WO2003101994A1 - Composes aromatiques bicycliques condenses utiles dans le traitement de dysfonctionnement sexuel - Google Patents

Composes aromatiques bicycliques condenses utiles dans le traitement de dysfonctionnement sexuel Download PDF

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Publication number
WO2003101994A1
WO2003101994A1 PCT/US2003/016878 US0316878W WO03101994A1 WO 2003101994 A1 WO2003101994 A1 WO 2003101994A1 US 0316878 W US0316878 W US 0316878W WO 03101994 A1 WO03101994 A1 WO 03101994A1
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group
alkyl
hydrogen
piperazinyl
methyl
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PCT/US2003/016878
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English (en)
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Marlon D. Cowart
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Abbott Laboratories
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Priority claimed from US10/158,370 external-priority patent/US20040002488A1/en
Priority claimed from US10/443,814 external-priority patent/US7057042B2/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of WO2003101994A1 publication Critical patent/WO2003101994A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the use of fused bicyclic aromatic compounds and compositions containing these compounds for the treatment of sexual dysfunction.
  • DA dopamine
  • PAG periaqueductal gray
  • PVN paraventricular nucleus
  • DA receptor agonists like apomorphine ((6aR) 5,6,6a,7- tetrahydro-6-methyl-4H-diben-zo[de,g]quinoline-10,ll-diol), quinpirole and (-) 3-(3- hydroxyphenyl)-N-propylpiperidine (3-PPP) facilitate penile erection in rats, an effect blocked by haloperidol, a central DA antagonist. As the erectogenic effect can not be blocked by domperidone, a peripheral DA antagonist, it is believed that the pro-erectile effect of DA agonists is centrally mediated.
  • Clinical data also indicates that DA systems in the CNS play a role on the regulation of male sexual behavior as indicated by the sexual stimulatory effect of L-dopa in Parkinson's patients and by the pro-erectile effect of apomorphine in humans.
  • DA receptors belong to a superfamily of protein receptors that signal across the cell membrane by coupling to intracellular GTP-binding proteins.
  • G proteins include Gs, Gq and Gi
  • the Drlike receptors include Dx and D 5 .
  • the D 2 -like receptors include D 2 , D 3 and D .
  • the Dplike family receptor subtypes are G s -coupled and can activate adenylate cyclase.
  • the D 2 -like family receptor subtypes are Gj-coupled and they increase intracellular calcium level and inhibit adenylate cyclase.
  • the D ⁇ like family members are G s -coupled receptors that can activate adenylate cyclase.
  • the O ⁇ receptor is the most abundant and widespread DA receptor in the CNS both by mRNA expression and by immunohistochemical studies. It is found in the striatum, nucleus accumbens and olfactory tubercle as well as the limbic system, hypothalamus and thalamus. The O ⁇ receptor expression has been reported in the heart and kidney, and despite mat the function of these peripheral O ⁇ receptors remains to be clarified, its role on the control of hemodynamic variables has been confirmed.
  • the D 5 receptor while having a higher affinity for DA than the O ⁇ receptor, is sparsely distributed in the CNS with no evidence of expression outside the CNS.
  • the D -like family members are Gj coupled receptors that inhibit adenylate cyclase and increase intracellular calcium levels.
  • the D receptor is the most abundant of the D -like receptors and is located in brain areas such as the striatum and substantia nigra, and in peripheral areas such as the heart, pituitary gland and kidney.
  • the D 3 receptor is found abundantly in the islands of Calleja with distinct cluster populations in the ventral striatum/nucleus accumbens regions, olfactory tubercle, dendate gyrus and striatal cortex.
  • D 4 receptor has been documented by in situ RNA hybridization and immunohistochemical studies. Recently, studies revealed that D 4 expression is highest in the entorhinal cortex, lateral septal nucleus, hippocampus and the medial preoptic area of the hypothalamus. Localization of D 4 is distinct from the distribution of D 2 in the brain, as D 2 receptors are most abundant in striatal areas.
  • the expression of D 4 receptors in the MPOA of the hypothalamus is of importance to the facilitation of penile erection in view of the role of the hypothalamus as an area of integration between the cortex and the spinal pathways. The participation of D 4 receptors in other CNS regions, thalamic, subthalamic and spinal can not be excluded.
  • the present invention identifies a therapeutic use for the compounds of formula (I) in the treatment of sexual dysfunction in mammals. More specifically, these compounds are useful in the treatment of sexual dysfunction including, but not limited to, male erectile dysfunction (MED).
  • MED male erectile dysfunction
  • the present invention relates to a method of treating sexual dysfunction in a mammal, in particular humans, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I)
  • A is selected from the group consisting of
  • X is selected from CRx or N;
  • Y is selected from Ry, O, or S;
  • V is selected from CRy or N; P is selected from CRp or N; Q is selected from CR Q or N; S is selected from CRs or N; T is selected from CRr or N; provided that 0, 1, or 2 of P, Q, S, or T are N; provided that when P is CR P , Q is CR Q , S is CRs, T is CRx, and Y is N, then X is CRx;
  • R P , R Q , Rs, R T , R V , and Rx are independently selected from hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z , (NZ 3 Z 4 )carbonyl, or (NZ 3 Z 4 )sulfonyl;
  • Ry is selected from hydrogen, alkenyl, alkoxycarbonyl, alkyl, arylalkyl, of (NZ 3 Z )carbonyl;
  • Zi and Z are each independently selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylalkylsulfonyl, arylsulfonyl, or formyl;
  • Z 3 and Z 4 are each independently selected from hydrogen, alkyl, aryl, or arylalkyl;
  • L is alkylene
  • D is selected from
  • RA is selected from hydrogen or alkyl
  • Z is selected from N, C or CH
  • — is a bond when Z is C and — is absent when Z is N or CH;
  • Bi is selected from
  • Ri, R 2 , R 3 , t and R 5 are each independently selected from hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z 2 , (NZ 3 Z 4 )carbonyl, or (NZ Z 4 )sulfonyl;
  • Xi is selected from N(R 6 ), O or S;
  • Yi is selected from C(R 7 ) or N;
  • Re is selected from hydrogen or alkyl
  • R is selected from hydrogen or alkyl; and provided that the compound of formula (I) is other than 5-fluoro-2- ⁇ [4-(2-pyridinyl)- 1 -piperazinyl]methyl ⁇ - 1 H-indole.
  • the present invention relates to a method of treating sexual dysfunction in a mammal, in particular humans, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I)
  • the present invention relates to a method of treating sexual dysfunction in a mammal, in particular humans, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I)
  • A is selected from the group consisting of
  • X is selected from CR X or N;
  • Y is selected from NRy, O, or S;
  • V is selected from CRy or N; P is selected from CRp or N; Q is selected from CR Q or N; S is selected from CRs or N; T is selected from CRp or N; provided that 0, 1, or 2 of P, Q, S, or T are N; provided that when P is CR P , Q is CR Q , S is CRs, T is CR T , and Y is N, then X is
  • RP, R Q , Rs, R T , Ry, and R are independently selected from hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z 2 , (NZ 3 Z 4 )carbonyl, or (NZ 3 Z 4 )sulfonyl;
  • RY is selected from hydrogen, alkenyl, alkoxycarbonyl, alkyl, arylalkyl, of (NZ 3 Z )carbonyl;
  • Z ⁇ and Z 2 are each independently selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylalkylsulfonyl, arylsulfonyl, or formyl;
  • Z 3 and Z 4 are each independently selected from hydrogen, alkyl, aryl, or arylalkyl;
  • L is alkylene
  • D is selected from , or RA wherein the left end is attached to L and the right end is attached to Bi;
  • R A is selected from hydrogen or alkyl
  • Z is selected from N, C or CH
  • — is a bond when Z is C and — is absent when Z is N or CH
  • Bi is selected from
  • Ri, R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ⁇ Z 2 , (NZ 3 Z 4 )carbonyl, or (NZ 3 Z 4 )sulfonyl;
  • Xi is selected fromN(R 6 ), O or S;
  • Y 1 is selected from C(R 7 ) or N;
  • R 6 is selected from hydrogen or alkyl
  • R 7 is selected from hydrogen or alkyl and provided that the compound of formula (I) is other than 5-fluoro-2- ⁇ [4-(2-pyridinyl)- 1 -piperazinyl]methyl ⁇ - 1 H-indole.
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt,
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R P , RQ, R S , R T , R X , Z, RI, R 2 , R 3 , R-j, RA, RY, and — are as defined in formula
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, N-
  • Y is selected from NR ⁇ 5 O, or S; Ry is selected from hydrogen or alkyl; Z is N; — is absent; R l5 R 2 , R 3 , and t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein A is ; Bi is
  • Y is selected from NRy, O, or S; Ry is selected from hydrogen or alkyl; Z is CH; — is absent; R ls R 2 , R 3 , and R t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • p is CRp .
  • Q is CRQ .
  • S is CRs .
  • ⁇ is CR ⁇ .
  • x is CR ⁇ .
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • Z is C; — is a bond; and
  • R ls R 2 , R 3 , and R- 4 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Y is selected from NRy, O, or S; Ry is selected from hydrogen or alkyl; Z is N; — is absent; R ls R 2 , R 3 , and j are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Rp is CRp .
  • Q js CRQ . g is CRs; T ig N . ⁇ js CR ⁇ .
  • Rp RQJ Rgj and R ⁇ are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • Z is CH; — is absent;
  • R 1? R 2 , R 3 , and R- 4 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • A is ; D is K A ; Bi is p is CRp .
  • Q is CRQ .
  • S is CRs; ⁇ i s N; x i s CR ⁇ ; Rp RQJ RSJ md R ⁇ a j .
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • Z is C; — is a bond;
  • R ls R 2 , R 3 , and R-- J are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Y is selected from NR y , O, or S; and RQ, RS, RT, RX, Z, R l5 R 2 , R 3 , RA, RA, RY, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • p is N .
  • Q s CRQ . S s C s; T is CR T ;
  • X is CR X ;
  • R Q , R s , R ⁇ , and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • Z is N; — is absent;
  • Ri, R , R 3 , and R 4 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and
  • R A is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein A is ; Bi is
  • Y is selected from NR ⁇ 5 O, or S;
  • RY is selected from hydrogen or alkyl;
  • Z is CH; — is absent;
  • R l5 R 2 , R 3 , and RA are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and
  • R A is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Pis ;QisCRQ;SisCRs;TisCR T ;XisCRx;R Q ,Rs,R T ,andR x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • Z is C; — is a bond;
  • R l5 R, R 3 , and R A are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and R A is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • p N .
  • Q is CRQ .
  • X is N;
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • R Q , Rs, and R T are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Z is N; — is absent;
  • Ri, R 2 , R 3 , and t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • A is T ⁇ ; D is KA ; Bi is ; p is N; Q is CR Q ; S is CR S ; T is CR T ; X is N; Y is selected from NR Y , O, or S; Ry is selected from hydrogen or alkyl; R Q , R S , and R T are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Z is C; — is a bond; R l3 R 2 , R 3 , and R are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • p is CRp .
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein A is
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • A is n X ⁇ ' ; D is X K ; B I is
  • p is CRp .
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • RQ, R S , R T , RX, R 1S R 2 , R 3 , R A , R Y , and R A are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R p is CRp .
  • Q is CRQ .
  • S is CRs .
  • ⁇ is CR ⁇ . ⁇ s CR X ;
  • R p R Q? R S , R TJ and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NR ⁇ 5 O, or S;
  • Ry is selected from hydrogen or alkyl;
  • R l5 R 2 , R 3 , and R are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and
  • R A is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Rp , R Q , Rs, Rx, Ri, R 2 , R 3 , RA, Ry, and RA are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • p is CRp .
  • Q is CRQ .
  • S is CRs; ⁇ is N ;
  • x is CR X ;
  • R Pj R Q , Rs, and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • R ls R 2 , R 3 , and R A are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and
  • RA are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • p is N .
  • Q is CRQ .
  • S ig CRg . ⁇ is CR ⁇ .
  • ⁇ is CR ⁇ .
  • Y is selected from NR Y , O, or S; and RQ, R S , R T , Rx, Ri, R2, R3, R4, RY, and R A are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein A is
  • P is N; Q is CR Q ; S is CRs; T is CR ⁇ ; X is CR ⁇ ; R Q , Rs, R ⁇ , and R ⁇ are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Y is selected from NRy, O, or S; Ry is selected from hydrogen or alkyl; R l5 R 2 , R 3 , and R A are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • p is N .
  • Q is CRQ .
  • S is CRg .
  • ⁇ is C R T ;
  • X is N;
  • Y is selected from NR y , O, or S; and
  • RQ, R S , RT, Ri, R2, R3, R4, RY, and RA are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • . p is N .
  • Q is CRQ .
  • S is CRs .
  • ⁇ is CR ⁇ .
  • ⁇ is N;
  • Y is selected from NR Y , O, or S;
  • Ry is selected from hydrogen or alkyl;
  • R Q , R S , and R ⁇ are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • R l3 R 2 , R 3 , and RA are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and
  • R A is as defined in formula
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R P , R Q , R S , R I , R 2 , R 3 , R f , Ry, and R A are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R A is as defined in formula
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein A is ; Bi is
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Rp, R Q , R S , R T , R X , RI, R2, R3, RA, R Y , and RA are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R A is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- or S; and Rp, R Q , R S , R X , Ri, R 2 , R 3 , R A , Ry, and RA are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • p is CRp .
  • Q is CRQ .
  • S is CRs .
  • T is N;
  • X is CR X ;
  • R P, R Q , R S , and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • R l3 R 2 , R 3 , and R are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • p is N .
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein A is ⁇ ; D ⁇ s ⁇ A ; Bi IS
  • R A are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • A is ⁇ ⁇ TX ⁇ - ;
  • D is R A ;
  • Bi is
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Rp is CRp
  • Q is CR Q
  • S is CRs
  • T is N
  • X is N
  • Y is selected from NR ⁇ , O, or S
  • Ry is selected from hydrogen or alkyl
  • Rp, R Q , and Rs are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen
  • R ls R 2 , R 3 , and R A are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen
  • RA are as defined in formula
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Rp, RQ, R S , R T , Rx, Z, R l5 R 2 , R3, RA, R 5 , RA, RY, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R P is CRp
  • Q is CR Q
  • S is CRs
  • T is CR T
  • X is CR
  • R P , R Q , R S , R T , and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen
  • Y is selected from NRy, O, or S
  • Ry is selected from hydrogen or alkyl
  • Z is CH; — is absent;
  • R l5 R 2 , R 3 , RA, and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R P , R Q , R s , R ⁇ , and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • Z is C; — is a bond;
  • Ri, R 2 , R 3 , RA, and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and R A is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R A is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • A is ; Bi is ; p is CR?; Q is CR Q ; S is CR S ; T is N; X is CR X ; R P, R Q , Rs, and R are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Y is selected from NRy, O, or S; Ry is selected from hydrogen or alkyl; Z is C; — is a bond; R 1? R , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R Q , R s , R ⁇ , and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • Z is CH; — is absent;
  • R l5 R 2 , R 3 , R- 4 , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • RQ, R S , R T , and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • Z is C; — is a bond;
  • R ls R , R 3 , RA, and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • A is ;
  • P is N;
  • Q is CR Q ;
  • S is CRs;
  • T is CR T ;
  • X is N;
  • Y is selected from NR Y , O, or S; and
  • R Q , R S , R T , Z, R l5 R 2 , R3, RA, R5, RA, RY, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R Q , R s , and R ⁇ are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • R Y is selected from hydrogen or alkyl;
  • Z is N; — is absent;
  • R ls R 2 , R 3 , R- 4 , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • P is N; Q is CR Q ; S is CRs; T is CR T ; X is N; R Q , R s , and R ⁇ are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Y is selected from NRy, , or S; Ry is selected from hydrogen or alkyl; Z is C; — is a bond; Ri, R 2 , R 3 , Rt, and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and R A is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • A is s. T x ⁇ - ; D is KA ; Bt is P is CR P ; Q is CR Q ; S is CR S ; T is N; X is N; Y is selected from NRy, O, or S; Ry is selected from hydrogen or alkyl; Rp, R Q , and Rs are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Z is N; — is absent; R l5 R 2 , R 3 , t , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Ry is selected from hydrogen or alkyl
  • Rp, R Q , and Rs are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen
  • Z is CH
  • — is absent
  • R l5 R , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Rp, RQ, RS, RT, RX, Ri, R2, R3, R4, R5, RA, and Ry are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R Pj R Q , Rs, RT, and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • R ⁇ is selected from hydrogen or alkyl;
  • R ls R 2 , R 3 , R t , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Rp, R Q , R S , R X , Ri, R 2 , R 3 , Rt, R 5 , RA, and Ry are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein A is ; B] is
  • RQ, R S , RT, RX, RI, R2, R3, R4, Rs, RA, and Ry are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • RQ, R S , R T , and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • RY is selected from hydrogen or alkyl;
  • R ls R 2 , R 3 , Rt, and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • P is N; Q is CR Q ; S is CR S ; T is CR T ; X is N; Y is selected from NR Y , O, or S; Ry is selected from hydrogen or alkyl; R Q , R S , and R T are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; R l5 R 2 , R 3 , R t , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Rp, RQ, R S , R I , R 2 , R 3 , R4, Rs, RA, and Ry are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • A is s. T ⁇ $- ; D is M A ; ⁇ is ; P is CRp; Q is CR Q ; S is CRs; T is N; X is N; Y is selected from NR Y , O, or S; Ry is selected from hydrogen or alkyl; Rp, R Q , and Rs are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; R l3 R 2 , R 3 , R t , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • A is and P, Q, S, T, X, Y, Z, R 2 , R 3 , R t , R A , and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • RQ, R S , RT, R X , Z, R 2 , R 3 , Rt, RA, Ry, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • P is N; Q is CR Q ; S is CRs; T is CR T ; X is CR X ; Y is selected from NR Y , O, or S; and R Q , R S , R T , Rx, Z, R , R 3 , R t , RA, RY, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein A is
  • P is N; Q is CR Q ; S is CR S ; T is CR T ; X is CR X ; R Q , R s , R ⁇ , and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Y is selected from NRY, O, or S; Ry is selected from hydrogen or alkyl; Z is N; — is absent; R 2 , R3, and t are independently selected from hydrogen, alkyl, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • P is N; Q is CR Q ; S is CR S ; T is CR T ; X is N; Y is selected from NR Y , O, or S; and RQ, R S , R T , Z, R 2 , R 3 , R 4 , RA, RY, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • P is N; Q is CR Q ; S is CR S ; T is CR T ; X is N; Y is selected from NR Y , O, or S; R ⁇ is selected from hydrogen or alkyl; R Q , R S , and R are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Z is N; — is absent; R 2 , R 3 , and R t are independently selected from hydrogen, alkyl, or halogen; and R is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • A is D is and P, Q, S, T, X, Y, Z, X ls Y l5 R 2 , R 3 , R A , and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • P is CRp; Q is CR Q ; S is CR S ; T is CR T ; X is CR X ; Y is selected from NR Y , O, or S; and R P , RQ, R S , R T , Rx, Z, Xi, Yi, R 2 , R3, RA, RY, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • A is P is CRp; Q is CR Q ; S is CR S ; T is CR T ; X is CR X ; R P> R Q , R s , R ⁇ , and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Y is selected from NRy, O, or S; Ry is selected from hydrogen or alkyl; Xi is S; Yi is N; Z is N; — is absent; R 2 and R 3 are independently selected from hydrogen, alkyl, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • P is N; Q is CR Q ; S is CR S ; T is CR T ; X is CR X ; Y is selected from NRy, O, or S; and R Q , R S ,
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein A is :x: f
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • P is N; Q is CR Q ; S is CRs; T is CR T ; X is N; Y is selected from NR Y , O, or S; and R Q , R S ,
  • R T , Z, XI, Yi, R 2 , R3, RA, R Y , and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • P is N; Q is CR Q ; S is CRs; T is CR T ; X is N; Y is selected from NR Y , O, or S; Ry is selected from hydrogen or alkyl; R Q , R S , and R T are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Xi is S; Yi is N; Z is N; — is absent; R 2 and R 3 are independently selected from hydrogen, alkyl, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • ⁇ RA, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • V is CRv
  • Y is selected from NR Y , O, or S
  • R P , R Q , Rs, R ⁇ , Rv, Z, R b R 2 , R 3 , R t , RA, Ry, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • CRp CRp
  • V is CRv
  • Rp, R Q , Rs, RT, and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen
  • Y is selected from NRy, O, or S
  • Ry is selected from hydrogen or alkyl
  • Z is N; — is absent
  • Ri, R 2 , R 3 , and t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • CRp CRp
  • V is CRv
  • Rp, R Q , RS, R T , and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen
  • Y is selected from NRy, O, or S
  • R Y is selected from hydrogen or alkyl
  • Z is CH
  • — is absent
  • R 1? R 2 , R 3 , and t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is D is - R A - ; Bi is Rl ⁇ > N R4 ; P is CR P ; Q is CR Q ; S is CR S ; T is
  • CRp CR V
  • Rp, R Q , R S , R T , and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen
  • Y is selected from NRy, O, or S
  • Ry is selected from hydrogen or alkyl
  • Z is C
  • — is a bond
  • R ls R , R 3 , and R t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • N is CRv
  • Y is selected from NRy, O, or S
  • Rp, R Q , R S , Ry, Z, R b R 2 , R 3 , Rt, R A , RY, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • N is CRy; Rp, R Q , R S , and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Y is selected from NRy, O, or S; Ry is selected from hydrogen or alkyl; Z is N; — is absent; R ls R 2 , R 3 , and t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • N is CRy; Rp, R Q , R S , and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Y is selected from NRy, O, or S; Ry is selected from hydrogen or alkyl; Z is CH; — is absent; Ri, R 2 , R3, and R t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • N is CRy
  • Rp , R Q , R S , and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen
  • Y is selected from NRy, O, or S
  • Ry is selected from hydrogen or alkyl
  • Z is C
  • — is a bond
  • R ls R 2 , R 3 , and R t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is D is ; Bi is P is N; Q is CR Q ; S is CR S ; T is
  • V is CR V ;
  • Y is selected from NRy, O, or S; and RQ, R S , R T , RV, Z, R 1; R 2 , R 3 , R t , R A ,
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is ; P is N; Q is CR Q ; S is CR S ; T is
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • a is D is P is N; Q is CR Q ; S is CR S ; T is
  • CRT CRT
  • V is CRy
  • R Q , RS, RT and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen
  • Y is selected from NRy, O, or S
  • Ry is selected from hydrogen or alkyl
  • Z is CH; — is absent
  • Ri, R 2 , R 3 , and R t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is ; B ⁇ is ; and P, Q, S, T, V, Y, Z, R ⁇ , R 2 , R 3 ,
  • R t , R 5 , RA, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula Q or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • V is CRy;
  • Y is selected from NR Y , O, or S; and
  • R P , R Q , R s , R ⁇ , Rv, Z, Ri, R 2 , R 3 , Rt, R 5 , RA, Ry, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • CRT; V is CRy; Rp, RQ, RS, RT, and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Y is selected from NR ⁇ 5 O, or S; Ry is selected from hydrogen or alkyl; Z is N; — is absent; Ri, R , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is ; P is CR P ; Q is CR Q ; S is CR S ; T is
  • CRx CRx
  • V is CRy
  • Rp, RQ, RS, RT, and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen
  • Y is selected from NRy, O, or S
  • Ry is selected from hydrogen or alkyl
  • Z is CH; — is absent
  • Ri, R 2 , R 3 , Rt, and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is D is ; P is CR P ; Q is CR Q ; S is CR S ; T is
  • V is CRy, Y is selected from NRy, O, or S; and R P , R Q , Rs, Ry, Z, R l5 R 2 , R 3 , R , R 5 , R A , R Y , and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • N is CRy; Rp, RQ, R S , and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Y is selected from NRy, O, or S; Ry is selected from hydrogen or alkyl; Z is N; — is absent; Ri, R , R 3 , Rj, and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is D is ; P is CR P ; Q is CR Q ; S is CRs; T is
  • N is CRy;
  • Rp, R Q , R S , and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • R ⁇ is selected from hydrogen or alkyl;
  • Z is CH; — is absent;
  • Ri, R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is ; P is CR P ; Q is CR Q ; S is CR S ; T is
  • N is CRy;
  • Rp, RQ, R S , and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NR Y , O, or S;
  • Ry is selected from hydrogen or alkyl;
  • Z is C; — is a bond;
  • Ri, R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is "T Y y ; D is - h R ⁇ A ; B ⁇ is X ⁇ R 5 ; P is N; Q is CR Q ; S is CRs; T is
  • CR T is CR V ;
  • Y is selected from NRy, O, or S; and RQ, R S , R T , Ry, Z, Ri, R 2 , R 3 , Rt, R 5 , RA, Ry, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is R 5 ; P is N; Q is CR Q ; S is CR S ; T is
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • N is CRy;
  • R Q , R s , R ⁇ and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • Z is CH; — is absent;
  • Ri, R 2 , R 3 , R t , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • V is CRy;
  • R Q , R S , R T and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NRy, O, or S;
  • Ry is selected from hydrogen or alkyl;
  • Z is C; — is a bond;
  • Ri, R 2 , R 3 , R t , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is ; B i is and Pj Qj Sj T ⁇ Vj ⁇ > Zj R 2> R 33 R 4?
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • CRT; V is CRy; Rp, R Q , RS, RT, and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Y is selected from NRy, O, or S; Ry is selected from hydrogen or alkyl; Z is N; — is absent; R 2 , R 3 , and t are independently selected from hydrogen, alkyl, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • V is CR V ;
  • Y is selected from NR Y , O, or S; and
  • R P , RQ, R S , Ry, Z, R 2 , R 3 , Rt, R A , R Y , and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • N is CR V ;
  • R P, R Q , R S , and Ry are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Y is selected from NR Y , O, or S;
  • RY is selected from hydrogen or alkyl;
  • Z is N; — is absent;
  • R 2 , R 3 , and t are independently selected from hydrogen, alkyl, or halogen; and
  • R A is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is ; P isN; Q is CR Q ; S is CRs; T is CR T ;
  • V is CRy; Y is selected from NRy, O, or S; and RQ, RS, RT, RV, Z, R 2 , R 3 , Rt, R , Ry, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein
  • A is P is N; Q is CR Q ; S is CR S ; T is
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • R ⁇ is selected from hydrogen or alkyl; Z is N; — is absent; Ri, R 2 , R 3 , and R f are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • the present invention relates to a method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Ry is selected from hydrogen or alkyl
  • Z is N
  • — is absent
  • Ri, R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy
  • RA is as defined in formula (I).
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof, wherein A ; and Z, R 2 , R 3 , R t , R ⁇ 5 RA, and — are as defined in formula (I).
  • the present invention relates to a method of treating sexual dysftmction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-
  • Ry is selected from hydrogen or alkyl; Z is N; — is absent; R 2 , R 3 , and Rt are independently selected from hydrogen, alkyl, or halogen; and RA is as defined in formula (I).
  • the present invention relates to method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
  • the present invention relates to method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof in combination with a phosphodiesterase 5 inhibitor.
  • the present invention relates to method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof in combination with an adrenergic receptor antagonist.
  • the present invention relates to method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N- oxide, or prodrug thereof in combination with a dopamine agonist.
  • the present invention relates to method of treating male erectile dysfunction in a male human comprising administering to the male human in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
  • the present invention relates to method of treating male erectile dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof in combination with a phosphodiesterase 5 inhibitor.
  • the present invention relates to method of treating male erectile dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof in combination with an adrenergic receptor antagonist.
  • the present invention relates to method of treating male erectile dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof in combination with a dopamine agonist.
  • the present invention relates to method of treating female sexual dysfunction in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
  • the present invention relates to method of treating female sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof in combination with a phosphodiesterase 5 inhibitor.
  • the present invention relates to method of treating female sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof in combination with an adrenergic receptor antagonist.
  • the present invention relates to method of treating female sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof in combination with a dopamine agonist.
  • the present invention relates to method of treating a disorder selected from cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorder, Alzheimer's disease, drug abuse, Parkinson's disease, schizophrenia, anxiety, mood disorders or depression in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof.
  • A is selected from the group consisting of
  • X is selected from CRx or N;
  • Y is selected from O, or S
  • V is selected from CRy or N; P is selected from CR P or N; Q is selected from CR Q or N; S is selected from CRs or N; T is selected from CR T or N; provided that 1, or 2 of P, Q, S, and T are N;
  • R P , RQ, Rs, RT, Rv, and Rx are independently selected from hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ⁇ Z 2 , (NZ 3 Z )carbonyl, or (NZ 3 Z 4 )sulfonyl;
  • Zi and Z 2 are each independently selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylalkylsulfonyl, arylsulfonyl, or formyl;
  • Z 3 and Z 4 are each independently selected from hydrogen, alkyl, aryl, or arylalkyl;
  • L is alkylene
  • D is selected from wherein the left end is attached to L and the right end is attached to Bi;
  • RA is selected from hydrogen or alkyl
  • Z is selected from N, C or CH
  • — is a bond when Z is C and — is absent when Z is N or CH;
  • Bi is selected from
  • Ri, R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ⁇ Z 2 , (NZ 3 Z 4 )carbonyl, or (NZ 3 Z 4 )sulfonyl;
  • Xi is selected from N(R 6 ), O or S;
  • Yi is selected from C(R 7 ) or N;
  • R ⁇ 5 is selected from hydrogen or alkyl
  • R 7 is selected from hydrogen or alkyl.
  • P is N; Q is CR Q ; S is CR S ; T is CR T ;
  • X is CRx; Y is selected from O or S; and Z, R Q , R S , R T , RX, RI R2, R 3 , Rt, R A and — are as defined in formula (II).
  • X is CRx; Y is selected from O or S; R Q , R S , R T , and Rx are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Z is N; — is absent; Ri, R 2 , R 3 , and R 4 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and R A is as defined in formula (II).
  • X is CR ; Y is selected from O or S; and RQ, R S , R T , and Z, R Q , R s , R ⁇ , R x , Ri R 2 , R3, , R5, R A and — are as defined in formula (II).
  • compounds of formula (II) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof are disclosed wherein A is D is ; B ⁇ is ; P is N; Q is CR Q ; S is CRs; T is CR T ;
  • X is CRx; Y is selected from O or S; R Q , R S , R T , and R x are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Z is N; — is absent; Ri, R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (II).
  • P is N; Q is CRQ; S is CR S ; T is CR T ;
  • X is N; Y is selected from O or S; and Z, RQ, R S , R T , R I R2, R 3 , R4, R A and — are as defined in formula (II).
  • X is N; Y is selected from O or S; R Q , R S , and R ⁇ are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Z is N; — is absent; Ri, R 2 , R 3 , and R t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and R A is as defined in formula (II).
  • compounds of formula (II) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof are disclosed wherein A is ; P is N; Q is CR Q ; S is CRs; T is CR T ;
  • X is N; Y is selected from O or S; and Z, RQ, RS, RT, RI RI, R3, R4, R 5 , RA and — are as defined in formula (II).
  • P is N;
  • Q is CR Q ;
  • S is CRs;
  • T is CR T ;
  • X is N; Y is selected from O or S; R Q , R S , and R T are independently selected from hydrogen, alkoxy, alkyl, haloalkyl, or halogen; Z is N; — is absent; Ri, R , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (II).
  • A is D is f R A ; B ⁇ is p is CR P ; Q is CR Q ; S is CR S ; T is N; X is N; Y is selected from O or S; and Z, Rp, R Q , R S , RI R 2 , R 3 , R t , R A and — are as defined in formula (II).
  • RA is as defined in formula (II).
  • A is D is p [s CRp .
  • Q is CRQ .
  • S is CRg .
  • ⁇ is N;
  • X is N;
  • Y is selected from O or S;
  • Rp, R Q , and Rs are independently selected from the group consisting of hydrogen, alkoxy, alkyl, haloalkyl, or halogen;
  • Z is CH; — is absent;
  • Ri, R , R 3 , and R t are independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and
  • R A is as defined in formula (II).
  • A is ; P is CR P ; Q is CR Q ; S is CR S ; T is N; X is N; Y is selected from O or S; and Z, Rp, R Q , R S , R I R 2 , R 3 , Rt, R 5 , R A and — are as defined in formula (II).
  • compounds of formula (II) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof are disclosed wherein
  • A is ; ; p j s CRp; Q i s CR Q ; S is CRs; T is
  • A is iiss p is CRp .
  • Q is CRQ .
  • a is D is P is CR P ; Q is CR Q ; S is CR S ; T is
  • N is N; Y is selected from O or S; and Xi, Y ls Z, R P , R Q , Rs, R 2 , R3, RA and — are as defined in formula (II).
  • A is R Y and Ry is as defined in formula (II).
  • R ⁇ is selected from hydrogen or alkyl; Z is N; — is absent; Ri, R 2 , R 3 , and t are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, or halogen; and R A is as defined in formula (II).
  • R ⁇ , R A , Z, R b R 2 , R 3 , R t , R 5 , and — are as defined in formula (II).
  • compounds of formula (II) or a pharmaceutically acceptable salt, ester, amide, N-oxide, or prodrug thereof are disclosed wherein A is D is ; BI is Ry is selected from hydrogen or alkyl; Z is N; — is absent; Ri, R 2 , R 3 , R4, and R 5 are independently selected from hydrogen, alkoxy, alkyl, alkylthio, cyano, halogen, or hydroxy; and RA is as defined in formula (II).
  • alkyl Z is N; — is absent; R , R3, and t are independently selected from hydrogen, alkyl, or halogen; and R A is as defined in formula (II).
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkoxy as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxycarbonyl as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylcarbonyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl- 1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
  • alkylcarbonyloxy means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
  • alkylene means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms.
  • Representative examples of alkylene include, but are not limited to, -CH 2 -, -CH(CH 3 )- -CH 2 CH 2 -, -CH 2 CH 2 CH -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH(CH 3 )CH 2 -.
  • alkylsulfinyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein.
  • Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulfinyl.
  • alkylsulfonyl means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
  • alkylthio as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • aryl as used herein, means a monocyclic-ring system, or a bicyclic- or a tricyclic-fused ring system wherein one or more of the fused rings are aromatic.
  • Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, 2,3-dihydroindenyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • aryl groups of this invention are substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ⁇ Z , (NZ 3 Z 4 )carbonyl, and (NZ 3 Z 4 )sulfonyl.
  • substituents independently selected from alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, carboxy, cyano
  • arylalkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3 -phenylpropyl, and 2-naphth-2-ylethyl.
  • arylalkylsulfonyl as used herein, means an arylalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group.
  • arylsulfonyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group.
  • carbonyl as used herein, means a -C(O)- group.
  • cyano as used herein, means a -CN group.
  • halo or halogen as used herein, means -CI, -Br, -I or -F.
  • haloalkoxy means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • haloalkoxy include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • hydroxy as used herein, means an -OH group.
  • hydroxyalkyl as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxy ⁇ entyl, and 2-ethyl-4-hydroxyheptyl.
  • mercapto as used herein, means a -SH group.
  • nitrogen protecting group means those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Nitrogen protecting groups comprise carbamates, amides, N-benzyl derivatives, and imine derivatives. Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl).
  • nitro as used herein, means a -NO 2 group.
  • (NZ 3 Z )carbonyl as used herein, means a -NZ 3 Z 4 group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (NZ 3 Z 4 )carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, benzylamino, phenylamino, and (ethylmethylamino)carbonyl.
  • (NZ 3 Z 4 )sulfonyl as used herein, means a -NZsZ 4 group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • sulfinyl as used herein, means a -S(O)- group.
  • sulfonyl as used herein, means a -SO 2 - group.
  • sexual dysfunction means sexual dysfunction in mammals including human male and human female sexual dysfunction.
  • male sexual dysfunction includes, but is not limited to, male erectile dysfunction or premature ejacualtion.
  • female sexual dysfunction as used herein includes, but is not limited to, female anorgasmia, clitoral erectile insufficiency, vaginal engorgement, dyspareunia, or vaginismus.
  • Stereoisomers may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom.
  • R and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Preferred compounds of the present invention include:
  • Compounds of general formula (3) can be treated with Burgess Reagent, thionyl chloride or an acid such as, but not limited to, sulfuric acid or trifluoracetic acid to provide dihyropyridines of general formula (4).
  • Dihyropyridines of general formula (4) can be deprotected using standard methods known to those of ordinary skill in the art to provide compounds of general formula (5).
  • Compounds of general formula (4) can also be treated with a metal catalyst such as palladium on carbon under a hydrogen atmosphere in a solvent such as ethyl acetate, ethanol, or methanol to provide compounds of general formula (6).
  • Example 1 2- ⁇ 1 - r 5 -chloro- 1 -benzothien-3 -yl)methyl1 -4-piperidinyl ⁇ pyridine 3-(Bromomethyl)-5-chloro-l-benzothiophene (150 mg 0.9 mmol) and 4-(2- pyridyl)piperidine (181 mg, 1.0 mmol) were processed as described in Example 2 to provide the title compound.
  • Example 2 l-r(5-chloro-l-benzothien-3-yl)methyl1-4-(6-methyl-2-pyridinyl)piperazine 3-(Bromomethyl)-5-chloro-l-benzothiophene (1 mmol, maybridge chemical) and 1- (6-methyl-2-pyridinyl)piperazine (1 mmol) were combined in 2 mL of acetonitrile and 1 mL of dimethylformamide and stirred at 25 °C for 5 minutes. The mixture was heated briefly to dissolve any solids and allowed to cool to 25 °C. The mixture was monitored by thin layer chromatography until disappearance of starting residue.
  • Example 3 2- ⁇ 4- 1 " (5 -chloro- 1 -benzothien-3 -yl)methyl1 - 1 -piperazinyl jbenzonitrile 3-(Bromomethyl)-5-chloro-l-benzothiophene and 2-(l-piperazinyl)benzonitrile were processed as described in Example 2 to provide the title compound.
  • Example 4 1 - 1 " (5 -chloro- 1 -benzothien-3 -yl)methyll -4-(2-pyridinyl)piperazine 3 -(Bromomethyl)-5 -chloro- 1-benzothiophene and l-(2-pyridinyl)piperazine were processed as described in Example 2 to provide the title compound. !
  • Example 5 1 - 1 ⁇ (5 -chloro- 1 -benzothien-3 -y l)methyl1 -4-(2-fluorophenyl)piperazine 3-(Bromomethyl)-5-chloro- 1-benzothiophene and l-(2-fluorophenyl)piperazine were processed as described in Example 2 to provide the title compound.
  • Example 6 2- ⁇ 4- l " (5-chloro- 1 -benzothien-3 -yl)methyl]- 1 -piperazinyl ⁇ pyrimidine 3-(Bromomethyl)-5-chloro- 1-benzothiophene and 2-(l -piperaziny l)pyrimidine were processed as described in Example 2 to provide the title compound.
  • MS (DCI NH3) m/z 345.0 (M+H) + ; Anal. Calcd for C ⁇ 7 H ⁇ 7 ClN 4 S: C, 53.04;H, 4.74; N, 14.55. Found: C, 52.79;H, 4.41; N, 14.55.
  • Example 7 1 -(1 -benzothien-3 -ylmethyl)-4-(2-pyridinyl)piperazine l-Benzothiophene-3-carbaldehyde (6.17 mmole), l-(2-pyridinyl)piperazine (6.17 mmole), and sodium triacetoxyborohydride (9.26 mmole) were combined in 25 mL of 1,2- dichloroethane and stirred at 0 °C for one hour. The mixture was allowed to warm to room temperature and stir for 12 hours. The mixture was poured into a diethyl ether:dichloromethane mixture and washed with a solution of saturated aqueous NaCl made basic with sodium hydroxide solution.
  • Example 8A 1 -benzothien-2-ylmethanol Benzothiophene (5.0g, 37.3 mmol) in anhydrous THF (100 ml) stirring at -20 °C was treated with n-butyllithium (34 ml, 1.6 M, 55.8mmol) and stirred for 1 hour. The mixture was cooled to -78 °C and treated with paraformaldehyde (7.8g, 261 mmol) in four portions. The mixture was allowed to slowly warm to room temperature with stirring overnight. The mixture was treated with 2N HCl (100 ml) and extracted with diethyl ether (2X 100 ml).
  • Example 8B 2-[4-(l-benzothien-2-ylmethyl)-l-piperazinyl1benzonitrile
  • the product from Example 8A 150 mg 0.9 mmol
  • methane sulfonic anhydride 159mg, 0.9 mmol
  • DIEA 475 ⁇ L 2.7 mmol
  • 2-(l- piperazinyl)benzonitrile 181 mg, 1.0 mmol
  • the mixture was concentrated and the residue was taken up in hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound.
  • Example 9 1 -( 1 -benzothien-2-ylmethyl)-4-(2-fluoropheny l)piperazine
  • the product from Example 8 A 150 mg 0.9 mmol
  • methane sulfonic anhydride 159mg, 0.9 mmol
  • DIEA 475 ⁇ L 2.7 mmol
  • l-(2- fluorophenyl)piperazine 181 mg, 1.0 mmol
  • Example 10 1 -(1 -benzothien-2-ylmethyl)-4-(2-pyridinyl)piperazine
  • the product from Example 8A 300 mg 1.8 mmol
  • methane sulfonic anhydride 313 mg, 1.8 mmol
  • DIEA 200 ⁇ L 5.4 mmol
  • l-(2- pyridinyl)piperazine 328 mg, 2.9 mmol
  • 4 ml DCM was also combined and the mixture was processed as described in Example 8B to provide the title compound.
  • Example 11 A tert-butyl 44(5 -fluoro- 1 H-indol-2-y Dcarbonyll - 1 ,4-diazepane- 1 -carboxylate tert-Butyl 1 ,4-diazepane- 1 -carboxylate (2.0g, 10 mmol, Aldrich), 5-fluoro-lH-indole- 2-carboxylic acid (1.79g, 10 mmol, Aldrich), and EDCI (1.92g, 10 mmol) were combined in CH C1 2 (30 mL) at room temperature and stirred for 24 hours.
  • Example 11B tert-butyl 4-r(5-fluoro- 1 H-indol-2-yl)methyll-l ,4-diazepane- 1 -carboxylate
  • the product from Example 1 IA (0.56g, 1.60mmol) in THF (20mL) was treated with LAH (4.70 mmol) and stirred at room temperature for 2 hours.
  • the mixture was treated with a saturated solution of Na 2 SO 4 , dried (MgSO ), filtered and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
  • Example 11C 2-( 1 ,4-diazepan- 1 -ylmethyl)-5-fluoro- 1 H-indole
  • the product from Example 1 IB (0.48 g, 1.40 mmol) in CH 2 C1 2 (20 mL) was treated with TFA (20 mL) and stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography
  • Example I IP 2- ⁇ 4- r(5-fluoro- 1 H-indol-2-yl)methyl1- 1 ,4-diazepan- 1 -yljbenzonitrile
  • the product from Example 1 IC (0.38 g, 1.5 mmol) and 2-bromobenzonitrile (0.28 g, 1.5 mmol, Aldrich) in toluene (15 mL) were treated with Pd 2 (DBA) 3 (0.028 g, 0.04mmol), BINAP (0.038 g, O.lOmmol), and CsCO 3 (0.99 g, 3.0 mmol) with stirring at 90 °C for 48 hours.
  • DBA Pd 2
  • BINAP 0.038 g, O.lOmmol
  • CsCO 3 (0.99 g, 3.0 mmol
  • the mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (5%MeOH/CH 2 Cl 2 ) to provide the title compound.
  • the maleate salt was formed and recrystallization from ethanol/diethyl ether.
  • Example 12 2- ⁇ 1 - r4-(2-methoxyphenyl)- 1 -piperazinyl] ethyl ⁇ - 1 H-indole l-(lH-indol-2-yl)ethanone and l-(2-methoxyphenyl)piperazine were processed as described in Example 7. The residue was purified by preparativeHPLC on a Waters Nova- PakHR C18 column (25mm X 100mm, 6um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8 minutes at a flow rate of 40mL/minutes to provide the title compound. MS (DCI/NH 3 ) m/z 336 (M+H) + .
  • Example 13 2- ⁇ r4-(2-methoxyphenyl)- 1 -piperazinyllmethyl ⁇ - 1 -methyl- 1 H-indole 1 -Methyl- lH-indole-2-carbaldehyde and l-(2-methoxyphenyl)piperazine were processed as described in Example 7 to provide the title compound.
  • Example 14 2- ⁇ 1 - [4-(2-pyridinyl)- 1 -piperazinyl] ethyl ⁇ - 1 H-indole l-(lH-indol-2-yl)ethanone and l-(2-pyridinyl)piperazine were processed as described in Example 7. The residue was purified by preparativeHPLC on a Waters Nova-PakHR CI 8 column (25mm X 100mm, 6um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8 minutes at a flow rate of 40mL/minutes to provide the title compound.
  • Example 15A tert-butyl (1 S,4S)-5-(2-pyridinyl -2,5-diazabicyclor2.2.
  • Hheptane-2-carboxylate tert-Butyl (lS,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate ( Og, 5.10 mmol, Aldrich) in 1,4-dioxane (10 mL) in a sealed tube was treated with 2-bromopyridine (0.40g, 2.50 mmol, Aldrich) and heated at 150 °C for 12 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure.
  • Example 15B (1 S,4S)-2-(2-pyridinyl)-2,5-diazabicyclor2.2.1 Iheptane
  • the product from Example 15A (0.52g, 1.90 mmol) in CH 2 C1 2 (20 mL) was treated with TFA (20 mL) and stirred for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography
  • Example 15C 5-fluoro-2- ⁇ r(lS,4S)-5-(2- ⁇ yridinyl)-2,5-diazabicyclor2.2.11hept-2-yllcarbonyl ⁇ -lH-indole
  • the product from Example 15B (0.40g, 1.5 mmol) in CH 2 C1 2 (30 mL) was treated with 5-fluoro-lH-indole-2-carboxylic acid (0.26 g, 1.5 mmol, Aldrich) and EDCI (0.26 g, 1.5 mmol) and stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (10%MeOH/CH 2 Cl 2 ) to provide the title compound.
  • Example 15D 5-fluoro-2- ⁇ r(lS,4 l S)-5-(2-pyridinyl)-2,5-diazabicvclor2.2.11hept-2-yllmethyl ⁇ -lH-indole
  • LAH 5.50 mmol
  • the mixture was treated with Na SO 4 decahydrate, filtered and the filtrate concentrated under reduced pressure.
  • the residue was purified by flash chromatography (10%MeOH/CH 2 Cl 2 ) to provide the title compound.
  • the maleate salt was formed and recrystallization from ethanol/diethyl ether.
  • Example 16B 1 -(2-pyridinyl)- 1 ,4-diazepane
  • CH C1 2 10 mL
  • TFA 10 mL
  • Example 16C 5-fluoro-2- ⁇ r4-(2-pyridinyl)- 1 ,4-diazepan- 1 -yllcarbonyl ⁇ - 1 H-indole
  • the product from Example 16B (0.68g, 3.8 mmol) in CH C1 2 (25 mL) was treated with 5-fluoro-lH-indole-2-carboxylic acid (0.68g, 3.8 mmol, Aldrich) and EDCI (0.73 g, 3.8 mmol) and stirred at room temperature for 48 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (10%MeOH/CH 2 Cl ) to provide the title compound.
  • Example 16D 5-fluoro-2- ⁇ r4-(2-pyridinyl)-l ,4-diazepan-l -yl]methyl ⁇ -l H-indole
  • the product from Example 16C in THF solution (10 mL) was treated with LAH (0.90 mmol of IM) and stirred at room temperature for 2 hours.
  • the mixture was treated with Na SO 4 decahydrate, filtered, and the filtrate concentrated under reduced pressure.
  • the residue was purified by flash chromatography (10%MeOH/CH 2 Cl ) to provide the title compound.
  • the maleate salt was formed and recrystallization from ethanol/diethyl ether as a white solid.
  • Example 17A 5 -fluoro-2- ⁇ r4-(2-pyridiny 1)- 1 -piperazinyl] carbonyl ⁇ - 1 H-indole 5-Fluoro-lH-indole-2-carboxylic acid (4.0 g) and EDCI (4.29 g) were combined in dichloromethane (90 mL) and treated with l-(2-pyridinyl)piperazine (3.64 g). After stirring at 25 °C for 24 hours, the mixture was washed with 150 mL of water and filtered.
  • Example 17B 5-fluoro-2- ⁇ T4-(2 -pyridinyl)- 1 -piperazinyl]methyl ⁇ - 1 H-indole
  • the product from Example 17A (3.50 g) in tetrahydrofuran (50 mL) was treated with lithium aluminum hydride (30 mmol).
  • the mixture was was treated by sequential addition of 1.14 mL of water, 1.14 mL of 15% aqueous sodium hydroxide, and 3.42 mL of water.
  • the slurry was filtered and the filtrate diluted with ethanol and then concentrated under reduced pressure.
  • Example 18 2- r4-( 1 H-pyrrolo [ " 2,3 -b]pyridin-2-ylmethyl)- 1 -piperazinyl]benzonitrile lH-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 2-(l -piperaziny l)benzomtrile (65 mg, 0.48 mmol), sodium acetate ( 72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were combined in water and glacial acetic acid (1 :2, 1 mL) and stirred at room temperature for 18 hours. The mixture was treated with a solution of 2M NaOH and concentrated under reduced pressure. The residue was treated with hot methanol.
  • Example 19 2- ⁇ [4-(2-pyrimidinyl)-l-piperazinyl]methyl ⁇ -lH-pyrrolo[2,3-b]pyridine 1 H-pyrrolo [2,3 -b]pyridine (47mg, 0.40 mmol), 2-(l -piperaziny l)pyrimidine (65 mg, 0.48 mmol), sodium acetate ( 72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound.
  • Example 20 2- ⁇ r4-(2-methoxyphenyl)- 1 -piperazinyl]methyl ⁇ - 1 H-pyrrolo [2,3 -b]pyridine lH-pyrrolo[2,3-b]pyridine (47mg, 0.40 mmol), l-(2-methoxyphenyl)piperazine (65 mg, 0.48 mmol), sodium acetate ( 72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound.
  • Example 21 2- ⁇ [4-(2-pyridinyl)- 1 -piperazinyl]methyl ⁇ - 1 H-pyrrolo [2,3 -b]pyridine
  • 1 H-pyrrolo [2,3 -b]pyridine 47mg, 0.40 mmol
  • l-(2-pyridinyl)piperazine 65 mg, 0.48 mmol
  • sodium acetate 72 mg, 0.53 mmol
  • formaldehyde (0.48 mmol
  • Example 22 2-[(4-phenyl-l-piperazinyl)methvn-lH-pyrrolo[2,3-b]pyridine lH-pyrrolo[2,3-b]pyridine (47mg, 0.40 mmol),l-phenylpiperazine (64.9 mg, 0.48 mmol), sodium acetate ( 72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound.
  • Example 23 2- ⁇ [4-(2-fluorophenyl)- 1 -piperazinyllmethyl ⁇ - 1 H-pyrrolo [2,3 -b]pyridine 1 H-pyrrolo [2,3 -b]pyridine (47mg, 0.40 mmol),l-(2-flurophenyl)piperazine (72.0 mg, 0.48 mmol), sodium acetate ( 72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound.
  • Example 24 2-[4-( 1 H-pyrrolo [2,3 -blpyridin-2-ylmethyl)- 1 -piperazinyllnicotinonitrile lH-pyrrolo[2,3-b]pyridine (47mg, 0.40 mmol), 2-(l -piperaziny l)nicotinonitrile (75 mg, 0.48 mmol), sodium acetate ( 72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound.
  • Example 25A ethyl 6-(trifluoromefhyl)thieno [3 ,2-b]pyridine-2-carboxylate 3-Chloro-5-(trifluoromethyl)-2-pyridinecarbaldehyde (Chemical Abstracts number 175277-50-6, purchase from Maybridge), potassium carbonate (4.95 g), and ethyl mercaptoacetate (2.52 g) were combined in N,N-dimethylformamide (25 mL) at 25 °C and stirred for 18 hours.
  • Example 25B [6-(trifluoromethyl)thieno [3 ,2-b]pyridin-2-yl]methanol
  • the product from Example 25A (2.80 g) in tetrahydrofuran (20 mL) and ethanol (20 mL) was treated with sodium borohydride (0.388 g) at 25 °C. After stirring for 24 hours, the mixture was treated with additional sodium borohydride (1 g) and additional ethanol. After an additional 24 hours, the mixture was poured into 0.2% NH 4 OH (200 mL) and extracted with dichloromethane. The organic phase was washed with water and concentrated under reduced pressure. The residue was purified by flash chromatography (97:3:0.1 dichloromethane methanol: sat.
  • Example 25C [6-(trifluoromethyl)thieno [3 ,2-b]pyridin-2-yl]methy 1 methanesulfonate
  • the product from Example 25B (732 mg) and methanesulfonic anhydride (547 mg) were combined and cooled to 0 °C.
  • the mixture was treated with dichloromethane (22 mL) and N,N-diisopropylethylamine (0.66 mL). After 30 minutes, the solution was used to in the next step.
  • Example 25D 4-(4- ⁇ [6-(trifluoromethyl)thieno[3 ,2-b]pyridin-2-ynmethyl ⁇ - 1 -piperazinyl)phenol
  • the solution from Example 25 C (2 mL) was treated with 4-(l -piperaziny l)phenol (178 mg) in DMSO (1 mL). After 72 hours, the mixture was concentrated under a stream of nitrogen gas and the residue recrystallized from DMSO:methanol (1:1) to provide the title compound.
  • Example 26 2- ⁇ [4-(2-methoxyphenyl)- 1 -piperazinyl]methyl ⁇ -6-(trifluoromethyl)thieno [3 ,2-b]pyridine
  • the solution from Example 25C (2 mL) and l-(2-methoxyphenyl)piperazine (192 mg) were processed as described in Example 25D to provide the title compound.
  • Example 27 2-(4- ⁇ [6-(trifluoromethyl)thieno [3 ,2-b]pyridin-2-yl]methy 11 - 1 -piperaziny l)benzonitrile
  • the solution from Example 25C (2 mL) and 2-(l -piperaziny l)benzonitrile (187 mg) were processed as described in Example 25D to provide the title compound.
  • Example 28 4- [4-(furo [3 ,2-b]pyridin-2-y lmethyl)- 1 -piperaziny l]phenol
  • the product from Example 35B, 4-(l -piperaziny l)phenol, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound.
  • Example 29 2-[(4-phenyl- 1 -piperazinyl)methyl]furo [3 ,2-b]pyridine
  • the product from Example 35B, 1-phenylpiperazine, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound.
  • Example 30 2- ⁇ [4-(2-methoxyphenyl)-l-piperazinyl1methyl ⁇ furo[3,2-b]pyridine
  • the product from Example 35B, l-(2-methoxyphenyl)piperazine, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound.
  • Example 31 2- [4-(furo [3 ,2-b]pyridin-2-ylmethyl)- 1 -piperaziny l]benzonitrile
  • the product from Example 35B, 2-(l -piperaziny l)benzonitrile, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound.
  • Example 32 2- ⁇ [4-(3 -methyl-2-pyridinyl)- 1 -piperazinyl]methyl> furo [3 ,2-b]pyridine
  • the product from Example 35B, l-(3-methyl-2-pyridinyl)piperazine, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound.
  • Example 33 2-[4-(furo[3,2-b]pyridin-2-ylmethyl)-l-piperazinyl]nicotinonitrile
  • the product from Example 35B, 2-(l -piperaziny l)nicotinonitrile, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound.
  • Example 34 2- ⁇ [4-(2-pyridinyl)- 1 -piperazinyl]methyl ⁇ furo [3 ,2-b]pyridine
  • the product from Example 35B, l-(2-pyridinyl)piperazine, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound.
  • Example 35a 2-(diethoxymethyl)furo [3 ,2-b]pyridine 2-Iodo-3-pyridinol (24 mmol), triethylamine (1.0 eq), 3,3-diethoxy-l-propyne (1.0 eq), bis(triphenylphosphine)palladium (II) chloride (0.02 eq), and copper(I) iodide (0.04 eq) were combined in DMF (14 mL) and allowed to stir for 17 hours. The mixture was diluted with ethyl acetate (100 mL) and filtered through a Celite pad.
  • Example 35B furo [3 ,2-b]pyridine-2-carbaldehyde
  • THF 50 mL
  • water 10 mL
  • trifluoroacetic acid 10 mL
  • the mixture was allowed to cool to room temperature, treated with water (200 mL), treated with sodium bicarbonate slowly to bring the pH to 8.0, and extracted with dichloromethane (100 mL).
  • the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure.
  • the residue was purified by flash chromatography on silica (5% methanol in dichloromethane) to provide the title compound.
  • Example 35C 2- ⁇ [4-(2-fluorophenyl)-l -piperazinyl]methyl ⁇ furo[3,2-b]pyridine l-(2-Fluorophenyl)piperazine (0.18 g, 1.0 mmol) and sodium triacetoxyborohydride (0.32 g, 1.5 mmol) in dichloroethane (2 mL) were treated with the product from Example 35B (2 mL, 1.0 mmol) as a 0.5M solution in dichloroethane dropwise. The mixture was allowed to stir at room temperature for 17 hours. The mixture was diluted with dichloromethane (10 mL) and washed with IN NaOH.
  • Example 36A 2-(chloromethyl)[l,31oxazolo[4,5-b]pyridine 2-Amino-3-pyridinol (1.1 g, Chemical Abstracts #16867-03-1) and chloromethyltrimethylorthoformate (2.27 g) were combined in diglyme (in 21 mL) and heated at 80 °C for 6 hours. The mixture was treated with p-toluenesulfonic acid hydrate (4 mg) and heated at 80 °C for an additional 48 hours. The mixture was allowed to cool to room temperature and diluted with chloroform (40 mL) and ethanol (10 mL). The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in methanol and filtered again.
  • Example 36B 2- ⁇ [4-(2-methoxyphenyl)-l-piperazinyl1methyl>[l,3]oxazolo[4,5-b]pyridine
  • the solution from Example 36A (7 mL) was treated with l-(2- methoxyphenyl)piperazine (160 mg) and stirred at 25 °C for 12 hours.
  • the mixture was poured into aqueous sodium chloride solution and extracted with dichloromethane :n-butanol (5:1).
  • the organic phase was concentrated under reduced pressure and the residue was purifed by flash chromatography on silica gel (98:2:0.1 dichloromethane:methanol:NH 4 OH) to provide the title compound.
  • Example 37 2-[4-([l,31oxazolo[4,5-b1pyridin-2-ylmethyl)-l-piperazinyl]benzonitrile
  • the solution from Example 36A (7 mL) and 2-(l -piperaziny l)benzonitrile (260 mg) were processed as described in Example 36B.
  • Example 38A 2-(chloromethyl)[l,31thiazolo[5,4-b1pyridine 3-Amino-2-pyridinethiol (5.0 g, 39.6 mmol) and 2-chloro-l,l,l-triethoxyethane (8.57g, 43.5 mmol) were combined in absolute ethanol (40 mL) and refluxed for 2 hours. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography (ethyl acetate:hexanes, 1 :4) to provide the title compound.
  • Example 38B 2- ⁇ [4-(2-pyridinyl)-l-piperidinyl1methyl)[l,31thiazolo[5,4-blpyridine
  • the product from Example 38A 50mg, 0.11 mmol
  • 2-(4-piperidinyl)pyridine 25mg, 0.13 mmol
  • DIEA 340 ⁇ L, 2.1 mmol
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was treated with hot methanol.
  • the methanol was filtered and the filter cake washed with cold methanol to provide the title compound.
  • Example 39 2- ⁇ [4-(l,3-thiazol-2-yl)-l-piperazinyl]methyl ⁇ [l,31thiazolo[5,4-b1pyridine
  • the product from Example 38A 200mg, 1.1 mmol
  • DIEA 340 ⁇ L, 2.1 mmol
  • Example 40 4- ⁇ 4- [(5 -methoxy [ 1 ,3 " lthiazolo [5 ,4-blpyridin-2-yl)methy 11- 1 -piperaziny 1) phenol
  • Example 40A 2-(chloromethyl)-5 -methoxy [ 1 ,3 Ithiazolo [5 ,4-blpyridine 3-Amino-6-methoxy-2-pyridinethiol (0.8 g, Maybridge Co.) and 2-chloro- 1,1,1 - triethoxyethane (1.26 g) were combined in ethanol (5 mL) and heated at 90 °C in a sealed tube for 2 hours. The mixture was allowd to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (2:1, dichloromethane :hexanes) to provide the title compound.
  • Example 40B 4- ⁇ 4- [(5 -methoxy [ 1 ,3]thiazolo [5 ,4-b1pyridin-2-yl)methyll- 1 -piperazinyljphenol
  • the product from Example 40 A (0.184 mmol) and 4-(l -piperaziny l)phenol (3 equivalents) were combined in acetonitrile (1 mL) and stirred at 25 °C for 24 hours. The mixture was evaporated to dryness and the residue was recrystallized from dimethylsulfoxide/methanol to provide the title compound.
  • Example 41 2- ⁇ [4-(2-fluorophenyl)-l-piperazinyllmethyl ⁇ -5-methoxy[l,31thiazolo[5,4-b1pyridine
  • the product from Example 40A (0.184 mmol) and l-(2-fluorophenyl)piperazine (3 equivalents) were processed as described in Example 40B to provide the title compound.
  • Example 40B The product from Example 40A (0.184 mmol) and l-[2- (methylthio)phenyl]piperazine (3 equivalents) were processed as described in Example 40B to provide the title compound.
  • Example 43 5-methoxy-2- ⁇ [4-(6-methyl-2-pyridinyl)-l-piperazinyllmethyl)[l,31thiazolo[5,4-b1pyridine
  • the product from Example 40A (0.184 mmol) and l-(6-methyl-2- pyridinyl)piperazine (3 equivalents) were processed as described in Example 40B to provide the title compound.
  • Example 44 5-methoxy-2- ⁇ [4-(2-pyridinyl)-l-piperazinyllmethyl ⁇ [l,31thiazolo[5 ,4-blpyridine
  • the product from Example 40A (0.184 mmol) and l-(2-pyridinyl)piperazine (3 equivalents) were processed as described in Example 40B to provide the title compound.
  • Example 45 5-methoxy-2- ⁇ [4-(2-pyrimidinyl)-l-piperazinyl1methyl ⁇ [l,31fhiazolo[5,4-b1pyridine
  • the product from Example 40A (0.184 mmol) and 2-(l -piperaziny l) ⁇ yrimidine (3 equivalents) were processed as described in Example 40B to provide the title compound.
  • Example 46 5-methoxy-2- ⁇ [4-(2-methoxyphenyl)-l -piperazinyllmethyl ⁇ [1 ,3 " lthiazolo[5 ,4-blpyridine
  • the product from Example 40A (0.184 mmol) and l-(2-methoxyphenyl)piperazine (3 equivalents) were processed as described in Example 40B to provide the title compound.
  • Example 47 2- ⁇ [4-(2-chlorophenyl)- 1 -piperazinyllmethyl ⁇ -5-methoxy [ 1 ,31thiazolo [5 ,4-blpyridine
  • the product from Example 40A (0.184 mmol) and l-(2-chlorophenyl)piperazine (3 equivalents) were processed as described in Example 40B to provide the title compound.
  • Example 48 2- ⁇ 4-[(5-methoxy[l,31thiazolo[5,4-b1pyridin-2-yl)methyl1-l-piperazinyl ⁇ benzonitrile
  • the product from Example 40 A (0.184 mmol) and 2-(l -piperaziny l)benzonitrile (3 equivalents) were processed as described in Example 40B to provide the title compound.
  • Example 49 5-methoxy-2-[(4-phenyl-l-piperazinyl)methyl1[l,31thiazolo[5,4-blpyridine
  • the product from Example 40 A (0.184 mmol) and 1-phenylpiperazine (3 equivalents) were processed as described in Example 40B to provide the title compound.
  • Example 50 2- ⁇ [4-(2-chloropheny 1)- 1 -piperaziny llmethyl ⁇ [ 1 ,3 Ithiazolo [5 ,4-blpyridine
  • the product from Example 38A 60mg, 0.3 mmol
  • l-(2-chlorophenyl)piperazine 70 mg, 0.31 mmol
  • DIEA 110 ⁇ L, 0.66 mmol
  • Example 51 2- ⁇ [4-(6-methyl-2-pyridinyl)- 1 -piperaziny llmethyl ⁇ [ 1 ,3 " ]thiazolo [5 ,4-blpyridine
  • the product from Example 38A 150mg, 0.81 mmol
  • l-(6-methyl-2- pyridinyl)piperazine 160mg, 0.98 mmol
  • DIEA 280 ⁇ L, 1.6 mmol
  • Example 52 2- ⁇ [4-(5 -chloro-2-methoxyphenyl)- 1 -piperazinyllmethyl) [ 1 ,31thiazolo [5 ,4-blpyridine
  • the product from Example 8A 150mg, 0.81 mmol
  • l-(5-chloro-2- methoxyphenyl)piperazine 160mg, 0.98 mmol
  • DIEA 280 ⁇ L, 1.6 mmol
  • Example 53 4-[4-([l,31thiazolo[5,4-blpyridin-2-ylmethyl)-l-pi ⁇ erazinyllphenol
  • the product from Example 38A (150mg, 0.81 mmol), 4-(l -piperaziny l)phenol (160mg, 0.98 mmol), and DIEA (280 ⁇ L, 1.6 mmol) were processed as described in Example 38B to provide the title compound.
  • Example 54 2-[4-([l,31thiazolo[5,4-blpyridm-2-ylmethyl)-l-piperazinyllnicotinonitrile
  • the product from Example 38A (150mg, 0.81 mmol), 2-(l-piperazinyl)nicotinonitrile (160mg, 0.98 mmol), and DIEA (280 ⁇ L, 1.6 mmol) were processed as described in Example 38B to provide the title compound.
  • Example 38A The product from Example 38A (150mg, 0.81 mmol), l-[2- (methylthio)phenyl]piperazine (160mg, 0.98 mmol), and DIEA (280 ⁇ L, 1.6 mmol) were processed as described in Example 38B to provide the title compound.
  • Example 56 2- ⁇ [4-(2-pyrimidinyl)- 1 -piperazinyllmethyl ⁇ [ 1 ,3 Ithiazolo [5 ,4-blpyridine
  • the product from Example 38A 150mg, 0.81 mmol
  • 2-(l-piperazinyl)pyrimidine 160mg, 0.98 mmol
  • DIEA 280 ⁇ L, 1.6 mmol
  • Example 57 2- ⁇ [4-(2-pyridinyl)-l-piperazinyllmethyl ⁇ [l,31thiazolo[5,4-blpyridine
  • the product from Example 38A 150mg, 0.81 mmol
  • l-(2-pyridinyl)piperazine 160mg, 0.98 mmol
  • DIEA 280 ⁇ L, 1.6 mmol
  • Example 58 2- ⁇ [4-(2 -fluorophenyl)- 1 -piperazinyllmethyl ⁇ [1 ,31thiazolo[5,4-blpyridine
  • the product from Example 38A 200mg, 1.1 mmol
  • l-(2-fluorophenyl)piperazine (215mg, 1.2 mmol)
  • DIEA 380 ⁇ L, 2.2mmol
  • Example 59 2-[4-([l,31thiazolo[5,4-blpyridin-2-ylmethyl)-l-piperazinyl1benzonitrile
  • the product from Example 38A (680mg, 3.7 mmol), 2-(l -piperaziny l)benzonitrile (823mg, 4.4 mmol), and DIEA (1.3 mL, 7.4mmol) were processed as described in Example 38B to provide the title compound.
  • Example 60 2- ⁇ [4-(2-methoxyphenyl)-l-piperazinyllmethyl ⁇ [l,31thiazolo[5 ,4-blpyridine
  • the product from Example 38A 200mg, 1.1 mmol
  • l-(2-methoxyphenyl)piperazine (229mg, 1.2 mmol)
  • DIEA 380 ⁇ L, 2.2mmol
  • the product from Example 38A (200mg, 1.1 mmol), 1-phenylpiperazine (193mg, 1.2 mmol), and DIEA (380 ⁇ L, 2.2mmol) were processed as described in Example 38B to provide the title compound.
  • Example 62A 2-(chloromethyl)-lH-thieno[3,4-dlimidazole 3,4-Thiophenediamine (0.5 g, Toronto Research Chemicals, Chemical Abstracts # 90069-81-1) and 2-chloro-l,l,l-triethoxyethane (0.9 g) were combined in dimethoxyethane (7 mL) in a sealed tube and heated at 95 °C for one hour. After allowing to cool to room temperature and stirring for 24 hours, the mixture was treated with hexane (10 mL) and filtered. The filter cake was dried under reduced pressure to provide the title compound. MS (DCI/NH3) m/z 173 (M+H) + .
  • Example 62B 2- ⁇ [4-(2 -fluorophenyl)- 1 -piperazinyllmethyl ⁇ - 1 H-thieno [3 ,4-dlimidazole
  • the product from Example 62A (0.23 mmole) and l-(2-fluorophenyl)piperazine (1 mmole) were combined in dimethylsulfoxide (1 mL) and stirred at 25 °C for 24 hours.
  • the mixture was partitioned between CH 2 C1 (4 L), butanol (0.1 mL), and diluted aqueous ammonia (15 mL). The organic phase was separated and concentrated under reduced pressure.
  • Example 63 2- ⁇ [4-(2-methoxyphenyl)- 1 -piperazinyllmethyl ⁇ - 1 H-thieno [3 ,4-dlimidazole
  • the product from Example 62A (0.23 mmol) and l-(2-methoxyphenyl)piperazine (1 mmole) were processed as described in Example 62B.
  • 1H NMR (CD 3 OD, 300 MHz) ⁇ 1.65 (m, 4H), 2.62 (2H, s), 2.90 (4H, m), 3.85 (3H, s), 6.9 (m, 5H), 7.05 (m, IH); MS (DCI/NH 3 ) m/z 329 (M+H) + .
  • Example 64 2- ⁇ [4-(2 -pyrimidinyl)- 1 -piperazinyllmethyl ⁇ - 1 H-thieno[3 ,4-dlimidazole
  • the product from Example 62A (0.23 mmol) and 2-(l -piperaziny l)pyrimidine (1 mmol) were processed as described in Example 62B.
  • Example 65 2- ⁇ [4-(2 -pyridinyl)- 1 -piperazinyllmethyl ⁇ - 1 H-thieno [3 ,4-dlimidazole
  • the product from Example 62A (0.23 mmol) and l-(2-pyridinyl)piperazine (1 mmol) were processed as described in Example 62B.
  • Example 66 2-[4-( 1 H-thieno [3 ,4-d]imidazol-2-ylmethyl)- 1 -piperazinyl]nicotinonitrile
  • the product from Example 62 A (0.23 mmol) and 2-(l -piperaziny l)nicotinonitrile (1 mmol) were processed as described in Example 62B.
  • Example 67 4- [4-( 1 H-thieno [3 ,4-dlimidazol-2-y lmethyl)- 1 -piperaziny llphenol
  • the product from Example 62A (0.23 mmol) and 4-(l -piperaziny l)phenol (1 mmol) were processed as described in Example 62B.
  • Example 68 2-( ⁇ 4- [2-(methylthio)phenyll- 1 -piperazinyl ⁇ methyl)- 1 H-thieno [3 ,4-dlimidazole
  • the product from Example 62A (0.23 mmol) and l-[2-(methylthio)phenyl]piperazine (1 mmol) were processed as described in Example 62B.
  • Synthesis of D4 agonists from Mcowart 051903
  • reaction mixture was stirred at -78°C for 30min and the cooling bath was removed to warm it up to room temperature ( ⁇ 1.5hr).
  • the reaction was quenched by saturated NaHCO 3 followed by extraction with ethyl ether and 5% citric acid.
  • the organic layer was then washed with INaOH (4x200mL), and water (2x200mL), and by saturated aqueous NaCl (lx200mL), dried over MgSO 4; and evaporated on rotary evaporator to give yellowish oil.
  • 3',6'-Dihydro-2'H-[2,4']bipyridinyl- -carboxylic acid tert-butyl ester (9.0g ) was hydrogenated using 10%Pd/C dry (900mg) at 60psi at room temperature for 1.5hr to give 8.9g (99%) of 3',4',5 , ,6'-tetrahydro-2 ⁇ -[2,4 , ]bipyridinyl- -carboxylic acid tert-butyl ester as a colorless oil.
  • 3-(Bromomethyl)-5-chloro-l-benzothiophene may be reacted with 1-(1- oxy-pyridin-2-yl)-piperazine to prepare l-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-4-(l-oxy- pyridin-2-yl)-piperazine.
  • lH-pyrrolo[2,3-b]pyridine may be reacted with formaldehyde and l',2',3',4',5',6'-hexahydro-[2,4'lbipyridinyl 1-oxide to prepare l'-(lH-Pyrrolo[2,3-b]pyridin-3- ylmethy ⁇ -r ⁇ ' ⁇ ' ⁇ ' ⁇ ' ⁇ '-hexahydro-p ⁇ 'lbipyridinyl 1-oxide.
  • furo[3,2-b]pyridine-2-carbaldehyde may be reacted with r,2',3',4',5',6'-hexahydro- [2,4']bipyridinyl 1-oxide to prepare r-Furo[3,2-b]pyridin-2-ylmethyl-r,2 , ,3 , ,4 , ,5',6*- hexahydro-[2,4']bipyridinyl 1 -oxide.
  • 2-(chloromethyl)[l,3]thiazolo[5,4-b]pyridine may be reacted with r,2',3',4',5',6'- hexahydro-[2,4']bipyridinyl 1-oxide to prepare -Thiazolo[5,4-b]pyridin-2-ylmethyl- l , ⁇ 3 ⁇ 4 ⁇ 5 6 , -hexahydro-[2,4 , ]Wpyridinyl 1-oxide.
  • 2-(chloromethyl)[l,3]thiazolo[5,4-b]pyridine may be reacted with l-(l-oxy- pyridin-2-yl)-piperazine to prepare 2-[4-(l-Oxy-pyridin-2-yl)-piperazin-l-ylmethyl]- thiazolo[5,4-b]pyridine.
  • Efficacies and potencies of compounds of the present invention at the human D 4 receptor were determined using a stable cell line containing the human D . 4 receptor and a chimeric G protein in HEK-293 cells.
  • This cell line allows a robust calcium signal detectable using a calcium fluorescent dye and a fluorescent imaging plate reader (FLIPR) (Coward et al., Anal. Biochem. 270: 242-248, 1999).
  • FLIPR fluorescent imaging plate reader
  • Cells were plated (20000/well) into 96 well dishes and cultured for 48 hours. Media is removed, Fluo-4 dye added and cells incubated 1 hour at room temperature. Cells are washed with phosphate buffered saline to remove excess dye and compounds to be tested added to the wells and signal measured in FLIPR.
  • Percent efficacy is the maximum response produced by the compound in relation to the maximum effect of 10 ⁇ M dopamine.
  • the EC 5 0 is the effective concentration of the compound that causes 50% of the compound's maximum
  • Representative compounds of the present invention exhibited EC 5 o s m the range of 7.5 nM to 3800 nM.
  • Wistar rats were used as a primary animal model to study penile erection in vivo. All experiments were carried out between 9:00 AM and 3:00 PM in a diffusely illuminated testing room with a red light. Animals were weighed and allowed to adapt to the testing room for 60 minutes before the beginning of experiments. Rats were placed individually in a transparent cage (20x30x30 cm) after drug injection. The number of penile erections were recorded by direct observation for a period of 60 minutes after drug dosing, and the number of animals exhibiting 1 or more erections was expressed as incidence (%). (L)- Ascorbic acid in saline (lmg/mL) was used as vehicle and apomorphine was used as a positive control at a dose of 0.1 ⁇ mol/kg.
  • Representative compounds of the present invention induced a minimum of 30% incidence of penile erections in rats after subcutaneous administration at doses of 0.01 ⁇ mol/kg to 1.0 ⁇ mol/kg.
  • compounds of the present invention can be used in combination with phosphodiesterase 5 inhibitors including, but not limited to, sildenafil or vardenafil as a method of treating sexual dysfunction in a mammal.
  • compounds of the present invention can be used in combination with an adrenergic receptor antagonist including, but not limited to, terazosin, prazosin or tamsulosin as method of treating sexual dysfunction in a mammal.
  • an adrenergic receptor antagonist including, but not limited to, terazosin, prazosin or tamsulosin as method of treating sexual dysfunction in a mammal.
  • compounds of the present invention can be used in combination with a dopamine agonist including, but not limited to, apomorphine as a method of treating sexual dysfunction in a mammal.
  • Compounds of the present invention are dopamine D 4 receptor agonists and therefore are useful for the treatment of male sexual dysfunction, female sexual dysfunction, attention deficit hyperactivity disorder, Alzheimer's disease, drug abuse, Parkinson's disease, anxiety, schizophrenia, mood disorders and depression, as described in:
  • the dopamine D 4 receptor a controversial therapeutic target, N.J. Hrib, Drugs of the future 25:587-611 (2000); Dopamine and sexual behavior, M. Melis and A. Argiolas, Neuroscience and Biobehavioral Reviews 19:19-38 (1995); and Dopamine receptors: from structure to function, C. Missale, S.R. Nash, S. Robinson, M. Jabber and M. Caron, Physiological Reviews 78: 189-225 (1998).
  • Dopamine D 4 receptor agonists are dopamine D 4 receptor agonists and therefore are useful for the treatment of cardiovascular disorders.
  • Dopamine and dopaminergic agents have been reported to exert pharmacologically significant cardiovascular effects on blood pressure and heart rate and are useful in the treatment of cardiovascular disorders, as described in: Chen FF, and Lin MT, Effects of dopamine, apomorphine gamma- hydroxybutyric acid, haloperidol, and pimozide on reflex bradycardia in rats, Journal of
  • Dopamine D receptor agonists are dopamine D receptor agonists and therefore are useful for the treatment of inflammation.
  • Dopaminergic agents can exert anti- inflammatory effects and are useful for the treatment of diseases where inflammation plays a deleterious role, as described in: Bendele AM, Spaethe SM, Benslay DN, and Bryant HU, Anti-inflammatory activity of pergolide, a dopamine receptor agonist, in Journal of Pharmacology of Pharmacology and Experimental Therapeutics (1991) 259 169-175.
  • Dopaminergic agents can also be of utility in the treatment of cancers, as described in: Lissoni P, Mandala M, Giani L, Malugani F, Secondino S, Zonato S, Rocco F, Gardani G, Efficacy of Bromocriptine in the Treatment of Metastatic Breast Cancer and Prostate Cancer- related Hyperprolactinemia, Neuroendocrinology Letters (2000) 21 405-408.
  • agonist means a compound of the present invention that exhibits 30% or greater efficacy in the in vitro assay described herein.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
  • Dosage forms for topical administration of a compound of the present invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated.
  • a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, amide, or prodrug form.
  • the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable carriers.
  • therapeutically effective amount means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of the present invention administered to a mammal, and particularly a human may range from about 0.001 to about 30 mg/kg/day.
  • more preferable doses can be in the range of from 0.01 to about 10 mg/kg/day.
  • the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • the present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of tlie intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of tlie intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tefrahydro-tofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifier
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non- irritating carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, and the like.
  • the preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
  • the present invention contemplates pharmaceutically active compounds either chemically synthesized or formed by in vivo biotransformation to compounds of formula (I).
  • the compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates.
  • solvated forms including hydrated forms, such as hemi-hydrates.
  • pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.
  • pharmaceutically acceptable salt, ester, amide, and prodrug refers to carboxylate salts, amino acid addition salts, zwitterions, esters, amides, and prodrugs of compounds of formula (I) which are within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • the compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, bis(tartrate), tartrate, (L) tartrate, bis((L) tartrate), (D) tartrate, bis((L)
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as maleic acid, fumaric acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, memylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • Preferred salts of the compounds of the present invention include phosphate, tris and acetate.
  • prodrug or “prodrug”as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Prodrugs of the present invention may be rapidly transformed in vivo to compounds of formula (I), for example, by hydrolysis in blood.
  • esters of compounds of the present invention refers to esters of compounds of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • examples of pharmaceutically acceptable, non-toxic esters of the present invention include C ⁇ -to-C 6 alkyl esters and C -to-C cycloalkyl esters, although C]-to-C 4 alkyl esters are preferred.
  • Esters of the compounds of formula (I) may be prepared according to conventional methods.
  • amide refers to non-toxic amides of the present invention derived from ammonia, primary C ⁇ -to-C 6 alkyl amines and secondary -to-Ce dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom.
  • -Amides derived from ammonia, C 1 -to-C 3 alkyl primary amides and C ⁇ -to-C 2 dialkyl secondary amides are preferred. Amides of the compounds of formula (I) may be prepared according to conventional methods.

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Abstract

La présente invention a trait à l'utilisation de composés de formule (I) pour le traitement de dysfonctionnement sexuel et à des compositions contenant des composés de formule (I) pour le traitement de dysfonctionnement sexuel.
PCT/US2003/016878 2002-05-29 2003-05-29 Composes aromatiques bicycliques condenses utiles dans le traitement de dysfonctionnement sexuel WO2003101994A1 (fr)

Applications Claiming Priority (4)

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US10/158,370 2002-05-29
US10/158,370 US20040002488A1 (en) 2002-05-29 2002-05-29 Fused bicyclic aromatic compounds that are useful in treating sexual dysfunction
US10/443,814 2003-05-23
US10/443,814 US7057042B2 (en) 2002-05-29 2003-05-23 Fused bicyclic aromatic compounds that are useful in treating sexual dysfunction

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7423054B2 (en) 2004-11-29 2008-09-09 Warner Lambert Company Llc Therapeutic pyrazolo[3,4-b]pyridines and indazoles
US7470691B2 (en) * 2002-05-29 2008-12-30 Abbott Laboratories Fused bicyclic aromatic compounds that are useful in treating sexual dysfunction
US9598401B2 (en) 2013-07-29 2017-03-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5182280A (en) * 1990-07-26 1993-01-26 Laboratorios Del Dr. Esteve, S. A. Derivatives of benzimidazole and their use as antihistamines
US5792768A (en) * 1993-03-30 1998-08-11 Merck, Sharp & Dohme Limited Antipsychotic benzimidazole derivatives
WO2001019802A1 (fr) * 1999-09-16 2001-03-22 Tanabe Seiyaku Co., Ltd. Composes cycliques aromatiques azotes a six elements

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5182280A (en) * 1990-07-26 1993-01-26 Laboratorios Del Dr. Esteve, S. A. Derivatives of benzimidazole and their use as antihistamines
US5792768A (en) * 1993-03-30 1998-08-11 Merck, Sharp & Dohme Limited Antipsychotic benzimidazole derivatives
WO2001019802A1 (fr) * 1999-09-16 2001-03-22 Tanabe Seiyaku Co., Ltd. Composes cycliques aromatiques azotes a six elements

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7470691B2 (en) * 2002-05-29 2008-12-30 Abbott Laboratories Fused bicyclic aromatic compounds that are useful in treating sexual dysfunction
US7423054B2 (en) 2004-11-29 2008-09-09 Warner Lambert Company Llc Therapeutic pyrazolo[3,4-b]pyridines and indazoles
US7485636B2 (en) 2004-11-29 2009-02-03 Pfizer Inc. Therapeutic pyrazolo[3,4-b]pyridines and indazoles
US9598401B2 (en) 2013-07-29 2017-03-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof

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