# Patent

## Title
Compounds as cannabinoid receptor ligands

## Abstract

The present invention relates to compounds of formula (I)




wherein A, E, L2, R1, R3, R4 and R5 are as defined in the herein, compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.

## Background
This application claims priority to U.S. Patent Application Ser. No. 60/851,216 filed Oct. 12, 2006 and is incorporated herein by reference.


TECHNICAL FIELD
The present invention relates to compounds that are CB2 receptor ligands, compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.
BACKGROUND OF THE INVENTION
(−)-Δ9-Tetrahydrocannabinol (Δ9-THC), the major psychoactive constituent of marijuana, exerts a broad range of biological effects through its interactions with two cannabinoid (CB) receptor subtypes, CB1 and CB2. CB1 receptors are highly expressed in the central nervous system and to a lesser degree in the periphery in a variety of tissues of the cardiovascular and gastrointestinal systems. By contrast, CB2 receptors are most abundantly expressed in multiple lymphoid organs and cells of the immune system, including spleen, thymus, tonsils, bone marrow, pancreas and mast cells.
The psychotropic effects caused by Δ9-THC and other nonselective CB agonists are mediated by CB1 receptors. These CB1 receptor-mediated effects, such as euphoria, sedation, hypothermia, catalepsy, and anxiety, have limited the development and clinical utility of nonselective CB agonists. Recent studies have demonstrated that CB2 modulators are analgesic in preclinical models of nociceptive and neuropathic pain without causing the adverse side effects associated with CB1 receptor activation. Therefore, compounds that selectively target CB2 receptors are an attractive approach for the development of novel analgesics.
Pain is the most common symptom of disease and the most frequent complaint with which patients present to physicians. Pain is commonly segmented by duration (acute vs. chronic), intensity (mild, moderate, and severe), and type (nociceptive vs. neuropathic).
Nociceptive pain is the most well known type of pain, and is caused by tissue injury detected by nociceptors at the site of injury. After the injury, the site becomes a source of ongoing pain and tenderness. This pain and tenderness are considered “acute” nociceptive pain. This pain and tenderness gradually diminish as healing progresses and disappear when healing is complete. Examples of acute nociceptive pain include surgical procedures (post-op pain) and bone fractures. Even though there may be no permanent nerve damage, “chronic” nociceptive pain results from some conditions when pain extends beyond six months. Examples of chronic nociceptive pain include osteoarthritis, rheumatoid arthritis, and musculoskeletal conditions (e.g., back pain), cancer pain, etc.
Neuropathic pain is defined as “pain initiated or caused by a primary lesion or dysfunction in the nervous system” by the International Association for the Study of Pain. Neuropathic pain is not associated with nociceptive stimulation, although the passage of nerve impulses that is ultimately perceived as pain by the brain is the same in both nociceptive and neuropathic pain. The term neuropathic pain encompasses a wide range of pain syndromes of diverse etiologies. The three most commonly diagnosed pain types of neuropathic nature are diabetic neuropathy, cancer neuropathy, and HIV pain. In addition, neuropathic pain is diagnosed in patients with a wide range of other disorders, including trigeminal neuralgia, post-herpetic neuralgia, traumatic neuralgia, phantom limb, as well as a number of other disorders of ill-defined or unknown origin.
Managing the spectrum of pain etiologies remains a major public health problem and both patients and clinicians are seeking improved strategies to effectively manage pain. No currently available therapies or drugs effectively treat all types of nociceptive and neuropathic pain states. The compounds of the present invention are novel CB2 receptor modulators that have utility in treating pain, including nociceptive and neuropathic pain.
The location of CB2 receptors on the surface of immune cells suggests a role for these receptors in immunomodulation and inflammation. Recent studies have demonstrated that CB2 receptor ligands have immunomodulatory and anti-inflammatory properties. Therefore, compounds that interact with CB2 receptors offer a unique pharmacotherapy for the treatment of immune and inflammatory disorders.
Accordingly, the need exists to further explore and develop CB2 receptor ligands that exhibit immunomodulatory and anti-inflammatory properties. These CB2 receptors ligands will offer a unique pharmacotherapy for the treatment of immune and inflammatory disorders.
SUMMARY OF THE INVENTION
The present invention generally provides compounds that are CB2 receptor ligands and pharmaceutical compositions and methods for the treatment of disorders using these compounds and pharmaceutical compositions.
In one embodiment, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof,




wherein

A is N or C(R2);
E is C(O) or C(S);
R1 is C3-C7 alkyl, alkenyl, alkoxy-(C2-C6 alkylene)-, alkoxycarbonylalkyl, alkylcarbonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, aryloxy-(C2-C6 alkylene)-, arylalkoxy-(C2-C6 alkylene)-, arylcarbonyloxy-(C2-C6 alkylene)-, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, haloalkyl, haloalkoxy-(C2-C6 alkylene)-, heteroaryl, heteroarylalkyl, heteroaryloxy-(C2-C6 alkylene)-, heteroarylcarbonyloxy-(C2-C6 alkylene)-, heterocycle, heterocyclealkyl, heterocycleoxy-(C2-C6 alkylene)-, hydroxy-(C2-C6 alkylene)-, RaRbN—(C2-C6 alkylene)-, RcRdN—C(O)-alkylene-, RcRdN—C(O)—NRc—(C2-C6 alkylene)-, ReO—N═C(Rz)-alkylene-, or RfRgN—N═C(Rz)-alkylene-;
R2 and R3 are each independently hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, arylalkyl, arylalkenyl, azidoalkyl, cyano, cycloalkyl, formyl, halogen, haloalkyl, heteroaryl, heterocycle, hydroxyalkyl, hydroxyalkynyl, hydroxyhaloalkyl, RjRkN—, RjRkN-alkylene-, RmRnN—C(O)—, RpO—N═C(Rz)-alkylene-, RpO—N═C(Rz)—, or RrRsN—N═C(Rz)-alkylene-, or
R2 and R3 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a heterocycle, or a cycloalkenyl ring;
R4 is C4-C10 alkyl, wherein the C4-C10 alkyl group is optionally substituted with one substituent selected from the group consisting of hydroxy, alkoxy, haloalkoxy, cyano, —C(O)N(Rz)2, and —N(Rz)C(O)Rz; alkenyl, alkynyl, naphthyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, wherein the naphthyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycle, the aryl moiety of the arylalkyl, the cycloalkyl moiety of the cycloalkylalkyl, the cycloalkenyl moiety of the cycloalkenylalkyl, the heteroaryl moiety of the heteroarylalkyl, and the heterocycle moiety of the heterocyclealkyl are each independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents as represented by R6;
or phenyl substituted with 1, 2, 3, 4, or 5 substituents as represented by R6;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, cyano, halogen, haloalkyl, oxo, —OReu, —O—(CRjuRku)x—N(Rwu)2, —OC(O)Reu, —SReu, —S(O)Rfu, —S(O)2Rfu, —S(O)2N(Rwu)(Rgu), —N(Rwu)(Rgu), —N(Rwu)C(O)Reu, —N(Rwu)C(O)OReu, —N(Rwu)S(O)2Rfu, —N(Rwu)C(O)N(Rwu)(Rgu), —N(Rwu)S(O)2N(Rwu)(Rgu), —C(O)Reu, —C(O)O(Reu), —C(O)N(Rwu)(Rgu), haloalkyl, —(CRjuRku)x—CN, —(CRjuRku)x—OReu, —(CRjuRku)x—OC(O)Reu, —(CRjuRku)x—SReu, —(CRjuRku)x—S(O)Rfu, —(CRjuRku)x—S(O)2Rfu, —(CRjuRku)x—N(Rwu)(Rgu), —(CRjuRku)x—N(Rwu)C(O)Reu, —(CRjuRku)x—N(Rwu)S(O)2Rfu, —(CRjuRku)x—N(Rwu)C(O)N(Rwu)(Rgu), —(CRjuRku)x—N(Rwu)S(O)2N(Rwu)(Rgu), —(CRjuRku)x—C(O)Reu, —(CRjuRku)x—C(O)O(Reu), —(CRjuRku)x—C(O)N(Rwu)(Rgu), —C(Rwu)═N—ORwu, aryl, heteroaryl, cycloalkyl, and heterocycle;
Rwu, at each occurrence, is independently hydrogen, alkyl, or haloalkyl;
Reu and Rgu, at each occurrence, are each independently hydrogen, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, haloalkoxyalkyl, or haloalkyl; wherein the cycloalkyl, the heterocycle, and the cycloalkyl moiety of the cycloalkylalkyl are each independently unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of alkyl, halogen, and haloalkyl;
Rfu, at each occurrence, is independently alkyl or haloalkyl;
Rju and Rku, at each occurrence, are each independently hydrogen, halogen, alkyl, or haloalkyl;
x is 1, 2, 3, 4, or 5;
R5 is hydrogen, alkyl, alkenyl, alkynyl, cyano, or halogen;
L2 is a bond, —N(Re)— or —O—;
Ra and Rb are each independently selected from group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl;
Rc and Rd, at each occurrence, are each independently hydrogen, alkyl, or haloalkyl;
Re, at each occurrence, is independently hydrogen, alkyl, alkenyl, alkoxyalkyl, alkynyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, or hydroxyalkyl;
Rf and Rg, are each independently hydrogen, alkyl, alkenyl, alkoxycarbonyl, alkoxyalkyl, alkynyl, arylalkyl, cyanoalkyl, cycloalkylalkyl, haloalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl or nitroalkyl; or Rf and Rg, together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocycle ring;
Rj and Rk, at each occurrence, are each independently hydrogen, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylalkyl, or —C(O)N(Rz)2;
Rm and Rn are each independently hydrogen, alkyl, or haloalkyl;
Rp, at each occurrence, is independently hydrogen, alkyl, alkenyl, alkoxyalkyl, alkynyl, cyanoalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxyalkyl, or nitroalkyl;
Rr and Rs are each independently hydrogen, alkyl, alkenyl, alkoxyalkyl, alkynyl, cyanoalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxyalkyl, or nitroalkyl; or
Rr and Rs, together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocycle ring; and
Rz, at each occurrence, is independently hydrogen, alkyl, or haloalkyl;
with the proviso that when A is —C(R2), R2 is hydrogen or C1-C5 alkyl, R3 is hydrogen or phenyl, E is C(O), L2 is a bond, and R4 is aryl, then R1 is not C3-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or 4-amino-2-methyl-5-pyrimidinyl)methyl.
In another embodiment, the present invention provides a method for treating pain (for example, neuropathic pain or nociceptive pain) in a mammal in need of such treatment. The method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present invention provides a method for treating a disorder selected from the group consisting of inflammatory disorders, immune disorders, neurological disorders, cancers of the immune system, respiratory disorders, and cardiovascular disorders in a mammal in need of such treatment. The method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention relates to a method for providing neuroprotection in a mammal in need of such treatment. This method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Yet another embodiment of the present invention relates to a method of treating an autoimmune disease selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus, myasthenia gravis, type I diabetes, irritable bowel syndrome, psoriasis, psoriatic arthritis, and hepatitis, in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Yet another embodiment of the present invention relates to a method of treating an immune related disorder including but not limited to tissue rejection in organ transplants, gluten-sensitive enteropathy (Celiac disease), asthma, chronic obstructive pulmonary disease, emphysema, bronchitis, acute respiratory distress syndrome, allergies, allergic rhinitis, dermatitis, and Sjogren's syndrome in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Yet another embodiment of the present invention relates to a method of treating a disorder selected form the group consisting of Alzheimer's disease, encephalomyelitis, inflammatory bowel disease, hepatic fibrosis, cough, asthma, osteoporosis, arthrosclerosis, ischemia, myocardial infarction in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers. The composition is preferably useful for the treatment of the disease conditions described above.
Further, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of the disease conditions described above.
Yet further, the present invention provides a method of treating a disorder wherein the disorder is ameliorated by modulating the cannabinoid receptor type 2 (CB2) receptor in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
These and other objects of the invention are described in the following paragraphs. These objects should not be deemed to narrow the scope of the invention.


DETAILED DESCRIPTION
Compounds of formula (I) are disclosed in this invention,




wherein R1, A, R3, L2, E, R4, and R5 are as defined above in the Summary of the Invention and below in the Detailed Description. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.

In various embodiments, the present invention provides at least one variable that occurs more than one time in any substituent or in the compound of the invention or any other formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds, which can be isolated from a reaction mixture.
a. DEFINITIONS
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:
The term “alkenyl” as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, isopropenyl, and 3-decenyl. The term “C2-C5 alkenyl” as used herein, means a straight or branched chain hydrocarbon containing from 2 to 5 carbons and containing at least one carbon-carbon double bond.
The term “alkoxy” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term “alkoxyalkoxy” as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.
The term “alkoxyalkoxyalkyl” as used herein, means an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of alkoxyalkoxyalkyl include, but are not limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy)methyl, and 2-(2-methoxyethoxy)ethyl.
The term “alkoxyalkyl” as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
The term “alkoxycarbonyl” as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert-butoxycarbonylethyl.
The term “alkoxysulfonyl” as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
The term “alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpropyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. The term “C3-C5 alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 3 to 5 carbon atoms. The term “C3-C7 alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 3 to 7 carbon atoms. The term “C4-C10 alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 4 to 10 carbon atoms.
The term “alkylcarbonyl” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
The term “alkylcarbonylalkyl” as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, 3,3-dimethyl-2-oxobutyl, and 3-oxopentyl.
The term “alkylcarbonyloxy” as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
The term “alkylene” means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms. Representative examples of alkylene include, but are not limited to, —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2C(CH3)(H)—, —C(C2H5)2—, and —CH2CH(CH3)CH2—. The term “C2-C6 alkylene” means a divalent group derived from a straight or branched chain hydrocarbon of from 2 to 6 carbon atoms.
The term “alkylsulfinyl” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulfinyl.
The term “alkylsulfinylalkyl” as used herein, means an alkylsulfinyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
The term “alkylsulfonyl” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
The term “alkylthio” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, and hexylthio.
The term “alkynyl” as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 3-methylbut-1-ynyl, 2-pentynyl, and 1-butynyl. The term “C2-C5 alkynyl” as used herein, means a straight or branched chain hydrocarbon containing from 2 to 5 carbons and containing at least one carbon-carbon triple bond.
The term “aryl,” as used herein, means phenyl, a bicyclic aryl or a tricyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl. Representative examples of the bicyclic aryl include, but are not limited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. The tricyclic aryl is exemplified by a bicyclic aryl fused to a monocyclic cycloalkyl, or a bicyclic aryl fused to a monocyclic cycloalkenyl, or a bicyclic aryl fused to a phenyl. Representative examples of tricyclic aryls include, but are not limited to, anthracene, phenanthrene, dihydroanthracenyl, fluorenyl, 1,2-dihydroacenaphthylenyl, and tetrahydrophenanthrenyl. The phenyl, bicyclic and tricyclic aryls are attached to the parent molecular moiety through any carbon atom contained within the phenyl, bicyclic and tricyclic aryls respectively.
The term “arylalkenyl” as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein.
The term “arylalkoxy” as used herein, refers to an arylalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
The term “arylalkyl” as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
The term “arylcarbonyl” as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group.
The term “arylcarbonyloxy” as used herein, refers to an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative example of arylcarbonyloxy includes, but not limited to, phenylcarbonyloxy.
The term “aryloxy” as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, and 3,5-dimethoxyphenoxy.
The term “azido” as used herein, means a —N3 group.
The term “azidoalkyl” as used herein, means an azido group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
The term “carbonyl” as used herein, means a —C(O)— group.
The term “carboxy” as used herein, means a —CO2H group.
The term “carboxyalkyl” as used herein, means a carboxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl.
The term “cyano” as used herein, means a —CN group.
The term “cyanoalkyl” as used herein, means a cyano group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.
The term “cycloalkenyl” as used herein, means a monocyclic or bicyclic ring system containing zero heteroatoms in the ring. The monocyclic cycloalkenyl has three-, four-, five-, six-, seven- or eight carbon atoms and zero heteroatoms. The three or four-membered ring systems have one double bond, the five- or six-membered ring systems have one or two double bonds, and the seven- or eight-membered ring systems have one, two or three double bonds. Representative examples of monocyclic cycloalkenyls include, but are not limited to, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and 3-cyclopenten-1-yl. Bicyclic cycloalkenyls are exemplified by a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl. Representative examples of bicyclic ring systems include, but are not limited to 3a,4,5,6,7,7a-hexahydro-1H-indenyl, 4,5,6,7-tetrahydro-3aH-indene, and octahydronaphthalenyl. The cycloalkenyl groups of the present invention are appended to the parent molecular moiety through any substitutable carbon atom within the groups, and may contain one or two alkylene bridges of 1, 2, 3, or 4 carbon atoms, wherein each bridge links two non-adjacent atoms within the groups.
The term “cycloalkenylalkyl” as used herein, means a cycloalkenyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
The term “cycloalkyl” as used herein, means a monocyclic, or a bicyclic cycloalkyl, or a spirocyclic cycloalkyl. The monocyclic cycloalkyl is a carbocyclic ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms and zero heteroatoms as ring atoms, and zero double bonds. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl is exemplified by a monocyclic cycloalkyl fused to a monocyclic cycloalkyl. Representative examples of bicyclic cycloalkyls include, but are not limited to, bicyclo[4.1.0]heptane, bicyclo[6.1.0]nonane, octahydroindene, and decahydronaphthalene. The monocyclic and the bicyclic cycloalkyl groups of the present invention may contain one or two alkylene bridges of 1, 2, 3, or 4 carbon atoms, wherein each bridge links two non-adjacent atoms within the groups. Examples of such bridged cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.3.1]nonane, adamantane (tricyclo[3.3.1.13,7]decane), and noradamantane (octahydro-2,5-methanopentalene). Spirocyclic cycloalkyl is exemplified by a monocyclic or a bicyclic cycloalkyl, wherein two of the substituents on the same carbon atom of the ring, together with said carbon atom, form a 4-, 5-, or 6-membered monocyclic cycloalkyl. An example of a spirocyclic cycloalkyl is spiro[2.5]octane. The monocyclic, bicyclic, and spirocyclic cycloalkyl groups of the present invention can be appended to the parent molecular moiety through any substitutable carbon atom of the groups.
The term “cycloalkylalkyl,” as used herein, means a cycloalkyl group appended to the parent molecular moiety through an alkylene group, as defined herein. Representative example of cycloalkylalkyl includes, but not limited to, bicyclo[2.2.1]heptylmethyl (including bicyclo[2.2.1]hept-2-ylmethyl).
The term “formyl” as used herein, means a —C(O)H group.
The term “formylalkyl” as used herein, means a formyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of formylalkyl include, but are not limited to, formylmethyl and 2-formylethyl.
The term “halo” or “halogen” as used herein, means F, Cl, Br, or I.
The term “haloalkoxy” as used herein, means an alkoxy group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen. Representative examples of haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, and pentafluoroethoxy.
The term “haloalkoxyalkyl” as used herein, means a haloalkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
The term “haloalkyl” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, or seven hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, trifluoromethyl, 4-fluorobutyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro-1,1-dimethylethyl, difluoromethyl, 3,3,3-trifluoropropyl, 2,2,2-trichloro-1,1-dimethylethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and 2-iodoethyl.
The term “heteroaryl,” as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a 5- or 6-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The 5-membered ring contains two double bonds and one, two, three, or four heteroatoms. The 6-membered ring contains three double bonds and one, two, three, or four heteroatoms. Representative examples of monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl is exemplified by a monocyclic heteroaryl fused to phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle. Representative examples of bicyclic heteroaryls include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothienyl, chromenyl, cinnolinyl, furopyridinyl, indolyl, indazolyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, quinolinyl, and thienopyridinyl. The monocyclic and the bicyclic heteroaryl groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the groups.
The term “heteroarylalkyl,” as used herein, means a heteroaryl group appended to the parent molecular moiety through an alkylene group, as defined herein.
The term “heteroarylcarbonyl” as used herein, refers to an heteroaryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group.
The term “heteroarylcarbonyloxy” as used herein, refers to an heteroarylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
The term “heteroaryloxy” as used herein, refers to an heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
The term “heterocycle” or “heterocyclic” as used herein, means a monocyclic, bicyclic, or a spirocyclic ring system containing at least one heteroatom. The monocyclic heterocycle is a 3-, 4- 5-, 6-, 7-, or 8-membered monocyclic ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The 3- or 4-membered ring contains 1 heteroatom selected from the group consisting of O, N and S, and optionally one double bond. The 5-membered ring contains zero or one double bond, and one, two or three heteroatoms in the ring selected from the group consisting of O, N and S. The 6-, 7-, or 8-membered ring contains zero, one, or two double bonds, and one, two, or three heteroatoms in the ring selected from the group consisting of O, N and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 4,5-dihydroisoxazol-5-yl, dihydropyranyl (including 3,4-dihydropyran-6-yl, 2,3-dihydropyranyl), 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl (including tetrahydropyran-4-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl), tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle of the present invention is exemplified by a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl group, or a monocyclic heterocycle fused to a monocyclic heterocycle group. Representative examples of bicyclic heterocycle include, but are not limited to, 1,3-benzodioxolyl (including 1,3-benzodioxol-4-yl and 1,3-benzodioxol-5-yl), 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl. Spirocyclic heterocycle means a monocyclic or bicyclic heterocycle ring wherein two substituents on the same carbon atom, together with said carbon atom, form a 4-, 5-, or 6-membered monocyclic cycloalkyl. One example of a spiroheterocycle is 5-oxaspiro[3,4]octane. The heterocycle groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the group. The monocyclic or bicyclic heterocycle groups of the present invention may contain an alkenylene bridge of 2, 3, or 4 carbon atoms, or one or two alkylene bridges of 1, 2, 3, or 4 carbon atoms, wherein each bridge links two non-adjacent carbon atoms within the groups. Examples of such bridged heterocycles include, but are not limited to, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, oxaadamantane (2-oxatricyclo[3.3.1.13,7]decane), octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, oxabicyclo[2.2.1]heptane and 2,4-dioxabicyclo[4.2.1]nonane.
The term “heterocyclealkyl,” as used herein, means a heterocycle group appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, tetrahydrofuran-2-ylmethyl, oxetan-3-ylmethyl, 3-methyloxetan-3-ylmethyl, 1,3-dioxolan-2-ylmethyl, 3-methyl-4,5-dihydroisoxazol-5-ylmethyl, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl, 5-oxotetrahydrofuran-2-ylmethyl, (5-methyltetrahydrofuran-2-yl)methyl, tetrahydro-2H-pyran-4-ylmethyl, tetrahydro-2H-pyran-2-ylmethyl, tetrahydro-2H-pyran-3-ylmethyl, and 1,4-dioxan-2-ylmethyl.
The term “heterocycleoxy” as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
The aryl, cycloalkyl, cycloalkenyl, heteroaryl, and the heterocycle moieties of this invention are optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group as described herein below, unless otherwise noted. The optional substituents are independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl, alkyl-S(O)2—, alkyl-S(O)2-alkyl-, alkyl-S—, alkyl-5-alkyl-, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, —SH, nitro, NZ1Z2-alkylene-O—, —NZ1Z2, and (NZ3Z4)carbonyl.
The term “hydroxy” or “hydroxyl” as used herein, means an —OH group.
The term “hydroxyalkyl” as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, 1-hydroxy-1-methylethyl, 1-ethyl-1-hydroxypropyl, 1-hydroxy-1-methylpropyl, and 2-ethyl-4-hydroxyheptyl.
The term “hydroxyhaloalkyl” as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through a haloalkyl group, as defined herein. Representative examples of hydroxyhaloalkyl include, but are not limited to, 2-fluoro-1-(fluoromethyl)-1-hydroxyethyl, 2,2,2-trifluoro-1-hydroxy-1-methylethyl, 2-fluoro-1-hydroxy-1-methylethyl, and 2,2-difluoro-1-hydroxy-1-methylethyl.
The term “hydroxyalkynyl” as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkynyl group, as defined herein. Representative example of hydroxyalkynyl includes, but is not limited to, 3-hydroxy-3-methylbut-1-ynyl.
The term “hydroxy-protecting group” or “O-protecting group” means a substituent that protects hydroxyl groups against undesirable reactions during synthetic procedures. Examples of hydroxy-protecting groups include, but are not limited to, substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)-ethoxymethyl, benzyl, and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and benzylidene acetal; cyclic ortho esters, for example, methoxymethylene; cyclic carbonates; and cyclic boronates. Commonly used hydroxy-protecting groups are disclosed in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
The term “mercapto” as used herein, means a —SH group.
The term “nitrogen protecting group” as used herein, means those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl, and triphenylmethyl(trityl).
The term “nitro” as used herein, means a —NO2 group.
The term “nitroalkyl” as used herein, means an nitro group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
The term “NZ1Z2” as used herein, means two groups, Z1 and Z2, which are appended to the parent molecular moiety through a nitrogen atom. Z1 and Z2 are each independently hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, haloalkyl, and formyl. In certain instances within the present invention, Z1 and Z2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring. Representative examples of NZ1Z2 include, but are not limited to, amino, methylamino, acetylamino, acetylmethylamino, phenylamino, benzylamino, azetidinyl, pyrrolidinyl and piperidinyl.
The term “NZ3Z4” as used herein, means two groups, Z3 and Z4, which are appended to the parent molecular moiety through a nitrogen atom. Z3 and Z4 are each independently hydrogen, alkyl, haloalkyl, aryl, and arylalkyl. Representative examples of NZ3Z4 include, but are not limited to, amino, methylamino, phenylamino and benzylamino.
The term “(NZ3Z4)carbonyl” as used herein, means a NZ3Z4 group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NZ3Z4)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
The term “oxo” as used herein, means a ═O moiety.
The term “sulfinyl” as used herein, means a —S(O)— group.
The term “sulfonyl” as used herein, means a —SO2— group.
b. COMPOUNDS
Compounds of the invention have the formula (I) as described above.
Particular values of variable groups in compounds of formula (I) are as follows. Such values may be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.
In compounds of formula (I), R1 is as described in the Summary section. One embodiment of the invention relates to compounds of formula (I) wherein R1 is C3-C7 alkyl. Examples of R1 as C3-C7 alkyl include, but are not limited to, isobutyl and n-butyl.
Other compounds of the invention include, but not limited to, those wherein R1 is alkoxy-(C2-C6 alkylene)- such as 2-methoxyethyl.
Yet other compounds of the invention include, but not limited to, those wherein
R1 is alkylcarbonylalkyl, for example, 3,3-dimethyl-2-oxobutyl.
Yet other compounds of the invention include, but are not limited to, those wherein R1 is arylcarbonyloxy-(C2-C6 alkylene)- wherein the aryl moiety is optionally substituted as described in the Detailed Description section. For example, R1 is phenylcarbonyloxyethyl wherein the phenyl moiety is optionally substituted, for example, the phenyl moiety is optionally substituted with substituents selected from alkyl, alkoxy, cyano, halogen, —NZ1Z2, haloalkyl, and haloalkoxy.
Further examples of compounds of the invention include, but are not limited to, those wherein R1 is haloalkyl (for example, 4-fluorobutyl).
Yet further examples of compounds of the invention include, but are not limited to, those wherein R1 is cycloalkylalkyl wherein the cycloalkyl moiety is optionally substituted as described in the Detailed Description. For example, R1 includes, but is not limited to, cyclopropylmethyl and cyclobutylmethyl, wherein the cyclopropyl and the cyclobutyl moieties are optionally substituted.
Yet another embodiment of the invention provides compounds of formula (I) wherein R1 is heterocyclealkyl wherein the heterocycle moiety is optionally substituted as described in the Detailed Description section. Examples of the heterocycle moiety of the heterocyclealkyl include, but are not limited to, morpholinyl, tetrahydrofuranyl, piperidinyl, aziridinyl, pyranyl, 1,3-dioxolanyl, and pyrrolidinyl, each of which is optionally substituted as described in the Detailed Description section. The alkyl moieties of the heterocyclealkyl include, but are not limited to, methyl and ethyl. Examples of the optional substituents of the heterocycle moiety of the heterocyclealkyl include, but are not limited to, alkyl, alkoxy, oxo, halogen, haloalkyl, haloalkoxy, hydroxy, and —NZ1Z2 wherein Z1, Z2 are, for example, independently hydrogen, alkyl, or haloalkyl. For example, R1 includes, but is not limited to, morpholinylethyl (including 2-morpholin-4-ylethyl), piperidinylmethyl, piperidinylethyl (including 2-piperidin-1-ylethyl), pyrrolidinylmethyl (including pyrrolidin-2-ylmethyl), pyranylmethyl, 1,3-dioxolanylmethyl and tetrahydrofuranylmethyl (including tetrahydrofuran-2-ylmethyl and tetrahydrofuran-3-ylmethyl) wherein each of the morpholinyl, piperidinyl, pyrrolidinyl, pyranyl, 1,3-dioxolanyl, and tetrahydrofuranyl are optionally substituted as described hereinabove.
One embodiment of the invention pertains to compounds of formula (I) wherein A is N. Such compounds are represented by formula (Ia)




wherein R1, R3, R4, R5, E, and L2 are as defined in the Summary and Detailed Description sections.
Yet another embodiment of the invention pertains to compounds of formula (I) wherein A is C(R2), as represented by formula (Ib)




wherein R1, R2, R3, R4, R5, E, and L2 are as defined in the Summary and Detailed Description sections.
R2 and R3 are as disclosed in the Summary.
One embodiment of the invention describes compounds of formula (I) wherein A is C(R2), and R2 and R3 are independently hydrogen, alkenyl (for example, isopropenyl), alkoxycarbonyl (for example, ethoxycarbonyl), alkylcarbonyl (for example, methylcarbonyl), alkyl (for example, methyl, tert-butyl), aryl (for example, phenyl), cycloalkyl (for example, cyclopropyl), formyl, halogen (for example, Br), haloalkyl (for example, trifluoromethyl), heterocycle (for example, 1,3-dioxolanyl, including 1,3-dioxolan-2-yl), hydroxyalkyl (for example, 1-hydroxy-1-methylethyl, 1-hydroxy-1-methylpropyl, 1-ethyl-1-hydroxypropyl), hydroxyalkynyl (for example, 3-hydroxy-3-methylbut-1-ynyl), hydroxyhaloalkyl (for example, 2-fluoro-1-(fluoromethyl)-1-hydroxyethyl, 2,2-difluoro-1-hydroxy-1-methylethyl, 2-fluoro-1-hydroxy-1-methylethyl, 2,2,2-trifluoro-1-hydroxy-1-methylethyl), RjRkN— wherein Rj and Rk are as described in the Summary (for example, Rj is hydrogen, Rk is alkoxycarbonyl such as tert-butoxycarbonyl), RjRkN-alkylene- wherein Rj and Rk are as described in the Summary (for example, RjRkN-alkylene- is 1-amino-1-ethylpropyl, 1-amino-1-methylethyl), RmRnN—C(O)— wherein Rm and Rn are as described in the Summary (for example, Rm and Rn are independently hydrogen or alkyl), or RpO—N═C(Rz)— wherein Rp and Rz are as described in the Summary (for example, Rp and Rz are independently hydrogen or alkyl), wherein the aryl moiety, the cycloalkyl moiety, and the heterocycle moiety are optionally substituted as described in the Detailed Description. For example, the aryl and the cycloalkyl are optionally substituted with 1 or 2 substituents selected from the group consisting of alkyl (for example, methyl), halogen, and haloalkyl (for example, trifluoromethyl). For example, the heterocycle moiety is optionally substituted with 1 or 2 substituents selected from the group consisting of oxo, alkyl (for example, methyl), halogen, and haloalkyl (for example, trifluoromethyl).
Another embodiment of the invention include compounds of formula (I) wherein A is C(R2), and R2 and R3 together with the carbon atoms to which they are attached from a ring as described in the Summary, and R1, R4, R5, E, L2 have values as described in the Summary and the Detailed Description.
Thus, one embodiment of the invention includes those having formula (Ic)




wherein R7 represents optional substituents, selected from alkyl, halogen, and haloalkyl, and E, R1, R4, R5, and L2 are as disclosed in the Summary and the Detailed Description sections.
Another embodiment of the invention includes those having formula (Id)




wherein G is N(H), N(alkyl), O, CH2, or CH2CH2, R8 represents optional substituents selected from the group consisting of alkyl, halogen, and haloalkyl, two R8 groups on the same carbon atom together with the carbon atom to which they are attached, optionally form a ═O group, and E, R1, R4, R5, and L2 are as disclosed in the Summary and the Detailed Description sections.
R5 is as described in the Summary section.
One embodiment of the invention is directed to compounds of formula (I) wherein
R5 is hydrogen.
Other embodiment includes, but not limited to, compounds of formula (I) wherein
R5 is halogen (for example, F).
Compounds of formula (I) include, but are not limited to, those wherein E is C(O).
Other compounds of the invention include, but are not limited to, those of formula (I) wherein E is C(S).
L2 is a bond, O or N(Re) wherein Re is as described in the Summary section. For example, Re is hydrogen or alkyl. In one embodiment, Re is hydrogen.
R4 is as described in the Summary section. One embodiment of the invention includes, but not limited to, those of formula (I) wherein R4 is substituted phenyl or optionally substituted naphthyl, the substituents of phenyl and the optional substituents of naphthyl are represented by R6, and R6 is as described in the Summary section. R6, for example, includes alkyl (for example, methyl, tert-butyl), cyano, halogen, haloalkyl (for example, trifluoromethyl), —OReu wherein Reu is as disclosed in the Summary (for example, Reu is alkyl such as methyl, ethyl, or haloalkyl such as trifluoromethyl), —N(Rwu)(Rgu) wherein Rwu and Rgu are as disclosed in the Summary section (for example, Rwu and Rgu are independently hydrogen or alkyl such as methyl), —N(Rwu)C(O)OReu wherein Rwu and Reu are as disclosed in the Summary section (for example, Reu is alkyl such as methyl, ethyl, and Rwu is hydrogen or alkyl such as methyl), or —C(O)OReu wherein Reu is as disclosed in the Summary section (for example, Reu is alkyl such as methyl, ethyl). In one embodiment, R4 is phenyl, substituted with one or two R6 groups wherein R6 is as disclosed in the Summary and the Detailed Description.
In yet another embodiment, R4 includes, but not limited to, C4-C10 alkyl such as 2,2-dimethylpropyl or haloalkyl (for example, 2,2,2-trichloro-1,1-dimethylethyl).
Another embodiment of the invention includes, but not limited to, those wherein R4 is cycloalkyl, optionally substituted as described in the Summary. For example, R4 is adamantyl, bicyclo[2.2.1]heptyl, cyclopropyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted as described in the Summary. Examples of the optional substituents include, but are not limited to, alkyl such as methyl, unsubstituted phenyl, and oxo.
Yet another embodiment of the invention includes, but not limited to, those wherein R4 is cycloalkylalkyl, and the cycloalkyl moiety of cycloalkylalkyl is optionally substituted as described in the Summary. For example, R4 is cyclopentylmethyl or bicyclo[2.2.1]heptylmethyl, and the cyclopentyl and the bicyclo[2.2.1]heptyl are optionally substituted as described in the Summary. Examples of the optional substituents include, but are not limited to, alkyl such as methyl, and oxo.
A further embodiment of the invention includes, but not limited to, those wherein R4 is arylalkyl such as benzyl.
Yet a further embodiment of the invention includes, but not limited to, those wherein R4 is heterocycle, optionally substituted as described in the Summary. For example, the optionally substituted heterocycle includes, but not limited to, morpholinyl, 1,3-benzodioxolyl, tetrahydropyranyl, and 2,3-dihydropyranyl, wherein the optional substituents are as described in the Summary.
Yet another embodiment of the invention includes, but not limited to, those wherein R4 is heteroaryl, optionally substituted as described in the Summary. For example, R4 is pyridinyl, quinolinyl, thienyl, 1,3-thiazolyl, benzofuranyl, and benzothienyl, each of which is optionally substituted as described in the Summary. Examples of the optional substituents include, but are not limited to, alkyl (for example, methyl, tert-butyl), cyano, halogen, haloalkyl (for example, trifluoromethyl), —OReu wherein Reu is as disclosed in the Summary (for example, Reu is alkyl such as methyl, ethyl, or haloalkyl such as trifluoromethyl), —N(Rwu)(Rgu) wherein Rwu and Rgu are as disclosed in the Summary section (for example, Rwu and Rgu are independently hydrogen or alkyl such as methyl), —N(Rwu)C(O)OReu wherein Rwu and Reu are as disclosed in the Summary section (for example, Reu is alkyl such as methyl, ethyl, and Rwu is hydrogen or alkyl such as methyl), or —C(O)OReu wherein Reu is as disclosed in the Summary section (for example, Reu is alkyl such as methyl, ethyl).
It is appreciated that the present invention contemplates compounds of formula (I) with combinations of the above embodiments, including particular, more particular and preferred embodiments.
Accordingly, one aspect of the invention is directed to compounds of formula (Ia) wherein E is C(O), and L2 is a bond.
Another aspect of the invention is directed to compounds of formula (Ia) wherein E is C(O), and L2 is N(Re) and Re is as disclosed in the Summary and the Detailed Description sections. For example, Re is hydrogen or alkyl. In one embodiment, Re is hydrogen.
Another aspect of the invention is directed to compounds of formula (Ia) wherein E is C(O), and L2 is O.
Yet another aspect of the invention is directed to compounds of formula (Ia) wherein E is C(S) and L2 is a bond.
Another aspect of the invention is directed to compounds of formula (Ia) wherein E is C(S), L2 is N(Re), and Re is as disclosed in the Summary and the Detailed Description sections. For example, Re is hydrogen or alkyl. In one embodiment, Re is hydrogen.
Another aspect of the invention is directed to compounds of formula (Ia) wherein E is C(S) and L2 is O.
A further aspect of the invention is directed to compounds of formula (Ib) wherein E is C(O) and L2 is a bond.
Yet a further aspect of the invention is directed to compounds of formula (Ib) wherein E is C(O), L2 is N(Re), and Re is as disclosed in the Summary and the Detailed Description sections. For example, Re is hydrogen or alkyl. In one embodiment, Re is hydrogen.
Another aspect of the invention is directed to compounds of formula (Ib) wherein E is C(O) and L2 is O.
Yet another aspect of the invention is directed to compounds of formula (Ib) wherein E is C(S) and L2 is a bond.
Another aspect of the invention is directed to compounds of formula (Ib) wherein E is C(S), L2 is N(Re), and Re is as disclosed in the Summary and the Detailed Description sections. For example, Re is hydrogen or alkyl. In one embodiment, Re is hydrogen.
Another aspect of the invention is directed to compounds of formula (Ib) wherein E is C(S) and L2 is O.
Within each of the foregoing compounds of formula (Ia) and (Ib), R1, R2, R3, R4 and R5 have meanings as described in the Summary and Detailed Description sections.
For example, within each of the foregoing compounds, examples of a group of compounds of formula (Ia) or (Ib) include those wherein R1 is C3-C7 alkyl, alkoxy-(C2-C6 alkylene)-, alkylcarbonylalkyl, arylcarbonyloxy-(C2-C6 alkylene)-, haloalkyl, cycloalkylalkyl, or heterocyclealkyl.
Thus, one embodiment of the invention provides a group of foregoing compounds of formula (Ia) or (Ib) wherein R1 is C3-C7 alkyl. Examples of R1 as C3-C7 alkyl include, but are not limited to, isobutyl and n-butyl.
Examples of another group of compounds having formula (Ia) or (Ib) include, but not limited to, those wherein R1 is alkoxy-(C2-C6 alkylene)- such as 2-methoxyethyl.
Examples of yet another group of compounds having formula (Ia) or (Ib) include, but not limited to, those wherein R1 is alkylcarbonylalkyl, for example, 3,3-dimethyl-2-oxobutyl.
Further examples of another group of compounds having formula (Ia) or (Ib) include, but are not limited to, those wherein R1 is arylcarbonyloxy-(C2-C6 alkylene)- wherein the aryl moiety is optionally substituted as described in the Detailed Description section. For example, R1 is phenylcarbonyloxyethyl wherein the phenyl moiety is optionally substituted, for example, the phenyl moiety is optionally substituted with substituents selected from alkyl, alkoxy, cyano, halogen, —NZ1Z2, haloalkyl, and haloalkoxy.
Further examples of yet another group of compounds having formula (Ia) or (Ib) include, but are not limited to, those wherein R1 is haloalkyl (for example, 4-fluorobutyl).
Yet other examples of a group of compounds having formula (Ia) or (Ib) include, but are not limited to, those wherein R1 is cycloalkylalkyl wherein the cycloalkyl moiety is optionally substituted as described in the Detailed Description. For example, R1 includes, but is not limited to, cyclopropylmethyl and cyclobutylmethyl, wherein the cyclopropyl and the cyclobutyl moieties are optionally substituted.
Yet other examples of another group of compounds of formula (Ia) or (Ib) include, but are not limited to, those wherein R1 is heterocyclealkyl wherein the heterocycle moiety is optionally substituted as described in the Detailed Description section. Examples of the heterocycle moiety of the heterocyclealkyl include, but are not limited to, morpholinyl, tetrahydrofuranyl, piperidinyl, aziridinyl, pyranyl, 1,3-dioxolanyl, and pyrrolidinyl, each of which is optionally substituted as described in the Definition. The alkyl moieties of the heterocyclealkyl include, but are not limited to, methyl and ethyl. Examples of the optional substituents of the heterocycle moiety of the heterocyclealkyl include, but are not limited to, alkyl, alkoxy, oxo, halogen, haloalkyl, haloalkoxy, hydroxy, and —NZ1Z2 wherein Z1, Z2 are, for example, independently hydrogen, alkyl, or haloalkyl. For example, R1 includes, but is not limited to, morpholinylethyl (including 2-morpholin-4-ylethyl), piperidinylmethyl, piperidinylethyl (including 2-piperidin-1-ylethyl), pyrrolidinylmethyl (including pyrrolidin-2-ylmethyl), pyranylmethyl, 1,3-dioxolanylmethyl, and tetrahydrofuranylmethyl (including tetrahydrofuran-2-ylmethyl and tetrahydrofuran-3-ylmethyl) wherein each of the morpholinyl, piperidinyl, pyrrolidinyl, pyranyl, 1,3-dioxolanyl, and tetrahydrofuranyl are optionally substituted as described hereinabove.
Within each group of compounds of formula (Ia) or (Ib) as described in the preceding paragraphs, R2, R3, R4, and R5, have values as defined in the Summary and the Detailed Description. R5, for example, is hydrogen or halogen (for example, fluorine).
Thus, of each groups of compounds of formula (Ia) or (Ib) as described in the preceding paragraphs, examples of a subgroup include, but are not limited to, those wherein R5 is hydrogen.
Examples of another subgroup of compounds of formula (Ia) or (Ib) include those wherein R5 is halogen. In one embodiment, R5 is fluorine.
Of all examples of the groups and subgroups of compounds of formula (Ia) or (Ib) as discussed herein-above, R2, R3, and R4 have values as defined in the Summary and the DETAILED DESCRIPTION
For example, for each of the foregoing groups and subgroups of compounds of formula (Ia) or (Ib), an example of R4 is substituted phenyl or optionally substituted naphthyl, the substituents of phenyl and the optional substituents of naphthyl are represented by R6, and R6 is as described in the Summary section. R6, for example, includes alkyl (for example, methyl, tert-butyl), cyano, halogen, haloalkyl (for example, trifluoromethyl), —OReu wherein Reu is as disclosed in the Summary (for example, Reu is alkyl such as methyl, ethyl, or haloalkyl such as trifluoromethyl), —N(Rwu)(Rgu) wherein Rwu and Rgu are as disclosed in the Summary section (for example, Rwu and Rgu are independently hydrogen or alkyl such as methyl), —N(Rwu)C(O)OReu wherein Rwu and Reu are as disclosed in the Summary section (for example, Reu is alkyl such as methyl, ethyl, and Rwu is hydrogen or alkyl such as methyl), or —C(O)OReu wherein Reu is as disclosed in the Summary section (for example, Reu is alkyl such as methyl, ethyl). In one embodiment, R4 is phenyl, substituted with one or two R6 groups wherein R6 is as disclosed in the Summary and the Detailed Description sections.
Another example of R4 for the foregoing groups and subgroups of compounds includes, but are not limited to, C4-C10 alkyl such as 2,2-dimethylpropyl or haloalkyl (for example, 2,2,2-trichloro-1,1-dimethylethyl).
Yet other example of R4 for the foregoing groups and subgroups of compounds includes, but not limited to, cycloalkyl, optionally substituted as described in the Summary. For example, R4 is adamantyl, bicyclo[2.2.1]heptyl, cyclopropyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted as described in the Summary. Examples of the optional substituents include, but are not limited to, alkyl such as methyl, unsubstituted phenyl, and oxo.
Yet another example of R4 for the foregoing groups and subgroups of compounds includes, but not limited to, cycloalkylalkyl, wherein the cycloalkyl moiety of cycloalkylalkyl is optionally substituted as described in the Summary. For example, R4 is cyclopentylmethyl or bicyclo[2.2.1]heptylmethyl, wherein the cyclopentyl and the bicyclo[2.2.1]heptyl are each optionally substituted as described in the Summary. Examples of the optional substituents include, but are not limited to, alkyl such as methyl, and oxo.
Yet another example of R4 for the foregoing groups and subgroups of compounds includes, but not limited to, arylalkyl (for example, benzyl).
Yet a further example of R4 for the foregoing groups and subgroups of compounds includes, but not limited to, heterocycle, optionally substituted as described in the Summary. For example, the heterocycle includes, but not limited to, morpholinyl, 1,3-benzodioxolyl, tetrahydropyranyl, and 2,3-dihydropyranyl, each of which is optionally substituted as described in the Summary.
Yet a further example of R4 for the foregoing groups and subgroups of compounds includes, but not limited to, heteroaryl, optionally substituted as described in the Summary. Examples of R4 as heteroaryl include, but are not limited to, pyridinyl, quinolinyl, thienyl, 1,3-thiazolyl, benzofuranyl, and benzothienyl, each of which is optionally substituted as described in the Summary. Examples of the optional substituents include, but are not limited to, alkyl (for example, methyl, tert-butyl), cyano, halogen, haloalkyl (for example, trifluoromethyl), —OReu wherein Reu is as disclosed in the Summary (for example, Reu is alkyl such as methyl, ethyl, or haloalkyl such as trifluoromethyl), —N(Rwu)(Rgu) wherein Rwu and Rgu are as disclosed in the Summary section (for example, Ru and Rgu are independently hydrogen or alkyl such as methyl), —N(Rwu)C(O)OReu wherein Ru and Reu are as disclosed in the Summary section (for example, Reu is alkyl such as methyl, ethyl, and Ru is hydrogen or alkyl such as methyl), or —C(O)OReu wherein Reu is as disclosed in the Summary section (for example, Reu is alkyl such as methyl, ethyl).
For each of the foregoing groups and subgroups of compounds of formula (Ia) or (Ib), examples of R3 include, but are not limited to, hydrogen, alkenyl (for example, isopropenyl), alkoxycarbonyl (for example, ethoxycarbonyl), alkylcarbonyl (for example, methylcarbonyl), alkyl (for example, methyl, tert-butyl), aryl (for example, phenyl), cycloalkyl (for example, cyclopropyl), formyl, halogen (for example, Br), haloalkyl (for example, trifluoromethyl), heterocycle (for example, 1,3-dioxolanyl, including 1,3-dioxolan-2-yl), hydroxyalkyl (for example, 1-hydroxy-1-methylethyl, 1-hydroxy-1-methylpropyl, 1-ethyl-1-hydroxypropyl), hydroxyalkynyl (for example, 3-hydroxy-3-methylbut-1-ynyl), hydroxyhaloalkyl (for example, 2-fluoro-1-(fluoromethyl)-1-hydroxyethyl, 2,2-difluoro-1-hydroxy-1-methylethyl, 2-fluoro-1-hydroxy-1-methylethyl, 2,2,2-trifluoro-1-hydroxy-1-methylethyl), RjRkN— wherein Rj and Rk are as described in the Summary (for example, Rj is hydrogen, Rk is alkoxycarbonyl such as tert-butoxycarbonyl), RjRkN-alkylene- wherein Rj and Rk are as described in the Summary (for example, RjRkN-alkylene- is 1-amino-1-ethylpropyl, 1-amino-1-methylethyl), RmRnN—C(O)— wherein Rm and Rn are as described in the Summary (for example, Rm and Rn are independently hydrogen or alkyl), and RpO—N═C(Rz)— wherein Rp and Rz are as described in the Summary (for example, Rp and Rz are independently hydrogen or alkyl), wherein the aryl moiety, the cycloalkyl moiety, and the heterocycle moiety are optionally substituted as described in the Summary. For example, the aryl and the cycloalkyl are optionally substituted with 1 or 2 substituents selected from the group consisting of alkyl (for example, methyl), halogen, and haloalkyl (for example, trifluoromethyl). For example, the heterocycle moiety is optionally substituted with 1 or 2 substituents selected from the group consisting of oxo, alkyl (for example, methyl), halogen, and haloalkyl (for example, trifluoromethyl).
For each of the foregoing groups and subgroups of compounds of formula (Ib), R2 has values as described in the Summary and Detailed Description (for example, R2 has the values as described for R3 in the preceding paragraph), with the proviso that when E is C(O), L2 is a bond, R4 is aryl, R1 is C3-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or 4-amino-2-methyl-5-pyrimidinyl)methyl, R3 is hydrogen or phenyl, then R2 is not hydrogen or C1-C5 alkyl.
Other examples of compounds of formula (Ib) include those groups and subgroups as described herein above wherein R2 and R3 together with the carbon atoms to which they are attached from a ring as described in the Summary.
Thus, one embodiment of the invention includes those groups and subgroups of compounds as described hereinabove, having formula (Ic)




wherein R7 represents optional substituents, independently selected the group consisting of from alkyl, halogen, and haloalkyl, and E, R1, R4, R5, and L2 are as in each of the foregoing groups and subgroups of compounds.
For example, one embodiment of the invention provides a group of compounds of formula (Ic) wherein E is C(O), L2 is a bond, R5 is hydrogen, and R1 is C3-C7 alkyl (for example, n-butyl, isobutyl).
Other examples of a group of compounds of formula (Ic) include, but are not limited to, those wherein E is C(O), L2 is a bond, R5 is hydrogen, and R1 is alkoxy-(C2-C6 alkylene)- such as 2-methoxyethyl.
Further examples of a group of compounds having formula (Ic) include, but are not limited to, those wherein E is C(O), L2 is a bond, R5 is hydrogen, and R1 is haloalkyl (for example, 4-fluorobutyl).
Yet other examples of a group of compounds of formula (Ic) include, but are not limited to, those wherein E is C(O), L2 is a bond, R5 is hydrogen, and R1 is cycloalkylalkyl wherein the cycloalkyl moiety is optionally substituted as described in the Detailed Description. For example, R1 includes, but is not limited to, cyclopropylmethyl and cyclobutylmethyl, wherein the cyclopropyl and the cyclobutyl moieties are optionally substituted as described in the Detailed Description.
Yet other examples of another group of compounds of formula (Ic) include, but are not limited to, those wherein E is C(O), L2 is a bond, R5 is hydrogen, and R1 is heterocyclealkyl wherein the heterocycle moiety is optionally substituted as described in the Detailed Description section. Examples of the heterocycle moiety of the heterocyclealkyl include, but are not limited to, morpholinyl, tetrahydrofuranyl, piperidinyl, aziridinyl, pyranyl, 1,3-dioxolanyl, and pyrrolidinyl, each of which is optionally substituted as described in the Detailed Description section. The alkyl moieties of the heterocyclealkyl include, but are not limited to, methyl and ethyl. Examples of the optional substituents of the heterocycle moiety of the heterocyclealkyl include, but are not limited to, alkyl, alkoxy, oxo, halogen, haloalkyl, haloalkoxy, hydroxyl, and —NZ1Z2 wherein Z1, Z2 are, for example, independently hydrogen, alkyl, or haloalkyl. For example, R1 includes, but is not limited to, morpholinylethyl (including 2-morpholin-4-ylethyl), piperidinylmethyl, piperidinylethyl (including 2-piperidin-1-ylethyl), pyrrolidinylmethyl (including pyrrolidin-2-ylmethyl), pyranylmethyl, 1,3-dioxolanylmethyl, and tetrahydrofuranylmethyl (including tetrahydrofuran-2-ylmethyl and tetrahydrofuran-3-ylmethyl) wherein each of the morpholinyl, piperidinyl, pyrrolidinyl, pyranyl, 1,3-dioxolanyl, and tetrahydrofuranyl are optionally substituted as described hereinabove.
Another embodiment of the invention includes those having formula (Id)




wherein G is N(H), N(alkyl), O, CH2, or CH2CH2, R8 represents optional substituents independently selected from the group consisting of alkyl, halogen, and haloalkyl, two R8 groups on the same carbon atom together with the carbon atom to which they are attached, optionally form a ═O group, and E, R1, R4, R5, and L2 have values as disclosed in each of the foregoing groups and subgroups of compounds as described hereinabove.
For example, one embodiment of the invention provides a group of compounds of formula (Id) wherein E is C(O), L2 is a bond, R5 is hydrogen, and R1 is C3-C7 alkyl (for example, n-butyl, isobutyl).
Other examples of a group of compounds of formula (Id) include, but are not limited to, those wherein E is C(O), L2 is a bond, R5 is hydrogen, and R1 is alkoxy-(C2-C6 alkylene)- such as 2-methoxyethyl.
Further examples of a group of compounds having formula (Id) include, but are not limited to, those wherein E is C(O), L2 is a bond, R5 is hydrogen, and R1 is haloalkyl (for example, 4-fluorobutyl).
Yet other examples of a group of compounds of formula (Id) include, but are not limited to, those wherein E is C(O), L2 is a bond, R5 is hydrogen, and R1 is cycloalkylalkyl wherein the cycloalkyl moiety is optionally substituted as described in the Detailed Description. For example, R1 includes, but is not limited to, cyclopropylmethyl and cyclobutylmethyl, wherein the cyclopropyl and the cyclobutyl moieties are optionally substituted as described in the Detailed Description
Yet other examples of another group of compounds of formula (Id) include, but are not limited to, those wherein E is C(O), L2 is a bond, R5 is hydrogen, and R1 is heterocyclealkyl wherein the heterocycle moiety is optionally substituted as described in the Detailed Description section. Examples of the heterocycle moiety of the heterocyclealkyl include, but are not limited to, morpholinyl, tetrahydrofuranyl, piperidinyl, aziridinyl, pyranyl, 1,3-dioxolanyl, and pyrrolidinyl, each of which is optionally substituted as described in the Detailed Description. The alkyl moieties of the heterocyclealkyl include, but are not limited to, methyl and ethyl. Examples of the optional substituents of the heterocycle moiety of the heterocyclealkyl include, but are not limited to, alkyl, alkoxy, oxo, halogen, haloalkyl, haloalkoxy, hydroxyl, and —NZ1Z2 wherein Z1, Z2 are, for example, independently hydrogen, alkyl, or haloalkyl. For example, R1 includes, but is not limited to, morpholinylethyl (including 2-morpholin-4-ylethyl), piperidinylmethyl, piperidinylethyl (including 2-piperidin-1-ylethyl), pyrrolidinylmethyl (including pyrrolidin-2-ylmethyl), pyranylmethyl, 1,3-dioxolanylmethyl, and tetrahydrofuranylmethyl (including tetrahydrofuran-2-ylmethyl and tetrahydrofuran-3-ylmethyl) wherein each of the morpholinyl, piperidinyl, pyrrolidinyl, pyranyl, 1,3-dioxolanyl, and tetrahydrofuranyl are optionally substituted as described hereinabove.
For each of the foregoing groups of compounds of formula (Ic) and (Id), R4 has meanings as defined in the Summary.
For example, for each of the foregoing groups of compounds of formula (Ic) and (Id), examples of a subgroup include those wherein R4 is substituted phenyl or optionally substituted naphthyl, wherein the substituents have values as described in the Summary and the Detailed Description.
Exemplary compounds of the invention having formula (I) include, but are not limited to:

    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-1-(1-adamantyl)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone;
    tert-butyl (2Z)-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)acetate;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-cyclohexylethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-cyclohexylacetamide;
    4-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]morpholine;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-(5-chloro-2-methoxyphenyl)acetamide;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-(3-propyl-1,3-benzothiazol-2(3H)-ylidene)ethanone;
    (2Z)-2-(5-bromo-3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (Z)-2-(5-acetyl-3-butyl-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (Z)-2-(3-butyl-5-(1-(hydroxyimino)ethyl)-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde;
    (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde oxime;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[4,5-dimethyl-3-(2-morpholin-4-ylethyl)-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-3-butyl-2-(2-oxo-2-pyridin-2-ylethylidene)-2,3-dihydro-1,3-thiazole-5-carbaldehyde;
    (2Z)-3-butyl-2-[2-(3,5-difluorophenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde;
    (2Z)-3-butyl-2-[2-(2-fluorophenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde;
    (2Z)-3-butyl-2-[2-(2,4-difluorophenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2-fluorophenyl)ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-pyridin-2-ylethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(3,5-difluorophenyl)ethanone;
    (2Z)-2-(3-butyl-3,4,5,6-tetrahydro-2H-cyclopenta[d][1,3]thiazol-2-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (Z)-2-(5-acetyl-4-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (Z)-2-(5-acetyl-3-butyl-4-methylthiazole-2(3H)-ylidene-1-(pyridine-2-yl)ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(3-chlorothien-2-yl)ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-cyclopentylethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-cyclohexylethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    6-[(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-2,2-dimethyl-2,3-dihydro-4H-pyran-4-one;
    (2Z)-1-(1-benzofuran-5-yl)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-fluoro-2-methoxyphenyl)ethanone;
    (2Z)-2-(3-butyl-4-phenyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    ethyl (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-4-carboxylate;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-N-(5-chloro-2-methoxyphenyl)acetamide;
    (2Z)-2-(3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-N-(5-chloro-2-methoxyphenyl)acetamide;
    (2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-cyclohexylethanone;
    (2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(3-chloro-1-benzothien-2-yl)ethanone;
    (2Z)-1-(1-adamantyl)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)ethanone;
    (1Z)-1-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-3-cyclopentylacetone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-cyclohexylethanone;
    (3Z)-1-[bicyclo[2.2.1]hept-2-yl]-3-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)acetone;
    (1Z)-1-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-3-(2-chlorophenyl)acetone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3-methylthien-2-yl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(1,3-thiazol-4-yl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2-methylphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2-chlorophenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3-chlorophenyl)ethanone;
    (2Z)-1-(2-bromophenyl)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)ethanone;
    (2Z)-1-(3-bromophenyl)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)ethanone;
    (2Z)-1-(4-bromophenyl)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-[3-(trifluoromethyl)phenyl]ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-[3-(trifluoromethoxy)phenyl]ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,3-dimethylphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,5-dimethylphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3,4-dimethylphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3,5-dimethylphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,3-dimethoxyphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,5-dimethoxyphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3,5-dimethoxyphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,3-dichlorophenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,4-dichlorophenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,5-dichlorophenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3,4-dichlorophenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3,5-dichlorophenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(5-fluoro-2-methylphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3-methoxy-4-methylphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(1-naphthyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2-naphthyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(4-tert-butylphenyl)ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-[2-fluoro-5-(trifluoromethyl)phenyl]ethanone;
    (2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-[2-chloro-5-(trifluoromethyl)phenyl]ethanone;
    (2Z)-1-(5-bromo-2-chlorophenyl)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2,6-difluorophenyl)ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2,4-dichlorophenyl)ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[2-(trifluoromethyl)phenyl]ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[3-(trifluoromethyl)phenyl]ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-cyclopentylethanone;
    4-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]benzonitrile;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(1-naphthyl)ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2,5-difluorophenyl)ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-pyridin-3-ylethanone;
    (2Z)-1-(1,3-benzodioxol-5-yl)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)ethanone;
    (2Z)-1-[2,5-bis(trifluoromethyl)phenyl]-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[5-fluoro-2-(trifluoromethyl)phenyl]ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(3-methylthien-2-yl)ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-fluoro-2-methylphenyl)ethanone;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-fluorophenyl)ethanone;
    (Z)-2-(3-butyl-5-((E)-1-(methoxyimino)ethyl)-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (Z)-2-(3-butyl-5-((Z)-1-(methoxyimino)ethyl)-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-[3-butyl-4-(trifluoromethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-[3-butyl-5-methyl-4-(trifluoromethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (Z)-1-(5-chloro-2-methoxyphenyl)-2-(5-((E)-1-(methoxyimino)ethyl)-4-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)ethanone;
    (Z)-1-(5-chloro-2-methoxyphenyl)-2-(5-((Z)-1-(methoxyimino)ethyl)-4-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)ethanone;
    (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-5,5-dimethyl-2,3,5,6-tetrahydro-1,3-benzothiazol-7(4H)-one;
    (2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-(5-tert-butyl-3-isobutyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-[3-butyl-4-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-[5-tert-butyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-isobutyl-5-methyl-4-(trifluoromethyl)-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2E)-2-(3-butyl-4-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)-2-fluoroethanone;
    (2E)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)-2-fluoroethanone;
    (2Z)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (1Z)-1-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-4,4-dimethylpentan-2-one;
    1-[(2Z)-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-4,5-dimethyl-1,3-thiazol-3(2H)-yl]-3,3-dimethylbutan-2-one;
    1-adamantyl (2Z)-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)acetate;
    (2Z)-2-[3-butyl-5-(3-hydroxy-3-methylbut-1-ynyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (1Z)-1-[3-(3,3-dimethyl-2-oxobutyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-4,4-dimethylpentan-2-one;
    (2E)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)-2-fluoroethanone;
    2-[(2Z)-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-4,5-dimethyl-1,3-thiazol-3(2H)-yl]ethyl 5-chloro-2-methoxybenzoate;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[2-(methylamino)phenyl]ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(4-fluorobutyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-1-(2-amino-5-chlorophenyl)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone;
    ethyl 2-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-4-chlorophenylcarbamate;
    (2E)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)-2-fluoroethanone;
    ethyl 2-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-4-chlorophenyl(methyl)carbamate;
    methyl 2-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-4-chlorobenzoate;
    (2Z)-2-[3-butyl-4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    2,2,2-trichloro-1,1-dimethylethyl (2Z)-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)acetate;
    2,2,2-trichloro-1,1-dimethylethyl (2Z)-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)acetate;
    (2Z)-2-[4-tert-butyl-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-[4-tert-butyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-[4-tert-butyl-3-(2-piperidin-1-ylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-N-methyl-2,3-dihydro-1,3-thiazole-4-carboxamide;
    (Z)-2-(5-acetyl-3-butylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    6-[(2Z)-2-(3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene)ethanoyl]-2,2-dimethyl-2,3-dihydro-4H-pyran-4-one;
    (2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-fluoro-2-methoxyphenyl)ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(3-chlorothien-2-yl)ethanone;
    6-[(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-2,2-dimethyl-2,3-dihydro-4H-pyran-4-one;
    (2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-iodo-2-methoxyphenyl)ethanone;
    (2Z)-1-(1-benzofuran-5-yl)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(2-ethoxypyridin-3-yl)ethanone;
    (2Z)-1-(1-benzofuran-5-yl)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)ethanone;
    (2Z)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)-1-(2-ethoxypyridin-3-yl)ethanone;
    (2Z)-2-[5-tert-butyl-3-(2-methoxyethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-[5-tert-butyl-3-(2-methoxyethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(2,3-dichlorophenyl)ethanone;
    (2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-[trans-2-phenylcyclopropyl]ethanone;
    (2Z)-2-[5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-[5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(2,3-dichlorophenyl)ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-2-[5-bromo-3-(cyclobutylmethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-4-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-2-[3-butyl-5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-2-[5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(2-chloropyridin-3-yl)ethanone;
    (2Z)-2-[5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(2-ethoxypyridin-3-yl)ethanone;
    (2Z)-2-[5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-[4-(trifluoromethyl)pyridin-3-yl]ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,3-dichlorophenyl)ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-hydroxy-1-methylpropyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-ethyl-1-hydroxypropyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(2-fluoro-1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(2,2-difluoro-1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-[2-(trifluoromethyl)phenyl]ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]ethanone;
    ethyl (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-5-(1-hydroxy-1-methylethyl)-2,3-dihydro-1,3-thiazole-4-carboxylate;
    (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-6,6-dimethyl-3,6-dihydrofuro[3,4-d][1,3]thiazol-4(2H)-one;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-hydroxyphenyl)ethanone;
    tert-butyl (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazol-4-ylcarbamate;
    (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[5-chloro-2-(dimethylamino)phenyl]ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-ethyl-1-hydroxypropyl)-1,3-thiazol-2(3H)-ylidene]ethanone;
    (2Z)-2-[5-(1-amino-1-ethylpropyl)-3-(cyclobutylmethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-[6-chloro-4-(trifluoromethyl)pyridin-3-yl]ethanone;
    (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-6,6-diethyl-2,3,5,6-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazol-4-one;
    (2Z)-2-[3-butyl-5-[2-fluoro-1-(fluoromethyl)-1-hydroxyethyl]-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)-1-[6-chloro-4-(trifluoromethyl)pyridin-3-yl]ethanone;
    (2Z)-2-[3-butyl-4-(1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
    (Z)-2-(4-acetyl-3-butylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
    (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-[2-fluoro-1-(fluoromethyl)-1-hydroxyethyl]-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
    ethyl (2Z)-5-(1-amino-1-methylethyl)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-4-carboxylate;
    (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-6,6-dimethyl-2,3,5,6-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazol-4-one; and
    (Z)-2-(3-butyl-4,5-dimethylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanethione.


Compounds of the present invention may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.
For example, compounds of formula (I) wherein R1 is tetrahydrofuran-2-ylmethyl can have stereoisomers including, but not limited to, those shown below:




wherein A, R3, R4, R5, E, and L2 are as disclosed in the Summary and the Detailed Description sections. It is understood that embodiments for A, R3, R4, R5, E, and L2, and combinations of embodiments, including particular, and more particular embodiments as described for formula (I) are also contemplated for compounds of formulae (Ie), and (If).

The present invention contemplates various stereoisomers (including enantiomers and diastereomers) and mixtures thereof. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution of the individual stereoisomer using methods that are known to those of ordinary skill in the art. Examples of resolution are, for example, (i) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, followed by liberation of the optically pure product; or (ii) separation of the mixture of enantiomers or diastereomers on chiral chromatographic columns.
Geometric isomers may exist in the present compounds. The invention contemplates the various geometric isomers and mixtures thereof resulting from the disposition of substituents around a carbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkyl group, or a heterocycle group. Substituents around a carbon-carbon double bond or a carbon-nitrogen double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or a heterocycle are designated as being of cis or trans configuration.
Within the present invention it is to be understood that compounds disclosed herein may exhibit the phenomenon of tautomerism.
Thus, the formulae drawings within this specification can represent only one of the possible tautomeric or stereoisomeric forms. It is to be understood that the invention encompasses any tautomeric or stereoisomeric form, and mixtures thereof, and is not to be limited merely to any one tautomeric or stereoisomeric form utilized within the naming of the compounds or formulae drawings.
c. BIOLOGICAL DATA
(i) In Vitro Methods—CB2 and CB1 Radioligand Binding Assays:
The CB1 and CB2 radioligand binding assays described herein are utilized to ascertain the selectivity of compounds of the present invention for binding to CB2 relative to CB1 receptors.
HEK293 cells stably expressing human CB2 receptors were grown until a confluent monolayer was formed. Briefly, the cells were harvested and homogenized in TE buffer (50 mM Tris-HCl, 1 mM MgCl2, and 1 mM EDTA) using a polytron for 2×10 second bursts in the presence of protease inhibitors, followed by centrifugation at 45,000×g for 20 minutes. The final membrane pellet was re-homogenized in storage buffer (50 mM Tris-HCl, 1 mM MgCl2, and 1 mM EDTA and 10% sucrose) and frozen at −78° C. until used. Saturation binding reactions were initiated by the addition of membrane preparation (protein concentration of 5 μg/well for human CB2) into wells of a deep well plate containing [3H]CP-55,940 (120 Ci/mmol, a nonselective CB agonist commercially available from Tocris) in assay buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl2, and 0.5 mg/mL fatty acid free BSA, pH 7.4). After 90 min incubation at 30° C., binding reaction was terminated by the addition of 300 μl/well of cold assay buffer followed by rapid vacuum filtration through a UniFilter-96 GF/C filter plates (pre-soaked in 1 mg/mL BSA for 2 hours). The bound activity was counted in a TopCount using Microscint-20. Saturation experiments were conducted with twelve concentrations of [3H]CP-55,940 ranging from 0.01 to 8 nM. Competition experiments were conducted with 0.5 nM [3H]CP-55,940 and five concentrations of displacing ligands selected from the range of 0.01 nM to 10 μM. The addition of 10 μM unlabeled CP-55,940 (Tocris, Ellisville, Mo.) was used to assess nonspecific binding.
HEK293 cells stably expressing rat CB2 receptors were grown until a confluent monolayer was formed. Briefly, the cells were harvested and homogenized in TE buffer (50 mM Tris-HCl, 1 mM MgCl2, and 1 mM EDTA) using a polytron for 2×10 second bursts in the presence of protease inhibitors, followed by centrifugation at 45,000×g for 20 minutes. The final membrane pellet was re-homogenized in storage buffer (50 mM Tris-HCl, 1 mM MgCl2, and 1 mM EDTA and 10% sucrose) and frozen at −78° C. until used. Saturation binding reactions were initiated by the addition of membrane preparation (protein concentration of 20 μg/well for rat CB2) into wells of a deep well plate containing [3H]CP-55,940 (120 Ci/mmol, a nonselective CB agonist commercially available from Tocris) in assay buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl2, and 0.5 mg/mL fatty acid free BSA, pH 7.4). After 45 min incubation at 30° C., binding reaction was terminated by the addition of 300 μl/well of cold assay buffer followed by rapid vacuum filtration through a UniFilter-96 GF/C filter plates (pre-soaked in 1 mg/mL BSA for 2 hours). The bound activity was counted in a TopCount using Microscint-20. Saturation experiments were conducted with twelve concentrations of [3H]CP-55,940 ranging from 0.01 to 8 nM. Competition experiments were conducted with 0.5 nM [3H]CP-55,940 and five concentrations of displacing ligands selected from the range of 0.01 nM to 10 μM. The addition of 10 μM unlabeled CP-55,940 (Tocris, Ellisville, Mo.) was used to assess nonspecific binding.
Representative compounds of the present invention bound to CB2 receptors with a Ki of less than about 1,000 nM, preferably less than 400 nM, more preferably less than 200 nM and, most preferably lower than 100 nM.
HEK293 human CB1 membranes were purchased from Perkin Elmer. Binding was initiated by the addition of membranes (8-12 μg per well) into wells (Scienceware 96-well DeepWell plate, VWR, West Chester, Pa.) containing [3H]CP-55,940 (120 Ci/mmol, Perkin Elmer, Boston, Mass.) and a sufficient volume of assay buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl2, and 0.5 mg/mL fatty acid free BSA, pH 7.4) to bring the total volume to 250 μL. After incubation (30° C. for 90 minutes), binding was terminated by the addition of 300 μL per well of cold assay buffer and rapid vacuum filtration (FilterMate Cell Harvester, Perkin Elmer, Boston, Mass.) through a UniFilter-96 GF/C filter plate (Perkin Elmer, Boston, Mass.) (pre-soaked in 0.3% PEI at least 3 hours), followed by five washes with cold assay buffer. The bound activity was counted in the TopCount using Microscint-20 (both from Perkin Elmer, Boston, Mass.). Competition experiments were conducted with 1 nM [3H]CP-55,940 and five concentrations (1 nM to 10 μM) of displacing ligands. The addition of 10 μM unlabeled CP-55,940 (Tocris, Ellisville, Mo.) was used to assess nonspecific binding.
Representative compounds of the present invention bound to CB1 receptors with Ki of about 10 fold to about 1000 fold higher than that for CB2 receptors. These results show that the compounds of the present invention preferably bind to CB2 receptors, therefore are selective ligands for the CB2 receptor.
(ii) In Vivo Data:
Animals
Adult male Sprague-Dawley rats (250-300 g body weight, Charles River Laboratories, Portage, Mich.) are used. Animal handling and experimental protocols are approved by the Institutional Animal Care and Use Committee (IACUC) at Abbott Laboratories. For all surgical procedures, animals are maintained under isoflurane anesthesia (4-5% to induce, 1-3% to maintain), and the incision sites are sterilized using a 10% povidone-iodine solution prior to and after surgeries.
Incisional Model of Postoperative Pain
A skin incision model of postoperative pain was produced using the procedures as described in Brennan et al., 1996, Pain, 64, 493. All rats were anesthetized with isoflurane delivered via a nose cone. Right hind paw incision was performed following sterilization procedures. The plantar aspect of the left hind paw was placed through a hole in a sterile plastic drape. A 1-cm longitudinal incision was made through the skin and fascia of the plantar aspect of the hind paw, starting 0.5 cm from the proximal edge of the heel and extending towards the toes, the plantar muscle was elevated and incised longitudinally leaving the muscle origin and insertion points intact. The skin was then closed with two mattress sutures (5-0 nylon). After surgery, animals were then allowed to recover for 2 hours, at which time tactile allodynia was assessed as described below. To evaluate the anti-nociceptive effects, animals were i.p. administered vehicle or test compound 90 minutes following skin incision and tactile allodynia was assessed 30 minutes after compound administration.
Tactile allodynia was measured using calibrated von Frey filaments (Stoelting, Wood Dale, Ill.) as described in Chaplan, S. R., F. W. Bach, J. W. Pogrel, J. M. Chung and T. L. Yaksh, 1994, Quantitative Assessment of Tactile Allodynia in the Rat Paw, J. Neurosci. Methods, 53, 55. Rats were placed into inverted individual plastic cage (20×12.5×20 cm) on top of a suspended wire mesh grid, and acclimated to the test chambers for 20 minutes. The von Frey filaments were applied perpendicularly from underneath the cage through openings in the wire mesh floor directly to an area within 1-3 mm (immediately adjacent) of the incision, and then held in this position for approximately 8 seconds with enough force to cause a slight bend in the filament. Positive responses included an abrupt withdrawal of the hind paw from the stimulus, or flinching behavior immediately following removal of the stimulus. A 50% withdrawal threshold was determined using an up-down procedure (Dixon, W. J., 1980, Efficient analysis of experimental observations, Ann. Rev. Pharmacol. Toxicol. 20, 441).
Representative compounds of the present invention showed a statistically significant change in paw withdrawal latency versus a saline vehicle at less than about 300 micromoles/kg in the incisional model of postoperative pain. In a more preferred embodiment, compounds of the present invention showed efficacy at less than about 50 micromoles/kg in the incisional model of postoperative pain.
Spinal Nerve Ligation Model of Neuropathic Pain
A model of spinal nerve ligation-induced (SNL model) neuropathic pain as originally described by Kim and Chung (Kim, S. H. and J. M. Chung, 1992, Pain 50, 355) can be used to test the compounds of the present invention The left L5 and L6 spinal nerves of the rat are isolated adjacent to the vertebral column and tightly ligated with a 5-0 silk suture distal to the DRG, and care is taken to avoid injury of the L4 spinal nerve. Sham rats undergo the same procedure, but without nerve ligation. All animals are allowed to recover for at least one week and not more than three weeks prior to assessment of tactile allodynia.
Tactile allodynia is measured using calibrated von Frey filaments (Stoelting, Wood Dale, Ill.) as described in Chaplan, S. R., F. W. Bach, J. W. Pogrel, J. M. Chung and T. L. Yaksh, 1994, Quantitative Assessment of Tactile Allodynia in the Rat Paw, J. Neurosci. Methods, 53, 55. Rats are placed into inverted individual plastic containers (20×12.5×20 cm) on top of a suspended wire mesh grid, and acclimated to the test chambers for 20 minutes. The von Frey filaments are presented perpendicularly to the plantar surface of the selected hind paw, and then hold in this position for approximately 8 sec with enough force to cause a slight bend in the filament. Positive responses include an abrupt withdrawal of the hind paw from the stimulus, or flinching behavior immediately following removal of the stimulus. A 50% withdrawal threshold is determined using an up-down procedure (Dixon, W. J., 1980, Efficient analysis of experimental observations, Ann. Rev. Pharmacol. Toxicol. 20, 441). Only rats with a baseline threshold score of less that 4.25 g are used in this study, and animals demonstrating motor deficit are excluded. Tactile allodynia thresholds are also assessed in several control groups, including naive, sham-operated, and saline infused animals as well as in the contralateral paws of nerve-injured rats.
Capsaicin-Induced Secondary Mechanical Hypersensitivity:
Rats were allowed to acclimate to the study room for 1 hour. They were then briefly restrained, and capsaicin was administered at 10 μg in 10 μL of vehicle (10% ethanol and 2-hydroxypropyl cyclodextrin) by intraplantar injection into the center of the right hind paw. Secondary mechanical hyperalgesia was measured at the heel away from the site of injection at 180 min following capsaicin (Joshi et al 2006, Neuroscience 143, 587-596). Compounds are injected (i.p.) 30 min before testing (150 min post-capsaicin).
Tactile allodynia was measured as described above.
Certain compounds of the present invention showed a statistically significant change in paw withdrawal latency versus a saline vehicle at less than about 300 micromoles/kg. In a more preferred embodiment, compounds of the present invention showed efficacy of less than about 50 micromoles/kg.
d. METHODS OF USING THE COMPOUNDS
One embodiment of the present invention provides a method for treating pain (for example, neuropathic pain or nociceptive pain) in a mammal in need of such treatment. The method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention provides a method for treating a disorder selected from the group consisting of inflammatory disorders, immune disorders, neurological disorders, cancers of the immune system, respiratory disorders, and cardiovascular disorders in a mammal in need of such treatment. The method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Yet another embodiment of the present invention relates to a method for providing neuroprotection in a mammal in need of such treatment. This method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In addition to the data contained herein, several lines of evidence support the assertion that CB2 receptors play a role in analgesia. For example, Zimmer et al. have reported that the nonselective cannabinoid agonist Δ9-THC retains some analgesic efficacy in CB1 receptor knockout mice (Zimmer, A., et al., Proc. Nat. Acad. Sci., 1999, 96, 5780-5785). HU-308 is one of the first highly selective CB2 agonists identified that elicits an antinociceptive response in the rat formalin model of persistent pain (Hanus, L., et al., Proc. Nat. Acad. Sci., 1999, 96, 14228-14233). The CB2-selective cannabinoid ligand AM-1241 exhibits robust analgesic efficacy in animal models of acute thermal pain (Malan, T. P., et al., Pain, 2001, 93, 239-245; Ibrahim, M. M., et al., Proc. Nat. Acad. Sci., 2005, 102(8), 3093-3098), persistent pain (Hohmann, A. G., et al., J. Pharmacol. Exp. Ther., 2004, 308, 446-453), inflammatory pain (Nackley, A. G., et al., Neuroscience, 2003, 119, 747-757; Quartilho, A. et al., Anesthesiology, 2003, 99, 955-60), and neuropathic pain (Ibrahim, M. M., et al., Proc. Nat. Acad. Sci., 2003, 100, 10529-10533). The CB2-selective partial agonist GW405833, also known as L768242, is efficacious in rodent models of neuropathic, incisional, and both chronic and acute inflammatory pain (Valenzano, K. J., et al., Neuropharmacology, 2005, 48, 658-672 and Clayton, N., et al., Pain, 2002, 96, 253-260). The analgesic effects induced by these CB2-selective ligands are blocked by CB2 and not by CB1 receptor antagonists. Furthermore, at fully efficacious doses, AM-1241 and GW405833 are devoid of typical CB1 receptor-mediated CNS side effects, providing evidence that modulation of CB2 receptors can produce broad-spectrum pain relief with reduced side-effect liability.
The potential exists for CB2 modulators to have opioid sparing effects. A synergy between the analgesic effects of morphine and the nonselective CB agonist Δ9-THC has been documented (Cichewicz, D. L., Life Sci. 2004, 74, 1317-1324). Therefore, CB2 ligands have additive or synergistic analgesic effects when used in combination with lower doses of morphine or other opioids, providing a strategy for reducing adverse opioid events, such as tolerance, constipation, and respiratory depression, without sacrificing analgesic efficacy.
CB2 receptors are present in tissues and cell types associated with immune functions and CB2 receptor mRNA is expressed by human B cells, natural killer cells, monocytes, neutrophils, and T cells (Galiegue et al., Eur. J. Biochem., 1995, 232, 54-61). Studies with CB2 knockout mice have suggested a role for CB2 receptors in modulating the immune system (Buckley, N. E., et al., Eur. J. Pharmacol. 2000, 396, 141-149). Although immune cell development and differentiation are similar in knockout and wild type animals, the immunosuppressive effects of Δ9-THC are absent in the CB2 receptor knockout mice, providing evidence for the involvement of CB2 receptors in immunomodulation. As such, selective CB2 modulators are useful for the treatment of autoimmune diseases including but not limited to multiple sclerosis, rheumatoid arthritis, systemic lupus, myasthenia gravis, type I diabetes, irritable bowel syndrome, psoriasis, psoriatic arthritis, and hepatitis; and immune related disorders including but not limited to tissue rejection in organ transplants, gluten-sensitive enteropathy (Celiac disease), asthma, chronic obstructive pulmonary disease, emphysema, bronchitis, acute respiratory distress syndrome, allergies, allergic rhinitis, dermatitis, and Sjogren's syndrome.
Microglial cells are considered to be the immune cells of the central nervous system (CNS) where they regulate the initiation and progression of immune responses. They are quiescent and resting having a ramified morphology as long as the CNS is healthy. Microglia express a variety of receptors enabling them to survey the CNS and respond to pathological events. Insult or injury to the CNS leads to microglial cell activation, which is characterized by various morphological changes allowing response to the lesion. Ramifications are retracted and microglia are transformed into amoeboid-like cells with phagocytic function. They can proliferate, rapidly migrate to the site of injury, and produce and release cytokines, chemokines and complement components (Watkins L. R., et al., Trends in Neuroscience, 2001, 24(8), 450; Kreutzberg, G. W., Trends Neurosci., 1996, 19, 312-318). CB2 receptor expression on microglia is dependent upon inflammatory state with higher levels of CB2 found in primed, proliferating, and migrating microglia relative to resting or fully activated microglial (Carlisle, S. J., et al. Int. Immunopharmacol., 2002, 2, 69). Neuroinflammation induces many changes in microglia cell morphology and there is an upregulation of CB2 receptors and other components of the endocannabinoid system. It is conceivable that CB2 receptors may be more susceptible to pharmacological effects during neuroinflammation (Walter, L., Stella, N., Br. J. Pharmacol. 2004, 141, 775-785). Neuroinflammation occurs in several neurodegenerative diseases, and induction of microglial CB2 receptors has been observed (Carrier, E. J., et al., Current Drug Targets—CNS & Neurological Disorders, 2005, 4, 657-665). Thus, CB2 ligands may be clinically useful for the treatment of neuroinflammation.
CB2 receptor expression has been detected in perivascular microglial cells within normal, healthy human cerebellum (Nunez, E., et al., Synapse, 2004, 58, 208-213). Perivascular cells are immunoregulatory cells located adjacent to CNS blood vessels and, along with parenchymal microglia and astrocytes, they play a pivotal role in maintaining CNS homeostasis and blood-brain barrier functionality (Williams, K., et al., Glia, 2001, 36, 156-164). CB2 receptor expression has also been detected on cerebromicrovascular endothelial cells, which represent a main component of the blood-brain barrier (Golech, S. A., et al., Mol. Brain. Res., 2004, 132, 87-92). A recent report demonstrated that CB2 receptor expression is up-regulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis (Benito, C., et al., J. Neurosci. 2005, 25(10), 2530-2536). Thus, compounds that affect CB2 signaling may protect the blood-brain barrier and be clinically useful in the treatment of neuroinflammation and a variety of neuroinflammatory disorders including retroviral encephalitis, which occurs with human immunodeficiency virus (HIV) infection in the CNS.
Multiple sclerosis is common immune-mediated disease of the CNS in which the ability of neurons to conduct impulses becomes impaired through demyelination and axonal damage. The demyelination occurs as a consequence of chronic inflammation and ultimately leads to a broad range of clinical symptoms that fluctuate unpredictably and generally worsen with age. These include painful muscle spasms, tremor, ataxia, motor weakness, sphincter dysfunction, and difficulty speaking (Pertwee, R. G., Pharmacol. Ther. 2002, 95, 165-174). The CB2 receptor is up-regulated on activated microglial cells during experimental autoimmune encephalomyelitis (EAE) (Maresz, K., et al., J. Neurochem. 2005, 95, 437-445). CB2 receptor activation prevents the recruitment of inflammatory cells such as leukocytes into the CNS (Ni, X., et al., Multiple Sclerosis, 2004, 10, 158-164) and plays a protective role in experimental, progressive demyelination (Arevalo-Martin, A.; et al., J. Neurosci., 2003, 23(7), 2511-2516), which are critical features in the development of multiple sclerosis. Thus, CB2 receptor modulators provide a unique treatment for demyelinating pathologies.
Alzheimer's disease is a chronic neurodegenerative disorder accounting for the most common form of elderly dementia. Recent studies have revealed that CB2 receptor expression is upregulated in neuritic plaque-associated microglia from brains of Alzheimer's disease patients (Benito, C., et al., J. Neurosci., 2003, 23(35), 11136-11141). In vitro, treatment with the CB2 agonist JWH-133 abrogated β-amyloid-induced microglial activation and neurotoxicity, effects that can be blocked by the CB2 antagonist SR144528 (Ramirez, B. G., et al., J. Neurosci. 2005, 25(8), 1904-1913). CB2 modulators possess both anti-inflammatory and neuroprotective actions and thus have clinical utility in treating neuroinflammation and in providing neuroprotection associated with the development of Alzheimer's disease.
Increased levels of epithelial CB2 receptor expression are observed in human inflammatory bowel disease tissue (Wright, K., et al., Gastroenterology, 2005, 129, 437-453). Activation of CB2 receptors re-established normal gastrointestinal transit after endotoxic inflammation was induced in rats (Mathison, R., et al., Br. J. Pharmacol. 2004, 142, 1247-1254). CB2 receptor activation in a human colonic epithelial cell line inhibited TNF-α-induced interleukin-8 (IL-8) release (Ihenetu, K. et al., Eur. J. Pharmacol. 2003, 458, 207-215). Chemokines released from the epithelium, such as the neutrophil chemoattractant IL-8, are upregulated in inflammatory bowel disease (Warhurst, A. C., et al., Gut, 1998, 42, 208-213). Thus, administration of CB2 receptor modulators represents a novel approach for the treatment of inflammation and disorders of the gastrointestinal tract including but not limited to inflammatory bowel disease, irritable bowel syndrome, secretory diarrhea, ulcerative colitis, Crohn's disease and gastroesophageal reflux disease (GERD).
Hepatic fibrosis occurs as a response to chronic liver injury and ultimately leads to cirrhosis, which is a major worldwide health issue due to the severe accompanying complications of portal hypertension, liver failure, and hepatocellular carcinoma (Lotersztajn, S., et al., Annu. Rev. Pharmacol. Toxicol., 2005, 45, 605-628). Although CB2 receptors were not detectable in normal human liver, CB2 receptors were expressed liver biopsy specimens from patients with cirrhosis. Activation of CB2 receptors in cultured hepatic myofibroblasts produced potent antifibrogenic effects (Julien, B., et al., Gastroenterology, 2005, 128, 742-755). In addition, CB2 knockout mice developed enhanced liver fibrosis after chronic administration of carbon tetrachloride relative to wild-type mice. Administration of CB2 receptor modulators represents a unique approach for the treatment of liver fibrosis.
CB2 receptors are involved in the neuroprotective and anti-inflammatory mechanisms induced by the interleukin-1 receptor antagonist (IL-Ira) (Molina-Holgado, F., et al., J. Neurosci., 2003, 23(16), 6470-6474). IL-Ira is an important anti-inflammatory cytokine that protects against ischemic, excitotoxic, and traumatic brain insults. CB2 receptors play a role in mediating these neuroprotective effects indicating that CB2 ligands are useful in the treatment of traumatic brain injury, stroke, and in mitigating brain damage.
Cough is a dominant and persistent symptom of many inflammatory lung diseases, including asthma, chronic obstructive pulmonary disease, viral infections, and pulmonary fibrosis (Patel, H. J., et al., Brit. J. Pharmacol., 2003, 140, 261-268). Recent studies have provided evidence for the existence of neuronal CB2 receptors in the airways, and have demonstrated a role for CB2 receptor activation in cough suppression (Patel, H. J., et al., Brit. J. Pharmacol., 2003, 140, 261-268 and Yoshihara, S., et al., Am. J. Respir. Crit. Care Med., 2004, 170, 941-946). Both exogenous and endogenous cannabinoid ligands inhibit the activation of C-fibers via CB2 receptors and reduce neurogenic inflammatory reactions in airway tissues (Yoshihara, S., et al., J. Pharmacol. Sci. 2005, 98(1), 77-82; Yoshihara, S., et al., Allergy and Immunology, 2005, 138, 80-87). Thus, CB2-selective modulators have utility as antitussive agents for the treatment of pulmonary inflammation, chronic cough, and a variety of airway inflammatory diseases including but not limited to asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis.
Osteoporosis is a disease characterized by reduced bone mass, which leads to deterioration of bone microstructure and increased susceptibility to fracture. Age is associated with bone loss and it is estimated that 50% of all Caucasian women will have osteoporosis by the age of 80 (Ralston, S. H., Curr. Opin. Pharmacol., 2003, 3, 286-290). There is a substantial genetic contribution to bone mass density and the CB2 receptor gene is associated with human osteoporosis (Karsak, M., et al., Human Molecular Genetics, 2005, 14(22), 3389-3396). Osteoclasts and osteoblasts are largely responsible for maintaining bone structure and function through a process called remodeling, which involves resorption and synthesis of bone (Boyle, W. J., et al., Nature, 2003, 423, 337-342). CB2 receptor expression has been detected on osteoclasts and osteoblastic precursor cells, and administration of a CB2 agonist in mice caused a dose-dependent increase in bone formation (Grotenhermen, F. and Muller-Vahl, K., Expert Opin. Pharmacother., 2003, 4(12), 2367-2371). Cannabinoid inverse agonists, including the CB2-selective inverse agonist SR144528, have been shown to inhibit osteoclast activity and reverse ovariectomy-induced bone loss in mice, which is a model for post-menopausal osteoporosis (Ralston, S. H., et al., Nature Medicine, 2005, 11, 774-779). Thus, CB2 modulators are useful for the treatment and prevention of osteoporosis, osteoarthritis, and bone disorders.
Arthrosclerosis is a chronic inflammatory disease and is a leading cause of heart disease and stroke. CB2 receptors have been detected in both human and mouse atherosclerotic plaques. Administration of low doses of THC in apolipoprotein E knockout mice slowed the progression of atherosclerotic lesions, and these effects were inhibited by the CB2-selective antagonist SR144528 (Steffens, S., et al., Nature, 2005, 434, 782-786). Thus, compounds with activity at the CB2 receptor are clinically useful for the treatment of atherosclerosis.
CB2 receptors are expressed on malignant cells of the immune system and targeting CB2 receptors to induce apoptosis may constitute a novel approach to treating malignancies of the immune system. Selective CB2 agonists induce regression of malignant gliomas (Sanchez, C., et al., Cancer Res., 2001, 61, 5784-5789), skin carcinomas (Casanova, M. L., et al., J. Clin. Invest., 2003, 111, 43-50), and lymphomas (McKallip, R. J., et al., Blood, 2002, 15(2), 637-634). Thus, CB2 modulators have utility as anticancer agents against tumors of immune origin.
Activation of CB2 receptors has been demonstrated to protect the heart against the deleterious effects of ischemia and reperfusion (Lepicier, P., et al., Brit. J. Pharm. 2003, 139, 805-815; Bouchard, J.-F., et al., Life Sci. 2003, 72, 1859-1870; Filippo, C. D., et al., J. Leukoc. Biol. 2004, 75, 453-459). Thus, CB2 modulators have utility for the treatment or prophylaxis of cardiovascular disease and the development of myocardial infarction.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Compounds of the invention can also be administered as a pharmaceutical composition comprising the compounds of interest in combination with one or more pharmaceutically acceptable carriers. The phrase “therapeutically effective amount” of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well-known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The total daily dose of the compounds of this invention administered to a human or animal range from about 0.1 mg/kg body weight to about 100 mg/kg body weight. More preferable doses can be in the range of from about 0.3 to 30 mg/kg body weight. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
e. PHARMACEUTICAL COMPOSITIONS
The present invention further provides pharmaceutical compositions that comprise compounds of the present invention or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical compositions comprise compounds of the present invention that may be formulated together with one or more non-toxic pharmaceutically acceptable carriers.
Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, alone or in combination with one or more nonsteroidal anti-inflammatory drug (NSAID).
The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term “parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
The term “pharmaceutically acceptable carrier” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase “pharmaceutically acceptable salt” means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
The term “pharmaceutically acceptable prodrug” or “prodrug” as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
The present invention contemplates compounds of formula (I) formed by synthetic means or formed by in vivo biotransformation of a prodrug.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.
f. GENERAL SYNTHESIS
This invention is intended to encompass compounds of the invention when prepared by synthetic processes or by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.
The compounds of the invention may be prepared by a variety of processes well known for the preparation of compounds of this class. For example, the compounds of the invention wherein the groups E, R1, R2, R3, R4, R5, A, L2, Re, Rp, and Rz have the meanings as set forth in the summary section unless otherwise noted, can be synthesized as shown in Schemes 1-7.
As used in the descriptions of the schemes and the examples, certain abbreviations are intended to have the following meanings: DCC for 1,3-dicyclohexylcarbodiimide, DIEA for diisopropylethyl amine, DMA for N,N-dimethylacetamide, DMAP for 4-dimethylaminopyridine, DMF for N,N-dimethylformamide, DMSO for dimethyl sulfonamide, EtOAc for ethyl acetate, CHCl3 for chloroform, CH2Cl2 for dichloromethane, CH3CN for acetonitrile, DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene, HATU for O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, HPLC for high performance liquid chromatography, THF for tetrahydrofuran, MeOH for methanol, TEA for triethyl amine, Ph for phenyl, TBAF for tetrabutyl ammonium fluoride.
Compounds of general formula (I) wherein R5 is hydrogen, E is C(O), and L2 is N(Re) can be prepared using, for example, using the general procedures as outlined in Scheme 1.




Compounds of formula 1 when heated in the presence of halides of formula R1—X1, wherein X1 is halogen, in a solvent such as, but not limited to, acetonitrile, provides compounds of formula 2. For example, the reaction conditions may be heated for 72-96 hours to effect complete consumption of starting material. Compounds of formula 2 when treated with isocyanates of formula R4RcNCO in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, and in a solvent such as, but not limited to, dichloromethane provides compounds of formula 3.
Compounds of general formula (I) wherein R5 is hydrogen can be prepared using general procedure as shown in Scheme 2.




Compounds of formula 2, when treated with compounds of formula R4L2ECl, in the presence of 4-dimethylaminopyridine, and in a solvent such as, but not limited to, dichloromethane, provides compounds of formula 4.
Compounds of general formula (I) wherein E is C(O) and R5 is hydrogen can be synthesized using general procedures as outlined below:




Compounds of formula 2 when treated with a reagent that can provide an electrophilic carbonyl group such as, but not limited to, di-tert butyl dicarbonyl or carbonyl diimidazole, provide intermediates of formula 5. The reaction is generally conducted in the presence of 4-dimethylaminopyridine and in a solvent such as DMF. Compounds of formula 5 when treated with appropriate reagents provide compounds of formula 6. For example, compounds of formula 5 when treated with primary amines, secondary amines, alcohols, or a heterocycle containing a secondary nitrogen atom, under heated conditions, provides compounds of formula 6 wherein L2 is N(Re) or O, or provides compounds wherein L2 is a bond and R4 is a heterocycle containing a secondary amine having the nitrogen atom of the heterocyclic ring attached to the carbonyl functional group. For example, the transformation can be effected by heating compounds of formula 5 with an appropriate reagent such as R4OH, R4—N(Re)(H) or a heterocycle containing a secondary nitrogen, in the presence of a non-nucleophilic base such as diisopropylethylamine or triethylamine, and in a solvent such as but not limited to acetonitrile or THF.
Compounds of general formula (I) wherein E is C(O) and A is C(R2) can be prepared using general procedure as shown in Scheme 4.




Compounds of formula 7 when treated with sodium hydride in DMF and R1—N═C═S at about 0° C., followed by the addition of compounds of formula 8 wherein X2 is halogen and then heating, provide compounds of formula 9.
Compounds of general formula (I) wherein R3 is RpON═C(Rz)— can be prepared using general procedures as shown in Scheme 5.




Compounds of formula 10 when treated with compounds of formula H2N—ORp provide compounds of formula 11. Typical conditions for this reaction include stirring the reagents in a solvent such as pyridine or mixtures of pyridine and ethanol at ambient temperature for about 16-24 hours.
Compounds of general formula (I) wherein E is C(O) and R5 is fluorine can be prepared, for example, by heating compounds of formula 6 with about equimolar amounts of SelectfluorTM, in a suitable solvent such as, acetonitrile, toluene, dioxane, chloroform, and the like, as shown in Scheme 6.




Compounds of general formula (I) wherein E is C(S) and L2 is a bond can be obtained, for example, by heating compounds of formula 13 with phosphorus pentasulfide in pyridine or THF, as shown in Scheme 7.




It will be appreciated that the synthetic schemes and specific examples as illustrated in the Examples section are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.
Optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Reactions may be worked up in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.
Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that may not be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention may be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.
Starting materials, if not commercially available, may be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.
When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
Similarly, when a pure geometric isomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.
Following Examples may be used for illustrative purposes and should not be deemed to narrow the scope of the invention.
g. EXAMPLES
Example 1
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
Example 1A
3-butyl-2,4,5-trimethyl-1,3-thiazol-3-ium iodide
A mixture of 2,4,5-trimethylthiazole (1.3 g, 10 mmol) and n-butyl iodide (7.4 g, 40 mmol) in anhydrous acetonitrile (30 mL) was refluxed for 72 hours and then concentrated under reduced pressure to provide the crude thiazolium salt. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=7 Hz, 3H), 1.39 (sextet, J=7 Hz, 2H), 1.65 (m, 2H), 2.43 (s, 6H), 2.96 (s, 3H), 4.25 (m, 2H).
Example 1B (Procedure A)
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
To a solution of Example 1A (780 mg, 2.5 mmol) and 5-chloro-2-methoxy-benzoyl chloride (515 mg, 2.5 mmol) in CH2Cl2 (25 mL) under N2 atmosphere at 0° C. was added 4-dimethylaminopyridine (DMAP) (1.22 g. 10 mmol) and the mixture was allowed to warm to room temperature. The mixture was stirred for 20 hours, washed sequentially with saturated sodium bicarbonate and brine. The methylene chloride solution was dried (anhydrous MgSO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography over silica gel (hexane-EtOAc 1:1 as eluent) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.39 (sextet, J=7 Hz, 2H), 1.66 (quintet, J=7 Hz, 2H), 2.15 (s, 3H), 2.20 (s, 3H), 3.85 (s, 3H), 3.90 (t, J=7 Hz, 2H), 6.54 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.40 (dd, J=9 Hz, 3 Hz, 1H), 7.65 (d, J=3 Hz, 1H); MS (ESI) m/z 352 (M+H)+. Anal calcd for C18H22ClNO2S: C, 61.44; H, 6.30; N, 3.98. Found: C, 61.34; H, 6.17; N, 3.86.
Example 1C (Procedure B)
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
A mixture of Example 1A (155 mg (0.5 mmol) and 5-chloro-2-methoxy-benzoic acid N-hydroxysuccinimide ester (142 mg, 0.5 mmol) in anhydrous DMF (5 mL) at 0° C. was treated with a solution of DBU (0.076 mL, 0.5 mmol) in DMF (5 mL) and then allowed to warm to ambient temperature and stirred for 16 hours. The mixture was partitioned between water and EtOAc. The EtOAc layer was washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Hexane-EtOAc 1:1) to provide the title compound.
Example 2
(2Z)-1-(1-adamantyl)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone
The title compound was prepared as described in Example 1B by replacing 5-chloro-2-methoxy-benzoyl chloride with 1-adamantanecarbonyl chloride. 1H NMR (300 MHz, DMSO-d6) δ 0.93 (t, J=7 Hz, 3H), 1.35 (sextet, J=7 Hz, 2H), 1.58 (quintet, J=7 Hz, 2H), 1.65 (m, 6H), 1.76 (m, 6H), 1.97 (m, 3H), 2.08 (s, 3H), 2.12 (s, 3H), 3.84 (m, 2H), 5.81 (s, 1H); MS (ESI) m/z 346 (M+H)+. Anal calcd for C21H31NOS.0.2H2O: C, 72.24; H, 9.06; N, 4.01. Found: C, 72.35; H, 9.04; N, 3.68.
Example 3
tert-butyl (2Z)-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)acetate
DMAP (200 mg, 1.6 mmol) was added at 0° C. to a solution of Example 1A (440 mg, 1.4 mmol) and di-t-butyl-dicarbonate (352 mg, 1.6 mmol) in DMF (15 mL). The mixture was stirred for 18 hours at room temperature and then purified by column chromatography over silica gel (Hexane-EtOAc 1:1 as eluent) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.91 (t, J=7 Hz, 3H), 1.36 (sextet, J=7 Hz, 2H), 1.40 (s, 9H), 1.50 (m, 2H), 2.03 (s, 3H), 2.06 (s, 3H), 3.66 (m, 2H), 4.87 (s, 1H); MS (ESI) m/z 284 (M+H)+. Anal calcd for C15H25NO2S.0.5H2O: C, 61.61; H, 8.96; N, 4.79. Found: C, 61.25; H, 8.80; N, 4.75.
Example 4
N-[1-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]pyridin-4(1H)-ylidene]-N-methylmethanaminium iodide
From the chromatographic purification of Example 3 was obtained the title compound after changing the elution solvent to (9:1) CH2Cl2-MeOH. 1H NMR (300 MHz, DMSO-d6) δ 1.00 (t, J=7 Hz, 3H), 1.38 (sextet, J=7 Hz, 2H), 1.64 (m, 2H), 2.03 (s, 3H), 2.06 (s, 3H), 3.31 (s, 6H), 4.14 (t, J=7 Hz, 2H), 6.23 (s, 1H), 7.07 (d, J=8 Hz, 2H), 8.83 (d, J=8 Hz, 2H); MS (ESI) m/z 332 (M)+. Anal calcd for C18H26IN3OS: C, 47.06; H, 5.70; N, 9.15. Found: C, 47.08; H, 5.85; N, 9.02.
Example 5
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-1,3-(2-methoxyethyl)-4,5-dimethyl-[3-thiazol-2(3H)-ylidene]ethanone
Example 5A
3-(2-methoxyethyl)-2,4,5-trimethyl-1,3-thiazol-3-ium bromide
The title compound was prepared as described in Example 1A by substituting 2-bromoethyl methyl ether for n-butyl iodide.
Example 5B (2Z)-1-(5-chloro-2-methoxyphenyl)-2-1,3-(2-methoxyethyl)-4,5-dimethyl-[3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared as described in Example 1B by substituting Example 5A for Example 1A. 1H NMR (300 MHz, DMSO-d6) δ 2.14 (s, 3H), 2.18 (s, 3H), 3.24 (s, 2H), 3.63 (t, J=6 Hz, 2H), 3.84 (s, 3H), 4.11 (t, J=6 Hz, 2H), 6.48 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.39 (d-d, J=9 Hz, 3 Hz, 1H), 7.61 (d, J=3 Hz, 1H); MS (ESI) m/z 354 (M+H)+. Anal calcd for C17H20ClNO3S: C, 57.70; H, 5.70; N, 3.96. Found: C, 57.66; H, 5.73; N, 3.85.
Example 6
(2Z)-2-(3-butyl-5-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 1B by substituting 3-butyl-2,4,5-trimethylthiazol-3-ium iodide for Example 1A. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.39 (sextet, J=7 Hz, 2H), 1.66 (quintet, J=7 Hz, 2H), 2.21 (d, J=1.5 Hz, 3H), 3.85 (s, 3H), 3.93 (t, J=7 Hz, 2H), 6.50 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.13 (d, J=1.5 Hz, 1H), 7.40 (d-d, J=9 Hz, 3 Hz, 1H), 7.64 (d, J=3 Hz, 1H); MS (ESI) m/z 338 (M+H).
Example 7
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-cyclohexylethanone
The title compound was prepared as described in Example 1B by replacing 5-chloro-2-methoxy-benzoyl chloride with cyclohexanecarbonyl chloride. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.25 (m, 8H), 1.66 (m, 6H), 2.07 (s, 3H), 2.12 (s, 3H), 2.18 (m, 1H), 3.81 (t, J=7 Hz, 2H), 5.74 (s, 1H); MS (ESI) m/z 294 (M+H)+.
Example 8
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-cyclohexylacetamide
To a solution of Example 1A (123 mg, 0.4 mmol) and cyclohexyl isocyanate (63 mg, 0.5 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a solution of DBU (0.076 mL, 0.5 mmol) in CH2Cl2 (5 mL). The mixture was allowed to warm to room temperature and stirred for 14 hours. The mixture was washed sequentially with water, brine and dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (CH2Cl2-MeOH 9:1) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.10 (m, 3H), 1.29 (m, 4H), 1.51 (m, 3H), 1.70 (m, 4H), 1.95 (s, 3H), 2.02 (s, 3H), 3.33 (m, 3H), 5.02 (s, 1H), 6.74 (br d, J=7 Hz, 1H); MS (ESI) m/z 309 (M+H)+. Anal calcd for C17H28N2OS.0.25H2O: C, 65.24; H, 9.18; N, 8.95. Found: C, 65.49; H, 9.30; N, 8.93.
Example 9
4-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]morpholine
A mixture of product from Example 4 (46 mg, 0.1 mmol) and morpholine (175 mg, 2 mmol) in dioxane (10 mL) was heated to 80° C. for 2 hours then concentrated in vacuo. Column chromatography over silica gel (CH2Cl2-MeOH 4:1) provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.32 (sextet, J=7 Hz, 2H), 1.53 (quintet, J=7 Hz, 2H), 2.00 (s, 3H), 2.05 (s, 3H), 3.29 (t, J=6 Hz, 4H), 3.55 9t, J=6 Hz, 4H), 3.72 (t, J=7 Hz, 2H), 5.30 (s, 1H); MS (ESI) m/z 297 (M+H).
Example 10
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-(5-chloro-2-methoxyphenyl)acetamide
The title compound was prepared as described in Example 8 by substituting 5-chloro-2-methoxy-phenyl isocyanate for cyclohexyl isocyanate. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=7 Hz, 3H), 1.37 (sextet, J=7 Hz, 2H), 1.58 (quintet, J=7 Hz, 2H), 2.03 (s, 3H), 2.07 (s, 3H), 3.68 (t, J=7 Hz, 2H), 3.85 (s, 3H), 5.69 (s, 1H), 6.87 (d-d, J=9 Hz, 3 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 8.33 (s, 1H), 8.41 (d, J=3 Hz, 1H); MS (ESI) m/z 367 (M+H)+. Anal calcd for C18H23ClN2O2S: C, 58.92; H, 6.32; N, 7.63. Found: C, 58.75; H, 6.58; N, 7.52.
Example 11
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-(3-propyl-1,3-benzothiazol-2(3H)-ylidene)ethanone
The title compound was prepared as described in Example 1B by substituting 2-methyl-3-propylbenzo[d]thiazol-3-ium iodide for Example 1A. 1H NMR (300 MHz, DMSO-d6) δ 0.98 (t, J=7 Hz, 3H), 1.79 (sextet, J=7 Hz, 2H), 3.90 (s, 3H), 4.19 (t, J=7 Hz, 2H), 6.72 (s, 1H), 7.16 (d, J=9 Hz, 1H), 7.25 (m, 1H), 7.45 (m, 2H), 7.58 (d, J=8 Hz, 1H), 7.65 (d, J=3 Hz, 1H), 7.83 (d-d, J=8 Hz, 1.5 Hz, 1H); MS (ESI) m/z 360 (M+H)+. Anal calcd for C19H18ClNO2S: C, 63.41; H, 5.04; N, 3.89. Found: C, 63.09; H, 5.17; N, 3.93.
Example 12
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-1,3-(2,4-difluorobenzyl)-4,5-dimethyl-[3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared as described in Example 1B by substituting 3-(2,4-difluorobenzyl)-2,4,5-trimethylthiazol-3-ium iodide for Example 1A. 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 2.21 (s, 3H), 3.67 (s, 3H), 5.12 (s, 2H), 6.44 (s, 1H), 6.94 (m, 1H), 7.04 (d, J=9 Hz, 1H), 7.29 (m, 1H), 7.37 (m, 2H), 7.58 (d, J=1.5 Hz, 1H); MS (ESI) m/z 422 (M+H). Anal calcd for C21H18F2ClNO2S: C, 59.79; H, 4.30; N, 3.32. Found: C, 59.35; H, 4.14; N, 3.25.
Example 13
(2Z)-2-(5-bromo-3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 1B by substituting 5-bromo-3-butyl-2,4-dimethylthiazol-3-ium iodide for Example. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.39 (sextet, J=7 Hz, 2H), 1.66 (quintet, J=7 Hz, 2H), 2.29 (s, 3H), 3.86 (s, 3H), 3.99 (t, J=7 Hz, 2H), 6.76 (s, 1H), 7.14 (d, J=9 Hz, 1H), 7.44 (d-d, J=9 Hz, 3 Hz, 1H), 7.64 (d, J=3 Hz, 1H); MS (ESI) m/z 416 (M+H)+. Anal calcd for C17H19BrClNO2S: C, 48.99; H, 4.60; N, 3.36. Found: C, 49.22; H, 4.45; N, 3.33.
Example 14
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was isolated from the chromatographic purification of Example 13. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.39 (sextet, J=7 Hz, 2H), 1.66 (quintet, J=7 Hz, 2H), 2.28 (d, J=1 Hz, 3H), 3.86 (s, 3H), 3.93 (t, J=7 Hz, 2H), 6.48 (s, 1H), 6.57 (d, J=1 Hz, 1H), 7.12 (d, J=9 Hz, 1H), 7.40 (d-d, J=9 Hz, 3 Hz, 1H), 7.65 (d, J=3 Hz, 1H); MS (ESI) m/z 338 (M+H)+. Anal calcd for C17H20ClNO2S.0.1H2O: C, 60.11; H, 5.99; N, 4.12. Found: C, 59.95; H, 5.68; N, 3.96.
Example 15
(2Z)-1-(1-adamantyl)-2-(3-ethyl-1,3-benzothiazol-2(3H)-ylidene)ethanone
The title compound was prepared as described in Example 1B by substituting 3-ethyl-2-methylbenzo[d]thiazol-3-ium iodide for Example 1A and 1-adamantanecarbonyl chloride for 5-chloro-2-methoxy-benzoyl chloride. 1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, J=7 Hz, 3H), 1.70 (m, 6H), 1.83 (m, 6H), 2.00 (m, 3H), 4.22 (t, J=7 Hz, 2H), 6.19 (s, 1H), 7.18 (m, 1H), 7.40 (m, 2H), 7.71 (d, J=7 Hz, 1H); MS (ESI) m/z 340 (M+H)+. Anal calcd for C21H25NOS.0.2H2O: C, 73.51; H, 7.46; N, 4.08. Found: C, 73.59; H, 7.29; N, 3.88.
Example 16
(Z)-2-(5-acetyl-3-butyl-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
To a stirred suspension of NaH (60% in mineral oil, 0.08 g, 2 mmol) in anhydrous DMF (3 mL) at 0° C. was added 5-chloro-2-methoxyacetophenone (0.37 g, 2 mmol) followed by subsequent addition of n-butylisothiocyanate (0.24 mL, 2 mmol) in DMF (3 mL). The mixture was stirred at 0° C. for 2 hours after which 3-chloropentane-2,4-dione (0.23 mL, 2 mmol) was added drop-wise. The mixture was stirred at 0° C. for 2 hours and then heated to 90° C. for 5 hours. The mixture was cooled to ambient temperature, diluted with water (30 mL) and extracted with ethyl acetate (3×35 mL). The combined organic layers were washed sequentially with water, brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 50% ethyl acetate in hexane to provide the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.3 Hz, 3 H), 1.27-1.55 (m, 2 H), 1.58-1.80 (m, 2 H), 2.45 (s, 3 H), 2.65 (s, 3 H), 3.88 (s, 3 H), 3.94-4.10 (m, 2 H), 6.78 (s, 1 H), 7.16 (d, J=8.8 Hz, 1 H), 7.47 (dd, J=8.8, 2.7 Hz, 1 H), 7.65 (d, J=2.7 Hz, 1 H). MS (DCI) m/z 380 (M+H).+ Anal calcd for C19H22ClNO3S: C, 60.07; H, 5.84; N, 3.69. Found: C, 59.56; H, 5.95; N, 3.68.
Example 17
(Z)-2-(3-butyl-5-((Z)-1-(hydroxyimino)ethyl)-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
Example 16 (38 mg, 0.1 mmol) in pyridine (2 mL) was treated with NH2OH_HCl (10 mg, 0.15 mmol) and stirred at 50° C. for 14 hours. The mixture was then poured into water and extracted with ethyl acetate (2×15 mL). The organic layers were combined, washed sequentially with water, brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate to provide the title compounds as a mixture of E and Z isomers. 1H NMR (300 MHz, DMSO-d6), 6 ppm 0.97 (t, J=7.3 Hz, 3 H), 1.31-1.51 (m, 2 H), 1.58-1.79 (m, 2 H), 2.07-2.27 (m, 3 H), 2.43 (s, 3 H), 3.79-3.93 (m, 3 H), 3.91-4.07 (m, 2 H), 6.61 (d, J=3.7 Hz, 1 H), 7.13 (d, J=8.8 Hz, 1 H), 7.42 (dd, J=8.8, 2.7 Hz, 1 H), 7.65 (d, J=2.7 Hz, 1 H), 11.11 (s, 0.4 H), 11.33 (s, 0.6 H). MS (DCI) m/z 395 (M+H)+, 379 (M+H-16)+.
Example 19
(2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde
The title compound was prepared as described in Example 16 by substituting 2-bromomalonaldehyde for 3-chloropentane-2-4-dione. 1H NMR (300 MHz, DMSO-d6), 6 ppm 0.95 (t, J=7.3 Hz, 3 H), 1.23-1.51 (m, 2 H), 1.65-1.90 (m, 2 H), 3.88 (s, 3 H), 4.10 (t, J=7.3 Hz, 2 H), 6.82 (s, 1 H), 7.17 (d, J=8.8 Hz, 1 H), 7.49 (dd, J=8.8, 3.1 Hz, 1 H), 7.64 (d, J=2.7 Hz, 1 H), 8.51 (s, 1 H), 9.77 (s, 1 H). MS (DCI) m/z 352 (M+H).+ Anal calcd for C17H18ClNO3S.0.5H2O: C, 56.58; H, 5.31; N, 3.88. Found: C, 56.69; H, 5.11; N, 3.68.
Example 20
(2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde oxime
A mixture of Example 19 (35 mg, 0.1 mmol) and NH2OH_HCl (10 mg, 0.15 mmol) in pyridine (2 mL) was stirred at room temperature for 14 hours. The mixture was poured into water and extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed sequentially with water and brine, dried over MgSO4, Filtered, and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate as an eluent to provide the title compounds as a mixture of E and Z isomers. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.3 Hz, 3 H), 1.25-1.42 (m, 2 H), 1.73 (m, 2 H), 3.86 (s, 3 H), 4.01 (m, 2 H), 6.58 (s, 0.6 H), 6.64 (s, 0.4 H), 7.04-7.20 (m, 1H), 7.35-7.49 (m, 1 H), 7.57 (s, 1 H), 7.61-7.70 (m, 1 H), 7.88 (s, 0.6 H), 8.19 (s, 0.4H), 11.26 (s, 0.4 H), 11.72 (s, 0.6 H), MS (DCI) m/z 368 (M+H)+, 352 (M+H-16)+.
Example 21
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[4,5-dimethyl-3-(2-morpholin-4-ylethyl)-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared as described in Example 16 by substituting with 2-(4-morpholino)-ethylisothiocyanate for n-butylisothiocyanate and 3-chloro-2-butanone for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, CDCl3) δ ppm 2.19 (s, 3 H), 2.21 (s, 3 H), 2.47-2.59 (m, 4 H), 2.69 (t, 2 H), 3.67-3.77 (m, 4 H), 3.87 (s, 3 H), 3.99 (t, J=13.9 Hz, 2 H), 6.49 (s, 1 H), 6.81-6.91 (m, 1 H), 7.13-7.37 (m, 1 H), 7.86 (d, J=2.7 Hz, 1 H). MS (DCI) m/z 409 (M+H)+ Anal calcd for C20H25ClN2O3SH2O: C, 56.26; H, 6.37; N, 6.56. Found: C, 56.38; H, 6.31; N, 6.18.
Example 23
(2Z)-3-butyl-2-(2-oxo-2-pyridin-2-ylethylidene)-2,3-dihydro-1,3-thiazole-5-carbaldehyde
The title compound was prepared as described in Example 16 by substituting 2-acetylpyridine for 5-chloro-2-methoxyacetophenone and 2-bromomalonaldehyde for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, CDCl3) δ ppm 1.02 (t, J=7.3 Hz, 3 H), 1.47 (dd, J=15.3, 7.5 Hz, 2 H), 1.81-2.07 (m, 2 H), 4.09 (t, J=7.3 Hz, 2 H), 7.30-7.43 (m, 2 H), 7.60 (s, 1 H), 7.74-7.94 (m, 1 H), 8.23 (d, J=7.8 Hz, 1 H), 8.53-8.77 (m, 1H), 9.80 (s, 1 H). MS (DCI) m/z 289 (M+H)+.
Example 25
(2Z)-3-butyl-2-[2-(3,5-difluorophenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde
The title compound was prepared as described in Example 16 by substituting 3,5-difluoroacetophenone for 5-chloro-2-methoxyacetophenone and 2-bromomalonaldehyde for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, CDCl3) δ ppm 0.91-1.14 (m, 3 H), 1.40-1.53 (m, 2 H), 1.78-2.04 (m, 2 H), 3.95-4.13 (m, 2 H), 6.38-6.57 (m, 1 H), 6.83-7.04 (m, 1 H), 7.33-7.49 (m, 2 H), 7.55-7.67 (m, 1 H), 9.73-9.89 (m, 1 H). MS (DCI) m/z 324 (M+H)+ Anal calcd for C16H15NO2SF2: C, 59.43; H, 4.68; N, 4.33. Found: C, 59.33; H, 4.60; N, 4.32.
Example 26
(2Z)-3-butyl-2-[2-(2-fluorophenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde
The title compound was prepared as described in Example 16 by substituting 2-fluoroacetophenone for 5-chloro-2-methoxyacetophenone and 2-bromomalonaldehyde for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, CDCl3) δ ppm 0.85-1.14 (m, 3 H), 1.35-1.53 (m, 2 H), 1.82-2.01 (m, 2 H), 3.85-4.13 (m, 2 H), 6.60-6.77 (m, 1 H), 7.02-7.16 (m, 1 H), 7.17-7.29 (m, 1 H), 7.35-7.47 (m, 1 H), 7.54-7.67 (m, 1 H), 7.91-8.20 (m, 1 H), 9.73-9.89 (m, 1 H).). MS (DCI) m/z 306 (M+H)+. Anal calcd for C16H16NO2SF: C, 62.93; H, 5.28; N, 4.59. Found: C, 62.31; H, 5.03; N, 4.48.
Example 27
(2Z)-3-butyl-2-[2-(2,4-difluorophenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde
The title compound was prepared as described in Example 16 by substituting 2,4-difluoroacetophenone for 5-chloro-2-methoxyacetophenone and 2-bromomalonaldehyde for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, CDCl3) δ ppm 1.02 (t, J=7.3 Hz, 3H), 1.31-1.52 (m, 2 H), 1.76-2.01 (m, 2 H), 4.00 (t, J=7.5 Hz, 2 H), 6.63 (s, 1 H), 6.76-6.90 (m, 1 H), 6.90-7.07 (m, 1 H), 7.58 (s, 1 H), 7.98-8.22 (m, 1 H), 9.79 (s, 1 H). MS (DCI) m/z 324 (M+H)+. Anal clad for C16H15NO2SF2: C, 59.43; H, 4.68; N, 4.33. Found: C, 59.31; H, 4.58; N, 4.12.
Example 28
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2-fluorophenyl)ethanone
The title compound was prepared as described in Example 16 by substituting 2-fluoroacetophenone for 5-chloro-2-methoxyacetophenone and 3-chloro-2-butanone for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.3 Hz, 3 H), 1.24-1.45 (m, 2 H), 1.56-1.75 (m, 2 H), 2.17 (s, 3 H), 2.20 (s, 3 H), 3.75-4.09 (m, 2H), 6.34 (s, 1 H), 7.12-7.31 (m, 2 H), 7.33-7.53 (m, 1 H), 7.66-7.90 (m, 1 H). MS (DCI) m/z 306 (M+H).+. Anal calcd for C17H20FNOS: C, 66.85; H, 6.60; N, 4.59. Found: C, 66.99; H, 6.83; N, 4.51.
Example 29
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-pyridin-2-ylethanone
The title compound was prepared as described in Example 16 by substituting 2-acetylpyridine for 5-chloro-2-methoxyacetophenone and 3-chloro-2-butanone for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.3 Hz, 3 H), 1.24-1.48 (m, 2 H), 1.56-1.72 (m, 2 H), 2.09-2.32 (m, J=8.5 Hz, 3 H), 2.18 (s, 3 H), 3.89-4.10 (m, 2 H), 7.07 (s, 1 H), 7.32-7.53 (m, 1 H), 7.81-7.95 (m, 1 H), 7.95-8.09 (m, 1 H), 8.62 (d, J=3.7 Hz, 1 H). MS (DCI) m/z 288 (M+H)+. Anal calcd for C21H24ClNO3S 0.2H2O: C, 65.81; H, 7.04; N, 9.59. Found: C, 65.93; H, 7.25; N, 9.28
Example 30
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(3,5-difluorophenyl)ethanone
The title compound was prepared as described in Example 16 by substituting 3,5-difluoroacetophenone for 5-chloro-2-methoxyacetophenone and 3-chloro-2-butanone for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3H), 1.39 (dd, J=15.1, 7.3 Hz, 2 H), 1.62 (d, J=6.4 Hz, 2 H), 2.17 (s, 3 H), 2.21 (s, 3 H), 3.89-4.33 (m, 2 H), 6.61 (s, 1 H), 7.18-7.37 (m, 1 H), 7.63 (dd, J=8.8, 2.4 Hz, 2 H). MS (DCI) m/z 324 (M+H).+
Example 31
(2Z)-2-(3-butyl-3,4,5,6-tetrahydro-2H-cyclopenta[d][1,3]thiazol-2-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 16 by replacing 2-chlorocyclopentanone for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.34 (dd, J=15.1, 7.6 Hz, 2 H), 1.50-1.82 (m, 2 H), 2.33-2.49 (m, 2 H), 2.74 (q, J=7.0 Hz, 4 H), 3.68-3.94 (m, 5 H), 6.55 (s, 1 H), 7.11 (d, J=8.8 Hz, 1 H), 7.36-7.44 (m, 1 H), 7.65 (d, J=2.7 Hz, 1 H). MS (DCI) m/z 364 (M+H)+. Anal calcd for C19H22ClNO2S: C, 62.71; H, 6.09; N, 3.85. Found: C, 62.33; H, 6.28; N, 3.77.
Example 32
(Z)-2-(5-acetyl-4-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 16 by substituting tetrahydrofuran-2-(ylmethyl)isothiocyanate for n-butylisothiocyanate. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.56-1.76 (m, 1 H), 1.77-1.99 (m, 2 H), 2.01-2.19 (m, 1 H), 2.46 (s, 3 H), 2.64 (s, 3 H), 3.57-3.72 (m, 1 H), 3.74-3.86 (m, 1 H), 3.87 (s, 3 H), 4.08-4.19 (m, 2 H), 4.18-4.33 (m, 1 H), 6.76 (s, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.46 (dd, J=8.8, 2.7 Hz, 1 H), 7.62 (d, J=2.7 Hz, 1 H). MS (DCI) m/z 408 (M+H)+. Anal calcd for C21H20ClNO3S: C, 58.89; H, 5.44; N, 3.43. Found: C, 58.61; H, 5.35; N, 3.38.
Example 34
(Z)-2-(5-acetyl-3-butyl-4-methylthiazole-2(3H)-ylidene-1-(pyridine-2-yl)ethanone
The title compound was prepared as described in Example 16 by substituting 2-acetylpyridine for 5-chloro-2-methoxyacetophenone. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.3 Hz, 3 H), 1.29-1.52 (m, 2 H), 1.58-1.84 (m, 2 H), 2.47 (s, 3 H), 2.66 (s, 3 H), 3.98-4.18 (m, 2 H), 7.29 (s, 1 H), 7.44-7.58 (m, 1 H), 7.96 (td, J=7.6, 1.7 Hz, 1 H), 8.04 (dt, 1 H), 8.67 (d, J=4.1 Hz, 1 H). MS (DCI) m/z 317 (M+H)+. Anal calcd for C21H20ClNO3S: C, 64.53; H, 6.37; N, 8.85. Found: C, 64.46; H, 6.43; N, 8.83.
Example 35
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(3-chlorothien-2-yl)ethanone
Example 35A
5-tert-butyl-2,4-dimethyl-1,3-thiazole
Dimethyl zinc (2 M in toluene, 60 mL, 120 mmol) was added to a solution of titanium(IV) chloride (13.1 mL, 120 mmol) in dichloroethane (60 mL) at 0° C. and the mixture was stirred for 15 minutes after which a solution of 5-acetyl-2,4-dimethyl thiazole (3.11 g, 20 mmol) in dichloroethane (20 mL) was added dropwise. The mixture was stirred overnight and diluted carefully with saturated ammonium hydroxide at 0° C. (30 mL). The mixture was filtered through silica gel and washed thoroughly with ethyl acetate. The filtrate was concentrated in vacuo to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.39 (s, 9 H) 2.44 (s, 3 H) 2.57 (s, 3 H); MS (ESI) m/z 170 (M+H)+.
Example 35B
3-butyl-5-tert-butyl-2,4-dimethyl-1,3-thiazol-3-ium iodide
The title compound was prepared as described in Example 1A, substituting Example 35A for 2,5-dimethyl thiadiazole. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91-0.98 (m, 3 H) 1.35-1.46 (m, 11 H) 1.64-1.76 (m, 2 H) 2.59 (s, 3 H) 2.96 (s, 3 H) 4.26-4.34 (m, 2 H); MS (ESI) m/z 229 (M)+.
Example 35C (2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(3-chlorothien-2-yl)ethanone
To a solution of Example 35B (51 mg, 0.15 mmol) and 4-dimethylamino pyridine (61 mg, 0.5 mmol) in dichloromethane (3 mL) was added 3-chlorothiophene-2-carbonyl chloride (27 mg, 0.15 mmol) and the mixture was stirred overnight. The mixture was washed with water, concentrated in vacuo and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 min run time) at a flow rate of 40 mL/min to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.3 Hz, 3 H), 1.32-1.46 (m, 12 H), 1.63-1.73 (m, 2 H), 2.36 (s, 3 H), 3.90-3.97 (m, 2 H), 6.58 (s, 1 H), 7.10 (d, J=5.4 Hz, 1 H), 7.72 (d, J=5.42 Hz, 1 H); MS (DCI/NH3) m/z 370 (M+H)+. Anal. Calcd for C18H24ClNOS2.0.1 C2HF3O2: C, 57.32; H, 6.37; N, 3.67. Found: C, 57.47; H, 6.37; N, 3.83.
Example 36
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)ethanone
The title compound was prepared as described in Example 35C, substituting 2-chloronicotinyl chloride for 3-chlorothiophene carbonyl chloride. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.3 Hz, 3 H), 1.32-1.45 (m, 11 H), 1.55-1.67 (m, 2 H), 2.36 (s, 3 H), 3.90-3.97 (m, 2 H), 6.07 (s, 1 H), 7.47 (dd, J=7.8, 4.8 Hz, 1 H), 7.91 (dd, J=7.5, 2.0 Hz, 1 H), 8.40 (dd, J=4.8, 2.0 Hz, 1 H); MS (DCI/NH3) m/z 365 (M+H)+. Anal. Calcd for C19H25ClN2S.0.1 C2HF3O2: C, 54.93; H, 5.82; N, 6.30. Found: C, 54.93; H, 5.77; N, 6.30.
Example 37
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-cyclopentylethanone
The title compound was prepared as described in Example 35C, substituting cyclopentane carbonyl chloride for 3-chlorothiophene carbonyl chloride. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.23-1.95 (m, 21 H), 2.27-2.45 (m, 3H), 2.66-2.93 (m, 1 H), 3.86-4.11 (m, 2 H), 5.84 (s, 1 H); MS (DCI/NH3) m/z 322 (M+H)+. Anal. Calcd for C19H31NOS.1.2 C2HF3O2: C, 55.23; H, 6.93; N, 3.28. Found: C, 55.52; H, 7.28; N, 3.14.
Example 38
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-cyclohexylethanone
The title compound was prepared as described in Example 35C, substituting cyclohexane carbonyl chloride for 3-chlorothiophene carbonyl chloride. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88-0.98 (m, 3 H), 1.10-1.49 (m, 15 H), 1.50-1.85 (m, 8 H), 2.21-2.31 (m, 1 H), 2.36 (s, 3 H), 3.99 (s, 2 H), 5.81 (s, 1 H); MS (DCI/NH3) m/z 336 (M+H)+. Anal. Calcd for C20H33NOS.1.2 C2HF3O2: C, 56.96; H, 7.30; N, 2.97. Found: C, 56.526; H, 7.29; N, 3.04.
Example 39
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 35C, substituting 5-chloro-2-methoxybenzoyl chloride for 3-chlorothiophene carbonyl chloride and the product was purified by flash chromatography (silica gel, 80:20 hexanes:ethyl acetate) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.3, Hz, 3 H), 1.31-1.46 (m, 11 H), 1.57-1.71 (m, J=7.71, Hz, 2 H), 2.34 (s, 3 H), 3.82-3.93 (m, 5 H), 6.47 (s, 1 H), 7.10 (d, J=8.8 Hz, 1 H), 7.39 (dd, J=8.7, 2.9 Hz, 1 H), 7.63 (d, J=2.7 Hz, 1 H); MS (DCI/NH3) m/z 394 (M+H)+. Anal. Calcd for C21H28ClNO2.0.3 H2O: C, 63.16; H, 7.22; N, 3.46. Found: C, 63.29; H, 7.00; N, 3.46.
Example 40
6-[(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-2,2-dimethyl-2,3-dihydro-4H-pyran-4-one
The title compound was prepared and purified as described in Example 35C, substituting 2,2-dimethyl-4-oxo-3,4-dihydro-2H-pyran-6-carbonyl chloride for 3-chlorothiophene carbonyl chloride. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.99 (t, J=7.3 Hz, 3 H), 1.35-1.47 (m, 17 H), 1.56-1.69 (m, 2 H), 2.38 (s, 3 H), 2.53 (s, 2 H), 3.90-4.03 (m, 2 H), 5.88 (s, 1 H), 6.33 (s, 1 H); MS (DCI/NH3) m/z 378 (M+H)+. Anal. Calcd for C19H31NOS.0.2 C2HF3O2.0.2 CH2Cl2: C, 62.16; H, 7.63; N, 3.36. Found: C, 62.31; H, 7.58; N, 3.51.
Example 41
(2Z)-1-(1-benzofuran-5-yl)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)ethanone
The title compound was prepared and purified as described in Example 35C, substituting benzofuran-5-carbonyl chloride for 3-chlorothiophene carbonyl chloride. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.3 Hz, 3 H), 1.30-1.78 (m, 13 H), 2.35 (s, 3 H), 3.97-4.12 (m, 2 H), 6.53 (s, 1 H), 7.00-7.06 (m, J=2.4 Hz, 1 H), 7.61 (d, J=8.5 Hz, 1 H), 7.88-7.95 (m, 1 H), 8.01-8.06 (m, J=2.0 Hz, 1 H), 8.22 (d, J=1.4 Hz, 1H); MS (DCI/NH3) m/z 370 (M+H)+. Anal. Calcd for C22H27NO2S.110 C2HF3O2.0.2 CH2Cl2: C, 57.34; H, 5.66; N, 2.75. Found: C, 57.20; H, 6.01; N, 3.06.
Example 42
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)ethanone
The title compound was prepared and purified as described in Example 35C, substituting 2,2-dimethyltetrahydro-2H-pyran-4-carbonyl chloride for 3-chlorothiophene carbonyl chloride. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.14 (s, 3 H), 1.18 (s, 3 H), 1.30-1.46 (m, 13 H), 1.51-1.65 (m, 4 H), 2.36 (s, 3 H), 2.63-2.78 (m, 1 H), 3.49-3.71 (m, 2 H), 3.99 (s, 2 H), 5.83 (s, 1 H); MS (DCI/NH3) m/z 366 (M+H)+. Anal. Calcd for C21H35NO2S.1.0 C2HF3O2.0.9 CH2Cl2: C, 51.63; H, 6.85; N, 2.52. Found: C, 51.91; H, 6.75; N, 2.70.
Example 43
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-fluoro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 35C, substituting 5-fluoro-2-methoxybenzoyl chloride for 3-chlorothiophene carbonyl chloride. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.3 Hz, 3 H), 1.32-1.48 (m, 11 H), 1.58-1.73 (m, 2 H), 2.37 (s, 3 H), 3.83 (s, 3 H), 3.90-3.98 (m, 2 H), 6.51 (s, 1H), 7.05-7.14 (m, 1 H), 7.16-7.26 (m, 1 H), 7.39-7.46 (m, J=9.5, 3.4 Hz, 1 H); MS (DCI/NH3) m/z 378 (M+H)+. Anal. Calcd for C21H35FNO2S.1.0 C2HF3O2.0.2 CH2Cl2: C, 54.83; H, 5.80; N, 2.75. Found: C, 54.98; H, 5.92; N, 3.04.
Example 44
(2Z)-2-(3-butyl-4-phenyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 16, substituting 2-bromoacetophenone for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.73 (t, J=7.3 Hz, 3 H), 1.07-1.19 (m, 2 H), 1.56-1.67 (m, 2 H), 3.82-3.89 (m, 5 H), 6.66 (d, J=1.4 Hz, 1 H), 6.79 (s, 1 H), 7.14 (d, J=9.2 Hz, 1 H), 7.43 (dd, J=8.8, 3.1 Hz, 1 H), 7.46-7.56 (m, 5 H), 7.68 (d, J=2.7 Hz, 1 H); MS (DCI/NH3) m/z 400(M+H)+. Anal. Calcd for C22H22ClNO2S.0.1 C2HF3O2: C, 64.82; H, 5.42; N, 3.41. Found: C, 64.55; H, 5.48; N, 3.44.
Example 45
ethyl (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-4-carboxylate
The title compound was prepared and purified as described in Example 16, substituting ethyl 2-bromopyruvate for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92-0.98 (m, 3 H), 1.35 (td, J=14.8, 7.3 Hz, 5 H), 1.67-1.79 (m, 2H), 3.87 (s, 3 H), 4.31 (q, J=7.12 Hz, 4 H), 6.69 (s, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.45 (dd, J=8.8, 2.71 Hz, 1 H), 7.66 (d, J=3.1 Hz, 1 H), 7.78 (s, 1 H); MS (DCI/NH3) m/z 400(M+H)+. Anal. Calcd for C19H22ClNO4S: C, 57.64; H, 5.60; N, 3.56. Found: C, 57.34; H, 5.61; N, 3.44.
Example 46
(2Z)-2-(3-butyl-4-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 16, substituting 1-bromopinacolone for 3-chloropentane-2,4-dione. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96-1.03 (m, 3 H), 1.35-1.42 (m, 9 H), 1.42-1.54 (m, 2 H), 1.68-1.82 (m, 2 H), 3.87 (s, 3 H), 4.03-4.15 (m, 2 H), 6.54 (d, J=14.9 Hz, 2 H), 7.13 (d, J=8.8 Hz, 1 H), 7.41 (dd, J=8.7, 2.9 Hz, 1 H), 7.66 (d, J=2.7 Hz, 1 H); MS (DCI/NH3) m/z 380(M+H)+. Anal. Calcd for C20H26ClNO2S.0.2 C2HF3O2: C, 60.84; H, 6.56; N, 3.69. Found: C, 61.18; H, 6.78; N, 3.62.
Example 47
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3 H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
Example 47A
3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide
A mixture of 2,5-dimethyl thiadiazole (570 mg, 5 mmol) and 1-iodobutane (2.27 mL, 20 mmol) in acetonitrile (8 mL) was heated at 90° C. for 4 days. The mixture was concentrated to give the title compound which was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (q, J=6.9 Hz, 3 H) 1.36 (dd, J=15.3, 7.5 Hz, 2H) 1.82-1.92 (m, 2 H) 2.82 (s, 3 H) 3.06 (s, 3 H) 4.49 (t, J=7.5 Hz, 2 H); MS (DCI/NH3) m/z 184 (M+H)+.
Example 47B
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
A solution of the product from Example 47A (298 mg, 1 mmol), 5-chloro-2-methoxy benzoic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (280 mg, 1.4 mmol) and 4-dimethylamino pyridine (121 mg, 1 mmol) in dichloromethane (4 mL) was stirred overnight. The solution was diluted with water (10 mL) and extracted with dichloromethane (3×5 mL). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minutes run time) at a flow rate of 40 mL/minute to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.3 Hz, 3 H), 1.33 (m, J=14.9, 7.4 Hz, 2 H), 1.75 (dq, J=7.5, 7.2 Hz, 2 H), 2.47 (s, 3 H), 3.86 (s, 3 H), 4.12 (t, J=7.1 Hz, 2 H), 6.56 (s, 1 H), 7.14 (d, J=8.8 Hz, 1 H), 7.45 (dd, J=8.8, 3.1 Hz, 1 H), 7.62 (d, J=2.7 Hz, 1 H); MS (DCI/NH3) m/z 339 (M+H)+.
Example 48
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-N-(5-chloro-2-methoxyphenyl)acetamide
A solution of the product from Example 47A (149 mg, 0.5 mmol), DBU (105 μL, 0.75 mmol) and 5-chloro-2-methoxy phenyl isocyanate (91 mg, 0.5 mmol) was stirred overnight. The solution was diluted with water (10 mL), extracted with dichloromethane (3×5 mL). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The residue was purified by the HPLC procedure specified in Example 47B to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.5 Hz, 3 H), 1.27-1.39 (m, 2 H), 1.64-1.75 (m, 2 H), 2.36 (s, 3 H), 3.82-3.91 (m, 5 H), 5.81 (s, 1 H), 6.92-7.01 (m, 2 H), 8.36 (d, J=2.4 Hz, 1 H), 8.68 (s, 1 H); MS (ESI) m/z 354 (M+H)+. Anal. Calcd for C16H20ClN3O2S.0.5 C2HF3O2: C, 48.92; H, 4.92; N, 9.99. Found: C, 49.28; H, 5.09; N, 10.07.
Example 49
2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-N,N′-bis(5-chloro-2,4-dimethoxyphenyl)malonamide
A solution of the product from Example 47A (116 mg, 0.4 mmol), DBU (130 μL, 0.88 mmol) and 5-chloro-2,4-dimethoxy phenyl isocyanate (170 mg, 0.8 mmol) was stirred overnight. The residue was purified by flash chromatography (silica gel, 80:20 hexanes:ethyl acetate) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.74 (t, J=7.3 Hz, 2 H), 1.02-1.14 (m, 1 H), 1.38-1.49 (m, 1 H), 2.44 (s, 2 H), 3.67 (t, J=7.1 Hz, 2 H), 3.80 (s, 2 H), 3.84-3.89 (m, 3 H), 3.96 (d, J=1.7 Hz, 5 H), 4.60 (s, 1 H), 6.91 (d, J=11.5 Hz, 2 H), 7.37 (s, 1 H), 8.11 (s, 1 H), 11.99 (s, 1 H); MS (DCI/NH3) m/z 597 (M+H)+. Anal. Calcd for C26H30Cl2N4O6S: C, 52.26; H, 9.06; N, 5.38. Found: C, 52.10; H, 5.06; N, 938.
Example 50
(2Z)-2-(3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
Example 50A
N′-acetyl-2,2-dimethylpropanohydrazide
To a mixture of 2,2-dimethyl-propionic acid hydrazide (2.32 g, 20 mmol), sodium bicarbonate (1.68 g, 20 mmol) in tetrahydrofuran and water (1:1, 40 mL) was added acetyl chloride (1.56 g, 20 mmol) dropwise. The mixture was stirred overnight and concentrated in vacuo. The residue was extracted with dichloromethane and isopropyl alcohol (10:1) (3×10 mL). The organic extracts were combined, dried over MgSO4 and concentrated to give a white solid. The solid was recrystallized from tetrahydrofuran and hexane (1:8) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11-1.14 (m, 9 H) 1.83 (s, 3 H) 9.28 (br s, 1 H) 9.53 (br s, 1 H); MS (ESI) m/z 159 (M+H)+.
Example 50B
2-tert-butyl-5-methyl-1,3,4-thiadiazole
A mixture of the product from Example 50A (158 mg, 1 mmol) and Lawesson's reagent (808 mg, 2 mmol) in tetrahydrofuran (4 mL) was heated at reflux for 2 hours. The solution was concentrated, dissolved in dichloromethane (15 mL) and washed with saturated sodium bicarbonate solution (10 mL). The resulting organic layer was passed through a silica pad and washed with dichloromethane and ethyl acetate (10:1). The solvent was evaporated to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 2.67 (s, 3 H); MS (ESI) m/z 157 (M+H)+.
Example 50C
3-butyl-5-tert-butyl-2-methyl-1,3,4-thiadiazol-3-ium iodide
The procedure in Example 47A was followed, substituting the product from Example 50B for 2,5-dimethyl thiadiazole. The product was obtained as a brownish liquid in 90% yield and was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H) 1.33-1.48 (m, 11 H) 1.83-1.95 (m, 2 H) 3.07 (s, 3 H) 4.51 (t, J=7.3 Hz, 2 H); MS (ESI) m/z 213 (M+H)+.
Example 50D
(2Z)-2-(3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The procedure in Example 47B was followed, substituting the product from Example 50C for the product from Example 47A to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.5 Hz, 3 H), 1.27-1.43 (m, 11 H), 1.69-1.80 (m, 2 H), 3.85 (s, 3 H), 4.13 (t, J=7.12 Hz, 2 H), 6.54 (s, 1 H), 7.14 (d, J=8.8 Hz, 1 H), 7.45 (dd, J=8.8, 2.7 Hz, 1 H), 7.60 (d, J=3.1 Hz, 1 H); MS (DCI/NH3) m/z 381 (M+H)+.
Example 51
(2Z)-2-(3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene)-N-(5-chloro-2-methoxyphenyl)acetamide
The title compound was prepared and purified as described in Example 48 substituting the product from Example 50C for the product from Example 47A. 1H NMR (300 MHz, DMSO-d6): 6 ppm 0.93 (t, J=7.3 Hz, 3 H), 1.27-1.37 (m, 12 H), 1.64-1.75 (m, 2 H), 3.85 (s, 3 H), 3.89 (t, J=7.1 Hz, 2 H), 6.92-7.01 (m, 2 H), 8.39 (d, J=2.4 Hz, 1 H), 8.68 (s, 1 H); MS (DCI/NH3) m/z 396 (M+H)+. Anal. Calcd for C19H26ClN3O2S.0.1 C2HF3O2: C, 48.17; H, 5.14; N, 4.60. Found: C, 48.03; H, 4.91; N, 4.96.
Example 52
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-N-(5-chloro-2-methoxyphenyl)acetamide
The title compound was prepared and purified as described in Example 48, substituting Example 35B for Example 47A. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.29 Hz, 3 H), 1.37-1.50 (m, 11 H), 1.62-1.77 (m, 2 H), 2.63 (s, 3 H), 3.89 (s, 3H), 4.26-4.38 (m, 2 H), 4.79 (s, 1 H), 7.11-7.23 (m, 2 H), 8.10 (d, J=2.71 Hz, 1 H), 10.05 (s, 1 H); MS (ESI) m/z 409 (M+H)+. Anal. Calcd for C21H29ClN2O2S.1.6 C2HF3O2.0.2 CH2Cl2: C, 48.92; H, 4.92; N, 9.99. Found: C, 49.28; H, 5.09; N, 10.07.
Example 53
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-[2-(trifluoromethyl)phenyl]ethanone
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 2-(trifluoromethyl)benzoyl chloride (33.4 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a Waters Sunfire C8 column (30×75 mm) eluting with a gradient of acetonitrile and 0.1% trifluoroacetic acid in water at a flow rate of 50 mL/min. Fractions selected by mass spectrometry to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.90 (t, 3 H) 1.27-1.38 (m, 2 H) 1.57-1.67 (m, 2 H) 2.27-2.32 (m, 3 H) 3.90-3.97 (m, 2 H) 5.99-6.02 (m, 1 H) 6.56-6.60 (m, 1 H) 7.53-7.62 (m, 2 H) 7.66-7.77 (m, 2 H); MS (ESI) positive ion 342 (M+H).
Example 54
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-[3-(trifluoromethyl)phenyl]ethanone
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 3-(trifluoromethyl)benzoyl chloride (33.4 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR, MS and LC/MS. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.91-0.98 (m, 3 H) 1.34-1.47 (m, 2 H) 1.61-1.72 (m, 2 H) 2.30-2.33 (m, 3 H) 4.07-4.16 (m, 2 H) 6.56-6.60 (m, 1 H) 6.66-6.72 (m, 1 H) 7.69 (t, 1 H) 7.80 (d, 1 H) 8.17-8.23 (m, 1 H) 8.27 (d, 1H); MS (ESI) positive ion 342 (M+H).
Example 55
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-cyclohexylethanone
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added cyclohexanecarbonyl chloride (23.5 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.09-1.44 (m, 7 H) 1.51-1.70 (m, 3 H) 1.69-1.88 (m, 4 H) 2.21-2.36 (m, 4 H) 3.95-4.01 (m, 2 H) 5.79-5.91 (m, 1 H) 6.57-6.73 (m, 1 H) MS (ESI) positive ion 280 (M+H).
Example 56
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(3-chloro-1-benzothien-2-yl)ethanone
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 3-chlorobenzo[b]thiophene-2-carbonyl chloride (37.0 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.98 (t, 3 H) 1.39-1.48 (m, 2 H) 1.70-1.80 (m, 2 H) 2.31-2.37 (m, 3 H) 4.00-4.09 (m, 2 H) 6.67-6.70 (m, 1 H) 6.85-6.89 (m, 1 H) 7.49-7.56 (m, 2 H) 7.85-7.92 (m, 1 H) 8.01-8.07 (m, 1 H); MS (ESI) positive ion 364 (M+H).
Example 57
(2Z)-1-(1-adamantyl)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)ethanone
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 1-adamantyl carbonylchloride (31.8 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR, MS and LC/MS. MS (ESI) positive ion 332 (M+H).
Example 58
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3 H)-ylidene)-1-[5-fluoro-2-(trifluoromethyl)phenyl]ethanone
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 5-fluoro-2-(trifluoromethyl)benzoyl chloride (36.2 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR, MS and LC/MS. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.90 (t, 3 H) 1.29-1.38 (m, 2H) 1.56-1.69 (m, 2 H) 2.28-2.32 (m, 3 H) 3.91-4.00 (m, 2 H) 6.00-6.05 (m, 1 H) 6.58-6.62 (m, 1 H) 7.37-7.45 (m, 2 H) 7.77-7.86 (m, 1 H); MS (ESI) positive ion 360 (M+H).
Example 59
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-fluoro-2-methylphenyl)ethanone
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 5-fluoro-2-methylbenzoyl chloride (27.6 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.28-1.41 (m, 2 H) 1.57-1.68 (m, 2 H) 2.28-2.31 (m, 3 H) 2.33-2.36 (m, 3 H) 3.92-4.03 (m, 2 H) 6.09-6.15 (m, 1 H) 6.54-6.59 (m, 1 H) 7.05-7.14 (m, 1 H) 7.19-7.27 (m, 2 H);); MS (ESI) positive ion 306 (M+H).
Example 60
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-fluorophenyl)ethanone
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 5-chloro-2-fluorobenzoyl chloride (30.9 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.95 (t, 3 H) 1.31-1.41 (m, 2 H) 1.57-1.77 (m, 2 H) 2.28-2.34 (m, 3 H) 3.95-4.02 (m, 2 H) 6.37-6.41 (m, 1 H) 6.55-6.68 (m, 1 H) 7.28-7.35 (m, 1 H) 7.48-7.54 (m, 1 H) 7.76-7.80 (m, 1 H); MS (ESI) positive ion 326 (M+H).
Example 61
(1Z)-1-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-3-cyclopentylacetone
In a 20 mL vial 2-cyclopentylacetic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.06-1.16 (m, 2 H) 1.24-1.34 (m, 2 H) 1.43-1.54 (m, 2 H) 1.53-1.61 (m, 2 H) 1.63-1.73 (m, 4 H) 2.14-2.23 (m, 1 H) 2.30-2.34 (m, 2 H) 2.39-2.43 (m, 3 H) 4.03 (t, 2 H) 5.90 (s, 1 H); MS (ESI) m/z 281 (M+H)+.
Example 62
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-cyclohexylethanone
In a 20 mL vial cyclohexanecarboxylic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.92 (m, 3 H) 1.10-1.39 (m, 8 H) 1.58-1.76 (m, 8 H) 2.23-2.31 (m, 1 H) 2.38-2.41 (s, 3 H) 4.04 (t, 2 H) 5.90 (s, 1 H); MS (ESI) m/z 281 (M+H)+.
Example 63
(3Z)-1-[bicyclo[2.2.1]hept-2-yl]-3-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)acetone
In a 20 mL vial 2-(bicyclo[2.2.1]heptan-2-yl)acetic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.90 (t, 3H) 0.98-1.18 (m, 4 H) 1.23-1.49 (m, 6 H) 1.62-1.73 (m, 2 H) 1.80-1.88 (m, 1 H) 1.89-1.95 (m, 1 H) 2.11-2.19 (m, 2 H) 2.23-2.31 (m, 1 H) 2.38-2.43 (m, 3 H) 4.02 (t, 2 H) 5.86-5.92 (m, 1 H); MS (ESI) m/z 307 (M+H)+.
Example 64
(1Z)-1-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-3-(2-chlorophenyl)acetone
In a 20 mL vial 2-(2-chlorophenyl)acetic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.79-0.88 (m, 3 H) 1.19-1.28 (m, 2 H) 1.57-1.69 (m, 2 H) 2.40 (s, 3 H) 3.76-3.81 (m, 2 H) 3.96 (t, 2 H) 5.77-5.85 (m, 1 H) 7.22-7.33 (m, 2 H) 7.34-7.40 (m, 1 H) 7.40-7.47 (m, 1 H); MS (ESI) m/z 323 (M+H)+.
Example 65
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3-methylthien-2-yl)ethanone
In a 20 mL vial 3-methylthiophene-2-carboxylic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3H) 1.28-1.39 (m, 2 H) 1.69-1.79 (m, 2 H) 2.45-2.48 (m, 3 H) 4.15 (t, 2 H) 6.18-6.22 (m, 1 H) 6.97 (d, 1 H) 7.55 (d, 1 H); MS (ESI) m/z 295 (M+H)+.
Example 66
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(1,3-thiazol-4-yl)ethanone
In a 20 mL vial thiazole-2-carboxylic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.25-1.38 (m, 2 H) 1.69-1.82 (m, 2 H) 2.46 (s, 3 H) 4.12-4.20 (m, 2 H) 6.81 (s, 1 H) 8.24 (s, 1 H) 9.15 (s, 1 H); MS (ESI) m/z 282 (M+H)+.
Example 67
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2-methylphenyl)ethanone
In a 20 mL vial 2-methylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.84-0.93 (m, 3 H) 1.27-1.37 (m, 2 H) 1.67-1.75 (m, 2 H) 2.36, (s, 3 H) 2.47 (s, 3 H) 4.11-4.17 (m, 2 H) 6.19-6.25 (m, 1 H) 7.17-7.26 (m, 2 H) 7.26-7.33 (m, 1 H) 7.43-7.51 (m, 1 H); MS (ESI) m/z 289 (M+H)+.
Example 68
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2-chlorophenyl)ethanone
In a 20 mL vial 2-chlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.25-1.36 (m, 2 H) 1.66-1.75 (m, 2 H) 2.49-2.50 (m, 3 H) 4.14 (t, 2 H) 6.20 (s, 1 H) 7.35-7.44 (m, 2H) 7.45-7.49 (m, 1 H) 7.50-7.55 (m, 1 H); MS (ESI) m/z 309 (M+H)+.
Example 69
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3-chlorophenyl)ethanone
In a 20 mL vial 3-chlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.92 (t, 3 H) 1.27-1.40 (m, 2 H) 1.72-1.80 (m, 2 H) 2.47-2.50 (m, 3 H) 4.27 (t, 2 H) 6.76 (s, 1 H) 7.46-7.53 (m, 1 H) 7.52-7.57 (m, 1 H) 7.94-7.99 (m, 1 H) 8.01-8.05 (m, 1 H); MS (ESI) m/z 309 (M+H)+.
Example 70
(2Z)-1-(2-bromophenyl)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)ethanone
In a 20 mL vial 2-bromobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.88 (t, 3 H) 1.26-1.37 (m, 2 H) 1.67-1.76 (m, 2 H) 2.47 (s, 3 H) 4.15 (t, 2 H) 6.16 (s, 1 H) 7.26-7.36 (m, 1 H) 7.39-7.51 (m, 2 H) 7.59-7.68 (m, 1 H); MS (ESI) m/z 353 (M+H)+.
Example 71
(2Z)-1-(3-bromophenyl)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)ethanone
In a 20 mL vial 3-bromobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.86-0.96 (m, 3 H) 1.27-1.41 (m, 2 H) 1.69-1.78 (m, 2 H) 2.47-2.49 (m, 3 H) 4.29 (t, 2 H) 6.77 (s, 1 H) 7.36-7.48 (m, 1 H) 7.64-7.70 (m, 1 H) 7.98-8.04 (m, 1 H) 8.12-8.19 (m, 1 H); MS (ESI) m/z 353 (M+H)+.
Example 72
(2Z)-1-(4-bromophenyl)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)ethanone
In a 20 mL vial 4-bromobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.85-0.94 (m, 3 H) 1.28-1.39 (m, 2 H) 1.67-1.80 (m, 2 H) 2.49 (s, 3 H) 4.20-4.23 (m, 2 H) 6.70 (m, 1 H) 7.64 (d, 2 H) 7.94 (d, 2 H); MS (ESI) m/z 353 (M+H)+.
Example 73
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-[3-(trifluoromethyl)phenyl]ethanone
In a 20 mL vial 3-(trifluoromethyl)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3H) 1.30-1.39 (m, 2 H) 1.72-1.80 (m, 2 H) 2.49-2.51 (m, 3 H) 4.30 (t, 2 H) 6.83-6.85 (m, 1 H) 7.69-7.74 (m, 1 H) 7.80-7.89 (m, 1 H) 8.25-8.30 (m, 1 H) 8.32-8.36 (m, 1H); MS (ESI) m/z 343 (M+H)+.
Example 74
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-[3-(trifluoromethoxy)phenyl]ethanone
In a 20 mL vial 3-(trifluoromethoxy)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.90 (t, 3H) 1.27-1.42 (m, 2 H) 1.69-1.80 (m, 2 H) 2.49 (s, 3 H) 4.27 (t, 2 H) 6.78 (s, 1 H) 7.43-7.53 (m, 1 H) 7.58-7.65 (m, 1 H) 7.92 (s, 1 H) 8.03-8.11 (m, 1 H); MS (ESI) m/z 359 (M+H)+.
Example 75
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3 H)-ylidene)-1-(2,3-dimethylphenyl)ethanone
In a 20 mL vial 2,3-dimethylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.85-0.91 (m, 3 H) 1.25-1.34 (m, 2 H) 1.65-1.75 (m, 2 H) 2.23 (s, 3 H) 2.27 (s, 3 H) 2.48 (s, 3 H) 4.12 (t, 2 H) 6.09-6.13 (m, 1 H) 7.07-7.14 (m, 1 H) 7.16-7.23 (m, 2 H); MS (ESI) m/z 303 (M+H)+.
Example 76
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,5-dimethylphenyl)ethanone
In a 20 mL vial 2,5-dimethylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.84-0.94 (m, 3 H) 1.27-1.33 (m, 2 H) 1.68-1.77 (m, 2 H) 2.30 (s, 6 H) 2.48 (s, 3 H) 4.12 (t, 2 H) 6.20 (1, 1 H) 7.10 (s, 2 H) 7.28 (s, 1 H); MS (ESI) m/z 303 (M+H)+.
Example 77
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3,4-dimethylphenyl)ethanone
In a 20 mL vial 3,4-dimethylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.95 (m, 3 H) 1.30-1.41 (m, 2 H) 1.69-1.80 (m, 2 H) 2.23-2.32 (m, 6 H) 2.47 (s, 3 H) 4.21 (t, 2 H) 6.65 (s, 1 H) 7.15-7.27 (m, 1 H) 7.65-7.80 (m, 2 H); MS (ESI) m/z 303 (M+H)+.
Example 78
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3,5-dimethylphenyl)ethanone
In a 20 mL vial 3,5-dimethylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.96 (m, 3 H) 1.28-1.39 (m, 2 H) 1.68-1.80 (m, 2 H) 2.33 (s, 6 H) 2.47 (s, 3 H) 4.21 (t, 2 H) 6.66 (s, 1 H) 7.14 (s, 1 H) 7.62 (s, 2 H); MS (ESI) m/z 303 (M+H)+.
Example 79
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,3-dimethoxyphenyl)ethanone
In a 20 mL vial 2,3-dimethoxybenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.86-0.95 (m, 3 H) 1.27-1.38 (m, 2 H) 1.71-1.77 (m, 2 H) 2.48 (s, 3 H) 3.75 (s, 3 H) 3.80 (s, 3 H) 4.10-4.14 (m, 2 H) 6.45 (s, 1 H) 7.08-7.19 (m, 3 H); MS (ESI) m/z 335 (M+H)+.
Example 80
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,5-dimethoxyphenyl)ethanone
In a 20 mL vial 2,5-dimethoxybenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.93 (t, 3 H) 1.30-1.36 (m, 2 H) 1.71-1.79 (m, 2 H) 2.47 (s, 3 H) 3.73 (s, 3 H) 3.80 (s, 3 H) 4.11 (t, 2 H) 6.59 (s, 1 H) 6.96-7.00 (m, 1 H) 7.02-7.06 (m, 1 H) 7.22 (d, 1 H); MS (ESI) m/z 335 (M+H)+.
Example 81
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3,5-dimethoxyphenyl)ethanone
In a 20 mL vial 3,5-dimethoxybenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.97 (m, 3 H) 1.28-1.37 (m, 2 H) 1.71-1.80 (m, 2 H) 2.46-2.48 (m, 3 H) 3.77-3.83 (m, 6 H) 4.23 (t, 2 H) 6.60-6.68 (m, 2 H) 7.10-7.14 (m, 2 H); MS (ESI) m/z 335 (M+H)+.
Example 82
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,3-dichlorophenyl)ethanone
In a 20 mL vial 2,3-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.83-0.92 (m, 3 H) 1.25-1.37 (m, 2 H) 1.67-1.75 (m, 2 H) 2.50 (s, 3 H) 4.15 (t, 2 H) 6.18 (s, 1 H) 7.37-7.48 (m, 2 H) 7.64-7.69 (m, 1 H); MS (ESI) m/z 343 (M+H)+.
Example 83
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,4-dichlorophenyl)ethanone
In a 20 mL vial 2,4-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.86-0.92 (m, 3 H) 1.25-1.35 (m, 2 H) 1.67-1.77 (m, 2 H) 2.50 (s, 3 H) 4.14 (t, 2 H) 6.21 (s, 1 H) 7.45-7.50 (m, 1 H) 7.56 (d, 1 H) 7.63-7.65 (m, 1 H); MS (ESI) m/z 343 (M+H)+.
Example 84
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,5-dichlorophenyl)ethanone
In a 20 mL vial 2,5-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.27-1.35 (m, 2 H) 1.67-1.76 (m, 2 H) 2.50 (s, 3 H) 4.16 (t, 2 H) 6.25 (s, 1 H) 7.46-7.53 (m, 2 H) 7.55-7.57 (m, 1 H); MS (ESI) m/z 343 (M+H)+.
Example 85
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3,4-dichlorophenyl)ethanone
In a 20 mL vial 3,4-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.94 (m, 3 H) 1.28-1.39 (m, 2 H) 1.71-1.80 (m, 2 H) 2.47 (s, 3 H) 4.27 (t, 2 H) 6.81 (s, 1 H) 7.73 (d, 1 H) 7.99 (d, 1 H) 8.22 (s, 1 H); MS (ESI) m/z 343 (M+H)+.
Example 86
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3,5-dichlorophenyl)ethanone
In a 20 mL vial 3,5-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.28-1.37 (m, 2 H) 1.71-1.82 (m, 2 H) 2.47-2.53 (m, 3 H) 4.29 (t, 2 H) 6.83 (s, 1 H) 7.73 (s, 1 H) 8.06 (s, 2 H); MS (ESI) m/z 343 (M+H)+.
Example 87
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(5-fluoro-2-methylphenyl)ethanone
In a 20 mL vial 5-fluoro-2-methylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.90 (t, 3 H) 1.68-1.76 (m, 2 H) 2.34 (s, 3 H) 2.48 (s, 3 H) 4.16 (t, 2 H) 6.26 (s, 1 H) 7.10-7.16 (m, 1 H) 7.23-7.32 (m, 2 H); MS (ESI) m/z 307 (M+H)+.
Example 88
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(3-methoxy-4-methylphenyl)ethanone
In a 20 mL vial 3-methoxy-4-methylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89-0.94 (m, 3 H) 1.29-1.37 (m, 2 H) 1.71-1.79 (m, 2 H) 2.20 (s, 3 H) 2.48 (s, 3H) 3.85 (s, 3 H) 4.23 (t, 2 H) 6.67 (s, 1 H) 7.22 (d, 1 H) 7.48 (s, 1 H) 7.53 (d, 1 H); MS (ESI) m/z 319 (M+H)+.
Example 89
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(1-naphthyl)ethanone
In a 20 mL vial 1-naphthoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.93 (m, 3 H) 1.27-1.35 (m, 2 H) 1.69-1.78 (m, 2 H) 2.51 (s, 3 H) 4.16-4.20 (m, 2 H) 6.40 (s, 1 H) 7.49-7.59 (m, 3 H) 7.73-7.78 (m, 1 H) 7.94-8.01 (m, 2 H) 8.37-8.43 (m, 1 H); MS (ESI) m/z 325 (M+H)+.
Example 90
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2-naphthyl)ethanone
In a 20 mL vial 2-naphthoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.93 (t, 3 H) 1.32-1.41 (m, 2 H) 1.75-1.83 (m, 2 H) 2.50 (s, 3 H) 4.28 (t, 2 H) 6.90 (s, 1 H) 7.93-8.00 (m, 2 H) 8.04-8.08 (m, 1 H) 8.10-8.15 (m, 1 H) 8.61 (s, 1 H); MS (ESI) m/z 325 (M+H)+.
Example 91
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(4-tert-butylphenyl)ethanone
In a 20 mL vial 4-tert-butylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.30 (s, 9 H) 1.32-1.38 (m, 2 H) 1.71-1.78 (m, 2 H) 2.48 (s, 3 H) 4.21 (t, 2 H) 6.67 (s, 1 H) 7.47 (d, 2 H) 7.91 (d, 2 H); MS (ESI) m/z 331 (M+H)+.
Example 92
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-[2-fluoro-5-(trifluoromethyl)phenyl]ethanone
In a 20 mL vial 2-fluoro-5-(trifluoromethyl)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.26-1.37 (m, 2 H) 1.72-1.79 (m, 2 H) 2.50 (s, 3 H) 4.19 (t, 2 H) 6.47 (s, 1 H) 7.50-7.58 (m, 1 H) 7.87-7.93 (m, 1 H) 8.09-8.12 (m, 1 H); MS (ESI) m/z 361 (M+H)+.
Example 93
(2Z)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-[2-chloro-5-(trifluoromethyl)phenyl]ethanone
In a 20 mL vial 2-chloro-5-(trifluoromethyl)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.26-1.36 (m, 2 H) 1.69-1.76 (m, 2 H) 2.50 (s, 3 H) 4.17 (t, 2 H) 6.29 (s, 1 H) 7.69-7.76 (m, 1 H) 7.77-7.82 (m, 2 H); MS (ESI) m/z 377 (M+H)+.
Example 94
(2Z)-1-(5-bromo-2-chlorophenyl)-2-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)ethanone
In a 20 mL vial 5-bromo-2-chlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.25-1.36 (m, 2 H) 1.68-1.76 (m, 2 H) 2.51 (s, 3 H) 4.16 (t, 2 H) 6.26 (s, 1 H) 7.42-7.46 (m, 1 H) 7.58-7.63 (m, 1 H) 7.65-7.68 (m, 1 H); MS (ESI) m/z 387 (M+H)+.
Example 95
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2,6-difluorophenyl)ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2,6-difluorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.28-1.38 (m, 2 H) 1.55-1.64 (m, 2 H) 2.20 (s, 3 H) 2.22 (s, 3 H) 3.91-3.96 (m, 2 H) 6.03 (s, 1 H) 7.07-7.15 (m, 2 H) 7.39-7.47 (m, 1 H); MS (ESI) m/z 324 (M+H)+.
Example 96
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2,4-dichlorophenyl)ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2,4-dichlorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.90 (t, 3 H) 1.30-1.40 (m, 2 H) 1.58-1.65 (m, 2 H) 2.21 (s, 3 H) 2.23 (s, 3 H) 3.94-3.99 (m, 2 H) 6.11 (s, 1 H) 7.46 (dd, 1 H) 7.52-7.57 (m, 1 H) 7.62 (d, 1 H); MS (ESI) m/z 356 (M+H)+.
Example 97
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[2-(trifluoromethyl)phenyl]ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2-(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.27-1.37 (m, 2 H) 1.56-1.63 (m, 2 H) 2.19 (s, 3 H) 2.21 (s, 3 H) 3.90-3.96 (m, 2 H) 5.99 (s, 1 H) 7.52-7.61 (m, 2 H) 7.66-7.71 (m, 1 H) 7.72-7.77 (m, 1 H); MS (ESI) m/z 356 (M+H)+.
Example 98
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[3-(trifluoromethyl)phenyl]ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 3-(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.94 (t, 3 H) 1.35-1.44 (m, 2 H) 1.61-1.68 (m, 2 H) 2.19 (s, 3H) 2.21 (s, 3 H) 4.07-4.13 (m, 2 H) 6.64 (s, 1 H) 7.66-7.70 (m, 1 H) 7.79 (d, 1 H) 8.18-8.20 (m, 1 H) 8.25 (d, 1H); MS (ESI) m/z 356 (M+H)+.
Example 99
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-cyclopentylethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by cyclopentanecarbonyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.88-0.97 (m, 3 H) 1.30-1.39 (m, 2 H) 1.51-1.62 (m, 4 H) 1.62-1.70 (m, 3 H) 1.77-1.87 (m, 2 H) 2.16-2.26 (m, 5 H) 2.73-2.86 (m, 1 H) 3.71-3.83 (m, 4 H) 5.84-5.94 (m, 1 H); MS (ESI) m/z 280 (M+H)+.
Example 100
4-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]benzonitrile
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 4-cyanobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.93 (t, 3 H) 1.32-1.45 (m, 2 H) 1.60-1.68 (m, 2 H) 2.19 (s, 3 H) 2.23 (s, 3 H) 4.06-4.12 (m, 2 H) 6.67 (s, 1 H) 7.90 (d, 2 H) 8.10 (d, 2 H); MS (ESI) m/z 313 (M+H)+.
Example 101
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(1-naphthyl)ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 1-naphthoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.29-1.39 (m, 2 H) 1.59-1.69 (m, 2 H) 2.26 (s, 6H) 4.02-4.07 (m, 2 H) 6.30 (s, 1 H) 7.50-7.59 (m, 3 H) 7.68-7.71 (m, 1 H) 7.94-8.01 (m, 2 H) 8.30-8.34 (m, 1 H); MS (ESI) m/z 338 (M+H)+.
Example 102
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2,5-difluorophenyl)ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2,5-difluorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.94 (t, 3 H) 1.33-1.41 (m, 2 H) 1.60-1.69 (m, 2 H) 2.19 (s, 3 H) 2.22 (s, 3 H) 3.93-4.00 (m, 2 H) 6.38 (s, 1 H) 7.24-7.35 (m, 2 H) 7.51-7.59 (m, 1 H); MS (ESI) m/z 324 (M+H)+.
Example 103
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-pyridin-3-ylethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by nicotinoyl chloride hydrochloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.94 (t, 3 H) 1.36-1.46 (m, 2 H) 1.61-1.68 (m, 2 H) 2.19 (s, 3 H) 2.22 (s, 3 H) 4.07-4.12 (m, 2 H) 6.69 (s, 1 H) 7.68-7.78 (m, 1 H) 8.54-8.61 (m, 1 H) 8.72-8.80 (m, 1 H) 9.18-9.29 (m, 1 H); MS (ESI) m/z 289 (M+H)+.
Example 104
(2Z)-1-(1,3-benzodioxol-5-yl)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by benzo[d][1,3]dioxole-5-carbonyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.93 (t, 3 H) 1.34-1.44 (m, 2 H) 1.58-1.68 (m, 2 H) 2.16 (s, 3 H) 2.20 (s, 3 H) 4.02-4.09 (m, 2 H) 6.08 (s, 2 H) 6.48 (s, 1 H) 6.93-6.99 (m, 1 H) 7.47-7.48 (m, 1 H) 7.49-7.54 (m, 1 H); MS (ESI) m/z 332 (M+H)+.
Example 105
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2-chloronicotinoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.91 (t, 3 H) 1.31-1.39 (m, 2 H) 1.58-1.67 (m, 2 H) 2.19 (s, 3 H) 2.21 (s, 3 H) 3.93-3.98 (m, 2 H) 6.15 (s, 1 H) 7.47 (dd, 1 H) 7.94 (dd, 1 H) 8.41 (dd, 1 H); MS (ESI) m/z 323 (M+H)+.
Example 106
(2Z)-1-[2,5-bis(trifluoromethyl)phenyl]-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2,5-bis(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.28-1.38 (m, 2 H) 1.56-1.64 (m, 2 H) 2.19 (s, 3 H) 2.23 (s, 3 H) 3.92-3.98 (m, 2 H) 6.02 (s, 1 H) 7.82-7.84 (m, 1 H) 7.93-7.97 (m, 1 H) 7.98-8.02 (m, 1 H); MS (ESI) m/z 424 (M+H)+.
Example 107
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[5-fluoro-2-(trifluoromethyl)phenyl]ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 5-fluoro-2-(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ PPM 0.89 (t, 3 H) 1.28-1.37 (m, 2 H) 1.56-1.63 (m, 2 H) 2.18 (s, 3 H) 2.21 (s, 3 H) 3.90-3.97 (m, 2 H) 5.99 (2, 1 H) 7.36-7.44 (m, 2 H) 7.79-7.83 (m, 1 H); MS (ESI) m/z 374 (M+H)+.
Example 108
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(3-methylthien-2-yl)ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 3-methylthiophene-2-carbonyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.95 (t, 3 H) 1.34-1.43 (m, 2 H) 1.60-1.71 (m, 2 H) 2.17 (s, 3 H) 2.20 (s, 3 H) 2.47 (s, 3 H) 3.92-3.98 (m, 2 H) 6.13 (s, 1 H) 6.91-6.96 (m, 1 H) 7.46-7.52 (m, 1 H); MS (ESI) m/z 308 (M+H)+.
Example 109
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-fluoro-2-methylphenyl)ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 5-fluoro-2-methylbenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.91 (t, 3 H) 1.30-1.41 (m, 2 H) 1.55-1.68 (m, 2 H) 2.20 (s, 3 H) 2.22 (s, 3 H) 2.33 (s, 3 H) 3.96-4.04 (m, 2 H) 6.09 (s, 1 H) 7.08-7.14 (m, 1 H) 7.19-7.27 (m, 2 H); MS (ESI) m/z 320 (M+H)+.
Example 110
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-fluorophenyl)ethanone
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 5-chloro-2-fluorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.93 (t, 3 H) 1.33-1.42 (m, 2 H) 1.61-1.68 (m, 2 H) 2.19 (s, 3 H) 2.23 (s, 3 H) 3.94-4.01 (m, 2 H) 6.36 (s, 1 H) 7.27-7.35 (m, 1 H) 7.47-7.53 (m, 1 H) 7.75-7.81 (m, 1H); MS (ESI) m/z 340 (M+H)+.
Example 111
(2Z)-2-(3-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
To a stirred suspension of NaH (60% in mineral oil, 0.04 g, 1 mmol) in anhydrous DMF (3 mL) at 0° C. was added 5-chloro-2-methoxyacetophenone (0.15 g, 1 mmol) followed by subsequent addition of n-butylisothiocyanate (0.24 mL, 2 mmol) in DMF (3 mL). The mixture was stirred at 0° C. for 2 hours after which 2-bromo-1,1-dimethoxyethane was added. The reaction mixture was stirred for 2 hr and then poured into brine, extracted with EtOAc. The organic layer was washed with brine (3×30 mL), dried (MgSO4) and concentrated. The residue was dissolved in toluene (10 mL) then treated with p-toluenesulfonic acid (1.5 mmol) and refluxed for 6 hr. The reaction mixture was concentrated and partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 50% ethyl acetate in hexane to provide the title compound as a yellow solid. (10 mg). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.32 (dd, J=15.1, 7.3 Hz, 2 H), 1.72 (t, J=7.3 Hz, 2 H), 3.86 (s, 3 H), 4.01 (t, J=7.1 Hz, 2 H), 6.57 (s, 1 H), 6.81 (d, J=4.4 Hz, 1 H), 7.12 (d, J=8.8 Hz, 1 H), 7.33-7.48 (m, 1 H), 7.34-7.49 (m, 1 H), 7.65 (d, J=3.1 Hz, 1 H). MS (DCI), m/z 324 (M+H)+.
Example 112
(Z)-2-(3-butyl-5-((E)-1-(methoxyimino)ethyl)-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 17 by replacing the NH2OH_HCl with NH2OCH3.HCl. The residue was purified by flash chromatography eluting with ethyl acetate to separate the mixture of E and Z isomers. E isomer (less polar). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.3 Hz, 3 H), 1.31-1.49 (m, 2 H), 1.59-1.81 (m, 2 H), 2.18 (s, 3 H), 2.44 (s, 3 H), 3.88 (d, J=9.2 Hz, 6H), 3.92-4.03 (m, 2 H), 6.64 (s, 1 H), 7.14 (d, J=8.8 Hz, 1 H), 7.43 (dd, J=8.8, 3.1 Hz, 1 H), 7.65 (d, J=3.1 Hz, 1 H). MS (DCI), m/z 409 (M+H)+. Anal calcd for C20H25ClN2O3S: C, 58.74; H, 6.16; N, 6.85. Found: C, 58.70; H, 6.12; N, 6.79.
Example 113
(Z)-2-(3-butyl-5-((Z)-1-(methoxyimino)ethyl)-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was isolated from the synthesis of example 112. Z isomer (more polar). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.3 Hz, 3 H), 1.32-1.51 (m, 2 H), 1.60-1.81 (m, 2 H), 2.13 (s, 3 H), 2.21 (s, 3 H), 3.81 (s, 3 H), 3.87 (s, 3 H), 3.89-4.04 (m, 2 H), 6.63 (s, 1 H), 7.13 (d, J=9.2 Hz, 1 H), 7.43 (dd, J=8.8, 2.7 Hz, 1 H), 7.65 (d, J=3.1 Hz, 1 H). MS (DCI), m/z 409 (M+H)+. Anal calcd for C20H25ClN2O3S: C, 58.74; H, 6.16; N, 6.85. Found: C, 58.65; H, 6.10; N, 6.69.
Example 114
(2Z)-2-[3-butyl-4-(trifluoromethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 16 by replacing the 3-chloropentane-2,4-dione with 3-bromo-1,1,1-trifluoropropan-2-one (40 mg). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.3 Hz, 3 H), 1.39-1.48 (m, 2 H), 1.67-1.79 (m, 2 H), 3.88 (s, 3 H), 3.95-4.04 (m, 2 H), 6.74 (s, 1 H), 7.17 (d, J=8.8 Hz, 1 H), 7.47 (dd, J=8.7, 2.9 Hz, 1 H), 7.63-7.76 (m, 2 H). MS (DCI), m/z 392 (M+H)+. Anal calcd for C17H17ClDF3NO2S: C, 52.11; H, 4.37; N, 3.57. Found: C, 51.85; H, 4.21; N, 3.42.
Example 115
(2Z)-2-[3-butyl-5-methyl-4-(trifluoromethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 16 by replacing the 3-chloropentane-2,4-dione with 3-bromo-1,1,1-trifluorobutan-2-one. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.3 Hz, 3 H), 1.33-1.51 (m, 2 H), 1.63-1.83 (m, 2 H), 2.38 (q, J=3.3 Hz, 3 H), 3.87 (s, 3 H), 3.89-4.01 (m, 2 H), 6.68 (s, 1 H), 7.16 (d, J=8.8 Hz, 1 H), 7.47 (dd, J=8.8, 3.1 Hz, 1 H), 7.66 (d, J=3.1 Hz, 1 H). MS (DCI), m/z 406 (M+H)+. Anal calcd for C18H19ClF3NO2S: C, 53.27; H, 4.72; N, 3.45. Found: C, 53.16; H, 4.40; N, 3.39
Example 116
(Z)-2-(5-acetyl-3-(3-fluorobenzyl)-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 16 by replacing the n-butylisothiocyanate with 3-fluorobenzylisothiocyanate (30 mg). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.64 (s, 3 H), 3.29 (s, 3 H), 3.64 (s, 3 H), 5.36 (s, 2 H), 6.68 (s, 1 H), 6.94-7.25 (m, 4 H), 7.36-7.52 (m, 2 H), 7.57 (d, J=2.7 Hz, 1 H). MS (DCI), m/z 432 (M+H)+. Anal calcd for C22H19ClFNO3S: C, 61.18; H, 4.43; N, 3.24. Found: C, 60.82; H, 4.30; N, 3.15
Example 117
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(3-fluorobenzyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared as described in Example 16 by replacing the 3-chloropentane-2,4-dione with 3-bromobutan-2-one and n-butylisothiocyanate with 3-fluorobenzylisothiocyanate (20 mg). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (d, J=7.5 Hz, 6 H), 3.62-3.67 (m, 3 H), 5.24 (s, 2 H), 6.47 (s, 1 H), 6.92-7.08 (m, 3 H), 7.09-7.22 (m, 1 H), 7.31-7.50 (m, 2 H), 7.57 (d, J=2.7 Hz, 1 H). MS (DCI), m/z 404 (M+H)+. Anal calcd for C21H19ClFNO2S: C, 62.45; H, 4.74; N, 3.47. Found: C, 62.38; H, 4.67; N, 3.39
Example 118
(Z)-1-(5-chloro-2-methoxyphenyl)-2-(5-((E)-1-(methoxyimino)ethyl)-4-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)ethanone
The title compound was prepared as described in Example 112 by replacing the n-butylisothiocyanate with 2-(isothiocyanatomethyl)tetrahydrofuran. The residue was purified by flash chromatography eluting with ethyl acetate to separate the mixture of E and Z isomers. E isomer (less polar): 1H NMR (300 MHz, DMSO-d6) δ ppm 1.66 (dd, J=11.9, 8.5 Hz, 1 H), 1.79-2.01 (m, 2 H), 2.01-2.14 (m, 1 H), 2.18 (s, 3 H), 2.44 (s, 3 H), 3.58-3.72 (m, 1 H), 3.80 (t, J=7.5 Hz, 1 H), 3.88 (d, J=11.5 Hz, 6 H), 4.07 (d, J=5.8 Hz, 2 H), 4.24 (t, J=6.1 Hz, 1 H), 6.63 (s, 1 H), 7.13 (d, J=8.8 Hz, 1 H), 7.43 (dd, J=8.8, 3.1 Hz, 1 H), 7.63 (d, J=2.7 Hz, 1 H). MS (DCI), m/z 437 (M+H)+.Anal calcd for C21H25ClN2O4S: C, 57.72; H, 5.77; N, 6.74. Found: C, 57.74; H, 5.84; N, 6.41.
Example 119
(Z)-1-(5-chloro-2-methoxyphenyl)-2-(5-((Z)-1-(methoxyimino)ethyl)-4-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)ethanone
The title compound was isolated from the reaction mixture of Example 118. Z isomer (more polar): 1H NMR (300 MHz, DMSO-d6) δ ppm 1.57-1.77 (m, 1 H), 1.78-1.97 (m, 2 H), 2.02-2.12 (m, 1 H), 2.11-2.16 (m, 3 H), 2.17-2.25 (m, 3 H), 3.59-3.71 (m, 1 H), 3.77-3.88 (m, 6 H), 3.96-4.09 (m, 2 H), 4.18-4.31 (m, 1 H), 5.75 (s, 1 H), 6.62 (s, 1 H), 7.13 (d, J=8.8 Hz, 1 H), 7.43 (dd, J=8.8, 2.7 Hz, 1 H), 7.63 (d, J=3.1 Hz, 1 H). MS (DCI), m/z 437 (M+H)+. Anal calcd for C21H25ClN2O4S: C, 57.72; H, 5.77; N, 6.74. Found: C, 57.73; H, 5.88; N, 6.46.
Example 120
(2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-5,5-dimethyl-2,3,5,6-tetrahydro-1,3-benzothiazol-7(4H)-one
The title compound was prepared as described in Example 16 by replacing the 3-chloropentane-2,4-dione with 2-chloro-5,5-dimethylcyclohexane-1,3-dione (13 mg). 1H NMR (300 MHz, CDCl3) δ ppm 0.98-1.07 (m, 3 H), 1.15-1.22 (m, 6 H), 1.36-1.53 (m, 2 H), 1.70-1.88 (m, 2 H), 2.44 (s, 2 H), 2.62 (s, 2 H), 3.80-3.92 (m, 5 H), 6.73 (s, 1 H), 6.88 (d, J=8.8 Hz, 1 H), 7.32 (dd, J=8.8, 2.7 Hz, 1 H), 7.86 (d, J=2.7 Hz, 1 H). MS (DCI), m/z 420 (M+H)+.
Example 121
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 35C by replacing 3-chlorothiophene-2-carbonyl chloride with 5-chloro-2-methoxy-benzoyl chloride and Example 35B with Example 153C. 1H NMR (300 MHz, CDCl3) δ ppm 0.99 (t, J=7.3 Hz, 3 H), 1.30-1.38 (m, 9 H), 1.38-1.48 (m, 2 H), 1.71-1.91 (m, 2 H), 3.78-3.91 (m, 5 H), 6.45 (s, 1 H), 6.50 (s, 1 H), 6.86 (d, J=8.5 Hz, 1 H), 7.28 (d, J=3.1 Hz, 1 H), 7.88 (d, J=2.7 Hz, 1 H). MS (DCI), m/z 380 (M+H)+. Anal calcd for C20H26ClNO2S: C, 63.22; H, 6.90; N, 3.69. Found: C, 62.40; H, 6.71; N, 3.62.
Example 122
(2Z)-2-(5-tert-butyl-3-isobutyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 16 by replacing 3-chloropentane-2,4-dione with 2-chloro-3,3-dimethylbutanal and replacing the n-butylisothiocyanate with isobutylisothiocyanate (16 mg). 1H NMR (300 MHz, CDCl3) δ ppm 0.99 (d, J=6.8 Hz, 6 H), 1.30-1.39 (m, 9 H), 2.18-2.41 (m, 1 H), 3.67 (d, J=7.1 Hz, 2 H), 3.82-3.92 (m, 3 H), 6.52 (s, 1 H), 6.86 (d, J=8.8 Hz, 2 H), 7.24-7.35 (m, 1 H), 7.87 (d, J=2.7 Hz, 1 H). MS (DCI), m/z 380 (M+H)+.
Example 123
(2Z)-2-[3-butyl-4-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
Example 123A
(Z)-2-(3-butyl-4-methyl-5-(1,1,1-trifluoro-2-(trimethylsilyloxy)propan-2-yl)thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
Example 16 (189 mg, 0.5 mmol) in THF was treated with trimethylsilyltrifluoromethane 0.5M solution in THF (2 ml, 1 mmol) and trimethylamine N-oxide (6 mg). The reaction mixture was stirred at room temperature for 18 hours then poured into brine, extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by flash chromatography using CH2Cl2+0-10% EtOAc as eluent to give 80 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.12-0.22 (m, 9 H), 0.96 (t, J=7.3 Hz, 3 H), 1.32-1.48 (m, 2 H), 1.67 (s, 2 H), 1.87 (s, 3 H), 2.41 (s, 3 H), 3.86 (s, 3 H), 3.96 (d, J=15.6 Hz, 2 H), 6.59 (s, 1 H), 7.13 (d, J=9.2 Hz, 1 H), 7.42 (dd, J=8.8, 2.7 Hz, 1 H), 7.63 (d, J=2.7 Hz, 1 H). MS (DCI), m/z 523 (M+H)+.
Example 123B
(2Z)-2-[3-butyl-4-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The product from Example 123A (80 mg, 0.015 mmol) in THF at 0° C. was treated with TBAF (0.015 mmol) and stirred for 1 hr. The reaction mixture was partitioned between EtOAc and brine, dried (MgSO4), concentrated and the residue was purified by flash chromatography eluting with 0-100% EtoAc in hexane to give 60 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.3 Hz, 3 H), 1.33-1.49 (m, 2 H), 1.66 (d, J=7.1 Hz, 2 H), 1.74 (s, 3 H), 2.41 (s, 3 H), 3.86 (s, 3 H), 3.90-4.01 (m, 2 H), 6.57 (s, 1 H), 7.05 (s, 1 H), 7.12 (d, J=8.8 Hz, 1 H), 7.42 (dd, J=8.8, 2.7 Hz, 1 H), 7.64 (d, J=3.1 Hz, 1 H). MS (DCI), m/z 450 (M+H)+. Anal calcd for C20H23ClF3NO3S: C, 53.39; H, 5.15; N, 3.11. Found: C, 53.20; H, 5.01; N, 2.89.
Example 124
(2Z)-2-[5-tert-butyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 16 by replacing 3-chloropentane-2,4-dione with 2-chloro-3,3-dimethylbutanal and replacing n-butylisothiocyanate with 2-isothiocyanatomethyltetrahydrofuran. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.30 (s, 9 H), 1.54-1.70 (m, 1 H), 1.76-1.91 (m, 2 H), 1.90-2.07 (m, 1 H), 3.59-3.73 (m, 1 H), 3.74-3.89 (m, 4 H), 3.90-4.10 (m, 2 H), 4.22 (d, J=6.1 Hz, 1 H), 6.49 (s, 1 H), 7.01-7.17 (m, 2 H), 7.39 (dd, J=8.6, 2.9 Hz, 1 H), 7.59 (d, J=2.7 Hz, 1 H). MS (DCI), m/z 408 (M+H)+. Anal calcd for C21H26ClNO3S: C, 61.83; H, 6.42; N, 3.43. Found: C, 61.51; H, 6.12; N, 3.35.
Example 125
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-isobutyl-5-methyl-4-(trifluoromethyl)-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared as described in Example 16 by replacing n-butylisothiocyanate with isobutylisothiocyanate and 3-chloropentane-2,4-dione with 3-bromo-1,1,1-trifluorobutan-2-one. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.8 Hz, 6 H), 2.38 (q, J=3.4 Hz, 4 H), 3.79-3.92 (m, 5 H), 6.71 (s, 1 H), 7.16 (d, J=8.8 Hz, 1 H), 7.46 (dd, J=8.8, 2.7 Hz, 1 H), 7.64 (d, J=2.7 Hz, 1 H). MS (DCI), m/z 406 (M+H)+. Anal calcd for C18H19ClF3NO2S: C, 53.27; H, 4.72; N, 3.45. Found: C, 53.34; H, 4.84; N, 3.44.
Example 126
(2E)-2-(3-butyl-4-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)-2-fluoroethanone
Example 46 (95 mg, 0.25 mmol) in CH2Cl2 was treated with SelectFluorTM (90 mg, 0.25 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The residue was partitioned between EtOAc and water, dried (MgSO4) and concentrated. Purification by silica gel flash chromatography using 0-10% EtOAc in CH2Cl2 provided the title compound. (30 mg). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.5 Hz, 3 H), 1.31-1.43 (m, 11 H), 1.65 (d, J=1.7 Hz, 2 H), 3.77 (s, 3 H), 4.15-4.30 (m, 2 H), 6.54 (d, J=1.7 Hz, 1 H), 7.10 (d, J=8.8 Hz, 1 H), 7.23 (d, J=2.7 Hz, 1 H), 7.43 (dd, J=8.8, 2.7 Hz, 1 H). MS (DCI), m/z 398 (M+H)+.
Example 127
(2E)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)-2-fluoroethanone
The title compound was prepared as described in Example 126 by replacing Example 46 with Example 121 (12 mg). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 0.95 (t, J=7.3 Hz, 3 H), 1.22-1.37 (m, 11 H), 1.78 (s, 2 H), 3.81 (s, 3 H), 4.01-4.11 (m, 2 H), 6.41 (s, 1 H), 6.86 (d, J=8.8 Hz, 1 H), 7.27-7.33 (m, 1 H), 7.37 (d, J=2.0 Hz, 1 H). MS (DCI), m/z 398 (M+H)+. Anal calcd for C20H25ClFNO2S: C, 60.37; H, 6.33; N, 3.52. Found: C, 60.01; H, 6.12; N, 3.32
Example 128
(2Z)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was isolated as a by-product from the synthesis of Example 121 (400 mg). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85-1.00 (m, 3 H), 1.25-1.43 (m, 2 H), 1.65-1.82 (m, 2 H), 2.04 (s, 3 H), 3.80-3.90 (m, 3 H), 3.98 (t, J=7.3 Hz, 2 H), 5.04 (d, J=19.8 Hz, 2 H), 6.58 (s, 1 H), 7.13 (d, J=9.1 Hz, 1 H), 7.43 (dd, J=8.7, 2.8 Hz, 1 H), 7.50 (s, 1 H), 7.64 (d, J=2.8 Hz, 1 H). MS (DCI), m/z 398 (M+H)+. Anal calcd for C19H22ClNO2S: C, 62.71; H, 6.09; N, 3.85. Found: C, 62.95; H, 5.97; N, 3.86
Example 129
(1Z)-1-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-4,4-dimethylpentan-2-one
The title compound was prepared as described in Example 1B by replacing 5-chloro-2-methoxy-benzoyl chloride with 3,3-dimethylbutanoyl chloride. 1H NMR (300 MHz, DMSO-d6) δ 0.93 (t+s, 12H), 1.34 (sextet, J=7 Hz, 2H), 1.57 (quintet, J=7 Hz, 2H), 2.07 (s, 2H), 2.12 (s, 3H), 2.14 (s, 3H), 3.80 (t, J=7 Hz, 2H), 5.68 (s, 1H); MS (ESI) m/z 282 (M+H)+. Anal calcd for C16H27NOS: C, 68.28; H, 9.67; N, 4.98. Found: C, 68.23; H, 9.85; N, 4.95.
Example 130
1-[(2Z)-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-4,5-dimethyl-1,3-thiazol-3(2H)-yl]-3,3-dimethylbutan-2-one
Example 130A
3-(3,3-dimethyl-2-oxobutyl)-2.4.5-trimethylthiazol-3-ium bromide
A mixture of 2,4,5-trimethylthiazole (640 mg, 5 mmol) and 1-bromo-3,3-dimethylbutan-2-one (1.8 g, 10 mmol) in anhydrous acetonitrile (20 mL) was stirred at 60° C. for 5 h. The mixture was then concentrated under reduced pressure, the residue was triturated with anhydrous ethyl ether and the solid was filtered and dried under reduced pressure to provide 1.4 g of the crude title compound.
Example 130B
1-[(2Z)-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-4,5-dimethyl-1,3-thiazol-3(2H)-yl]-3,3-dimethylbutan-2-one
The title compound was prepared as described in Example 1B by replacing Example 1A with Example 130A. 1H NMR (300 MHz, DMSO-d6) δ 1.23 (s, 9H), 2.00 (s, 3H), 2.17 (s, 3H), 3.79 (s, 3H), 5.18 (s, 2H), 6.27 (s, 1H), 7.07 (d, J=9 Hz, 1H), 7.38 (dd, J=9 Hz, 3 Hz, 1H), 7.41 (d, J=3 Hz, 1H); MS (ESI) m/z 394 (M+H)+. Anal calcd for C20H24ClNO3S: C, 60.98; H, 6.14; N, 3.56. Found: C, 60.70; H, 6.06; N, 3.55.
Example 131
(2Z)-2-[3-butyl-5-(4-fluorophenyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
A mixture of the product from Example 13 (126 mg, 0.3 mmol), 4-fluorophenylboronic acid (45 mg, 0.3 mmol0, triphenylphosphine (79 mg, 0.3 mmol), potassium carbonate (69 mg, 0.5 mmol) and Pd(Ph3P)4 (35 mg, 0.03 mmol) in dioxane (10 mL) was refluxed at 80° C. for 48 min. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (hexane-EtOAc 2:1) to afford 50 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=7 Hz, 3H), 1.44 (sextet, J=7 Hz, 2H), 1.74 (quintet, J=7 Hz, 2H), 2.32 (s, 3H), 3.87 (s, 3H), 4.02 (t, J=7 Hz, 2H), 6.68 (s, 1H), 7.13 (d, J=9 Hz, 1H), 7.33 (t, J=9 Hz, 2H), 7.47 (m, 3H), 7.66 (d, J=3 Hz, 1H); MS (ESI) m/z 432 (M+H)+. Anal calcd for C23H23ClFNO2S.0.25H2O: C, 63.29; H, 5.43; N, 3.21. Found: C, 63.20; H, 5.25; N, 3.04.
Example 132
1-adamantyl (2Z)-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)acetate
The title compound was prepared as described in Example 1B by replacing 5-chloro-2-methoxy-benzoyl chloride with 1-adamantane-fluoroformate. 1H NMR (300 MHz, DMSO-d6) δ 0.90 (t, J=7 Hz, 3H), 1.31 (sextet, J=7 Hz, 2H), 1.51 (m, 2H), 1.60 (s, 6H), 2.05 (m, 15H), 3.66 (t, J=7 Hz, 2H), 4.87 (s, 1H); MS (ESI) m/z 362 (M+H)+. Anal calcd for C21H31NO2S: C, 69.76; H, 8.64; N, 3.87. Found: C, 69.65; H, 8.83; N, 3.69.
Example 133
(2Z)-2-[3-butyl-5-(3-hydroxy-3-methylbut-1-ynyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
A mixture of product from Example 13 (33 mg, 0.08 mmol), 2-methylbut-3-yn-2-ol (10 mg, 0.1 mmol), CuI (2 mg, 0.01 mmol and Pd(Ph3P)4 (30 mg, 0.03 mmol) in triethylamine (10 mL) was heated at 100° C. for 1 hour. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (hexane-EtOAc 1:1) to afford 20 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=7 Hz, 3H), 1.40 (sextet, J=7 Hz, 2H), 1.67 (quintet, J=7 Hz, 2H), 2.34 (s, 3H), 3.85 (s, 3H), 3.95 (t, J=7 Hz, 2H), 5.50 (s, 1H), 6.72 (s, 1H), 7.13 (d, J=9 Hz, 1H), 7.43 (dd, J=9 Hz, 3 Hz, 1H), 7.66 (d, J=3 Hz, 1H); MS (ESI) m/z 420 (M+H)+. Anal calcd for C22H26ClNO3S: C, 62.92; H, 6.24; N, 3.34. Found: C, 62.85; H, 6.28; N, 2.92.
Example 134
(1Z)-1-[3-(3,3-dimethyl-2-oxobutyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-4,4-dimethylpentan-2-one
The title compound was prepared as described in Example 1B by replacing 5-chloro-2-methoxy-benzoyl chloride with 3,3-dimethylbutanoyl chloride and Example 1A with Example 130A. 1H NMR (300 MHz, DMSO-d6) δ 0.90 (s, 9H), 1.22 (s, 9H), 1.92 (s, 2H), 2.07 (s, 3H), 2.09 (s, 3H), 5.04 (s, 2H), 5.45 (s, 1H); MS (ESI) m/z 324 (M+H)+. Anal calcd for C18H29NO2S: C, 66.83; H, 9.04; N, 4.33. Found: C, 66.80; H, 9.07; N, 4.14.
Example 135
(2E)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl-2-fluoroethanone
A mixture of product from Example 1 (176 mg, 0.5 mmol) and SelectFluorTM (180 mg, 0.5 mmol) in acetonitrile (20 mL) was refluxed at 80° C. for 1 h. The mixture was then concentrated under reduced pressure and the residue was chromatographed (hexane-EtOAc 1:1) to afford 40 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.90 (t, J=7 Hz, 3H), 1.29 (sextet, J=7 Hz, 2H), 1.60 (quintet, J=7 Hz, 2H), 2.13 (s, 3H), 2.18 (s, 3H), 3.76 (s, 3H), 4.04 (t, J=7 Hz, 2H), 6.68 (s, 1H), 7.08 (d, J=9 Hz, 1H), 7.20 (d, J=3 Hz, 1H), 7.41 (dd, J=9 Hz, 3 Hz, 1H); MS (ESI) m/z 370 (M+H)+. Anal calcd for C18H21ClFNO2S.0.25H2O: C, 57.89; H, 5.78; N, 3.75. Found: C, 57.95; H, 5.15; N, 3.55.
Example 136
2-[(2Z)-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-4,5-dimethyl-1,3-thiazol-3(2H)-yl]ethyl 5-chloro-2-methoxybenzoate
The title compound was obtained as a side product of Example 5. 1H NMR (300 MHz, DMSO-d6) δ 2.15 (s, 3H), 2.20 (s, 3H), 3.73 (s, 3H), 3.80 (s, 3H), 4.34 (t, J=5 Hz, 2H), 4.55 (t, J=5 Hz, 2H), 6.58 (s, 1H), 7.05 (d, J=9 Hz, 1H), 7.15 (d, J=9 Hz, 1H), 7.38 (dd, J=9 Hz, 3 Hz, 1H), 7.55 (m, 3H); MS (DCI/NH3) m/z 508 (M+H)+. Anal calcd for C24H23Cl2NO5S: C, 56.70; H, 4.56; N, 2.75. Found: C, 56.87; H, 4.45; N, 2.68.
Example 137
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[2-(methylamino)phenyl]ethanone
A mixture of 1-methyl-1H-benzo[d][1,3]oxazine-2,3-dione (177 mg, 1 mmol), Example 1A (311 mg, 1 mmol) and DMAP (500 mg, 4 mmol) in CH2Cl2 (25 mL) was stirred at ambient temperature for 24 h. The product was then purified by column chromatography (EtOAc as eluent) to afford 105 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7 Hz, 3H), 1.37 (sextet, J=7 Hz, 2H), 1.62 (quintet, J=7 Hz, 2H), 2.13 (s, 3H), 2.18 (s, 3H), 2.79 (d, J=5 Hz, 3H), 3.98 (t, J=7 Hz, 2H), 6.40 (s, 1H), 6.57 (m, 2H), 7.20 (m, 1H), 7.70 (dd, J=9 Hz, 3 Hz, 1H), 8.46 (q, J=5 Hz, 1H); MS (DCI/NH3) m/z 315 (M+H)+. Anal calcd for C18H24N2OS: C, 68.32; H, 7.64; N, 8.85. Found: C, 68.20; H, 7.51; N, 8.54.
Example 138
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(4-fluorobutyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]ethanone
Example 138A
3-(4-fluorobutyl)-2,4,5-trimethyl-1,3-thiazol-3-ium iodide
The title compound was prepared as described in Example 1A by replacing 1-iodobutane with 4-fluoro-1-iodobutane.
Example 138B
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(4-fluorobutyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared as described in Example 1B by replacing Example 1A with Example 138A. 1H NMR (300 MHz, DMSO-d6) δ 1.67 (m, 4H), 2.15 (s, 3H), 2.20 (s, 3H), 3.85 (s, 3H), 3.97 (t, J=7 Hz, 2H), 4.43 (t, J=6 Hz, 1H), 4.60 (t, J=6 Hz, 1H), 6.54 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.39 (dd, J=9 Hz, 3 Hz, 1H), 7.63 (d, J=3 Hz, 1H); MS (ESI) m/z 370 (M+H)+. Anal calcd for C18H21ClFNO2S: C, 58.45; H, 5.72; N, 3.79. Found: C, 59.07; H, 5.50; N, 3.57.
Example 139
(2Z)-1-(2-amino-5-chlorophenyl)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone
The title compound was prepared as described in Example 137 by replacing 1-methyl-1H-benzo[d][1,3]oxazine-2,3-dione with 6-chloro-1H-benzo[d][1,3]oxazine-2,3-dione. 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7 Hz, 3H), 1.37 (sextet, J=7 Hz, 2H), 1.62 (quintet, J=7 Hz, 2H), 2.13 (s, 3H), 2.18 (s, 3H), 4.02 (t, J=7 Hz, 2H), 6.38 (s, 1H), 6.63 (d, J=9 Hz, 2H), 6.75 (broad s, 2H), 7.07 (dd, J=9 Hz, 3 Hz, 1H), 7.62 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 337 (M+H)+.
Example 140
ethyl 2-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-4-chlorophenylcarbamate
To a solution of Example 139 (17 mg, 0.05 mmol) and NaHCO3 (42 mg, 0.5 mmol) in EtOAc (5 mL) and H2O (5 mL) was added dropwise at room temperature a solution of ethyl chloroformate (0.06 mL, 0.06 mmol) in EtOAc (3 mL) and the reaction was continued for the next 4 h. The ethyl acetate layer was separated, washed with brine, dried with anhydrous MgSO4 and concentrated under reduced pressure. The residue was chromatographed (EtOAc as eluent) to afford 20 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7 Hz, 3H), 1.24 (t, J=7 Hz, 3H), 1.37 (sextet, J=7 Hz, 2H), 1.62 (quintet, J=7 Hz, 2H), 2.10 (s, 3H), 2.14 (s, 3H), 4.13 (m, 4H), 6.56 (s, 1H), 7.42 (dd, J=9 Hz, 3 Hz, 1H), 7.96 (d, J=3 Hz, 1H 8.23 (d, J=9 Hz, 1H), 11.98 (s, 1H); MS (DCI/NH3) m/z 409 (M+H)+. Anal calcd for C20H25ClN2O3S: C, 58.74; H, 6.16; N, 6.85. Found: C, 59.02; H, 5.98; N, 6.31.
Example 141
(2E)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)-2-fluoroethanone
The title compound was prepared as described in Example 135 by replacing Example 1 with Example 105. 1H NMR (300 MHz, DMSO-d6) δ 0.90 (t, J=7 Hz, 3H), 1.29 (sextet, J=7 Hz, 2H), 1.60 (quintet, J=7 Hz, 2H), 2.13 (s, 3H), 2.18 (s, 3H), 4.10 (t, J=7 Hz, 2H), 6.68 (s, 1H), 7.30 (dd, J=9 Hz, 5 Hz, 1H), 7.81 (dd, J=9 Hz, 3 Hz, 1H), 8.40 (dd, J=5 Hz, 3 Hz, 1H); MS (DCI/NH3) m/z 341 (M+H)+.
Example 142
ethyl 2-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-4-chlorophenyl(methyl)carbamate
A mixture of product from Example 140 (100 mg, 0.24 mmol) and 60% oil suspension NaH (40 mg, 0.6 mmol) in anhydrous THF (20 mL) was treated with iodomethane (0.5 mL) at 50° C. for 5 h and at room temperature for 10 h. The THF was removed under reduced pressure, the residue was partitioned between water and EtOAc. The ethyl acetate layer was separated, washed with brine, dried with anhydrous MgSO4 and concentrated under reduced pressure. The residue was chromatographed (hexane-EtOAc 1:1 as eluent) to provide 91 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.92 (m, 6H), 1.35 (sextet, J=7 Hz, 2H), 1.62 (m, 2H), 2.13 (s, 3H), 2.19 (s, 3H), 3.15 (s, 3H), 3.85 (m, 4H), 5.96 (s, 1H), 7.31 (d, J=9 Hz, 1H), 7.45 (dd, J=9 Hz, 3 Hz, 1H), 7.58 (d, J=3 Hz, 2H); MS (DCI/NH3) m/z 423 (M+H)+. Anal calcd for C21H27ClN2O3S.0.1H2O: C, 59.36; H, 6.45; N, 6.59. Found: C, 59.14; H, 6.43; N, 6.35.
Example 143
Methyl 2-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-4-chlorobenzoate
The title compound was prepared as described in Example 1B by replacing 5-chloro-2-methoxy-benzoyl chloride with methyl 4-chloro-2-(chlorocarbonyl)benzoate. 1H NMR (300 MHz, DMSO-d6) δ 0.93 (t, J=7 Hz, 3H), 1.38 (sextet, J=7 Hz, 2H), 1.62 (quintet, J=7 Hz, 2H), 2.15 (s, 3H), 2.20 (s, 3H), 3.69 (s, 3H), 3.99 (t, J=7 Hz, 2H), 6.25 (s, 1H), 7.51 (m, 1H), 7.60 (dd, J=9 Hz, 3 Hz, 1H), 7.80 (d, J=9 Hz, 1H); MS (DCI/NH3) m/z 380 (M+H)+. Anal calcd for C19H22ClN2O3S: C, 60.07; H, 5.84; N, 3.69. Found: C, 59.96; H, 5.84; N, 3.59.
Example 144
(2Z)-2-[3-butyl-4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
Example 144A
2,4-dimethyl-5-(2-methyl-1,3-dioxolan-2-yl)thiazole
To a solution of 5-acetyl-2-4-dimethyl thiazole (775 mg, 5 mmol) in toluene (20 mL) was added ethylene glycol (3.1 g, 50 mmol) and p-toluenesulfonic acid monohydrate (19 mg, 0.1 mmol) and refluxed overnight. After cooling, a saturated solution of sodium bicarbonate (10 mL) and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate (3×10 mL). The organics were combined, washed with brine, dried with sodium sulfate and concentrated. The residue was purified by chromatography over silica gel (hexane-EtOAc 4:1 as eluent) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.72 (s, 3 H) 2.42 (s, 3 H) 2.60 (s, 3 H) 3.87-3.92 (m, 2 H) 4.02-4.07 (m, 2 H). MS (DCI) m/z 200 (M+H)+.
Example 144B
3-butyl-2,4-dimethyl-5-(2-methyl-1,3-dioxolan-2-yl)thiazol-3-ium iodide
The title compound was prepared as described in Example 1A, replacing 2,4,5-trimethylthiazole with Example 144A. The thiazolium salt was carried on to the next step without purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.34 Hz, 3 H) 1.41 (dd, J=15.07, 7.54 Hz, 2 H) 1.65-1.77 (m, 5 H) 2.64 (s, 3 H) 2.98 (s, 3 H) 3.80-3.94 (m, 2 H) 4.04-4.16 (m, 2 H) 4.25-4.37 (m, 2 H). MS (DCI) m/z 256 (M).
Example 144C
(2Z)-2-[3-butyl-4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 1B, replacing Example 1A with Example 144B. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.29 Hz, 3 H) 1.33-1.46 (m, 2 H) 1.59-1.72 (m, 5 H) 2.32 (s, 3 H) 3.80-3.92 (m, 7 H) 3.96-4.06 (m, 2 H) 6.52 (s, 1 H) 7.11 (d, J=8.82 Hz, 1 H) 7.40 (dd, J=8.82, 2.71 Hz, 1 H) 7.62 (d, J=2.71 Hz, 1 H). MS (DCI) m/z 424 (M+H)+. Anal calcd for C21H26ClNO4S: C, 59.49; H, 6.18; N, 3.30. Found: C, 59.12; H, 6.03; N, 3.32.
Example 145
2,2,2-trichloro-1,1-dimethylethyl (2Z)-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)acetate
The title compound was prepared as described in Example 1B, replacing 5-chloro-2-methoxy-benzoyl chloride with 2,2,2-trichloro-1,1-dimethylethyl chloroformate. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.29 Hz, 3 H) 1.25-1.39 (m, 2 H) 1.49-1.60 (m, 2 H) 1.81-1.93 (s, 6 H) 2.09 (m, 6 H) 3.63-3.77 (m, 2 H) 4.95 (s, 1 H). MS (DCI) m/z 386 (M+H)+.
Example 146
2,2,2-trichloro-1,1-dimethylethyl (2Z)-(3-butyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)acetate
The title compound was prepared as described in Example 1B, replacing Example 1A with Example 47A and replacing 5-chloro-2-methoxy-benzoyl chloride with 2,2,2-trichloro-1,1-dimethylethyl chloroformate. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83-0.93 (m, 3 H) 1.24-1.37 (m, 2 H) 1.59-1.71 (m, 2 H) 1.86 (s, 6 H) 2.40 (s, 3 H) 3.94 (t, J=7.12 Hz, 2 H) 5.08 (s, 1 H). MS (DCI) m/z 373 (M+H)+.
Example 147
(2Z)-2-[4-tert-butyl-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 16, substituting 2-methoxyethylisothiocyanate for n-butylisothiocyanate and substituting 1-bromopinacolone for 3-chloropentan-2,4-dione. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9 H) 3.31 (s, 3 H) 3.71 (t, J=6.78 Hz, 2 H) 3.87 (s, 3 H) 4.33 (t, J=6.78 Hz, 2 H) 6.50 (s, 1 H) 6.61 (s, 1 H) 7.12 (d, J=9.15 Hz, 1 H) 7.41 (dd, J=8.81, 2.71 Hz, 1 H) 7.63 (d, J=3.05 Hz, 1 H). MS (DCI) m/z 382 (M+H)+. Anal calcd for C19H24ClNO3S.0.8H2O: C, 58.11; H, 6.47; N, 3.57. Found: C, 57.95; H, 6.49; N, 3.97
Example 148
(2Z)-2-[4-tert-butyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 16, substituting 2-isothiocyanatomethyltetrahydrofuran for n-butyl isothiocyanate and substituting 1-bromopinacolone for 3-chloropentan-2,4-dione. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (s, 9 H) 1.68-1.78 (m, 1 H) 1.81-1.95 (m, 2 H) 2.04-2.15 (m, 1 H) 3.56-3.66 (m, 1 H) 3.71-3.80 (m, 1 H) 3.84-3.87 (s, 3 H) 4.15-4.23 (m, 1 H) 4.31-4.46 (m, 2 H) 6.49 (s, 1 H) 6.58 (s, 1 H) 7.12 (d, J=8.82 Hz, 1 H) 7.40 (dd, J=8.82, 2.71 Hz, 1 H) 7.62 (d, J=3.05 Hz, 1 H). MS (DCI) m/z 408 (M+H)+. Anal calcd for C21H26ClNO3S.0.8H2O: C, 59.72; H, 6.59; N, 3.32. Found: C, 59.85; H, 6.45; N, 3.45.
Example 149
(2Z)-2-[4-tert-butyl-3-(2-piperidin-1-ylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 16, substituting 2-piperidinoethyl isothiocyanate for butyl isothiocyanate and substituting 1-bromopinacolone for 3-chloropentan-2,4-dione. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9 H) 1.43-1.57 (m, 6 H) 2.46 (m, 4 H) 2.57-2.72 (m, 2 H) 3.88 (s, 3 H) 4.20-4.33 (m, 2 H) 6.51 (s, 1 H) 6.66 (s, 1 H) 7.13 (d, J=9.16 Hz, 1 H) 7.42 (dd, J=8.82, 2.71 Hz, 1 H) 7.67 (d, J=3.05 Hz, 1 H). MS (DCI) m/z 435 (M+H)+. Anal calcd for C23H31ClN2O2S.1.2H2O: C, 60.50; H, 7.37; N, 6.13. Found: C, 60.24; H, 7.07; N, 6.13.
Example 150
(2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-N-methyl-2,3-dihydro-1,3-thiazole-4-carboxamide
To a solution of Example 45 in methanol was added a solution of methylamine in methanol and stirred overnight. The title compound was obtained by concentration of the reaction solution. 1H NMR (300 MHz, DMSO-D6) δ ppm 0.92 (t, J=7.29 Hz, 3 H) 1.23-1.37 (m, 2 H) 1.71 (m, 2 H) 2.74 (d, J=4.75 Hz, 4 H) 3.87 (s, 3 H) 4.15-4.24 (m, 2 H) 6.66 (s, 1 H) 7.14 (d, J=8.81 Hz, 1 H) 7.21 (s, 1 H) 7.44 (dd, J=8.82, 2.71 Hz, 1 H) 7.66 (d, J=2.71 Hz, 1 H) 8.77 (d, J=4.75 Hz, 1 H). MS (DCI) m/z 381 (M+H)+. Anal calcd for C18H21ClN2O3S.1.2H2O.0.3 NH4OH: C, 52.81; H, 6.03; N, 7.87. Found: C, 52.52; H, 5.70; N, 7.81.
Example 151
(Z)-2-(5-acetyl-3-butylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
Example 151A
sodium (Z)-4-oxopent-2-en-2-olate
To a stirred suspension of sodium methoxide (27 g, 0.5 mol) in ether (320 mL) was added a mixture of acetone (29 g, 0.5 mol) and ethyl formate (37 g, 0.5 mmol) dropwise. The reaction was stirred for 30 min before the solid was filtered and dried in vacuo. The solid was ground up using a mortar and pestle and used without further purification. 1H NMR (300 MHz, D2O) δ ppm 2.15 (s, 3 H) 5.24 (s, 1 H) 8.97 (d, J=10.51 Hz, 1 H).
Example 151B
3-bromo-4-hydroxypent-3-en-2-one
To a stirred suspension of Example 151A (34.1 g, 0.32 mol) in dichloromethane (250 mL) at −78° C. was added dropwise bromine (50.5 g, 0.32 mmol). The reaction was stirred for another 2 hrs before it was brought to room temperature. The solid was filtered and washed with dichloromethane. The filtrate was concentrated at room temperature to one-fourth the volume and the solid was filtered to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.32 (s, 3 H) 8.32 (b, 1 H) 12.1 (b, 1 H).
Example 151C
(Z)-2-(5-acetyl-3-butylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 16, replacing 3-chloropentane-2,4-dione with Example 151B. 1H NMR (300 MHz, CDCl3) δ ppm 1.02 (t, J=7.46 Hz, 3 H) 1.44 (dd, J=15.26, 7.46 Hz, 2 H) 1.81-1.91 (m, 2 H) 2.44 (s, 3 H) 3.88 (s, 3 H) 3.94 (t, J=7.29 Hz, 2 H) 6.70 (s, 1 H) 6.89 (d, J=8.82 Hz, 1 H) 7.32 (dd, J=8.82, 2.71 Hz, 1 H) 7.55 (s, 1 H) 7.87 (d, J=2.71 Hz, 1 H). MS (DCI) m/z 366 (M+H)+. Anal calcd for C18H20ClNO3S: C, 59.09; H, 5.51; N, 3.83. Found: C, 58.81; H, 5.46; N, 3.80.
Example 152
6-[(2Z)-2-(3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene)ethanoyl]-2,2-dimethyl-2,3-dihydro-4H-pyran-4-one
The procedure in Example 47B was followed, replacing 2-methoxy-5-chloro benzoic acid with 2,2-dimethyl-4-oxo-3,4-dihydro-2H-pyran-6-carboxylic acid and replacing Example 47A with Example 50C to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.00 (t, J=7.29 Hz, 3H) 1.40 (m, 11H) 1.51 (s, 6H) 1.86 (m, 2H) 2.54 (s, 2H) 4.14 (t, J=7.12 Hz, 2H) 6.26 (s, 1H) 6.32 (s, 1H). MS (DCI) m/z 365 (M+H)+.
Example 153
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)ethanone
Example 153A
5-acetyl-2-methylthiazole
To a solution of the product of Example 151B (14.5 g, 88 mmol) in acetone (220 mL) was added thioacetamide (6.6 g, 88 mmol) and stirred overnight. The solid was filtered to give the title compound as the hydrogen bromide salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.54 (s, 3 H) 2.71 (s, 3 H) 8.46 (s, 1 H). MS (DCI) m/z 142 (M+H)+.
Example 153B
5-tert-butyl-2-methylthiazole
The title compound was prepared and purified as described in Example 35A, replacing 5-acetyl-2,4-dimethyl thiazole with Example 153A. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (s, 9 H) 2.57 (s, 3 H) 7.33 (s, 1 H). MS (DCI) m/z 156 (M+H)+.
Example 153C
3-butyl-5-tert-butyl-2-methyl-1,3-thiazol-3-ium iodide
The title compound was prepared and purified as described in Example 1A, replacing 2,4,5-trimethyl thiazole with Example 153B. The compound was used without further purification.
Example 153D (2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)ethanone
The title compound was prepared and purified as described in Example 35C, replacing Example 35B with Example 153C and replacing 3-chlorothiophene-2-carbonyl chloride with 2-chloronicotinoyl chloride. 1H NMR (300 MHz, CDCl3) δ ppm 0.98 (t, J=7.29 Hz, 3 H) 1.34-1.37 (m, 9 H) 1.38-1.46 (m, 2 H) 1.75-1.85 (m, 2 H) 3.82-3.90 (m, 2 H) 6.18 (s, 1 H) 6.56 (s, 1 H) 7.29 (dd, J=7.46, 4.75 Hz, 1 H) 8.03 (dd, J=7.80, 2.03 Hz, 1 H) 8.38 (dd, J=4.75, 2.03 Hz, 1 H). MS (ESI) m/z 351 (M+H)+. Anal calcd for C18H23ClN2OS: C, 61.61; H, 6.61; N, 7.98. Found: C, 61.46; H, 6.91; N, 7.88.
Example 154
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-fluoro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 35C, replacing Example 35B with Example 153C and replacing 3-chlorothiophene-2-carbonyl chloride with 5-fluoro-2-methoxybenzoyl chloride. 1H NMR (300 MHz, CDCl3) δ ppm 1.00 (t, J=7.29 Hz, 3 H) 1.34 (s, 9 H) 1.41-1.46 (m, 2 H) 1.76-1.86 (m, 2 H) 3.83-3.88 (m, 5 H) 6.51 (s, 1 H) 6.54 (s, 1 H) 6.85-6.90 (m, 1 H) 6.98-7.05 (m, 1 H) 7.66 (dd, J=9.49, 3.39 Hz, 1 H). MS (ESI) m/z 364 (M+H).
Example 155
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(3-chlorothien-2-yl)ethanone
The title compound was prepared and purified as described in Example 35C, replacing Example 35B with Example 153C. 1H NMR (300 MHz, CDCl3) δ ppm 1.00 (t, J=7.46 Hz, 3 H) 1.34 (s, 9 H) 1.42 (m, 2 H) 1.79-1.89 (m, 2 H) 3.87-3.93 (m, 2 H) 6.55 (s, 1 H) 6.72 (s, 1 H) 6.91-6.97 (m, 1 H) 7.35 (d, J=5.09 Hz, 1 H). MS (ESI) m/z 356 (M+H)+. Anal calcd for C17H22ClNOS2: C, 57.36; H, 6.23; N, 3.94. Found: C, 57.10; H, 6.11;N, 3.82.
Example 156
6-[(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-2,2-dimethyl-2,3-dihydro-4H-pyran-4-one
The title compound was prepared and purified as described in Example 35C, replacing Example 35B with Example 153C and replacing 3-chlorothiophene-2-carbonyl chloride with 2,2-dimethyl-4-oxo-3,4-dihydro-2H-pyran-6-carbonyl chloride. 1H NMR (300 MHz, CDCl3) δ ppm 1.02 (t, J=7.29 Hz, 3 H) 1.34 (s, 9 H) 1.37-1.46 (m, 2 H) 1.48-1.52 (m, 6 H) 1.76-1.86 (m, 2 H) 2.53 (s, 2 H) 3.88-3.95 (m, 2 H) 6.28 (s, 1 H) 6.33 (s, 1 H) 6.60 (s, 1 H). MS (ESI) m/z 364 (M+H)+. Anal calcd for C20H29NO3S.0.06 CH2Cl2: C, 65.36; H, 7.96; N, 3.80. Found: C, 65.67; H, 7.56; N, 3.69.
Example 157
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-iodo-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 35C, replacing Example 35B with Example 153C and replacing 3-chlorothiophene-2-carbonyl chloride with 5-iodo-2-methoxybenzoyl chloride. 1H NMR (300 MHz, CDCl3) δ ppm 0.99 (t, J=7.46 Hz, 3 H) 1.35 (s, 9 H) 1.40 (m, 2 H) 1.75-1.85 (m, 2 H) 3.82-3.91 (m, 5 H) 6.57 (s, 1 H) 6.70 (d, J=8.82 Hz, 1 H) 7.60 (dd, J=8.48, 2.37 Hz, 1 H) 8.10 (d, J=2.37 Hz, 1 H). MS (ESI) m/z 472 (M+H)+.
Example 158
(2Z)-1-(1-benzofuran-5-yl)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)ethanone
The title compound was prepared and purified as described in Example 35C, replacing Example 35B with Example 153C and replacing 3-chlorothiophene-2-carbonyl chloride with benzofuran-5-carbonyl chloride. 1H NMR (300 MHz, CDCl3 ppm 0.98-1.04 (m, 3 H) 1.35-1.38 (m, 9 H) 1.39-1.50 (m, 2 H) 1.78-1.92 (m, 2 H) 3.92 (t, J=7.46 Hz, 2 H) 6.53 (s, 1 H) 6.84 (d, J=3.05 Hz, 1 H) 7.51 (d, J=8.48 Hz, 1 H) 7.64 (d, J=2.03 Hz, 1 H) 7.93 (dd, J=8.65, 1.86 Hz, 1 H) 8.22 (d, J=1.36 Hz, 1 H). MS (ESI) m/z 356 (M+H)+.
Example 159
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(2-ethoxypyridin-3-yl)ethanone
The title compound was prepared and purified as described in Example 35C, replacing Example 35B with Example 153C and replacing 3-chlorothiophene-2-carbonyl chloride with 2-ethoxynicotinoyl chloride. 1H NMR (300 MHz, CDCl3 ppm 1.00 (t, J=7.29 Hz, 3 H) 1.35 (s, 9 H) 1.37-1.45 (m, 2 H) 1.48 (t, J=7.12 Hz, 3 H) 1.76-1.89 (m, 2 H) 3.85-3.92 (m, 2 H) 4.49 (q, J=7.12 Hz, 2 H) 6.53 (s, 1 H) 6.98 (dd, J=7.46, 5.09 Hz, 1 H) 8.16 (dd, J=5.09, 2.03 Hz, 1 H) 8.42 (dd, J=7.46, 2.03 Hz, 1 H). MS (ESI) m/z 361 (M+H)+. Anal calcd for C20H28N2O2S.0.2 EtOH: C, 65.44; H, 8.26; N, 7.13. Found: C, 65.17; H, 8.53; N, 6.80.
Example 160
(2Z)-1-(1-benzofuran-5-yl)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)ethanone
This compound was isolated as a by-product from the procedure of Example 158. 1H NMR (300 MHz, CDCl3) m 0.97-1.06 (m, 3 H) 1.41-1.50 (m, 2 H) 1.85 (m, 2 H) 2.07 (s, 3 H) 3.94 (t, J=7.29 Hz, 2 H) 5.02 (m, 1 H) 5.26-5.30 (m, 1 H) 6.74 (s, 1 H) 6.84 (s, 1 H) 7.50-7.55 (m, 1 H) 7.63-7.69 (m, 1 H) 7.96 (dd, J=8.65, 1.86 Hz, 1 H) 8.21-8.26 (m, 1 H). MS (ESI) m/z 340 (M+H).
Example 161
(2Z)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)-1-(2-ethoxypyridin-3-yl)ethanone
The title compound was isolated as a by-product from the procedure of Example 159. 1H NMR (300 MHz, CDCl3) δ ppm 1.00 (t, J=7.29 Hz, 3 H) 1.47 (qd, J=7.23, 3.05 Hz, 5 H) 1.81-1.89 (m, 2 H) 2.06 (s, 3 H) 3.91 (t, J=7.46 Hz, 2 H) 4.50 (qd, J=6.89, 4.07 Hz, 2 H) 5.02 (m, 1 H) 5.26 (m, 1 H) 6.76 (s, 1 H) 6.99 (ddd, J=7.63, 4.75, 3.22 Hz, 2 H) 8.18 (dd, J=4.75, 2.03 Hz, 1 H) 8.42 (dd, J=7.46, 2.03 Hz, 1 H). MS (ESI) m/z 345 (M+H)+.
Example 162
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(2,4-dimethoxyphenyl)ethanone
Example 162A
3-butyl-2,4-dimethylthiazol-3-ium iodide
The title compound was prepared and purified as described in Example 1A, substituting 2,4-dimethylthiazole for 2,4,5-trimethyl thiazole. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.29 Hz, 3 H) 1.41 (qd, J=7.52, 7.29 Hz, 2 H) 1.65-1.77 (m, 2 H) 2.54 (s, 3 H) 2.98 (s, 3 H) 4.26-4.35 (m, 2H) 7.80 (s, 1 H).
Example 162B (2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(2,4-dimethoxyphenyl)ethanone
The title compound was prepared as described in Example 1B, substituting Example 162A for Example 1A and 2,5-dimethoxybenzoyl chloride for 5-chloro-2-methoxybenzoyl chloride. 1H NMR (300 MHz, CDCl3) δ ppm 1.02 (t, J=7.29 Hz, 3 H) 1.46 (m, 2 H) 1.80 (m, 2 H) 2.42 (s, 3 H) 3.86 (s, 3 H) 3.92 (s, 3 H) 4.14 (m, 2 H) 6.50 (m, J=2.37 Hz, 1 H) 6.61 (m, J=8.65, 2.54 Hz, 1 H) 6.72 (m, 1 H), 7.9 (m, 1 H). MS (DCI) m/z 334 (M+H)+.
Example 163
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(2,5-diethoxyphenyl)ethanone
The title compound was prepared as described in Example 1B, substituting Example 162A for Example 1A and 2,5-diethoxybenzoyl chloride for 5-chloro-2-methoxybenzoyl chloride. 1H NMR (300 MHz, CDCl3) δ ppm 1.00 (t, J=7.29 Hz, 3 H) 1.35-1.48 (m, 8 H) 1.79 (m, 2 H) 2.36 (s, 3 H) 3.96-4.11 (m, 6 H) 6.47 (s, 1 H) 6.86-6.95 (m, 2 H) 7.46 (d, J=2.71 Hz, 1 H). MS (DCI) m/z 362 (M+H)+.
Example 164
(2Z)-2-[5-tert-butyl-3-(2-methoxyethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
Example 164A
5-tert-butyl-3-(2-methoxyethyl)-2-methyl-1,3,4-thiadiazol-3-ium bromide
The title compound was prepared as described in Example 47A, substituting 2-bromoethyl methyl ether for butyl iodide and Example 50B for 2,5-dimethyl thiadiazole. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.46 (s, 9 H) 3.08 (s, 3 H) 3.27 (s, 3 H) 3.81-3.85 (m, 2 H) 4.73-4.80 (m, 2 H). MS (DCI) m/z 215 (M)+.
Example 164B
(2Z)-2-[5-tert-butyl-3-(2-methoxyethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 47B, substituting Example 164A for Example 47A. 1H NMR (300 MHz, CDCl3) δ ppm 1.41 (s, 9H) 3.38 (s, 3 H) 3.80 (d, J=4.41 Hz, 2 H) 3.86 (s, 3 H) 4.27 (t, J=5.76 Hz, 2 H) 6.88 (d, J=8.81 Hz, 1 H) 7.31 (dd, J=8.82, 2.71 Hz, 1 H) 7.71-7.74 (m, 1 H). MS (ESI) m/z 383 (M+H)+. Anal calcd for C18H23ClN2O3S.0.2 MeOH.0.4 TFA: C, 52.47; H, 5.61; N, 6.44. Found: C, 52.52; H, 5.35; N, 6.08.
Example 165
(2Z)-2-[5-tert-butyl-3-(2-methoxyethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(2,3-dichlorophenyl)ethanone
The title compound was prepared as described in Example 47B, substituting Example 164A for Example 47A and 2,3-dichlorobenzoic acid for 5-chloro-2-methoxybenzoic acid. 1H NMR (300 MHz, CDCl3) δ ppm 1.42 (s, 9H) 3.36 (s, 3 H) 3.78 (t, J=5.76 Hz, 2 H) 4.24 (t, J=5.59 Hz, 2 H) 7.20-7.26 (m, 1 H) 7.43 (dd, J=7.80, 1.70 Hz, 1 H) 7.45-7.49 (m, 1 H). MS (DCI) m/z 387 (M+H)+. Anal calcd for C17H20Cl2N2O2S.0.5 TFA: C, 48.60; H, 4.65; N, 6.30. Found: C, 48.56; H, 4.57; N, 6.47.
Example 166
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-[trans-2-phenylcyclopropyl]ethanone
The title compound was prepared as described in Example 1B, substituting Example 162A for Example 1A and trans-2-phenyl-1-cyclopropanecarbonyl chloride for 5-chloro-2-methoxybenzoyl chloride. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 0.99 (t, J=7.12 Hz, 3 H) 1.32-1.46 (m, 3 H) 1.68-1.81 (m, 3 H) 2.06-2.18 (m, 2 H) 2.28 (s, 3 H) 3.83-3.89 (m, 2 H) 6.25 (s, 1 H) 7.10-7.25 (m, 5 H). MS (DCI) m/z 314 (M+H)+.
Example 167
(2Z)-2-[5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
Example 167A
5-tert-butyl-3-(cyclobutylmethyl)-2-methyl-1,3,4-thiadiazol-3-ium bromide
The title compound was prepared as described in Example 47A, substituting (bromomethyl)cyclobutane for butyl iodide and Example 50B for 2,5-dimethyl thiadiazole. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.45 (s, 9 H) 1.76 (dd, J=6.78, 3.39 Hz, 4 H) 1.88-1.91 (m, 2 H) 2.91 (s, 1 H) 3.10 (s, 3 H) 4.58 (d, J=7.46 Hz, 2 H). MS (DCI) m/z 225 (M)+.
Example 167B (2Z)-2-[5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 47B, substituting Example 167A for Example 47A. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.35 (m, 9 H) 1.79-1.92 (m, 4 H) 1.94-2.05 (m, 2 H) 2.75-2.87 (m, 1 H) 3.85 (s, 3 H) 4.16 (d, J=7.12 Hz, 2 H) 6.55 (s, 1 H) 7.13 (d, J=8.81 Hz, 1 H) 7.45 (dd, J=8.81, 2.71 Hz, 1 H) 7.57 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 393 (M+H)+. Anal calcd for C20H25ClN2O2S.0.5H2O: C, 59.76; H, 6.52; N, 6.97. Found: C, 59.77; H, 6.30; N, 6.94.
Example 168
(2Z)-2-[5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(2,3-dichlorophenyl)ethanone
The title compound was prepared as described in Example 47B, substituting Example 167A for Example 47A and 2,3-dichlorobenzoic acid for 5-chloro-2-methoxybenzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36-1.39 (s, 9 H) 1.78-1.89 (m, 4 H) 1.90-2.02 (m, 2 H) 2.73-2.84 (m, 1 H) 4.18 (d, J=7.46 Hz, 2 H) 6.21 (s, 1 H) 7.40-7.44 (m, 2 H) 7.64-7.69 (m, 1 H). MS (ESI) m/z 397 (M+H)+. Anal calcd for C19H22Cl2OS.0.2 TFA: C, 55.46; H, 5.33; N, 6.67. Found: C, 55.57; H, 4.97; N, 6.87.
Example 169
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone
Example 169A
3-(cyclobutylmethyl)-2,4-dimethylthiazol-3-ium
The title compound was prepared as described in Example 1A, substituting (bromomethyl)cyclobutane for butyl iodide and 2,4-dimethylthiazole for 2,4,5-trimethylthiazole. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.77-1.90 (m, 4H) 1.93-2.05 (m, 2 H) 2.53 (d, J=1.36 Hz, 3 H) 2.71-2.83 (m, 1 H) 2.99 (s, 3 H) 4.42 (d, J=7.12 Hz, 2 H) 7.82 (s, 1 H). MS (ESI) m/z 182 (M)+.
Example 169B (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared as described in Example 1B, substituting Example 169A for Example 1A. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.82-1.90 (m, 4 H) 1.96-2.04 (m, 2 H) 2.30 (s, 3 H) 2.75-2.84 (m, 1 H) 3.87 (s, 3 H) 3.98-4.02 (m, 2 H) 6.53 (s, 1 H) 6.62 (s, 1 H) 7.13 (d, J=8.85 Hz, 1 H) 7.42 (dd, J=8.70, 2.90 Hz, 1 H) 7.63 (d, J=2.75 Hz, 1 H). MS (ESI) m/z 350 (M+H)+.
Example 170
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone
To a solution of Example 169B (140 mg, 4 mmol) in tetrahydrofuran (4 mL) at −78° C. was added lithium diisopropylamide (2 M, 0.6 mL). Acetone (81 μL, 1.2 mmol) was added after 5 min. The reaction was quenched with saturated ammonium chloride (10 mL) after 10 min and the reaction mixture was allowed to warm to room temperature. The reaction was extracted with ethyl acetate (3×10 mL). The organics were combined, washed with brine, dried with sodium sulfate and concentrated. The residue was purified by chromatography over silica gel (dichloromethane-EtOAc 5:1 as eluent) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.48 (s, 6 H) 1.80-1.93 (m, 4 H) 1.99-2.04 (m, 2 H) 2.35 (s, 3 H) 2.68-2.82 (m, 1 H) 3.86 (s, 3 H) 3.96 (d, J=6.78 Hz, 2 H) 5.49 (s, 1 H) 6.53 (s, 1 H) 7.10 (d, J=8.82 Hz, 1 H) 7.39 (dd, J=8.82, 2.71 Hz, 1 H) 7.63 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 408 (M+H)+. Anal calcd for C21H26ClNO3S.0.7H2O: C, 59.97; H, 6.57; N, 3.33. Found: C, 59.76; H, 6.76; N, 3.02.
Example 171
(2Z)-2-[5-bromo-3-(cyclobutylmethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
In a 20 mL vial, a solution of Example 169B (620 mg, 1.772 mmol) was dissolved in acetonitrile (4 ml). N-bromosuccinimide (268 mg, 1.506 mmol) was added and the reaction was stirred for 16 hrs. The reaction was concentrated and purified by chromatography over silica gel (hex-EtOAc 4:1 as eluent) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.82-1.93 (m, 4 H) 1.95-2.06 (m, 2 H) 2.29 (s, 3 H) 2.71-2.84 (m, 1 H) 3.88 (s, 3 H) 4.06 (d, J=7.12 Hz, 2 H) 6.82 (s, 1 H) 7.14 (d, J=8.82 Hz, 1 H) 7.44 (dd, J=8.82, 2.71 Hz, 1 H) 7.66 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 428 (M+H)+. Anal calcd for C19H22ClF2NO3S: C, 54.61; H, 5.31; N, 3.35. Found: C, 54.51; H, 5.26; N, 3.35.
Example 172
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-1,3-thiazol-2(3H)-ylidene]ethanone
Example 172A
3-(cyclobutylmethyl)-2-methylthiazol-3-ium
The title compound was prepared as described in Example 1A, substituting 2-methylthiazole for 2,4,5-trimethylthiazole and (bromomethyl)cyclobutane for iodobutane. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.80-1.92 (m, 4 H) 1.92-2.03 (m, 2 H) 2.80-2.91 (m, 1 H) 2.97 (s, 3 H) 4.46 (d, J=7.80 Hz, 2 H) 8.12 (d, J=4.07 Hz, 1 H) 8.37 (d, J=3.73 Hz, 1 H). MS (ESI) m/z 168 (M)+.
Example 172B
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared as described in Example 1B, substituting Example 172A for Example 1A. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.78-1.93 (m, 4 H) 1.95-2.02 (m, 2 H) 2.77-2.88 (m, 1 H) 3.85 (s, 3 H) 4.02-4.06 (m, 2 H) 6.56 (d, J=1.36 Hz, 1 H) 6.79-6.82 (m, 1 H) 7.11 (d, J=8.82 Hz, 1 H) 7.41 (dd, J=8.81, 2.71 Hz, 1 H) 7.45 (d, J=4.07 Hz, 1 H) 7.62 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 336 (M+H)+. Anal calcd for C17H18ClNO2S.0.1 H2O: C, 60.48; H, 5.43; N, 4.15. Found: C, 60.33; H, 5.61; N, 3.95.
Example 173
(2Z)-2-[5-tert-butyl-3-(2,4-difluorobenzyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
Example 173A
5-tert-butyl-3-(2,4-difluorobenzyl)-2-methyl-1,3,4-thiadiazol-3-ium bromide
The title compound was prepared as described in Example 47A, substituting 2,4-difluorobenzyl bromide for butyl iodide and Example 50B for 2,5-dimethyl thiadiazole. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 3.14-3.20 (m, 3 H) 5.81 (s, 2 H) 7.17-7.24 (m, 1 H) 7.36-7.44 (m, 1 H) 7.69 (td, J=8.65, 6.78 Hz, 1 H). MS (ESI) m/z 283 (M)+.
Example 173B (2Z)-2-[5-tert-butyl-3-(2,4-difluorobenzyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 47B, substituting Example 173A for Example 47A 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (s, 9 H) 3.80 (s, 3 H) 5.40 (s, 2 H) 6.61 (s, 1 H) 7.11-7.18 (m, 2 H) 7.31-7.39 (m, 2 H) 7.45 (dd, J=8.82, 2.71 Hz, 1 H) 7.59 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 451 (M+H)+. Anal calcd for C22H21ClF2N2O2S.0.6 CH2Cl2: C, 54.08; H, 4.46; N, 5.58. Found: C, 53.97; H, 4.10; N, 5.47.
Example 174
(2Z)-2-[5-tert-butyl-3-(2,4-difluorobenzyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(2,3-dichlorophenyl)ethanone
The title compound was prepared and purified as described in Example 47B, substituting Example 173A for Example 47A and 2,3-dichlorobenzoic acid for 5-chloro-2-methoxybenzoic acid. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.36 (s, 9 H) 5.43 (s, 2 H) 6.28 (s, 1 H) 7.08-7.15 (m, 1 H) 7.27-7.36 (m, 2 H) 7.37-7.45 (m, 2 H) 7.68 (dd, J=6.61, 2.88 Hz, 1 H). MS (ESI) m/z 455 (M+H)+. Anal calcd for C21H18Cl2F2N2OS: C, 55.39; H, 3.98; N, 6.15. Found: C, 55.04; H, 3.86; N, 6.18.
Example 175
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-4-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared and purified as described in Example 170, substituting 1,1,1-trifluoroacetone for acetone. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74 (s, 3 H) 1.81-1.91 (m, 4 H) 1.98-2.01 (m, 2 H) 2.40 (s, 3 H) 2.77 (m, 1 H) 3.86 (s, 3 H) 3.99-4.03 (m, 2 H) 6.62 (s, 1 H) 7.05 (s, 1 H) 7.12 (d, J=9.16 Hz, 1 H) 7.41 (dd, J=8.82, 3.05 Hz, 1 H) 7.62 (d, J=2.71 Hz, 1 H). MS (DCI) m/z 462 (M+H)+. Anal calcd for C21H23ClF3NO3S.0.1 CH2Cl2: C, 52.87; H, 4.86; N, 2.94. Found: C, 53.27; H, 4.67; N, 2.86.
Example 176
(2Z)-2-[3-butyl-5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
Example 176A
3-butyl-2-methylthiazol-3-ium iodide
The title compound was prepared as described in Example 1A, substituting 2-methylthiazole for 2,4,5-trimethylthiazole. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.29 Hz, 3 H) 1.26-1.39 (m, 2 H) 1.74-1.85 (m, 2 H) 2.95-2.99 (m, 3 H) 4.34-4.42 (m, 2 H) 8.12 (d, J=3.73 Hz, 1 H) 8.40 (d, J=3.73 Hz, 1 H). MS (ESI) m/z 156 (M)+.
Example 176B
(Z)-2-(3-butylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared as described in Example 1B, substituting Example 176A for Example 1A. MS (ESI) m/z 324 (M+H)+.
Example 176C (2Z)-2-[3-butyl-5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 170, substituting Example 176B for Example 169B. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.29 Hz, 3 H) 1.33 (dd, J=15.09, 7.29 Hz, 2 H) 1.47 (s, 6 H) 1.64-1.75 (m, 2 H) 3.85 (s, 3 H) 3.93 (t, J=7.29 Hz, 2 H) 5.44 (s, 1 H) 6.46 (s, 1 H) 7.11 (d, J=8.82 Hz, 1 H) 7.20 (s, 1 H) 7.40 (dd, J=8.82, 2.71 Hz, 1 H) 7.63 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 382 (M+H)+.
Example 177
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared and purified as described in Example 170, substituting Example 172B for Example 169B. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.47 (s, 6 H) 1.80-1.90 (m, 4 H) 1.96-2.04 (m, 2 H) 2.72-2.87 (m, 1 H) 3.85 (s, 3 H) 3.97 (d, J=7.12 Hz, 2 H) 5.44 (s, 1 H) 6.46 (s, 1 H) 7.10 (d, J=9.16 Hz, 1 H) 7.20 (s, 1 H) 7.40 (dd, J=8.82, 3.05 Hz, 1 H) 7.60 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 394 (M+H)+.
Example 178
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(2,4-difluorobenzyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone
Example 178A
3-(2,4-difluorobenzyl)-2,4-dimethylthiazol-3-ium bromide
The title compound was prepared as described in Example 47A, substituting 2,4-dimethylthiazole for 2,5-dimethyl thiadiazole and 2,4-difluorobenzylbromide for 1-iodobutane. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.41 (s, 3 H) 2.97 (s, 3 H) 5.72 (s, 2 H) 7.15 (td, J=8.65, 3.05 Hz, 1 H) 7.27 (td, J=8.65, 6.44 Hz, 1 H) 7.41 (ddd, J=11.36, 8.99, 2.71 Hz, 1 H) 7.89 (s, 1 H). MS (ESI) m/z 240 (M)+.
Example 178B
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(2,4-difluorobenzyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared as described in Example 1B, substituting Example 178A for Example 1A. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.29 (s, 3 H) 3.67 (s, 3 H) 5.24 (s, 2 H) 6.46 (d, J=1.36 Hz, 1 H) 6.59 (s, 1 H) 6.95 (td, J=8.65, 6.44 Hz, 1 H) 7.05 (d, J=8.81 Hz, 1 H) 7.07-7.14 (m, 1 H) 7.34-7.42 (m, 2 H) 7.58 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 408 (M+H)+.
Example 179
(2Z)-2-[5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(2-chloropyridin-3-yl)ethanone
The title compound was prepared and purified as described in Example 47B, substituting Example 167A for Example 47A and 2-chloronicotinic acid for 5-chloro-2-methoxybenzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (s, 9H) 1.78-1.90 (m, 4 H) 1.93-2.02 (m, 2 H) 2.75-2.86 (m, 1 H) 4.20 (d, J=7.12 Hz, 2 H) 6.31 (s, 1 H) 7.50 (dd, J=7.46, 4.75 Hz, 1 H) 7.93 (dd, J=7.46, 2.03 Hz, 1 H) 8.44 (dd, J=4.92, 1.86 Hz, 1 H). MS (ESI) m/z 364 (M+H)+.
Example 180
(2Z)-2-[5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(2-ethoxypyridin-3-yl)ethanone
The title compound was prepared and purified as described in Example 47B, substituting Example 167A for Example 47A and 2-ethoxynicotinic acid for 5-chloro-2-methoxybenzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36 (s, 9 H) 1.44 (q, J=6.67 Hz, 3 H) 1.80-1.93 (m, 4 H) 1.96-2.05 (m, 2 H) 2.87 (m, 1 H) 4.17 (d, J=7.12 Hz, 2 H) 4.43 (q, J=7.01 Hz, 2 H) 6.84 (s, 1 H) 7.08 (dd, J=7.46, 5.09 Hz, 1 H) 8.14 (dd, J=7.46, 2.03 Hz, 1 H) 8.21-8.25 (m, 1 H). MS (ESI) m/z 374 (M+H)+. Anal calcd for C19H25N3O2S.0.4 TFA.0.1H2O: C, 59.10; H, 6.63; N, 9.94. Found: C, 59.02; H, 6.92; N, 9.77.
Example 181
(2Z)-2-[5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-[4-(trifluoromethyl)pyridin-3-yl]ethanone
The title compound was prepared and purified as described in Example 47B, substituting Example 167A for Example 47A and 4-(trifluoromethyl)nicotinic acid for 5-chloro-2-methoxybenzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9 H) 1.79-1.90 (m, 4 H) 1.93-2.02 (m, 2 H) 2.72-2.87 (m, 1 H) 4.22 (d, J=7.46 Hz, 2 H) 6.36 (s, 1 H) 7.80 (d, J=5.09 Hz, 1 H) 8.86-8.90 (m, 2 H). MS (ESI) m/z 398 (M+H)+.
Example 182
(2Z)-2-(3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(2,3-dichlorophenyl)ethanone
The title compound was prepared as described in Example 47B, substituting Example 50C for Example 47A and 2,3-dichlorobenzoic acid for 5-chloro-2-methoxybenzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.34 Hz, 3 H) 1.14-1.21 (m, 2 H) 1.34-1.39 (m, 9 H) 1.71 (m, 2 H) 4.15 (t, J=7.14 Hz, 2 H) 6.17 (s, 1 H) 7.38-7.45 (m, 2 H) 7.67 (dd, J=6.54, 2.97 Hz, 1 H). MS (ESI) m/z 385 (M+H)+.
Example 183
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-hydroxy-1-methylpropyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared and purified as described in Example 170, substituting 2-butanone for acetone. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.76-0.86 (m, 3 H) 1.47 (s, 3 H) 1.69-1.78 (m, 2 H) 1.80-1.88 (m, 4 H) 1.96-2.03 (m, 2 H) 2.33 (s, 3 H) 2.69-2.84 (m, 1 H) 3.85 (s, 3 H) 3.96 (d, J=7.12 Hz, 2 H) 5.34 (s, 1 H) 6.50 (s, 1 H) 7.07-7.12 (m, 1 H) 7.38 (dd, J=8.65, 2.88 Hz, 1 H) 7.61 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 422 (M+H)+.
Example 184
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-ethyl-1-hydroxypropyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared and purified as described in Example 170, substituting 3-pentanone for acetone. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79 (t, J=7.54 Hz, 6 H) 1.71-1.85 (m, 8 H) 1.93-2.02 (m, 2 H) 2.30 (s, 3 H) 2.71-2.85 (m, 1 H) 3.85 (s, 3 H) 3.96 (d, J=6.74 Hz, 2 H) 5.02 (s, 1 H) 6.47 (s, 1 H) 7.10 (d, J=8.73 Hz, 1 H) 7.38 (dd, J=8.92, 2.97 Hz, 1 H), 7.61 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 436 (M+H)+. Anal calcd for C23H30ClNO3S.0.2H2O: C, 62.84; H, 6.97; N, 3.19. Found: C, 62.77; H, 7.00; N, 3.05.
Example 185
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(2-fluoro-1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared and purified as described in Example 170, substituting 1-fluoroacetone for acetone. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.53 (d, J=2.03 Hz, 3 H) 1.80-1.93 (m, 4 H) 1.95-2.03 (m, 2 H) 2.36 (s, 3 H) 2.70-2.81 (m, 1 H) 3.86 (s, 3 H) 3.98 (d, J=7.12 Hz, 2 H) 4.36 (d, J=47.81 Hz, 2 H) 5.94 (s, 1 H) 6.56 (s, 1 H) 7.11 (d, J=8.82 Hz, 1 H) 7.37-7.42 (m, 1 H) 7.62 (d, J=3.05 Hz, 1 H). MS (ESI) m/z 426 (M+H)+. Anal calcd for C21H25ClFNO3S: C, 59.22; H, 5.92; N, 3.29. Found: C, 58.95; H, 5.69; N, 3.25.
Example 186
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(2,2-difluoro-1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared and purified as described in Example 170, substituting 1,1-difluoroacetone for acetone. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.58 (s, 3 H) 1.79-1.91 (m, 4 H) 1.96-2.05 (m, 2 H) 2.38 (s, 3 H) 2.69-2.83 (m, 1 H) 3.86 (s, 3 H) 4.00 (d, J=6.74 Hz, 2 H) 5.97 (t, J=55.92 Hz, 1H) 6.39 (s, 1 H) 6.59 (s, 1 H) 7.12 (d, J=9.12 Hz, 1 H) 7.38-7.43 (m, 1 H) 7.62 (d, J=2.78 Hz, 1 H). MS (ESI) m/z 444 (M+H)+. Anal calcd for C21H24ClF2NO3S: C, 56.82; H, 5.45; N, 3.16. Found: C, 56.66; H, 5.54; N, 3.08.
Example 187
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-[2-(trifluoromethyl)phenyl]ethanone
The title compound was prepared and purified as described in Example 35C, substituting Example 153C for Example 35B and 2-trifluorobenzoic acid chloride for 2-chloronicotinoyl chloride. 1H NMR (300 MHz, CDCl3) δ ppm 0.96 (t, J=7.29 Hz, 3 H) 1.31-1.44 (m, 11 H) 1.72-1.82 (m, 2 H) 3.83-3.92 (m, 2 H) 6.67 (s, 1 H) 7.45-7.54 (m, 1 H) 7.55-7.61 (m, 2 H) 7.69 (d, J=7.80 Hz, 1 H). MS (ESI) m/z 384 (M+H).
Example 188
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]ethanone
Example 188A
3-(cyclobutylmethyl)-2-methyl-1,3,4-thiadiazol-3-ium bromide
The title compound was prepared as described in Example 47A, substituting 2-methylthiadiazole for 2,5-dimethylthiadiazole. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.79-1.94 (m, 4 H) 1.97-2.07 (m, 2 H) 2.85 (s, 3 H) 2.90 (m, 1 H) 4.70 (d, J=7.54 Hz, 2 H) 10.70 (s, 1 H). MS (ESI) m/z 169 (M+H)+.
Example 188B (2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]ethanone
The procedure in Example 47B was followed, substituting Example 188A for Example 47A to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.85-2.00 (m, 4 H) 2.05-2.16 (m, 2 H) 2.95 (m, 1 H) 3.88 (s, 3 H) 4.21 (d, J=7.14 Hz, 2 H) 6.89 (d, J=8.73 Hz, 1 H) 7.33 (dd, J=8.72, 2.78 Hz, 1 H) 7.75 (d, J=2.78 Hz, 1 H) 8.16 (s, 1 H). MS (ESI) m/z 337 (M+H)+.
Example 189
ethyl (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-5-(1-hydroxy-1-methylethyl)-2,3-dihydro-1,3-thiazole-4-carboxylate
The title compound was prepared and purified as described in Example 170, substituting Example 45 for Example 169B. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90-0.96 (m, 3 H) 1.29-1.38 (m, 5 H) 1.49 (s, 6 H) 1.70 (m, 2 H) 3.82-3.90 (m, 5 H) 4.36 (q, J=7.14 Hz, 2 H) 5.81 (s, 1 H) 6.55 (s, 1 H) 7.13 (d, J=8.72 Hz, 1 H) 7.43 (dd, J=8.92, 2.97 Hz, 1 H) 7.64 (d, J=2.78 Hz, 1 H). MS (ESI) m/z 454 (M+H)+.
Example 190
(2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-6,6-dimethyl-3,6-dihydrofuro[3,4-d][1,3]thiazol-4(2H)-one
Example 190A
(Z)-3-butyl-2-(2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene)-5-(2-hydroxypropan-2-yl)-2,3-dihydrothiazole-4-carboxylic acid
To a 50 mL round-bottomed flask, Example 189 (45 mg, 0.099 mmol) was dissolved in ethanol (5.00 mL), sodium hydroxide (14 mg, 0.350 mmol) in water (5 mL) was added and stirred for 2 hrs. To the reaction was added hydrogen chloride solution (2 N) till pH=5-6 and extracted with EtOAc (3×5 mL). The organic layers were combined and dried. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.34 Hz, 3 H) 1.34 (m, 3 H) 1.50 (s, 6 H) 1.66-1.76 (m, 2 H) 3.86 (s, 3 H) 3.89-3.96 (m, 2 H) 6.52 (s, 1 H) 7.11-7.16 (m, 1 H) 7.40-7.47 (m, 1 H) 7.63-7.67 (m, 1 H). MS (ESI) m/z 426 (M+H)+.
Example 190B (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-6,6-dimethyl-3,6-dihydrofuro[3,4-d][1,3]thiazol-4(2H)-one
In a 20 mL vial, Example 190A (60 mg, 0.141 mmol) was dissolved in CH2Cl2 (2 ml). Support-bound DCC (3 mmol/g, 100 mg) was added and shaken over weekend. The reaction mixture was filtered and the solvent was removed to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.34 Hz, 3 H) 1.31-1.41 (m, 2 H) 1.69 (s, 6 H) 1.70-1.79 (m, 2 H) 3.88 (s, 3 H) 4.12 (t, J=7.34 Hz, 2 H) 6.72 (s, 1 H) 7.17 (d, J=9.12 Hz, 1 H) 7.48 (dd, J=8.72, 2.78 Hz, 1 H) 7.64 (d, J=2.78 Hz, 1 H). MS (ESI) m/z 408 (M+H)+. Anal calcd for C20H22ClNO4S: C, 58.89; H, 5.44; N, 3.43. Found: C, 59.02; H, 5.52; N, 3.43.
Example 191
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-hydroxyphenyl)ethanone
Example 1 (180 mg, 0.5 mmol) in CHCl3 (12 mL) was treated with iodomethane (1 mL) and AlCl3 (133 mg, 1 mmol) at room temperature for 24 h. The mixture was washed with 10% solution of NaHCO3, brine, dried with anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography (hexane-EtOAc 1:1 as eluent) to afford 100 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=7 Hz, 3 H), 1.40 (sextet, J=7 Hz, 2 H), 1.64 (quintet, J=7 Hz, 2 H), 2.21 (s, 3 H), 2.25 (s, 3 H), 4.19 (t, J=7 Hz, 2 H), 6.67 (s, 1 H), 6.81 (d, J=9 Hz, 1 H), 7.30 (dd, J=9 Hz, 3 Hz, 1 H), 8.01 (d, J=3 Hz, 1 H), 14.59 (s, 1 H); MS (DCI/NH3) m/z 338 (M+H)+. Anal calcd for C17H20ClNO2S: C, 60.43; H, 5.97; N, 4.15. Found: C, 60.24; H, 5.76; N, 3.97.
Example 192
tert-butyl (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazol-4-ylcarbamate
Example 192A
(Z)-3-butyl-2-(2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene)-2,3-dihydrothiazole-4-carboxylic acid
The title compound was prepared and purified as described in Example 190A, substituting Example 45 for Example 189. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.54 Hz, 3 H) 1.29-1.42 (m, 2 H) 1.65-1.77 (m, 2H) 3.87 (s, 3 H) 4.32-4.39 (m, 2 H) 6.67 (s, 1 H) 7.14 (d, J=9.12 Hz, 1 H) 7.44 (dd, J=8.73, 2.78 Hz, 1 H) 7.66 (d, J=2.78 Hz, 1 H). MS (DCI/NH3) m/z 368 (M+H)+.
Example 192B
tert-butyl (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazol-4-ylcarbamate
To a 50 mL vial, Example 192A (650 mg, 1.767 mmol) was dissolved in toluene (8 ml). Diphenyl phosphorazide (584 mg, 2.120 mmol) was added followed by addition of triethylamine (0.493 mL, 3.53 mmol) and 2-methylpropan-2-ol (5 mL, 1.767 mmol) and heated at 85° C. for 2 hr. The reaction mix was concentrated and purified over silica gel (hexane-EtOAc 4:1 as eluent) to provide title compound as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (m, 3 H) 1.29-1.38 (m, 2 H) 1.40-1.50 (m, 9 H) 1.57-1.71 (m, 2 H) 3.80-3.90 (m, 5 H) 6.59 (m, 2 H) 7.12 (d, J=8.82 Hz, 1 H), 7.41 (m, 1H), 7.65 (m, 1H), 9.21 (s, 1H). MS (ESI) m/z 439 (M+H)+.
Example 193
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[5-chloro-2-(dimethylamino)phenyl]ethanone
In a 25 mL vial, Example 110 (70.0 mg, 0.206 mmol) was dissolved in dimethyl formamide (15 ml). Potassium carbonate (34.2 mg, 0.247 mmol) was added followed by addition of methylhydrazine (95 mg, 2.060 mmol) and stirred for 48 hrs at 110° C. The title compound was isolated as a by-product from the displacement of fluorine by dimethylamine from dimethyl formamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.29 Hz, 3 H) 1.32-1.43 (m, 2 H) 1.63 (m, 2 H) 2.15 (s, 3 H) 2.17 (s, 3 H) 2.68 (s, 6 H) 3.82-3.89 (m, 2 H) 6.41 (s, 1 H) 6.95 (d, J=8.82 Hz, 1 H) 7.26 (dd, J=8.82, 2.71 Hz, 1 H) 7.34 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 365 (M+H)+. Anal calcd for C19H25ClN2OS: C, 62.53; H, 6.90; N, 7.68. Found: C, 62.37; H, 6.66; N, 7.78.
Example 194
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-ethyl-1-hydroxypropyl)-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared and purified as described in Example 170, substituting Example 172B for Example 169B and 3-pentanone for acetone. 1H NMR (300 MHz, CDCl3) δ ppm 0.84-0.93 (m, 6 H) 1.82-1.95 (m, 8 H) 2.04-2.16 (m, 2 H) 2.82-2.96 (m, 1 H) 3.86-3.94 (m, 5 H) 6.46 (s, 1 H) 6.74 (s, 1 H) 6.87 (d, J=8.73 Hz, 1 H). MS (DCI) m/z 422 (M+H)+.
Example 195
(2Z)-2-[5-(1-amino-1-ethylpropyl)-3-(cyclobutylmethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
Example 195A
2-methyl-N-(pentan-3-ylidene)propane-2-sulfinamide
To a 40 mL vial, pentan-3-one (1.049 ml, 9.90 mmol) was dissolved in THF (17 ml). Titanium ethoxide (3.42 ml, 16.50 mmol) was added followed by addition of 2-methylpropane-2-sulfinamide (1.0 g, 8.25 mmol) and the reaction was heated to 90° C. for 36 hr. The reaction was poured into equal volume of brine and stirred for 30 min before filtration through a silica gel pad. The filtrate was dried with sodium sulfate, concentrated and purified over silica gel (hexane-EtOAc 4:1 as eluent) to provide title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 (m, 3 H) 1.06-1.13 (m, 3 H) 1.14 (s, 9 H) 2.50 (m, 2 H) 2.62 (m, 2 H). MS (DCI) m/z 190 (M+H)+.
Example 195B (2Z)-2-[5-(1-amino-1-ethylpropyl)-3-(cyclobutylmethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 170, substituting Example 172B for Example 169B and Example 195A for acetone. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77 (t, J=7.34 Hz, 6 H) 1.54-1.63 (m, 4 H) 1.74-1.88 (m, 4 H) 1.90-2.02 (m, 2 H) 2.72-2.86 (m, 1 H) 3.84 (s, 3 H) 3.97 (d, J=7.54 Hz, 2 H) 6.40 (s, 1H) 7.09 (d, J=8.72 Hz, 1 H) 7.13 (s, 1 H) 7.38 (dd, J=8.72, 2.78 Hz, 1 H) 7.57 (d, J=2.78 Hz, 1 H). MS (DCI) m/z 421 (M+H)+.
Example 196
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-[6-chloro-4-(trifluoromethyl)pyridin-3-yl]ethanone
The title compound was prepared and purified as described in Example 35C, substituting Example 153C for Example 35B and 6-chloro-4-(trifluoromethyl)nicotinoyl chloride for 2-chloronicotinoyl chloride. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85-0.93 (m, 3 H) 1.24-1.34 (m, 11 H) 1.61-1.71 (m, 2 H) 3.97 (t, J=7.46 Hz, 2 H) 6.09 (s, 1 H) 7.24 (s, 1 H) 7.94 (s, 1 H) 8.70 (s, 1 H). MS (DCI) m/z 419 (M+H)+.
Example 197
(2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-6,6-diethyl-2,3,5,6-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazol-4-one
The title compound was prepared and purified using the procedure described in Example 170, substituting Example 45 for Example 169B and Example 195A for acetone. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.72 (t, J=7.34 Hz, 6 H) 0.87-0.94 (m, 3 H) 1.24-1.37 (m, 2 H) 1.70-1.86 (m, 6 H) 3.87 (s, 3 H) 4.24 (t, J=6.94 Hz, 2 H) 6.67 (s, 1 H) 7.15 (d, J=9.12 Hz, 1 H) 7.46 (dd, J=8.72, 2.78 Hz, 1 H) 7.63 (d, J=2.78 Hz, 1 H) 8.64 (s, 1 H). MS (DCI) m/z 435 (M+H)+. Anal calcd for C22H27ClN2O3S: C, 60.75; H, 6.26; N, 6.44. Found: C, 60.65; H, 6.21; N, 6.55.
Example 198
(2Z)-2-[3-butyl-5-[2-fluoro-1-(fluoromethyl)-1-hydroxyethyl]-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was prepared and purified as described in Example 170, substituting Example 176B for Example 169B and 1,3-difluoroacetone for acetone. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.29 Hz, 3 H) 1.27-1.39 (m, 2 H) 1.64-1.76 (m, 2 H) 3.85 (s, 3 H) 3.97 (t, J=7.29 Hz, 2 H) 4.45-4.61 (m, 4 H) 6.49 (s, 1 H) 6.54 (s, 1 H) 7.12 (d, J=8.82 Hz, 1 H) 7.37 (s, 1 H) 7.41 (dd, J=8.82, 2.71 Hz, 1 H) 7.63 (d, J=2.71 Hz, 1 H). MS (DCI) m/z 418 (M+H)+. Anal calcd for C19H22ClF2NO3S: C, 54.61; H, 5.31; N, 3.35. Found: C, 54.51; H, 5.26; N, 3.35.
Example 199
(2Z)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)-1-[6-chloro-4-(trifluoromethyl)pyridin-3-yl]ethanone
This compound was separated as a by-product from the preparation of Example 196. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.29 Hz, 3 H) 1.29-1.35 (m, 2 H) 1.62-1.74 (m, 2 H) 2.05 (m, 3 H) 4.02 (t, J=7.29 Hz, 2 H) 5.05 (m, 1 H) 5.15 (m, 1 H) 6.24 (s, 1 H) 7.58 (s, 1 H) 7.97 (s, 1 H) 8.75 (s, 1 H). MS (DCI) m/z 403 (M+H)+.
Example 200
(2Z)-2-[3-butyl-4-(1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone
To a solution of Example 45 (60 mg, 0.152 mmol) in tetrahydrofuran (1 ml) at −78° C. was added methyllithium (0.284 ml, 0.455 mmol). The reaction was monitored by LC-MS and was quenched with saturated ammonium hydrochloride (5 mL) upon consumption of starting material. Upon warming to room temperature the resulting mixture was extracted with ethyl acetate (3×10 mL). The title compound was purified by HPLC specified in Example 35C. 1H NMR (300 MHz, CD3OD) δ ppm 1.05 (t, J=7.29 Hz, 3 H) 1.45-1.57 (m, 2 H) 1.65 (s, 6 H) 1.83-1.95 (m, 2 H) 3.91 (s, 3 H) 4.43 (d, J=8.81 Hz, 2 H) 6.67 (m, 1 H) 6.69 (m, 1 H) 7.07 (d, J=8.82 Hz, 1 H) 7.35 (dd, J=8.82, 2.71 Hz, 1 H) 7.71 (d, J=2.71 Hz, 1 H). MS (DCI) m/z 382 (M+H)+.
Example 201
(Z)-2-(4-acetyl-3-butylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone
The title compound was isolated from Example 200 as a by-product. 1H NMR (300 MHz, CD3OD) δ ppm 1.02 (t, J=7.46 Hz, 3 H) 1.45 (m, 2 H) 1.75-1.86 (m, 2 H) 2.56 (s, 3 H) 3.91 (s, 3 H) 4.34-4.43 (m, 2 H) 6.73 (d, J=1.36 Hz, 1 H) 7.08 (d, J=8.81 Hz, 1 H) 7.38 (dd, J=8.98, 2.88 Hz, 1 H) 8.02 (s, 1 H). MS (DCI) m/z 366 (M+H)+.
Example 202
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-[2-fluoro-1-(fluoromethyl)-1-hydroxyethyl]-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone
The title compound was prepared and purified as described in Example 170, substituting 1,3-difluoroacetone for acetone. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.78-1.90 (m, 4 H) 1.92-2.05 (m, 2 H) 2.70-2.81 (m, 1 H) 3.86 (s, 3 H) 4.00 (d, J=6.78 Hz, 2H) 4.45-4.55 (m, 2 H) 4.62-4.71 (m, 2 H) 6.47 (s, 1 H) 6.60 (s, 1 H) 7.12 (d, J=9.15 Hz, 1 H) 7.36-7.43 (m, 1 H) 7.62 (d, J=2.71 Hz, 1 H). MS (DCI) m/z 444 (M+H)+.
Example 203
ethyl (2Z)-5-(1-amino-1-methylethyl)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-4-carboxylate
Example 203A
2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide
The title compound was prepared and purified as described in Example 195A, substituting acetone for 3-pentanone. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.12 (s, 9 H) 2.14 (s, 3 H) 2.26 (s, 3 H). MS (DCI) m/z 162 (M+H)+.
Example 203B
ethyl (2Z)-5-(1-amino-1-methylethyl)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-4-carboxylate
The title compound was prepared and purified as described in Example 170, substituting Example 45 for Example 169B and Example 203A for acetone. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.29 Hz, 3 H) 1.38 (m, 5 H) 1.66 (s, 6 H) 1.74 (m, 2 H) 3.87 (s, 3 H) 3.91 (m, 2 H) 4.49 (q, J=7.12 Hz, 2 H) 6.73 (s, 1 H) 7.17 (d, J=9.16 Hz, 1 H) 7.44-7.50 (m, 1 H) 7.66 (d, J=3.05 Hz, 1 H) 8.52 (b, 2 H). MS (DCI) m/z 453 (M+H)+.
Example 204
(2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-6,6-dimethyl-2,3,5,6-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazol-4-one
The title compound was obtained as a by-product from Example 203B. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.46 Hz, 3 H) 1.27-1.40 (m, 2 H) 1.49 (s, 6 H) 1.68-1.78 (m, 2 H) 3.87 (s, 3 H) 4.20 (t, J=6.95 Hz, 2 H) 6.67 (s, 1 H) 7.15 (d, J=8.82 Hz, 1 H) 7.45 (dd, J=8.82, 2.71 Hz, 1 H) 7.64 (d, J=3.05 Hz, 1 H) 8.83 (s, 1 H). MS (DCI) m/z 407 (M+H)+.
Example 205
(Z)-2-(3-butyl-4,5-dimethylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanethione
A mixture of Example 1 (54 mg, 0.15 mmol) and P2S5 (115 mg, 0.5 mmol) in pyridine (10 mL) was refluxed for 2 h. The mixture was then concentrated under reduced pressure and the residue was partitioned between water and EtOAc. The ethyl acetate layer was washed with brine, dried with anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography (hexane-EtOAc 1:1 as eluent) to afford 25 mg of product. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=7 Hz, 3H), 1.37 (sextet, J=7 Hz, 2H), 1.70 (quintet, J=7 Hz, 2H), 2.26 (s, 3H), 2.32 (s, 3H), 3.78 (s, 3H), 4.15 (t, J=7 Hz, 2H), 7.05 (d, J=9 Hz, 1H), 7.28 (dd, J=9 Hz, 3 Hz, 1H), 7.41 (s, 1H), 7.53 (d, J=3 Hz, 1H); MS (ESI) m/z 368 (M+H)+. Anal calcd for C18H22ClNOS2: C, 58.76; H, 6.03; N, 3.81. Found: C, 58.35; H, 5.96; N, 3.66.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.

## Claims

1. A compound according to formula (I),




or a pharmaceutically acceptable salt thereof, wherein
A is C(R2);
E is C(O) or C(S);
R1 is C3-C7 alkyl, alkenyl, alkoxy-(C2-C6 alkylene)-, alkoxycarbonylalkyl, alkylcarbonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, aryloxy-(C2-C6 alkylene)-, arylalkoxy-(C2-C6 alkylene)-, arylcarbonyloxy-(C2-C6 alkylene)-, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, haloalkyl, haloalkoxy-(C2-C6 alkylene)-, heteroaryl, heteroarylalkyl, heteroaryloxy-(C2-C6 alkylene)-, heteroarylcarbonyloxy-(C2-C6 alkylene)-, heterocycle, heterocyclealkyl, heterocycleoxy-(C2-C6 alkylene)-, hydroxy-(C2-C6 alkylene)-, RaRbN—(C2-C6 alkylene)-, RAJN—C(O)-alkylene-, RcRdN—C(O)—NRc—(C2-C6 alkylene)-, ReO—N═C(Rz)-alkylene-, or RfRgN—N═C(Rz)-alkylene-;
R2 and R3 are each independently hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, arylalkyl, arylalkenyl, azidoalkyl, cyano, cycloalkyl, formyl, halogen, haloalkyl, heteroaryl, heterocycle, hydroxyalkyl, hydroxyalkynyl, hydroxyhaloalkyl, RjRkN—, RjRkN-alkylene-, RmRN—C(O)—, RpO—N═C(Rz)-alkylene-, RpO—N═C(Rz)—, or R,RsN—N═C(Rz)-alkylene-, or
R2 and R3 taken together with the carbon atoms to which they are attached form a heteroaryl, a heterocycle, or a cycloalkenyl ring;
R4 is C4-C10 alkyl, wherein the C4-C10 alkyl group is optionally substituted with one substituent selected from the group consisting of hydroxy, alkoxy, haloalkoxy, cyano, —C(O)N(Rz)2, and —N(Rz)C(O)Rz; alkenyl, alkynyl, naphthyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, wherein the naphthyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycle, the aryl moiety of the arylalkyl, the cycloalkyl moiety of the cycloalkylalkyl, the cycloalkenyl moiety of the cycloalkenylalkyl, the heteroaryl moiety of the heteroarylalkyl, and the heterocycle moiety of the heterocyclealkyl are each independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents as represented by R6;
or phenyl substituted with 1, 2, 3, 4, or 5 substituents as represented by R6;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, cyano, halogen, haloalkyl, oxo, —OReu, —O —(CRjuRku)x—N(Rwu)2, —OC(O )Reu, —SReu, —S(O)R , —S(O)2R fu, —S(O)2N(Rwu) (Rgu), —N(Rwu)(Rgu), —N(Rwu)C(O )Reu, —N(Rwu)C(O )0Reu, —N(Rwu)S(O)2Rfu, —N(Rwu)C(O)N(Rwu)(Rgu), —N(Rwu)S(O)2N(Rwii)(Rgu), —C (0)Reu—C(O )0(Reu), —C(0)1I(RwARgu), haloalkyl, —(CRjuRku)x—CN, —(CRjuRku)x—OReu, —(CRjuRku)x—OC(O )Reu, —(CRjuRku)x—SReu, CRjuRku)x—S(O)Rfu, —(CRjuRku)x—S(O)2Rfu, —(CRjuRku)x—N(Rwu)(Rgu), —(CRjuRku)x—N(Rwu)C(0)Reu, —(CRjuRku)x—N(Rwu)S(O)2Rfu, —(CRjuRku)x—N(Rwu)C(O)N(Rwu)(Rgu), —(CRjuRku)x—N(Rwu)S(0)2N(Rwu)(Rgu), —(CRjuRku)x—C(O)Reu, —(CRjuRku)x—C(O)0(Reu), —(CRjuRku)x—C(0)N(Rwu)(Rgu), —C(Rwu)=N—ORwu, aryl, cycloalkyl, and heterocycle;
Rwu, at each occurrence, is independently hydrogen, alkyl, or haloalkyl;
Reu and Rgu, at each occurrence, are each independently hydrogen, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, haloalkoxyalkyl, or haloalkyl;
wherein the cycloalkyl, the heterocycle, and the cycloalkyl moiety of the cycloalkylalkyl are each independently unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of alkyl, halogen, and haloalkyl;
Rfu, at each occurrence, is independently alkyl or haloalkyl;
Rju and Rku, at each occurrence, are each independently hydrogen, halogen, alkyl, or haloalkyl;
x is 1, 2, 3, 4, or 5;
R5 is hydrogen, alkyl, alkenyl, alkynyl, cyano, or halogen;
L2 is a bond, —N(Re)—or —O—;
Raand Rb are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl;
Rc and Rd, at each occurrence, are each independently hydrogen, alkyl, or haloalkyl;
Re, at each occurrence, is independently hydrogen, alkyl, alkenyl, alkoxyalkyl, alkynyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, or hydroxyalkyl;
Rf and Rg, are each independently hydrogen, alkyl, alkenyl, alkoxycarbonyl, alkoxyalkyl, alkynyl, arylalkyl, cyanoalkyl, cycloalkylalkyl, haloalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl or nitroalkyl; or Rf and Rg, together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocycle ring;
j and Rk, at each occurrence, are each independently hydrogen, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylalkyl, or —C(O)N(Rz)2;
Rm and Rn are each independently hydrogen, alkyl, or haloalkyl;
Rp, at each occurrence, is independently hydrogen, alkyl, alkenyl, alkoxyalkyl, alkynyl, cyanoalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxyalkyl, or nitroalkyl;
Rr and Rs are each independently hydrogen, alkyl, alkenyl, alkoxyalkyl, alkynyl, cyanoalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxyalkyl, or nitroalkyl; or Rr and Rs, together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7- membered heterocycle ring; and
Rz, at each occurrence, is independently hydrogen, alkyl, or haloalkyl;
with the proviso that when A is —C(R2), R2 is hydrogen or C1-C5 alkyl, R3 is hydrogen or phenyl, E is C(O), L2 is a bond, and R4 is aryl, then R1 is not C3-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or (4-amino-2-methyl-5-pyrimindinyl)methyl.

2. The compound of claim 1 of formula (Ib) or a pharmaceutically acceptable salt thereof,




wherein R1, R2, R3, R4, R5, E, and L2 are as defined in claim 1.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein E is C(O) and L2 is a bond.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R1 is C3-C7 alkyl, alkylcarbonylalkyl, arylcarbonyloxy-(C2-C6 alkylene)-, alkoxy-(C2-C6 alkylene)-, cycloalkylalkyl, haloalkyl, or heterocyclealkyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen or halogen.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R4 is C4-C10 alkyl, haloalkyl, naphthyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocycle, or substituted phenyl.

7. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein
E is C(O);
L2 is O;
R1 is C3-C7 alkyl;
R5 is hydrogen; and
R4 is cycloalkyl, C4-Cio alkyl, or haloalkyl.

8. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein
E is C(O);
L2 is N(Re);
Re is hydrogen or alkyl;
R1 is C3-C7 alkyl;
R5 is hydrogen; and
R4 is substituted phenyl.

9. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R2 and R3 taken together with the carbon atoms to which they are attached form, a heteroaryl, a heterocycle, or a cycloalkenyl ring.

10. The compound of claim 1 of formula (Id) or a pharmaceutically acceptable salt thereof



wherein
G is N(H), N(alkyl), 0, CH2, or CH2CH2,
R8 represents optional substituents selected from the group consisting of alkyl, halogen, and haloalkyl, two R8 groups on the same carbon atom together with the carbon atom to which they are attached, optionally form a ═O group, and
E, R1, R4, R5, and L2 are as set forth in claim 1.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof wherein G is O, CH2, or CH2CH2.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein
E is C(O);
L2 is a bond;
R5 is hydrogen; and
R1 is C3-C7 alkyl.

13. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of (2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-1-(1-adamantyl)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone;
tert-butyl (2Z)-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)acetate;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]ethanone;
(2Z)-2-(3-butyl-5-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-cyclohexylethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-cyclohexylacetamide;
4-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]morpholine;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-(5-chloro-2-methoxyphenyl)acetamide;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-(3-propyl-1,3-benzothiazol-2(3H)-ylidene)ethanone;
(2Z)-2-(5-bromo-3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(Z)-2-(5-acetyl-3-butyl-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(Z)-2-(3-butyl-5-(1-(hydroxyimino)ethyl)-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-3-butyl-242-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde;
(2Z)-3-butyl-242-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde oxime;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[4,5-dimethyl-3-(2-morpholin-4-ylethyl)- 1,3-thiazol-2(3H)-ylidene]ethanone;
(2Z)-3-butyl-2-(2-oxo-2-pyridin-2-ylethylidene)-2,3-dihydro-1,3-thiazole-5-carbaldehyde;
(2Z)-3-butyl-242-(3,5-difluorophenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde;
(2Z)-3-butyl-242-(2-fluorophenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde;
(2Z)-3-butyl-242-(2,4-difluorophenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-5-carbaldehyde;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2-fluorophenyl)ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-pyridin-2-ylethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(3,5-difluorophenyl)ethanone;
(2Z)-2-(3-butyl-3,4,5,6-tetrahydro-2H-cyclopenta[d][1,3]thiazol-2-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(Z)-2-(5-acetyl-4-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(Z)-2-(5-acetyl-3-butyl-4-methylthiazole-2(3H)-ylidene-1-(pyridine-2-yl)ethanone;
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(3-chlorothien-2-yl)ethanone;
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)ethanone;
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-cyclopentylethanone;
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-cyclohexylethanone;
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
6-[(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-2,2-dimethyl-2,3-dihydro-4H-pyran-4-one;
(2Z)-1-(1-benzofuran-5-yl)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)ethanone;
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)ethanone;
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(5-fluoro-2-methoxyphenyl)ethanone;
(2Z)-2-(3-butyl-4-phenyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
ethyl (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazole-4-carboxylate;
(2Z)-2-(3-butyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-N-(5-chloro-2-methoxyphenyl)acetamide;
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-cyclohexylethanone;
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-(3-chloro-l-benzothien-2-yl)ethanone;
(2Z)-1-(1-adamantyl)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2,6-difluorophenyl)ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2,4-dichlorophenyl)ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[2- (trifluoromethyl)phenyl]ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[3- (trifluoromethyl)phenyl]ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-cyclopentylethanone;
4-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]benzonitrile;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(1-naphthyl)ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2,5-difluorophenyl)ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-pyridin-3-ylethanone;
(2Z)-1-(1,3-benzodioxo1-5-yl)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)ethanone;
(2Z)-142,5-bis(trifluoromethyl)phenyl]-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[5-fluoro-2-(trifluoromethyl)phenyl]ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(3-methylthien-2-yl)ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-fluoro-2-methylphenyl)ethanone;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-fluorophenyl)ethanone;
(Z)-2-(3-butyl-54(E)-1-(methoxyimino)ethyl)-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(Z)-2-(3-butyl-54(Z)-1-(methoxyimino)ethyl)-4-methylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-2-[3-butyl-4-(trifluoromethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-2-[3-butyl-5-methyl-4-(trifluoromethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(Z)-1-(5-chloro-2-methoxyphenyl)-2-(54(E)-1-(methoxyimino)ethyl)-4-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)ethanone;
(Z)-1-(5-chloro-2-methoxyphenyl)-2-(54(Z)-1-(methoxyimino)ethyl)-4-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)ethanone;
(2Z)-3-butyl-242-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-5,5-dimethyl-2,3,5,6-tetrahydro-1,3-benzothiazol-7(4H)-one;
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-2-(5-tert-butyl-3-isobutyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-2[3-butyl-4-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-2-[5-tert-butyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-]3-isobutyl-5-methyl-4-(trifluoromethyl)-1,3-thiazol-2(3H)-ylidene]ethanone;
(2E)-2-(3-butyl-4-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)-2-fluoroethanone;
(2E)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)-2-fluoroethanone;
(2Z)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(1Z)- 1-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-4,4-dimethylpentan-2-one;
1-[(2Z)-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-4,5-dimethyl-1,3-thiazol-3(2H)-yl]-3,3-dimethylbutan-2-one;
1-adamantyl (2Z)-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)acetate;
(2Z)-2[3-butyl-5-(3-hydroxy-3-methylbut-1ynyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(1Z)-1-[3-(3,3-dimethyl-2-oxobutyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-4,4-dimethylpentan-2-one;
(2E)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)-2-fluoroethanone;
2-[(2Z)-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-4,5-dimethyl-1,3-thiazol-3(2H)-yl[ethyl 5 -chloro-2-methoxybenzoate;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[2-(methylamino)phenyl]ethanone;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(4-fluorobutyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]ethanone;
(2Z)-1-(2-amino-5-chlorophenyl)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanone;
ethyl 2-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-4-chlorophenylcarbamate;
(2E)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)-2-fluoroethanone;
ethyl 2-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-4-chlorophenyl(methyl)carbamate;
methyl 2-[(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-4-chlorobenzoate;
(2Z)-2-[3-butyl-4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone; 2,2,2,-trichloro-1,1dimethylethyl (2Z)-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H) -ylidene)acetate;
(2Z)-2-[4-tert-butyl-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-2-[4-tert-butyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-2[4-tert-butyl-3-(2-piperidin-1-ylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-N-methyl-2,3-dihydro-1,3-thiazole-4-carboxamide;
(Z)-2-(5-acetyl-3-butylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(2-chloropyridin-3-yl)ethanone;
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-fluoro-2-methoxyphenyl)ethanone;
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(3-chlorothien-2-yl)ethanone;
6-[(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)ethanoyl]-2,2-dimethyl-2,3-dihydro-4H-pyran-4-one;
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(5-iodo-2-methoxyphenyl)ethanone;
(2Z)-1-(1-benzofuran-5-yl)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)ethanone;
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-(2-ethoxypyridin-3-yl)ethanone;
(2Z)-1-(1-benzofuran-5-yl)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)ethanone;
(2Z)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)-1-(2-ethoxypyridin-3-yl)ethanone;
(2Z)-2-(3-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-1-[trans-2-phenylcyclopropyl]ethanone;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
(2Z)-2-[5-bromo-3-(cyclobutylmethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-1,3-thiazol-2(3H)- ylidene]ethanone;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-4-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]ethanone;
(2Z)-2[3-butyl-5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]ethanone;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-ethyl-1-hydroxypropyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(2-fluoro-1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(2,2-difluoro-1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-[2-(trifluoromethyl)phenyl]ethanone;
ethyl (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-5-(1-hydroxy-l-methylethyl)-2,3-dihydro-1,3-thiazole-4-carboxylate;
(2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-6,6-dimethyl-3,6-dihydrofuro[3,4-d][1,3]thiazol-4(2H)-one;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-(5-chloro-2-hydroxyphenyl)ethanone;
tert-butyl (2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-2,3-dihydro-1,3-thiazol-4-ylcarbamate;
(2Z)-2-(3-butyl-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-1-[5-chloro-2-(dimethylamino)phenyl]ethanone;
(2Z)- 1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-(1-ethyl-1-hydroxypropyl)-1,3-thiazol-2(3H)-ylidene]ethanone;
(2Z)-2-[5-(1-amino-1-ethylpropyl)-3-(cyclobutylmethyl)- 1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-2-(3-butyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene)-1-[6-chloro-4-(trifluoromethyl)pyridin-3-yl]ethanone;
(2Z)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-6,6-diethyl-2,3,5,6-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazol-4-one;
(2Z)-2-[3-butyl-5-[2-fluoro-1-(fluoromethyl)-1-hydroxyethyl]-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-2-(3-butyl-5-isopropenyl-1,3-thiazol-2(3H)-ylidene)-1-[6-chloro-4-(trifluoromethyl)pyridin-3-yl]ethanone;
(2Z)-2[3-butyl-4-(1-hydroxy-1-methylethyl)-1,3-thiazol-2(3H)-ylidene]-1-(5-chloro-2-methoxyphenyl)ethanone;
(Z)-2-(4-acetyl-3-butylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanone;
(2Z)-1-(5-chloro-2-methoxyphenyl)-2-[3-(cyclobutylmethyl)-5-[2-fluoro-1-(fluoromethyl)-1-hydroxyethyl]-4-methyl-1,3-thiazol-2(3H)-ylidene]ethanone;
ethyl (2Z)-5-(1 -amino-1-methylethyl)-3-butyl-2-[2-(5-chloro-2-methoxyphenyl)- 2-oxoethylidene]-2,3-dihydro-1,3-thiazole-4-carboxylate;
(2Z)-3-butyl-2[2-(5-chloro-2-methoxyphenyl)-2-oxoethylidene]-6,6-dimethyl-2,3,5,6-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazol-4-one; and
(Z)-2-(3-butyl-4,5-dimethylthiazol-2(3H)-ylidene)-1-(5-chloro-2-methoxyphenyl)ethanethione.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carrier.

15. A method for treating pain in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 of formula (I), or a pharmaceutically acceptable salt thereof.