EP1115694A1 - Substituierte n-aliphatisch- n-aromatisch tertiäre heteroalkylamine für die hemmung der aktivität des cholesteryl-ester-transfer-proteins - Google Patents

Substituierte n-aliphatisch- n-aromatisch tertiäre heteroalkylamine für die hemmung der aktivität des cholesteryl-ester-transfer-proteins

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Publication number
EP1115694A1
EP1115694A1 EP99948431A EP99948431A EP1115694A1 EP 1115694 A1 EP1115694 A1 EP 1115694A1 EP 99948431 A EP99948431 A EP 99948431A EP 99948431 A EP99948431 A EP 99948431A EP 1115694 A1 EP1115694 A1 EP 1115694A1
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EP
European Patent Office
Prior art keywords
group
methyl
fluoro
trifluoromethyl
amino
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP99948431A
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English (en)
French (fr)
Inventor
James A. Sikorski
Richard C. Durley
Margaret L. Grapperhaus
Deborah A. Mischke
Emily J. Reinhard
Barry L. Parnas
Melvin L. Rueppel
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Monsanto Co
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Monsanto Co
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Publication of EP1115694A1 publication Critical patent/EP1115694A1/de
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    • 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
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    • 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
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    • 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
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • C07C2601/14—The ring being saturated
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    • 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.

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CA2450957A1 (en) 2001-06-22 2003-01-03 Pfizer Products Inc. Pharmaceutical compositions of dispersions of drugs and neutral polymers
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AU2002361811A1 (en) 2001-12-19 2003-07-09 Atherogenics, Inc. 1,3-bis-(substituted-phenyl)-2-propyn-1-ones and their use to treat disorders
EP1465854A4 (de) 2001-12-19 2005-06-08 Atherogenics Inc Chalconderivate und deren verwendung zur behandlung von krankheiten
AR038375A1 (es) 2002-02-01 2005-01-12 Pfizer Prod Inc Composiciones farmaceuticas de inhibidores de la proteina de transferencia de esteres de colesterilo
WO2003063833A1 (en) 2002-02-01 2003-08-07 Pfizer Products Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
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DE60323536D1 (de) 2002-12-20 2008-10-23 Pfizer Prod Inc Dosierungsform enthaltend einen cetp-hemmer und einen hmg-coa reduktase hemmer
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CL2004001884A1 (es) 2003-08-04 2005-06-03 Pfizer Prod Inc Procedimiento de secado por pulverizacion para la formacion de dispersiones solidas amorfas de un farmaco y polimeros.
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