonyl][(Cr C6)alkyl]N-, (CrC6)alkylcarbonyl, (C6-Cio)aryl(CrC6)alkoxycarbonylamino, (C6-C10)aryl, (C2- C9)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b-[(Cr C6)alkyl]c- wherein a is O or 1 , b is 1 , 2, 3 or 4, and c is O or 1; R5R6N-, R5R6N-carbonyl, R5R6N- carbonylamino, R5R6N-carbonyl(CrC6)alkyl and R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (CrCβ)alkoxy, hydroxy, carboxy, HO3S-, amino, (C1-C6)alkylamino, R5R6N-, (CrC6)alkylthio, (CrCβ)alkylsulfinyl, (C1- C6)alkylsulfonyl or aminocarbonyl; •
R5 and R6 are each (Ci-C6)alkyl optionally independently substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (Ci-C6)alkylamino, [(C1-C6)alkyl]2N-, (Ci-C6)alkylthio, (C1- C6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl; or R5 and R6 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 ((CrC6)alkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(CrC6)alkyl]2N-, (CrC6)alkylthio, (CrCβ)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl. In certain embodiments, in the compound of Formula I, d is 1 , X is -O-, and R1 is (C1- C6)alkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(CrC6)alkyl, R4(Cr C6)alkoxy, R4(CrC6)alkoxycarbonyl, R4(CrCβ)alkylthio, R4(CrC6)alkylsulfinyl, R4(Cr C6)alkylsulfonyl, R4(CrC6)alkylaminosulfonyl, R4(Ci-C6)alkylsulfonylamino, R4(Cr
C6)alkylamino, R4(C1-C6)alkylcarboxy, R4(C1-C6)alkylaminocarbonyl, aminocarbonylamino, R4(CrC6)alkylaminocarbonylamino, aminocarbonyl(CrCβ)alkyl, R4(d- C6)alkylaminocarbonyl(Ci-C6)alkyl, aminocarbonyl-O-, amino(CrCβ)alkoxycarbonyl, R4(C1- C6)alkylaminocarbonyl-0-, R4(C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R4(Cr C6)alkoxycarbonylamino, R4(C1-C6)alkoxy(C1-C6)alkylamino, trifluoromethyl, trifluoromethyl(Cr C6)alkyl, trifluoromethylcarbonylamino, (C-rCeJalkylcarbonylamino, [(C1-C6)alkylcarbonyl][(C1- C6)alkyl]N-, (C1-Cβ)alkylcarbonyl, (C6-C10)aryl(C1-C6)alkoxycarbonylamino, (C6-C10)aryl, (C2- C9)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(CrC6)alkyl]a-(CF2)b-[(C.,- C6)alkyl]c- wherein a is 0 or 1 , b is 1 , 2, 3 or 4, and c is 0 or 1 ; R5R6N-, R5RβN-carbonyl, R5R6N- carbonylamino, R5R6N-carbony!(Ct-C6)alkyl and R5RβN-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (CrC6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (CrC6)alkylthio, (C.rC6)alkylsulfinyl, (C1- C6)alkylsulfonyl or aminocarbonyl;
R5 and R6 are each (C-i-C6)alkyl optionally independently substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (CrC6)alkylamino, [(C1-C6)alkyl]2N-, (CrC6)alkylthio, (C1- C6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl; or R5 and R6 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 ((CrC6)aIkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(CrCβ)a\ky\]2H-, (CrC6)alkylthio, (CrC6)alkylsulfinyI, (CrC6)alkylsulfonyl or aminocarbonyl.
In certain embodiments, in the compound of Formula I, d is 1 , X is R9N- wherein R9 is H -, and R1 is (Ci-C6)alkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(Cr C6)alkyl, R4(CrC6)alkoxy, R4(CrC6)alkoxycarbonyl, R4(CrC6)alkylthio, R4(CrC6)alkylsulfinyl, R4(C1-C6)alkylsulfonyl, R4(CrC6)alkylaminosulfonyl, R4(CrC6)alkylsulfonylamino, R4(C,- C6)alkylamino, R4(CrC6)alkylcarboxy, R4(CrC6)alkylaminocarbonyl, aminocarbonylamino, R4(C1-C6)alkylaminocarbonylamino, aminocarbonyl(C1-C6)alkyl, R4(Cr C6)alkylaminocarbonyl(Ci-C6)alkyl, aminocarbonyl-O-, amino(CrC6)alkoxycarbonyl, R4(Cr C6)alkylaminocarbonyl-O-, R4(C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R4(Ci- C6)alkoxycarbonylamino, R4(Ci-C6)alkoxy(CrC6)alkylamino, trifluoromethyl, trifluoromethyl(Cr C6)alkyl, trifluoromethylcarbonylamino, (Ci-C6)alkylcarbonylamino, [(CrC6)alkylcarbonyl][(Cr C6)alkyl]N-, (CrCeJalkylcarbonyl, (C6-C10)aryl(CrCe)alkoxycarbonylamino, (C6-C10)aryI, (C2- CB)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(CrC6)alkyl]a-(CF2)b-[(C1- C6)alkyl]c- wherein a is 0 or 1 , b is 1 , 2, 3 or 4, and c is 0 or 1 ; R5R6N-, R5R6N-carbonyl, R5R6N- carbonylamino, R5R6N-carbonyl(CrC6)alkyl and R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (Ci-C6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (C1- C6)alkylsulfonyl or aminocarbonyl; R5 and R6 are each (CrC6)alkyl optionally independently substituted by (C1-C6)BIkOXy, hydroxy, carboxy, amino, (C1-C6)alkylamino, [(C1-C6)BIkYl]2N-, (CrC6)alkylthio, (C1- C6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl; or R5 and R6 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 ((Ci-C6)alkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1- C6)alkyiamino, [(CrC6)alkyl]2N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl.
In certain embodiments, in the compound of Formula I, d is 1 , X is R9N- wherein R9 is (CrC6)alkyl, and R1 is (CrCe^lkyl, wherein the alkyl moiety of (CrC6)alkyi or R9 is independently optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(C-,-C6)alkyl, R4(Cr C6)alkoxy, R4(CrC6)alkoxycarbonyl, R4(CrC6)alkylthio, R4(CrC6)alkylsulfinyl, R4(Cr C6)alkylsulfonyl, R4(C1-C6)alkylaminosulfonyl, R4(C1-C6)alkylsulfonylamino, R4(Cτ C6)alkylamino, R4(CrC6)alkylcarboxy, R4(CrC6)alkylaminocarbonyl, aminocarbonylamino, R4(CrC6)alkylaminocarbonylamino, aminocarbonyl(CrC6)alky!, R4(Cr C6)alkylaminocarbonyl(C1-C6)alkyl, aminocarbonyl-O-, amino(C1-C6)alkoxycarbonyl, R4(Cr C6)alkylaminocarbonyl-O-, R4(C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R4(Cr C6)alkoxycarbonylamino, R4(CrC6)alkoxy(CrC6)alkylamino, trifluoromethyl, trifluoromethyl(Ci- C6)alkyl, trifluoromethylcarbonylamino, (CrC6)alkylcarbonylamino, [(Ci-C6)alkylcarbonyl][(Cr C6)alkyl]N-, (CrC6)alkylcarbonyl, (C6-Ci0)aryl(C1-C6)alkoxycarbonylamino, (C6-C10)aryl, (C2- C9)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b-[(C1- C6)alkyl]c- wherein a is O or 1 , b is 1 , 2, 3 or 4, and c is O or 1 ; R5R6N-, R5R6N-carbonyl, R5R6N- carbonylamino, R5R6N-carbonyl(C.i -C6)alkyl and R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (CrC6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (CrCβ)a!kylthio, (CrC6)alkylsulfinyl, (C1- C6)alkylsulfonyl or aminocarbonyl;
R5 and R6 are each (CrC6)alkyl optionally independently substituted by (C1-C6)BIkOXy, hydroxy, carboxy, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2N-, (CrC8)alkylthio, (C1- C6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl; or R5 and R6 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, S1 S(O), S(O)2, NH and ((CrC6)alkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(CrC6)alkyl]2N-, (CrC6)alkylthio, (CrCβ)alkylsulfinyl, (C1-C6)alkylsulfonyl or aminocarbonyl.
In certain embodiments, in the compound of Formula I, d is 1 , X is -0-, and R1 is (C3- C10)cycloalkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(C1-C6)alkyl, R4(C1- C6)alkoxy, R4(CrC6)alkoxycarbonyl, R4(CrC6)alkylthio, R4(CrC6)alkylsulfinyl, R4(Cr C6)alkylsulfonyl, R4(C1-Ca)alkylaminosulfonyl, R4(C1-C6)alkylsulfonylamino, R4(C,- C6)alkylamino, R4(CrC6)alkylcarboxy, R4(C1-C6)alkylaminocarbonyl, aminocarbonylamino, R4(C1-C6)alkylaminocarbonylamino, aminocarbonyl(C1-C6)alkyl, R4(Cr C6)aIkylaminocarbonyl(C1-C6)alkyl, aminocarbonyl-O-, amino(Ci-C6)alkoxycarbonyl, R4(Cr C6)alkylaminocarbonyl-O-, R4(C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R4(Cr C6)alkoxycarbonylamino, R4(C1-Ce)alkoxy(C1-C6)alkylamino, trifluoromethyl, trifiuoromethyl(Cr C6)alkyl, trifluoromethylcarbonylamino, (CrCeJalkylcarbonylamino, [(Ci-C6)alkylcarbonyl][(C1- C6)alkyl]N-, (CrCeJalkylcarbonyl, (C6-C10)aryl(C1-C6)alkoxycarbonyiamino, (C6-C10)aryl, (C2- C9)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b-[(C1-
C6)alkyl]0- wherein a is O or 1 , b is 1 , 2, 3 or 4, and c is O or 1 ; R5R6N-, R5R6N-carbonyl, R5R6N- carbonylamino, R5R6N-carbonyl(CrC6)alkyl and R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (CrC6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (CrC6)alkylthio, (CτC6)alkylsulfinyl, (C1- C6)alkyisulfonyl or aminocarbonyl;
R5 and R6 are each (C,-C6)alkyl optionally independently substituted by (Ci-Ce)alkoxy, hydroxy, carboxy, amino, (CrC6)alkylamino, [(C1-C6)alkyl]2N-, (CrC6)alkylthio, (Cr C6)alkylsulfinyl, (C1-C6)alkylsulfonyl or aminocarbonyl; or R5 and R6 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 ((C1-C6)alkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(Ci-C6)alkyl]2N-, (C1-C6)alkylthio, (CrC6)alkylsulfinyl, (C.rC6)alkylsulfonyl or aminocarbonyl.
In certain embodiments, in the compound of Formula I, d is 1 , X is R9N- wherein R9 is H -, and R1 is (C3-Ci 0)cycloalkyl optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(Cr Cβ)alkyl, R4(CrC6)alkoxy, R4(CrC6)alkoxycarbonyl, R4(CrC6)alkylthio, R4(CrC6)alkylsulfinyl, R4(CrC6)alkylsulfonyl, R4(CrC6)alkylaminosulfonyl, R4(CrC6)alkylsulfonylamino, R4(Cr C6)alkylamino, R4(CrC6)alkylcarboxy, R4(CrC6)alkylaminocarbonyl, aminocarbonylamino, R4(CrC6)alkylaminocarbonylamino, aminocarbonyl(CrC6)alkyl, R4(Cr
C6)alkylaminocarbonyl(Ci-C6)alkyl, aminocarbonyl-O-, amino(CrCβ)alkoxycarbonyl, R4(Cr C6)alkylaminocarbonyl-O-, R4(CrC6)alkylamino(CrC6)alkoxycarbonyl, R4(Cr C6)alkoxycarbonylamino, R4(CrC6)alkoxy(C1-C6)alkylamino, trifluoromethyl, trifluoromethyl(Cr C6)alkyl, trifluoromethylcarbonylamino, (C1-C6)alkylcarbonylamino, [(Ci-C6)alkylcarbonyl][(C.)- C6)alkyl]N-, (CrCB)alkylcarbonyl, (C6-C10)aryl(C1-C6)alkoxycarbonylamino, (C6-C10)aryl, (C2- C9)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(CrC6)alkyl]a-(CF2)b-[(Cr C6)alkyl]c- wherein a is O or 1 , b is 1 , 2, 3 or 4, and c is O or 1; R5R6N-, R5R6N-carbonyl, R5R6N- carbonylamino, R5R6N-carbonyl(CrC6)alkyl and R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (CrC6)alkoxy, hydroxy, carboxy, HO3S-, amino, (C1-C6)alkylamino, R5R6N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (C1- C6)alkylsulfonyl or aminocarbonyi;
R5 and R6 are each (C1-C6)BIk^ optionally independently substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (CrC6)alkylamino,
Figure imgf000013_0001
(CrC6)alkylthio, (C1- C6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl; or R5 and R6 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 ((CrC6)alkyl)-N-; and the ring so formed is optionally substituted by (Ci-C6)alkoxy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(CrC6)alkyl]2N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl.
In certain embodiments, in the compound of Formula I, d is 1, X is R9N- wherein R9 is (CrCe^lkyl, and R1 is (C3-C10)cycloalkyl, wherein the alkyl or cycloalkyl moieties of (C3- Cio)cycloalkyl or R9 are independently optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(CrC6)alkyl, R4(CrC6)alkoxy, R4(CrC6)alkoxycarbonyl, R4(CrC6)alkylthio, R4(CrC6)alkylsulfinyl, R4(CrC6)alkylsulfonyl, R4(CrC6)alkylaminosulfonyl, R4(Cr C6)alkylsulfonylamino, R4(CrC6)alkylamino, R4(CrC6)alkylcarboxy, R4(Cr C6)alkylaminocarbonyl, aminocarbonylamino, R4(CrC6)alkylaminocarbonylamino, aminocarbonyl(CrC6)alkyl, R4(C1-C6)alkylaminocarbonyl(Ci-Cβ)alkyl, aminocarbonyl-O-, amino(C1-C6)alkoxycarbonyl, R4(CrC6)alkylaminocarbonyl-O-, R4(C1-C6)alkylamino(C1- Cβ)alkoxycarbonyl, R4(CrC6)alkoxycarbonylamino, R4(C1-C6)alkoxy(C1-C6)alkylamino, trifluoromethyl, trifluoromethyl(CrC6)alkyI, trifluoromethylcarbonylamino, (C1- C6)alkylcarbonylamino, [(CrC6)alkylcarbonyl][(C1-C6)alkyl]N-, (CrC6)alkylcarbonyl, (C6- C10)aryl(C1-C6)alkoxycarbonylamino, (C6-C10)aryI, (C2-C9)heteroaryl, R4(CrC6)alkyl-F2C-) HF2C-O-, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b-[(C1-C6)a)kyl]i:- wherein a is 0 or 1, b is 1 , 2, 3 or 4, and c is 0 or 1 ; R5R6N-, R5R6N-carbonyl, R5R6N-carbonylamino, R5R6N-carbonyl(Ci-C6)alkyl and R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (CrC6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (CrC6)alkylthio, (C1-C6)alkylsulfinyl, (C1- C6)alkylsulfonyl or aminocarbonyl; R5 and R6 are each (C1-C6)BlRyI optionally independently substituted by (C1-C6)BIkOXy, hydroxy, carboxy, amino, (C1-C6)alkylamino, [(CrC6)alkyl]2N-, (Ci-C6)alkylthio, (C1- C6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl; or R5 and R6 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 ((CrC6)alkyl)-N-; and the ring so formed is optionally substituted by (C1-C6)BIkOXy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(CrC6)alkyl]2N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (CrCeJalkylsulfonyl or aminocarbonyl.
In certain embodiments, in the compound of Formula I, d is O and R1 is (C2- C9)heterocycloalkyl, [(CrC6)alkyl]2N-, [(CrC6)alkyl][(C3-C10)cycloalky!]N-, wherein the alkyl, cycloalkyl, and heterocycloalkyl, moieties of (C2-C9)heterocycloalkyl, [(Ci-C6)alkyl]2N-, [(C1- C6)alkyl][(C3-C10)cycIoalkyl]N- are independently optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, aminosulfonyl, R4(CrC6)alkyl, R4(CrC6)alkoxy, R4(CrC6)alkoxycarbonyl, R4(CrC6)alkylthio, R4(CrC6)alkylsulfinyl, R4(CrCs)alkylsulfonyl, R4(CrCB)alkylaminosulfonyl, R4(C1-C6)alkylcarbonylaminosulfonyl, R4(Ci-C6)alkylsulfonylamino, R4(C1-C6)alkylamino, R4(CrC6)alkylcarboxy, R4(C1-C6)alkylaminocarbonyl, aminocarbonylamino, R4(Cr C6)alkylaminocarbonylamino, aminocarbonyl(CrC6)alkyl, R4(CrC6)alkylaminocarbonyl(Cr C6)alkyl, aminocarbonyl-O-, amino(CrC6)alkoxycarbonyl, R4(CrC6)alkylaminocarbonyl-O-, R4(C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R4(C1-C6)alkoxycarbonylamino, R4(Cr C6)alkoxy(CrC6)alkylamino, trifluoromethyl, trifluoromethyl(CrC6)alkyl, trifluoromethylcarbonylamino, trifluoromethylsulfonylamino, (CrC6)alkylcarbonylamino, [(Cr
C6)alkylcarbonyl][(Ci-C6)alkyl]N-, (CfCeJalkylcarbonyl, (C6-C10)aryl(Cr
C6)alkoxycarbonylamino, (C6-C10)aryl, (C2-C9)heteroaryl, R4(Ct-C6)alkyl"-F2C-, HF2C-O-, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b-[(C1-C6)alkyl]c- wherein a is 0 or 1 , b is 1 , 2, 3 or 4, and c is 0 or 1 ; R5R6N-, R5R6N-carbonyl, R5R6N-carbonylamino, R5R6N-carbonyl(C1-C6)alkyl and
R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (Ci-C6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (C1-
C6)alkylsulfonyl, aminocarbonyl or aminosulfonyl; R5 and R6 are-each (CrC6)alkyl optionally independently substituted by (Ci-C6)alkoxy, hydroxy, carboxy, amino, (CrCβ)alkylamino, [(CrC6)alkyl]2N-, (CrC6)alkylthio, (C1-
C6)alkylsulfinyl, (CrC6)alkylsulfonyI or aminocarbonyl; or R5 and R6 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 ((CrC6)alkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1-
C6)alkylamino, [(CrC6)alkyl]2N-, (CrC6)alkylthio, (CrC6)alkylsulfinyI, (C1-C6)alkylsulfonyl or aminocarbonyl.
In certain embodiments, R3 is halo, cyano, nitro, carboxy, hydroxy, amino, aminocarbonyl, trifluoromethoxy, HF2C-O-, (C3-Ci0)cycloalkyl, R4(CrC6)alkyl, R4(CrC6)alkoxy,
R4(CrC6)alkylamino, trifluoromethyl, wherein R4 is one to three groups selected from hydrogen, (CrC6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (CrC6)alkylthio, (C1-CB)alkylsulfinyl, (C1-
C6)alkylsulfonyl or aminocarbonyl; R5 and R6 are each (C1-CB)alkyl optionally independently substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, [(Ci-C6)alkyl]2N-, (C1-C6)alkylthio, (C1-
C6)alkylsulfinyl, (CrC6)alkylsulfonyI or aminocarbonyl; or R5 and R6 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 ((CrC6)alkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1-
C6)alkylamino, [(CrC6)alkyl]2N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyi.
Those of skill in the art given the benefit of the present disclosure will appreciate that when d of (X)d of Formula I is O, the variable R1 is directly bonded to the main structure, notably a pyridyl ring carbon atom. That is, when d is O, R1 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:
Figure imgf000016_0001
Those of skill in the art given the benefit of the present disclosure will appreciate that when X of (X)d of Formula I is R9N-, wherein R8 is (CrC6)alkyl, the alkyl moiety of R9 can be substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, aminosulfonyl, R4(CrC6)alkyl, R4(Cr C6)alkoxy, R4(CrC6)alkoxycarbonyl, R4(CrC6)alkylthio, R4(CrC6)alkylsulfinyl, R4(C1-
C6)alkylsulfonyl, R4(C1-C6)alkylaminosulfonyl, R4(Ci-C6)alkylcarbonylaminosulfonyl, R4(Cr C6)alkylsulfonylamino, R4(CrC6)alkylamino, R4(CrC6)alkylcarboxy, R4(C,- C6)alkylaminocarbonyl, aminocarbonylamino, R4(CrC6)alkylaminocarbonyiamino, aminocarbonyl(CrC6)alkyl, R4(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, aminocarbonyl-O-, amino(Ci-C6)alkoxycarbonyl, R4(Ci-C6)alkylaminocarbonyl-O-, R4(C1-C6)alkylamino(C1- C6)alkoxycarbonyl, R4(CrC6)alkoxycarbonylamino, R4(C1-C6)alkoxy(C1-C6)aIkylamino, trifiuoromethyl, trifluoromethyl(Ci-C6)alkyl, trifluoromethylcarbonylamino, trifiuoromethylsulfonylamino, (C1-C6)alkylcarbonylamino, [(C1-C6)alkylcarbonyl][(C1-C6)alkyl]N-, (CrC6)alkylcarbonyl, (C6-C10)aryl(CrC6)alkoxycarbonylamino, (C6-C10)aryl, (C2-C9)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b-[(CrCe)alkyl]c- wherein a is 0 or 1 , b is 1, 2, 3 or 4, and c is 0 or 1; R5R6N-, R5R6N-carbonyl, R5R6N-carbonylamino, R5R6N- carbonyl(C1-C6)alkyl and R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (C1-C6)BIkOXy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R8N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (C1- C6)alkylsulfonyl, aminocarbonyl or aminosulfonyl;
R5 and R6 are each (Ci-C6)alkyl optionally independently substituted by (CrC^alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2N-, (CrC6)alkylthio, (C1- C6)alkyisulfinyl, (CrCeJalkylsulfonyl or aminocarbonyl; or R5 and R6 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 ((C1-C6)alkyl)-N-; and the ring so formed is optionally substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(C1-C6)BlRyI]2N-, (C,-C6)alkylthio, (CrC6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl.
In certain embodiments, in the compounds of Formula I1 R1 is (C2-C9)heterocycloalkyl optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO3S-, aminosulfonyl, (Cβ-Ci0)aryl, (C2-C9)heteroaryl1 R4(CrC6)alkyl, R4(Cr C6)alkoxy, R4(C1-Cβ)alkylthio, R4(CrC6)alkylamino and R4(CrC6)alkoxy(CrC6)alkylamino, wherein R4 is as defined above.
In certain embodiments, in the compounds of Formula I, R2 is R7-phenyl or R7-pyridinyl, wherein R7 is as defined above. In certain embodiments, in the compounds of Formula I1 R1 is (C2-C9)heterocycloalkyl optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO3S-, aminosulfonyl, (C6-Ci0)aryl, (C2-C9)heteroaryl, R4(CrC6)alkyl, R4CC1- C6)alkoxy, R4(CrC6)alkylthio, R4(CrC6)alkylamino and R4(C1-C6)alkoxy(C1-C6)alkylamino; and R2 is R7-phenyl or R7-pyridinyl, wherein R4 and R7 are as defined above. In certain embodiments, in the compounds of Formula I, R1 is pyrrolidinyl, piperidinyl or piperazinyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO3S-, aminosulfonyl, (C6-C10)aryl, (C2-C9 )heteroaryl, R4(Ct- Cβ)alkyl, R4(CrC6)alkoxy, R4(CrC6)alkylthio, R4(CrC6)alkylamino and R4(CrC6)alkoxy(Cr C6)alkylamino, wherein R4 is as defined above. In certain embodiments, in the compounds of Formula I, R1 is pyrrolidinyl, piperidinyl or piperazinyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO3S-, aminosulfonyl, (C6-C10)aryl, (C2-C9)heteroaryl, R4(C,- C6)alkyl, R4(CrC6)alkoxy, R4(CrC6)alkylthio, R4(CrCB)alkylamino and R4CC1-C6)BIkOXy(C1- C6)alkylamino; and R2 is R7-phenyl or R7-pyridinyl, wherein R4 and R7 are as defined above. In certain embodiments, in the compounds of Formula I, R1 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, HO3S-, aminosulfonyl, (C6-Ci0)aryl, (C2-C9)heteroaryl, R4(CrC6)alkyl, R4(Cr C6)alkoxy, R4(C1-C6)alkylthio, R4(C1-C6)alkylamino and R4(C1-C6)alkoxy(C1-C6)alkylamino, wherein R4 is as defined above; and R2 is R7-phenyl or R7-pyridinyl, and wherein R7 is as defined above.
In certain embodiments, in the compounds of Formula I, R2 is R7-phenyl or R7-pyridinyl, wherein R7 is selected from the group consisting of: cyano, halo, hydroxy, amino, R8(Cr C6)alkyl, R8(CrC6)alkoxy, R8(CrC6)alkylthio, R8(C3-C10)cycloalkyl, trifluoromethyl and trifluoromethoxy, and wherein R8 is as defined above. In certain embodiments, in the compounds of Formula I, R3 is hydrogen, halo, cyano, nitro, hydroxy, trifluoromethoxy, HF2C-O- ortrifluoromethyl.
In certain embodiments, in the compounds of Formula I, R1 is pyrrolidinyl, piperidinyl or piperazinyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO3S-, aminosulfonyl, (C6-C10)aryl, (C2-CB)heteroaryl, R4(Cr C6)alkyl, R4(CrC6)alkoxy, R4(CrC6)alkylthio, R4(CrC6)alkylamino and R4(CrC6)alkoxy(Cr Cβ)alkylamino; and R3 is hydrogen, halo, cyano, nitro, hydroxy, trifluoromethoxy, HF2CO- or trifluoromethyl, wherein R4 is as defined above.
In certain embodiments, in the compounds of Formula I, R2 is R7-phenyl or R7-pyridinyl; and R3 is hydrogen, halo, cyano, nitro, hydroxy, trifluoromethoxy, HF2CO- or trifluoromethyl, wherein R7 is as defined above.
In certain embodiments, in the compounds of Formula I, R1 is pyrrolidinyl, piperidinyl or piperazinyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO3S-, aminosulfonyl, (C6-Ci0)aryl, (C2-C9)heteroaryl, R4(Cr C6)alkyl, R4(CrC6)alkoxy, R4(C1-C6)alkylthio, R4(CrC6)alkylamino and R4(CrC6)alkoxy(Cr C6)alkylamino; R2 is R7-phenyl or R7-pyridinyl, wherein R7 is selected from the group consisting of: cyano, halo, hydroxy, amino, R8(CrC6)alkyl, R8(CrC6)alkoxy, R8(CrC6)alkylthio, R8(C3- Cio)cycloalkyl, trifluoromethyl and trifluoromethoxy; and R3 is hydrogen, halo, cyano, nitro, hydroxy, trifluoromethoxy, HF2C-O- ortrifluoromethyl, wherein R4 and R8 is as defined above. In certain embodiments, the presently disclosed compounds of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, are selected from the group consisting of:
Ethyl 1-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-yl)piperidine-4-carboxylate;
1-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-yl)piperidine-4-carboxylic acid;
2-(5-(5-chloro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)-3~hydroxypropanoic acid;
2-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)-3-hydroxypropanoic acid; 2-(5-(5-chloro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)butanoic acid;
2-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)butanoic acid;
2-(5-(5-chloro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)propanoic acid; and 2-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)propanoic acid.
With regard to the terms R4(CrC6)alkyl, R7(C6-C10)aryl, R8(CrC6)alkyl and similar terms used throughout this disclosure such as, e.g., R4(CrC6)alkoxy, R4(Ct- C6)alkoxycarbonyl, R7(C2-C9)heteroaryl, R8(C3-C10)cycloalkyl, R8(CrC6)alkoxy, etc., those of skill in the art will appreciate that when R4, R7, or R8, etc. (or more generally referred to here as "R group(s)") is hydrogen, the moiety to which the R group is attached is effectively unsubstituted by a group other than hydrogen. In that regard, 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. For example, in the term R4(Ci-C6)alkyl, where R4 is three groups selected from hydrogen and (CrC6)alkyl is a n-butyl radical, the resulting group is n-butyl having the chemical formula C4H9. In another example, in the term R7(C6-C10)aryl, wherein R7 is two groups selected from hydrogen and (C6-Ci0)aryl is a phenyl radical, the resulting group is phenyl radical having the chemical formula C6Hs. Of course, other variations will be readily apparent to those of skill in the art given the benefit of the present disclosure.
Throughout this disclosure, with regard to general formulas, 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. For example, the R3 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.
Further, when such a group is hydrogen, the other unsubstituted ring atoms continue to be "substituted" by an appropriate number of hydrogen atoms. Using Formula I as merely an example, when R3 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. As such, when R3 is hydrogen, the hydrogen atoms present on pyridyl ring prior to substitution are unaffected by the R3 substitution. Of course, other variations will be readily apparent to those of skill in the art given the benefit of the present disclosure.
In another aspect, a pharmaceutical composition is disclosed for (a) 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 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. In another aspect, a method Is disclosed for agonizing the TPO receptor in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
In another aspect, a method is disclosed 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.
In certain embodiments, 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.
In certain embodiments, the agent is selected from the group consisting of: G-CSF, GM-CSF, TPO, M-CSF, EPO, Gro-beta, IL-11 , SCF, FLT3 ligand, LIF, 1L-3, IL-6, IL-I, Progenipoietin, NESP, SD-01 , IL-8, and IL-S or a biologically active derivative of any of said agents. . in another aspect, a method is disclosed 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.
In another aspect, a method is disclosed 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.
In certain embodiments, 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, In certain embodiments, the mobilizing agent is selected from the group consisting of: G-CSF, GM-CSF, TPO, EPO, Gro-beta, 1 L-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. In certain embodiments, the agent causes terminal differentiation in certain types of hematopoietic malignancies. With regard to 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. In that regard, 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,
Definitions
As used herein, the term "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.
As used herein, the term "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. For example, 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. Of course, other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. As such, those of skill in the art will appreciate that certain of the presently disclosed compounds having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. 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.
As used herein, the term "(Ci-C6)alky!" means a saturated linear or branched free radical consisting essentially of 1 to 6 carbon atoms and a corresponding number of hydrogen atoms. Exemplary (CrC6)alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. Of course, other (CrC6)alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
As used herein, the term "(C3-Cio)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. As such, (C3-C10)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 (C3-C10)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. Of course, other (C3-Ci0)cycloalkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
As used herein, the term "(C2-C9)heterocycloalkyl" means a nonaromatic free radical having 3 to 10 atoms (i.e., ring atoms) thatform 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. As such, (C2-C9)heterocycloalkyl groups can be monocyclic or multicyclic. Individual rings of such multicyclic heterocycloalkyl groups can have different connectivities, e.g., fused, bridged, spiro, etc. in addition to covalent bond substitution. Exemplary (C2-C9)heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isdxazolidinyl, 1 ,3-oxazoIidin-3-yI, 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, 1 ,2- tetrahydrodiazin-2-yl, 1 ,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, piperizin-2- onyl, piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1 ,4- dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyI, 2,5-diazabicyclo[2.2.1]heptanyI, 2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1 ,2- ajpyrazinyl, 3-azabicyclo[4.1.OJheptanyl, 3~azabicyclo[3.1.0]hexanyl 2-azaspiro[4.4]nonanyl, 7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, octahydro-1 H-indolyl, etc. In general, the (C2-C9)heterocycloalkyl group typically is attached to the main structure via a carbon atom or a nitrogen atom. Of course, other (C2- C9)heterocycloalkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
As used herein, the term "(C2-C9)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. As such, (C2-C9)heteroaryi 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 (C2-C9)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-triazinyI, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro- quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indoiizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinyl, etc. In general, the (C2-C9)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. Of course, other (C2-C9)heteroaryl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. As used herein, the term "(Cβ-C10)aryr means phenyl or naphthyl. As used herein, the term "halo" means fluorine, chlorine, bromine, or iodine. As used herein, the term "amino" means a free radical having a nitrogen atom and 1 to 2 hydrogen atoms. As such, the term amino generally refers to primary and secondary amines. In that regard, as used herein and in the appended claims, a tertiary amine is represented by the general formula RR1N-, wherein R and R' are carbon radicals that may or may not be identical, Nevertheless, the term "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.
Abbreviations ACN refers to acetonitrile. DMF refers to N,N-dimethylformamide. DMSO refers to 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.
Additional features and advantages of compounds disclosed herein will be apparent from the following detailed description of certain embodiments.
DETAILED DESCRIPTION
Although specific embodiments of the present disclosure will now be described with reference to the preparations and schemes, it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible specific embodiments which can represent applications of the principles of the present disclosure. Various changes and modifications will be obvious to those of skill in the art given the benefit of the present disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which this disclosure belongs. Although other compounds or methods can be used in practice or testing, certain preferred methods are now described in the context of the following preparations and schemes. PREPARATION A
Figure imgf000025_0001
PREPARATION B
Figure imgf000026_0001
Figure imgf000026_0002
B-2
Figure imgf000026_0003
PREPARATION C
Figure imgf000027_0001
Figure imgf000027_0002
C-2
Figure imgf000027_0003
PREPARATION D
Figure imgf000028_0001
D-I D-2
Figure imgf000028_0002
Figure imgf000028_0003
D-3
PREPARATION E
Figure imgf000029_0001
Figure imgf000029_0002
PREPARATION F
Figure imgf000030_0001
F-2 F-3
Figure imgf000030_0002
HoN
SCHEME 1
Figure imgf000031_0001
B-2 A-3
Figure imgf000031_0002
SCHEME 2
Figure imgf000032_0001
C-2 A-2
Figure imgf000032_0002
SCHEME 3
Figure imgf000033_0001
SCHEME 4
Figure imgf000034_0001
D-3 A-2
Figure imgf000034_0002
IV-I
Figure imgf000034_0003
SCHEME 5
Figure imgf000035_0001
E-3 F-4
Figure imgf000035_0002
In reaction 1 of Preparation A, a compound of formula A-1 is reacted with sulfuryl chloride and stirred preferably at 40-600C 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.
In 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 00C 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.
In 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 00C. 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. In 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. In certain embodiments, 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.
In reaction 1 of Preparation D, the compound of formula D-1 is reacted with a compound of formula D-2 in the presence of Pd0 under Suzuki coupling conditions known by those of skill in the art to form a compound of formula D-3. In certain embodiments, 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. Methods known in the art for making such triflating compounds are described, e.g., in March, J., Advanced Organic Chemistry, (4th. ed., John Wiley & Sons, 1992), which is hereby incorporated herein by reference in its entirety for all purposes. In that regard, suitable leaving groups other than a triflate could be used in reaction 1 , and such leaving groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. In reaction 1 of Preparation E, the compound of formula E- 1 is reacted with a primary or secondary amine, e.g. of the formula R1R9N-, in the presence of a solvent such as anhydrous dioxane and potassium hydrogen phosphate. Those of skill in the art given the benefit of the present disclosure will realize that the aforementioned primary and secondary amine need not be of the formula R1R9N-, but rather can be a cyclic amine, such as piperidine, piperazine, morpholine, etc. The reaction mixture is stirred at reflux for about 12-18 hours. The reaction mixture is then worked-up by filtration and flash chromatography to afford a compound of formula E-2.
In reaction 2 of Preparation E, the compound of formula E-2 is dissolved in a solvent such as dichloromethane at room temperature. Thionyl chloride is then added and the reaction mixture is subsequently heated with stirring to about 40-500C for about 1-2 hours. The reaction mixture is then worked-up in accordance with methods known by those of skill in the art to afford the product E-3.
In reaction 1A of Preparation F1 the compound of formula F-1 is reacted with sulfuryl chloride in accordance with the procedure presented above for reaction 1 of Preparation A to afford a compound of formula F-2. In reaction 2A of Preparation F1 the compound of formula F-2 is reacted with
SELECTFLUOR® in the presence of an anhydrous protic solvent such as acetonitrile at 00C. The reaction mixture is stirred and allowed to warm to room temperature over the course of about 12-18 hours. The reaction mixture is worked-up by removing the solvent in vacuo and subsequently diluting the resulting residue in a solvent such as dichloromethane. Any precipitated quinuclidine salts are removed by vacuum filtration. The filtrate is preadsorbed on silica gel and subsequently chromatographed. Concentration of product containing fractions in vacuo affords a product of formula F-4.
In reaction 1B of Preparation F, the compound of formula F-1 is dissolved in sulfuryl chloride and stirred at about 40-60°Cfor about 12-18 hours. The reaction mixture is concentrated in vacuo to afford the compound of formula F-3, which is carried on without further work-up in the next reaction.
In reaction 2B of Preparation F, the compound of formula F-3 is reacted with thiourea in the presence of a polar solvent such as EtOH. The reaction mixture is heated to about 40- 6O0C for about 12-18 hours and subsequently worked-up in accordance with methods known by those of skill in the art to afford a product of formula F-4.
In reaction 1 of Scheme J., the ester compound of formula B-2 is reacted with the alumino-chloro compound of formula A-3 in the presence of a solvent, such as toluene, in an inert environment. The reaction mixture is heated to about 9O0C for about 24 hours. The reaction mixture is subsequently worked-up in accordance with methods known in the art to give a product of formula 1-1. In 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 4O0C and 6O0C, preferably 5O0C 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. In certain embodiments, R1 contains an ester moiety that can be subsequently saponified to afford the corresponding carboxylic acid. Those of skill in the art given the benefit of the present disclosure will realize that the aforementioned primary and secondary amine need not be of the formula R1R9N-, but rather can be a cyclic amine, such as piperidine, piperazine, morpholine, etc. In 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. The resulting reaction mixture is generally heated to about 600C 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. In 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. In certain embodiments, R1 contains an ester moiety that can be subsequently saponified to afford the corresponding carboxylic acid. Those of skill in the art given the benefit of the present disclosure will realize that the aforementioned primary and secondary amine need not be of the formula R1R9N-, but rather can be a cyclic amine, such as piperidine, piperazine, morpholine, etc. in reaction 1 of Scheme 3, the compound of formula 1-1/11-1 is reacted with a compound of formula R1-OM, where 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. Upon completion of the reaction, the product of formula 111-1 is isolated using methods known in the art. In certain embodiments, R1 contains an ester moiety that can be subsequently saponified to afford the corresponding carboxylic acid.
In 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 Pd0. The reaction is conducted in the presence of an anhydrous solvent, such as THF, in an inert environment. Upon completion of the reaction, the product of formula IV-1 is isolated using methods known in the art. In certain embodiments, R1 contains an ester moiety that can be subsequently saponified to afford the corresponding carboxylic acid.
In reaction 1 of Scheme 5, the compound of formula E-3 is reacted with a compound of formula F-4 in the presence of a solvent such as anhydrous pyridine at about 9O0C for about
12-18 hours. Removal of the solvent with a co-solvent such as MeOH and subsequent chromatography using methods known by those of skill in the art affords a compound of formula V- 1.
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. Although 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 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. Presently disclosed compounds that are acidic in nature, e.g., contain a COOH or tetrazole moiety, are generally capable of forming a wide variety of different salts with various inorganic and/or organic bases. Although 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. These 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. Alternatively, 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. In either case, 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.
Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, 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. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H1 13C, 14C, 15N, 180, 17O,
31 Pi 32P) 35S| 1β Fi and 36c|j respθctivθ|y
By isotopically-labeling the presently disclosed compounds, the compounds may be useful in drug and/or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) labeled compounds are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (2H) 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) and all optical isomers of a presently disclosed compound (e.g., R and S enantiomers), as well as 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. The present disclosure also provides pharmaceutical 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.
Presently disclosed pharmaceutical compositions can be used in an animal or human. Thus, 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. 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.
For oral administration, 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). The tablets may be coated by methods well known in the art. 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).
For buccal administration, 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. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
For topical administration, 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.
For intranasal administration or administration by inhalation, 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. In the case of a pressurized aerosol, 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 (made, for example, from gelatin) 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 20μg to about 10,000μg, preferably, about 20μg to about 1000μg of a presently disclosed compound. The overall daily dose with an aerosol will be within the range from about 100μg to about 100 mg. In certain embodiments, the overall daily dose with an aerosol generally will be within the range from about 10Oμg 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.
Pharmaceutical 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.
REPORTER ASSAY A murine hematopoietic IL3 dependent cell line BaF3 transfected with the human
TPO receptor (TPOr) and the STAT1/3 responsive β-lactamase reporter was used to assess the agonist activity of the presently disclosed compounds against the TPO receptor in the present assay. In particular, the present assay measures the induction of the β-lactamase enzymatic activity in response to TPOr stimulation. CCF4/AM, a membrane-permeant substrate ester derived from CCF4 and a fluorescent substrate for β-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 β-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. Approximately 12 hours before initiating the assay, 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 20μl_ 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. In particular, column 19 contained cells and 300ng/mL Peprotech hTPO; column 20 contained cells and 100ng/mL mlL3; column 21 contained cells and assay media; and column 22 contained only assay media. 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. Incubation occurred for about 5 hours at about 37°C under 5% CO2.
A loading solution was prepared from three solutions (Solution A=1 mM CCF4/AM in DMSO; Solution B and Solution C were provided by Aurora Biomed, Inc.) in the following proportions: for each ml_ of loading solution, 6μL Solution A was added to 60μl_ Solution B and vortexed. 1 ml. of Solution C was subsequently mixed with the foregoing solution. 10μL of the loading solution was added to each well of the 384-well plate via the Multi-drop. The plate was agitated for about two seconds using a horizontal plate shaker. Incubation proceeded in the dark at room temperature for about 1 hour. Activity was detected on a LJL Analyst (Molecular Devices) equipped with the 405-20 excitation filter, 2 emission filters (blue channel 460-40 and green channel 530-10) and a 425 dichroic. The Stimulation Index was as follows: [(460/530 ratio drug samples/460/530 No Stimulation Ratio)] -1. The reported EC50 values were calculated by plotting SI ratio drug against SI ratio hTPO control.
All of the exemplified compounds had an EC50 value of less than 10μM in the Reporter Assay.
EXPERIMENTAL
The following Examples illustrate the preparation of the presently disclosed compounds. Mass Spectral data were obtained using a Micromass ZMD APCI Mass Spectrometer equipped with a Gilson gradient high performance liquid chromatograph. Unless otherwise indicated, the following solvents and gradients were used for the analysis. Solvent A: 98% water/2% acetonirile/0.01% formic acid; and Solvent B: acetonitrile containing 0.005% formic acid. Typically, a gradient was run over a period of about 4 minutes starting at 95% solvent A and ending with 100% solvent B. The mass spectrum of the major eluting component was then obtained in positive or negative ion mode scanning a molecular weight range from 165 AMU to 1100 AMU. Specific rotations were measured at room temperature using the sodium D line (589 nm). Commercial reagents were utilized without further purification. 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 20-250C. 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).
One of ordinary skill in the art will appreciate that in some cases 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, (2nd Ed, John Wiley & Sons 1991). Analytical high performance liquid chromatography on reverse phase with mass spectrometry detection (LCMS) was done using Polaris 2x20 mm C18 column. 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.
Preparation A:
Reaction 1 : 5-Chloro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-amine To a 50OmL reaction vessel was added 2-chloro-1-(4-fluoro-3- (trifluoromethyl)phenyl)ethanone (175mmol) and sulfuryl chloride (350mmol). The reaction mixture was stirred at 500C for about 2 hours. The reaction mixture was then concentrated to dryness. EtOH (25OmL) and thiourea (180mmol) was added to the resulting residue. The reaction mixture was then refiuxed at 90°C for about 24 hours. Subsequent concentration yielded a residue that was suspended in chloroform (50OmL) and washed twice with saturated sodium bicarbonate (25OmL). The organic layer was dried over sodium sulfate, filtered; and concentrated. The product was triturated twice with hexanes (40OmL) and decanted to afford the desired product. MW = 296.67.
Reaction 2: N-(chloro(methyl)alumino)-4-(4-fluoro-3-(trifluoromethyl,5 chloro)phenyl)thiazol- 2-amine
To a 125mL reaction vessel flushed with argon was added 5-Chloro-4-(4-fluoro-3- (trifiuoromethyl)phenyl)thiazol-2-amine (7.8mmol) and ether (25mL). 2M hydrogen chloride in ether (4.5mL) was subsequently added and the reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was then concentrated to dryness, and the reaction vessel was evacuated and purged with argon. The resulting residue was dissolved in toluene (25mL) and cooled to 00C. A 2M solution of trimethylaluminum in toluene (7.8mmol) was added drop wise to the reaction mixture with subsequent stirring at room temperature for about 12-18 hours. The uncharacterized reaction product was brought forward in the synthesis, e.g., at Scheme 1.
Preparation B: Reaction 1 : Methyl 5, δ-dichloropyridine-S-carboxylate
To a 25OmL reaction vessel was added 5,6-dichloronicotinic acid (15.6mmol), toluene (5OmL), and methanol (50 mL). The reaction mixture was cooled to 0°C and a 2M solution of trimethylsilyldiazomethane in hexanes (23.4mmol) was subsequently added dropwise followed by stirring for about 1-2-18 hours. Concentration of the reaction mixture to dryness afforded the desired product (3.2g) as an off-white solid; MW = 206.03, yield = 100%, HPLC (min) = 3.96, LC-MS = 206, 208; dichloro fragment.
Preparation C: Reaction 1 : 5,6-dichloro-nicotinoyl chloride
5,6-dichloro-nicotinic acid pyridine (5.2mmol) and anhydrous toluene (2.6mL) were combined with thionyl chloride (8.84mmol), dropwise, followed by anhydrous DMF (1OuL). The reaction was refluxed for about 2.5 hours with stirring under nitrogen. Concentration of the reaction mixture afforded the desired product (985mg) as an oil that subsequently crystallized upon standing. MW = 210.44, yield = 90%, LC-MS = 210.
Preparation E:
Reaction 1 : 6-(4-(ethoxycarbonvπpiperidin-1-yl)-5-chloropyridine-3-carboxylic acid
To a 100OmL large-necked, round bottom flask was added 5,6-dichloropyridine-3- carboxylic acid (7.68g, 0.04mol), anhydrous dioxane (20OmL), ethyl piperidine-4-carboxyiate
(12.6g, O.Oδmol), and potassium hydrogen phosphate (17.4g, O.imol). The reaction was stirred at reflux (1010C) overnight. The reaction mixture was subsequently filtered to remove most of the potassium salts, and the filtrate was concentrated. Flash column chromatography (Combiflash Companion 333g silica gel column) using a 2 - 10% methanol / chloroform solvent system afforded the purified desired product as a yellow-white powder.
Yield = 6.75g; HPLC = 3.83min (100%), LC-MS = 313, 2.34min.
Reaction 2: Ethyl 1-(5-(chlorocarbonyl)-3-chloropyridin-2-yl)piperidine-4-carboxylate
To a solution of 6-(4-(Ethoxycarbonyl)piperidin-1-yl)-5-chloropyridine-3-carboxylic acid
(4.66 g, 14.9 mmol) in dichloromethane (120 mL) at room temperature, was added thionyl chloride (7.09 g, 59.6 mmol). The mixture was warmed to 450C with stirring for 90 minutes.
The solvent and any excess reagent were evaporated in vacuo and the resulting residue was dried under high vacuum to afford the desired product as a yellow semisolid. Yield = 5.35 g.
(100%); LCMS confirmed synthesis of the desired product; MS Ret. Time 2.88 min. (ESI+) for
C15H9CIN2O4 m/z 327.3 (M+H)+
Preparation F:
Reaction 1A: 4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-amine
To a 50OmL reaction vessel was added 4-fluoro-3-(trifluoromethyl)acetophenone
(175mmol) and sulfuryl chloride (350mmol). The reaction mixture was stirred at 500C for about 2 hours. The reaction mixture was then concentrated to dryness. EtOH (25OmL) and thiourea (180mmol) was added to the resulting residue. The reaction mixture was then refluxed at 9O0C for about 24 hours. Subsequent concentration yielded a residue that was suspended in chloroform (50OmL) and washed twice with saturated sodium bicarbonate (25OmL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The product was triturated twice with hexanes (40OmL) and decanted to afford the desired product. MW = 262.23.
Reaction 2A: 5-Fluoro-4-f4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-amine
SELECTFLUOR® (16.0 g, 44.5 mmol) was added to a stirred suspension of 4-(4-fluoro- 3-(trifluoromethyl)phenyl)thiazol-2-amine (10.49 g, 40.0 mmol) in anhydrous acetonitrile (200 mL) at O0C. The reaction mixture was allowed to warm to room temperature overnight. The solvent volume was reduced in vacuo and then subsequently diluted with dichloromethane (150 mL). The precipitated quinuclidine salts were removed by vacuum filtration and the combined filtrate and dichloromethane rinses were preadsorbed onto silica gel and chromatographed (ISCO COMBI FLASH™ 330 g REDISEP® cartridge, 5 to 55% ethyl acetate in hexanes over 1 hour). Fractions containing product were pooled, evaporated and dried under high vacuum to afford the desired product as a pinkish crystalline solid (polarized light microscopy). Yield = 4.96 g (41.8%); MS Ret. Time 2.84 min. (ESI+) for C10H5F5N2S m/z 281.3 (M+H)+; MS (ESI-) for C10H5F5N2S m/z 279.2 (M-H)".
Reaction 1B: 2,2-dichloro-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone
To a reaction vessel was added 4-fluoro-3-(trifluoromethyl)acetophenone (2.50 g, 12.13 mmol) and sullfuryl chloride (3 mL). The reaction mixture was stirred to about 500C overnight and subsequently concentrated in vacuo to afford the α, α-dichloroacetophenone in quantitative yield.
Reaction 2B: 5-Chloro-4-(4-fluoro-3-(trifluoromethvD phenyl)thiazol-2-amine
The 2,2-dichloro-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone obtained above was dissolved in ethanol (28 mL) and thiourea (0.800 g, 10.5 mmol) was subsequently added to the reaction vessel. The resulting mixture was heated to about 5O0C overnight. The solvent was evaporated in vacuo and the resulting residue was taken up in dichloromethane. The precipitated side product was filtered off, and the filtrate was preadsorbed onto silica gel and chromatographed (ISCO COMBIFLASH™ 120 g REDISEP® cartridge, 0 to 40% ethyl acetate in hexanes over 40 minutes). Fractions containing product were pooled, evaporated and dried under high vacuum to give 0.772 g (26.1%) of the desired product as a crystalline solid (polarized light microscopy). MS Ret. Time 2.9 min. (ESI+) for C10H5CiF4N2S m/z 297.1 (M+H)+; MS (ESI-) for C10H5F5N2S m/z 295.1 (M-H)". Examples 1-8 were prepared in accordance with Scheme 5. EXAMPLE 1
Ethyl 1-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyI)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-yl)piperidine-4-carboxylate
In a reaction vessel containing ethyl 1-(5-(chlorocarbonyl)-3-chloropyridin-2- yl)piperidine-4-carboxylate (5.353 g, 14.90 mmol) in anhydrous pyridine (15 mL) at room temperature was added 5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-amine (4.175 g,
14.90 mmol) and 4-dimethylaminopyridine (546 mg, 4.47 mmol). The reaction vessel was sealed and heated to about 900C overnight with stirring. The reaction mixture was diluted with about 30 mL methanol and evaporated to dryness. The resulting residue was dissolved in dichloromethane and methanol, preadsorbed onto silica gel, and subsequently chromatographed (ISCO COMBIFLASH™ 120 g REDISEP® cartridge, 5 to 50% ethyl acetate in hexanes over 40 minutes). Fractions containing product were pooled, evaporated and dried under high vacuum to afford 7.68 g (89.6%) of the named product as a yellowish crystalline solid (polarized light microscopy). MS Ret. Time 1.8 min. (ESI+) for C24H2OF5N4O3S m/z 575.0 (M+H)+.
Examples 2-8 were prepared in accordance with the procedure presented for Example 1.
EXAMPLE 2 I^S^δ-fluoro^-fΦfluoro-S-^rifluoromethylJphenylJthiazoI^-ylcarbamoylJ-S- chloropyridin-2-yl)piperidine-4-carboxylic acid
MW = 546.9, HPLC (min) = 1.47, LC-MS (M+1) = 547.
EXAMPLE 3
2-(5-(5-chloro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yicarbamoyl)-3- chloropyridin-2-ylamino)-3-hydroxypropanoic acid
MW = 538, LC-MS (min) = 3.1 , LC-MS (M+1) = 538.9
EXAMPLE 4
2-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyI)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)-3-hydroxypropanoic acid MW = 522, LC-MS (min) = 3.0, LC-MS (M+1 ) = 522.9
EXAMPLE 5 2-(5-(5-chloro-4-(4-fluoro-3-(trifluoromethyl)pheny])thiazol-2-ylcarbamoyI)-3- chloropyridin-2-ylamino)butanoic acid
MW = 536, LC-MS (min) = 3.4, LC-MS (M-1) = 534.9.
EXAMPLE 6
2-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)butanoic acid MW = 520, LC-MS (min) = 3.3, LC-MS (M-1) = 518.9.
EXAMPLE 7
2-(5-(5-chloro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thia2θl-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)propanoic acid MW = 522, LC-MS (min) = 3.3, LC-MS (M-1 ) = 520.9
EXAMPLE 8
2-{5-(5-fluoro-4-(4-fJuoro-3-(trifluoromethyl)phenyl)thia2ol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)propanoic acid
MW = 506, LC-MS (min) = 3.2, LC-MS (M-1 ) = 504.9
References to other documents, such as patents, patent applications, journals, books, etc., have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.
It is to be understood that the foregoing description is exemplary and explanatory in nature, and is intended to illustrate the presently disclosed general inventive concept and its preferred embodiments. Through routine experimentation, those of skill in the art given the benefit of the present disclosure may recognize apparent modifications and variations without departing from the spirit and scope of the present disclosure. Thus, the present disclosure is not limited by the above description, but rather by the following claims and their equivalents.

Claims

CLAIMSWhat is claimed is:
1. A compound of the Formula
Figure imgf000050_0001
or a pharmaceutically acceptable salt or prodrug thereof; wherein d is 0 or 1 ;
X is -O- or R9N-, wherein R9 is H or (CrC6)alkyl; Y is chloro orfluoro; R1 is (CrCβ)alkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, or (C2-C9)heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl moieties of (C1-C6)alkyl, (C3- Cio)cycloalkyl, (C2-C8)heterocycloalkyl, (C2-C9)heteroaryl, or R9 are independently optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, HO3S-, amino, aminocarbonyl, R4(C1-C3)alkyl, R4(CrC6)alkoxy, R4(Cr C6)alkoxycarbohyl, R4(C1-C6)alkylthio, R4(CrC6)alkylsulfinyI, R4(CrC6)alkylsulfonyl, R4(d- C6)alkylaminosulfonyl, R4(C1-C6)alkylsulfonylamino, R4(CrC6)alkylamino, R4(Ci- C6)alkylcarboxy, R4(C1-C6)alkylaminocarbonyl, aminocarbonylamino, R4(Cr C6)alkylaminocarbonylamino, aminocarbonyl(CrC6)alkyl, R4(C1-C6)alkylaminocarbonyl(C1- C6)alkyl, aminocarbonyl-O-, amino(CrC6)alkoxycarbonyl, R4(C1-C6)alkylaminocarbonyl-O-, R4(C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R4(CrC6)alkoxycarbonylamino, R4(Cr Cβ)alkoxy(CrC6)alkylamino, trifluoromethyl, trifluoromethyl(C1-C6)alkyI, trifluoromethylcarbonylamino, (C1-C6)alkylcarbonylamino, [(CrC6)alkylcarboπyl][(Ci-C6)alkyl]N- , (CrC6)alkylcarbonyl, (C6-C10)aryl(C1-C6)alkoxycarbonylamino, (CB-Ci0)aryl, (C2-CB)heteroaryl, R4(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(CrC6)alkyl]a-(CF2)b-[(CrC6)alkyl]c- wherein a is 0 or 1 , b is 1 , 2, 3 or 4, and c is 0 or 1 ; R5R6N-, R5R6N-carbonyI, R5R6N-carbonylamino, R5R6N- carbonyl(CrC6)alkyl and R5R6N-carbonyl-O-; wherein R4 is one to three groups selected from hydrogen, (CrC6)alkoxy, hydroxy, carboxy, HO3S-, amino, (CrC6)alkylamino, R5R6N-, (C1-C6)alkylthio, (CrC6)alkylsulfinyl, (C1- C6)alkylsulfonyl or aminocarbonyl; R5 and R6 are each (C1-C6)alkyl optionally independently substituted by (CrC6)alkoxy, hydroxy, carboxy, amino, (CrC6)alkylamino, [(CrC6)alkyl]2N-, (C1-C6)alkylthio, (C1- C6)alkylsulfinyl, (C1-C6)alkylsulfonyl or aminocarbonyl; or R5 and R6 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 ((CrC6)alkyl)-N-; and the ring so formed is optionally substituted by (C1-C6)BIkOXy, hydroxy, carboxy, amino, (C1- C6)alkylamino, [(CrC6)alkyl]2N-, (CrC6)alkylthio, (CrC6)alkylsulfinyl, (CrC6)alkylsulfonyl or aminocarbonyl;
R2 is R7(C6-C10)aryl or R7(C2-C9)heteroaryl; wherein R7 is one to three groups selected from hydrogen, halo, cyano, nitro, carboxy, hydroxy, amino, aminocarbonyl, R8(C1-C6)alkyl, R8(C3-C10)cycloalkyl, R8(CrC6)alkoxy, R8(CrC6)alkoxycarbonyl, R8(CrC6)alkylthio, R8(Cr C6)alkylsulfinyl, R8(CrC6)alkylsulfonyl, R8(CrC6)alkylaminosulfonyl, R8(Cr C6)alkylsulfonylamino, R8(CrC6)alkylamino, R8(CrC6)alkylcarboxy, R8(Cr C6)alkyiaminocarbonyl, aminocarbonylamino, RB(CrC6)alkylaminocarbonylamino, aminocarbonyl(CrCβ)alkyl, R8(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, aminocarbonyl-O-, amino(CrC6)alkoxycarbonyl, R8(CrC6)alkylaminocarbonyl-O-, RB(Ci-C6)alkylamino(Cr C6)alkoxycarbonyl, R8(CrC6)alkoxycarbonylamino-, R8(Ci-C6)alkoxy(Ci-C6)alkylamino1 trifluoromethyl, trifluoromethoxy, trifluoromethyl(C1-C6)alkyl, R8(CrC6)alkyl-F2C-, HF2C-O-, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b-[(C1-C6)alkyl]c-, wherein a is O or 1 , b is 1 , 2, 3 or 4, and c is O or 1; R5R6N-, R5R6N-carbonyl, R5R6N-carbonylamino-, R5R6N-carbonyl(CrC6)alkyl or R5R6N-carbonyl-O-, wherein R5 and R6 are as defined above; wherein R8 is one to three groups selected from hydrogen, (C1-C6)alkyl, (C3-
Cio)cycloalkyl, (CrC6)alkoxy, hydroxy, cyano, carboxy, amino, (CrC6)alkylamino, R5R6N-, (C1- C6)alkylthio, (CrC6)alkylsulfinyl, (C1-C6)alkylsulfonyl or aminocarbonyl, wherein R5 and R6 are as defined above;
R3 is hydrogen, halo, cyano, nitro, carboxy, hydroxy, amino, aminocarbonyl, trifluoromethoxy, HF2C-O-, (C3-C10)cycloalkyl, R4(CrC6)alkyl, R4(CrC6)alkoxy, R4(Cr C6)alkylamino, trifluoromethyl, wherein R4 is as defined above; with the proviso that when d is 1 , R1 cannot be (C2-C9)heterocycloalkyl or (C2- Cg)heteroaryl.
2. A compound according to claim 1 , wherein R1 is (C2-C9)heterocycloalkyl optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO3S-, aminosulfonyl, (C6-Ci0)aryl, (C2-C9)heteroaryl, R4(CrC6)alkyl, R4(Cr C6)alkoxy, R4(CrC6)alkylthio, R4(CrC6)alkylamino and R4(CrC6)alkoxy(CrC6)alkylamino; and R2 is R7-phenyl or R7-pyridinyl, wherein R4 and R7 are as defined above.
3. A compound according to claim 1 , wherein R1 is pyrrolidinyl, piperidinyl or piperazinyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO3S-, aminosulfonyl, (C6-C10)aryl, (C2-C3)heteroaryl, R4(Cr C6)alkyl, R4(CrC6)alkoxy, R4(CrC6)alkylthio, R4(CrC6)alkylamino and R4(C1-C6)alkoxy(C1- C6)alkylamino; and R2 is R7-phenyl or R7-pyridinyl, wherein R4 and R7 are as defined above.
4. A compound according to claim 1, wherein R1 is pyrrolidinyl, piperidinyl or piperazinyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO3S-, aminosulfonyl, (C6-C10)aryl, (C2-C9)heteroaryl, R4(Cr C6)alkyl, R4(CrC6)alkoxy, R4(CrC6)alkylthio, R4(CrC6)alkylamino and R4(CrCβ)alkoxy(Cr C6)alkylamino; and R3 is hydrogen, halo, cyano, nitro, hydroxy, trifluoromethoxy, HF2CO- or trifluoromethyl, wherein R4 is as defined above.
5. A compound according to claim 1, wherein R1 is pyrrolidinyl, piperidinyl or piperazinyl, each optionally substituted by one to three groups selected from the group consisting of: carboxy, hydroxy, HO3S-, aminosulfonyl, (C6-Cio)aryl, (C2-C9)heteroaryl, R4(Cr C6)alkyl, R4(C1-C6)alkoxy, R4(CrC6)alkylthio, R4(CrC6)alkylamino and R4CC1-C(OaIkOXy(C1- C6)alkylamino; R2 is R7-phenyl or R7-pyridinyl, wherein R7 is selected from the group consisting of: cyano, halo, hydroxy, amino, R8(CrC6)alkyl, R8(CrC6)alkoxy, R8(CrC6)alkylthio, R8(C3- Cio)cycloalkyl, trifluoromethyl and trifluoromethoxy; and R3 is hydrogen, halo, cyano, nitro, hydroxy, trifluoromethoxy, HF2C-O- or trifluoromethyl, wherein R4 and R8 is as defined above.
6. A compound according to claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, selected from the group consisting of: Ethyl 1-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyI)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-yl)piperidine-4-carboxylate; i-Cδ-Cδ-fluoro^^-fluoro-S-CtrifluoromethyOphenyOthiazol^-ylcarbamoyO-S- chloropyridin-2-yl)piperidine-4-carboxylic acid;
2-(5-(5-chloro-4-(4-fluoro-3-(trifluoromethyI)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)-3-hydroxypropanoic acid;
2-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)-3-hydroxypropanoic acid;
2-(5-(5-chloro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-y!amino)butanoic acid; 2-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)butanoic acid; 2-(5-(5-chloro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamiπo)propanoic acid; and
2-(5-(5-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)-3- chloropyridin-2-ylamino)propanoic acid.
7. A pharmaceutical composition for (a) 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 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 claim 1 or a pharmaceutically acceptable salt thereof, effective in such disorders or conditions and a pharmaceutically acceptable carrier.
8. Use of an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for agonizing the TPO receptor in a mammal, including a human.
9. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament 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.
10. The use of claim 9 further comprising 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.
11. The use of claim 10 wherein the agent is selected from the group consisting of: G-CSF, GM-CSF, TPO, M-CSF, EPO, Gro-beta, IL-11 , SCF, FLT3 ligand, LIF, 1 L-3, IL- 6, IL-I, Progenipoietin, NESP, SD-01 , IL-8, and IL-S or a biologically active derivative of any of said agents.
12. Use of a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof prior to platelet pheresis, blood donation or platelet donation for the manufacture of a medicament for enhancing platelet production obtained from a donor.
13. Use of a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof prior to leukapheresis for the manufacture of a medicament for enhancing the number of peripheral blood stem cells obtained from a. donor.
14. The use of claim 13 further comprising 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.
15. The use of claim 14 wherein 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.
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