WO2018085552A1 - Antagonistes de l'intégrine - Google Patents

Antagonistes de l'intégrine Download PDF

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Publication number
WO2018085552A1
WO2018085552A1 PCT/US2017/059733 US2017059733W WO2018085552A1 WO 2018085552 A1 WO2018085552 A1 WO 2018085552A1 US 2017059733 W US2017059733 W US 2017059733W WO 2018085552 A1 WO2018085552 A1 WO 2018085552A1
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substituted
alkoxy
alkyl
hydrogen
compound
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PCT/US2017/059733
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English (en)
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Peter G. Ruminski
Marvin L. MEYERS
Richard F. Heier
Michael P. RETTIG
John DIPERSIO
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Saint Louis University
Washington University
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Publication of WO2018085552A1 publication Critical patent/WO2018085552A1/fr
Priority to US16/401,950 priority Critical patent/US20190328706A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms

Definitions

  • the present disclosure relates to the fields of pharmaceuticals, medicine and cell biology. More specifically, it relates to pharmaceutical agents (compounds) which are useful as antagonists (i.e. inhibitors) of one or more integrins such as integrin ⁇ 4 ⁇ 1 (VLA-4).
  • hematopoietic stem cell transplants require the collection of the stem cells from peripheral blood. Due to the low amount of these cells in circulating peripheral blood, stimulating the stem cells can take almost a week and still the collection must be done over several days to achieve sufficient concentrations of the stem cells for transplantation. This greatly increases the cost of the transplant and results in a significant burden on the patient.
  • cytokines such as granulocyte-colony forming unit (G-CSF)
  • immunostimulants such as plerixafor
  • VLA-4 antagonists i.e. inhibitors
  • pharmaceutical compositions methods for their manufacture, and methods for their use.
  • the present disclosure provides compounds further defined by the formula:
  • Ri is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF 5 , alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra; wherein:
  • Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8);
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R2 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Y2-Rc; wherein:
  • Y2 is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8);
  • Rc is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • Xi is hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkoxy(c ⁇ 8), substituted aralkoxy(c ⁇ 8), or a substituent convertible in vivo to hydroxy; and R.3 and R.4 are each independently hydrogen, hydroxy, alkoxycc ⁇ 8) or substituted alkoxy(c ⁇ 8);
  • R.5 is hydrogen, -CH(ORd)R e , or -C(0)Rf, wherein:
  • Rd is hydrogen, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), acyl(c ⁇ 8), or substituted
  • R e and Rf are each independently alkyl(c ⁇ 8) or substituted alkyl(c ⁇ 8); and Z is a group of the formula:
  • p 0, 1, 2, or 3;
  • R6 is hydrogen or -C(0)X2; wherein:
  • X2 is amino, hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxycc ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), alkylamino(c ⁇ 8), substituted alkylamino(c ⁇ 8), dialkylamino(c ⁇ 8), substituted dialkylamino(c ⁇ 8), cycloalkylamino(c ⁇ 8), substituted cycloalkylamino(c ⁇ 8), alkenylamino(c ⁇ 8), substituted alkenyl- amino(c ⁇ 8), arylamino(c ⁇ 8), substituted arylamino(c ⁇ 8), aralkylamino(c ⁇ 8), substituted aralkyla
  • R7 and R8 are each independently hydrogen, halo, haloalkyl(c ⁇ 8), or substituted haloalkyl(c ⁇ 8);
  • R9 is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8); or
  • W is hydrogen, cyano, halo, hydroxy, or -C(0)X3, wherein:
  • X3 is amino, hydroxy, alkoxycc ⁇ 8), substituted alkoxycc ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxycc ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), alkylamino(c ⁇ 8), substituted alkylamino(c ⁇ 8), dialkylamino(c ⁇ 8), substituted dialkylamino(c ⁇ 8), cycloalkylamino(c ⁇ 8), substituted cycloalkylamino(c ⁇ 8), alkenylamino(c ⁇ 8), substituted alkenyl- amino(c ⁇ 8), arylamino(c ⁇ 8), substituted arylamino(c ⁇ 8), aralkylamino(c ⁇ 8), substituted aralkyla
  • Rio and R11 are each independently hydrogen or halo
  • R5 is hydrogen
  • W is -C(0)X 3
  • R9 is hydrogen
  • R h 1 ydrogen then R6 is not hydrogen
  • the compounds are further defined by the formula:
  • Ri is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra; wherein: Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8; and Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R2 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Y2-Rc; wherein: Y2 is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • Rc is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • Xi and X3 are each independently hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkoxy(c ⁇ 8), substituted aralkoxy(c ⁇ 8), or a substituent convertible in vivo to hydroxy; and
  • R3 and R4 are each independently alkoxy(c ⁇ 8) or substituted alkoxy(c ⁇ 8);
  • Ri and R2 are not both hydrogen
  • the compounds are further defined as:
  • Ri is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra; wherein: Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R2 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Y2-Rc; wherein: Y2 is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • Rc is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • R3 and R4 are each independently alkoxy(c ⁇ 8) or substituted alkoxy(c ⁇ 8);
  • Ri and R2 are not both hydrogen
  • the compounds are further defined as:
  • Ri is aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra; wherein:
  • Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8);
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R2 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Y2-Rc; wherein: Y2 is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • Rc is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • Xi and X3 are each independently hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkoxy(c ⁇ 8), substituted aralkoxy(c ⁇ 8), or a group convertible in vivo to hydroxy;
  • the compounds are further defined as:
  • R 1 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF 5 , alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra; wherein: Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R2 is aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Y2 ⁇ Rc; wherein: Y2 is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • Rc is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • Xi and X3 are each independently hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkoxy(c ⁇ 8), substituted aralkoxy(c ⁇ 8), or a group convertible in vivo to hydroxy;
  • the compounds are further defined as:
  • R 1 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF 5 , alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra; wherein:
  • Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8);
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R2 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Y2 ⁇ Rc; wherein:
  • Y2 is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8);
  • Rc is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • R 1 and R2 are not both hydrogen
  • the compounds are further defined as:
  • R 1 is alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxycc ⁇ 8), or -Yi-R a ;
  • Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8);
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either of these groups;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • the compounds are further defined as:
  • R 1 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF 5 , alkyl(c ⁇ 8 substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra, wherein: Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • Ra is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either group;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R2 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8 substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Y 2 -Rc, wherein:
  • Y2 is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8);
  • Rc is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either group; or R3 and R4 are each independently alkoxy(c ⁇ 8) or substituted alkoxy(c ⁇ 8); R.7 and R5 are each independently hydrogen, halo, haloalkyl(c ⁇ 8), or substituted haloalkyl(c ⁇ 8);
  • R6 is hydrogen or -C(0)X2
  • R9 is hydrogen, alkyl(c ⁇ 6), or substituted alkyl(c ⁇ 6);
  • p 0, 1, 2, or 3;
  • Xi and X2 are each independently hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), or a substituent convertible in vivo to hydroxy; provided that R a 1 nd R7 are not both hydrogen;
  • the compounds are further defined as:
  • R 1 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra, wherein: Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either group;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R7 and R8 are each independently hydrogen, halo, haloalkyl(c ⁇ 8), or substituted haloalkyl(c ⁇ 8);
  • R6 is hydrogen or -C(0)X2
  • R9 is hydrogen, alkyl(c ⁇ 6), or substituted alkyl(c ⁇ 6);
  • p is 0, 1, 2, or 3; and Xi and X2 are each independently hydroxy, alkoxycc ⁇ 8), substituted alkoxycc ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), or a substituent convertible in vivo to hydroxy; provided that R a 1 nd R7 are not both hydrogen;
  • the compounds are further defined as:
  • R 1 is aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra, wherein: Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either group;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R9 is hydrogen, alkyl(c ⁇ 6), or substituted alkyl(c ⁇ 6);
  • p 0, 1, 2, or 3;
  • Xi is hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), or a substituent convertible in vivo to hydroxy;
  • the compounds are further defined as:
  • R 1 is aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF 5 , alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra, wherein: Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either group;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R9 is hydrogen, alkyl(c ⁇ 6), or substituted alkyl(c ⁇ 6);
  • p 0, 1, 2, or 3;
  • Xi is hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), or a substituent convertible in vivo to hydroxy;
  • the compounds are further defined as:
  • R 1 is aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra, wherein: Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either group; or -X(CH 2 0) m -(CH2CH 2 0)n-Rb, wherein:
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R9 is hydrogen, alkyl(c ⁇ 6), or substituted alkyl(c ⁇ 6);
  • p 0, 1, 2, or 3;
  • Xi is hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), or a substituent convertible in vivo to hydroxy;
  • the compounds are further defined as:
  • Ri is aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra, wherein:
  • Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8);
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either group;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R2 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Y 2 -Rc, wherein: Y2 is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • Rc is alkoxy(c ⁇ i2), alkoxy(c ⁇ i2), or a substituted version of either group;
  • R.3 and R.4 are each independently alkoxycc ⁇ 8) or substituted alkoxycc ⁇ 8);
  • R 5 is hydrogen, -CH(ORd)R e , or -C(0)Rf, wherein:
  • Rd is hydrogen, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), acyl(c ⁇ 8), or substituted
  • R e and Rf are each independently alkyl(c ⁇ 8) or substituted alkyl(c ⁇ 8);
  • Xi is hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), or a substituent convertible in vivo to hydroxy;
  • the compounds are further defined as:
  • Ri is aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF 5 , alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra, wherein:
  • Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8);
  • R a is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either group;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R2 is hydrogen, aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF5, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Y 2 -Rc, wherein:
  • Y2 is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8);
  • Rc is alkoxy(c ⁇ i2), alkoxy(c ⁇ i2), or a substituted version of either group
  • R5 is hydrogen, -CH(ORd)R e , or -C(0)Rf, wherein:
  • Rd is hydrogen, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), acyl(c ⁇ 8), or substituted
  • R e and Rf are each independently alkyl(c ⁇ 8) or substituted alkyl(c ⁇ 8);
  • Xi is hydroxy, alkoxycc ⁇ 8), substituted alkoxycc ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), or a substituent convertible in vivo to hydroxy;
  • the compounds are further defined as:
  • R 1 is aminocarbonyl, carboxy, cyano, halo, hydroxy, -SF 5 , alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), or -Yi-Ra, wherein: Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8); and
  • Ra is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either group;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • R 5 is hydrogen, -CH(ORd)R e , or -C(0)Rf, wherein:
  • Rd is hydrogen, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), acyl(c ⁇ 8), or substituted
  • R e and Rf are each independently alkyl(c ⁇ 8) or substituted alkyl(c ⁇ 8);
  • Xi is hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), or a substituent convertible in vivo to hydroxy;
  • Z is:
  • W is hydrogen, cyano, halo, hydroxy, or -C(0)X3, wherein:
  • X3 is amino, hydroxy, alkoxycc ⁇ 8), substituted alkoxycc ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), alkylamino(c ⁇ 8), substituted alkylamino(c ⁇ 8), dialkylamino(c ⁇ 8), substituted dialkylamino(c ⁇ 8), cycloalkylamino(c ⁇ 8), substituted cycloalkylamino(c ⁇ 8), alkenylamino(c ⁇ 8), substituted alkenylamino(c ⁇ 8), arylamino(c ⁇ 8), substituted arylamino(c ⁇ 8), aralkylamino(c ⁇ 8), substituted aralkyla
  • Rio and R11 are each independently hydrogen or halo.
  • Z is:
  • p 0, 1, 2, or 3;
  • R6 is hydrogen or -C(0)X2; wherein:
  • X2 is amino, hydroxy, alkoxy(c ⁇ 8), substituted alkoxy(c ⁇ 8), cycloalkoxy(c ⁇ 8), substituted cycloalkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), substituted alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), substituted aryloxy(c ⁇ 8), aralkyloxy(c ⁇ 8), substituted aralkyloxy(c ⁇ 8), alkylamino(c ⁇ 8), substituted alkylamino(c ⁇ 8), dialkylamino(c ⁇ 8), substituted dialkylamino(c ⁇ 8), cycloalkylamino(c ⁇ 8), substituted cycloalkylamino(c ⁇ 8), alkenylamino(c ⁇ 8), substituted alkenylamino(c ⁇ 8), arylamino(c ⁇ 8), substituted arylamino(c ⁇ 8), aralkylamino(c ⁇ 8), substituted aralkyla
  • R.9 is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8).
  • R 1 is alkyl(c ⁇ 8) or substituted alkyl(c ⁇ 8) such as hydroxyalkyl(c ⁇ 8) or haloalkyl(c ⁇ 8).
  • i Rs 1 aminocarbonyl or carboxy.
  • R is 1 hydroxy, alkyl(c ⁇ 8), substituted alkyl(c ⁇ 8), alkoxy(c ⁇ 8), substituted alkoxycc ⁇ 8), or -Yi-Ra, wherein:
  • Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8);
  • Ra is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either group;
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8).
  • R i 1 s -Yi-Ra wherein: Yi is alkanediyl(c ⁇ 8) or substituted alkanediyl(c ⁇ 8) and Ra is alkoxy(c ⁇ i2), acyloxy(c ⁇ i2), or a substituted version of either group.
  • Yi is alkanediyl(c ⁇ 8), such as -CH 2 -
  • Ra is alkoxy(c ⁇ i2), such as ethoxy or hexyloxy.
  • Ra is acyloxy(c ⁇ i2), such as hexanoate.
  • X is a covalent bond or -0-
  • n 0 or 1
  • n 1, 2, 3, 4, 5, 6, 7, or 8;
  • Rb is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8).
  • X is a covalent bond.
  • m is 1.
  • n is 1, 2, or 3.
  • n is 1.
  • Rb is alkyl(c ⁇ 8), such as methyl.
  • R2 is hydrogen.
  • R3 is alkoxy(c ⁇ 6), such as methoxy.
  • R4 is alkoxy(c ⁇ 6), such as methoxy.
  • Xi is hydroxy.
  • Xi is a substituent convertible in vivo to hydroxy.
  • X2 is hydroxy.
  • X2 is a substituent convertible in vivo to hydroxy.
  • R7 is hydrogen. In other embodiments, R7 is halo, such as chloro. In some embodiments, Rs is hydrogen. In other embodiments, R.8 is halo, such as chloro. In some embodiments, R.6 is hydrogen. In some embodiments, R9 is hydrogen. In other embodiments, R9 is alkyl(c ⁇ 8). In some embodiments, R9 is alkyl(c ⁇ 4), such as methyl.
  • p is 0, 1, or 2. In some embodiments, p is 1 or 2. In some embodiments, Rio is halo, such as chloro. In some embodiments, R11 is halo, such as chloro. In some embodiments, W is hydrogen. In other embodiments, W is -C(0)X3. In other embodiments, X3 is hydroxy. In other embodiments, X3 is a substituent convertible in vivo to hydroxy.
  • the compound is further defined as:
  • compositions comprising:
  • the pharmaceutical composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, trans dermally, vaginally, in cremes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion.
  • the pharmaceutical composition is formulated for oral administration, intraarterial administration, intraperitoneal administration, intravenous administration, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for administration via intravenous infusion. In other embodiments, the pharmaceutical composition is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated as a unit dose. In some aspects, the present disclosure provides methods of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the disease or disorder is associated with integrin ⁇ 4 ⁇ 1. In other embodiments, the disease or disorder is associated with inflammation. In yet other embodiments, the disease or disorder is an autoimmune disorder.
  • the disease or disorder is associated with hematopoietic stem cells such as LSK-SLAM cells.
  • the disease or disorder is cancer or a reduced blood cell count such as reduced blood cell count resulting from a therapy for cancer.
  • the disease or disorder is a reduced blood cell count resulting from a therapy for cancer such as chemotherapy or radiation therapy.
  • the disease or disorder is cancer.
  • the compound or composition results in improved efficacy of the chemotherapy or radiotherapy.
  • the present disclosure provides methods of inducing the mobilization of hematopoietic stem cells or progenitor cells comprising contacting the hematopoietic stem cells or progenitor cells with an effective amount of a compound or composition disclosed herein.
  • the method is ex vivo or in vitro. In some embodiments, method is in vivo.
  • the present disclosure provides methods of collecting hematopoietic stem cells or progenitor cells from a patient comprising:
  • the present disclosure provides methods of collecting hematopoietic stem cells or progenitor cells from a patient who has been administered a compound or composition disclosed herein in an amount sufficient to mobilize hematopoietic stem cells or progenitor cells to the peripheral blood of the patient comprising subsequently drawing peripheral blood from the patient to collect the hematopoietic stem cells or progenitor cells.
  • the present disclosure provides methods of improving the harvest of hematopoietic stem cells or progenitor cells comprising administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.
  • the present disclosure provides methods of transplanting to a patient hematopoietic stem cells or progenitor cells comprising: (A) administering to the patient a compound or composition disclosed herein;
  • the present disclosure provides methods of transplanting to a patient hematopoietic stem cells or progenitor cells comprising transplanting the hematopoietic stem cells or progenitor cells collected from the patient who has been administered a therapeutically effective amount of a compound or composition disclosed herein.
  • the present disclosure provides methods of transplanting hematopoietic stem cells or progenitor cells comprising:
  • the present disclosure provides methods flnventionof transplanting hematopoietic stem cells or progenitor cells comprising transplanting the hematopoietic stem cells or progenitor cells collected from a first patient who has been administered a therapeutically effective amount of a compound or composition disclosed herein to a second patient.
  • the hematopoietic stem cells are collected from the patient before an event which results in a reduction of the amount of the patient's hematopoietic stem cells or progenitor cells. In some embodiments, the hematopoietic stem cells or progenitor cells are transplanted after an event which results in a reduction of the amount of the patient's hematopoietic stem cells or progenitor cells. In some embodiments, the first patient is a compatible hematopoietic stem cell donor. In some embodiments, the hematopoietic stem cells or progenitor cells are LSK-SLAM cells.
  • the present disclosure provides methods of improving the effectiveness of a treatment of cancer in a patient administered a chemotherapy or a radiotherapy comprising:
  • the present disclosure provides methods of improving the effectiveness of a treatment of cancer in patient who has been administered a chemotherapy or radiotherapy and a compound or composition disclosed herein.
  • the methods comprise administering the compound or composition once.
  • the methods comprise administering the compound or composition two or more times.
  • the compound or composition is administered intravenously.
  • the compound or composition is administered subcutaneously.
  • the patient is a mammal, such as a human.
  • FIG. 1 shows CFU-C mobilization. DBA/2 mice were treated SC with 3 mg/kg of inhibitors and the kinetics of CFU-C mobilization to the blood was measured.
  • FIG. 2 shows the results of the colony forming cell (CFC) assay.
  • the top graph shows the number of colonies formed as a function of time while the bottom graph shows the number of CFC units at a specific time point for each mouse. These results show the results for Example Compound 1610 (light gray) and Example Compound 1611 (dark gray).
  • integrin antagonists i.e. inhibitors
  • VLA-4 ⁇ 4 ⁇ 1 integrin
  • these compounds may be used in improving the harvest of hematopoietic stem cells or progenitor cells or to enhance an anti-cancer therapy.
  • the compounds of the present disclosure include the compounds described in the Examples and claims listed below. All these methods described above can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in March 's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated by reference herein.
  • Compounds employed in methods of the disclosure may contain one or more asymmetrically-substituted carbon or nitrogen atoms, and may be isolated in optically active or racemie form. Thus, all chirai, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained.
  • the chiral centers of the compounds of the present disclosure can have the S or the A 3 configuration, as defined by the IUPAC 1974 Recommendations. For example, mixtures of stereoisomers may be separated using the techniques taught in the Examples section below, as well as modifications thereof. Tautomeric forms are also included as well as pharmaceutically acceptable salts of such isomers and tautomers.
  • Atoms making up the compounds of the present disclosure are intended to include all isotopic forms of such atoms.
  • Compounds of the present disclosure include those with one or more atoms that have been isotopically modified or enriched, in particular those with pharmaceutically acceptable isotopes or those useful for pharmaceutically research.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium
  • isotopes of carbon include 13 C and 14 C.
  • one or more carbon atom(s) of a compound of the present disclosure may be replaced by a silicon atom(s).
  • one or more oxygen atom(s) of a compound of the present disclosure may be replaced by a sulfur or selenium atom(s).
  • prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in some methods of the disclosure may, if desired, be delivered in prodrug form.
  • the disclosure contemplates prodrugs of compounds of the present disclosure as well as methods of delivering prodrugs.
  • Prodrugs of the compounds employed in the disclosure may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a hydroxy, amino, or carboxylic acid, respectively. Additional details regarding prodrugs may be found in Smith and Williams, 1988, the contents of which are hereby incorporated by reference.
  • any salt of this disclosure is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pbannaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.
  • the compounds of the present disclosure include those that have been further modified to comprise substituents that are convertible to hydroxy in vivo.
  • hydrolyzable groups such as acyl groups, groups having an oxycarbonyl group, amino acid residues, peptide residues, o-nitrophenylsulfenyl, trimethylsilyl, tetrahydropyranyl, diphenylphosphinyl, and the like.
  • acyl groups include formyl, acetyl, trifluoroacetyl, and the like.
  • groups having an oxycarbonyl group include ethoxycarbonyl, tert-butoxycarbonyl (-C(0)OC(CH3)3, Boc), benzyloxycarbonyl, p- methoxybenzyloxycarbonyl, vinyloxycarbonyl, ⁇ -(p- toluenesulfonyl)ethoxycarbonyl, and the like.
  • Suitable amino acid residues include, but are not limited to, residues of Gly (glycine), Ala (alanine), Arg (arginine), Asn (asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid), His (histidine), IIe (isoleucine), Leu (leucine), Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline), 5-Hyl (5-hydroxylysine), Orn (ornithine) and ⁇ - Ala.
  • suitable amino acid residues also include amino acid residues that are protected with a protecting group.
  • suitable protecting groups include those typically employed in peptide synthesis, including acyl groups (such as formyl and acetyl), arylmethoxycarbonyl groups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert-butoxycarbonyl groups (-C(0)OC(CH3)3, Boc), and the like.
  • Suitable peptide residues include peptide residues comprising two to five amino acid residues. The residues of these amino acids or peptides can be present in stereochemical configurations of the D-form, the L- form or mixtures thereof.
  • amino acid or peptide residue may have an asymmetric carbon atom.
  • suitable amino acid residues having an asymmetric carbon atom include residues of Ala, Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr and Tyr.
  • Peptide residues having an asymmetric carbon atom include peptide residues having one or more constituent amino acid residues having an asymmetric carbon atom.
  • suitable amino acid protecting groups include those typically employed in peptide synthesis, including acyl groups (such as formyl and acetyl), arylmethoxycarbonyl groups (such as benzyloxycarbonyl and p- nitrobenzyloxycarbonyl), tert-butoxycarbonyl groups (-C(0)OC(CH3)3), and the like.
  • acyl groups such as formyl and acetyl
  • arylmethoxycarbonyl groups such as benzyloxycarbonyl and p- nitrobenzyloxycarbonyl
  • tert-butoxycarbonyl groups tert-butoxycarbonyl groups
  • Suitable reductively eliminable hydrogenolyzable groups include, but are not limited to, arylsulfonyl groups (such as o-toluenesulfonyl); methyl groups substituted with phenyl or benzyloxy (such as benzyl, trityl and benzyloxymethyl); arylmethoxycarbonyl groups (such as benzyloxycarbonyl and o-methoxy-benzyloxycarbonyl); and haloethoxycarbonyl groups (such as ⁇ , ⁇ , ⁇ -trichloroethoxycarbonyl and ⁇ -iodoethoxycarbonyl).
  • arylsulfonyl groups such as o-toluenesulfonyl
  • methyl groups substituted with phenyl or benzyloxy such as benzyl, trityl and benzyloxymethyl
  • arylmethoxycarbonyl groups such as benzyloxy
  • Compounds of the disclosure may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise.
  • compositions comprising compounds described above. These compounds and pharmaceutical compositions may be used to improve the harvest of hematopoietic stem cells or progenitor cells. Additionally, the compounds or compositions may be used to elevate the circulation of hematopoietic progenitor and/or stem cells, improve the collection of hematopoietic stem cells or progenitor cells for a transfusion, increase the sensitization of an anti-cancer therapy such as a chemotherapeutic or radiotherapy, or mobilize pre-cancerous or cancerous cells into the peripheral blood which may increase their sensitivity to an anti-cancer therapy.
  • an anti-cancer therapy such as a chemotherapeutic or radiotherapy
  • Hematopoietic stem cell transplant is used to facilitate repopulation of healthy bone marrow and immune system cells after high-dose chemotherapy treatment for cancers such as Hodgkin's and non-Hodgkin's lymphoma, multiple myeloma, and leukemia.
  • HSCT hematopoietic stem/progenitor cells
  • Successful HSCT requires the intravenous infusion of a minimum number of 2 x 10 6 CD34+ stem cells/kg body weight; however, a dose of 5 x 10 6 CD34+ cells/kg is considered preferable for early and long term multilineage engraftment.
  • G-CSF granulocyte colony-stimulating factor
  • VLA-4 the integrin ⁇ 4 ⁇ 1
  • BM bone marrow
  • HSPC mobilization has been achieved by disrupting the integrin ⁇ 4 ⁇ 1/VCAM-l axis with antibodies against integrin ⁇ 4 ⁇ 1 or VCAM-1.
  • Preclinical mouse studies in the DiPersio laboratory have shown that administration of the small molecule inhibitor of integrin ⁇ 4 ⁇ 1, BI05192, results in the rapid and reversible mobilization of HSPCs into the peripheral circulation with maximum mobilization occurring within 30 to 60 minutes and returning to baseline within 4 hours.
  • a superior treatment could be envisioned wherein a patient receives an integrin ⁇ 4 ⁇ 1 antagonist to continually inhibit integrin ⁇ 4 ⁇ 1 over the course of ⁇ 4 hours (average duration of CD34+ stem cell apheresis procedures), maximizing the mobilization of HSPCs that can be collected by apheresis during the same day of treatment.
  • BI05192 is a potent small molecule inhibitor of integrin ⁇ 4 ⁇ 1 and has demonstrated efficacy in mobilizing HSPCs in mice.
  • BI05192 has poor aqueous solubility, bioavailability, and pharmacokinetic properties and therefore has not been developed clinically.
  • a simpler, more soluble integrin ⁇ 4 ⁇ 1 antagonist is firategrast. Firategrast has been tested in clinical trials for the treatment of multiple sclerosis and has demonstrated efficacy in mobilizing HSPCs in mice but to a significantly lesser extent than BI05192 and at much higher doses. Neither of these currently available integrin ⁇ 4 ⁇ 1 antagonists have the appropriate properties to be useful for HSCT.
  • compositions or methods may also have the added advantage that the compositions or methods result in the mobilization in higher numbers, begin mobilization in a shorter period of time, over a more prolonged period of time, or mobilize increased numbers of early progenitor and/or stem cells, LSK-SLAM cells, CFU-C cells, or other progenitor and/or stem cells which are competent to achieve a successful engraftment into the patient.
  • the present disclosure relates to the fields of pharmaceuticals, medicine and cell biology.
  • this disclosure provides methods of inhibiting or antagonizing VLA-4 using one or more of the compounds disclosed herein, as well as pharmaceutical compositions thereof.
  • the compounds and compositions described herein may be used to increase the harvest of HSPCs for a variety of different applications. These compounds and compositions may be used to treat a patient who requires a transplantation. Alternatively, the compounds and compositions may be used to treat a patient who does not require a transplantation. The patient who needs a transplant of HSPCs requires either an allogenic, autologous, or tandem transplant of HSPCs. In some embodiments, the HSPCs may be used in either allogenic or autologous transplants. In another aspect, the present compounds and compositions described herein may be used to improve the circulation of cells to tissues which need repair. The increased circulation of HSPCs may be used to improve the repair of the target tissue in the patient.
  • HSPCs are harvested, these cells may be returned to the donor patient (autologous transplant) or may be donated to another patient that is sufficiently compatible to prevent rejection (allogeneic transplant).
  • autologous transplantation is in combination with radiation or chemotherapy in patients bearing tumors since the radiotherapeutic or chemotherapeutic methods deplete the patient's normal cells.
  • the patient's cells may be harvested prior to or during the therapeutic treatments, fractionated if necessary, cultured and optionally expanded, and then returned to the patient to restore the damaged immune system depleted by the therapy. Allogeneic recipients may receive the cells for the same purpose, or may have a condition that may be benefited by enhancing their hematopoietic systems.
  • the mobilized cells are collected from the donor by, for example, apheresis and then stored/cultured/expanded/fractionated as desired.
  • the compounds and compositions described herein may result in the need for apheresis being eliminated.
  • the present compounds and compositions described herein may be used to increase the circulation of pre-cancerous or cancerous cells out of the bone marrow into the peripheral blood. Without wishing to be bound by any theory, it is believed that increasing the circulation of pre-cancerous or cancerous cells out of the bone marrow may increase the effectiveness of an anti-cancer therapy.
  • these compounds and compositions may be used to treat patients who have or are at risk of a hematopoietic malignancy such as lymphoma, myeloma, or leukemia.
  • the compounds and compositions described herein may be administered or employed prior to, during, or subsequent to the anticancer therapy.
  • Two non-limiting examples of anti-cancer therapies that may be used in the methods described herein or conjunction with the compounds and compositions described herein include chemotherapeutic agents or radiotherapy.
  • the compounds and compositions described herein may be used to decrease inflammation which may result in increasing tissue repair.
  • the compounds and compositions described herein may be used to treat graft versus host disease.
  • these compounds and compositions may be used to treat diseases or disorders associated with cell adhesion-mediated inflammatory pathways.
  • Some non-limiting examples of cell adhesion-mediated inflammatory pathologies include asthma, multiple sclerosis, rheumatoid arthritis, atherosclerosis, and inflammatory bowel disease.
  • Such pharmaceutical compositions further comprise one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and if desired other active ingredients.
  • the compound is administered as part of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
  • the compounds and/or pharmaceutical compositions thereof may be administered orally, parenterally, or by inhalation spray, or topically in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrastemal, infusion techniques or intraperitoneally.
  • the compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat a medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
  • the compounds described above can be used in the treatment of patients suffering from the above pathological conditions.
  • selection of the most appropriate compound of the disclosure is within the ability of one with ordinary skill in the art and will depend on a variety of factors including assessment of results obtained in standard assay and animal models.
  • the compounds provided herein may be used in a variety of biological, prophylactic or therapeutic areas, including those in wherein VLA-4 plays a role.
  • the compounds in a therapeutically effective amount are ordinarily combined with one or more excipients appropriate to the indicated route of administration.
  • the compounds of the present disclosure are contemplated to be formulated in a manner amenable to treatment of a veterinary patient as well as a human patient.
  • the veterinary patient may be an avian such as chicken, turkey, or duck, a companion animal such as a cat or dog, livestock animals such as a cow, horse, pig, or goat, zoo animals, and wild animals.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and tableted or encapsulated for convenient administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • excipients and modes of administration are well and widely known in the pharmaceutical art and may be adapted to the type of animal being treated.
  • Description of potential administration routes which may be used to formulate the compositions described herein include those taught in Remington's Pharmaceutical Sciences, which is incorporated herein by reference.
  • compositions useful in the present disclosure may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical carriers and excipients such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
  • the compounds of the present disclosure may be administered by a variety of methods, e.g. , orally or by injection (e.g. subcutaneous, intravenous, intraperitoneal, etc.).
  • the active compounds may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound. They may also be administered by continuous perfusion/infusion of a disease or wound site.
  • the therapeutic compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent.
  • suitable diluents include saline and aqueous buffer solutions.
  • Liposomes include water-in- oil-in-water CGF emulsions as well as conventional liposomes.
  • the therapeutic compound may also be administered parenterally, intraperitoneally, intramuscularly, intraarterially, intraspinally, or intracerebrally.
  • Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • Pharmaceutical compositions may be suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the therapeutic compound into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e. , the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the therapeutic compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the therapeutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • the therapeutic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount of the therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient.
  • the therapeutic compound may also be administered topically to the skin, eye, or mucosa. Alternatively, if local delivery to the lungs is desired the therapeutic compound may be administered by inhalation in a dry-powder or aerosol formulation.
  • Active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient.
  • the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in a human or another animal, such as the model systems shown in the examples and drawings.
  • HED human equivalent dose
  • HED Animal dose (mg/kg) ⁇ (Animal Km/Human Km)
  • K m factors in conversion results in more accurate HED values, which are based on body surface area (BSA) rather than only on body mass.
  • BSA body surface area
  • K m values for humans and various animals are well known. For example, the K m for an average 60 kg human (with a BSA of 1.6 m 2 ) is 37, whereas a 20 kg child (BSA 0.8 m 2 ) would have a K m of 25.
  • K m for some relevant animal models are also well known, including: mice K m of 3 (given a weight of 0.02 kg and BSA of 0.007); hamster K m of 5 (given a weight of 0.08 kg and BSA of 0.02); rat K m of 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey K m of 12 (given a weight of 3 kg and BSA of 0.24).
  • Precise amounts of the therapeutic composition depend on the judgment of the practitioner and are peculiar to each individual. Nonetheless, a calculated HED dose provides a general guide. Other factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment and the potency, stability and toxicity of the particular therapeutic formulation.
  • the actual dosage amount of a compound of the present disclosure or composition comprising a compound of the present disclosure administered to a subject may be determined by physical and physiological factors such as type of animal treated, age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the subject and on the route of administration. These factors may be determined by a skilled artisan.
  • the practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. The dosage may be adjusted by the individual physician in the event of any complication.
  • the VLA-4 antagonist i.e. inhibitors
  • a specific VLA-4 inhibitor such as a compound of formula I may be administered in a range of about 1 mg/kg to about 200 mg/kg, or about 50 mg/kg to about 200 mg/kg, or about 50 mg/kg to about 100 mg/kg, or about 75 mg/kg to about 100 mg/kg, or about 100 mg/kg.
  • the effective amount may be less than 1 mg/kg/day, less than 500 mg/kg/day, less than 250 mg/kg/day, less than 100 mg/kg/day, less than 50 mg/kg/day, less than 25 mg/kg/day or less than 10 mg/kg/day. It may alternatively be in the range of 1 mg/kg/day to 200 mg/kg/day.
  • a dose may also comprise from about 1 microgram/kg/body weight, about 5 microgram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram/kg/body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body weight, about 350 milligram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein.
  • a range of about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 microgram/kg/body weight to about 500 milligram/kg/body weight, etc. can be administered, based on the numbers described above.
  • a pharmaceutical composition of the present disclosure may comprise, for example, at least about 0.1% of a compound of the present disclosure.
  • the compound of the present disclosure may comprise between about 1% to about 75% of the weight of the unit, or between about 25% to about 60%, for example, and any range derivable therein.
  • Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, subjects may be administered two doses daily at approximately 12 hour intervals. In some embodiments, the agent is administered once a day.
  • the agent(s) may be administered on a routine schedule.
  • a routine schedule refers to a predetermined designated period of time.
  • the routine schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined.
  • the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks therebetween.
  • the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc.
  • the disclosure provides that the agent(s) may taken orally and that the timing of which is or is not dependent upon food intake.
  • the agent can be taken every morning and/or every evening, regardless of when the subject has eaten or will eat.
  • the symbol means a single bond where the group attached to the thick end of the wedge is "out of the page.”
  • the symbol """HI means a single bond where the group attached to the thick end of the wedge is "into the page”.
  • the symbol means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.
  • R may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed.
  • R may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed.
  • R may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise.
  • Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g. , a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals -CH-), so long as a stable structure is formed.
  • R may reside on either the 5-membered or the 6- membered ring of the fused ring system.
  • the number of carbon atoms in the group or class is as indicated as follows: "Cn” defines the exact number (n) of carbon atoms in the group/class. "C ⁇ n” defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number as small as possible for the group/class in question, e.g., it is understood that the minimum number of carbon atoms in the group “alkenyl(c ⁇ 8)” or the class “alkene(c ⁇ 8)” is two. Compare with “alkoxy(c ⁇ io)", which designates alkoxy groups having from 1 to 10 carbon atoms.
  • Cn-n defines both the minimum (n) and maximum number ( ⁇ ') of carbon atoms in the group.
  • alkyl(C2-io) designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical groups or class it modifies and it may or may not be enclosed in parenthesis, without signifying any change in meaning.
  • the terms “C5 olefin”, “C5-olefin”, “olefin(C5)”, and “olefincs” are all synonymous.
  • saturated when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below.
  • the term when used to modify an atom, it means that the atom is not part of any double or triple bond.
  • substituted versions of saturated groups one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded.
  • saturated when used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution.
  • aliphatic when used without the "substituted” modifier signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic hydrocarbon compound or group.
  • the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic).
  • Aliphatic compounds/groups can be saturated, that is joined by single carbon-carbon bonds (alkanes/alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes/alkenyl) or with one or more carbon-carbon triple bonds (alkynes/alkynyl).
  • aromatic when used to modify a compound or a chemical group refers to a planar unsaturated ring of atoms with An +2 electrons in a fully conjugated cyclic ⁇ system.
  • alkyl when used without the “substituted” modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen.
  • alkanediyl when used without the "substituted” modifier refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen.
  • the groups -CH 2 - (methylene), -CH2CH2-, -CH 2 C(CH 3 ) 2 CH 2 -, and -CH2CH2CH2- are non-limiting examples of alkanediyl groups.
  • An “alkane” refers to the class of compounds having the formula H-R, wherein R is alkyl as this term is defined above.
  • haloalkyl is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to halo (i.e.
  • -F, -CI, -Br, or -I such that no other atoms aside from carbon, hydrogen and halogen are present.
  • the group, -CH 2 C1 is a non-limiting example of a haloalkyl.
  • fluoroalkyl is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present.
  • the groups -CH 2 F, -CF3, and -CH 2 CF 3 are non-limiting examples of fluoroalkyl groups.
  • cycloalkyl when used without the "substituted” modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forming part of one or more non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen.
  • Non-limiting examples include: -CH(CH 2 ) 2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy).
  • cycloalkanediyl when used without the “substituted” modifier refers to a divalent saturated aliphatic group with two carbon atoms as points of attachment, no carbon- double or triple bonds, and no atoms other than carbon and hydrogen.
  • the group is a non-limiting example of cycloalkanediyl group.
  • a "cycloalkane” refers to the class of compounds having the formula H-R, wherein R is cycloalkyl as this term is defined above.
  • one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -NO2, -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 , -OC(0)CH 3 , -NHC(0)CH 3 , -S(0) 2 OH, or -S(0) 2 NH 2 .
  • alkenyl when used without the "substituted” modifier refers to an monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen.
  • alkenediyl when used without the "substituted” modifier refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched, a linear or branched acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen.
  • alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure.
  • alkene and olefin are synonymous and refer to the class of compounds having the formula H-R, wherein R is alkenyl as this term is defined above.
  • terminal alkene and a-olefin are synonymous and refer to an alkene having just one carbon-carbon double bond, wherein that bond is part of a vinyl group at an end of the molecule.
  • aryl when used without the "substituted” modifier refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more six-membered aromatic ring structure, wherein the ring atoms are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present.
  • Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl.
  • the term "arenediyl” when used without the “substituted” modifier refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structure(s) wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen.
  • the term does not preclude the presence of one or more alkyl, aryl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting).
  • arenediyl groups include:
  • an "arene” refers to the class of compounds having the formula H-R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes. When any of these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH 3 , -NHCH3, -NHCH2CH3, -N(CH 3 ) 2 , -C(0)NH 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 , -OC(0)CH 3 , -NHC(0)CH 3 , -S(0) 2 OH, or -S(0) 2 NH 2 .
  • aralkyl when used without the “substituted” modifier refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above.
  • Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.
  • aralkyl When the term aralkyl is used with the "substituted" modifier one or more hydrogen atom from the alkanediyl and/or the aryl group has been independently replaced by -OH, -F, -CI, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH 3 , -NHCH3, -NHCH2CH3, -N(CH 3 ) 2 , -C(0)NH 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 , -OC(0)CH 3 , -NHC(0)CH 3 , -S(0) 2 OH, or -S(0)2NH2.
  • substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-l-yl.
  • -C(0)R in which R is a hydrogen, alkyl, cycloalkyl, or aryl as those terms are defined above.
  • the groups, -CHO, -C(0)CH 3 (acetyl, Ac), -C(0)CH 2 CH 3 , -C(0)CH(CH 3 ) 2 , -C(0)CH(CH2)2, -C(0)C6H5, and -C(0)C6H4CH3 are non-limiting examples of acyl groups.
  • a "thioacyl” is defined in an analogous manner, except that the oxygen atom of the group -C(0)R has been replaced with a sulfur atom, -C(S)R.
  • aldehyde corresponds to an alkyl group, as defined above, attached to a -CHO group.
  • one or more hydrogen atom (including a hydrogen atom directly attached to the carbon atom of the carbonyl or thiocarbonyl group, if any) has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH 3 , -NHCH3, -NHCH2CH3, -N(CH 3 ) 2 , -C(0) H 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 , -OC(0)CH 3 , -NHC(0)CH 3 , -S(0) 2 OH, or -S(0) 2 NH 2 .
  • the groups, -C(0)CH 2 CF 3 , -C0 2 H (carboxyl), -C0 2 CH 3 (methylcarboxyl), -C0 2 CH 2 CH 3 , -C(0)NH 2 (carbamoyl), and -CON(CH 3 ) 2 are non-limiting examples of substituted acyl groups.
  • R is an alkyl
  • Non-limiting examples include: -OCH 3 (methoxy), -OCH 2 CH 3 (ethoxy), -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 (isopropoxy), -OC(CH 3 ) 3 (tert-butoxy), -OCH(CH 2 ) 2 , -O-cyclopentyl, and -O-cyclohexyl.
  • cycloalkoxy when used without the “substituted” modifier, refers to groups, defined as -OR, in which R is cycloalkyl, alkenyl, aryl, aralkyl, and acyl, respectively.
  • alkylthio and “acylthio” when used without the “substituted” modifier refers to the group -SR, in which R is an alkyl and acyl, respectively.
  • alcohol corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group.
  • ether corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group.
  • substituted one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -NO2, -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 , -OC(0)CH 3 , -NHC(0)CH 3 , -S(0) 2 OH, or -S(0) 2 NH 2 .
  • alkylamino when used without the "substituted” modifier refers to the group -NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: -NHCH 3 and -NHCH 2 CH 3 .
  • dialkylamino when used without the “substituted” modifier refers to the group -NRR', in which R and R' can be the same or different alkyl groups, or R and R' can be taken together to represent an alkanediyl.
  • dialkylamino groups include: -N(CH 3 ) 2 and -N(CH 3 )(CH 2 CH 3 ).
  • cycloalkylamino when used without the “substituted” modifier, refers to groups, defined as -NHR, in which R is cycloalkyl, alkenyl, aryl, aralkyl, alkoxy, and alkylsulfonyl, respectively.
  • R is cycloalkyl, alkenyl, aryl, aralkyl, alkoxy, and alkylsulfonyl, respectively.
  • a non-limiting example of an arylamino group is -NHC6H5.
  • amido (acylamino), when used without the “substituted” modifier, refers to the group -NHR, in which R is acyl, as that term is defined above.
  • a non-limiting example of an amido group is -NHC(0)CH 3 .
  • alkylsulfonyl and alkylsulfinyl when used without the “substituted” modifier refers to the groups -S(0)2R and -S(0)R, respectively, in which R is an alkyl, as that term is defined above.
  • cycloalkylsulfonyl alkenylsulfonyl
  • alkynylsulfonyl alkynylsulfonyl
  • arylsulfonyl aralkylsulfonyl
  • heteroarylsulfonyl heteroarylsulfonyl
  • heterocycloalkylsulfonyl are defined in an analogous manner.
  • AI active ingredient
  • active compound also referred to as an active compound, active substance, active agent, pharmaceutical agent, agent, biologically active molecule, or a therapeutic compound
  • active pharmaceutical ingredient API
  • bulk active are also used in medicine, and the term active substance may be used for pesticide formulations.
  • Excipient is a pharmaceutically acceptable substance formulated along with the active ingredient(s) of a medication, pharmaceutical composition, formulation, or drug delivery system. Excipients may be used, for example, to stabilize the composition, to bulk up the composition (thus often referred to as “bulking agents,” “fillers,” or “diluents” when used for this purpose), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable versions of anti adherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles.
  • the main excipient that serves as a medium for conveying the active ingredient is usually called the vehicle.
  • Excipients may also be used in the manufacturing process, for example, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life.
  • the suitability of an excipient will typically vary depending on the route of administration, the dosage form, the active ingredient, as well as other factors.
  • HSPCs refers to hematopoietic stem and progenitor cells. HSPCs are a combination of progenitor cells and stem cells.
  • hydrate when used as a modifier to a compound means that the compound has less than one (e.g., hemihydrate), one (e.g. , monohydrate), or more than one (e.g. , dihydrate) water molecules associated with each compound molecule, such as in solid forms of the compound.
  • IC50 refers to an inhibitory dose which is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular active ingredient or other substance (inhibitor) is needed to inhibit a given biological, biochemical or chemical process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.
  • An "isomer" of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.
  • the term "patient” or “subject” refers to a living organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, avian, or transgenic species thereof.
  • the patient or subject is a primate.
  • Non-limiting examples of human patients are adults, juveniles, infants and fetuses.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salts” means salts of compounds of the present disclosure which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene- 1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this disclosure is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G.
  • a "pharmaceutically acceptable carrier,” “drug carrier,” or simply “carrier” is a pharmaceutically acceptable substance formulated along with the active ingredient medication that is involved in carrying, delivering and/or transporting a chemical agent.
  • Drug carriers may be used to improve the delivery and the effectiveness of drugs, including for example, controlled-release technology to modulate drug bioavailability, decrease drug metabolism, and/or reduce drug toxicity. Some drug carriers may increase the effectiveness of drug delivery to the specific target sites.
  • carriers include: liposomes, microspheres (e.g., made of poly (lactic-co-gly colic) acid), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virosomes, and dendrimers.
  • a "pharmaceutical drug” (also referred to as a pharmaceutical, pharmaceutical preparation, pharmaceutical composition, pharmaceutical formulation, pharmaceutical product, medicinal product, medicine, medication, medicament, or simply a drug) is a compound or composition used to diagnose, cure, treat, or prevent disease.
  • An active ingredient (AI) (defined above) is the ingredient in a pharmaceutical drug or a pesticide that is biologically active.
  • active pharmaceutical ingredient (API) and bulk active are also used in medicine, and the term active substance may be used for pesticide formulations.
  • Some medications and pesticide products may contain more than one active ingredient.
  • the inactive ingredients are usually called excipients (defined above) in pharmaceutical contexts.
  • pre-malignant cells refers to cells that can form malignant hematopoietic or myeloid cells.
  • the malignant hematopoietic or myeloid cells are those which characterize the conditions of myeloma, leukemia, and lymphoma.
  • Particular forms of these diseases include acute myelitic leukemia (AML), acute lymphatic leukemia (ALL), multiple myeloma (MM), chronic myelogenous leukemia (CML), chronic lymphatic leukemia (CLL), hairy cell leukemia (HCL), acute promyelocytic leukemia (APL), and various lymphomas.
  • Prevention includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.
  • Prodrug means a compound that is convertible in vivo metabolically into an active ingredient according to the present disclosure. The prodrug itself may or may not also have activity with respect to a given target protein.
  • a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound.
  • Suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-P-hydroxynaphthoate, gentisates, isethionates, di- ⁇ -toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, />-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like.
  • a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine
  • progenitor cells refers to cells that, in response to certain stimuli, can form differentiated hematopoietic or myeloid cells.
  • the presence of progenitor cells can be assessed by the ability of the cells in a sample to form colony -forming units of various types, including, for example, CFU-GM (colony-forming units, granulocyte- macrophage); CFU-GEMM (colony-forming units, multipotential); BFU-E (burst-forming units, erythroid); HPP-CFC (high proliferative potential colony -forming cells); or other types of differentiated colonies which can be obtained in culture using known protocols such as those described below.
  • CFU-GM colony-forming units, granulocyte- macrophage
  • CFU-GEMM colony-forming units, multipotential
  • BFU-E burst-forming units, erythroid
  • HPP-CFC high proliferative potential colony -forming cells
  • a “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs.
  • “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands.
  • “Diastereomers” are stereoisomers of a given compound that are not enantiomers.
  • Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer.
  • the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds.
  • a molecule can have multiple stereocenters, giving it many stereoisomers.
  • the total number of hypothetically possible stereoisomers will not exceed 2 n , where n is the number of tetrahedral stereocenters.
  • Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%.
  • enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures.
  • the phrase "substantially free from other stereoisomers" means that the composition contains ⁇ 15%, more preferably ⁇ 10%, even more preferably ⁇ 5%, or most preferably ⁇ 1% of another stereoisomer(s).
  • Stem cells are less differentiated forms of progenitor cells.
  • CD34+ cells can be assayed using fluorescence activated cell sorting (FACS) and thus their presence can be assessed in a sample using this technique.
  • FACS fluorescence activated cell sorting
  • CD34+ cells are present only in low levels in the blood, but are present in large numbers in bone marrow.
  • the stem cells may be hematopoietic stem cells that express the SLAM and LSK markers.
  • hematopoietic stem cells may be LSK cells or LSK-SLAM cells, which are considered early hematopoietic stem cells.
  • LSK refers to Lin " Scal + c-Kit + and SLAM is signaling lymphocyte activation molecules or Lin " CD41 " CD48 " CD150 + .
  • Treatment includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g. , arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g. , reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.
  • VLA-4 antagonists and “VLA-4 inhibitors” are used interchangeably herein.
  • LC-MS analyses were performed on an Agilent 1100 or 1200HPLC/MSD electrospray mass spectrometer in positive ion mode with scan range was 100-lOOOd.
  • Preparative normal phase chromatography was performed on a CombiFlash Rf+ (Teledyne Isco) with pre-packed RediSep Rf silica gel cartridges.
  • Preparative reverse phase HPLC was performed on a CombiFlash Rf+ (Teledyne Isco) equipped with RediSep Rf Gold pre-packed C18 cartridges and an acetonitrile/water/0.05% TFA gradient.
  • benzyl 4-bromo-2,6-dichlorobenzoate (Compound 2, 1.5 g, 4.17 mmol), palladium acetate (0.047 g, 0.208 mmol), 4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene (0.241 g, 0.417 mmol), 4- dimethylaminopyridine (2 g, 16.7 mmol), Octacarbonyldicobalt (0.60 g, 3.33 mmol) and toluene/methanol (2: 1, 15 mL).
  • the vial was crimped shut and irradiated at 90 °C for 30 minutes using microwaves.
  • the vial was crimped shut, sparged for 10 minutes with nitrogen gas and then heated overnight at 80 °C.
  • the reaction was cooled to room temperature and filtered through Celite®, rinsing with ethyl acetate.
  • the ethyl acetate layer was washed using additional water, dried using sodium sulfate and concentrated in vacuo.
  • the resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent.
  • the vial was crimped shut and sparged with nitrogen for 10 minutes and then heated for 48 hours at 120 °C.
  • the reaction was partitioned between ethyl acetate and water, layers were separated and the ethyl acetate layer was dried using sodium sulfate, filtered and concentrated in vacuo.
  • the residue was chromatographed on silica gel using ethyl acetate and hexanes as eluent.
  • the vial was crimped shut and sparged with nitrogen for 10 minutes and then heated for 48 hours at 120 °C.
  • the reaction was partitioned between ethyl acetate and water, layers were separated and the ethyl acetate layer was dried using sodium sulfate, filtered and concentrated in vacuo.
  • the residue was chromatographed on silica gel using ethyl acetate and hexanes as eluent.
  • the vial was crimped shut and sparged with nitrogen for 10 minutes and then heated for 24 hours at 120 °C.
  • the reaction was partitioned between ethyl acetate and water, layers were separated and the ethyl acetate layer was dried using sodium sulfate, filtered and concentrated in vacuo.
  • the residue was chromatographed on silica gel using ethyl acetate and hexanes as eluent.
  • reaction was concentrated in vacuo and then partitioned between ethyl acetate and saturated sodium bicarbonate, layers were separated and the ethyl acetate layer was dried using sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using methanol and dichloromethane as eluent.
  • Step 1 Preparation of benzyl (S)-2-(((S)-3-(2',6'-dimethoxy-4 , -((2 methoxyethoxy)methyl)-[l,l'-biphenyl]-4-yl)-l-methoxy-l-oxopropan-2- yl)carbamoyl)pyrrolidine-l-carboxylate (76)
  • Flow cytometry cell-based assay Compounds were tested for their ability to inhibit the binding of soluble VCAM-1 to human G2 acute lymphoblastic leukemia (ALL) cells. Briefly, G2 ALL cells are pre-incubated with increasing concentrations (0.001 to 1000 nM) of compounds for 30 minutes. Soluble VCAM/Fc chimera protein (R&D systems) is then added to the mixture and the cells incubated for an additional 30 minutes. Afterwards, cells are washed and VCAM-1 is detected using PE-conjugated secondary mAbs. In each experiment, an aliquot of cells will be stained with isotype control mAbs to serve as a negative control. The percentage of VCAM-1 binding cells was then determined by flow cytometry.
  • ALL G2 acute lymphoblastic leukemia
  • Table 3 Inhibition of s VCAM-1 binding to human G2 ALL cells.
  • mice DBA/2J mice were purchased from the Jackson Laboratory (Bar Harbor, ME, USA). Animals were housed at the Washington University Medical School vivarium under SPF conditions. All experiments were performed in accordance with the guidelines of the Washington University Animal Studies Committee and the institutional animal care and use committee (IACUC), in agreement with AAALAC guidelines.
  • IACUC institutional animal care and use committee
  • VLA-4 inhibitors Examples 1220, 1221, 1224, 1610, and 1611 were prepared in DMSO/10 mM sodium bicarbonate pH 8/saline (l%/49.5%/49.5%) and injected subcutaneously (SC) at a dose of 3 mg/kg.
  • CFC Colony forming cell assay.
  • Peripheral blood (PB) was drawn from the facial vein without anaesthesia into K/EDTA anti-coagulated tubes (Sarstedt AG & Co, Niimbrecht, Germany). Red blood cells were removed from 25 ⁇ _, aliquots of blood using hypotonic lysis (Ammonium-Chloride-Potassium, ACK buffer, 5-10 min at RT) and samples were mixed with 2.5 mL methylcellulose media supplemented with a cocktail of recombinant cytokines (MethoCult 3434; Stem Cell Technologies, Vancouver, BC, Canada). Cultures were plated in duplicate in 35 mm dishes and placed in a humidified chamber with 5% CO2 at 37 °C. After 7 d of culture, colonies containing at least 50 cells were counted using an inverted microscope in a blinded fashion.
  • hypotonic lysis Ammonium-Chloride-Potassium, ACK buffer, 5-10 min at RT
  • Results for Examples 1220, 1221, and 1224 are shown in FIG. 1.
  • Results for Examples 1610 and 1611 are shown in FIG. 2.

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Abstract

La présente invention concerne des agents thérapeutiques de formule : dans laquelle les variables sont telles que définies dans la description. La présente invention concerne également des compositions pharmaceutiques, des kits et des articles manufacturés comprenant lesdits agents thérapeutiques. L'invention concerne des méthodes d'utilisation de ces agents thérapeutiques.
PCT/US2017/059733 2016-11-02 2017-11-02 Antagonistes de l'intégrine WO2018085552A1 (fr)

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US11040955B2 (en) 2017-02-28 2021-06-22 Morphic Therapeutic, Inc. Inhibitors of (alpha-v)(beta-6) integrin
US11046685B2 (en) 2017-02-28 2021-06-29 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin
US11046669B2 (en) 2017-02-28 2021-06-29 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin
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US11021480B2 (en) 2018-08-29 2021-06-01 Morphic Therapeutic, Inc. Inhibiting (α-V)(β-6) integrin
US11739087B2 (en) 2018-08-29 2023-08-29 Morphic Therapeutic, Inc. Inhibiting (α-v)(β-6) integrin
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

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