WO2007117289A2

WO2007117289A2 - Methods for treating or preventing erectile dysfunction or urinary incontinence

Info

Publication number: WO2007117289A2
Application number: PCT/US2006/047199
Authority: WO
Inventors: Andrew L. Salzman
Original assignee: Inotek Pharmaceuticals Corporation
Priority date: 2005-12-14
Filing date: 2006-12-11
Publication date: 2007-10-18
Also published as: WO2007117289A3

Abstract

The invention relates to methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the invention.

Description

METHODS FOR TREATING OR PREVENTING ERECTILE DYSFUNCTION

OR URINARY INCONTINENCE

This application claims the benefit of U.S. Provisional Application No. 60/750,854, filed December 14, 2005, which is incorporated by reference herein in its entirety.

1. FIELD OF THE INVENTION

2. BACKGROUND OF THE INVENTION

Erectile dysfunction ("ED") is a significant male-health issue. While estimating its prevalence is difficult, estimates range from about 15 million to 30 million sufferers worldwide.

The etiology of erectile dysfunction can be multiple, and can include mechanical trauma to the nerves (such as during prostatectomy), or it can be due to diabetes mellitus, cardiovascular diseases, induced by radiation, certain drugs, or advanced age.

Urinary incontinence affects people of all ages and levels of physical health, both in health care settings and in the community at large. Persons suffering from urinary incontinence can be predisposed to also having urinary-tract infections, pressure ulcers, perineal rashes and urosepsis. Psychosocially, urinary incontinence can be associated with embarrassment, social stigmatization, depression and a risk of institutionalization (Herzo et al., Annu. Rev. Gerontol. Geriatr. 9:74 (1989)).

There remains, however, a need in the art for compounds useful for treating or preventing erectile dysfunction or urinary incontinence. Citation of any reference in Section 2 of this application is not an admission that the reference is prior art. 3. SUMMARY OF THE INVENTION

In one embodiment, the present invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound having the Formula (1-123):

or a pharmaceutically acceptable salt thereof, wherein: R₅ is -C₁-Ci₀ alkyl, -(halo-substituted-(d-C₅ alkyl)), -(HO-substituted-(d-C₅ alkyl)), -(carboxy-substituted-(Ci-C₅ alkyl)), -C(0)-C_rCιo alkyl, -C(O)-aryl, -C(O)-(3- to

7-membered monocyclic heterocycle), -C(O)-(7- to 10-membered bicyclic heterocycle) or

-glycoside;

X is -C(O)-, -CH₂-, -CH(halo)-, -(C(OH)((CH₂)_nCH₃))-, -(C(OH)(aryl))-, -O-, - NH-, -S-, -CH(NR₁ ,R₁₂)- or -N(SO₂Y)-, wherein Y is -OH, -NH₂, -(C₁-C₅ alkyl)-(3- to 7- membered monocyclic heterocycle), Or-(Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle) and n is an integer ranging from 0-5;

Ri i and Ri₂ are independently -hydrogen or -C1-C9 alkyl, or N, Ri ₁ and Ri₂ are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);

Ri, R₂, R₃, R4, R₇, Re, R₉ and Rio are independently -hydrogen, -halo, -hydroxy,

-0-(Ci-C₅ alkyl), -Ci-C,₀ alkyl, -(halo-substituted-(C_rC₅ alkyl)), -C₂-Ci₀ alkenyl,

-Ca-Cg-cycloalkyl, -aryl, -NH₂, -(amino-substituted-(Ci-C₅ alkyl)), -C(O)OH, -C(O)O(C₁-

C₅ alkyl), -OC(O)(Ci-C₅ alkyl), NO₂ or -A-B; A is -SO₂-, -SO₂NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-,

-CONH-, -CON(C₁-C₄ alkyl)-, -NH-, -CH₂-, -S- or -C(S)-;

B is -C|-Cio alkyl, -C₂-C₁₀ alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -C₃-Cs cycloalkyl, -aryl, -NZiZ₂, -(Ci-C₅ alkylene)-NZiZ₂, -(amino-substituted-(Cι-C₅ alkyl)), -N(Ci-C₅ alkyl)(Ci-C₅ alkyl), -(Ci-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle), Or -(Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle), -((H₂NC(O))- substituted aryl), -((H₂NC(O))-substituted pyridyl), -C(O)OH, -C(O)O-(Ci-C₅ alkyl),

-C(O)O-phenyl or -C(NH)NH₂, each of which is unsubstituted or substituted with one or more of -0-(Ci-C₅ alkyl), -halo, -(halo-substituted-(Cι-C₅ alkyl)), -(HO-substituted-(d- C₅ alkyl)), -(amino-substituted-(Ci-C₅ alkyl)), -hydroxy, -NO₂, -NH₂, -CN, -NH(Ci-C₅ alkyl), -N(Ci-C₅ alkyl)(Ci-C₅ alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -Ci-Cio alkyl, -C₂-Ct₀ alkenyl, -C₂-Ci₀ alkynyl, -aryl, -benzyl, -((C(O)NH₂)-substituted(Ci-C₅ alkyl)), -(carboxy-substituted-(C_rC₅ alkyl)), -C(O)OH, -Ci-C₅-alkylene-C(O)O-(C,-C₅ alkyl) or -C]-C₅ alkylene-OC(O)-(C_rC₅ alkyl); and

Z) and Z₂ are independently -H or -Ci-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Zs)(Z.*), where Z₃ and Z₄ are independently, -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z₄ are taken together to form a -(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Zi and Z₂ are taken together to form a - (nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a —(nitrogen- containing 7- to 10-membered bicyclic heterocycle).

In one embodiment, the present invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (Ib-123):

(Ib-123) or a pharmaceutically acceptable salt thereof, wherein: R₅ is -C|-Cio alkyl, -(halo-substituted-(Ci-C₃ alkyl)), -(HO-substituted-(C_!-C₅ alkyl)), -(carboxy-substituted-(C_rC₅ alkyl)), -C(O)-Ci-Ci₀ alkyl, -C(O)-aryl, -C(O)-(3- to 7-membered monocyclic heterocycle), -C(O)-(7- to 10-membered bicyclic heterocycle) or -glycoside;

Rn -H, -Ci-C₅ alkyl, -aryl, -C(O)-C₁-C₅ alkyl, or -SO₂Y, wherein Y is -OH, - NH₂ or -(C₁-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle), or -(Ci-Cs alkyl)-(7- to 10-membered bicyclic heterocycle);

Ri, R₂, R3, R₄, R7, R₈, R9 and Rio are independently -hydrogen, -halo, -hydroxy, -0-(Ci-C₅ alkyl), -Ci-Ci₀ alkyl, -(halo-substituted-(C_rC₅ alkyl)), -C₂-Ci₀ alkenyl, -Cs-Cg-cycloalkyl, -aryl, -NH₂, -(amino-substituted-(Ci-C₃ alkyl)), -C(O)OH, -C(O)O(Ci- C₅ alkyl), -OC(O)(C-C₅ alkyl), -NO₂ or -A-B;

A is -SO₂-, -SO₂NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Ci-C₄ alkyl)-, -NH-, -CH₂-, -S- or -C(S)-;

B is -Ci-Cio alkyl, -C₂-C 10 alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle),

-C₃-C₈ cycloalkyl, -aryl, -NZiZ₂, -(Ci-C₅ alkylene)-NZiZ₂, -(amino-substituted-(Ci-C₅ alkyl)), -N(Ci-C₅ alkyl)(C|-C₅ alkyl), -(Ci-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle), Or -(Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle), -((H₂NC(O))- substituted aryl), -((H₂NC(O))-substituted pyridyl), -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-phenyl or -C(NH)NH2, each of which is unsubstituted or substituted with one or more of -0-(Ci-C₅ alkyl), -halo, -(halo-substituted-(C|-C₅ alkyl)), -(HO-substituted-(Ci- C₅ alkyl)), -(amino-substituted-(C|-C₅ alkyl)), -hydroxy, -NO₂, -NH₂, -CN, -NH(Ci-C₅ alkyl), -N(Ci-Cs alkyl)(Ci-C₅ alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle)), -(nitrogen-containing 7- to 10-membered bicycloheterocyclic amine), -Q- Cio alkyl, -C₂-Ci₀ alkenyl, -C₂-C₁₀ alkynyl, -aryl, -benzyl, -((H₂NC(O))-substituted(Ci-C₅ alkyl)), -(carboxy-substituted-(C|-C₅ alkyl)), -C(O)OH, -Ci-C₅-alkylene-C(O)O-(Ci-C₅ alkyl) or -Ci-C₅ alkylene-OC(O)-(Cι-C₅ alkyl); and

Zi and Z₂ are independently -H or -Ci-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Za)(Z^, where Z₃ and Z₄ are independently, -H or -C₁-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z₄ are taken together to form a -(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Z| and Z₂ are taken together to form a — (nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a —(nitrogen- containing 7- to 10-membered bicyclic heterocycle).

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III- 123):

(HI-123) or a pharmaceutically acceptable salt thereof, wherein:

R₅ is O, NH or S;

R₆ is -H or -Ci-C₄ alkyl;

X is -C(O)-, -CH₂-, -CH(halo)-, -(C(OH)((CH₂),,CH₃))-, -(C(OH)(aryl))-, -O-, - NH-, -S-, -CH(NR_nRi₂)- or -N(SO₂Y)-, wherein Y is -OH, -NH₂, -(C₁-C₅ alkyl)-(3- to 7- membered monocyclic heterocycle), Or-(Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle) and n is an integer ranging from 0-5; Ri i and R₁₂ are independently -hydrogen or -C₁-C₉ alkyl, or N, Ri ₁ and R₁₂ are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -{nitrogen-containing 7- to 10-membered bicyclic heterocycle); one OfGi-G₄ is C-R₇ and the remaining G₁-G₄ are independently N or C-R₇; Ri, R2, R₃, and R4 are independently -hydrogen, -halo, -hydroxy, -0-(Ci-Cs alkyl),

-Ci-Cio alkyl, -(halo-substituted-(Ci-C₅ alkyl)), -C₂-Ci₀ alkenyl, -C₃-C₈-cycloalkyl, -aryl, -NH₂, -(amino-substituted-(C,-C₅ alkyl)), -C(O)OH, -C(O)O(Ci-C₅ alkyl), -OC(O)(Ci-C₅ alkyl), -NO₂ or -A-B;

B is -Ci-Cio alkyl, -C2-C1₀ alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -C₃-C₈ cycloalkyl, -aryl, -NZiZ₂, -(Ci-C₅ alkylene)-NZiZ₂, -(amino-substituted-(Ci-Cs alkyl)), -N(Ci-C₅ alkyl)(Ci-C₅ alkyl), -(Ci-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle),-(Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle), -((H₂NC(O))- substituted aryl), -((H₂NC(O))-substituted pyridyl), -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-phenyl or -C(NH)NH₂, each of which is unsubstituted or substituted with one or more Of-O-(Ci-C₅ alkyl), -halo, -(halo-substituted-(d-C₅ alkyl)), -(HO-substituted-(Ci- C₅ alkyl)), -(amino-substituted-(Ci-C₅ alkyl)), -hydroxy, -NO₂, -NH₂, -CN, -NH(Ci-C₅ alkyl), -N(Ci-C₅ alkyl)(C|-C₅ alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle)), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -C₁-C₁₀ alkyl, -C₂-Ci₀ alkenyl, -C₂-Ci₀ alkynyl, -aryl, -benzyl, -((H₂NC(O))-substituted(Ci-C₅ alkyl)), -(carboxy-substituted-(C|-C₅ alkyl)), -C(O)OH, -Ci-C₅-alkylene-C(O)O-(C,-C₅ alkyl) or -C,-C₅ alkylene-OC(O)-(C,-C₅ alkyl);

Z| and Z₂ are independently -H or -C₁-C₁₀ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently, -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z₄ are taken together to form a -(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to

10-membered bicyclic heterocycle); or N, Zj and Z₂ are taken together to form a - (nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen- containing 7- to 10-membered bicyclic heterocycle); and each R₇ is independently -H, -Ci-C₆ alkyl,-O-(d-C₆ alkyl), -S-(C₁-C₆ alkyl), -SO₂NH(C₁-C₆ alkyl) or -C(O)NH-(C-C₆ alkyl).

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (IV- 123):

or a pharmaceutically acceptable salt thereof, wherein:

R₅ is O, NH or S;

X is -C(O)-, -CH₂-, -CH(halo)-, -CH(OH)-, -(C(OH)((CH₂)_mCH₃))-, - (C(OH)(aryl))-, -O-, -N(Z₅)-, -S-, -CH(NR₁ ,R₁₂)- or -N(SO₂Y)-, wherein Y is -OH, - NH₂, -(C₁-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle), or -(C₁-C₅ alkyl)-(7- to

10-membered bicyclic heterocycle) and m is an integer ranging from 0-5;

Ri 1 and Ri₂ are independently -hydrogen or -C1-C₉ alkyl, or N, Ri 1 and Ri₂ are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle); one OfGi-G₄ is C-R₇ and the remaining G₁-G₄ are independently N or C-R₇;

Ri, R₂, R₃, and R₄ are independently -hydrogen, -halo, -hydroxy, -0-(Ci-Cs alkyl), -Ci-Cio alkyl, -(halo-substituted-(C|-C₅ alkyl)), -C₂-Ci₀ alkenyl, -C₃-C₈-cycloalkyl, -aryl, -NH₂, -(amino-substituted-(Cι-C₅ alkyl)), -C(O)OH, -C(O)O(Ci-C₅ alkyl), -OC(O)(Ci-C₅ alkyl), -NO₂ or -A-B; A is -SO₂-, -SO₂NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-,

-CONH-, -CON(Ci-C₄ alkyl)-, -NH-, -CH₂-, -S- or -C(S)-;

B is -Ci-Cio alkyl, -C₂-Ci_O alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -C₃-C₈ cycloalkyl, -aryl, -NZjZ₂, -(C₁-C₅ alkylene)-NZiZ₂, -(amino-substituted-(Ci-C₅ alkyl)), -N(Ci-C₅ alkyl)(C|-C₅ alkyl), -(Ci-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle),-(Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle), -((H₂NC(O))- substituted aryl), -((H₂NC(O))-substituted pyridyl), -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-phenyl or -C(NH)NH₂, each of which is unsubstituted or substituted with one or more of -O-(C_rC₅ alkyl), -halo, -(halo-substituted-(C_rC₅ alkyl)), -(HO-substituted-(Ci- C₅ alkyl)), -(amino-substituted-(C_rC₅ alkyl)), -hydroxy, -NO₂, -NH₂, -CN, -NH(Ci-C₅ alkyl), -N(Ci-C₅ alkyl)(Ci-C₅ alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -Ci-Cio alkyl, -C₂-Ci₀ alkenyl, -C₂-Ci₀ alkynyl, -aryl, -benzyl, -((H₂NC(O))-substituted(Ci-C₅ alkyl)), -(carboxy-substituted-(C|-C₃ alkyl)), -C(O)OH, -C_rC₅-alkylene-C(O)O-(Ci-C₅ alkyl) or -Ci -C₅ alkylene-OC(O)-(Ci-C₅ alkyl);

Zi and Z₂ are independently -H or -Ci-Ci₀ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Zs)(Z-O, where Z₃ and Z₄ are independently, -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z4 are taken together to form a -(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Z| and Z₂ are taken together to form a — (nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a — (nitrogen- containing 7- to 10-membered bicyclic heterocycle); each R₇ is independently -H, -Ci-C₆ alkyl,-O-(d-C₆ alkyl), -S-(Ci-C₆ alkyl), -SO₂NH(C₁-C₆ alkyl) or C(O)NH-(C₁-C₆ alkyl);

Z₅ is -H, -Ci-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -(CH₂)U -(7- to 10-membered bicyclic heterocycle), -(CH₂)_n- COO-(Ci-Cs alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, -

CONH-(CH₂)_n-COO-(C,-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(Ci-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_n-CONH-(C]-C₅ alkyl), -(CH₂)_n-CONH-aryl, - (CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), - (CH₂)n-CONH-(CH₂)_q-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(C_rC₅ alkyl), -(CH₂)_n-

CONH-(CH₂)_q-CON(C,-C₅ alkyl)₂, -C(O)(CH₂V(C₁-C₅ alkyl), -C(O)(CH₂)_n-aryl, - C(O)(CHz)_n-COOH, -C(O)(CH₂)_n-COO-(C₁-C₅alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_n-COO-(7- to 10-membered bicyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂)_n-phenyl, -C(O)O(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)n-phenyl)((CH₂)_q-3- to 7-membered monocyclic heterocycle), -C(O)N((CH₂)_n-phenyl)((CH₂)_q 7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-(3- to 7-membered monocyclic heterocycle)₂, - C(O)N((CH₂)_n-7- to 10-membered bicyclic heterocycle)₂, or -SO₂NH₂; each n is an integer ranging from 0 to 10; and q is an integer ranging from 0 to 10.

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (V-123):

or a pharmaceutically acceptable salt thereof, wherein:

R₅ is O, S, or NH; R|, R₂, R₃, R₄, R₆, R₇, R₈, and R₉ are independently -hydrogen, -halo, -hydroxy, -

NH₂ NO₂, or -A-B;

A is -SO₂-, -SO₂NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(C-C₄ alkyl)-, -NH-, -CH₂-, -S- or -C(S)-;

B is -Ci-C]O alkyl, -C₂-C_1O alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle),

-(3- to 7-membered monocyclic heterocycle), -(J- to 10-membered bicyclic heterocycle), -C₃-C₈ cycloalkyl, -aryl, -NZiZ₂, -(Ci-C₅ alkylene)-NZiZ₂, amino-substituted-(Ci-C₅ alkyl), -N(Ci-C₅ alkyl)(C_rC₅ alkyl), -(Ci -C₅ alkyl)-(3- to 7-membered monocyclic heterocycle),-(Ci-Cs alkyl)-(7- to 10-membered bicyclic heterocycle), -((H₂NC(O))- substituted aryl), -((H₂NC(O))-substituted pyridyl), -C(O)OH, -C(O)O-(C-C₅ alkyl), -C(O)O-phenyl or -C(NH)NH₂, each of which is unsubstituted or substituted with one or more Of-O-(C]-C₅ alkyl), -halo, -(halo-substituted-(C|-C₅ alkyl)), -(HO-substituted-(Ci- C₅ alkyl)), -(amino-substituted-(Ci-C₅ alkyl)), -hydroxy, -NO₂, -NH₂, -CN, -NH(C₁-C₅ alkyl), -N(Ci-C₅ alkyl)(Ci-C₅ alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle)), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -C₁-Ci_O alkyl, -C₂-C₁₀ alkenyl, -C₂-Ci₀ alkynyl, -aryl, -benzyl, -((H₂NC(O))-substituted(Ci-C₅ alkyl)), -(carboxy-substituted-(Ci-C₅ alkyl)), -C(O)OH, -C,-C₅-alkylene-C(O)O-(Ci-C₅ alkyl) or -C₁-C₅ alkylene-OC(O)-(C,-C₅ alkyl);

Z| and Z₂ are independently -H or -Ci-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z₃ and Z₄ are independently, -H or -C₁-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z4 are taken together to form a -(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to

10-membered bicyclic heterocycle); or N, Zi and Z₂ are taken together to form a — (nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a —(nitrogen- containing 7- to 10-membered bicyclic heterocycle); and

R₁₀ is -H, -Ci-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -(CH2)n -(7- to 10-membered bicyclic heterocycle), -(CH₂)_n-

COO-(Ci-C₅ alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, - CONH-(CH₂)_n-COO-(Ci-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(Ci-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_n-CONH-(Ci-C₅ alkyl), -(CH₂)_n-CONH-aryl, - (CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), -

(CH₂)_n-CONH-(CH₂)_q-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(C,-C₅ alkyl), -(CH₂)_n- CONH-(CH₂)_q-CON(Ci-C₅ alkyl)₂, -C(O)(CH₂)_n-(C_rC₅ alkyl), -C(O)(CH₂)_n-aryl, - C(O)(CH₂)_n-COOH, -C(O)(CH₂)_n-COO-(Ci-C₃alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_n-COO-(7- to 10-membered bicyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂)_n-phenyl, -C(O)O(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)_n-phenyl)((CH₂)_q-3- to 7-membered monocyclic heterocycle), -C(O)N((CH₂)_n-phenyl)((CH2)_q 7- to 10-membered bicyclic heterocycle), -C(O)NC(CHb)_n-Q - to 7-membered monocyclic heterocycle)₂, - C(O)N((CH₂)_n-7- to 10-membered bicyclic heterocycle)₂, or -SO₂NH₂; each n is an integer ranging from 0 to 10; p is an integer ranging from 0 to 5; and q is an integer ranging from 0 to 10.

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (VTΪ-123):

or a pharmaceutically acceptable salt thereof, wherein

R₅ is O, NH or S;

X is -C(O)-, -CH₂-, -CH(halo)-, -CH(OH)-, -(C(OH)((CH₂)_mCH₃))-, - (C(OH)(aryl))-, -O-, -N(Z₅)-, -S-, -CH(NR, ,R₁₂)- or -N(SO₂Y)-, wherein Y is -OH, - NH₂, -(C₁-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle), Or -(C₁-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle) and m is an integer ranging from 0-5;

Rn and R₁₂ are independently -hydrogen or -C₁-C₉ alkyl, or N, Rn and R₁₂ are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); one Of Gi-G₄ is C-R₇ and the remaining G₁-G₄ are independently N or C-R₇;

R_t, R₂, R₃, and R₄ are independently -hydrogen, -halo, -hydroxy, -0-(Ci-Cs alkyl), -Ci-Cio alkyl, -(halo-substituted-(Ci-C₅ alkyl)), -C₂-Ci₀ alkenyl, -C₃-C₈-cycloalkyl, -aryl, -NH₂, -(amino-substituted-(C,-C₅ alkyl)), -C(O)OH, -C(O)O(C₁-C₅ alkyl), -OC(O)(Ci-C₅ alkyl), -NO₂ or -A-B; A is -SO₂-, -SO₂NH-, -NHCO-, -NHCONH-, -0-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(C₁-C₄ alkyl)-, -NH-, -CH₂-, -S- or -C(S)-;

B is -Ci-Cio alkyl, -C2-C₁₀ alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle),

-C₃-C₈ cycloalkyl, -aryl, -NZiZ₂, -(Ci-C₅ alkyl ene)-NZi Z₂, amino-substituted-(Cι-C₅ alkyl), -N(Ci-C₅ alkyl)(C_rC₅ alkyl), -(C₁-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle),— (Ci -C₅ alkyl)-(7- to 10-membered bicyclic heterocycle), -((H₂NC(O))- substituted aryl), -((H₂NC(O))-substituted pyridyl), -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-phenyl or -C(NH)NH₂, each of which is unsubstituted or substituted with one or more of -0-(Ci-C₅ alkyl), -halo, -(halo-substituted-(Ci-C₅ alkyl)), -(HO-substituted-(Ci- C₅ alkyl)), -(amino-substituted-(Ci-C₅ alkyl)), -hydroxy, -NO₂, -NH₂, -CN, -NH(Ci-C₅ alkyl), -N(Ci-C₅ alkyl)(Ci-C₅ alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -C1-C10 alkyl, -C₂-C 1₀ alkenyl , -C₂-C _{( 0} alkynyl, -aryl, -benzyl, -((H₂NC(O))-substituted(C ₁ -C₅ alkyl)), -(carboxy-substituted-(C,-C₅ alkyl)), -C(O)OH, -C,-C₅-alkylene-C(O)O-(Ci-C₅ alkyl) or -C₁-C₅ alkylene-OC(O)-(Ci-C₅ alkyl);

Zi and Z₂ are independently -H Or -Ci-C₁O alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently, -H or -C]-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z₄ are taken together to form a —(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Zj and Z₂ are taken together to form a — (nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a — (nitrogen- containing 7- to 10-membered bicyclic heterocycle); each R₇ is independently -H, -Ci-C₆ alkyl, -O-(C_rC₆ alkyl), -S-(C₁-C₆ alkyl), -SO₂NH(C₁-C₆ alkyl) or -C(O)NH-(C₁-C₆ alkyl);

Z₅ is -H, -C₁-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -(CH₂)_n — (7- to 10-membered bicyclic heterocycle), -(CH₂)_n- COO-(C₁-C₅ alkyl), (CH₂)_n-CO0-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, -

CONH-(CH₂)_n-COO-(Ci-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(Ci-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_n-CONH-(C,-C₅ alkyl), -(CH₂)_n-CONH-aryl, - (CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), - (CH₂)_n-CONH-(CH₂)_q-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(C,-C₅ alkyl), -(CH₂)_n- CONH-(CH₂)_q-CON(C,-C₅ alkyl)₂, -C(O)(CH₂)_n-(C,-C₅ alkyl), -C(O)(CH₂)_n-aryl, - C(O)(CH₂)_n-COOH, -C(O)(CH₂)_n-COO-(C,-C₅alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_n-COO-(7- to 10-membered bicyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂)_n-phenyl, -C(O)O(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)_n-phenyl)((CH₂)_q-3- to 7-membered monocyclic heterocycle), -C(O)N((CH₂)_n-phenyl)((CH₂)_q 7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-(3- to 7-membered monocyclic heterocycle)2, - C(O)N((CH₂)_n-7- to 10-membered bicyclic heterocycle)₂, Or -SO₂NH₂; each n is an integer ranging from 0 to 10; and q is an integer ranging from 0 to 10.

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (1-145):

(1-145) or a pharmaceutically acceptable salt thereof, wherein:

R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are independently -H₃ -halo, -OH, -NH₂, -CN, -NO₂, or -A-B;

R⁵ is O, S or NH; A is -SO₂-, -SO₂NH-, -NHSO₂-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(C₁-C₅ alkyl)-, -NH-, -(CH₂)_P-, -S- or -C(S)-;

B is -Ci-Cio alkyl, -C₂-C₁₀ alkenyl, -C₂-CiO alkynyl, -C₃-C₈ monocyclic cycloalkyl, -Ce-Cu bicyclic cycloalkyl, -Cs-C₈ monocyclic cycloalkenyl, -C₈-Cu bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), -

(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZiZ₂, -(C₁- C₅ alkylene)-NZ,Z₂, -C(O)OH, -C(O)O-(C₁-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -0-(Ci-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -C_rCi₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(Ci-C₅ alkyl);

Zi and Z₂ are independently -H or -Ci -C 10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z₄ are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Z] and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen- containing 7- to 10-membered bicyclic heterocycle); R¹⁰ is -H, -Ci-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -(CH₂),, —(7- to 10-membered bicyclic heterocycle), -(CH₂),,- COO-(C₁-C₅ alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, - CONH-(CH₂)_n-COO-(Ci-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(C₁-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_n-CONH-(Ci-C₅ alkyl), -(CH₂)_n-CONH-aryl, - (CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-(7- to 10- membered monocyclic heterocycle), - (CH₂)_n-CONH-(CH₂)_q-CONH₂ -(CHj)_n-CONH-(CH₂VCONH-(C₁-C₅ alkyl), -(CH₂)_n- CONH-(CH₂)_q-CON(C,-C₅ alkyl)₂, -C(O)(CH₂)_n-(C,-C₅ alkyl), -C(O)(CH₂)_n-aryl, - C(O)(CH₂)_n-COOH, -C(O)(CH₂)H-COO-(C₁-C₅ alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_n-COO-(7- to 10-membered bicyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂),,- phenyl, -C(O)O(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -C(O)O(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N ((CH₂J_n- phenyl)((CH₂)_q-3- to 7- membered monocyclic heterocycle), -C(O)N((CH₂)_n- phenyl)((CH₂)_q 7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-(3- to 7- membered monocyclic heterocycle^, -C(O)N((CH₂)_n-7- to 10-membered bicyclic heterocycle)₂, or -SO₂NH₂;

R¹ ' is — H, or (-Ci-Ce alkyl), or Rio, Ri i and the nitrogen atom to which they are attached join to form a -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); each n is independently an integer ranging from 0 to 10; each p is independently an integer ranging from 0 to 5; and each q is independently an integer ranging from 0 to 10.

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (11-145):

(11-145) or a pharmaceutically acceptable salt thereof, wherein:

R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are independently -H, -halo, -OH, -NH₂, -CN, -NO₂, or -A-B;

R⁵ is O, S or NH;

A is -SO₂-, -SO₂NH-, -NHSO₂-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Ci-C₅ alkyl)-, -NH-, -(CH₂)_P-, -S- or -C(S)-; B is -Ci-Cio alkyl, -C₂-CiO alkenyl, -C2-C10 alkynyl, -C₃-Cg monocyclic cycloalkyl, -C_S-C_H bicyclic cycloalkyl, -Cs-C₈ monocyclic cycloalkenyl, -C₈-C_M bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), - (nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZ1Z2, -(C₁-

C₅ alkylene)-NZiZ₂, -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -O-(C,-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -Ci-Ci₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(C₁-C₅ alkyl); Zi and Z₂ are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z4 are independently -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z₃ and Z₄ are taken together to form a — (nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zi and Z₂ are taken together to form a —

(nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen- containing 7- to 10-membered bicyclic heterocycle);

R¹⁰ is -H, -C₁-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -(CH₂),, -(J- to 10-membered bicyclic heterocycle), -(CH₂)_n- COO-(C₁-C₅ alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, -

CONH-(CH₂)_n-COO-(C,-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(C₁-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_n-CONH-(Ci-C₅ alkyl), -(CH₂)_n-CONH-aryl, - (CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q -(7- to 10-membered bicyclic heterocycle), -(CH₂),,- CONH-(CH₂)_q-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(Ci-C₅ alkyl), -(CH₂)_n-CONH-

(CH₂)_q-CON(C,-C₅ alkyl)₂, -C(O)(CH₂)_n-(C,-C₅ alkyl), -C(O)(CH₂)ή-aryl, -C(O)(CH₂)_n- COOH, -C(O)(CH₂VCOO-(C₁-C₅ alkyl), -C(O)(CH₂)_π-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)H-COO -(7- to 10-membered bicyclic heterocycle), - C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(3- to 7- membered monocyclic heterocycle), - C(O)(CH₂)_n -(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂)_n-phenyl, -

C(O)O(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -C(O)O(CH₂)_n -(7- to 10- membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)_n- phenyl)((CH₂)_q-3- to 7- membered monocyclic heterocycle), -C(O)N((CH₂)_n- phenyl)((CH₂)_q -7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-3- to 7- membered monocyclic heterocycle)2, -C(O)N((CH2)_n-7- to 10-membered bi cyclic heterocycle)2, or -SO2NH2; each n is independently an integer ranging from 0 to 10; each p is independently an integer ranging from 0 to 5; and each q is independently an integer ranging from 0 to 10.

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III- 145):

(III-145) or a pharmaceutically acceptable salt thereof, wherein:

R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each independently -H, -0-(C₁-C₅ alkyl), -Ci- Coalkyl, -C₂-C₁₀ alkenyl, -aryl, -C(O)OH, -C(O)O(C-C₅ alkyl), -OC(O)(C₁-C₅ alkyl), - NO₂, -NHC(O)(CH₂)_n-NH₂, -NHSO₂NH(CH₂)n-NH2, -C(O)NH(CH₂)_n-NH₂, - SO₂NH(CH₂)U-NH₂, -halo, -OH, -NH₂, or -A-B;

R⁵ is O, S or NH;

A is -SO₂-, -SO₂NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, - CONH-, -CON(C₁-C₅ alkyl)-, -NH-, -(CH₂)_P-, -S- or -C(S)-;

B is -Ci-C₁O alkyl, -C₂-CiO alkenyl, -C₂-CiO alkynyl, -C3-C8 monocyclic cycloalkyl, -Cs-C₁₄ bicyclic cycloalkyl, -C₅-C₈ monocyclic cycloalkenyl, -Cg-Ci₄ bicyclic cycloalkenyl, -(nitrogen- containing 3- to 7- membered monocyclic heterocycle), - (nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(J- to 10-membered bicyclic heterocycle), -aryl, -NZ₁Z₂, -(C₁- C₅ alkylene)-NZ,Z₂, -C(O)OH, -C(O)O-(C₁-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZ₁Z₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -O-(C_rC₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -Ci-Ci₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(C₁-C₅ alkyl);

Zi and Z₂ are independently -H or -Cj-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z4), where Z₃ and Z₄ are independently -H or -C1-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z₃ and Z₄ are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zi and Z2 are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen- containing 7- to 10-membered bicyclic heterocycle);

R" is -H, -C₁-C₅ alkyl, -(CH₂)_n-aryl, -C(O)R¹², -C(O)OR¹²,-C(O)O-(C,-C₅ alkyl), -CONH₂, -C(O)NH-(CH₂)_n-C(O)OH, -(CH₂)_n-C(O)OH, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH₂)_p-(3- to 7-membered bicyclic heterocycle), - (CH₂)_p-(7- to 10-membered bicyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-CONH-(C ₁-C₅ alkyl), -(CH₂)_n-CONH-(CH₂)_q-CON(C,-C₅ alkyl)₂, -C(O)-(CH₂VC(O)O-(C₁-C₅ alkyl), - CONH-(CH₂)_p-(3- to 7- membered monocyclic heterocycle), -C(O)N(R¹²)₂, - C(O)NHNHR¹², -CONH(CH₂)_πN(R¹²)₂, -CONHN(Z₁)(Z₂), or -A-B; each occurrence of R¹² is independently -H, -(C₁-C₅ alkyl), -(CH₂)_p-phenyI, - (CH₂)_p-(3- to 7- membered monocyclic heterocycle), or -(CH₂)_p-(7- to 10-membered bicyclic heterocycle); each n is independently an integer ranging from 1 to 10; each p is independently an integer ranging from O to 5; and each q is independently an integer ranging from O to 10.

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (IV- 145):

(IV-145) or a pharmaceutically acceptable salt thereof, wherein: R¹ , R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are independently -H, -halo, -OH, -NH₂, -CN,

-NO₂, or -A-B;

A is -SO₂-, -SO₂NH-, -NHSO₂-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Ci-C₅ alkyl)-, -NH-, -(CH₂)_P-, -S- or -C(S)-;

B is -C|-Cio alkyl, -C₂-Ci_O alkenyl, -C₂-Ci_O alkynyl, -C₃-Cs monocyclic cycloalkyl, -Cg-C₁₄ bicyclic cycloalkyl, -Cs-Cg monocyclic cycloalkenyl, -C₈-Ci₄ bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), - (nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZiZ₂, -(Ci- C₅ alkylene)-NZ,Z₂, -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more of -C(O)NH₂, -O-(C,-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -C₁-C₁₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(C₁-C₅ alkyl);

Zi and Z₂ are independently -H or -Cj-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently -H or -C₁-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z₃ and Z₄ are taken together to form a — (nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zj and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen- containing 7- to 10-membered bicyclic heterocycle); R¹⁰ is -H, -Ci-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -(CH₂),, -(7- to 10-membered bicyclic heterocycle), -(CH₂),,- COO-(Ci-C₅ alkyl), -(CH₂)_π-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, - CONH-(CH₂)_n-COO-(Ci-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(Ci-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CHa)_n-CONH-(C₁-C₅ alkyl), -(CH₂)_n-CONH-aryl, -

(CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-(7- to 10- membered monocyclic heterocycle), - (CH₂VCONH-(CH₂)_C1-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(Ci-C₅ alkyl), -(CH₂),,- CONH-(CH₂)_q-CON(Ci-C₅ alkyl)₂, -C(O)(CH₂)n-(C|-C₅ alkyl), -C(O)(CH₂)_n-aryl, - C(O)(CH₂)_n-CO0H, -C(O)(CH₂)n-COO-(C!-C₅ alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_n-COO-(7- to 10-membered bicyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂)_n- phenyl, -C(O)O(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -C(O)O(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)_n- phenyl)((CH₂)_q-(3- to 7- membered monocyclic heterocycle), -C(O)N((CH₂)_n- phenyl)((CH₂)_q 7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-(3- to 7- membered monocyclic heterocycle)₂, -C(O)N((CH₂)_n-7- to 10-membered bicyclic heterocycle)₂, or -SO₂NH₂; R¹¹ is — H, or (-Ci -Cβ alkyl), or Ri o, Rn and the nitrogen atom to which they are attached join to form a -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);

R¹³ is -Ci-Cio alkyl, -C(O)-Ci-Ci₀ alkyl, -C(O)-aryl, -C(O)-(3- to 7- membered monocyclic heterocycle), or -glycoside, each of which is unsubstituted or substituted with one or more -halo, -C(O)OH, or -OH groups; each n is independently an integer ranging from O to 10; each p is independently an integer ranging from 0 to 5; and each q is independently an integer ranging from 0 to 10.

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (V-145):

(V-145) or a pharmaceutically acceptable salt thereof, wherein: R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are independently -H, -halo, -OH, -NH₂, -CN,

-NO₂, or -A-B;

B is -Ci-Cio alkyl, -C2-C10 alkenyl, -C2-C₁₀ alkynyl, -C₃-C8 monocyclic cycloalkyl, -Ce-Cu bicyclic cycloalkyl, -C₅-Cs monocyclic cycloalkenyl, -C₈-Cu bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), - (nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZjZ₂, -(Ci- C₅ alkylene)-NZ,Z₂, -C(O)OH, -C(O)O-(C, -C₃ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -0-(Ci-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -C,-C,o alkyl, -aryl, -C(O)OH, or -C(O)O-(C₁-C₅ alkyl);

Z| and Z₂ are independently -H or -C₁-C₁₀ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z-O, where Z₃ and Z₄ are independently -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z₃ and Z4 are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zi and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen- containing 7- to 10-membered bicyclic heterocycle);

R¹⁰ is -H, -Ci-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_π-aryl, -(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -(CHs)_n -(7- to 10-membered bicyclic heterocycle), -(CH₂)_n- COO-(Ci-C₅ alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, -

CONH-(CH₂)_n-COO-(C|-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(C₁-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_n-CONH-(C,-C₅ alkyl), -(CH₂)_n-CONH-aryl, - (CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q -(7- to 10-membered bicyclic heterocycle), -(CH₂)_n- CONH-(CH₂)_q-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(C,-C₅ alkyl), -(CH₂)_n-CONH-

(CH₂)_C-CON(C₁-C₅ alkyl)₂, -C(O)(CH₂)_n-C,-C₅ alkyl, -C(O)(CH₂)_π-aryl, -C(O)(CH₂)_n- COOH, -C(O)(CH₂)H-COO-(C₁-Cs alkyl), -C(O)(CH₂)_π-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_n-COO -(7- to 10-membered bicyclic heterocycle), - C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(3- to 7- membered monocyclic heterocycle), - C(O)(CH₂)_n -(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂)_n-phenyl, -

C(O)O(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -C(O)O(CH₂)_n -(7- to 10- membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)_n- phenyl)((CH₂)_q-3- to 7- membered monocyclic heterocycle), -C(O)N((CH₂)_n- phenyl)((CH₂)_q -7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-3- to 7- membered monocyclic heterocycle)₂, -C(O)N ((CH₂)_n-7- to 10-membered bicyclic heterocycle)₂, or -SO₂NH₂;

R¹³ is -Ci-Cio alkyl, -C(O)-C,-C|₀ alkyl, -C(O)-aryl, -C(O)-(3- to 7- membered monocyclic heterocycle), or -glycoside, each of which is unsubstituted or substituted with one or more -halo, -C(O)OH, or -OH groups; each n is independently an integer ranging from O to 10; each p is independently an integer ranging from O to 5; and each q is independently an integer ranging from O to 10.

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (VI- 145):

(VI-145) or a pharmaceutically acceptable salt thereof, wherein: R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each independently -H, -0-(Ci-C₅ alkyl), -C₁-

Co alkyl, -C₂-C₁₀ alkenyl, -aryl, -C(O)OH, -C(O)O(C₁-C₅ alkyl), -OC(O)(C₁-C₅ alkyl), - NO₂, -NHC(O)(CH₂)_n-NH₂, -NHSO₂NH(CH₂)_n-NH₂, -C(O)NH(CH₂)_n-NH₂, - SO₂NH(CH₂)n-NH₂, -halo, -OH, -NH₂, or -A-B;

B is -Ci-C₁O alkyl, -C₂-CiO alkenyl, -C₂-CiO alkynyl, -C3-C8 monocyclic cycloalkyl, -Cg-Cu bicyclic cycloalkyl, -C₅-Cg monocyclic cycloalkenyl, -C₈-C₁4 bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), - (nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZ₁Z₂, -(C₁-

C₅ alkylcnc)-NZ,Z₂, -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZ₁Z₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -0-(C₁-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -C₁-Ci₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(Ci-C₅ alkyl); Zi and Z₂ are independently -H or -C₁-C₁O alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently -H or -C₁-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z3 and Z₄ are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Z₁ and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a -{nitrogen- containing 7- to 10-membered bicyclic heterocycle);

R" is -H, -C₁-C₅ alkyl, -(CH₂)_n-aryl, -C(O)R¹², -C(O)OR¹², -C(O)O-(C₁-C₅ alkyl), -CONH₂, -C(O)NH-(CH₂)_n-C(O)OH, -(CH₂)_n-C(O)OH, -(CH₂)_n-CONH-(CH₂)_q- (3- to 7- membered monocyclic heterocycle), -(CH₂)_p-(3- to 7-membered bicyclic heterocycle), -(CH₂)_p-(7- to 10-membered bicyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q- CONH-(Ci-C₅ alkyl), -(CH₂)_H-CONH-(CH₂VCON(C₁-C₅ alkyl)₂, -C(O)-(CH₂)_n-C(O)O- (Ci-C₅ alkyl), -CONH-(CH₂)_p-(3- to 7- membered monocyclic heterocycle), - C(O)N(R¹²)₂, -C(O)NHNHR¹², -CONH(CH₂)nN(R^l2)₂, -CONHN(Zi)(Z₂), or -A-B;

R¹³ is -Ci-Cio alkyl, -C(O)-Ci-Ci₀ alkyl, -C(O)-aryl, -C(O)-(3- to 7- membered monocyclic heterocycle), or -glycoside, each of which is unsubstituted or substituted with one or more -halo, -C(O)OH, or -OH groups; each occurrence of R¹² is independently -H, -(Ci-C₅ alkyl), -(CH₂)_p-phenyl, - (CH₂)_p-(3- to 7- membered monocyclic heterocycle), or -(CH₂)_p-7- to 10-membered bicyclic heterocycle; each n is independently an integer ranging from 1 to 10; each p is independently an integer ranging from O to 5; and each q is independently an integer ranging from O to 10.

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (HI-154):

(III-154) or a pharmaceutically acceptable salt thereof, wherein: R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each independently -H, -0-(Ci-C₅ alkyl), -C,- Cio alkyl, -C₂-Ci₀ alkenyl, -aryl, -C(O)OH₃ -C(O)O(C-C₅ alkyl), -OC(O)(Ci-C₅ alkyl), - NO₂, -NHC(O)(CHz)_n-NH₂, -NHSO₂NH(CH₂)_n-NH₂, -C(O)NH(CH₂)_n-NH₂, - SO₂NH(CH₂)_n-NH₂, -halo, -OH, -NH₂, or -A-B; R⁵ is O, S or NH;

A is -SO₂-, -SO₂NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Ci-C₅ alkyl)-, -NH-, -(CH₂)_P-, -S- or -C(S)-;

B is -Ci-Cio alkyl, -C₂-CiO alkenyl, -C2-C10 alkynyl, -C3-C8 monocyclic cycloalkyl, -Cs-C ₁₄ bicyclic cycloalkyl, -C₅-Cs monocyclic cycloalkenyl, -C_S-C_H bi cyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), -

(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZiZ₂, -(C- C₅ alkylene^NZ^, -C(O)OH, -C(O)O-(C-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -O-(C_rC₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -Ci-C₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(C₁-C₅ alkyl);

Zi and Z₂ are independently -H or -Ci -Ci₀ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z₃ and Z₄ are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zi and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen- containing 7- to 10-membered bicyclic heterocycle); R¹¹ is -C(O)O-(C-C₅ alkyl)-NZ₅Z₆; one of Z₅ and Z₆ is — H, -Ci -Ce alkyl or —phenyl, and the other of Z₅ and Z_& is phenyl, wherein the —phenyl in each instance is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₇)(Zs), where N, Z₇ and Zs are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three groups of -C-C₅ alkyl, -halo, -halo-substituted Ci-C₅ alkyl, hydroxy, -O-C-C5 alkyl, -N(R^a)₂, -COOH, -C(O)O-(C-C₅ alkyl), -OC(O)-(C-C₅ alkyl), -C(O)NH₂, or -NO₂, wherein each occurrence of R^a is independently -H, -benzyl, or -Cp C ₁₀ alkyl; or N, Z₅ and Z(, are taken together to form a nitrogen-containing 3- to 7- membered monocyclic heterocycle, which is substituted with one to three groups of- Cj-C₅ alkyl, -halo, -(halo-substituted Ci-C₅ alkyl), hydroxy, -0-Ci-C₅ alkyl, -N(R³J₂, -COOH, -C(O)O-(C₁-C₅ alkyl), -OC(O)-(Ci-C₅ alkyl), -C(O)NH₂, or -NO₂, wherein each occurrence of R^a is independently -H, -benzyl, or -Ci-Ci o alkyl; each n is independently an integer ranging from 1 to 10; and each p is independently an integer ranging from O to 5.

In one embodiment, the invention provides methods for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula (IV-154):

(IV-154) or a pharmaceutically acceptable salt thereof, wherein:

R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each independently -H, -O-(C,-C₅ alkyl), -Ci - Cio alkyl, -C₂-C,₀ alkenyl, -aryl, -C(O)OH, -C(O)O(C-C₅ alkyl), -OC(O)(Ci-C₅ alkyl), - NO₂, -NHC(O)(CH₂)_n-NH₂, -NHSO₂NH(CH₂)_n-NH₂, -C(O)NH(CH₂)_n-NH₂, - SO₂NH(CH₂)_n-NH₂, -halo, -OH, -NH₂, or -A-B;

B is -C|-Cio alkyl, -C₂-CiO alkenyl, -C2-C10 alkynyl, -C3-C8 monocyclic cycloalkyl, -C₈-C_H bicyclic cycloalkyl, -C₅-Cs monocyclic cycloalkenyl, -C₈-Cu bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), - (nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZ₁Z₂, -(Ci- C₅ alkylene)-NZ,Z₂, -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZ)Z₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -0-(Ci-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -Ci-Ci₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(C₁-C₅ alkyl);

Z₁ and Z₂ are independently -H or -Ci-C ₁₀ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z^, where Z₃ and Z₄ are independently -H or -C₁-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z3 and Z4 are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Z| and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a — (nitrogen- containing 7- to 10-membered bicyclic heterocycle);

R¹¹ is -C(O)O-(C₁-C₅ alkyl)-NZ₅Z₆; one of Z₅ and Z_& is -H, -Ci-Ce alkyl or -phenyl, and the other of Z₅ and Z₆ is phenyl, wherein the -phenyl in each instance is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₇)(Zg), where N, Z₇ and Zg are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three groups of -Ci-C₅ alkyl, -halo, -halo-substituted Ci-C₅ alkyl, hydroxy, -O-C,-C₅ alkyl, -N(R^a)₂, -COOH, -C(O)O-(C₁-C₅ alkyl), -OC(O)-(C,-C₅ alkyl), -C(O)NH₂, or -NO₂, wherein each occurrence of R^a is independently — H, -benzyl, or -Ci- C_1O alkyl; or N, Z₅ and Z₆ are taken together to form a nitrogen-containing 3- to 7- membered monocyclic heterocycle, which is substituted with one to three groups of -

Ci-C₅ alkyl, -halo, -halo-substituted C₁-C₅ alkyl, hydroxy, -0-C₁-C₅ alkyl, -N(R^a)₂, -COOH, -C(O)O-(C₁-C₅ alkyl), -OC(O)-(Ci-C₅ alkyl), -C(O)NH₂, or -NO₂, wherein each occurrence of R^a is independently — H, -benzyl, or -Ci-Cio alkyl;

R¹³ is -Ci-Cio alkyl, -C(O)-Ci-C₁₀ alkyl, -C(O)-aryl, -C(O)-(3- to 7- membered monocyclic heterocycle), or —glycoside, each of which is unsubstituted or substituted with one or more -halo, -C(O)OH, or -OH groups; each n is independently an integer ranging from 1 to 10; and each p is independently an integer ranging from O to 5.

As used herein, a compound of Formula (1-123), (Ib-123), (III-123), (IV-123),

(V-123), (VIl-123), (1-145), (11-145), (III-145), (IV-145), (V-145), (VI-145), (III-154), or (IV-154) or a pharmaceutically acceptable salt thereof is a "compound of the invention." A compound of the invention is useful for treating or preventing erectile dysfunction or urinary incontinence (each being a "Condition") in a subject.

The present invention may be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non- limiting embodiments of the invention.

4. Detailed Description of the Invention

4.1 Compounds of Formula (1-123)

As stated above, the present invention encompasses methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (1-123)

(1-123) or a pharmaceutically acceptable salt thereof, where Ri, R₂, R3, R4, Rs₁R?, Rs, R₉, Rio, and X are defined above for the compounds of Formula (1-123).

In one embodiment X is O.

In one embodiment R₁-R₄, R₇ and Rio are hydrogen.

In another embodiment, at least one of R|, R₂, R₃, R₄, R₇, R₈, R₉ and Ri₀ is other than hydrogen.

In one embodiment R5 is -C₂-C10 alkyl.

In another embodiment R₅ is -C4-C10 alkyl.

In another embodiment R₅ is -Cβ-Cio alkyl.

In another embodiment the compounds of Formula (1-123) have the structure of Formula (I'-123):

(T-123) wherein X, R₅, Rs and R₉ are defined above for the compounds of Formula (I-

123).

4.2 Compounds of Formula (Ta-123)

In one embodiment, the compounds of Formula (1-123) have the Formula (Ia-

123):

(Ia-123) where Ri , R₂, R₃, R4, Rs₁ R₇, R₈, R₉, and Rio_, are defined above for the compounds of

Formula (1-123).

In one embodiment Ri -R₄, R₇ and Rio are hydrogen.

In another embodiment, at least one of Ri, R₂, R3, R4 R₇, Rs, R9 or R 10 is other than hydrogen. In one embodiment R₅ is -C₂-Ci_O alkyl.

In another embodiment R₅ is -C₄-C₁₀ alkyl. In another embodiment R5 is -C₆-C ₁₀ alkyl. In another embodiment compounds of Formula (Ia- 123) have the structure of

Formula (Ia'- 123):

(Ia'-123) wherein Rs, R₈, and R₉ are defined above for compounds of Formula (Ia-123). Illustrative compounds of Formula (Ia'-123) are set forth below:

(Ia'-123)

and pharmaceutically acceptable salts thereof.

4.3 Compounds of Formula (Ib-123)

The invention also relates to methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (Ib-123):

(Ib-123) or a pharmaceutically acceptable salt thereof, where Ri, R2, R₃, R4, Rs. R7, Rs, Rs_>, Rio, and Ri ₁ are defined above for the compounds of Formula (Ib- 123).

In one embodiment, R1-R4, R₇ and Rm are hydrogen.

In another embodiment, at least one of Ri, R₂, R₃, R₄, R₇, Rs, R₉ and Rio is other than hydrogen.

In one embodiment R₅ is -C2-C₁₀ alkyl. In another embodiment R₅ is -C₄-C 10 alkyl.

In another embodiment R₅ is -Cβ-Cio alkyl.

In a further embodiment Rs is -C(O)(Ci-Cs alkyl).

In yet another embodiment Rn is -C(O)(Ci-Cs alkyl).

In another embodiment the compounds of Formula (Ib-123) have the structure of Formula (Ib'-123):

(Ib'-123) wherein Rs and Ri i are defined above for Formula (Ib- 123).

An illustrative compound of Formula (Ib'-123) is compound 21a-123, set forth below:

(21a-123) and pharmaceutically acceptable salts thereof.

4.4 Compounds of Formula (HI-123)

As stated above, the present invention encompasses methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III- 123):

(III-123) or a pharmaceutically acceptable salt thereof, where Ri, R₂, R3, R4, Rs.R_δ. Gi, G₂, G₃, G4, and X are defined above for the compounds of Formula (III- 123).

In one embodiment R1-R4 are hydrogen.

In another embodiment, at least one of R|, R₂, R₃, R4 and R₇ is other than hydrogen.

In yet another embodiment R₅ is oxygen.

In still another embodiment, one OfGi-G₄ is N.

In another embodiment Gi is N; and G2-G4 are C-R₇.

In another embodment G₂ is N; and Gi, G3 and G4 are C-R₇.

In another embodiment G3 is N; and Gi, G₂ and G₄ are C-R₇.

In another embodiment G₄ is N; and Gi, G₂, and G₃ are C-R₇.

In another embodiment Gi and G₂ are N and G₃ and G₄ are C-R₇.

In another embodiment G| and G₃ are N and G₂ and G₄ are C-R₇.

In another embodiment Gi and G₄ are N and G₂ and G₃ are C-R₇.

In another embodiment G₂ and G3 are N and Gi and G₄ are C-R₇.

In another embodiment G₂ and G₄ are N and Gi and G₃ are C-R₇.

In another embodiment G3 and G₄ are N and Gi and G₂ are C-R₇.

In another embodiment compounds of Formula (III- 123) have the structure of Formula (III'-123):

(IIP-123) wherein X, and R₉ are defined above for Formula (III-123). An illustrative example of a compound of Formula (IH'-123) is set forth below:

and pharmaceutically acceptable salts thereof.

4.5 Compounds of Formula (IV-123)

As stated above, the present invention encompasses methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (IV-123):

(IV-123) or a pharmaceutically acceptable salt thereof, where Ri, R₂, R₃, R4, Rs₁Gi₁G₂, G₃, G₄, and X are defined above for the compounds of Formula (IV-123).

In one embodiment R₁-R4 are hydrogen.

In another embodiment, at least one of R|, R2, R₃, R₄ or R₇ is other than hydrogen.

In yet another embodiment R₅ is oxygen.

In still another embodiment, R₆ is hydrogen.

In still another embodiment, one Of Gi-G₄ is N.

In another embodiment Gi is N; and G₂-G₄ are C-R₇.

In another embodment G₂ is N, Gi, G₃, G4 are C-R₇.

In another embodiment G₃ is N, Gi, G₂, G₄ are C-R₇. In another embodiment G4 is N, Gi, G₂, and G3 are C-R₇. In another embodiment Gi and G₂ are N and G₃ and G₄ are C-R₇. In another embodiment Gi and G₃ are N and G₂ and G₄ are C-R₇. In another embodiment Gi and G₄ are N and G₂ and G₃ are C-R₇. In another embodiment G₂ and G₃ are N and G| and G₄ are C-R₇. In another embodiment G₂ and G4 are N and Gi and G₃ are C-R₇. In another embodiment G₃ and G₄ are N and Gi and G2 are C-R₇. In another embodiment compounds of Formula (IV- 123) have the structure of Formula (IV-123):

(IV-123) wherein X, R₉ and Rio are defined above for Formula (IV-123).

4.6 Compounds of Formula (V-123)

As stated above, the present invention encompasses methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (V-123):

(V-123) or a pharmaceutically acceptable salt thereof, where R|, R.2, R₃, R₄, R_S1 R_O, R₇, Rs, R₉, Rio and p are defined above for the compounds of Formula (V- 123).

In one embodiment, R₁-R4 are hydrogen. In another embodiment, at least one of Ri, R2, R3, R4, Re, R7, Re, and R9 is other than hydrogen. In still another embodiment Ri- R₄ and R₆-RgIs other than -0-(Ci-C₅ alkyl), and -A-B is other than -0-(Ci-Ci₀ alkyl). In one embodiment R₅ is O. In another embodiment R5 is NH. In a further embodiment R₅ is S.

In one embodiment, p is other than 0 when Rio is hydrogen.

In another embodiment compounds of Formula (V-123) have the structure of Formula (V-123):

(VM23) wherein Rs and Rio are defined above for Formula (V-123).

Illustrative compounds of Formula (V- 123) are set forth below:

(V'-123)

and pharmaceutically acceptable salts thereof.

4.7 Compounds of Formula (VII-123)

As stated above, the present invention encompasses methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (VII-123):

or a pharmaceutically acceptable salt thereof, where Ri, R.₂, R₃, R₄, Rs, G)₁ G₂, G₃, G₄, and

X are defined above for the compounds of Formula (VII-123).

In one embodiment, R₁-R4 are hydrogen.

In another embodiment R₅ is O.

In another embodiment, at least one of Ri, R₂, R3, and R₄ is other than hydrogen. In one embodiment Ri- R4 is other than -0-(Ci-C₅ alkyl), and -A-B is other than -0-(C₁-C₁₀ alkyl).

In another embodiment X is NH. In still another embodiment X is O.

In a further embodiment X is S. In another embodiment R₄ is NH₂, OCH₃, or

NO₂.

In still another embodiment, one OfGi-G₄ is N. In another embodiment Gi is N; and G₂-G₄ are C-R₇. In another embodment G₂ is N; and Gi, G₃ and G₄ are C-R₇. In another embodiment G₃ is N; and G], G₂ and G₄ are C-R₇. In another embodiment G4 is N; and Gi, G₂, and G3 are C-R₇. In another embodiment Gi and G₂ are N and G₃ and G₄ are C-R₇. In another embodiment Gi and G₃ are N and G₂ and G₄ are C-R₇. In another embodiment Gi and G₄ are N and G₂ and G₃ are C-R₇. In another embodiment G₂ and G₃ are N and G_t and G₄ are C-R₇. In another embodiment G₂ and G₄ are N and Gi and G₃ are C-R₇. In another embodiment G₃ and G₄ are N and Gi and G₂ are C-R₇. In another embodiment compounds of Formula (VII- 123) have the structure of Formula (Vir- 123):

(Vir-123) wherein X, Gi, G₃, and R₄ are defined above for Formula (VII-123). Illustrative compounds of Formula (VII'-123) are set forth below:

and pharmaceutically acceptable salts thereof.

4.8 Compounds of Formula (VHa-123)

In one embodiment, the compounds of Formula (VII- 123) have the Formula (VIIa-123):

where Ri, R₂, R₃, R4, Rs, R₇, and X are defined above for the compounds of Formula (VII-

123).

In one embodiment, R₁-R4 are hydrogen. In another embodiment, at least one of Ri, R₂, R₃, R4, R₆, and R₇, is other than hydrogen. In one embodiment R₁-R₄ and R₇ is other than -O-(C|-Cs alkyl), and -A-B is other than -0-(C|-Cιo alkyl). In another embodiment X is NH. In still another embodiment X is O. In a further embodiment X is

S. In another embodiment R₄ is -NH₂, -OCH₃, or -NO₂.

In another embodiment compounds of Formula (VIIa-123) have the structure of Formula (Vlla'-l 23):

(VIIa'-123) wherein R₄, and X are defined above for Formula (VIIa-123).

Illustrative compounds of Formula (VIIa'-123) are set forth below:

(VIIa'-123)

and pharmaceutically acceptable salts thereof.

4.9 Compounds of Formula (VIIb-123)

In one embodiment, the compounds of Formula (VII- 123) have the Formula (VIIb-123):

(VIIb-123) where R|, R₂, R₃, R₄, R_5,R_7>and X are defined above for the compounds of Formula (VIl- 123).

In one embodiment, R₁-R4 are hydrogen.

In another embodiment, at least one of R|, R₂, R₃, R₄, R₆, or R₇, is other than hydrogen.

In one embodiment R₁-R₄ and R₇ is other than -O-(C|-Cs alkyl), and -A-B is other than -0-(Ci-Ci₀ alkyl).

In another embodiment X is NH. In still another embodiment X is O. In a further embodiment X is S. In another embodiment R₄ is NH₂, OCH₃, or NO₂.

In another embodiment compounds of Formula (VIIb-123) have the structure of Formula (VIIb'-l 23):

(VIIb'-123) wherein X and R₄ are defined above for Formula (VIIb- 123).

Illustrative compounds of Formula (VIIb'-123) are set forth below:

(Vllb'-123)

and pharmaceutically acceptable salts thereof.

4.10 Compounds of Formula (VIIc-123)

In one embodiment, the compounds of Formula (VII- 123) have the Formula (VIIc-123):

(VIIc-123)

where Ri, R₂, R₃, R₄, R₅, R₇, and X are defined above for the compounds of Formula (VII- 123).

In one embodiment, Ri -R₄ are hydrogen. In another embodiment, at least one of

Ri, R₂, R₃, R₄, R₆, or R₇, is other than hydrogen. In one embodiment R₁-R₄ and R₇ is other than

-O-(C|-C5 alkyl), and -A-B is other than -0-(Ci-Cio alkyl). In another embodiment X is NH. In still another embodiment X is O. In a further embodiment X is S. In another embodiment R₄ is -NH₂, -OCH₃, or -NO₂.

In another embodiment compounds of Formula (VIIc-123) have the structure of

Formula (VIIc'-123):

(VIIc'-123) wherein X and R₄ are defined above for Formula (VIIc-123).

Illustrative compounds of Formula (VIIc- 123) are set forth below:

(VIIc'-123)

and pharmaceutically acceptable salts thereof.

4.11 Compounds of Formula (1-123). (Ia-123). (Ib-123). αiI-123), qV-123), (V-123). (VII-123), (VIIa-123). (VIIb-123). and (VIIc-123)

The compounds of the invention can exist in a keto or enol tautomeric form. This invention encompasses both the keto and enol forms of the compounds of the invention. Accordingly, Formula (1-123), (Ia-123) (Ib-123), (III-123), (IV-123), (V-123), (VII-123), (VIIa-123), (VIIb-123), and (VIIc-123), although depicting the keto form of the compounds, encompass both the keto and enol forms.

The present invention also includes compounds of the invention, wherein one or more hydrogen, carbon or other atoms are replaced by an isotope thereof. Such compounds are useful as research or diagnostic tools in metabolism pharmacokinetic studies and in binding assays. 4.12 Compounds of Formula (1-145)

As stated above, the present invention encompasses methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (1-145)

(1-145) or a pharmaceutically acceptable salt thereof, where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹ ' are defined above for the compounds of Formula (1-145).

In one embodiment R¹, R², R³ and R⁴ are independently -H, -NO₂, -NH₂, -F, -OH, or-O-(C|-C₅ alkyl).

In another embodiment R¹, R², R³ and R⁴ are each — H. In another embodiment R², R³ and R⁴ are each — H. In another embodiment R⁶, R⁷ and R⁹ are each — H. In another embodiment R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each -H.

In another embodiment R⁵ is oxygen.

In still another embodiment R¹, R², R³ and R⁴ are each hydrogen. In yet another embodiment R⁶, R⁷, R⁸ or R⁹ is -A-B, where A is -NHC(O)- and B is -(Ci-C₅ alkylene)-NZ]Z₂. In a further embodiment R⁶, R⁷, R⁸ or R⁹ is -A-B, where A is -SO₂NH-; B is -C_t-

C₅ alkylene)-N(Zi)(Z₂); and N, Zi and Z₂ are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.

In another embodiment R⁸ is -NHC(O)CH₂N(CH₃^. In a further embodiment R⁸ is -SO₂NH(CH₂)₃-(morpholin-4-yl).

In one embodiment R¹⁰ is -H, -C_rC₅ alkyl, -(CH₂)_n-aryl, -COO-(Ci-C₅ alkyl), - CONH₂, -CONH-(CH₂)_n-COOH, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-(7- to 10-membered bicyclic heterocycle), -(CH₂),,- CONH-(CH₂)_q-CONH-(Ci-C₅ alkyl), -(CH₂)_n-CONH-(CH₂)_q-CON-(Ci-C₅ alkyl>2, -C(O) -(Ci-C₅ alkyl) or -C(O)(CH₂)_n-COO-(C,-C₅ alkyl).

In another embodiment R⁵ is NH.

In yet another embodiment R is S.

In one embodiment, the compounds of Formula (1-145) are in isolated and purified form.

In another embodiment, the compounds of Formula (1-145) have the formula (Ia-

145):

(la-145) and pharmaceutically acceptable salts thereof, where Ri, R₈ and Rio are as defined above for the compounds of Formula (1-145).

Illustrative examples of the compounds of Formula (Ia-145) are as set forth below.

and pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of Formula (1-145) have the formula (Ib-

145):

(Ib-145) and pharmaceutically acceptable salts thereof, where Rio, Ri i and the nitrogen atom to which they are attached join to form a -(nitrogen-containing 3- to 7- membered monocyclic heterocycle); and wherein Rj, Rg are as defined above for the compounds of Formula (1-145).

Illustrative examples of the compounds of Formula (Ib-145) are as set forth below.

and pharmaceutically acceptable salts thereof. 4.13 Compounds of Formula (11-145)

As stated above, the present invention encompasses methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (11-145):

(11-145) or a pharmaceutically acceptable salt thereof, where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are defined above for the Compounds of Formula (11-145).

In one embodiment R¹, R², R³ and R⁴ are independently -H, -F, -NO₂, -NH₂, -OH,

Or -O-(Ci-C₅ alkyl).

In another embodiment R¹, R², R³ and R⁴ are each — H.

In another embodiment R , FL and R are each — H.

In another embodiment R⁶, R⁷ and R⁹ are each — H. In another embodiment R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each hydrogen.

In another embodiment R⁵ is oxygen.

In yet another embodiment R⁶, R⁷, R⁸ or R⁹ is -A-B, where A is -NHC(O)- and B is -(Ci-C₅ alkylene)-NZiZ₂.

In a further embodiment R⁶, R⁷, R⁸ or R⁹ is -A-B, where A is -SO₂NH- and B is - Ci-Cio alkyl, wherein the -Ci-Cio alkyl group is substituted with a heterocyclic amine.

In another embodiment R⁸ is -NHC(O)CH₂N(CH₃)₂.

In a further embodiment R⁸ is -SO₂NH(CH₂)₃-(morpholin-4-yl). In one embodiment R¹⁰ is -H, -Ci-C₅ alkyl, -(CH₂)_n-aryl, -COO-(Ci-C₅ alkyl), - CONH₂, -(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n -(I - to 10- membered bicyclic heterocycle), -CONH-(CH₂)_n-COOH, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH2)_n-CONH-(CH₂)_q-(7- to 10- membered bicyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-CONH-(C|-C₅ alkyl), -(CH₂)_n-CONH-(CH₂)_q- CON-(Ci-C₅ alkyl)₂, -C(O) -(C,-C₅ alkyl) or -C(O)(CH₂)_n-COO-(C,-C₅ alkyl).

In another embodiment R⁵ is NH.

In yet another embodiment R⁵ is S.

In one embodiment, the compounds of Formula (11-145) are in isolated and purified form.

In another embodiment, the compounds of Formula (11-145) have the formula (Ha-

145):

(IIa-145) and pharmaceutically acceptable salts thereof, where R¹, R⁸ and R¹⁰ are defined above for the compounds of Formula (11-145).

Illustrative examples of the compounds of Formula (IIa-145) are as set forth below.

and pharmaceutically acceptable salts thereof.

4.14 Compounds of Formula (HI-145)

As stated above, the present invention encompasses methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III- 145)

(III-145) or a pharmaceutically acceptable salt thereof, where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹ ' are defined above for the compounds of Formula (III-145).

Or -O-(C₁-C₅ alkyl).

In another embodiment R¹, R², R³ and R⁴ are each — H.

In yet another embodiment R², R³ and R⁴ are each — H.

In another embodiment R⁶ and R⁹ are each — H.

In another embodiment R⁶, R⁷, R⁸ and R⁹ are each -H.

In still another embodiment R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each -H.

In one embodiment R⁵ is O.

In another embodiment, R⁵ is S.

In yet another embodiment, R is NH. I Inn aannootthheerr eemmbboocdiment R⁷ is — H and R⁸ is -A-B, where A is -NHC(O)- and B is — (Ci-C₅ alkylene)-NZ,Z₂. In still another embodiment R⁸ is -H and R⁷ is -A-B, where A is -NHC(O)- and B is -(Ci-C₅ alkylene)-NZ,Z₂

7 8

In yet another embodiment R is — H and R is -A-B, where A is — SO₂NH-; B is — C₁-C₅ alkylene)-N(Zi)(Z₂); and N, Z] and Z₂ are taken together to form a nitrogen- containing 3- to 7-membered monocyclic heterocycle.

In a further embodiment R⁸ is -H and R⁷ is -A-B, where A is -SO₂NH-; B is -C₁- C₅ alkylene)-N(Z 0(Z₂); and N, Zi and Z₂ are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.

In another embodiment R⁷ is -H and R⁸ is -NHC(O)CH₂N(CH₃)₂. In another embodiment R⁷ is -H and R⁸ is -SO₂NH(CH₂)₃-(morpholin-4-yl).

In a further embodiment R⁸ is -H and R⁷ is — Sθ2NH(CH2)₃-(morpholin-4-yl).

In one embodiment R¹¹ is -C(O)R¹², -C(O)OR¹², -C(O)NH-(CH₂)_P-(3- to 7- membered monocyclic heterocycle), -C(O)N(R¹²)₂, -C(O)NH(CH₂)_nN(R^I2)₂, - C(O)NHNHR¹², -C(O)NH-N(Z₁)(Z₂), -(C₁-C₅ alkyl), -(CH₂)_p-phenyl, -(CH₂)_p-(3- to 7- membered monocyclic heterocycle), -(CH₂)_p-7- to 10-membered bicyclic heterocycle, or

-A-B.

In another embodiment R¹¹ is -C(O)O-(Ci-C₅ alkyl), or -C(O)O-(Ci-C₅ alkyl)- NZiZ₂

In a further embodiment R '-R⁴ are each — H, R⁵ is O, and R¹ ' is -C(O)O-(C₁-C₅ alkyl), or -C(O)O-(C-C₅ alkyl)-NZ,Z₂.

In one embodiment, when R¹¹ is -H and R⁵ is O, then R'-R⁴ and R⁶-R⁹ are not simultaneously — H.

In one embodiment, the compounds of Formula (III-145) are in isolated and purified form.

In another embodiment, the compounds of Formula (III-145) have the formula (IIIa-145):

(IIIa-145) and pharmaceutically acceptable salts thereof, where R¹, R⁷, R⁸ and R¹ ' are as defined above for the compounds of Formula (III-145).

Illustrative examples of the compounds of Formula (IIIa-145) are as set forth below.

and pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of Formula (IIIa-145) are those wherein

R , ι', R' and R⁸ are -H. In yet another embodiment, the compounds of Formula (IIIa-145) are those wherein R¹, R⁷ and R⁸ are -H; and R¹¹ is -C(O)O(Ci-C₅ alkyl), or -C(O)O-(Ci-C₅ alkyl)- NZ₁Z₂.

4.15 Compounds of Formula (IV-145)

As stated above, the present invention encompasses methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (IV-145)

(IV-145) or a pharmaceutically acceptable salt thereof, where R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹³ are defined above for the Compounds of Formula (IV-145).

In one embodiment R¹, R², R³ and R⁴ are independently -H, -NO₂, -NH₂, -F, -OH, Or -O-(Ci-C₅ alkyl).

In another embodiment R¹, R², R and R⁴ are each — H.

In another embodiment R², R³ and R⁴ are each — H.

In another embodiment R⁶, R⁷ and R⁹ are each -H.

In another embodiment R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each -H.

In still another embodiment R¹, R², R³ and R⁴ are each hydrogen.

In yet another embodiment R⁶, R⁷, R⁸ or R⁹ is -A-B, where A is -NHC(O)- and B is -(Ci-C₅ alkylene)-NZ|Z₂.

In a further embodiment R⁶, R⁷, R⁸ or R⁹ is -A-B, where A is -SO₂NH-; B is -Ci- C₅ alkylene)-N(Zi)(Z2); and N, Zj and Z₂ are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle. In another embodiment R⁸ is -NHC(O)CH₂N(CH₃)₂.

In a farther embodiment R⁸ is -SC>₂NH(CH2)3-(morpholin-4-yl).

In one embodiment R¹⁰ is -H, -Ci-C₅ alkyl, -(CH₂)_n-aryl, -COO-(Ci-C₅ alkyl), - CONH₂, -CONH-(CH₂)_n-COOH, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH₂)n-CONH-(CH₂)q-(7- to 10- membered bicyclic heterocycle), -(CH₂),,- CONH-(CH₂)_q-CONH-(C|-C₅ alkyl), -(CH₂)n-CONH-(CH₂)_q-CON-(Ci-C₅ alkyl)₂, -C(O) -(Ci-C₅ alkyl) or -C(O)(CH₂)_n-COO-(Ci-C₅ alkyl).

In one embodiment, the compounds of Formula (I V-145) are in isolated and purified form.

In another embodiment, the compounds of Formula (IV-145) have the formula (IVa-145):

(IVa-145) and pharmaceutically acceptable salts thereof, where R¹, R⁸, R¹⁰ and R¹³ are as defined above for the compounds of Formula (IV-145).

In another embodiment, the compounds of Formula (IV-145) have the formula (IVb-145):

(IVb- 145) and pharmaceutically acceptable salts thereof, where Rio, Rn and the nitrogen atom to which they are attached join to form a -(nitrogen-containing 3- to 7- membered monocyclic heterocycle); and wherein Ri, Rg, and R^ are as defined above for the compounds of Formula (ΪV-145).

4.16 Compounds of Formula CV-14S)

As stated above, the present invention encompasses methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (V-145):

(V-145) or a pharmaceutically acceptable salt thereof, where R¹, R², R³, R⁴, R⁶, R⁷-, R⁸, R⁹, R¹⁰,, - and R¹³ are defined above for the compounds of Formula (V-145).

In one embodiment R¹, R², R³ and R⁴ are independently -H, -F, -NO₂, -NH₂, -OH, Or-O-(C₁-C₅ alkyl).

In another embodiment R¹, R², R³ and R⁴ are each — H. In another embodiment R², R³ and R⁴ are each -H. In another embodiment R⁶, R⁷ and R⁹ are each -H.

In another embodiment R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each hydrogen. In yet another embodiment R⁶, R⁷, R⁸ or R⁹ is -A-B, where A is -NHC(O)- and B is -(Ci-C₅ alkylene)-NZiZ₂.

In a further embodiment R⁶, R⁷, R⁸ or R⁹ is -A-B, where A is -SO₂NH- and B is — C|-Cio alkyl, wherein the -Ci-Cio alkyl group is substituted with a heterocyclic amine.

In another embodiment R⁸ is -NHC(O)CH₂N(CH₃)₂. In a further embodiment R⁸ is -SO₂NH(CH₂)₃-(morpholin-4-yl).

In one embodiment R¹⁰ is -H, -Ci-C₅ alkyl, -(CH₂)_n-aryl, -COO-(Ci-C₅ alkyl), - CONH₂, -(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -(CH₂),, -(7- to 10- membered bicyclic heterocycle), -CONH-(CH₂)_n-COOH, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH2)_n-CONH-(CH₂)_q-(7- to 10- membered bicyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-CONH-(Ci-Cs alkyl), -(CH₂)_n-CONH-(CH₂)_q-

CON-(C₁-C₅ alkyl)₂, -C(O) -(C₁-C₅ alkyl) or -C(O)(CH₂)_n-COO-(C,-C₅ alkyl).

In one embodiment, the compounds of Formula (V-145) are in isolated and purified form. In another embodiment, the compounds of Formula (V-145) have the formula

(Va-145):

(Va-145) and pharmaceutically acceptable salts th leerreeooff,, i where R¹, R⁸, R¹⁰ and R¹³ are defined above for the compounds of Formula (V-145).

4.17 Compounds of Formula (VI-145)

As stated above, the present invention encompasses methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (VI-145)

(VI-145) or a pharmaceutically acceptable salt thereof, where R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹³ are defined above for the compounds of Formula (VI-145).

In one embodiment R¹, R², R³ and R⁴ are independently -H, -F, -NO₂, -NH₂, -OH, Or-O-(C₁-C₅ alkyl). In another embodiment R¹, R², R³ and R⁴ are each — H. In yet another embodiment R², R³ and R⁴ are each — H.

In another embodiment R⁶ and R⁹ are each -H.

In another embodiment R⁶, R⁷, R⁸ and R⁹ are each -H.

In still another embodiment R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each -H. In another embodiment R⁷ is — H and R⁸ is— A-B, where A is -NHC(O)- and B is —

(C-C₅ alkylene)-NZ,Z₂.

In still another embodiment R⁸ is — H and R⁷ is -A-B, where A is -NHC(O)- and B is -(Ci-C₅ alkylene)-NZiZ₂.

In yet another embodiment R⁷ is — H and R⁸ is -A-B, where A is — SO₂NH-; B is — C1-C₅ alkylene)-N(Zi)(Z₂); and N, Zi and Z₂ are taken together to form a nitrogen- containing 3- to 7-membered monocyclic heterocycle.

In a further embodiment R⁸ is -H and R⁷ is -A-B, where A is -SO₂NH-; B is -Q- C₅ alkylene)-N(Zi)(Z₂); and N, Zj and Z₂ are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle. In another embodiment R⁷ is -H and R⁸ is -NHC(O)CH₂N(CH₃)₂.

In another embodiment R⁷ is -H and R⁸ is -SO2NH(CH2)3-(morpholin-4-yl).

In a further embodiment R is -H and R is — SO₂NH(CH₂)₃-(morpholin-4-yl).

In one embodiment R^{1 1} is -C(O)R¹², -C(O)OR¹², -C(O)NH-(CH₂)_P-(3- to 7- membered monocyclic heterocycle), -C(O)N(R^I2)₂, -C(O)NH(CH₂)_nN(R¹²)₂, - C(O)NHNHR¹², -C(O)NH-N(Zi)(Z₂), -(C, -C₅ alkyl), -(CH₂)_p-phenyl, -(CH₂)_p-(3- to 7- membered monocyclic heterocycle), -(CH₂)_p-7- to 10-membered bicyclic heterocycle, or -A-B.

In another embodiment R^{1 1} is -C(O)O-(C_rC₅ alkyl), or -C(O)O-(Ci-C₅ alkyl)- NZ₁Z₂. In a further embodiment R'-R⁴ are each -H, and R¹ ' is -C(O)O-(Ci-C₅ alkyl), or -

C(O)O-(C₁-C₅ alkyl)-NZ,Z₂.

In another embodiment, the compounds of Formula (Via- 145) are those wherein R¹, R⁷ and R⁸ are -H.

In yet another embodiment, the compounds of Formula (Via- 145) are those wherein R¹ , R⁷ and R⁸ are -H; and R^{1 1} is -C(O)O(C₁-C₅ alkyl), or -C(O)O-(C₁-C₅ alkyl)-

NZ₁Z₂.

In one embodiment, when R¹ ' is -H and R⁵ is O, then R¹ -R⁴ and R⁶-R⁹ are not simultaneously -H. In one embodiment, the compounds of Formula (VI-145) are in isolated and purified form.

In another embodiment, the compounds of Formula (VI-145) have the formula (VIa-145):

(VIa-145) and pharmaceutically acceptable salts thereof, where R¹, R⁷, R⁸, R¹¹ and R¹³ are as defined above for the compounds of Formula (VI-145).

4.18 Compounds Of Formulas (1-145), (11-145). and (111-145)

The compounds of Formula (1-145), (11-145) and (III-145) can exist in a keto or enol tautomeric form. This invention encompasses both the keto and enol forms of the compounds of the invention. Accordingly, Formulas (1-145), (11-145), and (IΪI-145), although depicting the keto form of the compounds, encompass both the keto and enol forms.

The present invention also includes compounds, wherein one or more hydrogen, carbon or other atoms are replaced by an isotope thereof. Such compounds are useful as research or diagnostic tools in metabolism pharmacokinetic studies and in binding assays.

4.19 Compounds of Formula qiI-154) The present invention provides methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound according to Formula (III-154), below:

(III-154) or a pharmaceutically acceptable salt thereof, where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹¹ are defined above for the compounds of Formula (III- 154).

Tn one embodiment R¹, R², R³ and R⁴ are independently -H, -F, -NO₂, -NH₂, -OH, Or -O-(C₁-C₅ alkyl).

In another embodiment R¹, R², R³ and R⁴ are each — H. In yet another embodiment R², R³ and R⁴ are each -H. In another embodiment R⁶ and R⁹ are each -H.

In another embodiment R⁶, R⁷, R⁸ and R⁹ are each -H. In still another embodiment R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each -H. In one embodiment R⁵ is O. In another embodiment, R⁵ is S. In yet another embodiment, R⁵ is NH.

In another embodiment R⁷ is — H and R⁸ is— A-B, where A is -NHC(O)- and B is — (Ci-C₅ alkylene)-NZ|Z₂.

In still another embodiment R^8' is -H and R⁷ is -A-B, where A is -NHC(O)- and B is -(Ci-C₅ alkylene)-NZiZ₂. In yet another embodiment R⁷ is -H and R⁸ is -A-B, where A is -SO₂NH-; B is -

Ci -Cs alkylene)-N(Zi)(Z₂); and N, Z| and Z₂ are taken together to form a nitrogen- containing 3- to 7-membered monocyclic heterocycle.

In a further embodiment R⁸ is -H and R⁷ is -A-B, where A is -SO₂NH-; B is -Q- C₅ alkylene)-N(Zι)(Z2); and N, Zi and Z₂ are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle. In another embodiment R⁷ is -H and R⁸ is -NHC(O)CH₂N(CH₃)₂.

In another embodiment R⁷ is -H and R⁸ is -SO₂NH(CH₂)₃-(JV-morpholino). hi a further embodiment R⁸ is -H and R⁷ is -SO₂NH(CH₂)₃-(N-morpholino).

In a further embodiment R'-R⁴ are each -H, R⁵ is O, and R¹¹ is or -C(O)O-(Ci-C₅ alkyl)-NZiZ₂.

In various embodiments, R¹¹ is -C(O)O-(Ci-C₅ alkyl)-NZ₅Z₆, where -N(Z₅)(Z₆) is:

Other illustrative examples of the compounds of Formula (III- 154) include the compounds of Formula (Ilia- 154) as set forth below:

Compound | n -N(Z₅)(Z₆)

and pharmaceutically acceptable salts thereof.

4.20 Compounds of Formula (IV-154)

The present invention provides methods for treating or preventing a Condition, comprising administering to a subject in need thereof an effective amount of a compound according to Formula (IV-154), below:

(IV-154) or a pharmaceutically acceptable salt thereof, where R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹³ are defined above for the compounds of Formula (IV-154).

In one embodiment R¹, R², R³ and R⁴ are independently -H, -F, -NO₂, -NH₂, -OH, Or -O-(Ci-C₅ alkyl).

In another embodiment R¹, R², R³ and R⁴ are each -H. In yet another embodiment R², R³ and R⁴ are each — H. In another embodiment R⁶ and R⁹ are each -H.

In another embodiment R⁶, R⁷, R⁸ and R⁹ are each -H. In still another embodiment R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each -H. In another embodiment R⁷ is — H and R⁸ is— A-B, where A is -NHC(O)- and B is — (Ci-C₅ alkylene)-NZ|Z₂. In still another embodiment R⁸ is -H and R⁷ is -A-B, where A is -NHC(O)- and B is -(Ci-C₅ alkylene)-NZ|Z₂.

In yet another embodiment R⁷ is — H and R⁸ is -A-B, where A is -SO₂NH-; B is — C1-C₅ alkylene)-N(Z|)(Z₂); and N, Zj and Z₂ are taken together to form a nitrogen- containing 3- to 7-membered monocyclic heterocycle. In a further embodiment R⁸ is -H and R⁷ is -A-B, where A is -SO₂NH-; B is -Ci-

Cs alkylene)-N(Z|)(Z₂); and N, Zi and Z₂ are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.

In another embodiment R⁷ is -H and R⁸ is -NHC(O)CH₂N(CH₃)₂. In another embodiment R⁷ is -H and R⁸ is -SO₂NH(CH₂)₃-(./V-morpriolino). In a further embodiment R⁸ is -H and R⁷ is -SO₂NH(CH₂)3-(^-moφholino). In another embodiment, the compounds of Formula (IV) are those wherein R 1 , τ R>7 and R⁸ are -H.

In various embodiments, R¹' is -C(O)O-(Ci-C₅ alkyl)-NZ₅Z₆, where -N(Z₅)(Z₆) is: .

Other illustrative examples of the cmpounds of Formula (IV- 154) include the compounds of Formula (IVa-154) as set forth below:

and pharmaceutically acceptable salts thereof, wherein R¹³, n, Zs, and Ze are as set forth above for compounds of Formula IV-154. 4.21 DEFINITIONS

The term "-(Cι-Cio)alkyl" as used herein, refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative straight chain -(Ci-Cio)alkyls include -methyl, -ethyl, -M-propyl, -w-butyl, -n-pentyl, -/z-hexyl, -n-heptyl, -n-octyl, -n-nonly and -n-decyl. Representative branched -(Ci-Cio)alkyls include

-isopropyl, -.fee-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, 1 -methylbutyl, 2-methylbutyl, 3 -methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 -ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylbuty, -isopropyl, -sec-butyl, -isobutyl, 1-methylhexyl,

2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1 ,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1 ,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.

The term "-(Ci-C₉)alkyl" as used herein, refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 9 carbon atoms. Representative straight chain

-(Ci-C9)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -«-pentyl, -n-hexyl, -n-heptyl, -«-octyl, and -n-nonly. Representative branched -(Ci-CsOalkyls include -isopropyl, -sec-butyl, -isobutyl, -ter/-butyl, -isopentyl, -neopentyl, 1 -methylbutyl, 2-methylbutyl, 3 -methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 -ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl,

1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylbuty, -isopropyl, -sec-butyl, -isobutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.

The term "-(Cι-Cs)alkyl" as used herein, refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 5 carbon atoms. Representative straight chain -(Ci-Cs)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl and -n-pentyl. Representative branched -(Ci-Cs)alkyls include -isopropyl, -sec-butyl, -isobutyl, -ter/-butyl, -isopentyl, -neopentyl, 1 -methylbutyl, 2-methylbutyl, 3 -methylbutyl, 1,1-dimethylpropyl and

1,2-dimethylpropyl.

The term "-(C₂-C io)alkenyl" as used herein, refers to a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Representative straight chain and branched (C₂-C io)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-l-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl and the like.

The term "-(C₂-C ιo) alkynyl" as used herein, refers to a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at lease one carbon-carbon triple bond. Representative straight chain and branched -(C₂-C io)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl- 1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl,

-2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -l-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl and the like.

The term "-(C₃-C₈)cycloalkyl or -(C₃-Cg) monocyclic cycloalkyl" as used herein, refers to a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms. Representative (C₃-C₈)cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl,

-cycloheptyl and -cyclooctyl.

The term ^S'-(C₈-Ci₄)bicycloalkyl" as used herein, refers to a bi-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring. Representative -(C₈-C i4)bicycloalkyls include -indanyl, -1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphthyl, -perhydronaphthyl and the like.

The term "-(Cs-Ce) monocyclic cycloalkenyl" as used herein, refers to a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 8 carbon atoms. Representative (Cs-Cs) monocyclic cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl,

-cyclooctatrienyl, -cyclooctatetraenyl and the like.

The term "-(Cg-Cu) bicyclic cycloalkenyl" as used herein, refers to a bi-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms. Representative -(C₈-C 14) bicyclic cycloalkenyls include -indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl,

-1 ,2,7,8-tetrahydronaphthalenyl and the like.

A "3- to 7-membered monocyclic heterocycle" refers to a monocyclic 3- to 7- membered aromatic or non-aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom. The 3- to 7- membered monocyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom. Representative examples of a 3- to 7-membered monocyclic heterocycle group include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, and pyrimidinyl.

A "7- to 10-membered bi cyclic heterocycle" refers to a bicyclic 7- to 10- membered aromatic or non-aromatic bicyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom. The 7- to 10-membered bicyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom.

Representative examples of a 7- to 10-membered bicyclic heterocycle group include, but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl and indazolyl. A "nitrogen-containing 3- to 7-membered monocyclic heterocycle" refers to a 3- to 7-membered monocyclic heterocycle, defined above, which contains at least one ring nitrogen atom. The nitrogen-containing 3- to 7-membered monocyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom. Representative examples of nitrogen- containing-3- to 7-membered monocyclic heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, pyridinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyrimidinyl, and morpholinyl.

A "nitrogen-containing 7- to 10-membered bicyclic heterocycle" refers to a 7- to 10-membered bicyclic heterocycle, defined above, which contains at least one ring nitrogen atom. The nitrogen-containing 7- to 10-membered bicyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom. Representative nitrogen-containing 7- to 10-membered bicyclic heterocycles include -quinolinyl, -isoquinolinyl, -chromonyl, -indolyl, -isoindolyl, -indolizinyl, -indazolyl, -purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl -carbazolyl, -/?-carbolinyl and the like. The term "-aryl" as used herein, refers to a phenyl or naphthyl group.

"Halo-substituted-(Ci-C₅ alkyl)" refers to a Ci-Cs alkyl group, as defined above, wherein one or more of the C₁-C₅ alkyl group's hydrogen atoms has been replaced with - F, -Cl, -Br or -I. Representative examples of an alkylhalo group include, but are not limited to, -CH₂F, -CCl₃, -CF₃, -CH₂Cl, -CH₂CH₂Br, -CH₂CH₂I, -CH₂CH₂CH₂F, -CH₂CH₂CH₂Cl, -CH₂CH₂CH₂CH₂Br, -CH₂CH₂CH₂CH₂I, -CH₂CH₂CH₂CH₂CH₂Br, -CH₂CH₂CH₂CH₂CH₂I, -CH₂CH(Br)CH₃, -CH₂CH(Cl)CH₂CH₃, -CH(F)CH₂CH₃ and -C(CHa)₂(CH₂Cl).

"Amino-substituted-(Ci-Cs alkyl)" refers to a C₁-C₅ alkyl group, as defined above, wherein one or more of the C₁-C₅ alkyl group's hydrogen atoms has been replaced with

-NH₂. Representative examples of an alkyl amino group include, but are not limited to, -CH₂NH₂, -CH₂CH₂NH₂, -CH₂CH₂CH₂NH₂, -CH₂CH₂CH₂CH₂NH₂, -CH₂CH(NH₂)CH₃, -CH₂CH(NH₂)CH₂CH₃, -CH(NH₂)CH₂CH₃, -C(CH₃)₂(CH₂NH₂), -CH₂ CH₂CH₂CH₂CH₂NH₂, -CH₂CH₂CH(NH₂)CH₃, -CH₂CH(NH₂)CH₂CH₂CH₃, -CH₂CH(NH₂)CH₂CH₃ and -CH₂C(CHj)₂(CH₂NH₂).

"-(NH(Ci-Cs alkyl)" refers to an -NH group, the nitrogen atom of said group being attached to a C1-C₅ alkyl group, as defined above. Representative examples of an aminoalkyl group include, but are not limited to, -NHCH₃, -NHCH₂CH₃, -NHCH₂CH₂CH₃, -NHCH₂CH₂CH₂CH₃, -NHCH(CH₃)₂, -NHCH₂CH(CH₃)₂, -NHCH₂(CH₃)CH₂CH₃, -NH-CH₂CH₂C(CH₃);,, -NHCH₂CH₂CH₂CH₂CH₃,

-NHCH₂CH(CH₃)₂, -NHCH₂CH₂CH(CH₃)₂, -NHCH₂CH(CH₃)CH₂CH₃ and -NH-CH₂C(CH₃)-,.

"-N(Ci-Cs alkyl)(Ci-C₅ alkyl)" refers to a nitrogen atom which has attached to it two Ci -C₅ alkyl groups, as defined above. Representative examples of a aminodialkyl group include, but are not limited to, -N(CH₃)₂, -N(CH₂CH₃)(CH₃), -N(CH₂CH₃)₂,

-N(CH₂CH₂CH₃)₂, -N(CH₂CH₂CH₂CH-O₂, -N(CH(CH₃)₂)₂, -N(CH(CH₃)₂)(CH₃), -N(CH₂CH(CH₃)₂)₂, -NH(CH(CH₃)CH₂CH₃)₂, -N(C(CH₃)₃)₂ and -N(C(CH₃)₃)(CH₃).

"-(H₂NC(O))-substituted aryl" refers to an aryl group, as defined above, wherein one of the aryl group's hydrogen atoms has been replaced with one or more -C(O)NH₂ groups. Representative examples of an arylamido group include 2-C(O)NH₂-phenyl,

3-C(O)NH₂-phenyl, 4-C(O)NH₂-phenyl.

"-(H2NC(O))-substituted pyridyl" refers to an pyridyl group, wherein one of the pyridyl group's hydrogen atoms has been replaced with one or more -C(O)NH₂ groups. Representative examples of an arylamido group include 2-C(O)NH₂-pyridyl, 3-C(O)NH₂- pyridyl and 4-C(O)NH₂-pyridyl.

"-(H₂NC(O))-substituted-(Ci-C₅ alkyl)" refers to a Ci-C₅ alkyl group, as defined above, wherein one of the C1-C5 alkyl group's hydrogen atoms has been replaced with a -C(O)NH₂ group. Representative examples of an alkylamido group include, but are not limited to, -CH₂C(O)NH₂, -CH₂CH₂C(O)NH₂, -CH₂CH₂CH₂C(O)NH₂, -CH₂CH₂CH₂CH₂C(O)NH₂₁ -CH₂CH₂CH₂CH₂CH₂C(O)NH₂₅ -CH₂CH(C(O)NH₂)CH₃, -CH₂CH(C(O)NH₂)CH₂CH₃, -CH(C(O)NH₂)CH₂CH₃ and -C(CHs)₂CH₂C(O)NH₂.

"HO-substituted-(Ci-C₅ alkyl)" refers to a C₁-C₅ alkyl group, as defined above, wherein one of the C₁-C₅ alkyl group's hydrogen atoms has been replaced with a hydroxyl group. Representative examples of an alkanol group include, but are not limited to, -CH₂OH, -CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH₂CH₂CH₂CH₂OH, -CH₂CH₂CH₂CH₂CH₂OH, -CH₂CH(OH)CH₃, -CH₂CH(OH)CH₂CH₃, -CH(OH)CH₂CH₃ and -C(CHa)₂CH₂OH.

"Carboxy-substituted-(Ci-Cs alkyl)" refers to a C₁-C₅ alkyl group, as defined above, wherein one of the C₁-C₅ alkyl group's hydrogen atoms has been replaced with a

-COOH group. Representative examples of an alkylcarboxy group include, but are not limited to, -CH₂COOH, -CH₂CH₂COOH, -CH₂CH₂CH₂COOH, -CH₂CH₂CH₂CH₂COOH, -CH₂CH(COOH)CH₃, -CH₂CH₂CH₂CH₂CH₂COOH, -CH₂CH(COOH)CH₂CH₃, -CH(COOH)CH₂CH₃ and -C(CH₃)₂CH₂COOH. The term "glycoside" as used herein refers to a hexose or a pentose sugar forming an α- or β-glycosidic linkage. Representative examples of glycosides include, but are not limited to ribose, deoxyribose, fructose, galactose, glucuronic acid and glucose.

A "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, or baboon. In one embodiment, the subject is a human.

The phrase "pharmaceutically acceptable salt," as used herein, is a salt formed from an acid and a basic nitrogen group of one of the compounds of the invention. Illustrative salts include, but are not limited, to mesylate, camphorsulfonate, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,/?-toluenesulfonate, and pamoate (i.e., l,l '-methylene-bis-(2- OH-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of the invention having an acidic functional group, such as a carboxylic acid functional group or a sulfonic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2- OH-lower alkylamines), such as mono-; bis-, or tris-(2-OHethyl)amine, 2-OH ferf-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2- OHethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. As used herein, the term "pharmaceutically acceptable salt" also includes a hydrate of a compound of the invention. An "effective amount" when used in connection a compound of the invention is an amount effective for treating or preventing erectile dysfunction or urinary incontinence.

The following abbreviations are used herein and have the indicated definitions: AcOH is acetic acid, CEP is Cecal Ligation and Puncture, DMEM is Dulbecco's Modified Eagle Medium, DMF is ΛζiV-dimethylformamide, DMSO is dimethylsulfoxide,

Et is ethyl, EtOAc is ethyl acetate, EtOH is ethanol, HEPES is 4-(2-hydroxyethyl)- 1 -piperazineethanesulfonic acid, HPLC is high performance liquid chromatography, LPS is lipopolysaccharide, MeCN is acetonitrile, MeOH is methanol, MS is mass spectrometry, Ms is mesyl (methanesulfonyl), NaBH₄ is sodium borohydride, NEt₃ is triethylamine, NMR is nuclear magnetic resonance, PBS is phosphate-buffered saline (pH

7.4), PARP is poly(ADP-ribose)polymerase, PPA is polyphosphoric acid, Py is pyridine, SDS is dodecyl sulfate (sodium salt), STZ is streptozotocin, TCA is tricholoroacetic acid, Tf is triflyl (trifluoromethanesulfonyl), TFA is trifluoroacetic acid, THF is tetrahydrofuran; TLC is thin-layer chromatography, TNF is tumor necrosis factor, TRIS is Tris(hydroxymethyl)aminomethane and Ts is tosyl (p-toluenesulfonyl).

The compounds of the invention are disclosed in US 2004/0229895 Al, US 2005/0261288 Al or WO 2006/093666.

4.22 Methods for Making the Compounds of Formula (1-123), (Ib-123), (III-123Ϊ. (IV-123). (V-123Ϊ and (VII-123) Examples of synthetic pathways useful for making Compounds of Formula (I-

123), (Ib-123), (III-123), (IV-123), (V-123) and (VII-123) are set forth in the Examples below and generalized in the schemes.

Scheme 2-123 below illustrates methods useful for making compounds of Formula (1-123) and Formula (Ib-123), wherein R1-R4 and R₇-Rn are defined above for the compounds of Formula (1-123), Formula (Ia-123) and Formula (Ib-123); X' is -OH, - NHRi i, or -SH; X is -O-, -N(H)-, or -S-; each R_a is independently Ci-C₃ alkyl; and R_b is -Cl, -Br, -I, -OTs, -OMs or -OTf.

Scheme 2-123

3a-123:

R₀=CH₃ X'= -OH, -SH.orNHR,,

Rb= Br R I - R₄ ⁼ H R₅X or R₅C(O)OC(O)R₅ or R₅C(O)Cl

(1-123)

(Ia): X=O (Ib): X=NR₁₁ (Ic): X=S

A compound of Formula 15-123 can be prepared by reacting a compound of Formula 13-123 with a compound of Formula 14-123 in the presence of a base, such as triethylamine, sodium carbonate, or potassium carbonate, in a solvent such as acetonitrile, acetone or dim ethyl formamide (DMF).

A compound of Formula 15-123 can be transformed to a compound of Formula (1-123) upon treating 15-123 with an alkylating agent, an acylating agent or a glucuronidating agent, and further derivatization if necessary. Suitable alkylating and acylating agents include, but are not limited to, alkylhalides, such as iodomethane, iodoethane, 1-iodopropane and 2-bromopropane, 1-bromopropane, 1- bromobutane, 1 -bromopentane and 1-bromohexane, the alkyl group of which can be optionally substituted with -OH or -C(O)OH; acyl halides, such as acetyl chloride and propionyl chloride; and anhydrides, such as acetic anhydride and propionic anhydride. In one embodiment, the alkylating agent is methyl iodide.

In another embodiment, the allkylating agent is a hydroxy-substituted alkylhalide.

In still another embodiment, the alkylating agent is a carboxy-substituted alkylhalide. In one embodiment, the acylating agent is acetyl chloride.

In another embodiment, the acylating agent is acetic anhydride.

In yet another embodiment, R₅ is glucuronidyl and the glucuronidating agent is acetobromo-α-D-glucuronic acid methyl ester.

Scheme 3 below illustrates methodology useful for making compounds of Formula III-123, wherein R₁-R₄ and G₁-G₄ are defined above for the compounds of

Formula III- 123; R_b is -Cl, -Br, -I, -OTs, -OMs or -OTf; and R₀ is -Ci-C₃ alkyl.

Scheme 3-123

R₁ = -H, C,-C₅alkyl, -O(C,-C₅alkyl), NH(C,-C₃alkyl or N(C₁-C_SaIRyI)(C, -C₅alkyl)

26a-123: R₁ -R₄ = H; G₂-G₄ = CH; G₁ = N

Compounds of Formulas 22-123, 24-123, 26-123 and 28-123 can be made by reacting a compound of Formula 17-123

with a compound of Formula 21-123, 23-123, 25-123 or 27-123, respectively in the presence of a base.

In an alternate embodiment, compounds of Formulas 22-123, 24-123, 26-123 and 28-123 can be made by reacting a compound of Formula 13-123 with a compound of Formula 21-123, 23-123, 25-123 or 27-123, respectively in the presence of a base.

Suitable bases for use in the methods of Scheme 3-123 are organic bases such as triethyl amine, diisopropylamine, diisopropylethylamine, pyridine, lutidine sodium butoxide, sodium methoxide, and imidazole; and inorganic bases such as alkali metal carbonates, including sodium hydride, sodium carbonate, potassium carbonate and cesium carbonate.

In one embodiment, the base is triethylamine.

In another embodiment, the base is potassium carbonate.

The method can be carried out in the presence of a solvent, such as acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether, water or mixtures thereof.

In one embodiment, the solvent is acetonitrile.

In another embodiment, the solvent is DMF.

Scheme 4 below illustrates methods useful for making compounds of Formula (V- 123) wherein R₁-R4 and R₇-R₁₀ are defined above for the compounds of Formula (V-123).

Scheme 4-123

A B PPA-xylene Δ or ClSO₃H 0⁰C

Reduce

A compound of Formula A can be cyclized to the compounds of Formula B using bromo ethyl malonate in the presence of potassium carbonate. The compounds of Formula B can then be converted to the compounds of Formula C in the presence of ammonia in methanol. Fridel-Crafts mediated ring closure of C provides the compounds of Formula D, which, when reacted with a phosponate or phosphorus ylide via a Wittig- Horner procedure provides the compounds of Formula E, whose exocyclic double bond can subsequently be reduced using catalytic hydrogenation to provide the compounds of Formula (V-123) where p is > 2. In an alternate embodiment, compounds of Formula. (V- 123) where p = 0, can be synthesized via compounds of Formula D. The compounds of Formula D can be reduced to the corresponding compounds of Formula D' with subsequent conversion of the alcohol to the compounds of Formula D" to produce a good leaving group. The triflate intermediate can then be reacted with nucleophiles of the Formula

Rio^"M⁺ where M⁺ is a alkali metal such as Na⁺, or K⁺, thereby producing compounds of Formula (V-123) where p = 0. The compounds of Formula A can be produced from commercially starting materials using techniques known to one skilled in the art of organic synthesis. Scheme 5 below illustrates methods useful for making compounds of Formula (VII-123) wherein R1-R4, R7-R10, G1-G4, and X are defined above for the compounds of Formula (VII- 123):

SCHEME 5-123

(VIIb-123) (VIIc-123)

The compound of Formula N can be coupled with DPPA to provide the corresponding compounds of Formula O, which can then be thermally cyclized to provide the compound of Formula (II-123). Using the same synthetic method, the compounds of Formula Q (see Wacker et al., Tet. Lett., 43:5189-5191, 2002; and Bourdais, et al., J. Het. Chem., _J_2:1 1 1 1-1 1 15, 1975, for methods useful to make compounds of Formula Q) can be converted to the compounds of Formula (VII-123), Formula (VIIa-123), Formula (VIIb-123), and Formula (VIIc-123) via the compounds of Formula R.

Scheme 6 below illustrates methods useful for -making compounds of Formula (IV-123) wherein R₁-R4, R7-R10, and G1-G4 are defined above for the compounds of Formula (IV- 123):

SCHEME 6-123

The compounds of Formula (IV-123) can be made using a one-pot coupling/cyclization process by reacting a compound of Formula W with a compound of

Formula Y in the presence of sodium hydride.

Alternatively, a compound of Formula Z (see Wacker et al., Tet. Lett., 43:5189- 5191, 2002; and Bourdais, et al., J. Het. Chem., 12:1111-1115, 1975, for methods useful to make compounds of Formula Z) can be coupled with DPPA to provide the corresponding compounds of Formula AA, which can then be thermally cyclized to provide the compounds of Formula (IV-123).

4.23 Methods for Making the Compounds of Formula (1-145), (11-145), and (IH-145)

Compounds of Formula (1-145), (11-145), and (111-145) can be made using conventional organic synthesis or by the following illustrative methods shown in the schemes below.

Scheme 1-145 below illustrates a method useful for making the compounds of Formula (1-145), wherein R'-R¹ ' are as defined above for the compounds of Formula (I- 145).

PPA-xylene Δ

OrClSO₃H O ⁰C

Scheme 1-145

A compound of formula A can be cyclized to the compounds of formula B using bromo ethyl malonate in the presence of potassium carbonate. The compounds of formula B can then be converted to the compounds of formula C in the presence of ammonia in methanol. Fridel-Crafts mediated ring closure of C provides the compounds of formula D which can be coupled with a hydrazine to provide the compounds of Formula (1-145).

Scheme 2-145 further illustrates the formation of particular -NRioRn groups of

Formula (1-145). Reacting the compound of formula D with the particular hydrazines set forth in Scheme 2-145 in the presence of a suitable acid, such as acetic acid or hydrochloric acid, results in the formation of compounds 1-145, 7-145, 105-145, and 106- 145, respectively.

Scheme 2-145

Scheme 3-145 below illustrates a method useful for making the compounds of Formula (11-145), wherein R'-R¹⁰ are as defined above for the compounds of Formula (11-145).

PPA-xylene Δ or ClSO₃H O ⁰C

Scheme 3-145

A compound of formula E can be cyclized to the compound of formula F using bromo ethyl malonate in the presence of potassium carbonate. The compounds of formula F can then be converted to the compounds of formula G in the presence of ammonia in methanol. Fridel-Crafts mediated ring closure of G provides the compounds of formula H, which can be reacted with a phosphonate or phosphorus ylide via a Wittig procedure (see March, J, Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, p. 956-963 (4^th Ed. 1992)) to provide the compounds of Formula (11-145). Alternatively, the tetracyclic ketone intermediates of formula H can be reacted with a reagent such as R¹⁰CH₂Li followed by dehydration to provide the compounds of Formula (11-145).

The compounds of Formula (III-145) can be made using the methods described below in Scheme 4, wherein R'-R¹⁰ are as defined above for the compounds of Formula (III-145).

Scheme 4-145

The compound of formula J (see Wacker et al., Tet. Lett., 43:5189-5191, 2002; and Bourdais et al, J. Het. Chem., V2r.11 11-1115, 1975, for methods useful to make compounds of formula J) can be coupled with DPPA to provide the corresponding compounds of formula K, which can then be thermally cyclized by refluxing the compounds of formula K in diphenyl ether or by heating the neat compounds of formula K to between 300 ⁰C and 350 ⁰C to provide the compounds of Formula (III-145).

Alternatively, the compounds of Formula (ΪI1-145) can be made using a one-pot coupling/cyclization process by reacting a bromo intermediate of formula L with an aromatic nitrile of formula M in the presence of sodium hydride.

A compound of Formula (IV-145), (V-145), or (VI-145) can be made by reacting a compound of Formula (1-145), (11-145), or (111-145) respectively, with a compound having the formula: (a) R¹³X, where X is a leaving group such as halogen; or (b) R¹³- C(O)-O-C(O)-R¹³, under conditions well-known to those skilled in the art of organic synthesis.

4.24 Methods for Making the Compounds of Formula (III- 154) and (IV- 154)

The compounds of Formula (III-154) can be made using the methods described below in Scheme 2-154, wherein R'-R¹⁰ are as defined above for the compounds of Formula (111-154).

Scheme 2-154

63-154

A compound of formula 61-154 (see Wacker et al., Tet. Lett., 43:5189-5191, 2002; and Bourdais et al, J. Het. Chem., 12:1111-1115, 1975, for methods useful to make compounds of formula 61-154) can be coupled with DPPA to provide the corresponding compounds of formula 62-154, which can then be thermally cyclized by refluxing the compounds of formula 62-154 in diphenyl ether or by heating the neat compounds of formula 62-154 to between 300⁰C and 350⁰C to provide the compounds of Formula (III- 154). Alternatively, the compounds of Formula (III-154) can be made using a one-pot coupling/cyclization process by reacting a bromo intermediate of formula 63-154 with an aromatic nitrile of formula 64-154 in the presence of sodium hydride.

A compound of Formula (IV-154) can be made by reacting a compound of Formula (III-154) with a compound having the formula: (a) R¹³X, where X is a leaving group such as halogen; or (b) R^l3-C( O)-O-C(O)-R¹³, under conditions well-known to those skilled in the art of organic synthesis. In either instance, R¹³ is as defined above for the compounds of Formula (IV-154).

4.25 Therapeutic Uses of the Compounds of the Invention

The invention also includes pharmaceutical compositions comprising an effective amount of a compound of the invention and a pharmaceutically acceptable carrier or vehicle.

In accordance with the invention, the compounds of the invention are administered to a subject in need of treatment or prevention of a Condition. 4.25.1 Treatment or Prevention of Erectile Dysfunction

The compounds of the invention are useful for treating or preventing erectile dysfunction. Erectile dysfunction includes an inability to achieve or maintain a full erection, particularly that which is sufficient to achieve or maintain sexual intercourse. The inability can be a total inability, an inconsistent ability, or a tendency to maintain only a brief erection. Erectile dysfunction that is treatable or preventable according to the methods described herein includes idiopathic erectile dysfunction, as well as that which can result, for example, from trauma, including mechanical trauma, particularly that resulting from surgery, to the nerves (such as during prostatectomy); diabetes mellitus; a cardiovascular disease, including atherosclerosis; radiation; or certain drugs. The erectile dysfunction can also be age-related.

In one embodiment the erectile dysfunction results from prostate surgery.

In a further embodiment the erectile dysfunction results from prostate nerve injury.

4.25.2 Treatment or Prevention of Urinary Incontinence

The compounds of the invention are also useful for treating or preventing urinary incontinence. Urinary incontinence that is treatable or preventable according to the methods described herein, can result, for example, from trauma, including mechanical trauma, particularly during childbirth or that resulting from surgery, to the nerves (such as during prostatectomy or gynecological surgery); diabetes mellitus; a cardiovascular disease, including atherosclerosis; radiation; or certain drugs. The urinary incontinence can also be age-related.

In one embodiment the subject in need of urinary incontinence treatment or prevention is male. In one embodiment the subject in need of urinary incontinence treatment or prevention is female.

4.25.3 Therapeutic/Prophylactic Administration and Compositions of the Invention

Due to their activity, the compounds of the invention are advantageously useful in veterinary and human medicine. As described above, the compounds of the invention are useful for treating or preventing a Condition in a subject in need thereof.

When administered to a subject, the compounds of the invention can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. The present compositions, which comprise a compound of the invention, can be administered orally. The compounds of the invention of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e g-_> oral, rectal, and intestinal mucosa, etc.) and can be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be administered.

Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin. In some instances, administration will result in the release of the compounds of the invention into the bloodstream. The mode of administration is left to the discretion of the practitioner. In one embodiment, the compounds of the invention are administered orally.

In other embodiments, it can be desirable to administer the compounds of the invention locally. This can be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce the compounds of the invention into the central nervous system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal, and epidural injection, and enema. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of an inhaler of nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon oar, synthetic pulmonary surfactant. In certain embodiments, the compounds of the invention can be formulated as a suppository, with traditional binders and excipients such as triglycerides.

In another embodiment the compounds of the invention can be delivered in a vesicle, in particular a liposome {see Langer, Science 249:1527-1533 (1990) and Treat or prevent et al., Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)).

In yet another embodiment, the compounds of the invention can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 1 15-138 (1984)). Other controlled or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be used. In one embodiment a pump can be used (Langer, Science 249: 1527- 1533 (1990); Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 88:507 (1980); and Saudek et al., N. Engl. J Med. 321:574 (1989)). In another embodiment polymeric materials can be used (see Medical Applications of Controlled

Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, «Λ Macromol. ScL Rev. Macromol. Chem. 2:61 (1983); Levy et al., Science 228:190 (1935); During et al., Ann. Neural. 25:351 (1989); and Howard et al., J. Neurosurg. 7J_.:105 (1989)). In yet another embodiment, a controlled- or sustained-release system can be placed in proximity of a target of the compounds of the invention, e.g., the spinal column, brain, skin, lung, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the animal.

Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be saline, gum acacia; gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a particularly useful excipient when the compound of the invention is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions, emulsion, tablets, pills; pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment the composition is in the form of a capsule (see e.g. U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington 's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference. In one embodiment the compounds of the invention are formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving a compound of the invention are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment the excipients are of pharmaceutical grade. In another embodiment the compounds of the invention can be formulated for intravenous administration. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where desired, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized-powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where the compounds of the invention are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the compounds of the invention are administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

The compounds of the invention can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but arc not limited to, those described in U.S.. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354;556; and 5,733,556, each of which is incorporated herein by reference. Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.

Controlled- or sustained-release pharmaceutical compositions can have a common goal of improving drug therapy over that achieved by their non-controlled or non-sustained counterparts. In one embodiment a controlled- or sustained-release composition comprises a minimal amount of a compound of the invention to cure or control the condition in a minimum amount of time. Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the compound of the invention, and can thus reduce the occurrence of adverse side effects. Controlled- or sustained-release compositions can initially release an amount of a compound of the invention that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the compound of the invention to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of the compound of the invention in the body, the compound of the invention can be released from the dosage form at a rate that will replace the amount of compound of the invention being metabolized and excreted from the body. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

The amount of the compound of the invention that is effective in the treatment or prevention of a Condition can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, and the seriousness of the condition being treated and can be decided according to the judgment of the practitioner and each subject's circumstances in view of, e.g., published clinical studies. Effective dosage amounts of the present invention, when used for the indicated effects, range from about 0.05 to about 1000 mg of compound of the invention per day. Compositions for in vivo or in vitro use can contain about 0.5, 1.0, 2.5, 5.0, 10.0,

15.0, 25.0, 50.0, 100.0, 250.0, 500.0 or 1000.0 mg of compound of the invention. In one embodiment, the compositions are in the form of a tablet that can be scored. Effective plasma levels of the compounds of the invention can range from about 0.002 mg to about 50 mg per kg of body weight per day. Compounds of the invention can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, compounds of the invention can be administered in intranasal form via ^• topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen. Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of compound of the invention ranges from about 0.1% to about 15%, w/w or w/v. The compounds of the invention can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.

The present methods for treating or preventing a Condition in a subject in need thereof can further comprise administering another prophylactic or therapeutic agent to the subject being administered a compound of the invention. In one embodiment the other prophylactic or therapeutic agent is administered in an effective amount. The other prophylactic or therapeutic agent includes, but is not limited to, an anti-erectile dysfunction agent or an anti-urinary incontinence agent. In one embodiment, the other prophylactic or therapeutic agent is an agent useful for reducing any potential side effect of compound of the invention. Such potential side effects include, but are not limited to, nausea, vomiting, headache, low white blood cell count, low red blood cell count, low platelet count, headache, fever, lethargy, a muscle ache, general pain, bone pain, pain at an injection site, diarrhea, neuropathy, pruritis, a mouth sore, alopecia, anxiety or depression.

In one embodiment, the compound of the invention can be administered prior to, concurrently with, or after an anti-erectile dysfunction agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.

In one embodiment, the compound of the invention can be administered prior to, concurrently with, or after an anti-urinary incontinence agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.

A composition of the invention is prepared by a method comprising admixing a compound of the invention and a pharmaceutically acceptable carrier or vehicle. Admixing can be accomplished using methods well known for admixing a compound (or salt) and a pharmaceutically acceptable carrier or vehicle. In one embodiment the compound of the invention is present in the composition in an effective amount.

In one embodiment, the compounds of the invention are administered to a subject prior to, during, or subsequent to undergoing surgery, particularly prostate surgery.

5. EXAMPLES 5.1 General Methods

Proton NMR spectra were obtained using a Varian 300 MHz spectrophotometer and chemical shift values (δ) are reported in parts per million (ppm). TLC was performed using TLC plates precoated with silica gel 60 F-254, and preparative TLC was performed using precoated Whatman 6OA TLC plates. All intermediates and final compounds were characterized on the basis of ¹H NMR and MS data.

5.2 Example 1: Preparation of Illustrative Compounds of Formula (1-123). (Ia-123). (Ib-123). (III-123). (IV-123). (V-123). (VII-123). fVIIa-123), (VIIb-123). and (VIIc-

123)

a) Preparation of 2-(bromo-methoxycarbonyl-methyl)-benzoic acid methyl ester (α- Bromodimethylhomophthalate) (13a-123) (Scheme 2-123):

Dimethylhomophthalate (83.1 g, Aldrich Chemical Co.) was dissolved in dichloromethane (2 L), and N-bromosuccinimide (121 g, 1.7 eq) was added. The resultant suspension was irradiated for 18 h with a 500 wt quartz-halogen lamp, which brought the reaction mixture to reflux. The reaction mixture was then washed sequentially with saturated aqueous sodium bicarbonate (4 L), saturated aqueous sodium bisulfite (2 L), and saturated aqueous sodium chloride (2 L). The organic phase was dried using sodium sulfate with a small amount of silica added to remove polar impurities. The organic phase was filtered and concentrated in vacuo to provide compound 13a-123 as a dark orange oil. Yield = 120.3 g (100%).

b) Preparation of 8- Methoxy-6//-ll-oxa- 6-aza-benzo[α]fluoren-5-one (15a-123) (Scheme 2-123):

A mixture of α-Bromodirnethylhomophthalate (13a-123) (1.16 g) and 2-hydroxy- 5-methoxy-benzonitrile (14b-123), 0.6 g, 4 mmol, 1.0 eq) was dissolved by warming in acetonitrile (6 mL). Triethylamine (5.6 mL, 10 eq) was then added. The reaction mixture was heated at reflux for 48 h under inert atmosphere, then cooled to room temperature. The reaction mixture was diluted with saturated sodium bicarbonate (40 mL), and the resultant suspension was allowed to stir for 2 h, and was then filtered. The resultant filtercake was washed sequentially with 1 N HCl (2 x 50 mL), acetonitrile (2 x 50 mL) and dichloromethane (50 mL), then dried in a vacuum oven at 50°C fot three days to provide compound 15a-123 as an white solid. Yield = 0.81 mg (76%).

c) Preparation of 8-Hydroxy-6^'Jϊ-ll-oxa- 6-aza-benzo [α]lfluoren-5-one (15b-123) (Scheme 2-123): 8-Methoxy-67/-l l-oxa-6-aza-benzo[a]fluoren-5-one (15a-123) (5.0 g) was cooled using an ice bath, and boron tribromide (1 M in methylene chloride, 95 mL, 95 mmol, 5 eq) was added in a steady stream under nitrogen. The reaction mixture was heated at reflux under inert atmosphere for 2 h, then cooled to room temperature and poured into water (150 mL). The resultant suspension was allowed to stir for 1 h and then was filtered. The filtered solids were washed with water (2 x 200 mL). The solids were then suspended in of 5 N sodium hydroxide (600 mL), which was heated. The resultant solution was cooled to 0°C using an ice bath, and the solution was acidified to pH 1 using concentrated HCl. The resultant precipitate was vacuum filtered, and the solids were washed sequentially with water (3 x 300 mL) and diethyl ether (300 mL), then dried overnight using a vacuum oven at 50⁰C to provide compound 15b-123 as a gray solid. Yield = 4.74 g (100%).

d) Preparation of 6H-ll-oxa- 6-aza-benzo[α]fluoren-5-one (15c-123):

Using the method of Example b and substituting 14b-123 with 2-hydroxy- benzonitrile (14a-123), compound 15c-123 was prepared.

e) Preparation of 9-Methoxy-d//-ll-oxa-6-aza-benzo[α]fluoren-5-one (15d-123):

Using the method of Example b and substituting 14b-123 with 2-hydroxy- 4-methoxy-benzonitrile (14c-123), compound 15d-123 was prepared.

f) Preparation of 9-Hydroxy-6//-ll-oxa-6-aza-benzo[α]fluoren-5-one (15e-123):

Using the method of Example c and substituting compound 15a-123 with compound 15d-123, compound 15e-123 was prepared.

g) Preparation of Compound 16a-123 (Scheme 2-123): To a solution of compound 15b-123 (0.755 mmol) in acetone (4 mL) was added

2-bromoacetic acid (2.1 eq) and potassium carbonate (1.04 g, 10 eq). The resultant mixture was heated at reflux for 15 h under nitrogen atmosphere. The reaction mixture was poured into 20 mL of 1 N aqueous sodium hydroxide, stirred 0.5 h, and filtered. The filtered solids were washed twice with 10 mL volumes of water, then stirred for 1 h in 20 mL of 1 N aqueous hydrochloric acid. The solids were vacuum filtered, washed twice with 10 mL of water, twice with 10 mL of ether, and dried in vacuo to provide compound 16a-123 in 75% yield. h) Preparation of Compound 16b-123:

Using the method of Example g and substituting 2-bromoacetic acid with 3-bromo-l-propanol, compound 16b-123 was prepared from compound 15b-123.

i) Preparation of Compound 16c-123: Using the method of Example g and substituting 2-bromoacetic acid with

5-bromo-l-pentanol, compound 16c-123 was prepared from compound 15b-123.

j) Preparation of Compound 16d- 123:

Using the method of Example g and substituting 2-bromoacetic acid with 6-bromo-l-hexanol, compound 16d-123 was prepared from compound 15b-123.

k) Preparation of Compound 16e-123:

Using the method of Example g and substituting 2-bromoacetic acid with 5-bromo-l-pentanoic acid, compound 16e-123 was prepared from compound 15b-123.

1) Preparation of Compound 16M23:

To a solution of compound 15c-123 (0.755 mmol) in acetone (4 mL) was added iodomethane (52 μL, 1.1 eq) and potassium carbonate (1.04 g, 10 eq). The resultant mixture was heated at reflux for 15 h under nitrogen atmosphere. The reaction mixture was poured into 20 mL of 1 N aqueous sodium hydroxide, stirred 0.5 h, and filtered. The resultant solids were washed twice with 10 mL of water, then stirred for 1 h in 20 mL of 1 N aqueous hydrochloric acid. The resultant solids were vacuum filtered, washed twice with 10 mL of water, twice with 10 mL of ether, and dried in vacuo to provide 165 mg

(78%) of compound 16f-123.

m) Preparation of Acetic acid ll-oxa-6-aza-benzo[α]fluoren-5-yl ester (16g-123):

To a solution of compound 15c-123 (500 mg, 2.13 mmol) in pyridine (10 mL) was added acetic anhydride (4 mL). The resultant mixture was heated at 100⁰C for 9 h, then cooled slowly to room temperature overnight. The solvent was removed on the rotary evaporator and the residual oil was extracted into 50 mL ethyl acetate. The organic layer was washed with 50 mL of 1 N aqueous hydrochloric acid and dried (sodium sulfate), and the solvent was removed in vacuo to provide 308 mg (52% yield) of compound 16g-123 as a white powder.

n) Preparation of l^ll-Oxa-ό-aza-benzoIαlfluoren-S-yloxy^β-D-glucuronic acid (16h-123):

Preparation of methyl ester intermediate:

6//-1 l-Oxa-6-aza benzo[a]fluoren-5-one (15c-123) (500 mg, 2.13 mmol) (Scheme 2-123), silver carbonate (2.35 g, 4 eq), 4 angstrom molecular sieves (1.8 g), and 100 mL toluene were combined in a 500 mL 3- neck flask equipped with a dean-stark trap, a condenser, and an addition funnel. The mixture was brought to reflux under nitrogen atmosphere, and 30 mL of distillate were collected over 1 h. The addition funnel was charged with acetobromo-α-D-glucuronic acid methyl ester (930 mg, 1.1 eq) dissolved in 25 mL toluene, and this solution was added dropwise over 0.5 h to the refluxing reaction mixture. The reaction mixture was heated at reflux for another 6 h, then slowly cooled to room temperature overnight. The resultant suspension was vacuum filtered to remove solids, and the resultant filter cake was washed three times with 100 mL of ethyl acetate. The filtrate was concentrated to an oil on a rotary evaporator. The oil was loaded directly on a column of 30 g silica and purified using flash chromatography, eluting with 19:1 dichloromethane: ethyl acetate to provide the intermediate compound 1-(1 l-Oxa-6-aza- benzo[α]fluoren-5-yloxy)2,3,4-tri-O-acetyl-β-D-glucuronic acid methyl ester as a white powder.

Ester Hydrolysis to Provide Compound 16h-123:

1-(11 -Oxa-6-aza-benzo[α]fluoren-5-yloxy)-2,3,4-tri-O-acetyl-β-D-glucuronic acid methyl ester (779 mg, 1.81 mmol) was dissolved in 30 mL acetone, and 8 mL of 1 N aqueous sodium hydroxide followed by 12 mL water were added dropwise. The resultant mixture was stirred for 0.5 h, over which time a precipitate formed. The reaction mixture was titrated to pH 5 with 1 N aqueous hydrochloric acid and vacuum filtered. The resultant solids were washed with 30 mL of acetone and dried in vacuo to provide 288 mg (50%) of compound 16h-123 as a white powder.

o) 5,9-Dimethoxy-ll-oxa-6-aza-benzo[α]fluorine (16.-123):

9-Methoxy-dH-l l-oxa-6-aza-benzo[α]fluorine-5-one (15d-123) (200 mg, 0.755 mmol) was suspended in 4 mL acetone and to the suspension were added methyl iodide (52 μL, 1.1 eq) and potassium carbonate (1.04 g, 10 eq). The resultant mixture was allowed to reflux overnight under nitrogen atmosphere. Additional methyl iodide (25 μL, 0.5 eq) and acetone (4 mL) were added, and the reaction mixture refluxed overnight under nitrogen. The reaction mixture was poured into 20 mL of 1 N aqueous sodium hydroxide, stirred 0.5 h, and filtered. The resultant solids were washed twice with 10 mL of water, then stirred for 1 h in 20 mL of 1 N aqueous hydrochloric acid. The solids were vacuum filtered, washed twice with 10 mL of water, then twice with 10 mL volumes of ether. The solids were dried in vacuo to provide 165 mg (78%) of compound 16i-123 as a white powder.

p) Preparation of Compound 16J-123:

Using the method of Example g and substituting: 1) 2-bromoacetic acid with 3-bromo-l-propanol, and 2) compound 15b-123 with compound 15e-123, compound 16j- 123 was prepared.

q) Preparation of Compound 16k

Using the method of Example g and substituting: 1 ) 2-bromoacetic acid with 6-bromo-l-hexanol, and 2) compound 15b-123 with compound 15e-123, compound 16k- 123 was prepared.

r) Preparation of 9-Methyl-6//-ll-oxa-6,10-diaza-benzo[a]fluoren-5-one (26a-123) (Scheme 3-123)

To a solution of α-bromodimethylhomophthalate (2.00 g, 6.97 mmol) in DMF (15 mL) was added 3-cyano-2-hydroxy-6-methylpyridine (1.03 g, 1.1 eq) and potassium carbonate (4.82 g, 5 eq). The resultant mixture was allowed to stir at 100⁰C for 4 h under inert atmosphere. The reaction was cooled to room temperature and concentrated in vacuo. The resultant solid residue was diluted with 1 N aqueous HCl (60 mL) and stirred for 30 min. The resultant suspension was filtered and the filtered solids were washed with water. The aqueous filtrate was extracted with EtOAc (2 x 50 mL). The collected solids were added to the combined EtOAc extracts, and the resultant solution was dried over sodium sulfate, filtered and concentrated in vacuo to afford a crude residue. The crude residue was recrystallized from toluene at — 20⁰C over 18 h, vacuum filtered and dried to provide compound 26a-123 as a yellow solid. Yield = 500 mg (29%).

5.3 Example 2: Preparation of Illustrative Compounds of Formula (1-145), (11-145),

(III-145). (IV-145). (V-145) and (VI-145)

a) Preparation of 4-Phenyl-3-isocoumarincarboxylic acid (102-145):

102-145

Following a known procedure (Natsugary et al, J. Med. Chem. 1995, 38, 3106 — 3120), Compound 102-145 was synthesized. A suspension of 2-benzoyl-benzoic acid (33.9 g, 0.15 mol), anhydrous potassium carbonate (41.4 gm, 0.3 mol) and diethyl bromomalonate ((28.17 mL, 0.165 mol) in DMF (250 mL) was allowed to stir overnight at room temperature. The reaction mixture was then poured on cold water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue obtained was treated with acetic acid (1.0 L), followed by concentrated HCl (800 mL), and then refluxed for 6 hours. The reaction mixture was cooled to room temperature and poured on ice cold water, and the precipitate that formed was filtered, washed thoroughly with water, and dried to provide 32.6 g of Compound 102-145, a white solid, in 84% yield. b) Preparation of 4-phenyl-3-isoquinolinonecarboxylic acid (103-145)

103-145

A stirred suspension of Compound 102-145 (1.4 g, 0.0052 mol) in ammonia- methanol (7N, 125 mL) was reftuxed for 23 hours. The homogeneous reaction mixture was concentrated, and the residue obtained was acidified with diluted HCl. The solid precipitate was filtered, washed with water, and dried under vacuum to provide Compound 103-145 (1.225 g, 89%).

c) Preparation of 3-Oxoindeno[2,l-c]isoquinoIinone (104-145)

104-145

To a stirred suspension of Compound 103-145 (0.225 g, 0.85 mmol) in xylene (20 mL) was added polyphosphoric acid (0.600 gm). The reaction mixture was refluxed at 140 — 160⁰C for 6 hours. Xylene was separated from the residue, and residue was poured onto ice. The resultant solid was filtered, washed with water, and dried to provide Compound 104-145 (155 mg, 74%).

Alternatively, Compound 103-145 (500 mg, 0.0019 mol) was reacted with chlorosulfonic acid (2.5 ml) at 0 ⁰C for 5 minutes, and the reaction mixture was allowed to stir at room temperature for 5 minutes. After the reaction mixture became homogeneous, it was slowly poured onto ice. The red precipitate was filtered, washed with water, and dried to provide Compound 104-145 (395 mg, 85%).

d) Preparation of 3-Oxoindeno[2,l-c]isoquinolinone hydrazone (Compound 1-145)

1-145

To a mixture of Compound 104-145 (110 mg) and hydrazine monohydrate (0.1 ml) in methanol (10 ml) was added concentrated HCl (0.1 ml) at room temperature. The reaction mixture was refluxed overnight. The precipitate was filtered, washed with water, and dried under vacuum to provide Compound 1-145 (35 mg). MS (ES⁺): m/z 262.2 (M + 1).

e) Preparation of [(3-Oxoindeno[2,l-c|isoquinolinone)-2-cyanoethyl]-hydrazone (Compound 7-145)

7-145 To a mixture of compound 104-145 ( 150 mg) and 2-cyanoethyl hydrazine (0.3 ml) was added acetic acid (10 ml) at room temperature. The reaction mixture was then refluxed overnight. The reaction mixture was concentrated in vacuo and the residue was treated with methanol (25 ml). The precipitate was filtered, washed with methanol and water, and dried under vacuum to provide Compound 7-145 (115 mg). ¹H-NMR (DMSO-d₆): 3.15 (t, J = 6.6 Hz, 2H), 3.62- 3.68 (m, 2H), 7.22 (t, J = 7.5 Hz, IH), 7.37 (t, J = 7.5 Hz, IH), 7.48 (t, J = 8.1 Hz, IH), 7.80 (t, J = 7.5 Hz, IH), 8.03 (d, J = 7.8 Hz, 2H), 8.30 (d, J = 7.8 Hz, 2H), 8.95 (s, IH), 11.63 (s, IH).

f) Preparation of 3-Oxoindeno[2,l-c]isoquinoIinone iV-morpholino-hydrazone (Compound 105-145)

105-145

To a mixture of Compound 104-145 (75 mg) and N-morpholino hydrazine (0.3 ml) in ethanol (15 ml) was added concentrated hydrochloric acid (0.050 ml) at room temperature. The reaction mixture was refluxed for 6—7 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with water and ethyl acetate (25 ml each), then neutralized with sodium bicarbonate. The organic layer was separated, concentrated and dried under vacuum to provide Compound 105-145 (48 mg).

g) Preparation of 3-Oxoindeno[2,l-c]isoquinolinone iV-(JV-inethylpiperazino)- hydrazone (Compound 106-145)

106-145

To a mixture of Compound 104-145 (75 mg) and N-(N-methyl-piperazine) hydrazine (5 eq) in ethanol (15 ml) was added concentrated hydrochloric acid (0.050 ml) at room temperature. The reaction mixture was then refluxed for 6 - 7 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with water and ethyl acetate (25 ml each),, then neutralized with sodium bicarbonate. The organic layer was separated, concentrated and dried under vacuum to provide Compound 106-145 (55 mg). ¹H-NMR (DMSO-d₆): 2.24 (s, 3H), 2.57 - 2.60 )m, 4H), 3.25 - 3.28 (m, 4H), 7.27 (t, J = 7.5 Hz, IH), 7.40 (t, J = 7.5 Hz, IH), 7.55 (t, J = 7.5 Hz, IH), 7.68 (d, J = 7.5 Hz, IH), 7.82 (t, J = 6.9 Hz, IH), 7.99 (d, J = 7.5 Hz, IH), 8.30 - 8.34 (m, 2H), 11.48 (s, IH).

h) Preparation of EthyI-5-oxo-5,6-dihydro-indolo[3,2-c]isoquinoline-l 1-carboxylate (compound 63-145)

Homophthalic acid (50 g, 0.28 mol) was diluted with methanol (750 mL), and to the resultant solution was added sulfuric acid (3.75mL, 5% v/v). The reaction mixture was heated at reflux for 24 hours under an inert atmosphere, then cooled to 5 ⁰C. To the resultant mixture was added dropwise 5N sodium hydroxide (28 mL) with vigorous stirring. The reaction mixture was concentrated in vacuo, and the resultant oil was diluted with ethyl acetate (200 mL) and sequentially washed using water (100 mL), saturated aqueous sodium carbonate (300 mL), water (300 mL) and brine (300 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to provide dimethyl homophthalate as a light brown oil. Yield = 39.4 g (68%). Dimethyl homophthalate (19.27 g, 92.6 mmol) was diluted with benzene (300 mL), and to the resultant solution was added N-bromosuccinimide (21.43 g, 1.3 eq.). The reaction mixture was heated to reflux using a 500 Watt quartz halogen lamp. After nine hours at reflux, the reaction mixture was cooled to 6 ⁰C, then vacuum filtered through a glass frit. The filtrate was washed using saturated aqueous sodium carbonate (2 x 200 mL), then brine (200 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to provide α-bromodiethyl homophthalate as a brown oil. Yield = 26.59 g, (100%).

Anthranilonitrile (100.0 g, 0.85 mol) was diluted with pyridine (850 mL) and the resultant solution was cooled to 0⁰C. Ethyl chloroformate (85 mL, 1.05 eq.) was added dropwise over one hour and the reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo to provide an off-white oily solid residue. To the off- white oily solid residue was added 0.5N aqueous HCl (1 L), and the resulting slurry was mechanically stirred for 1 hour, then filtered through #1 filter paper. The filtered solids were washed with water (2 x IL), then dried in a vacuum oven for 96 hours. The dried solids were diluted with toluene (500 mL), and the resultant solution was distilled for 4 hours, during which time 300 mL of toluene was removed from the solution. The concentrated distillate was allowed to cool to room temperature and then was further cooled to 0⁰C. The resultant crystalline precipitate was filtered, then diluted with hexanes (250 mL). The resultant solution was allowed to stir at room temperature for 2 hours to provide a slurry, which was filtered through #1 filter paper. The collected solids were washed in the filter paper using hexanes (200 mL). The solids were then vacuum dried at room temperature to provide ethyl-N-(2-cyanophenyl)carbamate as a white crystalline solid. Yield = 117.89 g (73%). A 60% suspension of sodium hydride in oil (2.79 g, 2.0 eq.) was diluted with toluene (10 mL). To the resulting suspension was added a solution of ethyl-Λ^r-(2- cyanophenyl)carbamate in toluene (100 mL) via cannula. The cannula was washed using toluene (2 x 10 mL). To the resulting reaction mixture was added a solution of α- bromodimethyl homophthalate in toluene (40 mL) dropwise via cannula, and the resultant reaction mixture was stirred at reflux for 4 hours. The reaction mixture was then cooled to 0⁰C and and IN aqueous HCl (70 mL, 2.0 eq.) was added dropwise under an inert atmosphere. The resultant suspension was poured into a flask containing acetonitrile (200 mL) and stirred vigorously for 10 minutes. The resultant slurry was vacuum filtered, and the collected white solid was washed using acetonitrile (500 mL). The solid was dried in ^• a vacuum oven at 40⁰C to provide compound 63-145 as a white solid. Yield = 5.0 g

(47%). i) Prepraration of n-Propyl-5-oxo-5,6-dihydro-indolo[3,2-c]isoquinoline-ll- carboxylate (Compound 107-145)

107-145 Compound 107-145 was made according to the procedure of Radl, S., Konvicka, P.,

Vachal, P. J. Heterocycl. Chem. 2000, 37, 855 - 62 and Garcia, E. E.; Benjamin, L. E., Fryer, R. I. J. Heterocycl. Chem. 1973, 10, 51 - 3. Solid n-propyl N-(2-cyanophenyl)carbamate (5.0 g, 24.5 mmol) was added to a stirring suspension of sodium hydride (60% dispersion in oil, 1.3 g, 32.8 mmol) in dry toluene (90 mL) at room temperature under nitrogen. After 5 minutes a solution of α-bromodimethylhomophthalate (4.7 g, 16.4 mmol) in dry toluene (10 mL) was added via syringe. The resultant mixture was heated to reflux for 6 hour. The reaction mixture was cooled to 10 °C, and to it was added 1.0 N HCl (50 mL, 50 mmol) and acetonitrile (50 mL). The resultant suspension was filtered and the filtered solid was washed with acetonitrile (2 x 10 mL). The off-white solid was returned to the flask, washed by stirring in water (40 mL), and then collected via vacuum filtration. The dry solid was heated in refluxing acetonitrile (40 mL) for 8 hours, which was subsequently cooled to 10⁰C. The solid was collected via vacuum filtration to yield 3.8 g (51%) of Compound 107-145, an off-white powder: ¹H-NMR (300 MHz, ^₆-DMSO) 12.46 (s, IH), 8.38 (d, IH), 8.19 (d, IH), 8.11 (d, 2H), 7.78 (t, IH), 7.58-7.44 (m, 2H), 7.40 (t, IH), 4.49-4.41 (t, 2H), 1.86-1.75 (m, 2H), 0.99-0.88 (t, 3H); MS (ESI) m/z 321

(M + 1). j) Preparation of iso-Propyl-5-oxo-5,6-dihydro-indolo[3,2-c]isoquinoline-ll- carboxylate (Compound 108-145)

Following the above procedure for making Compound 107-145, 1.6 g (61%) of Compound 108-145, an off-white powder, was obtained, substituting isopropyl N- (cyanophenyl)carbamate for n-propyl N— (2-cyanophenyl)carbamate: ¹H-NMR (300 MHz, ^₆-DMSO) 12.49 (s, IH), 8.32 (d, IH), 8.16 (d, IH)₃ 8.12 (d, 2H), 7.78 (t, IH), 7.58-7.48 (m, 2H), 7.38 (t, IH), 5.33-5.21 (m, IH), 1.42 (d, 6H); MS (ESI) m/z 321 (M +

k) Preparation of n-Butyl-5-oxo-5,6-dihydro-indolo[3,2-c]isoquinoline-l 1- carboxylate (Compound 109-145)

109-145 Following the above procedure for making Compound 107-145, 1.9 g (44%) of

Compound 109-145, an off-white powder, was obtained, substituting n-butyl N- (cyanophenyl)carbamate for n-propyl N-(2-cyanophenyl)carbamate: ¹H-NMR (300 MHz, 4,-DMSO) 12.52 (s, IH), 8.37 (d, IH), 8.19 (d, IH), 8.12-8.07 (m, 2H), 7.81-7.75 (m, IH), 7.58-7.50 (m, 2H), 7.41 (t, IH), 4.50 (t, 2H), 1.81-1.69 (m, 2H), 1.44-1.35 (m, 2H), 0.91 (t, 3H); MS (ESI) m/z 335 (M+l). 1) Preparation of tert-Butyl-5-oxo-5,6-dihydroτindolo[3,2-c]isoquinoline-ll7 carboxylate (Compound 62-145)

62-145

Following the above procedure for making Compound 107-145, 1.5 g (33%) of Compound 62-145, an off-white powder, was obtained, substituting tert-butyl N-(cyanophenyl)carbamate for n-propyl N-(2-cyanophenyl)carbamate: ¹H-NMR (300 MHz, d₆-OMSO) δ 12.48 (s, IH), 8.58 (d, IH), 8.19 (d, IH), 8.11 (d, IH), 7.99 (t, IH), 7.78-7.64 (m, 2H), 7.47 (t, IH), 7.29 (t, IH), 1.57 (s, 9H); MS (ESI) m/z 335 (M + 1).

n) Preparation of iso-Butyl-5-oxo-5,6-dihydro-indolo[3,2-c]isoquinoline-ll- carboxylate (Compound 110-145)

110-145

Following the above procedure for making Compound 107-145, 0.8 g (51%) of Compound 110-145, an off-white powder, was obtained, substituting secbutyl N- (cyanophenyl)carbamate for n-propyl N— (2-cyanophenyl)carbamate: ¹H-NMR (300 MHz, fife-DMSO): 12.49 (s, IH), 8.42 (d, IH), 8.18 (d, IH), 8.10 (d, 2H), 7.99 (t, IH), 7.77-7.64 (m, 2H), 7.42 (t, IH), 5.14-4.91 (d, 2H), 2.25-2.08 (m, H), 1.09-0.98 (m, 6H); MS (ESI) m/z 335 (M + 1). o) Preparation of Methyl-5-oxo-5,6-dihydro-indolo[3,2-c]isoquinoline-ll- carboxylate (Compound 61-145)

61-145

Following the above procedure for making Compound 107-145, 90 mg (18%) of Compound 61-145, an off-white powder, was obtained, substituting methyl N- (cyanophenyl)carbamate for n-propyl N-(2-cyaπophenyl)carbamate: ¹H-NMR (300 MHz, ^₆-DMSO) 12.44 (s, IH), 8.38 (d, IH), 8.18 (d, IH), 8.12 (d, 2H), 7.78 (t, IH), 7.59-7.48 (m, 2H), 7.38 (t, IH), 4.09 (s, 3H); MS (ESI) m/z 293 (M + 1).

p) Preparation of N,N-dimethyl-5-oxo-5,6-dihydro-indolo[3,2-c]isoquinoline-ll- amide (Compound 94-145)

94-145

Following the above procedure for making Compound 107-145, 198 mg (9%) of Compound 94-145, an off-white powder, was obtained, substituting N',N'-dimethyl N- (cyanophenyl)urea for n-propyl N-(2-cyanophenyl)carbamate: ¹H-NMR (300 MHz, d(,- DMSO) 12.44 (s, IH), 8.39 (d, IH), 8.16 (d, IH), 7.81 (t, IH), 7.78 (t, IH), 7.69 (d, IH), 7.56 (t, IH), 7.42 (s, 2H), 7.37-7.24 (m, IH), 3.24 (s, 3H), 3.01 (s, 3H); MS (ESI) m/z 306 (M + 1). 5.4 Example 3: Effect of Compounds of the Invention in an in vivo Model of Erectile Dysfunction

Experiments are conducted in male Sprague-Dawley rats according to previously published methods for forceps-induced nerve crush injury and erectile function measurements (Rehman, J., et al., Urology 51 :640-644, 1998; Sezen, S.F., et al., Int. J.

Impot. Res. 14:506-12, 2002). Subjects are anesthetized with Phenobarbital. The prostate of the subjects is exposed and the cavernosa, nerve is clipped on either side with a forceps to induce mechanical injury (crush). This rat model mimics the nerve injury that develops during human male prostatectomy, leading to nerve injury and subsequent erectile dysfunction. Subjects are studied 2 weeks after the injury. Two groups of subjects are used, one group treated with vehicle and one group treated with a compound of the invention. A compound of the invention is injected at 30 mg/kg i.v. immediately before the crush injury, and on the following day at the same dose. Thereafter, for 12 days, subjects are treated with 60 mg/kg of the compound of the invention intraperitoneally. At 2 weeks, subjects are re-anesthetized and measured for mean arterial blood pressure (MAP) and intracavemosal pressure (ICP). Cavernosal nerve stimulation is conducted at 5 and 7.5 V using a square pulse stimulator for 30 msec. ICP is determined as the area under curve (mmHg X sec), hi addition, IPC/MAP ratios are determined. The results can demonstrate that a compound of the invention improves erectile function in a rat model that mimics the nerve injury that develops during human male prostatectomy.

The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of which have been incorporated herein in their entirety.

Claims

What is claimed is:

1. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula:

(1-123) or a pharmaceutically acceptable salt thereof, wherein: R₅ is -Cι-Cιo alkyl, -(halo-substituted-(Ci-C₅ alkyl)), -(HO-substituted-(Ci-C₅ alkyl)), -(carboxy-substituted-(Ci-C₅ alkyl)), -C(O)-Ci-Ci₀ alkyl, -C(O)-aryl, -C(O)-(3- to

-glycoside;

X is -C(O)-, -CH₂-, -CH(halo)-, -(C(OH)((CH₂)_nCH₃))-, -(C(OH)(aryl))-, -O-, - NH-, -S-, -CH(NR, ,R,₂)- or -N(SO₂Y)-, wherein Y is -OH, -NH₂, -(C₁-C₅ alkyl)-(3- to 7- membered monocyclic heterocycle), or -(Ci-Cs alkyl)-(7- to 10-membered bicyclic heterocycle) and n is an integer ranging from 0-5;

Ri i and R)₂ are independently -hydrogen or -C]-C₉ alkyl, or N, R| i and Ri₂ are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);

Ri, R₂, R3, R4, R₇, Re, R9 and Rio are independently -hydrogen, -halo, -hydroxy,

-0-(Ci-C₅ alkyl), -Ci-C₁₀ alkyl, -(halo-substituted-(Ci-C₅ alkyl)), -C₂-Ci₀ alkenyl,

-C₃-C₈-cycloalkyl, -aryl, -NH₂, -(amino-substituted-(C|-C₅ alkyl)), -C(O)OH, -C(O)O(Ci-

C₅ alkyl), -OC(O)(C₁-C₅ alkyl), -NO₂ or -A-B; A is -SO₂-, -SO₂NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-,

-CONH-, -CON(Ci-C₄ alkyl)-, -NH-, -CH₂-, -S- or -C(S)-; B is -Ci-Cio alkyl, -C2-C10 alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -C₃-C₈ cycloalkyl, -aryl, -NZ]Z₂, -(C]-C₅ alkylene)-NZ]Z₂, -(amino-substituted-(Ci-C₅ alkyl)), -N(Ci-C₅ alkyl)(Ci-C₅ alkyl), -(Ci-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle), Or -(Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle), -((H₂NC(O))- substituted aryl), -((H₂NC(O))-substiruted pyridyl), -C(O)OH, -C(O)O-(C₁-C₅ alkyl), -C(O)O-phenyl or -C(NH)NH₂, each of which is unsubstituted or substituted with one or more Of-O-(Ci-C₅ alkyl), -halo, -(halo-substituted-(C₍-C₅ alkyl)), -(HO-substituted-(Ci- C₅ alkyl)), -(amino-substituted-(C|-C₅ alkyl)), -hydroxy, -NO₂, -NH₂, -CN, -NH(C, -C₅ alkyl), -N(Ci-C₅ alkyl)(Ci-C₅ alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -C₁-C₁₀ alkyl, -C₂-Ci₀ alkenyl, -C₂-Ci₀ alkynyl, -aryl, -benzyl, -((C(O)NH₂)-substituted(Ci-C₅ alkyl)), -(carboxy-substituted-(Ci-C₅ alkyl)), -C(O)OH, -C|-C₅-alkylene-C(O)O-(C_rC₅ alkyl) or -C,-C₅ alkylene-OC(O)-(Ci-C₅ alkyl); and

Zi and Z₂ are independently -H or -C|-Cιo alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z^, where Z₃ and Z₄ are independently, -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z3 and Z4 are taken together to form a -(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to

10-membered bicyclic heterocycle); or N, Z| and Z₂ are taken together to form a — (nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a —(nitrogen- containing 7- to 10-membered bicyclic heterocycle).

2. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula:

(Ib-123) or a pharmaceutically acceptable salt thereof, wherein: R₅ is -Ci-Cio alkyl, -(halo-substituted-(Ci-C₅ alkyl)), -(HO-substituted-(C_rC₅ alkyl)), -(carboxy-substituted-(Ci-C₅ alkyl)), -C(O)-Ci-Ci₀ alkyl, -C(O)-aryl, -C(O)-(3- to 7-membered monocyclic heterocycle), -C(O)-(7- to 10-membered bicyclic heterocycle) or -glycoside;

Rn -H, -Ci-C₅ alkyl, -aryl, -C(O)-Ci-C₅ alkyl, Or -SO₂Y, wherein Y is -OH, - NH₂ or -(Ci-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle), or -(Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle);

Ri, R₂, R₃, R4, R₇, Rg, R₉ and Rio are independently -hydrogen, -halo, -hydroxy, -0-(Ci-C₅ alkyl), -Ci -C ₁₀ alkyl, -(halo-substituted-(C_rC₅ alkyl)), -C₂-Ci₀ alkenyl, -Cs-Cg-cycloalkyl, -aryl, -NH₂, -(amino-substituted-(Ci-C₅ alkyl)), -C(O)OH, -C(O)O(Ci- C₅ alkyl), -OC(O)(C₁-C₅ alkyl), -NO₂ or -A-B;

A is -SO₂-, -SO₂NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(C₁-C₄ alkyl)-, -NH-, -CH₂-, -S- or -C(S)-;

B is -Ci-Cio alkyl, -C2-C1₀ alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle),

-C₃-C₈ cycloalkyl, -aryl, -NZiZ₂, -(C_rC₅ alkyl ene)-NZi Z₂, -(amino-substituted-(C|-C₅ alkyl)), -N(Ci-C₅ alkyl)(Ci-C₅ alkyl), -(Ci-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle), or -(Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle), -((H₂NC(O))- substituted aryl), -((H₂NC(O))-substiruted pyridyl), -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-phenyl or -C(NH)NH₂, each of which is unsubstituted or substituted with one or more of -0-(Ci-C₅ alkyl), -halo, -(halo-substituted-(C_rC₅ alkyl)), -(HO-substituted-(C_r C₅ alkyl)), -(amino-substituted-(Ci-C₅ alkyl)), -hydroxy, -NO₂, -NH₂, -CN, -NH(Ci-C₅ alkyl), -N(Ci-Cs alkyl)(C|-Cs alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle)), -(nitrogen-containing 7- to 10-membered bicycloheterocyclic amine), -Cj- Cio alkyl, -C₂-Ci₀ alkenyl, -C₂-Ci₀ alkynyl, -aryl, -benzyl, -((H₂NC(O))-substituted(Ci-C₃ alkyl)), -(carboxy-substituted-(Ci-C₅ alkyl)), -C(O)OH, -Ci-C₅-alkylene-C(O)O-(Ci-C₅ alkyl) or -Ci-C₅ alkylene-OC(O)-(Ci-C₅ alkyl); and

Zi and Z₂ are independently -H or -Cj-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently, -H or -C₁-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z4 are taken together to form a -(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Zi and Z₂ are taken together to form a — (nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a —(nitrogen- containing 7- to 10-membered bicyclic heterocycle).

3. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula

(III-123) or a pharmaceutically acceptable salt thereof, wherein:

R₅ is O, NH or . S;

R₆ is -H or -Ci-C₄ alkyl;

X is -C(O)-, -CH₂-, -CH(halo)-, -(C(OH)((CH₂)_nCH₃))-, -(C(OH)(aryl))-, -O-, - NH-, -S-, -CH(NR₁₁R₁₂)- or -N(SO₂Y)-, wherein Y is -OH, -NH₂, -(C-C₅ alkyl)-(3- to 7- membered monocyclic heterocycle), Or -(Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle) and n is an integer ranging from 0-5; Ri i and R₁₂ are independently -hydrogen or -C1-C9 alkyl, or N, Ri 1 and R12 are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle); one of G₁-G₄ is C-R₇ and the remaining Gi-G₄ are independently N or C-R₇; Ri, R₂, R₃, and R₄ are independently -hydrogen, -halo, -hydroxy, -0-(Ci-C₅ alkyl),

-Ci-Cio alkyl, -(halo-substituted-(C|-C₅ alkyl)), -C₂-Ci₀ alkenyl, -C₃-C₈-cycloalkyl, -aryl, -NH₂, -(amino-substituted-(CrC₅ alkyl)), -C(O)OH, -C(O)O(Ci-C₅ alkyl), -OC(O)(Ci-C₅ alkyl), -NO₂ or -A-B;

B is -Ci-Cio alkyl, -C₂-C10 alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -C₃-C₈ cycloalkyl, -aryl, -NZiZ₂, -(Ci-C₅ alkyl ene)-NZ| Z₂, -(amino-substituted-(Ci-C₅ alkyl)), -N(C_rC₅ alkyl)(C|-C₅ alkyl), -(Ci-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle), Or -(Ci-Cs alkyl)-(7- to 10-membered bicyclic heterocycle), -((H₂NC(O))- substituted aryl), -((H₂NC(O))-substituted pyridyl), -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-phenyl or -C(NH)NH₂, each of which is unsubstituted or substituted with one or more of -0-(Ci-C₅ alkyl), -halo, -(halo-substituted-(C|-C₅ alkyl)), -(HO-substituted-(Ci- C₅ alkyl)), -(amino-substituted-(C,-C₅ alkyl)), -hydroxy, -NO₂, -NH₂, -CN, -NH(Ci-C₅ alkyl), -N(Ci-C₅ alkyl)(Ci-Cs alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -C1-C1₀ alkyl, -C₂-Ci₀ alkenyl, -C₂-C₁₀ alkynyl, -aryl, -benzyl, -((H₂NC(O))-substituted(C|-C₅ alkyl)), -(carboxy-substituted-(Ci-C₃ alkyl)), -C(O)OH, -C_rC₅-alkylene-C(O)O-(Ci-C₅ alkyl) or -C₁-C₅ alkyIene-OC(O)-(C_rC₅ alkyl);

Zi and Z₂ are independently -H or -C1-C1₀ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently, -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z₄ are taken together to form a-(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to

10-membered bicyclic heterocycle); or N, Zi and Z₂ are taken together to form a — (nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a -{nitrogen- containing 7- to 10-membered bicyclic heterocycle); and each R₇ is independently -H, -Ci-C₆ alkyl,-O-(Ci-C₆ alkyl), -S-(Ci-C₆ alkyl), -SO₂NH(Ci-C₆ alkyl) or -C(O)NH-(Ci-C₆ alkyl).

4. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula:

(IV-123) , or a pharmaceutically acceptable salt thereof, wherein:

R₅ is O, NH or S;

X is -C(O)-, -CH₂-, -CH(halo)-, -CH(OH)-, -(C(OH)((CH₂)_mCH₃))-, - (C(OH)(aryl))-, -O-, -N(Z_S)-, -S-, -CH(NR, iR,₂)- or -N(SO₂Y)-, wherein Y is -OH, - NH₂, -(Ci-Cs alkyl)-(3- to 7-membered monocyclic heterocycle), or — (C1-C₅ alkyl)-(7- to 10-membered bi cyclic heterocycle) and m is an integer ranging from 0-5;

Ri ₁ and Ri₂ are independently -hydrogen or -C₁-C₉ alkyl, or N, R( ₁ and Ri₂ are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle); one Of Gi-G₄ is C-R₇ and the remaining G1-G4 are independently N or C-R₇; Rι, R₂, R3, and R4 are independently -hydrogen, -halo, -hydroxy, -0-(Ci-Cs alkyl),

-Ci-Cio alkyl, -(halo-substituted-(C_rC₅ alkyl)), -C₂-Ci₀ alkenyl, -Ca-Cs-cycloalkyl, -aryl, -NH₂, -(amino-substituted-(C,-C₅ alkyl)), -C(O)OH, -C(O)O(C-C₅ alkyl), -OC(O)(Ci-C₅ alkyl), -NO₂ or -A-B;

B is -Ci-Cio alkyl, -C₂-Ci_O alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -C₃-C₈ cycloalkyl, -aryl, -NZ|Z₂, -(Ci-C₅ alkylene)-NZiZ₂, amino-substituted-(Ci-C₅ alkyl), -N(Ci-C₅ alkyl)(C]-C₅ alkyl), -(Ci-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle), Or -(Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle), -(H₂NC(O))- substituted aryl, -(H₂NC(O))-substituted pyridyl, -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-phenyl or -C(NH)NH₂, each of which is unsubstituted or substituted with one or more of-O-(Ci-C₅ alkyl), -halo, halo-substituted-(Ci-C₅ alkyl), HO-substituted-(C_rC₅ alkyl), amino-substituted-(C,-C₅ alkyl), -hydroxy, -NO₂, -NH₂, -CN, -NH(C_rC₅ alkyl), - N(Ci-Cs alkyl)(Ci-C₅ alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), 7- to 10-membered bicycloheterocyclic amine, -Ci-Cio alkyl, -C2-C10 alkenyl, -C₂-C]₀ alkynyl, -aryl, -benzyl, -(H₂NC(O))-substituted(Ci-C₅ alkyl), carboxy- substiruted-(Ci-C₅ alkyl), -C(O)OH, -Ci-C₃-alkylene-C(O)O-(Ci-C₅ alkyl) or -Ci -C₅ alkylene-OC(O)-(Ci-C₅ alkyl);

Zi and Z₂ are independently -H or -Ci-Ci o alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently, -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z4 are taken together to form a -(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a -{nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Zi and Z₂ are taken together to form a — (nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a —(nitrogen- containing 7- to 10-membered bicyclic heterocycle); each R₇ is independently -H, -Ci-C₆ alkyl,-O-(C|-C₆ alkyl), -S-(Ci-C₆ alkyl),

-SO₂NH(C₁-C₆ alkyl) or C(O)NH-(Ci-C₆ alkyl);

Z₅ is -H, -Ci-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -(CH₂)_n -(7- to 10-membered bicyclic heterocycle), -(CH₂),,- COO-(C₁-C₅ alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_π-COOH, - CONH-(CH₂)_H-COO-(C₁-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(Ci-C₅ alkyl), -

CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_n-CONH-(C|-C₅ alkyl), -(CH₂)_n-CONH-aryl, - (CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), - (CH₂)n-CONH-(CH₂)_q-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(C,-C₅ alkyl), -(CH₂)_n- CONH-(CH₂)_q-CON(C,-C₅ alkyl)₂, -C(O)(CH₂V(C₁-C₅ alkyl), -C(O)(CH₂)_n-aryl, -

C(O)(CH₂)_n-COOH, -C(O)(CH₂)_n-COO-(Ci-C₅alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_n-COO-(7- to 10-membered bicyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂)_n-phenyl, -C(O)O(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-ρhenyl)₂, -C(O)N((CH₂)n-phenyl)((CH₂)_q-3- to 7-membered monocyclic heterocycle), -C(O)N((CH₂)_n-phenyl)((CH2)_q 7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-(3- to 7-membered monocyclic heterocycle)₂, - C(O)N((CH₂)_n-7- to 10-membered bicyclic heterocycle)₂, or -SO₂NH₂; each n is an integer ranging from 0 to 10; and q is an integer ranging from 0 to 10.

5. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of Formula

(V-123) or a pharmaceutically acceptable salt thereof, wherein:

R₅ is O, S, or NH;

Ri₁ R₂, R₃, R4, Re, R₇, R₈, and R₉ are independently -hydrogen, -halo, -hydroxy, - NH₂ NO₂, or -A-B;

B is -Ci-Cio alkyl, -C2-C10 alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -C₃-C₈ cycloalkyl, -aryl, -NZiZ₂, -(Ci-C₅ alkylene)-NZiZ₂, amino-substituted-(Ci-C₅ alkyl), -N(Ci-C₅ alkyl)(C_rC₅ alkyl), -(Ci-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle),— (Ci-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle), -((H₂NC(O))- substituted aryl), -((H₂NC(O))-substituted pyridyl), -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-phenyl or -C(NH)NH₂, each of which is unsubstituted or substituted with one or more of -0-(Ci-C₅ alkyl), -halo, -(halo-substituted-(Ci-C₅ alkyl)_, -(HO-substiruted-(Ci- C₅ alkyl)), -(amino-substituted-(Ci-C₅ alkyl)), -hydroxy, -NO₂, -NH₂, -CN, -NH(Ci-C₅ alkyl), -N(Ci-C₅ alkyl)(Ci-C₅ alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -Ci-Cio alkyl, -C₂-Ci₀ alkenyl, -C₂-Ci₀ alkynyl, -aryl, -benzyl, -((H₂NC(O))-substituted(Ci-C₅ alkyl)), -(carboxy-substituted-(Ci-C₅ alkyl)), -C(O)OH, -Ci-C₅-alkylene-C(O)O-(C_rC₅ alkyl) or -C₁-C₅ alkylene-OC(O)-(C_rC₅ alkyl); Zi and Z₂ are independently -H or -Cj-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently, -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z₄ are taken together to form a -(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Zi and Z₂ are taken together to form a -

(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a —(nitrogen- containing 7- to 10-membered bicyclic heterocycle);

Rio is -H, -Ci-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -(CH₂)_n -(J- to 10-membered bicyclic heterocycle), -(CH₂),,- COO-(C₁-C₅ alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, -

CONH-(CH₂)_n-COO-(C,-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(Ci-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_n-CONH-(C,-C₅ alkyl), -(CH₂)_n-CONH-aryl, - (CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), - (CH₂)_n-CONH-(CH₂)_q-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(Ci-C₅ alkyl), -(CH₂)_n-

CONH-(CH₂VCON(C₁-C₅ alkyl)₂, -C(O)(CH₂)_n-(C,-C₅ alkyl), -C(O)(CH₂)_n-aryl, - C(O)(CH₂)_n-COOH, -C(O)(CH₂)_n-COO-(Ci-C₅alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_n-COO-(7- to 10-membered bicyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH2)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂)_n-phenyl, -C(O)O(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)_n-phenyl)((CH₂)_q-3- to 7-membered monocyclic heterocycle), -C(O)N((CH₂)_n-phenyl)((CH₂)_q 7- to 10-membered bicyclic heterocycle), -C(O)N((CH2)_n-(3- to 7-membered monocyclic heterocycle)₂, - C(O)N((CH₂)_n-7- to 10-membered bicyclic heterocycleh, or -SO₂NH₂; each n is an integer ranging from 0 to 10; p is an integer ranging from 0 to 5; and q is an integer ranging from 0 to 10.

6. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula

(VII-123) or a pharmaceutically acceptable salt thereof, wherein

R₅ is O, NH or S;

X is -C(O)-, -CH₂-, -CH(halo)-, -CH(OH)-, -(C(OH)((CH₂)_mCH₃))-, - (C(OH)(aryl)K -O-, -N(Z₅)-, -S-, -CH(NR, ,R₁₂)- or -N(SO₂Y)-, wherein Y is -OH, -

NH₂, — (C1-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle), or — (C₁-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle) and m is an integer ranging from 0-5;

Ri 1 and Ri₂ are independently -hydrogen or -C1-C₉ alkyl, or N, Rj ₁ and Ri₂ are taken together to form a -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle); one Of Gi-G₄ is C-R₇ and the remaining Gi-G₄ are independently N or C-R₇;

Ri, R₂, R₃, and R₄ are independently -hydrogen, -halo, -hydroxy, -O-(Cι-Cs alkyl), -Ci-Cio alkyl, -(halo-substituted-(Ci-C₃ alkyl)), -C₂-Ci₀ alkenyl, -C₃-C₈-cycloalkyl, -aryl, -NH₂, -(amino-substituted-(Ci-C₅ alkyl)), -C(O)OH, -C(O)O(C₁-C₅ alkyl), -OC(O)(Ci-C₅ alkyl), -NO₂ or -A-B; A is -SO₂-, -SO₂NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Ci-C₄ alkyl)-, -NH-, -CH₂-, -S- or -C(S)-;

B is -Ci-Cio alkyl, -C₂-C₁₀ alkenyl, -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7-membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle),

-C₃-C₈ cycloalkyl, -aryl, -NZ)Z₂, -(Ci-C₅ alkylene)-NZiZ₂, amino-substituted-(C_rC₅ alkyl), -N(Ci-C₅ alkyl)(Cj -C₅ alkyl), -(Ci-C₅ alkyl)-(3- to 7-membered monocyclic heterocycle),-(Cι-C₅ alkyl)-(7- to 10-membered bicyclic heterocycle), -((H₂NC(O))- substituted aryl), -((H₂NC(O))-substituted pyridyl), -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-phenyl or -C(NH)NH₂, each of which is unsubstituted or substituted with one or more Of -O-(C]-C₅ alkyl), -halo, -(halo-substiruted-(C-C₅ alkyl)), -(HO-substituted-(C- C₅ alkyl)), -(amino-substituted-(Ci-C₅ alkyl)), -hydroxy, -NO₂, -NH₂, -CN, -NH(Ci-C₅ alkyl), -N(Ci-C₅ alkyl)(Ci-C₅ alkyl), -(nitrogen-containing 3- to 7-membered monocyclic heterocycle), -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -C1-C1₀ alkyl, -C₂-C _i0 alkenyl, -C₂-Ci₀ alkynyl, -aryl, -benzyl, -((H₂NC(O))-substituted(Cι -C₅ alkyl)), -(carboxy-substituted-(C|-C₅ alkyl)), -C(O)OH, -Ci-C₅-alkylene-C(O)O-(Ci-C₅ alkyl) or -Ci-C₅ alkylene-OC(O)-(Ci-C₅ alkyl);

Zi and Z₂ are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently, -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z₄ are taken together to form a —(nitrogen- containing 3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); or N, Z| and Z₂ are taken together to form a - (nitrogen-containing 3- to 7-membered monocyclic heterocycle), or a — (nitrogen- containing 7- to 10-membered bicyclic heterocycle); each R₇ is independently -H, -Ci-C₆ alkyl, -0-(Ci-C₆ alkyl), -S-(Ci-C₆ alkyl), -SO₂NH(C-C₆ alkyl) or -C(O)NH-(Ci-C₆ alkyl);

Z₅ is -H, -Ci-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -(CH₂)_n —(7- to 10-membered bicyclic heterocycle), -(CH₂),,- COO-(C-C₅ alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, -

CONH-(CH₂)_n-COO-(C,-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(C-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂VCONH-(C-C₅ alkyl), -(CH₂)_n-CONH-aryl, - (CH₂)_n-CONH-(CH₂)_q-aryI, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-(3- to 7-membered monocyclic heterocycle), - (CH₂)_n-CONH-(CH₂)_q-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(Ci-C₅ alkyl), -(CH₂),,- CONH-(CH₂)_q-CON(C,-C₅ alkyl)₂, -C(G)(CH₂)_H-(C₁-C₅ alkyl), -C(O)(CH₂)_n-aryl, - C(O)(CH₂)_n-COOH, -C(O)(CH₂)_n-COO-(Ci-C₅alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH2)_n-COO-(7-'to 10-membered bicyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂)_n-phenyl, -C(O)O(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-ρhenyl, -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)_n-phenyl)((CH₂)_q-3- to 7-membered monocyclic heterocycle), -C(O)N((CH₂)_n-phenyl)((CH₂)_q 7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-(3- to 7-membered monocyclic heterocycle)₂, - C(O)N((CH₂)_n-7- to 10-membered bicyclic heterocycle)₂, or -SO₂NH₂; each n is an integer ranging from 0 to 10; and q is an integer ranging from 0 to 10.

7. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula

(1-145) or a pharmaceutically acceptable salt thereof, wherein:

B is -Cj-Cio alkyl, -C2-C₁₀ alkenyl, -C₂-Ci_O alkynyl, -C₃-C₈ monocyclic cycloalkyl, -C_S-C_H bicyclic cycloalkyl, -C₅-C₈ monocyclic cycloalkenyl, -C_S-C_H bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), -

(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZiZ₂, -(Ci- C₅ alkylene)-NZiZ₂, -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -0-(Ci-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -Ci-Ci₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(Ci-C₅ alkyl);

Zi and Z₂ are independently -H or -Ci -C ₁₀ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Zs)(Z₄), where Z₃ and Z₄ are independently -H or -Ci -C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH₂; or N, Z₃ and Z₄ are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zi and Z₂ are taken together to form a - (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen- containing 7- to 10-membered bicyclic heterocycle); R¹⁰ is -H, -C₁-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -(CH₂),, -(7- to 10-membered bicyclic heterocycle), -(CH₂)_n- COO-(C₁-C₅ alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, - CONH-(CH₂)_n-COO-(Ci-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(C-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_n-CONH-(Ci-C₅ alkyl), -(CH₂)_n-CONH-aryl, - (CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-(7- to 10- membered monocyclic heterocycle), - (CH₂)_n-CONH-(CH₂)_q-CONH2 -(CH₂)_n-CONH-(CH₂)_q-CONH-(Ci-C₅ alkyl), -(CH₂),,- CONH-(CH₂)_q-CON(C,-C₅ alkyl)₂, -C(O)(CH₂)_n-(C,-C₅ alkyl), -C(O)(CH₂)_n-aryl, - C(O)(CH₂)_n-COOH, -C(O)(CH₂)_n-COO-(C,-C₅ alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_n-COO-(7- to 10-membered bicyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂),,- phenyl, -C(O)O(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -C(O)O(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)_n- phenyl)((CH₂)_q-3- to 7- membered monocyclic heterocycle), -C(O)N((CH₂)_n- phenyl)((CH₂)_q 7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-(3- to 7- membered monocyclic heterocycle)2, -C(O)N((CH2)_n-7- to 10-membered bicyclic heterocycle)2, or -SO₂NH₂;

R¹ ' is -H, or (-Ci-C₆ alkyl),^'or Rio, Ri i and the nitrogen atom to which they are attached join to form a -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle); each n is independently an integer ranging from 0 to 10; each p is independently an integer ranging from 0 to 5; and each q is independently an integer ranging from 0 to 10.

8. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula

(11-145) or a pharmaceutically acceptable salt thereof, wherein:

R⁵ is O, S or NH;

B is -Ci-Cio alkyl, -C₂-CiO alkenyl, -C₂-Ci_O alkynyl, -C₃-C₈ monocyclic cycloalkyl, -Cs-Cu bicyclic cycloalkyl, -Cs-Cg monocyclic cycloalkenyl, -Cs-C^ bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), - (nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZiZ₂, -(Cj- C₅ alkylene)-NZ,Z₂, -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -0-(C₁-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -C₁-C₁₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(Ci-C₅ alkyl);

Z] and Z₂ are independently -H or -Ci-Cιo alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Zj)(Z₄), where Z₃ and Z₄ are independently -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z₃ and Z₄ are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zi and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a — (nitrogen- containing 7- to 10-membered bicyclic heterocycle);

R¹⁰ is -H, -C₁-C5 alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n -(7- to 10-membered bicyclic heterocycle), -(CH₂)_n- COO-(Ci-C₅ alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, - CONH-(CH₂)_n-COO-(C,-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(C₁-C₅ alkyl), - 0 CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_H-CONH-(C₁-C₅ alkyl), -(CH₂)_n-CONH-aryl, -

(CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q -(7- to 10-membered bicyclic heterocycle), -(CH₂)_n- CONH-(CH₂)_q-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(C_t-C₅ alkyl), -(CH₂)_n-CONH- (CH₂)_q-CON(C,-C₅ alkyl)₂, -C(O)(CH₂)_n-(C,-C₅ alkyl), -C(O)(CH₂)_n-aryl, -C(O)(CH₂)_n- 5 COOH, -C(O)(CH₂)_n-COO-(Ci-C₅ alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_P-COO -(7- to 10-membered bicyclic heterocycle), - C(O)(CH₂)_n-phenyl, -C(O)(CH ₂)_n-(3- to 7- membered monocyclic heterocycle), - C(O)(CH₂)_n -(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂)_n-phenyl, - C(O)O(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -C(O)O(CH₂)_n -(7- to 10- O . membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)_n- phenyl)((CH₂)_q-3- to 7- membered monocyclic heterocycle), -C(O)N((CH₂)_n- phenyl)((CH₂)_q -7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-3- to 7- membered monocyclic heterocycle)₂, -C(O)N((CH₂)_n-7- to 10-membered bicyclic heterocycle)₂, or -SO₂NH₂; each n is independently an integer ranging from 0 to 10; each p is independently an integer ranging from 0 to 5; and each q is independently an integer ranging from 0 to 10.

9. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula

(ITI-145) or a pharmaceutically acceptable salt thereof, wherein:

R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each independently -H, -0-(Ci-C₅ alkyl), -Cj- Cioalkyl, -C₂-C₁₀ alkenyl, -aryl, -C(O)OH, -C(O)O(C-C₅ alkyl), -OC(O)(C₁-C₅ alkyl), - NO₂, -NHC(O)(CH₂)_n-NH₂, -NHSO₂NH(CH₂)_n-NH₂, -C(O)NH(CH₂)_n-NH₂, - SO₂NH(CH₂)_n-NH₂, -halo, -OH, -NH₂, or -A-B; R⁵ is O, S or NH;

B is -Ci-Cio alkyl, -C₂-CiO alkenyl, -C2-C10 alkynyl, -C3-C8 monocyclic cycloalkyl, -Cs-Ci₄ bicyclic cycloalkyl, -C₅-C₈ monocyclic cycloalkenyl, -C_S-C_H bicyclic cycloalkenyl, -(nitrogen- containing 3- to 7- membered monocyclic heterocycle), -

(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZiZ₂, -(Ci- C₅ alkylene)-NZ!Z₂, -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -0-(Ci-C_-5 alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -C|-C,_o alkyl, -aryl, -C(O)OH, or -C(O)O-(C₁-C₅ alkyl); .

Zi and Z₂ are independently -H or -Ci-Ci o alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(ZiO, where Z₃ and Z4 are independently -H or -C₁-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z₃ and Z₄ are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zi and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen- containing 7- to 10-membered bicyclic heterocycle);

R" is -H, -C₁-C₅ alkyl, -(CH₂)_n-aryl, -C(O)R¹², -C(O)OR^l2,-C(O)O-(Ci-C₅ alkyl), -CONH₂, -C(O)NH-(CHz)_n-C(O)OH, -(CH₂)_n-C(O)OH, -(CH₂)_n-CONH-(CH₂)_<,-(3- to 7- membered monocyclic heterocycle), -(CH₂)_p-(3- to 7-membered bicyclic heterocycle), - (CH₂)p-(7- to 10-membered bicyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q-CONH-(Ci-C₅ alkyl), -(CH₂)_n-CONH-(CH₂)_q-CON(Ci-C₅ alkyl)₂, -C(O)-(CH₂)_n-C(O)O-(C, -C₅ alkyl), -

CONH-(CH₂)_p-(3- to 7- membered monocyclic heterocycle), -C(O)N(R^I2)₂, - C(O)NHNHR¹², -CONH(CH₂)_nN(R¹²)₂, -CONHN(Zi)(Z₂), or -A-B; each occurrence of R¹² is independently -H, -(Ci-C₅ alkyl), -(CH₂)_p-phenyl, - (CH₂)_p-(3- to 7- membered monocyclic heterocycle), or -(CH₂)_p-(7- to 10-membered bicyclic heterocycle); each n is independently an integer ranging from 1 to 10; each p is independently an integer ranging from O to 5; and each q is independently an integer ranging from O to 10.

10. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula

(IV-145) or a pharmaceutically acceptable salt thereof, wherein: R¹ , R², R³, R⁴, R⁶ _, R⁷, R⁸ and R⁹ are independently -H, -halo, -OH, -NH₂, -CN,

-NO₂, or -A-B;

B is -C]-Ci_O alkyl, -C₂-Ci_O alkenyl, -C₂-Ci₀ alkynyl, -C₃-C₈ monocyclic cycloalkyl, -C₈-Cu bicyclic cycloalkyl, -Cs-C₈ monocyclic cycloalkenyl, -Cs-Cu bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), - (nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZiZ₂, -(Ci- C₅ alkylene)-NZ,Z₂, -C(O)OH, -C(O)O-(C₁-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -0-(Ci-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -Ci-Ci₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(Ci-C₅ alkyl);

Zi and Z₂ are independently -H or -Cj -C ₁₀ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Zs)(Z_-J), where Z₃ and Z₄ are independently -H or -C1-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z3 and Z4 are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zi and Z₂ are taken together to form a - (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a — (nitrogen- containing 7- to 10-membered bicyclic heterocycle); R¹⁰ is -H, -Ci-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n -{7- to 10-membered bicyclic heterocycle), -(CH₂V COO-(Ci-C₅ alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH- (CH₂)_π-COOH, - CONH-(CHz)_n-COO-(C₁-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(C₁-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_H-CONH-(C₁-C₅ alkyl), -(CH₂)_π-CONH-aryl, -

(CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH2)_q-(7- to 10- membered monocyclic heterocycle), - (CH₂)_n-CONH-(CH₂)_q-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(C,-C5 alkyl), -(CH₂V CONH-(CH₂)_q-CON(Ci-C₅ alkyl)₂, -C(O)(CH₂V(Ci-C₅ alkyl), -C(O)(CH₂ Vary 1, - C(O)(CH₂VCOOH, -C(O)(CH₂)_H-COO-(C₁-C₅ alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_n-COO-(7- to 10-membered bicyclic heterocycle), -C(O)(CH₂)_n-phenyl, -C(O)(CH₂)_n-(3- to 7-membered monocyclic heterocycle), -C(O)(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂V phenyl, -C(O)O(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -C(O)O(CH₂)_n-(7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)_n- phenyl)((CH2)q-(3- to 7- membered monocyclic heterocycle), -C(O)N((CH₂)_n- phenyl)((CH₂)_q 7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-(3- to 7- rriembered monocyclic heterocycle)₂, -C(O)N((CH₂)_n-7- to 10-membered bicyclic heterocycle)2, or -SO₂NH₂; R¹¹ is — H, or (-Ci-C₆ alkyl), or Rio, Ri i and the nitrogen atom to which they are attached join to form a -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle);

R¹³ is -Ci-C₁₀ alkyl, -C(O)-Ci-Ci₀ alkyl, -C(O)-aryl, -C(O)-(3- to 7- membered monocyclic heterocycle), or —glycoside, each of which is unsubstituted or substituted with one or more -halo, -C(O)OH, or -OH groups; each n is independently an integer ranging from O to 10; each p is independently an integer ranging from O to 5; and each q is independently an integer ranging from O to 10.

1 1. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula

(V-145) or a pharmaceutically acceptable salt thereof, wherein: R¹ , R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are independently -H, -halo, -OH, -NH₂, -CN,

-NO₂, or -A-B;

A is -SO₂-, -SO₂NH-, -NHSO₂-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(C₁-C₅ alkyl)-, -NH-, -(CH₂)_P-, -S- or -C(S)-;

B is -Ci-Cio alkyl, -C₂-CiO alkenyl, -C₂-Ci₀ alkynyl, -C₃-Ce monocyclic cycloalkyl, -C_S-C_H bicyclic cycloalkyl, -Cs-C₈ monocyclic cycloalkenyl, -Cs-Cu bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), - (nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(I - to 10-membered bicyclic heterocycle), -aryl, -NZiZ₂, -(Ci- C₅ alkylene)-NZ,Z₂, -C(O)OH, -C(O)O-(C₁-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -0-(C₁-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -Ci-Ci₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(C₁-C₅ alkyl);

Zi and Z₂ are independently -H or -Ci-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z_» are independently -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z₃ and Z₄ are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a -(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zi and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen- containing 7- to 10-membered bicyclic heterocycle);

R¹⁰ is -H, -Ci-C₅ alkyl, -(CH₂)_n-CN, -(CH₂)_n-aryl, -(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -(CH₂),, -(7- to 10-membered bicyclic heterocycle), -(CH₂),,- COO-(C₁-C₅ alkyl), -(CH₂)_n-COO-aryl, -(CH₂)_n-COOH, -CONH-(CH₂)_n-COOH, -

CONH-(CH₂)_n-COO-(C,-C₅ alkyl), -CONH-(CH₂)_n-aryl, -CONHNH-(C₁-C₅ alkyl), - CONHNH-aryl, -(CH₂)_n-CONH₂, -(CH₂)_n-CONH-(Ci-C₅ alkyl), -(CH₂)_n-CONH-aryl, - (CH₂)_n-CONH-(CH₂)_q-aryl, -(CH₂)_n-CONH-(CH₂)_q-(3- to 7- membered monocyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q -(I - to 10-membered bicyclic heterocycle), -(CH₂),,- CONH-(CH₂)_q-CONH₂ -(CH₂)_n-CONH-(CH₂)_q-CONH-(C,-C₅ alkyl), -(CH₂)_n-CONH-

(CH₂)_C-CON(C₁-C₅ alkyl)₂, -C(O)(CH₂)_I1-C,-C₅ alkyl, -C(O)(CH₂)_n-aryl, -C(O)(CH₂)_n- COOH, -C(O)(CH₂)_n-COO-(C₁-C₅ alkyl), -C(O)(CH₂)_n-COO-(3- to 7- membered monocyclic heterocycle), -C(O)(CH₂)_n-COO -(7- to 10-membered bicyclic heterocycle), - C(O)(CH2)_n-phenyl, -C(O)(CH₂)_n-(3- to 7- membered monocyclic heterocycle), - C(O)(CH₂)_n -(7- to 10-membered bicyclic heterocycle), -C(O)O(CH₂)_n-phenyl, -

C(O)O(CH₂)_n-(3- to 7- membered monocyclic heterocycle), -C(O)O(CH₂)_n -(7- to 10- membered bicyclic heterocycle), -C(O)N((CH₂)_n-phenyl)₂, -C(O)N((CH₂)_n- phenyl)((CH₂)_q-3- to 7- membered monocyclic heterocycle), -C(O)N((CH₂)_n- phenyl)((CH₂)_q -7- to 10-membered bicyclic heterocycle), -C(O)N((CH₂)_n-3- to 7- membered monocyclic heterocycle)₂, -C(O)N((CH₂)_n-7- to 10-membered bicyclic heterocycle)₂, or -SO₂NH₂;

R¹³ is -Ci-Cio alkyl, -C(O)-C₁-C₁₀ alkyl, -C(O)-aryl, -C(O)-(3- to 7- membered monocyclic heterocycle), or —glycoside, each of which is unsubstituted or substituted with one or more -halo, -C(O)OH, or -OH groups; each n is independently an integer ranging from O to 10; each p is independently an integer ranging from O to 5; and each q is independently an integer ranging from O to 10.

12. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula

(VI-145) or a pharmaceutically acceptable salt thereof, wherein: R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each independently -H, -0-(Ci-C₅ alkyl), -C,-

Cio alkyl, -C₂-Ci₀ alkenyl, -aryl, -C(O)OH, -C(O)O(C₁-C₅ alkyl), -OC(O)(Ci-C₅ alkyl), - NO₂, -NHC(O)(CH₂)_n-NH₂, -NHSO₂NH(CH₂)_n-NH₂, -C(O)NH(CH₂)_n-NH₂, - SO₂NH(CH₂)n-NH₂, -halo, -OH, -NH₂, or -A-B;

B is -Ci-Cιo alkyl, -C₂-CiO alkenyl, -C₂-CiO alkynyl, -C₃-Cs monocyclic cycloalkyl, -Cg-Cu bicyclic cycloalkyl, -C₅-C₈ monocyclic cycloalkenyl, -C₈-Ci₄ bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), - (nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZ|Z₂, -(Ci-

C₅ alkylene)-NZ,Z₂, -C(O)OH, -C(O)O-(C₁-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -0-(Ci-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -Ci-Ci₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(Ci-C₅ alkyl); Zi and Z₂ are independently -H or -C|-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently -H or -Ci-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z3 and Z₄ are taken together to form a — (nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zi and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen- containing 7- to 10-membered bicyclic heterocycle);

R" is -H, -C₁-C₅ alkyl, -(CH₂)_n-aryl, -C(O)R¹², -C(O)OR¹², -C(O)O-(Ci-C₅ alkyl), -CONH₂, -C(O)NH-(CH₂)_n-C(O)OH, -(CH₂)_n-C(O)OH, -(CH₂)_n-CONH-(CH₂)_q- (3- to 7- membered monocyclic heterocycle), -(CH₂)_p-(3- to 7-membered bicyclic heterocycle), -(CH₂)_p-(7- to 10-membered bicyclic heterocycle), -(CH₂)_n-CONH-(CH₂)_q- CONH-(Ci-C₅ alkyl), -(CH₂)_n-CONH-(CH₂)_q-CON(C,-C₅ alkyl)₂, -C(O)-(CH₂)_π-C(O)O- (Ci -Cs alkyl), -CONH-(CH₂ )_p-(3- to 7- membered monocyclic heterocycle), - C(O)N(R^I2)₂, -C(O)NHNHR¹², -CONH(CHz)_nN(R¹²h, -CONHN(Z₁)(Z₂), or -A-B;

R¹³ is -Ci-Cio alkyl, -C(O)-Ci-Ci₀ alkyl, -C(O)-aryl, -C(O)-(3- to 7- membered monocyclic heterocycle), or —glycoside, each of which is unsubstituted or substituted with one or more -halo, -C(O)OH, or -OH groups; each occurrence of R¹² is independently -H, -(Ci-Cs alkyl), -(CH₂)_p-phenyl, - (CH₂)_p-(3- to 7- membered monocyclic heterocycle), or -(CH₂)_p-7- to 10-membered bicyclic heterocycle; each n is independently an integer ranging from 1 to 10; each p is independently an integer ranging from O to 5; and each q is independently an integer ranging from O to 10. ^

13. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula

(III-154) or a pharmaceutically acceptable salt thereof, wherein: R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each independently -H, -0-(C₁-C₅ alkyl), -C,- Co alkyl, -C₂-Ci₀ alkenyl, -aryl, -C(O)OH, -C(O)O(C₁-C₅ alkyl), -OC(O)(Ci-C₅ alkyl), - NO₂, -NHC(O)(CH₂)_n-NH₂, -NHSO₂NH(CH₂)_n-NH₂, -C(O)NH(CH₂)_n-NH₂, - SO₂NH(CH₂VNH₂, -halo, -OH, -NH₂, or -A-B; R⁵ is O, S or NH;

B is -Ci-Cio alkyl, -C₂-CiO alkenyl, -C2-C10 alkynyl, -C3-C8 monocyclic cycloalkyl, -C_S-C_H bicyclic cycloalkyl, -C₅-Cs monocyclic cycloalkenyl, -Cg-Cn bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), -

(nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZiZ₂, -(C]- C₅ alkylene)-NZiZ₂, -C(O)OH, -C(O)O-(C₁-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZiZ₂, C(O)OH, or -C(NH)NH₂, is unsubstituted or substituted with one or more Of-C(O)NH₂, -0-(Ci-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -Ci-Ci₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(C₁-C₅ alkyl);

Zi and Z₂ are independently -H or -C₁-C₁₀ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z₄), where Z₃ and Z₄ are independently -H or -C₁-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z3 and Z₄ are taken together to form a -(nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zi and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen- containing 7- to 10-membered bicyclic heterocycle); R¹ ' is -C(O)O-(Ci-C₅ alkyl)-NZ₅Z₆; one of Z₅ and Z₆ is — H, -Cj-Ce alkyl or —phenyl, and the other of Z₅ and Ze is phenyl, wherein the —phenyl in each instance is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₇)(Z₈), where N, Z₇ and Z₈ are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three groups of -Ci-C₅ alkyl, -halo, -halo-substituted C₁-C₅ alkyl, hydroxy, -0-C₁-C₅ alkyl, -N(R^a)₂, -COOH, -C(O)O-(Ci-C₅ alkyl), -OC(O)-(C₁-C₅ alkyl), -C(O)NH₂, or -NO₂, wherein each occurrence of R^a is independently — H, -benzyl, or -Cj- Cio alkyl; or N, Z₅ and Z6 are taken together to form a nitrogen-containing 3- to 7- membered monocyclic heterocycle, which is substituted with one to three groups of- Ci-C₅ alkyl, -halo, -halo-substituted Ci-C₅ alkyl, hydroxy, -0-C]-C₅ alkyl, -N(R³^, -COOH, -C(O)O-(C₁-C₅ alkyl), -OC(O)-(Ci-C₅ alkyl), -C(O)NH₂, or -NO₂, wherein each occurrence of R^a is independently — H, -benzyl, or -Ci-Cio alkyl; each n is independently an integer ranging from 1 to 10; and each p is independently an integer ranging from O to 5.

14. A method for treating or preventing erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of a compound of the Formula

(IV-154) or a pharmaceutically acceptable salt thereof, wherein:

R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each independently -H, -0-(Ci-C₅ alkyl), -C,- C₁₀ alkyl, -C₂-Ci₀ alkenyl, -aryl, -C(O)OH, -C(O)O(C,-C_S alkyl), -OC(O)(Ci-C₅ alkyl), - NO₂, -NHC(O)(CH₂)_n-NH₂, -NHSO₂NH(CH₂)_n-NH₂, -C(O)NH(CH₂)_n-NH₂, -

SO₂NH(CH₂)_n-NH₂, -halo, -OH, -NH₂, or -A-B;

A is -SO₂-, -SO₂NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(C₁-C₅ alkyl)-, -NH-, -(CH₂)_P-, -S- or -C(S)-;

B is -Ci-Cio alkyl, -C₂-CiO alkenyl, -C2-C10 alkynyl, -C3-C8 monocyclic cycloalkyl, -Cg-Cn bicyclic cycloalkyl, -C₅-Cs monocyclic cycloalkenyl, -Cs-Ci₄ bicyclic cycloalkenyl, -(nitrogen-containing 3- to 7- membered monocyclic heterocycle), - (nitrogen-containing 7- to 10-membered bicyclic heterocycle), -(3- to 7- membered monocyclic heterocycle), -(7- to 10-membered bicyclic heterocycle), -aryl, -NZiZ₂, -(Ci- C₅ alkylene)-NZiZ₂, -C(O)OH, -C(O)O-(Ci-C₅ alkyl), -C(O)O-aryl or -C(NH)NH₂, each of which other than -NZ]Z₂, C(O)OH, or -C(NH)NH₂, is unsubstiruted or substituted with one or more of -C(O)NH₂, -0-(C₁-C₅ alkyl), -halo, -OH, -NO₂, -NH₂, -CN, -Ci-Ci₀ alkyl, -aryl, -C(O)OH, or -C(O)O-(C₁-C₅ alkyl);

Zi and Z₂ are independently -H or -Ci-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₃)(Z4), where Z₃ and Z₄ are independently -H or -C₁-C₅ alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -NH₂; or N, Z₃ and Z₄ are taken together to form a — (nitrogen- containing-3- to 7-membered monocyclic heterocycle) or a —(nitrogen-containing 7- to 10-membered bicyclic heterocycle), or N, Zj and Z₂ are taken together to form a — (nitrogen-containing-3- to 7-membered monocyclic heterocycle) or a — (nitrogen- containing 7- to 10-membered bicyclic heterocycle);

R¹¹ is -C(O)O-(Ci-C₅ alkyl)-NZ₅Z₆; one of Z₅ and Ze is — H, -Ci-C₆ alkyl or —phenyl, and the other of Z₅ and Z₆ is phenyl, wherein the —phenyl in each instance is unsubstituted or substituted with one or more of -halo, -OH or -N(Z₇)(Z₈), where N, Z₇ and Z₈ are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three groups of -C₁-C₅ alkyl, -halo, -halo-substituted C₁-C₅ alkyl, hydroxy, -0-C₁-C₅ alkyl, -N(R^a)₂, -COOH, -C(O)O-(C₁-C₅ alkyl), -OC(O)-(C₁-C₅ alkyl), -C(O)NH2, or -NO2, wherein each occurrence of R^a is independently — H, -benzyl, or -C|- Cio alkyl; or N, Z₅ and Ze are taken together to form a nitrogen-containing 3- to 7- membered monocyclic heterocycle, which is substituted with one to three groups of -

Ci -C₅ alkyl, -halo, -halo-substituted Ci-C₅ alkyl, hydroxy, -0-Ci-C₅ alkyl, -N(R^a)₂, -COOH, -C(O)O-(C-C₅ alkyl), -OC(O)-(Ci-C₅ alkyl), -C(O)NH₂, or -NO₂, wherein each occurrence of R^a is independently — H, -benzyl, or -C|-Cιo alkyl;