WO2018085552A1

WO2018085552A1 - Integrin antagonists

Info

Publication number: WO2018085552A1
Application number: PCT/US2017/059733
Authority: WO
Inventors: Peter G. Ruminski; Marvin L. MEYERS; Richard F. Heier; Michael P. RETTIG; John DIPERSIO
Original assignee: University of Washington; St Louis University; Washington University in St Louis WUSTL
Current assignee: University of Washington; St Louis University; Washington University in St Louis WUSTL
Priority date: 2016-11-02
Filing date: 2017-11-02
Publication date: 2018-05-11
Anticipated expiration: 2019-05-02

Abstract

The present disclosure provides therapeutic agents including those of the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such therapeutic agents. Methods of using the therapeutic agents are also provided.

Description

DESCRIPTION

INTEGRIN ANTAGONISTS

This application claims the benefit of priority to United States Provisional Application Nos. 62/416,530, filed on November 2, 2016, 62/554,791, filed on September 6, 2017, and 62/558,045, filed on September 13, 2017, the entire contents of which are incorporated herein by reference.

BACKGROUND

I. Field

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 α4β1 (VLA-4).

II. Description of Related Art

Currently, 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. Currently, cytokines, such as granulocyte-colony forming unit (G-CSF), and immunostimulants, such as plerixafor, are used to increase the amount of hematopoietic stem cells in the peripheral blood. Unfortunately, even these methods often fail to increase the concentrations to sufficient levels for transplantation. Therefore, a need remains for better methods to harvest hematopoietic stem cells for transplantation.

SUMMARY

The present disclosure provides compounds which are VLA-4 antagonists (i.e. inhibitors), pharmaceutical compositions, methods for their manufacture, and methods for their use.

In some aspects, the present disclosure provides compounds further defined by the formula:

wherein:

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; or

-X(CH₂0)_m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 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 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:

wherein:

p is 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 aralkylamino(c<8), or a substituent convertible in vivo to hydroxy;

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

roup of the formula:

wherein: 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 aralkylamino(c<8), or a substituent convertible in vivo to hydroxy;

Rio and R11 are each independently hydrogen or halo,

provided that if R5 is hydrogen, then W is -C(0)X₃; and if W is -C(0)X₃ or Re is -C(0)X₂, then R9 is hydrogen; and if is R h₁ydrogen, then R6 is not hydrogen;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds are further defined by the formula:

wherein:

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

-X(CH₂0)_m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 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

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);

provided that Ri and R2 are not both hydrogen;

pharmaceutically acceptable salt thereof.

In some embodiments, the compounds are further defined as:

(III) wherein:

-X(CH20)_m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

Rc is alkoxy(c<i2), acyloxy(c<i2), or a substituted version of either of these groups; and

R3 and R4 are each independently alkoxy(c<8) or substituted alkoxy(c<8);

provided that Ri and R2 are not both hydrogen;

rmaceutically acceptable salt thereof.

In some embodiments, 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); and

-X(CH20)_m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

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;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds are further defined as:

wherein:

R₁ 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

-X(CH20)_m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

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

or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds are further defined as:

wherein:

R₁ 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

-X(CH20)m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 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

provided that R₁ and R2 are not both hydrogen;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds are further defined as:

wherein:

R₁ is alkyl(c<8), substituted alkyl(c<8), alkoxy(c<8), substituted alkoxycc<8), or -Yi-R_a;

wherein:

Yi is alkanediyl(c<8) or substituted alkanediyl(c<8); and

-X(CH20)_m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

or a pharmaceutically acceptable salt thereof.

In other embodiments, the compounds are further defined as:

(VII)

R₁ 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

Ra is alkoxy(c<i2), acyloxy(c<i2), or a substituted version of either group; or

-X(CH20)_m-(CH2CH₂0)n-Rb, wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 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 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 is 0, 1, 2, or 3; and

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 a₁nd R7 are not both hydrogen;

pharmaceutically acceptable salt thereof.

In some embodiments, the compounds are further defined as:

R₁ 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; or

-X(CH20)_m-(CH2CH₂0)n-Rb, wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(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 a₁nd R7 are not both hydrogen;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds are further defined as:

wherein:

R₁ 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

-X(CH20)_m-(CH2CH₂0)n-Rb, wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

R9 is hydrogen, alkyl(c<6), or substituted alkyl(c<6);

p is 0, 1, 2, or 3; and

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;

wherein:

R₁ 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

-X(CH20)_m-(CH2CH₂0)n-Rb, wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

R9 is hydrogen, alkyl(c<6), or substituted alkyl(c<6);

p is 0, 1, 2, or 3; and

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds are further defined as:

wherein:

R_a is alkoxy(c<i2), acyloxy(c<i2), or a substituted version of either group; or -X(CH₂0)_m-(CH2CH₂0)n-Rb, wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

R9 is hydrogen, alkyl(c<6), or substituted alkyl(c<6);

p is 0, 1, 2, or 3; and

rmaceutically acceptable salt thereof.

In other embodiments, 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); and

-X(CH20)_m-(CH2CH₂0)n-Rb, wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 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), alkoxy(c<i2), or a substituted version of either group; R.3 and R.4 are each independently alkoxycc<8) or substituted alkoxycc<8);

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);

rmaceutically acceptable salt thereof.

In some embodiments, 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); and

-X(CH₂0)_m-(CH2CH₂0)n-Rb, wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 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), 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;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds are further defined as:

wherein:

Ra is alkoxy(c<i2), acyloxy(c<i2), or a substituted version of either group; or

-X(CH₂0)_m-(CH2CH₂0)n-Rb, wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

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);

or a pharmaceutically acceptable salt thereof.

In some embodiments, Z is:

wherein:

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 aralkylamino(c<8), or a substituent convertible in vivo to hydroxy; and

Rio and R11 are each independently hydrogen or halo.

In some embodiments, Z is:

wherein:

p is 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 aralkylamino(c<8), or a substituent convertible in vivo to hydroxy; R.7 and Rs are each independently hydrogen, halo, haloalkyl(c<8), or substituted haloalkyl(c<8); and

R.9 is hydrogen, alkyl(c<8), or substituted alkyl(c<8).

In some embodiments, R₁ is alkyl(c<8) or substituted alkyl(c<8) such as hydroxyalkyl(c<8) or haloalkyl(c<8). In some embodiments, is a Rn₁ unbranched group. In some embodiments, R i₁s -CH₃, -CH2OH, -CH(CH₃)OH, -C(CH₃)₂OH, -CH2F, -CHF2, -CF3, -CH2OCH3, or -CH2OCH2CH3. In some embodiments, is alko Rxy₁ (c<8) or substituted alkoxy(c<8), such as methoxy or ethoxy. In other embodiments, i Rs ₁ aminocarbonyl or carboxy. In other embodiments, R is₁ 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); and

Ra is alkoxy(c<i2), acyloxy(c<i2), or a substituted version of either group; or

-X(CH20)_m-(CH2CH₂0)n-Rb, wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8).

In other embodiments, R i₁s -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. In some embodiments, Yi is alkanediyl(c<8), such as -CH₂- In some embodiments, Ra is alkoxy(c<i2), such as ethoxy or hexyloxy. In some embodiments, Ra is acyloxy(c<i2), such as hexanoate. In other embodiments, is R -X₁ (CH20)_m-(CH2CH20)n-Rb, wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8).

In some embodiments, X is a covalent bond. In some embodiments, m is 1. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1. In some embodiments, Rb is alkyl(c<8), such as methyl. In some embodiments, R2 is hydrogen. In some embodiments, R3 is alkoxy(c<6), such as methoxy. In some embodiments, R4 is alkoxy(c<6), such as methoxy. In some embodiments, Xi is hydroxy. In other embodiments, Xi is a substituent convertible in vivo to hydroxy. In some embodiments, X2 is hydroxy. In other embodiments, X2 is a substituent convertible in vivo to hydroxy. In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the compound is further defined as:

22

or a pharmaceutically salt thereof.

In some aspects, the present disclosure provides pharmaceutical compositions comprising:

(A) a compound disclosed herein; and

(B) a pharmaceutically acceptable excipient.

In some embodiments, 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.

In some embodiments, 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 α4β1. In other embodiments, the disease or disorder is associated with inflammation. In yet other embodiments, the disease or disorder is an autoimmune disorder. In still other embodiments, the disease or disorder is associated with hematopoietic stem cells such as LSK-SLAM cells. In yet other embodiments, the disease or disorder is cancer or a reduced blood cell count such as reduced blood cell count resulting from a therapy for cancer. In some embodiments, the disease or disorder is a reduced blood cell count resulting from a therapy for cancer such as chemotherapy or radiation therapy. In other embodiments, the disease or disorder is cancer. In some embodiments, the compound or composition results in improved efficacy of the chemotherapy or radiotherapy.

In some aspects, 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. In some embodiments, the method is ex vivo or in vitro. In some embodiments, method is in vivo.

In some aspects, the present disclosure provides methods of collecting hematopoietic stem cells or progenitor cells from a patient comprising:

(A) administering to the patient 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; and

(B) subsequently drawing peripheral blood from the patient to collect the hematopoietic stem cells or progenitor cells.

In some aspects, 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.

In other aspects, 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.

In yet other aspects, 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;

(B) collecting hematopoietic stem cells or progenitor cells from the patient;

(C) transplanting the hematopoietic stem cells or progenitor cells in the patient.

In some aspects, 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.

In some aspects, the present disclosure provides methods of transplanting hematopoietic stem cells or progenitor cells comprising:

(A) administering to a first patient a compound or composition described herein;

(B) collecting hematopoietic stem cells or progenitor cells from the first patient;

(C) transplanting the hematopoietic stem cells or progenitor cells in the second patient.

In some aspects, 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.

In some embodiments, 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.

In some aspects, the present disclosure provides methods of improving the effectiveness of a treatment of cancer in a patient administered a chemotherapy or a radiotherapy comprising:

(A) administering to the patient a therapeutically effective amount of a compound or composition disclosed herein;

(B) administering a chemotherapy or a radiotherapy to the patient.

In some aspects, 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. In some embodiments, the methods comprise administering the compound or composition once. In other embodiments, the methods comprise administering the compound or composition two or more times. In some embodiments, the compound or composition is administered intravenously. In other embodiments, the compound or composition is administered subcutaneously. In some embodiments, the patient is a mammal, such as a human.

Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. Note that simply because a particular compound is ascribed to one particular generic formula does not mean that it cannot also belong to another generic formula.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

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).

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Disclosed herein are new compounds and compositions which act as integrin antagonists (i.e. inhibitors) of, for example, α4β1 integrin (VLA-4), methods for their manufacture, and methods for their use, including for the treatment and/or prevention of disease. In some embodiments, these compounds may be used in improving the harvest of hematopoietic stem cells or progenitor cells or to enhance an anti-cancer therapy.

I. Compounds and Synthetic Methods

In some embodiments, 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 A³ 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, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium, and isotopes of carbon include ¹³C and ¹⁴C. Similarly, it is contemplated that one or more carbon atom(s) of a compound of the present disclosure may be replaced by a silicon atom(s). Furthermore, it is contemplated that one or more oxygen atom(s) of a compound of the present disclosure may be replaced by a sulfur or selenium atom(s).

Compounds of the present disclosure may also exist m prodrug form. Since 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. Thus, 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. Accordingly, 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.

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 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.

It should be further recognized that the compounds of the present disclosure include those that have been further modified to comprise substituents that are convertible to hydroxy in vivo. This includes those groups that may be convertible to a hydrogen atom by enzymological or chemical means including, but not limited to, hydrolysis and hydrogenolysis. Examples include hydrolyzable groups, such as acyl groups, groups having an oxycarbonyl group, amino acid residues, peptide residues, o-nitrophenylsulfenyl, trimethylsilyl, tetrahydropyranyl, diphenylphosphinyl, and the like. Examples of acyl groups include formyl, acetyl, trifluoroacetyl, and the like. Examples of groups having an oxycarbonyl group include ethoxycarbonyl, tert-butoxycarbonyl (-C(0)OC(CH3)3, Boc), benzyloxycarbonyl, p- methoxybenzyloxycarbonyl, vinyloxycarbonyl, β-(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 β- Ala. Examples of suitable amino acid residues also include amino acid residues that are protected with a protecting group. Examples of 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. In addition, the amino acid or peptide residue may have an asymmetric carbon atom. Examples of 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. Examples of 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. Other examples of substituents "convertible to hydroxy in vivo" include reductively eliminable hydrogenolyzable groups. Examples of 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 β,β,β-trichloroethoxycarbonyl and β-iodoethoxycarbonyl).

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. II. Biological Activity

It is another object of the disclosure to provide pharmaceutical 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.

Hematopoietic stem cell transplant (HSCT) 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. In HSCT, hematopoietic stem/progenitor cells (HSPCs) are collected from the patient's blood, harvested, frozen and then stored while the patient receives high-dose chemotherapy and/or radiation therapy. Successful HSCT requires the intravenous infusion of a minimum number of 2 x 10⁶ CD34+ stem cells/kg body weight; however, a dose of 5 x 10⁶ CD34+ cells/kg is considered preferable for early and long term multilineage engraftment.

Stem cells harvested from peripheral blood are the most commonly used graft source in HSCT. While granulocyte colony-stimulating factor (G-CSF) is the most frequently used agent for stem cell mobilization, the use of G-CSF alone results in suboptimal stem cell yields in a significant proportion of patients. Plerixafor (AMD3100), a small molecule CXCR4 antagonist, in combination with G-CSF increases total CD34+ HSPCs compared to G-CSF alone and is FDA approved for stem cell mobilization in Non-Hodgkin's lymphoma and multiple myeloma. However, a significant disadvantage of plerixafor is cost, adding $25,567 per patient compared to G-CSF alone. Furthermore, up to 24% of patients receiving plerixafor and G-CSF still fail to collect >2 x 10⁶ CD34+ cells/kg in 4 days of apheresis. Recent economic analysis has determined that reducing apheresis by 1 day has the potential to decrease medical costs by $6,600. Thus improved/alternative mobilizing agents and strategies are needed.

Mechanistic studies have shown that the integrin α4β1 (VLA-4) plays an important role in the retention of HSPCs within the bone marrow (BM) microenvironment. HSPC mobilization has been achieved by disrupting the integrin α4β1/VCAM-l axis with antibodies against integrin α4β1 or VCAM-1. Preclinical mouse studies in the DiPersio laboratory have shown that administration of the small molecule inhibitor of integrin α4β1, 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 α4β1 antagonist to continually inhibit integrin α4β1 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 α4β1 and has demonstrated efficacy in mobilizing HSPCs in mice. However, BI05192 has poor aqueous solubility, bioavailability, and pharmacokinetic properties and therefore has not been developed clinically. A simpler, more soluble integrin α4β1 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 α4β1 antagonists have the appropriate properties to be useful for HSCT. These compounds or compositions 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.

III. Therapeutic Methods

The present disclosure relates to the fields of pharmaceuticals, medicine and cell biology. In another aspect, 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.

In one aspect, 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.

If the 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). One non-limiting application of 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. In this application, 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. In a typical protocol for these types of transplants, the mobilized cells are collected from the donor by, for example, apheresis and then stored/cultured/expanded/fractionated as desired. In some embodiments, the compounds and compositions described herein may result in the need for apheresis being eliminated.

In some aspects, 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. In particular, 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.

In another aspect, the compounds and compositions described herein may be used to decrease inflammation which may result in increasing tissue repair. Thus, the compounds and compositions described herein may be used to treat graft versus host disease. Additionally, 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. These methods may be used to treat a blood disease or disorder such as sickle cell anemia or as a part of hematopoietic stem cell therapy to promote the development of stem cells. In some embodiments, the compound is administered as part of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. In some embodiments, 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. The term parenteral as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrastemal, infusion techniques or intraperitoneally. In some embodiments, 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.

Based upon standard laboratory experimental techniques and procedures well known and appreciated by those skilled in the art, as well as comparisons with compounds of known usefulness, the compounds described above can be used in the treatment of patients suffering from the above pathological conditions. One skilled in the art will recognize that 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.

In several aspects of the present disclosure, 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.

IV. Pharmaceutical Formulations and Routes of Administration

For administration to an animal especially a mammal in need of such treatment, 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. In some embodiments, 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. Alternatively, 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. Other 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.

The pharmaceutical 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.). Depending on the route of administration, 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.

To administer the therapeutic compound by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. For example, the therapeutic compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable 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. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. 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. In many cases, it may be useful to include 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. Generally, 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. In the case of sterile powders for the preparation of sterile injectable solutions, 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. For oral therapeutic administration, 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.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein 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. For example, 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.

An effective dose range of a therapeutic can be extrapolated from effective doses determined in animal studies for a variety of different animals. In general a human equivalent dose (HED) in mg/kg can be calculated in accordance with the following formula (see, e.g., Reagan-Shaw et al, FASEB J., 22(3):659-661, 2008, which is incorporated herein by reference):

HED (mg/kg) = Animal dose (mg/kg) ^χ (Animal Km/Human Km)

Use of the 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. 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 m²) is 37, whereas a 20 kg child (BSA 0.8 m²) 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.

In some embodiments, the VLA-4 antagonist (i.e. inhibitors) may be administered in an amount from about 1 mg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, or about 1 mg/kg to about 15 mg/kg, or about 1 mg/kg to about 10 mg/kg, or about 1 mg/kg to about 5 mg/kg, or about 3 mg/kg. In some embodiments, 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.

In other non-limiting examples, 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. In non-limiting examples of a derivable range from the numbers listed herein, 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.

In certain embodiments, a pharmaceutical composition of the present disclosure may comprise, for example, at least about 0.1% of a compound of the present disclosure. In other embodiments, 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.

Single or multiple doses of the agents are contemplated. 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. As used herein 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. For instance, 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. Alternatively, 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. In other embodiments, the disclosure provides that the agent(s) may taken orally and that the timing of which is or is not dependent upon food intake. Thus, for example, the agent can be taken every morning and/or every evening, regardless of when the subject has eaten or will eat.

V. Definitions

When used in the context of a chemical group: "hydrogen" means -H; "hydroxy" means -OH; "oxo" means =0; "carbonyl" means -C(=0)-; "carboxy" means -C(=0)OH (also written as -COOH or -CO2H); "halo" means independently -F, -CI, -Br or -I; "amino" means -NH2; "hydroxy amino" means -NHOH; "nitro" means -NO2; imino means =NH; "cyano" means -CN; "isocyanate" means -N=C=0; "azido" means -N3; in a monovalent context "phosphate" means -OP(0)(OH)₂ or a deprotonated form thereof; in a divalent context "phosphate" means -OP(0)(OH)0- or a deprotonated form thereof; "mercapto" means -SH; and "thio" means =S; "sulfonyl" means -S(0)₂-; and "sulfinyl" means -S(O)-.

In the context of chemical formulas, the symbol "-" means a single bond, "=" means a double bond, and "≡" means triple bond. The symbol

represents an optional bond, which if present is either single or double. The symbol represents a single bond or a

double bond. Thus, the formula

And it is understood that no one such ring atom forms part of more than one double

bond. Furthermore, it is noted that the covalent bond symbol when connecting one or two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it covers all stereoisomers as well as mixtures thereof. The symbol

"_; when drawn perpendicularly across a bond for methyl) indicates a point of attachment of the group. It is

noted that the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment. 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.

When a group "R" is depicted as a "floating group" on a ring system, for example, in the formula:

then 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. When a group "R" is depicted as a "floating group" on a fused ring system, as for example in the formula:

then 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. In the example depicted, R may reside on either the 5-membered or the 6- membered ring of the fused ring system. In the formula above, the subscript letter "y" immediately following the group "R" enclosed in parentheses, represents a numeric variable. Unless specified otherwise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydrogen atoms of the ring or ring system.

For the chemical groups and compound classes, 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 (η') of carbon atoms in the group. Thus, "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. Thus, the terms "C5 olefin", "C5-olefin", "olefin(C5)", and "olefincs" are all synonymous. When any of the chemical groups or compound classes defined herein is modified by the term "substituted", any carbon atom(s) in a moiety replacing a hydrogen atom is not counted. Thus methoxyhexyl, which has a total of seven carbon atoms, is an example of a substituted alkyl(ci-6).

The term "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. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of 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. When the term "saturated" is used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution.

The term "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. In aliphatic compounds/groups, 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).

The term "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 π system.

The term "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. The groups -CH3 (Me), -CH2CH3 (Et), -CH2CH2CH3 (n-Pr or propyl), -CH(CH₃)₂ (z-Pr, ^;Pr or isopropyl), -CH2CH2CH2CH3 (n-Bu), -CH(CH₃)CH₂CH₃ (sec-butyl), -CH₂CH(CH₃)₂ (isobutyl), -C(CH₃)₃ (tert-butyl, i-butyl, t-Bu or ^tBu), and ^~CH2C(CH₃)₃ (neo-pentyl) are non-limiting examples of alkyl groups. The term "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 -CH₂- (methylene), -CH2CH2-, -CH₂C(CH₃)₂CH₂-, and -CH2CH2CH2- are non-limiting examples of alkanediyl groups. The term "alkylidene" when used without the "substituted" modifier refers to the divalent group =CRR' in which R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: =CH2, =CH(CH2CH₃), and =C(CH₃)2. An "alkane" refers to the class of compounds having the formula H-R, wherein R is alkyl as this term is defined above. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH2, -NO2, -CO2H, -C0₂CH₃, -CN, -SH, -OCH₃, -OCH₂CH₃, -C(0)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(0)NH₂, -C(0)NHCH₃, -C(0)N(CH₃)₂, -OC(0)CH₃, -NHC(0)CH₃, -S(0)₂OH, or -S(0)₂NH₂. The following groups are non-limiting examples of substituted alkyl groups: -CH2OH, -CH2CI, -CF₃, -CH2CN, -CH₂C(0)OH, -CH₂C(0)OCH₃, -CH₂C(0)NH₂, -CH₂C(0)CH₃, -CH₂OCH₃, -CH₂OC(0)CH₃, -CH₂NH₂, -CH₂N(CH₃)₂, and -CH₂CH₂C1. The term "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, -CH₂C1 is a non-limiting example of a haloalkyl. The term "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 -CH₂F, -CF3, and -CH₂CF₃ are non-limiting examples of fluoroalkyl groups.

The term "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(CH₂)₂ (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). The term "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. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH₂, -NO2, -C0₂H, -C0₂CH₃, -CN, -SH, -OCH₃, -OCH₂CH₃, -C(0)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(0)NH₂, -C(0)NHCH₃, -C(0)N(CH₃)₂, -OC(0)CH₃, -NHC(0)CH₃, -S(0)₂OH, or -S(0)₂NH₂.

The term "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. Non-limiting examples include: -CH=CH₂ (vinyl), -CH=CHCH₃, -CH=CHCH₂CH₃, -CH₂CH=CH₂ (allyl), -CH₂CH=CHCH₃, and -CH=CHCH=CH₂. The term "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. The groups -CH=CH- -CH=C(CH3)CH₂- -CH=CHCH2-, and -CH2CH=CHCH2- are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms "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. Similarly the terms "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. 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, -NH₂, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH₂, -C(0)NHCH₃, -C(0)N(CH₃)2, -OC(0)CH3, -NHC(0)CH₃, -S(0)₂OH, or -S(0)₂NH₂. The groups -CH=CHF, -CH=CHC1 and -CH=CHBr are non-limiting examples of substituted alkenyl groups.

The term "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. As used herein, 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). Non-limiting examples of 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, -NH₂, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH₂, -C(0)NHCH₃, -C(0)N(CH₃)₂, -OC(0)CH₃, -NHC(0)CH₃, -S(0)₂OH, or -S(0)₂NH₂.

The term "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. 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)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH₂, -C(0)NHCH₃, -C(0)N(CH₃)₂, -OC(0)CH₃, -NHC(0)CH₃, -S(0)₂OH, or -S(0)2NH2. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-l-yl.

The term "acyl" when used without the "substituted" modifier refers to the group

-C(0)R, in which R is a hydrogen, alkyl, cycloalkyl, or aryl as those terms are defined above. The groups, -CHO, -C(0)CH₃ (acetyl, Ac), -C(0)CH₂CH₃, -C(0)CH(CH₃)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. The term "aldehyde" corresponds to an alkyl group, as defined above, attached to a -CHO group. When any of these terms are used with the "substituted" modifier 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, -NH₂, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0) H₂, -C(0)NHCH₃, -C(0)N(CH₃)₂, -OC(0)CH₃, -NHC(0)CH₃, -S(0)₂OH, or -S(0)₂NH₂. The groups, -C(0)CH₂CF₃, -C0₂H (carboxyl), -C0₂CH₃ (methylcarboxyl), -C0₂CH₂CH₃, -C(0)NH₂ (carbamoyl), and -CON(CH₃)₂, are non-limiting examples of substituted acyl groups.

The term "alkoxy" when used without the "substituted" modifier refers to the group

-OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: -OCH₃ (methoxy), -OCH₂CH₃ (ethoxy), -OCH₂CH₂CH₃, -OCH(CH₃)₂ (isopropoxy), -OC(CH₃)₃ (tert-butoxy), -OCH(CH₂)₂, -O-cyclopentyl, and -O-cyclohexyl. The terms "cycloalkoxy", "alkenyloxy", "aryloxy", "aralkoxy", and "acyloxy", when used without the "substituted" modifier, refers to groups, defined as -OR, in which R is cycloalkyl, alkenyl, aryl, aralkyl, and acyl, respectively. The term "alkylthio" and "acylthio" when used without the "substituted" modifier refers to the group -SR, in which R is an alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term "ether" corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH₂, -NO2, -C0₂H, -C0₂CH₃, -CN, -SH, -OCH₃, -OCH₂CH₃, -C(0)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(0)NH₂, -C(0)NHCH₃, -C(0)N(CH₃)₂, -OC(0)CH₃, -NHC(0)CH₃, -S(0)₂OH, or -S(0)₂NH₂.

The term "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: -NHCH₃ and -NHCH₂CH₃. The term "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. Non- limiting examples of dialkylamino groups include: -N(CH₃)₂ and -N(CH₃)(CH₂CH₃). The terms "cycloalkylamino", "alkenylamino", "arylamino", "aralkylamino", "alkoxyamino", and "alkylsulfonylamino" when used without the "substituted" modifier, refers to groups, defined as -NHR, in which R is cycloalkyl, alkenyl, aryl, aralkyl, alkoxy, and alkylsulfonyl, respectively. A non-limiting example of an arylamino group is -NHC6H5. The term "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)CH₃. The term "alkylimino" when used without the "substituted" modifier refers to the divalent group =NR, in which R is an alkyl, as that term is defined above. When any of these terms is used with the "substituted" modifier one or more hydrogen atom attached to a carbon atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH₂, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH₂, -C(0)NHCH₃, -C(0)N(CH₃)₂, -OC(0)CH₃, -NHC(0)CH₃, -S(0)₂OH, or -S(0)₂NH₂. The groups -NHC(0)OCH₃ and -NHC(0)NHCH₃ are non- limiting examples of substituted amido groups.

The terms "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. The terms "cycloalkylsulfonyl", "alkenylsulfonyl", "alkynylsulfonyl", "arylsulfonyl", "aralkylsulfonyl", "heteroarylsulfonyl", and "heterocycloalkylsulfonyl" are defined in an analogous manner. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH₂, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH₂, -C(0)NHCH₃, -C(0)N(CH₃)₂, -OC(0)CH₃, -NHC(0)CH₃, -S(0)₂OH, or -S(0)₂NH₂.

The use of the word "a" or "an," when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

An "active ingredient" (AI) (also referred to as an active compound, active substance, active agent, pharmaceutical agent, agent, biologically active molecule, or a therapeutic compound) is the ingredient in a pharmaceutical drug or a pesticide that is biologically active. The similar terms active pharmaceutical ingredient (API) and bulk active are also used in medicine, and the term active substance may be used for pesticide formulations.

The terms "comprise," "have" and "include" are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes" and "including," are also open-ended. For example, any method that "comprises," "has" or "includes" one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

The term "effective," as that term is used in the specification and/or claims, means adequate to accomplish a desired, expected, or intended result. "Effective amount," "Therapeutically effective amount" or "pharmaceutically effective amount" when used in the context of treating a patient or subject with a compound means that amount of the compound which, when administered to a subject or patient for treating or preventing a disease, is an amount sufficient to effect such treatment or prevention of the disease.

An "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.

As used herein, "HSPCs" refers to hematopoietic stem and progenitor cells. HSPCs are a combination of progenitor cells and stem cells.

The term "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.

As used herein, the term "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.

As used herein, 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. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human patients are adults, juveniles, infants and fetuses.

As generally used herein "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, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, gly colic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, pc-hlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, />-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. 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. Wermuth eds., Verlag Helvetica Chimica Acta, 2002). 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. Examples of 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. The similar terms 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. In contrast with the active ingredients, the inactive ingredients are usually called excipients (defined above) in pharmaceutical contexts.

As used herein, the term "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" or "preventing" 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. For example, 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. Similarly, a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.

The term "progenitor cells" as used herein 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.

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. In organic compounds, 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. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers will not exceed 2ⁿ, 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. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, 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. As used herein, 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", as used herein, are less differentiated forms of progenitor cells.

Typically, such cells are positive for CD34, but stem cells do not have to contain this marker. While other types of cells such as endothelial cells and mast cells also may exhibit this marker, CD34 is considered an one marker of stem cell presence. CD34+ cells can be assayed using fluorescence activated cell sorting (FACS) and thus their presence can be assessed in a sample using this technique. In general, CD34+ cells are present only in low levels in the blood, but are present in large numbers in bone marrow. Additionally, the stem cells may be hematopoietic stem cells that express the SLAM and LSK markers. Specifically, hematopoietic stem cells may be LSK cells or LSK-SLAM cells, which are considered early hematopoietic stem cells. The nomenclature, LSK, refers to Lin^"Scal⁺c-Kit⁺ and SLAM is signaling lymphocyte activation molecules or Lin^"CD41^"CD48^"CD150⁺.

"Treatment" or "treating" 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.

The terms "VLA-4 antagonists" and "VLA-4 inhibitors" are used interchangeably herein.

The above definitions supersede any conflicting definition in any of the reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the disclosure in terms such that one of ordinary skill can appreciate the scope and practice the present disclosure. VI. Examples

The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. A. Instrumentation and General Methods.

Commercially available reagents and solvents were used without further purification unless stated otherwise. 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. The purity of tested compounds was >95% as determined by HPLC analysis conducted on an Agilent 1100 or 1260 system using a reverse phase C18 column with diode array detector unless stated otherwise. NMR spectra were recorded on a Bruker 400 MHz spectrometer. The signal of the deuterated solvent was used as internal reference. Chemical shifts (δ) are given in ppm and are referenced to residual not fully deuterated solvent signal. Coupling constants (J) are given in Hz.

B. Preparation of Compounds

SCHEME 1: Preparation of Methyl (S)-3,5-dichloro-4-((l-methoxy-l-oxo-3-(4-i tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)carbamoyl)benzoate

d Final Products (1219-1224 1554-1555, 1570-1571)

Scheme 1, Step 1. Preparation of Benzyl 4-bromo-2,6-dichlorobenzoate (2)

4-Bromo-2,6-dichlorobenzoic acid (Compound 1, 3.58 g, 13.3 mmol) and cesium carbonate (7.56 g, 23.2 mmol) were suspended in acetonitrile (50 mL) at 0 °C and benzyl bromide (2.38 g, 13.93 mmol) was added drop wise. The reaction was heated for 4 hours at 60 °C and then the reaction was cooled to room temperature and solids were filtered off and rinsed using additional acetonitrile. The filtrate was concentrated in vacuo and purified by chromatography on silica gel, eluting with ethyl acetate/hexanes. Product, benzyl 4-bromo- 2,6-dichlorobenzoate, (Compound 2, 4.8 g, 99% yield) was isolated as a clear oil. LC-MS: tR=3.03 min; m+23=381, 382, 383, 385 (bromine/bis-chlorine isotope pattern).¹H NMR (400 MHz, DMSO- d6) δ ppm 7.95 (s, 2 H) 7.35 - 7.51 (m, 5 H) 5.42 (s, 2 H). Scheme 1, Step 2. Preparation of 1-Benzyl 4-methyl 2,6-dichlorobenzene-l,4- dicarboxylate (3)

To a 20 mL microwave vial was added 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 reaction was diluted with ethyl acetate, filtered through Celite® and concentrated in vacuo. The residue was taken up in ethyl acetate and washed using a 10% citric acid solution, then brine. The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/hexanes as eluent to give product, 1 -benzyl 4-methyl 2,6- dichlorobenzene-l,4-dicarboxylate, (Compound 3, 0.7 g, 81% yield) as a clear oil. LC-MS: tR=2.88 min; m+23=361, 363 (chlorine isotope).

Scheme 1, Step 3. Preparation of 2,6-Dichloro-4-(methoxycarbonyl)benzoic acid (4)

To a solution of 1 -benzyl 4-methyl 2,6-dichlorobenzene-l,4-dicarboxylate (Compound 3, 2.3 g, 6.78 mmol) in ethyl acetate (20 mL) was added 10% palladium on carbon (0.35 g, 0.34 mmol). The mixture was stirred at room temperature under a hydrogen atmosphere at ambient pressure for 1.5 hours. The reaction was filtered through Celite® and concentrated in vacuo to give product, 2,6-dichloro-4-(methoxycarbonyl)benzoic acid, (Compound 4, 1.69 g, quantitative yield) as a crystalline solid. LC-MS: tR=1.65 min; m+H=249, 251 (chlorine isotope). Scheme 1, Step 4. Preparation of methyl (S)-4-((3-(4-bromophenyl)-l-methoxy-l- oxopropan-2-yl)carbamoyl)- -dichlorobenzoate (6)

To a round bottom flask was added 2,6-dichloro-4-(methoxycarbonyl)benzoic acid

(Compound 4, 2.08 g, 8.38 mmol), benzotriazol-l-ol (0.25 g, 1.59 mmol), 3- [Bis(dimethylamino)-methyliumyl]-3H-benzotriazol-l -oxide hexafluorophosphate (3.33 g, 8.77 mmol) and DMSO (15 mL). NN-diisopropylethylamine (3.09 g, 23.93 mmol) was added and the reaction was stirred for 40 minutes at room temperature. At this time, methyl (5)-2-amino-3-(4-bromophenyl)propanoate hydrochloride (purchased from Ark Pharm) (Compound 5, 2.35 g, 7.98 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was diluted with water (50 mL), stirred for 20 minutes, then extracted using ethyl acetate (100 mL). 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. Product, methyl 4-[[(15 -l-[(4- bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]carbamoyl]-3,5-dichloro-benzoate,

(Compound 6, 3.42 g, 87% yield) was isolated as a white foam. LC-MS: tR=2.61 min; m+H=488, 489, 490, 491, 492 (bromine/bis-chlorine isotope pattern). NM¹RH (400 MHz, DMSO-d6) δ ppm 9.33 (d, J=8.31 Hz, 1 H) 7.91 (s, 2 H) 7.45 - 7.54 (d, 2 H) 7.26 (d, J=8.31 Hz, 2 H) 4.80 (ddd, J=10.09, 8.25, 4.89 Hz, 1 H) 3.89 (s, 3 H) 3.68 (s, 3 H) 3.16 (dd, J=14.06, 5.01 Hz, 1 H) 2.93 (dd, J=14.06, 10.15 Hz, 1 H).

Scheme 1, Step 5. Preparation of methyl (S)-3,5-dichloro-4-((l-methoxy-l-oxo-3-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)carbamoyl)benzoate

(7)

To a 20 mL microwave vial was added methyl 4-[[(15)-l-[(4-bromophenyl)methyl]- 2-methoxy-2-oxo-ethyl]carbamoyl]-3,5-dichloro-benzoate (Compound 6, 1 g, 2.04 mmole), Bis(pinacolato)diboron (0.675 g, 2.66 mmol), [l,l'-Bis(diphenylphosphino)ferrocene]- palladium(II) dichloride (0.100 g, 0.123 mmole, potassium acetate (0.6 g, 6.13 mmol) and 1,4-dioxane (10 mL). 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. Product, methyl (5)-3,5- dichloro-4-((l-methoxy-l-oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)propan-2-yl)carbamoyl)benzoate, (Compound 7, 0.9 g, 82% yield) was isolated as a white foam. LC-MS: tR=2.76 min; m+H=536.1, 538.0 (bis chlorine isotope pattern). ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (d, J=8.07 Hz, 1 H) 7.91 (d, J=0.49 Hz, 2 H) 7.60 (d, J=7.58 Hz, 2 H) 7.30 (d, J=7.58 Hz, 2 H) 4.73 - 4.84 (m, 1 H) 3.89 (d, J=0.49 Hz, 3 H) 3.67 (s, 3 H) 3.16 (dd, J=5.40 Hz, 1 H) 3.01 (dd, J=9.80 Hz, 1 H) 1.30 (s, 12 H).

Preparation of 4-Bromo-3,5-dimethoxybenzonitrile (9)

To a 50 mL 3-neck round bottom flask was added 4-bromo-3,5-dimethoxybenzoic acid (Compound 8, 2 g, 7.66 mmol), ammonium chloride (0.43 g, 8.04 mmol), triethylamine (1.2 mL, 8.27 mmol) and ethyl acetate (2 mL). The slurry was heated to 65 °C and 1- propanephosphonic acid cyclic anhydride (5.5 mL of a 50% solution in ethyl acetate, 9.19 mmol) was added over 20 minutes. Additional ethyl acetate was added and the heat was increased to 70 °C for 3 hours. The reaction was cooled and diluted using additional ethyl acetate and water. The aqueous layer was separated, filtered and rinsed using additional water. The isolated solid was dried overnight in vacuo. Product, 4-bromo-3,5- dimethoxybenzonitrile, (Compound 9, 0.929 g, 50% yield) was isolated as a white solid. LC- MS: t_R=2.937 min; m+H=242.9, 244.9. N¹MHR (400 MHz, DMSO-d6) δ ppm 7.42 (s, 2 H) 3.96 (s, 6 H).

Preparation of (4-bromo-3,5-dimethoxyphenyl)methanol (10)

To an oven dried round bottom flask was added 4-bromo-3,5-dimethoxybenzoic acid (Compound 8, 2 g, 7.66 mmol) and anhydrous tetrahydrofuran (24 mL). Borane dimethylsulfide complex (7.6 mL of 2M in tetrahydrofuran, 15.3 mmol) was added drop-wise at room temperature. The reaction was heated overnight at 40 °C. The reaction was quenched using hydrochloric acid (IN) and partitioned between ethyl acetate and water. The organic layer was washed using brine, dried with sodium sulfate, filtered and concentrated in vacuo.

Product, (4-bromo-3,5-dimethoxyphenyl)methanol, (compound 10, 1.89 g, quantitative yield) was isolated as a white solid. LC-MS: tR=1.748 min; m/z=229.0, 231.0 (dehydration). ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.71 (s, 2 H) 4.49 (s, 2 H) 3.82 (s, 6 H).

Preparation of 2-Bromo-5-(ethoxymethyl)-l,3-dimethoxybenzene (11)

To a round bottom flask was added (4-bromo-3,5-dimethoxyphenyl)methanol (compound 10, 1.1 g, 4.45 mmol) and NN-dimethylformamide (12 mL). The solution was cooled to 0 °C and sodium hydride (0.32 g of 60% (w/w) in mineral oil, 8.01 mmol) was added and the reaction was stirred for 1 hour at room temperature. Iodoethane (1 g, 6.68 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was quenched with methanol and concentrated in vacuo. The residue was taken up in ethyl acetate and washed using water, then brine. The organic layer was dried using sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent. Product, 2-bromo-5-(ethoxymethyl)-l,3-dimethoxybenzene, (Compound 11, 0.306 g, 25% yield) was isolated as a clear oil. LC-MS: tR=2.31 min; m/z=229.0, 231.0 (dehydration). N¹HMR (400 MHz, DMSO-d6) δ ppm 6.69 (s, 2 H) 4.44 (s, 2 H) 3.83 (s, 6 H) 3.51 (q, J=7.09 Hz, 2 H) 1.18 (t, J=6.97 Hz, 3 H).

Preparation of methyl 4-bromo-3,5-dimethoxybenzoate (12)

To a round bottom flask was added 4-bromo-3,5-dimethoxybenzoic acid (Compound 8, 4 g, 15.3 mmol) and methanol (100 mL). The solution was cooled to 0 °C and thionyl chloride (11.1 mL, 153 mmol) was slowly added. The reaction was heated to 80 °C for 2 hours. At this time the reaction was concentrated in vacuo and then taken up in ethyl acetate. The organic layer was washed with water, then brine. The ethyl acetate layer was dried using sodium sulfate, filtered and concentrated in vacuo. Product, methyl 4-bromo-3,5- dimethoxybenzoate, (Compound 12, 4.24 g, quantitative yield) was isolated as a crystalline white solid. LC-MS: TR=2.3 min; m+H=274.9, 277.0 (bromine isotopes).

Preparation of 2-(4-bromo-3,5-dimethoxyphenyl)propan-2-ol (13)

To a round bottom flask was added methyl 4-bromo-3,5-dimethoxybenzoate

(Compound 12, 2 g, 7.27 mmol) and tetrahydrofuran (30 mL). The solution was cooled to -40 °C and methylmagnesium bromide (10 mL of a 3M solution in diethyl ether, 29 mmol) was added. The reaction was stirred at -40 °C for 1 hour and then gradually warmed to 0 °C. The reaction was quenched using saturated ammonium chloride and extracted using ethyl acetate. The organic layer was washed with brine, dried using sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent. Product, 2-(4-bromo-3,5-dimethoxyphenyl)propan-2-ol, (Compound 13, 1.65 g, 82.5% yield) was isolated as a white solid. LC-MS: tR=1.97 min; m/z=257.0, 259.0 (dehydration). ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.80 (s, 2 H) 5.12 (s, 1 H) 3.83 (s, 6 H) 1.44 (s, 6 H). Preparation of 2-bromo-5-(fluoromethyl)-l,3-dimethoxybenzene (14)

To a round bottom flask was added (4-bromo-3,5-dimethoxy-phenyl)methanol (Compound 10, 0.5 g, 2.02 mmol) and dichloromethane (15 mL). The reaction was cooled to 0 °C and diethylaminosulfur trifluoride (0.360 g, 2.23 mmol) was added. The reaction was allowed to warm to room temperature and stir for 1 hour. The reaction was quenched using saturated sodium bicarbonate, the layers were separated and the organic layer was dried using sodium sulfate, filtered and concentrated in vacuo. The resulting solid was purified on silica gel using ethyl acetate and hexanes as eluent. Product, 2-bromo-5-(fluoromethyl)-l,3- dimethoxybenzene, (Compound 14, 0.171 g, 33.9% yield) was isolated as a pale yellow solid. LC-MS: tR=2.23 min; m+H=249.0, 251.0 (bromine isotopes).

Preparation of 2-Bromo-l,3-dimethoxy-5-((2-methoxyethoxy)methyl)benzene (15)

To a round bottom flask was added (4-bromo-3,5-dimethoxyphenyl)methanol

(compound 10, 1.95 g, 7.89 mmol) and NN-dimethylformamide (20 mL). The solution was cooled to 0 °C and sodium hydride (0.393 g of 60% (w/w) in mineral oil, 10.3 mmol) was added and the reaction was stirred for 1 hour at room temperature. l-Bromo-2- methoxy ethane (0.89 mL, 9.47 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was quenched with methanol and concentrated in vacuo. The residue was taken up in ethyl acetate and washed using water, then brine. The organic layer was dried using sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent. Product 2-Bromo-l,3- dimethoxy-5-((2-methoxyethoxy)methy)benzene (15, 2.22 g, 92% yield) was isolated as a pale yellow oil. LC-MS: tR=2.11 min; m/z+ 23=327.0, 329.0. NM¹HR (400 MHz, DMSO- d6) δ ppm 6.70 (s, 2 H) 4.48 (s, 2 H) 3.82 (s, 6 H) 3.53 - 3.62 (m, 2 H) 3.45 - 3.52 (m, 2 H) 3.26 (s, 3 H). Preparation of 2-Bromo-5-((hexyloxy)methyl)-l,3-dimethoxybenzene (16)

To a round bottom flask was added (4-bromo-3,5-dimethoxyphenyl)methanol (compound 10, 0.5 g, 2.02 mmol) and NN-dimethylformamide (10 mL). The solution was cooled to 0 °C and sodium hydride (0.100 g of 60% (w/w) in mineral oil, 2.61 mmol) was added and the reaction was stirred for 1 hour at room temperature. 1-Bromohexane (0.34 mL, 2.43 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was quenched with water and concentrated in vacuo. The residue was taken up in ethyl acetate and washed using water, then brine. The organic layer was dried using sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent. Product 2-Bromo-5-((hexyloxy)methyl)-l,3- dimethoxybenzene (16, 0.378 g, 56% yield) was isolated as a clear oil. LC-MS: tR=2.98 min; m/z+23=353.0, 355.0. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.68 (s, 2 H) 4.43 (s, 2 H) 3.82 (s, 6 H) 3.42 (t, J=6.48 Hz, 2 H) 1.45 - 1.63 (m, 2 H) 1.16 - 1.40 (m, 6 H) 0.85 (t, J=1.00

Hz, 3 H).

Preparation of l-(4-Bromo- -dimethoxyphenyl-2,5,8,ll-tetraoxadodecane (17)

To a round bottom flask was added (4-bromo-3,5-dimethoxyphenyl)methanol (compound 10, 1.9 g, 7.69 mmol) and NN-dimethylformamide (20 mL). The solution was cooled to 0 °C and sodium hydride (0.383 g of 60% (w/w) in mineral oil, 10 mmol) was added and the reaction was stirred for 1 hour at room temperature. 2-[2-(2- Methoxyethoxy)ethoxy] ethyl 4-methylbenzenesulfonate (2.8 mL, 9.23 mmol) was added and the reaction was stirred for six hours at room temperature. The reaction was quenched with water and concentrated in vacuo. The residue was taken up in ethyl acetate and washed using water, then brine. The organic layer was dried using sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent. Product l-(4-Bromo-3,5-dimethoxyphenyl-2,5,8,l l-tetraoxadodecane (17, 3.02 g, quant, yield) was isolated as a clear oil. LC-MS: TR=2.08 min; m/z+23=4\5.0, 417.0. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.70 (s, 2 H) 4.48 (s, 2 H) 3.82 (s, 6 H) 3.57 (s, 4 H) 3.47 - 3.55 (m, 6 H) 3.39 - 3.45 (m, 2 H) 3.22 (s, 3 H).

Preparation of 4-Bromo-3,5-dimethoxybenzyl hexanoate (18)

To a round bottom flask was added (4-bromo-3,5-dimethoxyphenyl)methanol (compound 10, 0.5 g, 2.02 mmol) and dichloromethane (10 mL). Triethylamine (0.56 mL, 4.05 mmol) and 4-dimethylaminopyridine (cat.) were added and the solution was cooled to 0 °C. Hexanoyl chloride (0.37 mL, 2.63 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane and washed using IN HCl, then brine. The organic layer was dried using sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent. Product 4-Bromo-3,5-dimethoxybenzyl hexanoate (18, 0.630 g, 90% yield) was isolated as an off-white waxy solid. LC-MS: tR=2.81 min; m z+ 3=367.0, 369.0.¹H NMR (400 MHz, DMSO-d6) δ ppm 6.74 (s, 2 H) 5.06 (s, 2 H) 3.83 (s, 6 H) 2.38 (t, J=7.34 Hz, 2 H) 1.49 - 1.62 (m, 2 H) 1.20 - 1.33 (m, 4 H) 0.82 - 0.89 (m, 3 H).

Scheme 1, Step 6: General Procedure A - Suzuki Coupling (Intermediates 19-28)

To a microwave vial was added methyl (5)-3,5-dichloro-4-((l-methoxy-l-oxo-3-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)carbamoyl)benzoate

(Compound 7, 100 mg, 0.186 mmol), aryl bromide coupling partner (Compounds 9-18, (0.28 mmol, 1.5 equivalent), tetrakis(triphenylphosphane)palladium(0) (11 mg, 0.009 mmol), cesium acetate (108 mg, 0.559 mmol), 1,4-dioxane (1 mL) and water (0.25 mL). The vial was crimped shut and sparged with nitrogen for 10 minutes and then heated overnight at 115 °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. Isolated products (see Table 1, compounds 19-28) were carried forward as-is.

TABLE 1: Intermediates

Scheme 1, Step 7: General Procedure B - Hydrolysis (Products 1219-1224)

To a flask was added the appropriate bis ester intermediate (19-28) from Table 1, acetonitrile (1 mL), water (1 mL) and lithium hydroxide monohydrate (5 equivalents). The solution was stirred at room temperature for 2 hours. Acetonitrile was removed in vacuo and the reaction was acidified using hydrochloric acid (IN). Water was then removed in vacuo and the residue was purified on CI 8 using acetonitrile and water (both with 0.1% formic acid as modifier). Pure fractions were pooled and concentrated in vacuo and the resulting material was lyophilized from acetonitrile and water (1 :4) overnight. Isolated products are shown in Table 2 (Products 1219-1224, 1554-1555, 1570-1571)

S -1611

32 33

Scheme 2, Step 1: Preparation of methyl (S)-3-(4-bromophenyl)-2-(tert- butoxycarbonyl) amino)propanoate (32)

To a round bottom flask was added methyl (2S)-2-amino-3-(4-bromophenyl) propanoate hydrochloride (compound 5, 3.35 g, 1 1.4 mmol), dichloromethane (40 mL) and triethylamine (3.2 mL, 22.7 mmol). The solution was cooled to 0 °C and di-tert-butyl dicarbonate (2.73 g, 12.5 mmol) was added. The reaction was stirred overnight at room temperature. Additional dichloromethane (200 mL) was added and the organic layer was washed using hydrochloric acid (50 mL, 1 N), water, and then brine. The dichloromethane layer was dried over sodium sulfate, filtered and concentrated in vacuo to give product methyl (S)-3-(4- bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (4.07 g, quant, yield) as a white, waxy solid. LC-MS: t_R=2.48 min; m/z +23=380.0, 382.0. ¹HMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 9 H) 2.82 (dd, J=13.69, 10.27 Hz, 1 H) 2.94 - 3.02 (m, 1 H) 3.62 (s, 3 H) 4.13 - 4.21 (m, 1 H) 7.20 (d, J=8.31 Hz, 2 H) 7.31 (d, J=8.07 Hz, 1 H) 7.48 (d, J=8.31 Hz, 2 H). Scheme 2, Step 2: Preparation of methyl (S)-2-(tert- butoxycarbonyl)amino)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (33)

To a round bottom pressure vessel was added methyl (,S)-3-(4-bromophenyl)-2-((tert- butoxycarbonyl)amino)propanoate (compound 32, 2 g, 5.58 mmol), bis(pinacolato) diboron (1.84 g, 7.26 mmol), Pd(dppf)Cl2 (0.245 g, 0.335 mmol), potassium acetate (1.64 g, 16.7 mmol) and 1,4-dioxane (20 mL). The vessel was sparged with nitrogen gas for 10 minutes, sealed, and heated overnight at 90 °C. The reaction was filtered through a plug of Celite® and rinsed with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, then filtered and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent. Product methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (2.26 g, quant, yield) was isolated as an oil. LC-MS: t_R=2.70 min; m/z+23=428.2.

Scheme 3: Preparation of Aryl Bromide Intermediate 37

Scheme 3, Step 1: Preparation of 4- romo-3,5-dimethoxybenzyl methanesulfonate (36)

To a round bottom flask was added (4-bromo-3,5-dimethoxyphenyl)methanol (compound 10, 2.8 g, 1 1.3 mmol) and dichloromethane (50 mL). The solution was cooled to 0 °C and triethylamine (2 mL, 14.7 mmol) was added followed by methanesulfonyl chloride (1 mL, 12.5 mmol) and the reaction was stirred at room temperature. Upon completion, the reaction was diluted with additional dichloromethane and washed using dilute HC1, then brine. The organic layer was dried using sodium sulfate, filtered and concentrated in vacuo to give product 4- bromo-3,5-dimethoxybenzyl methanesulfonate (36, 3.68 g, quant, yield) as an oil. LC: tR=2.12 min. The material was carried forward without further purification or characterization.

Scheme 3, Step 2: Preparation of 2- romo-5-(ethoxymethyl)-l,3-dimethoxybenzene (37)

To a microwave vial was added 4-bromo-3,5-dimethoxybenzyl methane sulfonate (36, 3.68 g, 1 1.3 mmol) and ethanol (20 mL). Potassium carbonate (2.34 g, 16.9 mmol) was added followed by potassium iodide (catalytic) and the reaction was irradiated with microwaves at 140 °C for 2 hours. The reaction was filtered through a plug of Celite® and rinsed with additional ethanol. The solvent was removed in vacuo and the resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent. Product 2-bromo-5-(ethoxymethyl)-l,3-dimethoxybenzene (37, 1.77 g, 57% yield) was isolated as an oil. LC: t_R=2.29 min. ¹MHR (400 MHz, OMSO- d6) δ ppm 6.69 (s, 2 H) 4.44 (s, 2 H) 3.83 (s, 6 H) 3.51 (q, J=7.09 Hz, 2 H) 1.18 (t, J=6.97 Hz, 3 H).

Scheme 2, Step 3: Preparation of methyl (S)-2-( tert- butoxycarbonyl)amino)-3-(4'- (ethoxymethyl)-2',6'-dimethoxy-[l,l'-biphenyl]-4-yl)propanoate (38)

To a microwave vial was added methyl (S)-2-(( tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (33, 1.26 g, 3.1 1 mmol), 2-bromo-5- (ethoxymethyl)-l,3-dimethoxybenzene (37, 1.26 g, 4.35 mmol), tetrakis (triphenylphosphane)palladium(O) (180 mg, 0.155 mmol), cesium acetate (1.79 g, 9.33 mmol), 1,4-dioxane (10 mL) and water (2 mL). 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. Pure fractions were pooled and concentrated in vacuo to give product methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4'-(ethoxymethyl)-2',6'-dimethoxy-[l, l'- biphenyl]-4-yl)propanoate (38, 0.72 g, 49% yield) as an oil. LC-MS: tR=2.72 min; m/z+ 23=496.2.

Scheme 2, Step 4: Preparation of methyl (S)-2-amino-3-(4'-(ethoxymethyl)-2',6'-dimethoxy- [l,l'-biphenyl]-4-yl)propanoat (39)

To a round bottom flask was added methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4'- (ethoxymethyl)-2',6'-dimethoxy-[l, l'-biphenyl]-4-yl)propanoate (38, 0.955 g, 2.02 mmol) and trifluoroacetic acid in dichloromethane (10 mL, 20% v/v) and the reaction was stirred overnight at room temperature. The 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. Pure fractions were pooled and concentrated in vacuo to give product methyl (,S)-2-amino-3-(4'-(ethoxymethyl)-2',6'-dimethoxy- [l, l'-biphenyl]-4-yl) propanoate (39, 0.6 g, 80% yield) as an oil. LC-MS: tR=1.96 min; m/z=374.2. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.15 (d, J=1.00 Hz, 2 H) 7.10 (d, J=1.00 Hz, 2 H) 6.68 (s, 2 H) 4.47 (s, 2 H) 3.65 (s, 6 H) 3.61 (s, 3 H) 3.59 (t, J=1.00 Hz, 1 H) 3.53 (q, J=7.01 Hz, 2 H) 2.91 (dd, J=13.69, 5.87 Hz, 1 H) 2.75 (dd, J=13.45, 7.58 Hz, 1 H) 1.80 (br. s., 2 H) 1.19 (t, J=6.97 Hz, 3 H).

Scheme 4: Preparation of Intermediates 43 and 45

Scheme 4, Step 1: Preparation of methyl (S)-2-methylpyrrolidine-2-carboxylate hydrochloride (41)

To a round bottom flask was added (,S)-2-methylpyrrolidine-2-carboxylic acid (40, purchased from TCI, 1.75 g, 13.5 mmol) and methanol (100 mL). The solution was cooled to 0 °C, thionyl chloride (25 mL, 340 mmol) was slowly added and the reaction was refluxed overnight. The reaction was concentrated in vacuo, repeatedly evaporated from methanol (4 x 50 mL), and then pulled overnight under a high vacuum. Product methyl (,S)-2-methylpyrrolidine-2- carboxylate hydrochloride (41, 2.43 g, quant, yield) was isolated as a solid. N¹MH R (400 MHz, DMSO- d6) δ ppm 1.59 (s, 3 H) 1.82 - 2.09 (m, 3 H) 2.14 - 2.37 (m, 1 H) 3.78 (s, 3 H) 3.88 - 4.48 (m, 2 H) 9.36 (br. s, 1 H) 10.24 (br. s, 1 H).

Scheme 4, Step 2: Preparation of methyl (S)-l-((3,5-dichlorophenyl)sulfonyl)-2- methylpyrrolidine-2-carboxylate (

To a round bottom flask was added methyl (,S)-2-methylpyrrolidine-2-carboxylate hydrochloride (41, 1.28 g, 7.13 mmol) and dichloromethane (10 mL). The reaction was cooled to 0 °C and 3,5-dichlorobenzenesulfonyl chloride (3.5 g, 14.3 mmol) was slowly added. Diisopropylethylamine (4.6 g, 35.6 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was taken up in ethyl acetate and washed with HC1 (IN), and then brine. The 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. Pure fractions were pooled and concentrated in vacuo to give product methyl (,S)-l-((3,5-dichlorophenyl)sulfonyl)-2-methylpyrrolidine-2-carboxylate (42, 2.21 g, 88% yield) as a crystalline solid. LC-MS: t_R=2.61 min; m/z=352.0, 354.0. NM¹HR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 3 H) 1.84 - 2.05 (m, 3 H) 2.05 - 2.23 (m, 1 H) 3.36 - 3.56 (m, 2 H) 3.64 (s, 3 H) 7.78 (d, J=1.71 Hz, 2 H) 8.00 (t, J=1.83 Hz, 1 H). Scheme 4, Step 3: Preparation of (S)-l-((3,5-dichlorophenyl)sulfonyl)-2-methylpyrrolidine- 2-carboxylic acid (43)

round bottom flask was added methyl (,S)-l-((3,5-dichlorophenyl)sulfonyl)-2- methylpyrrolidine-2-carboxylate (42, 2.1 g, 5.96 mmol), acetonitrile (5 mL), tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide hydrate (0.5 g, 11.9 mmol) was added and the reaction was stirred overnight at room temperature. The organic solvents were evaporated and the remaining aqueous solution was adjusted to pH~5 with HC1 (-2.4 mL, 5N). The aqueous layer was extracted using ethyl acetate, washed using brine, dried with sodium sulfate, filtered and evaporated. Product (,S)-l-((3,5-dichlorophenyl)sulfonyl)-2-methylpyrrolidine-2-carboxylic acid (43, 2.0 g, 99% yield) was isolated as an off-white solid. LC-MS: tR=2.30 min; m/z=338.0, 339.9. ¹H NMR (400 MHz, DMSO- d6) δ ppm 1.52 (s, 3 H) 1.85 - 2.01 (m, 3 H) 2.07 - 2.21 (m, 1 H) 3.35 - 3.51 (m, 2 H) 7.79 (d, J=1.96 Hz, 2 H) 7.97 (t, J=1.83 Hz, 1 H) 12.91 (br. s., 1 H).

Scheme 4, Step 4: Preparation of methyl (S)-2-methyl-l-(phenylsulfonyl)pyrrolidine-2- carboxylate (44)

To a round bottom flask was added methyl (,S)-2-methylpyrrolidine-2-carboxylate hydrochloride (41, 1.24 g, 6.90 mmol) and dichloromethane (10 mL). The reaction was cooled to 0 °C and benzenesulfonyl chloride (2.44 g, 13.8 mmol) was slowly added. Diisopropylethylamine (4.46 g, 34.5 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was taken up in ethyl acetate and washed with HC1 (IN), and then brine. The 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. Pure fractions were pooled and concentrated in vacuo to give product methyl (,S)-2-methyl-l-(phenylsulfonyl)pyrrolidine-2-carboxylate (44, 1.52 g, 78% yield) as an oil. LC-MS: t_R=2.05 min; m/z=284.1. N¹HMR (400 MHz, DMSO-d6) δ ppm 7.74 - 7.87 (m, 2 H) 7.54 - 7.72 (m, 3 H) 3.61 (s, 3 H) 3.29 - 3.49 (m, 2 H) 2.03 - 2.21 (m, 1 H) 1.80 - 1.97 (m, 3 H) 1.49 (s, 3 H).

Step 5: Preparation of (S)-2-methyl-l-(phenylsulfonyl)pyrrolidine-2-carboxylic

To a round bottom flask was added methyl (S)-2-methyl-l-(phenylsulfonyl)pyiTolidine-2- carboxylate (44, 1.52 g, 5.36 mmol), acetonitrile (5 mL), and water (5 mL). Lithium hydroxide hydrate (0.45 g, 10.7 mmol) was added and the reaction was stirred overnight at room temperature. The organic solvents were evaporated and the remaining aqueous solution was adjusted to pH~5 with HCl (~8 mL, 2N). The remaining aqueous layer was extracted using ethyl acetate, washed using brine, dried with sodium sulfate, filtered and evaporated. Product (S)-2- methyl-l-(phenylsulfonyl)pyrrolidine-2-carboxylic acid (45, 1.25 g, 86% yield) was isolated as an off-white solid. LC-MS: t_R=1.78 min; m/z+23=292.0. ¹HMR (400 MHz, DMSO-d6) δ ppm 12.72 (s, 1 H) 7.76 - 7.88 (m, 2 H) 7.52 - 7.70 (m, 3 H) 3.36 - 3.45 (m, 1 H) 3.26 - 3.36 (m, 1 H) 2.06 - 2.20 (m, 1 H) 1.77 - 1.97 (m, 3 H) 1.46 (s, 3 H).

Scheme 2, Step 5: General Procedure C - Amide Coupling (Intermediates 47-49)

47: Ri=CH₃, R₂=3,5-dichlorophenylsulphonyl

48: R-_| =CH₃, R₂=phenylsulphonyl

49: R-_| =H, R₂=benzyloxycarbonyl

To a round bottom flask was added the aryl-pyrrolidinyl-2-carboxylic acid coupling partner (Compounds 43, 45, 46 (purchased from Chem Impex International), 0.442 mmol, 1.1 equivalent), HBTU (183 mg, 0.483 mmol), HOBt (12 mg, 0.08 mmol), and dimethylsulfoxide (3 mL). N,N-Diisopropylethylamine (138 μL, 0.8 mmol) was added and the solution was stirred for 20 minutes at room temperature. At this time, methyl (,S)-2-amino-3-(4'-(ethoxymethyl)-2',6'- dimethoxy-[l, l'-biphenyl]-4-yl) propanoate (39, 0.15 g, 0.4 mmol) was added and the reaction was stirred overnight at room temperature. 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. Pure fractions were pooled and concentrated in vacuo. Isolated products (see Table 3, compounds 47-49) were carried forward as-is.

TABLE 3: Intermediates

Scheme 5: Preparation of Intermediates 51 and 52

Scheme 5, Step 1: Preparation of methyl (S)-3-(4'-(ethoxymethyl)-2',6'-dimethoxy-[l,l'- biphenyl]-4-yl)-2-((S)-pyrrolidine-2-carboxamido)propanoate (50)

To a round bottom flask was added benzyl (,S)-2-((R)-3-((4'-(ethoxymethyl)-2',6'- dimethoxy-[l, -biphenyl]-4-yl)methyl)-4-methoxy-4-oxobutanoyl)pyrrolidine-l-carboxylate (49, 0.334 g, 0.552 mmol) and methanol (5 mL). The flask was flushed with nitrogen gas, palladium on carbon (0.2 g of 10%) was added and the reaction was stirred overnight under a hydrogen atmosphere at ambient temperature and pressure. The reaction was filtered through a plug of Celite® and rinsed with additional methanol. The solvent was removed in vacuo to give product methyl (,S)-3-(4'-(ethoxymethyl)-2',6'-dimethoxy-[l, -biphenyl]-4-yl)-2-((₎S)-pyrrolidine -2-carboxamido)propanoate (50, 0.237 g, 91% yield) as an oil. LC-MS: tR=2.07 min; m/z=4712. Scheme 5, Step 2: Preparation of methyl (S)-3-(4'-(ethoxymethyl)-2',6'-dimethoxy-[l,l'- biphenyl]-4-yl)-2-((S)-l-(phenylsulfonyl)pyrrolidine-2-carboxamido)propanoate (51)

To a round bottom flask was added methyl (S)-3-(4'-(ethoxymethyl)-2',6'-dimethoxy- [l, l'-biphenyl]-4-yl)-2-((,S)-pyrrolidine-2-carboxamido)propanoate (compound 50, 0.1 18 g, 0.251 mmol) and dichloromethane (2 mL). The solution was cooled to 0 °C and benzenesulfonyl chloride (66 mg, 0.376 mmol) and diisopropylethylamine (215 μL, 1.25 mmol) were added. After stirring for 1 hour at room temperature, the reaction was taken up in ethyl acetate and washed with hydrochloric acid (10 mL, 1 N), water, and then brine. The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on C18 using acetonitrile and water (both with 0.1% formic acid as modifier). Pure fractions were pooled and concentrated in vacuo. Product methyl (,S)-3-(4'-(ethoxymethyl)-2',6'-dimethoxy- [l, l'-biphenyl]-4-yl)-2-((,S)-l-(phenylsulfonyl)pyrrolidine-2-carboxamido) propanoate (51, 0.1 12 g, 73% yield) was isolated as an oil. LC-MS: tR=2.66 min; m/z=6\ \ 2. Scheme 5, Step 3: Preparation of methyl (S)-2-((S)-l-((3,5-dichlorophenyl)sulfonyl)- pyrrolidine-2-carboxamido)-3-(4'-(ethoxymethyl)-2',6'-dimethoxy-[l,l'-biphenyl]-4- yl)propanoate (52)

To a round bottom flask was added methyl (S)-3-(4'-(ethoxymethyl)-2',6'-dimethoxy- [l, l'-biphenyl]-4-yl)-2-((,S)-pyrrolidine-2-carboxamido)propanoate (compound 50, 0.1 18 g, 0.251 mmol) and dichloromethane (2 mL). The solution was cooled to 0 °C and 3,5- dichlorobenzenesulfonyl chloride (66 mg, 0.376 mmol) and diisopropylethylamine (215 μL, 1.25 mmol) were added and the reaction was stirred overnight at room temperature. The reaction was taken up in ethyl acetate and washed with hydrochloric acid (10 mL, 1 N), water, and then brine. The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on C18 using acetonitrile and water (both with 0.1% formic acid as modifier). Pure fractions were pooled and concentrated in vacuo. Product methyl (S)-2-((S)-l- ((3,5-dichlorophenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-(4'-(ethoxymethyl)-2',6'-dimethoxy- [l, l'-biphenyl]-4-yl)propanoate (52, 0.121 g, 71% yield) was isolated as an oil. LC-MS: tR=2.92 min; m/z=679.1, 681.1.

Scheme 2, Step 6: General Procedure D - Hydrolysis (Examples 1608-1611)

To a flask was added the appropriate ester intermediate (Intermediates 47, 48, 51, 52), acetonitrile (1 mL), water (1 mL) and lithium hydroxide monohydrate (5 equivalents). The solution was stirred at room temperature for 2 hours. Acetonitrile was removed in vacuo and the reaction was acidified using hydrochloric acid (IN). Water was then removed in vacuo and the residue was purified on C18 using acetonitrile and water (both with 0.1% formic acid as modifier). Pure fractions were pooled and concentrated in vacuo and the resulting material was lyophilized from acetonitrile and water (1 :4) overnight. Isolated products are shown in Table 4 (Examples 1608-1611).

SCHEME 6: Preparation of Intermediates 27 and 28

Scheme 6, Step 1: Preparation of 2-Bromo-l,3-dimethoxy-5-((2-methoxyethoxy) methy)benzene (57)

To a round bottom flask was added (4-bromo-3,5-dimethoxyphenyl)methanol (compound 10, 1.95 g, 7.89 mmol) and N,N-dimethylformamide (20 mL). The solution was cooled to 0 °C and sodium hydride (0.393 g of 60% (w/w) in mineral oil, 10.3 mmol) was added and the reaction was stirred for 1 hour at room temperature. l-Bromo-2-methoxy ethane (0.89 mL, 9.47 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was quenched with methanol and concentrated in vacuo. The residue was taken up in ethyl acetate and washed using water, then brine. The organic layer was dried using sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent. Product 2-Bromo-l,3-dimethoxy-5-((2-methoxyethoxy)methy)benzene (57, 2.22 g, 92% yield) was isolated as a pale yellow oil. LC-MS: tR=2.1 1 min; m/z+ 23=327.0, 329.0. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.70 (s, 2 H) 4.48 (s, 2 H) 3.82 (s, 6 H) 3.53 - 3.62 (m, 2 H) 3.45 - 3.52 (m, 2 H) 3.26 (s, 3 H).

Preparation of l-(4-Brom -3,5-dimethoxyphenyl-2,5,8,ll-tetraoxadodecane (58)

To a round bottom flask was added (4-bromo-3,5-dimethoxyphenyl)methanol (compound 10, 1.9 g, 7.69 mmol) and N,N-dimethylformamide (20 mL). The solution was cooled to 0 °C and sodium hydride (0.383 g of 60% (w/w) in mineral oil, 10 mmol) was added and the reaction was stirred for 1 hour at room temperature. 2-[2-(2-Methoxyethoxy)ethoxy]ethyl 4- methylbenzenesulfonate (2.8 mL, 9.23 mmol) was added and the reaction was stirred for six hours at room temperature. The reaction was quenched with water and concentrated in vacuo. The residue was taken up in ethyl acetate and washed using water, then brine. The organic layer was dried using sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent. Product l-(4-Bromo-3,5- dimethoxyphenyl-2,5,8, l l-tetraoxadodecane (58, 3.02 g, quant, yield) was isolated as a clear oil. LC-MS: t_R=2.08 min; m/z+23=4\ 5.0, 417.0. ¹H MR (400 MHz, DMSO-d6) δ ppm 6.70 (s, 2 H) 4.48 (s, 2 H) 3.82 (s, 6 H) 3.57 (s, 4 H) 3.47 - 3.55 (m, 6 H) 3.39 - 3.45 (m, 2 H) 3.22 (s, 3 H).

-1746 and 2087-2088

Scheme 7, Step 1: Preparation of methyl (S)-2-(tert- butoxycarbonyl)amino)-3-(2',6'- dimethoxy-4'-((2-methoxyethoxy)methyl)-[l,l'-biphenyl]-4-yl)propanoate

(59)

To a microwave vial was added methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (33, 599 mg, 1.48 mmol), 2-Bromo-l ,3- dimethoxy-5-((2-methoxyethoxy)methy)benzene (57, 631 mg, 2.07 mmol), tetrakis (triphenylphosphane)palladium(O) (85 mg, 0.074 mmol), cesium acetate (851 mg, 4.43 mmol), 1,4-dioxane (5 mL) and water (1 mL). 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. Pure fractions were pooled and concentrated in vacuo to give product methyl (,S)-2-((tert-butoxycarbonyl)amino)-3-(2',6'-dimethoxy-4'-((2-methoxyethoxy) methyl)-[l, l'-biphenyl]-4-yl)propanoate (59, 262 mg, 35% yield) as an oil. LC-MS: t_R=2.59 min; m/z+ 23=526.1.

Scheme 7, Step 1: Preparation of methyl (S)-3-(4'-(2,5,8,ll-tetraoxadodecyl)-2',6'- dimethoxy-[l,l'-biphenyl]-4-yl)-2-(( tert- butoxycarbonyl)amino)propanoate (60)

To a microwave vial was added methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (33, 720 mg, 1.78 mmol), l-(4-Bromo- 3,5-dimethoxyphenyl-2,5,8, l l-tetraoxadodecane (58, 759 mg, 1.93 mmol), tetrakis (triphenylphosphane)palladium(O) (103 mg, 0.089 mmol), cesium acetate (1.02 g, 5.33 mmol), 1,4-dioxane (5 mL) and water (1 mL). 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. Pure fractions were pooled and concentrated in vacuo to give product methyl (5)-3-(4'-(2,5,8, l l-tetraoxadodecyl)-2',6'-dimethoxy-[l,r-biphenyl]-4-yl)-2- ((tert-butoxycarbonyl)amino)propanoate (60, 352 mg, 33.5% yield) as an oil. LC-MS: tR=2.56 min; m/z+ 23=614.3. Scheme 7, Step 2: Preparation of methyl (S)-2-amino-3-(2',6'-dimethoxy-4'-((2- methoxyethoxy)methyl)-[l,l'-biphenyl]-4-yl)propanoate (61)

To a round bottom flask was added methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2',6'- dimethoxy-4'-((2-methoxyethoxy)methyl)-[l, l'-biphenyl]-4-yl)propanoate (59, 262 mg, 0.520 mmol) and trifluoroacetic acid in dichloromethane (10 mL, 20% v/v) and the reaction was stirred for 30 minutes at room temperature. The 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. Pure fractions were pooled and concentrated in vacuo to give product methyl (,S)-2-amino-3-(2',6'-dimethoxy- 4'-((2-methoxyethoxy)methyl)-[l, l'-biphenyl]-4-yl)propanoate (61, 210 mg, 100% yield) as an oil. LC-MS: t_R=1.82 min; m/z=404.2.

Scheme 7, Step 2: Preparation of methyl (S)-3-(4'-(2,5,8,ll-tetraoxadodecyl)-2',6'- dimethoxy-[l,l'-biphenyl]-4-yl)-2-aminopropanoate (62)

To a round bottom flask was added methyl (,S)-3-(4'-(2,5,8, l l-tetraoxadodecyl)-2',6'- dimethoxy-[l, l'-biphenyl]-4-yl)-2-((tert-butoxycarbonyl)amino)propanoate (60, 352 mg, 0.595 mmol) and trifluoroacetic acid in dichloromethane (10 mL, 20% v/v) and the reaction was stirred for 30 minutes at room temperature. The 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. Pure fractions were pooled and concentrated in vacuo to give product methyl (S)-3-(4'-(2,5,8, l l- tetraoxadodecyl)-2',6'-dimethoxy-[l, l'-biphenyl]-4-yl)-2-aminopropanoate (62, 292 mg, 99.8% yield) as an oil. LC-MS: t_R=1.81 min; m/z=492.2.

SCHEME 8: Preparation of Intermediates 66 and 67

Scheme 8, Step 1: Preparation of (S)-l-(phenylsulfonyl)azetidine-2-carboxylic acid (66)

To a round bottom flask was added (,S)-azetidine-2-carboxylic acid (63, purchased from Chem Impex International, 500 mg, 4.95 mmol) and sodium hydroxide (6.9 mL of IN; 6.92 mmol). The reaction was cooled to 0 °C and benzenesulfonyl chloride (64, 0.96 g, 5.44 mmol) was added followed by N,N-diisopropylethylamine (0.97 mL, 5.69 mmol) and acetone (7 mL) and the reaction was stirred overnight at room temperature. The acetone was evaporated and the aqueous layer extracted with diethyl ether (3 x 50 mL). The aqueous layer was adjusted to pH=l using cone. HC1 and then extracted with ethyl acetate (3 x 75 mL). The ethyl acetate layers were pooled, dried using sodium sulfate, filtered and concentrated in vacuo to give product (S)-l- (phenylsulfonyl)azetidine-2-carboxylic acid (66, 1.14 g, 95% yield) as a white solid. LC-MS: tR=1.46 min; m/z=24\ .9. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.98 (s, 1 H) 7.80 - 7.89 (m, 2 H) 7.73 - 7.80 (m, 1 H) 7.64 - 7.72 (m, 2 H) 4.34 (t, J=8.68 Hz, 1 H) 3.69 (td, J=7.64, 5.75 Hz, 1 H) 3.60 (q, J=8.23 Hz, 1 H) 2.15 - 2.26 (m, 2 H). Scheme 8, Step 1: Preparation of (S)-l-((3,5-dichlorophenyl)sulfonyl)azetidine-2-carboxylic acid (67)

To a round bottom flask was added (,S)-azetidine-2-carboxylic acid (63, 51 1 mg, 5.05 mmol) and sodium hydroxide (7.0 mL of IN; 7.08 mmol). The reaction was cooled to 0 °C and 3,5-dichlorobenzenesulfonyl chloride (65, 1.36 g, 5.56 mmol) was added followed by N,N- diisopropylethylamine (1.0 mL, 5.81 mmol) and acetone (7 mL) and the reaction was stirred overnight at room temperature. The acetone was evaporated and the aqueous layer extracted with diethyl ether (3 x 50 mL). The aqueous layer was adjusted to pH=l using cone. HC1 and then extracted with ethyl acetate (3 x 75 mL). The ethyl acetate layers were pooled, dried using sodium sulfate, filtered and concentrated in vacuo to give product (,S)-l-((3,5- dichlorophenyl)sulfonyl)azetidine-2-carboxylic acid (67, 1.6 g, 100% yield) as a white solid. LC- MS: tR=2.06 min; m/z=309.8, 31 1.9. ¹ NHMR (400 MHz, DMSO-d6) δ ppm 13.08 (br. s., 1 H) 8.06 (t, J=1.83 Hz, 1 H) 7.85 (d, J=1.96 Hz, 2 H) 4.63 (dd, J=9.54, 7.58 Hz, 1 H) 3.67 - 3.88 (m, 2 H) 2.29 - 2.42 (m, 1 H) 2.13 - 2.28 (m, 1 H).

Scheme 7, Step 3: General Procedure E - Amide Coupling (Intermediates 68-71)

To a round bottom flask was added the aryl-azetidine-2-carboxylic acid coupling partner (Compounds 66 or 67, 1.1 equivalent), HATU (2.2 equivalents), HOBt (0.2 equivalent), and dimethylsulfoxide (1 mL). N,N-Diisopropylethylamine (3 equivalents) was added and the solution was stirred for 20 minutes at room temperature. At this time, the appropriate amine (61 or 62, 1 equivalent) was added and the reaction was stirred overnight at room temperature. 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. Pure fractions were pooled and concentrated in vacuo. Isolated products (see Table 5, compounds 68-71) were carried forward as-is.

TABLE 5: Intermediates

Scheme 7, Step 4: Hydrolysis (Examples 142-145)

Intermediates 68-71 were hydrolyzed using General Procedure D (Scheme 2, Step 6) to give examples 1745-1746 and 2087-2088 (see Table 6).

SCHEME 9: Preparation of Example 1747

Scheme 9, 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)

The compound was prepared from the amide coupling between intermediate 61 and Z-L- proline (46) using General Procedure C of Scheme 2 Step 5. Product benzyl (S)-2-(((S)-3-(2\&- dimethoxy-4'-((2-methoxy ethoxy)methyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 -methoxy- 1 -oxopropan-2- yl)carbamoyl)pyrrolidine-l-carboxylate (76, 86 mg, 78% yield) was isolated as an oil. LC-MS: tR=2.48 min; m/z=635.2

Scheme 9, Step 2: Preparation of methyl (S)-3-(2',6'-dimethoxy-4'-((2-methoxy ethoxy)methyl)-[l,l'-biphenyl]-4-yl)-2-((S)-pyrrolidine-2-carboxamido)propanoate (77)

The compound was prepared by the hydrogenolysis of intermediate 76 using the procedure of Scheme 5 Step 1. Product methyl (S)-3-(2',6'-dimethoxy-4'-((2-methoxy ethoxy)methyl)-[l, l'-biphenyl]-4-yl)-2-((,S)-pyrrolidine-2-carboxamido)propanoate (77, 64 mg, 94% yield) was isolated as an oil. LC-MS: tR=1.95 min; m/z=50\ 2. Scheme 9, Step 3: Preparation of methyl 4-(((S)-2-(((S)-3-(2',6'-dimethoxy-4'-((2- methoxyethoxy)methyl)-[l,l'-biphenyl]-4-yl)-l-methoxy-l-oxopropan-2- yl)carbamoyl)pyrrolidin-l-yl)sulfonyl)benzoate (78)

The compound was prepared by the reaction of intermediate 77 with the commercial reagent methyl 4-chlorosulfonylbenzoate using the procedure of Scheme 5 Step2. Product methyl 4-(((5)-2-(((5)-3 -(2',6'-dimethoxy-4'-((2-methoxyethoxy)methyl)-[ 1 , 1 '-bipheny l]-4-y 1)- 1 - methoxy-l-oxopropan-2-yl)carbamoyl)pyrrolidin-l-yl)sulfonyl)benzoate (78, 49.6 mg, 55% yield) was isolated as an oil. LC-MS: tR=2.58 min; m/z=699.2. Scheme 9, Step 4: Preparation of 4-(((S)-2-(((S)-l-carboxy-2-(2',6'-dimethoxy-4^,-((2- methoxyethoxy)methyl)-[l,l'-biphenyl]-4-yl)ethyl)carbamoyl)pyrrolidin-l-yl)

sulfonyl)benzoic acid (1747)

The compound was prepared by the hydrolysis of intermediate 78 using General

Procedure D of Scheme 2 Step 6. Example 4-(((5)-2-(((5)-l-carboxy-2-(2',6'-dimethoxy-4'-((2- methoxyethoxy)methyl)-[ 1 , 1 '-biphenyl]-4-yl)ethyl)carbamoyl)pyrrolidin- 1 -yl)sulfonyl)benzoic acid (1747, 29.8 mg, 62% yield) was isolated as a white solid. LC-MS: tR=2.09 min; m/z=61\ 3. ¾ MR (400 MHz, DMSO-d6) δ ppm 13.20 (br. s, 2 H) 8.19 (d, J=8.07 Hz, 1 H) 8.03 - 8.12 (m, 2 H) 7.86 - 7.91 (m, 2 H) 7.23 (d, J=8.31 Hz, 2 H) 7.1 1 (d, J=8.07 Hz, 2 H) 6.67 (s, 2 H) 4.43 - 4.53 (m, 3 H) 4.18 (dd, J=7.09, 3.91 Hz, 1 H) 3.61 (s, 6 H) 3.56 - 3.60 (m, 2 H) 3.47 - 3.53 (m, 2 H) 3.27 (s, 3 H) 3.07 - 3.22 (m, 3 H) 3.02 (m, J=9.00 Hz, 1 H) 1.54 - 1.67 (m, 3 H) 1.40 - 1.52 (m, 1 H).

Scheme 10. Preparation of 2-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (Intermediate 85).

Scheme 10, Step 1: Preparation of 2-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-4,4,5,5- tetram ethyl- 1 ,3 ,2-dioxaborolane (85)

To a 20 mL microwave vial was added, 2-bromo-5-(ethoxymethyl)-l,3-dimethoxy- benzene (37, 580 mg, 2.1 1 mmol), bis(pinacolato)diboron (700 mg, 2.74 mmol), Pd(dppf)Cl2 (95 mg, 0.126 mmol), potassium acetate (621 mg, 6.32 mmol) and 1,4-dioxane (5 mL). The vessel was sparged with nitrogen for 10 minutes and then heated overnight at 90 °C. An additional equivalent of bis(pinacolato)diboron (533 mg, 2.1 1 mmol) and additional Pd(dppf)Cl2 (95 mg, 0.126 mmol) were added, the vessel was sparged with nitrogen, sealed and heated for three days at 90 °C. The reaction was cooled, filtered through Celite® (rinsed with EtOAc) and concentrated in vacuo. The resulting 2.14 g of crude product was chromatographed on a 24 g silica gel column (linear gradient from pure hexanes to pure EtOAc) to give the title compound (85, 342 mg, 1.06 mmol, 50% yield). This material was used as-is. LC-MS: tR=1.755 min; m/z=323 (M+H).

Scheme 11. Preparation of (2,S)-2-(2,6-dichlorobenzamido)-3-(4'-(ethoxymethyl)-2-(l- hydroxyethyl)-2',6'-dimethoxy-[l, l'-biphenyl]-4-yl)propanoic acid (1633)

Scheme 11, Step 1: Methyl (,S)-3-(3-acetyl-4-hydroxyphenyl)-2-aminopropanoate hydrochloride (87)

(,S)-3-(3-Acetyl-4-hydroxyphenyl)-2-aminopropanoic acid hydrochloride (86, 4.64 g, 17.9 mmol) was dissolved in MeOH (50 mL) and cooled to 0 °C. Thionyl chloride (6.5 mL, 89.3 mmol) was slowly added and the reaction was heated to reflux for 1 h. The reaction was cooled to room temperature and concentrated in vacuo. Excess thionyl chloride was azeotroped with methanol to give the crude title product (87, 4.76 g, 17.4 mmol, 97%) as a red solid. LC-MS tR=1.36 min; m/z=238 (M+H).

Scheme 11, Step 2: Methyl (S)-3-(3-acetyl-4-hydroxyphenyl)-2-(2,6- di chl orob enzami do)propanoate (88)

To a 50 mL round bottom flask was added 2,6-dichlorobenzoic acid (748 mg, 3.84 mmol), HBTU (1.52 g, 4.02 mmol), HOBt (1 12 mg, 0.731 mmol) and DMSO (10 mL). DIEA (1.9 mL, 1 1.0 mmol) was added, and the solution was stirred for 20 minutes. Methyl (S)-3-(3- acetyl-4-hydroxyphenyl)-2-aminopropanoate hydrochloride (87, 1.00 g, 3.65 mmol) was added and the reaction was stirred at room temp for 1 h. The reaction was taken up in EtOAc and washed with dilute HCl, water, then brine. The EtOAc layer was dried (sodium sulfate), filtered and evaporated. The resulting 1.83 g of material was chromatographed on 24 g of silica gel (linear gradient from pure hexanes up to pure EtOAc) to provide the title compound as a white foam (88, 1.14 g, 2.78 mmol, 76%). LC-MS: t_R=2.24 min; m/z=432, 434 (M+H, dichloro isotopic pattern). ¹H MR (400 MHz, DMSO-^e) δ ppm 1 1.85 (s, 1 H), 9.22 (d, J=8.31 Hz, 1 H), 7.83 (d, J=1.96 Hz, 1 H), 7.40 - 7.51 (m, 4 H), 6.88 (d, J=8.56 Hz, 1 H), 4.75 (m, J=10.30, 8.30, 4.90 Hz, 1 H), 3.68 (s, 3 H), 3.12 (dd, J=14.06, 4.77 Hz, 1 H), 2.91 (dd, J=13.94, 10.27 Hz, 1 H), 2.61 (s, 3 H). Scheme 11, Step 3: Methyl (5)-3-(3-acetyl-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2-(2,6- di chl orob enzami do)propanoate (89)

To a 100 mL round bottom flask was added methyl (S)-3 -(3 -acetyl -4-hydroxypheny l)-2- (2,6-dichlorobenzamido)propanoate (88, 1.00 g, 2.44 mmol) and dichloromethane (10 mL). The solution was cooled to -10 °C and pyridine (0.50 mL, 6.09 mmol) was added followed by the drop-wise addition of triflic anhydride (2.9 mL of a 1M solution in dichloromethane, 2.93 mmol). The reaction was allowed to warm to room temperature for 2 h. The reaction was diluted with dichloromethane and washed with citric acid (40 mL of a 10% solution). The DCM layer was dried (sodium sulfate), filtered and evaporated to furnish the crude title compound as an orange foam (89, 1.33 g, 2.45 mmol, quant.). LC-MS: tR=2.48 min; m/z=542, 544 (M+H, dichloro isotopic pattern). The material was carried forward without further purification.

Scheme 11, Step 4: Methyl (5)-3-(2-acetyl-4'-(ethoxymethyl)-2',6'-dimethoxy-[l, r-biphenyl]-4- yl)-2-(2,6-dichlorobenzamido)propanoate (90)

To a 20 mL microwave vial was added methyl (,S)-3-(3-acetyl-4- (((trifluoromethyl)sulfonyl)oxy)phenyl)-2-(2,6-dichlorobenzamido)propanoate (89, 500 mg, 0.922 mmol), 2-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (85, 342 mg, 1.06 mmol), Pd(PPh₃)4 (55 mg, 0.0461 mmol), cesium acetate (535 mg, 2.77 mmol), dioxane (5 mL) and water (1 mL). The vial was crimped shut and sparged with nitrogen for 10 minutes and then heated overnight at 1 10 °C. The reaction was taken up in EtOAc and washed using water, then brine. The EtOAc layer was dried (sodium sulfate), filtered and evaporated. The resulting 1.06 g of orange oil was chromatographed on 12 g of silica gel (linear gradient from pure hexanes up to pure EtOAc). The title compound was isolated as an amber oil (90, 150 mg, 0.255 mmol, 27.6% yield). LC-MS: t_R=2.51 min; m/z=588, 590 (M+H, dichloro isotopic pattern). ¹H NMR (400 MHz, OMSO-d6) δ ppm 9.25 (d, J=8.31 Hz, 1 H), 7.60 (d, J=1.71 Hz, 1 H), 7.36 - 7.48 (m, 4 H), 7.09 (d, J=7.82 Hz, 1 H), 6.66 (s, 2 H), 4.79 - 4.88 (m, 1 H), 4.47 (s, 2 H), 3.71 (s, 3 H), 3.63 (d, J=2.20 Hz, 6 H), 3.53 (q, J=7.09 Hz, 2 H), 3.23 (dd, J=1.00 Hz, 1 H), 3.00 (dd, J=1 1.20 Hz, 1 H), 2.14 (s, 3 H), 1.19 (t, J=7.34 Hz, 3 H).

Scheme 11, Step 5: Methyl (25)-2-(2,6-dichlorobenzamido)-3-(4'-(ethoxymethyl)-2-(l- hydroxyethyl)-2',6'-dimetho -[l, l'-biphenyl]-4-yl)propanoate (91)

To a round bottom flask was added methyl (,S)-3-(2-acetyl-4'-(ethoxymethyl)-2',6'- dimethoxy-[l, l'-biphenyl]-4-yl)-2-(2,6-dichlorobenzamido)propanoate (90, 150 mg, 0.255 mmol) and MeOH (4 mL). The reaction was cooled to 0 °C and NaBH₄ (15 mg, 0.382 mmol) was added. The reaction was stirred at room temperature. Additional 15 mg aliquots of NaBH₄ were added at 30 min intervals until the starting material was consumed. The reaction was poured into a 5% HC1 (10 mL) solution and extracted using dichloromethane (3 x 50 mL). The organic layer was dried (sodium sulfate), filtered, and evaporated. The resulting 0.159 g of material was chromatographed on 12 g of silica gel (linear gradient from pure hexanes up to pure EtOAc). The title compound (91, 71 mg, 0.120 mmol, 47% yield) was isolated as a clear oil. LC- MS: tR=2.39 min; m/z=612, 614 (M+Na, dichloro isotopic pattern).

Scheme 11, Step 6: (25)-2-(2,6-dichlorobenzamido)-3-(4'-(ethoxymethyl)-2-(l -hydroxy ethyl)- 2',6'-dimethoxy-[l, l'-biphen -4-yl)propanoic acid (1633)

To a round bottom flask was added methyl (2,S)-2-(2,6-dichlorobenzamido)-3-(4'- (ethoxymethyl)-2-(l-hydroxyethyl)-2',6'-dimethoxy-[l, l'-biphenyl]-4-yl)propanoate (91, 71 mg, 0.120 mmol), acetonitrile (1 mL) and water (1 mL). Lithium hydroxide hydrate (15 mg, 0.361 mmol) was added and the reaction was stirred at room temperature for 1 h. The acetonitrile was evaporated and the reaction was acidified with 2 N HC1. The mixture was evaporated to dryness and chromatographed on a 15.5 g C18 RediSep Gold cartridge (linear gradient from 10% MeCN/water up to pure MeCN with 0.1% formic acid as modifier). The title compound was isolated as a white solid (1633, 54.0 mg, 0.0937 mmol, 78% yield). LC-MS: tR=2.27 min; m/z=598, 600 (M+Na, dichloro isotopic pattern). ¹H MR (400 MHz, DMSO-de) δ ppm 12.80 (br. s., 1 H), 9.10 (t, J=8.68 Hz, 1 H), 7.50 (dd, J=7.09, 1.47 Hz, 1 H), 7.32 - 7.46 (m, 3 H), 7.03 - 7.20 (m, 1 H), 6.78 (dd, J=7.70, 5.75 Hz, 1 H), 6.67 (s, 2 H), 4.64 - 4.83 (m, 2 H), 4.48 (s, 2 H), 4.35 (m, J=6.40, 3.20, 3.20 Hz, 1 H), 3.63 (s, 6 H), 3.54 (q, J=7.01 Hz, 2 H), 3.1 1 - 3.24 (m, 1 H), 2.93 (dd, J=14.06, 9.90 Hz, 1 H), 1.20 (t, J=7.09 Hz, 3 H), 1.02 (dd, J=7.70, 6.48 Hz, 3 H).

C. Biological Assay Results

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.

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.

HSPC mobilization. The 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.

Colony forming cell (CFC) 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 μΙ_, 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.

Results for Examples 1220, 1221, and 1224 are shown in FIG. 1. Results for Examples 1610 and 1611 are shown in FIG. 2.

All of the compounds, compositions, and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the disclosure may have focused on several embodiments or may have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and modifications may be applied to the compounds, compositions, and methods without departing from the spirit, scope, and concept of the disclosure. All variations and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the disclosure as defined by the appended claims.

REFERENCES

The following references to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference. Greene & Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley, 1999.

Handbook of Pharmaceutical Salts: Properties, and Use, Stahl and Wermuth (Eds.), Verlag

Helvetica Chimica Acta, 2002.

March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 2007.

Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008

Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Company, Easton, Pa.

Smith and Williams Introduction to the Principles of Drug Design, Smith, H. J.; Wright, 2nd ed., London, 1988.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula:

wherein:

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

Ra is alkoxy(c<i2), acyloxy(c<i2), or a substituted version of either of these groups; or

-X(CH₂0)m-(CH₂CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1;

n is 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

X1 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 R₄ are each independently hydrogen, hydroxy, alkoxy(c<8) or substituted alkoxy(c<8);

R5 is hydrogen, -CH(ORd)Re, or -C(0)Rf, wherein:

Rd is hydrogen, alkyl(c<8), substituted alkyl(c<8), acyl(c<8), or substituted acyl(c<8); and

Re and Rf are each independently alkyl(c<8) or substituted alkyl(c<8); and Z is a group of the formula:

wherein:

p is 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), cycloalkyl- amino(c<8), substituted cycloalkylamino(c<8), alkenylamino(c<8), substituted alkenylamino(c<8), arylamino(c<8), substituted arylamino(c<8), aralkylamino(c<8), substituted aralkylamino(c<8), or a substituent convertible in vivo to hydroxy;

R7 and Rs 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

a group of the formula:

wherein:

W is hydrogen, cyano, halo, hydroxy, or -C(0)X₃, wherein:

X3 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), cycloalkyl- amino(c<8), substituted cycloalkylamino(c<8), alkenylamino(c<8), substituted alkenylamino(c<8), arylamino(c<8), substituted arylamino(c<8), aralkylamino(c<8), substituted aralkylamino(c<8), or a substituent convertible in vivo to hydroxy;

Rio and R11 are each independently hydrogen or halo,

provided that if R5 is hydrogen, then W is -C(0)X₃; and if W is -C(0)X₃ or R₆ is

-C(0)X₂, then R9 is hydrogen; and if R₁ is hydrogen, then R₆ is not hydrogen; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 further defined as:

wherein: R₁ 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

-X(CH20)m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 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

R3 and R₄ are each independently alkoxy(c<8) or substituted alkoxy(c<8);

provided that R₁ and R2 are not both hydrogen;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 further defined as;

wherein:

Yi is alkanediyl(c<8) or substituted alkanediyl(c<8); and

-X(CH20)m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

Y2 is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R3 and R₄ are each independently alkoxy(c<8) or substituted alkoxy(c<8);

provided that R₁ and R2 are not both hydrogen;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1further defined as;

wherein:

R₁ 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

-X(CH20)m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

Y2 is alkanediyl(c<8) or substituted alkanediyl(c<8); and

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1further defined as;

wherein:

Yi is alkanediyl(c<8) or substituted alkanediyl(c<8); and

-X(CH20)m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

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

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1further defined as;

wherein:

Yi is alkanediyl(c<8) or substituted alkanediyl(c<8); and

-X(CH20)m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

Y2 is alkanediyl(c<8) or substituted alkanediyl(c<8); and

provided that R₁ and R2 are not both hydrogen;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 further defined as:

wherein:

R₁ is 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

-X(CH20)m-(CH2CH₂0)n-Rb; wherein:

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 further defined as:

(VII) wherein:

R₁ 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; or -X(CH20)m-(CH2CH₂0)n-Rb, wherein :

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

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 group; or

R3 and R₄ are each independently alkoxy(c<8) or substituted alkoxy(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, 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 R₁ and R7 are not both hydrogen;

or a pharmaceutically acceptable salt thereof.

9. The compound of either claim 1 or claim 8 further defined as:

wherein:

R₁ 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

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(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

or a pharmaceutically acceptable salt thereof.

The compound according to any one of claims 1, 8, and 9, further defined as:

wherein: R1 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

-X(CH20)m-(CH2CH₂0)n-Rb, wherein :

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

R9 is hydrogen, alkyl(c<6), or substituted alkyl(c<6);

p is 0, 1, 2, or 3; and

or a pharmaceutically acceptable salt thereof.

1 1. The compound accordin to any one of claims 1, 8, and 9, further defined as:

wherein:

R₁ 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

-X(CH20)m-(CH2CH₂0)n-Rb, wherein :

X is a covalent bond or -0-;

m is 0 or 1 ;

R.9 is hydrogen, alkyl(c<6), or substituted alkyl(c<6);

p is 0, 1, 2, or 3; and

or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1, 8, and 9, further defined as:

R₁ 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

-X(CH20)m-(CH2CH₂0)n-Rb, wherein :

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

R9 is hydrogen, alkyl(c<6), or substituted alkyl(c<6);

p is 0, 1, 2, or 3; and

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; or a pharmaceutically acceptable salt thereof.

13. The compound of cl im 1 further defined as:

Yi is alkanediyl(c<8) or substituted alkanediyl(c<8); and

-X(CH20)m-(CH2CH₂0)n-Rb, wherein :

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

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;

R3 and R₄ are each independently alkoxy(c<8) or substituted alkoxy(c<8);

R5 is hydrogen, -CH(ORd)Re, or -C(0)Rf, wherein:

Rd is hydrogen, alkyl(c<8), substituted alkyl(c<8), acyl(c<8), or substituted

Re and Rf are each independently alkyl(c<8) or substituted alkyl(c<8);

14. The compound of either claim 13 or claim 14 further defined as:

wherein:

Yi is alkanediyl(c<8) or substituted alkanediyl(c<8); and

-X(CH20)m-(CH2CH₂0)n-Rb, wherein :

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

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; R5 is hydrogen, -CH(ORd)Re, or -C(0)Rf, wherein:

Re and Rf are each independently alkyl(c<8) or substituted alkyl(c<8);

or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of claims 1, 13, or 14 further defined

wherein:

Yi is alkanediyl(c<8) or substituted alkanediyl(c<8); and

-X(CH20)m-(CH2CH₂0)n-Rb, wherein :

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

R5 is hydrogen, -CH(ORd)Re, or -C(0)Rf, wherein:

Re and Rf are each independently alkyl(c<8) or substituted alkyl(c<8);

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein Z is:

wherein:

W is hydrogen, cyano, halo, hydroxy, or -C(0)X₃, wherein: X3 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 alkenyl- amino(c<8), arylamino(c<8), substituted arylamino(c<8), aralkylamino(c<8), substituted aralkylamino(c<8), or a substituent convertible in vivo to hydroxy; and

R10 and R11 are each independently hydrogen or halo.

17. The compound of claim 1, wherein Z is:

wherein:

p is 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 cycloalkyl- amino(c<8), alkenylamino(c<8), substituted alkenylamino(c<8), arylamino(c<8), substituted arylamino(c<8), aralkylamino(c<8), substituted aralkylamino(c<8), or a substituent convertible in vivo to hydroxy; R.7 and Rs are each independently hydrogen, halo, haloalkyl(c<8), or substituted haloalkyl(c<8); and

R9 is hydrogen, alkyl(c<8), or substituted alkyl(c<8).

18. The compound according to any one of claims 1-17, wherein R₁ is alkyl(c<8) or substituted alkyl(c<8).

19. The compound of claim 18, wherein R is₁ hydroxyalkyl(c<8) or haloalkyl(c<8).

20. The compound of either claim 18 or claim 19, wherein is R a₁n unbranched group.

21. The compound of claim 18, wherein R is₁ -CH3, -CH2OH, -CH(CH₃)OH, -C(CH₃)₂OH, -CH2F, -CHF2, -CF₃, -CH₂OCH₃, or -CH₂OCH₂CH₃.

22. The compound according to any one of claims 1-6, wherein R₁ is alkoxy(c<8) or substituted alkoxy(c<8).

23. The compound of claim 22, wherein R is₁ methoxy or ethoxy.

24. The compound according to any one of claims 1-6, wherein R₁ is aminocarbonyl or carboxy.

25. The compound according to any one of claims 1-17, wherein R is₁ hydroxy, 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; or -X(CH20)m-(CH2CH₂0)n-Rb, wherein :

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8).

26. The compound of claim 25, wherein R₁ is -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.

27. The compound of either claim 25 or claim 26, wherein Yi is alkanediyl(c<8).

28. The compound of claim 27, wherein Yi is -CH2-.

29. The compound according to any one of claims 25-28, wherein R_a is alkoxy(c<i2).

30. The compound of claim 29, wherein R_a is ethoxy or hexyloxy.

31. The compound according to any one of claims 25-28, wherein R_a is acyloxy(c<i2).

32. The compound of claim 31, wherein R_a is hexanoate.

33. The compound of claim 25, wherein R₁ is -X(CH20)_m-(CH2CH20)n-Rb, wherein:

X is a covalent bond or -0-;

m is 0 or 1 ;

n is 1, 2, 3, 4, 5, 6, 7, or 8; and

Rb is hydrogen, alkyl(c<8), or substituted alkyl(c<8).

34. The compound of either claim 25 or claim 33, wherein X is a covalent bond.

35. The compound according to any one of claims 25, 33, and 34, wherein m is 1.

36. The compound according to any one of claims 25 and 33-35, wherein n is 1, 2, or 3.

37. The compound of claim 36, wherein n is 1.

38. The compound according to any one of claims 25 and 33-37, wherein Rb is alkyl(c<8).

39. The compound of claim 38, wherein Rb is methyl.

40. The compound according to any one of claims 1-39, wherein R2 is hydrogen.

41. The compound according to any one of claims 1, 3, and 16-40, wherein R3 is alkoxy(c<6).

42. The compound of claim 41, wherein R3 is methoxy.

43. The compound according to any one of claims 1, 3, and 16-42, wherein R₄ is alkoxy(c<6).

44. The compound of claim 41, wherein R₄ is methoxy.

45. The compound according to any one of claims 1, 2, 4, 5, 8-1 1, 13-15, and 16-44, wherein Xi is hydroxy.

46. The compound according to any one of claims 1, 2, 4, 5, 8-1 1, 13-15, and 16-44, wherein Xi is a substituent convertible in vivo to hydroxy.

47. The compound according to any one of claims 1, 2, 4, 5, 8, 9, and 16-46, wherein X2 is hydroxy.

48. The compound according to any one of claims 1, 2, 4, 5, 8, 9, and 16-46, wherein X2 is a substituent convertible in vivo to hydroxy.

49. The compound according to any one of claims 1, 8, 9, and 17-48, wherein R7 is hydrogen.

50. The compound according to any one of claims 1, 8, 9, and 17-48, wherein R7 is halo.

51. The compound of claim 50, wherein R7 is chloro.

52. The compound according to any one of claims 1, 8, 9, and 17-48, wherein R₈ is hydrogen.

53. The compound according to any one of claims 1, 8, 9, and 17-48, wherein R₈ is halo.

54. The compound of claim 53, wherein R₈ is chloro.

55. The compound according to any one of claims 1, 8, 9, and 17-54, wherein R₆ is hydrogen.

56. The compound according to any one of claims 1, 8-12, and 17-55, wherein R9 is hydrogen.

57. The compound according to any one of claims 1, 8-12, and 17-55, wherein R9 is alkyl(c<8).

58. The compound of claim 57, wherein R9 is alkyl(c<4).

59. The compound of claim 58, wherein R9 is methyl.

60. The compound according to any one of claims 1, 8-12, and 17-59, wherein p is 0, 1, or 2.

61. The compound of claim 60, wherein p is 1 or 2.

62. The compound according to any one of claim 1, 16, and 18-48, wherein Rio is halo.

63. The compound of claim 62, wherein Rio is chloro.

64. The compound according to any one of claim 1, 16, 18-48, 62, and 63 wherein R11 is halo.

65. The compound of claim 64, wherein Rio is chloro.

66. The compound according to any one of claims 1, 16, 18-48, and 62-65, wherein W is hydrogen.

67. The compound according to any one of claims 1, 16, 18-48, and 62-65, wherein W is -C(0)X₃.

68. The compound according to any one of claims 1, 4, 5, 16, 18-48, and 67, wherein X3 is hydroxy.

69. The compound according to any one of claims 1, 4, 5, 16, 18-48, and 67, wherein X3 is a substituent convertible in vivo to hydroxy.

or a pharmaceutically salt thereof.

71. A pharmaceutical composition comprising:

(A) a compound according to any one of claims 1-70; and

(B) a pharmaceutically acceptable excipient.

72. The pharmaceutical composition of claim 71, wherein 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, transdermally, 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.

73. The pharmaceutical composition of claim 72, wherein the pharmaceutical composition is formulated for oral administration, intraarterial administration, intraperitoneal administration, intravenous administration, or subcutaneous administration.

74. The pharmaceutical composition of claim 73, wherein the pharmaceutical composition is formulated for administration via intravenous infusion.

75. The pharmaceutical composition of claim 73, wherein the pharmaceutical composition is formulated for subcutaneous administration.

76. The pharmaceutical composition according to any one of claims 71-75, wherein the pharmaceutical composition is formulated as a unit dose.

77. A method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of a compound or composition according to any one of claims 1-76.

78. The method of claim 77, wherein the disease or disorder is associated with integrin α₄βι.

79. The method of claim 77, wherein the disease or disorder is associated with inflammation.

80. The method of claim 77, wherein the disease or disorder is an autoimmune disorder.

81. The method of claim 77, wherein the disease or disorder is associated with hematopoietic stem cells.

82. The method of claim 81, wherein the hematopoietic stem cells are LSK-SLAM cells.

83. The method of claim 77, wherein the disease or disorder is cancer or a reduced blood cell count resulting from a therapy for cancer.

84. The method of claim 83, wherein the disease or disorder is a reduced blood cell count resulting from a therapy for cancer.

85. The method of claim 84, wherein the therapy is chemotherapy or radiation therapy.

86. The method of claim 83, wherein disease or disorder is cancer.

87. The method of claim 86, wherein the compound or composition results in improved efficacy of the chemotherapy or radiotherapy

88. A method 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 according to any one of claims 1-76.

89. The method of claim 88, wherein the method is ex vivo or in vitro

90. The method of claim 88, wherein the method is in vivo.

91. A method of collecting hematopoietic stem cells or progenitor cells from a patient comprising:

(A) administering to the patient a compound or composition according to any one of claims 1-76 in an amount sufficient to mobilize hematopoietic stem cells or progenitor cells to the peripheral blood of the patient; and

92. A method of collecting hematopoietic stem cells or progenitor cells from a patient who has been administered a compound or composition according to any one of claims 1-76 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.

93. A method 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 according to any one of claims 1-76.

94. A method of transplanting to a patient hematopoietic stem cells or progenitor cells comprising:

(A) administering to the patient a compound or composition according to any one of claims 1-76;

(B) collecting hematopoietic stem cells or progenitor cells from the patient;

95. A method 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 according to any one of claims 1-76.

96. A method of transplanting hematopoietic stem cells or progenitor cells comprising:

(A) administering to a first patient a compound or composition according to any one of claims 1-76;

97. A method of 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 according to any one of claims 1-76 to a second patient.

98. The method of claim 94 or claim 95, wherein 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.

99. The method according to any one of claims 94, 95, and 98, wherein 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.

100. The method of either claim 96 or claim 97, wherein the first patient is a compatible hematopoietic stem cell donor.

101. The method according to any one of claims 88-100, wherein the hematopoietic stem cells or progenitor cells are LSK-SLAM cells.

102. A method of improving the effectiveness of a treatment of cancer in a patient administered a chemotherapy or a radiotherapy comprising:

(A) administering to the patient a therapeutically effective amount of a compound or composition according to any one of claims 1-76;

(B) administering a chemotherapy or a radiotherapy to the patient.

103. A method of improving the effectiveness of a treatment of cancer in patient who has been administered a chemotherapy or radiotherapy and a compound or composition according to any one of claims 1-76.

104. The method according to any one of claims 77-103, wherein the method comprises administering the compound once.

105. The method according to any one of claims 77-103, wherein the method comprises administering the compound two or more times.

106. The method according to any one of claims 77-105, wherein the compound or composition is administered intravenously.

107. The method according to any one of claims 77-105, wherein the compound or composition is administered subcutaneously.

108. The method according to any one of claims 77-84 and 93-107, wherein the patient is a mammal.

109. The method of claim 108, wherein the patient is a human.