WO2003059872A1

WO2003059872A1 - Avb3 and avb5 integrin antagonists and methods of treating diseases or conditions associated with avb3 and avb5 integrins

Info

Publication number: WO2003059872A1
Application number: PCT/US2002/041692
Authority: WO
Inventors: Julie Dixon; Catherine Brennan; Jacques Dumas; Holia Hatoum-Mokdad; Robert Sibley; Barry Hart; Uday Khire; William J. Scott; Jeffrey Johson; Peying Liu; Aniko Redman; Jill Wood
Original assignee: Bayer Pharmaceuticals Corporation
Priority date: 2001-12-31
Filing date: 2002-12-31
Publication date: 2003-07-24
Also published as: AU2002364260A1

Abstract

This invention relates to compounds having the formula (I) wherein w, x, y, D, L, Q, R, R7 and R¿11? are as defined in the specification. The compounds habe been found to be αvß3 and/or αvß5 integrin antagonists. Pharmaceutical compositions containing the compounds, methods of making them, and methods of treatment of conditions associated with the αvß3 integrin or αvß5 integrin by administering a therapeutically effective amount of the compounds are also described.

Description

α_vβ₃ and α_vβ₅ Integrin Antagonists and Methods of Treating Diseases or Conditions Associated with α_vβ₃ and α_vβ₅ Integrins

DESCRIPTION OF THE INVENTION The present invention relates to:

(1) compounds described by formula (I) or purified stereoisomers or stereoisomer mixtures, or their salts or prodrug forms thereof;

(2) pharmaceutical compositions comprising one or more of the compounds of formula (I) or purified stereoisomers or stereoisomer mixtures of (I), or their salts or prodrug forms, with a pharmaceutically acceptable ingredient;

(3) methods for preparing the compounds of formula (I); and

(4) a method of treating diseases or conditions associated the α_vβ₃ integrin and/or α_vβ₅ integrin by administering a therapeutically effective amount of the compound of formula (I) to a patient in need thereof.

Description of the Compounds

The compounds described as being part of the invention have the structural formula (I) defined below:

wherein:

Q is a substituent selected from the group consisting of:

(a) Y— C— H- wherein

Y is selected from the group consisting of: (al) d-Cs-alkyl,

(a2) C₃-C₈-cycloalkyl,

(a3) C₃-C₈-cycloalkyl-C₁-C₃-alkyl,

(a4) C₃-C₅-alkenyl,

(a5) C -C₈-cycloalkenyl, (a6) C₃-C₅-alkynyl, (a7) C₆-C₁₀-aryl,

(a8) C₆-C₁₀-aryl-C₁-C₃-alkyl,

(a9) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and

9 9

(a 10) (CH₂)_a-A wherein A is a four to ten membered saturated or unsaturated heterocychc ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein: (al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, Cj;-C₃-alkoxy, -C₃- alkylthio, C₆-C₁₀-aryl and -NZ*Z²; and

(a2) - (alO) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, CrCralkoxy, Cr -alkyl, C C₃-alkylthio, C₆-C₁₀-aryl or -NZ^², wherein

Z¹ and Z² are independently selected from the group consisting of hydrogen and -Cs-alkyl, or Z¹ and Z² may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle;

N II H

(b) Y^a-C-NH- wherein Y^a represents -NH₂ or -NH-Y;

X

(c) -NH- wherein X represents O, S or N(CN)

NH

(e) Y -C-

wherein for (c) - (e)

Y^b represents -NH₂, -NH-Y or -Y;

(f) Y°-NH-(CH₂)_U- wherein Y^c is a heterocycle selected from:

(fl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (f2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein:

(f2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and

(f2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (fl) - (f2) are optionally substituted by R; (g) Y^C=N- wherein Y^c is as defined in (f) above;

(h) Y^dY^e-N- wherein Y^d and Y^e are independently selected from the group consisting of hydrogen, Ci-C₅-alkyl, and CrCs-aminoalkyl; and

(i) when w = 0, Q forms a four to eight membered heterocyclic ring fused to the aryl group to which it is attached to form a bicyclic ring, wherein said heterocyclic ring contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and at least one carbon atom and said heterocyclic ring is optionally substituted with -Cs-alkyl or -NZ³Z⁴ wherein Z³ and Z⁴ are independently selected from the group consisting of hydrogen and - Cs-alkyl;

represents a substituent selected from the group consisting of: (a) halogen,

(b) Ci-C -alkyl, optionally substituted by halogen,

(c) C₆-C₁₀-aryl, optionally substituted by halogen,

(d) NO₂,

(e) CN, (f) OR¹,

(h) S(=O)₂OR¹, (i) NR*R², (j) C(=O)NR¹R², and (k) S(=O)₂NR¹R² ; wherein for (f)-(k):

R¹ and R² each independently represents a substituent selected from the group consisting of:

(1) hydrogen, (2) C₁-C₄-alkyl, optionally substituted by halogen, and

(3) C₃-C₈-cyclo alkyl, optionally substituted by halogen; or wherein for (i)-(k):

R¹ and R² together with the nitrogen to which they are attached represent a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom;

represents a substituent selected from the group consisting of:

(a) O,

(b) C(=O),

(c) CR³R⁴,

(d) N(R⁵),

(e) S(=O)_z,

(f) C(=O)N(R⁵),

(g) N(R⁵)C(=O),

(h) S(=O)₂N(R⁵)

(i) N(R⁵)S(=O)₂,

(D CR³R⁴-CR³R⁴,

(k) CH₂O,

(1) OCH₂,

(m) CH₂N(R⁵),

(n) N(R⁵)CH₂,

(o) CH=CH,

(P) "C^≡C" ; and

(q) C(=NR³)

R³ and R⁴ each independently represents a substituent selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) C_rC₃-alkyl, and (4) CrCralkoxy;

wherein: when one or two R³ groups are Cι-C₃-alkyl in L, said one or two R³ ^" groups may constitute spiro rings or nonspiro rings wherein:

(a) one group R³ is joined by a bond or by a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, to the carbon chain to which said group R³ is attached, and taken together with the carbon chain atom(s) to which said group R³ is attached, constitutes a ring of three to six members, wherein for CR³R⁴, when R³ is Ci -alkyl, the R³ group is joined by a heteratom as defined above, or

(b) two groups R³ are joined by a bond or by a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur and taken together with the carbon chain atom(s) to which said two groups R³ are attached, constitute a ring of 3-6 members; or

R⁵ represents a substituent selected from the group consisting of: (1) hydrogen,

(2) Ci-C₄-alkyl, optionally substituted by halogen, and

(3) C₃-C₈-cycloalkyl, optionally substituted by halogen;

represents a substituent selected from the group consisting of: (a) (CH₂)_V and

(b) N(R⁶) wherein R⁶ represents a substituent selected from the group consisting of:

(1) hydrogen, (2) C₁-C₄-alkyl, optionally substituted by halogen, and

(3) C₃-C₈-cycloalkyl, optionally substituted by halogen; and wherein:

L is not C(=O)N(R⁵), N(R⁵)C(=O), S(=O)₂N(R⁵) or N(R⁵)S(=O)₂- when D is -NH-; represents a substituent selected from the group consisting of:

(a) C₂-C₅-alkyl,

(b) C₃-C₈-cycloalkyl, (c) ^' C₃-C₈-cycloalkyl-Ci-C₃-alkyl,

(d) C₃-C₅-alkenyl,

(e) C -C₈-cycloalkenyl,

(f) C₂-C₅-alkynyl, where (a)-(f) are optionally substituted by (1) OR⁸,

(2) NR⁸R⁹, or

(3) halogen;

(g) C₆-C₁₀-aryl₅

(h) Ce-do-aryl-d-Cs-alkyl, (i) C_ό-Cio-aryl-CrCe-cycloalkyl, and

(j) (CH₂)_b-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (g)-G) are optionally substituted by one to three substituents selected from the group consisting of: (1) NO₂₎

(2) CN,

(3) halogen,

(4) S(=O)₂OH,

(5) S(=O)_nR¹⁰,

(6) S(=O)₂NR⁸R⁹,

(7) NR⁸R⁹,

(8) OR⁸,

(9) C(=O)R¹⁰,

(10) C(=O)OR⁸ ; or

(11) C(=O)NR⁸R⁹; wherein:

R and R are independently hydrogen or R 10 ^' . or optionally

when (g) - (j) are substituted by NR⁸R⁹, S(=O)₂NR⁸R⁹ or C(=O)NR⁸R⁹, ^"' R⁸ and R⁹ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom;

R¹⁰ represents a substituent selected from the group consisting of:

(a) Ci-Cs-alkyl,

(b) C₃-C₈-cycloalkyl, (c) C₃-C₈-cycloalkyl-Ci-C₃-alkyl;

(d) C₃-C₅-alkenyl,

(e) C₄-C₈-cycloalkenyl,

(f) C₃-C₅-alkynyl,

(g) C₆-C₁₀-aryl, (h) C₆-C₁₀-aryl-C₁-C₃-alkyl,

(i) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and

(j) (CH₂)_b-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (a)-(j) are optionally substituted with halogen;

represents a substituent selected from the group consisting of: (a) hydrogen,

(b) d-C₆-alkyl,

(c) C₃-C₆-cycloalkyl,

(d) C₃-C₆-alkenyl,

(e) C₅-C₆-cycloalkenyl, and (f) C₃-C₆-alkynyl wherein (b)-(f) are optionally substituted by:

(1) halogen,

(2) OR¹², or ^'* (3) NR¹²R¹³; wherein

19 1

R and R independently represent hydrogen or d-C₃-alkyl; or R¹² and R¹³ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom;

u is an integer from 0 - 2; v is an integer from 1 - 2; n, w and z are each independently an integer from 0 - 2; a, b, x and y are each independently an integer from 0 - 3;

or a purified stereoisomer or stereoisomer mixture of said compound, or a salt of said compound, stereoisomer or stereoisomer mixture.

Alternative embodiments In one embodiment, the compounds of the invention are sulfonamides having the formula

in which D is NH and the various other groups and units are preferably defined as follows:

Q is a substituent selected from the group consisting of: H

(a) Y— C— NH- wherein

Y is selected from the group consisting of: (al) d-d-alkyl, (a2) C₃-C₈-cycloalkyl, (a3) C₃-C₈-cycloalkyl-d-C₃-alkyl,

(a4) C -C₈-cycloalkenyl,

(a6) Ce-do-aryl-d-Cralkyl, and

(a7) (CH₂)_a-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein: (al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, d-C₃-alkoxy, d-C₃- alkylthio, C₆-C₁₀-aryl and -NZ^XZ²; and

(a2) - (a7) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, d-C₃-alkoxy, d-d- alkyl, d-C₃-alkylthio, C₆-C₁₀-aryl or -NZ*Z², wherein

Z¹ and Z² are independently selected from the group consisting of hydrogen and d-C₅-alkyl, or Z¹ and Z² may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle;

NH

(b) Y^a-C-NH- wherein Y^a represents -NH₂ or -NH-Y; (c) Y^b-C-NH-

NH

( Y^b-C- wherein for (c) - (d)

Y^b represents -NH₂, -NH-Y or -Y;

(e) Y^C-NH-(CH₂)_U- wherein Y° is a heterocycle selected from:

(el) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (e2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein:

(e2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and

(e2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (el) - (e2) are optionally substituted by R; (f) Y^C=N- wherein Y^c is as defined in (e) above;

R represents a substituent selected from the group consisting of: (a) halogen,

(b) d-C₄-alkyl, optionally substituted by halogen,

(c) C₆-C₁₀-aryl, optionally substituted by halogen,

(d) NO₂,

(e) CN, (f) OR¹, and

(g) NR^JR², wherein for (f) and (g), R¹ and R² each independently represents a substituent selected from the group consisting of: (1) hydrogen, (2) C C₄-alkyl, and

(3) C₃-C₈-cycloalkyl; or wherein for (g), R¹ and R² together with the nitrogen to which they are attached represent a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom;

L represents a substituent selected from the group consisting of: (a) CR³R⁴-CR³R⁴,

(b) CH₂O,

(c) OCH₂,

(d) CH=CH, and

(e) OO _;

(1) hydrogen,

(2) d-C₃-alkyl, and (3) Ci-d-alkoxy;

D represents NH;

R⁷ represents a substituent selected from the group consisting of:

(a) C₃-C₈-cycloalkyl,

(b) C₃-C₈-cycloalkyl-d-C₃-alkyl,

(c) C₃-C₅-alkenyl,

(d) C -C₈-cycloalkenyl, (e) d-d-alkynyl, where (a)-(e) are optionally substituted by

(1) OR⁸,

(2) NR⁸R⁹, or

(3) halogen; (f) d-do-aryl,

(g) Cβ-Cio-aryl-Ci-Ca-alkyl,

(h) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and

(i) (CH₂)_b-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (f)-(i) are optionally substituted by one to three substituents selected from the group consisting of:

(1) NO₂, (2) CN,

(3) halogen,

(4) S(=O)_nR¹⁰,

(5) NR⁸R⁹,

(6) OR⁸, or (7) C(=O)R¹⁰, wherein:

R⁸ and R⁹ are independently hydrogen or R¹⁰;

or optionally when (f) - (i) are substituted by NR⁸R⁹,

R⁸ and R⁹ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated - heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom;

R¹⁰ represents a substituent selected from the group consisting of:

(a) d-d-alkyl,

(b) C₃-C₈-cycloalkyl,

(c) C₃-C₈-cycloalkyl-d-C₃-alkyl; and wherein (a)-(c) are optionally substituted with halogen;

represents a substituent selected from the group consisting of:

(a) hydrogen,

(b) d-C₆-alkyl,

(c) C -C₆-cycloalkyl, (d) C₃-C₆-alkenyl,

(e) C₅-C₆-cycloalkenyl, and

(f) C₃-C₆-alkynyl wherein (b)-(f) are optionally substituted by: (1) halogen, or (2) OR¹², wherein R¹² represents hydrogen or d-C -alkyl;

u is an integer from 0 - 2; v is an integer from 1 - 2; n, w and z are each independently an integer from 0 - 2; a, b, x and y are each independently an integer from 0 - 3; or a purified stereoisomer or stereoisomer mixture of said compound, or a salt of said compound, stereoisomer or stereoisomer mixture.

In another embodiment, the compounds of the invention are sulfonamides having the formula

in which D is NH and the various groups and units are more preferably defined as follows:

Q is a substituent selected from the group consisting of:

NH (a) Y^a-C-NH- wherein

Y^a represents -NH₂ or -NH-Y; and

Y is selected from the group consisting of:

(al) d-C₅-alkyl, (a2) C₃-C₈-cycloalkyl,

(a3) C₃-C₈-cycloalkyl-d-C₃-alkyl,

(a4) C -C₈-cycloalkenyl,

(a5) C₆-do-aryl,

(a6) C₆-do-aryl-d-C₃-alkyl, and (a7) (CH₂)_a-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein:

(al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, d-C₃-alkoxy, d-C₃- alkylthio, C₆-C₁₀-aryl and -NZ^Z²; and (a2) - (a7) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, d-C₃-alkoxy, d-d- alkyl, Ci-d-alkylthio, C₆-C₁₀-aryl or -NZ^², wherein

O

(b) Y^b-C-NH- wherein Y^b represents -NH₂, -NH-Y or -Y;

(c) Y^C-NH-(CH₂)_U- wherein

Y° is a heterocycle selected from: (cl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (c2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein: (c2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and (c2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (cl) - (c2) are optionally substituted by R;

(d) Y^C=N- wherein Y^c is as defined in (c) above;

R represents a substituent selected from the group consisting of:

(a) halogen, (b) d-C₄-alkyl, optionally substituted by halogen,

(c) C₆-C₁₀-aryl, optionally substituted by halogen,

(d) NO₂,

(e) CN,

(f) OR¹, and (g) NR^XR², wherein for (f) and (g), R¹ and R² each independently represents a substituent selected from the group consisting of:

(1) hydrogen,

(2) d-C₄-alkyl, and (3) C₃-C₈-cycloalkyl; or wherein for (g), R¹ and R² together with the nitrogen to which they are attached represent a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom;

L represents a substituent selected from the group consisting of: (a) CR³R⁴-CR³R⁴, (b) CH₂O, and

(c) OCH₂,

R³ and R⁴ each independently represents H;

D represents NH;

R⁷ represents a substituent selected from the group consisting of: (a) C₃-C₈-cycloalkyl, (b) C₃-C₈-cycloalkyl-d-C₃-alkyl,

(c) C₃-C₅-alkenyl,

(d) d-C₈-cycloalkenyl,

(e) C₂-C₅-alkynyl, where (a)-(e) are optionally substituted by (1) OR⁸, or

(2) halogen;

(f) C₆-C₁₀-aryl,

(g) C₆-C₁₀-aryl-Cι-C₃-alkyl,

(h) C₆-C₁₀-aryl-C -C₆-cycloalkyl, and (i) (CH₂)_b-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (f)-(i) are optionally substituted by one to three substituents selected from the group consisting of:

(1) NO₂,

(2) CN,

(3) halogen,

(4) S(=O)_nR¹⁰

(5) NR⁸R⁹,

(6) OR⁸, or

(7) C(=O)R¹⁰, wherein:

R and R are independently hydrogen or R 10 ;. or optionally

when (f) - (i) are substituted by NR⁸R⁹, R⁸ and R⁹ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom;

R¹⁰ represents a substituent selected from the group consisting of:

(a) d-C₅-alkyl,

(b) C₃-C₈-cycloalkyl, (c) C₃-C₈-cycloalkyl-d-C₃-alkyl; and wherein (a)-(c) are optionally substituted with halogen;

R¹¹ represents a substituent selected from the group consisting of: (a) hydrogen, (b) d-Q-alkyl, and

(c) d-d-cycloalkyl, wherein (a)-(c) are optionally substituted by:

(1) halogen, or

(2) OR¹², wherein

R¹² represents hydrogen or d-C₃-alkyl;

or a purified stereoisomer or stereoisomer mixture of said compound, or a salt of said compound, stereoisomer or stereoisomer mixture. In another embodiment, the compounds of the invention are sulfones having the formula

in which D is CH₂ , L is a one-atom linker, and the various other groups and units are preferably defined as follows:

Q is a substituent selected from the group consisting of:

(a) Y— C r— H- wherein

Y is selected from the group consisting of: (al) d-d-alkyl,

(a2) C₃-C₈-cycloalkyl, (a3) C₃-C₈-cycloalkyl-d-C₃-alkyl, (a4) C₃-C₅-alkenyl, (a5) C₄-C₈-cycloalkenyl, (a6) C₃-C₅-alkynyl,

(a7) C₆-C₁₀-aryl, (a8) Cβ-Cio-atyl-Ci-Cs-alkyl, (a9) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and (alO) (CH₂)_a-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein: (al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, d~C₃-alkoxy, d-C₃- alkylthio, C₆-C₁₀-aryl and -NZ^²; and

(a2) - (alO) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, d-C₃-alkoxy, d-C₃-alkyl₅ d-d-alkylthio, C₆-C₁₀-aryl or -NZ^², wherein

NH n

(b) Y -C-NH- wherein Y^a represents -NH₂ or -NH-Y;

X

(c) Y^b-C-NH- wherein X represents O or N(CN) ;

(d)

NH (e) Y^b-C- wherein for (c) - (e)

Y represents -NH₂, -NH-Y or -Y;

(f) Y^C-NH-(CH₂)_U- wherein

Y^c is a heterocycle selected from:

(fl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (f2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ^■ heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein: (f2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and

(f2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (fl) - (£2) are optionally substituted by R;

(g) Y^C=N- wherein Y^c is as defined in (f) above;

(h) Y^dY^e-N- wherein Y and Y^e are independently selected from the group consisting of hydrogen, d-C₅-alkyl, and d-C₅-aminoalkyl; and

(i) when w = 0, Q forms a four to eight membered heterocyclic ring fused to the aryl group to which it is attached to form a bicyclic ring, wherein said heterocyclic ring contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and at least one carbon atom and said heterocyclic ring is optionally substituted with d-C₅-alkyl or -NZ³Z⁴ wherein Z³ and Z⁴ are independently selected from the group consisting of hydrogen and d- Cs-alkyl;

R represents a substituent selected from the group consisting of: (a) halogen,

(b) d-d-alkyl, optionally substituted by halogen,

(c) C₆-C₁₀-aryl, optionally substituted by halogen,

(d) NO₂,

(e) CN, (f) OR¹,

(g) C(=O)OR^J,

(h) s OfcOR¹,

(i) NR^!R²,

0) C(=O)NR¹R², and (k) S(-O)₂NR¹R² ;

wherein for (f)-(k):

R and R each independently represents a substituent selected from the group consisting of: (1) hydrogen,

(2) d-d-alkyl, optionally substituted by halogen, and

(3) C₃-C₈-cycloalkyl, optionally substituted by halogen; or wherein for (i)-(k): R¹ and R² together with the mtrogen to which they are attached represent a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom;

represents a substituent selected from the group consisting of:

(a) O,

(b) C(=O),

(c) CR³R⁴, (d) N(R⁵),

(e) S(=O)_z , and

(f) C(=NR³)

(1) hydrogen,

(2) d-C₃-alkyl, and

(3) d-C₃-alkoxy;

wherein: when an R³ group is d-C₃-alkyl in L, said R³ group may constitute a spiro or nonspiro ring wherein:

(a) the group R³ is joined by a bond or by a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, to the carbon chain to which said group R³ is attached, and taken together with the carbon chain atom(s) to which said group R³ is attached, constitutes a ring of three to six members, wherein for CR³R⁴, when R³ is Ci -alkyl, the R³ group is joined by a heteratom as defined above;

R⁵ represents a substituent selected from the group consisting of:

(1) hydrogen,

(2) d-C₄-alkyl, optionally substituted by halogen, and (3) C₃-C₈-cycloalkyl, optionally substituted by halogen;

D represents CH₂ ;

R⁷ represents a substituent selected from the group consisting of:

(a) C₂-C₅-alkyl,

(b) C₃-C₈-cycloalkyl,

(c) C₃-C₈-cycloalkyl-d-C₃-alkyl,

(d) C₃-C₅-alkenyl,

(e) C₄-C₈-cycloalkenyl, (f) d-d-alkynyl, where (a)-(f) are optionally substituted by

(1) OR⁸,

(2) NR⁸R⁹, or (3) halogen;

(h) C₆-C₁₀-aryl-C₁-C₃-alkyl, (i) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and

(j) (CH₂)_b-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (g)-(j) are optionally substituted by one to three substituents selected from the group consisting of: (1) NO₂,

(2) CN,

(3) halogen,

(4) S(=O)₂OH,

(5) S(X))_nR¹⁰, (6) S(=O)₂NR⁸R⁹,

(7) NR⁸R⁹,

(8) OR⁸,

(10) C(=O)OR⁸ ; or (11) C(=O)NR⁸R⁹; wherein:

R⁸ and R⁹ are independently hydrogen or R¹⁰;

or optionally

when (g) - (j) are substituted by NR⁸R⁹, S(=O)₂NR⁸R⁹ or C(=O)NR⁸R⁹ _,

R⁸ and R⁹ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom;

- R^{10 '} represents a substituent selected from the group consisting of:

(a) d-d-alkyl,

(b) C₃-C₈-cycloalkyl,

(c) C₃-C₈-cycloalkyl-d-C₃-alkyl;

(d) d-d-alkenyl, (e) C₄-C₈-cycloalkenyl,

(f) C₃-C₅-alkynyl,

(h) C₆-C₁₀-aryl-C₁-C₃-alkyl, (i) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and (j) (CH₂)_b-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (a)-(j) are optionally substituted with halogen;

represents a substituent selected from the group consisting of:

(a) hydrogen,

(b) d-C₆-alkyl, (c) C₃-C₆-cycloalkyl,

(d) C₃-C₆-alkenyl,

(e) d-d-cycloalkenyl, and

(f) C₃-C₆-alkynyl wherein (b)-(f) are optionally substituted by: (1) halogen,

(2) OR¹², or

(3) NR¹²R¹³; wherein

R¹² and R¹³ each independently represents hydrogen or d-d-alkyl; or

R¹² and R¹³ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional " heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom;

In another embodiment, the compounds of the invention are sulfones having the formula

in which D is CH , L is a one-atom linker, and the various other groups and units are more preferably defined as follows:

Q is a substituent selected from the group consisting of:

X

(a) Y^b-C-NH- wherein X represents O or N(CN) ;

Y^b represents -NH₂, -NH-Y or -Y; and Y is selected from the group consisting of: (al) d-d-alkyl, (a2) C₃-C₈-cycloalkyl, (a3) C₃-C₈-cycloalkyl-d-C₃-alkyl,

(a5) Ce-do-aryl-d-d-alkyl, and

(a6) (CH₂)_a-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein:

(al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, d-C₃-alkoxy, d-d- alkylthio, C₆-C₁₀-aryl and -NZ^JZ²; and (a2) - (a6) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, d-d-alkoxy, d-d- alkyl, C C₃-alkylthio, C₆-C₁₀-aryl or -NZ^², wherein

Z¹ and Z² are independently selected from the group consisting of hydrogen and d-d-alkyl, or

Z and Z may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle;

(b) Y^C-NH-(CH₂)_U- wherein

Y^c is a heterocycle selected from:

(bl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (b2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered ^{' •} saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein:

(b2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and

(b2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (b 1 ) - (b2) are optionally substituted by R;

(c) Y°=N- wherein Y^c is as defined in (b) above;

(d) Y^dY^e-N- wherein Y^d and Y^e are independently selected from the group consisting of hydrogen, d-d-alkyl, and d-d-aminoalkyl;

represents a substituent selected from the group consisting of: (a) halogen,

(b) d-C₄-alkyl, optionally substituted by halogen,

(c) C₆-do-aryl, optionally substituted by halogen,

(d) NO₂,

(e) CN, (f) OR¹, and

(g) NR'R²,

wherein for (f)-(g): R¹ and R² each independently represents a substituent selected from the group consisting of:

(1) hydrogen,

(2) d-C₄-alkyl, optionally substituted by halogen, and

(3) C₃-C₈-cycloalkyl, optionally substituted by halogen;

or

wherein for (i): R¹ and R² together with the nitrogen to which they are attached represent a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom;

represents a substituent selected from the group consisting of:

(a) O,

(b) C(=O),

(c) CR³R⁴,

(d) S(=O)_z , and

(e) C(=NR³)

R³ and R⁴ each independently represents a substituent selected from the group consisting of: (1) hydrogen, and

(2) d-C₃-alkoxy;

D represents CH₂ ;

R⁷ represents a substituent selected from the group consisting of:

(a) C₂-C₅-alkyl,

(b) C₃-C₈-cycloalkyl,

(c) C₃-C₈-cycloalkyl-d-C₃-alkyL

(d) C₃-d-alkenyl, (e) C₄-C₈-cycloalkenyl,

(f) d-d-alkynyl, where (a)-(f) are optionally substituted by (1) OR⁸, ^'' (2) NR⁸R⁹, or "

(3) halogen;

(h) C₆-C₁₀-aryl-d-C₃-alkyl, (i) C₆-do-aryl-C₃-C₆-cycloalkyl, and (j) (CH₂)_b-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (g)-(j) are optionally substituted by one to three substituents selected from the group consisting of:

(1) NO₂,

(2) CN,

(3) halogen,

(5) NR⁸R⁹,

(6) OR⁸, or

(7) C(=O)R¹⁰, wherein:

R⁸ and R⁹ are independently hydrogen or R¹⁰;

or optionally

when (g) - (j) are substituted by NR⁸R⁹, ,

R⁸ and R⁹ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom; R¹⁰ represents a substituent selected from the group consisting of:

(a) d-d-alkyl,

(b) C₃-C₈-cycloalkyl, (c) d-C₈-cycloalkyl-d-C₃-alkyl;

(d) d-d-alkenyl,

(e) C₄-C₈-cycloalkenyl,

(f) d-C₅-alkynyl,

(g) C₆-C₁₀-aryl, (h) d-do-aryl-d-d-alkyl,

(i) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and

represents a substituent selected from the group consisting of: (a) hydrogen,

(b) d-C₆-alkyl, and

(c) C₃-C₆-cycloalkyl, wherein (a)-(c) are optionally substituted by:

(1) halogen, (2) OR¹², or

(3) NR¹²R¹³; wherein

R¹² and R¹³ each independently represents hydrogen or d-C₃-alkyl; or R¹² and R¹³ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom;

in which D is CH₂ , L is a two-atom linker, and the various other groups and units are preferably defined as follows: is a substituent selected from the group consisting of:

NH (a) Y-C-NH- wherein

Y is selected from the group consisting of: (al) d-d-alkyl,

(a2) C₃-C₈-cycloalkyl,

(a3) C₃-C₈-cycloalkyl-d-C₃-alkyl,

(a4) C₃-C₅-alkenyl,

(a5) C₄-C₈-cycloalkenyl, (a6) d-d-alkynyl,

(a8) C₆-C₁₀-aryl-d-C₃-alkyl,

(a9) d-do-aryl-d-d-cycloalkyl, and

(alO) (CH₂)_a-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein:

(al) is optionally substituted by halogen up to perhalo, or by one to three substirutents selected from the group consisting of halogen, cyano, d-C₃~alkoxy, d-C₃- alkylthio, C₆-C₁₀-aryl and -NZ^JZ²; and

(a2) - (alO) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, d-C₃-alkoxy, d-d-alkyl, C C₃-alkylthio, C₆-C₁₀-aryl or -NZ^², wherein

Z¹ and Z² are independently selected from the group consisting of hydrogen and d-d-alkyl, or Z and Z may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle;

NH

(b) Y^a-C-NH- wherein Y^a represents -NH₂ or -NH-Y;

X

(c) Y^b-C-NH- wherein X represents O or N(CN) ;

(d)

NH

(e) Y^b-C— wherein for (c) - (e)

Y^b represents -NH₂, -NH-Y or -Y;

(f) Y^C-NH-(CH₂)_U- wherein

Y^c is a heterocycle selected from:

(fl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and

(£2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein:

(£2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and (f2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (fl) - (f2) are optionally substituted by R;

(g) Y^C=N- wherein Y^c is as defined in (f) above;

(h) Y^dY^e-N- wherein Y^d and Y^e are independently selected from the group consisting of hydrogen, d-d-alkyl, and d-C₅-aminoalkyl; and

when w = 0, Q forms a four to eight membered heterocyclic ring fused to the aryl group to which it is attached to form a bicyclic ring, wherein said heterocyclic ring contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and at least one carbon atom and said heterocyclic ring is optionally substituted with d-d-alkyl or -NZ³Z⁴ wherein Z³ and Z⁴ are independently selected from the group consisting of hydrogen and d- d-alkyl;

represents a substituent selected from the group consisting of: (a) halogen,

(b) d-C₄-alkyl, optionally substituted by halogen,

(c) C₆-do-aryl, optionally substituted by halogen,

(d) NO₂,

(e) CN, (f) OR¹,

(g) C(=O)OR¹,

(h) S(=O)₂OR¹,

(i) NR^!R²,

0^') C(=O)NR¹R², and (k) S(=O)₂NR¹R² ;

wherein for (f)-(k):

R¹ and R² each independently represents a substituent selected from the group consisting of: (1) hydrogen,

(2) d-C -alkyl, optionally substituted by halogen, and

(3) C₃-C₈-cycloalkyl, optionally substituted by halogen;

or wherein for (i)-(k):

represents a substituent selected from the group consisting of:

(a) C(=O)N(R⁵),

(c) S(=O)₂N(R⁵)

(d) N(R⁵)S(=O)₂,

(e) CR³R⁴-CR³R⁴

(f⁾ CH₂O,

(g) OCH₂,

(h) CH₂N(R⁵),

(i) N(R⁵)CH₂,

G) CH=CH, and

(k) OC- •

(1) hydrogen, (2) halogen,

(3) d-d-alkyl, and

(4) d-C₃-alkoxy;

wherein: when one or two R³ groups are d-C -alkyl in L, said one or two R³ groups may constitute spiro rings or nonspiro rings wherein:

(a) one group R is joined by a bond or by a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, to the carbon chain to which said group R³ is attached, and taken together with the carbon chain atom(s) to which said group R³ is attached, constitutes a ring of three to six members, wherein for CR³R⁴, when R³ is Ci -alkyl, the R³ group is joined by a heteratom as defined above, or (b) two groups R³ are joined by a bond or by a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur and taken together with the carbon chain atom(s) to which said two groups R³ are attached, constitute a ring of 3-6 members;

R⁵ represents a substituent selected from the group consisting of:

(1) hydrogen,

(2) d-C₄-alkyl, optionally substituted by halogen, and

(3) C₃-C₈-cycloalkyl, optionally substituted by halogen;

D represents CH₂ ;

R⁷ represents a substituent selected from the group consisting of: (a) C₂-d-alkyl, (b) C₃-d-cycloalkyl,

(c) d-d-cycloalkyl-Ci-d-alkyl,

(d) C₃-d-alkenyl,

(e) d-Cg-cycloalkenyl,

(f) d-d-alkynyl, where (a)-(f) are optionally substituted by

(1) OR⁸,

(2) NR⁸R⁹, or

(3) halogen;

(h) C₆-Ci₀-aryl-Ci-C₃-alkyl,

(i) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and

(j) (CH₂)_b-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (g)-(j) are optionally substituted by one to three substituents selected from the group consisting of: (1) NO_2;

(2) CN,

(3) halogen,

(4) S(=O)₂OH,

(5) S(=O)_nR¹⁰,

(6) S(=O)₂NR⁸R⁹,

(7) NR⁸R⁹,

(8) OR⁸,

(9) C(=O)R¹⁰,

(10) C(=O)OR⁸ ; or

(11) C(=O)NR⁸R⁹;

wherein:

R⁸ and R⁹ are independently hydrogen or R¹⁰;

or optionally

when (g) - (j) are substituted by NR 8^βτR> 9^y, c S(/_-O)v₂ -NvrRr> 8⁸τR9^y o „_r

R¹⁰ represents a substituent selected from the group consisting of:

(a) d-d-alkyl,

(b) C -C₈-cycloalkyl,

(c) d-d-cycloalkyl-d-d-alkyl;

(d) C₃-d-alkenyl, (e) C₄-C₈-cycloalkenyl,

(f) d-d-alkynyl,

(h) C₆-Cio-aryl-Ci-C₃-alkyl, ' (i) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and

represents a substituent selected from the group consisting of:

(a) hydrogen, (b) Ci-Ce-alkyl,

(c) C₃-C₆-cycloalkyl,

(d) C₃-C₆-alkenyl,

(e) C₅-C₆-cycloalkenyl, and

(f) d-d-alkynyl wherein (b)-(f) are optionally substituted by:

(1) halogen,

(2) OR¹², or

(3) NR¹²R¹³; wherein R¹² and R¹³ each independently represents hydrogen or d-C₃-alkyl; or R¹² and R¹³ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom;

in which D is CH₂ , L is a two-atom linker, and the various other groups and units are more preferably defined as follows:

Q is a substituent selected from the group consisting of:

X

(a) Y^b-C-NH- wherein X represents O or N(CN) ;

NH π

(b) Y^u-C—

wherein for (a) and (b), Y^b represents -NH₂, -NH-Y or -Y; and

Y is selected from the group consisting of: (al) Ci-d-alkyl, (a2) C₃-C₈-cycloalkyl, (a3) C₃-C₈-cycloalkyl-Ci-C₃-alkyl,

(a5) d-Cio-aryl-d-d-alkyl, (a6) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and (a7) (CH₂)_a-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein: ' (al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, d-C₃-alkoxy, d-C₃- alkylthio, C₆-C₁₀-aryl and -NZ^!Z²; and (a2) - (a7) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, d-C₃-alkoxy, d-d- alkyl, d-d-alkylthio, C₆-C₁₀-aryl or -NZ^², wherein Z¹ and Z² are independently selected from the group consisting of hydrogen and C ι -d-alkyl, or Z¹ and Z² may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle;

(c) Y°-NH-(CH₂)_U- wherein

Y^c is a heterocycle selected from: (cl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and

(c2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein:

(c2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and

(c2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (cl) - (c2) are optionally substituted by R;

(d) Y^C=N- wherein Y^c is as defined in (c) above;

(e) Y^dY^e-N- wherein Y^d and Y^e are independently selected from the group consisting of hydrogen, d-d-alkyl, and d-Cs-aminoalkyl; and

nts a substituent selected from the group consisting of:

(a) halogen,

(b) d-C₄-alkyl, optionally substituted by halogen,

(c) C₆-C₁₀-aryl, optionally substituted by halogen,

(d) NO₂,

(e) CN,

(f) OR¹, and

(g) NR^!R²,

wherein for (f)-(g) :

(1) hydrogen, (2) d-C₄-alkyl, optionally substituted by halogen, and

(3) d-d-cycloalkyl, optionally substituted by halogen;

or

wherein for (g):

L represents a substituent selected from the group consisting of:

(a) CR³R⁴-CR³R⁴, (b) CH₂O,

(c) OCH₂,

(d) CH₂N(R⁵),

(e) N(R⁵)CH₂,

(f) CH=CH, and (g) OO _;

(1) hydrogen, (2) halogen, and

(3) d-C₃-alkoxy;

R⁵ represents a substituent selected from the group consisting of: (1) hydrogen, (2) d-d-alkyl, optionally substituted by halogen, and

(3) C -C₈-cycloalkyl, optionally substituted by halogen;

D represents CH₂ ; R⁷ represents a substituent selected from the group consisting of:

(a) d-d-alkyl,

(b) C₃-C₈-cycloalkyl,

(c) C -Cs-cycloalkyl-d-C -alkyl, ^{" *} (d) C₃-d-alkenyl,

(e) C -C₈-cycloalkenyl,

(f) C₂-C₅-alkynyl, where (a)-(f) are optionally substituted by (1) OR⁸, (2) NR⁸R⁹, or

(3) halogen;

(g) C₆-do-aryl,

(h) C6-Cιo-aιyl-Cι-C₃-al yl, (i) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and (j) (CH₂)_b-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (g)-(j) are optionally substituted by one to three substituents selected from the group consisting of:

(1) NO_2;

(2) CN,

(3) halogen,

(4) S(=O)_nR¹⁰

(5) NR⁸R⁹,

(6) OR⁸, and

(7) C(=O)R¹⁰, wherein:

R⁸ and R⁹ are independently hydrogen or R¹⁰;

or optionally

when (g) - (j) are substituted by NR⁸R⁹, R⁸ and R⁹ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen • and sulfur, wherein said heterocyclic ring contains at least one carbon atom;

R¹⁰ represents a substituent selected from the group consisting of:

(a) d-C₅-alkyl, (b) C₃-C₈-cycloalkyl,

(c) C₃-C₈-cycloalkyl-d-C₃-alkyl;

(d) d-C₅-alkenyl,

(e) C₄-C₈-cyclo alkenyl,

(f) d-d-alkynyl, (g) C₆-Cιo-aryl,

(h) d-do-aryl-d-d-alkyl, (i) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and (j) (CH₂)_b-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (a)-(j) are optionally substituted with halogen;

represents a substituent selected from the group consisting of:

(a) hydrogen,

(b) d-C₆-alkyl, and

(c) C₃-C₆-cycloalkyl, wherein (b)-(c) are optionally substituted by: (1) halogen,

(2) OR¹², or

(3) NR¹²R¹³; wherein

R¹² and R¹³ each independently represents hydrogen or d-C -alkyl; or

R¹² and R¹³ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom;

The compounds of the present invention may contain asymmetric centers, depending upon the nature of the various substituents. Each such asymmetric center will produce two optical isomers. Multiple asymmetric centers in a compound will also produce diastereomers. In certain instances, asymmetry may also be present due to restricted rotation about a central bond joining the two aromatic rings of the specified compounds. It is intended that all isomers, either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the scope of the invention.

In cases in which the compounds have unsaturated carbon-carbon or carbon-nitrogen double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.

In cases where the compounds may exist in tautomeric forms, each tautomeric form is contemplated as being encompassed by the scope of the invention whether existing in equilibrium with its corresponding tautomeric form or forms, or whether set in that form through chemical derivatization. Pharmaceutically acceptable salts of these compounds as well as commonly used prodrugs of these compounds are also within the scope of the invention.

Salts are especially the pharmaceutically acceptable salts of compounds of formulae (I) or (II) such as, for example, organic or inorganic acid addition salts of compounds of formulae (I) or (II). Suitable inorganic acids include but are not limited to halogen acids (such as hydrochloric acid), sulfuric acid, or phosphoric acid. Suitable organic acids include but are not limited to carboxylic, phosphonic, sulfonic, or sulfamic acids, with examples including acetic acid, trifluoroacetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2- or 3-hydroxybutyric acid, γ-aminobutyric acid (GAB A), gluconic acid, glucosemonocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, fiimaric acid, oxalic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids (such as glutamic acid, aspartic acid, N-methylglycine, acetytaminoacetic acid, N-acetylasparagine or N- acetylcysteine), pyruvic acid, acetoacetic acid, phosphoserine, and 2- or 3-glycerophosphoric acid.

In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li⁺ Na⁺ or KX), alkaline earth cations (e.g., Mg⁺², Ca⁺² or Ba⁺²), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, NN-diethylamine, NN- dicyclohexylamine, pyridine, NN-dimethylaminopyridine (DMAP), 1,4- diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBΝ) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU).

Prodrugs are considered to be any covalently bonded carriers which release the active parent compound of formula (I) or (II) in vivo. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability and release time (see "Pharmaceutical Dosage Form and Drug Delivery Systems" (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference).

Commonly used prodrugs of the-disclosed compounds of formulae (I) and (II) are designed to take advantage of the major drug bio transformation reactions and are also to be considered within the scope of the invention. Major drug biotransformation reactions include N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N- oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al., publ. by McGraw-Hill, pages 12-18, (2001), which is hereby incorporated by reference).

Definition of Terms

The term "halogen" or "halo" includes fluorine, chlorine, bromine, and iodine substituents for the purposes of this invention. When halogen is a possible substituent on an alkyl group, the alkyl may be fully substituted, up to perhalo.

When "L" is a two-atom linker, it is to be understood that the left-most moiety of each of the "L" variants is connected to the ring drawn on the left of the group "L" in the general formulae, and that the right-most moiety of the linker is connected to the ring drawn on the right of the group "L" in the general formulae. For example, the use of the linker "-O-CH₂-" is depicted by Figure (1) and of the linker "-CH₂-O-" is depicted by Figure (2) below:

The term "fused bicyclic ring" as it appears in the specification and claims refers to a substituent which is a two ring structure which share two atoms (e.g. two carbons; one nitrogen and one carbon atom; or two nitrogen atoms). The bonding between the fused bicyclic ring and the compound and/or atom to which it is attached can be through either of the two rings.

Description of the Compositions The invention also includes pharmaceutical compositions comprising one or more of the compounds of formulae (I) and (II), purified stereoisomers or stereoisomer mixtures, or their salt or prodrug forms thereof or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient.

The invention also relates to pharmaceutical compositions containing compounds of formulae (I) and (II), purified stereoisomers or stereoisomer mixtures, or their salt or prodrug forms thereof and their use in combination with other drugs or therapies for the treatment of diseases and/or conditions associated with the α_vβ₃ integrin and/or α_vβ₅ integrin.

The pharmaceutical compositions are prepared so that they may be administered orally, dermally, parenterally, nasally, ophthalmically, otically, sublingually, rectally or vaginally. Dermal administration includes topical application or transdermal administration. Parenteral administration includes intravenous, intraarticular, intramuscular, and subcutaneous injections, as well as use of infusion techniques. One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable ingredients and optionally, other active anti-proliferative agents, to form the pharmaceutical composition. These compositions can be prepared by applying known techniques in the art such as those taught in Remington's Pharmaceutical Sciences (Fourteenth Edition), Managing Editor, John E. Hoover, Mack Publishing Co., (1970) or Pharmaceutical Dosage Form and Drug Delivery Systems (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, (1995), each of which is hereby incorporated by reference.

Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include:

acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CC1₂F₂, F₂C1C-

CC1F₂ and CC1F₃) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones and styrene-butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20,

FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerin, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas) plasticizers (examples include but are not limited to diethyl phthalate and glycerin); solvents (examples include but are not limited to alcohol, corn oil, cottonseed oil, glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerin, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate," kaolin, ^% lactose, mannitol, microcrystalline cellulose, powedered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnuba wax and white wax); thickening agents (examples include but are not limited to beewax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, povidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, polyethylene sorbitol monooleate, polyoxyethylene sorbitol monooleate, polyoxyethylene stearate,).

Depending on the route of administration, the compositions can take the form of aerosols, capsules, creams, elixirs, emulsions, foams, gels, granules, inhalants, lotions, magmas, ointments, peroral solids, powders, sprays, syrups, suppositories, suspensions, tablets and tinctures.

Compositions intended for oral use may be prepared according to any suitable method known to the art for ^'the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or π-propyl, ^-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.

Compounds of the invention may also be administered transdermally using methods known to those skilled in the art (see, for example: Chien; "Transdermal Controlled Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al. WO 94/04157 3Mar94). For example, a solution or suspension of a compound of formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of formula I may be formulated into a lotion or salve.

Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures one or more materials selected from lower alcohols, lower ketones , lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.

Suitable penetration enhancing materials for transdermal delivery systems are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C₈-C₁₈ fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C₈-C₁₈ fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tert-butyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing fonnulations may also include mixtures one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C₈- C₁₈ fatty alcohols, saturated or unsaturated C₈-C₁₈ fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.

Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene coploymers, and natural and synthetic rubbers. Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.

Optional anti-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11^th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowldeged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al, publ. by McGraw-Hill, pages 1389-1459, (2001), which is hereby incorporated by reference, such as aminoglutethimide, anastrazole, L- asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, camptothecin, diethylstilbestrol, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, exemestane, 5- fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, formestane, hydroxyprogesterone caproate, gemcitabine, idarubicin, IL-2, α-interferon, letrozole, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, oxaliplatin, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, • temozolomide, trimethylmelamine, uridine, vinorelbine and vorozole.

Other anti-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone.

Optional agents for the treatment of osteoporosis suitable for use with the composition of the invention include but are not limited to those compounds acknowldeged to be used in the treatment of osteoporosis in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), ed. Hardman et al., publ. by McGraw-Hill, pages 1736-1739, (2001), which is hereby incorporated by reference, which includes: (a) calcium-based anti-resorptive agents which include but are not limited to calcium carbonate, calcium citrate, calcium gluconate, calcium lactate, calcium phosphate and hydroxyapatite (Ca₅(OH)(PO )₃);

(b) vitamin D and its analogs which include but are not limited to calcitrio and lα- hydroxycholecalciferol; (c) estrogen-based compounds which include but are not limited to estrogen, conjugated equine estrogens and medroxyprogesterone acetate;

(d) selective estradiol receptor modulators which include but are not limited to raloxifene;

(e) bisphosphonate-based compounds which include but are not limited to alendronate, pamidronate and risendronate; (f) thiazide diuretic compounds which include but are not limited to hydrochlorothiazide; (g) calcitonin; and (h) nandrolone decanoate.

For all regimens of use disclosed herein for compounds of formulae (I) or (II), the daily oral dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of formulae (I) or (II) or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.

Description of Preparative Methods

EXAMPLES

All reactions were performed in dry glassware under a positive pressure of dry argon, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers to a vacuum of 0.4 - 1.0 mmHg.

All temperatures are reported uncorrected in degrees Celsius (°C). Unless otherwise indicated, all parts and percentages are by weight.

Commercial grade reagents and solvents were used without further purification.

Thin-layer chromatography (TLC) was performed using Whatman pre-coated glass-backed silica gel 60A F-254 250 μm plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating.

Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science silica gel.

Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared sprectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me Si (δ 0.00) or residual protonated solvent (CHC1₃ δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. Carbon (¹³C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1₃ δ 77.0; MeOD-d₃; δ 49.0; DMSO-d₆ δ 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (El) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Nacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 °C. Electron impact ionization was performed with electron energy of 70 eN and a trap current of 300 μA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept l-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (lxlO^"4 torr to 2.5xl0^"4 torr). The direct insertion desorption chemical ionization (DCI) probe (Naccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared ( ~l-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu using a variable ion time according to the number of ions in the source. Gas chromatography - ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eN). Elemental analyses are conducted by Robertson Microlit Labs, Madison ΝJ.

All compounds displayed ΝMR spectra, LRMS and either elemental analysis or HRMS consistant with assigned structures.

List of Abbreviations and Acronyms:

AcOH acetic acid anh anhydrous

9-BBΝ 9-borabicyclo[3.3.1 jnonane

BOC tert-butoxycarbonyl cone concentrated dec decomposition

DMF NN-dimethylformamide

DMSO dimethylsulfoxide

EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide

EtOAc ethyl acetate

EtOH ethanol (100%)

Et₂O diethyl ether

Et₃N triethylamine mCPBA metα-chloroperoxybenzoic Acid

MeOH methanol

THF tetrahydrofuran

TFA trifluoroacetic acid

Tf trifluoromethanesulfonyl

A. General Methods for Synthesis of Phenylsulfonyl Precursors

Al. General Method for Synthesis of Methyl 4-[(4-Hydroxyphenyl)sulfonyl]-3- arylbutanoate Analogues via Lactone opening:

Ala Methyl 4-[(4-Bromophenyl)sulfonyl]-3-phenylbutanoate

Ala Step 1

To a mixture of iodobenzene (200 g, 1 mol), (2Z)but-2-ene-l,4-diol (259 g, 3 mol, 3 equiv), Bu₄ΝCl (316 g, 0.98 mol, 1 equiv) and K₂CO₃ (406 g, 3 mol, 3 equiv) in anli. DMF (3 L) was added Pd(OAc)₂ (22 g, 0.1 mol, 0.1 equiv). The reaction mixture was heated at 90 °C overnight and allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (2 L), washed with water (4x500 mL), a saturated NaCl solution (500 mL), ), dried (Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient from 5% to 20% EtOAc/hex) to afford crude 4-phenyloxolan-2-ol (98 g) as an orange oil: TLC (25% EtOAc/hex) R 0.36; LCMS ES-MS m/z 165 (MH⁺). This product was taken to the next step without further purification.

Ala Step 2

To a 0 °C solution of crude 4-phenyloxolan-2-ol (5, 598 g) in CH₂C1₂ (500 mL) was added Florisil^®, followed by PCC (190 g, 0.9 mol). The reaction mixture was stirred for 10 min, then was allowed to warm to room temperature. The resulting mixture was concentrated under reduced pressure and filtered through a pad of Celite^® with the aid of EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (gradient from hex to 15% EtOAc/hex). The resulting oil was mixed with hexane and concentrated under reduced pressure to give 3-phenyl-butyrolactone (75 g, 46% for 2 steps) as a yellow solid: TLC (20% EtOAc/hex) R_f 0.46; 1H NMR (CDC1₃) δ 2.68 (dd, J=9.1, 17.3 Hz, IH), 2.94 (dd, J=8.6, 17.4 Hz, IH), 3.74-3.85 (m„ IH), 4.28 (app t, J=8.5 Hz, IH), 4.68 (app t, J=8.3H, IH), 7.22-7.40 (m, 5H).

Ala

To a mixture of NaH (1.3 g, 54 mmol, 1.1 equiv) in DMF (100 mL) was added dropwise a solution of 4-bromothiophenol (9.26 g, 49 mmol, 1.0 equiv) in DMF (20 mL) and the resulting mixture was stirred for. 10 min. 3-Phenyl-butyrolactone (8.0 g, 50 mmol) was then added and the reaction mixture was heated at 70 °C overnight, cooled to room temperature and treated with a IN HCl solution (100 mL). The resulting mixture was extracted with EtOAc, washed with water, dried (MgSO₄) and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient from hexane to 50% EtOAc/hex to EtOAc) to give 4-(4-bromophenylthio)-3-phenylbutanoic acid (12 g) as a slightly impure light yellow oil: 1H NMR (CDC1₃) δ 2.70 (dd, J=8.3, 16.2 Hz, IH), 2.99 (dd, J=6.1, 16.2 Hz, IH), 3.17 (d, J=7.5 Hz, 2H), 3.28-3.38 (m, IH), 7.15-7.46 (m, 9H), 10.13 (br

— >

5 s, IH).

Ala Step 4

To a solution of 4-(4-bromophenylthio)-3-phenylbutanoic acid (12 g, 34 mmol) in MeOH

10 (175 mL) was added cone H₂SO (0.2 mL). The reaction mixture was heated at 75 °C overnight and at 80 °C for 5 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with a saturated NaHCO₃ solution and water, dried (MgSO₄) and concentrated under reduced pressure to give 10.6 g of a yellow oil. The crude oil was dissolved in CH₂C1₂ (150 mL) and

15 treated with a solution of mCPBA (17.8 g, 103 mmol, 3.0 equiv) in CH₂C1₂ (100 mL). The reaction mixture was stirred at room temperature overnight and washed with a IN NaOH solution. The organic layer was dried (MgSO₄) and concentrated under reduced pressure to yield methyl 4-[(4-bromophenyl)sulfonyl]-3-phenylbutanoate (5.3 g, 27% for 3 steps) as a yellow solid: 1H NMR (CDC1₃) δ 2.72 (dd, J=8.0, 16.1 Hz, IH), 2.96 (dd, J=6.0, 16.1 Hz,

20 IH), 3.47 (dd, J=6.9, 14.2 Hz, IH), 3.57-3.82 (m, 6H), 7.04-7.07 (m, 2H), 7.19-7.21 (m, 3H),

7.58 (s, 5H); HPLC ES-MS m/z 398 ((M+l)⁺).

Alb: Methyl 4-[(4-Hydroxyphenyl)sulfonyl]-3-phenylbutanoate

25 Alb Step 1

To a 0 °C solution of 4-hydroxythiophenol (17.1 g, 136 mmol, 1.1 equiv.) in anh. DMF (200 mL) was added NaH (3.6 g, 148 mmol, 1.2 equiv.) in small portions. The resulting mixture was stirred for 40 min. at room temperature, treated with 2-phenylbutyrolactone (20.0 g, 123 mmol) and heated to 80 °C for 2 days. The mixture was then concentrated under reduced pressure. The residue was taken up in EtOAc (200 mL) and was extracted with a 1 N NaOH solution (2x100 mL). The organic layers were combined, washed with a saturated NaCl solution (100 mL), dried (Na SO ) and concentrated under reduced pressure. The crude product was purified by flash chromatography (11 cm x 10 cm SiO₂, gradient from 30% EtOAc/hexanes to 0.5% AcOH/EtOAc) to afford 4-(4-hydroxyphenylthio)-3-phenylbutanoic acid (32.9 g, 92%) as a yellow oil: 1H NMR (CDC1₃) δ 2.67 (dd, J = 8.5 Hz, J₂ = 15.8 Hz, IH), 3.00-3.29 (m, 4H), 6.75 (d, J= 6.6 Hz, 2H), 7.15-7.33 (m, 7H), 7.50-9.55 (br s, 2H).

Alb Step 2

A solution of 4-(4-hydroxyphenylthio)-3-phenylbutanoic acid (32.9 g, 114 mmol) in a mixture of MeOH (500 mL) and cone. H₂SO₄ (3 mL) was heated at the reflux temperature for 20 h. The mixture was concentrated under reduced pressure. The residue was taken up in EtOAc (500 mL) and washed with a saturated aqueous NaHCO₃ solution. The organic layer was concentrated under reduced pressure, treated with CH₂C1₂ and concentrated under reduced pressure again. The crude product was filtered through a plug of silica gel to afford methyl 4-(4-hydroxyphenylthio)-3-ρhenylbutanoate (27.3 g, 79%) as a yellow oil: TLC (20% EtOAc/hexanes) R 0.28; 1H NMR (CDC1₃) δ 2.68 (dd, J_} = 8.8 Hz, J₂ = 15.4 Hz, IH), 3.02- 3.17 (m, 3H), 3.27-3.35 (m, IH), 3.60 (s, 3H), 5.95 (s, IH), 6.77 (d, J= 7.0 Hz, 2H), 7.16- 7.33 (m, 7H); ES-LCMS m/z (rel abundance) 303 (MH⁺, 75%).

Alb Step 3

A solution of methyl 4-(4-hydroxyphenylthio)-3-phenylbutanoate (27.2 g, 90 mmol) in acetone (500 mL) was placed in water bath and treated with a slurry of Oxone^® (136 g, 221 mmol, 2.5 equiv.) in water (250 mL). The resulting mixture was stirred for 2 h. The mixture was concentrated nearly to dryness under reduced pressure and the residue was taken up into EtOAc (500 mL). The organic layer was washed with a saturated NaCl solution (200 mL), dried (Na₂SO ), concentrated under reduced pressure, treated with CH₂Cl₂/hexanes (1:1) and concentrated under reduced pressure again to afford methyl 4-[(4-hydroxyphenyl)sulfonyl]-3- phenylbutanoate (28.2 g, 94%) as a white solid: TLC (30% EtOAc/hexanes) R 0.17; 1H NMR (CDC1₃) δ 2.75 (dd, J - 8.8 Hz, J₂ = 15.8 Hz, IH), 3.05 (dd, J, = 5.5 Hz, J₂ = 15.8 Hz, IH), 3.40-3.73 (m, 6H), 6.85 (d, J= 7.3 Hz, 2H), 7.07 (d, J= 7.3 Hz, 2H), 7.15-7.28 (m, 4H), 7.63 (d, J= 8.8 Hz, 2H); HPLC ES-MS m/z (rel abundance) 335 ((M+l)⁺, 100%).

Ale: Methyl 4-[(4-hydroxyphenyl)sulfonyl]-3-phenylbutanoate

Ale Step 1

To a mixture of NaH (178 mg, 7.4 mmol, 1.2 equiv) in anh. DMF (20 mL) was added 4- hydroxythiophenol (0.78 g, 6.2 mmol), followed by 3-phenyl-butyrolactone (1.0 g, 6.2 mmol, 1 equiv). The reaction mixture was stirred at room temperature overnight and heated at 80 °C for 26 h. The resulting mixture was diluted with EtOAc (100 mL) and extracted with a IN NaOH solution (100 mL). The aqueous layer was adjusted to pH 1 using a cone. HCl solution and extracted with EtOAc (2x200 mL). The combined organic layers were washed with a saturated NaCl solution (50 mL), dried (Na SO₄) and concentrated under reduced pressure to give 4-(4-hydroxyphenylthio)-3-phenylbutanoic acid (1.84 g) as a yellow oil. TLC (30% EtOAc/hex) R/0.16. The crude product was used without further purification. Ale Step 2

To a solution of crude 4-(4-hydroxyphenylthio)-3-phenylbutanoic acid (38 g) in EtOH (100 mL) was added cone. H₂SO (5 mL). The reaction mixture was heated at the reflux temperature for 2 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL), washed with a saturated NaHCO₃ solution (2x500 mL) and a saturated NaCl solution (300 mL), dried (Na₂SO ) and concentrated under reduced pressure to give methyl 4-(4-hydroxyphenylthio)-3-phenylbutanoate (23.4 g) as an orange oil. The crude product was used without further purification.

Ale Step 3

To a 0 °C solution of ethyl 4-(4-hydroxyphenylthio)-3-phenylbutanoate (23.3 g) in acetone (500 mL) was added a slurry of Oxone^® (142 g, 231 mmol) in water (250 mL). The reaction mixture was stirred at room temperature for 3 d. The resulting mixture was filtered, the filtrate was concentrated to about 300 mL and extracted with EtOAc (500 mL). The organic layer was washed with a saturated NaCl solution (200 mL) and filtered through a pad of silica gel with the aid of EtOAc. The filtate was concentrated and the residue was purified by flash chromatography (10% EtOAc/hex) to give Methyl 4-[(4-hydroxyphenyl)sulfonyl]-3- phenylbutanoate (16.7 g, 37% for 3 steps) as a white solid: 1H NMR (CDC1₃) δ 2.74 (dd, J=8.7, 15.9 Hz, IH), 3.03 (dd, J=5.5, 16.1 Hz, IH), 3.42 (dd, J=6.0, 14.2 Hz, IH), 3.49-3.59 (m, 4H), 3.64-3.74 (m, IH), 6.80-6.85 (m, 2H), 7.03-7.07 (m, 2H), 7.13-7.28 (m, 3H), 7.34 (s, IH), 7.58-7.65 (m, 2H). Aid: Methyl 4-[(4-Fluorophenyl)sulfonyl]-3-phenylbutanoate

Aid Step 1

A 0 °C solution of 4-fluorobenzenethiol (11.8 g, 92.5 mmol, 1.5 equiv) in. DMF (100 mL) was treated with NaH (3.0 g, 123.3 mmol, 2.0 equiv), stirred for 30 min, then treated with 2- phenylbutyrolactone (10.0 g, 61.7 mmol). The reaction mixture was heated to 100 °C for 17 h, then let it cool to room temperature. The solvent was evaporated under reduced pressure. The residue was taken up into EtOAc (200 mL), and washed with IN aqueous HCl solution (200 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The cude mixture was purified by flash chromatography (11 cm x 13 cm SiO₂, gradient from 20% EtOAc/hexanes to 1% AcOH/EtOAc) to afford 4-[(4-fluorophenyl)thio]-3- phenylbutanoic acid (15.4 g, 86%) as a brown oil; 1H NMR (CDC1₃) δ 2.70 (dd, Jj = 7.7 Hz, J₂ = 15.8 Hz, IH), 3.01-3.34 (m, 4H), 6.97-7.03 (m, 2H), 7.17-7.40 (m, 7H), 11.0-11.7 (br s, IH); GC-MS m/z (rel abundance) 290 (M⁺, 61%).

Aid Step 2

A solution of 4-[(4-fluorophenyl)thio]-3-phenylbutanoic acid (15.4 g, 53 mmol) in MeOH (100 mL) was treated with 1 mL cone H₂SO₄ and was heated at the reflux temperature for 22 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up into EtOAc (200 mL) and was washed with saturated aqueous sodium bicarbonate solution (2x200 mL) and saturated sodium chloride solution (100 mL). The organic layer was dried (Na₂SO ) and concentrated under reduced pressure. The crude product was purified by flash chromatography (11 cm x 11 cm SiO₂, 5% EtOAc/hexanes) to afford methyl 4-[(4- fluorophenyl)thio]-3-phenylbutanoate (10.4 g, 63%) as a yellow oil; TLC (10% EtOAc/hexanes) R 0.49; 1H NMR (CDC1₃) δ 2.68 (dd, Jj = 8.5 Hz, J₂ = 15.8 Hz, IH), 2.97 (dd, J, = 6.6 Hz, J₂ = 15.8 Hz, IH), 3.17 (d, J= 7.9 Hz, 2H), 3.30-3.40 (m, IH), 3.59 (s, 3H), 6.97-7.03 (m, 2H), 7.17-7.36 (m, 7H).

Aid Step 3

To a 0 °C solution of methyl 4-[(4-fluorophenyl)thio]-3-phenylbutanoate (5.2 g, 17.1 mmol) in CHC1₃ (100 mL) was added mCPBA (14.7 g, 77%, 65.6 mmol, 3.8 equiv). The resulting white slurry was allowed to warm to room temperature and was stirred for 17 h followed by the addition of Na₂SO₃ (14.0 g, 111 mmol, 6.5 equiv) to quench the excess mCPBA. The reaction was stirred for 20 min, then washed with saturated aqueous sodium bicarbonate solution (100 mL). The layers were separated, the organic layer was dried (Na₂SO ) and concentrated under reduced pressure. The crude product was purified by flash chromatography (100 g SiO₂, gradient from 5% EtOAc/hexanes to 20% EtOAc/20%

CH₂Cl₂/hexanes) to afford methyl 4-[(4-fluorophenyl)sulfonyl]-3-phenylbutanoate (5.2 g,

91%) as a white solid; TLC (20% EtOAc/hexanes) R 0.22; 1H NMR (CDC1₃) δ 2.73 (dd, Jj

= 8.1 Hz, J₂ = 15.8 Hz, IH), 2.97 (dd, Jj = 5.5 Hz, J₂ = 15.8 Hz, IH), 3.44-3.76 (m, 6H), 7.05-7.27 (m, 7H), 7.74-7.78 (m, 2H); GCMS m/z (rel abundance) 337 (MH⁺, 3%).

A2. Synthesis of Methyl 4-[(4-Hydroxyphenyl)sulfonyl]-3-arylbutanoate Analogues via Michael Addition to Vinylidene Malonate: Diethyl 2-{l-(3,5-Dichlorophenyl)-2-[(4- hydroxyphenyl)sulfonyl]ethyl}malonate

A2 Step 1

To a solution of 4-methylsulphonylphenol (3.3 g, 19 mmol) in anh. THF (120 mL) was added «-BuLi (19 mL, 2.0 M in pentane) dropwise at -78 °C. After stirring for 2 h, the yellow slurry was transferred via syringe to a solution of diethyl (3,5- dichlorobenzylidene)malonate (5.9 g, 18.6 mmol) in THF (20 mL) at -78 °C. The resulting clear solution was stirred for 2 hrs, then partitioned between EtOAc (300 mL) and a 1 M HCl solution (130 mL). The organic phase was washed with a saturated NaHCO₃ solution, dried (MgSO ) and concentrated under reduced pressure to afford diethyl 2-{l-(3,5- dichlorophenyl)-2-[(4-hydroxyphenyl)sulfonyl]ethyl}malonate as a white solid (5.8 g, 64% yield): R/ (EtO Ac-hexane, 4:6) 0.36; 1H NMR (DMSO-d₆): 0.85 (t, 3H), 1.15 (t, 3H), 3.35 (s, IH), 3.48 (dd, IH), 3.6(t, IH), 3.85 (q, 2H), 3.92 (d, IH), 4.00 (d, IH), 4.15 (q, 2H), 6.78 (d, 2H), 7.20 (s, 2H), 7.35 (s, IH), 7.40 (d, 2H).

A solution of diethyl 2-{l-(3,5-dichlorophenyl)-2-[(4-hydroxyphenyl)-sulfonyl]- ethyl}malonate (0.5 g,1.0 mmol) and 0.25 g of KOH (4.0 mmol) in a mixture of 50 mL of MeOH and 1.5 mL of water was stirred at room temperature for 2 hrs. The solution was acidified with a 1.0 M HCl solution, then extracted with EtOAc. The organic phase was dried (MgSO ) and concentrated under reduced pressure. The residue was dissolved in CH₃CN (20 mL), treated with Cu₂O (0.030 g, 0.08 mmol) and heated at the reflux temperature for 2.5 hrs. The mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (SiO₂; gradient from 30% EtOAc/hexane to 50% EtOAc/hexane, then with 100% EtOAc, and then to 10% MeOH/CH₂Cl₂) to give 3- (3,5-dichlorophenyl)-4-[(4-hydroxypbenyl)sulfonyl]butanoic acid (0.14 g, 24%): R (10% MeOH/CH₂Cl₂) 0.36.

A2 Step 3

A solution of 0.14 g of 3-(3,5-dichlorophenyl)-4-[(4-hydroxyphenyl)sulfonyl]butanoic acid (0.14 g, 0.36 mmol) in MeOH that had been treated with 3 drops of H₂SO₄ was heated at the reflux temperature for 4 h. The mixture was then concentrated, and the residue was dissolved in EtOAc. The organic solution was washed with water twice, dried (MgSO₄) and concentrated under reduced pressure to afford methyl 3-(3,5-dichlorophenyl)-4-[(4- hydroxyphenyl)sulfonyl]butanoate as an oil (0.137 g, 94%): R (50% EtOAc/hexane) 0.58.

A3. Synthesis of Methyl 4-[(4-Hydroxyphenyl)sulfonyl]-3-arylbutanoate Analogues via Addition to Vinylsulfone

A3a: 4-[(4-Fluorophenyl)sulfonyl]-3-phenylbutanoic Acid

A3a Step 1

A solution of 4-fluorophenylsulfonyl chloride (609 g, 3.13 moles), styrene (486 g, 4.67 moles) and copper(II) chloride (20.95 g, 156 mmol) in CH₃CN (4 L) was heated under a gentle reflux under argon. An exotherm occurred upon reaching the reflux temperature, which initially caused a temporary increase of 5 °C. After heating for 18 hr, the solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (6 L). The organic mixture was washed with a saturated NaCl solution (4 x 2 L), cooled in a MeOH/ice bath (~5 °C) and treated with Et₃N (580 mL, 4.16 mol). After 20 min, the resulting white solid was removed by Alteration and washed with EtOAc (1.5 L). The combined EtOAc mixtures were concentrated under reduced pressure until a solid began to precipitate, then the mixture was treated with hexane (4 L). The resultant solid was removed by filtration and air- dried to provide l-fluoro-4-{[(E)-2-phenylethenyl]sulfonyl}benzene as a white crystalline compound (769 g, 94%): 1H-NMR (CDC1₃): δ 6.85 (d, J = 15.1 Hz, IH); 7.22 (dd, J = 8.7, 8.7 Hz, 2H); 7.44 (m, 5H); 7.69 (d, J = 15.1 Hz, IH); 7.97 (dd, J = 5.1, 8.7 Hz, 2H); GC-MS (negative ionizaton) m/z 262 (M^~). Anal. Calcd for C₁₄H_uFO₂S: C, 64.11; H, 4.23; F, 7.24; S, 12.22. Found: C, 63.99; H, 4.24; F, 7.43; S, 12.16.

A3 a Step 2

A suspension of potassium tert-butoxide (420 g, 3.75 mol) in dry dimethylformamide (4300 mL) was treated with dimethyl malonate (445 mL, 3.89 mol) in one portion. An exotherm occurred which raised the internal temperature to 45 °C. The clear yellow solution was stirred at room temperature under argon for 60 minutes, then l-fluoro-4-{[(E)-2- phenylethenyl]sulfonyl}benzene (892 g, 3.40 mol) was added in one portion. An endotherm occurred which cooled the solution to ~20 °C. The clear yellow solution was stirred at room temperature under argon for 18 hours, at which time TLC analysis (silica gel 60, 25% EtOAc/hexane, UN detection) indicated complete reaction. The contents were poured into a bilayer containing 2 Ν aqueous HCl (2 L) in a saturated ΝaCl solution (6 L) and EtOAc (8 L). The organic layer was washed with a saturated ΝaCl solution (4 x 8 L) and concentrated under reduced pressure to near dryness. The residue crystallized on standing, and was then triturated with hexane (4 mL) and air-dried to afford dimethyl 2-{2-[(4- fluorophenyl)sulfonyl]-l-phenylethyl}malonate (1.31 Kg, 98%) as white crystals: 1H-ΝMR (DMSO-d₆): δ 3.29 (s, 3H); 3.63 (m, 5H); 3.90 (d, J = 9.7 Hz, IH); 4.09 (m, IH); 7.09 (m, 5H); 7.25 (m, 2H); 7.60 (m, 2H). HPLC MS (negative ionization): m/z 393 ((M - 1)^"). Anal. Calcd for C₁₉H₁₉FO₆S: C, 57.86; H, 4.86; S, 8.13. Found: C, 57.64; H, 4.88; S, 8.11.

A3a

A suspension of dimethyl 2-{2-[(4-fluorophenyl)sulfonyl]-l-phenylethyl}malonate (660.0 g,

1.67 moles) in an aqueous 6 N HCl solution (5 L) was heated at the reflux temperature with vigorous stirring for 17 h. The suspension was then slowly cooled to 35 °C with vigorous stirring. The resulting precipitate was removed by filtration, washed with water (4 x 2 L) and dried under reduced pressure (-0.2 torr) at 40 °C to provide 4-[(4-fluorophenyl)sulfonyl]-3- phenylbutanoic acid as a white solid (533 g, 99%): 1H-NMR (DMSO-d₆): δ 2.52 (dd, J = 9.2, 16.2 Hz, IH); 2.82 (dd, J = 5.6, 16.2 Hz, IH); 3.43 (m, IH); 3.74 (dd, J = 5.7, 14.7 Hz, IH); 3.82 (dd, J = 8.5, 14.7 Hz, IH); 7.11 (m, 5H); 7.31 (dd, J = 9.1, 9.1 Hz, 2H); 7.72 (dd, J = 5.4, 9.1 Hz, 2H); 12.14 (br s, IH). HPLC-MS (negative ionization): m/z 321 ((M - 1)^"). Anal. Calcd for C₁₆H₁₅FO₄S: C, 59.62; H, 4.69; F, 5.89; S, 9.95. Found: C, 59.51; H, 4.68; F, 6.02; S, 10.14.

A3b: (3R)-4-[(4-Fluorophenyl)sulfonyl]-3-phenylbutanoic acid via chiral resolution

A3b Step 1

To a solution of 4-[(4-fluorophenyl)sulfonyl]-3-phenylbutanoic acid (145 g, 0.45 mol) in acetonitrile (1.45 L) at room temperature was added (-)-ephedrine (75.0 g, 0.45 mol, 1.0 equiv) in one portion. The solution was then stirred vigorously for 4 h. The resulting thick suspension was filtered, the solids were washed with acetonitrile (2x150 mL) and dried under reduced pressure for 18 hours to give (3R)-4-[(4-fluorophenyl)sulfonyl]-3- phenylbutanoic acid ephedrine salt (114 g, 52%, 60% e.e. by chiral HPLC). The ephedrine salt was recrystallized using acetonitrile (1250 mL) to give (3R)-4-[(4- fluorophenyl)sulfonyl] -3 -phenylbutanoic acid ephedrine salt (84.6 g, 93.4% e.e.).

To a vigorously stirred suspension of the ephedrine salt in CH₂C1 (1100 mL) was added a IN HCl solution (1 L). The resulting mixture was stirred for 15 min and the aqueous layer was extracted with CH₂C1₂ (500 mL). The combined organic layers were washed with water (2x600 mL) and a saturated NaCl solution (600 mL), dried (Na₂SO₄) and concentrated to a thick slurry (about 150 mL). The white slurry was cooled in a freezer (-14 °C) for 1 h. The solids were collected by filtration, washed with a small amount of cold CH₂C1₂ and dried under reduced pressure to give (3R)-4-[(4-fluorophenyl)sulfonyl]-3-phenylbutanoic acid as a white solid (50.6 g, 99.5% e.e., 34.8% overall yield).

A3b Step 2

A solution of (3R)-4-[(4-fluorophenyl)sulfonyl]-3-phenylbutanoic acid (48.1 g, 149 mmol) in a IN NaOH solution (1 L) was heated at the reflux temperature for 22 h, cooled to 0 °C and acidified to pH 1-2 using cone. HCl. The precipitate was filtered and washed with water. The solid was dissolved in EtOAc (1 L) and the layers were separated. The organic layer was washed with a saturated NaCl solution (300 mL). The combined aqueous layers were back-extracted with EtOAc (500 mL). The combined organic layers were dried (Na₂SO ) and concentrated under reduced pressure to give (3R)-4-[(4-hydroxyphenyl)sulfonyl]-3- phenylbutanoic acid (43.9 g) as a white solid. The acidic filtrate was extracted with EtOAc (1 L) to give additional product (3.3 g, total 47.2 g, 99%): TLC (0.5% AcOH/2% MeOH/CH₂Cl₂) R 0.14; 1H NMR (DMSO-d₆) δ 2.52 (dd, J=6.3, 16.1 Hz, IH), 2.81 (dd, J=5.0, 16.0 Hz, IH), 3.34-3.68 (m, 3H), 6.80-6.85 (m, 2H), 7.08-7.20 (m 5H), 7.50-7.54 (m, 2H), 10.52 (s, IH), 12.1 (br s, IH).

A3b Step 3

To a 0 °C solution of (3R)-4-[(4-hydroxyphenyl)sulfonyl] -3 -phenylbutanoic acid (47.2 g, 147 mmol) in MeOH (1 L) was added chlorotrimethylsilane (41 mL, 324 mmol, 2.2 mol). The reaction mixture was allowed to warm to room temperature, stirred for 3 days and concentrated under reduced pressure. The residue was dissolved in CH₂C1 , diluted with hexanes and concentrated under reduced pressure to give methyl (3R)-4-[(4- hydroxyphenyl)sulfonyl]-3-phenylbutanoate (48.8 g, 99%) as an off-white solid: TLC (0.5% AcOH/2% MeOH/CH₂Cl₂) R/ 0.51; 1H NMR (DMSO-d₆) δ 2.61 (dd, J=9.3, 16.0 Hz, IH), 2.92 (dd, J=5.0, 16.0 Hz, IH), 3.35-3.71 (m, 6H), 6.81 (d, J=8.7 Hz, 2H), 7.09-7.20 (m, 5H), 7.53 (d, J=8.7 Hz, 2H), 10.53 (s, IH).

A4. Synthesis of 3-Arylsulfonylamido-3-arylpropionate Analogues Reaction of 3- Aminopropionate esters:

A4a:

A4a Step 1

To a solution of benzyl 3-amino-3-phenylpropionate (3.00 g) in dry CH₂C1₂ (35 mL) at room temperature was added 3-bromobenzenesulfonyl chloride (3.30 g) followed by the dropwise addition of Et₃N (1.80 mL). The homogenous mixture was stirred at room temperature for 72 h, then was concentrated under reduced pressure. The oily residue was dissolved in EtOAc (75 ml) and stirred 20 h at room temperature. The white solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residual material was purified by silica gel chromatography (EtOAc/hexane) to give the desired sulfonamide as an oil, which was crystallized to give a white solid (4.60 g, 83%): mp 79 °C; TLC (20% EtOAc/hexane) R = 0.28. A4a Step 2

To a solution of 2-methylthio-2-imidazoline hydroiodide (80.8 g) and NaHCO₃ (91.8 g) in H₂O (700 mL) at 0 °C was added benzylchloroformate (62.14 g) dropwise over lh. The resulting mixture was warmed to room temperature and stirred 20 h, then cooled to 10 °C and filtered. The resulting white solid was washed thoroughly with H₂0 at 5 °C (4x500 mL) then dried in vacuo under P₂O₅ to a constant weight. The white solid was dissolved in minimal EtOAc at 65 °C (150 mL) and recrystallized at -20 °C to yield 2- thiomethylimidazole as white crystals (45.0 g, 54%): mp 61 °C TLC (50% EtOAc/hexane) R_f 0.20; HPLC ES-MS m/z 251 ((M+l)⁺).

A4a Step 3

A mixture of 3-aminophenylacetylene (94 mg) and the 2-thiomethylimidazole (200 mg) was stirred to homogeneity then heated to a melt under argon at 120 °C for 1 h. TLC indicated the presence of starting materials. More of the 2-thiomethylimidazole (800 mg) was added and the reaction was heated at 120 °C for 16 h. The neat reaction mixture was purified by silica gel chromatography (hexane/EtOAc) to give the desired phenylacetylene as a white solid (134 mg, 52%): TLC (33% EtOAc/hexane) R 0.45; HPLC ES-MS m/z ((M+l)⁺).

A4a Step 4

To a solution of the sulfonamide (466 mg) and the phenylacetylene (285 mg) in a mixture of anh DMF (6 mL) and anh Et₃N (6 mL) was added Cul (43 mg), trørø-(Ph₃P)₂PdCl₂ (157 mg), and Ph₃P (59 mg). The reaction was stirred under argon heating to 80 °C over 0.5 h, then was held at 80 °C for lh. The reaction was treated with H₂O (200 mL) and extracted with Et₂O (3x300 mL). The ether extracts were washed with a saturated NaCl solution, dried (MgSO₄), and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (hexane/EtOAc) to afford the desired diphenylacetylene (350 mg, 55%): TLC (50% EtOAc/hexane) R/0.60; HPLC ES-MS: 713 ((M+l)⁺).

A5. Synthesis of 3-Arylsulfanylamido-3-arylbutanoate Analogues. A5a. Methyl 3-Phenyl-4-phenylthiobutanoate

To a -70 °C solution of benzenethiol (6.37 mL, 62.1 mmol) dissolved in Et₂O (40 mL) and THF (20 mL) was added nBuLi (2.5M in hexanes, 23.64 mL, 59.1 mmol) over 15 min. The reaction was allowed to warm to room temperature and stirred for lh. The reaction solution was concentrated and DMF (100 mL) was added followed by the addition of 4- phenyldihydro-2(3H)-furanone. The reaction was heated to 60 °C for 12 h and was cooled to room temperature followed by quenching with 0.1 N HCl. The solution was washed with H₂O (100 mL) and the aqueous phase was back-extracted with EtOAc (100 mL). The combined organic phases were dried (Na₂SO ), filtered and concentrated in vacuo and placed on high vacuum to remove traces of DMF. The crude acid was dissolved in MeOH (100 mL) and cone. HCl (2 mL) was added and the reaction was refluxed for 20 h, cooled then concentrated. The crude organic residue was purified by flash silica chromatography (15% EtOAc/hexane) to afford methyl 3-phenyl-4-phenylthiobutanoate as a white powder (11.07 g, 62% over 2 steps): 1H NMR (CDC1₃) δ 7.34-7.17 (m, 10 H), 3.57 (s, 3 H), 3.38-3.35 (m, 1 H), 3.22-3.18 (m, 2 H), 2.98 (dd, J= 16.07, 6.66 Hz, 1 H), 2.68 (dd, J = 15.77, 8.76 Hz, 1 H); TLC (EtOAc/Hex, 3/17) R/0.60.

B. General Methods for Synthesis of Phenylamines

Bl. General Method for Coupling of Hydroxyphenylsulfones with Fluoronitrobenzene: Methyl 4-{[4-(4-Nitrophenoxy)phenyl]sulfonyl}-3- phenylbutanoate

Bl Step 1

4-Nitrofluorobenzene (4.0 g, 28.2 mmol) and K₂CO₃ (3.90 g, 28.2 mmol) were added to the methyl 4-[(4-hydroxyphenyl)sulfonyl]-3-phenylbutanoate (3.15 g, 9.4 mmol) in DMF (40 mL). The solution was heated to 80 °C for 18 h then cooled to room temperature. The solution was then diluted with H₂O and extracted with EtOAc. The combined organic layers were washed with a saturated NaCl solution then dried over Na₂SO₄. The solution was filtered and concentrated in vacuo to give 2.82 g of a yellow oil. The oil was purified by flash chromatography (gradient from 25% EtOAc/75% hexanes to 40% EtOAc/60% hexanes) to give 3.75 g (88%) of the diphenyl ether as a white powder.

B2. General Method for Coupling of an Aminobenzenethiol with a Fluorophenylsulfone

B2a: Methyl 4-({4-[(4-Aminophenyl)thio]phenyl}sulfonyl)-3-phenylbutanoate

B2a Step 1

A solution of 4-aminobenzenethiol (0.37 g, 3.0 mmol, 1 equiv) in. DMF (20 mL) was treated with NaH (78 mg, 3.3 mmol, 1.1 equiv), stirred for 40 min, then treated with methyl 4-[(4- fluorophenyl)sulfonyl]-3-phenylbutanoate (1.0 g, 3.0 mmol). The reaction mixture was stirred for 21 h, quenched with H₂O (100 mL) and extracted with EtOAc. The organic layer was washed with a 0.2 N aqueous HCl solution (2 x 100 mL), dried (Na₂SO ) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (100 g SiO₂, gradient from 5% EtOAc/CH₂Cl₂ to 10% EtOAc/CH₂Cl₂) to afford methyl 4-({4-[(4-aminophenyl)thio]phenyl}sulfonyl)-3-phenylbutanoate (1.10 g, 84%) as a white solid: TLC (30% EtOAc/hex) R 0.14; ^JNMR (CDC1₃) δ 2.72 (dd, J₇ = 8.4 Hz, J₂ = 16.2 Hz, IH), 3.01 (dd, J_} = 5.5 Hz, J₂ = 16.2 Hz, IH), 3.39 (dd, J; = 6.3 Hz, J₂ = 14.3 Hz, IH), 3.51-3.57 (m, 4H), 3.67-3.74 (m, IH), 3.97 (s, 2H), 6.74 (dd, J; = 6.6 Hz, J₂ = 1.5Hz, 2H), 7.05 (dd, J, = 7.0 Hz, J₂ = 8.4 Hz, 4H), 7.20-7.24 (m, 3H), 7.32 (dd, J, = 6.6 Hz, J₂ = 1.5 Hz, 2H), 7.54 (dd, J₇ = 7.0 Hz, J₂ = 1.5 Hz, 2H) ES-LCMS m/z (rel abundance) 442 ((M+l)⁺).

B2b: Ethyl 4-{[4-(4-aminophenylthio)phenyl]sulfonyl}-3-phenylbutanoate

B2b

To a 0 °C solution of ethyl 4-[(4-bromophenyl)sulfonyl]-3-phenylbutanoate (1.4 g, 3.4 mmol) and 4-aminobenzenethiol (0.43 g, 3.4 mmol, 1 equiv) in anh. DMF (20 mL) was added K₂CO₃ (1.0 g, 7.2 mmol, 2 equiv). The reaction mixture was heated at 80 °C for 17 h, treated with 4- aminobenzenethiol (0.43 g, 3.4 mmol, 1 equiv) and continued heating for 6 h. The resulting mixture was allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with H₂O (2 x 100 mL). The combined aqueous layers were back-extracted with EtOAc (50 mL). The combined organic layers were washed with a 0.2 N HCl solution (2 x 100 mL), a saturated NaCl solution (100 mL), dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient from 30% to 50% EtOAc/hex) to give ethyl 4-{[4-(4-aminophenylthio)phenyl]sulfonyl}-3- phenylbutanoate (0.80 g, 52%) as a white solid: TLC (40% EtOAc/hex) R 0.47; 1H NMR (CDC1₃) δ 1.23 (t, J- 7.1 Hz, 3H), 2.69 (dd, J= 8.7, 15.7 Hz, IH), 2.98 (dd, J- 5.8, 15.5 Hz, IH), 3.39 (dd, J= 6.6, 14.4 Hz, IH), 3.53 (dd, J= 7.3, 14.4 Hz, IH), 3.68-3.74 (m, IH), 3.93-4.05 (m, 4H), 6.72-6.76 (m, 2H), 7.01-7.08 (m, 4H), 7.17-7.27 (m, 3H), 7.30-7.35 (m, 2H), 7.51-7.58 (m, 2H). B3 General Method for Coupling of Benzyl Electrophiles with Phenols: Methyl 3-

(3,5-Dichlorophenyl)-4-[(4-{[3-nitro-5-

(trifluoromethyl)benzyl]oxy}phenyl)sulfonyl]butanoate

B3 Step 1

^0zN -

CF₃ A solution of 3-nitro-5-(trifluoromethyl)benzoic acid (5.81 g, 24.7 mmol) in tetrahydrofuran (70 mL) was slowly treated with borane methyl sulfide complex (29.7 mL, 29.6 mmol), and the mixture was held at the reflux temperature for 6 hours. The mixture was then cooled to room temperature and quenched with methyl alcohol (100 mL). Reaction mixture was concentrated under reduced pressure to afford a yellow oil which was passed through silica gel plug to isolate 5-nitro-3-(trifluoromethyl)phenyl]methan-lol as pale yellow oil (4.46 g): TLC (40% EtOAc/Hex) R_f 0.51.

B3 Step 2

A solution of [5-nitro-3-(trifluoromethyl)phenyl]methanol (4.46 g, 20.16 mmol) in Et₂O (30 mL) was stirred vigorously as it was treated with carbon tetrabromide (7.09 g, 21.37 mmol) followed by slow addition of PPh₃ (5.61g, 21.37 mmol). This mixture was stirred at room temperature overnight. The resulting slurry was filtered and concentrated under reduced pressure to afford an orange oil. The oil was passed through silica gel plug to afford [5- nitro-3-(trifluoromethyl)phenyl]methyl bromide as a pale yellow oil (5.26 g, 92%): TLC (10% EtOAc/hexane) R 0.80; 1H NMR (CDC1₃) δ 8.43-8.45 (d, 2H); 7.95 (s, 1 H); 4.58 (s, 2 H). HPLC ES-MS m/z 284 ((M+l)⁺).

B3 Step 3

A solution of 0.13 g of [5-nifro-3-(trifluoromethyl)phenyl]methyl bromide, phenol (0.17 g, 0.42 mmol) and 0.27 g of CsCO₃ (0.84 mmol) in 10 mL of acetone was heated at the reflux tempereature for 1 h. The heat was removed and mixture was partitioned between EtOAc and an aqueous 1 M HCl solution. The organic phase was dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography column (50% EtOAc/hexane) to give methyl 3-(3,5-dichlorophenyl)-4-[(4-{[3-nitro-5-

(trifluoromethyl)benzyl]oxy}phenyl)sulfonyl]butanoate (0.30 g, 88%).

B3 Step 4

Ethyl 3-(phenyl)-4-[(4- { [3-nitro-5-(trifluoromethyl)benzyl]oxy}phenyl)sulfonyl]butanoate (0.800 g, 1.53 mmol) was dissolved in CH₃CN (7 mL), treated with diphenyl cyanocarbonimidate (0.37 g, 1.53 mmol), and heated at the reflux temperature for 7 days. This mixture was then cooled to room temperature and concentrated under reduced pressure to afford a brown oil. The residue was diluted with CH₂C1₂ (10 mL). A third of this material was treated with 3-(aminomethyl)pyridine (0.0519 mL, 0.00051 mmol) heated to 60 °C, and stirred overnight. Reaction mixture was cooled to room temperature, and concentrated to an oily residue under reduced pressure. Purification by plug filtration column chromatography (EtOAc) afforded ethyl 3-(phenyl)-4-[(4-{[3-amino-5-(trifluoromethyl)benzyl]- oxy}phenyl)sulfonyl]butanoate (0.226 g, 93%) as a white solid. B4 General Method for Suzuki Coupling of Organoboronates with Aryl Triflates B4a: Methyl 4-({4-[2-(3-Nitrophenyl)ethyl]phenyl}sulfonyl)-3-phenylbutanoate

B4a Step 1

A suspension of methyl 4-[(4-hydroxyphenyl)sulfonyl]-3-phenylbutanoate (521.0 g, 1.56 mol) in dry CH₂C1₂ (7500 mL) was freated with dry pyridine (165 mL, 161.37 g, 2.04 moles), followed by dropwise addition of trifluoromethanesulfonic anhydride (340 mL, 570 g, 2.02 moles) at 5 °C at a rate that maintained the internal temperature below 15 °C. The reddish-orange solution was stirred at room temperature for 90 minutes, at which time TLC (silica gel 60, 40% EtOAc/hexane, UN detection) analysis suggested complete reaction. The solution was washed with a saturated ΝaCl solution (4 L), dried (Νa₂SO ) and concentrated to provide methyl 3-phenyl-4-[(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)sulfonyl]butanoate (728 g, 1.56 moles, 100%) as a pale-pink solid. 1H-NMR (CDC1₃): 2.72 (dd, J = 7.8, 16.0 Hz, IH, -CH₂CO₂CH₃); 2.89 (dd, J = 6.5, 16.0 Hz, IH); 3.56 (dd, J = 7.8, 14.4 Hz, IH); 3.59 (s, 3H); 3.67 (dd, J = 5.9, 14.4 Hz, IH, -SO₂CH₂-); 3.77 (m, IH); 7.03 (m, 2H); 7.15 (m, 3H); 7.28, 7.76 (AA'BB' quartet, 4H). Anal. Calcd for C₁₈H₁₇F₃O₇S₂ • 0.50 H₂O: C, 45.47; H, 3.82; F, 11.99; Found: C, 45.44; H, 3.61; F, 11.77.

B4a Step 2

A solution of 9-BBN (0.5 M in THF, 3.44 L) was added to 3-nitrostyrene (256.0 g,

1.72 moles) at -5 °C under argon at a rate that maintained the internal temperature below -2 °C. After final addition, the suspension was allowed to warm to room temperature. A clear yellow solution was observed after 2 hours. Stirring was continued for 14 hours, at which time, TLC (silica gel 60, 10% EtOAc/hexane, UN detection) suggested complete reaction of the hydroborate and loss of the nitrostyrene. The yellow solution was treated with THF (3.3 L), Et₃Ν (1.00 L, 726.0 g, 7.17 moles) and methyl 3-phenyl-4-[(4- {[(trifluoromethyl)sulfonyl]oxy}phenyl)sulfonyl]butanoate (727 g, 1.56 moles). The resultant solution was degassed with a brisk stream of argon below the medium surface for 20 minutes, prior to addition of the catalyst (40.0 g, 48.98 mmol, ~3 mole%) and degassed water (980 mL). The solution immediately turned reddish-purple, then very dark purple, and an exotherm occurred which increased the internal temperature to 42 °C. The mixture was stirred at room temperature for 60 minutes, at which time TLC (silica gel 60, 40% EtOAc/hexane, UN detection) suggested complete reaction. The dark solution was concentrated and the solids were redissolved in CH₂C1₂ (6000 mL). The organics were washed with a saturated ΝaCl solution (2x2 L) and treated with silica gel (3000 g). The silica mix was concentrated, divided into three batches and each batch was placed onto a plug of silica gel (200 g). The product was eluted from each batch (gradient from 20% EtOAc/hexane to 100% EtOAc) to provide a yellow semi-solid. This material was triturated with methanol (4 L) to afford methyl 4-({4-[2-(3-nifrophenyl)ethyl]phenyl}sulfonyl)-3- phenylbutanoate (251 g, 537 mmol) as a yellow solid: 1H-ΝMR (CDC1₃): 2.75 (dd, J = 8.6, 15.9 Hz; IH); 3.04 (m, 5H); 3.43 (dd, J = 6.1, 14.3 Hz, IH); 3.57 (m, 4H); 3.72 (m, IH); 7.09 (dd, J = 2.0, 8.0 Hz, 2H); 7.21 (m, 5H); 7.46 (m, 2H); 7.71 (AA'BB' quartet, J = 8.1 Hz, 2H); 8.08 (m, 2H). Mass spectrum (HPLC/ES) m/e 485 ((M+NH₄)⁺). Anal. Calcd for C₂₅H₂₅NO₆S: C, 64.23; H, 5.39; N, 3.00; S, 6.86. Found: C, 64.59; H, 5.29; N, 2.73; S, 6.73.

The filtrate was concenfrated to give methyl 4-({4-[2-(3- aminophenyl)ethyl]phenyl}sulfonyl)-3-phenylbutanoate (328 g, 750 mmol) as a dark yellow oil. 1H-NMR (DMSO-d₆): δ 2.65 (dd, J = 9.3, 16.0 Hz, IH); 2.73 (m, 2H); 2.90 (m, 2H-); 2.94 (dd, J = 5.6, 16.0 Hz, IH); 3.43 (s, 3H); 3.45 (m, IH); 3.72 (m, 2H); 6.38 (m, 2H); 6.45 (m, IH); 6.90 (t, J = 7.8 Hz, IH); 7.12 (m, 5H); 7.36, 7.61 (AA'BB' quartet, J = 8.7 Hz, 4H). Mass spectrum (HPLC/ES) m/z 438 ((M+l)⁺); 875 ((2M+1)⁺). The combined materials gave an overall yield for this process of 83%. B5 General Method for Heck Coupling of Styrenes with Aryl Electrophiles

B5a: Methyl 4-({4-[(iB)-2-(3-Nitrophenyl)ethenyI]phenyl}sulfonyl)-3-phenyIbutanoate

"'B5a Step l

To a solution of methyl 4-[(4-bromophenyl)sulfonyl]-3-phenylbutanoate (5.0 g, 13.0 mmol, l.Oequiv.) in DMF (10ml.) was added a catalytic amount of sodium iodide and the reaction was allowed to stir for 10 min. To this was added 3-nitrostyrene (3.89 g, 26.1 mmol, 2.0 equiv.), palladium acetate (1.0 g, 20 mol%), Et₃N (2.64 g, 26.1 mmol, 2.0 equiv.), and n- BU NTCl (1.0 g) and the reaction mixture was heated to 85 °C overnight. The mixture was cooled to room temperature, diluted with EtOAc, washed with water, dried (MgSO ) and filtered. The organic layer was allowed to evaporate over the 3 days during which crystals formed. The crude product was purified by column chromatography (gradient from 0%-75% EtOAc/ Hex) to yield methyl 4-({4-[(E)-2-(3-nitrophenyl)ethenyl]phenyl}sulfonyl)-3- phenylbutanoate (130 mg, 2.2%).

B6. General Method for Friedel-Crafts Acylation Reaction B6a Methyl 4-([4-(nitrobenzoyl)phenyl]sulfanyl)-3-phenylbutanoate

B6a Step 1

3-Nitrobenzoylchloride (260 mg, 1.40 mmol) was added to a solution of methyl 3-phenyl-4- (phenylsulfanyl)butanoate (400 mg, 1.40 mmol) and 1,2-dichloroethane (35 mL). The resulting reaction mixture was cooled to 0 °C (ice/H₂O bath) and 1 equivalent of A1C1₃ (410 mg, 3.08 mmol) was added. The reaction was allowed to stir for 15 min at this temperature and the cold bath was removed followed by addition of an additional equivalent of A1C1₃. The reaction solution turned a dark greenish/yellow and was allowed to stir at room temperature for 18 h, after which time the reaction was treated slowly with H₂O (50 mL). The mixture was diluted with CH₂C1₂ (50 mL) and washed with H₂O (3 x 50 mL), and the combined organic phases were washed with a saturated NaCl solution (50 mL), dried (MgSO₄), and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (EtOAc/hexane, 1/4) to afford methyl 4-{4-[(3- nitrophenyl)carbonyl]phenylthio}-3-phenylbutanoate as an oil (320 mg, 53%). TLC (10% MeOH/CH₂Cl₂) R 0.51; 1H NMR (300 MHz, CDC1₃) δ 7.34-7.17 (m, 13 H), 3.57 (s, 3 H), 3.41-3.33 (m, 1 H), 3.22-3.19 (m, 2 H), 2.99 (dd, J= 15.66, 6.27 Hz, 1 H), 2.68 (dd, J = 15.8, 8.48 Hz, 1 H); HPLC EI-MS m/z 436 ((M+l)⁺).

B7 General Method for the Synthesis of

((Aminophenyl)difluoromethyl)phenylsulfonybutanoates

B7a Methyl 4-({4-[Difluoro(4-nitrophenyl)methyl]phenyl}sulfonyl)-3- phenylbutanoate

B7a Step 1

Methyl 4-({4-[(4-nitrophenyl)carbonyl]phenyl}sulfonyl)-3-phenylbutanoate (200 mg, 0.656 mmol) was dissolved in CH₂C1₂ (1 mL) and BF₃'2HOAc (90 μL, 0.656 mmol) was added via syringe. The reaction was allowed to stir for 10 min until all solids had dissolved and then ethanethiol (110 μL, 1.311 mmol) was added slowly via syringe. The reaction was quenched (satd. NaHCO₃), extracted with CH₂C1₂, and the organic phases were combined, dried (MgSO ), filtered, and concentrated to give methyl 4-({4-[2-(4-nitrophenyl)(l,3-dithiolan-2- yl)]phenyl}sulfonyl)-3-phenylbutanoate as a white solid. The resulting crude product was used without further purification: TLC (10% MeOH/CH₂Cl₂) R/0.51; 1H NMR (CDC1₃) δ 8.54-8.53 (t, 1 H), 8.14-8.10 (m, 1 H), 7.77-7.74 (m, 1 H), 7.66-7.58 (m, 4 H), 7.49-7.44 (t, IH), 7.20-7.04 (m, 5H), 3.79-3.75 (m, IH), 3.63-3.44 (m, 4 H), 3.55 (s, 3H), 3.46 (s, 4H), 2.99-2.92 (dd, IH), 2.76-2.68 (dd, IH); HPLC EI-MS m/z 543 ((M+l)⁺).

B7a Step 2

A solution of methyl 4-({4-[2-(4-nifrophenyl)(l,3-dithiolan-2-yl)]phenyl}sulfonyl)-3- phenylbutanoate (102 mg, 0.178 mmol) in CH₂C1₂ (2 mL) was added to a solution of NO⁺BF₄ ^" (46 mg, 0.392 mmol), HF-pyridine (0.4 mL) in CH₂C1₂ (2 mL) at room temperature. After the addition was complete the reaction was stirred for 1 h at ambient temperature. The reaction mixture was diluted with CH₂C1₂, passed through a plug column (Al₂O₃/MgSO₄, 1/1), and concentrated. The crude organic material was purified by silica gel column chromatography (10% EtOAc/hexane) to afford methyl 4-({4-[difluoro(4- nitrophenyl)methyl]phenyl}sulfonyl)-3-phenylbutanoate (40 mg, 46%). 1H NMR (CDC1₃) δ 8.34-8.31 (m, 2 H), 7.79-7.74 (m, 3 H), 7.67-7.62 (m, 1 H), 7.54-7.51 (m, 2 H), 7.12-7.06 (m, 3 H), 7.01-6.98 (m, 2 H, 3.74-3.71 (m, IH), 3.65-3.46 (m, 5H), 2.94-2.86 (dd, IH), 2.74- 2.66 (dd, IH); HPLC EI-LRMS m/z 490 ((M+l)⁺).

B8 General Method for the Synthesis of

((Aminophenyl)methyl)phenylsulfonybutanoates

B8a Methyl 4-({4-[(4-Aminophenyl)methyI]phenyl}sulfonyl)-3-phenylbutanoate

Raney Ni (~1 g) was washed with CH₃OH (4 5 ml) until the solution became clear. Methanol (30 mL) was added, followed by methyl 4-({4-[2-(4-nitrophenyl)(l,3-dithiolan-2- yl)]phenyl}sulfonyl)-3-phenylbutanoate ( Procedure B7a, Step 1; 200 mg, 0.369 mmol). The mixture was put under hydrogen atmosphere with stirring for 2 days. The reaction solution was filtered through a pad of Celite and washed with methanol. The solution was concentrated in vacuo then purified by silica gel column chromatography (gradient from 25% EtOAc/hexane to 40% EtOAc/hexane) to afford methyl 4-({4-[(4- aminophenyl)methyl]phenyl}sulfonyl)-3-phenylbutanoate (37.4 mg, 23%): TLC (EtOAc) R 0.19.

C. General Methods for Interconversion of Phenylamines

Cl. General Method for Oxidation of Diphenylsulfides to Diphenylsulfones: Methyl 4-({4-[(4-Aminophenyl)sulfonyl]phenyl}sulfonyl)-3-phenylbutanoate

Cl Step 1

To a solution of methyl 4-({4-[(4-aminophenyl)thio]phenyl}sulfonyl)-3-phenylbutanoate (1.0 g, 2.3 mmol) in CHC1₃ (50 mL) was added K₂CO₃ (3.2 g, 23 mmol, 10 equiv) followed by mCPBA (2.0 g, 11.3 mmol, 5 equiv). The resulting mixture was stirred for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (75 g silica gel, gradient from 10% EtOAc/CH₂Cl₂ to 20% EtOAc/CH₂Cl₂) to afford methyl 4-({4-[(4- aminophenyl)sulfonyl]phenyl}sulfonyl)-3-phenylbutanoate (0.55 g, 51%) as a wliite solid: TLC (50% EtOAc/hex) R 0.38; HPLC ES-MS m/z (rel abundance) 474 ((M+l⁺).

D. General Methods for Modification of Phenylamines

Dl. General Method for Urea Synthesis using Phosgene: Dla Step 1

To a solution of ethyl 3-(3-pyridyl)-4-[(4-{[3-aminobenzyl]oxy}phenyl)sulfonyl]butanoate (60 mg, 0.132 mmol), and pyridine (32 uL) inCH₂Cl₂ (3 mL) was added phosgene (20% in toluene, 88 uL) at 0 °C. After stirring at 0 °C for 2 hrs, the mixture was concentrated under reduced pressure. The residue was redissolved in CH₂C1₂ (3 mL) and 3- (aminomethyl)pyridine (40 uL) was added. The solution was stirred at room temperature overnight. The mixture was purified using column chromatography (MeOH in CH₂C1₂) to give the desired urea (25 mg, 32%): HPLC ES-MS m/z 589 ((M+l)⁺).

D2. General Method for Urea Synthesis using Isocyanates:

D2a: Ethyl 4-[(4-{4-[(ethylamino)carbonylamino]phenylthio}phenyl)sulfonyl]-3- phenylbutanoate

D2a Step 1

A solution of ethyl 4-{[4-(4-aminophenylthio)phenyl]sulfonyl}-3-phenylbutanoate (200 mg, 0.44 mmol) and ethyl isocyanate (72 mg, 1 mmol, 2.3 equiv) in CH₂C1₂ (5 mL) was stirred at room temperature for 17 h. The reaction mixture was treated with ethyl isocyanate (140 mg, 2 mmol, 4.6 equiv) and heated at 40 °C for 3h. The resulting mixture was treated with ethyl isocyanate (ImL) and stirred at room temperature for 17 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (40% EtOAc/hex followed by 40% EtOAc/CH₂Cl₂) to yield ethyl 4-[(4-{4-

[(ethylamino)carbonylamino]phenylthio}phenyl)sulfonyl]-3-phenylbutanoate (184 mg, 79%) as a white solid: TLC (50% EtOAc/hex) R 0.23; 1H NMR (CDC1₃) δ 1.05-1.22 ( , 6H), 2.64 (dd, J= 8.3, 15.7 Hz, IH), 2.77-2.94 (m, 3H), 3.22 (q, J= 7.1 Hz, 2H), 3.39 (dd, J = 6.6, 14.4 Hz, IH), 3.50 (dd, J- 7.2, 14.4 Hz, IH), 3.61-3.68 (m, IH), 3.96 (q, J = 7.0 Hz, 2H), 6.98-7.02 (m, 4H), 7.10-7.19 (m, 3H), 7.32-7.48 (m, 6H).

D5 General Method for Cyanoguanidine Synthesis: Ethyl 4-({4-[(3-{[(E)-

(Cyanoimino)(methylamino)methyl]amino}benzyl)oxy]phenyl}sulfonyl)-3-(3- pyridinyl)butanoate

A solution of ethyl 4-({4-[(3-{[(E)-methyl]amino}benzyl)oxy]phenyl}sulfonyl)-3-(3- pyridinyl)butanoate (150 mg, 0.33 mmol) and diphenylcyanocarbonimidate (90 mg, 0.38 mmol) in CH₃CN (10 mL) was heated at the reflux temperature for 4 h. The mixture was allowed to cool, and was concentrated under reduced pressure to afford an intermediate: TLC (ΕtOAc) R 0.58. The intermediate was used for next reaction without further purification. A solution of the crude intermediate (0.165 mmol assumed) and methylamine (2.0 M in THF; 0.2 mL) in THF (3 mL) was heated at 40 °C for 12 hrs. The mixture was then concentrated under reduced pressure, and purified by chromatography (gradient from 50% ΕtOAc/hexane to 100% ΕtOAc) to give ethyl 4-({4-[(3-{[(E)- (cyanoimino)(methylamino)methyl]amino}benzyl)oxy]phenyl}sulfonyl)-3-(3- pyridinyl)butanoate (69 mg, 0.129 mmol, yield 78%): mp 59-64 °C; TLC (5% MeOH/CH₂Cl₂), R 0.20; HPLC ΕS-MS m/z 536 ((M+l)⁺).

D6 General Method for Squaric Acid Synthesis

D6a: Methyl 4-{[4-(4-{[2-(Cyclopropylamino)-3,4-dioxo-l-cyclobuten-l- yl] amino}phenoxy)phenyl] su!fonyl}-3-phenylbutanoate D6a Step 1

3,4-Dimethoxy-3-cyclobutene-l,2-dione (87 mg, 0.58 mmol) was added to a solution of methyl 4-{[4-(4-aminophenoxy)phenyl]sulfonyl}-3-phenylbutanoate (248 mg, 0.58 mmol) in isopropyl alcohol (8 mL). The reaction mixture was heated to 80 °C for 18 h under argon. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (60% EtOAc / hex) to give methyl 4-{[4-(4-{[2- (cyclopropylamino)-3 ,4-dioxo- 1 -cyclobuten- 1 -yl] amino } phenoxy)phenyl] sulfonyl} -3 - phenylbutanoate as a yellow foam (150 mg, 48%).

D6b Methyl 4-{ [4-(4-{ [2-((3-Pyridinylmethylamino)-3,4-dioxo-l-cyclobuten-l- yl] amino}phenoxy)phenyl] sulfonyl}-3-phenylbutanoate

D6b Step 1

A solution of 3,4-dimethoxy-3-cyclobutene-l,2-dione (1.36 g, 9.56 mmol) and methyl 4-{[4- (4-aminophenoxy)phenyl] sulfonyl} -3 -phenylbutanoate (3.70 g, 8.69 mmol) in isopropyl alcohol (60 mL) was heated to 80 °C for 18 h under argon. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (gradient from 35% EtOAc/hexane to 65% EtOAc/hexane) to give methyl 4-{[4-(4-{[2-((2- pyridinylmethylamino)-3 ,4-dioxo- 1 -cyclobuten- 1 -yl] amino }phenoxy)phenyl] sulfonyl} -3- phenylbutanoate a yellow-orange solid (3.02 g, 65%).

D6b Step 2

A solution of methyl 4- {[4-(4-{ [2-((2-pyridinylmethylamino)-3 ,4-dioxo- 1 -cyclobuten- 1- yl]amino}phenoxy)phenyl]sulfonyl}-3-phenylbutanoate (3.0 g, 5.6 mmol) and 3- aminomethylpyridine (1.14 ml, 11 mmol) in THF (60 mL) was heated at the reflux temperature under argon. After ~5 min at the reflux temperature, a white precipitate formed. After 18 h, the mixture was cooled to room temperature, concentrated under reduced pressure and the residue was purified by flash chromatography (gradient froml% MeOH/CH₂Cl₂ to 5% MeOH/CH₂Cl₂) to give methyl 4-{[4-(4-{[2-((3- pyridinylmethylamino)-3,4-dioxo-l-cyclobuten-l-yl]amino}phenoxy)phenyl]sulfonyl}-3- phenylbutanoate as a yellow solid (2.77 g, 81%).

D7 General Method for the Synthesis of 4,5-Dihydro-lH-imidazol-2-ylamines: Methyl 4-[(4-{ [3-(4,5-Dihydro-lH-imidazol-2-ylamino)-5- (trifluoromethyl)benzyl]oxy}phenyl)sulfonyl]-3-phenylbutanoate

D7 Step 1

Methyl 3-(3,5-dichlorophenyl)-4-[(4- {[3-amino-5-

(trifluoromethyl)benzyl]oxy}phenyl)sulfonyl]butanoate (2.5g, 4.93mmol) was dissolved in CH₂C1₂ (25 mL) and freated with thiophosgene (413 uL, 5.42mmol). The reaction mixture was stirred at room temperature for 2h and then concentrated under reduced pressure. The residue was diluted with EtOAc and passed through silica gel plug to afford methyl (3R)-4- [(4-{[3-isothiocyanato-5-(trifluoromethyl)phenyl]methoxy}phenyl)sulfonyl]-3- phenylbutanoate.

D7 Step 2

Methyl (3R)-4-[(4- {[3-isothiocyanato-5-(trifluoromethyl)phenyl]methoxy}phenyl)sulfonyl]- 3 -phenylbutanoate was dissolved in abs. EtOH (30 mL), and allowed to stir at 50 °C for 18 h. Reaction was cooled to room temperature and concenfrated under erduced pressure to afford an orange oil. The residue was purified using a silica gel plug (40% EtOAc/ hexanes) to afford methyl (3R)-4- { [4-( {3-[(ethoxythioxomethyl)amino]-5-(trifluoromethyl)phenyl} - methoxy)phenyl] sulfonyl} -3 -phenylbutanoate as a pale beige solid (1.68 g).

D7 Step 3

Methyl (3R)-4-{[4-({3-[(ethoxythioxomethyl)amino]-5-(trifluoromethyl)phenyl}methoxy)- phenyl]sulfonyl}-3-phenylbutanoate (1.68 g, 2.82mmol) was diluted with toluene (5 mL) and treated with ethylenediamine (0.186 g, 3.1 mmol). The resulting mixture was heated at 100 °C for 18 h. Reaction was allowed to cool to room temperature, diluted with EtOAc followed by a small amount of MeOH to clear up the turbid reaction mixture. The resulting solution was concenfrated to light yellow solids under reduced pressure, redissolved in EtOAc, adsorbed onto silica gel and purified by filtration through a plug of silica gel (gradient from 3% Et₃N/EtOAc to 10% MeOH/3% Et₃N EtOAc) to afford methyl 4-[(4-{[3- (4,5-dihydro-lH-imidazol-2-ylamino)-5-(trifluoromethyl)benzyl]oxy}phenyl)sulfonyl]-3- phenylbutanoate as a pale beige solid (0.76 g).

D8 General Method for the Synthesis of 2-Thiazolylamines D8a. Methyl 4-({4-[4-(5,6-Dihydro-4H-cyclopenta[d] [l,3]thiazol-2- ylamino)phenoxy]phenyl} sulfonyl)-3-phenylbutanoate

D8a Step 1

To a solution of methyl 4- {[4-(4-aminophenoxy)phenyl] sulfonyl} -3 -phenylbutanoate (3.20 g, 7.52 mmol) in anh. CH₂C1₂ (70 mL), was added thiophosgene (0.75 mL, 9.8 mmol) under argon. The reaction mixture was stirred 18 h at room temperature, then heated at the reflux temperature for 2 h. Concentration under reduced pressure after cooling to room temperature gave a brown oil. The residue was purified by flash chromatography (10% EtOAc/hexanes) to give methyl 4-{[4-(4-isothiocyanatophenoxy)phenyl]sulfonyl}-3-phenylbutanoate (3.38 g 96%) as a white solid.

D8a Step 2

To a solution of methyl 4-{[4-(4-isothiocyanatoρhenoxy)phenyl]sulfonyl}-3-phenylbutanoate (3.38 g, 7.2 mmol) in CH₂C1₂ (70 mL) was added NH₃ (2 M in MeOH, 7.2 mL, 14.5 mmol) under argon. The reaction mixture was stirred overnight at room temperature. Concentration under reduced pressure gave methyl 4-[(4-{4-[(aminothioxomethyl)amino]phenoxy}- phenyl)sulfonyl]-3-phenylbutanoate as a white solid (3.51 g, 100%).

D8a Step 3

To a suspension of methyl 4-[(4-{4-[(aminothioxomethyl)amino]phenoxy}phenyl)sulfonyl]- 3 -phenylbutanoate (2.26 g, 4.66 mmol) in anh benzene (60 mL), was added 2- chlorocyclopentanone (1.50 g, 12.6 mmol). The reaction mixture was heated in the presence of a Dean-Stark trap at the reflux temperature for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / 80% hexanes) to give methyl 4-({4-[4-(5,6-dihydro-4H- cyclopenta[d] [ 1 ,3]thiazol-2-ylamino)phenoxy]phenyl} sulfonyl)-3-phenylbutanoate as a foam-like solid (1.72 g, 68%).

D8b: Methyl 4-[(4-{2-[3-(4,5-Dihydro-l,3-thiazol-2- ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoate

D8b Step 1

A mixture of methyl 4-[(4-{2-[3-aminophenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoate

(0.250 g, 0.57 mmol), toluene (3 mL), and thiazoline (0.015 g, 0.114 mmol) were heated at the reflux temperature for 72 h and then concentrated to an oil under reduced pressure. The crude mixture was purified by silica gel chromatography (10% MeOH/CHCl₃) to afford methyl 4-[(4- {2-[3-(4,5-dihydro- 1 ,3-thiazol-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]-3- phenylbutanoate (0.047 g).

D8c: Ethyl 3-phenyl-4-({4-[4-(l,3-thiazol-2-ylamino)phenylthio]phenyl}sulfonyl)- butanoate D8c Step 1

A solution of ethyl 4-{[4-(4-aminophenylthio)phenyl]sulfonyl}-3-phenylbutanoate (102 mg, 0.22 mmol) and thiophosgene (27 mg, 0.23 mmol, 1.05 equiv) in anh. toluene (10 hiL) was heated at 80 °C for 2 days. The resulting mixture was allowed to cool to room temperature and concentrated under reduced pressure to give ethyl 4-{[4-(4- isothiocyanatophenylthio)phenyl]sulfonyl}-3-phenylbutanoate as a white solid: TLC (20% EtOAc/hexanes) R 0.33.

D8c Step 2

To a solution of crude ethyl 4-{[4-(4-isothiocyanatophenylthio)phenyl]sulfonyl}-3- phenylbutanoate (0.22 mmol) in CH₂C1₂ (5 mL) was added a 2M solution of NH₃ in EtOH (5 mL, 10 mmol). The reaction mixture was stirred at room temperature for 4 h and concenfrated under reduced pressure to give ethyl 4-[(4-{4- [(aminothioxomethyl)amino]phenylthio}phenyl)sulfonyl]-3-phenylbutanoate: TLC (50% EtOAc/hexanes) R 0.35.

D8c Step 3

A mixture of crude ethyl 4-[(4-{4-[(aminothioxomethyl)amino]phenylthio}phenyl)sulfonyl]- 3 -phenylbutanoate (0.22 mmol) and chloroacetaldehyde (50% in water; 1 mL) in benzene (10 mL) was heated in a Dean-Stark apparatus for 4 h. The resulting mixture was purified by flash chromatography (30% EtOAc/hex) to give ethyl 3-phenyl-4-({4-[4-(l,3-thiazol-2- ylamino)phenylthio]phenyl}sulfonyl)butanoate (98 mg, 83% for 3 steps) as an off-white solid: TLC (50% EtOAc/hexanes) R 0.19; 1H NMR (CDC1₃) δ 1.04 (t, J= 7.2 Hz, 3H), 2.61 (dd, J= 9.0, 15.9 Hz, IH), 2.89 (dd, J= 5.5, 15.5 Hz, IH), 3.34 (dd, J= 6.5, 14.3 Hz, IH), 3.44-3.68 (m, 2H), 3.89-3.98 (m, 2H), 6.67 (d, J- 3.4 Hz, IH), 6.97-7.03 (m, 4H), 7.09-7.16 (m, 3H), 7.28 (d, J= 3.5 Hz, IH), 7.38-7.50 (m, 7H).

D9 General Method for the Synthesis of 2-Thiazinylamines D9a. Methyl 3-Phenyl-4-[(4-{2-[3-(4H,5H,6H-l,3-thiazin-2- ylamino)phenyl]ethyl}phenyl)sulfonyl]butanoate

D9a Step 1

To a solution of methyl 4-[(4-{2-[3-aminophenyl]etlιyl}phenyl)sulfonyl]-3-phenylbutanoate (0.59 g, 1.35 mmol) in CH₂C1₂ (10 mL) was added thiophosgene (0.17 g; 1.48 mmol) at room temperature. The reaction stirred overnight and was concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford methyl 4-({4-[2- (3-isothiocyanatophenyl)ethyl]phenyl}sulfonyl)-3-phenylbutanoate (0.43 g).

D9a Step 2

Methyl 4-( {4- [2-(3-isothiocyanatophenyl)ethyl]phenyl}sulfonyl)-3 -phenylbutanoate (0.250 g; 0.521 mmol) was treated with 1-chloropropylamine HCl salt (0.102 g, 0.784 mmol) and Et₃N (0.105 g, 1.04 mmol). The crude product was purified by silica gel chiOinatography to afford methyl 3-phenyl-4-[(4-{2-[3-(4H,5H,6H-l,3-thiazin-2- ylamino)phenyl]ethyl}phenyl)sulfonyl]butanoate (0.185 g).

D9b: Methyl 4-[(4-{2-[3-(5,6-Dihydro-4H-l,3-thiazin-2- ylamino)phenyl] ethyl} phenyl)sulfonyl]-3-phenylbutanoate

D9b Step 1

To a mixture of methyl 3-phenyl-4-[(4-{(E)2-[3-(l,3-thiazolin-2-ylamino)phenyl]- ethyl}phenyl)sulfonyl]-butanoate (0.04 g, 0.084 mmol) and chloropropylamine hydrochloride (0.016 g, 0.126 mmol, 1.5 equiv.) in CH₂C1₂ (5 mL) was added Et₃N (.024 mL, .167 mmol). The reaction mixture was stirred at room temperature for 2 h and concenfrated under reduced pressure. The crude residue gave methyl 4-[(4-{2-[3-(5,6- dihydiO-4H-l,3-thiazin-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoate (0.020 g, 44% yield). D10 General Method for the Synthesis of 2-Pyridinylylamines DlOa. Methyl 3-Phenyl-4-({4-[4-(2- pyridinylamino)phenoxy]phenyl}sulfonyl)butanoate:

DlOa Step l

Methyl 3-phenyl-4-({4-[4-aminophenoxy]phenyl}sulfonyl)butanoate (150 mg, 0.35 mmol) and 2-chloropyridine (0.3 mL, 3.1 mmol) were suspended in DMF (2 mL) and heated at the reflux temperature for 18 h. The resulting mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (40% EtOAc/60%> hexanes) to give methyl 3-phenyl-4-({4-[4-(2-pyridinylamino)phenoxy]phenyl}sulfonyl)butanoate as a white foam (48 mg, 27%).

Dll General Method for the Synthesis of 3,4-Dihydro-2H-pyrrol-5-ylamines Dlla. Methyl 4-[(4-{2-[3-(3,4-Dihydro-2H-pyrrol-5- ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoate:

Dlla Step 1

To a solution of methyl 4-[(4-{2-[3-aminophenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoate (0.50, 01.14 mmol) in isopropyl alcohol (5 mL) at 80 °C was added Et₃N (0.16 g, 1.60 mmol) and the electrophile (0.36 g, 1.48 mmol). The reaction mixture was stirred for 72 h at 65 °C and was concentrated under reduced pressure. The residue was purified by column chromatography to afford methyl 4-[(4-{2-[3-(3,4-dihydro-2H-pyrrol-5- ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoate (0.050 g). D12 General Methods for Synthesis Amides from Phenyl Amines D12a:

D12a Step 1

To a solution of picolinic acid (39 mg, 0.32 mmol, 1.5 equiv) in CH₂C1₂ (20 mL) was added a 2M solution of oxalyl chloride in CH₂C1₂ (0.2 mL, 0.4 mmol, 2 equiv). The resulting deep red solution was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was diluted with CH₂C1₂ and treated with a solution of methyl 4-({4- [(4-aminophenyl)sulfonyl]phenyl}sulfonyl)-3-phenylbutanoate (100 mg, 0.21 mmol) in CH₂C1₂ (20 mL). The reaction mixture was stirred at room temperature for 3 days. TLC indicated partial reaction. To a solution of picolinic acid (39 mg, 0.32 mmol, 1.5 equiv) in CH₂C1₂ (20 mL) was added a 2M solution of oxalyl chloride in CH₂C1₂ (0.2 mL, 0.4 mmol, 2 equiv). The resulting deep red solution was stirred at room temperature for 2 h and concenfrated under reduced pressure. The residue was diluted with CH₂C1₂ and added to the reaction mixture, which was then stirred for 4 h. The resulting mixture was diluted with EtOAc (100 mL), washed with a saturated NaHCO₃ solution (100 mL), a saturated NaCl solution, dried (Na₂SO ) and concentrated under reduced pressure to give the desired picolinamide (130 mg, 100%) as a beige solid: TLC (50% EtOAc/hex) R_f 0.27; 1H NMR (CDC1₃) δ 2.56 (dd, J = 7.5, 16.1 Hz, IH), 2.73 (dd, J = 6.5, 15.6 Hz, IH), 3.46-3.64 (m, 6H), 3.73 (s, IH), 6.85 (s, 5H), 7.44-7.48 (m, IH), 7.63 (d, J = 8.4 Hz, 2H), 7.77-7.95 (m, 6H), 8.16 (d, J= 7.5 Hz, IH), 8.54 (d, J= 4.4 Hz, IH).

E. General Method for Hydrolysis of Esters to Carboxylic Acids El. General Method for KOH Saponification of Esters Ela. 4-{[4-(4-{[2-(Cyclopropylamino)-3,4-dioxo-l-cyclobuten-l- yl] amino}phenoxy)phenyl] sulfonyl}-3-phenylbutanoic Acid Ela Step 1

To a solution of methyl 4- {[4-(4-{ [2-(cyclopropylamino)-3 ,4-dioxo- 1 -cyclobuten- 1 - yl] amino }phenoxy)phenyl] sulfonyl} -3 -phenylbutanoate (45 mg, 0.08 mmol) in MeOH (4.5 mL) and water (1.5 mL) was added KOH (300 mg, 5.3 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the aqueous solution was neutralized to pH = 6.0 with IN HCl. The solution was extracted with CH₂C1₂ and the combined organic layers were washed with a saturated NaCl solution then dried (Na₂SO₄) and concentrated under reduced pressure to give 4-{[4-(4- {[2-(cyclopropylamino)-3,4-dioxo-l-cyclobuten-l-yl]amino}phenoxy)phenyl]sulfonyl}-3- phenylbutanoic acid as a colorless solid (32 mg, 73%).

Elb: 4-{[4-({4-[(ΕthyIamino)carbonylamino]phenyl}sulfonyl)phenyl]sulfonyl}-3- phenylbutanoic acid

To a solution of ethyl 4-{[4-({4-[(ethylamino)carbonylamino]phenyl}sulfonyl)- phenyl] sulfonyl} -3 -phenylbutanoate (142 mg, 0.25 mmol) in MeOH (2 mL) was added a 0.33 M KOH solution (10% H₂O/90% MeOH, 1 mL, 0.33 mmol, 1.3 equiv). The reaction mixture was stirred at room temperature for 2 days, treated with a 1 N HCl solution (1 mL) and concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with H₂O (25 mL) and a saturated NaCl solution (25 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure to give 4-{[4-({4- [(ethylamino)carbonylamino]phenyl}sulfonyl)phenyl]sulfonyl}-3-phenylbutanoic acid (113 mg, 85%) as a white solid: mp 168 °C, dec; TLC (1% AcOH/EtOAc) R 0.54; 1H NMR (DMSO-d₆) δ 1.01 (t, J= 7.2 Hz, 3H), 2.40 (dd, J= 8.9, 16.0 Hz, IH), 2.72 (dd, J= 5.8, 16.1 Hz, IH), 3.03-3.12 (m, IH), 3.30-3.44 (m, 2H), 3.74 (dd, J= 4.5, 14.4 Hz, IH), 3.97 (dd, J= 9.8, 15.1 Hz, IH), 6.31 (t, J= 5.4 Hz, IH), 6.72-6.77 (m, 3H), 6.92-6.95 (m, 2H), 7.63-7.67 (m, 4H), 7.79-7.85 (m, 4H), 9.07 (s, IH), 12.16 (br s, IH).

Elc: 4-{[4-(4-{[2-((3-pyridinylmethylamino)-3,4-dioxo-l-cyclobuten-l- yl] amino}phenoxy)phenyl] sulfonyl}-3-phenylbutanic acid

Elc Step 1

A solution of the compound from Step B (2.50 g, 4.1 mmol) and KOH (245 mg, 6.14 mmol) in MeOH (30 mL) and water (1.5 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the aqueous solution was brought to pH 2-3 with cone. HCl. The mixture was then further concentrated under reduced pressure and the residue placed under high vacuum. The solid was dissolved into DMF and filtered. The resulting solution was concentrated under reduced pressure and the residue triturated in EtOAc. The suspension was filtered, giving 900 mg of solid. Upon sitting, another 984 mg of solid precipitated from the filtrate and was also collected. The solids were combined, washed with EtOAc, and dried under vacuum to give 4-{[4-(4-{[2-((3- pyridinylmethylamino)-3 ,4-dioxo- 1 -cyclobuten- 1 -yl] amino } phenoxy)phenyl] sulfonyl } -3 - phenylbutanoic acid HCl salt (1.84 g, 72%) as a yellow solid.

E2. General Method for Palladium-Mediated Hydrolysis of Allyl Esters E2a.

E2a Step 1

To a 0 °C solution of allyl 4-{[4-({4-[4,5-Dihydro-l,3-thiazol-2-ylamino amino]phenyl}sulfonyl)phenyl]sulfonyl}-3-phenylbutanoate (0.1 g, 0.17 mmol) in CH₃CN (10 mL) was added Pd (Ph₃P)₄ (0.05 g, 0.04 mmol, 0.25 equiv), followed by Ph₃P (0.02 g, 0.08 mmol, 0.5 equiv) and pyrrolidine (0.01 g, 0.17 mmol, 1 equiv). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was purified by HPLC (CH₃CN/H₂O) to give 3-phenyl-4-[(4-{[4-(l,3-thiazolin-2- ylamino)phenyl]sulfonyl}phenyl)sulfonyl]butanoic acid (10 mg, 7%): TLC (0.05% ACOH/ 95.5% ETOAC) RF 0.19; HPLC ES-MS m/z 545 ((M+l)⁺, 100%).

E3. General Method for Hydrogenation of Benzyl Esters

E3a. 3-{[(3-{2-[3-(2-Imidazojj -2-ylamino)phenyl]ethyl}phenyl)sulfonyl]amino}-3- phenylpropanoic Acid

E3a Step 1

To a solution of the benzyl ester described in Section A4a Step 4 (300 mg) in MeOH (50 ml) under argon was added 10% Pd/C (600 mg) and the mixture was hydrogenated at 1 arm at room temperature for 6 h. The reaction was filtered through a pad of Celite washing well with MeOH. The MeOH mixture was concentrated under reduced pressure to give crude product (110 mg). The Celite/Pd/C was stirred in 4:4:1 CH3CN/MeOH/H2O (500 ml) for 16 h. This was again filtered through a pad of Celite washing well with MeOH. The MeOH mixture was concenfrated under reduced pressure to yield more crude product (50 mg). The combined crude oils were purified by silica gel chromatography (CH₃CN/H₂O). 3 3-{[(3-{2- [3 -(2-hnidazolin-2-ylamino)phenyl] ethyl } phenyl)sulfonyl] amino } -3 -phenylpropanoic acid was obtained as a white powder (62 mg, 30%): TLC 20% H₂O/CH₃CN R 0.55; HPLC ES- MS m/z ((M+l)⁺).

F . Modification of Final Esters and Acids Fl. General Method for Oxidation of Diphenyl Sulfides

Fla: Ethyl 4-{[4-({4-[(ethylamino)carbonylamino]phenyl}sulfonyl)phenyl]sulfonyl}-3- phenylbutanoate

Fla

A mixture of ethyl 4-[(4-{4-[(ethylamino)carbonylamino]phenylthio}phenyl)sulfonyl]-3- phenylbutanoate (164 mg, 0.31 mmol) and mCPBA (187 mg, 1.1 mmol, 3.5 equiv) in CHC1₃ (5 mL) was stirred at room temperature for 17 h. The resulting mixture was freated with Na₂SO₃ (100 mg, 0.79 mmol, 2.5 equiv) and filtered through a pad of basic alumina (10% MeOH/EtOAc). The filtrate was concentrated under reduced pressure and purified by flash chromatography (70% EtOAc/hex) to give ethyl 4-{[4-({4-[(ethylamino)carbonylamino]- phenyl}sulfonyl)phenyl]sulfonyl}-3-phenylbutanoate (136 mg, 78%) as a white solid: TLC (50% EtOAc/hex) R 0.25; HPLC ES-MS m/z 559 (MH⁺, 100%); 1H NMR (CDCI₃) δ 1.05- 1.14 (m, 6H), 2.65 (dd, J= 7.4, 16.0 Hz, IH), 2.82 (dd, J= 6.8, 16.1 Hz, IH), 3.17-3.26 (m, 2H), 3.57-3.76 (m, 3H), 4.01 (q, J= 6.7 Hz, 2H), 5.50 (t, J= 5.5 Hz, IH), 6.96 (s, 5H), 7.47- 7.85 (m, 8H).

F2. General Method for Chiral HPLC Resolution Resolution of Esters and Acids

F2a: 3R)-3-Phenyl-4-[(4-{2-[3-(l,3-thiazolin-2- ylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic Acid and (3S)-3-Phenyl-4-[(4-{2-[3-(l,3- thiazolin-2-ylamino)phenyl] ethyl} -phenyl)sulfonyl]butanoic Acid F2a Step 1

Racemic 3 -phenyl-4- [(4-{2-[3-(l ,3 -thiazolin-2-ylamino)-phenyl] ethyl } phenyl)sulfonyl] - butanoic acid was separated on Chiralpak AD column (flow rate 24 mL/min, Eluent A: hexane, 0.1% Et₃N, Eluent B: 1:1 MeOH:EtOH, 0.1% Et₃N; Isocratic 75:25 Eluent A: Eluent B for 30 min) to give (3R)-3-phenyl-4-[(4-{2-[3-(l,3-thiazolin-2-ylamino)phenyl]ethyl}- phenyl)sulfonyl]butanoic acid ((R)-l): Retention Time 7.26 min, followed by (3S)-3-phenyl- 4-[(4-{2-[3-(l,3-thiazolin-2-ylamino)phenyl]ethyl}-phenyl)sulfonyl]butanoic acid ((S)-l): Retention Time 9.86 min.

The compounds of the invention, which include those compounds described by Tables 1 - 8 below, may be prepared by using the above described procedures or known chemical reactions and procedures which are within the purview of one of ordinary skill in the art.

Table 1 (Examples 1- 61) depicts the described compounds wherein L is either CH₂NH or CH₂O and D is CH₂.

Table 2 (Examples 62 and 63) depicts the described compounds wherein L is OCH₂ and D is CH₂.

Table 3 (Examples 64 - 161) depicts the described compounds wherein L is CH₂CH₂, -C=C- or OC- _{and D is C}H₂

Table 4 (Examples 162 - 174) depicts the described compounds wherein L is C(=O) or C(=N-OCH₃) and D is CH₂.

Table 5 (Examples 175 - 185) depicts the described compounds wherein L is CH₂, CF₂, or CH(OH) and D is CH₂.

Table 6 (Examples 186 - 275) depicts the described compounds wherein L is O and D is CH₂. Table 7 (Examples 276 - 290) depicts the described compounds wherein L is S or S(=O)₂, and D is CH₂.

Table 8 (Examples 291 - 305) depicts the described compounds wherein L is CH₂CH₂ and D is NH.

Table 9 lists the IUPAC names of the compounds exemplified in Tables 1-8 as determined using Nomenclator^® version 3.01 (Chemlnnovation Software, Inc.).

Table 1.

a The compound displayed an IC₅o of less than or equal to 10 nM in the indicated assay. b The compound displayed an IC₅₀ of greater than 10 nM and less than or equal to 100 nM in the indicated assay. c The compound displayed an IC₅₀ of greater than 100 nM and less than or equal to 1 μM in the indicated assay.

Table 9. Names of Exemplified Compounds

4-({4-[(5-{[(lE)-2-aza-2-cyano-l-(methylanjino)v yl]ammo}-2-cMorophenyl)methoxy]phenyl}sulfonyl)-3-phenylbutanoic acid

4-({4-[(3-{[(lE)-2-aza-2-cyano-l-(methylamino)vinyl]amino}-4-methylphenyl)methoxy]phenyl}sulfonyl)-3-ρhenylbutanoic acid

4-[(4-{[3-(2-inιidazolin-2-ylanjiαo)-5-(triιluoromethyl)phenyl]methoxy}phenyl)sulfonyl]-3-phenylbutanoic acid

4-{[4-({3-[(l-me yl(2-imidazolm-2-yl))ammo]-5-(trifluoro acid

4-{[4-({3- [(ethylanjJno)carbonylaminol -4-fluorophenyl} methoxy)ρhenyl] sulfonyl} -3 -phenylbutanoic acid

4-{[4-({3-[(ethylammo)carbonylan ino]phenyl}methoxy)phenyl]sulfonyl}-3-(3-ρyridyl)butanoic acid

4-({4-[(4-fluoro-3-{[(3-pyridyiinethyl)anuno]carbony

4-{[4-({2-fluoro-5-[(me ylam o)carbonylamino]phenyl}methoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

3-(3-ρyridyl)-4-({4-[(3-{[(3-ρyridylmemyl)ammo]carbonylanιino}phenyl)methoxy]phenyl}sulfonyl)butanoic acid

4-{[4-({3-[(cyclopropylanjino)carbonylamino]phenyl}methoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

3-phenyl-4-({4-[(3-{[(2,2,2-trifluoroethyl)anjino]carbonylamjiio}phenyl)methoxy]phenyl}sulfonyl)butanoic acid

4-{[4-({3-[(me ylanιmo)carbonylammo]-5-(trifluoromethyl)phenyl}methoxy)phenyl]sulfonyl}-3-ρhenylbutanoic acid

4-{[4-({4-cMoro-3-[(me ylamino)carbonylamino]phenyl}methoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

4-{[4-({2-memoxy-5-[(methylammo)carbonylarjjLino]ρhenyl}methoxy)ρhenyl]sulfonyl}-3-phenylbutanoic acid

3-ρhenyl-4-({4-[(3-{[(3-ρyridylmemyl)ammo]carbonylamino}-5-(trifluorome yl)phenyl)methoxy]ρhenyl}sulfony

3-(4-cMoro-3-fluorophenyl)-4-({4-[(3-{[(3-pyridyj^etfayl)amino]carbonylammo}ρhenyl)memoxy]phenyl}sulfonyl)butanoic acid

4-{[4-({3-[(cyclopropylanjmo)carbonylaminol-5-(trifluoromemyl)phenyl}methoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

3-phenyl-4-({4-[(3-{[(3-ρyridyj^ethyl)am o]carbonylamino}phenyl)methoxy]phenyl}sulfonyl)butanoic acid

4-{[4-({4-methyl-3-[(memylam o)carbonylamino]phenyl}methoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

4-({4-[(3-{[(3-ρyridyiιnethyl)anιmolcarbonylanmo}phen^

4-{[4-({2-cMoro-5-[(methylanuno)carbonylamino]phenyl}me1hoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

3-phenyl-4-({4-[(3-{| ^enzylanι o]carbonylamino}phenyl)methoxy]phenyl}sulfonyl)butanoic acid

3-ρhenyl-4-{[4-({3-[(ρhenylammo)carbonylamino]phenyl}methoxy)ρhenyl]sulfonyl}butanoic acid

4-{[4-({5-[(cyclopropylarnmo)carbonylamino]-2-methoxyphenyl}methoxy)phenyl]sulfonyl}-3-phenylbutanoic acid 4-{[4-({4-cMoro-3-[(cyclopropylarn o)carbonylaminolphenyl}metfaoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

3-(3,5-dichlorophenyl)-4-{[4-({3-[(ethylanjino)carbonylanιino]phenyl}methoxy)phenyl]sulfonyl}butanoic acid

4-({4-[(3-{[(2-moφholm-4-ylethyl)aιnino]carbonylam o}phenyl)methoxy]phenyl}sulfonyl)-3-phenylbutanoic acid

4-{[4-({3-[(cyclopropylarrιino)carbonylarmno]-4-methylphenyl}methoxy)phenyl]sulfonyl}-3-ρhenylbutanoic acid

3-(3,5-dichlorophenyl)-4-({4-[(3-{[(memylethyl)amino]carbonylammo}phenyl)methoxy]phenyl}sulfonyl)butanoic acid

4-{[4-({4-[(ethylaιnino)carbonylamino]ρhenyl}methoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

4-{[4-({3-[(eflιylamino)carbonylamino]phenyl}methoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

3-phenyl-4-[(4-{[3-(4H,5H,6H-l,3-thiazin-2-ylamino)phenoxy]methyl}phenyl)sulfonyl]butanoic acid

3-ρhenyl-4-[(4-{[3-(l,3-tMazolin-2-ylamino)phenoxy]methyl}phenyl)sulfonyl]butanoic acid

3-phenyl-4-[(4-{2-[3-(2-pyridylcarbonylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid

4- {[4-(2- {3-[2-(memylamino)acelylamino]phenyl} ethyl)phenyl]sulfonyl} -3 -phenylbutanoic acid

3-ρhenyl-4-[(4-{2-[3-(propanoylaιrjino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid

3-phenyl-4-[(4-{2-[3-(l,3-Mazol-4-ylcarbonylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid, 2,2,2-trifluoroacetic acid

4-{[4-(2-{3-[(immo-2-tMenylme yl)amino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

3-ρhenyl-4-[(4-{2-[3-(l-pyj olm-2-ylamino)phenyl]etfayl}phenyl)sulfonyllbutanoic acid

4-{[4-(2-{3-[(inι ophenylme yl)amino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

4-{[4-(2-{3-f(5-oxo(l-pyrrolin-2-yl))amino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

4-({4-[2-(3-aminophenyl)ethyl]phenyl}sulfonyl)-3-phenylbutanoic acid

(3R)-4-{[4-(2-{3-[(2-ammoethyl)aminolphenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

4-( {4-[2-(2-anjinobenzothiazol-5-yl)ethyl]phenyl} sulfonyl)-3-phenylbutanoic acid

4-[(4-{2-[3-(l,3-oxazolm-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoic acid

4-({4-[2-(6-amino(3-pyridyl))ethyl]phenyl}sulfonyl)-3-phenylbutanoic acid

4-[(4-{2-[6-(2,5-dimethylpyrrolyl)(3-pyridyl)]ethyl}phenyl)sulfonyl]-3-ρhenylbutanoic acid

(3R)-3-ρhenyl-4-[(4-{2-[3-(2-pyridylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid

3-phenyl-4-{[4-(2-{3-[(2-pyridylme yl)amino1phenyl}ethyl)phenyl]sulfonyl}butanoic acid

3-(4-fluorophenyl)-4-[(4-{2-[3-(4H,5H,6H-l,3-tMazin-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid

3-(4-fluorophenyl)-4-[(4-{2-[3-(4H,5H,6H-l,3-τMaz -2-ylamino)ρhenyl]ethyl}phenyl)sulfonyl]butanoic acid

4-[(4-{2-[4-fluoro-3-(4H,5H,6H-l,3-tfaiaz -2-ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoic acid

4-[(3-cMoro-4-{2-[3-(4H,5H,6H-l,3-tMazm-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-(4-fluorophenyl)butanoic acid

(3R)-4-[(4-{2-[2-methoxy-5-(4H,5H,6H-l,3-ι^azm-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-ρhenylbutanoic acid

3-ρhenyl-4-[(4-{2-[3-(4H,5H,6H-l,3-t azin-2-ylamino)phenyl]ethyl}ρhenyl)sulfonyl]butanoic acid

(3R)-3-phenyl-4-{[4-(2-{3-[(4H,5H,6H-l,3-tMazin-2-ylamino)methyl]ρhenyl}ethyl)phenyl]sulfonyl}butanoic acid

3-ρhenyl-4-[(3-{2-[3-(4H,5H,6H-l,3-tMazin-2-ylamino)phenyl]ethyl}ρhenyl)sulfonyl]butanoic acid

3-phenyl-4-[(3-{2-[4-(4H,5H,6H-l,3-1hiaz -2-ylamino)phenyl]etfayl}phenyl)sulfonyl]butanoic acid

3-phenyl-4-[(4-{2-[4-(4H,5H,6H-l,3- azin-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid

3-phenyl-4-[(4-{2-[3-(l,3-<Mazolin-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid

(3R)-3-ρhenyl-4-{[4-(2-{3-[(l,3-tMazolin-2-ylammo)methyl]ρhenyl}ethyl)phenyl]sulfonyl}butanoic acid

3-phenyl-4-[(4-{2-[3-(l,3-t azolm-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid

4-{[4-(2-{3-[(5-methyl(l,3-tMazolm-2-yl))anjino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

4-{[4-(2-{3-[(4-metfayl(l,3-lMazolin-2-yl))amino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

(3R)-4-{[4-(2-{3-[(4-me yl(l,3-tMazolin-2-yl))amino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

3 -ρhenyl-4- [(4-{2-[4-(l,3 -tfaiazolin-2-ylamino)phenyl] ethyl} phenyl) sulfonyl]butanoic acid

3-(4-fluorophenyl)-4-[(4- {2-[3-(l ,3-tMazolin-2-ylamino)ρhenyllethyl}phenyl)sulfonyl]butanoic acid

4-[(3-cMoro-4-{2-[3-(l,3-tMazolin-2-ylanιino)phenyl]ethyl}phenyl)sulfonyl]-3-(4-fluorophenyl)butanoic acid

4-[(4-{2-[4-fluoro-3-(l,3-tMazolin-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoic acid

101 3-(4-fluorophenyl)-4-[(4-{2-[3-(l,3-Mazol-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid

102 3-(4-fluoroρhenyl)-4-[(4-{2-[3-(4,5,6-trihyάtocyclopenta[^

103 (3R)-4-[(4-{2-[2-memoxy-5-(l,3-thiazolin-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoic acid

104 (3R)-4-{[4-(2-{5-[(4,4-dύnethyl(l,3-tMazolin-2-yl))ammo]-2-memoxyphenyl}ethyl)phenyllsulfonyl}-3-pheny

105 (3R)-4-[(4-{2-[2-methoxy-5-(4,5,6-trihyOJOcyclopentø^^

106 (3R)-4-[(4-{2-[2-memoxy-5-(l,3-Mazol-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-ρhenylbutanoic acid

107 3-phenyl-4-[(4-{2-[3-(4,5,6-trιlιydrocycloρenta[l,2-d]l,3-tMazo ^

108 4-{[4-(2-{3-[(4,5-dimethyl(l,3-iMazol-2-yl))aniino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

109 3-phenyl-4-{[4-(2-{3-[(4-ρhenyl(l,3-t azol-2-yl))amino]phenyl}ethyl)phenyl]sulfonyl}butanoic acid

110 4-{[4-(2-{3-[(4-methyl(l,3-tMazol-2-yl))amino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

111 4-[(4-{2-[3-(^eικoMazol-2-ylamino)phenyl]ethyl}ρhenyl)sulfonyl]-3-phenylbutanoic acid

112 4-{[4-(2-{3-[(4,4-dime yl(l,3-tMazolin-2-yl))anιino]ρhenyl}ethyl)phenyl]sulfonyl}-3-ρhenylbutanoic acid

113 (3R)-4-{[4-(2-{3-[(4,4-d]methyl(l,3-thiazolin-2-yl))amino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

114 4-{[3-(2-{4-[(4,4-dimethyl(l,3-tMazol -2-yl))aπjjbιo]phenyl}e1jιyl)phenyl]sulfonyl}-3-phenylbutano

115 4-{[3-(2-{3-[(4,4-djmethyl(l,3- azoliα-2-yl))amino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

116 4-{[4-(2-{3-[(4,5-dime yl(l,3-tMazol-2-yl))anιino]phenyl}ethyl)phenyl]sulfonyl}-3-(3-ρyridyl)butanoic acid

117 3-ρhenyl-4-{[4-(2-{3-[(5-phenyl(l,3-Mazolm-2-yl))amino]phenyl}ethyl)ρhenyl]sulfonyl}butanoic acid

118 4-{[4-(2-{3-[(4-oxo(l,3-lMazolin-2-yl))amino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

119 4-{[4-(2-{3-[(l-aza-3-tMaspjτo[4.4]non-l-en-2-yl)anιino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

120 4-{[4-(2-{3-[(4-methyl-5-phenyl(l,3-tMazolm-2-yl))aιnino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

121 4-{[4-(2-{3-[(5-methyl-4-oxo(l,3-thiazol -2-yl))amino]phenyl}ethyl)ρhenyl]sulfonyl}-3-phenylbutanoic acid

122 (3R)-4-{[4-(2-{3-[(5-methyl(l,3-thiazolin-2-yl))anιmo]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

123 (3R)-4-{[4-(2-{3-[(5,5-dimethyl(l,3-tMazolin-2-yl))ammo]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

124 3-ρhenyl-4-[(4-{2-[3-(l,3-thiazol-2-ylamino)phenyl]ethyl}ρhenyl)sulfonyl]butanύic acid

125 (3R)-3-phenyl-4-[(4-{2-[3-(l,3-tfaiazol-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid

126 (3S)-3-phenyl-4-[(4-{2-[3-(l,3-tMazol-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid

127 4-{[4-(2-{3-[(4,5-dimethyl(l,3-t azol-2-yl))aιnino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

128 4-({4-[2-(3-{[(lE)-2-aza-2-cyano-l-(me ylamino)vinyl]amino}phenyl)ethyl]phenyl}sulfonyl)-3-(4-fluorophenyl)butanoic acid

129 3-(4-fluorophenyl)-4-[(4-{2-[3-(3,4,5,6-tetrahydropyrj^din-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]butanoic acid

130 4- { [4-(2- {3-[(5,5-dimethyl(2-nmdazolin-2-yl))am o]phenyl} ethyl)phenyl] sulfonyl} -3 -(4-fluorophenyl)butanoic acid

131 3-(4-fluorophenyl)-4-[(4-{2-[3-(2-imidazolm-2-ylamino)phenyl]etfayl}phenyl)sulfonyl]butanoic acid

132 4-{[4-(2-{3-[(5,5-djmethyl(3,4,5,6-tetrahyo^opyrimidm-2-yl))ammo]phenyl}ethyl)phenyl]sulfonyl}-3-(4-fl^ acid

133 (3R)-4-{[4-(2-{3-[(5-hyά Oxy(3,4,5,6-tefrahydropyri]^

134 (3R)-4-[(4-{2-[3-(2-immoimidazoUdinyl)phenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoic acid

135 (3R)-4-[(4-{2-[3-(benziιmdazol-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoic acid, 2,2,2-trifluoroacetic acid

136 4-{[4-(2-{3-[(4-oxo(2-inn^azolin-2-yl))amino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid, 2,2,2-trifluoroacetic acid

137 4-[(4-{2-[3-(2-iι dazolm-2-ylamino)phenyl]ethyl}phenyl)sulfonyl]-3-phenylbutanoic acid

138 4-[(3-{2-[3-(2-imidazolm-2-ylajiιino)ρhenyl]ethyl}ρhenyl)sulfonyl]-3-ρhenylbutanoic acid

139 4-({4-[2-(3-{[4-(cyclopropylamino)-2,3-dioxocyclobut-l(4)-enyl]amino}phenyl)ethyl]phenyl}sulfonyl)-3-phenylbutanoic acid

140 4-{ [4-(2- {4-fluoro-3-[(me ylamino)carbonylamino]phenyl} ethyl)phenyl]sulfonyl} -3-phenylbutanoic acid

141 4-{[4-(2-{3-[(ethylamino)carbonylarnino]-4-fluorophenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

142 4-{[4-(2-{3-[(ethylamino)carbonylamino]phenyl}ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

143 (3R)-4- { [4-(2- {3-[(e1hιylammo)carbonylamino]phenyl} ethyl)phenyl]sulfonyl}-3-phenylbutanoic acid

144 3-phenyl-4-({4-[2-(3-{[(2-pyridylmemyl)ammo]carbonylamino}phenyl)ethyllphenyl}sulfonyl)butanoic acid

145 4-{[4-(2-{3-[(cyclopropylarmno)carbonylamino]phenyl}ethyl)phenyl]sulfonyl}-3-(2-fluorophenyl)butanoic acid

146 3-(2-c orophenyl)-4-{[4-(2-{3-[(cycloproρylarnmo)carbonylamino]phenyl}ethyl)phenyl]sulfonyl}butanoic acid

147 3-(2-fluorophenyl)-4-({4-[2-(3-{[(2-pyridyJ^ethyl)ammo]carbonylanιmo}phenyl)ethyl]phenyl}sulfonyl)butanoic acid

148 4-{[4-(2-{3-[(ethylanjino)carbonylanjmo]phenyl}ethyl)phenyl]sulfonyl}-3-[3-(trifluorome yl)phenyl]bu^ acid

149 4-{[4-(2-{3-[(cycloproρylanιmo)carbonylarnino]phenyl}ethyl)phenyllsulfonyl}-3-(4-phenoxyphenyl)butanoic acid

150 3-(2-cMorophenyl)-4-{[4-(2-{4-[(cyclopropylarmno)carbonylamino]phenyl}ethyl)phenyl]sulfonyl}butanoic acid

151 3-[3,5-bis(trifluoromemyl)ρhenyl]-4-{[4-(2-{3-[(cyclopropylamino)carbonylammo]ρhenyl}ethyl)phenyl]sulfonyl}butanoic acid

152 3-(4-phenoxyphenyl)-4-({4-[2-(3-{[(2-pyridylmemyl)aj ιino]carbonylamino}phenyl)ethyllphenyl}sulfonyl)butanoic acid

153 -(4-cyanophenyl)-4-({4-[2-(4-{[(2-pyridyj^ethyl)aminolcarbonylanιmo}phenyl)ethyl]phenyl}sulfonyl)butanoic acid

154 3-(4-cyanophenyl)-4-({4-[2-(3-{[(2-ρyridyjjnethyl)aminolcarbonylamino}ρhenyl)e1hyl]phenyl}sulfonyl)butanoic a

155 3-(4-cyanophenyl)-4-{[4-(2-{3-[(cyclόρropylam o)carbonylamino]phenyl}ethyl)phenyl]sulfonyl}butanoic acid

156 3-(4-cyanophenyl)-4- { [4-(2- {4-[(cyclopropylam o)carbonylamino]phenyl} ethyl)ρhenyl]sulfonyl}butanoic acid

157 3-phenyl-4-[(4- {2-[3-(4H,5H,6H-l ,3- azin-2-ylamino)phenyl]ethynyl}phenyl)sulfonyl]butanoic acid

158 3-phenyl-4-[(4-{2-[3-(l,3-t azolin-2-ylaιijino)phenyl]ethynyl}phenyl)sulfonyl]butanoic acid

159 3-ρhenyl-4-[(4-{2-[3-(l,3-t azol-2-ylamino)ρhenyl]ethynyl}ρhenyl)sulfonyl]butanoic acid

160 4-[(4-{(lE)-2-[3-(4H,5H,6H-l,3-thiaz -2-ylamino)phenyl]vinyl}phenyl)sulfonyl]-3-phenylbutanoic acid, 2,2,2-trifluoroacetic acid

161 4-[(4-{(lE)-2-[3-(l,3-tMazolm-2-ylaιnino)phenyl]vinyl}phenyl)sulfonyl]-3-phenylbutanoic acid, 2,2,2-trifluoroacetic acid

162 4-({4-[(4-aminoρhenyl)carbonyl]phenyl}sulfonyl)-3-phenylbutanoic acid

163 4-{[4-({4-[(5-hydroxy(3,4,5,6-tetrahydropyrirmdm-2-yl))ammo]phenyl}carbonyl)phenyl]s fonyl}-3-phenylbutano acid

164 3-phenyl-4-[(4-{[4-(4H,5H,6H-l,3-tMazm-2-ylamino)phenyl]carbonyl}ρhenyl)sulfonyl]butanoic acid

165 4-[(4-{(lE)-2-aza-2-memoxy-l-[4-(4H,5H,6H-l,3-tMaz -2-ylanιmo)phenyl]vinyl}phenyl)sulfonyl]-3-phenylbutanoic acid

166 4-[(4-{(lZ)-2-aza-2-memoxy-l-[4-(4H,5H,6H-l,3-ιluazin-2-ylanjino)phenyl]'vdnyl}phenyl)sulfonyl]-3-phenylbutanoic acid

167 3-phenyl-4-[(4-{[3-(4H,5H,6H-l,3-tMazin-2-ylamino)ρhenyl]carbonyl}ρhenyl)sulfonyl]butanoic acid

168 4- { [4-( {4-[(5-methyl(l ,3-tMazolin-2-yl))amino]phenyl} carbonyl)phenyl]sulfonyl} -3-phenylbutanoic acid

169 4-{[4-({4-[(4-me yl(l,3-t azolin-2-yl))amino]phenyl}carbonyl)phenyl]sulfonyl}-3-phenylbutanoic acid

170 3-phenyl-4-[(4-{[4-(l,3-tMazolm-2-ylamino)phenyl]carbonyl}phenyl)sulfonyl]butanoic acid

206 4-[(3- {4-[(4-methyl(l ,3-t azolin-2-yl))aminolphenoxy}ρhenyl)sulfonyl]-3-phenylbutanoic acid

207 3-phenyl-4-[(4-{4-[(l,3-tMazolin-2-ylamino)methyllphenoxy}ρhenyl)sulfonyl]butanoic acid

208 3-phenyl-4-[(4-{4-[(4H,5H,6H-l,3-tfaiazin-2-ylamino)methyl]phenoxy}ρhenyl)sulfonyl]butanoic acid

209 3-phenyl-4-({3-[4-(l,3-tMazoJ^-2-ylamino)phenoxy]phenyl}sulfonyl)butanoic acid

210 3-ρhenyl-4-[(3- {4-[(l ,3-tMazol -2-ylamino)methyl]phenoxy}phenyl)sulfonyl]butanoic acid

211 4-[(3-{4-[(5-me yl(l,3-tMazolin-2-yl))amino]phenoxy}ρhenyl)sulfonyl]-3-phenylbutanoic acid

212 3-ρhenyl-4-[(3-{4-[(4H,5H,6H-l,3-tfaiazin-2-ylamino)methyl]phenoxy}phenyl)sulfonyl]butanoic acid

213 3-(3-pyridyl)-4-({4-[4-(4,5,6-trihydrocyclopenta[l,2-d]l,3-tM

214 3-ρhenyl-4-[(4-{4-[(l,3-tfaiazol-2-ylamino)metfayl]phenoxy}phenyl)sulfonyl]butanoic acid

215 3-ρhenyl-4-({4-[4-(4,5,6-trihydrocyclopenta[l,2-d]l,3-lMazol-2-ylanιino)phenoxy]phenyl}sulfonyl)butanoic acid

216 4-({4-[3-bromo-4-(l,3-tMazolm-2-ylamino)ρhenoxy]ρhenyl}sulfonyl)-3-phenylbutanoic acid

217 4-[(4-{3-[(5-methyl(l,3-1hiazolin-2-yl))amino]phenoxy}phenyl)sulfonyl]-3-phenylbutanoic acid

218 4-[(4-{3-[(4-metfayl(l,3-thiazolin-2-yl))amino]phenoxy}phenyl)sulfonyl]-3-phenylbutanoic acid

219 4-[(4-{3-[(4,4-dimemyl(l,3-tMazolin-2-yl))amino]phenoxy}phenyl)sulfonyl]-3-ρhenylbutanoic acid

220 3-ρhenyl-4-({4-[3-(l,3-tMazolin-2-ylamino)phenoxy]ρhenyl}sulfonyl)butanoic acid

221 3-phenyl-4-[(3- {4-[(4,5,6-trihydrocyclopenta[l ,2-d] 1 ,3-tMazol-2-ylamino)methyl]phenoxy}ρhenyl)sulfonyl]butanoic acid

222 4-{[4-(4-{[(5-methyl(l,3-tMazolin-2-yl))amino]methyl}phenoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

223 4-{[4-(4-{[(4-methyl(l,3-tMazol -2-yl))aj jino]methyl}ρhenoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

224 3-ρhenyl-4-({4-[3-(l,3-tMazol-2-ylamino)phenoxy]phenyl}sulfonyl)butanoic acid

225 3-phenyl-4-( {4-[3-(4,5,6-trihydrocyclopenta[l ,2-d] 1 ,3-thiazol-2-ylamino)ρhenoxy]ρhenyl} sulfonyl)butanoic acid

226 4-[(4-{4-[(4,5-dimemyl(l,3-tMazol-2-yl))amino]phenoxy}phenyl)sulfonyl]-3-phenylbutanoic acid

227 3-phenyl-4-({3-[4-(4,5,6-trihydrocyclopenta[l,2-d]l,3-tMazol-2-ylanιino)phenoxy]phenyl}sulfonyl)butanoic acid

228 4-{[4-(4-{[4-(4-fluorophenyl)(l,3-thiazol-2-yl)]amino}phenoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

229 4-[(3-{4-[(4,5-dime yl(l,3-tMazol-2-yl))amino]phenoxy}phenyl)sulfonyl]-3-phenylbutanoic acid

230 4-[(4- {4-[(4-methyl(l ,3-thiazol-2-yl))amino]phenoxy}ρhenyl)sulfonyl]-3-phenylbutanoic acid

231 3-ρhenyl-4-({4-[4-(l,3-tMazol-2-ylamiπo)ρhenoxy]ρhenyl}sulfonyl)butanoic acid

232 4-[(3-{4-[(4-memyl(l,3-Mazol-2-yl))amino]phenoxy}phenyl)sulfonyl]-3-phenylbutanoic acid

233 3-phenyl-4-({3-[4-(l,3-tMazol-2-ylamino)phenoxy]phenyl}sulfonyl)butanoic acid

234 3-ρhenyl-4-[(3-{4-[(4-phenyl(l,3-tMazol-2-yl))amino]ρhenoxy}phenyl)sulfonyl]butanoic acid

235 3-ρhenyl-4-({3-[4-(4,5,6,7-te1τahydrobeij :otfaiazol-2-ylamino)phenoxy]phenyl}sulfonyl)butanoic acid

236 4-({4-[4-(benzotMazol-2-ylamino)phenoxy]phenyl}sulfonyl)-3-phenylbutanoic acid

237 4-{[3-(4-{[4-(4-fluorophenyl)(l,3-thiazol-2-yl)]amino}phenoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

238 4-{[3-(4-{[4-(tert-butyl)(l,3-thiazol-2-yl)]amino}phenoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

239 3-phenyl-4-({3-[3-(l ,3-tfaiazol-2-ylamino)phenoxy]phenyl} sulfonyl)butanoic acid

240 4-( {3 ,5-dichloro-4-[2-chloro-4-(l ,3-tmazolin-2-ylamino)phenoxy]phenyl} sulfonyl)-3 -phenylbutanoic acid

241 4-({3,5-dicMoro-4-[2-cMoro-4-(4,5,6-trihydrocyclopenta[l,2-d^

242 4-({4-[4-({2,3-dioxo-4-[(3-pyridylme yl)amino]cyclobut-l(4)-enyl}amino)phenoxy]phenyl}sulfonyl)-3-phenylbutanoic acid, chloride

243 4-{[4-(4-{[4-(cyclopropylammo)-2,3-dioxocyclobut-l(4)-enyl]anιino}phenoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

244 4- [(3 - {3 -[(ethylamino) carbonylamino]phenoxy} ρhenyl)sulfonyl] -3 -phenylbutanoic acid

245 4- { [3-(4- { [(ethylamino)carbonylamino]methyl} phenoxy)phenyl] sulfonyl} -3-phenylbutanoic acid

246 4-[(3-{4-[(ethylanι o)carbonylamino]phenoxy}phenyl)sulfonyl]-3-phenylbutanoic acid

247 4-[(3-{4-[(ammotMoxomemyl)amino]phenoxy}phenyl)sulfonyl]-3-phenylbutanoic acid

248 4-[(4-{3-[(ethylam o)carbonylamino]phenoxy}phenyl)sulfonyl]-3-phenylbutanoic acid

249 3 -(3 -pyridyl)-4- { [4-(4- { [(3 -pyridylmethyl)amino] carbonylamino } phenoxy)phenyl] sulfonyl} butanoic acid

250 4-[(4-{4-[(ethylamino)carbonylamino]phenoxy}phenyl)sulfonyl]-3-phenylbutanoic acid

251 3-phenyl-4-{[4-(4-{[(2-pyridylmetiιyl)ammo]carbonylamino}phenoxy)ρhenyl]sulfonyl}butanoic acid

252 4-[(4-{4-[(cycloproρylanjino)carbonylamino]phenoxy}phenyl)sulfonyl]-3-ρhenylbutanoic acid

253 4-[(3,5-dicMoro-4-{2-cMoro-4-[(ethylanjjύao)carbonylarnino]phenoxy}phenyl)sulfonyl]-3-ρhenylbutanoic acid

254 3-phenyl-4-{[4-(4-{[(2-Menyj^ethyl)am o]carbonylamino}phenoxy)phenyl]sulfonyl}butanoic acid

255 4-{[4-(4-{[(cycloproρyjjnethyl)anjino]carbonylamino}phenoxy)phenyl]sulfonyl}-3-phenylbutanoic acid

256 -{[4-(2,6-dicMoro-4-{[(cycloproρylmethyl)ammo]carbonylam o}ρhenoxy)-3-cMoroρhenyl]sulfonyl}-3-phenylbutanoic

257 4-[(3,5-dicMoro-4-{2-chloro-4-[(cyclopropylarn o)carbonylamino]phenoxy}phenyl)sulfonyl]-3-ρhenylbutanoic acid

258 4-{[4-(2,6-dicMoro-4-{[(2,2,2-trifluoroethyl)arnmo]carbonylanjJno}phenoxy)-3-cMorophenyl]sulfonyl}-3-phenylbutm^

259 4-({4-[4-({[(2-fluorophenyl)memyl]ammo}carbonylamino)phenoxy]phenyl}sulfonyl)-3-phenylbutanoic acid

260 4-({4-[4-({[(3-fluorophenyl)memyl]amino}carbonylamino)ρhenoxy]phenyl}sulfonyl)-3-phenylbutanoic acid

261 4-{[4-(4-{[(2-cyanoethyl)ammo]carbonylamino}phenoxy)phenyl]sulfonyl}-3-ρhenylbutanoic acid

262 4-{[4-(2,6-dicMoro-4-{[(2-tMenyj^ethyl)aιnmo]carbonylamino}phenoxy)-3-chlorophenyl]sulfonyl}-3-phenylbutanoic acid

263 4-({4-[4-({[(4-fluorophenyl)me yl]anjino}carbonylamino)phenoxy]phenyl}sulfonyl)-3-phenylbutanoic acid

264 4-({4-[2,6-dicMoro-4-({[(2-fluoroρhenyl)memyl]am o}carbonylammo)phenoxy]-3-cMorophenyl}sulfonyl)-3-phenylbut^

265 4- { [4-(4- { [(2,2-dimemylρropyl)anιino]carbonylamino}ρhenoxy)phenyl]sulfonyl} -3-phenylbutanoic acid

266 4-({4-[2,6-dicMoro-4-({[(3-fluoroρhenyl)memyl]aιnmo}carbonylarnino)phenoxy]-3-cMorophenyl}sulfonyl)-3-phenylbutanoic ac

267 3-phenyl-4-{[4-(4-{[(2,2,2-trifluoroethyl)aιnmo]carbonylamino}phenoxy)phenyl]sulfonyl}butanoic acid

268 4-{[4-(2,6-dic oro-4-{[(2-cyanoethyl)ammo]carbonylarnino}phenoxy)-3-chloroρhenyl]sulfonyl}-3-phenylbutanoic acid

269 4-{[4-(4-{[(me ylethyl)amino]carbonylamnιo}phenoxy)phenyl]sulfonyl}-3-ρhenylbutanoic acid

270 4-{[4-(2,6-dicMoro-4-{[(me yle1hyl)anιmo]carbonylamino}phenoxy)-3-chlorophenyl]sulfonyl}-3-ρhenylbutanoic acid

271 4-({4-[2,6-dicMoro-4-({[(4-fluorophenyl)memyl]amjjio}carbonylanimo)phenoxy]-3-chlorophenyl}sulfonyl)-3-phenylbutanoic acid

272 4-{[4-(4-{[(2,2-ά^ethylρropyl)amino]carbonylanjino}-2,6-dicMorophenoxy)-3-cMoroρhenyl]sulfonyl}-3-phenylbutanoic acid

273 4-{[4-(2,6-dicMoro-4-{[(2-me oxyethyl)amino]carbonylamino}phenoxy)-3-chlorophenyl]sulfonyl}-3-phenylbutanoic acid

274 4-{[4-(4-{[(2-memoxyetfayl)ammo]carbonylamino}phenoxy)phenyl]sulfonyl}-3-ρhenylbutanoic acid

275 4-{[4-(4-{[(cyclopropylammo)carbonylanιino]methyl}phenoxy)ρhenyl]sulfonyl}-3-phenylbutanoic acid

276 3-phenyl-4-({4-[4-(l,3-thiazol-2-ylamino)phenylthio]phenyl}sulfonyl)butanoic acid

277 4-[(3-{3-[(ethylammo)carbonylamino]phenylthio}phenyl)sulfonyl]-3-phenylbutanoic acid

278 4-[(3-{4-[(ethylarnmo)carbonylamino]phenylthio}phenyl)sulfonyl]-3-phenylbutanoic acid

279 4-[(4-{3-[(ethylanι o)carbonylamino]phenylthio}phenyl)sulfonyl]-3-phenylbutanoic acid

280 4-[(4-{4-[(ethylamino)carbonylamino]phenylthio}phenyl)sulfonyl]-3-ρhenylbutanoic acid

281 3-ρhenyl-4-[(4-{[4-(2-pyridylcarbonylamino)phenyl]sulfonyl}phenyl)sulfonyl]butanoic acid

282 4-({4-[(4-aminophenyl)sulfonyl]phenyl}sulfonyl)-3-phenylbutanoic acid

283 3-phenyl-4-[(3-{[3-(l,3-tMazol -2-ylamino)phenyl]sulfonyl}phenyl)sulfonyl]butanoic acid

284 4-{[3-({3-[(ethylammo)carbonylamino]phenyl}sulfonyl)phenyl]sulfonyl}-3-phenylbutanoic acid

285 4- { [3-( {4-[(etfaylanj o)carbonylamino]phenyl} sulfonyl)phenyl] sulfonyl} -3-phenylbutanoic acid

286 4-{[4-({3-[(ethylamino)carbonylamino]phenyl}sulfonyl)phenyl]sulfonyl}-3-phenylbutanoic acid

287 4-{[4-({4-[(ethylamino)carbonylamino]phenyl}sulfonyl)phenyl]sulfonyl}-3-phenylbutanoic acid

288 3-phenyl-4-({4-[(4-{[(2-pyridyhτιe yl)am o]carbonylamrno}phenyl)sulfonyl]ρhenyl}sulfonyl)butanoic acid

289 3-phenyl-4-({4-[(4-{[(2-ρyridylιnethyl)ammo]carbonylanιino}phenyl)sulfonyl]phenyl}sulfonyl)butanoic acid

290 3-phenyl-4-({4-[(4-{[(2-pyridyjjnethyl)ammo]carbonylamino}phenyl)sulfonyl]phenyl}sulfonyl)butanoic acid

291 -{[(3-{2-[3-(l,3-oxazolin-2-ylammo)phenyl]ethyl}phenyl)sulfonyl]amino}-3-phenylpropanoic acid

292 3-{[(3-{2-[3-(2-]^dazolm-2-ylanjino)phenyl]ethyl}phenyl)sulfonyl]an]ino}-3-phenylpropanoic acid

293 (3R)-3-{[(3-{2-[3-(2-imidazolm-2-ylanj o)phenyl]ethyl}ρhenyl)sulfonyl]amino}-3-phenylρropanoic acid, 2,2,2-trifluoroacetic acid

294 (3S)-3-{[(3-{2-[3-(2-imidazolin-2-ylamino)phenyl]etfayl}phenyl)sulfonyl]amino}-3-ρhenylρropanoic acid, 2,2,2-trifluoroacetic acid

295 3-{[(4-{2-[3-(2-imidazoj^-2-ylanjmo)phenyl]ethyl}phenyl)sulfonyl]amino}-3-phenylpropanoic acid

296 (3R)-3-({ [3-(2- {3-[(ethylammo)carbonylamino]phenyl} ethyl)phenyl]sulfonyl} amino)-3-phenylpropanoic acid

297 (3R)-3-({[3-(2-{3-[(cycloρropylaιnmo)carbonylanm o]ρhenyl}ethyl)ρhenyl]sulfonyl}amino)-3-phenylρropanoic acid

298 3-[({3-[2-(3-{[(memylethyl)ammo]carbonylarmno}pheny

299 (3R)-3-[({3-[2-(3-{[N-((lS,2R)-2-phenylcyclopropyl)carbamoyl]amino}phenyl)e1jιyl]phenyl}sulfonyl)ammo]-3-phenylpropano

300 (3R)-3-[({3-[2-(3-{[(4-memoxyphenyl)anmo]carbonylanιmo}

301 (3R)-3-[({3-[2-(3-{[(2,4-difluorophenyl)anιino]carbonylammo}ρhenyl)e1hyl]ρhenyl}sulfonyl)anιmo]-3-phenylproρanoic acid

302 (3R)-3-{[(3-{2-[3-({[4-(dύne1jιylanjino)phenyl]ammo}carbonylamino)phenyl]ethyl}phenyl)sulfonyl]anm

303 3-[({3-[2-(3-{[(3,5-dimethylisoxazol-4-yl)aιn o]carbonylaπjino^^

304 (3R)-3-[({3-[2-(3-{[(4-me ylthioρhenyl)amino]carbonylanιmo}phenyl)ethyl]phenyl}sulfonyl)amino]-3-ρhenylpropanoic acid

305 3-phenyl-3-({ [3-(2- {3-[(phenylaιnmo)carbonylamino]phenyl} ethyl)phenyl]sulfonyl} amino)propanoic acid

Description of Treatment of Diseases or Conditions Associated with ec_vβ₃ α«rf _vβs integrin

Integrins are heterodimeric transmembrane proteins found on the surface of cells, which play an important part in the adhesion of the cells to an extracellular matrix. They recognize extracellular glycoproteins such as fϊbronectin or vitronectin on the extracellular matrix by means of the RGD sequence occurring in these proteins (RGD is the single letter code for the amino acid sequence arginine-glycine-aspartate).

The vitronectin integrin is a member of the integrin family and refers to three different integrins, α_vβιι; α_vβ₃ and α_vβ₅. Each of these integrins play an important part in biological processes such as cell migration and cell-matrix adhesion and in diseases/conditions where these processes are crucial steps. These diseases/conditions include angiogenesis, arteriosclerosis, cancer, ophthalmia and osteoporosis and restenosis (Schoop et al., WO 00/41469; Albers et al. WO 00/35864; Sugrue et al., U.S. Patent 5,900,414 which is hereby incorporated by reference); diabetic retinopathy, and conditions related to inhibition of bone resorption (which includes osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease and immobilization-induced osteopenia) (Duggan et al., WO 99/30713, WO 99/30709, WO 98/31359 and WO 98/08840; Chen et al., U.S. Patent 5,852,210 which are hereby incorporated by reference); macular degeneration (Duggan et al., ibid.); and inflammation and viral disease (Askew et al., WO 99/31061; Chen et al., U.S. Patent 5,852,210 which are hereby incorporated by reference).

The α_vβ integrin binds to a wide range of ligands including fibrin, fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand's factor, osteospontin and bone sialoprotein I (Brooks et al., U.S. Patent 5,766,591 which is hereby incorporated by reference) which explains the association of the wide variety of diseases and conditions mentioned above with the α_vβ₃ integrin.

The α_vβ₃ integrin is responsible for the interaction between osteoclasts, i.e. cells resorbing mineralized tissue, and the bone structure. The first step in the degradation of bone tissue is the adhesion of osteoclasts to the bone. This cell-matrix interaction takes place via the α_vβ₃ integrin, which is why the corresponding integrin plays an important part in this process (S.B. Rodan et al, J Endocrinology, vol. 154: S47-S56, (1997) which is hereby incorporated by reference). Osteolytic diseases such as osteoporosis are induced by an inequilibrium between bone formation and bone destruction, i.e. the resorption of bone material caused by accumulation of osteoclasts predominates.

The degradation of bone tissue can be suppressed by blockage of the α_vβ₃ integrins of the osteoclasts, since these are then unable to accumulate on the bone in order to absorb its substance (Hoffman et al., WO 98/18461; Fisher et al., Endocrinology, vol. 132: 1411, (1993) which are hereby incorporated by reference).

It is well known in the art that angio genesis plays a significant role in the establishment or exacerbation of a number of disorders including blindness (macular degeneration, diabetic retinopathy, corneal transplant, myopic degeneration), inflammation (arthritis, psoriasis, inflammatory bowel disease) and solid tumor cancer (lung, breast, prostate, colon, bladder, pancreas, melanoma, renal, glioblastoma, neuroblastoma, etc.) (cf. Narner, "The role of vascular cell integrins α_vβ₃ and α_vβ₅ in angiogenesis", from Regulation of Angiogenesis, ed. Goldberg and Rosen, publ. Birkhauser Nerlag, pages 361-390, (1997) which is hereby incorporated by reference)

The α_vβ₃ integrin occurs in large amounts on growing endothelial cells (as well as being expressed on other cell types such as smooth muscle, osteoclasts and tumor cells) and makes possible their adhesion to an extracellular matrix. As such, the α_vβ integrin plays an important part in angiogenesis, which is a crucial prerequisite for tumor growth and metastasis formation in carcinoses.

It has also been shown that the blockage of the α_vβ integrin is an important starting point for the treatment of disorders of this type. If the adhesion of growing endothelial cells to an extracellular matrix is suppressed by blocking the α_yβ₃ integrin, for example, by a cyclic peptide or a monoclonal antibody, the endothelial cells die. Therefore, angiogenesis does not occur, which leads to a cessation or regression of the growth tumor (Brooks et al., Cell, vol. 79: 1157-1164, (1994) which is hereby incorporated by reference) and the invasive properties of tumor cells and their capability for metastasis formation are markedly decreased if their α_vβ₃ integrin is blocked by an antibody (Brooks et al., J. Clin. Invest., vol. 96: 1815, (1995) which is hereby incorporated by reference). Likewise, it has been reported by Narner that administering antagonists for α_vβ₅ integrin has been efficacious in blocking NGEF, TGF-α and PMA-induced angiogenesis (Narner, ibid. and Friedlander et al., Science, vol. 270: 1500-1502, (1995) each of which is hereby incorporated by reference).

By means of the blockage of the α_vβ₃ integrin on cells of the smooth aorta vascular musculature with the aid of integrin integrin antagonists, the migration of these cells into the neointima and thus angioplasty leading to arteriosclerosis and restenosis can be suppressed (Brown et al., Cardiovascular Res., vol. 28: 1815, (1994) which is hereby incorporated by reference). Restenosis is also thought to be prevented by antagonists of α_vβ₃ integrin or α_vβ₅ integrin as the antagonists act to prevent the binding of osteopontin, a ligand for α_vβ₃ integrin or α_vβ₅ integrin which is implicated in the calcification of atherosclerotic plaques (Narner, ibid.)

Therefore, the state of the art supports that the administering of compounds which are antagonists of the α_vβ₃ integrin or α_vβ₅ integrin will be efficacious in the treatment of diseases and conditions related to the α_vβ₃ integrin or α_vβ₅ integrin.

For the purpose of the method of treatment of diseases and conditions related to the α_vβ₃ integrin or α_vβ₅ integrin, the scope of the compounds used also includes compounds which have the formula (N):

wherein the variables w, x, y, Q, R, L, D and R⁷ are as defined for the compound of formula (I). The difference between the compound of formula (I) and (V) is the presence of a - CH₂OH in formula (N) in place of -CO₂Rⁿ in formula (I). The compounds of formula (N) are prodrugs of compounds of formula (I) capable of undergoing biotransformation in vivo to afford the active carboxylic acid.

Other embodiments of the invention will be apparent to the skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

Biological Protocols α_vβ₃ Binding Assay: α_vβ₃ from human A375 cells was purified analogously to a procedure which was described by Wong et al. (Molecular Pharmacology, vol. 50, pages 529-537, (1996) - which is hereby incorporated by reference). In each case, 10 μL of α_vβ₃ (5 ng) in TBS pH 7.6, 2 mM CaCl₂, 1 mM MgCl₂, 1% n-octyl-glucopyranoside (Sigma); 10 μL of test compound in TBS pH 7.6, 0.1% DMSO and 45 μL of TBS pH 7.6, 2 mM CaCl₂, 1 mM MgCl₂, 1 mM MnCl₂ were incubated at room temperature for 1 h. In each case, 25 μL of WGA SPA beads (Amersham, 4 mg/mL) and 10 μL of echistatin (0.1 μCi, Amersham, chloramine-T labelled) were then added. After 16 hours at room temperature, the samples were measured in a scintillation measuring apparatus (Wallac 1450).

All of the compounds in Tables 1 - 8 had an IC₅₀ less than or equal to 1 μM. Selected compounds identified in Tables 1 - 8 also had an IC₅₀ less than or equal to 10 nM.

Bone Resorption Assay: Resorption of bone by osteoclasts was measured by analysis of resorption pits excavated by osteoclasts on slices of bovine femur. In performing the in vitro bone resorption assay, five-day-old rabbits were euthanized, their limbs removed and the cells from the bones were isolated. The cells were counted and plated onto bovine cortical bone chips( 4 mm x 4 mm x 400 microns) in 96-well plates containing compounds to be tested and the appropriate controls. After 48 h, the chips were washed (0.1 M cacodylate buffer, 0.25 M NH₄OH, H O, acetone), and stained (1% toluidine blue in 1% borax) to highlight the resorption pits. The pits were counted under a light microscope and averages were determined.

Angiogenesis Inhibition Assay: Using a modified version of the mouse Matrigel model of angiogenesis described by Kerr et al. (Anticancer Res., 19: 959-968, (1999) which is hereby incorporated by reference), the selected compounds were tested for angiogenesis inhibiting activity. Growth inhibition test on tumor cell lines: The human large intestine cell lines SW 480 and HT29 (ATCC No. CCL 228 and HTB38), the human breast cell lines MDA-MB 231, MCF-7 and BT-20 (ATCC No. HTB-, 26, 22 and 23) and the mouse melanoma cell line B16F10 (CRL 6475) were grown to confluence in Roux dishes in RPMI 1640 medium with addition of 10% FCS. They were then trypsinized and taken up in RPMI plus 10% FCS to a cell count of 50,000 cells or, for B16F10, 20,000 cell per mL. 100 μL of cell suspension well were added to a 96 microwell plate and incubated at 37 °C for 1 day in a CO₂ incubator. A further 100 μL of RPMI medium and 1 μL of DMSO were then added with the test substances. The growth was checked after day 6. For this, 25 μL of MTT solution (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was added to each starting well at a starting concentration of 5 mg/niL of H₂O. The plate was incubated at 37 °C for 5 hours in a CO₂ incubator. The medium was then aspirated and 100 μL of isopropanol/well were added. After shaking with 100 μL of H₂O for 30 min., the extinction was measured at 595 nm using a Multiplate Reader (BIO-RAD 3550-UV). Cystostatic action is indicated as an IC₅₀ value.

In vivo inhibition of tumor growth:

Material: In all in vivo experiments investigating the inhibition of tumor growth, athymic nude mice (NMRI nu/nu strain) were used. The tumor was developed by serial passage in nude mice. The human origin of the tumor was confirmed by isoenzymatic and immunohistochemical methods.

Experimental Setup: The tumor was implanted subcutaneously in both flanks of nu/nu nude mice 6 to 8 weeks old. The treatment was started, depending on the doubling time, as soon as the tumors had reached a diameter of 5 - 7 mm. The mice assigned to the treatment group or the control group (5 mice per group having 8 - 10 assessable tumors) by randomization. The individual tumors of the control group all grew progressively.

The size of the tumors was measured in two dimensions by means of a slide gauge. The tumor volume, which correlated well with the cell count, was then used for all assessments. The volume was calculated according to the formula "length x breadth x breadth 2" ([a x b²]/ 2. wherein a and b represent two diameters arranged at right angles. The values of the relative tumor volume (RTN) were calculated for each individual tumor by dividing the tumor size on day X with the tumor size on day 0 (at the time of randomization). The average values of the RTN were then used for further assessment.

The inhibition of the increase of the tumor volume (tumor volume of the test group/control group, T/C, in percent) was the final measured value.

Treatment: The compounds can be administered with a daily or an intermittent therapy schedule through a couple of days by intraperitoneal, intravenous, oral or subcutaneous means.

CSF-induced proliferation of hemapoietic stem cells: Bone marrow cells were flushed out of the femur mice. 10⁵ cells were incubated in McCoy 5 A medium (0.3% agar) together with recombinant murine GM-CSF (Genzyme, parent cell colony formation) and the substances (10^"4 to 100 μg/mL) at 37 °C and 7% CO₂. Seven days later, the colonies (<50 cells) and clusters (17-50 cells) were counted.

Other embodiments of the invention will be apparent to the skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the scope and spirit of the invention being indicated by the following claims.

Claims

AIM: A compound of formula (I) wherein: Q is a substituent selected from the group consisting of: (a) Y-C-NH- wherein Y is selected from the group consisting of: (al) d-Cs-alkyl, (a2) C -C8-cycloalkyl, (a3) C3-C8-cycloalkyl-C1-C3-alkyl, (a4) C3-C5-alkenyl, (a5) C4-C8-cycloalkenyl, (a6) C3-C5-alkynyl, (a8) Ce-do-aryl-d-Cs-alkyl, (a9) C6-C10-aryl-C3-C6-cycloalkyl, and (alO) (CH2)a-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein: (al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, Ci-C3-alkoxy, Q-C3- alkylthio, C6-C10-aryl and -NZ*Z2; and (a2) - (alO) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, Q-Q-alkoxy, d-d-alkyl, C1-C3-alkylthio, C6-Cι0-aryl or -NZ Z2, wherein 1 Z and Z are independently selected from the group consisting of hydrogen and d-d-alkyl, or 1 - Z and Z may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle; wherein Ya represents -NH or -NH-Y; (c) Y -C-NH- wherein X represents O, S or N(CN) ; NH (e) Yb-C— wherein for (c) - (e) YD represents -NH2, -NH-Y or -Y; (f) YC-NH-(CH2)U- wherein Yc is a heterocycle selected from: (fl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (f2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein: (f2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and (f2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (fl) - (f2) are optionally substituted by R; (g) YC=N- wherein Yc is as defined in (f) above; (h) YdYe-N- wwhheerreeiinn Yd and Ye are independently selected from the group consisting of hydrogen, d-d-alkyl, and d-C5-aminoalkyl; and (i) when w = 0, Q forms a four to eight membered heterocyclic ring fused to the aryl group to which it is attached to form a bicyclic ring, wherein said heterocyclic ring contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and at least one carbon atom and said heterocyclic ring is optionally substituted with d-C5-alkyl or -NZ3Z4 wherein Z3 and Z4 are independently selected from the group consisting of hydrogen and d- d-alkyl; represents a substituent selected from the group consisting of: (a) halogen, (b) C1-C4-alkyl, optionally substituted by halogen, (c) C6-do-aryl, optionally substituted by halogen, (d) NO2, (e) CN, (f) OR1, (g) C(=O)OR1, (h) S(=O)2OR1, (i) NR*R2, 0") C(=O)NR!R2, and (k) S(=O)2NR1R2 ; wherein for (f)-(k): R1 and R2 independently represent a substituent selected from the group consisting of: (1) hydrogen, (2) d-C -alkyl, optionally substituted by halogen, and (3) C3-C8-cycloalkyl, optionally substituted by halogen; or wherein for (i)-(k): R1 and R2 together with the nitrogen to which it is attached represents a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom; L represents a substituent selected from the group consisting of: (a) O, (b) C(=O), (c) CR3R4, (d) N(R5), (e) S(=O)z, ( ) C(=O)N(R5), (g) N(R5)C(=O), (h) S(=O)2N(R5) (i) N(R5)S(=O)2, 0) CR3R4-CR3R4, (k) CH2O, (1) OCH2, ( ) CH2N(R5), (n) N(R5)CH2, (o) CH=CH, (P) "C≡C" ; and (q) C(=NR3) R3 and R4 independently represents a substituent selected from the group consisting of: (1) hydrogen, (2) halogen, (3) d-d-alkyl, and (4) d-C3-alkoxy; wherein: when one or two R3 groups are d-C3-alkyl in L, said one or two R3 groups may constitute spiro rings or nonspiro rings wherein: (a) one group R3 is joined by a bond or by a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, to the carbon chain to which said group R is attached, and taken together with the carbon chain atom(s) to which said group R is attached, constitutes a ring of three to six members, wherein for CR3R4, when R3 is d-alkyl, the R3 group is joined by a heteratom as defined above, or (b) two groups R3 are joined by a bond or by a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur and taken together with the carbon chain atom(s) to which said two groups R3 are attached, constitute a ring of 3-6 members; or R5 represents a substituent selected from the group consisting of: (1) hydrogen, (2) d-C4-alkyl, optionally substituted by halogen, and (3) C -C8-cycloalkyl, optionally substituted by halogen; D represents a substituent selected from the group consisting of: (a) (CH2)v and (b) N(R6) wherein R6 represents a substituent selected from the group consisting of: (1) hydrogen, (2) d-C -alkyl, optionally substituted by halogen, and (3) C -C8-cycloalkyl, optionally substituted by halogen; and wherein: L is not C(=O)N(R5), N(R5)C(=O), S(=O)2N(R5) or N(R5)S(=O)2- when D is -NH-; R7 represents a substituent selected from the group consisting of: (a) C2-d-alkyl, (b) C3-C8-cycloalkyl, (c) d-C8-cycloalkyl-d-C3-alkyl, (d) C3-d-alkenyl, (e) C4-C8-cycloalkenyl, (f) C2-d-alkynyl, where (a)-(f) are optionally substituted by (1) OR8, (2) NR8R9, or (3) halogen; (g) C6-Cιo-aryl, (h) d-do-aryl-d-d-alkyl, (i) C6-C10-aryl-C3-C6-cycloalkyl, and (j) (CH2)b-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (g)-(j) are optionally substituted by one to three substituents selected from the group consisting of: (1) NO2; (2) CN, (3) halogen, (4) S(=O)2OH, (5) S(=O)nR10, (6) S(=O)2NR8R9, (7) NR8R9, (8) OR8, (9) C(=O)R10, (10) C(=O)OR8 ; or (11) C(=O)NR8R9; wherein: R8 and R9 are independently hydrogen or R10; or optionally when (g) - 0) are substituted by NR8R9, S(-O)2NR8R9 or C(-O)NR8R9, R8 and R9 together with the nitrogen to which it is attached represents a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitro gen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom; R10 represents a substituent selected from the group consisting of: (a) d-d-alkyl, (b) d-C8-cycloalkyl, (c) C3-C8-cycloalkyl-d-C3-alkyl; (d) d-d-alkenyl, (e) C4-C8-cycloalkenyl, (f) d-d-alkynyl, (g) C6-C10-aryl, (h) d-do-aryl-d-d-alkyl, (i) C6-C10-aryl-C3-C6-cycloalkyl, and (j) (CH2)b-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (a)-(j) are optionally substituted with halogen; represents a substituent selected from the group consisting of: (a) hydrogen, (b) d-C6-alkyl, (c) C3-C6-cycloalkyl, (d) d-C6-alkenyl, (e) C5-C6-cycloalkenyl, and (f) d-d-alkynyl wherein (b)-(f) are optionally substituted by: (1) halogen, (2) OR12, or (3) NR12R13; wherein R12 and R13 independently represent hydrogen or d-C3-alkyl; or R12 and R13 together with the nitrogen to which it is attached represents a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom; u is an integer from 0 - 2; v is an integer from 1 - 2; n, w and z are each independently an integer from 0 - 2; a, b, x and y are each independently an integer from 0 - 3; or a purified stereoisomer or stereoisomer mixture of said compound, or a salt of said compound, stereoisomer or stereoisomer mixture. The compound of claim 1 having the foπnula wherein Q is a substituent selected from the group » consisting of: f (a) Y- -C I "— NH- wherein Y is selected from the group consisting of: (al) d-d-alkyl, (a2) C3-C8-cycloalkyl, (a3) C3-C8-cycloalkyl-d-C3-alkyl, (a4) C4-C8-cycloalkenyl, (a5) C6-C10-aryl, (a6) C6-C10-aryl-d-C3-alkyl, and (a7) (CH2)a-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein: (al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, d-C3-alkoxy, d-C3- alkylthio, C6-C10-aryl and -NZ*Z2; and (a2) - (a7) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, d-C3-alkoxy, d-d- alkyl, d-d-alkylthio, C6-C10-aryl or -NZ*Z2, wherein Z1 and Z2 are independently selected from the group consisting of hydrogen and d-d-alkyl, or Z1 and Z2 may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle; NH (b) Ya-C-NH- wherein Ya represents -NH2 or -NH-Y; O (c) Yb-C-NH- NH (d) vb-c- ; wherein for (c) - (d) Yb represents -NH2, -NH-Y or -Y; (e) YC-NH-(CH2)U- wherein Yc is a heterocycle selected from: (el) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (e2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein: (e2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and (e2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (el) - (e2) are optionally substituted by R; (f) YC=N- wherein Yc is as defined in (e) above; represents a substituent selected from the group consisting of: (a) halogen, (b) d-C4-alkyl, optionally substituted by halogen, (c) ' d-Cio-aryl, optionally substituted by halogen, (d) NO2, (e) CN, (f) OR1, and (g) NRJR2, wherein for (f) and (g), R1 and R2 each independently represents a substituent selected from the group consisting of: (1) hydrogen, (2) d-C4-alkyl, and (3) C3-C8-cycloalkyl; or wherein for (g), R1 and R2 together with the nitrogen to which they are attached represent a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom; L represents a substituent selected from the group consisting of: (a) CR3R4-CR3R4, (b) CH2O, (c) OCH2, (d) CH=CH, and (e) oc- • r R> 3 a „„nd A T R> 4 e ΛancΛlh. i*n*d , e ✓■_p.--.e,-.ndently represents a substituent selected from the group consisting of: (1) hydrogen, (2) d-d-alkyl, and (3) d-d-alkoxy; D represents NH; R7 represents a substituent selected from the group consisting of: (a) d-C8-cycloalkyl, (b) C3-C8-cycloalkyl-d-C3-alkyl, (c) d-d-alkenyl, (d) C -C8-cycloalkenyl, (e) C2-d-alkynyl, where (a)-(e) are optionally substituted by (1) OR8, (2) NR8R9, or (3) halogen; (f) C6-do-aryl, (g) C6-C10-aryl-d-C3-alkyl, (h) C6-C10-aryl-C3-C6-cycloalkyl, and (i) (CH2)b-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (f)-(i) are optionally substituted by one to three substituents selected from the group consisting of: (1) NO2, (2) CN, (3) halogen, (5) NR8R9, (6) OR8, or (7) C(=O)R10, wherein: R8 and R9 are independently hydrogen or R10; or optionally when (f) - (i) are substituted by NR8R9, R8 and R9 together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom; R10 represents a substituent selected from the group consisting of: (a) d-d-alkyl, (b) d-d-cycloalkyl, (c) C3-d-cycloalkyl-d-C3-alkyl; and wherein (a)-(c) are optionally substituted with halogen; R11 represents a substituent selected from the group consisting of: (a) hydrogen, (b) d-C6-alkyl, (c) C3-C6-cycloalkyl, (d) C3-C6-alkenyl, (e) C5-C6-cycloalkenyl, and (f) C3-C6-alkynyl wherein (b)-(f) are optionally substituted by: (1) halogen, or (2) OR12, wherein 19 R represents hydrogen or d-C3-alkyl; u is an integer from 0 - 2; v is an integer from 1 - 2; n, w and z are each independently an integer from 0 - 2; a, b, x and y are each independently an integer from 0 - 3; or a purified stereoisomer or stereoisomer mixture of said compound, or a salt of said compound, stereoisomer or stereoisomer mixture. The compound of claim 2 having the formula wherein Q is a substituent selected from the group consisting of: NH (a) Ya-C-NH- wherein Ya represents -NH2 or -NH-Y; and Y is selected from the group consisting of: (al) d-d-alkyl, (a2) C3-C8-cycloalkyl, (a3) C3-C8-cycloalkyl-Cι-C3-alkyl, (a4) C4-C8-cycloalkenyl, (a5) C6-C10-aryl, (a6) C6-C10-aryl-d-C3-alkyl, and (a7) (CH2)a-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein: (al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, d-C3-alkoxy, d-C3- alkylthio, C6-C10-aryl and -NZ!Z2; and (a2) - (a7) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, d-C3-alkoxy, d-C3- alkyl, C C3-alkylthio, C6-C10-aryl or -NZ^2, wherein Z1 and Z2 are independently selected from the group consisting of hydrogen and d-d-alkyl, or Z1 and Z2 may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle; I I (b) YD-C-NH wherein Yb represents -NH2, -NH-Y or -Y; (c) YC-NH-(CH2)U- wherein Yc is a heterocycle selected from: (cl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (c2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein: (c2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and (c2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (cl) - (c2) are optionally substituted by R; (d) YC=N- wherein Yc is as defined in (c) above; represents a substituent selected from the group consisting of: (a) halogen, (b) d-d-alkyl, optionally substituted by halogen, (c) C6-C10-aryl, optionally substituted by halogen, (d) NO2, (e) CN, (f) OR1, and (g) NRJR2, wherein for (f) and (g), R1 and R2 each independently represents a substituent selected from the group consisting of: (1) hydrogen, (2) Cι-C4-alkyl, and (3) C3-C8-cycloalkyl; or wherein for (g), R1 and R2 together with the nitrogen to which they are attached represent a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom; L represents a substituent selected from the group consisting of: (a) CR3R4-CR3R4, (b) CH2O, and (c) OCH2, R3 and R4 each independently represents H; D represents NH; R7 represents a substituent selected from the group consisting of: (a) d-C8-cycloalkyl, (b) d-C8-cycloalkyl-Cι-d-alkyl, (c) d-d-alkenyl, (d) C4-C8-cycloalkenyl, (e) C2-d-alkynyl, where (a)-(e) are optionally substituted by (1) OR8, or (2) halogen; (g) d-do-aryl-d-d-alkyl, (h) C6-C10-aryl-C3-C6-cycloalkyl, and (i) (CH2)b-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (f)-(i) are optionally substituted by one to three substituents selected from the group consisting of: (1) ' NO2) (2) CN, (3) halogen, (4) S(=O)nR10, (5) NR8R9, (6) OR8, or (7) C(=O)R10, wherein: R8 and R9 are independently hydrogen or R10; or optionally when (f) - (i) are substituted by NR8R9, R8 and R9 together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom; R10 represents a substituent selected from the group consisting of: (a) d-d-alkyl, (b) d-d-cycloalkyl, (c) d-d-cycloalkyl-d-d-alkyl; and wherein (a)-(c) are optionally substituted with halogen; R11 represents a substituent selected from the group consisting of: (a) hydrogen, (b) d-C6-alkyl, and (c) d-C6-cycloalkyl, wherein (a)-(c) are optionally substituted by: ' (1) halogen, or (2) OR12, wherein R12 represents hydrogen or d-C3-alkyl; u is an integer from 0 - 2; v is an integer from 1 - 2; n, w and z are each independently an integer from 0 - 2; a, b, x and y are each independently an integer from 0 - 3; or a purified stereoisomer or stereoisomer mixture of said compound, or a salt of said compound, stereoisomer or stereoisomer mixture. The compound of claim 1 having the formula wherein Q is a substituent selected from the group consisting of: NH (a) Y-C-NH- wherein Y is selected from the group consisting of: (al) d-d-alkyl, (a2) d~C8-cycloalkyl, (a3) d-d-cycloalkyl-d-d-alkyl, (a4) C3-C5-alkenyl, (a5) C4-C8-cycloalkenyl, (a6) d-d-alkynyl, (a7) C6-C10-aryl, (a8) d-do-aryl-d-d-alkyl, (a9) C6-do-aryl-C3-C6-cycloalkyl, and (alO) (CH2)a-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein: (al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, d-C3 -alkoxy, d-C3- 1 9 alkylthio, C6-do-aryl and -NZ Z ; and (a2) - (alO) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, d-C3-alkoxy, d-d-alkyl, d-C3-alkylthio, C6-C10-aryl or -NZJZ2, wherein Z1 and Z2 are independently selected from the group consisting of hydrogen and d-d-alkyl, or Z1 and Z2 may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle; NH (b) Ya-C-NH- wherein Ya represents -NH2 or -NH-Y; X II (c) Yb-C-NH- wherein X represents O or N(CN) ; (d) NH (e) Yb-C- wherein for (c) - (e) Yb represents -NH2, -NH-Y or -Y; (f) Y°-NH-(CH2)U- wherein Yc is a heterocycle selected from: (fl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (£2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein: (£2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and (f2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (fl) - (f2) are optionally substituted by R; (g) Y°=N- wherein Yc is as defined in (f) above; (h) YdYe-N- wherein Yd and Ye are independently selected from the group consisting of hydrogen, d-C5-alkyl, and d-C -aminoalkyl; and (i) when w = 0, Q forms a four to eight membered heterocyclic ring fused to the aryl group to which it is attached to form a bicyclic ring, wherein said heterocyclic ring contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and at least one carbon atom and said heterocyclic ring is optionally substituted with d-d-alkyl or -NZ3Z4 wherein Z3 and Z4 are independently selected from the group consisting of hydrogen and d- d-alkyl; represents a substituent selected from the group consisting of: (a) halogen, (b) d-C4-alkyl, optionally substituted by halogen, (c) C6-do-aryl, optionally substituted by halogen, (d) NO2, (e) CN, (±) OR1, (g) C(=O)OR1, (h) S^O^OR1, (i) N^R2, ω C(-O)NR1R2, and (k) S(=O)2NR1R2 ; wherein for (f)-(k): 1 9 R and R each independently represents a substituent selected from the group consisting of: (1) hydrogen, (2) d-C4-alkyl, optionally substituted by halogen, and (3) C -d-cycloalkyl, optionally substituted by halogen; or wherein for (i)-(k): R1 and R2 together with the nitrogen to which they are attached represent a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom; represents a substituent selected from the group consisting of: (a) O, (b) C(=O), (c) CR3R4, (d) N(R5), (e) S(=O)z , and (1) C(=NR3) R3 and R4 each independently represents a substituent selected from the group consisting of: (1) hydrogen, (2) d-d-alkyl, and (3) d-C3-alkoxy; wherein: ' when an R 3 group is d-C3-alkyl in L, said R 3 group may constitute a spiro or nonspiro ring wherein: (a) the group R3 is joined by a bond or by a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, to the carbon chain to which said group R3 is attached, and taken together with the carbon chain atom(s) to which said group R3 is attached, constitutes a ring of three to six members wherein for CR3R4, when R3 is Ci -alkyl, the is joined by a heteratom as defined above; R > 5 represents a substituent selected from the group consisting of: (1) hydrogen, (2) C1-C4-alkyl, optionally substituted by halogen, and (3) C3-C8-cycloalkyl, optionally substituted by halogen; D represents CH2 ; R7 represents a substituent selected from the group consisting of: (a) d-d-alkyl, (b) C3-C8-cycloalkyl, (c) C3-C8-cycloalkyl-d-d-alkyl, (d) d-d-alkenyl, (e) C4-C8-cycloalkenyl, (f) C2-d-alkynyl, where (a)-(f) are optionally substituted by (1) OR8, (2) NR8R9, or (3) halogen; (g) C6-do-aryl, (h) d-do-aryl-d-d-alkyl, (i) d-do-aryl-d-d-cycloalkyl, and (j) (CH2)b-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (g)-(j) are optionally substituted by one to three substituents selected from the group consisting of: (1) NO2; (2) CN, (3) halogen, (4) S(=O)2OH, (5) S(=O)nR10, (6) S(=O)2NR8R9, (7) NR8R9, (8) OR8, (10) C(=O)OR8 ; or (11) C(-O)NR8R9; wherein: R8 and R9 are independently hydrogen or R ιo. or optionally when (g) - (j) are substituted by NR8R9, S(=O)2NR8R9 or C(=O)NR8R9, R8 and R9 together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom; R10 represents a substituent selected from the group consisting of: (a) d-d-alkyl, (b) C -C8-cycloalkyl, (c) C3-C8-cycloalkyl~d-C3~alkyl; (d) d-d-alkenyl, (e) C4-C8-cycloalkenyl, (f) C3-C5-alkynyl, (g) C6-C10-aryl, (h) C6-C10-aryl-d-C3-alkyl, (i) C6-C10-aryl-C3-C6-cycloalkyl, and (j) (CH2)b-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (a)-(j) are optionally substituted with halogen; represents a substituent selected from the group consisting of: (a) hydrogen, (b) d-d-alkyl, (c) C3-d-cycloalkyl, (d) d-C6-alkenyl, (e) C5-C6-cycloalkenyl, and (f) d-C6-alkynyl wherein (b)-(f) are optionally substituted by: (1) halogen, (2) OR12, or (3) NR12R13; wherein R12 and R13 each independently represents hydrogen or d-C3-alkyl; or R12 and R13 together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom; u is an integer from 0 - 2; v is an integer from 1 - 2; n, w and z are each independently an integer from 0 - 2; a, b, x and y are each independently an integer from 0 - 3; or a purified stereoisomer or stereoisomer mixture of said compound, or a salt of said compound, stereoisomer or stereoisomer mixture. 5. The compound of claim 4 having the formula wherein Q is a substituent selected from the group consisting of: X (a) Yb-C-NH- wherein X represents O or N(CN) ; Yb represents -NH2, -NH-Y or -Y; and Y is selected from the group consisting of: (al) d-d-alkyl, (a2) C3-C8-cycloalkyl, (a3) d-C8-cycloalkyl-Cι-d-alkyl, (a4) C6-do-aryl, (a5) d-do-aryl-d-d-alkyl, and (a6) (CH2)a-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein: (al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, d-C3-alkoxy, d-d- alkylthio, C6-C10-aryl and -NZ:Z2; and (a2) - (a6) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, d-C3-alkoxy, d-d- alkyl, d-d-alkylthio, C6-C10-aryl or -NZ^2, wherein Z1 and Z2 are independently selected from the group consisting of hydrogen and C i -C5-alkyl, or Z1 and Z2 may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle; (b) YC-NH-(CH2)U- wherein Yc is a heterocycle selected from: (bl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (b2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein: (b2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and (b2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (bl) - (b2) are optionally substituted by R; (c) Yc-N- wherein Yc is as defined in (b) above; wwhheeπrein Y and Ye are independently selected from the group consisting of hydrogen, d-d-alkyl, and d-d-aminoalkyl represents a substituent selected from the group consisting of: (a) halogen, (b) d-C4-alkyl, optionally substituted by halogen, (c) d-do-aryl, optionally substituted by halogen, (d) NO2, (e) CN, (f) OR1, and (g) NR!R2, wherein for (f)-(g) : R1 and R2 each independently represents a substituent selected from the group consisting of: (1) hydrogen, (2) d-C -alkyl, optionally substituted by halogen, and (3) C -C8-cycloalkyl, optionally substituted by halogen; or wherein for (i): R1 and R2 together with the nitrogen to which they are attached represent a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom; L represents a substituent selected from the group consisting of: (a) O, ( ) C(=O), (c) CR3R4, (d) S(=O)z , and (e) C(=NR3) R3 and R4 each independently represents a substituent selected from the group consisting of: (1) hydrogen, and (2) d-d-alkoxy; D represents CH ; R represents a substituent selected from the group consisting of: (a) d-d-alkyl, (b) C3-C8-cycloalkyl, (c) d-C8-cycloalkyl-d-C3-alkyl, (d) d-d-alkenyl, (e) C4-C8-cycloalkenyl, (f) C2-d-alkynyl, where (a)-(f) are optionally substituted by (1) OR8, (2) NR8R9, or (3) halogen; (g) C6-do-aryl, (h) d-do-aryl-d-d-alkyl, (i) d-do-aryl-d-d-cycloalkyl, and (j) (CH2)b-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (g)-(j) are optionally substituted by one to three substituents selected from the group consisting of: (1) NO2> 2) CN, 3) halogen, 4) S(=O)nR10, 5) NR8R9, 6) OR8, or 7) C(=O)R10, wherein: R and R are independently hydrogen or R 10. or optionally when (g) - (j) are substituted by NR8R9, , R and R together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom; R10 represents a substituent selected from the group consisting of: (a) d-d-alkyl, (b) C3-C8-cycloalkyl, (c) C3-C8-cycloalkyl-d-C3-alkyl; (d) d-d-alkenyl, (e) C4-C8-cycloalkenyl, (f) C3-C5-alkynyl, (g) C6-C10-aryl, (h) d-do-aryl-d-d-alkyl, (i) C6-C10-aryl-C3-C6-cycloalkyl, and (j) (CH2)b-A2 wherein A2 is a foxxr to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (a)-(j) are optionally substituted with halogen; represents a substituent selected from the group consisting of: (a) hydrogen, (b) d-d-alkyl, and (c) C3-C6-cycloalkyl, wherein (a)-(c) are optionally substituted by: (1) halogen, (2) OR12, or (3) NR12R13; wherein 1 1 ^ R and R each independently represents hydrogen or d-C -alkyl; or 19 1 R and R together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom; u is an integer from 0 - 2; v is an integer from 1 - 2; n, w and z are each independently an integer from 0 - 2; a, b, x and y are each independently an integer from 0 - 3; or a purified stereoisomer or stereoisomer mixture of said compound, or a salt of said compound, stereoisomer or stereoisomer mixture. 6. The compound of claim 1 having the formula wherein Q is a substituent selected from the group consisting of: NH (a) Y-C-NH- wherein Y is selected from the group consisting of: (al) d-d-alkyl, (a2) d-d-cycloalkyl, (a3) d-C8-cycloalkyl-d-C3-alkyl, (a4) C3-d-alkenyl, (a5) C4-C8-cycloalkenyl, (a6) d-d-alkynyl, (a8) C6-C10-aryl-C1-C3-alkyl, (a9) C6-C10-aryl-C3-C6-cycloalkyl, and (alO) (CH2)a-A2 wherein A2 is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein: (al) is optionally substituted by halogen up to perhalo, or by one to three substirutents selected from the group consisting of halogen, cyano, d-C3-alkoxy, d-C3- alkylthio, C6-do-aryl and -NZ^2; and (a2) - (alO) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, d-C3-alkoxy, d-C3-alkyl, d-C3-alkylthio, C6-C10-aryl or -NZ!Z2, wherein Z and Z are independently selected from the group consisting of hydrogen and d-C5-alkyl, or Z1 and Z2 may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle; N π H (b) Ya-C-NH- wherein Ya represents -NH2 or -NH-Y; X II (c) Yϋ-C-NH- wherein X represents O or N(CN) ; (d) NH b u (e) Y -C- wherein for (c) - (e) Yb represents -NH2, -NH-Y or -Y; (f) YC-NH-(CH2)U- wherein Yc is a heterocycle selected from: (fl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (f2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein: (f2a) the ring bonded to NH contains a nitrogen atom and optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and (f2b) the ring not bonded to NH contains zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein (fl) - (£2) are optionally substituted by R; (g) YC=N- wherein Yc is as defined in (f) above; (h) YdYe-N- wherein Yd and Ye are independently selected from the group consisting of hydrogen, d-d-alkyl, and d-d-aminoalkyl; and (i) when w = 0, Q forms a four to eight membered heterocyclic ring fused to the aryl group to which it is attached to form a bicyclic ring, wherein said heterocyclic ring contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and at least one carbon atom and said heterocyclic ring is optionally substituted with d-d-alkyl or -NZ3Z4 wherein Z3 and Z4 are independently selected from the group consisting of hydrogen and d- d-alkyl; represents a substituent selected from the group consisting of: (a) halogen, (b) d-C -alkyl, optionally substituted by halogen, (c) C6-C10-aryl, optionally substituted by halogen, (d) NO2, (e) CN, (f) OR1, (g) C(=O)OR1, (h) S(=O)2OR1, (i) NR!R2, 0') C(=O)NR1R2, and (k) S(-O)2NR1R2 ; wherein for (f)-(k): R1 and R2 each independently represents a substituent selected from the group consisting of: (1) hydrogen, (2) d-C4-alkyl, optionally substituted by halogen, and (3) C3-C8-cycloalkyl, optionally substituted by halogen; or wherein for (i)-(k): R1 and R2 together with the nitrogen to which they are attached represent a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom; represents a substituent selected from the group consisting of: (a) C(=O)N(R5), (b) N(R5)C(=O), (c) S(=O)2N(R5) (d) N(R5)S(-O)2, (e) CR3R4-CR3R4, (D CH2O, (g) OCH2, (h) CH2N(R5), (i) N(R5)CH2, (j) CH=CH, and (k) -C≡C- • R3 and R4 each independently represents a substituent selected from the group consisting of:

(1) hydrogen,

(2) halogen, (3) d-d-alkyl, and

(4) d-C₃-alkoxy;

wherein: when one or two R³ groups are d-C₃-alkyl in L, said one or two R³ groups may constitute spiro rings or nonspiro rings wherein:

(a) one group R³ is joined by a bond or by a heteroatom selected from the group consisting of oxygen, nitrogen ^• and sulfur, to the carbon chain to which said group R³ is attached, and taken together with the carbon chain atom(s) to which said group R³ is attached, constitutes a ring of three to six members, wherein for CR³R⁴, when R³ is d-alkyl, the R³ group is joined by a heteratom as defined above, or

(b) two groups R³ are joined by a bond or by a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur and taken together with the carbon chain atom(s) to which said two groups R³ are attached, constitute a ring of 3-6 members;

R⁵ represents a substituent selected from the group consisting of: (1) hydrogen, (2) d-C₄-alkyl, optionally substituted by halogen, and

(3) C₃-C₈-cycloalkyl, optionally substituted by halogen;

D represents CH₂ ;

R⁷ represents a substituent selected from the group consisting of:

(a) d-d-alkyl,

(b) C₃-C₈-cycloalkyl,

(c) d-d-cycloalkyl-d-d-alkyl,

(d) C₃-d-alkenyl, (e) C₄-C₈-cycloalkenyl,

(f) C₂-d-alkynyl, where (a)-(f) are optionally substituted by (1) OR⁸, (2) NR⁸R⁹, or

(3) halogen;

(h) d-do-aryl-d-d-alkyl, (i) C₆-C₁₀-aryl-C₃-C₆-cycloalkyl, and

(2) CN,

(3) halogen,

(4) S(=O)₂OH,

(5) S(=O)_nR¹⁰,

(6) S(=O)₂NR⁸R⁹,

(7) NR⁸R⁹,

(8) OR⁸,

(9) C(=O)R¹⁰,

(10) C(=O)OR⁸ ; or

(11) C(=O)NR 8^δ-Rr>9^y;.

wherein: R and x.m

hy.dArogen or R r> 10.

or optionally

when (g) - (j) are substituted by NR⁸R⁹, S(=O)₂NR⁸R⁹ or C(=O)NR⁸R⁹, R⁸ and R⁹ together with the nitrogen to which they are attached represent a four to eight membered saturated or unsaturated heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom;

R¹⁰ represents a substituent selected from the group consisting of: ^'' (a) d-d-alkyl,

(b) C₃-C₈-cycloalkyl,

(c) C₃-C₈-cycloalkyl-d-C₃-alkyl;

(d) d-d-alkenyl,

(e) C₄-C₈-cycloalkenyl, (t) d-d-alkynyl,

(g) C₆-C₁₀-aryl, (h) C₆-C₁₀-aryl-d-C₃-alkyl, (i) d-do-aryl-d-d-cycloalkyl, and (j) (CH₂)_b-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (a)-(j) are optionally substituted with halogen;

represents a substituent selected from the group consisting of:

(a) hydrogen,

(b) d-d-alkyl,

(c) C₃-C₆-cycloalkyl, (d) d-d-alkenyl,

(e) d-C -cycloalkenyl, and

(f) d-d-alkynyl wherein (b)-(f) are optionally substituted by: (1) halogen, (2) OR¹², or

(3) NR¹²R¹³; wherein R¹² and R¹³ each independently represents hydrogen or d-C₃-alkyl; or

7. The compound of claim 6 having the formula

wherein Q is a substituent selected from the group consisting of:

(a) Y^b-C-NH- wherein X represents O or N(CN) ;

NH

(b) Y"-C-

wherein for (a) and (b),

Y represents -NH₂, -NH-Y or -Y; and Y is selected from the group consisting of: (al) d-C₅-alkyl, (a2) d-d-cycloalkyl, (a3) d-C₈-cycloalkyl-d-d-alkyl, (a4) C₆-C₁₀-aryl,

(a5) d-do-aryl-d-d-alkyl, (a6) C₆-Cio-aryl-C₃-C₆-cycloalkyl, and (a7) (CH₂)_a-A² wherein A² is a four to ten membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein:

(al) is optionally substituted by halogen up to perhalo, or by one to three substitutents selected from the group consisting of halogen, cyano, Crd-alkoxy, d-C₃- alkylthio, C₆-C₁₀-aryl and -NZ^JZ²; and (a2) - (a7) are optionally substituted by halogen up to perhalo, or by one to three substituents selected from the group consisting of halogen, cyano, Crd-alkoxy, d-d- alkyl, d-C₃-alkylthio, C₆-C₁₀-aryl or -NZ^², wherein

Z¹ and Z² may be joined by a chemical bond or by an N, O, or S heteroatom, and taken together with the nitrogen atom to which they are bound, form a 5-6 membered saturated or unsaturated heterocycle;

(c) Y^C-NH-(CH₂)_U- wherein Y^c is a heterocycle selected from: (cl) a five to seven membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (c2) a fused bicyclo ring wherein one ring is a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or unsaturated four to eight membered saturated or unsaturated ring which contains zero to four heteroatoms and at least one carbon atom, wherein:

(d) Y^C=N- wherein Y^c is as defined in (c) above;

(e) Y^dY^e-N- wherein Y^d and Y^e are independently selected from the group consisting of hydrogen, d-d-alkyl, and d-d-aminoalkyl; and

represents a substituent selected from the group consisting of: (a) halogen, (b) d-C₄-alkyl, optionally substituted by halogen,

(c) C₆-C₁₀-aryl, optionally substituted by halogen,

(d) NO₂,

(e) CN,

(f) OR¹, and

(g) NR^rR²,

wherein for (f)-(g):

(1) hydrogen,

(2) d-C₄-alkyl, optionally substituted by halogen, and

(3) C₃-C₈-cycloalkyl, optionally substituted by halogen;

or

wherein for (g):

R¹ and R² together with the nitrogen to which they are attached represent a four to eight membered heterocyclic ring which optionally contains one to three additional heteroatoms selected from the group consisting of nifrogen, oxygen and sulfur wherein said heterocyclic ring contains at least one carbon atom;

represents a substituent selected from the group consisting of: (a) CR³R⁴-CR³R⁴,

(b) CH₂O,

(c) OCH₂,

(d) CH₂N(R⁵),

(e) N(R⁵)CH₂, (f) CH=CH, and

(g) OO ; R³ and R⁴ each independently represents a substituent selected from the group consisting of:

(1) hydrogen,

(2) halogen, and (3) d-C₃-alkoxy;

R⁵ represents a substituent selected from the group consisting of:

(1) hydrogen,

(2) C₁-C₄-alkyl, optionally substituted by halogen, and (3) C₃-C₈-cycloalkyl, optionally substituted by halogen;

D represents CH₂ ;

R⁷ represents a substituent selected from the group consisting of: (a) C₂-d-alkyl,

(b) d-d-cycloalkyl,

(c) d-d-cycloalkyl-Ci-d-alkyl,

(d) d-d-alkenyl,

(e) C -C₈-cycloalkenyl, (f) d-d-alkynyl, ' where (a)-(f) are optionally substituted by (1) OR⁸,

(2) NR⁸R⁹, or

(3) halogen;

(g) C₆-do-aryl,

(h) d-do-aryl-d-d-alkyl,

(i) C₆-do-aryl-C₃-C₆-cycloalkyl, and

9 9

(j) (CH₂)_b-A wherein A is a fox unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (g)-(j) are optionally substituted by one to three substituents selected from the group consisting of: (1) NO_2,

(2) CN,

(3) halogen,

(5) NR⁸R⁹,

(6) OR⁸, and

(7) C(=O)R¹⁰, wherein:

R⁸ and R⁹ are independently hydrogen or R¹⁰;

or optionally

when (g) - (j) are substituted by NR⁸R⁹,

R¹⁰ represents a substituent selected from the group consisting of:

(a) d-d-alkyl,

(b) C₃-C₈-cycloalkyl,

(c) C₃-C₈-cycloalkyl-d-d-alkyl; (d) d-d-alkenyl,

(e) C -C₈-cycloalkenyl,

(f) d-d-alkynyl,

(g) d-do-aryl,

(h) d-Cio-aryl-d-d-alkyl, (i) C₆-do-aryl-C₃-d-cycloalkyl, and

R^u represents a substituent selected from the group consisting of:

(a) hydrogen,

(b) d-d-alkyl, and

(2) OR¹², or

(3) NR¹²R¹³; wherein

R¹² and R¹³ each independently represents hydrogen or d-d-alkyl; or

A pharmaceutical composition comprising a compound of claim 1 and at least one additional pharmaceutically acceptable ingredient.

9. A pharmaceutical composition comprising a compound of claim 2 and at least one additional phannaceutically acceptable ingredient.

10. A phannaceutical composition comprising a compound of claim 4 and at least one ^• 5 additional pharmaceutically acceptable ingredient.

11. A pharmaceutical composition comprising a compound of claim 6 and at least one additional pharmaceutically acceptable ingredient.

10 12. A method for treating a disease or condition associated with the α_vβ₃ and/or α_vβ₅ receptor(s), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

13. The method of claim 12 wherein the disease or condition treated is selected from the 15 group consisting of angiogenesis, arteriosclerosis, cancer, diabetic retinopathy, inflammation, macular degeneration, ophthamia, osteoporosis, restenosis, viral disease, and conditions related to inhibition of bone resorption.

14. The method of claim 13 wherein said disease or condition is selected from the group 20 consisting of angiogenesis, cancer, osteoporosis, restenosis, and diabetic retinopathy.