WO2000018723A1 - Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity - Google Patents

Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity Download PDF

Info

Publication number
WO2000018723A1
WO2000018723A1 PCT/US1999/022123 US9922123W WO0018723A1 WO 2000018723 A1 WO2000018723 A1 WO 2000018723A1 US 9922123 W US9922123 W US 9922123W WO 0018723 A1 WO0018723 A1 WO 0018723A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
methyl
fluoro
trifluoromethyl
amino
Prior art date
Application number
PCT/US1999/022123
Other languages
French (fr)
Inventor
James A. Sikorski
Richard C. Durley
Margaret L. Grapperhaus
Deborah A. Mischke
Emily J. Reinhard
Barry L. Parnas
Melvin L. Rueppel
Original Assignee
Monsanto Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Monsanto Company filed Critical Monsanto Company
Priority to EP99948431A priority Critical patent/EP1115694A1/en
Priority to CA002345108A priority patent/CA2345108A1/en
Priority to JP2000572185A priority patent/JP2002525350A/en
Priority to AU61610/99A priority patent/AU6161099A/en
Publication of WO2000018723A1 publication Critical patent/WO2000018723A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/12—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic the nitrogen atom of the amino group being further bound to hydrocarbon groups substituted by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/16—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring not being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/90—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. amino-diphenylethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • This invention is in the field of treating cardiovascular disease, and specifically relates to compounds, compositions and methods for treating atherosclerosis and other coronary artery disease. More particularly, the invention relates to substituted N-Aliphatic-N-Aromaticrem ⁇ rv-
  • Heteroalkylamine compounds that inhibit cholesteryl ester transfer protein also known as plasma lipid transfer protein-I.
  • CETP cholesteryl ester transfer protein
  • HDL high density lipoprotein
  • LDL low density lipoprotein
  • VLDL very low density lipoprotein
  • Atherosclerosis Since low- levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.
  • Atherosclerosis underlies most coronary artery disease (CAD), a major cause of morbidity and mortality in modern society.
  • High LDL cholesterol (above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis.
  • Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDIJLDL ratios.
  • Inhibition of CETP by the subject compounds is shown to effectively modify plasma HDL LDL ratios, and to check the progress and/or formation of these diseases.
  • CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall, J. Lipid Res., 34, 1255-74 ( 1993)). The movement of cholesteryl ester from
  • HDL to LDL by CETP has the effect of lowering HDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (McCarthy. Medicinal Res. Revs., 13, 139-59 ( 1993); Sitori, Pharmac. Ther., 67,443-47 ( 1995)).
  • This exact phenomenon was first demonstrated by Swenson et al., (/. Biol. Chem., 264, 14318 (1989) with the use of a monoclonal antibody that specifically inhibited CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al. (Biochim.
  • CETP inhibitors Barrett et al. (J. Am. Chem. Soc, 188, 7863-63 (1996)) and Kuo et al. (J. Am. Chem. Soc, 117, 10629-34 (1995)) describe cyclopropane-containing CETP inhibitors. Pietzonka et al. (Bioorg. Med. Chem. Lett, 6, 1951-54( 1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al. (Bioorg. Med. Chem. Lett., 5, 605-610 (1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds as CETP inhibitors. Japanese Patent Application No.
  • 10287662-A describes polycyclic, non-amine containing, polyhydroxylic natural compounds possessing CETP inhibition properties.
  • Lee et al. J. Antibiotics, 49, 693-96 (1996)
  • Busch et al. Lipids, 25. 216-220. (1990)
  • cholestervl acetyl bromide as a CETP inhibitor.
  • Morton and Zilversmk J. Lipid Res., 35, 836-47 (1982) describe that p-chloromercuriphenyl sulfonate.
  • p- hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP.
  • Some substituted heteroalkylamine compounds are known.
  • Schmidt et al. describe 2-aryl- substituted pyridines as cholesteryl ester transfer protein inhibitors useful as cardiovascular agents.
  • One substitutent at C3 of the pyridine ring can be an hydroxyalkyl group.
  • Dow and Wright describe heterocyclic derivatives substituted with an aldehyde addition product of an alkylamine to afford 1 -hydroxy- 1 -amines. These are reported to be ⁇ 3-adrenergic receptor agonists useful for treating diabetes and other disorders.
  • Fisher et al. Fisher et al.
  • U.S. Patent 2.700.686 further describes a process to prepare the N-(2- haloalkyl-2-hydroxyethyl)amines by reacting halogenated-lJ-epoxyalkanes with the corresponding aliphatic amines and N-alkylanilines and their use as dye intermediates.
  • the present invention provides a class of compounds that can be used to inhibit cholesteryl ester transfer protein (CETP) activity and that have the general structure:
  • the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier.
  • this invention relates to methods of using these inhibitors as therapeutic agents in humans to inhibit cholesteryl ester transfer protein (CETP) activity, thereby decreasing the concentrations of low density lipoprotein (LDL) and raising the level of high density lipoprotein (HDL), resulting in a therapeutically beneficial plasma lipid profile.
  • the compounds and methods of this invention can also be used to treat dyslipidemia (hypoalphalipoproteinemia), hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteine ia), peripheral vascular disease, hypercholesterolaemia, atherosclerosis, coronary artery disease and other
  • CETP-mediated disorders can also be used in prophylactic treatment of subjects who are at risk of developing such disorders.
  • the compounds can be used to lower the risk of atherosclerosis.
  • the compounds of this invention would be also useful in prevention of cerebral vascular accident (CVA) or stroke.
  • CVA cerebral vascular accident
  • these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals such as primates, rabbits, pigs, horses, and the like.
  • the present invention relates to a class of compounds comprising substituted N-Aliphatic-N-Aromatictertz ' ? ⁇ -Heteroalkylamines which are beneficial in the therapeutic and prophylactic treatment of coronary artery disease as given in Formula I-WA (also referred to herein as "alicyclic/cyclic aryl/heteroaryl heteroalkylamines”):
  • n is an integer selected from 1 through 4;
  • a and Q are independently selected from the group consisting of
  • v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R 33 , R ⁇ R 3 ⁇ , and R 3 g is aryl or heteroaryl;
  • u and w are integers independently selected from 0 through 6;
  • a j is C(R 30 );
  • D j , O . i . an K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one of Di , D2, J j , J2 and K j is a covalent bond, no more than one of
  • Dj , D2, Jj, 2 a nd Kj is O, no more than one of Dj, D2, J ⁇ , Jj anc ⁇ 1 ⁇ s S-
  • i ⁇ , ⁇ 2 anc ⁇ K-l are O and S, and no more than four of Dj, D2, J ⁇ , J2 nd Kj are N;
  • B j , B , D 3 . D4, J 3 , J and K - > are independently selected from the
  • B2 more than two of B
  • B t , B2, D 3 , D4, J 3 , J4 and K2 are S, no more than two of B j , B2, D 3 , D4,
  • J , J4 and 2 are simultaneously O and S, and no more than two of B j , B2,
  • D3, D 4 , J 3 , J 4 and K 2 are N;
  • R j g is selected from the group consisting of hydrido. alkyl, acyl, aroyl, heteroaroyl, and trialkylsilyl;
  • X is selected from the group consisting of O, H. F, S, S(O),
  • R 16 wherein X is H or F; R j is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
  • R is selected from the group consisting of hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl;
  • R 3 is selected from the group consisting of hydrido, hydroxy. cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl ;
  • Y is selected from a group consisting of a covalent single bond
  • R j 4 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxy alkyl, monocyanoalkyl, dicyanoalkyl. carboalkoxycyanoalkyl, carboalkoxy, carboxamide. carboxamidoalkyl: Z is selected from the group consisting of covalent single bond,
  • j and k are integers independently selected from 0 through 2:
  • R ⁇ 5 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl. monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl. carboalkoxy, carboxamide. and carboxamidoalkyl:
  • R3 Q is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R 0 is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
  • said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members:
  • R3 Q when bonded to A ⁇ , is taken together to form an intra-ring
  • intra-ring branched spacer is selected to form two rings selected from the group consisting of cycloalkyl having from 3 through 10 contiguous members, cycloalkenyl having from 5 through 10 contiguous members, and heterocyclyl having from 5 through 10 contiguous members:
  • R , R 3 5, and R 3 g are independendy selected from the group consisdng of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfmyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfmyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,
  • heteroarylthio heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonvl. heterocvclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl. cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl.
  • carboalkoxyalkyl carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl. cyano, carbohaloalkoxy, phosphono. phosphonoalkyl. diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that
  • R 3 g are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the R 33 and R 3 substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R35 and R ⁇ substituents are simultaneously selected from other than the group consistubg of hydrido and halo;
  • R3I ' and R32 are independently selected to
  • B , B2, D , D4, J3, J4 and K ? are independently selected from the group consisting of C and S. no more than two of R9, R JQ, RJ J, R 2, 13, 31, and R 2 are simultaneously oxo, and that
  • R32 and R ⁇ , and R ⁇ and Ri are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group __ consisting of spacer pairs R and R5, R ⁇ and Rg. Rg and R7. and R7 and Rg, are used at the same time and that no more than one of the group consisting of spacer pairs R and R Q, R ⁇ and R ⁇ , R J J and R j , R 3 ⁇ and R 2, R 3 2 and
  • Rj2> and Rj2 an ⁇ ⁇ R-13 are used at the same time;
  • R and Ri j Rg and R ⁇ - R9 and R j 3 , R9 and R 3 , R9 and R-32,
  • R ⁇ and R ⁇ - l0 an( R l3' R ⁇ o ancl R3 l -* o and R 2 .
  • u and R ⁇ , Ru and R ⁇ , R -Q and R 2, R 2 and R31, R 3 and R 3 ⁇ , and R13 and R 3 2 re independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 3 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 through 8 contiguous members with the provisos that no more than one of said group of spacer pairs is used at the same time:
  • R37 and R3g are independently selected from die group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy. and haloalkoxyalkyl .
  • compounds of Formula I-WA compounds are alcohols and have the Formula I-WO (also referred to herein as "alicyclic/cyclic aryl/heteroaryl aminoalkanols”):
  • R ⁇ is hydrido
  • R2 > R3 n.
  • A, Y, Q, and Z arc defined as given above for Formula
  • n is an integer selected from 1 through 2;
  • A is selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, and C3-C8 hydroxyhaloalkyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R 33 , R 3 , R 3 ⁇ , and R 3 g with the provisos that R ⁇ 3 , R 3 4, R 3 5, and R 3 g
  • R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
  • R j is selected from the group consisting of haloalkyl and haloalkoxy methy 1 ;
  • R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
  • R 3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
  • Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene
  • R4 and Rg are independently selected from the group consisting of hydrido and halo;
  • R5, R , and R ⁇ are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
  • R4 and R5, R5 and R ⁇ , Rg and R7, and R7 and Rg are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and
  • R5, R5 and R ⁇ , R and R7, and R7 and Rg, is used at the same time;
  • R 33 , R 3 , R 3 5- and R ⁇ ⁇ are independently selected from the group group consisting of alkyl, halo, hydroxy, cyano, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, aryl sulfonyl, aryloxy. aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy. cycloalkylalkanoyl. heteroaryl, cycloalkyl, haloalkylthio. hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
  • n is an integer selected from 1 through 2;
  • A is selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R , a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with Rg or RJ , a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R j 0 > a ring carbon or nitrogen atom adjacent to the R- ⁇ position and two
  • atoms from the point of attachment may be substituted with Ri2 > a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the - R o position may be substituted with R j , a ring carbon or nitrogen atom
  • R j is selected from the group consisting of haloalkyl and haloalkoxymethy 1 ;
  • R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
  • R 3 is selected from the group consisting of hydrido. aryl. alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
  • Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene
  • R4 and Rg are independently selected from the group consisting of hydrido and halo;
  • Rg and R j is halo
  • R5, R5 and R ⁇ , R ⁇ and R7, and R7 and Rg, is used at the same time;
  • R j Q, R 11 - R 12 ' R31 ' nd R32 are independently selected from the group group consisting of alkyl, halo, haloalkyl, haloalkoxy, and, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
  • R30 is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl. alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
  • n is an integer selected from 1 through 2:
  • A is selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, and C3-C8 hydroxyhaloalkyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of 33 ' RJ4- R 35 ' anc -- R 36 Wlt ⁇ t ' ⁇ e P rov '- sos th t R 33 , R34. 3 5 , and R 3 g must not be attached to the carbon directly linking A to Z and that R 33 , R 3 4,
  • R 3 5, and R g must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond; Di , D2, J j . J2 and K j are independently selected from the group consisting of C, N, 0. S and a covalent bond with the provisos that no more than one of D j , D2. J ⁇ , J2 and K is a covalent bond, no more than one of
  • J ⁇ , J2 and K are O and S, and no more than four of D j , D2, J ⁇ . J2 and K j are N;
  • R j is selected from the group consisting of haloalkyl and haloalkoxymethyl
  • R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl. haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl. and heteroaryl;
  • R 3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl. and haloalkoxyalkyl; Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene:
  • R4 and Rg are independently selected from the group consisting of hydrido and halo:
  • R ⁇ , R ⁇ , and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl. alkylthio. arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl. cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl. cycloalkyl, haloalkylthio. hydroxyhaloalkyl. heteroaralkoxy, heterocyclyloxy. aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
  • R4 and R5, R5 and R ⁇ , R ⁇ and R7, and R7 and Rg are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and
  • R5, R5 and R ⁇ , R ⁇ and R7, and R7 and Rg, is used at the same time;
  • R 33 , R 3 4, R 3 5, and R 3 g are independently selected from the group group consisting of alkyl, halo, hydroxy, cyano, haloalkyl. haloalkoxy, aryl, alkylthio, arylamino. arylthio, aroyl, arylsulfonyl. aryloxy. aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio. hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
  • n is an integer selected from 1 through 2;
  • A is selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or RJ3, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R j O' a ri n g carbon or nitrogen atom adjacent to the R13 position and two
  • atoms from the point of attachment may be substituted with R* ⁇ - a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R O position may be substituted with R ⁇ , a ring carbon or nitrogen atom
  • R 2 be substituted with R 2
  • a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R j j and R 3 2 positions may be
  • D j , D2, J - [ , J2 and K ⁇ are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D j , D 9 .
  • J j , J2 and K j i is a covalent bond, no more than one of
  • D j , D2, J j , J2 and K j is O, no more than one of D j , D2, 5 [ , J2 and K j is S,
  • J ⁇ , J2 and K j are O and S, and no more than four of D ⁇ , D2, J , J2 and K j are N;
  • is selected from the group consisting of haloalkyl and haloalkoxymethyl ;
  • R2 is selected from the group consisting of hydrido, aryl. alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
  • R is selected from the group consisting of hydrido, aryl. alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
  • Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene
  • R4 and Rg are independently selected from the group consisting of hydrido and halo;
  • R9 and R ] 3 is halo:
  • R5, R ⁇ , and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl. alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl.
  • R4 and R5, R5 and Rg, Rg and R7, and R7 and Rg are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and
  • R5, R5 and Rg, Rg and R7, and R7 and Rg, is used at the same time;
  • R Q, Ri R j 2 > 31, and R 2 are independently selected from the group group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio.
  • R 3 0 is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
  • n is the integer 1 ;
  • R j is selected from the group consisting of trifluoromethyl, 1,1,2,2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethy 1 , and pentafl uoroethyl ;
  • R2 is selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, 1,1,2,2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, pentafluoroethyl, trifluoromethyl, and 2,2.3,3,3-pentafIuoropropyl;
  • R 3 is selected from the group consisting of hydrido, phenyl, 4- trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
  • Y and Z are independently selected from the group consisting of a ⁇ covalent single bond, oxy. and methylene with the proviso that only one of Y and Z are simultaneously oxy;
  • R4 and Rg are independently selected from the group consisting of hydrido and fluoro;
  • R5 is selected from the group consisting of 4-aminophenoxy. benzoyl, benzyl, benzyloxy. 5-bromo-2-fluorophenoxy. 4-bromo-3-fiuorophenoxy.
  • Rg is selected from the group consisting of chloro. fluoro. hydrido. pentafiuoroethyl, lJJJ-tetrafluoroethoxy. trifluoromethyl, and trifluoromethoxy;
  • R7 is selected from the group consisting of hydrido. fluoro. and trifluoromethyl.
  • n is the integer 1 ;
  • R is selected from the group consisting of trifluoromethyl. 1J.2,2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafiuoroethyl;
  • R2 is selected from the group consisting of hydrido, methyl, ethyl, phenyl, 4-trifluoromethylphenyl. trifluoromethoxymethyl, 1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, pentafiuoroethyl, trifluoromethyl, and 2J3J,3-pentafluoro ⁇ ropyl;
  • R 3 is selected from the group consisting of hydrido, phenyl.
  • Y and Z are independently selected from a covalent single bond and methylene; R4 and Rg are independently selected from the group consisting of hydrido and fluoro; R5 is selected from the group consisting of benzyloxy, 5-bromo-2- fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy.
  • Rg is selected from the group consisting of chloro, fluoro, hydrido, pentafiuoroethyl, lJJJ-tetrafluoroethoxy, and trifluoromethyl;
  • R is selected from the group consisting of hydrido, fluoro, and trifluoromethvl.
  • n is the integer 1;
  • R j is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafiuoroethyl;
  • R2 is hydrido, pentafiuoroethyl, and trifluoromethyl
  • R 3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl
  • Y and Z are independently selected from the group consisting of a covalent single bond and methylene;
  • R4 and Rg are independently selected from the group consisting of hydrido and fluoro:
  • R5 is selected from the group consisting of 5-bromo-2-fluorophenoxy.
  • Rg is selected from the group consisting of fluoro and hydrido:
  • R7 is selected from the group consisting of hydrido and fluoro.
  • A is selected from the group consisting of ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, isobutyl, 2- methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3- pentynyl, 2-pentyl, l-methyl-2-butenyl, l-methyl-3-butenyl, l-methyl-2- butynyl, 3-pentyl, l-ethyl-2-propenyl, 2- methyl butyl, 2-methyl-2-butenyl, 2- methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexeny
  • each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of
  • R 3 , R 3 4, R35, and R3g with the provisos that R3 3 , R34, R35, and R3g
  • R35, and R g must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
  • R33, R34, R35, and R3 are independently selected from the group consisting of cyano. hydroxy, 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,
  • A is selected from the group consisting of ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl. sec-butyl, isobutyl. 2-methylpropenyl. 1 -pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentyl, l-methyl-2-butenyl. 1- methyl-3-butenyl, 3-pentyl, l-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2- butenyl, 2-methyl-3-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3- butenyl.
  • each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R 33 , R 3 4,
  • R 3 5, and R 3 g with the provisos that R 33 , R 3 _ R ⁇ ⁇ - and R g must not be
  • R 33 , R 3 4, R 3 5, and R 3 g must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
  • R33, R34. R35, and R 3 g are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3- fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3- chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cycl
  • thiophen-2-yl 2JJ-trifluoroethoxy, 2JJ-trifluoroethyl, 333-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxy benzyloxy, 4-trifluoromethoxy benzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy.
  • A is selected from the group consisting of 1-propenyl, propyl. isopropyl, butyl, 2-butenyl, 3-butenyl, sec-butyl, isobutyl, 2-methylpropenyl.
  • each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34,
  • R35, and R3g with the provisos that R 33 , R34, R35, and R 3 g must not be
  • R 33 , R34, R35, and R3g must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
  • R 3 5, and R g are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 23-dichlorophenoxy, 3,4-dichlorophenoxy, 3- difluoromethoxyphenoxy. 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy,
  • D , D2, J j . J2 , and K j are independently selected from the group consisting of C. N, O. S and a covalent bond to form the group consisting of 2-thienyl. 3-thienyl. 2-furyl. 3-furyl, 2-pyrrol l. rrolyl. 2-imidazolyl. 4- ⁇ imidazolyl, l.
  • atoms from the point of attachment may be substituted with R7, and a ring
  • R7 positions may be substituted with Rg.
  • D j , D2, J 1 , 2 and K j are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl.
  • attachment may be substituted with R-7. and a ring carbon atom three atoms ""
  • , J2 and K j are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4- imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may
  • R5 a ring carbon atom adjacent to the Rg position and two atoms from the
  • Rg may be substituted with Rg.
  • A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyctopent-2-enyl, cyclopent-3-enyl, cyclohexyl, 4- methylcyclohexyl, 4-chloro-3-ethylphenoxycyciohexyl, 3- trifluoromethoxyphenoxycyclohexyl.
  • cyclohex-3-enyi cycloheptyl, cyclohept-2-enyl, cyclohept-3 ⁇ enyl, cycl ⁇ octyl, e ⁇ clooct-2-en) l, cyclo ⁇ ct-3-enyl, cyclooct-4-enyl, 2- mo holinyl, 3-morpholinyl, 4-mo ⁇ holinyi, 1-piperazinyl. 2-piperazinyl, 1- piperidinyl, 2-piperidinyl. 3-pipe ⁇ dinyl. 4-piperidinyl, 1-pyrrolidinyl. 2- pyrrolidinyl. 3-pyrrolidinyl. 2-dioxanyl.
  • Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with Rg or R j3 , a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with
  • R 0 a ring carbon or nitrogen atom adjacent to the R j3 position and two
  • atoms from the point of attachment may be substituted with R j2
  • a " n ⁇ carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R j O position may be substituted with R j j
  • R9 and R j3 are fluoro; R j O and R j 2 are independently selected from the group consisting of
  • phenylamino 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1 ,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2J-trifluoroethoxy,
  • R 3 0 is selected from the group consisting of chloro, __ ethoxy, ethyl, fluoro, heptafluoropropyl, l JJ ,333-hexafluoropropyl, isobutyl, isobutoxy, isopropoxy, isopropyl, isopropylthio, methyl, propyl, pen tafl uoroethyl , 2,2,3.3 ,3 -pen tafl uoropropy 1 , 1 J ,3 ,3 ,3 -pentafl uoropropy I . lJJJ3-pentafluoropropyl.
  • A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3- ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3- trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis- trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbomyl, norbornenyl, 7-oxabicyclo[2JJ]heptan-2-yl, bicyclo[3.L01hexan-6-yl.
  • ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with RJQ, a ring carbon or nitrogen
  • R ⁇ 2 - a ring carbon or nitrogen atom three atoms from
  • R 32 a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R j j and R32 positions may be substituted with R3 ⁇ ;
  • Rn and R j3 are fluoro
  • RJQ and Ryi are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3 -chloro-4-ethylphenoxy , 3 -chloro-4-methy lphenoxy ,
  • 3-chloro-4-fluorophenoxy 4-chloro-3-fluorophenoxy.4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl. cyclopentylcarbonyl. cyclopropylmethoxy, 23-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,
  • 3,4-difluorophenoxyJ 3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy,3-dimethylaminophenoxy, 3, 4-dimethyl benzyloxy, 3 ,5-dimethylbenzyloxy , 3 ,5-dimethylphenoxy , 3 ,4-dimethylphenoxy ,
  • 2-oxazolyl 4-oxazolyl, 5-oxazolyl, pentafiuoroethyl, pentafluoroethylthio.
  • R j , and R 32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafiuoroethyl, 1,1,2,2- tetrafluoroethoxy, and trifluoromethyl;
  • R 3 0 is selected from the group consisting of chloro, ethyl, fluoro. heptafluoropropyl, lJJ,3,33-hexafluoropropyl, isobutyl, isopropyl, methyl, pentafiuoroethyl. 2J3,3,3-pentafluoropropyl, lJ333-pentafluoropropyl.
  • A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.4-methylcyclohexyl, 4-chloro-3- ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl.
  • R j2 may be substituted with R j2 , a ring carbon or nitrogen atom three atoms from
  • R-32 a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R j j and R 3 2 positions may be substituted with R j ;
  • Ro, and R j3 are fluoro
  • R j O and R ⁇ are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl,
  • l 1 ' 31' anc * 32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafiuoroethyl, 1,1 JJ-tetrafluoroethoxy, and trifluoromethyl.
  • Standard single letter elemental symbols are used to represent specific types of atoms unless otherwise defined.
  • the symbol “C represents a carbon atom.
  • the symbol “O” represents an oxygen atom.
  • the symbol “N” represents a nitrogen atom.
  • the symbol “P” represents a phosphorus atom.
  • the symbol “S” represents a sulfur atom.
  • the symbol ' ⁇ ” represents a hydrogen atom. Double letter elemental symbols are used as defined for the elements of the periodical table (i.e., CI represents chlorine, Se represents selenium, etc.).
  • alkyl means an acyclic alkyl radical containing from 1 to about 10, preferably from 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl. aminopentyl. iso-amyl, hexyl, octyl and the like.
  • alkenyl refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond.
  • alkenyl radicals contain from about 2 to about 10 carbon atoms, preferably from about 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms.
  • Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl. buten-1-yl.
  • alkynyl refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 3 to about 8 carbon atoms and more preferably having 3 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-l-yl, butyn-2-yl.
  • pentyn-1-yl pentyn-2-yl, 4- methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3- yl, 3 -dimethylbutyn-l-yl radicals and the like.
  • carbon radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.
  • 'cyano denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.
  • hydroxyalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.
  • alkanoyl embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include ⁇ oxalyl, malonyl, and succinyl.
  • alkylene radical denotes linear or branched radicals having from 1 about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene. ethylene. ethylidene, methy lethylene, and isopropylidene.
  • alkenylene radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have either a bromo, chloro or a fluoro atom within the radical.
  • Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
  • More preferred haloalkyl radicals are "lower haloalkyl" radicals having one to about six carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl. trifluoromethyl, chloromethyl, dichloromethyl, tri chloromethyl, trifluoroethyl, pentafiuoroethyl, heptafluoropropyl, difluorochloromethyl. dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • hydroxyhaloalkyl embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above.
  • examples of “hydroxyhaloalkyl” radicals include hexafl uorohy doxy propyl .
  • haloalkylene radical denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above.
  • Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo -* radicals.
  • More preferred haloalkylene radicals are "lower haloalkylene” radicals having one to about six carbon atoms.
  • Examples of “haloalkylene” radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene. alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
  • haloalkenyl denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above.
  • Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
  • alkoxy and alkoxyalkyl embrace linear or branched oxy- containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical.
  • alkoxyalkyl also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxy alkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls.
  • alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" and "haloalkoxyalkyl” radicals.
  • haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
  • haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl.
  • alkenyloxy and “alkenyloxyalkyl” embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical.
  • alkenyloxyalkyl also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are "lower alkenyloxy" radicals having two to six carbon atoms.
  • radicals examples include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls.
  • the "alkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkenyloxy” radicals.
  • haloalkenyloxy examples include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fluoropropenyloxy.
  • haloalkoxyalkyl also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals.
  • haloalkenyloxy also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals.
  • haloalkenyloxyalkyl also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.
  • alkylenedioxy denotes alkylene radicals having at least two oxygens bonded to a single alkylene group.
  • alkyl enedioxy examples include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy.
  • haloalkylenedioxy denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group.
  • haloalkylenedioxy radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused.
  • fused means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring.
  • fused is equivalent to the term “condensed”.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaph hyl, indane and biphenyl.
  • perhaloaryl embraces aromatic radicals such as phenyl. naphthyl. tetrahydronaphthyl. indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.
  • heterocyclyl embraces saturated and partially saturated heteroatom-containing ring-shaped radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom.
  • Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused.
  • saturated heterocyclic radicals include saturated 3 to 6- membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g.
  • partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran. dihydrofuran and dihydrothiazole.
  • heterocyclic radicals include 2- pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2H- ⁇ yranyl, 4H- pyranyl, piperidinyl, 1,4-dioxanyl, mo ⁇ holinyl, 1,4-dithianyl, thiomo ⁇ holinyl, and the like.
  • heteroaryl embraces fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom.
  • Heteroaryl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused.
  • heteroaryl radicals include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-lJ,4-triazolyl, lH-l,23-triazolyl, 2H-1,2,3- triazolyl, etc.] tetrazolyl [e.g.
  • unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indolyl. isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocvclic group containing a sulfur atom.
  • unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indolyl. isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, in
  • 2-thienyl, 3-thienyl. etc. unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazotyl, oxadiazolyl (e.g., 1.2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • benzoxazolyi, benzoxadiazolyl, etc. unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl. thiadiazolyl [e.g., 1 ,2,4- thiadiazolyl. 1 ,3.4- thiadiazolyl, 1.2.5-thiadiazolyl. etc.) etc.: unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like.
  • the term also embraces radicals where heterocyclic radicals are fused with aryl radicals.
  • fused bicyclic radicals examples include benzofuran. benzothiophene. and the like. Said "heterocyclyl" group may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals.
  • heteroaryl radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2- imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3.4-thiadiazolyl.
  • alkylsulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO;-- "Alkylsulfonyl”, embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above.
  • Alkylsulfonylalkyl embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • Haloalkylsulfonyl embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above.
  • Haloalkylsulfonylalkyl embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • the term “aminosulfonyl” denotes an amino radical attached to a sulfonyl radical.
  • alkylsulfinyl embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above.
  • Alkylsulfinylalkyl embraces alkylsulfmyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • Haloalkylsulfinyl embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above.
  • Haloalkylsulfinylalkyl embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • aralkyl embraces aryl-substituted alkyl radicals.
  • Preferable aralkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl.
  • benzyl and phenylmethyl are interchangeable.
  • heteroarylkyl embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals.
  • perhaloaralkyl embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.
  • aralkylsulfmyl embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above.
  • “Aralkylsulfinylalkyl embraces aralkylsulfmyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • aralkylsulfonyl embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above.
  • Aralkylsulfonylalkyl embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • cycloalkyl embraces radicals having from 3 through 15 carbon atoms. Cycloalkyl radicals may contain one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused. Examples of cycloalkyl radicals having two or more rings include adamantyl, norbornyl, and 7-oxabicyclo[2.2.1]heptanyl. More preferred cycloalkyl radicals are "lower cycloalkyl” radicals having from 3 through 8 carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • cycloalkyl also embraces radicals where cycloalkyl radicals are fused with aryl radicals or heterocyclyl radicals.
  • cycloalkylalkyl embraces cycloalkyl-substituted alkyl radicals.
  • Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to alkyl radicals having from one through six carbon atoms. Examples of such radicals include cyclohexylhexyl.
  • cycloalkenyl embraces radicals having three to fifteen carbon atoms and one or more carbon-carbon double bonds.
  • Cycloalkenyl radicals may contain one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused. Examples of cycloalkenyl radicals having two or more rings include norbomenyl. Preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cyclohepteny .
  • halocycloalkyl embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above.
  • a monohalocycloalkyl radical may have either a bromo, chloro or a fluoro atom within the radical.
  • Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
  • More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having three to about eight carbon atoms.
  • halocycloalkyl radicals examples include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl.
  • halocycloalkenyl embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.
  • cycloalkoxy embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy.
  • cycloalkoxyalkyl also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxyethyl.
  • cycloalkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkoxy” and "halocycloalkoxyalkyl” radicals.
  • cycloalkylalkoxy embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cy clopentylmethoxy .
  • cycloalkenyloxy embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy.
  • cycloalkenyloxy alkyl also embraces alkyl radicals having one or more cycloalkenyloxy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxyethyl.
  • cycloalkenyloxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkenyloxy” and "halocycloalkenyloxyalkyl” radicals.
  • cycloalkylenedioxy radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group.
  • alkylenedioxy radicals include 1.2-dioxycyclohexylene.
  • cycloalkylsulfinyl embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above.
  • Cycloalkylsulfinylalkyl embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • Cycloalkylsulfonyl embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above.
  • Cycloalkylsulfonylalkyl embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • cycloalkylalkanoyl embraces radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl, cyclohexylacetyl, and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1,2- dicarbonylcyclohexane..
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having one to six carbon atoms. An example of “lower alkylthio” is methylthio (CH 3 -S-).
  • the "alkylthio" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkylthio" radicals.
  • radicals include fluoromethylthio, chloromethylthio, trifiuoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.
  • alkyl aryl amino embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline, and N-methyl-4-trifluoromethoxyaniline.
  • alkylamino denotes “monoalkylamino” and “dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical.
  • arylamino denotes "monoarylamino" and “diarylamino " containing one or two aryl radicals, respectively, attached to an amino radical.
  • examples of such radicals include N-phenylamino and N-naphthylamino.
  • aralkylamino embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above.
  • aralkylamino denotes “monoaralkylamino” and “diaralkylamino” containing one or two aralkyl radicals, respectively, attached to an amino radical.
  • aralkylamino further denotes "'monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
  • arylsulfinylalkyl denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
  • arylsulfonyl embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above
  • arylsulfonylalkyl embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • heteroarylsulfinylalkyl denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
  • Heteroarylsulfonyl embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above.
  • Heteroarylsulfonylalkyl embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • aryloxy embraces aryl radicals, as defined above, attached to an oxygen atom.
  • radicals include phenoxy, 4-chloro-3- ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4- dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3- trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2- fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 4-tert -butylphenoxy.
  • aroyl embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.
  • aralkanoyl embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above.
  • examples of such radicals ⁇ include, for example, phenylacetyl.
  • aralkoxy embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy” radicals having phenyl radicals attached to lower alkoxy radical as described above. Examples of such radicals include benzyloxy, 1- phenylethoxy, 3-trifJuoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5- difluorobenyloxy, 3-bromobenzyloxy. 4-propylbenzyloxy, 2-fluoro-3- trifluoromethylbenzyloxy. and 2-phenylethoxy.
  • aryloxy alkyl embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.
  • haloaryloxyalkyl embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.
  • heteroaroyl embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
  • heteroaralkanoyl embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.
  • heteroaralkoxy embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy” radicals having heteroaryl radicals attached to lower alkoxy radical as described above.
  • haloheteroaryloxyalkyl embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.
  • heteroarylamino embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.
  • heteroarylaminoalkyl embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pvridylmethylamino.
  • heteroaryloxy embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2- thiophenyloxy, 2-pyrimidyloxy, 2- ⁇ yridyloxy, 3-pyridyloxy, and 4- pyridyloxy.
  • heteroaryloxyalkyl embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2-pyridyl oxymethyl, 3-pyridyloxyethyI, and 4-pyridyloxymethyl.
  • arylthio embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
  • arylthioalkyl embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenyl thi omethyl .
  • alkylthioalkyl embraces alkylthio radicals, as defined above. attached to an alkyl group. Examples of such radicals include methylthiomethyl.
  • alkoxyalkyl embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.
  • carbonyl denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom.
  • carboxy embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group.
  • carbboxamide embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group.
  • carbboxamidoalkyl embraces carboxamide radicals, as defined above, attached to an alkyl group.
  • carboxyalkyl embraces a carboxy radical, as defined above, attached to an alkyl group.
  • 'carboalkoxy embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group.
  • carboaralkoxy embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group.
  • monocarboalkoxy alkyl embraces one carboalkoxy radical, as defined above, attached to an alkyl group.
  • dicarboalkoxyalkyl embraces two carboalkoxy radicals, as defined above, attached to an alkylene group.
  • dicyanoalkyl embraces one cyano radical, as defined above, attached to an alkyl group.
  • dicyanoalkylene embraces two cyano radicals, as defined above, attached to an alkyl group.
  • 'carboalkoxycyanoalkyl embraces one cyano radical, as defined above, attached to an carboalkoxyalkyl group.
  • acyl alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, _ dialkylamino, aralkoxy, arylthio, and alkylthioalkyl.
  • a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, halo
  • acyl are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.
  • haloalkanoyl embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutanoyl.
  • diacyl alone or in combination, means having two or more carbonyl or thionocarbonyl groups bonded to a radical selected from, for example, alkylene, alkenylene, alkynylene, haloalkylene. alkoxyalkylene. aryl, heterocyclyl, heteroaryl, aralkyl, cycloalkyl, cycloalkylalkyl, and cycloalkenyl.
  • examples of "diacyl” are phthaloyl, malonyl, succinyl, adipoyl, and the like.
  • benzylidenyl radical denotes substituted and unsubstituted benzyl groups having attachment points for two covalent bonds.
  • One attachment point is through the methylene of the benzyl group with the other attachment point through an ortho carbon of the phenyl ring.
  • the methylene group is designated for attached to the lowest numbered position. Examples include the base compound benzylidene of structure:
  • phenoxylidenyl radical denotes substituted and unsubstituted phenoxy groups having attachment points for two covalent bonds. One attachment point is through the oxy of the phenoxy group with the other attachment point through an ortho carbon of the phenyl ring. The oxy group is designated for attached to the lowest numbered position. Examples include the base compound phenoxylidene of structure:
  • phosphono embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical.
  • dialkoxyphosphono denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds.
  • diaralkoxyphosphono denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds.
  • dialkoxyphosphonoalkyl denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical.
  • diaralkoxyphosphonoalkyl denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.
  • heteroarylsulf ⁇ nyl J
  • heteroarylamino may optionally have 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfmyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino.
  • cycloalkoxy cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxv, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino. thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl.
  • hydroxyhaloalkyl hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl.
  • spacer may include a covalent bond, a linear moiety having a backbone of 1 to 7 continous atoms, and a branched moiety having three branches connecting to a common atom with a total of from 1 through 8 atoms.
  • the spacer may have 1 to 7 atoms of a univalent or multi-valent chain.
  • R 17 is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkyl thioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl. heteroaryloxyalkyl. heteroarylthioalkyl, and heteroarylalkenyl.
  • Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms, a straight chain of 1 or 2 or 3 or 4 or 5 or 6 atoms with a side chain, or a branched chain made up of 1 or 2 or 3 or 4 atoms in each of the three branches.
  • the chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, -O-, -O-CH 2 -, -S-CH 2 -, -CH 2 CH 2 -. ethenyl,
  • -CH CH(OH)-, -OCH 2 O-, -0(CH 2 ) 2 O-, -NHCH 2 -, -OCH(R 17 )O-,
  • Side chains may include substituents such as 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfmyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl
  • Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S- enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention.
  • Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention.
  • cis and trans denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond ("cis”) or on opposite sides of the double bond ("trans").
  • Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
  • Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto” form and in part or principally as one or more "enol” forms of each aldehyde and ketone group present. Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both “keto” and “enol” tautomeric forms. Some of the compounds described herein may contain one or more - amide carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system.
  • Such carbonyl groups may exist in part or principally in the "keto” form and in part or principally as one or more "enol” forms of each amide group present.
  • Compounds of the present invention having amidic carbonyl groups are meant to include both “keto” and “enol” tautomeric forms.
  • Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the “imine” form and in part or principally as one or more "enamine” forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both “imine” and “enamine” tautomeric forms.
  • the present invention comprises a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formulas VII- H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, in association with at least one - pharmaceutically-acceptable carrier, adjuvant or diluent.
  • the present invention also comprises a treatment and prophylaxis of coronary artery disease and other CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically- effective amount of a compound of Formula I-WA:
  • R ⁇ , R 2 , R 3 , n, R14, R ⁇ , R j g, A, Q, X, Y, and Z are as defined above for the compounds of Formula I-WA; or a pharmaceutically-acceptable salt thereof.
  • Compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC are capable of inhibiting activity of cholesteryl ester transfer protein (CETP), and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by CETP, such as peripheral vascular disease, hyperlipidaemia, hypercholesterolemia, and other diseases attributable to either high LDL and low HDL or a combination of both, or a procedure to study the mechanism of action of the cholesteryl ester transfer protein (CETP) to enable the design of better inhibitors.
  • CETP cholesteryl ester transfer protein
  • the compounds of Formulas I-WA. I-WO, I-WOHA, I- WOPC, I-WOHA, and I-WOHC would be also useful in prevention of cerebraL vascular accident (CVA) or stroke.
  • pharmaceutically-acceptable salts are also included in the family of compounds of Formulas I-WA, I-WO, I- WOHA, I-WOPC, I-WOHA, and I-WOHC.
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I-WA may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid.
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I-WA include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compounds of Formulas I-WA, I- WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC by reacting, for example, the appropriate acid or base with the compounds of Formulas I-WA, I-WO, I- WOHA, I-WOPC, I-WOHA, and I-WOHC.
  • compositions comprising the active compounds of Formula I-WA in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients.
  • carrier non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants
  • the active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, _ subcutaneously, intramuscularly or topically.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
  • the amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely.
  • the pharmaceutical compositions may contain active ingredients in the range of about OJ to 2000 mg, and preferably in the range of about 0.5 to 500 mg.
  • a daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate.
  • the daily dose can be administered in one to four doses per day.
  • the compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0J to 20% w/w and most preferably 0.4 to 15% w/w.
  • the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil- in-water cream base.
  • the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane- 1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof.
  • the topical formulation may desirably include a compound which enhances abso ⁇ tion or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
  • the compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.
  • the encapsulating agent may also function as the membrane.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. For therapeutic pu ⁇ oses, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl _ alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • XIIIA-H "Secondary Heteroaryl Amines" which are intermediates in the preparation of the compounds of the present invention corresponding to Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols”) and Formula I-WA (“Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines”) wherein one substituent (A or Q) on the nitrogen is AQ-1 which can be independently selected from the group consisting of aryl and heteroaryl, which are preferably substituted with one or more groups, and another substituent (A or Q) on the nitrogen is AQ-2 which can be independently selected from the group consisting of AQ-2 and -CH 2 (CR 37 R 3 g) v -(CR 33 R 34 ) u -T-
  • H can be independently selected from the group consisting of C3-C8 alkyl, C3- C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, C3-C8 hydroxyhaloalkyl.
  • Schemes 1 through 14 taken together, prepare tertiary heteroalkylamine compounds of the present invention by addition of a halogenated, heteroatom (for example, oxygen, sulfur, or nitrogen) containing precursor to a resulting secondary amine to introduce a heteroatom containing alkyl group wherein one of the two groups making up the secondary amine is aromatic groups and the other is aliphatic (for example, C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, C3-C8 hydroxyhaloalkyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl), C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl.
  • a halogenated, heteroatom for example, oxygen, sulfur, or nitrogen
  • Heteroaryl Imines corresponding to Formulas XII-AH, CXII- AH, CKXII-AH can be prepared through dehydration techniques generally known in or adaptable from the art by reacting "Heteroaryl Amine" of Formula X-AH or a "Heteroaryl Carbonyl” of Formula XI-AH with a suitable an aliphatic, saturated heterocyclic, or partially saturated heterocyclic amine or carbonyl compound as shown in Schemes 1, 3, 4, 5, 6, 12, and subsequent specific examples.
  • the two reactants (AQ-2A and XI-AH) react by refluxing them in an aprotic solvent, such as hexane, toluene, cyclohexane, benzene, and the like, using a Dean-Stark type trap to remove water. After about 2-8 hours or until the removal of water is complete, the aprotic solvent is removed in vacuo to yield the "Heteroaryl Imine" of Formula XII-AH.
  • an aprotic solvent such as hexane, toluene, cyclohexane, benzene, and the like
  • the "Secondary Cyclic Heteroaryl Amines" of Formula XIIIA-H can be prepared from the corresponding "Generic Imine” of Formula XII, "Cyclic Heteroaryl Imine” of Formulas XII-AH.
  • CXII-AH, and CKXII-AH can be prepared in several ways.
  • the "Generic Imine” of Formula XII-AH is partially or completely dissolved in presence of a lower alcohol containing sufficient organic or mineral acid, as described in WO Patent Application No. 9738973, Swiss Patent CH 441366 and U. S. Patent Nos. 3359316 and 3334017, which are inco ⁇ orated herein by reference, and then hydrogenated at 0-100°C, more preferably 20-50°C, and most preferably between 20-30°C and pressures of
  • Bromide-1 Generic Bromide-2
  • Heteroaryl Bromide and the like halides, tosylates, mesylates, triflates, and precursor alcohols required to prepare the "Secondary Cyclic Heteroaryl Amine" compounds are available from commercial sources or can be prepared by one skilled in the art from published procedures. Commercial sources include but are not limited to Aldrich
  • Synthetic Schemes 2, 10 and 11 show the preparation of the class of compounds of the present invention corresponding to Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines").
  • Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines
  • Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines in which the heteroatom (O, N, or S) is attached to an alkyl group removed from the amine by two or more carbons are readily prepared by anion chemistry using the method of Scheme 2.
  • the anion of "Secondary Amine " amines and hydroxylamines of Formula XIII are readily formed by dissolving the specific amine, hydroxylamine, or hydrazine in an aprotic solvent, such as tetrahydrofuran, toluene, ether, dimethylformamide, and dimethylformamide, under anhydrous conditions. The solution is cooled to a temperature between -
  • 78 and 0°C preferably between -78 and -60°C and the anion formed by the addition of at least one equivalent of a strong, aprotic, non-nucleophillic base such as NaH or n-butyllithium under an inert atmosphere for each acidic group present. Maintaining the temperature between -78 and 0°C, preferably between
  • alkyl halide alkyl benzenesulfonate
  • alkyl mesylate alkyl mesylate
  • alkyl triflate alkylating reagent of the general structure:
  • X can be RN, O, and S
  • M is a readily displaceable group such as chloride, bromide, iodide, tosylate, triflate, and mesylate.
  • Aryl/Heteroaryl Aminoalcohols and Formula I-WA (“'Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines” compounds is Method A of Schemes 2, 10, 11, and 14. Oxirane reagents useful in Method A are exemplified, but not limited to those in Table 1.
  • Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl l-Amino-2-alcohol
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary 2-Heteroalkylamine
  • the oxiranes are prepared by reaction of epoxidation reagents such as MCPBA and similar type reagents readily selectable by a person of skill-in-the-art with alkenes.
  • epoxidation reagents such as MCPBA and similar type reagents readily selectable by a person of skill-in-the-art with alkenes.
  • Fieser and Fieser in Reagents for Organic Synthesis John Wiley & Sons' provides, along with cited references, numerous suitable epoxidation reagents and reaction conditions, which are inco ⁇ orated herein by reference.
  • Heteroalkylamine compounds, wherein the 2-hetero group is an amino, substituted amino, or thiol, can be prepared by using appropriate aziridines and thirranes according to Method A of Scheme 2.
  • Aziridine and thiirane reagents useful in Method A are exemplified, but not limited to those in Table 1.
  • a mixture of a "Secondary Amine" amine or hydroxylamine and an oxirane of Formula XX are stirred and heated to 40-90°C for 5 to 48 hours in a tightly capped or contained reaction vessel.
  • a Lewis acid such as ytterbium triflate in acetonitrile may be added to speed up reaction and improve yield.
  • the reaction should be carried out under inert, anhydrous conditions using a blanket of dry nitrogen or argon gas.
  • reaction product After cooling to room temperature and testing the reaction mixture for complete reaction by thin layer chromatography or high pressure liquid chromatography (hplc), the reaction product is added to water and extracted with a water immiscible solvent such as diethyl ether or methylene chloride. (Note: If the above analysis indicates that reaction is incomplete, heating should be resumed until complete with the optional addition of more of the oxirane).
  • This material is purified by eluting through silica gel with 5-40% of a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield the Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA (“Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines”) compounds. Products are tested for purity by HPLC.
  • a medium polar solvent such as ethyl acetate
  • a non-polar solvent such as hexanes
  • Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines
  • Formula VII Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines
  • intermediates in which the hydroxyl or oxy group of said intermediates are replaced with an amino, substituted amino, aza, or thiol, can be converted using the numerous specific Examples and Schemes disclosed in the present invention to other Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA (“Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines”) compounds.
  • Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines
  • Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines
  • Schemes 12 and 13 detail such procedures to prepare compounds of the present invention by initial formation of an halogenated, oxygen containing primary alkylamine XL ("Generic Substituted Alkylamine”).
  • Said halogenated, oxygen containing primary alkylamine XL, formed in Scheme 12 is itself converted to secondary amine LX-H ("Heteroaryl Alkyl Amine) using procedures disclosed above.
  • Primary alkylamine XL is first reacted with an aldehydic or ketonic carbonyl compound, XI-AH ("Heteroaryl Carbonyl") with azeotropic distillation to form imines, L-H ("Heteroaryl Imine”). Said imine L-H are then reduced with or without prior isolation by Reduction Methods 1, 2 or 3 as disclosed above and in Scheme 1 to yield secondary amines LX-H ("Heteroaryl Alkyl Amine). Said secondary amine LX-H can be converted according to Scheme 14 to Formula I- WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols"). Formula I-WO (“Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines
  • Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols
  • Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl 2- hydroxyalkylamines
  • Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines
  • R 5 or R 7 position substituent in Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines
  • R 5 or R 7 position substituent in Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines
  • R 10 position substituent in Formulas I-WA or I-WO is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups.
  • R 6 , R ⁇ l , and R j 2 substituents in Formulas I-WA or I-WO is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups.
  • Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols
  • Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Tertiary 2-hydroxyalkylamines
  • a 3-bromo substituent at the R 5 position in Formula I-WO (Alicyclic/Cyclic 3-Bromoaryl Tertiary 2-Hydroxyalkylamines") can be reacted with a phenol to afford 3-phenoxy compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Phenoxyaryl Tertiary 2- Hydroxyalkylamines").
  • a 3-bromo substituent at the R 5 position in Formula I-WO can, be reacted, for example, with a phenol to afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Aryloxyaryl, 3- Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylamines").
  • Formula I-WO (Alicyclic/Cyclic 3-BromomethylaryI Tertiary 2- hydroxyalkylamine) by reaction with an aryl borinate can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3- Arylmethylaryl Tertiary 2-Hydroxyalkylamine").
  • WO "Alicyclic/Cyclic 3 -Hydroxy heteroaryl Tertiary 2-hydroxyalkylamine" by reaction with an aryl bromide or heteroaryl bromide can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3- Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3- Aryloxyheteroaryl Tertiary 2-Hydroxyalkylamines").
  • WO "Alicyclic/Cyclic 3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylamine" by reaction with an aralkyl bromide or heteroaralkyl bromide can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Aralkyloxyaryl, 3-Heteroaralkyloxyaryl, 3- Heteroaralkyloxyheteroaryl, and 3-Aralkyloxyheteroaryl Tertiary 2- Hydroxyal kylami nes"). Conversion of a 3-hydroxyl substituent at the R 5 position in Formula I-
  • Alicyclic/Cyclic 3-thioaryl Tertiary 2-hydroxyalkylamine by reaction with a displaceable organo bromide can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Organothiaaryl Tertiary 2- Hydroxyalkylamine").
  • Alicyclic/Cyclic 3-Organothiaaryl Tertiary 2- Hydroxyalkylamines can be oxidized to sulfonyl compounds of 3-
  • Formula I-WO Alicyclic/Cyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylamines
  • Formula I-WO Alicyclic/Cyclic 3-Acylaminoaryl Tertiary 2-Hydroxyalkylamine
  • Formula I-WO (Alicyclic/Cyclic 3-CarbomethoxyaryI Tertiary 2- hydroxyalkylamine) by reaction with amination reagents can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3- Carboxamidoaryl Tertiary 2-Hydroxyalkylamine").
  • Hydroxyalkylamines can be reduced to hydroxyl compounds of Formula I- WO ("Alicyclic/Cyclic 3-Hydroxysubstitutedmethylaryl Tertiary 2- Hydroxyalkylamine").
  • Formula I-WO (Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine) by reaction with lithium aluminum hydride can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Hydroxymethylaryl Tertiary 2-Hydroxyalkylamine”). Conversion of a 3-methoxycarbonyl substituent at the R, 0 position in
  • Formula I-WO (Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine) by reaction with an alkylation reagent can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-(bis-Organo-hydroxymethyl)aryl Tertiary 2- Hydroxyalkylamine”). Conversion of a 3-methoxycarbonyl substituent at the R, 0 position in
  • Formula I-WO (Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine) by reaction intially with an amidation reagent and then an organometallic reagent can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-(Organo-carbonyl)aryl Tertiary 2-Hydroxyalkylamine").
  • Formula I-WO Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols
  • Formula I-WA Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines
  • hydroxyl group X wherein R j g is a hydrogen
  • compounds of the present invention can be readily converted to esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids.
  • acylation to form a carboxylic acid ester is readily effected using a suitable acylating reagent such as an aliphatic acid anhydride or acid chloride.
  • a suitable acylating reagent such as an aliphatic acid anhydride or acid chloride.
  • the corresponding aryl and heteroaryl acid anhydrides and acid chlorides can also be used.
  • Such reactions are generally carried out using an amine catalyst such as pyridine in an inert solvent.
  • compounds that have at least one hydroxyl group present in the form of an alcohol or phenol can be acylated to its corresponding esters.
  • carbamic acid esters (urethans) can be obtained by reacting any hydroxyl group with isocyanates and carbamoyl chlorides.
  • Sulfonate, phosphonate, and phosphate esters can be prepared using the corresponding acid chloride and similar reagents.
  • Compounds that have at least one thiol group present can be converted to the corresponding thioesters derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions.
  • Compounds of Formulas I-WA, I-WO. and other compounds of the present invention that have at least one primary or secondary amine group present can be converted to the corresponding amide derivatives.
  • Amides of carboxylic acids can be prepared using the appropriate acid chloride or anhydrides with reaction conditions analogous to those used with alcohols and phenols.
  • Ureas of the corresponding primary or secondary amine can be prepared using isocyanates directly and carbamoyl chlorides in the presence of an acid scavenger such as triethylamine or pyridine.
  • Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of aqueous sodium hydroxide. Suitable procedures and methods for preparing these derivatives can be found in House's Modem Synthetic Reactions, W. A. Benjamin, Inc.,shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1. John Wiley & Sons.
  • Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas I-WA, I-WO, and other compounds of the present invention are available from commerical sources or the references cited " above, which are inco ⁇ orated herein by reference.
  • Formula I-WA (Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") and other compounds of this invention posssessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety derivatives.
  • WO, and other compounds of the present invention can be readily converted to ethers.
  • Alkylation to form an ether is readily effected using a suitable alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate.
  • a suitable alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate.
  • alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate.
  • alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate.
  • the corresponding aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also
  • Such reactions are generally carried out using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n- butyl lithium using an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents, amine catalyst such as pyridine in an inert solvent.
  • an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n- butyl lithium
  • an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents
  • amine catalyst such as pyridine in an inert solvent.
  • compounds of Formulas I-WA, I-WO, and the like that have at least one hydroxyl group present in the form of an alcohol or phenol can be alkylated to their corresponding ethers.
  • Compounds of Formulas I-WA, I-WO, and other compounds that have at least one thiol group present can be converted to the corresponding thioether derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions.
  • Compounds of Formulas I-WA, I-WO, and other compounds that have at least one primary, secondary or tertiary amine group present can be converted to the corresponding quaternary ammonium derivatives.
  • Quaternary ammonium derivatives can be prepared using the appropriate bromides, iodides, and sulfonates analogous to those used with alcohols and phenols.
  • Conditions involve reaction of the amine by warming it with the alkylating reagent with a stoichiometric amount of the amine (i.e., one equivalent with a tertiary amine, two with a secondary, and three with a primary).
  • a stoichiometric amount of the amine i.e., one equivalent with a tertiary amine, two with a secondary, and three with a primary.
  • primary and secondary amines two and one equivalents, respectively, of an acid scavenger are used concurrently.
  • Tertiary amines can be prepared from the corresponding primary or secondary amine by reductive alkylation with aldehydes and ketones using reduction methods 1, 2, or 3 as shown in Scheme 1. Suitable procedures and methods for preparing these derivatives can be found in House's Modem Synthetic Reactions, W. A.
  • I-WA O, S, NH
  • I-WO I-WOFA
  • AQ-2CCA Alicyclic Carboxylic Acid
  • EX-IB The benzylamine product from EX-1A (1.08 g, 4 mmol) and 3JJ-trifluoro-l J-epoxypropane (0.67 g, 6 mmol) were dissolved in 1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.21 g, 0J3 mmol) was added, and the stirred solution was warmed to 50 °C for 2 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no amine starting material remained. The reaction was quenched with water and extracted with ether. The
  • the ice bath was removed, and the reaction was stirred at 23 °C for 18 h.
  • the resulting solution was diluted with ethyl acetate and washed with water and brine.
  • the organic layer was dried (MgSO4) and concentrated under a nitrogen stream.
  • the crude residue was dissolved in 2.0 mL of THF and treated with tetrabutylammonium fluoride (1 M in THF, 1.2 eq, 0.446 mmol, 0.446 mL).
  • the reaction mixture was stirred at 23 °C for 3 h.
  • the reaction was diluted with ethyl acetate and washed with water and brine.
  • the organic layer wad dried (MgSOzj) and concentrated under a nitrogen stream.
  • substituted 3- [(N-aryl)[[cycloalkyl]-methyl]amino]-halo-2-propanols and substituted 3-[(N- aryl)[[haloalkyl]methyl]amino]-halo-2-propanols are prepared by one skilled in the art using analogous methods, as shown in Example Tables 6 and 7.
  • CETP Cholesteryl Ester Transfer Protein
  • CETP and assay buffer 50 mM tris(hydroxymethyl)aminomethane, pH 7.4; 150 mM sodium chloride; 2 mM ethylenediamine -tetraacetic acid (EDTA); 1% bovine serum albumin
  • Inhibitors were included in the assay by diluting from a 10 mM DMSO stock solution into 16% (v/v) aqueous DMSO so that the final concentration of inhibitor was 800 ⁇ M.
  • the inhibitors were then diluted 1:1 with CETP in assay buffer, and then 25 ⁇ L of that solution was mixed with 175 ⁇ L of lipoprotein pool for assay.
  • LDL was differentially precipitated by the addition of 50 ⁇ L of 1% (w/v) dextran sulfate/0.5 M magnesium chloride, mixed by vortex, and incubated at room temperature for 10 minutes. A potion of the solution (200 ⁇ L) was transferred to a filter plate (Millipore). After filtration, the radioactivity present in the precipitated LDL was measured by liquid scintillation counting. Correction for non-specific transfer or precipitation was made by including samples that do not contain CETP. The rate of [ HJCE transfer using this assay was linear with respect to time and CETP concentration, up to 25-30% of [ H]CE transferred.
  • the potency of test compounds was determined by performing the above described assay in the presence of varying concentrations of the test compounds and determining the concentration required for 50% inhibition of transfer of
  • the IC50 values determined from this assay are accurate when the IC50 is greater than 10 nM. In the case where compounds have greater inhibitory potency, accurate measurements of IC50 may be determined using longer incubation times (up to 18 hours) and lower final concentrations of CETP ( ⁇ 50 nM). Examples of IC50 values determined by these methods are summarized in Table 3.

Abstract

The invention relates to substituted N-Aliphatic-N-Aromatic tertiary-Heteroalkylamine compounds useful as inhibitors of cholesteryl ester transfer protein (CETP; plasma lipid transfer protein-I) and compounds, compositions and methods for treating atherosclerosis, dyslipidemia, and other coronary artery disease.

Description

Substituted N-Aliphatic-N-Aromatictertzαry-Heteroalkylamines
Useful for Inhibiting Cholesteryl Ester Transfer Protein Activity
FIELD OF THE INVENTION
This invention is in the field of treating cardiovascular disease, and specifically relates to compounds, compositions and methods for treating atherosclerosis and other coronary artery disease. More particularly, the invention relates to substituted N-Aliphatic-N-Aromaticremαrv-
Heteroalkylamine compounds that inhibit cholesteryl ester transfer protein (CETP), also known as plasma lipid transfer protein-I.
BACKGROUND OF THE INVENTION
Numerous studies have demonstrated that a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye, Atherosclerosis, 121, 1-12 (19%)). HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Since low- levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.
Atherosclerosis underlies most coronary artery disease (CAD), a major cause of morbidity and mortality in modern society. High LDL cholesterol (above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis. Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDIJLDL ratios. Inhibition of CETP by the subject compounds is shown to effectively modify plasma HDL LDL ratios, and to check the progress and/or formation of these diseases.
CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall, J. Lipid Res., 34, 1255-74 ( 1993)). The movement of cholesteryl ester from
HDL to LDL by CETP has the effect of lowering HDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (McCarthy. Medicinal Res. Revs., 13, 139-59 ( 1993); Sitori, Pharmac. Ther., 67,443-47 ( 1995)). This exact phenomenon was first demonstrated by Swenson et al., (/. Biol. Chem., 264, 14318 (1989) with the use of a monoclonal antibody that specifically inhibited CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al. (Biochim. Biophys. Acta 795. 743-480 ( 1984)), Morton et al. (J. Lipid Res. 35, 836- 847 (1994)) and Tollefson et al. (Am. J. PhysioL, 255, (Endocrinol. Metab. 18, E894-E902 ( 1988))) describe proteins from human plasma that inhibit CETP. U.S. Patent 5,519,001, issued to Kushwaha et al., describes a 36 amino acid peptide derived from baboon apo C-l that inhibits CETP activity. Cho et al. (Biochim. Biophys. Acta 1391, 133-144 (1998)) describe a peptide from hog plasma that inhibits human CETP. Bonin et al. (/. Peptide Res., 51, 216-225 (1998)) disclose a decapeptide inhibitor of CETP. A depsipeptide fungal metabolite is disclosed as a CETP inhibitor by Hedge et al. in Bioorg. Med. Chem. Lett., 8, 1277-80 ( 1998). There have been several reports of non-peptidic compounds that act as
CETP inhibitors. Barrett et al. (J. Am. Chem. Soc, 188, 7863-63 (1996)) and Kuo et al. (J. Am. Chem. Soc, 117, 10629-34 (1995)) describe cyclopropane-containing CETP inhibitors. Pietzonka et al. (Bioorg. Med. Chem. Lett, 6, 1951-54( 1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al. (Bioorg. Med. Chem. Lett., 5, 605-610 (1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds as CETP inhibitors. Japanese Patent Application No. 10287662-A describes polycyclic, non-amine containing, polyhydroxylic natural compounds possessing CETP inhibition properties. Lee et al. (J. Antibiotics, 49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. (Lipids, 25. 216-220. (1990)) describe cholestervl acetyl bromide as a CETP inhibitor. Morton and Zilversmk (J. Lipid Res., 35, 836-47 (1982)) describe that p-chloromercuriphenyl sulfonate. p- hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP. Connolly et al. (Biochem. Biophys. Res. Comm. 223, 42-47 ( 1996)) describe other cysteine modification reagents as CETP inhibitors. Xia et al. describe 1,3,5-triazines as CETP inhibitors (Bioorg. Med. Chem. Lett.. 6, 919-22 ( 1996)). Bisgaier et al. (Lipids, 29, 81 1-8 ( 1994)) describe 4-phenyl-5- tridecyl-4H-lJ,4-triazole-thiol as a CETP inhibitor. Oomura et al. disclose non-peptidic tetracyclic and hexacyclic phenols as CETP inhibitors in Japanese Patent Application No. 10287662. In WO Patent Application No. 09914204, Sikorski describes lJ,4-triazolylthiols useful as chlolesteryl ester transf er protein inhibitors.
Some substituted heteroalkylamine compounds are known. In European Patent Application No. 796846, Schmidt et al. describe 2-aryl- substituted pyridines as cholesteryl ester transfer protein inhibitors useful as cardiovascular agents. One substitutent at C3 of the pyridine ring can be an hydroxyalkyl group. In European Patent Application No. 801060, Dow and Wright describe heterocyclic derivatives substituted with an aldehyde addition product of an alkylamine to afford 1 -hydroxy- 1 -amines. These are reported to be β3-adrenergic receptor agonists useful for treating diabetes and other disorders. In Great Britain Patent Application No. 2305665, Fisher et al. disclose 3-agonist secondary amino alcohol substituted pyridine derivatives useful for treating several disorders including cholesterol levels and artherosclerotic diseases. In European Patent Application No. 818448, Schmidt et al. describe tetrahydroquinoline derivatives as chlolesteryl ester transfer protein inhibitors. European Patent Application No. 818197, Schmek et al. describe pyridines with fused heterocycles as cholesteryl ester transfer protein inhibitors. Brandes et al. in German Patent Application No. 19627430 describe bicyclic condensed pyridine derivatives as cholesteryl ester transfer protein inhibitors. In WO Patent Apphcation No. 09839299, Muller-Gliemann et al. describe quinoline derivatives as cholesteryl ester transfer protein inhibitors. U.S. Patent 2,700,686, issued to Dickey and Towne, describes N- (2-haloalkyl-2-hydroxyethyl)amines in which the amine is further substituted with either 1 to 2 aliphatic groups or one aromatic group and one aliphatic group. U.S. Patent 2.700.686 further describes a process to prepare the N-(2- haloalkyl-2-hydroxyethyl)amines by reacting halogenated-lJ-epoxyalkanes with the corresponding aliphatic amines and N-alkylanilines and their use as dye intermediates.
SUMMARY OF THE INVENTION
The present invention provides a class of compounds that can be used to inhibit cholesteryl ester transfer protein (CETP) activity and that have the general structure:
Figure imgf000006_0001
In another aspec , the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier.
In another aspect, this invention relates to methods of using these inhibitors as therapeutic agents in humans to inhibit cholesteryl ester transfer protein (CETP) activity, thereby decreasing the concentrations of low density lipoprotein (LDL) and raising the level of high density lipoprotein (HDL), resulting in a therapeutically beneficial plasma lipid profile. The compounds and methods of this invention can also be used to treat dyslipidemia (hypoalphalipoproteinemia), hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteine ia), peripheral vascular disease, hypercholesterolaemia, atherosclerosis, coronary artery disease and other
CETP-mediated disorders. The compounds can also be used in prophylactic treatment of subjects who are at risk of developing such disorders. The compounds can be used to lower the risk of atherosclerosis. The compounds of this invention would be also useful in prevention of cerebral vascular accident (CVA) or stroke. Besides beina useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals such as primates, rabbits, pigs, horses, and the like.
DESCRIPTION OF THE INVENTION
The present invention relates to a class of compounds comprising substituted N-Aliphatic-N-Aromatictertz' ?Υ-Heteroalkylamines which are beneficial in the therapeutic and prophylactic treatment of coronary artery disease as given in Formula I-WA (also referred to herein as "alicyclic/cyclic aryl/heteroaryl heteroalkylamines"):
Figure imgf000007_0001
or a pharmaceutically-acceptable salt thereof, wherein; n is an integer selected from 1 through 4; A and Q are independently selected from the group consisting of
-CH2(CR37R38)V-(CR33R34)U-T-(CR35R36)W-H,
Figure imgf000007_0002
with th provisos that one of A and Q must be AQ-1 and that one of A and Q must be selected from the group consisting of AQ-2 and
-CH2(CR37R38)V-(CR33R34)U-T-(CR35R36)W-H; T is selected from the group consisting of a single covalent bond, O. S. S(O), S(O)2, C(R33)=C(R35), and C≡C; v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R33, R ψ R3^, and R3g is aryl or heteroaryl; u and w are integers independently selected from 0 through 6;
Aj is C(R30);
Dj, O . i . an K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one of Di , D2, Jj, J2 and Kj is a covalent bond, no more than one of
Dj , D2, Jj, 2 and Kj is O, no more than one of Dj, D2, J\, Jj anc ^1 ιs S-
one of D , D2, J * , J2 a d Kj must be a covalent bond when two of Dj, D2,
i{, ^2 anc^ K-l are O and S, and no more than four of Dj, D2, J}, J2 nd Kj are N;
B j, B , D3. D4, J3, J and K -> are independently selected from the
group consisting of C. C(R3Q). N, O, S and a covalent bond with the provisos
that no more than 5 of B 1 , B2, D3, D4, J3, J4 and K2 are a covalent bond, no
more than two of B|, B2, D3, D4, J3, J4 and K2 are O, no more than two of
B t , B2, D3, D4, J3, J4 and K2 are S, no more than two of B j, B2, D3, D4,
J , J4 and 2 are simultaneously O and S, and no more than two of B j , B2,
D3, D4, J3, J4 and K2 are N;
B ^ and D3, D3 and J3, J3 and K2, K2 and J4, J4 and D4, and D4
and B2 are independently selected to form an in-ring spacer pair wherein said
spacer pair is selected from the group consisting of C(R33)=C(R35) and N=N with the provisos that AQ-2 must be a ring of at least five contiguous members. that no more than two of the group of said spacer pairs are simultaneously C(R33)=C(R35), and that no more than one of the group of said spacer pairs
can N=N unless the other spacer pairs is other than C(R )=C(R 5), O, N, and S; Rjg is selected from the group consisting of hydrido. alkyl, acyl, aroyl, heteroaroyl, and trialkylsilyl;
X is selected from the group consisting of O, H. F, S, S(O),
NH, N(OH), N(alkyl), and N(alkoxy) with the proviso that there is no R16 wherein X is H or F; Rj is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
R is selected from the group consisting of hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl;
R3 is selected from the group consisting of hydrido, hydroxy. cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl ;
Y is selected from a group consisting of a covalent single bond,
(C(R 14)2)0 wherein q is an integer selected from 1 through 4 and
(CH(R*L4))σ-O-(CH(Ri ))D wherein g and p are integers independently selected from 0 through 2;
Rj4 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxy alkyl, monocyanoalkyl, dicyanoalkyl. carboalkoxycyanoalkyl, carboalkoxy, carboxamide. carboxamidoalkyl: Z is selected from the group consisting of covalent single bond,
(C(R 15)2)0 wherein q is an integer selected from 1 through 2, and
Figure imgf000010_0001
wherein j and k are integers independently selected from 0 through 2:
R^5 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl. monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl. carboalkoxy, carboxamide. and carboxamidoalkyl:
R3Q is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R 0 is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R Q, when bonded to AjJs taken together to form an intra-ring linear
spacer connecting the A carbon at the point of attachment of R30 to the point
of bonding of a group selected from the group consisting of R JQ, R J J , R γ^-
R3 j , and R32 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members:
R3Q, when bonded to A^, is taken together to form an intra-ring
branched spacer connecting the A γ -carbon at the point of attachment of R3 to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R JQ and R J , R JQ and R3 j,
RjQ and R32, R jQ nd R^, Ru and R j , Ri j and R32, R J J and Rj2- 3 j
and R 2- 3 and R^. and R-39 and Rj2 and wherein said intra-ring branched spacer is selected to form two rings selected from the group consisting of cycloalkyl having from 3 through 10 contiguous members, cycloalkenyl having from 5 through 10 contiguous members, and heterocyclyl having from 5 through 10 contiguous members:
R 5 , 6< 7. Rg. R9< R10< R M R12' R13* R31 - R32 • R33-
R , R35, and R3g are independendy selected from the group consisdng of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfmyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfmyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N- heteroarylamino-N-alkylamino, heteroarylaminoalkyl.haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy. cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfmyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl. heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonvl. heterocvclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl. cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl. halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido. alkylamidocarbonylamido, arylamidocarbonylamido. carboalkoxyalkyl. carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl. cyano, carbohaloalkoxy, phosphono. phosphonoalkyl. diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that
Rψ R5, R6, R7, R8, R9, R10, Rn, R12, R13, R3 1, R32 , R33, R34, R35,
and R3g are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the R33 and R3 substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R35 and R^ substituents are simultaneously selected from other than the group consistubg of hydrido and halo;
R9, Rio Ru, 2. 13. R3I' and R32 are independently selected to
be oxo with the provisos that B , B2, D , D4, J3, J4 and K ? are independently selected from the group consisting of C and S. no more than two of R9, R JQ, RJ J, R 2, 13, 31, and R 2 are simultaneously oxo, and that
9' 10' 11 ' R 12' R 13 ' 31 > anc R32 are eac^ independendy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R4 and R5, R5 and R^, Rg and R-y, R7 and Rg, R9 and R^Q, R JQ and
R* j j. Ru and R3 * , R and R3 . R32 and R^, and R^ and Ri are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group __ consisting of spacer pairs R and R5, R^ and Rg. Rg and R7. and R7 and Rg, are used at the same time and that no more than one of the group consisting of spacer pairs R and R Q, R^ and R^, R J J and R j, R3 ι and R 2, R32 and
Rj2> and Rj2 an<^ R-13 are used at the same time;
R and Ri j. Rg and R^- R9 and Rj 3, R9 and R3 , R9 and R-32,
R^ø and R^- l0 an( Rl3' Rιo ancl R3l-* o and R 2. u and R^, Ru and R^ , R -Q and R 2, R 2 and R31, R 3 and R3 ^, and R13 and R32 re independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 3 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 through 8 contiguous members with the provisos that no more than one of said group of spacer pairs is used at the same time:
R37 and R3g are independently selected from die group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy. and haloalkoxyalkyl . In another embodiment of compounds of Formula I-WA, compounds are alcohols and have the Formula I-WO (also referred to herein as "alicyclic/cyclic aryl/heteroaryl aminoalkanols"):
Figure imgf000014_0001
or a pharmaceutically acceptable salt thereof, wherein;
R^ is hydrido;
Figure imgf000014_0002
R2> R3 n. A, Y, Q, and Z arc defined as given above for Formula
I-WA.
In a more specific embodiment of compounds of Formula I-WO, compounds have the Formula I-WOPA:
Figure imgf000014_0003
or a pharmaceutically acceptable salt thereof, wherein; n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, and C3-C8 hydroxyhaloalkyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R3 , R3^, and R3g with the provisos that R^3, R34, R35, and R3g
must not be attached to the carbon directly linking A to Z and that R33, R34,
R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond; Rj is selected from the group consisting of haloalkyl and haloalkoxy methy 1 ;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl; R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and Rg are independently selected from the group consisting of hydrido and halo;
R5, R , and Rγ are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R5, R5 and Rβ, Rg and R7, and R7 and Rg are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and
R5, R5 and Rβ, R and R7, and R7 and Rg, is used at the same time;
R33, R3 , R35- and R^β are independently selected from the group group consisting of alkyl, halo, hydroxy, cyano, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, aryl sulfonyl, aryloxy. aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy. cycloalkylalkanoyl. heteroaryl, cycloalkyl, haloalkylthio. hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
In another more specific embodiment of compounds of Formula I-WO. compounds have the Formula I-WOPC:
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, wherein; n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R , a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with Rg or RJ , a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with Rj0> a ring carbon or nitrogen atom adjacent to the R-β position and two
atoms from the point of attachment may be substituted with Ri2> a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the - R o position may be substituted with Rj , a ring carbon or nitrogen atom
three atoms from the point of attachment and adjacent to the Rj2 position may
be substituted with R32- and a ring carbon or nitrogen atom four atoms from
the point of attachment and adjacent to the R^ and R32 positions may be
substituted with R3 j;
Rj is selected from the group consisting of haloalkyl and haloalkoxymethy 1 ;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl; R3 is selected from the group consisting of hydrido. aryl. alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and Rg are independently selected from the group consisting of hydrido and halo;
Rg and Rj is halo;
R5, Rβ. and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl. haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl; R4 and R , R5 and Rβ, Rβ and R7, and R7 and Rg are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a ~ partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R and
R5, R5 and Rβ, Rβ and R7, and R7 and Rg, is used at the same time;
R j Q, R 11 - R 12' R31 ' nd R32 are independently selected from the group group consisting of alkyl, halo, haloalkyl, haloalkoxy, and, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R30 is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl. alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
In another more specific embodiment of compounds of Formula I-WO, compounds have the Formula I-WOHA:
Figure imgf000018_0001
or a pharmaceutically acceptable salt thereof, wherein; n is an integer selected from 1 through 2: A is selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, and C3-C8 hydroxyhaloalkyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of 33' RJ4- R35' anc-- R36 Wlt^ t'ιe Prov'-sos th t R33 , R34. 35, and R3g must not be attached to the carbon directly linking A to Z and that R33, R34,
R35, and R g must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond; Di , D2, J j . J2 and K j are independently selected from the group consisting of C, N, 0. S and a covalent bond with the provisos that no more than one of Dj, D2. J^, J2 and K is a covalent bond, no more than one of
Dj, D2. J* [, 2 and Kj is O. no more than one of Dj, D2. Jj. J2 aQd Kj is S,
one of D 1 , D2, J 1. J2 and K must be a covalent bond when two of D , D2,
J}, J2 and K are O and S, and no more than four of Dj, D2, J^. J2 and Kj are N;
Rj is selected from the group consisting of haloalkyl and haloalkoxymethyl ; R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl. haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl. and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl. and haloalkoxyalkyl; Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene:
R4 and Rg are independently selected from the group consisting of hydrido and halo: R^, Rβ, and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl. alkylthio. arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl. cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl. cycloalkyl, haloalkylthio. hydroxyhaloalkyl. heteroaralkoxy, heterocyclyloxy. aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R5, R5 and Rβ, Rβ and R7, and R7 and Rg are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and
R5, R5 and Rβ, Rβ and R7, and R7 and Rg, is used at the same time;
R33, R34, R35, and R3g are independently selected from the group group consisting of alkyl, halo, hydroxy, cyano, haloalkyl. haloalkoxy, aryl, alkylthio, arylamino. arylthio, aroyl, arylsulfonyl. aryloxy. aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio. hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
In still another more specific embodiment of compounds of Formula I- WO, compounds have the Formula I-WOHC:
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof, wherein; n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or RJ3, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with RjO' a ring carbon or nitrogen atom adjacent to the R13 position and two
atoms from the point of attachment may be substituted with R*^- a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R O position may be substituted with R^ , a ring carbon or nitrogen atom
three atoms from the point of attachment and adjacent to the R 2 position may
be substituted with R 2, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the Rj j and R32 positions may be
substituted with R3 j ;
Dj, D2, J -[, J2 and K^ are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of Dj, D9. J j, J2 and Kji is a covalent bond, no more than one of
Dj, D2, J j, J2 and Kj is O, no more than one of Dj, D2, 5 [, J2 and Kj is S,
one of Dj, D2, J j. J2 and Kj must be a covalent bond when two of Dj, D2,
J ^, J2 and Kj are O and S, and no more than four of D^, D2, J , J2 and Kj are N; R| is selected from the group consisting of haloalkyl and haloalkoxymethyl ;
R2 is selected from the group consisting of hydrido, aryl. alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl; R is selected from the group consisting of hydrido, aryl. alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and Rg are independently selected from the group consisting of hydrido and halo;
R9 and R] 3 is halo:
R5, Rβ, and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl. alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl. heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl; R4 and R5, R5 and Rg, Rg and R7, and R7 and Rg are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and
R5, R5 and Rg, Rg and R7, and R7 and Rg, is used at the same time;
R Q, Ri
Figure imgf000023_0001
Rj2> 31, and R 2 are independently selected from the group group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio. aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R30 is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
In a preferred specific embodiment of compounds of Formulas I-
WOPA, I-WOHA, I-WOPC, and I-WOHC, n is the integer 1 ;
Rj is selected from the group consisting of trifluoromethyl, 1,1,2,2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethy 1 , and pentafl uoroethyl ;
R2 is selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, 1,1,2,2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, pentafluoroethyl, trifluoromethyl, and 2,2.3,3,3-pentafIuoropropyl; R3 is selected from the group consisting of hydrido, phenyl, 4- trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; Y and Z are independently selected from the group consisting of a ~ covalent single bond, oxy. and methylene with the proviso that only one of Y and Z are simultaneously oxy;
R4 and Rg are independently selected from the group consisting of hydrido and fluoro; R5 is selected from the group consisting of 4-aminophenoxy. benzoyl, benzyl, benzyloxy. 5-bromo-2-fluorophenoxy. 4-bromo-3-fiuorophenoxy. 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichloroρhenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,
3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyρhenoxy, 3-dimethylaminophenoxy, 3,5-dimethylρhenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3, 4-dimethyl benzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy. lJ-dioxan-2-yl, l,4-dioxan-2-yl, l,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy. 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,
3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy. 4-fIuoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fIuoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, lJJ,3,3,3-hexafluoroρropyl, 2-hydroxy-3JJ-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy. 3-isoxazolyl. 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl. 4-isopropylbenzyloxy. 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyI, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylρrop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy,
4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl. 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, l JJJJ-pentafluoropropyl, l JJJJ-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-i'ec-butylphenoxy,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1,1,2,2-tetrafiuoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2J,5-trifluorobenzyIoxy, 2JJ-trifluoroethoxy,
2,2,2-trifluoroethyl, 3J,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxyJrifluoromethyl, 3-trifluoromethyl benzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, lJ-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl. 3,5-bis-trifluoromethylbenzyloxy. 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy. 3-trinuoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 23,4-trifluorophenyl, 2.3,5-trifluorophenoxy, 3J.5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(lJJJ-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio :
Rg is selected from the group consisting of chloro. fluoro. hydrido. pentafiuoroethyl, lJJJ-tetrafluoroethoxy. trifluoromethyl, and trifluoromethoxy;
R7 is selected from the group consisting of hydrido. fluoro. and trifluoromethyl.
In a more preferred specific embodiment of compounds of Formulas I-
WOPA, I-WOHA, I-WOPC, and I-WOHC, n is the integer 1 ;
R is selected from the group consisting of trifluoromethyl. 1J.2,2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafiuoroethyl;
R2 is selected from the group consisting of hydrido, methyl, ethyl, phenyl, 4-trifluoromethylphenyl. trifluoromethoxymethyl, 1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, pentafiuoroethyl, trifluoromethyl, and 2J3J,3-pentafluoroρropyl; R3 is selected from the group consisting of hydrido, phenyl.
4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl ;
Y and Z are independently selected from a covalent single bond and methylene; R4 and Rg are independently selected from the group consisting of hydrido and fluoro; R5 is selected from the group consisting of benzyloxy, 5-bromo-2- fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy. 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methyIphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chiorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy. 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2.3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl. 3,5-dichlorobenzyl, 3,4-dichloroρhenoxy, 3,4-difIuorophenoxyJJ-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy,3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, l,3-dioxolan-2-yi, 3-ethylbenzyloxy, 3-ethylphenoxy. 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,
3-fluoro- trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fIuorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy. 2-furyl, 3-furyl, heptafluoropropyl, lJJJJ,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isoproρylphenoxy. isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3- methy lphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1 -methy lpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafiuoroethyl, pentafluoroethylthio, 2,2JJJ-pentafluoropropyl, 1 , 1 ,3,3,3-pentafluoropropyl, lJJJJ-pentafluoropropyl, pheπoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy. 4-propoxyphenoxy, thiophen-3-yl.tert -butoxy. 3-tert -butylphenoxy, 4-tert -butylphenoxy. lJJJ-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2JJ-trifluoroethoxy, 2,2,2-trifluoroethyl. 3J,3-trifluoro-2-hydroxypropyl, trifluoromethoxy. 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, IJ-bis-trifluoromethyl-l-hydroxymethyl, 3-trifluoromethylbenzyl. 3.5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy,
3-trifluoromethylphenyl, 2J,4-trifluorophenoxy, 2J,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafIuoroethylphenoxy. 3-( lJJJ-tetrafluoroethoxy)phenoxy. 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;
Rg is selected from the group consisting of chloro, fluoro, hydrido, pentafiuoroethyl, lJJJ-tetrafluoroethoxy, and trifluoromethyl;
R is selected from the group consisting of hydrido, fluoro, and trifluoromethvl.
In an even more preferred specific embodiment of compounds of Formulas I-WOPA. I-WOHA, I-WOPC, and I-WOHC. n is the integer 1;
Rj is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafiuoroethyl;
R2 is hydrido, pentafiuoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl
Y and Z are independently selected from the group consisting of a covalent single bond and methylene;
R4 and Rg are independently selected from the group consisting of hydrido and fluoro: R5 is selected from the group consisting of 5-bromo-2-fluorophenoxy.
4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4- dichlorophenoxy, 3-difluoromethoxyphenoxy, 3.5-dimethylphenoxy, 3,4- dimethylphenoxy. 3-ethylphenoxy, 3-ethyl-5-methylphenoxy. 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy. 3-isopropylphenoxy, 3-methylphenoxy, pentafiuoroethyl, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy. lJJJ-tetrafluoroethoxy, 3-(lJJJ-tetrafluoroethoxy)phenoxy, 2-(5.6,7,8-tetrahydronaphthyloxy), trifluoromethoxy, 3-trifluoromethoxy benzyloxy 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, lJ-bis-trifluoromethyl-1- hydroxymethyl, trifiuoromethylthio, and 3-trifluoromethylthiophenoxy;
Rg is selected from the group consisting of fluoro and hydrido:
R7 is selected from the group consisting of hydrido and fluoro.
In a preferred specific embodiment of compounds of Formulas I-
WOPA and I-WOHA,
A is selected from the group consisting of ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, isobutyl, 2- methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3- pentynyl, 2-pentyl, l-methyl-2-butenyl, l-methyl-3-butenyl, l-methyl-2- butynyl, 3-pentyl, l-ethyl-2-propenyl, 2- methyl butyl, 2-methyl-2-butenyl, 2- methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3- methyl-3-butenyl, 1-hexyl, 2-hexenyl. 3-hexenyl, 4-hexenyl, 5-hexenyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3- pentenyl, l-methyl-4-pentenyl, 1 -methy 1-2-pentynyl, l-methyl-3-pentynyl, 3- hexyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2-propenyl, l-ethyl-2- butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, 1 -methy 1-3-hexenyl, l-methyl-4-hexenyl, 1 -methy 1-5-hexenyl, l-methyl-2- hexynyl, l-methyl-3-hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2- pentenyl, l-ethyl-3-pentenyl, 1 -ethyl -4-pentenyl, l-butyl-2-propenyl, 1-ethyl- 2-pentynyl, l-ethyl-3-pentynyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5- octenyl, 6-octenyl, 7-octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6- octvnvl. 2-octyl, l-methvl-2-heptenvl, l-methvl-3-heptenyl. l-methvl-4- heptenyl, l-methyl-5-heptenyl, l-methyl-6-heptenyl. l-methyl-2-heptynyl, 1- methyl-3-heptynyl. 1 -methy l-4-heptenyl, l-methyl-5-heptenyl, l-methyl-6- heptenyl. l-methyl-2-heptenyl, 1 -methy 1-3-heptynyl, l-methyl-4-heptynyl, 1- methyl-5-heptynyl. 3-octyl, l-ethyl-2-hexenyl, l-ethyl-3-hexenyl, l-ethyl-4- hexenyl, l-ethyl-2-hexynyl, l-ethyl-3-hexynyl, l-ethyl-4-hexynyl, l-ethyl-5- hexenyl, l-pentyl-2-propenyl, 4-octyl, l-propyl-2-pentenyl, l-propyl-3- pentenyl, 1 -propyl -4-pentenyl, l -butyl-2-butenyl, l -propyl-2-pentynyl, 1- propyl-3-pentynyl. l-butyl-2-butynyl, l-butyI-3-butenyl, 2J-difluoropropyl, 4-trifluoromethyl-5.5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5.5.6.6,6- pentafluorohexyl, 333-trifluoropropyl, 2-methoxyethyl, 2-ethoxyethyl, 2- propoxyethyl, 2-isopropoxyethyl. 2-butoxy ethyl, 2-isobutoxyethyl, 2-5ec- butoxyethyl, 2-pentoxyethyl, 2-hexoxy ethyl, 3-methoxypropyl, 2- methoxyisopropyl. 3-ethoxypropyl. 2-ethoxyisopropyl. 3-propoxypropyl. 2- propoxyisopropyl. 3-isopropoxypropyl, 2-isopropoxyisopropyl, 3- butoxypropyl, 2-butoxyisopropyl. 3-isobutoxypropyl, 2-isobutoxyisopropyl, 3-pentoxypropyl, and 2-pentoxyisopropyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of
R 3, R34, R35, and R3g with the provisos that R33, R34, R35, and R3g
must not be attached to the carbon directly linking A to Z and that R33, R34,
R35, and R g must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond; R33, R34, R35, and R3 are independently selected from the group consisting of cyano. hydroxy, 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,
4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy.
4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro,
3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy,
4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy,
4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy,
4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro^l-ethylphenoxy,
3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy. 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 23-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl. 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy. 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy. 3,4-difluorophenyl.3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2.5-difluorophenoxy,
3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl. 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy. 2J-dimethylpropoxy. l,3-dioxan-2-yl. l,4-dioxan-2-yl, l,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitroρhenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, lJJ,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, methylbenzyloxy, 3-methylphenoxy, 3-methyl- methylthiophenoxy, 4-methylphenoxy, 1 -methy Ipropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl. 4-nitrophenylthio, 2-oxazolyl. 4-oxazolyl. 5-oxazolyl. pentafiuoroethyl, pentafluoroethylthio, 2J3.33-pentafiuoropropyl. l J ,3,33-pentafluoropropyl, lJ JJ,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy. propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, .vec-butyl,
4-sec-butylphenoxy.tert -butoxy, 3-tert -butylphenoxv . 4-tert -butylphenoxv .
1 , 1 JJ-tetrafluoroethoxy, tetrahydrofuran-2-y! ,
2-(5,6.7.8-tetrahydronaphthyloxy). thiazol-2-yl, thiazoi-4-yl. thiazoi-5-yl, thiophen-2-yl, 23.5-trifluorobenzyloxy, 2J.2-triflucroethoxy. 2,2,2-trifluoroethyl, 3,3,3-tπfluoro-2-hydroxypropyl. trifluoromethoxy,
3-trifluoromethoxybenzyloxy. 4-trifluoromethoxybenzyloxy.
3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl,
3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy.
2,4-bis-trifluoromethylbenzyloxy, lJ-bis-trifluoromethyl-1-hydroxymethyl. 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy,
4-trifiuoromethylphenoxy, 3-trifluoromethylphenoxy,
3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy,
4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy,
2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3.4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy,
3-(lJ JJ-tetrafluoroethoxy )phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio.
In a preferred specific embodiment of compounds of Formulas I- WOPA and I-WOHA,
A is selected from the group consisting of ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl. sec-butyl, isobutyl. 2-methylpropenyl. 1 -pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentyl, l-methyl-2-butenyl. 1- methyl-3-butenyl, 3-pentyl, l-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2- butenyl, 2-methyl-3-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3- butenyl. 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl. 5-hexenyl, 2-hexyl, 1- methyl-2-pentenyl, l-methyl-3-pentenyl, l-methyl-4-pentenyl, 3-hexyl, 1- ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2-propenyl. 1-heptyl, 2-heptenyl 3-heptenyl, 4-heptenyl, 5-heptenyl. 6-heptenyl, 2-heptyl, l-methyl-2-hexenyl. l-methyl-3-hexenyl, l-methyl-4-hexenyl, l-methyl-5-hexenyl, 3-heptyl, 1- ethyl-2-pentenyl, l -ethyl-3-pentenyl. l -ethyl-4-pentenyl, l-butyl-2-propenyl. 1-octyl, 2-octenyl. 3-octenyl.4-octenyl. 5-octenyl, 6-octenyl, 7-octenyl, 2- octyl, l-methyl-2-heptenyl. l-methyl-3-heptenyl, l-methyl-4-heptenyl, 1- methyl- heptenyl, l-methyl-6-heptenyl, l-methyl-4-heptenyl, l-methyl-6- heptenyl, 1 -methy 1-2-heptenyl. 3-octyl, l-ethyl-2-hexenyl, l-ethyl-3-hexenyi. 1-ethy 1-4- hexenyl, l-ethyl-5-hexenyl, l-pentyl-2-propenyl, 4-octyl, l-propyl-__ 2-pentenyl, l-propyl-3-pentenyl, l-propyl-4-pentenyl, l-butyl-2-butenyl, 1- butyl-3-butenyl, 2J-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6.6-pentafluorohexyl. and 3,3,3- trifluoropropyl. wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34,
R35, and R3g with the provisos that R33, R3 _ R^ζ- and R g must not be
attached to the carbon directly linking A to Z and that R33, R34, R35, and R3g must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
R33, R34. R35, and R3g are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3- fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3- chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy. 23-dichlorophenoxy, 2,4-dichlorophenoxy, 2.4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxyJ3-difluorobenzyloxy.3,5-difluorobenzyioxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,
3,5-dimethoxyphenoxy,3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethyIphenoxy, l,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy. 4-fluoro-3-methylbenzyl. 4-fluorobenzyloxy, 2~fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy. 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy. 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,
4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, l J J ,33,3-hexafluoropropyl, 2-hydroxy-333-trifluoropropoxy, isobutoxy. isobutyl. 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy. 3-isopropylbenzyloxy, 3-isopropylphenoxy. isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3- methylphenoxy, 3-methyl-4-methylthiophenoxy. 4-methylphenoxy. 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafiuoroethyl, pentafluoroethylthio, 2,2333-pentafluoropropyl, 1J 333-pentafluoropropyl, lJ,2J3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1J JJ-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl. thiophen-2-yl, 2JJ-trifluoroethoxy, 2JJ-trifluoroethyl, 333-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxy benzyloxy, 4-trifluoromethoxy benzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy. trifluoromethyl, 3-trifluoromethylbenzyloxy, lJ-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,
3-pentafluoroethy lphenoxy, 3-( 1 ,1 JJ-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio.
In an even more preferred specific embodiment of compounds of
Formulas I-WOPA and I-WOHA. A is selected from the group consisting of 1-propenyl, propyl. isopropyl, butyl, 2-butenyl, 3-butenyl, sec-butyl, isobutyl, 2-methylpropenyl. 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl. 2-pentyl, l-methyl-2-butenyl, 1- methyl-3-butenyl. 3-pentyl. l-ethyl-2-propenyl, 2-methylbutyl. 2-methyl-2- butenyl, 2-methyl-3-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3- _ butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexyl, 1- methyl-2-pentenyl. l-methyl-3-pentenyl, l-methyI-4-pentenyl, 3-hexyl, 1- ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2-propenyl, l-ethyl-2-pentenyl. l-ethyl-3 -pentenyl, l-ethyl-4-pentenyl, l-butyl-2-propenyl, l-ethyl-2-hexenyl, l-ethyl-3-hexenyl, l-ethyl-4-hexenyl, l-ethyl-5-hexenyl, l-pentyl-2- propenylJ-propyl-2-pentenyl, l-propyl-3-pentenyl, l-propyl-4-pentenyl, 1- butyl-2-butenyl, l-butyl-3-butenyl, 2J-difluoropropyl, 4-trifluoromethyl- 5.5.5-trifluoropentyl. 4-trifluoromethylpentyl. 5.5.6,6.6-pentafluorohexyl. and 33,3-trifluoropropyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34,
R35, and R3g with the provisos that R33, R34, R35, and R3g must not be
attached to the carbon directly linking A to Z and that R33, R34, R35, and R3g must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
R3 , R34. R35, and R g are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 23-dichlorophenoxy, 3,4-dichlorophenoxy, 3- difluoromethoxyphenoxy. 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy,
3-ethyl-5-methylphenoxy. 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isoρropylphenoxy, 3-methylphenoxy, pentafiuoroethyl, 3-pentafluoroethylphenoxy. 3-tert -butylphenoxy, 1 , 1 JJ-tetrafluoroethoxy, 3-( 1 ,1 JJ-tetrafluoroethoxy jphenoxy , 2-(5,6,7,8-tetrahydronaphthyloxy),trifluoromethoxy,
3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, lJ-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy. In a preferred specific embodiment of compounds of Formulas I- WOHA and I-WOHC.
D , D2, J j . J2, and Kj are independently selected from the group consisting of C. N, O. S and a covalent bond to form the group consisting of 2-thienyl. 3-thienyl. 2-furyl. 3-furyl, 2-pyrrol l.
Figure imgf000036_0001
rrolyl. 2-imidazolyl. 4- ~ imidazolyl,
Figure imgf000036_0002
l. l J,4-triazol-5-yl, lJ,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, i ,3.4-oxadiazol-3-y l, 13,4- oxadiazol-5-yi, 3 -isothiazolyl, 5-isothiazoi>i, 2-oxazoh l, 2-thiazolyl, 3- isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl. 4-pyridazinyl, 13,5-triazin-2-yl, lJ.4-triazin-3-yl, l J.4-triazin-5-yl, l J.4-triazin-6-yl. l J,3-triazin-4-yl. 1-indolizinyl. 7-indolizinyl. 1-isoquinolyl. and 2-quinolyl. wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or Rg, a ring carbon atom
adjacent to the RA position and two atoms from the point of attachment may be
substituted with R5, a ring carbon atom adjacent to the Rg position and two
atoms from the point of attachment may be substituted with R7, and a ring
carbon atom three atoms from the point of attachment and adjacent to the R5
and R7 positions may be substituted with Rg.
In a more preferred specific embodiment of compounds of Formulas I- WOHA and I-WOHC,
Dj, D2, J 1 , 2 and Kj are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl. 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4- imidazolyl, 3-pyrazolyl, 4-pyrazoIyl, 2-oxazolyl. 2-thiazolyl, 3-isoxazolyl, 5- isoxazolyl, 2-pyridyl. 3-pyridyl. 4-pyridyl. 2-pyrazinyl. 2-pyrimidinyl. 4- pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl. 4-pyridazinyl, 13.5-triazin-2-yl. 1- indolizinyl, 7-indolizinyl, 1-isoquinolyl, and 2-quinolyl. wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or Rg, a ring carbon atom adjacent to the R position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the Rg position and two atoms from the point of
attachment may be substituted with R-7. and a ring carbon atom three atoms ""
from the point of attachment and adjacent to the R^ and R7 positions may be
substituted with Rg.
In an even more preferred specific embodiment of compounds of Formulas I-WOHA and I-WOHC, D , D9, J|, J2 and Kj are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4- imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or Rg, a ring carbon atom adjacent to the R4 position and two atoms from the point of attachment may be substituted with
R5, a ring carbon atom adjacent to the Rg position and two atoms from the
point of attachment may be substituted with R7, and a ring carbon atom three
atoms from the point of attachment and adjacent to the R5 and R7 positions
may be substituted with Rg.
In a preferred specific embodiment of compounds of Formulas I- WOPC and I-WOHC.
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyctopent-2-enyl, cyclopent-3-enyl, cyclohexyl, 4- methylcyclohexyl, 4-chloro-3-ethylphenoxycyciohexyl, 3- trifluoromethoxyphenoxycyclohexyl. 3-trifluoromethylcyclohexyl.4- trifluoromethylcyclohexyl, 3.5-bis-trifluoromethylcyclohexyl, adamantyl.3- trifluoromethylada antyl, norbornyl, 3-trifluoromethylnorbornyI, norbornenyl, 7-oxabicyclo[2J.1 Jheptan-2-yl, bicyclo[3J.0]hexan-6-yl, cyclohex-2-enyl. cyclohex-3-enyi, cycloheptyl, cyclohept-2-enyl, cyclohept-3^ enyl, cyclυoctyl, e\ clooct-2-en) l, cycloυct-3-enyl, cyclooct-4-enyl, 2- mo holinyl, 3-morpholinyl, 4-moφholinyi, 1-piperazinyl. 2-piperazinyl, 1- piperidinyl, 2-piperidinyl. 3-pipeπdinyl. 4-piperidinyl, 1-pyrrolidinyl. 2- pyrrolidinyl. 3-pyrrolidinyl. 2-dioxanyl. 2H-2-pyranyl. 2H-3-pyranyl, 2H-4- pyranyl. 4H-2-pyranyl, 4H-3-pyranyl. 4H-4-pyranyl, 2H-pyran-2-one-3-yl, 2H-ρyran-2-one-4-yl, 2H-pyran-2-one-5-yl, 4H-pyran-4-one-2-yl, 4H-pyran- 4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3- tetrahydropyranyl. 4-tetrahydropyranyl. 2-tetrahydrothienyl. and 3- tetrahydrothienyl. wherein each ring carbon may be optionally substituted with R3Q, a ring carbon other than the ring carbon at the point of attachment of A to
Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with Rg or Rj3, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with
R 0> a ring carbon or nitrogen atom adjacent to the Rj3 position and two
atoms from the point of attachment may be substituted with Rj2, a "n§ carbon or nitrogen atom three atoms from the point of attachment and adjacent to the RjO position may be substituted with Rj j , a ring carbon or nitrogen atom
three atoms from the point of attachment and adjacent to the Rj2 position may
be substituted with R^o, and a ring carbon or nitrogen atom four atoms from
the point of attachment and adjacent to the Rj and R32 positions may be
substituted with R3 j ;
R9 and Rj3 are fluoro; RjO and Rj 2 are independently selected from the group consisting of
4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy. 3-bromobenzyloxy, 4-bromobenzyloxy. 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro. 3-chlorobenzyl, 2-chlorophenoxy, 4- chlorophenoxy,
4-chloro-3-ethylphenoxy. 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl. 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy. 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy. 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy. 2,4-dichlorophenoxy, 2.4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy. 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3.5-dimethylbenzyloxy, 2J-dimethylpropoxy, l,3-dioxan-2-yl, l,4-dioxan-2-yl, l,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylρhenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl.4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,
3-fluoro-5-trifl uoromethyl benzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yIoxy, 2-furyl, 3-furyl, heptafluoropropyl, lJJ,3,3,3-hexafluoropropyl. 2-hydroxy-3,33-trifluoropropoxy. 3-iodobenzyloxy. isobutyl, isobutylamino, isobutoxy. 3-isoxazolyl, 4-isoxazolyl, 5-isoxazoIyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl. 4-methoxycarbonylbutoxy. 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino.3-methylbenzyloxy. 4-methylbenzyloxy, 3-methylphenoxy. 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1 -methy Ipropoxy, 2-methylpyrid-5-yloxy,
4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy. 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl. 5-oxazolyl, pentafiuoroethyl. pentafluoroethylthio. 2J333-pentafluoropropyl. lJ333-pentafluoropropyl, lJJJ3-pentafluoropropyl, phenoxy. phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1 ,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2J-trifluoroethoxy,
2JJ-trifluoroethyl, 3,3,3-trifluoro-2-hydroxyproρyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy. 2,4-bis-trifluoromethylbenzyloxy, lJ-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethyl benzyl, 3 ,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylρhenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethyiphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3 -difl uoromethoxy phenoxy , 3 -pentafl uoroethy lphenoxy , 3-(lJJJ-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifl uoromethy Ithio ; Rj j, R3 j, and R 2 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafiuoroethyl, I J JJ- tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy:
R30 is selected from the group consisting of chloro, __ ethoxy, ethyl, fluoro, heptafluoropropyl, l JJ ,333-hexafluoropropyl, isobutyl, isobutoxy, isopropoxy, isopropyl, isopropylthio, methyl, propyl, pen tafl uoroethyl , 2,2,3.3 ,3 -pen tafl uoropropy 1 , 1 J ,3 ,3 ,3 -pentafl uoropropy I . lJJJ3-pentafluoropropyl. propoxy, sec-butyl, tert -butoxy, 1.1,2.2- tetrafluoroethoxy, 2JJ-trifluoroethoxy, 2,2,2-trifluoroethyI, trifluoromethoxy, and trifluoromethyl.
In a more preferred specific embodiment of compounds of Formulas I- WOPC and I-WOHC,
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3- ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3- trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis- trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbomyl, norbornenyl, 7-oxabicyclo[2JJ]heptan-2-yl, bicyclo[3.L01hexan-6-yl. cycloheptyl, cyclooctyl, 2-morpholinyl.3- moφholinyl, 4-moφholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2- piperidinyl, 3-piperidinyl.4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H- pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3- tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4- tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon may be optionally substituted with R3Q, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R^, a
ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with RJQ, a ring carbon or nitrogen
atom adjacent to the R^3 position and two atoms from the point of attachment
may be substituted with R^2- a ring carbon or nitrogen atom three atoms from
the point of attachment and adjacent to the RJQ position may be substituted
with [ [, a ring carbon or nitrogen atom three atoms from the point of
attachment and adjacent to the R γ position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the Rj j and R32 positions may be substituted with R3 γ ;
Rn and Rj3 are fluoro;
RJQ and Ryi are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3 -chloro-4-ethylphenoxy , 3 -chloro-4-methy lphenoxy ,
3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy.4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl. cyclopentylcarbonyl. cyclopropylmethoxy, 23-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,
3,4-difluorophenoxyJ,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy,3-dimethylaminophenoxy, 3, 4-dimethyl benzyloxy, 3 ,5-dimethylbenzyloxy , 3 ,5-dimethylphenoxy , 3 ,4-dimethylphenoxy ,
13-dioxolan-2-yl, 3-ethylbenzyloxy. 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylρhenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy. 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy. 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl. 1 J J ,3,3,3-hexafluoropropyl , 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy. isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropyl phenoxy, isopropylthio, 4-isopropyI-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino. 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1 -methy lpropoxy. 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl. 2-oxazolyl. 4-oxazolyl, 5-oxazolyl, pentafiuoroethyl, pentafluoroethylthio. 2J,3,3,3-pentafluoropropyl, lJ ,333-pentafluoropropyl, lJ,2J,3-pentafIuoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy. 1,1 JJ-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2J-trifluoroethoxy, 2J,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifIuoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, lJ-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy,
3-trifluoromethylphenyl, 2,3, 4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-( lJ,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;
R\ \. R j , and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafiuoroethyl, 1,1,2,2- tetrafluoroethoxy, and trifluoromethyl; R30 is selected from the group consisting of chloro, ethyl, fluoro. heptafluoropropyl, lJJ,3,33-hexafluoropropyl, isobutyl, isopropyl, methyl, pentafiuoroethyl. 2J3,3,3-pentafluoropropyl, lJ333-pentafluoropropyl. lJ,2J,3-pentafl uoropropy I. propyl. sec-butyl. 1J JJ-tetrafluoroethoxy, 2JJ-trifluoroethoxy. 2.2,2-trifluoroethyl. trifluoromethoxy, and trifluoromethyl.
In an even more preferred specific embodiment of compounds of Formulas I-WOPC and I-WOHC, A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.4-methylcyclohexyl, 4-chloro-3- ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl. 3- trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis- trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbomyl, 3-trifluoromethylnorbornyl, norbomenyl, 7-oxabicyclo[2JJ]heptan-2-yl, bicyclo[3.L0]hexan-6-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2- tetrahydrothienyl, and 3-tetrahydrothienyl, wherein a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R*β, a ring
carbon or nitrogen atom adjacent to the R9 position and two atoms from the
point of attachment may be substituted with R , a ring carbon or nitrogen
atom adjacent to the R^3 position and two atoms from the point of attachment
may be substituted with Rj2, a ring carbon or nitrogen atom three atoms from
the point of attachment and adjacent to the R^Q position may be substituted
with R j j , a ring carbon or nitrogen atom three atoms from the point of
attachment and adjacent to the Rj 2 position may be substituted with R-32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the Rj j and R32 positions may be substituted with R j ;
Ro, and R j3 are fluoro;
RjO and R^ are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl,
23-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-rnethylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isoproρylphenoxy, 3-methylphenoxy, pentafiuoroethyl, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 1.1 JJ-tetrafluoroethoxy. 3-( 1 J JJ-tetrafluoroethoxy )phenoxy. 2-(5,6,7,8-tetrahydronaphthyloxy),trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, lJ-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy; l 1' 31' anc* 32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafiuoroethyl, 1,1 JJ-tetrafluoroethoxy, and trifluoromethyl.
DEFINITIONS
The use of generic terms in the description of the compounds are herein defined for clarity.
Standard single letter elemental symbols are used to represent specific types of atoms unless otherwise defined. The symbol "C represents a carbon atom. The symbol "O" represents an oxygen atom. The symbol "N" represents a nitrogen atom. The symbol "P" represents a phosphorus atom. The symbol "S" represents a sulfur atom. The symbol 'Η" represents a hydrogen atom. Double letter elemental symbols are used as defined for the elements of the periodical table (i.e., CI represents chlorine, Se represents selenium, etc.).
As utilized herein, the term "'alkyl", either alone or within other terms such as "haloalkyl" and "alkylthio", means an acyclic alkyl radical containing from 1 to about 10, preferably from 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl. aminopentyl. iso-amyl, hexyl, octyl and the like.
The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such alkenyl radicals contain from about 2 to about 10 carbon atoms, preferably from about 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl. buten-1-yl. isobutenyl, penten-1-yl, 2- 2-methylbuten-l-yl, 3-methylbuten-l-yl, hexen-1-yl, 3-hydroxyhexen-l-yl, hepten-1-yl, and octen-1-yl. and the like.
The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 3 to about 8 carbon atoms and more preferably having 3 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-l-yl, butyn-2-yl. pentyn-1-yl, pentyn-2-yl, 4- methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3- yl, 3 -dimethylbutyn-l-yl radicals and the like.
The term "hydrido" denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a ''hydroxyl" radical, one hydrido radical may be attached to a carbon atom to form a "methine" radical (=CH-), or two hydrido radicals may be attached to a carbon atom to form a "methylene" (-CH2-) radical.
The term "carbon" radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds. The term "'cyano" radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.
The term "hydroxyalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals. The term "alkanoyl" embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include^ oxalyl, malonyl, and succinyl.
The term "alkylene" radical denotes linear or branched radicals having from 1 about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene. ethylene. ethylidene, methy lethylene, and isopropylidene.
The term "alkenylene" radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds. Examples of such radicals are 1,1-vinylidene (CH2=C), 1,2-vinylidene (-CH=CH-). and 1 ,4-butadienyl (-CH=CH-CH=CH-).
The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms.
The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are "lower haloalkyl" radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl. trifluoromethyl, chloromethyl, dichloromethyl, tri chloromethyl, trifluoroethyl, pentafiuoroethyl, heptafluoropropyl, difluorochloromethyl. dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
The term "hydroxyhaloalkyl" embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above. Examples of "hydroxyhaloalkyl" radicals include hexafl uorohy doxy propyl . The term "haloalkylene radical" denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo-* radicals. More preferred haloalkylene radicals are "lower haloalkylene" radicals having one to about six carbon atoms. Examples of "haloalkylene" radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene. alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
The term "haloalkenyl" denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy- containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term "alkoxyalkyl" also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxy alkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" and "haloalkoxyalkyl" radicals. Examples of such haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl.
The terms "alkenyloxy" and "alkenyloxyalkyl" embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical. The term "alkenyloxyalkyl" also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are "lower alkenyloxy" radicals having two to six carbon atoms. Examples of such radicals include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The "alkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkenyloxy" radicals. Examples of such radicals include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fluoropropenyloxy. The term "haloalkoxyalkyl" also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term "haloalkenyloxy" also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term "haloalkenyloxyalkyl" also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.
The term "alkylenedioxy" radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of "alkyl enedioxy" radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term "haloalkylenedioxy" radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of "haloalkylenedioxy" radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.
The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused. The term "fused" means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term "fused" is equivalent to the term "condensed". The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaph hyl, indane and biphenyl. The term "perhaloaryl" embraces aromatic radicals such as phenyl. naphthyl. tetrahydronaphthyl. indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.
The term "heterocyclyl" embraces saturated and partially saturated heteroatom-containing ring-shaped radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include saturated 3 to 6- membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. moφholinyl. etc.]: saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazohdinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran. dihydrofuran and dihydrothiazole. Non-limiting examples of heterocyclic radicals include 2- pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2H-ρyranyl, 4H- pyranyl, piperidinyl, 1,4-dioxanyl, moφholinyl, 1,4-dithianyl, thiomoφholinyl, and the like.
The term "heteroaryl" embraces fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heteroaryl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of "heteroaryl" radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-lJ,4-triazolyl, lH-l,23-triazolyl, 2H-1,2,3- triazolyl, etc.] tetrazolyl [e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl. isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocvclic group containing a sulfur atom. for example. 2-thienyl, 3-thienyl. etc.: unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazotyl, oxadiazolyl (e.g., 1.2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyi, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl. thiadiazolyl [e.g., 1 ,2,4- thiadiazolyl. 1 ,3.4- thiadiazolyl, 1.2.5-thiadiazolyl. etc.) etc.: unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran. benzothiophene. and the like. Said "heterocyclyl" group may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals. Non-limiting examples of heteroaryl radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2- imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3.4-thiadiazolyl. pyrazinyl, piperazinyl, 13.5-triazinyl, 1,3.5-trithianyl, benzo(b)thiophenyl, benzimidazoyl, quinolinyl, tetraazolyl, and the like.
The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO;-- "Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. "Alkylsulfonylalkyl", embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfonyl". embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above. "Haloalkylsulfonylalkyl", embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aminosulfonyl" denotes an amino radical attached to a sulfonyl radical.
The term "sulfmyl", whether used alone or linked to other terms such as alkylsulfmyl, denotes respectively divalent radicals -S(O)-. "Alkyl sulfinyl", embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. "Alkylsulfinylalkyl", embraces alkylsulfmyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfinyl", embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. "Haloalkylsulfinylalkyl", embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable. The term "heteroaralkyl" embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals. The term "perhaloaralkyl" embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above. The term "aralkylsulfmyl", embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above. "Aralkylsulfinylalkyl", embraces aralkylsulfmyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aralkylsulfonyl", embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above. "Aralkylsulfonylalkyl", embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "cycloalkyl" embraces radicals having from 3 through 15 carbon atoms. Cycloalkyl radicals may contain one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused. Examples of cycloalkyl radicals having two or more rings include adamantyl, norbornyl, and 7-oxabicyclo[2.2.1]heptanyl. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having from 3 through 8 carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "cycloalkyl" also embraces radicals where cycloalkyl radicals are fused with aryl radicals or heterocyclyl radicals. The term "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals having cycloalkyl radicals attached to alkyl radicals having from one through six carbon atoms. Examples of such radicals include cyclohexylhexyl. The term "cycloalkenyl " embraces radicals having three to fifteen carbon atoms and one or more carbon-carbon double bonds. Cycloalkenyl radicals may contain one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused. Examples of cycloalkenyl radicals having two or more rings include norbomenyl. Preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cyclohepteny . The term "halocycloalkyl" embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. A monohalocycloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term "halocycloalkenyl" embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.
The term "cycloalkoxy" embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy. The term "cycloalkoxyalkyl" also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxyethyl. The "cycloalkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkoxy" and "halocycloalkoxyalkyl" radicals. The term "cycloalkylalkoxy" embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cy clopentylmethoxy .
The term "cycloalkenyloxy" embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy. The term "cycloalkenyloxy alkyl" also embraces alkyl radicals having one or more cycloalkenyloxy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxyethyl. The "cycloalkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkenyloxy" and "halocycloalkenyloxyalkyl" radicals. _
The term "cycloalkylenedioxy" radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group. Examples of "alkylenedioxy" radicals include 1.2-dioxycyclohexylene.
The term "cycloalkylsulfinyl", embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above. "Cycloalkylsulfinylalkyl", embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "Cycloalkylsulfonyl", embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above. "Cycloalkylsulfonylalkyl", embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "cycloalkylalkanoyl" embraces radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl, cyclohexylacetyl, and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1,2- dicarbonylcyclohexane..
The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having one to six carbon atoms. An example of "lower alkylthio" is methylthio (CH3-S-). The "alkylthio" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkylthio" radicals. Examples of such radicals include fluoromethylthio, chloromethylthio, trifiuoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.
The term "alkyl aryl amino" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline, and N-methyl-4-trifluoromethoxyaniline. The terms alkylamino denotes "monoalkylamino" and "dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical.
The terms arylamino denotes "monoarylamino" and "diarylamino" containing one or two aryl radicals, respectively, attached to an amino radical. Examples of such radicals include N-phenylamino and N-naphthylamino.
The term "aralkylamino", embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term aralkylamino denotes "monoaralkylamino" and "diaralkylamino" containing one or two aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes "'monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
The term "arylsulfinyl" embraces radicals containing an aryl radical, as defined above, attached to a divalent S(=O) atom. The term "arylsulfinylalkyl" denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
The term "arylsulfonyl", embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above, "arylsulfonylalkyl", embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "heteroarylsulfinyl" embraces radicals containing an heteroaryl radical, as defined above, attached to a divalent S(=O) atom. The term "heteroarylsulfinylalkyl" denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term "Heteroarylsulfonyl", embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. "Heteroarylsulfonylalkyl", embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aryloxy" embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy, 4-chloro-3- ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4- dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3- trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2- fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 4-tert -butylphenoxy. 3-pentafluoroethylphenoxy, and 3- ( 1 ,1 ,2,2-tetrafl uoroethoxy )phenoxy . The term "aroyl" embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.
The term "aralkanoyl" embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals^ include, for example, phenylacetyl.
The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having phenyl radicals attached to lower alkoxy radical as described above. Examples of such radicals include benzyloxy, 1- phenylethoxy, 3-trifJuoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5- difluorobenyloxy, 3-bromobenzyloxy. 4-propylbenzyloxy, 2-fluoro-3- trifluoromethylbenzyloxy. and 2-phenylethoxy.
The term "aryloxy alkyl" embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.
The term "haloaryloxyalkyl" embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.
The term "heteroaroyl" embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
The term "heteroaralkanoyl" embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.
The term "heteroaralkoxy" embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy" radicals having heteroaryl radicals attached to lower alkoxy radical as described above.
The term "haloheteroaryloxyalkyl" embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.
The term "heteroarylamino" embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.
The term "heteroarylaminoalkyl" embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pvridylmethylamino. The term "heteroaryloxy" embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2- thiophenyloxy, 2-pyrimidyloxy, 2-ρyridyloxy, 3-pyridyloxy, and 4- pyridyloxy. The term "heteroaryloxyalkyl" embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2-pyridyl oxymethyl, 3-pyridyloxyethyI, and 4-pyridyloxymethyl.
The term "arylthio" embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio. The term "arylthioalkyl" embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenyl thi omethyl .
The term "alkylthioalkyl" embraces alkylthio radicals, as defined above. attached to an alkyl group. Examples of such radicals include methylthiomethyl. The term "alkoxyalkyl" embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.
The term ""carbonyl" denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom. The term "carboxy" embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboxamide" embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term "carboxamidoalkyl" embraces carboxamide radicals, as defined above, attached to an alkyl group. The term "carboxyalkyl" embraces a carboxy radical, as defined above, attached to an alkyl group. The term "'carboalkoxy" embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboaralkoxy" embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "monocarboalkoxy alkyl" embraces one carboalkoxy radical, as defined above, attached to an alkyl group. The term "dicarboalkoxyalkyl" embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term "monocyanoalkyl" embraces one cyano radical, as defined above, attached to an alkyl group. The term "dicyanoalkylene" embraces two cyano radicals, as defined above, attached to an alkyl group. The term "'carboalkoxycyanoalkyl" embraces one cyano radical, as defined above, attached to an carboalkoxyalkyl group. The term "acyl", alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, _ dialkylamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of "acyl" are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like. The term "haloalkanoyl" embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutanoyl. The term "diacyl", alone or in combination, means having two or more carbonyl or thionocarbonyl groups bonded to a radical selected from, for example, alkylene, alkenylene, alkynylene, haloalkylene. alkoxyalkylene. aryl, heterocyclyl, heteroaryl, aralkyl, cycloalkyl, cycloalkylalkyl, and cycloalkenyl. Examples of "diacyl" are phthaloyl, malonyl, succinyl, adipoyl, and the like. The term "benzylidenyl" radical denotes substituted and unsubstituted benzyl groups having attachment points for two covalent bonds. One attachment point is through the methylene of the benzyl group with the other attachment point through an ortho carbon of the phenyl ring. The methylene group is designated for attached to the lowest numbered position. Examples include the base compound benzylidene of structure:
Figure imgf000058_0001
The term "phenoxylidenyl" radical denotes substituted and unsubstituted phenoxy groups having attachment points for two covalent bonds. One attachment point is through the oxy of the phenoxy group with the other attachment point through an ortho carbon of the phenyl ring. The oxy group is designated for attached to the lowest numbered position. Examples include the base compound phenoxylidene of structure:
Figure imgf000059_0001
The term "phosphono" embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical. The term "dialkoxyphosphono" denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "diaralkoxyphosphono" denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "dialkoxyphosphonoalkyl" denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term "diaralkoxyphosphonoalkyl" denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical. Said "alkyl", "alkenyl", "alkynyl". "alkanoyl", "alkylene", "alkenylene",
"benzylidenyl", "phenoxylidenyl", "hydroxyalkyl", "haloalkyl", "haloalkylene", "haloalkenyl", "alkoxy", "alkenyloxy", "alkenyloxyalkyl", "alkoxyalkyl", "aryl", ""perhaloaryl", "haloalkoxy", "haloalkoxyalkyl", "haloalkenyloxy", "'haloalkenyloxyalkyl", "alkylenedioxy", "'haloalkylenedioxy", "heterocyclyl", "heteroaryl", "hydroxyhaloalkyl", "alkylsulfonyl", "haloalkylsulfonyl", "alkylsulfonylalkyr. "haloalkylsulfonylalkyl"J"alkylsulfmyr, "alkylsulfinylalkyl", "haloalkylsulfinylalkyl", "aralkyl", "heteroaralkyl", "'perhaloaralkyl", "aralkylsulfonyl", "aralkylsulfonylalkyl", "aralkylsulfmyl", "aralkylsulfinylalkyl", "cycloalkyl", "cycloalkylalkanoyl", "cycloalkylalkyl", "cycloalkenyl", "halocycloalkyl", "halocycloalkenyl", "cycloalkylsulfinyl", "'cycloalkylsulfinylalkyr'J'cycloalkylsulfonyl"J'cycloalkylsulfonylalkyl", "cycloalkoxy", "cycloalkoxyalkyl", "cycloalkylalkoxy", "cycloalkenyloxy", "cycloalkenyloxyalkylV'cycloalkylenedioxy", "halocycloalkoxy", "halocycloalkoxyalkyl", "halocycloalkenyloxy", "halocycloalkenyloxyalkyl", "alkylthio", "haloalkylthio", "alkylsulfmyl", "amino", "oxy", "thio", "alkylamino", "'arylamino", "aralkylamino", "arylsulfinyl", "arylsulfmylalkyl", "arylsulfonyl", "arylsulfonylalkyl". "heteroarylsulfιnyl"J"heteroarylsulfinylalkyl", ""heteroarylsulfonyl", "heteroarylsulfonylalkyl", "heteroarylamino", "heteroarylaminoalkyP, "heteroaryloxy", "heteroaryloxylalkyl", "aryloxy", ""aroyl", "aralkanoyl", "aralkoxy", "'aryloxyalkyl", "haloaryloxyalkyl", "heteroaroyl", "heteroaralkanoyl", "heteroaralkoxy". "heteroaralkoxyalkyl", "arylthio", "arylthioalkyl", "alkoxyalkyl", "acyl" and "diacyl" groups defined above may optionally have 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfmyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino. N-heteroaryiamino- N-alkyiamino, heteroarylaminoalkyl, heteroaryloxy. heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxy lalkyl, heteroaralkoxy. cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxv, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino. thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl. arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfmyl, alkylsulfinylalkyl, arylsulfmylalkyl, arylsulfonylalkyl, heteroarylsulfiny lalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyi, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy. hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl. haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
The term "spacer" may include a covalent bond, a linear moiety having a backbone of 1 to 7 continous atoms, and a branched moiety having three branches connecting to a common atom with a total of from 1 through 8 atoms. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted bv a radical selected from =C(H)-, =C(R17K -O-, -S-, -S(O)-, -S(O)2-, -NH-, -N(R17)-, -N=, -CH(OH)-,
=C(OH)-, -CH(OR17)-, =C(OR17)-, and -C(O)- wherein R17 is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkyl thioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl. heteroaryloxyalkyl. heteroarylthioalkyl, and heteroarylalkenyl. Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms, a straight chain of 1 or 2 or 3 or 4 or 5 or 6 atoms with a side chain, or a branched chain made up of 1 or 2 or 3 or 4 atoms in each of the three branches. The chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, -O-, -O-CH2-, -S-CH2-, -CH2CH2-. ethenyl,
-CH=CH(OH)-, -OCH2O-, -0(CH2)2O-, -NHCH2-, -OCH(R17)O-,
-O(CH2CHR17)O-, -OCF2O-, -O(CF2)20-, -S-, -S(O)-, -S(O)2-, -N(H)-,
-N(H)O-, -N(R17)O-, -N(R17)-, -C(O)-, -C(O)NH-, -C(O)NR17-, -N=,
-OCH2-, -SCH2-, S(O)CH2-, -CH2C(O)-, -CH(OH)-, =C(OH)-,
-CH(OR17)-, =C(OR17)-, S(O)2CH2-, and -NR1?CH2- and many other radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may include substituents such as 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfmyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfmyl, alkylsulfinylalkyl, arylsulfmylalkyl, arylsulfonylalkyl, heteroarylsulfiny lalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, _ arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S- enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention. Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention. The terms "cis" and "trans" denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond ("cis") or on opposite sides of the double bond ("trans").
Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or "E" and "Z" geometric forms.
Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more "enol" forms of each aldehyde and ketone group present. Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both "keto" and "enol" tautomeric forms. Some of the compounds described herein may contain one or more - amide carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more "enol" forms of each amide group present. Compounds of the present invention having amidic carbonyl groups are meant to include both "keto" and "enol" tautomeric forms. Said amide carbonyl groups may be both oxo (C=O) and thiono (C=S) in type.
Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the "imine" form and in part or principally as one or more "enamine" forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both "imine" and "enamine" tautomeric forms.
The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes are as follows: "AA" represents amino acids, "BINAP" represents 2J'-bis(diphenylphosphino)- lJ'-binaphthyl, "Boc" represents tert-butyloxycarbonyl, "BOP" represents benzotriazol-l-yl-oxy-tris-(dimethylamino), "bu" represents butyl, "dba" represents dibenzylideneacetone, "DCC" represents 13- dicyclohexylcarbodiimide, "DIBAH" represents diisobutylaluminum hydride, "DIPEA" represents diisopropylethylamine, "DMF" represents dimethylformamide, "DMSO" represents dimethylsulfoxide, "Fmoc" represents 9-fluorenylmethoxycarbonyl, "LDA" represents lithium diisopropylamide, "PHTH" represents a phthaloyl group, "pnZ" represents 4- nitrobenzyloxycarbonyl, "PTC" represents a phase transfer catalyst, "p-TsOH" represents paratoluenesulfonic acid, "TBAF' represents tetrabutylammonium fluoride, "TBTU" represents 2-(lH-benzotriozole-l-yl)-lJ,3,3-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, "THF' represents tetrahydrofuran, "TMS" represents trimethylsilyl, and "Z" represents benzyloxycarbonyl. PHARMACEUTICAL UTILITY AND COMPOSITION
The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formulas VII- H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, in association with at least one - pharmaceutically-acceptable carrier, adjuvant or diluent.
The present invention also comprises a treatment and prophylaxis of coronary artery disease and other CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically- effective amount of a compound of Formula I-WA:
Figure imgf000064_0001
wherein R^, R2, R3, n, R14, R^, Rjg, A, Q, X, Y, and Z are as defined above for the compounds of Formula I-WA; or a pharmaceutically-acceptable salt thereof.
As a further embodiment, compounds of the present invention of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC, or a pharmaceutically-acceptable salt thereof as defined above and further comprise a treatment and prophylaxis of coronary artery disease and other CETP- mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of compounds of Formulas I- WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC, of the present invention or a pharmaceutically-acceptable salt thereof. Compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC are capable of inhibiting activity of cholesteryl ester transfer protein (CETP), and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by CETP, such as peripheral vascular disease, hyperlipidaemia, hypercholesterolemia, and other diseases attributable to either high LDL and low HDL or a combination of both, or a procedure to study the mechanism of action of the cholesteryl ester transfer protein (CETP) to enable the design of better inhibitors. The compounds of Formulas I-WA. I-WO, I-WOHA, I- WOPC, I-WOHA, and I-WOHC would be also useful in prevention of cerebraL vascular accident (CVA) or stroke.
Also included in the family of compounds of Formulas I-WA, I-WO, I- WOHA, I-WOPC, I-WOHA, and I-WOHC are the pharmaceutically-acceptable salts thereof. The term "pharmaceutically-acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I-WA may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I-WA include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compounds of Formulas I-WA, I- WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC by reacting, for example, the appropriate acid or base with the compounds of Formulas I-WA, I-WO, I- WOHA, I-WOPC, I-WOHA, and I-WOHC.
Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of Formula I-WA in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, _ subcutaneously, intramuscularly or topically.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely. The pharmaceutical compositions may contain active ingredients in the range of about OJ to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0J to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil- in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane- 1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absoφtion or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. For therapeutic puφoses, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl _ alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
All mentioned references are incoφorated by reference as if here written. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.
GENERAL SYNTHETIC PROCEDURES
The compounds of the present invention can be synthesized, for example, according to the following procedures of Schemes 1 through 14 below, wherein the substituents are as defined for Formulas I-WA, I-WO, I- WOHA, I-WOPC, I-WOHA, and I-WOHC above except where further noted. Synthetic Scheme 1 shows the preparation of compounds of formula
XIIIA-H ("Secondary Heteroaryl Amines") which are intermediates in the preparation of the compounds of the present invention corresponding to Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") wherein one substituent (A or Q) on the nitrogen is AQ-1 which can be independently selected from the group consisting of aryl and heteroaryl, which are preferably substituted with one or more groups, and another substituent (A or Q) on the nitrogen is AQ-2 which can be independently selected from the group consisting of AQ-2 and -CH2(CR37R3g)v-(CR33R34)u-T-
(CR35R36)W-H. AQ-2 and -CH2(CR37R3g)v-(CR33R34)u-T-(CR35R36)w-
H can be independently selected from the group consisting of C3-C8 alkyl, C3- C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, C3-C8 hydroxyhaloalkyl. C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl. and C4-C9 partially saturated heterocyclyl, wherein said group may be optionally substituted. Schemes 1 through 14, taken together, prepare tertiary heteroalkylamine compounds of the present invention by addition of a halogenated, heteroatom (for example, oxygen, sulfur, or nitrogen) containing precursor to a resulting secondary amine to introduce a heteroatom containing alkyl group wherein one of the two groups making up the secondary amine is aromatic groups and the other is aliphatic (for example, C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, C3-C8 hydroxyhaloalkyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl), C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl.
The "Heteroaryl Imines" corresponding to Formulas XII-AH, CXII- AH, CKXII-AH can be prepared through dehydration techniques generally known in or adaptable from the art by reacting "Heteroaryl Amine" of Formula X-AH or a "Heteroaryl Carbonyl" of Formula XI-AH with a suitable an aliphatic, saturated heterocyclic, or partially saturated heterocyclic amine or carbonyl compound as shown in Schemes 1, 3, 4, 5, 6, 12, and subsequent specific examples. For example in Scheme 3, the two reactants (AQ-2A and XI-AH) react by refluxing them in an aprotic solvent, such as hexane, toluene, cyclohexane, benzene, and the like, using a Dean-Stark type trap to remove water. After about 2-8 hours or until the removal of water is complete, the aprotic solvent is removed in vacuo to yield the "Heteroaryl Imine" of Formula XII-AH.
The "Secondary Cyclic Heteroaryl Amines" of Formula XIIIA-H can be prepared from the corresponding "Generic Imine" of Formula XII, "Cyclic Heteroaryl Imine" of Formulas XII-AH. CXII-AH, and CKXII-AH can be prepared in several ways. For example, in one synthetic scheme (Reduction Method- 1), the "Generic Imine" of Formula XII-AH is partially or completely dissolved in presence of a lower alcohol containing sufficient organic or mineral acid, as described in WO Patent Application No. 9738973, Swiss Patent CH 441366 and U. S. Patent Nos. 3359316 and 3334017, which are incoφorated herein by reference, and then hydrogenated at 0-100°C, more preferably 20-50°C, and most preferably between 20-30°C and pressures of
10-200 psi hydrogen or more preferably between 50-70 psi hydrogen in the presence of a noble metal catalyst such as PtO .
In another synthetic scheme (Reduction Method-2), the "Cyclic Heteroaryl Imine" of Formulas XII-AH, CXII-AH, and CKXII-AH is slurried in a lower alcohol such as ethanol, methanol or like solvent at 0-10°C and solid sodium borohydride is added in batches over 5-10 minutes at 0-10°C with stirring. The reaction mixture is stirred below 10°C for 30-90 minutes and then is warmed gradually to 15-30°C. After about 1-10 hours, the mixture is cooled and acid is added until the aqueous layer was just acidic (pH 5-7).
In yet another synthetic scheme (Reduction Method-3), which is preferred when Z is an oxygen, the "Cyclic Heteroaryl Imine" of Formulas XII-AH, CXII-AH, and CKXII-AH is slurried in a lower alcohol solvent at 0-
10°C and acidified to a pH less than 4 and sodium cyanoborohydride is added in batches over 30-90 minutes at 0-20°C with stirring and addition of a suitable organic or mineral acid to keep the pH at or below 4. The reaction mixture is stirred and warmed gradually to about 20-25°C. After about 1-10 hours, the mixture is cooled and base added until the mixture was just slightly alkaline. The "Secondary Cyclic Heteroaryl Amines" of Formulas XIII-AH, CXIIIA-H, and CKXIII-AH can also be prepared, according to Schemes 1 and 3, by an alkylation procedure based on the nucleophilic substitution of bromides by amines. In one synthetic alkylation scheme (Alkylation Method- 1), a "Cyclic Amine" of Formula AQ-2A or a "Generic Amine-l" of Formula X is reacted with a "Heteroaryl Bromide" of Formula XXI-AH or "Generic Bromide" of Formula XXI as described in Vogel's Textbook of Practical Organic Chemistry, Fifth Edition, 1989, pages 902 to 905 and references cited therein all of which are incoφorated herein by reference. In an alternate synthetic alkylation scheme exemplified in Scheme 1, an "Amine" of Formula XXII is reacted with a "Heteroaryl Bromide" in a method employing palladium, catalyzed carbon-nitrogen bond formation. Suitable procedures for this conversion are described in Wagaw and Buchwald, J. Org. Chem.(1996), 61, 7240-7241, Wolfe, Wagaw and Buchwald, J. Am. Chem. Soc. (1996), 118, 7215-7216, and Wolfe and Buchwald, Tetrahedron Letters (1997), 38(36), 6359-6362 and references cited therein all of which are incoφorated herein by reference.
The "Generic Secondary Amine", "Heteroaryl Amine", '"Cyclic Amine", "Alicyclic Amine", and "Heteoaryl Hydroxylamine" amines and hydroxylamines, the "Generic Carbonyl", "Heteroaryl Carbonyl", "Cyclic Carbonyl", and "Cyclic Ketone" aldehydes and ketones, and "Generic
Bromide-1", Generic Bromide-2", "Heteroaryl Bromide", and the like halides, tosylates, mesylates, triflates, and precursor alcohols required to prepare the "Secondary Cyclic Heteroaryl Amine" compounds are available from commercial sources or can be prepared by one skilled in the art from published procedures. Commercial sources include but are not limited to Aldrich
Chemical, TCI-America, Lancaster-Synthesis, Oakwood Products, Acros Organics, and Maybridge Chemical. Disclosed procedures for "Generic Amine" amines, hydroxylamines, and hydrazines include Sheradsky and Nov, J. Chem. Soc, Perkin Trans.l (1980), ( 12), 2781-6; Marcoux, Doye, and Buchwald, J. Am. Chem. Soc. (1997), 119, 1053-9; Sternbach and Jamison, Tetrahedron Lett. (1981), 22(35), 3331-4; U. S. Patent No. 5306718; EP No. 314435; WO No. 9001874; WO No. 9002113; JP No. 05320117; WO No. 9738973; Swiss Patent No. CH 441366; U. S. Patents Nos. 3359316 and 3334017; and references cited therein which are incoφorated herein by reference.
Synthetic Schemes 2, 10 and 11 show the preparation of the class of compounds of the present invention corresponding to Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines"). Derivatives of "Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols" or
"Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines", in which the heteroatom (O, N, or S) is attached to an alkyl group removed from the amine by two or more carbons are readily prepared by anion chemistry using the method of Scheme 2. The anion of "Secondary Amine" amines and hydroxylamines of Formula XIII are readily formed by dissolving the specific amine, hydroxylamine, or hydrazine in an aprotic solvent, such as tetrahydrofuran, toluene, ether, dimethylformamide, and dimethylformamide, under anhydrous conditions. The solution is cooled to a temperature between -
78 and 0°C, preferably between -78 and -60°C and the anion formed by the addition of at least one equivalent of a strong, aprotic, non-nucleophillic base such as NaH or n-butyllithium under an inert atmosphere for each acidic group present. Maintaining the temperature between -78 and 0°C, preferably between
-78 and -60°C, with suitable cooling, an appropriate alkyl halide, alkyl benzenesulfonate such as a alkyl tosylate, alkyl mesylate, alkyl triflate or similar alkylating reagent of the general structure:
Figure imgf000072_0001
where m is zero, X can be RN, O, and S, and M is a readily displaceable group such as chloride, bromide, iodide, tosylate, triflate, and mesylate. After allowing the reaction mixture to warm to room temperature, the reaction product is added to water, neutralized if necessary, and extracted with a water- immiscible solvent such as diethyl ether or methylene chloride. The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO4 and concentrated in vacuo to yield crude Formula I- WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines"). This material is purified, for example, by eluting through silica gel with a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield purified Formula I-WA and Formula I-WO. Products are structurally confirmed by low and high resolution mass spectrometry and NMR. Compounds of Formula (XXX), which can be used to prepare I-WA, I-WO, I-WOPA, I-WOPC, I-WOHA, and I-WOHC, are given in Table 2. Reagents la and 2a in Table 2 are prepared from the corresponding alcohols. The tosylates are readily obtained by reacting the corresponding alcohol with tosyl chloride using procedures found in House's Modem Synthetic Reactions^ Chapter 7, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons, which are incoφorated herein by reference. A preferred procedure for Formula I-WO ("'Alicyclic/Cyclic
Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("'Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines" compounds is Method A of Schemes 2, 10, 11, and 14. Oxirane reagents useful in Method A are exemplified, but not limited to those in Table 1. Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl l-Amino-2-alcohol") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary 2-Heteroalkylamine") compounds are prepared by using "Secondary Cyclic Heteroaryl Amine" and "Alicyclic Heteroaryl Amine" amines and hydroxylamines of Formulas XIIIA-H, CXIIIA-H, CKXIII-AH, ACXIIIA-H, and RACXIIIA-H prepared above with oxiranes of the type listed in Table 1 and represented by the general structure:
Figure imgf000073_0001
In some cases, the oxiranes are prepared by reaction of epoxidation reagents such as MCPBA and similar type reagents readily selectable by a person of skill-in-the-art with alkenes. Fieser and Fieser in Reagents for Organic Synthesis, John Wiley & Sons' provides, along with cited references, numerous suitable epoxidation reagents and reaction conditions, which are incoφorated herein by reference.
Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary 2-
Heteroalkylamine") compounds, wherein the 2-hetero group is an amino, substituted amino, or thiol, can be prepared by using appropriate aziridines and thirranes according to Method A of Scheme 2. Aziridine and thiirane reagents useful in Method A are exemplified, but not limited to those in Table 1. These Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary 2-Heteroalkylamine") compounds, wherein the 2-hetero group is an amino, substituted amino, or thiol, can be prepared by using "Secondary Cyclic Heteroaryl Amine" and "Alicyclic Heteroaryl Amine" amines and hydroxylamines of Formulas XIIIA^. H, CXIIIA-H, CKXIII-AH, ACXIIIA-H, and RACXIIIA-H prepared above with aziridines and thiiranes of the type listed in Table 1 and represented by the general structure:
Figure imgf000074_0001
wherein X is selected from N and S and R16
, „ is hydrogen or another suitable group when X is N.
Table 1. Structure of Oxirane, Aziridine, and Thiirane Reagents.
R 1 6
Figure imgf000075_0001
Figure imgf000075_0002
Table 1. (continued) Structure of Oxirane. Aziridine, and Thiirane Reagents.
Figure imgf000076_0001
Table 2. Structure and Source of Alcohol and Glycol Reagents.
Figure imgf000077_0001
-J
Wl
Figure imgf000077_0002
A mixture of a "Secondary Amine" amine or hydroxylamine and an oxirane of Formula XX are stirred and heated to 40-90°C for 5 to 48 hours in a tightly capped or contained reaction vessel. A Lewis acid such as ytterbium triflate in acetonitrile may be added to speed up reaction and improve yield. When a Lewis acid is used, the reaction should be carried out under inert, anhydrous conditions using a blanket of dry nitrogen or argon gas. After cooling to room temperature and testing the reaction mixture for complete reaction by thin layer chromatography or high pressure liquid chromatography (hplc), the reaction product is added to water and extracted with a water immiscible solvent such as diethyl ether or methylene chloride. (Note: If the above analysis indicates that reaction is incomplete, heating should be resumed until complete with the optional addition of more of the oxirane). The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO4 and concentrated in vacuo to yield crude Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds. This material is purified by eluting through silica gel with 5-40% of a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield the Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds. Products are tested for purity by HPLC. If necessary, the Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds are purified by additional chromatography or recrystallization. Products are structurally confirmed by low and high resolution mass spectrometry and NMR. Examples of specific Formula VII Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") prepared are summarized in the Examples and Example Tables 1 through 7. Specific Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl
Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") analogs of the Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds summarized in the Examples and Example Tables 1 through 7, wherein the hydroxyl or oxy group are replaced with an amino, substituted amino, aza, or thiol, can be prepared by using the appropriate aziridine reagents or thiirane reagents readily by adapting the procedures in the numerous specific Examples and Schemes disclosed in the present invention. Similarly, intermediates, in which the hydroxyl or oxy group of said intermediates are replaced with an amino, substituted amino, aza, or thiol, can be converted using the numerous specific Examples and Schemes disclosed in the present invention to other Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds.
Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1, 2, and 3. Schemes 12 and 13 detail such procedures to prepare compounds of the present invention by initial formation of an halogenated, oxygen containing primary alkylamine XL ("Generic Substituted Alkylamine"). Said halogenated, oxygen containing primary alkylamine XL, formed in Scheme 12, is itself converted to secondary amine LX-H ("Heteroaryl Alkyl Amine) using procedures disclosed above. Primary alkylamine XL is first reacted with an aldehydic or ketonic carbonyl compound, XI-AH ("Heteroaryl Carbonyl") with azeotropic distillation to form imines, L-H ("Heteroaryl Imine"). Said imine L-H are then reduced with or without prior isolation by Reduction Methods 1, 2 or 3 as disclosed above and in Scheme 1 to yield secondary amines LX-H ("Heteroaryl Alkyl Amine). Said secondary amine LX-H can be converted according to Scheme 14 to Formula I- WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols"). Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and
Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds can further be prepared in an alternate manner to procedures disclosed above and in additional Schemes.
Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") are alternately referred to as Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl 2- hydroxyalkylamines").
Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds can themselves serve as intermediates for conversion to additional compounds of this invention. Compounds of the present invention useful as intermediates include those in which the R5 or R7 position substituent in Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups. Other preferred compounds of the present invention useful as intermediates include those in which the R10 position substituent in Formulas I-WA or I-WO is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups. Other compounds of Formulas I-WA or I-WO and the present invention useful as intermediates include those in which one or more of R6, R{ l , and Rj 2 substituents in Formulas I-WA or I-WO is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups.
Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") are alternately referred to as Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Tertiary 2-hydroxyalkylamines").
A 3-bromo substituent at the R5 position in Formula I-WO ("Alicyclic/Cyclic 3-Bromoaryl Tertiary 2-Hydroxyalkylamines") can be reacted with a phenol to afford 3-phenoxy compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Phenoxyaryl Tertiary 2- Hydroxyalkylamines").
A 3-bromo substituent at the R5 position in Formula I-WO ("Alicyclic/Cyclic 3-Bromoheteroaryl Tertiary 2-hydroxyalkylamine") can, be reacted, for example, with a phenol to afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Aryloxyaryl, 3- Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylamines"). A 3-bromo substituent at the R5 position in Formula I-WO
("Alicyclic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") can be reacted with a phenol to afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Phenylaryl Tertiary 2- Hydroxyalkylamine"). Conversion of a 3-bromo substituent at the R5 position in Formula I-
WO ("Alicyclic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") by reaction with a primary or secondary amine can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3- R22aminoaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-bromo substituent at the R position in Formula I-
WO ("Alicyclic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") by reaction with an aryl borinate can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-PhenylaryI Tertiary 2- Hydroxyalkylamine").
Conversion of a 3-bromo substituent at the R5 position in Formula I-
WO ("Alicyclic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") by reaction with a heteroaryl dibutyl tin compound can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3- Heteroarylaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-bromomethyl substituent at the R5 position in
Formula I-WO ("Alicyclic/Cyclic 3-BromomethylaryI Tertiary 2- hydroxyalkylamine") by reaction with an aryl borinate can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3- Arylmethylaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-hydroxyl substituent at the R5 position in Formula I-
WO ("Alicyclic/Cyclic 3 -Hydroxy heteroaryl Tertiary 2-hydroxyalkylamine") by reaction with an aryl bromide or heteroaryl bromide can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3- Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3- Aryloxyheteroaryl Tertiary 2-Hydroxyalkylamines").
Conversion of a 3-hydroxyl substituent at the R5 position in Formula I-
WO ("Alicyclic/Cyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylamine") by reaction with an aryl bromide can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Phenoxyaryl Tertiary 2- Hydroxyalkylamine").
Conversion of a 3-hydroxyl substituent at the R5 position in Formula I-
WO ("Alicyclic/Cyclic 3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylamine") by reaction with an aralkyl bromide or heteroaralkyl bromide can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Aralkyloxyaryl, 3-Heteroaralkyloxyaryl, 3- Heteroaralkyloxyheteroaryl, and 3-Aralkyloxyheteroaryl Tertiary 2- Hydroxyal kylami nes"). Conversion of a 3-hydroxyl substituent at the R5 position in Formula I-
WO ("Alicyclic/Cyclic 3-HydroxyaryI Tertiary 2-hydroxyalkylamine") by reaction with an aralkyl bromide can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Aralkyloxyaryl Tertiary 2-Hydroxyalkylamine"). Conversion of a 3-hydroxyl substituent at the R3 position in Formula I-
WO ("Alicyclic/Cyclic Polycyclic 3-Hydroxyaryl Tertiary 2- hydroxyalkylamine") by reaction with a displaceable organo bromide can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Organooxyaryl Tertiary 2-Hydroxyalkylamine"). Conversion of a 3-thio substituent at the R5 position in Formula I-WO
("Alicyclic/Cyclic 3-thioaryl Tertiary 2-hydroxyalkylamine") by reaction with a displaceable organo bromide can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Organothiaaryl Tertiary 2- Hydroxyalkylamine"). "Alicyclic/Cyclic 3-Organothiaaryl Tertiary 2- Hydroxyalkylamines" can be oxidized to sulfonyl compounds of 3-
Organosulfonylaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-nitro substituent at the R5 position in Formula I-WO
("Alicyclic/Cyclic 3-Nitroaryl Tertiary 2-hydroxyalkylamine") by hydrogenation can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Aminoaryl Tertiary 2-
Hydroxyalkylamine"). Formula I-WO ("Alicyclic/Cyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylamines") can be acylated to acyl amide compounds of Formula I-WO ("Alicyclic/Cyclic 3-Acylaminoaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-amino substituent at the R5 position in Formula I- WO ("Alicyclic/Cyclic 3-Aminoaryl Tertiary 2-hydroxyalkylamine") by reaction with carbonyl compounds can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-(Saturated Nitrogen Heterocycl-lyl)aryl Tertiary 2-Hydroxyalkylamine" and "Alicyclic/Cyclic 3- (Unsaturated Nitrogen Heterocycl-lyl)aryl Tertiary 2-Hydroxyalkylamine"). Conversion of a 3-methoxycarbonyl substituent at the R5 position in
Formula I-WO ("Alicyclic/Cyclic 3-CarbomethoxyaryI Tertiary 2- hydroxyalkylamine") by reaction with amination reagents can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3- Carboxamidoaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-cyano substituent at the R5 position in Formula I-
WO ("Alicyclic/Cyclic 3-Cyanoaryl Tertiary 2-hydroxyalkylamine") by reaction with organometallic reagents can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Acylaryl Tertiary 2- Hydroxyalkylamine"). Said "Alicyclic/Cyclic 3-Acylaryl Tertiary 2-
Hydroxyalkylamines", can be reduced to hydroxyl compounds of Formula I- WO ("Alicyclic/Cyclic 3-Hydroxysubstitutedmethylaryl Tertiary 2- Hydroxyalkylamine").
Conversion of a 3-methoxycarbonyl substituent at the R, 0 position in Formula I-WO ("Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine") by reaction with amination reagents can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3- Carboxamidoaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-methoxycarbonyl substituent at the Rj 0 position in Formula I-WO ("Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine") by reaction with an organometallic reagent can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-(bis-Organohydroxymethyl)aryl Tertiary 2- Hydroxy alkylamine"). Conversion of a 3-methoxycarbonyl substituent at the Rl 0 position in
Formula I-WO ("Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine") by reaction with lithium aluminum hydride can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Hydroxymethylaryl Tertiary 2-Hydroxyalkylamine"). Conversion of a 3-methoxycarbonyl substituent at the R, 0 position in
Formula I-WO ("Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine") by reaction with an alkylation reagent can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-(bis-Organo-hydroxymethyl)aryl Tertiary 2- Hydroxyalkylamine"). Conversion of a 3-methoxycarbonyl substituent at the R, 0 position in
Formula I-WO ("Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine") by reaction intially with an amidation reagent and then an organometallic reagent can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-(Organo-carbonyl)aryl Tertiary 2-Hydroxyalkylamine").
Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") and other compounds of this invention posssessing hydroxyl, thiol, and amine functional groups can be converted to a wide variety derivatives. The hydroxyl group X, wherein Rjg is a hydrogen, of compounds of the present invention can be readily converted to esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids. Acylation to form a carboxylic acid ester is readily effected using a suitable acylating reagent such as an aliphatic acid anhydride or acid chloride. The corresponding aryl and heteroaryl acid anhydrides and acid chlorides can also be used. Such reactions are generally carried out using an amine catalyst such as pyridine in an inert solvent. In like manner, compounds that have at least one hydroxyl group present in the form of an alcohol or phenol can be acylated to its corresponding esters. Similarly, carbamic acid esters (urethans) can be obtained by reacting any hydroxyl group with isocyanates and carbamoyl chlorides. Sulfonate, phosphonate, and phosphate esters can be prepared using the corresponding acid chloride and similar reagents. Compounds that have at least one thiol group present can be converted to the corresponding thioesters derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas I-WA, I-WO. and other compounds of the present invention that have at least one primary or secondary amine group present can be converted to the corresponding amide derivatives. Amides of carboxylic acids can be prepared using the appropriate acid chloride or anhydrides with reaction conditions analogous to those used with alcohols and phenols. Ureas of the corresponding primary or secondary amine can be prepared using isocyanates directly and carbamoyl chlorides in the presence of an acid scavenger such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of aqueous sodium hydroxide. Suitable procedures and methods for preparing these derivatives can be found in House's Modem Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1. John Wiley & Sons. Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas I-WA, I-WO, and other compounds of the present invention are available from commerical sources or the references cited" above, which are incoφorated herein by reference.
Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and
Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") and other compounds of this invention posssessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety derivatives. The hydroxyl group X, wherein Rj is a hydrogen, of compounds of Formulas I-WA, I-
WO, and other compounds of the present invention can be readily converted to ethers. Alkylation to form an ether is readily effected using a suitable alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate. The corresponding aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be used. Such reactions are generally carried out using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n- butyl lithium using an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents, amine catalyst such as pyridine in an inert solvent. In like manner, compounds of Formulas I-WA, I-WO, and the like that have at least one hydroxyl group present in the form of an alcohol or phenol can be alkylated to their corresponding ethers. Compounds of Formulas I-WA, I-WO, and other compounds that have at least one thiol group present can be converted to the corresponding thioether derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas I-WA, I-WO, and other compounds that have at least one primary, secondary or tertiary amine group present can be converted to the corresponding quaternary ammonium derivatives. Quaternary ammonium derivatives can be prepared using the appropriate bromides, iodides, and sulfonates analogous to those used with alcohols and phenols. Conditions involve reaction of the amine by warming it with the alkylating reagent with a stoichiometric amount of the amine (i.e., one equivalent with a tertiary amine, two with a secondary, and three with a primary). With primary and secondary amines, two and one equivalents, respectively, of an acid scavenger are used concurrently. Tertiary amines can be prepared from the corresponding primary or secondary amine by reductive alkylation with aldehydes and ketones using reduction methods 1, 2, or 3 as shown in Scheme 1. Suitable procedures and methods for preparing these derivatives can be found in House's Modem Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons. Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas I-WA, I-WO, and the like are available from commerical sources or the references cited above, which are incoφorated herein by reference.
The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
Figure imgf000087_0001
Generic Bromide-2 (XXIII) Scheme 2
-78°C
-
Figure imgf000088_0001
I-WA (X = O, S, NH), I-WO, I-WOFA,
I-WOPC, I-WOHA, and I-WOHC (X = 0 in others) Scheme 3
AQ-2A: Cyclic Amine
Figure imgf000089_0001
Scheme 4
Figure imgf000090_0001
Secondary Cyclic Heteroaryl Amine (CXI IIA-H) Scheme 5
Figure imgf000091_0001
Scheme 6
Figure imgf000092_0001
Scheme 7
NH2-CH2(CR37R38)V-(CR33R34)U-T-(CR35R36)W-H AQ-2AA: Alicyclic Amine
I-AH) :Alicyclic ryl Amide
Figure imgf000093_0001
)U-T-(CR35R36)W-H
(RACXIIIA-H) :Alicyclic
Heteroaryl Amine
Figure imgf000093_0002
HNCH2(CR37R38)V-(CR33R34)U-T-(CR35R36)W-H Scheme 8
HO—C(CR37R38)V-(CR33R34)U-T-(CR35R36)W-H
AQ-2CCA: Alicyclic Carboxylic Acid
Figure imgf000094_0001
Scheme 9
NH2-CH2(CR37R38)V-(CR33R34)U-T-(CR35R36)W-H AQ-2AA: Alicyclic Amine
I-AH) :Alicyclic ryl Amide
Figure imgf000095_0001
HNCH2(CR37R38)V-(CR33R34)U-T-(CR35R36)W-H
(RACXIIIA-H) :Alicyclic Heteroaryl Amine
Figure imgf000095_0002
)v-(CR33R34)u-T-(CR35R36)w-H Scheme 10
(I-WO/I-WOPA/I-WOHA) :Alicyclic Aryl/Heteroaryl Aminoalcoholcs
Figure imgf000096_0001
Figure imgf000096_0002
(RACXIIIA-H) :Alicyclic
Heteroaryl Amine Scheme 11
Figure imgf000097_0001
R-,
Secondary Cyclic Heteroaryl Amine (XIIIA-H) Scheme 12
Figure imgf000098_0001
Scheme 13
Figure imgf000099_0001
Scheme 14
Figure imgf000100_0001
The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. Compounds containing multiple variations of the structural modifications illustrated in the preceding schemes or the following Examples are also contemplated. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
One skilled in the art may use these generic methods to prepare the following specific examples, which have been or may be properly characterized by 'H NMR and mass spectrometry. These compounds also may be formed in vivo.
The following examples contain detailed descriptions of the methods of preparation of compounds of Formula V-H. These detailed descriptions fall within the scope and are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are Degrees centigrade unless otherwise indicated.
EXAMPLE 1
Figure imgf000102_0001
3-[(4-methylcyclohexyl)[[(3-trifluoromethyl)phenyl]methyl]amino]- l,l»l-trifluoro-2-propanoI
EX-1A) 4-Methylcyclohexylamine (1.15 g, 10 mmol, 97%, mixture of cis and trans isomers) and 3-trifluoromethylbenzaldehyde (1J4 g, 10 mmol) were dissolved in anhydrous chloroform (25 mL) and heated under reflux for 4 h using a Dean-Stark trap to remove water. The volatile components were removed in vacuo to give the desired imine (2.69 g) product quantitatively as a colorless oil, MS m/z = 269 [M ]. The oil was dissolved in methanol, and after cooling to 0
°C, solid sodium borohydride was added (0.64 g, 17 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h, then acidified with 1 N HC1 solution. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with diethyl ether (3 x 20 mL). The organic layer was washed with brine and water, then dried over anhydrous MgSO and evaporated to give 1.96 g (68.4%) of the desired N-(4-methylcyclohexyl)[[3-
(trifluoromethyl)-phenyl]methyl]amine product as a colorless oil, which was
+ greater than 90% pure by reverse phase HPLC analysis. MS m/z = 271 [M ].
EX-IB) The benzylamine product from EX-1A (1.08 g, 4 mmol) and 3JJ-trifluoro-l J-epoxypropane (0.67 g, 6 mmol) were dissolved in 1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.21 g, 0J3 mmol) was added, and the stirred solution was warmed to 50 °C for 2 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no amine starting material remained. The reaction was quenched with water and extracted with ether. The
ether layer was washed with water and brine, then dried over anhydrous MgSO
The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1 : 12) to give 1 J 8 g (77%) of the desired 3- [(4-methyl-cyclohexyl) [[(3 -trifluoromethy l)phenyl] -methyl] amino] -1,1,1- trifluoro-2-propanol product as a light amber oil. 99% pure by HPLC analysis.
HRMS calculated for C18H23F6NO: 384.1762 [M+H]+, found: 384.1754. H
NMR (CDCI3) δ 0.92 (dd, 3H), 1.17-1.81 (m, 8H), 1.93 (m, 1H). 2.48 (m, 1H),
2.80 (m, 2H), 3.76 (d, 2H), 3.79 (m, 1H), 3.94 (s, 1H), 7.45-7.60 (m, 4H). 19F
NMR (CDCI3) δ -79.2 (d, 3F), -63 J (s, 3F).
Additional substituted 3-[(N-alkyl and N-cycloalkyl) [aryl] methyl] amino- lJJ-trifluoro-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 1.
Example Table 1. Substituted 3-[(N-alkyl and N-cycloalkyl)[aryl]methyl]amino-
1,1,1 -trifluoro-2-propanols.
Figure imgf000104_0001
Figure imgf000104_0003
EXAMPLE 8
Figure imgf000104_0002
3-[(3-methyI-2-butenyI)[(3-(trifluoromethoxy)phenyl] amino]-l,l,l-trifluoro-2-propanol
EX-8A) 3-Trifluoromethoxy aniline (23.81 g, 134.4 mmol) and 3,3,3- trifluoro-lJ-epoxypropane (3.76 g, 33.6 mmol) were placed into a sealed tube and heated at 80 °C for 24 h. The excess aniline was removed by distillation (70 °C at 80 torr). The resulting residue contained 8.6 g (>95%) of the desired 3- [[(trifluoromethoxy)phenyl]-amino]-lJJ-trifluoro-2-propanol product as a light
yellow oil. H NMR (CDC13) δ 3.29-3.37 (m, 1H), 3.55 (dd, 1H), 4.20 (m, 1H),
19 6.48-6.63 (m, 3H), 7.12 (t, 1H). F NMR (CDCI3) δ -79.36 (s, 3F), -58.44 (s, 3F).
EX-8B) The 3-[[(trifluoromethoxy)phenyl]amino]- 1,1.1 -trifluoro-2- propanol product from EX-8A (18.68 g, 64.6 mmol) and imidazole (10.99 g, 0J62 mmol) were dissolved in dimethylformamide (40.0 mL) and t- butyldimethylsilylchloride (11.69 g, 77.6 mmol) was added in 3.0 g portions over 15 min. The reaction was stirred at 23 °C for 18 h. The resulting solution was diluted with ethyl acetate and washed with water and brine. The organic layer
was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 25% ethyl acetate in hexane to afford 17.08g of the desired silylated product as a light golden oil. FABMS m/z = 404 [M+H]+. H NMR (CDCI3) δ 0.042 (s, 3H), 0.085 (s, 3H), 0.91 (s, 9H),
3.25-3.35 (m, 1H), 3.50 (dd, 1H), 4.10 (m, 1H), 6.40 (bs, 1H), 6.50 (dd, 1H), 6.59 (d, lH), 7J7 (t, 1H).
EX-8C) The silylated product from EX-8B (0.15 g, 0.372 mmol ) was dissolved in THF (0.5 mL) in a 2-dram glass vial with stir bar and cooled to 0 °C in an ice bath. KOtBu ( 1 M in THF, 1.2 eq, 0.446 mmol, 0.446 mL) was added to the cold solution in one portion. The reaction mixture was stirred at 0 °C for 5 min, then l-chloro-3-methyl-2-butene (38.9 mg. 0.372 mmol) in 0.5 mL of THF was added in one portion to the cold reaction mixture. The ice bath was removed, and the reaction was stirred at 23 °C for 18 h. The resulting solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4) and concentrated under a nitrogen stream. The crude residue was dissolved in 2.0 mL of THF and treated with tetrabutylammonium fluoride (1 M in THF, 1.2 eq, 0.446 mmol, 0.446 mL). The reaction mixture was stirred at 23 °C for 3 h. The reaction was diluted with ethyl acetate and washed with water and brine. The organic layer wad dried (MgSOzj) and concentrated under a nitrogen stream. The crude residue was purified using 0.5 g of silica gel eluting with hexane (100%) followed by 30% ethyl acetate in hexane to give 59.1 mg (44.4% yield) of the desired 3-[(3-methyl-2-butenyl)[(3-(trifluoromethoxy)- phenyl] amino]- lJJ-trifluoro-2-propanol product as a golden oil. FABMS m/z
= 358 [M+H]+. Additional examples of substituted 3-[(N-alkyl, N-alkenyl and N-alkynyl)-
[(trifluoromethoxy)phenyl] amino]-lJJ-trifluoro-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 2.
Example Table 2. 3-[(N-alkyl, N-alkenyl and N- alkynyl)[(trifluoromethoxy)phenyl] amino]- 1 J J -trifluoro-2-propanols.
Figure imgf000107_0001
Figure imgf000107_0003
EXAMPLE 15
Figure imgf000107_0002
l,l'-[(Phenylmethyl)imino]bis[3,3,3-trifluoro-2-propanol]
Benzylamine (1.5 eq, 2.88 g, 2.94 mL, 26.8 mmol) was combined with J,3-trifluoro-l,2-epoxypropane (2.0 g, 17.86 mmol) in a sealed glass tube and heated at 80 °C for 18 h. Upon cooling to room temperature, the reaction mixture formed a slushy white solid. The solid was collected by filtration and washed with diethyl ether. The mother liquor was concentrated in vacuo to give
1.71 g (43%) of the desired lJ '-[(phenyl-methyl)imino]bis[3JJ-trifluoro-2- -
+ 1 propanol] product as a colorless oil. FABMS m/z = 332 [M+H] . H NMR
(CDC13) δ 2.85-2.96 (m, 4H) , 3.94 (s, 2H), 3.94-3.97 (m, 2H), 7.24- 7.37 (m,
5H).
Additional examples of substituted lJ '-[(phenylmethyl)imino]bis[3JJ- tri-fluoro-2-propanols] can be prepared by one skilled in the art using similar methods, as shown in Example Table 3.
Example Table 3. Substituted l, -[(phenylmethyl)imino]bis[3,3J-trifluoro-2- propanols]
Figure imgf000108_0001
Figure imgf000108_0002
EXAMPLE 18
Figure imgf000109_0001
3-[[3-(4-chloro-3-ethylphenoxy)phenyl][3-cyclohexyImethyl]amino]- l,1 -trifluoro-2-propanol
EX-18A) To a solution of 1,3-dinitrobenzene (16.8 g, OJ mol) and 4- chloro-3-ethylphenol (15.6 g, 0J mol) in 200 mL of dimethylsulfoxide was added cesium carbonate (65 g, 0J mol). The reaction mixture was heated at 100 °C under nitrogen overnight then cooled to room temperature. The reaction mixture was filtered through celite then rinsed with diethyl ether and a small amount of water. The filtrate was extracted several times with diethyl ether. The organic layers were combined, washed with water and brine, dried over MgSO and concentrated in vacuo to give 21.8 g (78%) of the desired 3-(4-chloro-3- ethylphenoxy)-l -nitrobenzene product as a dark orange oil, which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for Ci4H12ClNO3: 295.0849 [M+NH4]+, found 295.0862.
EX-18B) To a solution of 3-(4-chloro-3-ethylphenoxy)-l -nitrobenzene (10 g, 0.036 mol) from EX-18A in 400 mL of glacial acetic acid and 1 mL of water was added zinc metal (20 g, 0J05 mol) at room temperature, and the resultant mixture was stirred for 1 h. The reaction mixture was filtered through celite. The filtrate was neutralized with ammonium hydroxide and extracted with diethyl
ether. The organic layer was washed with water and brine, dried over MgSO and concentrated in vacuo to give 10 g ( 100%) of the desired 3-(4-chloro-3- ethylphenoxy)aniline product as a dark orange oil. which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for C14H14CINO: 248.0842
[M+H]+, found: 248.0833.
EX-18C) The 3-(4-chloro-3-ethylphenoxy)aniline (0.545 g, 0.002 mol) product from EX-18B was mixed with neat 3JJ-trifluoro-lJ-epoxypropane
(0J20 g, 0.002 mol) in a pressurized vial. The resulting mixture was heated at 90 °C for 18 h, cooled, and the excess 3JJ-trifluoro-lJ-epoxypropane was removed in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with 1 :4 ethyl acetate in hexane to give 0J54 g (35%) of the desired 3-[[3-(4-chloro-3-ethyl-phenoxy)phenyl]amino]-lJJ- trifluoro-2-propanol product as a pure orange oil. Anal calcd. for
C17H17NOF3CI: C, 56.75; H, 4.76; N, 3.89. Found: C, 56.72; H, 4.70; N, 3.85.
HRMS calcd.: 360.0978 [M+H]+, found: 360.0969. lH NMR (CDCI3) δ 1.50
(t, 3H), 2.72 (m, 2H), 3.36 (m, 1H), 3.54 (m, 1H), 4.20 (m, 1H), 6.42 (m, 2H), 6.81 (dd, 1H), 6.94 (d, 1H), 7.18 (d, 1H), 725 (m, 2H).
The 3-[[3-(4-chloro-3-ethylphenoxy)phenyl]amino]- 1,1,1 -trifluoro-2- propanol product from EX-18C was dissolved in 12 mL of tetrahydrofuran. To this stirred solution was added cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol), followed by sodium tri-acetoxyborohydride (0.079 g, 0J70 mmol and concentrated acetic acid (0.020 g, 0.325 mmol). The resulting mixture was stirred at room temperature for 18 h. Additional cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol) was added and the mixture was allowed to stir at room temperature for another 18 h. The reaction was quenched with saturated sodium bicarbonate and extracted with methylene chloride. The organic layers were combined, dried
over MgSO4 and concentrated to an orange/brown oil. The crude product was purified by flash column chromatography on silica gel eluting with 1 :4 ethyl acetate in hexane to give 0.080 g (61%) of the desired 3-[[3-(4-chloro-3- ethylphenoxy)phenyl] [3-cyclohexylmethyl]amino]- 1 J J -trifluoro-2-propanol product as a yellow-orange oil (>95% pure by HPLC). HRMS calcd.: 456.1.917
[M+H]+, found: 456.1942. H NMR (CDC13) δ 0.82-1.01 (m, 2H). 1.22-1.27 (m, 3H), 1.73-1.76 (m, 5H), 2.74 (dd, 2H), 3.15 (dd, 2H), 3.23 (dd, IH), 3.52 (m, IH), 3.80 (dd, IH), 4.28 (m, IH), 6.34 (d, 2H). 6.42 (d, IH), 6.83 (dd, IH). 6.98
(d, IH), 7.19 (t, IH), 7.29 (d, IH). 19F NMR (CDCI3) δ -79.06 (d, 3F).
Based on the preceding procedures, additional substituted 3-[(N-alkyl)- [[aryl]methylJamino]-lJJ-trifluoro-2-propanols and 3-l(N-cycloalkyl)- [[aryl]methyl]-amino]-halo-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Tables 4 and 5. Similarly, substituted 3- [(N-aryl)[[cycloalkyl]-methyl]amino]-halo-2-propanols and substituted 3-[(N- aryl)[[haloalkyl]methyl]amino]-halo-2-propanols are prepared by one skilled in the art using analogous methods, as shown in Example Tables 6 and 7.
Example Table 4. 3-[(N-alkyl)Uaryl jmethyl lamino]- 1 J J -trifluoro-2-propanols.
Figure imgf000112_0001
Figure imgf000112_0002
Figure imgf000112_0003
Example Table 4. (cont.) 3-[(N-alkyl)[[aryl]methyljamino]-lJJ-trifluoro-2- propanols.
Figure imgf000113_0001
Figure imgf000113_0002
Figure imgf000113_0003
Example Table 4. (cont.) 3-[(N-alkyl)[[arylI96methyllamino]-lJJ-trifluoro-2- propanols.
Figure imgf000114_0001
Figure imgf000114_0002
Figure imgf000114_0003
Example Table 4. (cont.) 3-[(N-alkyl)[[aryl ]methyl|amino]-l,Ll-trifluoro-2- propanols.
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000115_0003
Example Table 4. (cont.) 3-[(N-alkyl)[[aryl [methyl |amino]-lJJ -trifluoro-2- propanols.
Figure imgf000116_0001
Figure imgf000116_0002
Figure imgf000116_0003
Example Table 5. 3-[(N-cycloalkyl)[[aryl]methyI]aminol-lJJ-trifluoro-2-
Figure imgf000117_0001
Figure imgf000117_0002
Figure imgf000117_0003
Example Table 5. (cont). 3-[(N-cycloalkyl)[[aryl]methyl]amino]-halo-2- propanols.
Figure imgf000118_0001
Figure imgf000118_0002
Figure imgf000118_0003
Example Table 5. (cont.). 3-[(N-cycloalkyl)[[aryl]methyl]amino]-halo-2- propanols.
Figure imgf000119_0001
Figure imgf000119_0002
Figure imgf000119_0003
Example Table 5. (cont). 3-[(N-cycloalkyl)[[aryl]methyl]amino]-halo-2- propanols.
Figure imgf000120_0001
Figure imgf000120_0002
Figure imgf000120_0003
Example Table 5. (cont). 3-[(N-cycloalkyI)[|aryl|methyl]amino]-halo-2- propanols.
Figure imgf000121_0001
Figure imgf000121_0002
Figure imgf000121_0003
Example Table 5. (cont). 3-[(N-cycloalkyI)[[aryl|methyl]amino]-halo-2- propanols.
Figure imgf000122_0001
Figure imgf000122_0002
Figure imgf000122_0003
Example Table 5. (cont). 3-[(N -cycloalkyl)! | aryl [methyl |amino]-halo-2- propanols.
Figure imgf000123_0001
Figure imgf000123_0002
Figure imgf000123_0003
Example Table 5. (cont). 3-[(N -cycloalkyl)! [aryl ]methyl]amino|-halo-2- propanols.
Figure imgf000124_0001
Figure imgf000124_0002
Figure imgf000124_0003
Example Table 5. (cont). 3-[(N-cycloalkyl)([aryl]methyl]amino]-halo-2- propanols.
Figure imgf000125_0001
Figure imgf000125_0002
Figure imgf000125_0003
Example Table 5. (cont). 3-[(N-cycloalkyl)| [aryl [methyl ]amino]-halo-2- propanols.
Figure imgf000126_0001
Figure imgf000126_0002
Figure imgf000126_0003
Example Table 5. (cont). 3-[(N-cycloalkyl)|[aryllmethyl]amino]-halo-2- propanols.
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000127_0003
Example Table 5. (cont). 3-[(N -cycloalkyl)! (aryl ]methyl]amino]-halo-2- propanols.
Figure imgf000128_0001
Figure imgf000128_0002
Figure imgf000128_0003
Example Table 5. (cont). 3-[(N -cycloalkyl)! [aryl ]methyl]amino]-halo-2- propanols.
Figure imgf000129_0001
Figure imgf000129_0002
Figure imgf000129_0003
Example Table 5. (cont). 3-[(N -cycloalkyl)! [aryl |methyl]amino]-halo-2- propanols.
Figure imgf000130_0001
Figure imgf000130_0002
Figure imgf000130_0003
Example Table 5. (cont). 3-[(N -cycloalkyl)! [aryl lmethyl]amino]-halo-2- propanols.
Figure imgf000131_0001
Figure imgf000131_0002
Figure imgf000131_0003
Example Table 5. (cont). 3-[(N-cycloalkyl)|faryl]methyl]aminol-halo-2- propanols.
Figure imgf000132_0001
Figure imgf000132_0002
Figure imgf000132_0003
Example Table 5. (cont.). 3-[(N-cycloaIkyl)(|aryllmethyl]amino]-halo-2- propanols.
Figure imgf000133_0001
Figure imgf000133_0002
Figure imgf000133_0003
Example Table 5. (cont). 3-[(N -cycloalkyl)! [aryl ]methyl]amino]-halo-2- propanols.
Figure imgf000134_0001
Figure imgf000134_0002
Figure imgf000134_0003
Example Table 6. 3-[(Λ/-aryl)[[cycloalkyl]methyl]amιno]-halo-2-propanols
Figure imgf000135_0001
Figure imgf000135_0002
Figure imgf000135_0003
34
Figure imgf000136_0002
Figure imgf000136_0003
Example Table 6 (cont). 3-[(N-aryl)[[cycloalkyl]methyl]ammo]-halo-2- propanols.
Figure imgf000136_0001
Figure imgf000136_0004
Figure imgf000136_0005
Figure imgf000137_0002
Figure imgf000137_0003
Example Table 6 (cont).3-[(N-aryl)[[cycloalkyl]methyl]amino]-halo-2- propanols.
Figure imgf000137_0001
Figure imgf000137_0004
Figure imgf000137_0005
Figure imgf000138_0002
Figure imgf000138_0003
Example Table 6 (cont).3-[(N-aryl)[[cycloalkyl]methyl]amino]-halo-2- propanols.
Figure imgf000138_0001
Figure imgf000138_0004
Figure imgf000138_0005
Figure imgf000139_0001
Figure imgf000139_0002
Example Table 6 (contΛ 3-[(N-aryl)[[cycloalkyl]methyI]amino]-halo-2- propanols.
Figure imgf000140_0001
Figure imgf000140_0002
Figure imgf000140_0003
Figure imgf000141_0002
Figure imgf000141_0003
Example Table 6 (cont).3-[(Λ-aryl)[[cyclυalk>l]methyl]amino]-haio-2- propanols.
Figure imgf000141_0001
Figure imgf000141_0004
Figure imgf000141_0005
Figure imgf000142_0002
Figure imgf000142_0003
Example Table 6 (cont).3-[(N-aryl)[[cycloaikyl]methyl]amino]-halo-2- propanols.
Figure imgf000142_0001
Figure imgf000142_0004
Figure imgf000142_0005
Figure imgf000143_0002
Figure imgf000143_0003
Example Table 6 (cont).3-[(N-aryl)[[cycloalkyl]methyl]amino]-halo-2- propanols.
Figure imgf000143_0001
Figure imgf000143_0004
Figure imgf000143_0005
42
Figure imgf000144_0001
Figure imgf000144_0002
Example Table 6 (cont). 3-[(N-aryl)[[cycloalkyl]methyl]amino]-halo-2- propanols.
Figure imgf000145_0001
Figure imgf000145_0002
Figure imgf000145_0003
Figure imgf000146_0002
Figure imgf000146_0003
Example Table 6 (cont).3-[(N-aryl)[[cydoalkyl]memγl]amino]-halo-2- propanols.
Figure imgf000146_0001
Figure imgf000146_0004
Figure imgf000146_0005
45
Figure imgf000147_0002
Figure imgf000147_0003
Example Table 6 (cont). 3-[(N-aryl)[[cycloalkyl]methyl]amino]-halo-2- propanols.
Figure imgf000147_0001
Figure imgf000147_0004
Figure imgf000147_0005
Figure imgf000148_0002
Figure imgf000148_0003
Example Table 6 (cont). 3-[(/V-aryl)[[cycloalkyl]methyl]arnino]-halo-2- propanols.
Figure imgf000148_0001
Figure imgf000148_0004
Figure imgf000148_0005
Figure imgf000149_0001
Figure imgf000149_0002
Example Table 7. 3-[(N-aryl)[[haloalkyl]methyl]amino]-halo-2-propanols.
Figure imgf000150_0001
Figure imgf000150_0002
Figure imgf000150_0003
Figure imgf000151_0002
Figure imgf000151_0003
Example Table 7 (cont) 3-[(V-aryl)[[haloa!kyl]methyl]amιno]-ha!o-2-propanols.
Figure imgf000151_0001
Figure imgf000151_0004
Figure imgf000151_0005
Figure imgf000152_0002
Figure imgf000152_0003
Example Table 7 (cont.).3-[(N-aryl)[[haloalkyl]methyl]amino]-halo-2-propanols.
Figure imgf000152_0001
Figure imgf000152_0004
Figure imgf000152_0005
Figure imgf000153_0002
Figure imgf000153_0003
Example Table 7 (cont).3-[(N-aryl)[[haloalkyl]methyl]amino]-halo-2-propanols.
Figure imgf000153_0001
Figure imgf000153_0004
Figure imgf000153_0005
Figure imgf000154_0001
Figure imgf000154_0002
BIOASSAYS
CETP Activity In Vitro
ASSAY OF CETP INHIBITION USING PURIFIED COMPONENTS (RECONSTITUTED BUFFER ASSAY)
The ability of compounds to inhibit CETP activity was assessed using an in vitro assay that measured the rate of transfer of radiolabeled cholesteryl ester
([ H]CE) from HDL donor particles to LDL acceptor particles. Details of the assay are provided by Glenn, K. C. et al. (Glenn and Melton, "Quantification of Cholesteryl Ester Transfer Protein (CETP): A) CETP Activity and B) Immunochemical Assay of CETP Protein." Meth. Enzymol, 263, 339-351 (1996)). Human recombinant CETP can be obtained from the serum-free conditioned medium of CHO cells transfected with a cDNA for CETP and purified as described by Wang, S. et al. (J. Biol. Chem. 267, 17487-17490 (1992)). To measure CETP activity, [3H]CE-Iabeled-HDL, LDL. CETP and assay buffer (50 mM tris(hydroxymethyl)aminomethane, pH 7.4; 150 mM sodium chloride; 2 mM ethylenediamine -tetraacetic acid (EDTA); 1% bovine serum albumin) were incubated in a final volume of 200 μL, for 2 hours at 37 °C in 96 well plates. Inhibitors were included in the assay by diluting from a 10 mM DMSO stock solution into 16% (v/v) aqueous DMSO so that the final concentration of inhibitor was 800 μM. The inhibitors were then diluted 1:1 with CETP in assay buffer, and then 25 μL of that solution was mixed with 175 μL of lipoprotein pool for assay. Following incubation, LDL was differentially precipitated by the addition of 50 μL of 1% (w/v) dextran sulfate/0.5 M magnesium chloride, mixed by vortex, and incubated at room temperature for 10 minutes. A potion of the solution (200 μL) was transferred to a filter plate (Millipore). After filtration, the radioactivity present in the precipitated LDL was measured by liquid scintillation counting. Correction for non-specific transfer or precipitation was made by including samples that do not contain CETP. The rate of [ HJCE transfer using this assay was linear with respect to time and CETP concentration, up to 25-30% of [ H]CE transferred.
The potency of test compounds was determined by performing the above described assay in the presence of varying concentrations of the test compounds and determining the concentration required for 50% inhibition of transfer of | H|CE from HDL to LDL. This value was defined as the IC50. The IC50 values determined from this assay are accurate when the IC50 is greater than 10 nM. In the case where compounds have greater inhibitory potency, accurate measurements of IC50 may be determined using longer incubation times (up to 18 hours) and lower final concentrations of CETP (< 50 nM). Examples of IC50 values determined by these methods are summarized in Table 3.
Table 3. Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay.
Figure imgf000157_0001

Claims

What we claim is:
The compound having the formula of:
Figure imgf000158_0001
or a pharmaceutically acceptable salt thereof, wherein; n is an integer selected from 1 through 2; A and Q are independently selected from the group consisting of
-CH2(CR37R38)V-(CR33R34)U-T-(CR35R36)V -H,
Figure imgf000158_0002
with the provisos that one of A and Q must be AQ- 1 and that one of A and Q must be selected from the group consisting of AQ-2 and
-CH2(CR37R38)V-(CR33R34)U-T-(CR35R36)W-H;
T is selected from the group consisting of a single covalent bond, O, S, S(O), S(O)2, C(R33)X(R35), and OX, v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R33, R34, R35. and R^ is aryl or heteroaryl; u and w are integers independently selected from 0 through 6; Aj is C(R30);
Dj, D2, J • , J2 and K j are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D j , D9, J j , J9 and K j is a covalent bond, no more than one of
Dj. D2. J j . J and K-j is O. no more than one of D j . D2. J ] . J2 and Kj is S.
one of Dj, D2. J ^. J2 and K j must be a covalent bond when two of Dj , D2-
Jj, J2 and Kj are O and S, and no more than four of Dj. D2. J j. J2 and Kj are N;
B , B . D3, D4, J3, J4 and K2 are independently selected from the
group consisting of C, C(R3Q), N, O, S and a covalent bond with the provisos
that no more than 5 of B j, B2, D3, D4, J3, J and K2 are a covalent bond, no
more than two of B j, B2, D3, D4, J3, J4 and K2 are O, no more than two of
B j, B , D3, D4, J3, J and K2 are S, no more than two of B j, B , D3, D4,
J3, J4 and K2 are simultaneously O and S. and no more than two of B j. B2.
D3, D4, J3, .^ and K2 are N;
B j and D3, D3 and J3, J3 and K2, K2 and J4, J4 and D4, and D
and B2 are independently selected to form an in-ring spacer pair wherein said
spacer pair is selected from the group consisting of C(R33)=C(R35) and N=N with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously
C( 33
Figure imgf000159_0001
and that no more than one of the group of said spacer pairs is
N=N unless the other spacer pairs are other than C(R33)=C(R35), O. N, and S: R is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the group consisting of hydrido, aryl, alkyl. alkenyl. haloalkyl, haloalkoxy, haloalkoxyalkyl. perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y is selected from the group consisting of a covalent single bond,
(CH2)q wherein q is an integer selected from 1 through 2, and (CH2):-0-
(CH^)^ wherein j and k are integers independently selected from 0 through 1; Z is selected from the group consisting of covalent single bond, (CH2)q wherein q is an integer selected from 1 through 2. and (CH2):-O-
(CH^ wherein j and k are integers independently selected from 0 through 1;
R4, Rg, R9. and R J3 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl ;
R30 is selected from the group consisting of hydrido, alkoxy. alkoxyalkyl. halo, haloalkyl. alkylamino. alkylthio. alkylthioalkyl. alkyl. alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R30 is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen:
R3Q, when bonded to A j, is taken together to form an intra-ring linear
spacer connecting the A j -carbon at the point of attachment of R3Q to the point
of bonding of a group selected from the group consisting of RJQ. J J . J2-
R } , and R 2 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members;
R3Q, when bonded to A j, is taken together to form an intra-ring
branched spacer connecting the A j -carbon at the point of attachment of R Q to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs RJQ and R j, R J and R3 j,
R ø and R32, Rjø and Rj2, Rj j and R j, Rj j and R39, Rj j and Rj2, R J
and R32, R3 j and R j2, and R32 and Rj2 and wherein said intra-ring branched spacer is selected to form two rings selected from the group consisting of cycloalkyl having from 3 through 10 contiguous members, cycloalkenyl having from 5 through 10 contiguous members, and heterocyclyl having from 5 through 10 contiguous members;
Rψ R5, R6, R7, R8, R9, R10, Rπ, R12, 13. 31> R32 ' R33> R34, R35, and R3 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfmyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N- heteroarylamino-N-alkylamino, heteroarylaminoalkyLhaloalkylthio, alkanoyloxy, alkoxy. alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfmyl, alkylsulfinylalkyl, arylsulfmylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl. alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl. arylsulfonamido, diarylamidosuifonyl, monoalkyl monoaryl amidosulfonyl. arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonvl, heterocvclylthio, alkanoyl, alkenoylJ aroyl. heteroaroyl. aralkanoyl. heteroaralkanoyl. haloalkanoyl. alkyl. alkenyl. alkynyl. alkenyloxy. alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy. hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl. saturated heterocyclyl, partially saturated heterocyclyl. heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that
R 5> R6. R7> R8> R9' R K> R l l' R 12- R 13< R3 X R32 > R33> R3 R35' and R^β are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the R33 and R34 substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R35 and R^ substituents are simultaneously selected from other than the group consistubg of hydrido and halo ;
R9, jQ> j i> Ri2' R13' R3 I' an(* R32 are independently selected to
be oxo with the provisos that B j , B , D3, D4, J3, J and K2 are independently selected from the group consisting of C and S, no more than two of R9, R JQ, R j j, R j , Rj^, R^ j, and R37 are simultaneously oxo, and that
R9. R JQ. R j j. Rj2- i3- R31- and R3 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen:
R4 and R5, R5 and Rβ, Rβ and R-. R7 and Rg. R9 and RJQ. R JQ and
R j j, R j j and R3 j , R j and R 2, R 2 and R 2, and Rj 2 and Rj are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R^, Rβ and R-j, and R7 and Rg, is used at the same time and that no more than one of the group consisting of spacer pairs R9 and RJQ, R JQ and R j, Rj j and R3 j, R3 j and R3-), R 2 and
Rj2' anc R-12 anc R-13 ιs usec* a* ^ same time;
R9 and Rj j, R9 and R 2, Rg and Rj3, R9 and R3 j, R9 and R32,
Rjø and Rj2, RjQ and Rj3, RjQ and R3 j , R Q and R32, R j j and Rj 2, Rj j
and Rj . Rj and R 2. R 2 and R3 j . Rj and R3 j . and Rj3 and R3 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 3 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 through 8 contiguous members with the provisos that no more than one of said group of spacer pairs is used at the same time;
R37 and R3g are independently selected from the group consisting of hydrido. alkoxy. alkoxyalkyl. hydroxy. amino. thio. halo, haloalkyl. alkylamino, alkylthio, alkvlthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
2. The compound as recited in Claim 1 having the formula of:
Figure imgf000164_0001
or a pharmaceutically acceptable salt thereof, wherein; n is an integer selected from 1 through 2; A and Q are independently selected from the group consisting of
-CH2(CR37R38)V-(CR33R34)U-T-(CR35R36)W-H,
Figure imgf000164_0002
with the provisos that one of A and Q must be AQ- 1 P and that one of A and Q must be selected from the group consisting of AQ-2 and
-CH2(CR37R38)V-(CR33R34)U-T-(CR35R36)W-H;
T is selected from the group consisting of a single covalent bond, 0, S,
Figure imgf000164_0003
v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R33, R34. R35. and R^ is aryl or heteroaryl; u and w are integers independently selected from 0 through 6; Aj is C(R 0);
B j , B2, D3, D4, J3, J4 and K2 are independently selected from the
group consisting of C, QR30). N, O, S and a covalent bond with the provisos
that no more than 5 of B j . B2. D3. D4. J3. J4 and K-> are a covalent bond, no
more than two of B j, B9, D3, D4, J3, J4 and K9 are O. no more than two of
B j, B2. D3, D4, J3. J4 and K2 are S, no more than two of B j, B2. D3, D4.
J3, J4 and K2 are simultaneously O and S, and no more than two of B j. B ,
D3, D4, J3, J4 and K9 are N;
B and D3. D3 and J3. J3 and K2. K2 and J4. J4 and D4. and D4
and B2 are independently selected to form an in-ring spacer pair wherein said
spacer pair is selected from the group consisting of C(R33)=C(R35) and N=N with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously
Figure imgf000165_0001
and that no more than one of the group of said spacer pairs is
Figure imgf000165_0002
O, N, and
S;
R j is selected from the group consisting of haloalkyl and haloalkoxymethyl ; R9 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl. haloalkyl. haloalkoxy, haloalkoxyalkyl. perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl; Y is selected from the group consisting of a covalent single bond, (CH2)q wherein q is an integer selected from 1 through 2, and (CH2):-O-
Figure imgf000166_0001
wherein j and k are integers independently selected from 0 through 1; Z is selected from the group consisting of covalent single bond, (CH2)q wherein q is an integer selected from 1 through 2, and (Q-L- j-O-
(CHo)^ wherein j and k are integers independently selected from 0 through 1;
R3Q is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R Q is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R3Q, when bonded to A , is taken together to form an intra-ring linear
spacer connecting the A j -carbon at the point of attachment of R3Q to the point
of bonding of a group selected from the group consisting of RJQ, R J J , Ri2>
R j , and R39 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members;
R3Q, when bonded to A -j, is taken together to form an intra-ring
branched spacer connecting the A j -carbon at the point of attachment of R3Q to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs Rjø and Rj j, R JQ and R J,
RjQ and R 2, R JQ and Rj2, R J J and R J, Rj j and R32, Rj j and Rj , R3J and R32, R3 j and Rj , and R3 and Rj and wherein said intra-ring branched spacer is selected to form two rings selected from the group consisting of cycloalkyl having from 3 through 10 contiguous members, cycloalkenyl having from 5 through 10 contiguous members, and heterocyclyl having from 5 through 10 contiguous members;
Rψ R5, R6. R7, Rg, R9, R JQ, Rj j, R12. R 13. R3 1. R32 • R33-
R34, R35, and R36 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acvlalkvl. acvlalkoxv. arovlalkoxv. heterocvclvloxv. aralkvlarvl. aralkyl, aralkenyl. aralkynyl, heterocyclyl, perhaloaralkyl. aralkylsulfonyl. aralkylsulfonylalkyl, aralkylsulfmyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycioalkylsulfonylalkyl, heteroarylamino, N- he teroaryl amino-N-alky lamino , he teroary laminoalky 1 ,haloalkyl thio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxv, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfmyl. alkylsulfinylalkyl. arylsulfmylalkyl. arylsulfonylalkyl, heteroarylsulfiny lalkyl, heteroarylsulfonylalkyl. alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl. heterocyclyl sulfonyl, heterocvclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl. aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl. halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl. hydroxyalkyl. hydoxyheteroaralkyl. haloalkoxyalkyl. aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy. phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that R5< R6- R7- R8- R9< RlO- Rl l- R12* R 13- R3 L R32 - R33- R34- R35- and R^ are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the R33 and R34 substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R35 and R^β substituents are simultaneously selected from other than the group consistubg of hydrido and halo;
R9, R , R . R j2. R j3- R3 , and R32 are independently selected to
be oxo with the provisos that B j, B2, D3, D4, J3, J4 and K2 are independently selected from the group consisting of C and S, no more than two of R9, RJ , Rj j , Rj , R| 3, R3 j , and R32 are simultaneously oxo, and that
R9, R Q, R j , R j , R J , R3 j, and R39 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R4 and R5, R5 and Rβ, Rg and R7, R7 and Rg, R9 and RJQ, RJQ and
Rj j, Rj j and R3 j, R3J and R32, R3 and Rj2. and Rj and Rj3 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocycl l ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R and R5, R5 and Rβ, Rβ and R7, and R7 and Rg, is used at the same time and that no more than one of the group consisting of spacer pairs R9 and R JQ, R JQ and Rj j. R and R3 j, R3 j and R o, R32 and
Rj2, and R j2 and R j is used at the same time;
R9 and R j, R9 and Rj2, R9 and Rj , R9 and R3 j, R9 and R 9,
Rj and Rj2, Rj and R 3, RjQ and R3 j , R JQ and R32, Rj j and R j2, Rj j
and R 3, R j and R32, R and R3 , R J and R3 j, and Rj3 and R32 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 3 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 through 8 contiguous members with the provisos that no more than one of said group of spacer pairs is used at the same time: R37 and R3g are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio. alkvlthioalkyl. cyano. alkyl, alkenyl, haloalkoxy. and haloalkoxyalkyl.
3. The compound as recited in Claim 2 having the formula of:
Figure imgf000170_0001
or a pharmaceutically acceptable salt thereof, wherein; n is an integer selected from 1 through 2; A is selected from the group consisting of C3-C 10 cycloalkyl, C5-C 10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R3Q, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R or R j , a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with
R Q, a ring carbon or nitrogen atom adjacent to the R 3 position and two
atoms from the point of attachment may be substituted with R j , a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R JQ position may be substituted with R j j, a ring carbon or nitrogen atom
three atoms from the point of attachment and adjacent to the R j2 position may
be substituted with R3 , and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R j j and R32 positions may be
substituted with R3 j ;
R j is selected from the group consisting of haloalkyl and haloalkoxymethyl; R is selected from the group consisting of hydrido. aryl. alkyl. alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido. aryl. alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl; Y and Z are independently selected from the group consisting of a covalent single bond, oxv and alkvlene;
R4 and Rg are independently selected from the group consisting of hydrido and halo;
R9 and R j3 are halo;
R5, Rβ, and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R5, R5 and Rβ, Rβ and R7. and R7 and Rg are independently- selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and
R^, R^ and Rβ, Rβ and R7, and R7 and Rg, is used at the same time;
RJQ, Rj j, R j2, R3 j, and R32 are independently selected from the group group consisting of alkyl, halo, haloalkyl. haloalkoxy. aryl. alkylthio. arylamino, arylthio, aroyl. arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R3Q is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
4. The compound as recited in Claim 3 or a pharmaceutically acceptable salt thereof, wherein; n is the integer 1 :
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexyl, 4- methyl cyclohexyl, 4-chloro-3-ethylphenoxy cyclohexyl, 3- trifluoromethoxyphenoxycyclohexyl.3-trifiuoromethylcyclohexyl, 4- trifluoromethylcvclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3- trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbomenyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cyclohex-2-enyl, cyclohex-3-enyl, cycloheptyl, cyclohept-2-enyl, cyclohept-3- enyl, cyclooctyl, cyclooct-2-enyl, cyclooct-3-enyl, cyclooct-4-enyl, 2- moφholinyl, 3-morpholinyl, 4-morpholinyl, l-piperazinyl, 2-piperazinyl, 1- piperidinyl, 2-piperidinyl, 3-pipcridinyl, 4-piperidinyl, 1-pyrrolidinyl, 2- pyrrolidinyl, 3-pyrrolidinyl. 2-dioxanyl. 2H-2-pyranyl, 2H-3-pyranyl, 2H-4- pyranyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 2H-pyran-2-one-3-yl, 2H-pyran-2-one-4-yl, 2H-pyran-2-one-5-yl, 4H-pyran-4-one-2-yl, 4H-pyran- 4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3- tetrahydropyranyl, 4-tetrahydropyranyl. 2-tetrahydrothienyl. and 3- tetrahydrothienyl, wherein each ring carbon may be optionally substituted with
R3Q. a ring carbon other than the ring carbon at the point of attachment of A to
Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms _ adjacent to the carbon atom at the point of attachment may be optionally substituted with R or R J3. a ring carbon or nitrogen atom adjacent to the R position and two atoms from the point of attachment may be substituted with
R Q, a ring carbon or nitrogen atom adjacent to the Rj3 position and two
atoms from the point of attachment may be substituted with R j2. a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the RJQ position may be substituted with R j j , a ring carbon or nitrogen atom
three atoms from the point of attachment and adjacent to the Rj2 position may
be substituted with R32, and a ring carbon or nitrogen atom four atoms from
the point of attachment and adjacent to the R j j and R32 positions may be
substituted with R3 j ;
Rj is selected from the group consisting of trifluoromethyl, 1,1,2.2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafiuoroethyl;
R2 is selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, vinyl, phenyl. 4-trifluoromethylphenyl, 1.1.2,2- tetrafluoroethoxymethyl. trifluoromethoxymethyl, difluoromethyl, pentafiuoroethyl, trifluoromethyl, and 2J,3J3-pentafluoropropyl;
R3 is selected from the group consisting of hydrido, phenyl, 4- trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl, trifluoromethoxymethyl. difluoromethyl, chlorodifluoromethyl. and pentafiuoroethyl; Y and Z are independently selected from the group consisting of a covalent single bond, oxy, and methylene with the proviso that only one of Y and Z are simultaneously oxy;
R4 and Rg are independently selected from the group consisting of hydrido and fluoro;
R9 and Rj3 are fluoro;
R5, RJQ and Rj2 are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy.4-bromo-2-nitrophenoxy. 3-bromobenzyloxy. 4-bromobenzyloxy, 4-bromophenoxy, 5-bromoρyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chIoro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2.3-dichlorophenoxy, 2.4-dichlorophenoxy. 2.4-dichlorophenyl. 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluoroρhenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimcthylphcnoxy, 3,4-dimethylbcnzyl, 3,4-dimethylbcnzyloxy. 3,5-dimethylbenzyloxy, 2J-dimethylpropoxy, l,3-dioxan-2-yl, l,4-dioxan-2-yl, l,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyI-5-methylphenoxy. fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyi. 4-fluoro-3-methylbenzoyl.4-fluorobenzyloxy. 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fiuoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethyrDenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy. 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy. 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fIuoro-4-trifluoromethylphenoxy. 4-fluoropyrid-2-y oxy. 2-furyl. 3-furyl, heptafluoropropyl, 1J J ,3 JJ-hexafl uoropropy!.
2-hydroxy-3,3J-trif!uoropropoxy. 3-iodobenzyloxy. isobutyl, isobutylamino. isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio. 4-isopropyl-3-methylphenoxy, 3-isothiazolyl.4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyi, 4-methoxycarbonylbutoxy. 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino.3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1 -methy lpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafiuoroethyl. pentafluoroethylthio. 2J3.3.3-pentafluoropropyl, lJ,3J,3-pentafluoropropyl, lJJ,2,3-pentafluoropropyl, phenoxy. phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyρhenoxy. thiophen-3-yl, ver-butyl, 4-seobutylphenoxy,tert -butoxy. 3-tert -butylphenoxy. 4-tert -butylphenoxy. 1 J JJ-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 23,5-trifluorobenzyloxy, 2,2J-trifluoroethoxy, 2,22-trifiuoroethyl, 3J,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxy benzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromcthylbcnzyloxy.4-trifluoromcthylbcnzyloxy,
2,4-bis-trifluoromethyl benzyloxy, lJ-bis-trifluoromethyl- 1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy. 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2.3,4-trifluorophenoxy. 2,3,4-trifluorophenyl, 2J,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(lJJJ-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifiuoromethylthio; Rβ, R j j , R3 j , and R 2 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafiuoroethyl, 1,1,2,2- tetrafiuoroethoxy, trifluoromethyl, and trifluoromethoxy;
R is selected from the group consisting of hydrido, fluoro, and trifluoromethyl; R3Q is selected from the group consisting of chloro, ethoxy, ethyl, fluoro, heptafluoropropyl, lJ J,3J,3-hexafluoropropyl, isobutyl. isobutoxy, isopropoxy. isopropyl, isopropylthio, methyl pentafiuoroethyl , 2,2,3 ,3 ,3 -pentafluoropropy 1 , 1 ,1 ,3 ,3 ,3 -pentafluoropropyl , 1,1,2,2,3-pentafluoropropyl, propoxy, propyl, iec-butyl, tert -butoxy, 1,1 JJ-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, trifluoromethoxy. and trifluoromethyl.
5. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein; n is the integer 1;
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methyl cyclohexyl, 4-chloro-3- ethylphenoxy cyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3- trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis- trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorboπιyl, norbomenyl, 7-oxabicyclo[2J. l]heptan-2-yl. bicyclo[3J.01hexan-6-yl, cycloheptyl, cyclooctyl. 2-moφholinyl, 3- moφholinyl. 4-moφholinyl. 1-piperazinyl. 2-piperazinyl. 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H- pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3- tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4- tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon may be optionally substituted with R3Q, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R or Rj3. a
ring carbon or nitrogen atom adjacent to the R9 position and two atoms from
the point of attachment may be substituted with RJQ, a ring carbon or nitrogen
atom adjacent to the RJ position and two atoms from the point of attachment
may be substituted with Rj , a ring carbon or nitrogen atom three atoms from
the point of attachment and adjacent to the RJQ position may be substituted
with R j j, a ring carbon or nitrogen atom three atoms from the point of
attachment and adjacent to the Rj2 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R j j and R32 positions may be substituted with R3 j ;
Rj is selected from the group consisting of trifluoromethyl, 1.1,2.2- tetrafluoroetiioxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafiuoroethyl;
R2 is selected from the group consisting of hydrido, methyl, ethyl, phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl, l,l,2,2Jetrafluoroethoxymethyl, difluoromethyl, pentafiuoroethyl, trifluoromethyl, and 2,23,3 ,3-pcntafluoropropyl;
R is selected from the group consisting of hydrido. phenyl.
4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl;
Y and Z are independently selected from a covalent single bond and methylene; R4 and Rg are independently selected from the group consisting of hydrido and fluoro;
R9 and Rj are fluoro;
R5, R JQ and Rj 9 are independently selected from the group consisting of benzyloxy. 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy.
3-bromobenzyloxy. 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methy!phenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy. 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy.4-chlorophenylamino. 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy,2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy. 2.4-difluorophenoxy. 2.5-difluorophenoxy, 3, 5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3, 4-dimethylbenzyl oxy, 3,5-dimethylbenzyloxy, 3.5-dimethylρhenoxy, 3,4-dimethylphenoxy, 13-dioxolan-2-yl , 3-ethylbenzy loxy , 3 -ethy Iphenoxy , 4-ethy laminophenoxy , 3-ethyl-5-methylphenoxy.4-fluoro-3-methylbenzyl. 4-fluorobenzyloxy. 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,
4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropy 1 , 1 ,1 ,1 ,3 ,3 ,3 -hexafluoropropy 1 , 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl. 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy. 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthioρhenoxy, 4-methylphenoxy. 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy. 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafiuoroethyl, pentafluoroethylthio, 2,2,3,33-pentafluoropropyI, lJ,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy. 4-proρoxyphenoxy, thiophen-3-yl.tert -butoxy, 3-tert -butylphenoxy. 4-tert -butylphenoxy, 1 J JJ-tetrafluoroethoxy. tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy). thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2JJ-trifluoroethoxy, 2JJ-trifluoroethyl, 333-trifluoro-2-hydroxyρropyl, trifluoromethoxy, 3-trifluoromethoxvbenzvloxv.4-trifluoromethoxvbenzvloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy , trifluoromethyl. 3-trifluoromethylbenzyloxy, 1 , 1 -bis-trifluoromethyl- 1 -hydroxymethyl, 3 -trifluoromethyl benzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy,
3-trifluoromethylphenyl, 2,3 ,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromefhoxyphenoxy, 3 -pentafluoroethy Iphenoxy, 3-(l ,lJ,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifiuoromethylthio;
Rβ, R j j, R3 j, and R3 are independently selected from the group consisting of chloro. fluoro, hydrido, pentafiuoroethyl, 1,1,2,2- tetrafluoroethoxy , and trifluoromethyl;
R is selected from the group consisting of hydrido, fluoro, and trifluoromethyl;
R3Q is selected from the group consisting of chloro, ethyl, methyl, propyl, fluoro, heptafluoropropyl, lJJ,3,3 -hexafluoropropyl, isobutyl, isopropyl, pentafiuoroethyl, 2J.3,33-pentafluoropropyl, l J,3,33-pentafluoropropyl, lJ JJ3-pentafluoropropyl. .Tec-butyl, 1,1 JJ-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.
6. The compound as recited in Claim 5 or a pharmaceutically acceptable salt thereof, wherein; n is the integer 1:
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3- ethylphenoxycyclohexyi, 3-triftuoromethoxyphenoxycyclohexyi, 3- trifluoromethylcyciohexy 1, 4-trifiuoromethy lcyclohexy I, 3 ,5-bis- trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorborayl, norbomenyl, 7-oxabicyclo[2JJ]heptan-2-yl, bicyclo[3.L0]hexan-6-yl, 2-tεtrahydrofuranyl. 3-tetrahydrofuranyl. 2-tetrahydropyranyl, 3-tetrahydroρyranyl. 4-tetrahydropyranyl, 2-tetrahydrothienyl. and 3-tetrahydrothienyl, wherein a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R j3, a
ring carbon or nitrogen atom adjacent to the R9 position and two atoms from
the point of attachment may be substituted with RJQ, a ring carbon or nitrogen
atom adjacent to the R j3 position and two atoms from the point of attachment
may be substituted with R j2, a ring carbon or nitrogen atom three atoms from
the point of attachment and adjacent to the RJQ position may be substituted
with R j j , a ring carbon or nitrogen atom three atoms from the point of
attachment and adjacent to the R j7 position may be substituted with R39, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R j j and R32 positions may be substituted with R3 j :
R j is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafiuoroethyl; R2 is hydrido, pentafiuoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y is methylene; Z is a covalent single bond;
R4 and Rg are independently selected from the group consisting of hydrido and fluoro:
R9 and Rj 3 are fluoro;
R5, R JQ and Rji are independently selected from the group consisting of 5-bromo-2-fluorophenoxy. 4-chloro-3-ethylphenoxy, cyclopentyl, 2,3- dichlorophcnoxy, 3,4-dichlorophcnoxy, 3-difluoromethoxyphcnoxy, 3,5- dimethy Iphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5- methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, pentafiuoroethyl, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 1 ,1 ,2.2- tetrafluoroethoxy, 3-(l.L2J-tetrafluoroethoxy)phenoxy. 2-(5.6,7.8- tetrahydronaphthyloxy),trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3- trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1J- bis-trifluoromethyl-1-hydroxymethyl, trifiuoromethylthio, and 3- trifluoromethylthiophenoxy;
Rβ, R j j, R3 j, and R are independently selected from the group consisting of chloro, fluoro, hydrido, pentafiuoroethyl, 1,1,2,2- tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido and fluoro.
7. The compound as recited in Claim 5 or a pharmaceutically acceptable salt thereof, wherein; n is the integer 1 ; A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3- ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3- trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis- trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbomyl,"" 3-trifluoromethylnorbornyl. norbomenyl, 7-oxabicyclo[2JJ]heptan-2-yl. bicyclo[3J.0]hexan-6-yl. 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R j3, a
ring carbon or nitrogen atom adjacent to the R9 position and two atoms from
the point of attachment may be substituted with RJQ, a ring carbon or nitrogen
atom adjacent to the R j position and two atoms from the point of attachment
may be substituted with Rj2, a ring carbon or nitrogen atom three atoms from
the point of attachment and adjacent to the RJQ position may be substituted
with R j j , a ring carbon or nitrogen atom three atoms from the point of
attachment and adjacent to the Rj position may be substituted with R 2, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R j j and R32 positions may be substituted with R3 j ;
R j is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafiuoroethyl; R2 is hydrido, pentafiuoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y is a covalent single bond; Z is methylene;
R4 and Rg are independently selected from the group consisting of hydrido and fluoro; R9 and Rj3 are fluoro:
R5, R j Q and R j are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 23- dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5- dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy. 3-ethyl-5- methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 1,1,2.2- tetrafiuoroethoxy, 3-(lJJJ-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8- tetrahydronaphthyloxy),trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3- trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1J- bis-trifluoromethyl-1-hydroxymethyl, trifiuoromethylthio, and 3- trifluoromethylthiophenoxy;
Rβ, R j j, R3 j, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2- tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido and fluoro.
8. The compound as recited in Claim 2 having the formula of:
Figure imgf000184_0001
or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl. C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, and C3-C8 hydroxyhaloalkyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of 33' R34' R35' anc R36 w^ t-ne Provisos ^a R33' R34' R35' anc* R36 must not be attached to the carbon directly linking A to Z and that R33, R 4,
R3^, and R3g must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond; R j is selected from the group consisting of haloalkyl and haloalkoxymethy 1 ;
R2 is selected from the group consisting of hydrido. aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl. perhaloaryloxyalkyl. and heteroaryl; R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl; Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and Rg are independently selected from the group consisting of hydrido and halo; R^, R , R7, R33. R34. 3^. and R^β are independently selected from the group consisting of hydrido. alkyl. halo, haloalkyl. haloalkoxy. aryl. alkylthio, arylamino. arylthio. aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl. cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl. heteroaralkoxy, heterocyclyloxy. aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R , R3 and Rβ, R and R7, and R7 and Rg are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R and
R5. R5 and Rβ. Rβ and R7. and R7 and Rg. is used at the same time:
9. The compound as recited in Claim 8 or a pharmaceutically acceptable salt thereof, wherein; n is the integer 1 ; A is selected from the group consisting of ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butcnyl, 3-butcnyl, .sec-butyl, isobutyl, 2-mcthylpropcnyl, 1 -pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl. 2-pentyl. I -methy 1-2- butenyl, 1- methyl-3-butenyl, 3-pentyl, l-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2- butenyl, 2-methyl-3-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3- butenyl, l -hexyl, 2-hexenyl, 3-hexenyl. 4-hexenyl, 5-hexenyl, 2-hexyl, 1- methyl-2-pentenyl. l-methyl-3-pentenyl. l-methyl^l~pentenyl.3-hexyl. 1- ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2-propenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl. 2-heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, l-methyl-4-hexenyl, l-methyl-5-hexenyl, 3-heptyl, 1- ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-4-pentenyl, l-butyl-2-propenyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 2- octyl. 1 -methyl -2-heptenyl, l-methyl-3-heptenyl. l-methyl-4-heptenyl, 1- methyl-5-heptenyl. l-methyl-6-heptenyl. l-methyl-4-heptenyl. l-methyl-6- heptenyl, 1 -methy 1-2-heptenyl, 3-octyl, l-ethyl-2-hexenyl, l-ethyl-3-hexenyl, 1 -ethyl -4-hexenyl, l-ethy!-5-hexenyl, l-pentyl-2-propenyl, 4-octyl, 1-propyl- 2-pentenyl, l-propyl-3-pentenyl, l-propyl-4-pentenyl, l-butyl-2-butenyl, 1- butyl-3-butenyl, 2J-difluoropropyl, 4-trifluoromethyl-5.5.5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6.6,6-pentafluorohexyl. and 33.3- trifluoropropyl, wherein each member of group A may be optionally- substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34,
R35, and R3g with the provisos that R3 , R34, R35, and R^β must not be
attached to the carbon directiy linking A to Z and that R 3, R3 , R3^, and R^β must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond; Rj is selected from the group consisting of trifluoromethyl, 1,1,2,2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R9 is selected from the group consisting of hydrido, methyl, ethyl, phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl, 1,12,2-tetrafluoroethoxymethyl, difluoromethyl, pentafluoroethyl, trifluoromethyl, and 2,23 3-pentafluoropropyl;
R3 is selected from the group consisting of hydrido, phenyl,
4-trifluoromethylphenyl, methyl, trifluoromethyl. difluoromethyl, and chlorodifluoromethyl; Y and Z are independently selected from a covalent single bond and methylene; R4 and Rg are independently selected from the group consisting of hydrido and fluoro;
R5, R3 , R34, R35, and R^ are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy.3-chlorobenzyloxy. 2-chlorophenoxy. 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3 -chloro-4-ethylphenoxy , 3 -chloro-4-methy 1 phenoxy , 3-chloro-4~fluorophenoxy , 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophcnoxy, 2,4-dichIorophenoxy. 2,4-dichlorophenyl. 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxyJ,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3.5-dimethoxyphenoxy.3-dimethylaminophenoxy.3. -dimethylbenzyloxy. 3 ,5-dimethylbenzyloxy, 3 ,5-dimethylρhenoxy , 3 ,4-dimethylphenoxy , l,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,
4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-fur>'l, heptafluoropropyl, lJJ3 3-hexafluoropropyl, 2-hydroxy-3,33-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy. 3-isopropylphenoxy. isopropylthio. 4-isopropyl-3-methylphenoxy. 3 -isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3- methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, lJ,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1 , 1 JJ-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2.2.2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,33-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,
4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy. trifluoromethyl, 3-trifluoromethylbenzyloxy, lJ-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethyl benzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 23,5-trifluorophenoxy, 3 ,4,5- trime thy Iphenoxy , 3 -difluorome thoxy phenoxy , 3-pentafluoroethylphenoxy, 3-(l,l,2,2-tetrafluoroethoxy)ρhenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifiuoromethylthio; Rβ is selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1 JJ-tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
10. The compound as recited in Claim 9 or a pharmaceutically acceptable salt thereof, wherein; n is the integer 1 ;
A is selected from the group consisting of 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-bulenyl, Λe -butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentyl, l-methyl-2-butenyl, 1- methyl-3-butenyl, 3-pentyl, l-ethyl-2-propenyl, 2-methylbutyl. 2-methyl-2- butenyl, 2-methy 1-3 -butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3- butenyl, l-hexyl. 2-hexenyI, 3-hexenyl. 4-hexenyl, 5-hexenyl, 2-hexyl, 1- methyl-2-pentenyl, l-methyl-3-pentenyl, l-methyl-4-pentenyl, 3-hexyl, 1- ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2-propenyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-4-pentenyl, l-butyl-2-propenyl, l-ethyl-2-hexenyl. l-ethyl-3-hexenyl, l-ethyl-4-hexenyl, l-ethyl-5-hexenyl, l-pentyl-2- propenylJ-propyl-2-pentenyl, l-propyl-3-pentenyl, l-propyl-4-pentenyl, 1- butyl-2-butenyt. l-butyl-3-butenyl. 2,2-difluoropropyl. 4-trifluoromethyl- 5.5,5-trifluoropentyl. 4-trifluoromethylpentyl, 5,5.6.6.6-pentafluorohexyl. and 3,3,3-trifluoropropyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33. R3 ,
R 5, and R g with the provisos that R33. R34, R35, and R3g must not be
attached to the carbon directly linking A to Z and that R33. R34. R35, and R^ must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond; Rj is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is hydrido, pentafluoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y is a covalent single bond;
Z is methylene;
R4 and Rg are independently selected from the group consisting of hydrido and fluoro;
R5, R33, R34, R35, and R3g are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl. 23-dichlorophenoxy. 3,4-dichlorophenoxy, 3- difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3, dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy. 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3- methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert - butylphenoxy , 1,1 ,2,2-tetrafl uoroethoxy ,
3-(lJJJ-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), trifluoromethoxy, 3-trifluoromethoxybenzyloxy3-trifluoiOmethoxyphenoxy, - trifluoromethyl. 3-trifluoromethylbenzyloxy. 1 ,1 -bis-trifluoromethyl- l- hydroxymethyl. trifiuoromethylthio, and 3-trifluoromethylthiophenoxy;
R^ is selected from the group consisting of fluoro and hydrido;
R7 is selected from the group consisting of hydrido and fluoro.
11. The compound as recited in Claim 9 or a pharmaceutically acceptable salt thereof, wherein; n is the integer 1 ;
A is selected from the group consisting of 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, sec-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentyl, l-methyl-2-butenyl, 1- methyl-3-butenyl, 3-pentyl, 1 -ethyl -2-propenyl, 2-methylbutyl, 2-methyl-2- butenyl. 2-methyl-3-butenyl, 3-methylbutyl.3-methyl-2-butenyl, 3-methyl-3- butenyl, l-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexyl, 1- methyl-2-pentenyl, l-methyl-3-pentenyl, l-methyl-4-pentenyl, 3-hexyl, 1- ethyl-2-butenyl, l-ethyl-3-butenyl, l-ρropyl-2-propenyl, l-ethyl-2-pentenyl, 1 -ethy 1-3 -pentenyl, l-ethyl-4-pentenyl, l-butyl-2-propenyl, l-ethyl-2-hexenyl, l-ethyl-3-hexenyl, 1-ethyl^l-hexenyl, l-ethyl-5-hexenyl, l-pentyl-2- propenylJ-propyl-2-pentenyl, l-propyl-3-pentenyl, l-propyl-4-pentenyl, 1- butyl-2-butenyl, l-butyl-3 -butenyl, 2J-difluoropropyl, 4-trifluoromethyl- 5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 333-trifluoropropyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R3 ,
R 5, and R^β with the provisos that R33, R34. R35, and R^β must not be
attached to the carbon directly linking A to Z and that R33, R3 , R35, and R^β must be selected from other than aryl and heteroar l when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
Rj is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; R2 is hydrido. pentafluoroethyl. and trifluoromethyl:
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y is methvlene; Z is a covalent single bond; R4 and Rg are independently selected from the group consisting of hydrido and fluoro;
R , R33, R34, R3^, and R^β are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3- difluoromethoxyphenoxv, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy.3-ethyl-5-methylphenoxy.4-fluoro-3-methylphenoxy. 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3- methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert - butylphenoxy , 1,1 ,2,2- tetrafluoroethoxy , 3-( 1 ,1 JJ-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl , 3 -trifluoromethylbenzyloxy , 1,1 -bis-trifluoromethyl- 1 - hydroxymethyl, trifiuoromethylthio, and 3-trifluoromethylthiophenoxy;
R^ is selected from the group consisting of fluoro and hydrido;
R7 is selected from the group consisting of hydrido and fluoro.
12. The compound as recited in Claim 1 having the formula of:
Figure imgf000192_0001
or a pharmaceutically acceptable salt thereof, wherein; n is an integer selected from 1 through 2; A and Q are independently selected from the group consisting of
-CH2(CR37R3S)V-(CR33R34)U-T-(CR35R36)W-H
Figure imgf000192_0002
with the provisos that one of A and Q must be AQ-IH and that one of A and Q must be selected from the group consisting of AQ-2 and -CH2(CR37R38)V-(CR33R34)U-T-(CR35R36)W-H;
T is selected from the group consisting of a single covalent bond. O, S.
S(O). S(O)2. C(R33)=C(R35). and C≡C: v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R . R34. R3^, and R^ is aryl or heteroaryl; u and w are integers independently selected from 0 through 6;
Aj is C(R30); Dj, D2, J j, J2 and Kj are independently selected from the group consisting of C, N. O, S and a covalent bond with the provisos that no more than one of Dj, D9, J j , J2 and Kj is a covalent bond, no more than one of
Dj. Do, J j, J9 and Kj is 0. no more than one of D j, D9, J j , J9 and Kj is S,
one of Dj . D2. J j . J9 and Kj must be a covalent bond when two of D j . D9.
J j, J9 and Kj are O and S, and no more than four of Dj, D2. Jj, J2 and Kj are N;
B j, B2, D3, D4, J3, J and K are independently selected from the
group consisting of C, C(R Q), N, O, S and a covalent bond with the provisos
that no more than 5 of B j , B2, D3, D4, J3, J4 and K2 are a covalent bond, no
more than two of B j, B2, D , D4, J3, J and K2 are O, no more than two of
Bi , B2, D , D4, J3, J and K2 are S, no more than two of B j, B2, D , D4,
J3, J and K are simultaneously O and S. and no more than two of B j, B2,
D3, D4, J3, J4 and K2 are N:
B j and D3, D3 and J3, J3 and K2. K2 and J4, J4 and D4, and D4
and B9 are independently selected to form an in-ring spacer pair wherein said
spacer pair is selected from the group consisting of
Figure imgf000193_0001
and N=N with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously
Figure imgf000193_0002
and that no more than one of the group of said spacer pairs is
N=N unless the other spacer pairs are other than C(R33)=C(R35), O, N, and S; Rj is selected from the group consisting of haloalkyl and haloalkoxvmethvl;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y is selected from the group consisting of a covalent single bond,
(CH2)q wherein q is an integer selected from 1 through 2, and (CH2):-0-
(CH2)j wherein j and k are integers independently selected from 0 through 1 ; Z is selected from the group consisting of covalent single bond, (CH2)q wherein q is an integer selected from 1 through 2, and (CH2):-O-
(CH2)j wherein j and k are integers independently selected from 0 through 1;
R3Q is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R3Q is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R3Q, when bonded to A -j, is taken together to form an intra-ring linear
spacer connecting the A j-carbon at the point of attachment of R3Q to the point
of bonding of a group selected from the group consisting of RJQ, R J J , RJ ,
R3 J, and R32 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members; R3Q, when bonded to A jJs taken together to form an intra-ring
branched spacer connecting the A j -carbon at the point of attachment of R3Q to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs RJQ and R j j , RJQ and R3 j,
RjQ and R32. RjQ and Rj , Rj j and R j , R J J and R32, Rj j and Rj2, R3 j
and R3 , R j and Rj2, and R 2 and Rj2 and wherein said intra-ring branched spacer is selected to form two rings selected from the group consisting of cycloalkyl having from 3 through 10 contiguous members, cycloalkenyl having from 5 through 10 contiguous members, and heterocyclyl having from 5 through 10 contiguous members;
Rψ R5, R6, R7, Rg, R9, RJQ, Rπ, R12, R13, R31, R32 - R33'
R34, R35, and R3g are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfmyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N- heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxy lalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfmyl, alkylsulfinylalkyl, arylsulfmylalkyl, arylsulfonylalkyl, heteroarylsulfiny lalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diary lamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenylJower cycloalkylalkylJower cycloalkenylalkyl. halo, haloalkyl, haloalkenyl. haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl. heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido. alkylamidocarbonylamido. arylamidocarbonylamido, carboalkoxyalkyl. carboalkoxyalkenyl. carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that Rψ R5, R6, R7, Rg, R9, R10, Rj j, R12, R j3, R3 1, R32 , R33, R34. R35,
and R3g are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the R 3 and R3 substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R^ and R ^ substituents are simultaneously selected from other than the group consistubg of hydrido and halo;
R-9' lO' R l 1' Rl2' ^' R31' anc R^2 are independently selected to
be oxo with the provisos that B j, B2. D3, D4. J , J and K2 are independently selected from the group consisting of C and S, no more than two of R9> R JQ, R J J , R J2. R i3> R3 J , and R32 are simultaneously oxo, and that
R9. R JQ, R j j . j9, R j , R3 j, and R32 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; R4 and R5, R5 and Rβ, Rβ and R7, R7 and Rg, Rg and R JQ, R JQ and
RJ J , R J J and R3 j, R j and R 2, R32 and Rj2, and Rj2 and R j3 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R and R5, R5 and R^, Rβ and R7, and R7 and Rg, is used at the same time and that no more than one of the group consisting of spacer pairs R9 and RJQ, RJQ and Rj j, Rj j and R3 j, R3 j and R32, R 2 and
Rj2, and Rj2 and Rj3 is used at the same time;
R9 and Rj j, R9 and Rj2, R and Rj3, R9 and R3 j, R9 and R32,
RjQ and Rj2. RjQ and Rj . RjQ and R3 j. RjQ and R 2. Rj j and Rjo. Rj j
and Rj3, Rj j and R32, Rj2 and R3 j, Rj and R3 j, and Rj3 and R 2 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 3 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 through 8 contiguous members with the provisos that no more than one of said group of spacer pairs is used at the same time;
R37 and R3g are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio. halo, haloalkyl, alkylamino, alkylthio, alkvlthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
13. The compound as recited in Claim 12 having the formula of:
Figure imgf000198_0001
or a pharmaceutically acceptable salt thereof, wherein; n is an integer selected from 1 through 2; A is selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R3Q, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or Rj3, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with
R JQ, a ring carbon or nitrogen atom adjacent to the R J position and two
atoms from the point of attachment may be substituted with R j2. a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the RJQ position may be substituted with R j j , a ring carbon or nitrogen atom
three atoms from the point of attachment and adjacent to the R j2 position may
be substituted with R3 , and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R j j and R32 positions may be
substituted with R3 j ;
Dj, D , J j, J2 and Kj are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of Dj. D2, J j, J2 and Kj is a covalent bond, no more than one of
Dj, D2, J j, J2 and Kj is O, no more than one of Dj, D2, J j, J2 and Kj is S,
one of D j, D2, J j, J2 and K j must be a covalent bond when two of D j, D2,
J j, J9 and Kj are O and S, and no more than four of Dj, D2, J j, J2 and Kj are N; Rj is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R9 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl; R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and Rg are independently selected from the group consisting of hydrido and halo;
R9 and Rj3 are halo;
Rζ, Rβ, and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl; R4 and R5, R5 and Rβ, R and R7, and R7 and Rg are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R and
R5, R5 and R^, Rβ and R7, and R7 and Rg, is used at the same time;
RJQ, Rj j, Rj , R3 j, and R32 are independently selected from the group group consisting of alkyl, halo, haloalkyl. haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy. cycloalkylalkanoyl, heteroaryl. cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R3Q is selected from the group consisting of alkoxy, alkoxyalkyl, halo. haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
14. The compound as recited in Claim 13 or a pharmaceutically acceptable salt thereof, wherein; n is the integer 1 ;
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexyl, 4- methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3- trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4- trifluoromethylcyclohexyl, 3, bis-trifluoromethylcyclohexyl, adamantyl, 3- trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbomenyl, 7-oxabicyclo[2JJ]heptan-2-yl, bicyclo[3J.0]hexan-6-yl, cyclohex-2-enyl, cydohex-3-enyl, cycloheptyl, cyclohept-2-enyl, cyclohept-3- enyl, cyclooctyl, cyclooct-2-enyl, cyclooct-3-enyl, cyclooct-4-enyl, 2- moφholinyl, 3-moφholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1 -pyrrolidinyl, 2- pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 2H-2-pyranyl, 2H-3-pyranyl, 2H-4- pyranyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 2H-pyran-2-one-3-yl, 2H-pyran-2-one-4-yl, 2H-pyran-2-one-5-yl, 4H-pyran-4-one-2-yl, 4H-pyran- 4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3- tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3- tetrahydrothienyl. wherein each ring carbon may be optionally substituted with
R Q, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R j3, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with RJQ, a ring carbon or nitrogen atom adjacent to the Rj3 position and two
atoms from the point of attachment may be substituted with R j2, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R JQ position may be substituted with R j j , a ring carbon or nitrogen atom
three atoms from the point of attachment and adjacent to the R j2 position may
be substituted with R32, and a ring carbon or nitrogen atom four atoms from
the point of attachment and adjacent to the R j j and R39 positions may be
substituted with R j ;
Dj, D2, J j, J2 and Kj are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4- imidazolyl, 3-pyrazolyl, 4-pyrazolyl, l,2.4-triazol-3-yl, l,2,4-triazol-5-yl, l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l,3,4-oxadiazol-3-yl, 1,3,4- oxadiazol-5-yl, 3-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3- isoxazolyl, 5-isoxazolyl. 2-pyridyl. 3-pyridyl. 4-pyridyl, 2-pyrazinyl. 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-p ridazιnyl, 4-pyridazinyl, l,3,5-triazin-2-yl, l,2,4-triazin-3-yl, l,2,4-triazin-5-yl, lJ,4-triazin-6-yl. lJ,3-triazin-4-yl, 1-indolizinyl, 7-indolizinyl, 1-isoquinolyl, and 2-quinoiyl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R or Rg, a ring carbon atom
adjacent to the R4 position and two atoms from the point of attachment may be
substituted with R5, a ring carbon atom adjacent to the Rg position and two
atoms from the point of attachment may be substituted with R7, and a ring
carbon atom three atoms from the point of attachment and adjacent to the R5
and R7 positions may be substituted with Rg;
Rj is selected from the group consisting of trifluoromethyl, 1,1,2.2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the group consisting of hydrido. methyl, ethyl. propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, 1,1,2,2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, pentafiuoroethyl, trifluoromethyl, and 2,2,3 ,33-pentafluoropropyl;
R is selected from the group consisting of hydrido, phenyl, 4- trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy, and methylene with the proviso that only one of Y and Z arc simultaneously oxy; R and Rg are independently selected from the group consisting of hvdrido and fluoro;
R9 and R j3 are fluoro; R5, R JQ and Rj2 are independently selected from the group consisting of 4-aminophenoxy. benzoyl, benzyl, benzyloxy. 5-bromo-2-fl uorophenox . 4-bromo-3-fl orophenoxy . 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy,
4-chioro-3-ethylphenoxy. 3-chioro-4-fluorobenzyl, 3-chloro-4-fluorophenyi, 3-chloro-2-fluorobenzylox> , 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy. 2-chloro-4-fl uorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy. 4-chloro-3-fl uorophenoxy, 4-chlorophenylamino. 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl. cyclopropylmethoxy. cyclopropoxy. 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difiuorobenzyloxy, 3 ,4-difluorobenzyloxy , 2,5-difl uorobenzylox , 3 ,5-difluorophenoxy , 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2, 4-difl uorophenoxy. 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy. 3-dimethylaminophenoxy. 3.5-dimethylphenoxy. 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 13-dioxan-2-yl, l,4-dioxan-2-yl, l,3-dioxolan-2-yl, ethoxy. 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro. 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3 -methylphenoxy, 3-fiuoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,
3-fluoro-5-lrifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromεthylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafl uoropropy 1, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutyiamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isoρropyl-3-methyiphenoxy.3-isothiazolyl.4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylρropoxy. 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazotyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2J333-pentafluoroρropyl, lJ,3,3,3-pentafluoropropyl, lJJJ,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy.tert -butoxy, 3-tert -butylphenoxy, 4-fert -butylphenoxy, 1 , 1 JJ-tetrafluoroethoxy, tetrahydrof uran-2-yl , 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2JJ-trifluoroethoxy, 2JJ-trifluoroethyl, 333-trifluoro-2-hydroxyρropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy.4-trifluoromethoxybenzyloxy. 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,
2,4-bis-trifluoromethylbenzyloxy, lJ-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3 ,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromcthylthiobcnzyloxy, 2,3,4-trifluorophenoxy,
23,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy.
3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy,
3-( 1 J JJ-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifiuoromethylthio; Rβ, R j j, R3 j, and R32 are independently selected from the group consisting of chloro, fluoro. hydrido, pentafluoroethyl. 1 ,1 JJ- tetrafluoroethoxy, trifluoromethyl. and trifluoromethoxy;
R is selected from the group consisting of hydrido, fluoro, and trifluoromethyl;
R Q is selected from the group consisting of chloro, ethoxy, ethyl, fluoro, heptafluoropropyl, l J J,3.3,3-hexafluoropropyl, isobutyl, isobutoxy, isopropoxy. isopropyl, isopropylthio, methyl, pentafluoroethyl, 2,2,3 3 -pentafluoropropyl, lJ3,33-pentafluoropropyl, 1 JJJ3-ρentafluoropropyl. propoxy. propyl. sec-butyl, tert -butoxy, 1,1 JJ-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.
15. The compound as recited in Claim 14 or a pharmaceutically acceptable salt thereof, wherein; n is the integer 1 ;
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl. cyclohexyl, 4-methylcyclohexyl, 4-chloro-3- ethylphenoxycyclohexyl. 3-trifluoromethoxyphenoxycyclohexyl, 3- trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis- trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbomyl, 3-trifluoromethylnorbomyl, norbomenyl, 7-oxabicyclo[2JJ]heptan-2-yl, bicyclo[3J.0]hexan-6-yl, cycloheptyl, cyclooctyl. 2-moφholinyl, 3- moφholinyl. 4-moφholinyl, 1-piperazinyl. 2-piperazinyl. 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-piperidinyI, 1 -pyrrolidinyl. 2-pyrrolidinyl, 3- pyrrolidinyl. 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H- ρyran-4-one-2-yl, 4H-ρyran-4-one-3-yl, 2-tetrahydrofuranyl, 3- tetrahydrofuranyl, 2-tetrahydrυpyranyl, 3-tetrahydropyranyl, 4- tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon may be optionally substituted with R Q, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R or Rj3, a
ring carbon or nitrogen atom adjacent to the R9 position and two atoms from ~
the point of attachment may be substituted with RJ Q. ring carbon or nitrogen
atom adjacent to the Rj3 position and two atoms from the point of attachment
may be substittited with Rj2, a ring carbon or nitrogen atom three atoms from
the point of attachment and adjacent to the RJQ position may be substituted
with RJ J , a ring carbon or nitrogen atom three atoms from the point of
attachment and adjacent to the Rj 2 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R j j and R32 positions may be substituted with R3 j ;
Dj, D2. J j. J2 and Kj are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl. 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4- imidazolyl, 3-pyrazolyl. 4-pyrazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl. 5- isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, l,3,5-triazin-2-yl, 1- indolizinyl, 7-indolizinyl, 1-isoquinolyl, and 2-quinolyl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or Rg, a ring carbon atom adjacent to the R position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the Rg position and two atoms from the point of
attachment may be substituted with R7, and a ring carbon atom three atoms from the point of attachment and adjacent to the R5 and R7 positions may be
substituted with R^;
Rj is selected from the group consisting of trifluoromethyl, 1,1,2,2- _ tetrafluoroethoxy methyl, trifluoromethoxymethyl. difluoromethyl. chlorodifluoromethyl. and pentafluoroethyl:
Ro is selected from the group consisting of hydrido. methyl, ethvl, phenyl. 4-trifluoromethylphenyl. trifluoromethoxymethyl, lJJJ-tetrafluoroethoxymethyl, difluoromethyl. pentafluoroethyl, trifluoromethyl, and 2,2,3 ,3,3-pentafluoropropyl; R3 is selected from the group consisting of hydrido, phenyl,
4-trifluoromethylphcnyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl;
Y and Z are independently selected from a covalent single bond and methylene; R4 and Rg are independently selected from the group consisting of hydrido and fluoro;
R9 and Rj3 are fluoro;
R5. R JQ and Rj2 are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy. 4-chloro-3-ethylphenoxy. 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylρhenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl. cyclopentylcarbonyl. cyclopropylmethoxy. 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3.4-dichlorophenoxy, 3,4-difluorophenoxy,23-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3, 5-difl uorophenoxy, 3,4-difluorophenyl,
2.3-difl uorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy,3-dimethylaminophenox\ . 3,4-dimethylbenzyloxy, 3.5-dimethylbenzyloxy, 3.5-dimethylphenoxy, 3,4-dimethylphenoxy, l,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy. 3-f!uoro-4-methyiphenoxy. 3-fluorophenoxy. 3-fluoro-2-nitrophenoxy. 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethy!benzyloxy, 2-fluorophenoxy, 4-fluorophenoxy. 2-fluoro-3-trifluoromethy!phenoxy, 2-fluorobenzyloxy. 4-fluorophenylamino, 2-fluoro-4-trifluoromethyl phenoxy, 2-furyl, 3-furyl, heptafluoropropyl. lJJ 333-hexafIuoropropyl, 2-hydroxy-333-trifluoropropoxy. isobutoxy, isobutyl. 3-isoxazolyl. 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy. isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl,
4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3- methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1 -methy lpropoxy, 2-methyiρyrid-5-yloxy. 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy. 3-nitrophenyl. 2-oxazolyl. 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2 ,2,3 ,3 ,3 -pentafluoropropyl , 1 J ,3 ,3 ,3 -pentafluoropropy 1 , l,l,2J3-pentafluoropropyl, phenoxy, phenylamino. 1-phenylethoxy, 4-propy Iphenoxy.4-propoxyphenoxy. thiophen-3-yl.tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1J JJ-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2JJ-trifluoroethoxy, 2JJ-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromcthylbcnzyloxy, lJ-bis-trifluoromcthyl-1-hydroxymcthyl. 3 -trifluoromethyl benzyl. 3,5-bis-trifluoromethylbenzyloxy. 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 23,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy. 3-( 1 J JJ-tetrafluoroethoxy )phenoxy. 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzy loxy, and trifiuoromethylthio;
Rβ, Rj j, R3 j, and R 2 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2- tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido. fluoro. and trifluoromethyl;
R3Q is selected from the group consisting of chloro, ethyl, fluoro. heptafluoropropyl, lJJ,333-hexafluoropropyl, isobutyl, isopropyl, methyl, pentafluoroethyl, 2,2333-pentafluoroρropyl, lJ333-pentafluoropropyl. lJJJ,3-pentafluoropropyl, propyl, sec-butyl, 1J JJ-tetrafluoroethoxy, 2,2J-trifluoroethoxy, 2,2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.
16. The compound as recited in Claim 15 or a pharmaceutically acceptable salt thereof, wherein: n is the integer 1 ;
A is selected from the group consisting of cyclopropyl, cyclobutyl. cyclopentyl, cyclohexyl, 4-methylcyciohexyl, 4-chloro-3- ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycycIohexyl, 3- trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis- trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbomenyl, 7-oxabicyclo[2JJ]heptan-2-yl, bicyclo[3J.0]hexan-6-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2- tetrahydrothienyl, and 3-tetrahydrothienyl, wherein a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R j3, a ring
carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R JQ, a ring carbon or nitrogen
atom adjacent to the R j 3 position and two atoms from the point of attachment
may be substituted with Rj 2, a ring carbon or nitrogen atom three atoms from _
the point of attachment and adjacent to the RJ position may be substituted
with RJ J , a ring carbon or nitrogen atom three atoms from the point of
attachment and adjacent to the Rj2 position may be substituted with R3 , and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the Rj j and R32 positions may be substituted with R3 j;
Dj, D9, J j, J9 and Kj are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4- imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl.3-pyridazinyl.4-pyridazinyl. and 13.5-triazin-2-yl. wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or Rg, a ring carbon atom adjacent to the R4 position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the Rg position and two atoms from the
point of attachment may be substituted with R7, and a ring carbon atom three
atoms from the point of attachment and adjacent to the R5 and R7 positions
may be substituted with Rg;
R j is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is hydrido. pentafluoroethyl, and trifluoromethyl; R3 is selected from the group consisting of hydrido. methyl, trifluoromethyl, and difluoromethyl Y is a covalent single bond: Z is methylene; R4 and Rg are independently selected from the group consisting of hydrido and fluoro:
R9 and Rj3 are fluoro;
R5, RJQ and Rj2 are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl. 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy,
3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy.
3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy,
2-furyl. isobutyl, isopropoxy. 3-isopropylphenoxy. 3-methylphenoxy. pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 1,1 JJ-tetrafluoroethoxy, 3-(l,l,2,2-tetrafluoroethoxy)phenoxy,
2-(5,6,7,8-tetrahydronaphthyloxy),trifluoromethoxy,
3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl,
3-trifluoromethylbenzyloxy, lJ-bis-trifluoromethyl-1 -hydroxy methyl, trifiuoromethylthio, and 3-trifluoromethylthiophenoxy; Rβ, R j j , R3 j , and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2- tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido and fluoro.
17. The compound as recited in Claim 15 or a pharmaceutically acceptable salt thereof, wherein; n is the integer 1;
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3- ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3- trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis- trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl. 3-trifluoromethylnorbomyl, norbomenyl, 7-oxabicyclo[2JJ]heptan-2-yl, bicyclo[3J.0]he.\an-6-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2- tetrahvdrothienvl, and 3-tetrahvdrothienvl, wherein a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R or Rj3, a ring
carbon or nitrogen atom adjacent to the R position and two atoms from the
point of attachment may be substituted with RJQ, a ring carbon or nitrogen
atom adjacent to the R j3 position and two atoms from the point of attachment
may be substituted with R j , a ring carbon or nitrogen atom three atoms from
the point of attachment and adjacent to the RJQ position may be substituted
with RJ J , a ring carbon or nitrogen atom three atoms from the point of
attachment and adjacent to the Rj2 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R j j and R32 positions may be substituted with R3 j ;
Dj. Do, J j, J2 and Kj are independently selected from the group consisting of C. N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4- imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-lriazin-2-yl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or Rg, a ring carbon atom adjacent to the R4 position and two atoms from the point of attachment may be substituted with R5. a ring carbon atom adjacent to the Rg position and two atoms from the
point of attachment may be substituted with R7, and a ring carbon atom three
atoms from the point of attachment and adjacent to the R5 and R7 positions
may be substituted with Rg;
R j is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is hydrido, pentafluoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y is methylene;
Z is a covalent single bond;
R4 and R are independently selected from the group consisting of hydrido and fluoro;
R9 and Rj3 are fluoro;
R5, RJQ and Rj9 are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3 -ethyl phenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4~fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy. 3-isopropylphenoxy, 3-methylphenoxy. pentafluoroethyl. 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 1 ,1 JJ-tetrafluoroethoxy, 3-( lJ JJ-tetrafluoroethoxy )phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy),trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, lJ-bis-trifluυromethyl-1-hydroxymethyl, trifiuoromethylthio, and 3-trifluoromethylthiophenoxy; Rg, Rj j, R3 j, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1 ,1 JJ- tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido and fluoro.
18. A compound as recited in Claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclohexylmethyI)amino]-lJJ- trifluoro-2-propanol ;
3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopentylmethyl)amino]- 1 , 1,1- trifluoro-2-propanol;
3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopropylmethyl)amino]-lJJ- trifluoro-2-propanol ;
3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl- methyl]amino]- 1 , 1 J-trifluoro-2-propanol; 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl- methyl]amino]- 1,1,1 -trifluoro-2-propanol;
3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl- methyl]amino]- 1 ,1 ,1 -trifluoro-2-propanol ;
3-[[3-(4-chloro-3-ethylphenoxy)phenyl] [[3-( 1 , 1 ,2,2- tetrafluoroethoxy)cyclo-hexylmethyl]amino]- 1 , 1 , l-trifluoro-2-propanol ;
3-[[3-(3-trifluoromethoxyphenoxy)ρhenyl](cyclohexylmethyl)amino]- 1 J J -trifluoro-2-propanol ;
3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopcntylmcthyl)amino]- 1 J J -trifluoro-2-propanol ; 3-[[33-trifluoromethoxyphenoxy)phenyl](cyclopropylmethyl)amino]- 1 J J - trifluoro-2-propanol ;
3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl- methyl ]amino]- 1 J J -trifluoro-2-propanol ; 3-||3-(3-trifluoromethoxyphenoxy)phenyl||(3-pentafluoroethyl)cyclohexyl- m ethyl ]amino]- 1 J J -trifluoro-2-propanol ;
3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3- trifluoromethoxy)cyclohexyl-methyl]amino]-lJJ-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(l JJJ- ~ tetrafluoroethoxy)cyclo-hexylmethyl]amino]- 1,1,1 -trifluoro-2-propanol :
3-[[3-(3-isopropylphenoxy)phenyl](cyc!ohexylmethyl)amino]- lJJ- trifluoro-2-propanol ;
3-[[3-(3-isopropylphenoxy)phenyl] cyclopentylmethyl)amino]-lJJ- trifluoro-2-propanol ;
3-[[3-(3-isopropylphenoxy)phenyl](cyclopropylmethyl)amino]-l,Ll- trifluoro-2-propanol ;
3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl- methyl]amino]-lJJ-trifluoro-2-propanol; 3-[[3-(3-isopropylphenoxy)phenyl][(3-pentafluoroethyl)cyciohexyl- methyl]amino]- 1 J J -trifluoro-2-propanol ;
3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl- methyl]amino]-lJJ-trifluoro-2-propanol;
3-[[3-(3-isopropylphenoxy)phenyl|[[3-( lJJJ-tetrafluoroethoxy)cyclo- hexyl]methyl]amino]- 1 , lJ-trifluoro-2-propanol;
3-[[3-(23-dichlorophenoxy)phenyl](cyclohexylmethyl)amino]- 1 ,1 ,1- trifIuoro-2-propanol ;
3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopentylmethyl)amino]-lJJ- trifluoro-2-propanol ; 3-[[3-(23-dichlorophenoxy)phenyl] cyclopropylmethyl)amino]-lJJ- trifluoro-2-propanol ;
3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl- methyl]amino]-lJJ-trifluoro-2-propanol;
3-[[3-(2,3-dichlorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl- methy 1 ]amino]- 1 J J -trifluoro-2-propanol;
3-[[3-(23-dichlorophenoxy)pheny!][(3-trifluoromethoxy)cyclohexyl- methyl |amino|- 1 J J -trifluoro-2-propanol;
3-[[3-(23-dichlorophenoxy)phenyl][[3-( 1 , 1 JJ-tetrafluoroethoxy)cyclo- hexylmethylja ino]- 1 J J -tri fluoro- 2- propanol: 3-| |3-(4-fluorophenoxy)phenyl |(cyclohexylmethyI)amino|-lJJ-trifluoro- 2-propanol;
3-[[3-(4-fluorophenoxy)phenyl](cyclopentylmethyl)amino]-lJJ-trifluoro- 2-propanol; 3-[[3-(4-fluorophenoxy)phenyl](cyclopropylmethyl)amino]-lJJ-trifluoro-
2-propanol;
3-[[3-(4-fluorophenoxy)phenyl][(3-trif!uoromethyl)cyclohexyl- methyljamino]- 1,1,1 -trifluoro-2-propanol;
3-[[3-(4-fluorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl- methyl jamino]- 1 J J -trifluoro-2-propanol ;
3-[[3-(4-fluorophenoxy phenyl][(3-trifluoromethoxy)cyclohexyl- methyl]amino]- 1,1,1 -trifluoro-2-propanol ;
3-[[3-(4-fluorophenoxy)phenyl][[3-( 1 J JJ-tetrafluoroethoxy)cyclo- hexylmethyl]amino]- 1 , 1 J-trifluoro-2-propanol ; 3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclohexylmethyl)amino]-
1 ,1 , l-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopentylmethyl)amino]- 1 J J -trifluoro-2-propanol ;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopropylmethyl)amino]- lJJ-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3- trifluoromethyl)cyclohexyl-methyl]amino]- 1 J J -trifluoro-2-propanol ;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3- pentafluoroethyl)cyclohexyl-methyl]amino]- 1 J J -trifluoro-2-propanol ; 3-[[3-(3-trifl uoromethoxy benzyloxy )phenyl] [(3- trifluoromethoxy)cyclohexyl-methyl]amino]- 1 J J -trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl] [[3-( 1 , 1 ,2,2- tetrafluoroethoxy)-cyclohexylmethyl]amino]- 1 , 1 J -trifluoro-2-propanol;
3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclohexylmethyl)amino]- lJJ-trifluoro-2-propanol;
3-|[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopentylmethyl)amino|- 1 , 1 J-trifluoro-2-propanol;
3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopropylmethyl)amino]- 1 ,1 , 1 -tri fl uoro-2-propanol ; 3-[[3-(3-trifluoromethylbenzyloxy)phenyl ||(3-trifluoromethyl)cyclohexyl- methyl]amino]- 1 J J -trifluoro-2-propanol ;
3-[[3-(3-trifluoromethylbenzyIoxy)phenyl][(3-pentafluoroethyl)cyclohexyl- methyljamino]- 1 J J -trifluoro-2-propanol ; 3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3- trifluoromethoxy)cyclohexy!-methyl]amino]- 1 J J -trifluoro-2-propanol :
3-[[3-(3-trifluoromethylbenzyloxy)phenyl][[3-( lJJJ- tetrafluoroethoxy)cyclo-hexylmethyl]amino]- 1 J J-trifluoro-2-propanol;
3-[[[(3-trifluoromethyl)phenyljmethyl](cyc!ohexyl)amino]-l,lJ-trifluoro- 2-propanol;
3-[[[(3-pentafluoroethyl)phenyl]methylJ(cyclohexyl)amino]-lJJ-trifluoro- 2-proρanol;
3-[[[(3-trifluoromethoxy)phenyl |methyl](cyclohexyl)amino]-lJJ- trifluoro-2-propanol ; 3-[[[3-(lJ JJ-tetrafluoroethoxy )phenyIjmethyl](cyclohexyl)amino]-
1 J J -trifluoro- 2-propanol ;
3-[[[(3-trifluoromethyl)phenyl]methyl](4-methylcyclohexyl)amino]-lJJ- trifluoro-2-proρanol ;
3-[[[(3-pentafluoroethyl)phenyl]methyl](4-methylcyclohexyl)amino]-lJJ- trifluoro-2-propanol ;
3-[[[(3-trifluoromethoxy)phenyl]methyl](4-methylcyclohexyl)amino]- 1 J J -trifluoro- 2-propanol;
3-[[[3-(lJJJ-tetrafluoroethoxy)phenyl]methyl](4- methylcyclohexyDamino]- 1,1 , 1-trifluoro- 2-propanol ; 3-[[[(3-trifluoromethyl)pheny l]methyl](3- trifluoromethylcyclohexyl)amino]- 1 ,1 ,1 -trifluoro-2-propanol ;
3-[[[(3-pentafluoroethyl)phenyl]methyl](3- trifluoromethylcyclohexyl)amino]- 1 J J -trifluoro- 2-propanol ;
3-[[[(3-trifluoromethoxy)phenyl]methyl](3- trifluoromcthylcyclohexyl)amino]- 1 J J -trifl uoro-2-propanol ;
3-[[[3-( lJJJ-tetrafluoroethoxy)phenyl]methyl](3-trifluoromethylcyclo- hexyl)amino j- 1 , 1 , 1 -trifl uoro-2-propanol;
3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo- hexyl]amino]-l ,1 ,1 -trifluoro-2-propanol; 3-[r[(3-pentafluoroethyl)phenyl|methyl ||3-(4-chloro-3-ethylphenoxy)cyclo- hexyljamino]- 1 J J -trifl uoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chioro-3- ethy Iphenoxy )cyclo-hexyl] amino]- 1 ,1 , 1 - trifl uoro-2-propanol; 3-[[[3-(lJJJ-tetrafluoroethoxy)phenyl]methyl] [3-(4-chloro-3- ethylphenoxy)-cyclohexyl]amino]- 1 ,1 ,1 -trifluoro-2-ρropanol:
3-[[[(3-trifluoromethyl)phenyl|methyl](3-phenoxycyc!ohexyl)amino]- 1 J J -trifl uoro-2-propanol;
3-[[[(3-pentafluoroethyl)phenyl]methyl](3-phenoxycyclohexyl)amino]- lJJ-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)ρhenyl]methyl](3-phenoxycyclohexyπamino]- 1ΛΛ -trifl uoro-2-propanol ;
3-[[[3-(lJJ,2-tetrafluoroethoxy)phenyl|methyl](3- phenoxycyclohexyl)amino]- 1 , 1 J-trifluoro-2-propanol; 3-[[[(3-trifIuoromethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-
1 ,1 , 1 -trifl uoro-2-propanol ;
3-[[[(3-pentafluoroethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]- 1 J J -trifl uoro-2-propanol ;
3-[[[(3-trifluoromethoxy)phenyl]methyl](3-isopropoxycyclohexyl)amino]- lJJ-trifluoro-2-propanol;
3-[[[3-(lJ,2,2-tetrafluoroethoxy)ρhenyl]methyl](3- isopropoxycyclohexyl)-amino]-lJJ-trifluoro- 2-propanol;
3-[[[(3-trifluoromethyl)phenyl]methyl](3- cyclopentyloxycyclohexyDamino]- 1 JJ-trifluoro-2-propanol; 3-[[[(3-pentafluoroethyl)phenyl]methyl](3- cyclopentyloxycyclohexyl)amino]- 1 , 1 J-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl](3- cycloρentyloxycyclohexyl)amino]- 1 , 1 J-trifluoro-2-proρanol ;
3-[[[3-( 1 , 1 ,2J-tetrafluoroethoxy)phenyl]methyl](3- cyclopentyloxycyclohcxyl)-amino]-lJJ-trifluoro- 2-propanol;
3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl|(3- isopropoxycyclohexyl)amino|- 1 , 1 J-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-cyclopentyloxycyclohexyl)- amino]- 1 ,1 ,1 -trifl uoro-2-propanol ; 3-[[[(2-trifluoromethyl)pyrid-6-yl|methyl|(3-phenoxycyclohexyl)amino|- 1 ,1 ,1 -trifluoro-2-propanol ;
3-[[[(2-trifluoromethyl)pyrid-6-yl]methyI](3- trifluoromethylcyclohexyl)amino]-lJJ-trifluoro- 2-propanol; 3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(4-chloro-3- ethylphenoxy)cyclo-hexyl]amino]- 1 J J -trifl uoro-2-propanol :
3-[[[(2-trifluoromethyl)pyrid-6-yl Jmethyl][3-( 1 , 1 JJ- tetrafluoroethoxy )cyclo-hexyl]amino]- 1 J J -trifluoro- 2-propanol;
3-[[[(2-trifluoromethyl)pyrid-6-ylJmethyl](3-pentafluoroethylcyclohexylh amino]- 1 J J -trifluoro-2-propanol ;
3-[[[(2-trifluoromethyl)pyrid-6-ylJmethyll(3-trifluoromethoxycyclohexyl - amino] -1,1.1 -trifluoro-2-propanoI :
3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3- ethylphenoxy)propyl]-amino]- 1 ,1 , 1 -trifluoro-2-propanol ; 3-[[[(3-ρentafluoroethyl)phenyl]methyl][3-(4-chloro-3- ethylphenoxy)propyl]-amino]-lJJ-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3- ethylphenoxy)propyl]-amino]- 1 , 1 , l-trifluoro-2-propanol;
3-[[[3-(lJ,2,2-tetrafluoroethoxy)ρhenyl]methyl] [3-(4-chloro-3- ethylphenoxy)-propyl] amino]- 1 J J-trifluoro-2-propanol;
3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,- di-fluroropropyl]amino]- 1 ,1 ,1 -trifl uoro-2-proρanol ;
3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2J. di-fluroropropyl]amino]- 1 , 1 J-trifluoro-2-propanol; 3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-
2,2,-di-fluroropropyl]amino]- 1,1,1 -trifluoro-2-propanol ;
3-[[[3-(lJ,2,2-tetrafluoroethoxy)phenyl]methyl] [3-(4-chloro-3- ethylphenoxy)- 2,2,-difluroropropyl]amino]-lJJ-trifIuoro-2-propanol;
3-[[[(3-trifluoromethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]- lJJ-trifluoro-2-propanol;
3-[[|(3-pentafluoroethyl)phenyl]methyl][3-(isopropoxy)propyl[amino|- 1 J ,1 -trifl uoro-2-propanol ;
3-l[[(3-trifluoromethoxy)phenyl]methyl][3-(isopropoxy)propyl]amino]- 1 ,1 ,1 -trifl uoro-2-propanol ; 3-| | |3-( lJJJ-tetrafluoroethoxy)phenyl|methyl |[3- (jsopropoxy)propyl]amino] -lJJ-trifluoro-2-propanol; and
3-[[[3-(lJ,2,2-tetrafiuoroethoxy)phenyl]methyl][3- (phenoxy)propy ljamino] -1,1,1 -trifluoro-2-propanol. 5
19. A pharmaceutical composition comprising a compound of one of claims 1 through 18 together with a pharmaceutically acceptable carrier.
20. A method of treating coronary arten disease or other CETP-mediated 0 disorders in a subject by administering a therapeutically effective amount of a compound of one of claims 1 through 18.
21. A method of preventing coronary artery disease or other CETP-mediated 5 disorders in a subject by administering a therapeutically effective amount of a compound of one of claims 1 through 18.
22. A method of treating or preventing cerebral vascular accident (CVA) or o other CETP-mediated disorders in a subject by administering a therapeutically effective amount of a compound of one of claims 1 through 18.
23. A method of treating or preventing dyslipidemia and other CETP- mediated disorders in a subject by administering a therapeutically effective amount of a compound of one of claims 1 through 18.
PCT/US1999/022123 1998-09-25 1999-09-23 Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity WO2000018723A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP99948431A EP1115694A1 (en) 1998-09-25 1999-09-23 Substituted n-aliphatic-n-aromatic (tertiary)-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity
CA002345108A CA2345108A1 (en) 1998-09-25 1999-09-23 Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity
JP2000572185A JP2002525350A (en) 1998-09-25 1999-09-23 Substituted N-aliphatic-N-aromatic tertiary heteroalkylamines effective for inhibiting cholesterol ester transfer protein activity
AU61610/99A AU6161099A (en) 1998-09-25 1999-09-23 Substituted n-aliphatic-n-aromatic (tertiary)-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10166098P 1998-09-25 1998-09-25
US60/101,660 1998-09-25

Publications (1)

Publication Number Publication Date
WO2000018723A1 true WO2000018723A1 (en) 2000-04-06

Family

ID=22285773

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/022123 WO2000018723A1 (en) 1998-09-25 1999-09-23 Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity

Country Status (5)

Country Link
EP (1) EP1115694A1 (en)
JP (1) JP2002525350A (en)
AU (1) AU6161099A (en)
CA (1) CA2345108A1 (en)
WO (1) WO2000018723A1 (en)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003000295A2 (en) * 2001-06-21 2003-01-03 Pfizer Products Inc. Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors
WO2003063832A1 (en) 2002-02-01 2003-08-07 Pfizer Products Inc. Pharmaceutical compositions comprising a solid amorphous dispersion of cholesteryl ester transfer protein inhibitors
WO2004020393A1 (en) * 2002-08-30 2004-03-11 Japan Tobacco Inc. Dibenzylamine compound and medicinal use thereof
US7094801B2 (en) 2001-12-19 2006-08-22 Atherogenics, Inc. Chalcone derivatives and their use to treat diseases
US7115279B2 (en) 2000-08-03 2006-10-03 Curatolo William J Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US7202247B2 (en) 2001-12-19 2007-04-10 Atherogenics, Inc. 1,3-bis-(substituted-phenyl)-2-propyn-1-ones and their use to treat disorders
US7276536B2 (en) 2003-03-17 2007-10-02 Japan Tobacco Inc. Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino) phenyl] 2-methylpropanethioate
US7365085B2 (en) * 2002-03-27 2008-04-29 Smithkline Beecham Corporation Compounds and methods
EP1961419A1 (en) 2002-12-20 2008-08-27 Pfizer Products Inc. Dosage forms comprising a CETP inhibitor and an HMG-CoA reductase inhibitor
EP2275091A1 (en) 2001-06-22 2011-01-19 Pfizer Products Inc. Pharmaceutical compositions comprising adsorbates of an amorphous drug
US7887840B2 (en) 2001-06-22 2011-02-15 Bend Research, Inc. Pharmaceutical compositions comprising drug and concentration-enhancing polymers
EP2283822A2 (en) 2003-08-04 2011-02-16 Bend Research, Inc. Spray drying processes for forming solid amorphous dispersions of drugs and polymers
EP2316447A1 (en) 2003-09-26 2011-05-04 Japan Tobacco, Inc. Method of inhibiting remnant lipoprotein production
EP2548894A1 (en) 2005-02-03 2013-01-23 Bend Research, Inc. Pharmaceutical compositions with enhanced performance
US9023393B2 (en) 2003-08-04 2015-05-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US9468604B2 (en) 2001-06-22 2016-10-18 Bend Research, Inc. Pharmaceutical compositions of dispersions of drug and neutral polymers
US9486410B2 (en) 2002-02-01 2016-11-08 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1942428A (en) * 2004-04-13 2007-04-04 默克公司 CETP inhibitors
WO2006098394A1 (en) * 2005-03-14 2006-09-21 Japan Tobacco Inc. Method for inhibiting lipid absorption and lipid absorption inhibitor

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2700686A (en) * 1951-02-15 1955-01-25 Eastman Kodak Co Hydroxy substituted polyfluorinated compounds
WO1996004249A1 (en) * 1994-08-05 1996-02-15 Sri International Fluorinated 2-nitroimidazole analogs for detecting hypoxic tumor cells
GB2305665A (en) * 1995-09-26 1997-04-16 Merck & Co Inc Selective ß3 agonists for the treatment of diabetes aand obesity
EP0801060A1 (en) * 1996-04-09 1997-10-15 Pfizer Inc. Heterocyclic Beta-3 Adrenergenic Agonists
EP0818197A1 (en) * 1996-07-08 1998-01-14 Bayer Ag Heterocyclic condensed pyridines as CETP inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2700686A (en) * 1951-02-15 1955-01-25 Eastman Kodak Co Hydroxy substituted polyfluorinated compounds
WO1996004249A1 (en) * 1994-08-05 1996-02-15 Sri International Fluorinated 2-nitroimidazole analogs for detecting hypoxic tumor cells
GB2305665A (en) * 1995-09-26 1997-04-16 Merck & Co Inc Selective ß3 agonists for the treatment of diabetes aand obesity
EP0801060A1 (en) * 1996-04-09 1997-10-15 Pfizer Inc. Heterocyclic Beta-3 Adrenergenic Agonists
EP0818197A1 (en) * 1996-07-08 1998-01-14 Bayer Ag Heterocyclic condensed pyridines as CETP inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DUNN C ET AL: "THE SYNTHESIS OF FLUORINE-CONTAINING PTERINS", TETRAHEDRON,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 52, no. 40, pages 13017-13026, XP002063653, ISSN: 0040-4020 *

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7235259B2 (en) 2000-08-03 2007-06-26 Pfizer Inc Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US8389011B2 (en) 2000-08-03 2013-03-05 Bend Research, Inc. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US7115279B2 (en) 2000-08-03 2006-10-03 Curatolo William J Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US8197848B2 (en) 2000-08-03 2012-06-12 Bend Research, Inc. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US8048452B2 (en) 2000-08-03 2011-11-01 Bend Research, Inc. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitor
WO2003000295A3 (en) * 2001-06-21 2004-05-27 Pfizer Prod Inc Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors
US6962931B2 (en) 2001-06-21 2005-11-08 Pfizer Inc. Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors
WO2003000295A2 (en) * 2001-06-21 2003-01-03 Pfizer Products Inc. Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors
US9468604B2 (en) 2001-06-22 2016-10-18 Bend Research, Inc. Pharmaceutical compositions of dispersions of drug and neutral polymers
US8703199B2 (en) 2001-06-22 2014-04-22 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drug
US8389006B2 (en) 2001-06-22 2013-03-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drug
EP2275091A1 (en) 2001-06-22 2011-01-19 Pfizer Products Inc. Pharmaceutical compositions comprising adsorbates of an amorphous drug
US7887840B2 (en) 2001-06-22 2011-02-15 Bend Research, Inc. Pharmaceutical compositions comprising drug and concentration-enhancing polymers
US7202247B2 (en) 2001-12-19 2007-04-10 Atherogenics, Inc. 1,3-bis-(substituted-phenyl)-2-propyn-1-ones and their use to treat disorders
US7094801B2 (en) 2001-12-19 2006-08-22 Atherogenics, Inc. Chalcone derivatives and their use to treat diseases
US10357455B2 (en) 2002-02-01 2019-07-23 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
US9486410B2 (en) 2002-02-01 2016-11-08 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
WO2003063832A1 (en) 2002-02-01 2003-08-07 Pfizer Products Inc. Pharmaceutical compositions comprising a solid amorphous dispersion of cholesteryl ester transfer protein inhibitors
EP2305217A1 (en) 2002-02-01 2011-04-06 Bend Research, Inc. Method for the preparation of pharmaceutical compositions comprising a solid amorphous dispersion of cholesteryl ester transfer protein inhibitors
JP2005523895A (en) * 2002-02-01 2005-08-11 ファイザー・プロダクツ・インク Pharmaceutical composition comprising a solid amorphous dispersion of a cholesteryl ester transfer protein inhibitor
US7365085B2 (en) * 2002-03-27 2008-04-29 Smithkline Beecham Corporation Compounds and methods
EP1829858A3 (en) * 2002-08-30 2007-10-03 Japan Tobacco, Inc. Dibenzylamine compounds and pharmaceutical use thereof
WO2004020393A1 (en) * 2002-08-30 2004-03-11 Japan Tobacco Inc. Dibenzylamine compound and medicinal use thereof
US7332514B2 (en) 2002-08-30 2008-02-19 Japan Tobacco Inc. Dibenzylamine compound and medicinal use thereof
US7807701B2 (en) 2002-08-30 2010-10-05 Japan Tobacco Inc. Dibenzylamine compounds and pharmaceutical use thereof
EP1961419A1 (en) 2002-12-20 2008-08-27 Pfizer Products Inc. Dosage forms comprising a CETP inhibitor and an HMG-CoA reductase inhibitor
US7276536B2 (en) 2003-03-17 2007-10-02 Japan Tobacco Inc. Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino) phenyl] 2-methylpropanethioate
US9023393B2 (en) 2003-08-04 2015-05-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
EP2283822A2 (en) 2003-08-04 2011-02-16 Bend Research, Inc. Spray drying processes for forming solid amorphous dispersions of drugs and polymers
USRE47033E1 (en) 2003-08-04 2018-09-11 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
EP2319509A1 (en) 2003-09-26 2011-05-11 Japan Tobacco, Inc. Method of Inhibiting remnant lipoprotein production
EP2316447A1 (en) 2003-09-26 2011-05-04 Japan Tobacco, Inc. Method of inhibiting remnant lipoprotein production
EP2548894A1 (en) 2005-02-03 2013-01-23 Bend Research, Inc. Pharmaceutical compositions with enhanced performance

Also Published As

Publication number Publication date
EP1115694A1 (en) 2001-07-18
AU6161099A (en) 2000-04-17
CA2345108A1 (en) 2000-04-06
JP2002525350A (en) 2002-08-13

Similar Documents

Publication Publication Date Title
EP1115695B1 (en) (r)-chiral halogenated 1-substitutedamino-(n+1)-alkanols useful for inhibiting cholesteryl ester transfer protein activity
US6787570B2 (en) Substituted N-cycloalkyl-N-benzyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
US6544974B2 (en) (R)-chiral halogenated substituted fused heterocyclic amino compounds useful for inhibiting cholesteryl ester transfer protein activity
WO2000018723A1 (en) Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity
US20030032644A1 (en) Substituted polycyclic aryl and heteroaryl tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity
US6482862B1 (en) Method of using substituted N-benzyl-N-phenyl aminoalcohols for inhibiting cholesteryl ester transfer protein activity

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref document number: 2345108

Country of ref document: CA

Ref country code: CA

Ref document number: 2345108

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1999948431

Country of ref document: EP

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 572185

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1999948431

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWR Wipo information: refused in national office

Ref document number: 1999948431

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1999948431

Country of ref document: EP